阅读说明：本技术 一种八臂聚乙二醇、制备方法、官能化衍生物及修饰的生物相关物质 (Eight-arm polyethylene glycol, preparation method, functionalized derivative and modified biologically-relevant substance ) 是由 翁文桂 刘超 闫策 林毅 于 2016-04-21 设计创作，主要内容包括：本发明公开一种八臂聚乙二醇(式1)、制备方法、官能化衍生物及修饰的生物相关物质。其中,八价中心结构CORE中含有八羟基二糖分子脱羟基后的残基,所述八羟基二糖分子含有八个裸露的羟基；所述八羟基二糖分子的八个裸露羟基分布在两个单糖单元上,两个单糖单元相同,且分布方式为4+4；n为聚乙二醇链的聚合度,选自1～2000。所述八臂聚乙二醇具有单分散性或多分散性。引发剂分子成本低,纯度高,大大降低生产成本,聚合产物及官能化衍生物的分子量及其分布控制更加精确,对于其修饰的生物相关物质,有利于提高产物纯度和性能。本发明八臂聚乙二醇及其衍生物还可具有天然手性中心。<Image he="92" wi="700" file="DDA0002231261950000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses eight-arm polyethylene glycol (formula 1), a preparation method, a functionalized derivative and a modified biologically-relevant substance. Wherein, the octavalent central structure CORE contains residues of the dihydroxyl disaccharide molecule after dehydroxylation,the octahydroxydisaccharide molecule contains eight naked hydroxyl groups; eight naked hydroxyl groups of the octahydroxydisaccharide molecule are distributed on two monosaccharide units, the two monosaccharide units are the same, and the distribution mode is 4+ 4; n is the polymerization degree of the polyethylene glycol chain and is selected from 1-2000. The eight-arm polyethylene glycol has monodispersity or polydispersity. The initiator has low molecular cost and high purity, greatly reduces the production cost, controls the molecular weight and the distribution of the polymerization product and the functionalized derivative more accurately, and is beneficial to improving the purity and the performance of the product for biological related substances modified by the initiator. The eight-arm polyethylene glycol and derivatives thereof of the invention may also have a natural chiral center.)

1. An eight-arm polyethylene glycol having an eight-valent central structure and eight PEG chains, characterized by the following general formula:

the octavalent central structure CORE contains residues of eight-hydroxy disaccharide molecules after dehydroxylation, and the eight-hydroxy disaccharide molecules contain eight naked hydroxy groups; the octahydroxydisaccharide molecule is a structure in which two monosaccharide units are covalently linked; the connecting group for covalently connecting the two monosaccharide units is selected from any one of glycosidic bonds, amido bonds and ester bonds; eight naked hydroxyl groups of the octahydroxydisaccharide molecule are distributed on two monosaccharide units, the two monosaccharide units are the same, and the distribution mode is 4+ 4; n is the polymerization degree of a polyethylene glycol chain and is selected from 1-2000; the polymerization degrees of the eight PEG chains, which may be the same or different from each other, are respectively represented by n₁、n₂、n₃、n₄、n₅、n₆、n₇、n₈(ii) a The eight-arm polyethylene glycol has monodispersity or polydispersity.

2. The eight-arm polyethylene glycol of claim 1, wherein n is₁≈n₂≈n₃≈n₄≈n₅≈n₆≈n₇≈n₈；

The number average molecular weight per PEG chain is preferably about 150,250,500,600,700,800,900,1000,1500,2000,2500,3000,3350,3500,4000,5000,5500,6000,6500,7000,7500,8000,8500,9000,9500,10000,11000,12000,13000,14000,15000,16000,17000,18000,19000 or 20000 Da.

3. The eight-arm polyethylene glycol according to claim 1, wherein the number average molecular weight of each of the eight PEG chains is selected from 2kDa to 40kDa or from 1 Da to 1500 Da; more preferably 2-1000 Da; more preferably 2-500 Da; more preferably 30-250 Da; more preferably 34 to 150 Da.

4. The eight-arm polyethylene glycol according to claim 1, wherein the number average degree of polymerization of each of the eight PEG chains is selected from the group consisting of 22 to 2000; more preferably 44 to 2000; more preferably 90 to 2000; more preferably 113 to 2000.

5. The eight-arm polyethylene glycol according to claim 1, wherein the number average degree of polymerization of each of the eight PEG chains is selected from 1 to 113; more preferably 1 to 90; more preferably 1 to 44; more preferably 1 to 22.

6. The eight-arm polyethylene glycol according to claim 1, wherein each of the eight PEG chains has monodispersity, preferably n₁＝n₂＝n₃＝n₄＝n₅＝n₆＝n₇＝n₈(ii) a The number of EO units is 2 to 70; more preferably 3 to 70; more preferably 3 to 70; more preferably 3 to 50; more preferably 3 to 25; preferably selected from any of 2,3,4,5,6, 7,8, 9, 10,11, 12,13, 14, 15, 16, 18, 20, 22, 24, 26, 27, 28, 29, 30, 32, 34, 36, 38, 40, 42, 44, 45, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 67, 68, 70.

7. The eight-armed polyethylene glycol according to claim 1, wherein the eight-valent group CORE (O-)₈Can exist stably or degradable connecting groups exist; the conditions under which the difference can exist stably and be degraded are selected from any one of the following conditions: light, heat, low temperature, enzyme, redox, acidic, alkaline, physiological conditions, in vitro simulated environment;

the eight-valent group CORE (O-)₈Degradable linkers are present, with a single degradation mode, or a combined degradation mode; when the combined degradation mode is preferred, the gradient degradation mode with different degradation rates or different degradation conditions is preferred;

the CORE is preferably stable under anionic polymerization conditions.

8. The eight-armed polyethylene glycol according to claim 1,

the monosaccharide unit is selected from monovalent residues of monosaccharide, sugar alcohol, deoxysugar, aminosugar derivative, sugar acid and glucoside or derivatives thereof;

the molecular formula of the sugar alcohol is C₄H₁₀O₄、C₅H₁₂O₅、C₆H₁₄O₆、C₇H₁₆O₇(ii) a Preferably erythritol, xylitol, sorbitol, lactitol, mannitol;

the deoxy sugar is preferably deoxyribose or fucose;

the amino sugar is preferably glucosamine, galactosamine, mannosamine, aminodeoxyglucose;

amide derivatives of said amino sugars;

said sugar acids, preferably gluconic acid, heptonic acid, glucuronic acid;

the glycoside, preferably methyl glycoside, ethyl glycoside, propyl glycoside;

said monosaccharide unit is selected from aldose or ketose;

the monosaccharide unit is selected from tetrose, pentose, hexose and heptose;

the tetrose has a molecular formula C₄H₈O₄(ii) a Preferably erythrose, erythrulose;

said pentose, formula C₅H₁₀O₅Or C₅H₁₀O₄(ii) a Preferably ribose, arabinose, lyxose, xylose, deoxyribose, ribulose;

the hexose of formula C₆H₁₂O₆Or C₆H₁₂O₅(ii) a Preferably glucose, allose, altrose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, tagatose, inositol, fucose;

said heptose has the molecular formula C₇H₁₄O₇Or C₇H₁₄O₆(ii) a Mannoheptulose is preferred.

9. The eight-armed polyethylene glycol according to claim 1,

the glycosidic bond is selected from O-glycoside, N-glycoside, S-glycoside, and C-glycoside;

the glycosidic bond is selected from alpha-type glycosidic bond and beta-type glycosidic bond;

the glycosidic bond is any one of 1, 1-glycosidic bond, 1, 2-glycosidic bond, 1, 3-glycosidic bond, 1, 4-glycosidic bond, 1, 6-glycosidic bond and 2, 1-glycosidic bond;

the glycosidic bond is any one of alpha-1, 4-glycosidic bond, alpha-1, 6-glycosidic bond, beta-1, 4-glycosidic bond, alpha, beta-1, 2-glycosidic bond, beta-1, 6-glycosidic bond, alpha-1, 1-glycosidic bond, beta-1, 3-glycosidic bond and beta-2, 1-glycosidic bond;

the octahydroxydisaccharide molecule is most preferably a structure formed by connecting two furan-type or pyran-type hexose rings through a glycosidic bond;

the molecule of octahydroxydisaccharide is preferably trehalose, cellobiose, maltose, isomaltose, gentiobiose, kojibiose, laminaribiose, mannobiose, alpha-glucose-alpha-glucoside;

the octahydroxydisaccharide molecule is also preferably of any of the following structures, or of any structure in which the O-glycoside is substituted with an S-glycoside, an N-glycoside or a C-glycoside:

10. the method for preparing the eight-arm polyethylene glycol of any one of claims 1 to 9, which is characterized by comprising the following steps:

step one, adopting small molecule CORE (OH) containing eight hydroxyl groups₈The initiator system of (1); wherein, CORE (O-)₈Is stable under anionic polymerization conditions;

the octahydroxy disaccharide micromolecule is used as an initiator and forms a co-initiator system with alkali;

initiating ethylene oxide polymerization;

and step three, adding a proton source into the intermediate product system with eight polyethylene glycol chains obtained in the step two after the reaction is finished, and obtaining the hydroxyl-terminated eight-arm polyethylene glycol.

11. The method for preparing the eight-arm polyethylene glycol of any one of claims 1 to 9, which is characterized by comprising the following steps:

coupling reaction is carried out on the disaccharide-based micromolecules and linear functionalized polyethylene glycol containing naked hydroxyl groups to obtain eight-arm polyethylene glycol;

or the disaccharide-based micromolecule and linear functionalized polyethylene glycol containing protected hydroxyl are subjected to coupling reaction to obtain protected eight-arm polyethylene glycol, and then the protected eight-arm polyethylene glycol is subjected to deprotection reaction to obtain eight-arm polyethylene glycol;

wherein the disaccharide-based small molecule is an octahydroxydisaccharide molecule CORE (OH)₈Or a functionalized octahydroxydisaccharide molecule;

the linear functionalized polyethylene glycol comprises a reactive end and a hydroxyl end; wherein, the reaction end contains a reactive group which can react with the small disaccharide-based molecule to form a covalent linking group; the hydroxyl end contains a naked hydroxyl group or a protected hydroxyl group.

12. A functionalized eight-arm polyethylene glycol is characterized in that the structural general formula is as follows:

wherein the CORE with an eight-valent central structure contains residues of eight-hydroxyl disaccharide molecules after dehydroxylation, and the eight hydroxyl groupsThe disaccharide molecule contains eight naked hydroxyl groups; the octahydroxydisaccharide molecule is a structure in which two monosaccharide units are covalently linked; the connecting group for covalently connecting the two monosaccharide units is selected from any one of glycosidic bonds, amido bonds and ester bonds; eight naked hydroxyl groups of the octahydroxydisaccharide molecule are distributed on two monosaccharide units, the two monosaccharide units are the same, and the distribution mode is 4+ 4; n is the polymerization degree of a polyethylene glycol chain and is selected from 1-2000; the polymerization degrees of the eight PEG chains, which may be the same or different from each other, are respectively represented by n₁、n₂、n₃、n₄、n₅、n₆、n₇、n₈；

Wherein k is_HThe number of PEG chains with hydroxyl at the end of PEG in a single molecule, k_HLess than 8, i.e. at least one PEG chain end is functionalized, k_HSelected from 0,1, 2,3,4,5,6, 7; the remaining 8-k_HEach PEG chain end contains a functional group; f is a hydrogen atom orWherein q and q are₁Each independently is 0 or 1, Z₁、Z₂Each independently is a divalent linking group, R₀₁Is a functional group capable of interacting with a biologically relevant substance; f is a hydrogen atom and participates in forming a terminal functional group, namely hydroxyl, amino or sulfydryl;

k is the number of F in a single functionalized end and is selected from 1 or 2-250; 8-k in a single molecule_HEach k is independently equal or different;

in a single functionalized PEG chain, g is 0 or 1; g is a terminal branching group selected from a trivalent or higher valent connecting group which connects the PEG chain segment with a terminal functional group; l is₀Is a divalent linking group which connects the PEG chain segment with the terminal branching group G;

when g is 0, k is 1, L₀G is not present, F is not a hydrogen atom, hydroxyethyl, hydroxyl terminated PEG chain;

when G is 1, G is present, L₀May be present or absent, k is 2 to 250, where F is allowed to be a hydrogen atom;

general formula (VII)(20) In (1)

13. The functionalized eight-arm polyethylene glycol according to claim 12, wherein the functionalized eight-arm polyethylene glycol has a general formula of any one of general formulas (2), (6) and (7);

general formula (2), k_H0, wherein 8 PEG chains are all functionally modified,

general formula (6), k_H7, wherein only one PEG chain is functionally modified,

general formula (7), k_H＝7，g＝0，k＝1。

14. The functionalized eight-armed polyethylene glycol according to claim 12,

g at the ends of the eight PEG chains are all equal; the functionalized eight-arm polyethylene glycol is selected from any one of the following general formulas:

(1) g is 0, G is absent, k is 1, and formula (2) is represented by formula (21):

(2) g is 1, G exists, k is more than or equal to 2, and the general formula (2) is shown as a formula (22), wherein k is selected from 2,3,4,5,6, 7,8, 9, 10,11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32 or 33-250;

(3) g is 1, G is present, and k is equal at the end of eight PEG chains; k is 2, the general formula (2) is shown as a formula (23), and all the terminal branched groups G are trivalent branched groups;

(4) g is 1, G is present, and k is equal at the end of eight PEG chains; k is 3, the general formula (2) is shown as a formula (24), and the terminal branched groups G are all tetravalent branched groups;

(5) g ═ 1, G contains a dendritic structure, and k is selected from any of the following: 2²,2³,2⁴,2⁵,2⁶,3²,3³,3⁴,3⁵,4²,4³,4⁴And 2 times, 3 times or 4 times any of k above;

(6) g is 1, G is a comb structure, k is more than or equal to 3, preferably 100 is more than or equal to k is more than or equal to 3, more preferably 50 is more than or equal to k is more than or equal to 3, and more preferably 25 is more than or equal to k is more than or equal to 3;

(7) g is 1, G is a furanose ring or pyranose ring structure, G (F)_kThe tail end of the compound is hydroxyl, amino and sulfydryl, or functional groups obtained by functional modification of the hydroxyl, the amino and the sulfydryl;

(8)g＝1，G(F)_kall being residues of open-chain monosaccharides, open-chain disaccharides or open-chain polysaccharidesThe end is hydroxyl or a functional group obtained by functional modification of the hydroxyl;

(9)g＝1，G(F)_kis cyclodextrin residue, the cyclodextrin is alpha-, beta-or gamma-cyclodextrin, and the end is hydroxyl or functional group obtained by functional modification of the hydroxyl.

15. The functionalized eight-armed polyethylene glycol according to claim 12,

the R is₀₁The interaction with the biologically relevant substance is selected from the group consisting of covalent bond formation, hydrogen bond formation, fluorescence, and targeting;

the R is₀₁Preferably reactive groups, reactive group variants, functional groups with therapeutic targeting, fluorescent functional groups; the variant is selected from any one of a precursor of a reactive group, an active form thereof as a precursor, a substituted active form, a protected form, a deprotected form;

the R is₀₁Any one of the functional groups of the A-type to the H-type or a variation thereof is preferable; the variant is selected from any one of a precursor of a reactive group, an active form thereof as a precursor, a substituted active form, a protected form, a deprotected form:

class A: activated ester groups and analogous structures of activated ester groups; the active ester group is selected from a succinimide active ester group, a p-nitrobenzene active ester group, an o-nitrobenzene active ester group, a benzotriazole active ester group, a1, 3, 5-trichlorobenzene active ester group, a fluoro-phenyl active ester group and an imidazole active ester group; similar structures of the active ester group are selected from 2-thione-3-thiazolidine formate group, 2-thiothiothiazolidine-3-carboxylic acid ester group, 2-thiopyrrolidine-N-formate group, 2-thiobenzothiazole-N-formate group and 1-oxo-3-thiooxoisoindoline-N-formate group;

class B: sulfonate, sulfinate, sulfone, sulfoxide, 1, 3-disulfonyl-2-propylcarbonylphenyl, sulfone methacryl;

class C: hydroxylamino group, mercapto group, amino group, halogen atom, haloacetamido group, tetramethylpiperidinyloxy group, dioxopiperidinyloxy group, ammonium salt, hydrazine group, residue of disulfide, ester group, thioester group, carbonate group, thiocarbonate group, dithiocarbonate group, trithiocarbonate group, xanthate group, peroxythiocarbonate group, tetrathiodiester group, O-carbonylhydroxylamino group, amide group, imide group, hydrazide group, sulfonylhydrazine group, hydrazone group, imino group, enamine group, alkynylamine group, protected hydroxyl group or mercapto group, protected amino group; the amino group comprises a primary amino group and a secondary amino group; the protected hydroxyl or thiol group is preferably a carbamate, monothiocarbamate, dithiocarbamate; the protected amino group is preferably a carbamate, monothiocarbamate, dithiocarbamate;

class D: carboxyl, sulfonic, sulfenic, hydroxamic, thiohydroxamic, xanthic, acid halide, sulfonyl chloride, aldehyde, glyoxal, acetal, hemiacetal, hydrated aldehyde, keto, ketal, hemiketal, ketal, hydrated keto, orthoacid, orthoester, cyanate, thiocyanate, isocyanurate, isothiocyanate, ester, oxycarbonylhalide, dihydrooxazolyl, thioaldehyde, thioketo, thioacetal, thioketone hydrate, thioketal, hemithioketal, thioester, dithiodiester, thiohemiacetal, monothiohydrate, dithiohydrate, thiohydrate, thiocarboxylic, urea, thiourea, guanidine and protonated forms thereof, amidino and protonated forms thereof, acid anhydride, squaric ester, Hemisquarylium group, N-carbamoyl-3-imidazolyl group, N-carbamoyl-3-methylimidazolium iodide group, imido group, nitrone group, oxime group, ureido group, thioureido group, pseudoureido group; the dihydrooxazolyl group comprises oxazolinyl and isoxazolinyl; the thiocarboxylic acid group comprises a thiocarboxylic acid group and a dithiocarboxylic acid group;

class E: maleimide group, acrylate group, N-acrylamide group, methacrylate group, N-methacrylamide group, protected maleimide group, maleamidyl group, 1,2, 4-triazoline-3, 5-diketone group, azo group, cyclic olefin group; the cycloalkenyl is preferably any one of cyclooctenyl, norbornenyl, 7-oxa-bicyclo [2.2.1] hept-5-en-2-yl, bicycloheptadiene/2, 5-norbornadiene and 7-oxabicycloheptadienyl;

class F: epoxy, alkenyl hydrocarbyl, alkynyl hydrocarbyl; the alkenyl group is preferably an ethenyl group or a propenyl group; the alkenyl hydrocarbon group is preferably an allyl group; the alkynyl group is preferably propynyl; the alkynyl hydrocarbyl is preferably propargyl;

the class of the signal is a class G,

class Ga: cycloalkynylalkyl, cycloalkynheteroalkyl, conjugated dienyl, hybrid conjugated dienyl, 1,2,4, 5-tetrazinyl;

class Gb: azido, nitrile oxide groups, cyanooxide groups, cyano, isocyano, aldoximo, diazo, diazonium ions, azoxy, nitrilo imino, N-oxyaldoimino, tetrazolo, 4-acetyl-2-methoxy-5-nitrophenoxy and diazotized forms thereof; a functional group capable of undergoing a1, 3-dipolar cycloaddition reaction;

class H: hydroxyl, protected hydroxyl, siloxy, protected bishydroxy, trihydroxysilyl, protected trihydroxysilyl; the hydroxyl is selected from any one of alcoholic hydroxyl, phenolic hydroxyl, enol hydroxyl and hemiacetal hydroxyl.

16. The functionalized eight-armed polyethylene glycol according to claim 12,

the R is₀₁When it is an active ester group, - (Z)₁)_q1-R₀₁An active ester form selected from any one of: carbonate, acetate, propionate, butyrate, valerate, hexanoate, heptanoate, octanoate, nonanoate, decanoate, ethanedioate, malonate, methyl malonate, ethyl malonate, butyl malonate, succinate, 2-methyl succinate, 2-dimethyl succinate, 2-ethyl-2-methyl-succinate, 2, 3-dimethyl succinate, glutarate, 2-methyl glutarate, 3-methyl glutarate, 2-dimethyl glutarate, 2, 3-dimethyl glutarateEsters, 3-dimethylglutarates, adipates, pimelates, suberates, azelates, sebacates, maleates, fumarates, amino acid esters, polypeptide acid esters, polyamino acid esters;

the R is₀₁When it is amino, - (Z)₁)_q1-R₀₁Primary amino obtained by losing non-amino hydrogen atoms of primary amine or secondary amino obtained by losing amino hydrogen atoms of primary amine, and secondary amino obtained by losing non-amino hydrogen atoms of secondary amine;

the R is₀₁When it is an aldehyde group, - (Z)₁)_q1-R₀₁Selected from the group consisting of monovalent functional groups or carboxaldehyde groups corresponding to aldehyde compounds lacking a non-aldehyde hydrogen atom;

the R is₀₁When it is a carboxyl group, - (Z)₁)_q1-R₀₁The compound comprises univalent functional groups corresponding to monoacid after one non-carboxyl hydrogen atom is lost and univalent functional groups obtained by removing one molecular of hydroxyl from diacid;

the R is₀₁When the halogen atom is an acid halide group, the halogen atom is selected from a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; - (Z)₁)_q1-R₀₁Comprises univalent groups obtained by removing 1 hydrogen atom from acyl chloride compounds, and acyl halide groups formed by combining diacyl and a halogen atom;

the R is₀₁When the acid anhydride group is an acid anhydride group, the chain is open or intramolecular acid anhydride is formed; - (Z)₁)_q1-R₀₁Including monovalent functional groups corresponding to anhydrides having lost one hydrogen atom;

the R is₀₁When it is an intramolecular carbonylimino group, - (Z)₁)_q1-R₀₁In the form of the imide corresponding to the intramolecular anhydride;

when R is₀₁When it is a maleimide group, - (Z)₁)_q1-R₀₁From 3,4,5, 6-tetrahydrophthalimide, maleimidoacetyl, 3-maleimidopropionyl, 4-maleimidobutyryl, 5-maleimidovaleryl, 6- (maleimido) hexanoyl, 3-maleimidobenzoyl, 4- (N-maleimido)A maleimide group selected from the group consisting of methyl) cyclohexane-1-formyl group, 4- (4-maleimidophenyl) butyryl group, 11- (maleimido) undecanoyl group, N- (2-aminoethyl) maleimide, N- (4-aminophenyl) maleimide and 2-maleimidoethyl group;

the R is₀₁When it is alkynyl, - (Z)₁)_q1-R₀₁Any one of ethynyl, propynyl, propargyl, cycloalkynyl and any hydrocarbyl substituted form thereof;

the R is₀₁When cyano (-) - (Z)₁)_q1-R₀₁Including monovalent functional groups corresponding to cyano compounds lacking a hydrogen atom;

the R is₀₁When it is hydroxy, - (Z)₁)_q1-R₀₁Including monovalent functional groups corresponding to monohydric alcohols lacking one non-hydroxyl hydrogen atom.

17. The functionalized eight-armed polyethylene glycol according to claim 12,

the R is₀₁When it is amino, - (Z)₁)_q1-R₀₁Primary amino obtained by losing non-amino hydrogen atoms of primary amine or secondary amino obtained by losing amino hydrogen atoms of primary amine, and secondary amino obtained by losing non-amino hydrogen atoms of secondary amine; the primary amine is selected from any one of methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, cyclohexylamine and aniline; the secondary amine is selected from any one of dimethylamine, diethylamine, dipropylamine, dibutylamine, dipentylamine, dihexylamine, diheptylamine, dioctylamine, dicyclohexylamine, N-methylaniline, N-ethylaniline, N-propylaniline, N-isopropylaniline, N-butylaniline, N-cyclohexylaniline, azetidine, pyrrolidine and piperidine; the R is₀₁When it is amino, - (Z)₁)_q1-R₀₁Also preferred are residues formed after an amino acid, amino acid derivative, omega-aminocarboxylic acid, polypeptide or polypeptide derivative has lost the hydroxyl group of the C-carboxyl group or pendant carboxyl group;

the R is₀₁When it is an aldehyde group, - (Z)₁)_q1-R₀₁Selected from aldehyde groupsA monovalent functional group corresponding to a compound lacking a non-aldehydic hydrogen atom; the aldehyde-based compound is selected from acetaldehyde, propionaldehyde, butyraldehyde, valeraldehyde, caproaldehyde, heptaldehyde, caprylic aldehyde, nonanal, decanal, crotonaldehyde, acrolein, methacrolein, 2-ethylacroldehyde, monochloroacetaldehyde, iodoacetaldehyde, dichloroacetaldehyde, benzaldehyde, phenylacetaldehyde, tolualdehyde, cinnamaldehyde, nitrocinnamaldehyde, bromobenzaldehyde, chlorobenzaldehyde; when 2 or more than 2 structural forms exist, any one of the structural forms can be adopted;

The R is₀₁When it is a carboxyl group, - (Z)₁)_q1-R₀₁The compound comprises univalent functional groups corresponding to monoacid after one non-carboxyl hydrogen atom is lost and univalent functional groups obtained by removing one molecular of hydroxyl from diacid; the monobasic acid is selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, arachidic acid, heneicosanoic acid, behenic acid, isobutyric acid, 3-methylbutyric acid, acrylic acid, methacrylic acid, citric acid, vinylacetic acid, tiglic acid, 6-heptenoic acid, itaconic acid, citronellac acid, monochloroacetic acid, dichloroacetic acid, monofluoroacetic acid, difluoroacetic acid, benzoic acid, methylbenzoic acid, monofluorobenzoic acid, ethoxybenzoic acid, methoxybenzoic acid, ethylbenzoic acid, vinylbenzoic acid, propylbenzoic acid, 2-isopropylbenzoic acid, 2-butylbenzoic acid, 2-isobutylbenzoic acid, carbamoylmaleic acid, N-phenylmaleic acid, maleic acid, arachidonic acid, tetracosanoic acid, lauric acid, Any one of eicosatetraenoic acid, glycolic acid, lactic acid, isonicotinic acid, ascorbic acid, gentisic acid, gluconic acid, uronic acid, sorbic acid, and N- (omega-aminocarboxylic acid) group; the dibasic acid is selected from oxalic acid, malonic acid, methyl malonic acid, ethyl malonic acid, butyl malonic acid, succinic acid, 2-methylsuccinic acid, 2-dimethylsuccinic acid, 2-ethyl-2-methyl-succinic acid, 2, 3-dimethylsuccinic acid, glutaric acid, 2-methylglutaric acid, 3-methylglutaric acid, 2-dimethylglutaric acid, 2, 3-dimethylglutaric acid, 3-dimethylglutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, oxaloacetic acid, diacetic acid, malonic acid, succinic acid, 2-dimethylglutaric acid, 2, 3-dimethylglutaric acid, 3-dimethylglutaric acid, adipic acid, pimMethyl malonic acid, isopropyl malonic acid, benzyl malonic acid, 1-epoxydicarboxylic acid, 1-cyclobutyl dicarboxylic acid, dibutyl malonic acid, ethyl (1-methylpropyl) malonic acid, ethyl (1-methylbutyl) malonic acid, ethyl (isopentyl) malonic acid, phenylmalonic acid, 2-oxoglutaric acid, 3-oxoglutaric acid, 5-norbornene-endo-2, 3-dicarboxylic acid, 1, 4-cyclohexanedicarboxylic acid, 1, 3-cyclohexanedicarboxylic acid, 1, 2-cyclohexanedicarboxylic acid, pyrrolidine-3, 4-dicarboxylic acid, camphoric acid, chlorendic acid, cyclic acid, 5-methylisophthalic acid, phthalic acid, 4-methyl-1, 2-benzenedicarboxylic acid, 4-chlorophthalic acid, 3, 4-pyridinedicarboxylic acid, 2, 3-pyridinedicarboxylic acid, 2, 4-pyridinedicarboxylic acid, 3, 5-pyridinedicarboxylic acid, 2, 6-pyridinedicarboxylic acid, 2, 4-dimethylpyrrole-3, 5-dicarboxylic acid, pyridine-2, 3-dicarboxylic acid, 5-methylpyridine-2, 3-dicarboxylic acid, 5-ethylpyridine-2, 3-dicarboxylic acid, 5-methoxymethyl-2, 3-pyridinedicarboxylic acid, 4, 5-pyridazinedicarboxylic acid, 2, 3-pyrazinedicarboxylic acid, 5-methylpyrazine-2, 3-dicarboxylic acid, 4, 5-imidazoledicarboxylic acid, 2-propylimidazoledicarboxylic acid, biphenyldicarboxylic acid, 4 '-diphenylethylenedicarboxylic acid, 2, 7-naphthalenedicarboxylic acid, 4' -diphenyletherdicarboxylic acid, di-carboxylic acid, 2,2' -bipyridine-5, 5' -dicarboxylic acid, 2' -bipyridine-3, 3' -dicarboxylic acid, 4-pyrone-2, 6-dicarboxylic acid, catechol-O, O ' -diacetic acid, thiophene-2, 3-dicarboxylic acid, 2, 5-thiophenedicarboxylic acid, 2, 5-dicarboxylic acid-3, 4-ethylenedioxythiophene, 1, 3-acetonedicarboxylic acid, itaconic acid, 2-methyl-2-butenedioic acid, 1, 3-butadiene-1, 4-dicarboxylic acid, butynedioic acid, norbornene-2, 3-dicarboxylic acid, bicyclo [2.2.1 ] butane dicarboxylic acid]Hept-2-ene-2, 3-dicarboxylic acid, diglycolic acid, dithiol dihydroxyacetic acid, malic acid, tartaric acid, 2, 3-dimercaptosuccinic acid, 2, 3-dibromosuccinic acid, pyrazololytic acid, 4' -dichloro-2, 2' -dicarboxybiphenyl, 4' -dibromo-2, 2' -dicarboxybiphenyl, glucaric acid, saccharonic acid, pamoic acid, 2-bromosuccinic acid, 2-mercaptosuccinic acid, 1, 3-adamantanedicarboxylic acid, 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylic acid, carbonylmalonic acid, ethoxymethylidene-malonic acid, 3' -dithiodipropionic acid, 5-exo-methyl-2-norbornene-5, any one of 6-cis-dicarboxylic acid and acetyl malonic acid; the R is₀₁When it is a carboxyl group, - (Z)₁)_q1-R₀₁Also preferred are amino acids, amino acid derivatives, polypeptides or polypeptide derivativesA residue formed after the biological loss of one hydrogen atom of the N-amino group or pendant amino group;

the R is₀₁When the halogen atom is an acid halide group, the halogen atom is selected from a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; - (Z)₁)_q1-R₀₁Comprises univalent groups obtained by removing 1 hydrogen atom from acyl chloride compounds, and acyl halide groups formed by combining diacyl and a halogen atom; the acyl chloride compound is any one of acetyl chloride, acetyl bromide, monochloroacetyl chloride, dichloroacetyl chloride, propionyl bromide, butyryl chloride, 3-cyclopentyl propionyl chloride, 2-chloropropionyl chloride, tert-butyl acetyl chloride, valeryl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, lauroyl chloride, myristoyl chloride, palmitoyl chloride, stearoyl chloride, oleoyl chloride, behenoyl chloride, cyclopentanecarbonyl chloride, methoxyacetyl chloride and acetoxyacetyl chloride; the diacyl is selected from any one of oxalyl, malonyl, methylmalonyl, ethylmalonyl, butylmalonyl, succinyl, 2-methylsuccinyl, 2-dimethylsuccinyl, 2-ethyl-2-methyl-succinyl, 2, 3-dimethylsuccinyl, glutaryl, 2-methylglutaryl, 3-methylglutaryl, 2-dimethylglutaryl, 2, 3-dimethylglutaryl, 3-dimethylglutaryl, adipoyl, pimeloyl, suberoyl, azelaioyl, sebacoyl, maleoyl and fumaroyl;

the R is₀₁When the acid anhydride group is an acid anhydride group, the chain is open or intramolecular acid anhydride is formed; - (Z)₁)_q1-R₀₁Including monovalent functional groups corresponding to anhydrides having lost one hydrogen atom; the anhydride is selected from acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, hexanoic anhydride, heptanoic anhydride, octanoic anhydride, nonanoic anhydride, decanoic anhydride, lauric anhydride, myristic anhydride, palmitic anhydride, stearic anhydride, behenic anhydride, crotonic anhydride, methacrylic anhydride, oleic anhydride, linoleic anhydride, chloroacetic anhydride, iodoacetic anhydride, dichloroacetic anhydride, succinic anhydride, methylsuccinic anhydride, 2-dimethylsuccinic anhydride, itaconic anhydride, maleic anhydride, glutaric anhydride, diethanol anhydride, benzoic anhydride, phenylsuccinic anhydride, phenylmaleic anhydride, perphthalic anhydride, maleic anhydrideAny one of isatoic anhydride and phthalic anhydride; the intramolecular acid anhydride is selected from succinic anhydride, 2-dimethylsuccinic anhydride, cyclopentane-1, 1-diacetic anhydride, 1-cyclohexyldiacetic anhydride, 2-methylenesuccinic anhydride, glutaric anhydride, caronic anhydride, cyclobutane-1, 2-dicarboxylic anhydride, hexahydrophthalic anhydride, methylhexahydrophthalic anhydride, 1,2,3, 6-tetrahydrophthalic anhydride, 1,2,5, 6-tetrahydrophthalic anhydride, 3-methyltetrahydrophthalic anhydride, citraconic anhydride, 2, 3-dimethylmaleic anhydride, 2, 3-dichloromaleic anhydride, 3,4,5, 6-tetrahydrophthalic anhydride, 3-methylphthalic anhydride, 4-tert-butylphthalic anhydride, 1, 8-naphthalic anhydride, 1-cyclohexylacetic anhydride, 2-methylenesuccinic anhydride, 2-methyltetrahydrophthalic anhydride, 3-tetrahydrophthalic anhydride, 3-dimethylmaleic anhydride, 1, 3-tetrahydrophthalic anhydride, 1, any one anhydride of 2,2' -biphenyldicarboxylic anhydride, 4-fluorophthalic anhydride, 3-fluorophthalic anhydride, 4-bromophthalic anhydride, 4-chlorophthalic anhydride, 3, 6-dichlorophthalic anhydride, 3-nitrophthalic anhydride, 4-bromo-1, 8-naphthalic anhydride, 4, 5-dichloro-1, 8-naphthalic anhydride, 4-nitro-1, 8-naphthalic anhydride, nadic anhydride, methylendomethylenetetrahydrophthalic anhydride, norcantharidin, 2, 3-pyridinedicarboxylic anhydride, 2, 3-pyrazinedicarboxylic anhydride, and benzothioxanthene dicarboxylic anhydride;

the R is₀₁When it is an intramolecular carbonylimino group, - (Z)₁)_q1-R₀₁Imide forms corresponding to any one of the intramolecular anhydrides described above;

the R is₀₁When cyano (-) - (Z)₁)_q1-R₀₁Including monovalent functional groups corresponding to cyano compounds lacking a hydrogen atom; the cyano compound is selected from any one of formonitrile, acetonitrile, butyronitrile, valeronitrile, capronitrile, enanthonitrile, caprylonitrile, nonanonitrile, decylonitrile, undecyl nitrile, allyl nitrile, acrylonitrile, crotononitrile, methacrylonitrile, dichloroacetonitrile, fluoroacetonitrile, benzonitrile, benzylnitrile, methylbenzonitrile, chlorobenzonitrile and methylbenzonitrile;

the R is₀₁When it is hydroxy, - (Z)₁)_q1-R₀₁Comprises a monovalent functional group corresponding to a monohydric alcohol having lost one non-hydroxyl hydrogen atom; the monohydric alcohol is selected from methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, hexanol, butanol, and mixtures thereof,Nonanol, decanol, undecanol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, oleyl alcohol, benzyl alcohol, isoproyl, phenol, cresol, ethylphenol, propylphenol, cinnamyl phenol, naphthol, cyclopentanol, cyclohexanol.

18. The functionalized eight-armed polyethylene glycol according to claim 12, wherein R is₀₁Is a residue derived from any one of cholesterol or a derivative thereof, biotin or a derivative thereof, fluorescein or a derivative thereof, rhodamine or a derivative thereof, anthracene or a derivative thereof, pyrene or a derivative thereof, carbazole pyrene or a derivative thereof, imidazole or a derivative thereof, indole or a derivative thereof;

the R is₀₁When it is a residue of cholesterol or a derivative thereof, - (Z)₁)_q1-R₀₁A residue formed by modifying any one molecule selected from cholesterol derivatives and cholesteryl hydrogen succinate on the tail end of PEG;

the R is₀₁When it is a residue of biotin or a derivative thereof, - (Z)₁)_q1-R₀₁Selected from biotin-N-succinimidyl ester, 3- [3- [2- (biotinimido) ethyl]Amino-3-oxopropyl radical]Dithio radical]Propionic acid succinimidyl ester, 3- [ [2- (biotinimido) ethyl ester]Dithio radical]Sulfosuccinimidyl propionate, N- (3-azidopropyl) biotin amine, N-biotin-3, 6-dioxaoctane-1, 8-diamine, N-biotin-3, 6, 9-trioxaundecane-1, 11-diamine, biotinyl-6-aminoquinoline, N- (6- [ biotin amine)]Hexyl) -3'- (2' -pyridyldithio) propionamide, 15- [ D- (+) -biotin amino]-4,7,10, 13-tetraoxapentadecanoic acid, 3- (4- (N-biotin-6-aminocaprocarboxy) phenyl) propionic acid, N-Fmoc-N' -biotin-L-lysine, D-biotin hydrazide, biotin-aspartyl-glutamyl-valyl-aspartyl aldehyde, or a residue formed after modification of the PEG terminus with any molecule;

the R is₀₁When it is a residue of fluorescein or a derivative thereof, - (Z)₁)_q1-R₀₁Selected from the group consisting of 5-carboxyfluorescein succinimidyl ester, 6-carboxyfluorescein succinimidyl ester, 5-aminofluorescein, 6-aminofluorescein, 5(6) -Aminofluorescein, 5- (aminomethyl) fluorescein hydrochloride, 6- ([4, 6-dichlorotriazin-2-yl)]Amino) fluorescein hydrochloride, 5' -fluorescein phosphoramidate, fluorescein 5-maleimide, fluorescein 6-maleimide, 5-carboxyfluorescein, 6-carboxyfluorescein, 2, 7-bis (2-carboxyethyl) -5(6) -carboxyfluorescein, 5- (4, 6-dichlorotriazine) aminofluorescein, and CI 45350, wherein the residues are formed by modifying any one molecule of the molecules at the end of PEG;

the R is₀₁When it is a residue of rhodamine or a derivative thereof, - (Z)₁)_q1-R₀₁Selected from the group consisting of tetramethylrhodamine, tetraethylrhodamine, rhodamine 3G, rhodamine 6G, rhodamine 590, 5-carboxy-X-rhodamine, 6-carboxy-X-rhodamine, sulforhodamine B, sulforhodamine G, sulforhodamine 101, rhodamine X, rhodamine 101, rhodamine 110, rhodamine 123, rhodamine 700, rhodamine 800, 5-carboxytetramethylrhodamine, 6-carboxytetramethylrhodamine, 5-carboxytetramethylrhodamine succinimidyl ester, 6-carboxytetramethylrhodamine succinimidyl ester, 5-carboxyrhodamine 6G succinimidyl ester, 6-carboxytetramethylrhodamine 6G succinimidyl ester, 5-carboxyrhodamine 6G succinimidyl ester, 6-carboxyrhodamine 6G succinimidyl ester, tetramethylrhodamine-5-maleimide, tetramethylrhodamine-6-maleimide, 6-carboxy-X-rhodamine succinimidyl ester, A residue formed by modifying any one molecule of tetramethyl rhodamine-5-isothiocyanate, tetramethyl rhodamine-6-isothiocyanate, tetramethyl rhodamine B-5-isothiocyanate, tetramethyl rhodamine B-6-isothiocyanate, rhodamine chloride 101 and sulfonated rhodamine B at the tail end of PEG;

the R is₀₁When it is a residue of anthracene or a derivative thereof, - (Z)₁)_q1-R₀₁A residue formed by modifying any one molecule of 9-anthracene methanol, 1-amino anthracene, 2-amino anthracene, 9-anthracene formaldehyde, 10-methyl anthracene-9-formaldehyde, 9-anthracene formic acid, acrylic acid-9-anthracene methyl ester, methacrylic acid-9-anthracene methyl ester, 9-anthracene aldehyde oxime and 9-anthracene acrolein at the end of PEG;

the R is₀₁When it is a residue of pyrene or a derivative thereof, - (Z)₁)_q1-R₀₁Selected from 1-pyrene methanol, 7,8,9, 10-tetrahydrobenzo [ a]Pyrene-7-ol, N-hydroxysuccinimide ester 1-pyrenebutanoic acid, 1-pyrene formaldehyde, 1-pyrenebutanoic acid, 1-pyrene methylAcid, 1-pyreneacetic acid, 10- (1-pyrene) decanoic acid, 1-pyrenedodecanoic acid, Fmoc-3- (1-pyrenyl) -L-alanine, tert-butyloxycarbonyl-3- (1-pyrenyl) -D-alanine, tert-butyloxycarbonyl-3- (1-pyrenyl) -L-alanine, 1-aminopyrene, 1, 3-diaminopyrene, 1, 8-diaminopyrene, 1, 6-diaminopyrene, 1-pyrenemethylamine and N- (1-pyrenyl) maleimide, wherein the residue is formed after modification of any molecule of PEG terminals;

the R is₀₁When it is a residue of carbazole pyrene or a derivative thereof, - (Z)₁)_q1-R₀₁A residue formed by modifying any one molecule of carbazole, 9-carbazole ethanol, 2-hydroxy carbazole, 2- (9H-carbazolyl) ethyl boronic acid pinacol ester, 2- (9H-carbazolyl) ethyl boronic acid diethanol amine ester, N-aminocarbazole, 9- (4-aminophenyl) carbazole and 9-carbazolylacetic acid at the end of PEG;

the R is₀₁When it is a residue of imidazole or a derivative thereof, - (Z)₁)_q1-R₀₁Selected from the group consisting of 4- (hydroxymethyl) imidazole, 4-hydroxyethylimidazole, 1- (2-hydroxyethyl) imidazole, 1-methyl-2-hydroxymethyl-1H-imidazole, 1- (2-hydroxypropyl) imidazole, 1- (. beta. -hydroxyethyl) -2-methylimidazole, 4-hydroxymethyl-5-methyl-2-phenylimidazole, 1-hydroxyethyl-3-methylimidazole chloride salt, 4-hydroxymethyl-5-methylimidazole, 4-bromo-1H-imidazole, 2-bromo-1H-imidazole, 1-methyl-2-bromo-1H-imidazole, 5-chloro-1-methylimidazole, 2-aminoimidazole, 4-aminoimidazole, 1- (3-aminopropyl) imidazole, 1-methyl-4-imidazolecarboxylic acid, 4-imidazolecarboxaldehyde, 1-formylimidazole, 2-formylimidazole, 4- (imidazol-1-yl) benzaldehyde, 1-methyl-2-imidazolecarboxaldehyde, 2-butyl-1H-imidazole-4-carbaldehyde, 5-methylimidazole-4-carbaldehyde, 2-ethyl-4-formylimidazole, 2-ethyl-4-methyl-5-imidazolecarboxaldehyde, 1-benzyl-1H-imidazole-5-carbaldehyde, 5-amino-1H-imidazole-4-carbonitrile, a salt thereof, a hydrate thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, Histidine is a residue formed after any molecule of the histidine is modified at the end of PEG;

the R is₀₁When it is a residue of indole or a derivative thereof, - (Z)₁)_q1-R₀₁Selected from 4-hydroxyindole, 5-hydroxyindole, 6-hydroxyindole, 7-hydroxyindole, 5-hydroxy-2-methylindole, 4-hydroxy-2-methylindole, 3- (2-methylaminoethyl) indole, 2- (2-aminoethyl) indole, 3- (2-aminoethyl) ketone6-methoxyindole, 4-aminoindole, 5-aminoindole, 6-aminoindole, 7-aminoindole, 4-methyl-5-aminoindole, 3-bromoindole, 4-bromoindole, 5-bromoindole, 6-bromoindole, 7-bromoindole, 5-bromo-1-methyl-1H-indole, 3- (2-aminoethyl) indol-5-ol, 5-hydroxyindole-2-carboxylic acid, 6-hydroxy-2-indolecarboxylic acid, 7-hydroxyindole-2-carboxylic acid, 5-bromoindole-2-carboxylic acid, 6-bromoindole-2-carboxylic acid, 7-bromoindole-2-carboxylic acid, 6-bromoindole-2-carboxylic acid, 4-aminoindole, 5-aminoindole, 6-aminoindole, 7-bromoindole-2-carboxylic acid, 3-bromoindole-5-methyl-1-, 5-bromoindole-3-formic acid, 6-bromoindole-3-formic acid, 4-bromoindole-3-formaldehyde, 6-bromoindole-3-formaldehyde and 5-bromo-1H-indole-3-ethanol.

19. The functionalized eight-armed polyethylene glycol according to claim 12,

the R is₀₁A functional group selected from any one of the following classes a to J, a variant of any one of classes a to H, a functional derivative of any one of classes I to J; the variant is selected from any one of a precursor of a reactive group, an active form thereof as a precursor, a substituted active form, a protected form, a deprotected form:

class A:

or class B:

or class C:

or class D:

or class E:

or class F:

or class G:

class Ga:

or class Gb:

or class H:

or class I:

or class J:

wherein M is₅Is a ring-forming atom selected from any one of carbon atom, nitrogen atom, phosphorus atom and silicon atom; m₅The ring structure is 3-50A cyclic ring, preferably a 3-32 cyclic ring, more preferably a 3-18 cyclic ring, still more preferably a 5-18 cyclic ring; the cyclic structure is selected from any one of the following groups, a substituted form of any one, or a hybridized form of any one: cyclohexane, furanose ring, pyranose ring, benzene, tetrahydrofuran, pyrrolidine, thiazolidine, cyclohexene, tetrahydropyran, piperidine, 1, 4-dioxane, pyridine, pyridazine, pyrimidine, pyrazine, 1,3, 5-triazine, 1,4, 7-triazacyclononane, tripeptide, indene, indane, indole, isoindole, purine, naphthalene, dihydroanthracene, xanthene, thioxanthene, dihydrophenanthrene, 10, 11-dihydro-5H-dibenzo [ a, d ] s]Cycloheptane, dibenzocycloheptene, 5-dibenzocycloheptenone, quinoline, isoquinoline, fluorene, carbazole, iminodibenzyl, naphthylene ring, dibenzocyclooctyne, aza-dibenzocyclooctyne;

wherein, Y₁Is a leaving group attached to sulfonyl, sulfinyl, oxysulfonyl or oxysulfinyl, selected from any one of methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, vinyl, phenyl, benzyl, p-methylphenyl, 4- (trifluoromethoxy) phenyl, trifluoromethyl, 2,2, 2-trifluoroethyl;

wherein W is F, Cl, Br or Il;

wherein, W₂Is F, Cl, Br or I;

wherein, W₃Is a leaving group selected from F, Cl, Br, I, PhS;

wherein the content of the first and second substances,each is a cyclic structure containing a nitrogen atom, a nitrogen onium ion, a double bond, an azo, a triple bond, a disulfide bond, an anhydride, an imide, a diene on the ring backbone, the cyclic structure being selected from a carbocycle, a heterocycle, a benzoheterocycle, a substituted carbocycle, a substituted heterocycle, or a substituted benzoheterocycle;

wherein M is a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom on the ring;

wherein M is₈Is a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom located on the ring; m₈In the ringThe number of ring-forming atoms is 4-50;

wherein M is₂₂Is a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom on an alicyclic or alicyclic ring; m₂₂The number of ring atoms of the ring is 4,5,6, 7 or 8;

wherein R is₂Is a terminal group or a divalent linking group to which an oxygen or sulfur atom is bonded, selected from a hydrogen atom, R₂₁Or R₃Any one atom or group;

wherein R is₂₁Is a divalent linking group and participates in ring formation; r₂₁Is selected from C_1-20Alkylene, divalent C_1-20Heterohydrocarbyl, substituted C_1-20Alkylene, substituted divalent C_1-20Any divalent linking group or any two or any three of divalent linking groups in the heterohydrocarbon group; r₂₁Preferably methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, 1, 2-phenylene, benzylene, C_1-20Oxaalkylene, C_1-20Thiaalkylene group, C_1-20Any one group of azaalkylene and azaaralkyl, a substituted form of any one group, any two or more of the same or different groups, or a combination of substituted forms thereof;

wherein R is₃Is a terminal group linked to an oxy or thio group, selected from C_1-20Hydrocarbyl radical, C_1-20Heterohydrocarbyl radical, C_1-20Substituted hydrocarbyl radical, C_1-20Any of substituted heterohydrocarbyl groups; preferably any one or substituted form of any one of methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, benzyl, allyl;

wherein R is₄Is- (R)₄)C＝N⁺＝N^—Or- (R)₄)C^--N⁺A hydrogen atom, a substituent atom or a substituent on C in the structure of [ identical to ] N; preferably any one atom or group of hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, allyl group, propenyl group, vinyl group, phenyl group, methylphenyl group, butylphenyl group, benzyl group;

wherein R is₈、R₉、R₁₀、R₁₁、R₁₂Each independently is a hydrogen atom, a substituent atom or a substituent on a double bond (-C-), and R is in the same molecule₈、R₉、R₁₀、R₁₁、R₁₂May be the same as or different from each other; r₈、R₉、R₁₀、R₁₁、R₁₂Each independently selected from: hydrogen atom, fluorine atom, methyl group; in class E3, R₈Preferably methyl;

wherein R is₂₄Is a terminal group linked to a disulfide bond selected from: c_1-20Alkyl, aryl, hybrid phenyl;

wherein R is₂₇Is a substituent attached to azo selected from: phenyl, substituted phenyl or hybrid phenyl;

wherein R is₃₀Is a hydrocarbyl group selected from: c_1-20Alkyl, benzyl, phenyl ring hydrogen atoms by C_1-20A hydrocarbyl-substituted benzyl group;

wherein M is₁₉、M₂₀、M₂₁Each independently is an oxygen atom or a sulfur atom, and may be the same as or different from each other in the same molecule;

wherein, X₆Is a terminal group attached to the oxygen atom of the ester group and is selected from a hydroxyl protecting group or the group LG₄；LG₄Is selected from C_1-20Alkyl, aryl, aralkyl, C_1-20Heteroalkyl, heteroaryl, heteroaralkyl, C_1-20Alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, C_1-20Heteroalkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, C_1-20Alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, C_1-20Alkylthio-carbonyl, arylthio-carbonyl, aralkylthiocarbonyl, C_1-20Alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, C_1-20Heteroalkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, C_1-20Heteroalkylthio-carbonyl, heteroarylthio-carbonyl, heteroaralkylthio-carbonyl, C_1-20Heteroalkylaminocarbonyl, heteroarylaminoAlkylcarbonyl, heteroaralkylaminocarbonyl, C_1-20Alkylthio, arylthio, aralkylthiocarbonyl, C_1-20Heteroalkylthiocarbonyl, heteroarylthiocarbonyl, heteroarylalkylthiocarbonyl, C_1-20Alkoxythiocarbonyl, aryloxylthiocarbonyl, aralkyloxythiocarbonyl, C_1-20Alkylthio thiocarbonyl, arylthio thiocarbonyl, aralkylthio thiocarbonyl, C_1-20Alkylaminothiocarbonyl, arylaminothiocarbonyl, aralkylaminothiocarbonyl, C_1-20Heteroalkyloxythiocarbonyl, heteroaryloxythiocarbonyl, heteroarylalkoxythiocarbonyl, C_1-20Heteroalkylthio thiocarbonyl, heteroarylthio thiocarbonyl, heteroarylalkylthio thiocarbonyl, C_1-20(ii) any one of a heteroalkylaminothiocarbonyl, heteroarylaminothiocarbonyl or a substituted version of any one of the groups; wherein, the substituent atom or the substituent group is fluorine atom, alkoxy or nitro;

wherein, X₁₁Is a terminal group attached to a carbonyl or thiocarbonyl group, selected from C_1-20An alkyl group;

wherein, X₁₂Is a terminal group to which a carbonate or thiocarbonate group is attached, selected from C_1-20A hydrocarbyl group;

wherein, X₁₃Is a terminal group for attaching a sulfur group selected from: mercapto-protecting group, group LG₂；

Wherein LG is₂Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, allyl, trityl, phenyl, benzyl, methylbenzyl, nitrobenzyl, t-butylthio, benzylthio, 2-pyridylthio, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, t-butyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, t-butylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, 2-pyridylcarbonyl, phenylthiocarbonyl, phenylthiocarb,Methylaminocarbonyl, ethylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, ethylthiocarbonyl, phenylmethylthiocarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, tert-butyloxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, methylthiothiocarbonyl, ethylthiocarbonyl, tert-butylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiocarbonyl, methylaminothiocarbonyl, ethylaminothiocarbonyl, tert-butylaminothiocarbonyl, benzylaminothiocarbonyl, C_1-10Any one of a halogenated hydrocarbon group, a trifluoroacetyl group, a nitrophenyl group, or a substituted form of any one of the groups; wherein, the substituent atom or the substituent group is fluorine atom, alkoxy or nitro;

wherein Q is an atom or substituent contributing to the induction of unsaturated bond electrons, conjugation effect; when Q is on a ring, the number is one or more; when the number is multiple, the structure is the same, or the combination of two or more different structures; when a substituent group, Q has a linear structure, a branched structure containing a pendant group, or a cyclic structure;

wherein Q is₃An H atom or a group contributing to the induction of the electrons of unsaturated bonds, a conjugation effect, selected from any atom or group of hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, n-propyl group, isopropyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, vinyl group, propenyl group, allyl group, propynyl group, propargyl group, cyclopropyl group, cyclopropenyl group, phenyl group, benzyl group, butylphenyl group, p-methylphenyl group, p-nitrophenyl group, o-nitrophenyl group, p-methoxyphenyl group, azaphenyl group, methoxy group, ethoxy group, phenoxy group, benzyloxy group, methylthio group, ethylthio group, phenylthio group, benzylthio group, trifluoromethyl group, 2,2, 2-trifluoroethyl group, or a substituted form of any group;

wherein Q is₅Is H atom, methyl, ethyl or propyl; when Q is₅When located on a ring, the number is one or more; when more than 1, the structure is the same, or the combination of two or more different structures;

wherein Q is₆Is a hydrogen atom or a methyl group; q₇Is a hydrogen atom, a methyl group, a phenyl group or a substituted phenyl group; in the same molecule, Q₆And Q₇May be the same or different;

wherein Q is₈Is a substituent atom or a substituent group on the imidazolyl group, and is selected from any one of H atoms, methyl groups, ethyl groups, propyl groups, butyl groups and phenyl groups; when Q is₈Is one or more; when more than 1, the structure is the same, or the combination of two or more different structures;

wherein Q is₁₁Is a substituent on the nitrogen atom of tetrazole, and is selected from any one of phenyl, substituted phenyl and aza-phenyl;

wherein PG₂Is a thiol protecting group, the protected thiol group being denoted as SPG₂Selected from any one of thioether, disulfide, silicon-based thioether and thioester;

wherein PG₃Is an alkynyl protecting group selected from silicon;

wherein PG₄Is a hydroxy protecting group, the protected hydroxy group being represented by OPG₄Selected from any one of ether, silicon ether, ester, carbonate and sulfonate;

wherein PG₅Is an amino protecting group, the protected amino group being represented by NPG₅Selected from the group consisting of carbamates, amides, imides, N-alkylamines, N-arylamines, imines, enamines, imidazoles, pyrroles, indoles;

wherein PG₆Is a bishydroxy protecting group, and PG₆An acetal structure which forms a five-membered ring or a six-membered ring with two oxygen atoms; PG (Picture experts group)₆Is methylene or substituted methylene; wherein PG₆The substituent(s) is a hydrocarbyl substituent or a heteroatom-containing substituent selected from: methylene, 1-methylmethylene, 1-dimethylmethylene, 1-cyclopentylene, 1-cyclohexylene, 1-phenylmethylene, 3, 4-dimethylphenylmethylene;

wherein PG₈Protecting groups for orthocarbonic acid or orthosilicic acid.

20. The functionalized eight-arm polyethylene glycol of claim 12, wherein the functionalized eight-arm polyethylene glycol is stably present or degradable; when degradable, the number of degradable sites in the same molecule may be 1 or more; the functionalized eight-arm polyethylene glycol preferably satisfies any one of the following conditions:

(1) the functionalized eight-arm polyethylene glycol has stable CORE (O-)₈And a stable terminus;

(2) the functionalized eight-arm polyethylene glycol has stable CORE (O-)₈And a degradable tip;

(3) the functionalized eight-arm polyethylene glycol has degradable CORE (O-)₈And a stable terminus;

(4) the functionalized eight-arm polyethylene glycol has degradable CORE (O-)₈And a degradable tip;

wherein, when g is 0, it has an unbranched terminal-O (Z)₂)_q(Z₁)_q1-; g is 1, has a branched end-O-L₀-G-((Z₂)_q(Z₁)_q1-)_k。

21. The functionalized eight-armed polyethylene glycol according to claim 12, wherein g, q are g, q₁Each independently is 0 or 1; l is₀(g＝1)、Z₁、Z₂Each independently includes, but is not limited to, a linear structure, a branched structure, or a cyclic-containing structure;

g、q、q₁each independently is 0 or 1; l is₀(g＝1)、Z₁、Z₂Each independently having 1 to 50 non-hydrogen atoms; more preferably 1 to 20 non-hydrogen atoms; more preferably 1 to 10 non-hydrogen atoms; the non-hydrogen atom is a carbon atom or a heteroatom; the heteroatom is selected from O, S, N, P, Si and B; when the number of the non-hydrogen atoms is 1, the non-hydrogen atoms are carbon atoms or heteroatoms; when the number of the non-hydrogen atoms is more than 1, the types of the non-hydrogen atoms are 1,2 or more than 2; when the number of the non-hydrogen atoms is more than 1, the carbon atoms and the carbon atoms, the carbon atoms and the heteroatoms, and the heteroatoms are combined;

g、q、q₁each independently is0 or 1; l is₀(g＝1)、(Z₂)_q-(Z₁)_q1Any one of the divalent linking groups or any one of the divalent linking groups consisting of a group with an adjacent heteroatom is each independently a stably existing linking group STAG or a degradable linking group DEGG;

wherein the STAG can stably exist under any condition of light, heat, low temperature, enzyme, oxidation reduction, acidity, alkaline condition, physiological condition and in-vitro simulation environment;

wherein the DEGG is degradable under any one of light, heat, low temperature, enzyme, redox, acidity, alkalinity, physiological condition, and in vitro simulated environment;

the STAG is selected from the group consisting of alkylene, divalent heteroalkyl, double bond, triple bond, divalent dienyl, divalent cycloalkyl, divalent cycloalkenyl, divalent cycloalkyne, aromatic ring, alicyclic ring, hetero-phenyl ring, aromatic heterocyclic group, hetero-fused heterocyclic group, substituted alkylene, substituted divalent heteroalkyl, substituted double bond, substituted dienyl, substituted divalent cycloalkyl, substituted divalent cycloalkenyl, substituted divalent cycloalkyne, substituted aromatic ring, substituted alicyclic ring, substituted hetero-heterocyclic group, substituted hetero-phenyl ring, substituted aromatic heterocyclic group, substituted hetero-fused heterocyclic group, ether bond, thioether bond, urea bond, thiourea bond, carbamate group, thiocarbamate group, -P (═ O) -, divalent silicon group containing no active hydrogen, divalent linking group containing boron atom, secondary amino group, tertiary amino group, carbonyl group, thiocarbonyl group, amide group, thiocarbamide group, Sulfonamide, enamine, triazolyl, 4, 5-dihydroisoxazolyl, and the like,

the DEGG contains a disulfide bond, a vinyl ether bond, an ester group, a thioester group, a dithioester group, a carbonate group, a thiocarbonate group, a dithiocarbonate group, a thiocarbonate group, a carbamate group, a thiocarbamate group, a dithiocarbamate group, an acetal group, a cyclic acetal group, a mercaptide group, an azaacetal group, an azathiolacetal group, a dithioacetal group, a hemiacetal group, a thiohemiacetal group, an azahemiacetal group, a ketal group, a mercaptide group, an azaketal group, an azathioketal group, an azothioketal group, an imine bond, a hydrazone bond, a hydrazide bond, an oxime bond, a sulfoximine group, a semicarbazide ether group, a semicarbazone bond, a thiosemicarbazone bond, a hydrazine group, a hydrazide group, a thiocarbohydrazide group, an azocarbohydrazide group, a thioazohydrazide group, a hydrazinocarbothioate group, a carbazate group, a, Thiocarbazoyl, azo, isoureido, isothioureido, allophanate, thioallophanate, guanidino, amidino, aminoguanidino, amidino, imido, thioesterimidate, sulfonate, sulfinate, sulfonylhydrazino, sulfonylureido, maleimido, orthoester, benzyloxycarbonyl, phosphate, phosphite, hypophosphite, phosphinate, phosphonate, phosphosilane, silanol, carbonamide, thioamide, sulfonamido, polyamide, phosphonamide, phosphoramidite, pyrophosphoamide, cyclic phosphoramidide, isocyclophosphamide, thiophosphoramide, aconityl, polypeptide fragment, nucleotide and derivative backbone, any divalent linking group of deoxynucleotide and derivative backbone, or a combination of any two or more divalent linking groups.

22. The functionalized eight-arm polyethylene glycol according to claim 12, wherein g-1; the terminal branched groups G of the eight-arm polyethylene glycol derivative have the same structure type, and the structure type of the G is any one of branched, cyclic structure-containing, comb-shaped, tree-shaped and hyperbranched types; g is degradable or can exist stably;

the G is preferably of any one of the following structures:

wherein k is 2 and G is a trivalent group; l is₀-G comprises a structure selected from any one of the following groups: e₀,

Wherein, E is₀Contains any one of the following structures:

said E₀Also preferred are end-capping structures containing the above structure with a divalent linking group selected from 1,2 or 3 of the same or different divalent linking groups selected from oxy, thio, secondary amino, divalent tertiary amino and carbonyl groups;

said E₀Also preferred is any of the following structures:

said E₀Also preferred are trivalent backbone structures of amino acids or derivatives thereof; wherein the amino acid is_LIs of type or_D-type; the amino acid or the derivative thereof is derived from any one of the following: serine, threonine, cysteine, tyrosine, hydroxyproline, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, citrulline, histidine, tryptophan;

k is 3 and G is fourA valent group; tetravalent G containing atoms CM₄And unsaturated bond CB₄Ring structure CC₄Any tetravalent core structure, or comprises two trivalent core structures; l is₀-G contains any of the following structures:

when k is more than or equal to 3, namely the valence state of G is more than or equal to 4, the G with the valence of k +1 contains 1 k +1 valence nuclear structure, or is formed by directly connecting and combining 2-k-1 3-k valence low-valence groups or is formed by 1 or more than 1 divalent spacer L₁₀Indirectly combining the components; the 3-k valent low-valent groups can be the same or different, and the valences can be the same or different; for a k + 1-valent nuclear structure, when k is more than or equal to 4 and contains a k + 1-valent nuclear structure, the k + 1-valent nuclear structure is a ring structure; when containing two or more L₁₀When L is₁₀May be the same as or different from each other; when k is more than or equal to 4, the combination mode of the G with the k +1 valence formed by direct or indirect combination is any one of a comb combination mode, a tree combination mode, a branching combination mode, a hyperbranched combination mode and a ring combination mode;

when k is more than or equal to 4, the combination mode of the G with the k +1 valence formed by direct or indirect combination is any one of a comb combination mode, a tree combination mode, a branching combination mode, a hyperbranched combination mode and a ring combination mode;

in the case of a tree-like composite structure, G is preferably any of the following:

wherein, the basic unit of the multivalent G forming the branched or hyperbranched combined structure is selected from trivalent G and tetravalent G and is a mixed combination of the multivalent G and the lower valence form thereof;

wherein, the basic unit of the multivalent G forming the comb-shaped combined structure is trivalent G, tetravalent G or pentavalent G; preferably, any one of the basic units of the following group constitutes a comb-like composite structure: polyglycerols, polypentaerythritol, substituted propylene oxides, substituted propylene oxide and carbon dioxide groups, acrylates and derivatives thereof, methacrylates and derivatives thereof, basic units containing acetal structures, amino acids and derivatives thereof containing hydroxyl or thio groups, acidic amino acids and derivatives thereof, basic amino acids and derivatives thereof, or acetalized glucans formed by connecting D-glucopyranose units end to end via any one of β -1,6 glycosidic linkages, α -1,6 glycosidic linkages, β -1,4 glycosidic linkages, α -1,4 glycosidic linkages, β -1,3 glycosidic linkages, α -1,3 glycosidic linkages, and oxidized forms of the above polymers;

among them, polyvalent G in cyclic combination is preferably: a residue of a cyclic peptide or a derivative thereof, a residue of a cyclic monosaccharide or a derivative thereof, a residue of a cyclic polysaccharide or a derivative thereof, a backbone of 1,4, 7-tri-tert-butoxycarbonyl-1, 4,7, 10-tetraazacyclododecane, a backbone of 2-hydroxymethylpiperidine-3, 4, 5-triol, a backbone of 6-amino-4- (hydroxymethyl) -4-cyclohexyl- [4H,5H ] -1,2, 3-triol.

23. A process for the preparation of a functionalized eight-armed polyethylene glycol according to any one of claims 12 to 22, characterized in that it is obtained by any one of the following means: (i) the modified polyethylene glycol is obtained by performing end functionalization modification on eight-arm polyethylene glycol, (ii) or is obtained by performing coupling reaction on pre-modified linear functionalized polyethylene glycol and a disaccharide-based small molecule;

wherein the disaccharide-based small molecule is an octahydroxydisaccharide molecule CORE (OH)₈Or a functionalized octahydroxydisaccharide molecule; wherein the pre-modified linear functionalized polyethylene glycol comprises a reactive end and a pre-modified end; wherein, the reaction end contains a reactive group which can react with the small disaccharide-based molecule to form a covalent linking group; the pre-modified end carries the terminal functional group of the desired modification or a protected form thereof; when the pre-modified end is in a protected form of the terminal functional group of the desired modification, the functionalized eight-arm polyethylene glycol can be obtained by further deprotection after the coupling reaction.

24. A functionalized eight-arm polyethylene glycol modified bio-related substance is characterized by having the following structural general formula:

the octavalent central structure CORE contains residues of eight-hydroxy disaccharide molecules after dehydroxylation, and the eight-hydroxy disaccharide molecules contain eight naked hydroxy groups; the octahydroxydisaccharide molecule is a structure in which two monosaccharide units are covalently linked; the connecting group for covalently connecting the two monosaccharide units is selected from any one of glycosidic bonds, amido bonds and ester bonds; eight naked hydroxyl groups of the octahydroxydisaccharide molecule are distributed on two monosaccharide units, the two monosaccharide units are the same, and the distribution mode is 4+ 4; n is the polymerization degree of a polyethylene glycol chain and is selected from 1-2000; the degree of polymerization of the eight PEG chains may be the same or different from each other;

k is the number of F in a single functionalized end and is selected from 1 or 2-250;

in a single functionalized PEG chain, g is 0 or 1; g is a terminal branching group selected from a trivalent or higher valent linking group to a PEG segmentA functional group bonded to a terminal; l is₀Is a divalent linking group which connects the PEG chain segment with the terminal branching group G;

when g is 0, k is 1, L₀G is not present;

when G is 1, G is present, L₀May be present or absent, k is 2-250;

EF may be expressed as ED (structure is) Or EF₁(structure is

the functionalized eight-arm polyethylene glycol modified bio-related substance can exist stably or can be degraded; in the same molecule, L₀、G、(Z₂)_q-(Z₁)_q1、(Z₂)_q-any of the linking groups formed by L with adjacent groups are each independently stably present or degradable; in the same molecule, L₀、G、(Z₂)_q-(Z₁)_q1、(Z₂)_qEach L is independently stably present or degradable.

25. The eight-arm polyethylene glycol derivative-modified bio-related substance according to claim 24,

the g is 0, and the functionalized eight-arm polyethylene glycol modified bio-related substance has the following structure (4):

or the g is 1, the D content is 100%, and the structure of the bio-related substance modified by the functionalized eight-arm polyethylene glycol is shown as the formula (5):

26. the functionalized eight-armed polyethylene glycol modified biologically relevant substance of claim 24,

in the same molecule, k at the end of eight PEG chains_DAll satisfy k being more than or equal to 1_DK, i.e. at least one D is attached to each branch chain;

preferably, the same molecule has k at the end of eight PEG chains_DAll satisfy k, i.e. all terminal reactive sites in the eight-arm polyethylene glycol derivative molecule are independently linked to a D;

the average content of D in a single molecule is greater than 75%, equal to 75%, or less than 75%; preferably greater than 80%; more preferably greater than 85%; more preferably greater than about 90%; more preferably greater than 94%; most preferably equal to 100%.

27. The functionalized eight-armed polyethylene glycol-modified biologically-relevant substance according to any one of claims 24 to 26, wherein the L at each of the eight PEG chain ends of the same molecule is not exactly the same or the L at each of the eight PEG chain ends is the same;

each L is independently a linear structure, a branched structure or a cyclic structure; each L is independently a divalent linking group or a trivalent linking group;

any one of L is independently stable or degradable, and the linking group of L and the adjacent heteroatom group is stable or degradable; the conditions under which the difference can exist stably and be degraded are selected from any one of the following conditions: light, heat, enzymes, redox, acidic, basic, physiological conditions or in vitro simulated environments;

preferably, the L at the ends of the eight PEG chains of the same molecule have the same stability, i.e. are both stably present or both degradable; the functionalized eight-arm polyethylene glycol modified bio-related substance preferably meets any one of the following conditions:

(1) g-0, stable CORE (O-)₈stabilized-O- (Z)₂)_q-L-；

(2) g-0, stable CORE (O-)₈degradable-O- (Z)₂)_q-L-；

(3) g-0, with degradable CORE (O-)₈degradable-O- (Z)₂)_q-L-；

(4) g-1, stable CORE (O-)₈stabilized-O-L₀-G- (G and Z are excluded)₂Connection of), stable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(5) g-1, stable CORE (O-)₈degradable-O-L₀-G- (G and Z are excluded)₂Connection of), stable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(6) g-1, stable CORE (O-)₈stabilized-O-L₀-G- (G and Z are excluded)₂Linked) degradable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(7) g 1, withWith degradable CORE (O-)₈stabilized-O-L₀-G- (G and Z are excluded)₂Connection of), stable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(8) g 1, with degradable CORE (O-)₈degradable-O-L₀-G- (G and Z are excluded)₂Connection of), stable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(9) g 1, with degradable CORE (O-)₈stabilized-O-L₀-G- (G and Z are excluded)₂Linked) degradable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(10) g-1, stable CORE (O-)₈degradable-O-L₀-G- (G and Z are excluded)₂Linked) degradable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(11) g 1, with degradable CORE (O-)₈degradable-O-L₀-G- (G and Z are excluded)₂Linked) degradable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(12) g-0, stable CORE (O-)₈stabilized-O- (Z)₂)_q-, degradable L;

(13) g-1, stable CORE (O-)₈stabilized-O-L₀-G-[(Z₂)_q-]_kA degradable L;

(14) g-0, stable CORE (O-)₈stabilized-O- (Z)₂)_qDegradable L-D;

(15) g-1, stable CORE (O-)₈stabilized-O-L₀-G-[(Z₂)_q-]_kDegradable L-D;

preferably, each L independently contains a stably-available linker group selected from any one of the following groups: ether linkages, thioether linkages, urea linkages, thiourea linkages, carbamate groups, thiocarbamate groups, secondary amino groups, tertiary amino groups, amide groups, imide groups, thioamide groups, sulfonamide groups, enamine groups, triazole groups, isoxazolyl groups, or degradable linking groups comprising any of the following: disulfide bond, vinyl ether bond, ester group, thioester group, dithioester group, carbonate group, thiocarbonate group, dithiocarbonate group, trithiocarbonate group, carbamate group, thiocarbamate group, dithiocarbamate group, acetal group, cyclic acetal group, thioketal group, azaacetal group, azathiaketal group, dithioacetal group, hemiacetal group, thiohemiacetal group, azahemiacetal group, ketal group, thioketal group, azaketal group, azathioketal group, azothioketal group, imine bond, hydrazone bond, acylhydrazone bond, oxime bond, sulfoximine group, semicarbazone bond, thiosemicarbazone bond, hydrazine group, hydrazino group, thiocarbonyl group, azocarbonylhydrazine group, thioazocarbonylhydrazide group, hydrazinoformate group, hydrazinothiocarbamate group, carbazoyl group, thiocarbazohydrazide group, thiocarbazoyl group, thiocarbonate group, thiocarb, Azo groups, isoureido groups, isothioureido groups, allophanate groups, thioallophanate groups, guanidino groups, amidino groups, aminoguanidino groups, aminoamidino groups, imino groups, thioimidate groups, sulfonate groups, sulfinate groups, sulfonamide groups, sulfonylhydrazide groups, sulfonylurea groups, maleimide groups, orthoester groups, phosphate groups, phosphite groups, phosphinate groups, phosphonate groups, phosphosilane groups, silane ester groups, carbonamide groups, thioamide groups, phosphoramide groups, phosphoramidite groups, pyrophosphoamide groups, cyclic phosphoramide groups, isocyclophosphamide groups, thiophosphoramide groups, aconityl groups, peptide bonds, thioamide groups;

preferably, each L independently contains a linking group selected from the group consisting of a triazole group, a 4, 5-dihydroisoxazolyl group, an ether bond, a thioether group, an amide bond, an imide group, an imine bond, a secondary amine bond, a tertiary amine bond, a urea bond, an ester group, a thioester group, a disulfide group, a thioester group, a dithiocarbamate group, a dithioester group, a thiocarbonate group, a sulfonate group, a sulfonamide group, a carbamate group, a thiocarbamate group, a dithiocarbamate group, a hemiacetal group, and a carbonate group.

28. The functionalized eight-armed polyethylene glycol-modified biologically-relevant substance according to claims 24-26, wherein said biologically-relevant substance is selected from any one of: drugs, proteins, polypeptides, oligopeptides, protein mimetics, fragments, enzymes, antigens, antibodies and fragments thereof, receptors, gene-related substances, aptamers, polysaccharides, proteoglycans, glycoproteins, lipid compounds, hormones, vitamins, vesicles, liposomes, dyes, fluorescent substances, targeting factors, cytokines, neurotransmitters, extracellular matrix substances, plant or animal extracts, viruses, vaccines, cells, micelles; more preferably any of the following: small molecule drugs, nucleosides, nucleotides, oligonucleotides, antisense oligonucleotides, polynucleotides, steroids; more preferably any of the following: nucleic acids, steroids, phospholipids, glycolipids;

the biologically-relevant substance is selected from any one of the following states: biologically relevant substances are any of themselves, dimers or multimers, partial subunits or fragments, precursors, activation states, derivatives, isomers, mutants, mimetics, polymorphs, pharmaceutically acceptable salts, fusion proteins, chemically modified substances, genetically recombinant substances, and agonists, activators, inhibitors, antagonists, modulators, receptors, ligands or ligands, antibodies and fragments thereof, substrates for acting enzymes or enzymes of any thereof;

the bio-related substance is a bio-related substance, a modified bio-related substance, or a composite bio-related substance; allowing a target molecule, an adjunct or a delivery vehicle to bind to the biologically-relevant substance before or after binding to the eight-armed polyethylene glycol derivative to form a modified biologically-relevant substance or a complexed biologically-relevant substance;

the biologically-relevant substance is selected from any one of the following drugs: a medicament for treating any one of cancer, tumor, liver disease, diabetes, gout, rheumatism, rheumatoid, senile dementia, cardiovascular disease, antiallergic drug, anti-infective agent, antibiotic agent, antiviral agent, antifungal agent, central nervous system inhibitor, central nervous system stimulant, psychotropic drug, respiratory drug, peripheral nervous system drug, drug acting at synaptic or neuroeffector junction, smooth muscle active drug, histaminergic agent, antihistaminic agent, blood and hematopoietic drug, gastrointestinal drug, steroid agent, cell growth inhibitor, anthelmintic agent, antimalarial agent, antiprotozoal agent, antimicrobial agent, anti-inflammatory agent, immunosuppressive agent, Alzheimer's drug or compound, imaging agent, antidote, antispasmodic agent, muscle relaxant, anti-inflammatory agent, appetite suppressant, Migraine-treating agents, muscle contractants, antimalarials, antiemetics, bronchodilators, antithrombotic agents, antihypertensive agents, antiarrhythmic agents, antioxidants, antiasthmatic agents, diuretics, lipid regulating agents, antiandrogens, antiparasitic agents, anticoagulant agents, neoplastic agents, hypoglycemic agents, nutritional agents, food additives, growth supplements, anti-enteritis agents, vaccines, antibodies, diagnostic agents, contrast agents, hypnotic agents, sedatives, psychostimulants, tranquilizers, anti-parkinson agents, analgesics, anxiolytic agents, muscle infective agents, and auditory disease agents; the biologically-relevant substance is preferably an anticancer or antitumor drug selected from anticancer or antitumor drugs for treating any one of the following diseases: breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, gastrointestinal cancer, intestinal cancer, metastatic large intestinal cancer, rectal cancer, colon cancer, colorectal cancer, gastric cancer, squamous cell cancer, laryngeal cancer, esophageal cancer, malignant tumors, lung cancer, small-cell lung cancer, non-small cell lung cancer, liver cancer, thyroid cancer, renal cancer, bile duct cancer, brain cancer, skin cancer, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, nasopharyngeal cancer, head and neck cancer, gallbladder and bile duct cancer, retinal cancer, renal cell cancer, gallbladder adenocarcinoma, multidrug resistant cancer, melanoma, lymphoma, non-Hodgkin's lymphoma, adenoma, leukemia, chronic lymphocytic leukemia, multiple myeloma, brain tumor, Wilms' tumor, liposarcoma, endometrial sarcoma, rhabdomyosarcoma, neuroblastoma, and AIDS related cancers, A sarcoma or carcinosarcoma;

the biologically relevant substance is preferably a small molecule drug selected from the group consisting of: biologically relevant substances with molecular weight not more than 1000Da and small molecular mimicry or active fragment of any biologically relevant substance; the small molecule drug is selected from any small molecule drug, or any derivative, or any pharmaceutically acceptable salt;

the molecular weight of the small molecule drug is selected from any one of the following intervals: 0-300 Da, 300-350 Da, 350-400 Da, 400-450 Da, 450-500 Da, 500-550 Da, 550-600 Da, 600-650 Da, 650-700 Da, 700-750 Da, 750-800 Da, 800-850 Da, 850-900 Da, 900-950 Da, 950-1000 Da;

the small molecule drug is preferably any one of flavonoid, terpenoid, carotenoid, saponin, steroid, quinone, anthraquinone, fluoquinone, coumarin, alkaloid, porphyrin, polyphenol, macrolide, single-lactam ring, phenylpropanoid phenol, anthracycline and amino glycoside;

the small molecule drug is selected from any one of the following therapeutic fields: anti-cancer drugs, anti-tumor drugs, anti-hepatitis drugs, diabetes treatment drugs, anti-infective drugs, antibiotics, anti-viral agents, antifungal agents, vaccines, anti-respiratory drugs, anti-spasmodics, muscle relaxants, anti-inflammatory drugs, appetite suppressants, migraine agents, muscle contractants, antirheumatics, antimalarials, antiemetics, bronchodilators, antithrombotic agents, antihypertensive agents, cardiovascular agents, antiarrhythmics, antioxidants, antiasthmatic agents, diuretics, lipid regulators, antiandrogenic agents, antiparasitics, anticoagulants, neoplastic agents, hypoglycemic agents, nutritional and food additives, growth supplements, anti-enteritis agents, antibodies, diagnostic agents, contrast agents;

the small molecule drug is preferably any one of SN38, irinotecan, resveratrol, cantharidin and derivatives thereof, chrysin, tripterygium wilfordii extract, flavone or flavonoid drug, salvia miltiorrhiza extract and silybum marianum extract or any one of derivatives or any one of pharmaceutically acceptable salts; the pharmaceutically acceptable salt is preferably hydrochloride, oxalate, malate, citrate; most preferably the hydrochloride salt; the derivatives comprise molecular modified derivatives, glycosides, nucleosides, amino acids and polypeptide derivatives.

Technical Field

The invention relates to the field of polymer synthesis, in particular to eight-arm polyethylene glycol, a preparation method, a functionalized derivative and a modified biologically-relevant substance.

Background

Pegylation (PEGylation) is one of the important means for drug modification. The functionalized polyethylene glycol (PEG) can be coupled with drug molecules (including protein drugs and organic small molecule drugs), peptides, saccharides, lipids, oligonucleotides, affinity ligands, cofactors, liposomes, biological materials and the like through covalent bonds by utilizing active groups contained in the functionalized polyethylene glycol (PEG), so that the polyethylene glycol modification of drugs and other biologically relevant substances is realized. The modified drug molecule has many excellent properties of polyethylene glycol (such as hydrophilicity, flexibility, anticoagulation, etc.). Meanwhile, due to the steric exclusion effect, the drug modified by the polyethylene glycol avoids the filtration of glomeruli and biological reactions such as immunoreaction, so that the drug has longer half-life in blood than the unmodified drug. For example: greenwald et al (J.org.chem.1995,331-336) modify paclitaxel by means of coupling with polyethylene glycol to increase its aqueous solubility.

Multi-arm polyethylene glycol derivatives have lower viscosities and can provide higher drug loadings than linear polyethylene glycol derivatives. The common multi-arm polyethylene glycol on the market is three-arm, four-arm, six-arm, eight-arm and the like.

The presently disclosed eight-arm polyethylene glycol structure is trimeric pentaerythritol (-O [ CH ]₂C(CH₂O-)₂CH₂O]₃-) and hexaglycerol (-O [ CH)₂CH(O-)CH₂O]₆-) two eight-valent central structures, to our knowledge there are no cases of entry into preclinical studies or clinical stages. Furthermore, document CN104877127A discloses a functionalized eight-arm polyethylene glycol having a symmetric eight-valent central structure, which can have a narrower molecular weight distribution.

The preparation of the functionalized eight-arm polyethylene glycol is mainly obtained by initiating ethylene oxide polymerization by octal initiator molecules, which all need to be synthesized by a chemical method. Especially, octameric polyethylene glycols based on tripentaerythritol and hexaglycerol, exemplified by hexaglycerol, are practically mixtures of a series of oligomers having a number of monomer units of around "6" and are difficult to separate simply and completely, due to the difficulty in precisely controlling the number of monomer units in their preparation. This results in the eight-arm polyethylene glycol and its derivatives mixed with seven-arm and nine-arm mixtures such as penta-poly and hepta-poly, the target product has low purity, and the molecular weight distribution is wide and is not easy to control. The preparation method of the symmetrical structure of CN104877127A is not easy to generate non-target initiators, and can obtain target products with high purity, but the preparation of the octatomic alcohol initiator molecule still needs to be synthesized in the early stage.

In view of the above background, there is a need to develop a novel eight-arm initiator molecule that is simple to prepare, readily available, and inexpensive.

Disclosure of Invention

The invention provides eight-arm polyethylene glycol, a preparation method, functionalized eight-arm polyethylene glycol and a modified biologically-relevant substance against the background.

The purpose of the invention is realized by the following technical scheme: an eight-arm polyethylene glycol has a structural general formula as follows:

wherein, the octavalent central structure CORE contains residues after the dehydroxylation of octahydroxy disaccharide molecules, and n is the polymerization degree of the polyethylene glycol chain and is selected from 1-2000. The eight-arm polyethylene glycol has monodispersity or polydispersity. When monodisperse, the polydispersity PDI is 1. In the case of polydispersity, PDI >1, where the closer the PDI to 1, the narrower the molecular weight distribution.

The invention provides a preparation method of eight-arm polyethylene glycol, which is prepared by the following technical scheme:

step one, adopting small molecule CORE (OH) containing eight hydroxyl groups₈The initiator system of (1); the octahydroxy micromolecule is preferably an octahydroxy disaccharide micromolecule;

initiating ethylene oxide polymerization;

and step three, adding a proton source into the intermediate product system with eight polyethylene glycol chains obtained in the step two after the reaction is finished, and obtaining the hydroxyl-terminated eight-arm polyethylene glycol.

The invention also provides a preparation method of the eight-arm polyethylene glycol, which can be prepared by the following technical scheme:

coupling reaction is carried out on the disaccharide-based micromolecules and linear functionalized polyethylene glycol containing naked hydroxyl groups to obtain eight-arm polyethylene glycol; or the disaccharide-based micromolecule and the linear functionalized polyethylene glycol containing protected hydroxyl are subjected to coupling reaction to obtain protected eight-arm polyethylene glycol, and then the protected eight-arm polyethylene glycol is obtained through deprotection reaction. Wherein the disaccharide-based small molecule is an octahydroxydisaccharide molecule CORE (OH)₈Or functionalized octahydroxydisaccharide molecules. The linearly functionalized polyethylene glycol includes a reactive end and a hydroxyl end. Wherein the reactive end contains a reactive group that can react with the octahydroxydisaccharide molecule or a functionalized derivative thereof to form a covalent linkage. The hydroxyl end contains a naked hydroxyl group or a protected hydroxyl group.

The invention also provides a functionalized eight-arm polyethylene glycol, which has the following structural general formula:

the functionalized eight-arm polyethylene glycol is also sometimes referred to herein as an "eight-arm polyethylene glycol derivative".

Wherein, the definitions of CORE and n are consistent with the general formula (1), and are not repeated herein.

Wherein k is_HThe number of PEG chains with hydroxyl at the end of PEG in a single molecule, k_HLess than 8, i.e. at least one PEG chain end is functionalized; the remaining 8-k_HEach PEG chain end contains a functional group; f is a hydrogen atom or

Wherein q and q are₁Each independently is 0 or 1, Z₁、Z₂Each independently is a divalent linking group, R₀₁Is a functional group capable of interacting with a biologically relevant substance; f is a hydrogen atom and participates in forming a terminal functional group of hydroxyl, amino or sulfhydryl.

k is the number of F in a single functionalized end and is selected from 1 or 2-250; 8-k in a single molecule_HEach k is independently equal or different;

in a single functionalized PEG chain, g is 0 or 1; g is a terminal branching group selected from a trivalent or higher valent connecting group which connects the PEG chain segment with a terminal functional group; l is₀Is a divalent linking group which connects the PEG chain segment with the terminal branching group G;

when g is 0, k is 1, L₀G is not absent, F is not a hydrogen atom, hydroxyethyl, hydroxyl terminated PEG chain;

when G is 1, G is present, L₀May be present or absent, k is 2 to 250, where F is allowed to be a hydrogen atom;

in the general formula (20)

Can exist stably or can be degraded; in the same molecule, CORE, L₀、G、(Z₂)_q-(Z₁)_q1Any one of the linking groups formed with the adjacent group may each independently be stably present or degradable; in the same molecule, CORE, L₀、G、(Z₂)_q-(Z₁)_q1Each independently may be stable or degradable.

When k is_HWhen 0, the functionalized eight-armPolyethylene glycol is obtained by: the polyethylene glycol is obtained by performing functional modification on eight-arm polyethylene glycol or by performing coupling reaction on pre-modified linear functionalized polyethylene glycol and a disaccharide-based small molecule. The disaccharide based small molecules are in accordance with the above definition. The pre-modified linear functionalized polyethylene glycol includes a reactive end and a pre-modified end. Wherein, the reaction end contains a reactive group which can react with the small disaccharide-based molecule to form a covalent linking group. The pre-modified end carries the terminal functional group of the desired modification or a protected form thereof. When the pre-modified end is in a protected form of the terminal functional group of the desired modification, the functionalized eight-arm polyethylene glycol can be obtained by further deprotection after the coupling reaction.

The invention also provides a functionalized eight-arm polyethylene glycol modified biologically-relevant substance, which has the following structural general formula:

wherein, CORE, n, L₀、G、k、Z₁、Z₂、q、q₁The definition of (A) is consistent with that of the general formula (2), and the description is omitted here.

Wherein g is 0 or 1; EF may be expressed as ED (structure is

) Or EF₁(structure is

) Wherein D is not equal to E₀₁. Wherein D is a residue formed after the modified bio-related substance reacts with the functionalized eight-arm polyethylene glycol; e₀₁Is selected from R₀₁Protected R₀₁Deprotected R₀₁Or blocked R₀₁；R₀₁Is a reactive group capable of reacting with a biologically relevant substance; l is a linking group formed after the reaction of a reactive group in the functionalized eight-arm polyethylene glycol and a biologically relevant substance. Wherein the number of D at the end of one branch chain is marked by k_D，0≤k_DK is not more than k, is used togetherK of each branched chain in one molecule_DEach independently the same or different, and the sum of the numbers of D (N) in any one of the functionalized eight-armed polyethylene glycol molecules_D) At least 1, preferably at least 8. When G is 1, G- (EF)_kCan be expressed as

The functionalized eight-arm polyethylene glycol modified bio-related substance can exist stably or can be degraded; in the same molecule, L₀、G、(Z₂)_q-(Z₁)_q1、(Z₂)_q-any of the linking groups formed by L with adjacent groups are each independently stably present or degradable; in the same molecule, L₀、G、(Z₂)_q-(Z₁)_q1、(Z₂)_qEach L is independently stably present or degradable.

Compared with the prior art, the invention has the following beneficial effects:

(1) the eight-arm polyethylene glycol can be obtained by polymerization reaction of initiator molecules containing octahydroxy disaccharide molecule residues. Compared with the existing eight-arm polyethylene glycol product with the structure, the system replaces the existing octahydric alcohol molecules with structures such as trimeric pentaerythritol, hexaglycerol and the like with octahydric disaccharide molecules or derivative forms based on the octahydric disaccharide molecules as initiator molecules; the octahydroxy disaccharide molecule is cheap and easy to obtain, compared with the prior art, the octahydroxy disaccharide molecule does not need to be obtained by a chemical synthesis method, and the production cost is greatly reduced; the product has high purity, has more advantages in purity compared with tripentaerythritol and hexaglycerol, has more accurate control on molecular weight and distribution thereof in the polymerization process of the product, has a single structure, does not have the structures of other multi-arm products, has better performance, reduces the purification difficulty, can reduce the dosage of organic reagents in purification, reduces the cost, and is more green and environment-friendly; and has natural chiral center, and the obtained eight-arm polyethylene glycol and functionalized derivatives thereof can be used for drug screening.

(2) The eight-arm polyethylene glycol can also be obtained by coupling reaction (which can also comprise subsequent deprotection treatment) by using octahydroxydisaccharide molecules or functionalized derivatives thereof as raw materials. The high purity of the octahydroxydisaccharide molecules can also endow the octa-arm polyethylene glycol with accurate molecular weight, narrower molecular weight distribution and natural chiral center, and can reduce the difficulty of purification and separation, reduce the dosage of organic reagents and the cost in the subsequent purification process, the functionalization modification process of the octa-arm polyethylene glycol and the purification process of the functionalized octa-arm polyethylene glycol, thereby being more green and environment-friendly.

(3) The functionalized eight-arm polyethylene glycol can have a natural chiral center, precise molecular weight, narrower molecular weight distribution and better functional group substitution rate (the ratio of the terminal hydroxyl group of the eight-arm polyethylene glycol to the target functional group). When the method is used for modifying biologically-related substances, a relatively more determined structure and molecular weight can be obtained, the degree of standardized control and production is higher, the difficulty of purification and separation is reduced, and the obtained product has more uniform quality and higher performance.

Detailed Description

The terms related to the present invention are mostly disclosed in the document CN104877127A and the cited documents, and the explanations of the terms and the related structures are incorporated into the present invention by reference, and are not repeated herein. This is generally described before the examples.

1. An eight-arm polyethylene glycol, which has a general formula shown in formula (1):

wherein, the CORE with an eight-valent central structure contains eight-valent residues after eight hydroxyl groups of an octahydroxy disaccharide molecule are removed, and n is the polymerization degree of a polyethylene glycol chain and is selected from 1-2000.

1.1. Degree of polymerization and dispersibility of polyethylene glycol chain

In the general formula (1), the polymerization degrees of the eight PEG chains may be the same or different from each other, and may be represented by n₁、n₂、n₃、n₄、n₅、n₆、n₇、n₈. Even if the number of EO units of eight PEG chains in the same molecule is allowed to be the same as each otherOr different, it is also permissible that in the macropolymer, the polymerization degrees of the eight PEG chains are the same as or different from each other. The eight-arm polyethylene glycol can be polydisperse or monodisperse. Wherein, the PEG chain n_i(i ═ 1,2,3,4,5,6,7or 8) can be both monodisperse, both polydispersions, or any combination of monodisperse and polydispersions, preferably both monodisperse and polydispersions.

Eight polyethylene glycol chains are obtained in a polymerization mode, and the polydispersity is the same.

The PDI of the eight-armed polyethylene glycol obtained by coupling depends on the polydisperse nature of the starting material, preferably the eight polyethylene glycol chains are both monodisperse or both polydisperse.

In the present invention, the "molecular weight" is not particularly limited, and is "number average molecular weight", and M_nIt may be either a polydisperse block or a molecular weight of a substance or a monodisperse block or a molecular weight of a substance, and unless otherwise specified, a polydisperse polymer is generally specified. When not specifically written, the units are daltons, Da.

For a polydisperse PEG chain, the number average molecular weight is preferably 1 to about 1500 Da; more preferably from 2 to about 1000 Da; more preferably from 2 to about 500 Da; more preferably from 5 to about 500 Da; more preferably from about 11 to about 500 Da; more preferably from about 22 to about 500 Da; more preferably from about 30 to about 250 Da; more preferably from about 34 to about 150 Da. The number average polymerization degrees of the eight PEG chains are all selected from 22-2000; more preferably 44 to 2000; more preferably 90 to 2000; more preferably 113 to 2000. The number average polymerization degrees of the eight PEG chains are also selected from 1-113; more preferably 1 to 90; more preferably 1 to 44; more preferably 1 to 22. The more preferable the above, the more conventional the molecular weight of the corresponding PEG segment is, the simpler and easier the preparation, and the narrower the PDI (polydispersity index) of the molecular weight is, the more uniform the performance is. The linear PEG obtained by the common polymerization method has a number average molecular weight of about 2kDa to 40 kDa. In the present invention, the number average molecular weight of eight PEG chains can be selected from 2kDa to 40kDa by a polymerization method. The number average molecular weight is preferably about 150,250,500,600,700,800,900,1000,1500,2000,2500,3000,3350,3500,4000,5000,5500,6000,6500,7000,7500,8000,8500,9000,9500,10000,11000,12000,13000,14000,15000,16000,17000,18000,19000 or 20000 in Da. More preferably about 1000,1500,2000,2500,3000,3350,3500,4000,5000,5500,6000,6500,7000,7500,8000,8500,9000,9500,10000,11000 or 12000 Da. More preferably about 1000,1500,2000,3000,3350,3500,4000,5000,6000,7000,8000,9000 or 10000 Da. More preferably about 1000,1500,2000,3350,3500,4000,5000 or 6000 Da.

For monodisperse PEG blocks, the molecular weight is defined by the number of oxyethylene units (described as EO units). The number of EO units of monodisperse polyethylene glycols prepared according to the prior art is between about 1 and 70, including but not limited to the EO units recited in references { Extert Rev.mol.Diagn.2013,13(4), 315-. Typical numbers of EO units for monodisperse PEG include, but are not limited to, 1,2,3,4,5,6,7, 8,9,10, 12, 13, 16, 20, 22, 24, 27, 29, 36, 44, 48, 56, 62, 64, 67, and the like. It is specifically noted that the polydispersity of the eight-arm polyethylene glycol of formula (1) is determined collectively by the combination of eight PEG chains, and the eight-arm polyethylene glycol species may be a single component or a mixture of different components, as long as the PDI of the polymer is 1. When a single component, eight PEG chains have the same number of EO units. When a mixture of different components, the total molecular weight of each eight-arm polyethylene glycol molecule in the polymer is fixed, but where the number of EO units of the eight PEG chains may each independently be the same or different. Preferably the relative mole percentages of PEG chain components of different numbers of EO units are determined. Most preferably, the eight PEG chains have the same number of EO units. When a mixture of different components is used, the corresponding number average degree of polymerization may be an integer or a non-integer. Polymers composed of monodisperse blocks of different EO unit numbers still form polydisperse blocks or species if the contents of the individual components are undefined and the PDI is greater than 1. The number of EO units of the monodisperse PEG block is preferably 2-70; more preferably 3 to 70; more preferably 3 to 70; more preferably 3 to 50; more preferably 3 to 25. The more preferable, the more various the production method. The number of EO units of the monodisperse PEG chain is preferably selected from any of 2,3,4,5,6,7, 8,9,10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24, 26, 27, 28, 29, 30, 32, 34, 36, 38, 40, 42, 44, 45, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 67, 68, 70.

For the entire eight-arm polyethylene glycol, the polydispersity coefficient may be the same or different than that of the individual PEG chains. But the lower the PDI of the whole compound, the better. Therefore, for the chain length distribution of the eight PEG chains of the eight-arm polyethylene glycol represented by the general formula (1), n is preferable₁≈n₂≈n₃≈n₄≈n₅≈n₆≈n₇≈n₈(in which case the number average molecular weights of the eight chains may each independently be the same or close together) or n₁＝n₂＝n₃＝n₄＝n₅＝n₆＝n₇＝n₈(in this case eight chains have a fixed molecular weight and are equal to each other). At the moment, the chain lengths of the PEG chains are equal or similar, and the biological related substances modified by the PEG chains can obtain a uniform structure more easily, so that the purity and the performance of the product are improved. n is₁≈n₂≈n₃≈n₄≈n₅≈n₆≈n₇≈n₈The situation applies to polydisperse structures, which can satisfy the requirements of different molecular weights, and n₁＝n₂＝n₃＝n₄＝n₅＝n₆＝n₇＝n₈The situation of (2) is suitable for a monodispersity structure, the product structure is controlled more accurately, and a modified product with better quality can be obtained.

1.2. Eight-valent central structure CORE

The octavalent CORE contains an octavalent residue of an octahydroxydisaccharide molecule after removal of eight hydroxyl groups. The CORE is preferably stable under anionic polymerization conditions.

The octahydroxydisaccharide molecule, as the name implies, contains eight naked hydroxyl groups and has the structure represented by CORE (OH)₈. The CORE is preferably an octavalent residue of an octahydroxydisaccharide molecule after removal of eight hydroxyl groups. CORE may also be a de-octanedioic moleculeAn octavalent group formed by combining an octavalent residue after a hydroxyl group and a proper divalent linking group. Preferably CORE (O-)₈Exist stably under the condition of anionic polymerization.

The octahydroxydisaccharide molecule is a structure in which two monosaccharide units are covalently linked; mainly glycosidic bond. Can be natural disaccharide molecules, and can also be synthetic or semi-synthetic disaccharide molecules. It can be condensation product of two monosaccharide molecules, or decomposition product of polysaccharide such as starch and cellulose. It may also be a condensation product formed by the participation of a functionalized monosaccharide such as an aminosugar.

The two monosaccharide units forming the octahydroxydisaccharide molecule may be the same or different.

The monosaccharide unit may be selected from monovalent residues including, but not limited to, any one of monosaccharides, sugar alcohols, deoxy sugars, amino sugar derivatives (such as amide derivatives), sugar acids, glycosides, or derivatives thereof. Such as amino residues formed by removing 1 amino hydrogen atom from aminosugars, and acyl residues formed by removing carboxyl hydroxyl from sugar acids. The monosaccharides may include, but are not limited to, aldoses (polyhydroxy aldehydes), ketoses (polyhydroxy ketones). Such as alkyl ether derivatives, methyl ether derivatives, such as quebrachitol, for example.

The number of carbon atoms of the two monosaccharide molecules forming the octahydroxydisaccharide molecule may be the same or different, including but not limited to tetrose, pentose, hexose, heptose. Pentoses and hexoses are preferred. In addition, the invention also discloses an octahydroxy micromolecule which takes triose, tetrose, pentose, hexose, heptose or any derivative thereof as a basic unit.

D-fructose of the formula C₄H₈O₄Including but not limited to erythrose, erythrulose, and the like.

Pentose sugar of the formula C₅H₁₀O₅Or C₅H₁₀O₄Including but not limited to ribose, arabinose, lyxose, xylose, deoxyribose, ribulose, and the like.

Hexose of the formula C₆H₁₂O₆Or C₆H₁₂O₅Including but not limited to glucose,Allose, altrose, mannose, gulose (gulose), idose, galactose, talose (tylose), psicose, fructose, sorbose, tagatose, inositol (also known as inositol, inositol), fucose, and the like.

Heptose, formula C₇H₁₄O₇Or C₇H₁₄O₆Including but not limited to mannoheptulose and the like.

Sugar alcohol: molecular formula C₄H₁₀O₄、C₅H₁₂O₅、C₆H₁₄O₆、C₇H₁₆O₇And the like, including but not limited to erythritol, xylitol, sorbitol, lactitol, mannitol, and the like.

Deoxy sugars, also known as deoxy sugars, such as: deoxyribose (C)₅H₁₀O₄) Fucose (C)₆H₁₂O₅) And the like.

Amino sugars such as glucosamine, galactosamine, mannosamine, aminodeoxyglucose, and the like. The residues thereof after deamination of a hydrogen atom are exemplified by the following:

amide derivatives of amino sugars, such as N-acetylglucosamine (as shown above), and the like.

Sugar acids, e.g. HOCH gluconate₂(CHOH)₄COOH, heptonic acid HOCH₂(CHOH)₅COOH, glucuronic acid C₆H₁₀O₇And the like. The corresponding monovalent residues are exemplified by:

glycosides, including but not limited to methyl glycoside, ethyl glycoside, propyl glycoside, and the like, are exemplified by the following:

the groups carried by the two monosaccharide molecules constituting the octahydroxydisaccharide molecule are not particularly limited as long as the disaccharide molecule has eight naked hydroxyl groups, allowing the presence of other groups such as aldehyde groups; but preferably the bare end groups are all hydroxyl groups.

The structures of the two monosaccharide molecules constituting the octahydroxydisaccharide molecule are not particularly limited. The two monosaccharide structures may each independently be a cyclic structure or an open chain structure, e.g. may be both cyclic, both open chain structures, or a combination of cyclic and open chain structures, preferably both disaccharide units are hexose ring structures, preferably five-membered rings, six-membered rings.

The molecule of octahydroxydisaccharide can also be a structure in which the oxygen atom other than the terminal group is thio, such as thiocellobiose.

The linker covalently linking the two monosaccharide units is mainly determined by the two materials providing the monosaccharide units, and mainly comprises glycosidic bonds, amide bonds, ester bonds and the like, as long as the covalent linker can be generated by the reaction between the molecules of the monosaccharide and the derivative thereof. Glycosidic linkages are most preferred. Glycosidic linkages may be linked by any of the groups including, but not limited to, oxygen, nitrogen, sulfur, and carbon, and the corresponding glycosides are O-glycoside, N-glycoside, S-glycoside, and C-glycoside, respectively. The glycosidic bond may be an α -type glycosidic bond or a β -type glycosidic bond, and the position forming the glycosidic bond may be any of a1, 1-glycosidic bond, a1, 2-glycosidic bond, a1, 3-glycosidic bond, a1, 4-glycosidic bond, a1, 6-glycosidic bond, and a2, 1-glycosidic bond. Examples of glycosidic linkages include, but are not limited to, alpha-1, 4-glycosidic linkages (e.g., maltose), alpha-1, 6-glycosidic linkages (e.g., isomaltose), beta-1, 4-glycosidic linkages (e.g., lactose, cellobiose), alpha, beta-1, 2-glycosidic linkages (e.g., sucrose), alpha-1, 6-glycosidic linkages (e.g., galactose), beta-1, 6-glycosidic linkages (e.g., gentiobiose), alpha-1, 1-glycosidic linkages (e.g., disaccharide trehalose), alpha-1, 6-glycosidic linkages (e.g., melibiose), beta-1, 3-glycosidic linkages (e.g., chondriose), beta-1, 3-glycosidic linkages (hyaluronan), beta-2, 1-glycosidic linkages (e.g., inulinobiose), and the like. It should be noted that the disaccharides exemplified in this paragraph are merely illustrative of the type of glycosidic bond, and are not necessarily applicable to the disaccharide component having the eight-valent central structure of the present invention.

The steric structure of the two monosaccharides that form the molecule of the octahydroxydisaccharide is not particularly limited, and includes, but is not limited to, any of conformational isomers, configurational isomers (optical isomers, cis-trans isomers), and the like, and for example, may be D-type or L-type, may be α -type or β -type. When the six-membered ring structure is contained, the conformation of any one of the six-membered rings is not particularly limited, and may be a chair-type conformation or a boat-type conformation.

The eight naked hydroxyl groups of the octahydroxydisaccharide molecule are distributed on two monosaccharide units in a mode of any one of 2+6, 3+5 and 4+ 4. The combination of 4+4 is preferred.

The octahydroxydisaccharide molecule is most preferably a structure in which two furan-type or pyran-type hexose rings are linked by any of the above-described glycosidic bonds. The octavalent residue of such an octahydroxydisaccharide molecule after removal of the eight hydroxyl groups is also the most preferred structure for CORE.

Specifically, the octahydroxydisaccharide molecule preferably includes, but is not limited to, sucrose, trehalose, lactose, cellobiose, maltose, isomaltose, gentiobiose, melibiose, kojibiose, turanose, melibiose, nigerobiose, laminaribiose, mannobiose, α -glucose- α -glucoside, maltulose, isomalt, palatinose, and the like. More preferably sucrose, lactose, maltose, trehalose, cellobiose. More preferably sucrose, lactose, maltose. More preferably sucrose or maltose. Most preferred is sucrose. The configuration is not particularly limited, and examples thereof include D (+) -melibiose, D-cellobiose, D (+) -cellobiose, beta-lactose, 4-beta-galactobiose, beta-gentiobiose, and D-leucrose.

Examples are as follows:

1.3. eight-valent group CORE (O-)₈Stability of (2)

Eight-valent group CORE (O-)₈The degradable linker may be present stably or may be present.

When degradable, the degradable mode can be divided into any one or combination of any several of the following:

(1) CORE can be degraded, the degradation site is located at the connection site of two monosaccharide units, such as hydrolyzable ester bond connection, e.g. enzymatic O-glycoside connection, etc.;

(2) the two monosaccharide units are connected through glycosidic bonds, and the connecting position of CORE and O can be degraded; at this time, CORE (O-)₈In addition to the dehydroxyoctavalent residue of the disaccharide molecule, a suitable divalent linking group is also included which forms a degradable linking group with the oxy group of the PEG segment, e.g., an ester group, a carbamate group, and the like.

Allowing for a single degradation mode, or a combination of degradation modes. When a combined degradation mode is used, a gradient degradation mode having different degradation rates or different degradation conditions is preferred.

2. A preparation method of eight-arm polyethylene glycol comprises the following steps:

step one, adopting small molecule CORE (OH) containing eight hydroxyl groups₈The initiator system of (1); octahydroxyl micromolecules are used as an initiator to form a co-initiator system with alkali; the octahydroxy micromolecule is preferably an octahydroxy disaccharide micromolecule;

initiating ethylene oxide polymerization;

and step three, adding a proton source into the intermediate product system with eight polyethylene glycol chains obtained in the step two after the reaction is finished, and obtaining the hydroxyl-terminated eight-arm polyethylene glycol.

The above step may be carried out with or without a solvent, and the solvent is not particularly limited, but is preferably an aprotic solvent such as toluene, benzene, xylene, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform, dichloromethane, dimethyl sulfoxide, dimethylformamide or dimethylacetamide, and more preferably dimethyl sulfoxide, dimethylformamide, toluene or tetrahydrofuran.

2.1. Initiator system

The definition of the octahydroxydisaccharide molecule is identical to that described above and is not described in further detail here. The structure of the compound can be characterized and confirmed by the existing conventional technical means, including but not limited to nuclear magnetism, circular dichroism, MALDI-TOF, HPLC, ultraviolet spectrophotometer, FT-IR, mass spectrum, Raman spectrum, single crystal diffraction and the like. The hydroxyl value of the octahydroxydisaccharide molecule can be measured by means existing in the prior related fields, including but not limited to GB/T12008.3-2009 (phthalic anhydride-pyridine method), HG/T2709-95 (acetic anhydride-pyridine method), other acylation methods (such as acetic anhydride-perchloric acid-ethyl acetate catalyzed acylation method, acetic anhydride-perchloric acid-dichloroethane catalyzed acylation method, acetic anhydride-N-methylimidazole-DMF catalyzed acylation method and the like), normal-temperature catalyzed acylation method can be adopted, and heating reflux acylation method can also be adopted. GB/T12008.3-2009 or HG/T2709-95 are preferred.

The initiator system also contains a base, so that the octahydroxydisaccharide molecule is deprotonated under the catalysis of the base to form oxyanions.

Deprotonation is carried out under basic conditions. The base used for deprotonation is not particularly limited, but is preferably metallic sodium, potassium, sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, lithium naphthalene, n-butyllithium, t-butyllithium, potassium t-butoxide or diphenylmethyl potassium, more preferably metallic sodium, potassium or diphenylmethyl potassium, and most preferably diphenylmethyl potassium. The catalyst is used in an amount of 5 to 320 mol%, preferably 5 to 80 mol%. If the amount of the catalyst used is less than 5 mol%, the polymerization rate is slow and the cumulative heat increases, resulting in the formation of by-products, such as vinyl ether compounds, by elimination of the terminal hydroxyl group. In the reaction in the absence of a solvent, the amount of the catalyst exceeding 50 mol% may result in an increase in the viscosity of the reaction solution or precipitation of solids, resulting in imbalance of the reaction and difficulty in purification. When toluene or tetrahydrofuran is used as a solvent, the problem of viscosity increase or solid precipitation of a reaction solution can be solved, and the amount of the catalyst can be correspondingly increased to 80 mol% or more.

Deprotonation is generally carried out at from 10 ℃ to 50 ℃ and preferably from 25 ℃ to 50 ℃. When the temperature is less than 10 ℃, deprotonation is incomplete, and the base participates in anionic polymerization as a nucleophile to obtain low molecular weight impurities with the target polymer chain being 0.5 times of the target molecular weight. Such impurities may react with biologically relevant substances and alter their physical properties. If the species used to initiate the polymerization of ethylene oxide contains protecting groups, temperatures above 50 deg.C can result in partial cleavage and deprotection of the protecting groups to yield high molecular weight impurities above the target molecular weight of the polymer chain of interest. When the drug is modified in a state containing such impurities, the drug preparation is inevitably uneven, the quality is unstable, and the modification of the high-purity drug cannot be satisfied.

The deprotonation time, preferably from 10 minutes to 24 hours, varies with the base. In general, strong bases with weak basicity or relatively low solubility in organic solvents (such as sodium methoxide, potassium methoxide, sodium hydride, potassium hydride, etc.) require a long deprotonation time, generally 1 to 24 hours; on the other hand, bases having strong basicity and good solubility in organic solvents (e.g., diphenylmethyl potassium, n-butyl lithium, t-butyl lithium, etc.) are sufficiently miscible with the initiator even in the absence of a solvent, and have a high deprotonation rate, generally in the range of 10 minutes to 24 hours, preferably 20 minutes to 1 hour. When the deprotonation time is short and the deprotonation is incomplete, taking alkali as a nucleophilic reagent to participate in anionic polymerization to obtain low-molecular-weight impurities with target molecular weight of the target polymer chain being 0.5 times; if the material used to initiate the polymerization of ethylene oxide contains a protecting group, then a deprotonation time greater than 24 hours will result in partial cleavage and deprotection of the protecting group to yield a high molecular weight impurity above the target molecular weight; modification of a drug in a state containing such impurities cannot satisfy modification of a high-purity drug.

When potassium methoxide, potassium tert-butoxide, sodium methoxide are used as the catalyst, potassium methoxide is preferred, and the amount thereof is 5 mol% to 80 mol%, and the reaction is carried out at 25 ℃ to 80 ℃, preferably 50 ℃ to 60 ℃, except that, in addition, the reaction is conducted under reduced pressure to promote proton exchange. Because potassium methoxide, potassium tert-butoxide or sodium methoxide itself will also polymerize with ethylene oxide under the polymerization conditions, the end-etherified polyethylene glycol with the target polymer chain molecular weight 0.5 times of the target molecular weight is obtained, interfering the subsequent reaction to generate byproducts. Such reactions require removal of the lower alcohol by operation at reduced pressure while ensuring complete protonation at higher temperatures (preferably 50 ℃ to 60 ℃).

2.2. Polymerization of ethylene oxide

The amount of ethylene oxide used is determined by the design molecular weight of the polyethylene glycol chain, and the metered amount of ethylene oxide is added.

When the polymerization is carried out under aprotic solvent conditions, it is preferably carried out at 50 ℃ to 70 ℃. When the temperature is lower than 50 ℃, the molecular weight is gradually increased along with the polymerization, the viscosity of reaction liquid is increased or solids are separated out, so that the reaction system is not uniform, and the obtained target product is wide in distribution and is not suitable for modification of high-purity medicaments; when the temperature is higher than 70 ℃, the reaction system is easy to explode or generate side reactions, such as the elimination of terminal alcohol to obtain vinyl ether.

When the polymerization is carried out in the absence of a solvent, it is preferably carried out at 50 ℃ to 130 ℃, more preferably at 80 ℃ to 110 ℃. When the temperature is lower than 50 ℃, the polymerization rate is lower, and the accumulated heat is increased, so that the quality of the target product is reduced; in addition, when the temperature is higher than 130 ℃, side reactions such as elimination of a terminal alcohol are liable to occur to give a vinyl ether. Also, as the polymerization proceeds, the molecular weight gradually increases, the viscosity of the reaction liquid may increase or solidification may occur, so that the reaction is not uniform and the distribution of the target product obtained is broad.

The polymerization process may be carried out in a solvent or without a solvent, and the solvent is not particularly limited, but is preferably an aprotic solvent such as toluene, benzene, xylene, acetonitrile, ethyl acetate, tetrahydrofuran, chloroform, dichloromethane, dimethyl sulfoxide, dimethylformamide or dimethylacetamide. In general, preference is given to working in aprotic solvents, preferably in dimethyl sulfoxide, dimethylformamide, toluene or tetrahydrofuran.

2.3. Terminating the polymerization reaction

The polymerization product obtained after the second step is a mixture of alcohol and oxygen anions. When polymerized to a certain extent, a proton source is added to give a hydroxyl-terminated intermediate compound having a specific degree of polymerization. Wherein the proton source is required to provide active hydrogen.

The protonating agent is not particularly limited, and is preferably selected from water, acetic acid, ethanol, and methanol. In general, the amount of protonating agent used is from 1 to 100 times, preferably from 2 to 10 times, that of the deprotonating agent. If the amount of the protonating agent is less than 1 time of the molar equivalent of the deprotonating agent, incomplete protonation is caused, active oxygen anions cause unstable product structure, and impurities with molecular weight larger than the target molecular weight are formed after being placed in air for a long time, so that the molecular weight distribution is widened. When the amount of the protonating agent is more than 20 times the molar equivalent of the deprotonating agent, an excess of the agent or compound causes troubles in purification and may cause side reactions.

The protonation is generally carried out at from 30 ℃ to 100 ℃, preferably from 50 ℃ to 80 ℃. When the temperature is less than 30 ℃, the high molecular weight polymerization product is liable to cause incomplete protonation of the product due to uneven stirring of the reaction system caused by an increase in viscosity or solidification. When the temperature is higher than 100 ℃, the product is easy to chain transfer, so that the molecular weight is increased and the distribution is widened.

The protonation time is preferably 10 minutes to 60 minutes, and the time control varies depending on the acidity of the protonating agent. Generally, under the condition of weak acidity or two-phase reaction, protonation needs longer time, generally between 30 minutes and 60 minutes; the protonation speed is higher under the condition of stronger acidity or homogeneous reaction, and can be finished within 10 to 30 minutes generally.

2.4. Molecular weight and PDI determination

The measurement is carried out by GPC, MALDI-TOF or the like. The molecular weight deviation is controlled within 10 percent, and can reach within 8 percent in some cases, even can reach within 5 percent. PDI is controlled to be less than 1.10-1.08, and for most molecular weights of 5-40 kDa, the molecular weight is stably controlled to be less than 1.05, and part of the molecular weight is less than 1.03, and can be less than 1.02, and the best is about 1.01.

3. A preparation method of eight-arm polyethylene glycol comprises the following steps:

coupling reaction is carried out on the disaccharide-based micromolecules and linear functionalized polyethylene glycol containing naked hydroxyl groups to obtain eight-arm polyethylene glycol; or the disaccharide group micromolecule and the linear functionalized polyethylene glycol containing protected hydroxyl are subjected to coupling reaction to obtain protected eight-arm polyethylene glycol, and then the protected eight-arm polyethylene glycol is subjected to deprotection reaction to obtain the eight-arm polyethylene glycolPolyethylene glycol. Wherein the disaccharide-based small molecule is an octahydroxydisaccharide molecule CORE (OH)₈Or functionalized octahydroxydisaccharide molecules.

3.1. Octahydroxydisaccharide molecules or functionalized octahydroxydisaccharide molecules

The definition of the octahydroxydisaccharide molecule is identical to that described above and is not described in further detail here.

The functionalized octahydroxydisaccharide molecule is characterized in that a functional group with reactivity is introduced after the hydroxyl is functionalized and modified, and can generate coupling reaction with a reaction end in linear functionalized polyethylene glycol to form covalent connection. The functionalization modification method and the type of functional group (i.e. active group) that can be introduced here can be selected from any suitable reactive group from the following terminal reactive groups class a to class H of functionalized eight-arm polyethylene glycol, and the corresponding terminal linear functionalization method, which are not described herein again.

3.2. Linear functionalized polyethylene glycols

The linearly functionalized polyethylene glycol includes a reactive end and a hydroxyl end. Wherein the reactive end contains a reactive group that can react with the octahydroxydisaccharide molecule or a functionalized derivative thereof to form a covalent linkage. The hydroxyl end contains a naked hydroxyl group or a protected hydroxyl group. When the molecular weight of the linear functionalized polyethylene glycol is a mixture of different molecular weights, n can also be obtained₁、n₂、n₃、n₄、n₅、n₆、n₇、n₈Independently of one another, may be the same or different.

3.3. Coupling reaction process

The scope of choice of the coupling reaction described in the present invention is not particularly limited, as long as two identical or different reactive groups can form a covalent linking group upon reaction. The reaction conditions, depending on the type of covalent linking group formed by the reaction, can be as described in the prior art. Including but not limited to documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and the references cited therein. For example, CN104530417A corresponds to segments [1212] to [1280], and CN104877127A corresponds to segments [0992] to [0997 ]. Including but not limited to any of the reactive groups disclosed in the present invention and the cited documents, can undergo a reaction that produces a covalent linking group. Other types of reactions mentioned in the present invention are also included. The valence of the covalent linking group may be divalent or trivalent, with divalent predominating.

The coupling reaction can produce stable groups as well as degradable groups.

In general terms, for example: the amino is respectively reacted with active ester, formic acid active ester, sulfonate, aldehyde, alpha, beta-unsaturated bond, carboxylic acid group, epoxide, isocyanate and isothiocyanate to obtain bivalent connecting groups such as amido, urethane group, amino, imino (which can be further reduced into secondary amino), amino, amido, amino alcohol, urea bond, thiourea bond and the like; reacting a sulfhydryl group with a divalent linking group containing an active ester, a formic acid active ester, a sulfonic ester, a sulfhydryl group, maleimide, aldehyde, an alpha, beta-unsaturated bond, a carboxylic acid group, iodoacetamide and an anhydride to obtain a thioester group, a thiocarbonate, a thioether, a disulfide, a thioether, a hemithioacetal, a thioether, a thioester, thioether, imide and the like; unsaturated bonds react with sulfydryl to obtain thioether groups; carboxyl or acyl halide reacts with sulfhydryl and amino respectively to obtain thioester group, amide group and other groups; hydroxyl reacts with carboxyl, isocyanate, epoxide and chloroformyl to obtain divalent linking groups such as ester group, carbamate group, ether bond, carbonate group and the like; reacting carbonyl or aldehyde group with amino, hydrazine and hydrazide to obtain divalent connecting groups such as imine bond, hydrazone, acylhydrazone and the like; reactive groups such as azide, alkynyl, alkenyl, sulfydryl, azide, diene, maleimide, 1,2, 4-triazoline-3, 5-diketone, dithioester, hydroxylamine, hydrazide, acrylate, allyloxy, isocyanate, tetrazole and the like are subjected to click chemistry reaction to generate corresponding divalent connecting groups containing structures such as triazole, isoxazole, thioether bonds and the like. The types of click reactions and resulting linkers reported in and cited in the document adv. funct. mater, 2014,24,2572 are incorporated herein by reference, such as azide-alkynyl cycloaddition, Diels-Alder addition, oxime or acylhydrazone production, mercapto-vinyl addition, mercapto-alkynyl addition, mercapto-isocyanate, 13-dipolar cycloaddition reaction, and the like. Also included, but not limited to, cycloaddition reactions, Diels-Alder addition reactions, 1, 3-dipolar cycloaddition reactions, and the like, which can occur in the following class G. The primary amine reacts with one molecule of sulfonate, halide, epoxide and alpha, beta-unsaturated bond to obtain divalent secondary amino group, and reacts with two molecules to form trivalent tertiary amino group. Also as in the reaction between a B5 or B6-type functional group and a disulfide bond of the present invention, a trivalent linking group can be formed. As another example, the reactive group E13 reacts with a disulfide bond to form a trivalent linking group

Also as follows for the reaction of hydrazine and aldehyde groups

Typical examples of the divalent linking group to be formed include an amide bond, a urethane bond, an ester group, a secondary amine bond, a thioether bond, a triazole group and the like. When an amide bond (-CONH-) or an imide (-CON (-)₂) When used, the synthesis may be carried out in a manner including, but not limited to: (1) obtained by condensation reaction between amino and carboxyl; (2) obtained by reaction between an amino group and a carboxylic acid derivative; (3) the method is realized by amidation reaction of substrate amine and acyl halide, wherein the acyl halide is preferably acyl chloride. When a urethane linkage (-OCONH-) is formed, the compound can be obtained by condensation reaction of a terminal amino group and a terminal active carbonate derivative; wherein the active formate can be a derivative which can react with amino to obtain a urethane bond, and the derivative comprises but is not limited to Succinimidyl Carbonate (SC), p-nitrophenol carbonate (p-NPC), 2,4, 6-trichlorophenol carbonate, imidazole carbonate, N-hydroxybenzotriazole carbonate, preferably Succinimidyl Carbonate (SC), o-nitrophenol carbonate (o-NPC) and the like; urethane linkages can also be obtained by reacting hydroxyl groups with isocyanates. When a monothio or dithio carbamate linkage is formed, it can be obtained by reacting a terminal amino group with a terminal thiooxycarbonylchloride, reacting a hydroxyl or mercapto group with an isothiocyanate, or reacting a mercapto group with an isocyanate. When an ester bond (-OCO-) is formed, the compound can be obtained by condensation reaction of a terminal hydroxyl group and a terminal carboxyl group or acyl halideThe acid halide is preferably an acid chloride. When a secondary amine linkage (-CH) is formed₂NHCH₂-) can be obtained by condensation and reduction reaction between aldehyde group and amino group, or by alkylation reaction between primary amine and sulfonate or halide. When a thioether bond is formed: (>CHS-) can be obtained by addition reaction between a terminal mercapto group and maleimide or other reactive group containing an unsaturated bond ({ Angew. chem. int. Ed.,2010,49,3415-3417}), or by alkylation reaction between a terminal mercapto group and a sulfonate or halide. When a triazole group is formed, it can be obtained by a click reaction between an alkynyl group and an azide. When 4, 5-dihydroisoxazole is formed, it is obtained by a1, 3-dipolar cycloaddition reaction between a cyanoxide and an alkynyl group.

Typical reactions to form stable divalent linking groups are of the alkylation type, including but not limited to the alkylation of hydroxyl, mercapto or amino groups with sulfonates or halides, which in turn correspond to the formation of ether linkages, thioether linkages, secondary or tertiary amino groups.

4. A functionalized eight-arm polyethylene glycol has the following structural general formula:

wherein, the definitions of CORE and n are consistent with the general formula (1), and are not repeated herein.

Wherein k is_HThe number of PEG chains with hydroxyl at the end of PEG in a single molecule, k_HLess than 8, i.e. at least one PEG chain end is functionalized; the remaining 8-k_HEach PEG chain end contains a functional group; f is a hydrogen atom orWherein q and q are₁Each independently is 0 or 1, Z₁、Z₂Each independently is a divalent linking group, R₀₁Is a functional group capable of interacting with a biologically relevant substance; f is a hydrogen atom and participates in forming a terminal functional group of hydroxyl, amino or sulfhydryl.

k is a single officerThe number of F in the functionalized end is 1 or 2-250; 8-k in a single molecule_HEach k is independently equal or different;

in a single functionalized PEG chain, g is 0 or 1; g is a terminal branching group selected from a trivalent or higher valent connecting group which connects the PEG chain segment with a terminal functional group; l is₀Is a divalent linking group which connects the PEG chain segment with the terminal branching group G;

when g is 0, k is 1, L₀G is not absent, F is not a hydrogen atom, hydroxyethyl, hydroxyl terminated PEG chain;

when G is 1, G is present, L₀May be present or absent, k is 2 to 250, where F is allowed to be a hydrogen atom;

in the general formula (20)

Can exist stably or can be degraded; in the same molecule, CORE, L₀、G、(Z₂)_q-(Z₁)_q1Any one of the linking groups formed with the adjacent group may each independently be stably present or degradable; in the same molecule, CORE, L₀、G、(Z₂)_q-(Z₁)_q1Each independently may be stable or degradable.

One of the preferences of the above formula (20) is k_H0, i.e. 8 PEG chains are all functionally modified, corresponding to general formula (2):

another preference is k_H7, i.e. only one PEG chain is functionally modified, corresponding to general formula (6):

more preferably, in the above general formula (6), g is 0, k is 1, and corresponds to general formula (7):

4.1. terminal branching group G

In the case where no particular designation is made, the k +1(k ═ 2 to 250) valent group G may be directed from any one of the linking ends to the polyethylene glycol unit. G is marked with an asterisk, the connecting end marked with an asterisk points to the polyethylene glycol unit.

In the general formula (1), k represents a functional group R to which the terminal can be bonded₀₁The number of (a) is 1 or 2 to 250, and k at the ends of the eight branched chains may be equal to or different from each other.

When k is 1, G is 0, then G is absent;

when k is 2 to 250, G is 1, where G is present and G is a linker of valence k +1, L₀May or may not be present. In this case, k may be 2,3,4,5,6,7, 8,9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, or 33 to 250. Correspondingly, the valence state of G is 3-251, that is, G is a connecting group of trivalent, tetravalent, pentavalent, hexavalent, heptavalent, eighty valent, nine valent, ten valent, decavalent, twelve divalent, thirteen valent, ten pentavalent, ten hexavalent, ten heptavalent, ten eighty valent, nineteen valent, twenty monovalent, twenty divalent, twenty trivalent, twenty tetravalent, twenty pentavalent, twenty hexavalent, twenty heptavalent, twenty eighty valent, thirty monovalent, thirty divalent, thirty trivalent or 34-251 valent.

k is preferably 1 to 100 and can be subdivided into 1,2,3,4,5,6,7, 8,9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32 or 33 to 100; more preferably 1,2,3,4,5,6,7, 8,9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32 or 33 to 64; more preferably 1,2,3,4,5,6,7, 8,9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

Preferably, k is equal at all ends of the eight PEG chains.

One preferred case is when G is 0, G is absent, and k is 1, in which case formula (2) represents formula (21):

in a preferred case, G is 1, G is present, and k.gtoreq.2, in which case formula (2) represents formula (22):

a more preferred case is when G ═ 1, G is present, and k ═ 2, where formula (2) represents as shown in formula (23), where the terminal branching group G is a trivalent branching group

Another more preferred case is when G ═ 1, G is present, and k ═ 3, in which case formula (2) represents as shown in formula (24), in which case the terminal branching group G is a tetravalent branching group.

Another more preferred case is when G ═ 1, G contains a dendritic structure, and k is selected from the following: 2²,2³,2⁴,2⁵,2⁶,3²,3³,3⁴,3⁵,4²,4³,4⁴Any one of k is 2 times, 3 times or 4 times as large as that of the above. It should be noted that although k is 2⁴Or 4²The values are equal, but the combination modes of k F are different, the former is a four-level tree structure, and the latter is a two-level tree structure.

Another more preferred case is G ≧ 1, G is a comb-like structure, k ≧ 3, preferably 100 ≧ k ≧ 3, more preferably 50 ≧ k ≧ 3, more preferably 25 ≧ k ≧ 3.

Another more preferred is the case where G is 1, G is a furanose ring or pyranose ring structure, G (F)_kThe terminal of (A) is hydroxyl, amino, mercaptoOr a functional group obtained by functional modification of a hydroxyl group, an amino group or a thiol group.

Another more preferred aspect is g ═ 1, G (F)_kIs the residue of open chain monosaccharide, open chain disaccharide or open chain polysaccharide, and the end is hydroxyl or functional group obtained by functional modification of the hydroxyl.

Another more preferred aspect is g ═ 1, G (F)_kIs cyclodextrin residue, the cyclodextrin can be alpha-, beta-or gamma-cyclodextrin, and the end is hydroxyl or functional group after functional modification of the hydroxyl.

For any one k selected from 2 to 250, G is selected from the group G of k +1 valent groups^k+1Any one of k +1 valent groups.

Set G^k+1The stability of any one of the k + 1-valent groups is not particularly limited, and may be a group which can be stably present or a degradable group. The conditions which can be stably present, degradable conditions are in accordance with the term moiety.

Including the set G³、G⁴Set G of inner^k+1Examples of the k +1(k 2-250) valent group included in (k 2-250) and preferred examples thereof include, but are not limited to, those described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and the respective references cited therein. Including but not limited to the document CN104877127A paragraph [0104]～[0264]Section [0664]]～[0683]Groups described and exemplified.

4.1.1. Trivalent terminal group nucleus structure

Set G³The trivalent group in (a) contains a trivalent core structure. The trivalent nucleus structure may be an atom CM₃One unsaturated bond CB₃Or a cyclic structure CC₃. Trivalent nuclear atom CM₃And a trivalent unsaturated bond nucleus structure CB₃Trivalent ring nucleus structure CC₃And preferred versions of the three include, but are not limited to, those described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and the respective cited documents. Taking CN104530417A as an example, corresponding to segment [0211]～[0284]. Taking CN104877127A as an example, the corresponding segment [0117 ]]～[0143]。

Wherein, threeNucleus of valence CM₃There is no particular limitation as long as three covalent single bonds are allowed to be formed simultaneously. By way of example, trivalent nitrogen nuclei, trivalent carbon nuclei

Trivalent silicon nucleus

Trivalent phosphorus nuclei (e.g. of the formula

) And the like. The trivalent nuclear atom may be free of any atoms or groups, such as a trivalent nitrogen nucleus, or may be bound to other atoms or groups, such as a trivalent carbon nucleus, a trivalent silicon nucleus, a trivalent phosphorus nucleus, and the like.

R₃₇Substituents being the branching centre of trivalent silicon, selected from hydrocarbon radicals, preferably C_1-20Hydrocarbyl, more preferably C_1-20Alkyl, most preferably methyl.

R₁Is a hydrogen atom or a substituent attached to a carbon atom.

When taken as a substituent, R₁Are not particularly limited. Substituents which are stable under the conditions of anionic polymerization are preferred.

When taken as a substituent, R₁The number of carbon atoms of (A) is not particularly limited, but is preferably 1 to 20, more preferably 1 to 10.

When taken as a substituent, R₁May or may not contain heteroatoms.

When taken as a substituent, R₁The structure of (a) is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. Among them, the cyclic structure is not particularly limited, and the above-mentioned aliphatic ring, aromatic ring, sugar ring, and condensed ring are preferable.

R₁Is a hydrogen atom or is selected from C_1-20Hydrocarbyl, substituted C_1-20Hydrocarbyl, etc. middle renA group of (a). Wherein R is₁The substituent atom or substituent in (1) is not particularly limited, and includes, but is not limited to, any substituent atom or any substituent group of the term moiety selected from any one of a halogen atom, a hydrocarbon group substituent, and a heteroatom-containing substituent group.

R₁Preferably a hydrogen atom or C_1-20Alkyl, aralkyl, C_1-20Open-chain heterocarbyl, heteroaralkyl, substituted C_1-20Alkyl, substituted aryl, substituted C_1-20An open-chain heterocarbon group, a substituted heteroaromatic hydrocarbon group, or the like.

Specifically, as an example R₁Selected from a hydrogen atom or from the group comprising, but not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, benzyl, substituted C_1-20Alkyl, substituted aryl, substituted C_1-20An open-chain heterocarbon group, a substituted heteroaromatic hydrocarbon group, or the like. Wherein, butyl includes but is not limited to n-butyl and tert-butyl. Octyl includes, but is not limited to, n-octyl, 2-ethylhexyl. Wherein the substituent atom and the substituent are selected from any one of a halogen atom, a hydrocarbon substituent and a hetero atom-containing substituent, and preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, C_1-6Alkyl, alkoxy or nitro.

R₁Preferably a hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, C group_1-10Halohydrocarbyl, haloacetyl or alkoxy substituted C_1-10An aliphatic hydrocarbon group. Wherein, the halogen atom is F, Cl, Br or I.

R₁Most preferably a hydrogen atom, a methyl group or an ethyl group.

Wherein, the trivalent unsaturated bond has a nuclear structure CB₃There is no particular limitation as long as three covalent single bonds can be formed simultaneously. The unsaturated bond may have two or more bonding atoms. Preferably 2 or 3. More preferably 2. As a liftingE.g. as

And the like.

Wherein, the trivalent ring nucleus structure CC₃There is no particular limitation as long as three covalent single bonds can be simultaneously extracted. The ring-forming atoms from which the covalent single bond is derived are not particularly limited and include, but are not limited to, N, C, Si, P, and the like. The cyclic structure is selected from the group consisting of, but not limited to, aliphatic rings, aromatic rings, sugar rings, and condensed rings. The cyclic structure may be a single ring, such as a trivalent ring from cyclohexane, furanose, pyranose, benzene, pyridine, triazole, triazacyclononane, and the like; and may be polycyclic, such as rings from fluorene, carbazole, adamantane, and the like. Can be a naturally occurring cyclic structure, such as any trivalent monocyclic ring from any cyclic monosaccharide, or a trivalent ring generated by chemical reaction, such as cyclic peptide, lactone, lactam, lactide, etc. The covalent single bond to be extracted may be directly extracted from the ring-forming atom, or may be extracted through an unsaturated bond. Three single covalent bonds may be drawn simultaneously from three ring-forming atoms, e.g.Or wherein two single covalent bonds are from the same ring-forming atom

Wherein M is₅、M₆、M₇、M₂₃Are ring-forming atoms, i.e. atoms located on a ring. M₅、M₆、M₇、M₂₃Each independently is a carbon atom or a heteroatom, and may be the same as or different from each other in the same molecule. M₅、M₆、M₇、M₂₃Each independently is preferably a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom. M₅、M₆、M₇、M₂₃The ring is a 3-to 50-membered ring, preferably a 3-to 32-membered ring, more preferably a 3-to 18-membered ring, and still more preferably a 5-to 18-membered ring.

M₂₃Is on a ringA carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom from which 2 single bonds are derived. When a nitrogen atom, it is present in the form of a quaternary ammonium cation.

M₅、M₆、M₇Ring in which M is located₂₃、M₆The ring is not particularly limited, including but not limited to

And the like. The number of ring-forming atoms is not particularly limited, but is preferably 3 to 50-membered rings, more preferably 3 to 32, and still more preferably 3 to 18.

Wherein, the aliphatic ring

Is any alicyclic or alicyclic ring, and the ring-forming atoms are each independently a carbon atom or a heteroatom; the hetero atom is not particularly limited and includes, but is not limited to, a nitrogen atom, an oxygen atom, a sulfur atom, a phosphorus atom, a silicon atom, a boron atom, and the like. The hydrogen atom on the ring-forming atom of the alicyclic ring may be substituted with any substituent atom or substituent, or may be unsubstituted. The substituted heteroatom or substituent is not particularly limited and includes, but is not limited to, any substituted heteroatom or any substituent of the term moiety selected from any of a halogen atom, a hydrocarbyl substituent, and a heteroatom-containing substituent. Broadly, the alicyclic and alicyclic rings include, but are not limited to, any one of the ring structures or any combination of two or more of the ring types in monocyclic, polycyclic, spiro, bridged, fused, carbocyclic, heterocyclic, alicyclic, heteromonocyclic, heteromulticyclic, heterospiro, heterobridged, heteroalicyclic.

Wherein the aromatic ringIs any aromatic ring or aromatic heterocyclic ring, and the ring-forming atoms are each independently carbon atoms or heteroatoms; the hetero atom is not particularly limited and includes, but is not limited to, a nitrogen atom, a phosphorus atom, a silicon atom, a boron atom, and the like. Aromatic hydrocarbonThe hydrogen atom on the ring-forming atom of the ring may be substituted with any substituent atom or any substituent, or may be unsubstituted. The substituted heteroatom or substituent is not particularly limited and includes, but is not limited to, any substituted heteroatom or any substituent of the term moiety selected from any of a halogen atom, a hydrocarbyl substituent, and a heteroatom-containing substituent. The substituent atom is preferably a halogen atom. The substituent is preferably a group that contributes to the induction, conjugation effect of the unsaturated bond electrons. Broadly, the aromatic rings and aromatic heterocycles: including, but not limited to, any one of the ring structures or any combination of two or more of the ring types monocyclic, polycyclic, fused ring, fused aromatic ring, fused heteroaromatic ring, carbocyclic ring, heterocyclic ring, aromatic heterocyclic ring, hetero-monocyclic, hetero-polycyclic, hetero-fused ring, and hetero-aromatic ring. The aromatic ring is preferably the above-mentioned benzene, pyridine, pyridazine, pyrimidine, pyrazine, 1,3, 5-triazine, tetrazine (1,2,3,4-, 1,2,4, 5-and 1,2,3, 5-three isomers), indene, indane, indole, isoindole, purine, naphthalene, dihydroanthracene, xanthene (xanthene), thioxanthene, dihydrophenanthrene, 10, 11-dihydro-5H-dibenzo [ a, d ] s]Cycloheptane, dibenzocycloheptene, 5-dibenzocycloheptenone, quinoline, isoquinoline, fluorene, carbazole, iminodibenzyl, naphthylethyl, dibenzocyclooctyne, azabenzocyclooctyne, and the like, substituted versions of any, or hybridized versions of any.

Wherein, the sugar ring

Is a skeleton of a saccharide or a saccharide derivative having a cyclic monosaccharide skeleton. The saccharide or saccharide derivative is derived from natural monosaccharide or unnatural monosaccharide. The structure of the cyclic monosaccharide is any one form or a combination form of any two or more than two of an isomer, a chiral isomer, an optical isomer, a conformational isomer and a rotational isomer of the cyclic monosaccharide. For example, the pyranose ring may be in either the boat or chair conformation.

Selected from the group consisting of cyclicSkeletons of monosaccharides or cyclic monosaccharide derivatives

Backbones of oligosaccharides or oligosaccharide derivatives

Polysaccharide or polysaccharide derivative backbone

Any of the above.

And preferred versions of the three include, but are not limited to, those described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and the respective cited documents. Taking CN104530417A as an example, the corresponding segment [0231]～[0234]。

The skeleton of the cyclic monosaccharide or the cyclic monosaccharide derivative has 3,4,5,6 or 7 carbon atoms, and the structure of the skeleton is any one form or a combination form of any two or more forms of an isomer, a chiral isomer, an optical isomer, a conformational isomer and a rotational isomer. Monosaccharides or monosaccharide derivatives having a cyclic monosaccharide backbone of 6 carbon atoms are preferred, and include, by way of example and not limitation, any monosaccharide of glucose, allose, altrose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, tagatose, inositol. The cyclic structure is preferably a five-membered ring or a six-membered ring.

The skeletons of the oligosaccharides or oligosaccharide derivatives are combined in a linear, branched, hyperbranched, dendritic, comb-like or cyclic monosaccharide skeleton. The number of monosaccharide units is 2-10. Taking a cyclic mode as an example, any one of alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin or derivatives thereof can be combined to form the cyclodextrin.

The combination mode of the polysaccharide or polysaccharide derivative skeleton and the cyclic monosaccharide skeleton thereof includes but is not limited to linear, branched, hyperbranched, dendritic, comb-shaped and cyclic modes. The number of monosaccharide units is more than 10. By way of example, the D-glucopyranose units are linked in sequence by α -1,4 glycosidic linkages to form a linear combination; the linear structures are connected end to end, and a ring combination mode can be formed. For another example, when at least one D-glucopyranose unit is bonded to an adjacent glucose unit via at least two glycosidic linkages, such as an alpha-1, 2 glycosidic linkage, an alpha-1, 3 glycosidic linkage, an alpha-1, 4 glycosidic linkage, and an alpha-1, 6 glycosidic linkage, a combination of branching and hyper-branching is formed. When all glucose units are repeatedly linked in a regular manner by specific three or more glycosidic linkages, a comb-like pattern of combinations can be formed. Specifically, the polysaccharide or polysaccharide derivative may be any one of starch, chitin, cellulose, and dextran, for example.

Wherein, condensed ring

A ring containing a chemical bond formed by condensation of an amide bond, an ester bond, an imide, an acid anhydride, or the like. Examples are lactones, lactides, lactams, cyclic imides, cyclic anhydrides, cyclic peptides, etc.

CC₃The trivalent ring structure of (A) is preferably selected from the group consisting of cyclohexane, furanose, pyranose, benzene, tetrahydrofuran, pyrrolidine, thiazolidine, cyclohexene, tetrahydropyran, piperidine, 1, 4-dioxane, pyridine, pyridazine, pyrimidine, pyrazine, 1,3, 5-triazine, 1,4, 7-triazacyclononane, cyclic tripeptide, indene, indane, indole, isoindole, purine, naphthalene, dihydroanthracene, xanthene (e.g. xanthene), thioxanthene, dihydrophenanthrene, 10, 11-dihydro-5H-dibenzo [ a, d-dihydrodibenzo [ a, d ] and mixtures thereof]Cycloheptane, dibenzocycloheptene, 5-dibenzocycloheptenone, quinoline, isoquinoline, fluorene, carbazole, iminodibenzyl, naphthylethyl, dibenzocyclooctyne, azabenzocyclooctyne, and the like, substituted versions of any, or hybridized versions of any.

4.1.2. Tetravalent end group nucleus structure

Set G⁴The tetravalent group in (a) contains two trivalent core structures or one tetravalent core structure.

The trivalent nucleus structure is as described above for G³The definitions in (1) are not repeated here.

The tetravalent core structure may be an atom CM₄One unsaturated bond CB₄Or a cyclic structure CC₄。CM₄、CB₄、CC₄And preferred versions of the three include, but are not limited to, those described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and the respective cited documents. Taking CN104530417A as an example, corresponding segment [0287 ]]～[0291]. Taking CN104877127A as an example, the corresponding segment [0144 ]]～[0164]。

Wherein a tetravalent nuclear atom CM₄There is no particular limitation as long as four covalent single bonds can be simultaneously formed. Examples thereof include a tetravalent carbon nucleus, a tetravalent silicon nucleus, a tetravalent phosphorus nucleus and the like.

Wherein, the core structure of tetravalent unsaturated bond CB₄There is no particular limitation as long as four covalent single bonds can be simultaneously formed. The unsaturated bond may have two or more bonding atoms. Preferably 2 or 3. More preferably 2.

Wherein, the tetravalent cyclic nucleus structure CC₄There is no particular limitation as long as four covalent bonds can be simultaneously extracted. The ring-forming atoms from which the covalent bond is derived are not particularly limited and include, but are not limited to, N, C, Si, P, and the like. The cyclic structure is selected from the group consisting of, but not limited to, aliphatic rings, aromatic rings, sugar rings, and condensed rings. May be a naturally occurring ring structure, such as a sugar ring; or a ring formed by a chemical reaction. The extracted covalent single bond may be directly extracted from a ring-forming atom or may be extracted through an unsaturated bond. Any one of the single covalent bonds may be independently derived from one ring-forming atom, or two single covalent bonds may be simultaneously derived from the same ring-forming atom. Comparative typical CC₄The structure of (a) is such that four covalent single bonds are simultaneously drawn from four ring-forming atoms. CC (challenge collapsar)₄The tetravalent ring structure of (A) preferably includes, but is not limited to, a furanose ring, pyranose ring, cycleanine, cyclotetrapeptide, tetrahydrofuran, pyrrolidine, thiazolidine, cyclohexane, benzene, cyclohexene, tetrahydropyran, piperidine, 1, 4-dioxane, pyridine, pyridazine, pyrimidine, pyrazine, indene, indane, indole, isoindole, purine, naphthalene, dihydroanthracene, xanthene (e.g., xanthene), thioxantheXanthene, dihydrophenanthrene, 10, 11-dihydro-5H-dibenzo [ a, d ]]Cycloheptane, dibenzocycloheptene, 5-dibenzocycloheptenone, quinoline, isoquinoline, fluorene, carbazole, iminodibenzyl, tetramethyltetrahydroindene, the dipyridamole skeleton, the ring skeleton of tetravalent trimeric glyoxal hydrate, the six-membered ring skeleton of tetravalent D-sorbitol in which two hydroxyl groups at 2, 4-positions are protected, and the like, a substituted form of any one, or a hybridized form of any one.

4.1.3. Nucleus structure with more than four valence terminal groups

Any one of the sets G^k+1The k + 1-valent group in (k is more than or equal to 4) can contain a k + 1-valent cyclic core structure CC_k+1The core may have 2 or more low-valent cyclic core structures having a valence of 3 to k. Including but not limited to documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and groups described and exemplified in each of the cited documents. Taking CN104530417A as an example, the corresponding segment [0292]～[0295]. Take CN104877127A as an example, corresponding to segment [0165 ]]～[0167]。

By way of example only, the following may be mentioned,

where k is 4, set G⁵Middle, ring nucleus structure CC₅Cyclic core structures that are derivatives of five single covalent bonds from five ring-forming atoms include, but are not limited to, cyclic monosaccharide core structures, cyclic peptides, saturated carbocycles, azacycloalkanes, and the like. By way of example, from the pyranose ring, from cyclic peptides and the like

And the like.

Wherein, when k is more than or equal to 5, the set G^k+1(k.gtoreq.5) middle, cyclic nucleus structure CC_k+1Including but not limited to cyclic peptides, azacycloalkanes, polymer rings, and the like.

4.1.4. Parts other than core structure of terminal branching group

Any one of the sets G^k+1When the group having a valence of k +1 in (k.gtoreq.2) has a 3-to k + 1-valent core structure, the group may or may not have a part other than the 3-to k + 1-valent core structure. Including but not limited to documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and groups described and exemplified in each of the cited documents. With CN104877127A as an example, corresponding to the segment [0168 ]]～[0234]。

When the core contains a moiety other than the 3-k + 1-valent core structure, the core may contain carbon atoms, may not contain carbon atoms, and may contain or may not contain heteroatoms. The moiety other than the 3-k +1 valent core structure may be selected from a divalent linking group containing a heteroatom, and an alkylene group containing no heteroatom. The heteroatoms include, but are not limited to, O, S, N, P, Si, F, Cl, Br, I, B, and the like. The number of the hetero atoms may be one, or two or more. The heteroatoms may be present as substituent atoms; may also be present independently as a divalent linking group, such as-O- (oxy or ether linkage), -S- (thio or thioether linkage), -N (R)₇) - (secondary amino group or divalent tertiary amino group), etc.; may also be present as divalent substituents, such as, for example, - -C (═ O) - -, - -C (═ S) - -, - -P (═ O) - -, - -S (═ O)₂-, -S (═ O) -, etc.; specific covalent bonds may also be combined, such as, for example, -C (═ O) -N (R)₇)-、-N(R₇)-C(＝O)-、-S-S-、-C(＝O)-O-、-O-C(＝O)-、-C(＝O)-S-、-S-C(＝O)-、-C(＝S)-O-、-O-C(＝S)-、-C(＝S)-S-、-S-C(＝S)-、-O-C(＝O)-O-、-S-C(＝O)-O-、-O-C(＝S)-O-、-O-C(＝O)-S-、-S-C(＝S)-O-、-O-C(＝S)-S-、-S-C(＝O)-S-、-S-C(＝S)-S-、-N(R₇)-C(＝O)-O-、-O-C(＝O)-N(R₇)-、-N(R₇)-C(＝S)-O-、-O-C(＝S)-N(R₇)-、-N(R₇)-C(＝O)-S-、-S-C(＝O)-N(R₇)-、-N(R₇)-C(＝S)-S-、-S-C(＝S)-N(R₇)-、-N(R₁₉)-N(R₁₈)-、-N(R₁₉)-C(＝O)-N(R₁₈)-、-N(R₁₉)-C(＝S)-N(R₁₈)-、-N(R₁₈)-N(R₁₉)-C(＝O)-、-C(＝O)-N(R₁₉)-N(R₁₈)-、-N(R₁₈)-N(R₁₉)-C(＝S)-、-C(＝S)-N(R₁₉)-N(R₁₈)-、-(R₁₅)C＝N-、-N＝C(R₁₅)-、-(R₁₅)C＝N-N(R₇)-、-N(R₇)-N＝C(R₁₅)-、-(R₁₅)C＝N-N(R₇)-C(＝O)-、-C(＝O)-N(R₇)-N＝C(R₁₅)-、-(R₁₅)C＝N-O-、-O-N＝C(R₁₅)-、-(R₁₅)C＝N-S-、-S-N＝C(R₁₅)-、-N＝N-、-N(R₁₈)-N(R₁₉)-C(＝O)-N＝N-、-N＝N-C(＝O)-N(R₁₉)-N(R₁₈)-、-N(R₁₈)-C(＝O)-N(R₁₉)-、-C(＝NR₇)-N(R₂₃)-、-N(R₂₃)-C(＝NR₇)-、-N(R₇)-C(＝NH₂ ⁺)-、-C(＝NH₂ ⁺)-N(R₇)-、-C(＝NR₇)-O-、-O-C(＝NR₇)-、-O-C(＝NH₂ ⁺)-、-C(＝NH₂ ⁺)-O-、-C(＝NR₇)-S-、-S-C(＝NR₇)-、-S-C(＝NH₂ ⁺)-、-C(＝NH₂ ⁺)-S-、-S(＝O)₂-O-、-O-S(＝O)₂-、-S(＝O)-O-、-O-S(＝O)-、-S(＝O)₂-N(R₇)-、-N(R₇)-S(＝O)₂-、-S(＝O)₂-N(R₁₈)-N(R₁₉)-、-N(R₁₉)-N(R₁₈)-S(＝O)₂-and the like. The alkylene group containing no hetero atom is not particularly limited, and is preferably C_1-10Alkylene groups.

Parts other than the core structure, preferably C_1-6Alkylene groups, ether linkages, thioether linkages, secondary amino groups, divalent tertiary amino groups, amide linkages, urethane linkages, thiocarbamate linkages or C_1-6A divalent linking group formed by combining an alkylene group with any of the others. More preferably C_1-6Alkylene groups, ether linkages.

Wherein R is₇、R₁₈、R₁₉、R₂₃Each independently a hydrogen atom to which an amino group is attached, an amino protecting group or a group LG₅. And in the same molecule, R₇、R₁₈、R₁₉、R₂₃May be the same as or different from each other.

Wherein LG is₅The number of carbon atoms of (a) is not particularly limited. LG (Ligno-lead-acid)₅The number of carbon atoms of (A) is preferably 1 to 20, more preferably 1 to 10.

LG₅The structure of (a) is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. Wherein the cyclic structure isThe aliphatic ring, aromatic ring, sugar ring, and condensed ring are preferable, though not particularly limited.

LG₅May or may not contain heteroatoms.

LG₅Is selected from C_1-20Hydrocarbyl radical, C_1-20Heterohydrocarbyl, substituted C_1-20Any one of a hydrocarbon group and a substituted heterohydrocarbon group. Wherein LG is₅The substituted heteroatom or substituent in (1) is not particularly limited, including but not limited to any substituted heteroatom or any substituent of the term moiety selected from any of halogen atoms, hydrocarbyl substituents, heteroatom-containing substituents.

LG₅More preferably C_1-20Alkyl radical, C_1-20Unsaturated aliphatic, aryl, C_1-20Heterohydrocarbyl radical, C_1-20Fatty hydrocarbyl acyl radical, C_1-20Lipoheteroalkylacyl, arylacyl, heteroarylacyl, C_1-20Hydrocarbyloxyacyl group, C_1-20Hydrocarbyl thioacyl, C_1-20Hydrocarbyl aminoacyl radical, C_1-20Heterohydrocarbyloxyacyl group, C_1-20Heterocarbylthioacyl radical, C_1-20Any one group or substituted version of any one group of a heterocarbylaminoacyl group. Wherein LG is₅The acyl group in (1) is not particularly limited, including but not limited to any acyl type of the term moiety. By way of example, LG₅The acyl group in (1) may be selected from a carbonyl group, a sulfonyl group, a sulfinyl group, a phosphoryl group, a hypophosphoryl group, a nitroxyl group, a nitrosyl group, a thiocarbonyl group, an imidoyl group, a thiophosphoryl group, a dithiophosphoryl group, a trithiophosphoryl group, a thiophosphorous group, a dithiophosphoryl group, a thiophosphoryl group, a dithiophosphoryl group, a thiophosphoryl group and the like. Any of acyl groups such as a carbonyl group, a thiocarbonyl group, a sulfonyl group, and a sulfinyl group is preferable. LG (Ligno-lead-acid)₅The acyl group is more preferably a carbonyl group, thiocarbonyl group or sulfonyl group.

LG₅More preferably C_1-20Alkyl radical, C_1-20Alkenyl radical, C_1-20Alkenyl hydrocarbon group, aryl group, aralkyl group, C_1-20Heteroalkyl, heteroaryl, heteroaralkyl, C_1-20Alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, C_1-20Heteroalkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, C_1-20Alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, C_1-20Alkylthio-carbonyl, arylthio-carbonyl, aralkylthiocarbonyl, C_1-20Alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, C_1-20Heteroalkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, C_1-20Heteroalkylthio-carbonyl, heteroarylthio-carbonyl, heteroaralkylthio-carbonyl, C_1-20Heteroalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylalkylaminocarbonyl, C_1-20Alkylthio, arylthio, aralkylthiocarbonyl, C_1-20Heteroalkylthiocarbonyl, heteroarylthiocarbonyl, heteroarylalkylthiocarbonyl, C_1-20Alkoxythiocarbonyl, aryloxylthiocarbonyl, aralkyloxythiocarbonyl, C_1-20Alkylthio thiocarbonyl, arylthio thiocarbonyl, aralkylthio thiocarbonyl, C_1-20Alkylaminothiocarbonyl, arylaminothiocarbonyl, aralkylaminothiocarbonyl, C_1-20Heteroalkyloxythiocarbonyl, heteroaryloxythiocarbonyl, heteroarylalkoxythiocarbonyl, C_1-20Heteroalkylthio thiocarbonyl, heteroarylthio thiocarbonyl, heteroarylalkylthio thiocarbonyl, C_1-20A heteroalkylaminothiocarbonyl group, a heteroarylaminothiocarbonyl group, or a substituted version of any group.

LG₅More preferably C_1-20Alkyl radical, C_1-20Alkenyl radical, C_1-20Alkenyl hydrocarbon group, aryl group, aralkyl group, C_1-20Any one group or substituted version of any one group of heteroalkyl, heteroaryl, heteroaralkyl.

Specifically, LG₅Selected from the group consisting of, but not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecylOctadecyl, nonadecyl, eicosyl, allyl, benzyl, trityl, benzyl, methylbenzyl, 1,3, 5-dioxoazacyclohexyl, formyl, acetyl, benzoyl, methoxyacyl, ethoxyacyl, tert-butyloxyacyl, phenoxyacyl, benzyloxyacyl, 9-fluorenylmethyloxycarbonyl, 2-methylsulfonylethylcarbonyl, 2-p-toluenesulfonylethoxycarbonyl, methylthioacyl, ethylthioacyl, tert-butylthioacyl, phenylthioacyl, benzylthioacyl, methylaminoacyl, ethylaminoacyl, tert-butylaminoacyl, benzylaminoacyl, and the like, or a substituted form of any of these groups. Wherein, butyl includes but is not limited to n-butyl and tert-butyl. Octyl includes, but is not limited to, n-octyl, 2-ethylhexyl. The substituent atom or substituent is selected from any one of a halogen atom, a hydrocarbon substituent and a heteroatom-containing substituent, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkoxy group, an alkenyl group or a nitro group.

LG₅More preferred is methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, allyl, trityl, phenyl, benzyl, methylbenzyl, 1,3, 5-dioxoazacyclohexyl, formyl, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2-methylsulfonylethylcarbonyl, 2-p-toluenesulfonylethoxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, tert-butylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, T-butylaminocarbonyl, benzylaminocarbonyl, ethylthiocarbonyl, phenylmethylthiocarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, t-butyloxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, methylthiothiocarbonyl, ethylthiothiocarbonyl, t-butylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiocarbonyl, phenylthiothiocarbonyl,Methylaminothiocarbonyl, ethylaminothiocarbonyl, tert-butylaminothiocarbonyl, benzylamino-thiocarbonyl, 2-methylsulfonylethyloxycarbonyl, C_1-10Halogenated alkyl, trifluoroacetyl, 2-iodoethoxycarbonyl, halogenated phenyl, halogenated benzyl, nitrobenzyl, p-methoxybenzyl, trifluoromethyl benzyl and the like or substituted forms of any of these groups. Among them, the substituent atom or the substituent is preferably a fluorine atom, an alkoxy group or a nitro group.

LG₅More preferably, it is any of methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, allyl, trityl, phenyl, benzyl, nitrobenzyl, p-methoxybenzyl, trifluoromethylbenzyl, 1,3, 5-dioxazacyclohexyl, 9-fluorenylmethyloxycarbonyl, 2-methylsulfonylethylcarbonyl, 2-p-toluenesulfonylethoxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, formyl, acetyl, trifluoroacetyl and the like.

LG₅More preferably, it is any of methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, allyl, trityl, phenyl, benzyl, nitrobenzyl, p-methoxybenzyl, trifluoromethylbenzyl, and the like.

LG₅Most preferred is methyl, ethyl, allyl or benzyl.

R₇、R₁₈、R₁₉、R₂₃Each independently most preferably a hydrogen atom, a methyl group, an ethyl group or a benzyl group.

R₁₅Is a hydrogen atom, a substituent atom or a substituent on C in a structure containing a C ═ N bond. By way of example, structures containing a C ═ N bond include, but are not limited to, -C ═ N-, -C ═ N⁺＝N^—And the like, -C ═ N-NH-C (═ O) -, and the like. In the present invention, C ═ N is referred to as an imine bond.

When taken as a substituent atom, R₁₅Selected from any one of halogen atoms. Fluorine atoms are preferred.

When taken as a substituent, R₁₅The number of carbon atoms of (A) is not particularly limited, but is preferably 1 to 20, more preferably 1 to 10.

When taken as a substituent, R₁₅The structure of (a) is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. Among them, the cyclic structure is not particularly limited, and the above-mentioned aliphatic ring, aromatic ring, sugar ring, and condensed ring are preferable.

When taken as a substituent, R₁₅May or may not contain heteroatoms.

R₁₅Selected from hydrogen atoms, halogen atoms, C_1-20Hydrocarbyl radical, C_1-20Heterohydrocarbyl, substituted C_1-20Hydrocarbyl or substituted heterohydrocarbyl. Wherein R is₁₅The substituent atom or substituent in (1) is not particularly limited, and includes, but is not limited to, any substituent atom or any substituent group of the term moiety selected from any one of a halogen atom, a hydrocarbon group substituent, and a heteroatom-containing substituent group.

R₁₅Preferably a hydrogen atom, a halogen atom, C_1-20Hydrocarbyl radical, C_1-20Heterohydrocarbyl, substituted C_1-20Hydrocarbyl or substituted heterohydrocarbyl.

R₁₅More preferably a hydrogen atom, a halogen atom, C_1-20Alkyl radical, C_1-20Unsaturated aliphatic, aryl, C_1-20Heterohydrocarbyl radical, C_1-20Hydrocarbyloxyacyl group, C_1-20Hydrocarbyl thioacyl, C_1-20Any atom or group of a hydrocarbylaminoacyl group, or a substituted version of any group. Wherein R is₁₅The acyl group in (1) is not particularly limited, including but not limited to any acyl type of the term moiety. By way of example, R₁₅The acyl group in (1) may be selected from a carbonyl group, a sulfonyl group, a sulfinyl group, a phosphoryl group, a hypophosphoryl group, a nitroxyl group, a nitrosyl group, a thiocarbonyl group, an imidoyl group, a thiophosphoryl group, a dithiophosphoryl group, a trithiophosphoryl group, a thiophosphorous group, a dithiophosphoryl group, a thiophosphoryl group, a dithiophosphoryl group, a thiophosphoryl group and the like. Any of acyl groups such as a carbonyl group, a thiocarbonyl group, a sulfonyl group, and a sulfinyl group is preferable. R₁₅The acyl group in (1) is more preferably a carbonyl group or a thiocarbonyl group.

R₁₅More preferably a hydrogen atom, a halogen atom, C_1-20Alkyl radical, C_1-20Alkenyl, aryl, arylalkyl, C_1-20Aliphatic heterocarbyl, heteroaryl, heteroaromatic hydrocarbyl, C_1-20Alkoxyacyl, aryloxyacyl, C_1-20Alkylthio acyl, arylthio acyl, C_1-20Any one of an alkylaminoacyl group, an arylaminoacyl group, or a substituted version of any one of the groups. Among them, the substituent atom or the substituent is selected from any one of a halogen atom, a hydrocarbon substituent and a heteroatom-containing substituent, and is preferably a halogen atom, an alkenyl group or a nitro group.

R₁₅More preferably a hydrogen atom, a halogen atom, C_1-20Alkyl radical, C_1-20Alkenyl, aryl, arylalkyl, C_1-20Aliphatic heterocarbyl, heteroaryl, heteroaromatic hydrocarbyl, C_1-20Alkoxycarbonyl, aryloxycarbonyl, C_1-20Alkylthio carbonyl, arylthio carbonyl, C_1-20Alkylaminocarbonyl, arylaminocarbonyl, C_1-20Alkoxythiocarbonyl, aryloxylthiocarbonyl, C_1-20Alkylthio thiocarbonyl, arylthio thiocarbonyl, C_1-20Any one atom or group of an alkylaminothiocarbonyl group, arylaminothiocarbonyl group, or a substituted version of any one group. Among them, the substituent atom or the substituent is selected from any one of a halogen atom, a hydrocarbon substituent and a heteroatom-containing substituent, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkenyl group or a nitro group.

Specifically, R₁₅Selected from the group consisting of, but not limited to, hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, n-propyl group, isopropyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, eicosyl group, allyl group, propenyl group, vinyl group, phenyl group, methylphenyl group, butylphenyl group, benzyl group, methoxycarbonyl group, ethoxycarbonyl group, phenoxycarbonyl group, benzyloxycarbonyl group, methylthiocarbonyl group, ethylthiocarbonyl group, phenylthiocarbonyl group, benzylthiocarbonyl group, ethylamino groupCarbonyl, benzylaminocarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, methylthiothiocarbonyl, ethylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiothiocarbonyl, ethylaminothiocarbonyl, benzylaminothiocarbonyl, substituted C_1-20Alkyl, substituted C_1-20Alkenyl, substituted aryl, substituted arylalkyl, substituted C_1-20Aliphatic heterocarbyl, substituted heteroaryl, substituted heteroarylalkyl, substituted C_1-20Alkoxycarbonyl, substituted aryloxycarbonyl, substituted C_1-20Alkylthio carbonyl, substituted arylthio carbonyl, substituted C_1-20Alkylaminocarbonyl, substituted arylaminocarbonyl, substituted C_1-20Alkoxythiocarbonyl, substituted aryloxythiocarbonyl, substituted C_1-20Alkylthio thiocarbonyl, substituted arylthio thiocarbonyl, substituted C_1-20An alkylaminothiocarbonyl group, a substituted arylaminothiocarbonyl group, or the like. Wherein, butyl includes but is not limited to n-butyl and tert-butyl. Octyl includes, but is not limited to, n-octyl, 2-ethylhexyl. Among them, the substituent atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent and a heteroatom-containing substituent, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or a nitro group.

R₁₅More preferably a hydrogen atom, fluorine atom, methyl group, ethyl group, n-propyl group, isopropyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, allyl group, propenyl group, vinyl group, phenyl group, methylphenyl group, butylphenyl group, benzyl group, C group_1-10Any one of halogenated hydrocarbon group, halogenated phenyl group, halogenated benzyl group, nitrophenyl group, methoxycarbonyl group, ethoxycarbonyl group, phenoxycarbonyl group, benzyloxycarbonyl group, methylthiocarbonyl group, ethylthiocarbonyl group, phenylthiocarbonyl group, benzylthiocarbonyl group, ethylaminocarbonyl group, benzylaminocarbonyl group, methoxythiocarbonyl group, ethoxythiocarbonyl group, phenoxythiocarbonyl group, benzyloxythiocarbonyl group, methylthiothiocarbonyl group, ethylthiocarbonyl group, phenylthiocarbonyl group, benzylthiocarbonyl group, ethylaminothiocarbonyl group, benzylaminothiocarbonyl group, and benzylaminothiocarbonyl groupAn atom or group, or a substituted version of any group.

R₁₅Most preferably a hydrogen atom, a fluorine atom or a methyl group.

Taking the trivalent group of k ═ 2 as an example (trivalent G), the part other than the trivalent core structure does not comprise the trivalent group of heteroatoms, including but not limited to the groups described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and the respective cited groups. E.g., including but not limited to CN104530417A segment [0314 ]]～[0315]CN104877127A paragraph [0198]～[0199]Groups described and exemplified. Moieties other than trivalent nuclear structures include trivalent groups of heteroatoms including, but not limited to, groups described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A, and various cited groups. E.g., including but not limited to CN104530417A segment [0316 ]]～[0320]Section CN104877127A [0200 ]]～[0217]Groups described and exemplified. The above example is for better illustration of the set G³Middle trivalent radical, not to G set³Is limited in scope.

Taking the tetravalent group of k ═ 3 as an example (tetravalent G), the tetravalent group excluding the tetravalent core structure does not comprise heteroatoms, including but not limited to those described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and the respective cited groups. Including but not limited to those described and exemplified in paragraphs [0321] to [0323] CN104530417A and paragraph [0218] CN 104877127A. Moieties other than the tetravalent core structure include heteroatom tetravalent groups including, but not limited to, those described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and the respective cited groups. For example, CN104530417A corresponds to segments [0324] to [0325 ].

4.1.5. Spacer groups for the combination into terminal-branched groups

When k is greater than or equal to 3, i.e. the valence state of G is greater than or equal to 4, the set G^k+1The k + 1-valent radical in (A) contains a corresponding k + 1-valent cyclic core structure CC_k+1Or 2-k-1 low-valence groups with valence of 3-k are directly connected and combined or are connected and combined through 1 or more than 1 divalent spacer groups L₁₀Indirectly combined together. For example, when k is 3For tetravalent groups, 2 three groups can be combined; for pentavalent groups, the pentavalent group can be formed by combining 3 trivalent groups, and can also be formed by combining 1 trivalent group and 1 tetravalent group.

When containing two or more L₁₀And may be the same as or different from each other.

Said L₁₀There is no particular limitation. L is₁₀May or may not contain carbon atoms; l is₁₀May or may not contain heteroatoms; l is₁₀May be a subunit formed by a single atom, or may be a subunit composed of two or more atoms.

L₁₀May be a monoatomic subunit such as-O-or-S-, and may also be a secondary amino group or a divalent tertiary amino group.

L₁₀May be a hetero atom-free alkylene group, preferably having 1 to 20 carbon atoms, and particularly preferably C_1-20Alkylene radical, C_1-20Divalent alkenyl radical, C_1-20Divalent alkenylhydrocarbon group, C_1-20Divalent alkynyl radical, C_1-20Divalent alkynyl hydrocarbon group, C_1-20Divalent cycloalkyl radical, C_1-20Any one of a divalent cycloalkane group, a phenylene group, a divalent fused aryl group, and a divalent aromatic hydrocarbon group;

L₁₀may also be-N (R)₇)-、-C(＝O)-、-C(＝S)、-C(＝NH)-、--C(＝O)-N(R₇)-、-N(R₇)-C(＝O)-、-S-S-、-C(＝O)-O-、-O-C(＝O)-、-C(＝O)-S-、-S-C(＝O)-、-C(＝S)-O-、-O-C(＝S)-、-C(＝S)-S-、-S-C(＝S)-、-O-C(＝O)-O-、-S-C(＝O)-O-、-O-C(＝S)-O-、-O-C(＝O)-S-、-S-C(＝S)-O-、-O-C(＝S)-S-、-S-C(＝O)-S-、-S-C(＝S)-S-、-N(R₇)-C(＝O)-O-、-O-C(＝O)-N(R₇)-、-N(R₇)-C(＝S)-O-、-O-C(＝S)-N(R₇)-、-N(R₇)-C(＝O)-S-、-S-C(＝O)-N(R₇)-、-N(R₇)-C(＝S)-S-、-S-C(＝S)-N(R₇)-、-N(R₁₉)-N(R₁₈)-、-N(R₁₉)-C(＝O)-N(R₁₈)-、-N(R₁₉)-C(＝S)-N(R₁₈)-、-N(R₁₈)-N(R₁₉)-C(＝O)-、-C(＝O)-N(R₁₉)-N(R₁₈)-、-N(R₁₈)-N(R₁₉)-C(＝S)-、-C(＝S)-N(R₁₉)-N(R₁₈)-、-(R₁₅)C＝N-、-N＝C(R₁₅)-、-(R₁₅)C＝N-N(R₇)-、-N(R₇)-N＝C(R₁₅)-、-(R₁₅)C＝N-N(R₇)-C(＝O)-、-C(＝O)-N(R₇)-N＝C(R₁₅)-、-(R₁₅)C＝N-O-、-O-N＝C(R₁₅)-、-(R₁₅)C＝N-S-、-S-N＝C(R₁₅)-、-N＝N-、-N(R₁₈)-N(R₁₉)-C(＝O)-N＝N-、-N＝N-C(＝O)-N(R₁₉)-N(R₁₈)-、-N(R₁₈)-C(＝O)-N(R₁₉)-、-C(＝NR₇)-N(R₂₃)-、-N(R₂₃)-C(＝NR₇)-、-N(R₇)-C(＝NH₂ ⁺)-、-C(＝NH₂ ⁺)-N(R₇)-、-C(＝NR₇)-O-、-O-C(＝NR₇)-、-O-C(＝NH₂ ⁺)-、-C(＝NH₂ ⁺)-O-、-C(＝NR₇)-S-、-S-C(＝NR₇)-、-S-C(＝NH₂ ⁺)-、-C(＝NH₂ ⁺)-S-、-S(＝O)₂-O-、-O-S(＝O)₂-、-S(＝O)-O-、-O-S(＝O)-、-S(＝O)₂-N(R₇)-、-N(R₇)-S(＝O)₂-、-S(＝O)₂-N(R₁₈)-N(R₁₉)-、-N(R₁₉)-N(R₁₈)-S(＝O)₂-、-CH₂-O-、-O-CH₂-、-CH₂CH₂-O-、-O-CH₂CH₂-、-O-CH₂CH₂-O-、-O-R₂₉-、-R₂₉-O-、-O-R₂₉-O-and the like, or substituted forms thereof. Wherein R is₇、R₁₈、R₁₉、R₂₃、R₁₅The definitions of (a) and (b) are consistent with the above. Wherein R is₂₉Is selected from C_3-20An alkylene group, the structure of which is not particularly limited, and which may be a linear, branched or cyclic structure; r₂₉The number of carbon atoms of (C) is preferably C_3-12A hydrocarbyl group; r₂₉The structure of (A) is preferably a linear structure.

Said L₁₀More preferably, oxy, thio, secondary amino or divalent tertiary amino groups, in which case a stable linkage is formed. Said L₁₀Most preferably, an oxy group, such as an alcoholic hydroxyl group, is condensed with an alcoholic hydroxyl group to form an ether linkage.

L₁₀May also be-CH₂CH₂-O-、-O-CH₂CH₂-、-O-R₂₉-、-R₂₉-O-in any form of monodisperse multimers, the number of repeating units being selected from 2 to 20, preferably 2 to 10.

By way of example of tetravalent radicals with k ═ 3, the group G⁴The tetravalent radical in (A) can be formed from the group G, in addition to the tetravalent core structure³Any two trivalent groups in the composition. The combination may be a direct linkage, for example, a tetravalent group derived from erythritol may be considered to be a linkage of two trivalent groups. As another example, a tetravalent group formed by directly linking two molecular amino acids or their derivative backbones, and the like. The combination of the two or more may be by 1 or more divalent spacers L₁₀And (4) indirectly connecting. When set G⁴Wherein the tetravalent group contains two or more L₁₀And may be the same as or different from each other. Some common tetravalent groups of tetraols formed by condensation of two-molecule triols can be of the type linked by ether linkage spacers after removal of the hydroxyl or hydroxyl hydrogen atom.

Set G⁴The tetravalent groups in (a) include, but are not limited to, those described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and the respective cited documents. Including but not limited to CN104530417A segment [0321]～[0325]CN104530417A paragraph [0334]～[0339]CN104877127A paragraph [0229]～[0231]Groups described and exemplified.

The pentavalent group with k equal to 4 is taken as an example. Including but not limited to documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and groups described and exemplified in each of the cited documents. Including but not limited to CN104530417A section [0341]CN104877127A paragraph [0232]～[0233]Groups described and exemplified. Wherein the content of the first and second substances,

including but not limited to the pentavalent carbon skeleton of D-ribose, D-arabinose, D-xylose, D-lyxose. Pentavalent groups also include, but are not limited to, pentavalent backbone structures of six-membered cyclic monosaccharides such as glucose, allose, altrose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, tagatose, and the like.

Examples of the hexavalent group having k-5, the heptavalent group having k-6, and the octavalent group having k-7 are given. Including but not limited to documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and groups described and exemplified in each of the cited documents. Including but not limited to CN104530417A section [0342]～[0347]CN104877127A paragraph [0234 ]]Groups described and exemplified. Wherein hexavalent radical also includes, but is not limited to, (i)

(ii) A hexavalent carbon skeleton derived from inositol, sorbitol, mannitol, D-glucosamine, 1-mercaptosorbitol, N-methyl-D-glucosamine, tris (2, 3-dichloropropyl) phosphate or D-sorbitol 3-phosphate, from which 6 hydrogen atoms located at the hydroxyl group, amino group or/and mercapto group have been removed, (iii) a hexavalent carbon skeleton derived from D-allose, D-altrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose, D-talose, D-psicose, etc.

When k is more than or equal to 4, namely the valence state of G is more than or equal to 5, the divalent organic compound is formed by directly connecting and combining 3-k-1 low-valence groups with 3-k valence or by 1 or more than 1 divalent spacer L₁₀Set G of indirectly combined k +1 groups^k+1The combination of 3 to k-1 of the lower valent groups is not particularly limited. Including but not limited to documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and groups described and exemplified in each of the cited documents. Including but not limited to CN104530417A section [0348]～[0407]CN104877127A paragraph [0235]～[0236]Groups described and exemplified. Including but not limited to comb combinations, tree combinations, branched combinations, hyperbranched combinations, cyclic combinations, and the like. For comb-like, tree-like or hyperbranched groups formed by combining a plurality of low-valence groups, a plurality of groupsThe individual lower-valent groups may be the same as or different from each other, and are preferably combined from the same lower-valent group.

The composition set G^k+1(k is more than or equal to 4), the number of the low-valence groups in the k + 1-valence groups in the low-valence groups in the medium-valence groups in the comb combination mode, the tree combination mode, the branching combination mode, the hyperbranched combination mode and the cyclic combination mode is 3-150; preferably 3 to 100, more preferably 3 to 50. The tree combination mode is 2-6 generations; preferably 2 to 5 generations, more preferably 2,3 or 4 generations.

4.2. Examples of terminal branched structures G

The structure of G is not particularly limited and includes, but is not limited to, branched, cyclic-containing, comb-like, dendritic, hyperbranched, and the like types. G may be degradable or may exist stably.

L₀The divalent linking group, which is used to link the PEG segment to the terminal branched structure G, may or may not be present. L is₀May be stable or degradable. L is₀Can be selected from any suitable stably existing linker STAG or degradable linker DEGG disclosed in the present invention and the cited documents. STAG is preferred.

The terminal branching groups G of the functionalized eight-arm polyethylene glycol have the same structure type, such as a triple-branching structure, or a quadruple-branching structure, or a comb-like structure, or a tree-like structure, or a hyperbranched structure, or a cyclic structure. In the case of the same structure type, the structure of the eight PEG chain ends is not allowed to be completely identical. For example, for a comb structure, differences in valence states due to the non-uniform number of repeating units are allowed; for hyperbranched structures, the number of branching units is not required to be strictly uniform, but rather allows the branching units to be randomly linked. Therefore, in the same molecule, when the end of the PEG chain is a comb-shaped or hyperbranched structure, the k at the end can be different. For tree and ring structures, the structures are preferably identical, and the corresponding k is also identical. In addition, the invention also discloses the condition that when the tree structure and the ring structure are in the same structure type but not consistent k, such as the three-level tree structure

The eight terminal hydroxyl groups of (a) are further functionally modified, preferably at or near 100%, while other instances in which the degree of substitution is greater than 0 and less than 100% are also disclosed.

In the present invention, G is selected from the group including, but not limited to, any of the above-mentioned groups having a valence of k +1(k ═ 2 to 250). Preferred structures of G include, but are not limited to, the structures described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and the respective cited documents. Including but not limited to those described and exemplified in paragraphs [824] to [0825] of CN104530417A and paragraphs [0664] to [0683] of CN 104877127A.

4.2.1. Terminal reaction site k ═ 2

When the terminal reaction site k is 2, G is a trivalent group, including but not limited to the above group G³A trivalent group in (1). L is₀-G is preferably the middle part [0240 ] of document CN104877127A]～[0245]Section [0669 ]]Groups described and exemplified.

Said L₀G is equal in structure to the trivalent radical E₀Or contain E₀。

E₀Preferably contains

Any one of the trivalent nucleus structures. Wherein R is₁、R₃₇、M₅、M₆、M₇、M₂₃And M₅、M₆、M₇、M₂₃The definition of the ring is consistent with the above. M₁₉Is an oxygen atom or a sulfur atom.

E₀Selected from the group comprising, but not limited to, any of the trivalent radicals mentioned above, paragraph [0732 ] of document CN104530417A]～[0736]The trivalent radicals listed and preferred in (1).

E₀Preferably contains any of the following structures:

and the like.

E₀Further preferred are structures containing the above structure terminated with 1,2 or 3 divalent linking groups selected from the group consisting of oxy, thio, secondary amino, divalent tertiary amino and carbonyl groups, which may be the same or different. Wherein Q is₅Selected from a hydrogen atom, a substituent atom or a substituent group, is not particularly limited, and is preferably selected from a H atom, a methyl group, an ethyl group or a propyl group. When Q is₅When located on a ring, may be one or more. When the number is more than 1, the structures may be the same, or a combination of two or more different structures may be used. Q₅The ring includes, but is not limited to, fluorene, carbazole, norbornene, 7-oxa-bicyclo [2.2.1 ]]Hept-5-en-2-yl. By way of example, E₀May be selected from any of the following structures:

and the like. Q₅The definitions of (a) and (b) are consistent with the above.

E₀May also be selected from the trivalent skeleton structure of amino acids or derivatives thereof; wherein the amino acid is_L-type,_D-form or a mixture thereof. By way of example trivalent G may be derived from amino acids including but not limited to the following or derivatives thereof: amino acids containing hydroxyl or sulfur and their derivatives, serine, threonine, cysteine, leucine, hydroxyproline; acidic amino acids and their derivatives, aspartic acid, glutamic acid, asparagine, glutamine; basic amino acids and their derivatives, lysine, arginine, citrulline, histidine, tryptophan.

L₀G may also be selected from

And the like.

4.2.2. Terminal reaction site k ═ 3

When the terminal reaction site k is 3, G is a tetravalent group, including but not limited to the above group G⁴A tetravalent group of (1); tetravalent G preferably contains the atom CM₄And unsaturated bond CB₄Ring structure CC₄Either tetravalent core structure, or contains two trivalent core structures. L is₀-G further preferably comprises any of the following structures:

and the like.

Wherein, X₁A hydrogen atom, a hydroxy-protecting group or a group LG for attachment to an oxy group₄。

When it is a hydroxyl protecting group, X₁Is selected from PG₄Hydroxyl protecting groups in the combinations listed. The protected hydroxyl group is designated as OPG₄. The hydroxyl protecting group is not particularly limited.

Wherein LG is₄The number of carbon atoms of (a) is not particularly limited. LG (Ligno-lead-acid)₄The number of carbon atoms of (A) is preferably 1 to 20, more preferably 1 to 10.

LG₄The structure of (a) is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. Among them, the cyclic structure is not particularly limited, and the above-mentioned aliphatic ring, aromatic ring, sugar ring, and condensed ring are preferable.

LG₄May or may not contain heteroatoms.

LG₄Is selected from C_1-20Hydrocarbyl radical, C_1-20Heterohydrocarbyl, substituted C_1-20Any one of a hydrocarbon group and a substituted heterohydrocarbon group. Wherein LG is₄The substituted heteroatom or substituent in (1) is not particularly limited, including but not limited to any substituted heteroatom or any substituent of the term moiety selected from any of halogen atoms, hydrocarbyl substituents, heteroatom-containing substituents.

LG₄More preferably C_1-20Alkyl radical, C_1-20Unsaturated aliphatic, aryl, C_1-20Heterohydrocarbyl radical, C_1-20Fatty hydrocarbyl acyl radical, C_1-20Lipoheteroalkylacyl, arylacyl, heteroarylacyl, C_1-20Hydrocarbyloxyacyl group, C_1-20Hydrocarbyl thioacyl, C_1-20Hydrocarbyl aminoacyl radical, C_1-20Heterohydrocarbyloxyacyl group, C_1-20Heterocarbylthioacyl radical, C_1-20Any one group or substituted version of any one group of a heterocarbylaminoacyl group. Wherein LG is₄The acyl group in (1) is not particularly limited, including but not limited to any acyl type of the term moiety. By way of example, LG₄The acyl group in (1) may be selected from a carbonyl group, a sulfonyl group, a sulfinyl group, a phosphoryl group, a hypophosphoryl group, a nitroxyl group, a nitrosyl group, a thiocarbonyl group, an imidoyl group, a thiophosphoryl group, a dithiophosphoryl group, a trithiophosphoryl group, a thiophosphorous group, a dithiophosphoryl group, a thiophosphoryl group, a dithiophosphoryl group, a thiophosphoryl group and the like. Any of acyl groups such as a carbonyl group, a thiocarbonyl group, a sulfonyl group, and a sulfinyl group is preferable. LG (Ligno-lead-acid)₄The acyl group is more preferably a carbonyl group, thiocarbonyl group or sulfonyl group.

LG₄More preferably C_1-20Alkyl radical, C_3-20Alkylene, aryl, aralkyl, C_1-20Heteroalkyl, heteroaryl, heteroaralkyl, C_1-20Alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, C_1-20Heteroalkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, C_1-20Alkoxycarbonyl radicalAryloxycarbonyl, aralkyloxycarbonyl, C_1-20Alkylthio-carbonyl, arylthio-carbonyl, aralkylthiocarbonyl, C_1-20Alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, C_1-20Heteroalkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, C_1-20Heteroalkylthio-carbonyl, heteroarylthio-carbonyl, heteroaralkylthio-carbonyl, C_1-20Heteroalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylalkylaminocarbonyl, C_1-20Alkylthio, arylthio, aralkylthiocarbonyl, C_1-20Heteroalkylthiocarbonyl, heteroarylthiocarbonyl, heteroarylalkylthiocarbonyl, C_1-20Alkoxythiocarbonyl, aryloxylthiocarbonyl, aralkyloxythiocarbonyl, C_1-20Alkylthio thiocarbonyl, arylthio thiocarbonyl, aralkylthio thiocarbonyl, C_1-20Alkylaminothiocarbonyl, arylaminothiocarbonyl, aralkylaminothiocarbonyl, C_1-20Heteroalkyloxythiocarbonyl, heteroaryloxythiocarbonyl, heteroarylalkoxythiocarbonyl, C_1-20Heteroalkylthio thiocarbonyl, heteroarylthio thiocarbonyl, heteroarylalkylthio thiocarbonyl, C_1-20A heteroalkylaminothiocarbonyl group, a heteroarylaminothiocarbonyl group, or a substituted version of any group.

LG₄More preferably C_1-20Alkyl radical, C_3-20Alkylene, aryl, aralkyl, C_1-20Any one group or substituted version of any one group of heteroalkyl, heteroaryl, heteroaralkyl.

Specifically, LG₄Selected from the group consisting of, but not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, allyl, benzyl, trityl, benzyl, methylbenzyl, 1-ethoxyethyl, methoxyethoxymethyl, benzyloxymethyl, methylthio, benzyl, ethoxyethyl, ethoxymethylMethyl, tetrahydropyranyl, acetyl, benzoyl, methoxyacyl, ethoxyacyl, t-butyloxyacyl, phenoxyacyl, benzyloxyacyl, methylthioacyl, ethylthioacyl, t-butylthioacyl, phenylthioacyl, benzylthioacyl, methylaminoacyl, ethylaminoacyl, t-butylaminoacyl, benzylaminoacyl, and the like, or a substituted form of any of these groups. Wherein, butyl includes but is not limited to n-butyl and tert-butyl. Octyl includes, but is not limited to, n-octyl, 2-ethylhexyl. The substituent atom or substituent is selected from any one of a halogen atom, a hydrocarbon substituent and a heteroatom-containing substituent, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkoxy group, an alkenyl group or a nitro group.

LG₄More preferred is methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, allyl, trityl, phenyl, benzyl, methylbenzyl, 1-ethoxyethyl, methoxyethoxymethyl, benzyloxymethyl, methylthiomethyl, tetrahydropyranyl, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, tert-butylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, tert-butylaminocarbonyl, benzylamino-carbonyl, ethylthiocarbonyl, tert-butylaminocarbonyl, benzylthiocarbonyl, tert-butylaminocarbonyl, or a, Methylthiocarbonyl, ethoxythiocarbonyl, tert-butyloxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, methylthiothiocarbonyl, ethylthiothiocarbonyl, tert-butylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiocarbonyl, methylaminothiocarbonyl, ethylaminothiocarbonyl, tert-butylaminothiocarbonyl, benzylaminothiocarbonyl, C_1-10Halogenated hydrocarbon group, trifluoroacetyl group, halogenated phenyl group, halogenated benzyl group, nitrobenzyl group, p-methoxybenzyl group, trifluoromethylbenzyl group, etcA group or a substituted form of any one of the groups. Among them, the substituent atom or the substituent is preferably a fluorine atom, an alkoxy group or a nitro group.

LG₄More preferably, it is any of methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, allyl, trityl, phenyl, benzyl, 1-ethoxyethyl, 2-ethoxyethyl, methoxyethoxymethyl, benzyloxymethyl, methylthiomethyl, tetrahydropyranyl, nitrobenzyl, p-methoxybenzyl, trifluoromethylbenzyl, tert-butyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, acetyl, trifluoroacetyl and the like.

LG₄More preferably, it is any of methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, allyl, trityl, phenyl, benzyl, nitrobenzyl, p-methoxybenzyl, trifluoromethylbenzyl, and the like.

LG₄Most preferred is methyl, ethyl, allyl or benzyl.

4.2.3. Terminal reaction site k >3

Terminal reaction site k>At 3, i.e. the valence of G>At 4, a K +1 valent G includes, but is not limited to, the above-mentioned group G^k+1The k + 1-valent group in (1). The G with the valence of k +1 can contain 1 nuclear structure with the valence of k +1, or is formed by directly connecting and combining 2-k-1 low-valence groups with the valence of 3-k or is formed by 1 or more than 1 divalent spacer groups L₁₀Indirectly combined together. The 3 to k-valent lower groups may be the same or different, and the valences thereof may be the same or different. For example: two different trivalent groups are combined

For a k +1 valent core structure, when k.gtoreq.4, and when a k +1 valent core structure is contained, the k +1 valent core structure is preferably a cyclic structure. When containing two or more L₁₀When L is₁₀May be the same as or different from each other. L is₁₀The definitions of (a) and (b) are consistent with the above.

The direct or indirect combination of K +1(k is more than or equal to 4) G, the combination mode includes but is not limited to comb combination mode, tree combination mode, branched combination mode, hyperbranched combination mode, cyclic combination mode, etc. For example, in the case of a comb-like, tree-like or hyperbranched group in which a plurality of low-valent groups are combined, the plurality of low-valent groups may be the same as or different from each other, and are preferably combined from the same low-valent group.

Wherein, the tree-like combination structure formed by the tree-like combination mode is DENR (U)_denrNONE, d) or DENR (U)_denr,L₁₀D) represents U_denrRepresents a polyvalent radical repeating unit, NONE represents a direct linkage of polyvalent repeating units, L₁₀Denotes a polyvalent repeating unit via a divalent linking group L₁₀Indirectly connected, d represents the generation of a tree combination mode, d is preferably 2-6 generations, more preferably 2-5 generations, and most preferably 2,3 or 4 generations. Among them, the basic unit of the polyvalent G constituting the tree-like composite structure is preferably trivalent G or tetravalent G.

Examples of the tree-like composite structure are

And the like. Wherein ng represents the algebra of the tree combination mode.

Among them, the basic unit of the polyvalent G constituting the branched or hyperbranched composite structure is preferably trivalent G or tetravalent G. The preferred basic units include, but are not limited to, the tree combination method described above, and further include

And the like. The branched or hyperbranched composite structure differs from the above-described dendritic composite structure in that it is a mixed combination of multivalent G and its lower valent form. Lower forms of said polyvalent G, for example

Is selected from

Among them, the basic unit of the polyvalent G constituting the comb-like composite structure is preferably trivalent G, tetravalent G or pentavalent G. Preferred are the repeating units described in the stages [824] to [0825] of CN104530417A, and the stages [1130] and [1143] of CN 104530413A. The basic units of the polyvalent G constituting the comb-like composite structure include, but are not limited to, polyglycerin, polypentaerythritol, substituted propylene oxide, a group of substituted propylene oxide and carbon dioxide, acrylate and derivatives thereof, methacrylate and derivatives thereof, acetal structure-containing basic units (e.g., (1 → 6) β -D glucopyranoside), hydroxyl or thio group-containing amino acids and derivatives thereof, acidic amino acids and derivatives thereof, basic amino acids and derivatives thereof, and the like. G may be acetalized dextran formed by connecting D-glucopyranose units end to end via any of the glycosidic linkages such as β -1,6 glycosidic linkage, α -1,6 glycosidic linkage, β -1,4 glycosidic linkage, α -1,4 glycosidic linkage, β -1,3 glycosidic linkage, and α -1,3 glycosidic linkage, or an oxidized form of the above multimer. The repeating units of the comb-like composite structure may also be in the form of suitable trihydric alcohols, suitable tetrahydric alcohols, open chain pentitols, open chain hexitols, the corresponding starting materials preferably being in any form in which the hydroxyl groups other than the hydroxyl groups of the ether bond are protected, such as glycerol, trimethylolethane, trimethylolpropane.

Among them, the polyvalent G in cyclic combination is preferably a residue of a cyclic peptide or a derivative thereof, a residue of a cyclic monosaccharide or a derivative thereof, a residue of a cyclic polysaccharide or a derivative thereof (e.g., a functionalized derivative of cyclodextrin), a skeleton of 1,4, 7-tri-t-butoxycarbonyl-1, 4,7, 10-tetraazacyclododecane, a skeleton of 2-hydroxymethylpiperidine-3, 4, 5-triol, a skeleton of 6-amino-4- (hydroxymethyl) -4-cyclohexyl- [4H,5H ] -1,2, 3-triol, or the like.

For example, when the terminal reactive site k is 4, G is a pentavalent group, including but not limited to the above-mentioned group G⁵A pentavalent group in (1). Pentavalent G can include 1 pentavalent nuclear structure, 1 tetravalent nuclear structure, and 1 trivalent nuclear structure,or 3 trivalent nuclear structures. L is₀-G preferably contains any one of the following structures:

a dendritic structure formed by directly or indirectly combining 3 trivalent G, a comb-shaped structure formed by directly or indirectly combining 3 trivalent G, and the like. Among them, examples of the dendritic structure in which 3 trivalent gs are directly or indirectly combined include a structure in which d is 2 as described above. Comb structure formed by directly combining 3 trivalent groups, including but not limited to a trilysine skeleton, a triglutamic acid skeleton, a tripolyaspartic acid skeleton, a triglycerol skeleton, etc., such as

(ii) a A comb structure formed by indirectly combining 3 trivalent groups, such as three lysines combined by taking amino acids such as glycine, alanine and the like as spacers.

For example, when the terminal reaction site k is 5, G is a hexavalent group, including but not limited to the above set G⁶The hexavalent group of (1). Hexavalent G may include 1 hexavalent core structure, 1 pentavalent core structure and 1 trivalent core structure, 2 tetravalent core structures, 1 tetravalent core structure and 2 trivalent core structures, or 4 trivalent core structures. L is₀-G preferably contains any one of the following structures: a comb structure composed of 4 trivalent G groups (e.g., tetrapolyglycerol, tetrapolylysine, tetrapolyaspartic acid, tetrapolyglutamic acid, etc.),

and the like.

4.3. Functional group (F)

The following description is made for the case where F is not a hydrogen atom, and in this case, contains a functional group R₀₁。

4.3.1. Functional group R₀₁Definition of (1)

R₀₁Is a functional group capable of interacting with biologically relevant substances. The interaction with the bio-related substance includes, but is not limited to, formation of covalent bonds, formation of hydrogen bonds, fluorescence, and targeting. R₀₁Selected from reactive groups, variations of reactive groups, functional groups with therapeutic targeting properties, functional groups with fluorescent properties. The reactive group is reactive, forms a linkage by a bonding reaction with a bio-related substance, and mainly means a reaction of forming a covalent bond, and when forming a non-covalent linkage, performs a complex through a double hydrogen bond or multiple hydrogen bonds. The covalent bond includes, but is not limited to, a covalent bond that can exist stably, a degradable covalent bond, and a dynamic covalent bond. Such variations include, but are not limited to, precursors to reactive groups, reactive forms that are precursors thereto, substituted reactive forms, protected forms, deprotected forms, and the like. The precursor of the reactive group refers to a structure which can be converted into the reactive group through at least one process of oxidation, reduction, hydration, dehydration, electronic rearrangement, structural rearrangement, salt complexation and decomplexing, ionization, protonation, deprotonation and the like. The precursor may be reactive or non-reactive. The modified form of the reactive group refers to a form (still reactive group) in which a reactive group remains active after at least one process of oxidation, reduction, hydration, dehydration, electronic rearrangement, structural rearrangement, salt complexation and decomplexing, ionization, protonation, deprotonation, substitution, deprotection, and the like, or a non-active form after being protected. Fluorescent functional groups can be classified as fluorescent functional groups as long as the fluorescent functional groups can emit fluorescence, or can emit fluorescence through in vivo microenvironment action (such as fluorescein diacetate) or can emit fluorescence through clinical stimulation (such as light stimulation, thermal stimulation and the like). The dynamic covalent bond includes, but is not limited to { Top Curr Chem (2012)322:1-32}, { Top Curr Chem (2012)322:291-em.int.ed.2002,41, 898-; 177-.

R₀₁Including but not limited to groups A through H or variations thereof, groups R₀₁Is a reactive group or a variant thereof is a reactive group.

Class A: active ester groups (including but not limited to succinimide active esters (e.g., A1, A6), p-nitrophenyl active esters (e.g., A2, A7), o-nitrophenyl active esters (e.g., A11, A12), benzotriazole active esters (e.g., A5, A10), 1,3, 5-trichlorobenzene active esters (e.g., A3, A8), fluorophenyl active esters (e.g., A13, e.g., 1,3, 5-trifluorobenzene active esters, pentafluorobenzene active esters), imidazole active esters (e.g., A4, A9)), and active ester groups of similar structure A16-A18 (e.g., 2-thione-3-thiazolidinecarboxylate (tetrahydrothiazole-2-thione-N-formate), 2-sulfoxothiazolidine-3-carboxylate, 2-thiopyrrolidine-N-formate, N-thiopyrrolidine-carboxylate, and mixtures thereof, 2-thiobenzothiazole-N-formate, 1-oxo-3-thiooxoisoindoline-N-formate, etc.);

class B: sulfonate, sulfinate, sulfone, sulfoxide, 1, 3-disulfonyl-2-propylcarbonylphenyl, sulfone methacryl, and the like;

class C: hydroxylamine, mercapto, amino (primary amino, such as C4, or secondary amino, such as C5, C15), halogen atoms, haloacetamido (such as iodoacetamido), tetramethylpiperidinyloxy, dioxopiperidinyloxy (3, 5-dioxo-1-cyclohexylamine-N-oxy), ammonium salts (amine salts), hydrazine, disulfide/disulfide compounds (such as linear orthopyridyl disulfide, and the like, such as cyclic lipoic acid, and the like), C17 (ester, thioester), C18 (carbonate, thiocarbonate, dithiocarbonate, trithiocarbonate/trithiocarbonate), C19 (hydroxylamine amide), xanthate, peroxythiocarbonate, tetrathiodiester, O-carbonylhydroxylamine, amide, imide, hydrazide, sulfonylhydrazide, hydrazone, imine, enamine, alkynylamine, protected hydroxy or mercapto (carbamate), hydroxyl or mercapto (hydroxylamine), or a salt thereof, Monothiocarbamates, dithiocarbamates), protected amino groups (carbamates, monothiocarbamates, dithiocarbamates), and the like;

class D: carboxy, sulfo, sulfenyl, hydroxamic, thiohydroxamic, xanthic, acyl halide, sulfonyl chloride, aldehyde, glyoxal, acetal, hemiacetal, aldehyde hydrate, ketone, ketal, hemiketal, ketal, ketone hydrate, orthoester, cyanate, thiocyanate, isonitrile ester, isothiocyanate, ester, oxycarbonyloxide, dihydrooxazole (oxazoline D13, isoxazoline), thioaldehyde, thione, thioacetal, thioketone hydrate, thioketal, hemithioketal, thioester (e.g., D26), thioester (e.g., D27), bisthioester (e.g., D18), thiohemiacetal, monothiomonohydrate, dithiohydrate, thiol hydrate, thiocarboxylic [ monothiocarboxylic acid (thiocarbonyl D16 or thiol D15), dithiocarboxylic acid D17], ureido, thioureido, guanidino and protonated forms thereof, amidino and protonated forms thereof, Acid anhydrides, squaric acids, squarates, hemisquaric acids, hemisquarates, N-carbamoyl-3-imidazoles or N-carbamoyl-3-methylimidazolium iodide, imidines, nitrones, oximes, ureas, thioureas, pseudoureas, and the like;

class E: maleimides, acrylates, N-acrylamides, methacrylates, N-methacrylamides, protected maleimides (e.g. E5), maleamic acid, 1,2, 4-triazoline-3, 5-diones, azo groups (e.g. linear azo compounds, cyclic E7, etc.), cycloalkene groups (e.g. cyclooctene, norbornene, 7-oxa-bicyclo [2.2.1 ] etc.)]Hept-5-en-2-yl, bicycloheptadiene/2, 5-norbornadiene, 7-oxabicycloheptadiene, etc.), and the like, wherein W in E13₃Including but not limited to halogen, PhS-, etc. leaving groups;

class F: epoxy groups (glycidyl ether groups), alkenyl groups (including vinyl groups, propenyl groups, etc.), alkenyl hydrocarbon groups (such as allyl groups, etc.), alkynyl groups (such as propynyl groups), alkynyl hydrocarbon groups (such as propargyl groups), etc.;

the class of the signal is a class G,

class Ga: cycloalkynyls or cycloalkynheteroalkyls (e.g., G1, G2, G3, G4, G7, G8, G9, G10), conjugated dienes (e.g., linear butadienyl, such as cyclic cyclopentadiene), hybrid conjugated dienes (e.g., furan), 1,2,4, 5-tetrazinyl, and the like;

class Gb: azido, nitrile oxide/cyanide oxide, cyano, isocyano, aldoxime, diazo, diazonium ion, azoxy, nitrilimine, aldimine N-oxide, tetrazole, 4-acetyl-2-methoxy-5-nitrophenoxy (G31) and diazotized forms thereof (G32), and the like; other functional groups capable of undergoing 1, 3-dipolar cycloaddition are also included in the present invention;

class H: a hydroxyl group (including but not limited to alcoholic hydroxyl, phenolic hydroxyl, enolic hydroxyl, hemiacetal hydroxyl, and the like), a protected hydroxyl group, a siloxy group, a protected dihydroxy group, a trihydroxysilyl group, a protected trihydroxysilyl group, and the like;

functional groups related to the click reaction reported in and cited in adv.funct.mater, 2014,24,2572 are incorporated herein by reference. CN is its oxidized form C ≡ N⁺O^-A precursor of (2), -NH₂Is ammonium ion-NH₃ ⁺Amine salt-NH₂HCl precursor-COOH is its sodium salt-COONa, anion-COO^—G25 and G26 are precursors of each other, G5 and G6 are precursors of G2 and G3, respectively, and G31 is a precursor of G32, and the like. Protected forms include, but are not limited to, protected hydroxyl (e.g., H2), protected dihydroxy (e.g., H3), protected trihydroxy (e.g., H5), protected orthocarbonic acid (D8), protected thiol (e.g., C2), protected amino (e.g., C6, C16), protected carboxy (e.g., D11), protected aldehyde (e.g., D7), protected maleimide (e.g., E4), protected alkynyl (e.g., F4), and the like. Substituted forms are also included in A13, A14, E9-E12. -NH (C ═ NH)₂ ⁺)NH₂Is a protonated form of the guanidino group. One functional group can belong to both subcategories simultaneously. The ortho-pyridyl disulfide in C13 is also a protected form of the sulfhydryl group. C9 is both a protected amino group and a protected dihydroxy H3. Esters, thioesters of C17, and carbonates or thiocarbonates of C18 also belong to the group of protected hydroxy or mercapto groups。

4.3.2. The use of the above functional groups (including variations thereof) includes, by way of example, but is not limited to:

groups of class a can be modified with amino groups to form amide or carbamate linkages.

The sulfonic acid ester or sulfinic acid ester in the group of the B can be used for alkylation modification, and the group containing a sulfone group or a sulfoxide group can be used for modification of a sulfydryl group or a disulfide bond.

C-like groups are also frequently present at modified sites of biologically relevant substances, such as sulfhydryl groups, amino groups, disulfide bonds, etc. Within this class are predominantly groups with similar reactivity (e.g., hydroxylamine, hydrazine), protected forms, salt forms, and the like, and in addition include readily leaving halogens, and the like. C10 such as iodoacetamide may also be modified with a thiol group. C13 and C14 may also belong to the protected mercapto group C3. Typical examples of C14 are lipoic acid.

Groups of class D or deprotected forms may be reactive with hydroxyl groups or groups of class C, such as D1-D6, D9, D10, D12, D13, D14-D16, D19, D20, D21, D22, D23, D25, D29, or deprotected forms of D7, D8, D11, D18, D24, D26-D28, with appropriate groups of amino, mercapto, hydroxyl, or halo. Groups in class D may also react with other groups in this class, for example D25 may react with D1 and D13 may react with D1, D4. Wherein, the guanidyl can form a dihydrobond with two carbonyl groups of the tanshinone IIa.

Groups of class E contain α, β -unsaturation and can undergo 1, 2-addition reactions, for example with amino groups in class C, mercapto groups, and hydroxyl groups in class H. E13 can also undergo a substitution reaction with a dimercapto group.

The F-like groups, the most common structures of which have similarities in preparation methods, can be obtained by substitution reactions of the corresponding halides. The epoxy group includes, but is not limited to, a dihydroxy group exposed by ring opening, a ring-opening addition reaction with an amino group, and the like. The alkenyl group of F2 may undergo an addition reaction. F3 and deprotected F4 are common groups for click reactions.

The groups of the class G can carry out click reaction and are divided into two subclasses of Ga and Gb, cycloalkyne and precursor thereof in Ga, conjugated diene and 1,2,4, 5-tetrazine group can carry out cycloaddition or Diels-Alder addition reaction, and allyl, propargyl, allene and other groups in Gb can carry out 1, 3-dipolar cycloaddition reaction. In addition, G31 can be converted into a reactive group represented by G32 by treatment with hydrazine or the like, and G32 can react with a carboxyl group to form an ester bond.

H-like groups are hydroxyl, dihydroxy, trihydroxy, or any protected form thereof, and are important functional modifications of the present invention as the starting group (e.g., from the PEG terminus), and groups containing hydroxyl groups or their deprotonated forms are also necessary constituents of the initiator core for initiating ethylene oxide polymerization in the present invention. The hydroxyl group in class H may also be present at the modified site of the biologically relevant substance. In addition, H6, H7 can be converted to enolic hydroxyl under light conditions, which in turn can undergo addition reactions with α, β -unsaturated bonds as in class E.

R₀₁Or does not react with the biologically relevant substance, and has special functions, including two types of functional groups, namely a targeting group and a fluorescent group, or substituted forms thereof. The substituted forms need to still have the corresponding special function and can be classified as corresponding targeting groups and fluorescent groups. Such R₀₁Including but not limited to class I to class J:

class I: targeting groups and pharmaceutically acceptable salts thereof, such as folic acid and derivatives thereof, cholesterol and derivatives thereof, biotin and derivatives thereof, and the like. Derivatives of biotin such as D-desthiobiotin, 2-iminobiotin and the like.

Class J: examples of the photosensitive group or the fluorescent group include phthalocyanine complexes, fluorescein, rhodamine, anthracene, pyrene, coumarin, fluorescein 3G, carbazole, imidazole, indole, alizarin violet, and any of the above functional derivatives. The derivatives of rhodamine include, but are not limited to, tetramethylrhodamine, tetraethylrhodamine (rhodamine B, RB200), rhodamine 3G, rhodamine 6G (rhodamine 590), 5-carboxy-X-rhodamine, 6-carboxy-X-rhodamine, sulforhodamine B, sulforhodamine G, sulforhodamine 101, rhodamine X (R101), rhodamine 101, rhodamine 110, rhodamine 123, rhodamine 700, rhodamine 800, and the like, and further include, but are not limited to, the rhodamine derivatives described in the document { Progress in Chemistry,2010,22(10):1929-1939} and citations thereof.

In the present invention, - (Z)₁)_q1-R₀₁Functional groups as a whole. Among them, functional groups such as active ester, amino group, aldehyde group, carboxyl group, acid halide, acid anhydride, cyano group, alkynyl group, hydroxyl group and the like include, but are not limited to, groups described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN 104530417A. Including but not limited to CN104530417A paragraph [0423]～[0432]CN104877127A paragraph [0280]～[0505]Are listed. In general terms, the use of a single,

such as R₀₁When it is an active ester, - (Z)₁)_q1-R₀₁Including, but not limited to, carbonates, acetates, propionates, butyrates, valerates, caproates, heptanoates, caprylates, pelargonates, caprates, oxalates, malonates, methyl malonates, ethyl malonates, butyl malonates, succinates, 2-methyl succinate, 2-dimethyl succinate, 2-ethyl-2-methyl succinate, 2, 3-dimethyl succinate, glutarates, 2-methyl glutarates, 3-methyl glutarates, 2-dimethyl glutarates, 2, 3-dimethyl glutarates, 3-dimethyl glutarates, adipates, pimelates, suberates, azelates, sebacates, maleates, fumarates, amino acid esters, and mixtures thereof, Polypeptide acid ester, polyamino acid ester, etc.

Such as R₀₁When it is amino, - (Z)₁)_q1-R₀₁Including primary amino groups obtained by the primary amine losing non-amino hydrogen atoms or secondary amino groups obtained by the primary amine losing amino hydrogen atoms, and secondary amino groups obtained by the secondary amine losing non-amino hydrogen atoms. The primary amines include, but are not limited to, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, cyclohexylamine, aniline, and the like. The secondary amines include, but are not limited to, dimethylamine, diethylamine, dipropylamine, dibutylamine, dipentylamine, dihexylamine, diheptylamine, dioctylamine, dicyclohexylamine, N-methylaniline, N-ethylaniline, N-propylaniline, N-Isopropylaniline, N-butylaniline, N-cyclohexylaniline, azetidine, pyrrolidine, piperidine and the like. - (Z)₁)_q1-R₀₁It may also be an amino acid, an amino acid derivative, an omega-aminocarboxylic acid (e.g., beta-alanine, gamma-butylamino acid, delta-pentylamino acid, epsilon-hexylamino acid, etc.), a polypeptide or a polypeptide derivative, which has lost the C-carboxyl group or the hydroxyl group of a pendant carboxyl group, in which case R is a residue formed by loss of the C-carboxyl group or the hydroxyl group of a pendant carboxyl group₀₁Is an N-amino group or an amino group located in a side group.

Such as R₀₁When it is an aldehyde group, - (Z)₁)_q1-R₀₁Including monovalent functional groups corresponding to aldehyde compounds lacking a non-aldehyde hydrogen atom (excluding formaldehyde). The aldehyde-based compound includes, but is not limited to, formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, valeraldehyde, caproaldehyde, heptaldehyde, caprylic aldehyde, nonanal, decanal, crotonaldehyde, acrolein, methacrolein, 2-ethylacroldehyde, monochloroacetaldehyde, iodoacetaldehyde, dichloroacetaldehyde, benzaldehyde, phenylacetaldehyde, tolualdehyde, cinnamaldehyde, nitrocinnamaldehyde, bromobenzaldehyde, chlorobenzaldehyde, and the like. When 2 or more than 2 structural forms such as isomers exist, any one of the structural forms may be adopted. By way of example, the butyraldehyde includes, but is not limited to, n-butyraldehyde, isobutyraldehyde (including 2-methylpropionaldehyde), 2-dimethylacetal.

Such as R₀₁When it is a carboxyl group, - (Z)₁)_q1-R₀₁Comprises univalent functional groups corresponding to monoacid after one non-carboxyl hydrogen atom is lost, and univalent functional groups obtained by removing one molecular of hydroxyl from diacid. The monobasic acids include, but are not limited to, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, arachidic acid, heneicosanoic acid, behenic acid, isobutyric acid, 3-methylbutyric acid, acrylic acid, methacrylic acid, citric acid, vinylacetic acid, tiglic acid, 6-heptenoic acid, itaconic acid, citronellac acid, monochloroacetic acid, dichloroacetic acid, monofluoroacetic acid, difluoroacetic acid, benzoic acid, methylbenzoic acid, monofluorobenzoic acid, ethoxybenzoic acid, methoxybenzoic acid, ethylbenzoic acid, vinylbenzoic acid, propylbenzoic acid, 2-isopropylbenzoic acid, 2-butylbenzoic acid, 2-isobutylbenzoicBenzoic acid, carbamoylmaleic acid, N-phenylmaleic acid, maleamic acid, arachidonic acid, tetracosanoic acid, arachidonic acid (nervonic acid), glycolic acid, lactic acid, isonicotinic acid, ascorbic acid, gentisic acid, gluconic acid, uronic acid, sorbic acid, N- (omega-aminocarboxylic acid) group and the like. The dibasic acids include, but are not limited to, oxalic acid, malonic acid, methyl malonic acid, ethyl malonic acid, butyl malonic acid, succinic acid, 2-methylsuccinic acid, 2-dimethylsuccinic acid, 2-ethyl-2-methyl-succinic acid, 2, 3-dimethylsuccinic acid, glutaric acid, 2-methylglutaric acid, 3-methylglutaric acid, 2-dimethylglutaric acid, 2, 3-dimethylglutaric acid, 3-dimethylglutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, oxaloacetic acid, dimethylmalonic acid, isopropylmalonic acid, benzylmalonic acid, 1-epoxydicarboxylic acid, 1-cyclobutyldicarboxylic acid, dibutylmalonic acid, ethyl (1-methylpropyl) malonic acid, Ethyl (1-methylbutyl) malonic acid, ethyl (isopentyl) malonic acid, phenylmalonic acid, 2-oxoglutaric acid, 3-oxoglutaric acid, 5-norbornene-endo-2, 3-dicarboxylic acid, 1, 4-cyclohexanedicarboxylic acid, 1, 3-cyclohexanedicarboxylic acid, 1, 2-cyclohexanedicarboxylic acid, pyrrolidine-3, 4-dicarboxylic acid, camphoric acid, chlorendic acid, cyclic acid, 5-methylisophthalic acid, phthalic acid, 4-methyl-1, 2-benzenedicarboxylic acid, 4-chlorophthalic acid, 3, 4-pyridinedicarboxylic acid, 2, 3-pyridinedicarboxylic acid, 2, 4-pyridinedicarboxylic acid, 3, 5-pyridinedicarboxylic acid, 2, 6-pyridinedicarboxylic acid, 2, 4-dimethylpyrrole-3, 5-dicarboxylic acid, pyridine-2, 3-dicarboxylic acid, 5-methylpyridine-2, 3-dicarboxylic acid, 5-ethylpyridine-2, 3-dicarboxylic acid, 5-methoxymethyl-2, 3-pyridinedicarboxylic acid, 4, 5-pyridazinedicarboxylic acid, 2, 3-pyrazinedicarboxylic acid, 5-methylpyrazine-2, 3-dicarboxylic acid, 4, 5-imidazoledicarboxylic acid, 2-propylimidazoledicarboxylic acid, biphenyldicarboxylic acid, 4 '-diphenylethylenedicarboxylic acid, 2, 7-naphthalenedicarboxylic acid, 4' -diphenyletherdicarboxylic acid, 2 '-bipyridine-5, 5' -dicarboxylic acid, 2 '-bipyridine-3, 3' -dicarboxylic acid, 4-pyrone-2, 6-dicarboxylic acid, catechol-O, O' -diacetic acid, thiophene-2, 3-dicarboxylic acid, 2, 5-thiophenedicarboxylic acid, 2, 5-dicarboxylic acid-3, 4-ethylenedioxythiophene, 1, 3-acetonedicarboxylic acid, itaconic acid, 2-methyl-2-butenedioic acid (citraconic acid and mesaconic acid), 1, 3-butadiene-1, 4Dicarboxylic acids, butynedioic acids, norbornene-2, 3-dicarboxylic acids (bicyclo [ 2.2.1)]Hept-5-ene-2, 3-dicarboxylic acid), bicyclo [2.2.1]Hept-2-ene-2, 3-dicarboxylic acid, diglycolic acid, dithiol dihydroxyacetic acid, malic acid, tartaric acid, 2, 3-dimercaptosuccinic acid, 2, 3-dibromosuccinic acid, pyrazololytic acid, 4' -dichloro-2, 2' -dicarboxybiphenyl, 4' -dibromo-2, 2' -dicarboxybiphenyl, glucaric acid, saccharonic acid, pamoic acid, 2-bromosuccinic acid, 2-mercaptosuccinic acid, 1, 3-adamantanedicarboxylic acid, 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylic acid, carbonylmalonic acid, ethoxymethylidene-malonic acid, 3' -dithiodipropionic acid, 5-exo-methyl-2-norbomene-5, 6-endo-cis-dicarboxylicacid, acetylmalonic acid, and the like. The structure comprises various isomeric forms such as cis form, trans form, D form, L form and the like, for example, malic acid comprises D form and L form. - (Z)₁)_q1-R₀₁It may also be a residue of an amino acid, amino acid derivative, polypeptide or polypeptide derivative which has lost one hydrogen atom of the N-amino group or of a pendant amino group, in which case R₀₁Is a C-carboxyl group or a carboxyl group of a side group.

Such as R₀₁In the case of the acid halide, the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and a chlorine atom and a bromine atom are preferred. At this time, - (Z)₁)_q1-R₀₁Comprises a univalent group obtained by removing 1 hydrogen atom from an acyl chloride compound and an acyl halide group formed by combining a diacyl with a halogen atom. The acid chloride compounds include, but are not limited to, acetyl chloride, acetyl bromide, monochloroacetyl chloride, dichloroacetyl chloride, propionyl bromide, butyryl chloride, 3-cyclopentylpropionyl chloride, 2-chloropropionyl chloride, 3-chloropropionyl chloride, t-butylacetyl chloride, valeryl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, lauroyl chloride, myristoyl chloride, palmitoyl chloride, stearoyl chloride, oleoyl chloride, behenoyl chloride, cyclopentanecarbonyl chloride, methoxyacetyl chloride, acetoxyacetyl chloride, and the like. The diacyl group includes, but is not limited to, oxalyl, malonyl, methylmalonyl, ethylmalonyl, butylmalonyl, succinyl, 2-methylsuccinyl, 2-dimethylsuccinyl, 2-ethyl-2-methyl-succinyl, 2, 3-dimethylsuccinyl, glutaryl, 2-methylsuccinylGlutaryl group, 3-methylglutaryl group, 2-dimethylglutaryl group, 2, 3-dimethylglutaryl group, 3-dimethylglutaryl group, adipoyl group, pimeloyl group, suberoyl group, azeloyl group, sebacoyl group, maleoyl group, fumaroyl group and the like. The acyl group of the dibasic acid herein refers to the residue after removal of 2 hydroxyl groups.

Such as R₀₁In the case of anhydrides, they may be open-chain or intramolecular anhydrides, and examples thereof include- (Z)₁)_q1-R₀₁Including monovalent functional groups corresponding to anhydrides having lost one hydrogen atom. The anhydrides include, but are not limited to, acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, hexanoic anhydride, heptanoic anhydride, octanoic anhydride, nonanoic anhydride, decanoic anhydride, lauric anhydride, myristic anhydride, palmitic anhydride, stearic anhydride, behenic anhydride, crotonic anhydride, methacrylic anhydride, oleic anhydride, linoleic anhydride, chloroacetic anhydride, iodoacetic anhydride, dichloroacetic anhydride, succinic anhydride, methylsuccinic anhydride, 2-dimethylsuccinic anhydride, itaconic anhydride, maleic anhydride, glutaric anhydride, diethanol anhydride, benzoic anhydride, phenylsuccinic anhydride, phenylmaleic anhydride, perphthalic anhydride, isatoic anhydride, phthalic anhydride, and the like. Intramolecular anhydrides also include, but are not limited to, those derived from succinic anhydride, 2-dimethylsuccinic anhydride, cyclopentane-1, 1-diacetic anhydride, 1-cyclohexyldiacetic anhydride, 2-methylenesuccinic anhydride, glutaric anhydride, caronic anhydride, cyclobutane-1, 2-dicarboxylic anhydride, hexahydrophthalic anhydride, methylhexahydrophthalic anhydride, 1,2,3, 6-tetrahydrophthalic anhydride, 1,2,5, 6-tetrahydrophthalic anhydride, 3-methyltetrahydrophthalic anhydride, citraconic anhydride, 2, 3-dimethylmaleic anhydride, 2, 3-dichloromaleic anhydride, 3,4,5, 6-tetrahydrophthalic anhydride, 3-methylphthalic anhydride, 4-tert-butylphthalic anhydride, 1, 8-naphthalic anhydride, and mixtures thereof, 2,2' -Biphenyldicarboxylic anhydride, 4-fluorophthalic anhydride, 3-fluorophthalic anhydride, 4-bromophthalic anhydride, 4-chlorophthalic anhydride, 3, 6-dichlorophthalic anhydride, 3-nitrophthalic anhydride, 4-bromo-1, 8-naphthalic anhydride, 4, 5-dichloro-1, 8-naphthalic anhydride, 4-nitro-1, 8-naphthalic anhydride, nadic anhydride, methyl endomethylenetetrahydrophthalic anhydrideNorcantharidin (7-oxabicyclo [ 2.2.1)]Heptane-2, 3-dicarboxylic anhydride), 2, 3-pyridinedicarboxylic anhydride, 2, 3-pyrazinedicarboxylic anhydride, benzothioxanedicarboxylic anhydride, and the like.

Such as R₀₁When it is an intramolecular carboimide, - (Z)₁)_q1-R₀₁Including but not limited to any of the above imide forms corresponding to intramolecular anhydride, such as succinimide corresponding to succinic anhydride, maleimide corresponding to maleic anhydride, phthalimide corresponding to phthalic anhydride, etc., and are not described in detail. But also include, but are not limited to, o-sulfonylbenzoylimines.

When R is₀₁When it is a maleimide group, - (Z)₁)_q1-R₀₁Including but not limited to those derived from 3,4,5, 6-tetrahydrophthalimide, maleimidoacetyl, 3-maleimidopropionyl, 4-maleimidobutyryl, 5-maleimidopentanoyl, 6- (maleimido) hexanoyl, 3-maleimidobenzoyl, 4- (N-maleimidomethyl) cyclohexane-1-formyl, 4- (4-maleimidophenyl) butyryl, 11- (maleimido) undecanoyl, N- (2-aminoethyl) maleimide, and mixtures thereof, Maleimide groups such as N- (4-aminophenyl) maleimide and 2-maleimidoethyl.

Such as R₀₁When it is alkynyl, - (Z)₁)_q1-R₀₁Including but not limited to ethynyl, propynyl, propargyl, cycloalkynyl, and the like, and hydrocarbyl-substituted versions of any.

Such as R₀₁When cyano (-) - (Z)₁)_q1-R₀₁Including monovalent functional groups corresponding to cyano compounds lacking one hydrogen atom. The cyano compounds include, but are not limited to, carbonitrile, acetonitrile, butyronitrile, valeronitrile, capronitrile, enanthonitrile, caprylonitrile, nonanenitrile, decanonitrile, undecylnitrile, allylnitrile, acrylonitrile, crotononitrile, methacrylonitrile, dichloroacetonitrile, fluoroacetonitrile, benzonitrile, benzylnitrile, methylbenzonitrile, chlorobenzonitrile, methylbenzonitrile, and the like.

Such as R₀₁When it is hydroxy, - (Z)₁)_q1-R₀₁Including monovalent functional groups corresponding to monohydric alcohols lacking one non-hydroxyl hydrogen atom. The monohydric alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol, undecanol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, oleyl alcohol, benzyl alcohol, isopropyl alcohol, phenol, cresol, ethylphenol, propylphenol, cinnamyl phenol, naphthol, cyclopentanol, cyclohexanol, and the like.

When R is₀₁When cholesterol or a derivative thereof, - (Z)₁)_q1-R₀₁Including but not limited to cholesterol derivatives, cholesteryl hydrogen succinate and the like, and residues formed after molecular modification of PEG terminals.

When R is₀₁When biotin or a derivative thereof, - (Z)₁)_q1-R₀₁Including but not limited to biotin-N-succinimidyl ester, 3- [3- [2- (biotinimido) ethyl]Amino-3-oxopropyl radical]Dithio radical]Propionic acid succinimidyl ester, 3- [ [2- (biotinimido) ethyl ester]Dithio radical]Sulfosuccinimidyl propionate, N- (3-azidopropyl) biotin amine, N-biotin-3, 6-dioxaoctane-1, 8-diamine, N-biotin-3, 6, 9-trioxaundecane-1, 11-diamine, biotinyl-6-aminoquinoline, N- (6- [ biotin amine)]Hexyl) -3'- (2' -pyridyldithio) propionamide, 15- [ D- (+) -biotin amino]Residues formed after molecular modification of 4,7,10, 13-tetraoxapentadecanoic acid, 3- (4- (N-biotin-6-aminocaprocarboxy) phenyl) propionic acid, N-Fmoc-N' -biotin-L-lysine, D-biotin hydrazide, biotin-aspartyl-glutamyl-valyl-aspartyl-aldehyde, etc., at the PEG terminus.

When R is₀₁When it is fluorescein or a derivative thereof, - (Z)₁)_q1-R₀₁Including but not limited to 5-carboxyfluorescein succinimidyl ester, 6-carboxyfluorescein succinimidyl ester, 5-aminofluorescein, 6-aminofluorescein, 5(6) -aminofluorescein, 5- (aminomethyl) fluorescein hydrochloride, 6- ([4, 6-dichlorotriazin-2-yl)]Amino) fluorescein hydrochloride, 5' -fluorescein phosphoramidate, fluorescein 5-maleimide, fluorescein 6-maleinimideAnd residues formed by modifying molecules on the tail end of PEG, such as imine, 5-carboxyfluorescein, 6-carboxyfluorescein, 2, 7-bis (2-carboxyethyl) -5(6) -carboxyfluorescein, 5- (4, 6-dichlorotriazine) aminofluorescein, and CI 45350.

When R is₀₁When it is rhodamine or a derivative thereof, - (Z)₁)_q1-R₀₁Including but not limited to tetramethylrhodamine, tetraethylrhodamine (rhodamine B, RB200), rhodamine 3G, rhodamine 6G (rhodamine 590), 5-carboxy-X-rhodamine, 6-carboxy-X-rhodamine, sulforhodamine B, sulforhodamine G, sulforhodamine 101, rhodamine X (R101), rhodamine 101, rhodamine 110, rhodamine 123, rhodamine 700, rhodamine 800, 5-carboxytetramethylrhodamine, 6-carboxytetramethylrhodamine, 5-carboxytetramethylrhodamine succinimidyl ester, 6-carboxytetramethylrhodamine succinimidyl ester, 5-carboxytetramethylrhodamine 6G succinimidyl ester, 6-carboxyrhodamine 6G succinimidyl ester, tetramethylrhodamine-5-maleimide, tetramethylrhodamine-6-maleimide, 6-carboxyl-X-rhodamine succinimide ester, tetramethyl rhodamine-5-isothiocyanate, tetramethyl rhodamine-6-isothiocyanate, tetramethyl rhodamine B-5-isothiocyanate, tetramethyl rhodamine B-6-isothiocyanate, rhodamine chloride 101, sulfonated rhodamine B and other molecules are modified on the tail end of PEG to form residues.

When R is₀₁When it is anthracene or a derivative thereof, - (Z)₁)_q1-R₀₁Including but not limited to 9-anthracene methanol, 1-amino anthracene, 2-amino anthracene, 9-anthracene formaldehyde, 10-methyl anthracene-9-formaldehyde, 9-anthracene formic acid, acrylic acid-9-anthracene methyl ester, methacrylic acid-9-anthracene methyl ester, 9-anthracene aldehyde oxime, 9-anthracene acrolein, etc. molecules modified on PEG terminal to form residues.

When R is₀₁When pyrene or a derivative thereof, - (Z)₁)_q1-R₀₁Including but not limited to 1-pyrene methanol, 7,8,9, 10-tetrahydrobenzo [ a ]]Pyrene-7-ol, N-hydroxysuccinimide ester 1-pyrenebutanoic acid, 1-pyrene formaldehyde, 1-pyrenebutanoic acid, 1-pyrenecarboxylic acid (1-pyrenecarboxylic acid), 1-pyreneacetic acid, 10- (1-pyrene) decanoic acid, 1-pyrenedodecanoic acid, Fmoc-3- (1-pyrenyl) -L-alanine, t-butyloxycarbonyl-3- (1-pyrenyl) -D-alanine, t-butyloxycarbonyl-3- (1-pyrenyl) -L-alanineAmino acid, 1-aminopyrene, 1, 3-diaminopyrene, 1, 8-diaminopyrene, 1, 6-diaminopyrene, 1-pyrenemethylamine, N- (1-pyrenyl) maleimide and the like are molecularly modified on the end of PEG to form residues.

When R is₀₁When the carbazole pyrene or derivative thereof is (Z)₁)_q1-R₀₁Including, but not limited to, carbazole, 9-carbazoleethanol, 2-hydroxy carbazole, 2- (9H-carbazolyl) ethyl boronic acid pinacol ester, 2- (9H-carbazolyl) ethyl boronic acid diethanol amine ester, N-aminocarbazole, 9- (4-aminophenyl) carbazole, 9-carbazoloacetic acid and the like, which are formed after molecules are modified at the end of PEG.

When R is₀₁When it is imidazole or a derivative thereof, - (Z)₁)_q1-R₀₁Including but not limited to 4- (hydroxymethyl) imidazole, 4-hydroxyethylimidazole, 1- (2-hydroxyethyl) imidazole, 1-methyl-2-hydroxymethyl-1H-imidazole, 1- (2-hydroxypropyl) imidazole, 1- (. beta. -hydroxyethyl) -2-methylimidazole, 4-hydroxymethyl-5-methyl-2-phenylimidazole, 1-hydroxyethyl-3-methylimidazole chloride salt, 4-hydroxymethyl-5-methylimidazole, 4-bromo-1H-imidazole, 2-bromo-1H-imidazole, 1-methyl-2-bromo-1H-imidazole, 5-chloro-1-methylimidazole, 2-aminoimidazole, 4-aminoimidazole, 1- (3-aminopropyl) imidazole, 1-methyl-4-imidazolecarboxylic acid, 4-imidazolecarboxaldehyde (4-formylimidazole), 1-formylimidazole, 2-formylimidazole, 4- (imidazol-1-yl) benzaldehyde, 1-methyl-2-imidazolecarboxaldehyde, 2-butyl-1H-imidazole-4-carbaldehyde, 5-methylimidazole-4-carbaldehyde, 2-ethyl-4-formylimidazole, 2-ethyl-4-methyl-5-imidazolecarboxaldehyde, 1-benzyl-1H-imidazole-5-carbaldehyde, 5-amino-1H-imidazole-4-carbonitrile, a salt thereof, a hydrate thereof, a salt thereof, a hydrate thereof, and a pharmaceutically acceptable salt thereof, Histidine and the like are formed after molecular modification of PEG terminal.

When R is₀₁When indole or its derivative is substituted, - (Z)₁)_q1-R₀₁Including but not limited to 4-hydroxyindole, 5-hydroxyindole, 6-hydroxyindole, 7-hydroxyindole, 5-hydroxy-2-methylindole, 4-hydroxy-2-methylindole, 3- (2-methylaminoethyl) indole, 2- (2-aminoethyl) indole, 3- (2-aminoethyl) -6-methoxyindole, 4-aminoindole, 5-aminoindole, 6-aminoindole, 7-aminoindole, 4-methyl-5-aminoindole, 3-bromoindole, 4-bromoindole, 5-bromoindole, 6-bromoindole, 7-bromoindoleIndole, 5-bromo-1-methyl-1H-indole, 3- (2-aminoethyl) indol-5-ol, 5-hydroxyindole-2-carboxylic acid, 6-hydroxy-2-indolecarboxylic acid, 7-hydroxyindole-2-carboxylic acid, 5-bromoindole-2-carboxylic acid, 6-bromoindole-2-carboxylic acid, 7-bromoindole-2-carboxylic acid, 5-bromoindole-3-carboxylic acid, 6-bromoindole-3-carboxylic acid, 4-bromoindole-3-formaldehyde, 6-bromoindole-3-formaldehyde, 5-bromo-1H-indole-3-ethanol, and the like, which are molecularly modified at the end of PEG.

4.3.3. Functional group R₀₁Structural classification of

Specifically, R₀₁Including but not limited to functional groups in any of classes a through J, variations of classes a through H, functional derivatives of class I-class J:

class A:

or class B:

or class C:

or class D:

or class E:

or class F:

or class G:

class Ga:

or class Gb:

or class H:

or class I:

or class J: and the like.

Wherein Q is₅、M₅And M₅The rings are consistent with the above definitions and are not described further herein.

Wherein, Y₁Is a leaving group attached to a sulfonyl, sulfinyl, oxysulfonyl or oxysulfinyl group. Y is₁There is no particular limitation. Y is₁Preferably having C_1-10Hydrocarbyl or fluoro C_1-10A hydrocarbyl group. Y is₁More preferably having C_1-10Alkyl radical, C_1-10Alkenyl, phenyl, and the like, or substituted forms thereof. Wherein the substituent atom or substituent group is a halogen atomAlkenyl, alkoxy or nitro. Specifically, as an example Y₁Can be selected from any one of the group including, but not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, vinyl, phenyl, benzyl, p-methylphenyl, 4- (trifluoromethoxy) phenyl, trifluoromethyl, 2,2, 2-trifluoroethyl, and the like. Wherein, butyl includes but is not limited to n-butyl and tert-butyl. Octyl includes, but is not limited to, n-octyl, 2-ethylhexyl. Y is₁More preferably, it is any of methyl, p-methylphenyl, 2,2, 2-trifluoroethyl, trifluoromethyl, vinyl, and the like.

Wherein W is F, Cl, Br or I, preferably Br or Cl.

Wherein, W₃Is a leaving group including, but not limited to, F, Cl, Br, I, PhS-, preferably Br or Cl.

Wherein, W₂Is F, Cl, Br or I, preferably I.

Wherein the content of the first and second substances,each of which is a cyclic structure containing a nitrogen atom, a nitrogen onium ion, a double bond, an azo, a triple bond, a disulfide bond, an anhydride, a diene in the ring backbone, including but not limited to a carbocycle, heterocycle, benzoheterocycle, substituted carbocycle, substituted heterocycle, or substituted benzoheterocycle, and the like.

Wherein M is a carbon or heteroatom in the ring, including but not limited to carbon, nitrogen, phosphorus, silicon.

Wherein M is₈Is a carbon atom or a heteroatom located on the ring. M₈Preferably a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom. M₈The number of ring-forming atoms of the ring is not particularly limited, but is preferably 4 to 50, more preferably 4 to 32, still more preferably 5 to 18, and most preferably 5 to 8. M₈Can be a carbon atom or a heteroatom in a 4-50 membered ring, preferably a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom in a 4-32 membered ring, more preferably a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom in a 5-18 membered ring; optimization ofCarbon atoms, nitrogen atoms, phosphorus atoms or silicon atoms on 5-8 membered rings are selected.

Wherein M is₂₂Is a carbon atom or a hetero atom on an alicyclic or alicyclic ring, and may be selected from a carbon atom, a nitrogen atom, a phosphorus atom or a silicon atom. M₂₂The number of ring-forming atoms of the ring is 4,5,6,7or 8, preferably 4,5 or 6.

Wherein PG₈Is a protecting group for orthocarbonic acid or orthosilicic acid, D8 is a protected form of orthosilicic acid, H5 is a protected form of orthosilicic acid. PG (Picture experts group)₈May be a single trivalent end group such as

Taking D8 as an example, corresponding to

PG₈It may also be two or three separate end groups, and D8 corresponds to

H5 corresponds to

Wherein R is₂Is an end group or a divalent linking group connecting oxygen or sulfur atoms in an acetal, ketal, hemiacetal, hemiketal, orthoester, thioacetal, thioketal, thiohemiacetal, thiohemiketal, thioorthoester, orthosilicate ester and the like structure, such as D7, D18, D8 and H5.

R₂Can be selected from hydrogen atoms, R₂₁Or R₃Any one atom or group.

Wherein R is₂₁Is a divalent linking group and participates in ring formation.

R₂₁The number of carbon atoms of (A) is not particularly limited, but is preferably 1 to 20, more preferably 1 to 10.

R₂₁The structure of (a) is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. Wherein the cyclic structure is not particularly limited, preferablyThe above-mentioned aliphatic ring, aromatic ring, sugar ring and condensed ring are selected.

R₂₁May or may not contain heteroatoms.

R₂₁Is selected from C_1-20Alkylene, divalent C_1-20Heterohydrocarbyl, substituted C_1-20Alkylene, substituted divalent C_1-20Any divalent linking group or any combination of two or three of the divalent linking groups in the heterohydrocarbyl group. Wherein, the substituent atom or substituent is not particularly limited, including but not limited to any substituent atom or any substituent group of the term moiety, selected from any one of halogen atom, hydrocarbyl substituent group, heteroatom-containing substituent group.

R₂₁Preferably C_1-20Open-chain alkylene, C_1-20Alkenyl radical, C_1-20Cycloalkylene radical, C_1-20Cycloalkylene, arylene, divalent C_1-20Aliphatic heteroalkyl, divalent C_1-20Lipoheteroalkenyl, divalent heteroaryl, divalent heteroarylalkyl, substituted alkylene, substituted C_1-20Open alkenylene, substituted C_1-20Cycloalkylene, substituted C_1-20Cycloalkylene radical, substituted arylene radical, substituted divalent C radical_1-20Lipoheteroalkyl, substituted divalent C_1-20Any one of divalent linking groups of lipoheteroalkenyl, substituted divalent heteroaryl, substituted divalent heteroarylalkyl, a combination of any two, or a combination of any three. Among them, the substituent atom or the substituent is preferably a halogen atom, an alkoxy group and a nitro group.

R₂₁More preferably C_1-10Open-chain alkylene, C_1-10Alkenyl radical, C_3-10Cycloalkylene radical, C_1-10Cycloalkylene, arylene, divalent C_1-10Aliphatic heteroalkyl, divalent C_1-10Lipoheteroalkenyl, divalent heteroaryl, divalent heteroarylalkyl, substituted alkylene, substituted C_1-10Open alkenylene, substituted C_1-10Cycloalkylene, substituted C_1-10Cycloalkylene radical, substituted arylene radical, substituted aralkylene radical, substituted divalent C_1-10Lipoheteroalkyl, substituted divalent C_1-10Any one of divalent linking groups of lipoheteroalkenyl, substituted divalent heteroaryl, substituted divalent heteroarylalkyl, a combination of any two, or a combination of any three.

Specifically, R₂₁Selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, 1, 2-phenylene, benzylene, C_1-20Oxaalkylene, C_1-20Thiaalkylene group, C_1-20Any one group of azaalkylene and azaaralkyl, substituted forms of any one group, and any two or more of the same or different groups or substituted forms thereof. Among them, the substituent atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent and a heteroatom-containing substituent, and is preferably a halogen atom, an alkoxy group or a nitro group.

R₂₁More preferred are 1, 2-ethylene group and 1, 3-propylene group.

Wherein R is₃Are terminal groups to which an oxygen or sulfur group is attached.

R₃The number of carbon atoms of (A) is not particularly limited, but is preferably 1 to 20, more preferably 1 to 10.

R₃The structure of (a) is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. Among them, the cyclic structure is not particularly limited, and the above-mentioned aliphatic ring, aromatic ring, sugar ring, and condensed ring are preferable.

R₃May or may not contain heteroatoms.

R₃Is selected from C_1-20Hydrocarbyl radical, C_1-20Heterohydrocarbyl radical, C_1-20Substituted hydrocarbyl radical, C_1-20Any of substituted heterohydrocarbyl groups. For substitution of R₃The heteroatom or substituent of (a) is not particularly limited and includes, but is not limited to, any heteroatom or any substituent of the term moiety, preferably any one selected from a halogen atom, a hydrocarbyl group, a heteroatom-containing substituent.

R₃Preferably C_1-20Alkyl radical, C_3-20Alkenyl, arylAromatic hydrocarbon group, C_1-20Aliphatic heterocarbyl, heteroaryl, heteroaromatic hydrocarbyl, substituted C_1-20Alkyl, substituted C_3-20Alkylene, substituted aryl, substituted aralkyl, substituted C_1-20Any one of aliphatic heterocarbon group, substituted heteroaryl group and substituted heteroaromatic hydrocarbon group. Wherein the substituent atom or substituent is selected from any one of halogen atom, alkyl substituent and heteroatom-containing substituent.

R₃Preferably C_1-20Straight chain alkyl, C_1-20Branched alkyl radical, C_3-20Cycloalkyl, aryl, aralkyl, C_1-20Aliphatic heterocarbyl, heteroaryl, heteroaromatic hydrocarbyl, substituted C_1-20Straight chain alkyl, substituted C_1-20Branched alkyl, substituted C_3-20Cycloalkyl, substituted aryl, substituted arylalkyl, substituted C_1-20Any one of aliphatic heterocarbon group, substituted heteroaryl group and substituted heteroaromatic hydrocarbon group. Wherein the substituent atom or substituent is selected from any one of halogen atom, alkyl substituent and heteroatom-containing substituent, preferably halogen atom, alkoxy, alkyl, aryl or nitro.

R₃More preferably C_1-10Straight chain alkyl, C_1-10Branched alkyl radical, C_3-10Cycloalkyl, aryl, aralkyl, C_1-20Aliphatic heterocarbyl, heteroaryl, heteroaromatic hydrocarbyl, substituted C_1-10Straight chain alkyl, substituted C_1-10Branched alkyl, substituted C_3-10Cycloalkyl, substituted aryl, substituted arylalkyl, substituted C_1-10Any one of aliphatic heterocarbon group, substituted heteroaryl group and substituted heteroaromatic hydrocarbon group. Wherein, the substituent atom or substituent group is selected from any one of halogen atom, alkyl substituent group and substituent group containing hetero atom, preferably fluorine atom, chlorine atom, bromine atom, iodine atom, alkyl, aryl or nitro; more preferably a halogen atom, an alkoxy group or a nitro group.

Specifically, R₃Selected from any one or any one of methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, benzyl, allyl and the like. Wherein butyl includes but is not limited toLimited to n-butyl, t-butyl. Octyl includes, but is not limited to, n-octyl, 2-ethylhexyl. Wherein, the substituent atom or substituent group is selected from any one of halogen atom, alkyl substituent group and substituent group containing hetero atom, preferably fluorine atom, chlorine atom, bromine atom, iodine atom, alkyl, aryl or nitro; more preferably a halogen atom, an alkoxy group or a nitro group.

R₃Most preferred is methyl, ethyl or benzyl.

Wherein R is₄Is- (R)₄)C＝N⁺＝N^—Or- (R)₄)C^--N⁺A hydrogen atom, a substituent atom or a substituent on C in the structure of [ identical to ] N.

When taken as a substituent atom, R₄Selected from any one of halogen atoms. Fluorine atoms are preferred.

When taken as a substituent, R₄The number of carbon atoms of (A) is not particularly limited, but is preferably 1 to 20, more preferably 1 to 10.

When taken as a substituent, R₄The structure of (a) is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. Among them, the cyclic structure is not particularly limited, and the above-mentioned aliphatic ring, aromatic ring, sugar ring, and condensed ring are preferable.

When taken as a substituent, R₄May or may not contain heteroatoms.

R₄Selected from hydrogen atoms, halogen atoms, C_1-20Hydrocarbyl radical, C_1-20Heterohydrocarbyl, substituted C_1-20Hydrocarbyl or substituted heterohydrocarbyl. Wherein R is₄The substituent atom or substituent in (1) is not particularly limited, and includes, but is not limited to, any substituent atom or any substituent group of the term moiety selected from any one of a halogen atom, a hydrocarbon group substituent, and a heteroatom-containing substituent group.

R₄More preferably a hydrogen atom, a halogen atom, C_1-20Alkyl radical, C_1-20Unsaturated aliphatic, aryl, C_1-20Heterohydrocarbyl radical, C_1-20Hydrocarbyloxyacyl group, C_1-20Hydrocarbyl thioacyl, C_1-20Any of the hydrocarbyl aminoacyl groupsAn atom or group, or a substituted version of any group. Wherein R is₄The acyl group in (1) is not particularly limited, including but not limited to any acyl type of the term moiety. R₄The acyl group in (1) is more preferably a carbonyl group or a thiocarbonyl group.

R₄More preferably a hydrogen atom, a halogen atom, C_1-20Alkyl radical, C_1-20Alkenyl, aryl, arylalkyl, C_1-20Aliphatic heterocarbyl, heteroaryl, heteroaromatic hydrocarbyl, C_1-20Alkoxyacyl, aryloxyacyl, C_1-20Alkylthio acyl, arylthio acyl, C_1-20Any one of an alkylaminoacyl group, an arylaminoacyl group, or a substituted version of any one of the groups.

R₄More preferably a hydrogen atom, a halogen atom, C_1-20Alkyl radical, C_1-20Alkenyl, aryl, arylalkyl, C_1-20Aliphatic heterocarbyl, heteroaryl, heteroaromatic hydrocarbyl, C_1-20Alkoxycarbonyl, aryloxycarbonyl, C_1-20Alkylthio carbonyl, arylthio carbonyl, C_1-20Alkylaminocarbonyl, arylaminocarbonyl, C_1-20Alkoxythiocarbonyl, aryloxylthiocarbonyl, C_1-20Alkylthio thiocarbonyl, arylthio thiocarbonyl, C_1-20Any one atom or group of an alkylaminothiocarbonyl group, arylaminothiocarbonyl group, or a substituted version of any one group.

Specifically, R₄Selected from the group consisting of, but not limited to, hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, n-propyl group, isopropyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, eicosyl group, allyl group, propenyl group, vinyl group, phenyl group, methylphenyl group, butylphenyl group, benzyl group, methoxycarbonyl group, ethoxycarbonyl group, phenoxycarbonyl group, benzyloxycarbonyl group, methylthiocarbonyl group, ethylthiocarbonyl group, phenylthiocarbonyl group, benzylthiocarbonyl group, ethylaminocarbonyl group, benzylaminocarbonyl group, methoxythiocarbonyl group, ethoxythiocarbonyl groupSubstituted carbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, methylthiothiocarbonyl, ethylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiothiocarbonyl, ethylaminothiocarbonyl, benzylaminothiocarbonyl, substituted C_1-20Alkyl, substituted C_1-20Alkenyl, substituted aryl, substituted arylalkyl, substituted C_1-20Aliphatic heterocarbyl, substituted heteroaryl, substituted heteroarylalkyl, substituted C_1-20Alkoxycarbonyl, substituted aryloxycarbonyl, substituted C_1-20Alkylthio carbonyl, substituted arylthio carbonyl, substituted C_1-20Alkylaminocarbonyl, substituted arylaminocarbonyl, substituted C_1-20Alkoxythiocarbonyl, substituted aryloxythiocarbonyl, substituted C_1-20Alkylthio thiocarbonyl, substituted arylthio thiocarbonyl, substituted C_1-20An alkylaminothiocarbonyl group, a substituted arylaminothiocarbonyl group, or the like. Wherein, butyl includes but is not limited to n-butyl and tert-butyl. Octyl includes, but is not limited to, n-octyl, 2-ethylhexyl. Among them, the substituent atom or the substituent is selected from any one of a halogen atom, a hydrocarbon substituent and a heteroatom-containing substituent, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkenyl group or a nitro group.

R₄More preferred is a hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, allyl group, propenyl group, vinyl group, phenyl group, methylphenyl group, butylphenyl group, benzyl group, methoxycarbonyl group, ethoxycarbonyl group, phenoxycarbonyl group, benzyloxycarbonyl group, methylthiocarbonyl group, ethylthiocarbonyl group, phenylthiocarbonyl group, benzylthiocarbonyl group, ethylaminocarbonyl group, benzylaminocarbonyl group, methoxythiocarbonyl group, ethoxythiocarbonyl group, phenoxythiocarbonyl group, benzyloxythiocarbonyl group, methylthiothiocarbonyl group, ethylthiocarbonyl group, phenylthiocarbonyl group, benzylthiocarbonyl group, ethylaminothiocarbonyl group, benzylaminothiocarbonyl group, C_1-10Halogenated hydrocarbon group, halogenated phenyl, halogenated benzyl, nitro phenyl and any kind of atom or group, or any kind of substituted form of group.

R₄Preferably any one atom or group of hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, allyl group, propenyl group, vinyl group, phenyl group, methylphenyl group, butylphenyl group, and benzyl group.

R₄Most preferably a hydrogen atom, a methyl group or a benzyl group.

Wherein R is₈、R₉、R₁₀、R₁₁、R₁₂Each independently is a hydrogen atom, a substituent atom or a substituent on a double bond (-C-), and R is in the same molecule₈、R₉、R₁₀、R₁₁、R₁₂May be the same as or different from each other.

When it is a substituted atom, R₈、R₉、R₁₀、R₁₁、R₁₂Each independently selected from any one halogen atom of F, Cl, Br and I. Each independently preferably being a fluorine atom.

When it is a substituent, R₈、R₉、R₁₀、R₁₁、R₁₂The number of carbon atoms of (a) is not particularly limited. R₈、R₉、R₁₀、R₁₁、R₁₂The number of carbon atoms of (A) is preferably 1 to 20, more preferably 1 to 10, independently of each other.

When it is a substituent, R₈、R₉、R₁₀、R₁₁、R₁₂The structure of (a) is not particularly limited, and each independently includes, but is not limited to, a linear structure, a branched structure containing a pendant group, or a cyclic structure. Among them, the cyclic structure is not particularly limited, and the above-mentioned aliphatic ring, aromatic ring, sugar ring, and condensed ring are preferable.

When it is a substituent, R₈、R₉、R₁₀、R₁₁、R₁₂Each independently may or may not contain a heteroatom.

R₈、R₉、R₁₀、R₁₁、R₁₂Each independently selected from a hydrogen atom, a halogen atom, C_1-20Hydrocarbyl radical, C_1-20Heterohydrocarbyl, substituted C_1-20Hydrocarbyl or substituted heterohydrocarbyl. Wherein R is₈The substituent atom or substituent in (1) is not particularly limited, and includes, but is not limited to, any substituent atom or any substituent group of the term moiety selected from any one of a halogen atom, a hydrocarbon group substituent, and a heteroatom-containing substituent group.

R₈、R₉、R₁₀、R₁₁、R₁₂Each independently more preferably a hydrogen atom, a halogen atom, C_1-20Alkyl radical, C_1-20Unsaturated aliphatic, aryl, C_1-20Heterohydrocarbyl radical, C_1-20Hydrocarbyloxyacyl group, C_1-20Hydrocarbyl thioacyl, C_1-20Any atom or group of a hydrocarbylaminoacyl group, or a substituted version of any group. Wherein R is₈The acyl group in (1) is not particularly limited, including but not limited to any acyl type of the term moiety.

R₈、R₉、R₁₀、R₁₁、R₁₂Each independently more preferably a hydrogen atom, a halogen atom, C_1-20Alkyl radical, C_1-20Alkenyl, aryl, arylalkyl, C_1-20Aliphatic heterocarbyl, heteroaryl, heteroaromatic hydrocarbyl, C_1-20Alkoxyacyl, aryloxyacyl, C_1-20Alkylthio acyl, arylthio acyl, C_1-20Any one of an alkylaminoacyl group, an arylaminoacyl group, or a substituted version of any one of the groups. The substituent atom or substituent is selected from any one of halogen atom, alkyl substituent and hetero atom-containing substituent, preferably halogen atom, alkenyl or nitro

R₈、R₉、R₁₀、R₁₁、R₁₂Each independently more preferably a hydrogen atom, a halogen atom, C_1-20Alkyl radical, C_1-20Alkenyl, aryl, arylalkyl, C_1-20Aliphatic heterocarbyl, heteroaryl, heteroaromatic hydrocarbyl, C_1-20Alkoxycarbonyl, aryloxycarbonyl, C_1-20Alkylthio carbonyl, arylthio carbonyl, C_1-20Alkylaminocarbonyl, arylaminocarbonyl, C_1-20Alkoxycarbonyl thiocarbonyl radicalRadical, aryloxy thiocarbonyl radical, C_1-20Alkylthio thiocarbonyl, arylthio thiocarbonyl, C_1-20Any one atom or group of an alkylaminothiocarbonyl group, arylaminothiocarbonyl group, or a substituted version of any one group. R₈The acyl group in (1) is more preferably a carbonyl group or a thiocarbonyl group. Among them, the substituent atom or the substituent is selected from any one of a halogen atom, a hydrocarbon substituent and a heteroatom-containing substituent, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkenyl group or a nitro group.

Specifically, R₈、R₉、R₁₀、R₁₁、R₁₂Each independently selected from the group consisting of, but not limited to, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an eicosyl group, an allyl group, a propenyl group, a vinyl group, a phenyl group, a methylphenyl group, a butylphenyl group, a benzyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a phenoxycarbonyl group, a methylthiocarbonyl group, a benzyloxycarbonyl group, a methylthiocarbonyl group, an ethylthiocarbonyl group, Benzylthiothiocarbonyl, ethylaminothiocarbonyl, benzylaminothiocarbonyl, substituted C_1-20Alkyl, substituted C_1-20Alkenyl, substituted aryl, substituted arylalkyl, substituted C_1-20Aliphatic heterocarbyl, substituted heteroaryl, substituted heteroarylalkyl, substituted C_1-20Alkoxycarbonyl, substituted aryloxycarbonyl, substituted C_1-20Alkylthio carbonyl, substituted arylthio carbonyl, substituted C_1-20Alkylaminocarbonyl, substituted arylaminocarbonyl, substituted C_1-20Alkoxythiocarbonyl, substituted aryloxythiocarbonyl, substituted C_1-20Alkylthio thiocarbonyl, substituted arylthioThiocarbonyl, substituted C_1-20An alkylaminothiocarbonyl group, a substituted arylaminothiocarbonyl group, or the like. Wherein, butyl includes but is not limited to n-butyl and tert-butyl. Octyl includes, but is not limited to, n-octyl, 2-ethylhexyl. Among them, the substituent atom or the substituent is selected from any one of a halogen atom, a hydrocarbon substituent and a heteroatom-containing substituent, and is preferably a halogen atom, an alkenyl group or a nitro group.

R₈、R₉、R₁₀、R₁₁、R₁₂Further preferred are, independently of one another, a hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, allyl group, propenyl group, vinyl group, phenyl group, methylphenyl group, butylphenyl group, benzyl group, methoxycarbonyl group, ethoxycarbonyl group, phenoxycarbonyl group, benzyloxycarbonyl group, methylthiocarbonyl group, ethylthiocarbonyl group, phenylthiocarbonyl group, benzylthiocarbonyl group, ethylaminocarbonyl group, benzylaminocarbonyl group, methoxythiocarbonyl group, ethoxythiocarbonyl group, phenoxythiocarbonyl group, benzyloxythiocarbonyl group, methylthiothiocarbonyl group, ethylthiocarbonyl group, phenylthiocarbonyl group, benzylthiocarbonyl group, ethylaminothiocarbonyl group, benzylaminothiocarbonyl group, C thiocarbonyl group, C_1-10Halogenated hydrocarbon group, halogenated phenyl, halogenated benzyl, nitro phenyl and any kind of atom or group, or any kind of substituted form of group. Among them, the substituent atom or the substituent is selected from any one of a halogen atom, a hydrocarbon substituent and a heteroatom-containing substituent, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkenyl group or a nitro group.

R₈、R₉、R₁₀、R₁₁、R₁₂Each independently is more preferably a hydrogen atom, a fluorine atom or a methyl group.

In class E3, R₈Most preferred is methyl.

Wherein R is₂₄For attachment to the end groups of disulfide bonds, C is preferred_1-20Alkyl, aryl, heteroaryl, and the like, such as ortho-pyridyl.

Wherein R is₂₇For the substituent attached to the azo, phenyl, substituted are preferredOr a hybrid phenyl group.

Wherein R is₃₀Is a hydrocarbon radical, preferably C_1-20Alkyl, benzyl, phenyl ring hydrogen atoms by C_1-20Hydrocarbyl-substituted benzyl.

Wherein M is₁₉、M₂₀、M₂₁Each independently an oxygen atom or a sulfur atom, and may be the same as or different from each other in the same molecule.

Wherein, X₁₁To attach a carbonyl or thiocarbonyl end group, preferably C_1-20Alkyl groups, more preferably methyl, ethyl, isopropyl, tert-butyl.

Wherein, X₁₂Terminal groups to which carbonate or thiocarbonate groups are attached, selected from hydrocarbon groups (which may or may not include a benzene ring), preferably C_1-20Hydrocarbyl, more preferably C_1-20Alkyl, phenylhydrocarbyl or hydrocarbyl substituted phenyl.

Wherein, X₁₃Is a terminal group for attachment of a thio group, selected from a mercapto-protecting group or the group LG₂。

When it is a mercapto-protecting group, X₁₃Is selected from PG₂Thiol protecting groups in the listed groups.

Wherein LG is₂The number of carbon atoms of (a) is not particularly limited. LG (Ligno-lead-acid)₂The number of carbon atoms of (A) is preferably 1 to 20, more preferably 1 to 10.

LG₂The structure of (a) is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. Among them, the cyclic structure is not particularly limited, and the above-mentioned aliphatic ring, aromatic ring, sugar ring, and condensed ring are preferable.

LG₂May or may not contain heteroatoms.

LG₂Is selected from C_1-20Hydrocarbyl radical, C_1-20Heterohydrocarbyl, substituted C_1-20Any one of a hydrocarbon group and a substituted heterohydrocarbon group. Wherein LG is₂The substituted heteroatom or substituent in (1) is not particularly limited, including but not limited to any substituted heteroatom or any substituent of the term moiety selected from any of halogen atoms, hydrocarbyl substituents, heteroatom-containing substituents.

LG₂More preferably C_1-20Alkyl radical, C_1-20Unsaturated aliphatic, aryl, C_1-20Heterohydrocarbyl radical, C_1-20Alkylthio radical, C_1-20Aliphatic heterocarbylthio, arylthio, C_1-20Aliphatic aralkyl acyl radical, C_1-20Lipoheteroalkylacyl, arylacyl, heteroarylacyl, C_1-20Hydrocarbyloxyacyl group, C_1-20Hydrocarbyl thioacyl, C_1-20Hydrocarbyl aminoacyl radical, C_1-20Heterohydrocarbyloxyacyl group, C_1-20Heterocarbylthioacyl radical, C_1-20Any one group or substituted version of any one group of a heterocarbylaminoacyl group. Wherein LG is₂The acyl group in (1) is not particularly limited, including but not limited to any acyl type of the term moiety. By way of example, LG₂The acyl group in (1) may be selected from a carbonyl group, a sulfonyl group, a sulfinyl group, a phosphoryl group, a hypophosphoryl group, a nitroxyl group, a nitrosyl group, a thiocarbonyl group, an imidoyl group, a thiophosphoryl group, a dithiophosphoryl group, a trithiophosphoryl group, a thiophosphorous group, a dithiophosphoryl group, a thiophosphoryl group, a dithiophosphoryl group, a thiophosphoryl group and the like. Any of acyl groups such as a carbonyl group, a thiocarbonyl group, a sulfonyl group, and a sulfinyl group is preferable. LG (Ligno-lead-acid)₂The acyl group in (1) is more preferably a carbonyl group, thiocarbonyl group or sulfonyl group.

LG₂More preferably C_1-20Alkyl, aryl, aralkyl, C_1-20Heteroalkyl, heteroaryl, heteroaralkyl, C_1-20Alkylthio, arylthio, aralkylthio, C_1-20Heteroalkylthio, heteroarylthio, heteroaralkylthio, C_1-20Alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, C_1-20Heteroalkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, C_1-20Alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, C_1-20Alkylthio-carbonyl, arylthio-carbonyl, aralkylthiocarbonyl, C_1-20Alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, C_1-20Heteroalkyloxycarbonyl, heteroaryloxycarbonylAlkyl, heteroaralkyloxycarbonyl, C_1-20Heteroalkylthio-carbonyl, heteroarylthio-carbonyl, heteroaralkylthio-carbonyl, C_1-20Heteroalkylaminocarbonyl, heteroarylaminocarbonyl, heteroarylalkylaminocarbonyl, C_1-20Alkylthio, arylthio, aralkylthiocarbonyl, C_1-20Heteroalkylthiocarbonyl, heteroarylthiocarbonyl, heteroarylalkylthiocarbonyl, C_1-20Alkoxythiocarbonyl, aryloxylthiocarbonyl, aralkyloxythiocarbonyl, C_1-20Alkylthio thiocarbonyl, arylthio thiocarbonyl, aralkylthio thiocarbonyl, C_1-20Alkylaminothiocarbonyl, arylaminothiocarbonyl, aralkylaminothiocarbonyl, C_1-20Heteroalkyloxythiocarbonyl, heteroaryloxythiocarbonyl, heteroarylalkoxythiocarbonyl, C_1-20Heteroalkylthio thiocarbonyl, heteroarylthio thiocarbonyl, heteroarylalkylthio thiocarbonyl, C_1-20A heteroalkylaminothiocarbonyl group, a heteroarylaminothiocarbonyl group, or a substituted version of any group.

LG₂More preferably C_1-20Alkyl, aryl, aralkyl, C_1-20Heteroalkyl, heteroaryl, heteroaralkyl, C_1-20Alkylthio, arylthio, aralkylthio, C_1-20Any one of the groups or substituted versions of any one of the groups heteroarylthio, heteroaralkylthio.

Specifically, LG₂Selected from the group consisting of, but not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, allyl, trityl, phenyl, benzyl, methylbenzyl, nitrobenzyl, tert-butylthio, benzylthio, 2-pyridylthio, ethylacyl, phenylformyl, methoxyacyl, ethoxyacyl, tert-butyloxyacyl, phenoxyacyl, benzyloxyacyl, methylthioacyl, ethylthioacyl, benzylthio, 2-pyridylthio, phenylthio, phenyl,T-butylthioacyl, thiophenoyl, benzylthioacyl, 2-pyridylcarbonyl, methylaminoacyl, ethylaminoacyl, t-butylaminoacyl, benzylaminoacyl, and the like, or a substituted form of any of them. Wherein, butyl includes but is not limited to n-butyl and tert-butyl. Octyl includes, but is not limited to, n-octyl, 2-ethylhexyl. Among them, the substituent atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent and a heteroatom-containing substituent, and is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or a nitro group.

LG₂More preferred is methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, allyl, trityl, phenyl, benzyl, methylbenzyl, nitrobenzyl, tert-butylthio, benzylthio, 2-pyridylthio, acetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, tert-butylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, 2-pyridylcarbonyl, methylaminocarbonyl, ethylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, ethylthiocarbonyl, tert-butylaminocarbonyl, benzylthiocarbonyl, tert-butylaminocarbonyl, tert-propyl, Methylthiocarbonyl, ethoxythiocarbonyl, tert-butyloxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, methylthiothiocarbonyl, ethylthiothiocarbonyl, tert-butylthiothiocarbonyl, phenylthiothiocarbonyl, benzylthiocarbonyl, methylaminothiocarbonyl, ethylaminothiocarbonyl, tert-butylaminothiocarbonyl, benzylaminothiocarbonyl, C_1-10Halogenated hydrocarbon group, three fluorine acetyl, halogenated phenyl, halogenated benzyl, nitrophenyl and any kind of groups or any kind of groups of substituted forms. Among them, the substituent atom or the substituent is preferably a fluorine atom, an alkoxy group or a nitro group.

LG₂More preferably tert-butyl, trityl, phenyl, benzyl, methylbenzyl, tert-butylButylthio, benzylthio, 2-pyridylthio, 2-pyridylcarbonyl, tert-butyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, tert-butyloxythiocarbonyl, phenoxythiocarbonyl, benzyloxythiocarbonyl, tert-butylthiothiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, trifluoroacetyl and the like.

LG₂More preferably, it is any of tert-butyl, trityl, phenyl, benzyl, methylbenzyl, tert-butylthio, benzylthio, 2-pyridylthio and the like.

LG₂Most preferred is methyl, ethyl, allyl or benzyl.

Wherein, X₆Is a terminal group attached to the oxygen atom of the ester group and is selected from a hydroxyl protecting group or the group LG₄. Wherein LG is₄The definitions of (a) and (b) are consistent with the above.

In this case, Q is not particularly limited as long as it contributes to the induction of unsaturated bond electrons and the conjugation effect.

When Q is on the ring, it may be one or more. When a plurality of structures are used, the same structure may be used, or a combination of two or more different structures may be used.

Q may be an atom or a substituent.

When atomic, Q is selected from a hydrogen atom or a halogen atom, preferably a hydrogen atom or a fluorine atom.

When a substituent, Q is selected from the group consisting of, but not limited to, all combinations of substituents listed in the term part. May or may not contain carbon atoms. In the case where no carbon atom is contained, for example, a nitro group may be mentioned. When carbon atoms are contained, the number of carbon atoms is not particularly limited, but 1 to 20 carbon atoms are preferable, and 1 to 10 carbon atoms are more preferable.

When a substituent, the structure of Q is not particularly limited, and includes, but is not limited to, a linear structure, a branched structure containing a pendant group, or a cyclic structure. Among them, the cyclic structure is not particularly limited, and the above-mentioned aliphatic ring, aromatic ring, sugar ring, and condensed ring are preferable.

Q may be selected from any one atom or group of a hydrogen atom, a halogen atom, a non-carbon containing substituent, a hydrocarbyl group, a heterohydrocarbyl group, a substituted hydrocarbyl group or a substituted heterohydrocarbyl group.

Q is preferably a hydrogen atom, a halogen atom, a nitro group-containing substituent, an acyl group-containing substituent, or C_1-20Haloalkyl, C_1-20Alkyl radical, C_2-20Alkenyl radical, C_3-20Open-chain alkenyl, C_3-20Cycloalkyl, aryl, arylalkyl, C_1-20Heteroalkyl, heteroaryl, heteroaralkyl, C_1-20Alkoxy, aryloxy, aralkyloxy, C_1-20Heteroalkyloxy, heteroaryloxy, heteroarylhydrocarbyloxy, C_1-20Alkylthio, arylthio, aralkylthio, C_1-20Any one atom or group, or substituted version of any one group, of heteroalkylthio, heteroarylthio, heteroarylalkylthio, and the like. Wherein, the substituted heteroatom or substituent in Q is not particularly limited, including but not limited to any substituted heteroatom or any substituent of the term moiety, selected from any of halogen atoms, hydrocarbyl substituents, heteroatom-containing substituents.

Q is more preferably a hydrogen atom, a halogen atom, a nitro group-containing substituent, an acyl group, an ester group-containing substituent at the terminal, a thioester group-containing substituent at the terminal, an amide bond-containing substituent at the terminal, C_1-20Haloalkyl, C_2-20Alkenyl radical, C_3-20Open-chain alkenyl, C_3-20Cycloalkyl, aryl, arylalkyl, C_1-20Heteroalkyl, heteroaryl, heteroaralkyl, C_1-20Alkoxy, aryloxy, aralkyloxy, C_1-20Heteroalkyloxy, heteroaryloxy, heteroarylhydrocarbyloxy, C_1-20Alkylthio, arylthio, aralkylthio, C_1-20Any one atom or group, or substituted version of any one group, of heteroalkylthio, heteroarylthio, heteroarylalkylthio, and the like. Wherein the acyl group is not particularly limited, including but not limited to any acyl type of the term moiety. As an example, the acyl group in Q may be selected from the group consisting of carbonyl, sulfonyl, sulfinyl, phosphoryl, phosphorylidene, hypophosphoryl, nitroxyl, nitrosyl, thiocarbonyl, imidoyl, thiophosphoryl, dithiophosphoryl, thiophosphorylAcyl, thiophosphorous acyl, dithiophosphorousyl, thiophosphoryl, thiophosphonyl, dithiophosphophonyl, thiophosphinyl and the like. Any of acyl groups such as a carbonyl group, a thiocarbonyl group, a sulfonyl group, and a sulfinyl group is preferable. More preferably, the acyl group is a carbonyl group, thiocarbonyl group, sulfonyl group or sulfinyl group.

Q is more preferably a hydrogen atom, a halogen atom, a nitro group-containing substituent, or C_1-20Carbonyl group, C_1-20Alkylthio carbonyl of C_1-20Sulfonyl radical, C_1-20Alkyloxycarbonyl, C_1-20Alkylthio carbonyl group, C_1-20Alkylaminocarbonyl radical, C_1-20Alkyloxythiocarbonyl radical, C_1-20Alkylthio thiocarbonyl radical, C_1-20Alkylamino thiocarbonyl radical, C_1-20Alkyloxysulfonyl, C_1-20Alkyloxysulfinyl, arylthiocarbonyl, aryloxycarbonyl, arylthiocarbonyl, arylaminocarbonyl, aryloxysulfonyl, aryloxysulfinyl, aralkylthiocarbonyl, aralkyloxycarbonyl, aralkylthiocarbonyl, aralkylaminocarbonyl, aralkyloxythiocarbonyl, aralkylthiothiocarbonyl, aralkylaminothiocarbonyl, aralkyloxysulfonyl, aralkyloxysulfinyl, C_1-20Alkyl radical, C_2-20Alkenyl radical, C_3-20Open-chain alkenyl, C_3-20Cycloalkyl, aryl, arylalkyl, C_1-20Heteroalkyl, heteroaryl, heteroaralkyl, C_1-20Alkoxy, aryloxy, aralkyloxy, C_1-20Heteroalkyloxy, heteroaryloxy, heteroarylhydrocarbyloxy, C_1-20Alkylthio, arylthio, aralkylthio, C_1-20Heteroalkylthio, heteroarylthio, heteroarylalkylthio, C_1-20Haloalkyl, and the like, or substituted versions of either group.

Q is more preferably a hydrogen atom, a halogen atom, a nitro group-containing substituent, or C_1-10Carbonyl group, C_1-10Alkylthio carbonyl of C_1-10Sulfonyl, alpha-amino acid or alpha-amino acid,C_1-10Alkyloxycarbonyl, C_1-10Alkylthio carbonyl group, C_1-10Alkylaminocarbonyl radical, C_1-10Alkyloxythiocarbonyl radical, C_1-10Alkylthio thiocarbonyl radical, C_1-10Alkylamino thiocarbonyl radical, C_1-10Alkyloxysulfonyl, C_1-10Alkyloxysulfinyl, arylthiocarbonyl, aryloxycarbonyl, arylthiocarbonyl, arylaminocarbonyl, aryloxysulfonyl, aryloxysulfinyl, aralkylthiocarbonyl, aralkyloxycarbonyl, aralkylthiocarbonyl, aralkylaminocarbonyl, aralkyloxythiocarbonyl, aralkylthiothiocarbonyl, aralkylaminothiocarbonyl, aralkyloxysulfonyl, aralkyloxysulfinyl, C_1-20Alkyl radical, C_2-10Alkenyl radical, C_3-10Open-chain alkenyl, C_3-10Cycloalkyl, aryl, arylalkyl, C_1-10Heteroalkyl, heteroaryl, heteroaralkyl, C_1-10Alkoxy, aryloxy, aralkyloxy, C_1-10Heteroalkyloxy, heteroaryloxy, heteroarylhydrocarbyloxy, C_1-10Alkylthio, arylthio, aralkylthio, C_1-10Heteroalkylthio, heteroarylthio, heteroarylalkylthio, C_1-10Haloalkyl, and the like, or substituted versions of either group.

Specifically, Q may be selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, a nitrophenyl group, an acetyl group, a benzoyl group, a p-toluenesulfonate group, a methanesulfonate group, a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butyloxycarbonyl group, a phenoxycarbonyl group, a benzyloxycarbonyl group, a methylthioacyl group, an ethylthioacyl group, a tert-butylthiocarbonyl group, a phenylthiocarbonyl group, a benzylthiocarbonyl group, an ethylaminoacyl group, a tert-butylaminocarbonyl group, a phenylaminocarbonyl group, a benzylaminocarbonyl group, a methoxythiocarbonyl group, an ethoxythiocarbonyl group, a tert-butyloxycarbonyl group, a phenoxythiocarbonyl group, a benzyloxythiocarbonyl group, a methylthiothiocarbonyl group, an ethylBenzylthiocarbonyl, ethylaminoacyl, tert-butylaminothiocarbonyl, phenylaminothiocarbonyl, benzylaminothiocarbonyl, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, heptyl, 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, vinyl, propenyl, allyl, propynyl, propargyl, cyclopropyl, cyclopropenyl, phenyl, benzyl, butylphenyl, p-methylphenyl, methoxy, ethoxy, phenoxy, benzyloxy, methylthio, ethylthio, phenylthio, benzylthio, C_1-20Haloalkyl, and the like, or substituted versions of either group. Wherein, butyl includes but is not limited to n-butyl and tert-butyl. Octyl includes, but is not limited to, n-octyl, 2-ethylhexyl. Among them, the substituent atom or the substituent is selected from any one of a halogen atom, a hydrocarbon substituent and a heteroatom-containing substituent, and is preferably a halogen atom, an alkoxy group, an alkenyl group, an aryl group or a nitro group.

Q is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, a nitrophenyl group, an acetyl group, a benzoyl group, a p-toluenesulfonyl group, a methanesulfonic group, a methoxyacyl group, an ethoxyacyl group, a tert-butyloxycarbonyl group, a phenoxycarbonyl group, a benzyloxycarbonyl group, a methylthioacyl group, an ethylthioacyl group, a tert-butylthiocarbonyl group, a phenylthiocarbonyl group, a benzylthiocarbonyl group, an ethylaminoacyl group, a tert-butylaminocarbonyl group, a phenylaminocarbonyl group, a benzylaminocarbonyl group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, a vinyl group, a propenyl group, an allyl group, a propynyl group, a propargyl group, a cyclopropyl group, a cyclop, Trifluoromethyl, 2,2, 2-trifluoroethyl, and the like, or a substituted version of any. Among them, the substituent atom or the substituent is preferably a fluorine atom, an alkoxy group, an alkenyl group, an aryl group or a nitro group.

Q is more preferably any one atom or group selected from a hydrogen atom, a fluorine atom, a methyl group, a trifluoromethyl group, a methoxy group, a methyloxycarbonyl group, a p-toluenesulfonyl group, a methanesulfonyl group and the like.

Q is more preferably any one atom or group selected from a hydrogen atom, a fluorine atom, a methyl group, a trifluoromethyl group, a methoxy group, a methyloxycarbonyl group and the like.

Wherein Q is₃Is an H atom or a group that contributes to the induction, conjugation effect of unsaturated bond electrons;

Q₃selected from the group consisting of, but not limited to, all of the substituent atoms and combinations of substituents listed in the term part, as long as they contribute to the induction, conjugation effect of the unsaturated bond electrons.

Q₃May or may not contain carbon atoms. In the case where no carbon atom is contained, for example, a nitro group may be mentioned. When carbon atoms are contained, the number of carbon atoms is not particularly limited, but 1 to 20 carbon atoms are preferable, and 1 to 10 carbon atoms are more preferable.

Q₃The structure of (a) is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. Among them, the cyclic structure is not particularly limited, and the above-mentioned aliphatic ring, aromatic ring, sugar ring, and condensed ring are preferable.

Q₃Can be selected from any atom or group of hydrogen atom, halogen atom, substituent without carbon, alkyl, heteroalkyl, substituted alkyl or substituted heteroalkyl. Wherein Q is₃The substituted heteroatom or substituent in (1) is not particularly limited, including but not limited to any substituted heteroatom or any substituent of the term moiety selected from any of halogen atoms, hydrocarbyl substituents, heteroatom-containing substituents.

Q₃More preferably a hydrogen atom, a halogen atom, C_1-20Alkyl radical, C_2-20Alkenyl radical, C_3-20Open-chain alkenyl, C_3-20Cycloalkyl, aryl, arylalkyl, C_1-20Heteroalkyl, heteroaryl, heteroaralkyl, C_1-20Alkoxy, aryloxy, aralkyloxy, C_1-20Heteroalkyloxy, heteroaryloxy, heteroarylhydrocarbyloxy, C_1-20HeteroalkanesAlkylthio, heteroarylthio, heteroarylalkylthio, C_1-20Haloalkyl, and the like, or substituted versions of either group.

Q₃More preferably a hydrogen atom, a halogen atom, C_1-10Haloalkyl, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_3-10Open-chain alkenyl, C_3-10Cycloalkyl, aryl, arylalkyl, C_1-10Heteroalkyl, heteroaryl, heteroaralkyl, C_1-10Alkoxy, aryloxy, aralkyloxy, C_1-10Any atom or group, or substituted version of any group, of heteroalkyloxy, heteroaryloxy, heteroarylhydrocarbyloxy, and the like.

Specifically, Q₃Can be selected from hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, n-propyl group, isopropyl group, butyl group, pentyl group, hexyl group, heptyl group, 2-ethylhexyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, eicosyl group, vinyl group, propenyl group, allyl group, propynyl group, propargyl group, cyclopropyl group, cyclopropenyl group, phenyl group, benzyl group, butylphenyl group, p-methylphenyl group, nitrophenyl group, p-methoxyphenyl group, azaphenyl group, methoxy group, ethoxy group, phenoxy group, benzyloxy group, methylthio group, ethylthio group, phenylthio group, benzylthio group, C_1-20Haloalkyl, and the like, or substituted versions of either group. Wherein, butyl includes but is not limited to n-butyl and tert-butyl. Octyl includes, but is not limited to, n-octyl, 2-ethylhexyl. Among them, the substituent atom or the substituent is selected from any one of a halogen atom, a hydrocarbon substituent and a heteroatom-containing substituent, and is preferably a halogen atom, an alkoxy group, an alkenyl group or a nitro group.

Q₃Preferably a hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, n-propyl group, isopropyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, vinyl group, propenyl group, allyl group, propynyl group, propargyl group, cyclopropyl group, cyclopropenyl group, phenyl group, benzyl group, butyl groupPhenyl, p-methylphenyl, p-nitrophenyl, o-nitrophenyl, p-methoxyphenyl, azaphenyl, methoxy, ethoxy, phenoxy, benzyloxy, methylthio, ethylthio, phenylthio, benzylthio, trifluoromethyl, 2,2, 2-trifluoroethyl, and the like, or a substituted version of any of these. Among them, the substituent atom or the substituent is preferably a fluorine atom, an alkoxy group, an alkenyl group or a nitro group. The azaphenyl group is preferably pyridyl, pyrimidine, pyrazine, 1,3, 5-triazine.

Q₃More preferably any atom or group of a hydrogen atom, a methyl group, a trifluoromethyl group, a phenyl group, a p-nitrophenyl group, an o-nitrophenyl group, a pyridyl group or a substituted form thereof, a diaza-phenyl group or a substituted form thereof, a triaza-phenyl group or a substituted form thereof, and the like.

Q₃More preferably a hydrogen atom, methyl group, phenyl group, pyridyl group, diazophenyl group, triazophenyl group.

Q₃More preferably a hydrogen atom, a methyl group, a phenyl group or a pyridyl group.

Q₃Most preferably a hydrogen atom, a phenyl group or a pyridyl group.

Wherein Q is₆Is a hydrogen atom or a methyl group. Q₇Is hydrogen atom, methyl, phenyl or substituted phenyl. Such as p-methoxyphenyl. In the same molecule, Q₆And Q₇May be the same or different.

Wherein Q is₈The substituent atom or substituent on the imidazolyl group is not particularly limited, and is preferably selected from the group consisting of an H atom, a methyl group, an ethyl group, a propyl group, a butyl group and a phenyl group. When Q is₈May be one or more. When the number is more than 1, the structures may be the same, or a combination of two or more different structures may be used.

Wherein Q is₁₁Is a substituent on the nitrogen atom of tetrazole, preferably phenyl, substituted phenyl or aza phenyl.

Wherein PG₂Is a thiol protecting group, the protected thiol group being denoted as SPG₂。

Wherein PG₃For alkynyl protecting groups, protected alkynyl denotesIs C ≡ CPG₃。

Wherein PG₄Is a hydroxy protecting group, the protected hydroxy group being represented by OPG₄。

Wherein PG₅Is an amino protecting group, the protected amino group being represented by NPG₅。

PG₂、SPG₂、PG₃、PG₄、OPG、PG₅、NPG₅Including but not limited to the structures described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and the respective cited documents. Take CN104530417A as an example, corresponding to section [0520]～[0530]. In general terms, the use of a single,

the SPG₂Preferred are thioether, disulfide, silyl sulfide, thioester, and the like. In particular, SPG₂Any one of tert-butyl sulfide, trityl sulfide, substituted trityl sulfide, tert-butyl dimethyl silyl sulfide, triisopropyl silyl sulfide, benzyl sulfide, substituted benzyl sulfide, p-nitrobenzyl sulfide, o-nitrobenzyl sulfide, acetyl thioester, benzoyl thioester, trifluoroacetyl thioester, tert-butyl disulfide, substituted phenyl disulfide, 2-pyridine disulfide and the like is preferable.

The PG₃Preferred silicon groups include, but are not limited to, the following structures: trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, dimethyl (1,1, 2-trimethylpropyl) silyl group, dimethyl [1, 1-dimethyl-3- (tetrahydrofuran-2H-2-oxy) propyl group]Silicon group, biphenyl dimethyl silicon group, triisopropyl silicon group, biphenyl diisopropyl silicon group, tert-butyl diphenyl silicon group, 2- (2-hydroxy) propyl group and the like.

The PG₄It may be a protecting group for alcoholic hydroxyl group or phenolic hydroxyl group. OPG₄Preferred are ether, silyl ether, ester, carbonate, sulfonate, and the like. In particular, OPG₄Preferably methyl ether, 1-ethoxyethyl ether, tert-butyl ether, allyl ether, benzyl ether, p-methoxybenzyl ether, o-nitrobenzyl ether, p-nitrobenzyl ether, 2-trifluoromethylbenzyl ether, methoxymethyl ether, 2-methoxyethoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, methylthiomethyl ether, methylthio methyl ether, benzyl ether,tetrahydropyranyl ether, trimethylsilyl ether, triethylsilyl ether, triisopropylsilyl ether, tert-butyldimethylsilyl ether, acetate, chloroacetate, trifluoroacetate, carbonate, and the like. Among the ether protective structures, 1-ethoxyethyl ether, benzyl ether, p-methoxybenzyl ether, o-nitrobenzyl ether, p-nitrobenzyl ether, 2-trifluoromethylbenzyl ether, vinyl ethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, tetrahydropyranyl ether are preferable.

The PG₅May be a protecting group for primary amine, secondary amine, hydrazine, etc. NPG₅Preferred are structures such as carbamate, amide, imide, N-alkylamine, N-arylamine, imine, enamine, imidazole, pyrrole, indole, and the like. In particular, NPG₅Preferably, it is any of formamide, acetamide, trifluoroacetamide, tert-butyl carbamate, 2-iodoethyl carbamate, benzyl carbamate, 9-fluorenemethyl carbamate, 2-trimethylsilylethyl carbamate, 2-methylsulfonylethyl carbamate, 2- (p-toluenesulfonyl) ethyl carbamate, phthalimide, diphenylmethyleneamine, 1,3, 5-dioxazacyclohexane, methylamino, triphenylmethylamino, tert-butylamino, allylamino, benzylamino, 4-methoxybenzylamino, benzylimine, and the like.

Wherein PG₆Is a bishydroxy protecting group, and PG₆And two oxygen atoms form an acetal structure of a five-membered ring or a six-membered ring. PG (Picture experts group)₆Selected from methylene or substituted methylene. The PG₆The substituent(s) of (a) is a hydrocarbyl substituent or a heteroatom-containing substituent, including, but not limited to, the following: methylene, 1-methylmethylene, 1-dimethylmethylene, 1-cyclopentylene, 1-cyclohexylene, 1-phenylmethylene, 3, 4-dimethylphenylmethylene, and the like.

4.3.4. Containing functional groups- (Z)₁)_q1-R₀₁Examples of (2)

By way of example, - (Z)₂)_q-(Z₁)_q1-R₀₁Including but not limited to documents CN104877127A, CN104877127A, CN104530413A, CN104530415A, CN104530417A and the references cited thereinThe structures listed. Including but not limited to CN104530417A paragraph [0531]～[0592]CN104877127A paragraph [0458]～[0505]The structures listed.

4.4. Degradability

The functionalized eight-arm polyethylene glycol can be stable or degradable. When degradable, the number of degradable sites in the same molecule may be 1 or more. With respect to the degradable site: (1) can be located in CORE, L₀、G、(Z₂)_q-(Z₁)_q1Any one of the degradable groups; (2) but not for Z, at the junction of any of the above groups with an adjacent group₁-R₀₁The degradability of the attachment site of (a) is defined. In the first case, the degradable group may contain a degradable divalent linking group DEGG such as an ester group, a carbonate group, etc. For the second case, the selection may be made at CORE-O, O-L₀、L₀-G、G-Z₂、Z₂-Z₁Degradation of either attachment site can occur.

According to the number of degradable sites and the position difference of the degradable sites in the functionalized eight-arm polyethylene glycol, the stability of the polymer and the releaseability of the modified drug are greatly influenced. (1) When degradation can occur between the functional groups at the ends of the eight polyethylene glycol chains and the polyethylene glycol chain, i.e., - (Z)₂)_q-(Z₁)_q1-the position of the drug molecule and the polyethylene glycol structure are separated, so that the active site of the drug molecule is exposed to the maximum extent, and the drug molecule can approach the unmodified state to the maximum extent. (2) When in the eight-valent central structure CORE (O-)₈When the degradation occurs at the position of CORE-O, the molecular weight of polyethylene glycol which can be connected with the medicine is reduced, thereby reducing the package of the medicine and increasing the medicine effect.

Several degradation modes are typical as follows: (a) when g is 0 or 1, when degradation occurs only at the attachment position of CORE-O, it can be degraded into eight PEG single-chain structures; (b) when g is 0 or 1, when g is only in- (Z)₂)_q-(Z₁)_q1-is degraded at the position containing its linker with the adjacent group on the PEG side,degraded into eight-arm PEG structure and independent functional group residue; (c) when g is 1, and is only in L₀Position (including L)₀Internal, O-L₀Connection, L₀-G-linkage) to an eight-arm PEG structure and a cluster of multiple functional groups linked by G; (d) when G is 1, and degradation occurs only in G, degradation occurs to eight-arm PEG, independent functional group residues, or residues of multiple functional clusters.

The functionalized eight-arm polyethylene glycol allows 1 or more than 1 degradation mode to exist. When more than one degradation mode exists, gradient degradation can occur, and the degradation kinetic process of the modified product can be controlled more flexibly; for PEG modified drugs, the control of pharmacokinetics in vivo is more flexible and fine, and the requirement of complex treatment effect can be met.

A simple eight-valent center CORE (O-)₈And functionalized terminal two types of positions. Wherein, when g is 0, it has an unbranched terminal-O (Z)₂)_q(Z₁)_q1-; g is 1, has a branched end-O-L₀-G-((Z₂)_q(Z₁)_q1-)_k. Including but not limited to the following:

(1) the functionalized eight-arm polyethylene glycol has a stable eight-valent center and stable ends.

(2) The functionalized eight-arm polyethylene glycol has a stable eight-valent center and degradable ends.

(3) The functionalized eight-arm polyethylene glycol has a degradable octavalent center and stable ends.

(4) The functionalized eight-arm polyethylene glycol has a degradable octavalent center and a degradable end.

The functionalized eight-arm polyethylene glycols of the present invention having the structures represented by the general formulae (1) to (3) all have a stable eight-valent center. The ends of which may be stable or degradable. One of the above combinations is preferred to have stable octavalent centers, including (1) and (2).

4.5. Divalent linking group

In the above formula, L is a hydrogen atom when F is not a hydrogen atom₀(g＝1)、Z₁、Z₂Are each a divalent linking group, and each is independent of the other, and may be the same as or different from each other in the same molecule.

L₀(g＝1)、Z₁、Z₂The structure of (a) is not particularly limited, and each independently includes, but is not limited to, a linear structure, a branched structure, or a cyclic-containing structure.

L₀(g＝1)、Z₁、Z₂The number of the non-hydrogen atoms of (b) is not particularly limited, and each is independently preferably 1 to 50 non-hydrogen atoms; more preferably 1 to 20 non-hydrogen atoms; more preferably 1 to 10 non-hydrogen atoms. The non-hydrogen atom is a carbon atom or a heteroatom. The heteroatoms include, but are not limited to, O, S, N, P, Si, B, and the like. When the number of non-hydrogen atoms is 1, the non-hydrogen atoms may be carbon atoms or hetero atoms. When the number of non-hydrogen atoms is more than 1, the kind of non-hydrogen atoms is not particularly limited; may be 1 species, or may be 2 or more than 2 species; when the number of non-hydrogen atoms is more than 1, any combination of carbon atoms and carbon atoms, carbon atoms and hetero atoms, and hetero atoms may be used.

L₀(g＝1)、Z₁、Z₂Each independently preferably having 1 to 50 non-hydrogen atoms; wherein the non-hydrogen atom is C, O, S, N, P, Si or B; when the number of the non-hydrogen atoms is more than 1, the kind of the non-hydrogen atoms is 1,2, or more than 2, and the non-hydrogen atoms are any combination of carbon atoms and carbon atoms, carbon atoms and heteroatoms, and heteroatoms.

L₀(g＝1)、(Z₂)_q-(Z₁)_q1Is not particularly limited, and any one of the divalent linking groups or any one of the divalent linking groups consisting of a group with an adjacent heteroatom is independently a stably existing linking group STAG or a degradable linking group DEGG. For the preferred case, L₀(g＝1)、(Z₂)_q-(Z₁)_q1Any one of the divalent linking groups or any one of the divalent linking groups consisting of a group with an adjacent heteroatom is independently a stably available linking group STAG or a degradable linking group DEGG.

4.5.1. Description of the groups which can be stabilized and degraded

The linker STAG or the degradable linker DEGG which can be stably present in the present invention may be present in the above-mentioned L₀(g＝1)、Z₁、Z₂Any divalent linking group, or a divalent linking group consisting of any divalent linking group and an adjacent heteroatom group, may also be present at the connecting position of CORE-O.

4.5.1.1. Stag, a bivalent connecting group stably existing in the present invention

The stable presence condition of the STAG is not particularly limited, and the stable presence condition may be any condition including, but not limited to, light, heat, low temperature, enzyme, redox, acidic, alkaline condition, physiological condition, in vitro simulated environment, and the like, and preferably any condition including light, heat, enzyme, redox, acidic, alkaline, and the like.

The type of STAG is not particularly limited and includes, but is not limited to, alkylene, divalent heteroalkyl, double bond, triple bond, divalent dienyl, divalent cycloalkyl, divalent cycloalkenyl, divalent cycloalkenylhydrocarbyl, aromatic ring, alicyclic ring, heterocyclic ring, fused heterocyclic ring, substituted alkylene, substituted heteroalkyl, substituted divalent heteroalkyl, substituted double bond, substituted triple bond, substituted diene, substituted divalent cycloalkyl, substituted divalent cycloalkenyl, substituted divalent cycloalkenylhydrocarbyl, substituted aromatic ring, substituted alicyclic ring, substituted heterocyclic ring, substituted aromatic heterocyclic ring, substituted fused heterocyclic ring, ether bond, thioether bond, urea bond, thiourea bond, carbamate group, thiocarbamate group, -P (═ O) -, divalent silicon group containing no active hydrogen, divalent linking group containing a boron atom, divalent linking group, divalent heterocyclic group, and the like, Secondary amino, tertiary amino, carbonyl, thiocarbonyl, amido, thioamido, sulfonamido, enamine, triazole, 4, 5-dihydroisoxazole,Any divalent linking group in the skeleton of the amino acid and the derivative thereof, and a stable divalent linking group formed by any two or more than two groups.

In particular, STAGs include, but are not limited to, the structures described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and the respective cited documents. For example, CN104530417A corresponds to the segments [0627] to [0704 ]. The manner in which two or more species of divalent linking groups that can be stably present are combined to form STAG is not particularly limited. Including but not limited to segment [704] of CN 104530417A.

Briefly, a STAG includes, but is not limited to, any one of the following structures, any two or a combination of any two or more of the following structures: -L₇-、-(R₅)_r1-C(R₈)＝C(R₉)-(R₆)_r2-、-(R₅)_r1-C≡C-(R₆)_r2-、-(R₅)_r1-C(R₈)＝C(R₉)-C(R₁₀)＝C(R₁₁)-(R₆)_r2-、-(R₅)_r1-O-(R₆)_r2-、-(R₅)_r1-S-(R₆)_r2-、-(R₅)_r1-N(R₁₈)-C(＝O)-N(R₁₉)-(R₆)_r2-、-(R₅)_r1-N(R₁₈)-C(＝S)-N(R₁₉)-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝O)-O-(R₆)_r2-、-(R₅)_r1-O-C(＝O)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝S)-O-(R₆)_r2-、-(R₅)_r1-O-C(＝S)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝O)-S-(R₆)_r2-、-(R₅)_r1-S-C(＝O)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝S)-S-(R₆)_r2-、-(R₅)_r1-S-C(＝S)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-(R₆)_r2-、-(R₅)_r1-C(＝O)-(R₆)_r2-、-(R₅)_r1-C(＝S)-(R₆)_r2-、-(R₅)_r1-P(＝O)-(R₆)_r2-、-(R₅)_r1-(R₃₈)P(＝O)-(R₆)_r2-、-(R₅)_r1-(R₃₈O)P(＝O)-(R₆)_r2-、-(R₅)_r1-P(＝S)-(R₆)_r2-、-(R₅)_r1-(R₃₈)P(＝S)-(R₆)_r2-、-(R₅)_r1-(R₃₈O)P(＝S)-(R₆)_r2-、-(R₅)_r1-C(＝O)N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)C(＝O)-(R₆)_r2-、-(R₅)_r1-CH₂N(R₇)CH₂-(R₆)_r2-、-(R₅)_r1-NHCH₂-(R₆)_r2-、-(R₅)_r1-CH₂NH-(R₆)_r2-、-(R₅)_r1-CH₂-N(R₇)-CH₂-(R₆)_r2-、-(R₅)_r1-C(R₈)＝C(R₉)-(R₆)_r2-、-(R₅)_r1-C≡C-(R₆)_r2-、-(R₅)_r1-N(R₇)C(＝O)CH₂-S-(R₆)_r2-、-(R₅)_r1-S-CH₂C(＝O)N(R₇)-(R₆)_r2-、-(R₅)_r1-S(＝O)₂-(R₆)_r2-、-(R₅)_r1-S(＝O)-(R₆)_r2-、-(R₅)_r1-(R₈)C＝C(NR₇R₃₉)-(R₆)_r2-、-(R₅)_r1-(NR₇R₃₉)C＝C(R₈)-(R₆)_r2-、-(R₅)_r1-M₁₇(R₂₂)-(R₆)_r2-、

Skeleton of omega-amino carboxylic acids, derived from amino acid skeletonA divalent linking group of a scaffold or amino acid derivative backbone. The preferred case of the omega-aminocarboxylic acids is in accordance with the above.

Wherein r1 and r2 are each independently 0 or 1. The comparison is typically r 1-0. Wherein R is₇、R₁₈、R₁₉、R₈、R₉、R₁₀、R₁₁、M₅、M₆And M₅And M₆The definition of the ring is the same as above, and is not repeated here.

Wherein R is₃₉Is a hydrogen atom or a substituent attached to a nitrogen atom, preferably from a hydrogen atom or C_1-20The hydrocarbon group is more preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or a benzyl group. The above-mentioned-NR₇R₃₉In, R₇And R₃₉May be the same or different. NR (nitrogen to noise ratio)₇R₃₉Preferably NH₂、NHR₃₉、N(R₃₉)₂。

Examples of more typical STAGs include, but are not limited to: r₇、R₁₈、R₁₉Each independently a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentyl, hexyl, allyl, trityl, phenyl, benzyl, nitrobenzyl, p-methoxybenzyl or trifluoromethylbenzyl; r₈、R₉、R₁₀、R₁₁Each independently is a hydrogen atom or a methyl group.

Wherein L is₇Is alkylene or substituted alkylene which can be present stably. Wherein, the substituted heteroatom or substituent is not particularly limited, including but not limited to any substituted heteroatom or any substituent of the term moiety, selected from any one of halogen atoms, hydrocarbyl substituents, heteroatom-containing substituents. L is₇The structure of (b) is not particularly limited and includes, but is not limited to, a linear structure, a branched structure or a cyclic-containing structure. L is₇The number of carbon atoms of (A) is not particularly limited, but preferably 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms. L is₇Preferably C which can exist stably_1-20Alkylene or C_1-20A substituted alkylene group. The conditions under which stable existence is possible are in part consistent with the term。L₇More preferably C which is stable under light, heat, low temperature, enzyme, redox, acidic, alkaline, etc_1-20Alkylene or C_1-20A substituted alkylene group. Corresponding to [633 ] in addition to the divalent linking groups as exemplified in CN104530417A]～[657]A segment comprising an alkylene, methylene or substituted methylene group having a cyclic structure, L₇But are also not limited to phenyl substituted methylene-CH (Ph) -, benzyl substituted methylene-CH (Bn) -, and the like.

-N(R₇) Structures of-include but are not limited to R₇Is methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, phenyl, benzyl.

Wherein R is₅、R₆Can exist stably and are selected from alkylene and substituted alkylene respectively and independently; and in the same molecule, R₅、R₆May be the same as or different from each other. The conditions under which stable presence is possible are in part consistent with the term. R₅、R₆The structure of (a) is not particularly limited, and each independently includes, but is not limited to, a linear structure, a branched structure, or a cyclic-containing structure. R₅、R₆The number of carbon atoms of (A) is not particularly limited, but each is independently preferably 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms. R₅、R₆Can be respectively and independently selected from C which can be stably existed_1-20Alkylene or C_1-20Any of substituted alkylene groups. R₅、R₆Each independently more preferably any alkylene group of a linear alkylene group, a branched alkylene group, a cycloalkyl group, a phenyl group, a fused aryl group, an aralkyl group or any of them substituted by C_1-6Alkyl, phenyl, benzyl, methylphenyl or butylphenyl substituted hydrocarbylene.

R₅、R₆Each independently more preferably having 1 to 10 carbon atoms.

Specifically, R is exemplified by₅、R₆May each independently be selected from the group including, but not limited to, methylene, 1-ethylene, 1, 2-ethylene, 1, 3-propylene, 1, 2-propylene, isopropylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, decamethyleneAny alkylene group of dialkyl, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, cyclopropylene, cyclohexylene, cyclooctylene, cyclodecylene, p-phenylene, o-phenylene, m-phenylene, benzylene, or a substituted form of any one, or a combination of any two or more alkylene groups or substituted alkylene groups. Wherein the substituent is selected from C_1-6Any one of alkyl, phenyl, benzyl, methylphenyl and butylphenyl. Wherein, pentylene includes but is not limited to 1, 5-pentylene, 3-pentylene. Wherein. Heptylene includes, but is not limited to, 1, 7-heptylene, 1-diisopropylmethylene.

R₅、R₆Each independently is more preferably a methylene group, a1, 2-ethylene group, a1, 3-propylene group, a1, 2-propylene group, an isopropylene group, a butylene group, a pentylene group, a hexylene group, a1, 7-heptylene group, a1, 1-diisopropylmethylene group, an octylene group, a cyclopropylene group, a p-phenylene group, an o-phenylene group, an m-phenylene group, a benzylene group, a 1-benzylmethylene group, a 1-phenylmethylene group or the like.

R₅、R₆Most preferably any of methylene, 1, 2-ethylene, 1, 3-propylene, 1, 4-butylene, 1, 5-pentylene, and 1, 6-hexylene.

-M₁₇(R₂₂) A1, 1-cyclic divalent linking group having a ring-forming atom number of preferably 3 to 8(3, 4,5,6,7or 8).

Wherein M is₁₇Is a carbon atom or a heteroatom located on the ring. Preferably a carbon atom, a phosphorus atom or a silicon atom on the ring.

Wherein R is₂₂Is a divalent linking group and participates in ring formation.

R₂₂The number of carbon atoms of (A) is not particularly limited, but is preferably 1 to 20, more preferably 1 to 10.

R₂₂The structure of (a) is not particularly limited and includes, but is not limited to, a linear structure, a branched structure containing a side group, or a cyclic structure. Among them, the cyclic structure is not particularly limited, and the above-mentioned aliphatic ring, aromatic ring, sugar ring, and condensed ring are preferable.

R₂₂May or may not contain heteroatoms.

R₂₂Is selected from C_1-20Alkylene group, C_1-20Divalent heterocarbyl, substituted C_1-20Alkylene, substituted C_1-20Any divalent linking group or any two or any three of divalent heterocarbon groups. Wherein, the substituent atom or substituent is not particularly limited, including but not limited to any substituent atom or any substituent group of the term moiety, selected from any one of halogen atom, hydrocarbyl substituent group, heteroatom-containing substituent group.

R₂₂More preferably C_1-20Open-chain alkylene, C_1-20Alkenyl radical, C_3-20Cycloalkylene radical, C_1-20Cycloalkylene radical, arylene radical, C_1-20Divalent lipoheteroalkyl radical, C_1-20Divalent lipoheteroalkenyl, divalent heteroarylalkyl, substituted alkylene, substituted C_1-20Open alkenylene, substituted C_1-20Cycloalkylene, substituted C_1-20Cycloalkylene radical, substituted aralkylene radical, substituted C_1-20Bivalent lipoheteroalkyl, substituted C_1-20Any one of divalent linking groups of divalent lipoheteroalkenyl groups, substituted divalent heteroaralkyl groups, or any two or any three of the divalent linking groups in combination. Among them, the hetero atom is not particularly limited, and O, S, N, P, Si is preferred.

R₂₂More preferably C_1-10Open-chain alkylene, C_1-10Alkenyl radical, C_3-10Cycloalkylene radical, C_1-10Cycloalkylene radical, arylene radical, C_1-10Divalent lipoheteroalkyl radical, C_1-10Divalent lipoheteroalkenyl, divalent heteroarylalkyl, substituted alkylene, substituted C_1-10Open alkenylene, substituted C_1-10Cycloalkylene, substituted C_1-10Cycloalkylene radical, substituted aralkylene radical, substituted C_1-10Bivalent lipoheteroalkyl, substituted C_1-10Any one of divalent linking groups of divalent lipoheteroalkenyl groups, substituted divalent heteroaralkyl groups, or any two or any three of the divalent linking groups in combination.

Specifically, R₂₂Selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, C_1-20Divalent oxaalkyl radical, C_1-20Divalent thiaalkyl radical, C_1-20Any one of a divalent azaalkyl group, a divalent azaaralkyl group, a substituted version of any one of the groups, a combination of any two or more of the same or different groups, or substituted versions of the groups. Among them, the substituent atom or the substituent is selected from any one of a halogen atom, a hydrocarbon group substituent and a heteroatom-containing substituent, and is preferably a halogen atom, an alkoxy group or a nitro group.

R₂₂Preference is given to 1, 2-ethylene, 1, 2-vinylene or 1, 3-propylene.

Wherein, for example, R₂₂When it is a1, 2-ethylene group, -M₁₇(R₂₂) -correspond to

R₂₂When it is a1, 2-vinylidene group, -M₁₇(R₂₂) -correspond to

R₃₈Is a hydrocarbon radical, preferably C_1-20Hydrocarbyl, more preferably C_1-20Alkyl, more preferably methyl, ethyl, propyl, butyl, pentyl or hexyl.

As a combination of any two or more of the structures, for example, -CH₂O-、-OCH₂-、-CH₂CH₂O-、-OCH₂CH₂-、-OCH₂CH₂O-、-(CH₂)₃O-、-O(CH₂)₃-、-(CH₂)₃O-、-O(CH₂)₃-and the like. As examples of L₀An oligopeptide or polypeptide or the like formed end-to-end of the N-segment and C-terminus, which may comprise a plurality of amino acids, which may be the same or different, but does not include a polypeptide fragment that is degradable by in vivo biological enzymes. Furthermore, L₀In one aspect, the composition may further comprise (L)₇O)_nj-、-(OL₇)_nj-、-(R₂₉O)_nj-、-(OR₂₉)_nj-、-(CH₂CH₂O)_nj-、-(OCH₂CH₂)_nj-and the like. Wherein L is₇、R₂₉The definitions of (a) and (b) are consistent with the above. Wherein the integer nj is the number of the repeating units with a monodisperse structure, and is selected from 2-20, preferably 2-10. However, the CORE (O-)₈Does not include the removal of-CH₂CH₂A heteroatom-containing repeating unit other than O-.

4.5.1.2. Degradable divalent linking group DEGG in the invention

The DEGG is degradable under any conditions including, but not limited to, light, heat, low temperature, enzyme, redox, acidic, basic, physiological conditions, in vitro simulated environment, and the like, preferably under any conditions of light, heat, enzyme, redox, acidic, basic, and the like.

The divalent linking group formed by any combination of DEGG and any STAG remains a degradable linking group. For the degradable divalent linking group containing the aromatic ring, the aromatic ring and the degradable divalent linking group can be combined.

The type of DEGG is not particularly limited and includes, but is not limited to, compounds containing disulfide bonds, vinyl ether bonds, ester groups, thioester groups, dithioester groups, carbonate groups, thiocarbonate groups, dithiocarbonate groups, trithiocarbonate groups, carbamate groups, thiocarbamate groups, dithiocarbamate groups, acetals, cyclic acetals, mercaptals, azaacetals, azacyclic acetals, azathioketals, dithioacetals, hemiacetals, thiohemiacetals, azahemiacetals, ketals, thioketals, azaketals, thioketals, imine bonds, hydrazone bonds, acylhydrazone bonds, oxime bonds, sulfoximine groups, semicarbazide bonds, thiosemicarbazone bonds, hydrazino groups, hydrazide groups, thiocarbonyl groups, azohydrazide groups, thioazodicarbohydrazide groups, hydrazonohydrazide groups, hydrazinoformate groups, hydrazonothiocarbamate groups, carbazoyl groups, thiocarbonate groups, thiohydrazone groups, thiosemicarbazide, Thiocarbazoyl, azo, isoureido, isothioureido, allophanate, thioallophanate, guanidino, amidino, aminoguanidino, amidino, imido, thioesterimidate, sulfonate, sulfinate, sulfonylhydrazino, sulfonylureido, maleimide, orthoester, benzyloxycarbonyl, phosphate, phosphite, hypophosphite, phosphonate, phosphosilicate, silanol, carbonamide, thioamide, sulfonamido, polyamide, phosphoramide, phosphoramidite, pyrophosphoroamide, cyclophosphamide, ifosfamide, thiophosphoramide, aconityl, polypeptide fragment, nucleotide and derivative backbone thereof, any divalent linking group in deoxynucleotide and derivative backbone thereof, or a combination of any two or more divalent linking groups.

The carbamate group, the thiocarbamate group, the carbamide group, the phosphoramide group and the like may be used as a linker which can exist stably or as a degradable linker. Depending on the environmental characteristics of its use.

Specifically, DEGG includes, but is not limited to, structures described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A, and the respective cited documents. Taking CN104530417A as an example, corresponding to segment [705]～[0725]. Briefly, alternative structures of DEGG include, but are not limited to, structures comprising any one of the following, combinations of any two or more of the following: - (R)₅)_r1-S-S-(R₆)_r2-、-(R₅)_r1-C(R₈)＝C(R₉)-O-(R₆)_r2-、-(R₅)_r1-O-C(R₉)＝C(R₈)-(R₆)_r2-、-(R₅)_r1-C(＝O)-O-(R₆)_r2-、-(R₅)_r1-C(＝O)-O-(R₆)_r2-、-(R₅)_r1-C(＝O)-S-(R₆)_r2-、-(R₅)_r1-S-C(＝O)-(R₆)_r2-、-(R₅)_r1-C(＝S)-O-(R₆)_r2-、-(R₅)_r1-O-C(＝S)-(R₆)_r2-、-(R₅)_r1-C(＝S)-S-(R₆)_r2-、-(R₅)_r1-S-C(＝S)-(R₆)_r2-、-(R₅)_r1-O-C(＝O)-O-(R₆)_r2-、-(R₅)_r1-S-C(＝O)-O-(R₆)_r2-、-(R₅)_r1-O-C(＝S)-O-(R₆)_r2-、-(R₅)_r1-O-C(＝O)-S-(R₆)_r2-、-(R₅)_r1-S-C(＝S)-O-(R₆)_r2-、-(R₅)_r1-O-C(＝S)-S-(R₆)_r2-、-(R₅)_r1-S-C(＝O)-S-(R₆)_r2-、-(R₅)_r1-S-C(＝S)-S-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝O)-O-(R₆)_r2-、-(R₅)_r1-O-C(＝O)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝S)-O-(R₆)_r2-、-(R₅)_r1-O-C(＝S)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝O)-S-(R₆)_r2-、-(R₅)_r1-S-C(＝O)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝S)-S-(R₆)_r2-、-(R₅)_r1-S-C(＝S)-N(R₇)-(R₆)_r2-、-(R₅)_r1-CH(OR₃)-O-(R₆)_r2-、-(R₅)_r1-O-CH(OR₃)-(R₆)_r2-、-(R₅)_r1-CH(OR₃)-S-(R₆)_r2-、-(R₅)_r1-S-CH(OR₃)-(R₆)_r2-、-(R₅)_r1-CH(SR₃)-O-(R₆)_r2-、-(R₅)_r1-O-CH(SR₃)-(R₆)_r2-、-(R₅)_r1-CH(SR₃)-S-(R₆)_r2-、-(R₅)_r1-S-CH(SR₃)-(R₆)_r2-、-(R₅)_r1-CH(OR₃)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-CH(OR₃)-(R₆)_r2-、-(R₅)_r1-CH(NR₁₈R₁₉)-O-(R₆)_r2-、-(R₅)_r1-O-CH(NR₁₈R₁₉)-(R₆)_r2-、-(R₅)_r1-CH(NR₁₈R₁₉)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-CH(NR₁₈R₁₉)-(R₆)_r2-、-(R₅)_r1-(R₁₈R₁₉N)C(SR₃)-(R₆)_r2-、-(R₅)_r1-CH(SR₃)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-CH(SR₃)-(R₆)_r2-、-(R₅)_r1-CH(NR₁₈R₁₉)-S-(R₆)_r2-、-(R₅)_r1-S-CH(NR₁₈R₁₉)-(R₆)_r2-、-(R₅)_r1-CH(OH)-O-(R₆)_r2-、-(R₅)_r1-O-CH(OH)-(R₆)_r2-、-(R₅)_r1-CH(OH)-S-(R₆)_r2-、-(R₅)_r1-S-CH(OH)-(R₆)_r2-、-(R₅)_r1-CH(OH)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-CH(OH)-(R₆)_r2-、-(R₅)_r1-CR₁₃(OR₃)-O-(R₆)_r2-、-(R₅)_r1-O-CR₁₃(OR₃)-(R₆)_r2-、-(R₅)_r1-CR₁₃(OR₃)-S-(R₆)_r2-、-(R₅)_r1-S-CR₁₃(OR₃)-(R₆)_r2-、-(R₅)_r1-CR₁₃(SR₃)-O-(R₆)_r2-、-(R₅)_r1-O-CR₁₃(SR₃)-(R₆)_r2-、-(R₅)_r1-CR₁₃(SR₃)-S-(R₆)_r2-、-(R₅)_r1-S-CR₁₃(SR₃)-(R₆)_r2-、-(R₅)_r1-CR₁₃(OR₃)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-CR₁₄(OR₃)-(R₆)_r2-、-(R₅)_r1-CR₁₄(NR₁₈R₁₉)-O-(R₆)_r2-、-(R₅)_r1-O-CR₁₃(NR₁₈R₁₉)-(R₆)_r2-、-(R₅)_r1-CR₁₃(NR₁₈R₁₉))-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-CR₁₃(NR₁₈R₁₉)-(R₆)_r2-、-(R₅)_r1-CR₁₃(SR₃)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-CR₁₃(SR₃)-(R₆)_r2-、-(R₅)_r1-CR₁₃(NR₁₈R₁₉)-S-(R₆)_r2-、-(R₅)_r1-S-CR₁₃(NR₁₈R₁₉)-(R₆)_r2-、-(R₅)_r1-CR₁₃(OH)-O-(R₆)_r2-、-(R₅)_r1-O-CR₁₃(OH)-(R₆)_r2-、-(R₅)_r1-CR₁₃(OH)-S-(R₆)_r2-、-(R₅)_r1-S-CR₁₃(OH)-(R₆)_r2-、-(R₅)_r1-CR₁₃(OH)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-CR₁₃(OH)-(R₆)_r2-、-(R₅)_r1-(R₁₅)C＝N-(R₆)_r2-、-(R₅)_r1-N＝C(R₁₅)-(R₆)_r2-、-(R₅)_r1-(R₁₅)C＝N-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-N＝C(R₁₅)-(R₆)_r2-、-(R₅)_r1-(R₁₅)C＝N-N(R₇)-C(＝O)-(R₆)_r2-、-(R₅)_r1-C(＝O)-N(R₇)-N＝C(R₁₅)-(R₆)_r2-、-(R₅)_r1-(R₁₅)C＝N-O-(R₆)_r2-、-(R₅)_r1-O-N＝C(R₁₅)-(R₆)_r2-、-(R₅)_r1-(R₁₅)C＝N-S-(R₆)_r2-、-(R₅)_r1-S-N＝C(R₁₅)-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝O)-N(R₁₈)-N＝C-(R₆)_r2-、-(R₅)_r1-C＝N-N(R₁₈)-C(＝O)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝S)-N(R₁₈)-N＝C-(R₆)_r2-、-(R₅)_r1-C＝N-N(R₁₈)-C(＝S)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-N(R₁₈)-(R₆)_r2-、-(R₅)_r1-N(R₇)-N(R₁₈)-C(＝O)-(R₆)_r2-、-(R₅)_r1-C(＝O)-N(R₁₈)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-N(R₁₈)-C(＝S)-(R₆)_r2-、-(R₅)_r1-C(＝S)-N(R₁₈)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-N(R₁₈)-C(＝O)-N＝N-(R₆)_r2-、-(R₅)_r1-N＝N-C(＝O)-N(R₁₈)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-N(R₁₈)-C(＝S)-N＝N-(R₆)_r2-、-(R₅)_r1-N＝N-C(＝S)-N(R₁₈)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₁₈)-N(R₇)-C(＝O)-O-(R₆)_r2-、-(R₅)_r1-O-C(＝O)-N(R₇)-N(R₁₈)-(R₆)_r2-、-(R₅)_r1-N(R₁₈)-N(R₇)-C(＝S)-O-(R₆)_r2-、-(R₅)_r1-O-C(＝S)-N(R₇)-N(R₁₈)-(R₆)_r2-、-(R₅)_r1-N(R₁₈)-N(R₇)-C(＝O)-S-(R₆)_r2-、-(R₅)_r1-S-C(＝O)-N(R₇)-N(R₁₈)-(R₆)_r2-、-(R₅)_r1-N(R₁₈)-N(R₇)-C(＝S)-S-(R₆)_r2-、-(R₅)_r1-S-C(＝S)-N(R₇)-N(R₁₈)-(R₆)_r2-、-(R₅)_r1-N(R₇)-N(R₁₈)-C(＝O)-N(R₁₉)-N(R₂₃)-(R₆)_r2-、-(R₅)_r1-N(R₇)-N(R₁₈)-C(＝S)-N(R₁₉)-N(R₂₃)-(R₆)_r2-、-(R₅)_r1-N＝N-(R₆)_r2-、-(R₅)_r1-O-C(＝NR₁₈)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝NR₁₈)-O-(R₆)_r2-、-(R₅)_r1-O-C(＝NH₂ ⁺)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝NH₂ ⁺)-O-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝NR₁₈)-S-(R₆)_r2-、-(R₅)_r1-S-C(＝NR₁₈)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝NH₂ ⁺)-S-(R₆)_r2-、-(R₅)_r1-S-C(＝NH₂ ⁺)-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₁₈)-C(＝O)-N(R₇)-C(＝O)-O-(R₆)_r2-、-(R₅)_r1-O-C(＝O)-N(R₇)-C(＝O)-N(R₁₈)-(R₆)_r2-、-(R₅)_r1-N(R₁₈)-C(＝S)-N(R₇)-C(＝O)-O-(R₆)_r2-、-(R₅)_r1-O-C(＝O)-N(R₇)-C(＝S)-N(R₁₈)-(R₆)_r2-、-(R₅)_r1-N(R₁₈)-C(＝NR₇)-N(R₁₉)-(R₆)_r2-、-(R₅)_r1-N(R₁₈)-C(＝NH₂ ⁺)-N(R₁₉)-(R₆)_r2-、-(R₅)_r1-C(＝NR₇)-N(R₁₉)-(R₆)_r2-、-(R₅)_r1-N(R₁₉)-C(＝NR₇)-(R₆)_r2-、-(R₅)_r1-N(R₁₈)-C(＝NH₂ ⁺)-(R₆)_r2-、-(R₅)_r1-C(＝NH₂ ⁺)-N(R₁₈)-(R₆)_r2-、-(R₅)_r1-N(R₂₃)-N(R₁₈)-C(＝NR₇)-N(R₁₉)-(R₆)_r2-、-(R₅)_r1-N(R₁₉)-C(＝NR₇)-N(R₁₈)-N(R₂₃)-(R₆)_r2-、-(R₅)_r1-N(R₇)-N(R₁₈)-C(＝NH₂ ⁺)-N(R₁₉)-(R₆)_r2-、-(R₅)_r1-N(R₁₉)-C(＝NH₂ ⁺)-N(R₁₈)-N(R₇)-(R₆)_r2-、-(R₅)_r1-C(＝NR₇)-N(R₁₈)-N(R₁₉)-(R₆)_r2-、-(R₅)_r1-N(R₁₉)-N(R₁₈)-C(＝NR₇)-(R₆)_r2-、-(R₅)_r1-N(R₁₉)-N(R₁₈)-C(＝NH₂ ⁺)-、-(R₅)_r1-C(＝NH₂ ⁺)-N(R₁₈)-N(R₁₉)-(R₆)_r2-、-(R₅)_r1-C(＝NR₇)-O-(R₆)_r2-、-(R₅)_r1-O-C(＝NR₇)-(R₆)_r2-、-(R₅)_r1-O-C(＝NH₂ ⁺)-(R₆)_r2-、-(R₅)_r1-C(＝NH₂ ⁺)-O-(R₆)_r2-、-(R₅)_r1-C(＝NR₇)-S-(R₆)_r2-、-(R₅)_r1-S-C(＝NR₇)-(R₆)_r2-、-(R₅)_r1-S-C(＝NH₂ ⁺)-(R₆)_r2-、-(R₅)_r1-C(＝NH₂ ⁺)-S-(R₆)_r2-、-(R₅)_r1-S(＝O)₂-O-(R₆)_r2-、-(R₅)_r1-O-S(＝O)₂-(R₆)_r2-、-(R₅)_r1-S(＝O)-O-(R₆)_r2-、-(R₅)_r1-O-S(＝O)-(R₆)_r2-、-(R₅)_r1-S(＝O)₂-N(R₇)-(R₆)_r2-、-(R₅)_r1-N(R₇)-S(＝O)₂-(R₆)_r2-、-(R₅)_r1-N(R₁₉)-S(＝O)₂-N(R₁₈)-(R₆)_r2-、-(R₅)_r1-S(＝O)₂-N(R₁₈)-N(R₁₉)-(R₆)_r2-、-(R₅)_r1-N(R₁₉)-N(R₁₈)-S(＝O)₂-(R₆)_r2-、-(R₅)_r1-S(＝O)₂-N(R₁₈)-C(＝O)-N(R₇)-(R₆)_r2-(R₆)_r2-、-(R₅)_r1-N(R₇)-C(＝O)-N(R₁₈)-S(＝O)₂-(R₆)_r2-、-(R₅)_r1-N(R₇)-(CH₂)_r3-O-C(＝O)-、-(R₅)_r1-N(R₇)-(CH₂)_r3-O-C(＝O)-(R₆)_r2-、-(R₅)_r1-O-Si(R₄₁R₄₂)-O-(R₆)_r2-, orthoester groups, phosphate groups, phosphite groups, hypophosphite groups, phosphonate groups, phosphosilane groups, silane groups, carbonamides, thioamides, sulfonamides, polyamides, phosphoramides, phosphoramidites, pyrophosphamides, cyclophosphamides, ifosfamides, thiophosphamides, aconityl groups, polypeptide fragments, divalent linking groups for nucleotides and derivatives thereof, divalent linking groups for deoxynucleotides and derivatives thereof, salts of the corresponding derivatives, salts of the corresponding,

Etc.; wherein R is₃、R₅、R₆、R₇、R₁₈、R₁₉、R₂₃、R₈、R₉、R₁₅、M₁₉、M₂₀、M₅、M₆And M₅And M₆The definition of the ring is the same as above, and is not repeated here. R₄₁、R₄₂Each independently selected from C_1-20Alkyl, phenyl, benzyl, C_1-20Alkyl-substituted phenyl, C_1-20Alkyl-substituted benzyl, C_1-20Any of the alkoxy groups, preferably C_1-6Alkyl, phenyl, benzyl, C_1-6Alkyl-substituted phenyl, C_1-6Alkyl-substituted benzyl, C_1-6Any of alkoxy groups, more preferably C_1-6Any one of alkyl, phenyl and benzyl. In addition, such asThe linker of (a) can exist stably under physiological conditions, but can be degraded under special lighting conditions. Common ester bonds are degradable under acid and alkali conditions. Such as

The ester group in (B) may also be degraded under special lighting conditions ({ Journal of Polymer Science: Part A: Polymer Chemistry,2008,46, 6896-.

Wherein r1 and r2 are each independently 0 or 1.

Wherein r3 is 2,3,4,5 or 6.

Wherein M is₁₅Is a heteroatom selected from oxygen atom, sulfur atom, nitrogen atom; PG (Picture experts group)₉To correspond to M₁₅A protecting group of (a); when M is₁₅When is O, PG₉Corresponding to the protecting group PG for hydroxyl₄When M is₁₅When is S, PG₉Corresponding to mercapto-protecting group PG₂When M is₁₅When is N, PG₉Corresponding to the amino protecting group PG₅。

Wherein n is₁₁The number of double bonds is selected from 0 or a natural number of 1 to 10.

Wherein the content of the first and second substances,is a ring structure that can be degraded into at least two separate fragments. Such as lactide rings, cyclic peptides, etc., as examples.

Wherein R is₁₃、R₁₄Is a hydrogen atom, a heteroatom or a substituent on a secondary or tertiary carbon.

R₁₃、R₁₄The hetero atom and the substituent in (1) are not particularly limited.

R₁₃、R₁₄The number of carbon atoms of (a) is not particularly limited. The aliphatic hydrocarbon group or the aliphatic heterohydrocarbon group is preferably one having 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms, independently of each other. The number of carbon atoms of the aryl group, the arylalkyl group, the heteroaryl group, the heteroarylalkyl group, and the fused heterocycloalkyl group is not particularly limited.

R₁₃、R₁₄Each independently selected from the group consisting of, but not limited to, hydrogen atom, halogen atom, C_1-20Hydrocarbyl radical, C_1-20Heterohydrocarbyl, substituted C_1-20Hydrocarbyl, substituted C_1-20An atom or group of any one of heterohydrocarbyl groups and the like.

Wherein, the substituted atom or substituent is not particularly limited, including but not limited to all substituted atoms and substituents listed in the term part, and is selected from any one of halogen atom, alkyl substituent and heteroatom-containing substituent.

R₁₃、R₁₄Each independently preferably represents a hydrogen atom, a halogen atom, C_1-20Alkyl radical, C_3-20Unsaturated hydrocarbon group, C_1-20Straight chain aliphatic hydrocarbon group, C_3-20Branched aliphatic hydrocarbon group, C_3-20Alicyclic hydrocarbon group, aryl group, aromatic hydrocarbon group, C_1-20Open chain heterohydrocarbyl, C_3-20Alicyclic hydrocarbon group, heteroaryl group, heteroaromatic hydrocarbon group, fused heteroaromatic hydrocarbon group, C_1-20Hydrocarbyloxy radical, C_1-20Hydrocarbylthio radical, C_1-20Alkylamino radical, C_1-20Fatty alkyl acyl, aryl alkyl acyl, C_1-20Lipoheteroalkylacyl, heteroarylacyl, C_1-20Hydrocarbyloxyacyl group, C_1-20Hydrocarbyl thioacyl, C_1-20Hydrocarbyl aminoacyl radical, C_1-20Hydrocarbyl acyloxy radical, C_1-20Hydrocarbyl acylthio radical, C_1-20Hydrocarbyl acylamino groups, and the like, or substituted versions of any of these. Wherein the substituent atom and the substituent are preferably fluorine atom, chlorine atom, bromine atom, iodine atom, C_1-6Alkyl radical, C_1-6Alkenyl, aryl, alkoxy or nitro.

Wherein the acyl group is not particularly limited, including but not limited to any acyl type of the term moiety. Preferred are carbonyl, sulfonyl, sulfinyl, phosphoryl, phosphorylidene, hypophosphoryl, nitroxyl, nitrosyl, thiocarbonyl, imidoyl, thiophosphoryl, dithiophosphoryl, trithiophosphoryl, thiophosphorous, dithiophosphorylidene, thiophosphoryl, dithiophosphoryl, thiophosphorylidene, and the like. More preferably any of an acyl group such as a carbonyl group, thiocarbonyl group, sulfonyl group and sulfinyl group.

R₁₃、R₁₄Each independently more preferably a hydrogen atom, a halogen atom, C_1-20Alkyl radical, C_2-20Alkenyl radical, C_2-20Alkynyl, C_4-20Dienyl radical, C_3-20Alkylene radical, C_3-20Alkynyl radical, C_5-20Diene radical, C_1-20Straight chain aliphatic hydrocarbon group, C_3-20Branched aliphatic hydrocarbon group, C_3-20Cycloalkyl radical, C_3-20Cycloalkenyl radical, C_3-20Cycloalkyne radical, C_5-20Cyclodiolefinyl, phenyl, fused cyclic alkyl, aromatic alkyl, C_1-20Open chain heterohydrocarbyl, C_3-20Alicyclic hydrocarbon group, heteroaryl group, heteroaromatic hydrocarbon group, aromatic fused heteroaromatic hydrocarbon group, heteroaromatic fused heteroaromatic hydrocarbon group, C_1-20Alkoxy radical, C_2-20Alkenyloxy radical, C_2-20Alkynyloxy, aryloxy, aralkyloxy, C_1-20Alkylthio radical, C_2-20Alkenylthio radical, C_2-20Alkynylthio, aralkylthio, C_1-20Alkylamino radical, C_2-20Alkenylamino group, C_1-20Alkyl acyl radical, C_2-20Alkenyl acyl, C_2-20Alkynoyl, aryloyl, aralkoyl, C_1-20Lipoheteroalkylacyl, heteroarylacyl, C_1-20Alkoxyacyl, aryloxyacyl, C_1-20Alkylthio acyl, arylthio acyl, C_1-20Alkylaminoacyl radical, C_1-20Alkyl acyloxy, aryl acyloxy, C_1-20Alkylacylthio, arylylthio, C_1-20An alkyl acylamino group, or the like, or a substituted version of any of these groups.

Specifically, R₁₃、R₁₄Each independently selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an eicosyl group, a cyclopropyl group, a cyclohexyl group, a phenyl group, a benzyl group, a butylphenyl group, a p-methylphenyl group, a vinyl group, a propenyl group, an allyl group, a propynyl group, a propargyl group, a methoxy group, an ethoxy group, aEthyl acyl, phenyl acyl, methoxy acyl, ethoxy acyl, phenoxy acyl, benzyloxy acyl, methylthio acyl, ethylthio acyl, phenylthio acyl, benzylthio acyl, methylaminoacyl, ethylaminoacyl, phenylaminoacyl, benzylaminoacyl, ethyl acyloxy, phenylacyloxy, ethyl acylthio, phenylacylthio, ethyl acylamino, phenylacylamino, C_1-20Haloalkyl, and the like, or substituted versions of any of these groups. Wherein, butyl includes but is not limited to n-butyl and tert-butyl. Octyl includes, but is not limited to, n-octyl, 2-ethylhexyl. The acyl group is any one of the acyl groups described above. Wherein the substituent atom or substituent is selected from any one of halogen atom, hydrocarbyl substituent and heteroatom-containing substituent, preferably halogen atom, C_1-6Alkyl, alkoxy, C_1-6Any one of alkenyl and nitro.

R₁₃、R₁₄More preferably, each independently, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an eicosyl group, a cyclopropyl group, a cyclohexyl group, a phenyl group, a benzyl group, a butylphenyl group, a p-methylphenyl group, a vinylphenyl group, a vinyl group, a propenyl group, an allyl group, a propynyl group, a propargyl group, a nitrophenyl group, a p-methoxyphenyl group, a methoxy group, an ethoxy group, a phenoxy group, a benzyloxy group, a methylthio group, an ethylthio group, ethylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, methylthiocarbonyl, ethylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, benzylaminocarbonyl, methoxysulfonyl, ethoxysulfonyl, phenoxysulfonyl, benzyloxysulfonyl, acetyloxy, benzoyloxy, acetylthioA group, benzoylthio group, acetylamino group, benzoylamino group, ethylthiocarbonyl group, phenylthiocarbonyl group, methoxythiocarbonyl group, ethoxythiocarbonyl group, phenoxythiocarbonyl group, benzyloxythiocarbonyl group, methylthiothiocarbonyl group, ethylthiothiocarbonyl group, phenylthiocarbonyl group, benzylthiocarbonyl group, methylthiothiocarbonyl group, an atom or group selected from ethylthiocarbonyl, phenylthiocarbonyl, benzylthiocarbonyl, methylaminothiocarbonyl, ethylaminothiocarbonyl, phenylaminothiocarbonyl, benzylaminothiocarbonyl, ethylthiocarbonyloxy, phenylthiocarbonyloxy, ethylthiocarbonylthio, phenylthiocarbonylthio, ethylthiocarbonylamino, phenylthiocarbonylamino, trifluoromethyl, 2,2, 2-trifluoroethyl, and the like, or a substituted form of any of them. Wherein, butyl includes but is not limited to n-butyl and tert-butyl. Octyl includes, but is not limited to, n-octyl, 2-ethylhexyl.

R₁₃、R₁₄Each independently is more preferably any one atom or group selected from a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an eicosyl group, a cyclopropyl group, a cyclohexyl group, a phenyl group, a benzyl group, a butylphenyl group, a p-methylphenyl group, a vinylphenyl group, a propenyl group, an allyl group, a nitrophenyl group, a p-methoxyphenyl group, a methoxy group, an ethoxy group, a phenoxy group, a benzyloxy group, a methylthio group, an ethylthio group, a phenylthio group, a benzylthio group, a methylamino. Among them, the substituent atom or the substituent is preferably a fluorine atom or C_1-6Alkyl, alkoxy, C_1-6Any one of alkenyl and nitro.

R₁₃、R₁₄Each independently is more preferably a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a butyl group, a phenyl group, a benzyl group, a butylphenyl group, a p-methylphenyl group, a trifluoromethyl group, a2, 2, 2-trifluoro-phenyl groupAny one atom or group of an ethyl group, or a substituted version of any one of the groups.

R₁₃、R₁₄Each independently most preferably a hydrogen atom or a methyl group.

DEGG is further preferably selected from the group of structures described above that satisfy the following conditions: R1-R2-0, R₇＝R₁₈＝R₁₉＝R₂₃Is a hydrogen atom or a methyl group, R₈＝R₉＝R₁₃＝R₁₄＝R₁₅＝H，R₃Preferably a methyl, ethyl or benzyl group,

DEGG also includes combinations of any of the above degradable divalent linking groups with any suitable stable divalent linking group

4.5.1.3. Degradable polyvalent radical

The degradable trivalent or tetravalent or higher group needs to contain at least one degradable divalent linking group DEGG.

For degradable trivalent groups, but not limited to, groups composed of a stable trivalent group containing a trivalent atomic nucleus structure and a degradable divalent linking group, groups composed of a trivalent aromatic ring and a degradable divalent linking group, combinations of a degradable trivalent ring structure and a divalent linking group that can exist stably, combinations of a degradable trivalent ring structure and a degradable divalent linking group, trivalent forms of any of the degradable divalent linking groups described above. Wherein a degradable trivalent ring structure refers to a trivalent ring structure that is degradable into at least two separate segments. The structure can be a trivalent closed ring structure formed by connecting 2 or more degradable groups in series. For example, cyclic peptides, such as cyclic structures in which 2 or more ester bonds are connected in series. Including but not limited to the structures described and exemplified in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A and the respective cited documents. For example, CN104530417A corresponds to segments [726] to [0731 ].

5. A preparation method of functionalized eight-arm polyethylene glycol is obtained by the following steps:

(i) obtained by end-functionalization modification of an eight-arm polyethylene glycol, (ii) or by coupling reaction of a pre-modified linear functionalized polyethylene glycol with a disaccharide-based small molecule.

The disaccharide based small molecules are in accordance with the above definition and are octahydroxydisaccharide molecules or functionalized derivatives thereof.

The pre-modified linear functionalized polyethylene glycol includes a reactive end and a pre-modified end. Wherein, the reaction end contains a reactive group which can react with the small disaccharide-based molecule to form a covalent linking group. The pre-modified end carries the terminal functional group of the desired modification or a protected form thereof. When the pre-modified end is a protected form of the terminal functional group of the desired modification, the functionalized eight-arm polyethylene glycol represented by the general formula (20) can be obtained by further deprotection after the coupling reaction.

When the substitution rates of the 8 PEG chains are all close to or equal to 100% (at least greater than 90%), it corresponds to the general formula (2).

Controlling the amount of charge for the functionalization modification in (i), preferably less than 1 molar equivalent (relative to the PEG end), or (ii) mixing the hydroxyl end of the linear functionalized polyethylene glycol pre-modified with protected hydroxyl groups, gives k_HA functionalized eight-arm polyethylene glycol other than 0.

For k_HApproximately equal to 1,2,3,4,5,6 or 7, can pass through a variety of k_HThe product of (i) is purified and separated, or the content of the raw material with protected hydroxyl at the hydroxyl end in (ii) is controlled.

5.1. End functionalization

The process of modifying a hydroxyl group or a non-target functional group located at the end of a polyethylene glycol chain into a target functional group is end functionalization, which can be classified into end linear functionalization and end branched functionalization. The functional groups include, but are not limited to, the functional groups listed in class A through class J. When the polyethylene glycol ends with a hydroxyl group after the initiation of ethylene oxide polymerization, g is 0, k is 1, and F is a hydrogen atom, the end forms a hydroxyethyl group.

When F is not a hydrogen atom, the terminal functionalization process when G is 0 is terminal linear functionalization, in which case the corresponding G is absent, k is 1, the functional group R at the end of the polyethylene glycol chain₀₁The number of (2) is 1; the terminal functionalization process when g in F is 1 is terminal-branched functionalization,in this case, k is 2 to 250, G is a branched group having a valence of k +1, and a functional group R is at the end of a polyethylene glycol chain₀₁The number of (2) is k.

When k in F is 1, performing terminal linear functionalization; and when k in F is greater than 1, performing terminal branching functionalization.

The specific method of end-functionalization is described in detail later and will not be expanded here.

5.1.1. Linear functionalization of polyethylene glycol chain ends

The method of terminal linear functionalization is not particularly limited, depending on the type of the final functional group. The functionalization may be linear functionalization based on the hydroxyl group at the end of the polyethylene glycol chain, or conversion to the target functional group based on the reactive group, or a combination of both. Techniques known in the art may be used. And include, but are not limited to, those described and exemplified in documents CN104530413A, CN104530415A, CN 104530417A. For example, CN104530413A corresponds to segments [960] to [1205 ]. The reaction temperature, reaction time, dosage, solvent condition, reaction condition (such as strong basicity and acidity), catalyst, deprotonation reagent, oxidant, reducing agent, alkylation reagent, halogenated reagent, weak acidic salt and other parameters and the optimization of each parameter are well known to those skilled in the art, or can be obtained by optimization through limited experiments, and are not repeated herein, but the reaction principle, reaction raw materials, reaction routes and the like of the reaction types involved (such as condensation reaction, ring-opening reaction, ring-closing condensation reaction, esterification reaction, oxidation reaction, addition reaction, substitution reaction, alkylation reaction, dehydrogenation reaction and the like) are mainly described in general, and the relevant details or the preferred conditions are also well known to those skilled in the art and can be obtained through limited experiments.

5.1.1.1. Class A: r₀₁Functionalization selected from class A

The functional group in class A is an active ester or an analog of an active ester. The preparation method includes, but is not limited to, the following methods.

a: the corresponding active esters (a6-a10, a12, a14) can be obtained by condensation reaction of the terminal hydroxyl intermediate with the corresponding carbonates (N, N '-disuccinimidyl carbonate, di (p-nitrophenyl) carbonate, di (o-nitrophenyl) carbonate, bis-benzotriazol carbonate, etc.), haloformates (p-nitrophenyl chloroformate, o-nitrophenyl chloroformate, trichlorophenyl chloroformate, etc.), N' -carbonyldiimidazole in the presence of a base. The corresponding ring-substituted derivatives of hydrogen atoms can also be obtained in an analogous manner, e.g. by reaction with 1, 1' -carbonylbis (2-methylimidazole) to give the active ester of 2-methylimidazole. The corresponding haloformate is selected from chloro, bromo or iodo, preferably chloro.

b: the corresponding active esters (A1-A5, A11, A13) can also be obtained by condensation reactions. The terminal hydroxyl group is reacted in one step or multiple steps to obtain terminal carboxyl group, and then the terminal carboxyl group is reacted with corresponding alcohol (N-hydroxysuccinimide, p-nitrophenol, o-nitrophenol, trichlorophenol, 1-hydroxybenzotriazole and the like) in the presence of a condensing agent to obtain corresponding active ester.

c: analogs of the active esters (A15-A18) can be prepared by reacting the terminal carboxyl group with the corresponding amine (e.g., thiazole-2-thione, pyrrolidine-2-thione, benzo [ d ] thiazole-2 (3H) -thione, 4-oxo-2-thioxothiazolidine, etc.) in the presence of a condensing agent to give the corresponding amide. The corresponding derivatives in which the hydrogen atom of the ring is substituted can also be obtained in an analogous manner, for example by reacting with 4-isopropyl-1, 3-thiazolidine-2-thione, (R) -4-isopropylthiazoline-2-thione, 4-phenylthiazoline-2-thione, etc., to give the corresponding active ester analogs.

The condensing agent is not particularly limited, but is preferably N, N ' -Dicyclohexylcarbodiimide (DCC), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl), 2- (7-azobenzotriazol) -N, N ' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N ' -tetramethyluronium Hexafluorophosphate (HBTU), and most preferably DCC. The solvent may be a non-solvent or an aprotic solvent. The base includes generally organic bases, preferably triethylamine, pyridine.

5.1.1.2. Class B: r₀₁Functionalization selected from class B

The sulfonic acid or sulfinate derivatives (B1, B2) can be reacted with a leaving group Y through a terminal hydroxyl group₁The sulfonyl chloride and sulfinyl chloride are obtained by esterification in the presence of alkali. Y is₁The definitions of (a) and (b) are consistent with the above. The solvent may be a non-solvent or an aprotic solvent. The base includes an organic base or an inorganic base, preferably an organic base, more preferably triethylamine, pyridine.

The sulfone or sulfoxide derivative (B3, B4) can be modified by containing a leaving group Y₁The sulfoxide intermediate or thioether intermediate is prepared by oxidation reaction. Y is₁The definitions of (a) and (b) are consistent with the above. The oxidizing agent is not particularly limited as long as it is a compound or a combination of compounds capable of raising the valence of the substrate. The solvent may be a non-solvent or an aprotic solvent.

The sulfone derivative (B3) can be obtained by deprotonation of the terminal hydroxyl group by reaction with a base, and addition reaction with vinyl sulfone.

The disulfonyl derivative (B5) and its modified forms (B6) can be prepared by the methods of the reference { Advanced Drug Delivery Reviews,2008,60,3-12 }.

5.1.1.3. Class C: r₀₁Functionalization selected from class C

The hydroxylamine compound (C1) can be obtained by reacting a terminal hydroxyl group with an excess of hydroxylamine hydrochloride under strongly basic conditions (e.g., diphenylmethyl potassium).

The mercapto derivative (C2) can be obtained by reacting a terminal hydroxyl group with thiourea, and the reaction can be carried out in a solvent or without a solvent, and the solvent is not limited, and preferably water, toluene, benzene, xylene, acetonitrile, ethyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, chloroform, dichloromethane, dimethyl sulfoxide, dimethylformamide or dimethylacetamide, and preferably water, tetrahydrofuran, dichloromethane, acetonitrile.

The mercapto derivative (C2) can also be obtained by reacting a sulfonate compound with a potassium xanthate compound, followed by decomposition with a primary amine. This reaction can be carried out without solvent or with a solvent, which is not limited, and an aprotic solvent is preferred.

The protected sulfur compound (C7) can be prepared by reacting the corresponding sulfur compound (C2) with the corresponding protecting agent. The method of preparation is not limited, including but not limited to the following methods: a. thioether-protected sulfides can be prepared by reacting a sulfur compound with a corresponding alkylating agent having a leaving group in the presence of a base. The solvent may be a non-solvent or an aprotic solvent. b. Thioesters (C7& C17) can be prepared from sulfur compounds by reaction with the corresponding acid halides in the presence of a base. The solvent may be a non-solvent or an aprotic solvent.

The amine derivative (C4) can be subjected to coupling reaction of terminal hydroxyl and acrylonitrile or the like under the catalysis of alkali, and then the cyano can be reduced in an autoclave under the catalysis of palladium or nickel to obtain the corresponding amine. This reaction can be carried out without solvent or under solvent conditions, the solvent being not limited, preferably water or 1, 4-dioxane and combinations thereof. The base includes organic base or inorganic base, preferably inorganic base, more preferably sodium hydroxide, potassium hydroxide.

The amine derivative (C4) can also be obtained by reacting a sulfonate compound (B1) with aqueous ammonia.

Protected amine compounds (C6) can be prepared by reacting the corresponding amine (C3) with the corresponding protecting reagent. The method of preparation is not limited, and includes, but is not limited to, the following methods:

a. the carbamate compounds can be prepared by reacting amines with the corresponding haloformates in the presence of a base. The solvent may be a non-solvent or an aprotic solvent. The base includes an organic base or an inorganic base, preferably an organic base, more preferably triethylamine, pyridine.

b. The amide compound can be prepared by reacting amine with corresponding acyl halide in the presence of alkali.

c. Alkylated amino compounds can be prepared by reacting an amine with a corresponding alkylating agent having a leaving group in the presence of a base. The solvent may be an aprotic or non-protic solvent base including organic or inorganic bases, preferably organic bases, more preferably triethylamine, pyridine, sodium hydride, DPMK, potassium hydride, sodium alkoxide.

d. Another process for the preparation of alkylated amine compounds is that the imine (Schiff base) is reduced to the corresponding alkylated amine compound (C5) in the presence of a reducing agent after the imine has been prepared by reacting the amine with the corresponding aldehyde or ketone. The corresponding aldehyde or ketone is not particularly limited. The solvent may be a protic solvent or an aprotic solvent, and the solvent includes toluene, benzene, xylene, acetonitrile, ethyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methanol, ethyl acetate, dimethylformamide or dimethylacetamide, preferably tetrahydrofuran, methanol, ethyl acetate. The reducing agent is not particularly limited as long as it can reduce the Schiff base formed from ammonia and aldehyde or ketone to an amino group; preferably one or a combination of sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, borane, diborane, diisobutylaluminum hydride, diisopinocampheylborane, lithium borohydride, zinc borohydride, borane-pyridine, borane-methyl sulfide, borane-tetrahydrofuran, and the like; more preferably sodium cyanoborohydride.

The halide (C7), tetramethylpiperidinyloxy compound (C8), and dioxopiperidinyloxy compound (C9) can be obtained by reacting the sulfonate compound (B1) with the corresponding halide salt, 2,6, 6-tetramethylpiperidine-nitrogen-hydroxy, 3, 5-dioxo-1-cyclohexylamine. The bromine salt is not limited as long as free bromide ions are generated in the solvent, and sodium bromide and potassium bromide are preferable.

The halogenated compound (C7) can also be obtained by reacting a terminal hydroxyl group with a halogenating agent. The halogenating agent is not particularly limited as long as it can convert a hydroxyl group into a corresponding halogen atom, and is preferably one or a combination of thionyl chloride, phosphorus trichloride, phosphorus tribromide, dibromosulfoxide, and the like. The solvent may be a non-solvent or an aprotic solvent.

The ester and thioester compound (C17) can be obtained by condensation of a terminal hydroxyl group, a mercapto group, and a terminal carboxyl group or an acid halide, preferably an acid chloride.

Thioester compounds (C7) can also be obtained by reaction between a sulfhydryl group and an activated ester. Reference is made to the document { Journal of Controlled Release,2014,194: 301-.

The carbonate or thiocarbonate compound (C18) can be obtained by condensation reaction of a terminal hydroxyl group, a mercapto group and an oxycarbonylchloride compound. Such as ethyl chloroformate, ethyl thiocarbonate.

The trithiocarbonate derivative (C18) can also be obtained by coupling reaction of a trithiocarbonate-containing small molecule compound (such as 3- (benzylthio-thiocarbonylthio) propionic acid) with a functionalized polyethylene glycol carrying a suitable functional group.

The ester compound (D11) is treated with ammonia water and hydrazine hydrate to obtain the amide compound (C20) and the hydrazide compound (C21), respectively.

The halogenated acetamide compound (C10) can be obtained by reacting halogenated acetic acid with polyethylene glycol amine derivative (C4) under the action of a condensing agent to generate amide bond.

The lipoic acid derivative (C14) can be obtained by condensation reaction of lipoic acid with corresponding alcohol (H1) or amine (C4).

5.1.1.4. Class D: r₀₁Functionalization selected from class D

The ester compounds (D11) and thioester compounds (D26, D27, D28) can be obtained by deprotonating the terminal hydroxyl group and then subjecting the resulting product to substitution reaction with an α -haloester. For example, ethyl chloroacetate and ethyl bromoacetate.

Thioesters (D26) are also obtained by reaction of the corresponding ester (D11) with a thiol.

The ester compound (D11) is hydrolyzed with an alkaline solution to give a carboxylic acid compound (D1).

The acid halide compound (D4) can be obtained by reacting a carboxylic acid compound (D1) with a halogenating agent. The halogenating agent is not particularly limited as long as it can convert a hydroxyl group in the carboxylic acid into a corresponding halogen atom, and is preferably one or a combination of thionyl chloride, phosphorus trichloride, phosphorus tribromide, dibromosulfoxide, and the like. The solvent may be a non-solvent or an aprotic solvent.

The acid anhydride derivative (D11) can be obtained by reacting the carboxylic acid derivative (D4) with an acid halide, a small-molecule acid anhydride, or a small-molecule mixed acid anhydride. The acid halide, the small-molecule acid anhydride, and the small-molecule mixed acid anhydride reagent are not particularly limited as long as they can convert a carboxylic acid into the corresponding acid anhydride, and C is preferred_1-10Acid chloride, C_1-10Acyl bromide, C_1-10Anhydride, and the like, or combinations thereof.

The sulfonic acid derivative (D2) can be obtained by alkylating a haloalkylsulfonic acid (e.g., 2-bromoethylsulfonic acid) with a terminal hydroxyl group.

The acetaldehyde derivative (D6) can be obtained by direct oxidation of the terminal hydroxyl group. The oxidizing agent is not particularly limited, but preferably pdc (pyridinium chloride), pcc (pyridinium dichloride), DCC + DMSO, oxalyl chloride + MDSO, sulfur trioxide pyridine + DMSO, trifluoroacetic anhydride + DMSO, MnO are used₂Preferably DCC + DMSO. The reaction solvent is not particularly limited, and an aprotic solvent is preferred. In addition, a weakly acidic salt should be added in this reaction, and there is no particular limitation, but pyridine trifluoroacetate, triethylamine trifluoroacetate, pyridine hydrochloride, triethylamine hydrochloride, pyridine sulfate, triethylamine sulfate and the like are preferable, and pyridine trifluoroacetate is more preferable.

Propionaldehyde and other aldehyde derivatives (D6) can be deprotonated by the terminal hydroxyl group and then reacted with a halide to give an acetal intermediate (D7), and the compound (D7) is hydrolyzed under acidic conditions to give the corresponding aldehyde. The base used for deprotonation is not particularly limited, and sodium, potassium, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, or diphenylmethyl potassium is preferred, and sodium hydride or diphenylmethyl potassium is more preferred. The reaction solvent is not particularly limited, and an aprotic solvent is preferred. The acetal deprotection is carried out under acidic conditions, the solution pH preferably being 1 to 4. The acid is not particularly limited, but acetic acid, phosphoric acid, sulfuric acid, hydrochloric acid, nitric acid are preferable, and hydrochloric acid is more preferable. The reaction solvent is not particularly limited as long as it can dissolve the reactants and the product, and water is preferred.

The aldehyde derivative (D6) can also be introduced through a coupling reaction of a small molecule reagent containing an acetal structure and acetal deprotection. For example, the corresponding-C (═ O) - (CH) can be obtained by amidation reaction of polyethylene glycol amine with 2, 2-diethoxyacetic acid, 3-diethoxypropionic acid, 4-diethoxybutyric acid, 5-diethoxypentanoic acid, and removing acetal protection₂)_0～3A CHO aldehyde derivative.

The acetal derivative (D7) can also be prepared by reacting polyethylene glycol aldehyde derivative (D6) with corresponding alcohol under the catalysis of acid to obtain polyethylene glycol (D7) in aldehyde protection form. The acid is not particularly limited, and may be a protonic acid or a Lewis acid, and among them, hydrochloric acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, aluminum trichloride, stannic chloride and the like are preferable. Among them, protonic acids are preferable, and hydrochloric acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, phosphoric acid, and nitric acid are more preferable. The protonic acid is preferred, and the alcohol is more preferred, but not particularly limited, and may be a monohydric alcohol, a dihydric alcohol or a polyhydric alcohol, among which methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, 1, 3-propanediol, 1, 4-butanediol, and the like are preferred. The solvent may be a non-solvent or an aprotic solvent.

The isocyanate (D9) and thioisocyanate (D10) derivatives can be obtained by reacting an alcohol (H1) and an amine derivative (C4) with an excess of diisocyanate or dithioisocyanate. The diisocyanate and dithioisocyanate are not particularly limited, and preferably contain C_1-10Diisocyanate, C_1-10A dithioisocyanate. The solvent may be a non-solvent or an aprotic solvent. The diisocyanate includes, but is not limited to, 1, 6-hexamethylene diisocyanate, dimethylbiphenyl diisocyanate, methylene di-p-phenylene diisocyanate, toluene-2, 4-diisocyanate, 1, 5-naphthalene diisocyanate, m-xylylene isocyanate, isophorone diisocyanate, 4-diisocyanate dicyclohexylmethane, bis (2-isocyanate) -5-norbornene-2, 3-dicarboxylate.

The oxycarbonylchloride derivative (D12) can be obtained by reacting a terminal hydroxyl group (H1) with triphosgene under basic conditions. The base is preferably an organic base, such as dimethylaminopyridine, for example. The solvent is preferably an aprotic solvent, such as, for example, dichloromethane.

Squaric acid ester (D24) can be obtained by the reaction between an amine derivative (C4) and a squaric acid diester.

5.1.1.5. Class E: r₀₁Functionalization selected from class E

The maleimide derivative (E1) can be prepared by the ring-opening reaction of an amine compound (C4) and maleic anhydride to obtain an acid intermediate (E5), and then the ring-closing condensation reaction is carried out under the catalysis of acetic anhydride or sodium acetate. The reaction solvent is not particularly limited, and an aprotic solvent is preferred. In the ring-closing condensation reaction, the solvent is not limited, and the above-mentioned aprotic solvent or acetic anhydride is preferable.

The maleimide derivative (E1) can also be obtained by condensation reaction of an amine compound (C3) with an acid or an active ester containing a maleimide group (MAL group). Acids containing MAL groups include, but are not limited to, 3-maleimidopropionic acid, 4-maleimidobenzoic acid, 6-maleimidocaproic acid, 11-maleimidoundecanoic acid. Active esters containing MAL groups include, but are not limited to, maleimidoacetate succinimidyl ester, 3-maleimidopropionate hydroxysuccinimide ester, 6- (maleimido) hexanoate succinimidyl ester, 3-maleimidobenzoate succinimidyl ester, 4- (N-maleimidomethyl) cyclohexane-1-carboxylate succinimidyl ester, 4- (4-maleimidophenyl) butyrate succinimidyl ester, 11- (maleimido) undecanoate succinimidyl ester, N- (4-maleimidobutyryl) succinimide. Similarly, the diaza maleimide derivative (E6) can also be obtained by condensation reaction of an amine compound (C3) with a corresponding acid or active ester.

The maleimide derivative (E1) can also be obtained by condensation reaction of an active ester derivative (A1-A14) and an amine containing an MAL group. The amine containing MAL groups include, but are not limited to, N- (2-aminoethyl) maleimide, N- (4-aminophenyl) maleimide.

The α, β -unsaturated esters (E2, E3) can be obtained by deprotonating the terminal hydroxyl group and then reacting with the corresponding halide. The base to be deprotonated is not limited, and is preferably metallic sodium, potassium, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide or diphenylmethyl potassium, more preferably sodium hydride or diphenylmethyl potassium. The reaction solvent is not limited, and an aprotic solvent is preferred. Examples of the halide include acryloyl chloride and methacryloyl chloride.

The derivative (E5) can also be prepared by reacting an amine derivative (C5) with a corresponding dicarboxylic acid in the presence of a condensing agent to obtain a corresponding amide derivative. The condensing agent is not particularly limited, but DCC, EDC · HCl, HATU, HBTU are preferred, and DCC is most preferred. The solvent may be a non-solvent or an aprotic solvent. The base includes generally organic bases, preferably triethylamine, pyridine.

Azo compounds (E7), cyclic compounds containing unsaturated double bonds (E8), norbornene compounds (E9), 2, 5-norbornadiene compounds (E10) and 7-oxa-bicyclo [2.2.1] hept-5-ene compounds (E11) can be obtained by condensation reaction of alcohol, carboxylic acid, amine, amide and methyl ester derivatives containing corresponding ring structures with corresponding reactive groups to generate linking groups including but not limited to ester bonds, amide bonds, urethane bonds, carbonate bonds, hydrazide bonds and the like. Such as cyclooctene-4-methanol of the type (E8), methyl-4-cycloocten-1-yl carbonate, cyclooctene-4-carboxylic acid. Examples of compounds such as (E9) include, but are not limited to, 5-norbornene-2-methanol, 5-norbornene-2-carboxylic acid (2-hydroxyethyl) ester, a-dimethylbicyclo [2.2.1] hept-5-ene-2-methanol, 5-norbornene-2-methylamine, 5-norbornene-2-carboxylic acid, 2-methylbicyclo [2.2.1] hept-5-ene-2-carboxylic acid, hydrogen succinate-1- (1-bicyclo [2.2.1] hept-5-ene-2-ethyl) ester, 5-norbornene-2-carboxamide, 2-methylbicyclo [2.2.1] hept-5-ene-2-carboxamide, 2-cyano-5-norbornene, 5-norbornen-2-yl (ethyl) chlorodimethylsilane, N- [4- (4-aminophenyl) phenyl ] -5-norbornene-2, 3-dicarboximide, N-hydroxy-5-norbornene-2, 3-dicarboximide, 5-norbornene-2-carbaldehyde, nadic anhydride, methylendomethylenetetrahydrophthalic anhydride, N-methyl-N-propargyl- (5-norbornadiene-2-methylamine).

5.1.1.6. Class F: r₀₁Functionalization selected from class F

The compounds (F1, F2, F3 and F4) can be obtained by deprotonating a terminal hydroxyl and then carrying out substitution reaction with a corresponding halide. The base to be deprotonated is not limited, and is preferably metallic sodium, potassium, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide or diphenylmethyl potassium, more preferably sodium hydride or diphenylmethyl potassium. The reaction solvent is not particularly limited, and an aprotic solvent is preferred. Examples of the halogenated compound corresponding to the epoxy compound (F1) include epichlorohydrin, 2-chloromethyl-2-methyloxirane, 3-chlorophenyloxirane, epifluoropropane, epibromohydrin, 4-bromo-1, 2-epoxybutane, 6-bromo-1, 2-epoxyhexane, etc.; epichlorohydrin is preferred. Examples of the halogenated compound corresponding to the vinyl compound (F1) include 3-vinyl chloride and 3-vinyl bromide. Examples of the halide corresponding to the acetylene compound include 3-bromopropyne. Examples of the halide corresponding to the protected acetylene compound include 3-methylsilylbromopropyne and 3-tert-butyldimethylsilylbromidepyne.

5.1.1.7. Class G: r₀₁Functionalization selected from class G

Cycloalkyne compounds (G1-G7), cyclodiolefine compounds (G8, G9) and furan compounds (G10) can be obtained by condensation reaction of alcohol, carboxylic acid, amine, amide and methyl ester derivatives containing corresponding ring structures with corresponding reactive groups to generate linking groups including but not limited to ester bonds, amide bonds, urethane bonds, carbonate bonds, hydrazide bonds and the like. The following are exemplified as raw materials:

and the like.

The azide compound (G21) can be obtained by reacting the sulfonate compound (B1) with the corresponding azide salt. The azide salt is not limited as long as a free azide ion is generated in the solvent, and sodium azide and potassium azide are preferable. The solvent for the reaction is not limited, and is preferably carried out in a solvent of water, ethanol, acetonitrile, dimethyl sulfoxide, dimethylformamide or dimethylacetamide, preferably water and dimethylformamide.

The cyanohydrin (G22) can be obtained by oxidizing an aldehyde derivative (D6) and hydroxylamine to form an oxime (G24). The oxime is formed in a solvent which may be a non-solvent or an aprotic solvent. In the oxidation process, the oxidizing agent is not particularly limited, and is preferably one or a combination of N-iodosuccinimide, N-chlorosuccinimide, N-bromosuccinimide, and the like. The solvent may be a non-solvent or an aprotic solvent.

The nitrile compound (G23) can be obtained by an addition reaction between a terminal hydroxyl group and acrylonitrile under basic conditions. Or the amine derivative (C4) is obtained by firstly pressurizing with ammonia and then pressurizing with hydrogen under the catalysis of nickel or palladium carbon, and then carrying out dehydrogenation reaction under the condition of high temperature.

Compounds (G31) and (G32) can be prepared using the methods of the literature PCT/US2013/046,989.

5.1.1.8. Class H: r₀₁Functionalization selected from class H

The product obtained after initiating the polymerization of ethylene oxide is a mixture of alcohol and oxyanion, and is protonated to obtain a polyethylene glycol chain with terminal hydroxyl groups (H1).

The hydroxyl-terminated alcohol derivative (H1) may also be obtained by modifying a non-hydroxyl-reactive group, for example, by reacting ethylene carbonate with a secondary amine to form-NH-CH (═ O) CH₂CH₂An alcohol of OH structure.

The hydroxyl-terminated alcohol derivative (H1) can also be obtained by diazotizing an amine derivative (C4) with a nitrite and hydrolyzing under low-temperature acidic conditions. The acid is not particularly limited, and may be a protonic acid or a Lewis acid, among which protonic acids are preferable, and hydrochloric acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, phosphoric acid, and nitric acid are more preferable. The low temperature is preferably about 0 ℃.

The protected hydroxyl group (H2) can be obtained by reacting a terminal hydroxyl group with a protecting agent, and the protecting agent is not particularly limited, but a halosilane, a carboxylic acid, an acid chloride, an acid anhydride, a halogenated hydrocarbon, a sulfonyl chloride, an alkenyl ether, a carbonyl group, and the like are preferable.

A. Typically, the terminal hydroxyl group is reacted with a halosilane, acid chloride, acid anhydride, sulfonyl chloride, halohydrocarbon under neutral conditions or in the presence of a base to afford the protected form (H2). The solvent may be a non-solvent or an aprotic solvent. The base includes an organic base or an inorganic base, preferably an organic base, more preferably triethylamine, pyridine. Protected forms of the ether structure OPG₄In accordance with the foregoing.

B. The terminal hydroxyl group is reacted with a carboxylic acid in the presence of a base and a condensing agent under reaction conditions to produce (H2)₀₁The process for preparing active esters selected from class A is similar.

C. The terminal hydroxyl group is subjected to addition reaction with an alkenyl ether in the presence of an acid to give (H2), and the alkenyl ether is not particularly limited, but ethyl vinyl ether and tetrahydropyran are preferable. Among them, the acid is not particularly limited, and may be a protonic acid or a Lewis acid. The solvent may be a non-solvent or an aprotic solvent.

D. The terminal hydroxyl group and tert-butyldimethylchlorosilane, vinyl ether, dihydropyran, benzyl bromide and di-tert-butyl dicarbonate can be respectively protected by silicon base, vinyl ether base, dihydropyran base, benzyl and Boc.

The end-protected bishydroxy group (H3) can be obtained by a method including, but not limited to, references { Macromol. biosci.2011,11,1570-1578}, references { J.Am. chem. Soc., Vol.123, No.25,2001 }.

The photoreactive groups (H6) and (H7) which can be converted into enolic hydroxyl groups can be prepared by the method of document U.S. Pat. No. 3, 14,021,040.

5.1.1.9. Class I: r₀₁Functionalization selected from class I

The pegylated folic acid (I1) can be obtained by condensation reaction of carboxyl group in folic acid with polyethylene glycol alcohol or its alcohol derivative (H1) and amine derivative (C4), and among them, the condensation agent is not particularly limited, but DCC, EDC HCl, HATU, HBTU, and DCC are preferred. While the condensing agent is generally 1 to 20 times, preferably 5 to 10 times, the molar equivalent of folic acid, and a suitable catalyst (e.g., 4-dimethylaminopyridine) may be added for this reaction. The solvent may be a non-solvent or an aprotic solvent. The base includes generally organic bases, preferably triethylamine, pyridine.

The pegylated cholesterol (I2) can be obtained by condensation reaction of terminal hydroxyl group of polyethylene glycol with carboxylic acid (D1), acid halide (D4), sulfonyl chloride (D5), isocyanate (D9), isothiocyanate (D10), and the like. The pegylated cholesterol may also be obtained by coupling of a derivative of cholesterol with a suitable group. Taking cholesteryl hydrogen succinate as an example, the cholesteryl hydrogen succinate can be obtained by condensation reaction with the terminal hydroxyl of polyethylene glycol.

The pegylated biotin (I3) can be obtained by condensation reaction of carboxyl group in biotin with polyethylene glycol or its alcohol derivative (H1) and amine derivative (C4). The reaction conditions are the same as those described above for the reaction between carboxyl groups and hydroxyl groups. Biotin derivatives such as D-desthiobiotin and 2-iminobiotin can also be obtained by condensation of carboxyl groups with polyethylene glycol or its alcohol derivatives (H1) and amine derivatives (C4).

The pegylated biotin (I3) can also be obtained by coupling reaction of biotin derivatives including but not limited to those disclosed above in the present invention with suitable polyethylene glycol or derivatives thereof selected from the group consisting of polyethylene glycol, amine derivatives of polyethylene glycol (C4), alkyne derivatives (F3, G1-G7), carboxylic acid derivatives (D1), acid halide derivatives (D4), aldehyde derivatives (D6), and the like. Wherein, the amine derivative and the alcohol derivative of the biotin can also be subjected to alkylation reaction with corresponding polyethylene glycol sulfonate or polyethylene glycol halide.

5.1.1.10. Class J: r₀₁Functionalization selected from class J

Fluorescein and its derivatives (including but not limited to J1, J3), rhodamine and its derivatives (including but not limited to J2), anthracene and its derivatives (J4), pyrene and its derivatives (J5), coumarin and its derivatives (including but not limited to J6), fluorescein 3G and its derivatives (including but not limited to J7), carbazole and its derivatives (J8), imidazole and its derivatives (J9), indole and its derivatives (J10), and succinimide active esters (A1, A6), carboxyl (D1), primary amino (C4), secondary amino (C15), hydrazine or substituted hydrazine (C12), such as N-aminocarbazole, cyano (G23), unsaturated bonds of maleimide (E1), maleimide (C21), aldehyde groups (D6), acrylate groups (E2), methacrylate groups (E3), oxime groups (G24), and derivatives (J3957), And (3) carrying out coupling reaction on the hydroxyl (H1) and the functionalized polyethylene glycol to obtain the polyethylene glycol modified bio-related substance. The coupling reaction includes, but is not limited to, the coupling reaction described above. Among them, the starting materials of the category (J1-J10) include, but are not limited to, the fluorescent reagents disclosed above in the present invention.

5.1.1.11. Conversion to target functional groups based on reactive groups

The method can be realized by any one of the following modes: (1) and (3) direct modification, namely, based on the direct modification of the reactive group, obtaining the target functional group. By way of example, such as the conversion of a carboxyl group to an active ester, an active ester analog, an acid halide, a hydrazide, an ester, a thioester, a dithioester, such as the conversion of a hydroxyl group, a thiol group, an alkynyl group, an amino group, a carboxyl group, etc., to the corresponding protected structure, and the like. For example, the acid anhydride modifies a hydroxyl group, an amino group, or the like. (2) Coupling reaction between two reactive groups, using a heterofunctional reagent containing 1 reactive group and a target functional group as a raw material, and introducing the target functional group through the reaction between one of the reactive groups and the reactive group at the tail end of a polyethylene glycol chain. The reaction mode and method between two reactive groups are not particularly limited, and include, but are not limited to, the above-mentioned coupling reaction methods such as alkylation reaction, α, β -unsaturated bond addition reaction, alkynyl addition reaction, schiff base reaction combined reduction reaction, condensation reaction, azide-alkyne cycloaddition reaction, 1, 3-dipolar cycloaddition reaction, Diels-Alder reaction, thiol-yne reaction, thiol-ene reaction, thiol-vinyl reaction, condensation reaction, and the like. Among them, the alkylation reaction is preferably a reaction based on alkylation of a hydroxyl group, a mercapto group or an amino group, which in turn corresponds to formation of an ether bond, a thioether bond, a secondary amino group or a tertiary amino group. Wherein the condensation reaction includes, but is not limited to, a condensation reaction to form an ester group, a thioester group, an amide group, an imine linkage, a hydrazone linkage, a carbamate group, and the like. For example, the target functional group is introduced by click reaction using a heterofunctionalizing agent containing groups such as azide, alkynyl, alkenyl, trithiocarbonate, mercapto, dienyl, furyl, 12,4, 5-tetrazinyl, cyanooxide and the like and the target functional group as raw materials. The reaction between the two reactive groups is accompanied by the formation of a new bond, and typical examples of the newly formed divalent linking group are an amide bond, a urethane bond, an ester group, a secondary amine bond, a thioether bond, a triazole group, and the like. (3) The target functional group is obtained by a combination of direct modification and coupling reaction.

5.1.2. Branched functionalization of polyethylene glycol chain ends

Branched functionalization refers to the introduction of a branching group at the end of a polyethylene glycol chain to attach a functional group. At this time, the number of functional groups at the end of the corresponding polyethylene glycol chain is more than 1. The polyethylene glycol chain ends to which the branching groups are introduced may be hydroxyl groups or linear functionalized reactive groups selected from class a-class H.

5.1.2.1. Terminal branching functionalization process

Functionalized modification of branched endsThe process comprises two links of introducing a branched group and introducing a functional group. The order of these two steps is not particularly limited. In this case, the terminal-branching functionalization can be achieved in several ways including, but not limited to: (1) the functionalized branched group directly reacts with the hydroxyl at the end of the polyethylene glycol chain; (2) carrying out functional modification on the terminal hydroxyl of the main chain polyethylene glycol, and then reacting with a functional branched group; (3) firstly introducing a branching group, and then carrying out functional modification on the branching group. Wherein the introduction of the branching groups may or may not form the linking group L₀. Taking the terminal hydroxyl of polyethylene glycol as an example: when the branching group is attached by alkylation, the branching agent loses the leaving group and the hydroxyl group loses the hydrogen atom, at which time it is believed that no linking group is formed, or it is believed that a new linking ether bond is formed, at which time L₀Comprises CH₂CH₂O; for another example, when the terminal hydroxyl group of polyethylene glycol reacts with a group such as isocyanate group or carboxyl group, the whole or part of NHCO, CO, etc. forming a new bond NHCOO, COO, etc. is contained in L₀Performing the following steps; as another example, succinic acid-functionalized polyethylene glycol termini can be reacted with a branching agent to form a linker containing a succinyl group. The method for the functional modification of the branched group is not particularly limited, and includes a functional modification based on a hydroxyl group, and also includes conversion to a new functional group based on a non-hydroxyl functional group.

The method for introducing the above-mentioned branched group is not particularly limited, and the existing techniques in the chemical field may be employed as long as the covalent bonding can be formed, including but not limited to the various coupling reactions described above. Examples include Macromolecules 2013,46,3280-3287, Macromolecules 2012,45,3039-3046, Macromolecules Chem 2012,3,1714-1721, US5,811,510, US7,790,150, US7,838,619, etc., and examples include Journal of Polymer Science, Part A, Polymer Chemistry,2013,51,995-1019, macromolecule Biosci 2010, 11, 3-propan-2, hyperbranched structures 1565, Langiu 2010,26(11, 3-propan-8881, hyperbranched structures 2011pidd. mu.2010, 31,1811-1815, 9, 2011-propan. 20, 2011-20, 31, 1551-250-8881, etc., hyperbranched structures contained in Macromolecules 20135, 2011-8875, 27035, Polyp # 2703-250-31, 97-250, 97-250, etc., such as Macromolecules 27035, 2673, 20143, 2673, 20143, 1553, etc. The branched structures described in the above documents and the methods for their preparation are incorporated herein by reference.

The method of functionalizing the terminal of the branched group is not particularly limited, and includes, but is not limited to, the above-mentioned linear functionalizing methods.

5.1.2.2. Terminal branched functionalized feedstock

When end-difunctional, it is preferably selected from the group consisting of heterofunctional small molecules htriSM, aldehydes containing 1 epoxy group, alcohols containing 1 epoxy group (e.g. htriSM, htr

) Sulfonate containing 1 epoxy group, halide containing 1 epoxy group, compound containing one epoxy group and 1 other reactive group. Also included are combinations of Michael addition reactions of primary amines with 2 molecules of acrylates. Or the lipoic acid is adopted to carry out end capping, and then the disulfide bond is reduced to open the ring, so that two sulfydryl groups at the tail end are obtained.

The heterofunctionalized small molecule htriSM includes but is not limited to the structures listed and cited in paragraphs [0902] to [0979] of the document CN 104877127A.

The heterofunctional small molecule htriSM contains two different functional groups, wherein one functional group is 1, and the other functional group is two. Pairs of heterofunctional groups that may be present simultaneously include, but are not limited to: hydroxyl and protected hydroxyl, hydroxyl or protected hydroxyl and non-hydroxyl reactive groups of class A-class H (such as amino, protected amino, amine salt, aldehyde group, active ester group, maleimide group, carboxyl, protected carboxyl, alkynyl, protected alkynyl, azido, alkenyl, acrylic group, acrylate group, methacrylate group, epoxy group, isocyanate group and the like), hydroxyl or protected hydroxyl and functional groups of class I-class J or derivatives thereof (such as targeting group, photosensitive group and the like), active ester group and maleimide groupActive ester group and aldehyde group, active ester group and azide group, active ester group and alkyne group or protected alkyne group, active ester group and acrylate group, active ester group and methacrylate group, active ester group and acrylate group, maleimide group and azide group, maleimide group and alkyne group or protected alkyne group, maleimide group and acrylate group, maleimide group and methacrylate group, maleimide group and acrylate group, maleimide group and carboxyl group, maleimide group and amino group or protected amino group or amine salt, maleimide group and isocyanate group, maleimide group and protected thiol group, aldehyde group and azide group, aldehyde group and acrylate group, aldehyde group and methacrylate group, aldehyde group and acrylate group, aldehyde group and epoxy group, aldehyde group and carboxyl group, aldehyde group and alkyne group or protected alkyne group, azide group and thiol group or protected thiol group, Azido and amino or protected amino or amine salt, azido and acrylate group, azido and methacrylate group, azido and acrylate group, azido and carboxyl, acrylate group and amino or protected amino or amine salt, acrylate group and isocyanate group, acrylate group and epoxy group, acrylate group and methacrylate group, acrylate group and carboxyl, methacrylate group and amino or protected amino or amine salt, methacrylate group and isocyanate group, methacrylate group and epoxy group, alkynyl or protected alkynyl and amino or protected amino or amine salt, alkynyl or protected alkynyl and isocyanate group, alkynyl or protected alkynyl and acrylate group, alkynyl or protected alkynyl and methacrylate group, alkynyl or protected alkynyl and acrylate group, and, Alkynyl or protected alkynyl and epoxy group, alkynyl or protected alkynyl and carboxyl group, protected alkynyl and azido group, acrylic group and isocyanate group, acrylic group and acrylate group, acrylic group and epoxy group, acrylic group and carboxyl group, carboxyl group and mercapto group or protected mercapto group, carboxyl group and amino group or protected amino or amine salt, carboxyl group and isocyanate group, carboxyl group and epoxy group, amino group or protected amino or amine salt and mercapto group or protected mercapto group, targeting group and non-targeting groupHydroxyl-reactive groups, photosensitive groups, non-hydroxyl-reactive groups, and the like. Wherein the active ester includes, but is not limited to, any one of the active esters of succinimide (such as succinimide carbonate), p-nitrophenyl active ester, o-nitrophenyl active ester, benzotriazole active ester, 1,3, 5-trichlorobenzene active ester, 1,3, 5-trifluorobenzene active ester, pentafluorobenzene active ester, imidazole active ester, 2-thiothioxothiazolidine-3-carboxylate, 2-thiopyrrolidine-1-carboxylate, etc.; the amino group includes primary and secondary amino groups. The amine salt is preferably in the form of the hydrochloride salt of an amino group such as NH₂HCl。

The htriSM includes, but is not limited to, alcohols, thiols, primary amines, secondary amines, sulfonates or halides containing two naked or two protected hydroxyl groups (again, for example, triethanolamine p-toluenesulfonate, glycerol monothioglycolate, 3, 4-dihydroxy-2' -chloroacetophenone, and protected forms of the hydroxyl groups of htriSM described above), alcohols, thiols, primary amines, secondary amines, sulfonates or halides containing two or two protected thiol groups (again, for example, dimercaprol and protected forms of the thiol groups thereof), alcohols, thiols, primary amines, secondary amines, two protected primary amines or two protected secondary amines, thiols, sulfonates or halides, and the like. Among them, alcohols containing two primary amines are exemplified by 1, 3-diamino-2-propanol.

The htriSM also includes, but is not limited to: primary amines containing 2 hydroxyl groups, aldehydes containing 2 protected hydroxyl groups, aldehydes containing 1 epoxy group, primary amines containing 1 epoxy group, secondary amines containing 2 primary amino groups, sulfonic acids containing 2 hydroxyl groups, carboxylic acids containing 2 hydroxyl groups, azide compounds containing two hydroxyl groups, and protected forms of the hydroxyl groups described above. The primary amine containing 2 hydroxyl groups includes, but is not limited to, 2-amino-1, 3-propanediol, 2-amino-2-methyl-1, 3-propanediol, N-bis (2-hydroxyethyl) ethylenediamine, 3-amino-1, 2-propanediol, 2-amino-1- [4- (methylthio) phenyl ] glycol]1, 3-propanediol, 2-amino-1-phenyl-1, 3-propanediol, 2- (3, 4-dihydroxyphenyl) ethylamine, 2-amino-1, 3-benzenediol, and the like. The secondary amines containing 2 primary amino groups include, but are not limited to, diethylenetriamine, N- (3-aminopropyl) -1, 4-butanediamine, 3' -diaminodipropylamine, N- (2-aminoethyl) -1, 3-propanediamine, 3, 6-diaminocarbazole, and the like. Said containsSulfonic acids having two hydroxyl groups include, but are not limited to, 6, 7-dihydroxynaphthalene-2-sulfonic acid, 1, 4-dihydroxyanthraquinone-2-sulfonic acid. The carboxylic acid having 2 hydroxyl groups (dihydroxy monocarboxylic acid) includes, but is not limited to, 2, 3-dihydroxypropionic acid, 2-dimethylolpropionic acid, 2, 4-dihydroxy-3, 3-dimethylbutyric acid, N-dihydroxyethylglycine, 2, 3-dihydroxybenzoic acid, 2, 4-dihydroxybenzoic acid, 2, 5-dihydroxybenzoic acid, 2, 6-dihydroxybenzoic acid, 3, 4-dihydroxybenzoic acid, 3, 5-dihydroxybenzoic acid, 3, 4-dihydroxycinnamic acid, 2, 6-dihydroxypyridine-4-carboxylic acid, 4, 8-dihydroxyquinoline-2-carboxylic acid. The azide compound containing two hydroxyl groups includes but is not limited to 3-azido-2, 3-dideoxy-1-O- (tert-butyldimethylsilyl) -beta-D-arabino-hexapyranose, 2-dimethylolpropionic acid azidohexyl ester. Wherein both hydroxy groups are protected, e.g. with a bishydroxy group, e.g.

The htriSM also includes, but is not limited to: 3-allyloxy-1, 2-propanediol, 5-norbornene-2, 3-dicarboxylic acid, 1-propynylglycerol ether, 2, 6-dihydroxy-3-cyano-4-methylpyridine, 1, 3-dibromo-2-propanol, 2, 3-dibromo-1-propanol, 1, 4-dibromo-2-butanol, 1, 4-diazido-2-butanol, 1, 3-dichloropropanol, 4' -dichlorobenzhydrol, 2-bromomalonaldehyde, 2-hydroxyhexanal, 2- (4-chlorophenyl) malonaldehyde, 2- (3-hydroxycarbonyl-6-pyridyl) malonaldehyde, 7-amino-1, 3-naphthalenedisulfonic acid, 4-chloro-1, 2-phenylenediamine, 4-bromoo-phenylenediamine, 6, 8-dimercaptooctanoic acid, 4-chloro-1, 3-benzenedithiol, 2, 6-bis (p-azidobenzylidene) -4-carboxycyclohexanone, hydroxy dicarboxylic acids (including but not limited to tartronic acid, L-malic acid, D-malic acid, citramalic acid, 3-hydroxyglutaric acid), aminodicarboxylic acids (including but not limited to 2-aminomalonic acid, diethyl 2-aminomalonate, 3-aminoglutaric acid), mercaptodicarboxylic acids (including but not limited to mercaptosuccinic acid), 4-chlorophthalic acid, 2-bromosuccinic acid, itaconic acid, 4-amino-2- (2-.Aminoethylamino) butyric acid, 4-amino-2- (2-aminoethylamino) butyric acid in which both amino groups are protected, glycerol dimethacrylate, 2-bis (allyloxymethyl) -1-butanol, a salt of a compound of formula (I),

And the like, and a form in which any of the above-mentioned functional groups in an amount of 2 is protected.

The htriSM also includes, but is not limited to: lysine, lysine with two amino groups protected, glutamic acid and aspartic acid.

Since both hydrogens in the primary amine can be substituted to form a trivalent N branching center, heterofunctionalized small molecules containing one primary amino group and another reactive group can also be used as htriSM. Examples thereof include diglycolamine, 2- (2-aminoethylmercapto) ethanol, 1-amino-2-propanol, 4-hydroxyphenylethylamine, mercaptoethylamine, N-methyl-1, 3-propanediamine, N-ethyl-1, 3-propanediamine, and N-isopropyl-1, 3-propanediamine.

When the terminal trifunctional is carried out, the method includes but is not limited to the use of tetrafunctional small molecule htetraSM containing three hydroxyl groups and another reactive group, and includes but is not limited to: N-Trimethylol-2-aminoethanesulfonic acid, trimethylol-methylaminopropanesulfonic acid, methyl-6-O-p-toluenesulfonyl-alpha-D-glucoside, 2- (bromomethyl) -2- (hydroxymethyl) -1, 3-propanediol, tris, 2-amino-1, 3, 4-octadecanetriol, 3-aminopropylsilanetriol, 4- (2-amino-1-hydroxyethyl) -1, 2-benzenediol, 4- [ (2-isopropylamino-1-hydroxy) ethyl ] -1, 2-benzenediol, 3, 4-dihydroxy-alpha- ((methylamino) methyl) benzyl alcohol, 2, 5-anhydro-1-azido-1-deoxy-D-glucitol, 2,3, 4-trihydroxybutyraldehyde (L-erythrose, D-erythrose, L- (+) -threose, D- (+) -threose), 2,3, 4-trihydroxybenzaldehyde, 3,4, 5-trihydroxybenzaldehyde, tris (hydroxymethyl) methylglycine, 2,3, 4-trihydroxybutyric acid (including but not limited to erythronic acid, threonic acid), 2,4, 6-trihydroxybenzoic acid, shikimic acid, 3,4, 5-trihydroxybenzoic acid, 2,3, 4-trihydroxybenzoic acid, arjunolic acid, 1,4, 7-tri-tert-butoxycarbonyl-1, 4,7, 10-tetraazacyclododecane, tri-tert-butoxycarbonyl spermine, 1,4, 7-tri-tert-butoxycarbonyl-1, 4,7, 10-tetraazacyclododecane, and the like, and hydroxyl groups of any of the foregoing are protected. The surfactant may be selected from the group consisting of citric acid, agaricic acid, N-hydroxyethylethylenediaminetriacetic acid, pentaerythritol triacrylate, aminomethane tripropionic acid, and tri-tert-butyl aminomethane tripropionate. Also included are terminal branching reactions based on alkenyl, trichlorosilane and allylmagnesium chloride, referred to as Macromolecules, Vol.33, No.12,2000, to form tetravalent silicon-based branching centers. Also included are terminal branching reactions based on alkenyl, trichlorosilane, and allyl alcohol to form tetravalent siloxane branching centers. Also included are tri-functionalized small molecules such as 1,4, 7-tris (t-butoxycarbonylmethyl) -1,4,7, 10-azacyclotetradecane (NOTA), which require an excess of such tri-functionalized small molecules.

When the terminal tetrafunctionalization is carried out, the raw material may be selected from pentafunctionalized xylitol, 1, 5-anhydroglucitol, bis (2-hydroxyethyl) amino (trihydroxymethyl) methane, miglitol, D- (+) -talose, arbutin, diethylenetriaminepentaacetic acid, and the like. But preferably heteropentafunctional small molecules containing 2 functional groups. Including but not limited to 1,2,5, 6-diisopropylidene-alpha-D-isofuranose, 2,3,5, 6-di-O-cyclohexylidene-alpha-D-mannose, 2-azido-1, 3-bis [ (2, 2-dimethyl-1, 3-dioxan-5-yl) oxo ] propane, etc., containing four protected hydroxyl groups and one reactive group. But also molecules containing 2 epoxy groups and 1 reactive group. It may also be preferred to have a pentafunctional small molecule hpentSM with two functional groups, one in 4 and the other in 1: 2- (2-hydroxyethylamino) -2-hydroxymethyl-1, 3-propanediol, 2-hydroxymethylpiperidine-3, 4, 5-triol, 6-amino-4- (hydroxymethyl) -4-cyclohexyl- [4H,5H ] -1,2, 3-triol, fenoterol, benserazide, 1-azido-1-deoxy- β -D-galactopyranoside, 2-azidoethyl- β -D-glucopyranoside, 2,3,4, 5-tetrahydroxypentanal (including but not limited to ribose, arabinose, xylose, lyxose), 2,3,4, 5-tetrahydroxypentanoic acid (including but not limited to ribonic acid, arabinonic acid, xylonic acid, lyxonic acid), Diethylenetriamine, N- (3-aminopropyl) -1, 4-butanediamine, and the like, and 4-numbered functional groups of any of the above.

When the terminal penta-functionalization is performed, the starting material preferably contains two functional groups, one of which is a5 number and the other of which is a1 number hexafunctional small molecule hhexaSM, including but not limited to: sorbitol, mannitol, D-talitol, D-glucosamine, 1-mercaptosorbitol, N-methyl-D-glucosamine, 2,3,4,5, 6-pentahydroxyhexanal (including but not limited to beta-D-allose, D-altrose, D-anhydroglucose, D- (+) -mannose, L (-) -mannose, D-gulose, idose, D-galactose, L- (-) -talose, D- (+) -talose), 2,3,4,5, 6-pentahydroxyhexanoic acid (including but not limited to allose, altronic acid, gluconic acid, mannonic acid, gulonic acid, idonic acid, galactic acid, talonic acid), D-sorbitol-3-phosphate, and the like, and forms of any of the foregoing in which the number of functional groups is 5 is protected .

The starting material for the preparation of the dendritic structure may be selected from the group comprising, but not limited to, the following structures: htriSM, htetraSM, hpentSM, hhexaSM, an heterofunctionalized molecule containing 1 epoxy group and another reactive group, htriSM containing two ethynyl groups or a protected ethynyl group and another reactive group, diallyl (meth) silane, combinations of acrylates and diamines (repeating Michael addition reaction of primary amines to 2 molecules of acrylate, amidation reaction of ester groups), combinations of propargyl glycidyl ether with mercaptoethylamine, mercaptoethylamine hydrochloride, or amino-protected mercaptoethylamine (repeating addition reaction of primary amino groups to epoxy groups, click reaction of alkynyl groups to 2 mercapto groups), diallylmethylsilane, and the like. Specific examples are as follows

Epichlorohydrin, amino-protected lysine, glutamic acid, aspartic acid, N-dihydroxyethylglycine and its hydroxyl-protected form, dihydroxymonocarboxylic acid and its hydroxyl-protected form, hydroxydicarboxylic acid and its hydroxyl-protected form, aminodicarboxylic acid and its amino-protected form, mercaptodicarboxylic acid and its sulfhydryl-protected form, glyceraldehyde and its hydroxyl-protected form, methyl-6-O-p-toluenesulfonyl-alpha-D-glucoside, 3-aminopropylsilanetriol, 2,3, 4-trihydroxybutyraldehyde2,3, 4-trihydroxy butyric acid, citric acid, N-hydroxyethyl ethylenediamine triacetic acid,

2-azido-1, 3-bis [ (2, 2-dimethyl-1, 3-dioxan-5-yl) oxo]Propane, and the like. Among them, 2-dimethylolpropionic acid is preferable as the dihydroxy monocarboxylic acid. The hydroxy dicarboxylic acid is preferably malic acid or 3-hydroxyglutaric acid.

Monomers for preparing hyperbranched structures include, but are not limited to, monomers disclosed in the literature [ Journal of Polymer Science, Part A: Polymer Chemistry,2013,51, 995-: epoxy propanol, epoxy propanol,

(3-ethyl-3-oxetanylcarbinol),

Combinations of acrylates with diamines, and the like.

Monomers for preparing comb structures having repeating units include, but are not limited to: glycerol in which the 2-hydroxyl group is protected (forming a polyglycerol structure), pentaerythritol in which two hydroxyl groups are protected (e.g., monophenylol pentaerythritol, forming polypentaerythritol), and mixtures thereof,

(F is as defined above, preferably in protected form, one of the preferred forms being protected hydroxy OPG₄Such as 1-ethoxyethyl-2, 3-epoxypropyl ether, benzyl glycidyl ether, tert-butyl glycidyl ether, allyl glycidyl ether, propargyl glycidyl ether, glycidyl methacrylate, glycidyl ether,

(e.g., azidopropyl methacrylate), carbon dioxide and

combinations of (e.g. { Macromolecules 2013,46,3280-3287}, and further e.g. carbon dioxide with a compound selected from the group consisting of

Propargyl glycidyl ether, and the like), a combination of a diisocyanate and a diol containing 1 reactive group or a protected form thereof,

In combination with diamines (forming combs with multiple thiol groups suspended, { Macromol. Rapid Commun.2014,35,1986-1993}), D-glucopyranose units (forming acetalized glycan structures, such as poly (1 → 6) hexose, 2, 1-polyfructose, in particular dextran and its oxidized structures, polyfructose structures as described in US5,811,510, US7,790,150, US7,838,619), lysine, aspartic acid, glutamic acid, etc. Other trihydric alcohols, trihydric alcohols containing one protected hydroxyl group, tetrahydric alcohols containing 2 protected hydroxyl groups, and polyhydric alcohols containing 2 naked hydroxyl groups and other protected hydroxyl groups can be used as raw materials for preparing the comb-shaped structure. The comb-like structure may be a non-repeating structure, for example, a polypeptide structure formed by linking 2 or more amino acids selected from any 1 or more amino acids selected from lysine, aspartic acid, and glutamic acid with other amino acids (e.g., glycine) as a spacer. In addition, including but not limited to the above-mentioned 2,3,4, 5-tetrahydroxypentanal, 2,3,4, 5-tetrahydroxypentanoic acid, 2,3,4,5, 6-pentahydroxyhexanal, 2,3,4,5, 6-pentahydroxyhexanoic acid, D-glucosamine, 1-mercaptosorbitol, N-methyl-D-glucosamine, D-sorbitol-3-phosphate and the like can be directly used as a raw material for preparing the comb-like branched terminals.

Starting materials for the preparation of cyclic structures include, but are not limited to: 2, 5-anhydro-1-azido-1-deoxy-D-glucitol, 1,4, 7-tri-tert-butoxycarbonyl-1, 4,7, 10-tetraazacyclododecane, 2-hydroxymethylpiperidine-3, 4, 5-triol, 6-amino-4- (hydroxymethyl) -4-cyclohexyl- [4H,5H ] -1,2, 3-triol, 1-azido-1-deoxy-beta-D-galactopyranoside, 2-azidoethyl-beta-D-glucopyranoside, propargyl-alpha-D-mannopyranoside, propargyl-alpha-L-fucopyranoside, propargyl-beta-D-lactoside, beta-lactoside, and mixtures thereof, Monofunctional cyclodextrins (e.g., mono-6-O- (azido) - β -cyclodextrin, mono-6-O- (p-toluenesulfonyl) - γ -cyclodextrin, mono-2-O- (p-toluenesulfonyl) - γ -cyclodextrin, mono-6-O- (p-toluenesulfonyl) - β -cyclodextrin, mono-2-O- (p-toluenesulfonyl) - α -cyclodextrin), and the like.

5.1.2.3. Formation of the branching centres in the terminal G

The branching centers in the terminal G are each independently selected from the group consisting of, but not limited to, carbon atoms, nitrogen atoms, phosphorus atoms, silicon atoms, cyclic structures, combinations of any 2 or more of the foregoing. The trivalent branching center may be of a symmetrical structure or an asymmetrical structure.

The above-mentioned branching centers may be derived either directly from the starting materials or by coupling reactions between the starting materials.

As an example of being directly derived from the starting material, for example, the symmetrical trivalent carbon branching center may be derived fromSerinol, 2-dimethylolpropionic acid, etc., asymmetric trivalent carbon branching center can be derived from epichlorohydrin, 3-methylamino-1, 2-propanediol, malic acid, 3-hydroxyglutaric acid, lysine, glutamic acid, aspartic acid, etc., symmetric trivalent N branching center can be derived from N, N-bis (2-hydroxyethyl) ethylenediamine, N-dihydroxyethylglycine, etc., tetravalent carbon branching center can be derived from pentaerythritol, citric acid, etc., cyclic branching center can be derived from 3, 6-diaminocarbazole, 2, 5-anhydro-D-glucitol, methyl-D-mannoside, dihydroxybenzoic acid (including various isomers with different substitution positions), etc, Amino-benzenediol (including various isomers with different substitution positions),

And the phosphorus atom branching center can be obtained by taking phosphoric acid, phosphate ester, thiophosphoric acid and thiophosphate as raw materials.

Branching centers obtained by coupling reactions between the starting materials. For example, alkylation or amidation of a secondary amine can give a trivalent nitrogen center. Such as primary amines with 2-molecule sulfonates, halides, epoxides, alpha, beta-unsaturation (e.g., acrylates), may also yield trivalent nitrogen branching centers. As another example, reaction between an alkynyl group and 2 molecules of a thiol group can result in an asymmetric trivalent carbon branching center. As another example, a reaction between a B5 or B6-type functional group and a disulfide bond may form a trivalent carbon branching center. As another example, a tetravalent silicon branching center may be obtained by the above-described terminal branching reaction based on alkenyl, trichlorosilane, and allylmagnesium chloride, or based on alkenyl, trichlorosilane, and allyl alcohol. As another example, a trivalent silicon branching center can be obtained by reaction of diallylmethylsilane as a repeating unit. Asymmetric carbon-branched dimercapto can be obtained by reduction of the disulfide bond of the five-membered ring of the lipoic acid. By acetalization of p-hydroxymethylbenzaldehyde, a trivalent carbon branching center of an acetal structure can be obtained, and the branching center can be degraded. Also, reactive groups such as class B5 or class B6 react with disulfide bonds to give symmetric trivalent carbon branching centers.

5.2. Purification and characterization of intermediates and products

The intermediates or products prepared in the present invention can be purified by purification methods including, but not limited to, extraction, recrystallization, adsorption treatment, precipitation, reverse precipitation, membrane dialysis, or supercritical extraction. The structure, molecular weight and molecular weight distribution of key intermediates and products are characterized and confirmed by methods including but not limited to nuclear magnetism, electrophoresis, ultraviolet-visible spectrophotometer, FTIR, AFM, GPC, HPLC, MALDI-TOF, circular dichroism method and the like. For monodisperse functionalized eight-arm polyethylene glycols, the molecular weight is preferably confirmed by MALDI-TOF. Methods for determining the attribution of characteristic peaks in nuclear magnetic tests include, but are not limited to, those described and recited in documents CN104877127A, CN104530413A, CN104530415A, CN104530417A, and each of the cited documents. The end functionalization rate (substitution rate) of the functionalized eight-arm polyethylene glycol, namely the mole percentage of the end hydroxyl group of the eight-arm polyethylene glycol which is functionalized and modified, is determined by the characteristic peak-CH of the end hydroxyl group in the nuclear magnetism characteristic peak of the eight-arm polyethylene glycol raw material₂CH₂OH and EO Block characteristic Peak-CH₂CH₂O-, andfunctional group characteristic peak and EO block characteristic peak-CH in functionalized eight-arm polyethylene glycol product nuclear magnetism characteristic peak₂CH₂The integral ratio of O-is obtained by conversion, and the conversion method is well known to those skilled in the art and is not described in detail herein.

5.3. Others

The preparation of the eight-arm polyethylene glycol has been described above. The preparation method of the linear functionalized polyethylene glycol and the coupling reaction method of the linear functionalized polyethylene glycol and the disaccharide-based small molecule can be realized by combining the conventional technology in the field with the related method of the invention, and the detailed description is omitted.

6. The invention also provides a functionalized eight-arm polyethylene glycol modified biologically-relevant substance, which has the following structural general formula:

wherein, CORE, n, L₀、G、k、Z₁、Z₂、q、q₁The definition of (A) is consistent with that of the general formula (2), and the description is omitted here.

Wherein g is 0 or 1; EF may be expressed as ED (structure is) Or EF₁(structure is) Wherein D is not equal to E₀₁. Wherein D is a residue formed after the modified bio-related substance reacts with the functionalized eight-arm polyethylene glycol; e₀₁Is selected from R₀₁Protected R₀₁Deprotected R₀₁Or blocked R₀₁；R₀₁Is a reactive group capable of reacting with a biologically relevant substance; l is a linking group formed after the reaction of a reactive group in the functionalized eight-arm polyethylene glycol and a biologically relevant substance. Wherein the number of D at the end of one branch chain is marked by k_D，0≤k_DK is not more than k, k of each branched chain in the same molecule_DEach independently the same or different, and any one of the functionalized eight-armed polyethylene glycolsSum of D numbers in the molecule (N)_D) At least 1, preferably at least 8. When G is 1, G- (EF)_kCan be expressed as

The functionalized eight-arm polyethylene glycol modified bio-related substance can exist stably or can be degraded; in the same molecule, L₀、G、(Z₂)_q-(Z₁)_q1、(Z₂)_q-any of the linking groups formed by L with adjacent groups are each independently stably present or degradable; in the same molecule, L₀、G、(Z₂)_q-(Z₁)_q1、(Z₂)_qEach L is independently stably present or degradable.

K at the end of eight PEG chains in the same molecule_DPreferably all satisfy 1. ltoreq. k_DK, i.e.at least one D is attached to each branch chain. Ideally, k is at the end of eight PEG chains in the same molecule_DAll satisfy k_DK, i.e. all terminal reaction sites are each independently linked to a D, the percentage of D reaching 100%.

The D is from the same biologically relevant substance, but allows for different reaction sites with R₀₁The residue formed after the reaction. Especially when there are multiple identical reactive groups in the biologically relevant material.

The D content (the number of D relative to the percentage of the reaction site) in a single molecule is not particularly limited and may be greater than about 75% or less than about 75%. The amount of D in each molecule of the macroscopic material constituting the functionalized eight-arm polyethylene glycol modified product may be the same or different, such as equal to 100%, or such as between 65% and 90%, or such as between 75% and 94%, for example. The higher the content of D, that is, the higher the drug loading rate, the more easily the effect of the biologically relevant substances is improved, and simultaneously, the higher the uniformity of the product structure is, the better the performance is. When there are a plurality of reaction sites in the bio-related substance, the same bio-related substance is used with the same R₀₁After the reaction, identical or different residues D, preferably identical residues D, can be obtained, in which caseThe more uniform and stable the properties of the product. Preferably, the D content in a single molecule is greater than about 75%, more preferably greater than about 80%, more preferably greater than about 85%, more preferably greater than about 90%, more preferably greater than about 94%, and most preferably equal to 100%. For macroscopic materials, the average content of D may be greater than about 75% and also less than about 75%, preferably greater than about 75%, more preferably greater than about 80%, more preferably greater than about 85%, more preferably greater than about 90%, more preferably greater than about 94%, and most preferably equal to 100%.

Wherein k is_DThe number of sites actually reacting with biologically-relevant substances in functional groups in a single molecule is expressed as a mean value for macroscopic substances, namely the number of reaction sites in one functionalized eight-arm polyethylene glycol molecule can be an integer or a non-integer; wherein the integer k in a single molecule_DEach independently is 0,1 or 2 to 250. The invention also covers the substances of one molecule of the biologically relevant substance combined with 2 or more functionalized eight-arm polyethylene glycol molecules, but preferably 1 molecule of the biologically relevant substance reacts with only 1 functional group, namely only one functionalized eight-arm polyethylene glycol molecule is connected, and the corresponding quality controllability is strong. I.e. k_DAlso indicated is the number of bio-related substance molecules bound in F (expressed as a mean value for macroscopic substances, i.e. the number of bio-related substances to which on average one functionalized eight-armed polyethylene glycol molecule is attached). The functional group modified by the functionalized eight-arm polyethylene glycol can be completely or partially involved in the modification of the biological related substances. Preferably all participate in the modification of the biologically relevant substance. In the functionalized eight-arm polyethylene glycol modified bio-related substance, the functional group which is not combined with the bio-related substance can be in a structural form before reaction, can also be in a protected form, can also be in a deprotection form, and can also be blocked by a non-bio-related substance.

L may be covalently or non-covalently attached. Preferably a covalent linker; it may also be a double or multiple hydrogen bond. Since reactions with different sites from the same biologically relevant substance are allowed, eight PEG chain ends of the same molecule are allowed to correspond to different L, preferably the L of the eight PEG chain ends are the same.Any one of L is each independently stably present or degradable, and the linking group of L to the adjacent heteroatom group is stably present or degradable. Accordingly, any one of (Z)₂)_qEach L is independently stably present or degradable, and (Z)₂)_qThe linking group of-L to the adjacent heteroatom group may be stable or degradable. Preferably, the eight PEG chain end L's have the same stability, i.e., are both stably present or both degradable, in which case the eight PEG chain end (Z)₂)_q-L also has the same stability.

The difference of the stability property (also called degradability) of the functionalized eight-arm polyethylene glycol modified bio-related substance according to the degradation position includes but is not limited to the following cases:

(1) g-0, stable octavalent CORE (O-)₈stabilized-O- (Z)₂)_q-L-；

(2) g-0, stable octavalent CORE (O-)₈degradable-O- (Z)₂)_q-L-；

(3) g-0, with a degradable octavalent center CORE (O-)₈degradable-O- (Z)₂)_q-L-；

(4) g-1, stable octavalent CORE (O-)₈stabilized-O-L₀-G- (G and Z are excluded)₂Connection of), stable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(5) g-1, stable octavalent CORE (O-)₈degradable-O-L₀-G- (G and Z are excluded)₂Connection of), stable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(6) g-1, stable octavalent CORE (O-)₈stabilized-O-L₀-G- (G and Z are excluded)₂Linked) degradable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(7) g1, with a degradable octavalent center CORE (O-)₈stabilized-O-L₀-G- (G and Z are excluded)₂Connection of), stable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(8) g1, with a degradable octavalent center CORE (O-)₈degradable-O-L₀-G- (G and Z are excluded)₂Connection of), stable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(9) g1, with a degradable octavalent center CORE (O-)₈stabilized-O-L₀-G- (G and Z are excluded)₂Linked) degradable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(10) g-1, stable octavalent CORE (O-)₈degradable-O-L₀-G- (G and Z are excluded)₂Linked) degradable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(11) g1, with a degradable octavalent center CORE (O-)₈degradable-O-L₀-G- (G and Z are excluded)₂Linked) degradable- (Z)₂)_q-L- (containing G and Z)₂The connection of (c);

(12) g-0, stable octavalent CORE (O-)₈stabilized-O- (Z)₂)_q-, degradable L;

(13) g-1, stable octavalent CORE (O-)₈stabilized-O-L₀-G-[(Z₂)_q-]_kA degradable L;

(14) g-0, stable octavalent CORE (O-)₈stabilized-O- (Z)₂)_qDegradable L-D;

(15) g-1, stable octavalent CORE (O-)₈stabilized-O-L₀-G-[(Z₂)_q-]_kDegradable L-D.

The combination of the different degradation amounts and degradation positions has been described above and will not be described further here. Wherein, (1), (4), (12), (13) correspond to the eight-arm polyethylene glycol of stable functionalization; (3) degradable functionalized eight-arm polyethylene glycol corresponding to the (5), (7) and (11); (2) provided that (Z) in (1) and (6)₂)_q- (containing Z)₂Attachment to the PEG terminus O or G) and L) may be degradable, and thus may correspond to a stable functionalized eight-arm polyethylene glycol containing degradable L, as well as to a degradable functionalized eight-arm polyethylene glycol containing stable L. One preference of the above combination is to have a stable center of eighty (O-)₈Comprises (1), (2), (4), (5), (6), (10), (12), (13), (14) and (15). Wherein, for the two cases (1) and (4), the PEG part is not degradable, and the connection between the PEG part and the bio-related substance also exists stably, and the bio-related substance modified by the polyethylene glycol can be a modified bio-related substance; when the PEG is a basic drug, if other spacers are not connected between the basic drug and the PEG to generate degradable groups, the PEG can be metabolized as a whole, and the PEG has the advantages of accelerating solubilization, improving the interaction rate of the drug and a focus point or target tissue, improving the treatment effect and the like. For (14) and (15), D and (Z) may be passed₁)_q1-R₀₁Can produce degradable L, and can also produce stable L: when D itself is not degradable, L may be degradable; when D itself is degradable, wherein the base drug and the spacer contain a degradable ester group, then L is preferably stably present, or a more stable degradable group (e.g., a more stable urethane linkage than an ester group) is preferred.

For g equal to 0, EF₁Preferably, it is

At this time, the D content is 100%, and the structure is shown in formula (4).

For the above (3), when g is 1, the D content may preferably be 75% or less, preferably more than 80%, more preferably more than 85%, more preferably more than 90%, more preferably more than 94%, and most preferably 100%. Wherein the structure of the compound is shown in formula (5) when g is 1 and the content of D is 100%.

6.1. Biologically relevant substances

The bio-related substance of the general formula (3) may be a bio-related substance, a modified bio-related substance, or a complex bio-related substance. Wherein the compound bio-related substances are chemical conjugates of 2 or more than 2 bio-related substances.

The bio-related substance may be a naturally occurring bio-related substance or an artificially synthesized bio-related substance. The biologically-relevant substance is obtained in a manner not particularly limited, and includes, but is not limited to, natural extracts and derivatives thereof, degradation products of natural extracts, gene recombination products (molecular cloning products), chemically synthesized substances, and the like. The hydrophilicity and hydrophobicity of the bio-related substance is not particularly limited, and may be hydrophilic or water-soluble, or may be hydrophobic or fat-soluble. The charge property of the bio-related substance is not particularly limited.

The biologically-relevant substance may be the biologically-relevant substance itself, or may be a dimer or multimer, partial subunit or fragment thereof, or the like.

The biologically-relevant substance may be a biologically-relevant substance itself, or a precursor, an activated state, a derivative, an isomer, a mutant, an analog, a mimetic, a polymorph, a pharmaceutically-acceptable salt, a fusion protein, a chemically-modified substance, a gene recombinant substance, or the like thereof, or a corresponding agonist, activator, inhibitor, antagonist, modulator, receptor, ligand or ligand, an antibody or a fragment thereof, an acting enzyme (e.g., a kinase, a hydrolase, a lyase, an oxidoreductase, an isomerase, a transferase, a deaminase, a deiminase, a invertase, a synthetase, or the like), a substrate for an enzyme (e.g., a substrate for a coagulation cascade protease, or the like), or the like. The derivatives include, but are not limited to, glycosides, nucleosides, amino acids, and polypeptide derivatives. Chemical modification products of new reactive groups and modification products generated by additionally introducing structures such as functional groups, reactive groups, amino acids or amino acid derivatives, polypeptides and the like belong to chemical modification substances of biological related substances. The biologically-relevant substance may also allow for a target molecule, adjunct or delivery vehicle to bind to it, either before or after binding to the functionalized eight-armed polyethylene glycol, to form a modified biologically-relevant substance or a complexed biologically-relevant substance. Wherein, the pharmaceutically acceptable salt can be inorganic salt, such as hydrochloride, or organic salt, such as oxalate, malate, citrate, etc.

The source of the biologically-relevant substance is not particularly limited and includes, but is not limited to, human, rabbit, mouse, sheep, cow, pig, and the like.

The application fields of the above biologically-relevant substances are not particularly limited, and include, but are not limited to, medical, regenerative medicine, tissue engineering, stem cell engineering, bioengineering, genetic engineering, polymer engineering, surface engineering, nano engineering, detection and diagnosis, chemical staining, fluorescent labeling, cosmetics, foods, food additives, nutrients, and the like. The medical bio-related substances including but not limited to drugs, drug carriers and medical devices can be used for various aspects such as disease treatment and prevention, wound treatment, tissue repair and replacement, image diagnosis and the like. By way of example, the related substances may also include: dye molecules for quantitative or semi-quantitative analysis; fluorocarbon molecules and the like which are useful for imaging diagnosis, blood substitutes, and the like; for example, antiparasitic agents such as primaquine and the like; for example, as a carrier for antidotes such as the chelating agents ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA) and the like. When the bio-related substance is used as a drug, the therapeutic field thereof is not particularly limited, and includes, but is not limited to, drugs for treating cancer, tumor, liver disease, hepatitis, diabetes, gout, rheumatism, rheumatoid, senile dementia, cardiovascular disease and the like, anti-allergic drugs, anti-infective agents, antibiotic agents, antiviral agents, antifungal agents, vaccines, central nervous system inhibitors, central nervous system stimulants, psychotropic drugs, respiratory tract drugs, peripheral nervous system drugs, drugs acting at synaptic or neuroeffector junction sites, smooth muscle active drugs, histaminergic agents, antihistaminicergic agents, blood and hematopoietic system drugs, gastrointestinal tract drugs, steroid agents, cell growth inhibitors, anthelmintic agents, antimalarial agents, antiprotozoal agents, antimicrobial agents, anti-inflammatory agents, immunosuppressive agents, alzheimer's drugs or compounds, Imaging agents, antidotes, anticonvulsants, muscle relaxants, anti-inflammatory agents, appetite suppressants, migraine agents, muscle contractants, antimalarials, antiemetics/antiemetics, bronchodilators, antithrombotic agents, antihypertensive agents, antiarrhythmics, antioxidants, anti-asthma agents, diuretics, lipid regulating agents, antiandrogens, antiparasitics, anticoagulants, anti-neoplastic agents, hypoglycemic agents, nutritional agents, additives, growth supplements, anti-enteritis agents, vaccines, antibodies, diagnostic agents (including but not limited to contrast agents), contrast agents, hypnotics, sedatives, psychostimulants, tranquilizers, anti-parkinson agents, analgesics, anxiolytics, muscle infectives, auditory disease agents, and the like. Wherein typical anti-cancer or anti-tumor drugs include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, gastrointestinal cancer, intestinal cancer, metastatic large intestine cancer, rectal cancer, colon cancer, colorectal cancer, gastric cancer, squamous cell cancer, laryngeal cancer, esophageal cancer, carcinoma, lung cancer, small cell lung cancer (small cell lung cancer), non-small cell lung cancer, liver cancer, thyroid cancer, kidney cancer, bile duct cancer, brain cancer, skin cancer, pancreatic cancer, prostate cancer, bladder cancer, testicular cancer, nasopharyngeal cancer, head and neck cancer, gallbladder and bile duct cancer, retinal cancer, renal cell cancer, gallbladder adenocarcinoma, multidrug resistant cancer, melanoma, lymphoma, non-Hodgkin's lymphoma, adenoma, leukemia, chronic lymphocytic leukemia, multiple myeloma, brain tumor, Wilms's tumor, liposarcoma, endometrial sarcoma, rhabdomyosarcoma, sarcoma, and colon cancer, Primary or secondary carcinoma, sarcoma or carcinosarcoma such as neuroblastoma, AIDS-related cancer (such as Kaposi's sarcoma).

"drug" in the context of the present invention includes any agent, compound, composition or mixture that provides a physiological or pharmacological effect, either in vivo or in vitro, and often provides a beneficial effect. The class is not particularly limited and includes, but is not limited to, pharmaceuticals, vaccines, antibodies, vitamins, foods, food additives, nutritional agents, nutraceuticals, and other agents that provide a beneficial effect. The "drug" is not particularly limited in the range that produces physiological or pharmacological effects in vivo, and may be a systemic effect or a local effect. The activity of the "drug" is not particularly limited, and is mainly an active substance that can interact with other substances, and may also be an inert substance that does not interact with other substances; however, inert drugs can be converted to the active form by in vivo action or some stimulus.

The species of the bio-related substance is not particularly limited, and includes, but is not limited to, the following: drugs, proteins, polypeptides, oligopeptides, protein mimetics, fragments and analogs, enzymes, antigens, antibodies and fragments thereof, receptors, small molecule drugs, nucleosides, nucleotides, oligonucleotides, antisense oligonucleotides, polynucleotides, nucleic acids, aptamers, polysaccharides, proteoglycans, glycoproteins, steroids, lipids, hormones, vitamins, vesicles, liposomes, phospholipids, glycolipids, dyes, fluorescent substances, targeting factors, cytokines, neurotransmitters, extracellular matrix substances, plant or animal extracts, viruses, vaccines, cells, micelles, and the like.

The biologically relevant substances are classified and listed below. A biologically relevant substance may be present in one or more of the following categories. In general terms, the use of a single,

the biologically relevant substances of the general formula (2) of the present invention include, but are not limited to, those described and exemplified in documents CN104877127A, CN104530413A, CN104530415A and CN 104530417A. CN104530413A includes paragraphs [0813] to [0921], paragraphs [0971] to [1146], examples, CN104877127A paragraphs [0827] to [0870], and paragraphs [0889] to [0901 ].

(1) Proteins and polypeptides and related materials. Without particular limitation, including but not limited to hormones, serum proteins, cytokines and fragments thereof, polypeptides, enzymes and corresponding zymogens, immunoglobulins, monoclonal or polyclonal antibodies and fragments thereof, antigens, polyamino acids, vaccines and the like. The enzymes and corresponding zymogens also include, but are not limited to, neprilysin, phorbol oligopeptidase, leukotriene A4 hydrolase, endothelin converting enzyme, ste24 protease, mitochondrial intermediate peptidase, interstitial collagenase, macrophage elastase, gelatinase, transmembrane peptidase, procollagen C-endopeptidase, procollagen N-endopeptidase, ADAM and ADAMTM metalloprotease, myelin-associated metalloprotease, amelysin, tumor necrosis factor alpha-converting enzyme, insulinolytic enzyme, nardilysin, mitochondrial processing peptidase, magnosyn, dactylysin-like metalloprotease, neutrophil collagenase, matrix metalloproteinase, membrane type matrix metalloproteinase, SP2 endopeptidase, trypsin, I-reducing calpain, trypsin elastase, trypsin endopeptidase, enteropeptidase, leukocyte elastase, chymotrypsin, trypsin-like enzymes, enzyme enzymes, enzymes, Cuticle chymotrypsin, acrosin, kallikrein, alternative complement pathway c3/c5 convertase, mannose binding protein-associated serine protease, thrombin, cathepsin G, hepatic serine, serine proteolytic enzymes, hepatocyte growth factor activating endopeptidase, subtilisin/kexin type proprotein convertase, furin, proprotein convertase, prolyl peptidase, acylaminoacyl peptidase, peptidyl-glycaminase, signal peptidase, N-terminal nucleophile aminohydrolase, 20s proteasome, gamma-glutamyl transpeptidase, mitochondrial endopeptidase Ia, htra2 peptidase, site 1 protease, asparaginyl endopeptidase, cathepsin D, cysteine cathepsin, calpain, ubiquitin isopeptidase T, caspase, Glycosylphosphatidylinositol protein transamidase, prohormone thiol protease, gamma-glutamyl hydrolase, bleomycin hydrolase, pepsin, chymosin, pepsin, yeast aspartase (memapsin), cyclosporine synthase, canine urate oxidase, and the like. Such biologically-relevant substances also include, but are not limited to, lysin, stromelysin, fibroblast activation protein, human fibroblast activation protein, stromal lytic factor, complement components and factors, coagulation factors, renin, cancer procoagulants, prostate-specific antigen, protein c, u and t plasminogen activators, cyclosporine, canine leptin polypeptide, subgroup J avian leukosis virus immunosuppressive polypeptide, vascular endothelial growth factor mimetic peptide, and the like.

But are also not limited to dimers and multimers, subunits and fragments thereof, precursors, activation states, derivatives, isomers, mutants, analogs, mimetics, polymorphs, pharmaceutically acceptable salts, fusion proteins, chemically modified substances, recombinant substances, and the like of the above-mentioned related substances, as well as corresponding agonists, activators, inhibitors, antagonists, modulators, receptors, ligands or ligands, antibodies and fragments thereof, enzymes (e.g., kinases, hydrolases, lyases, oxidoreductases, isomerases, transferases, deaminases, deiminases, invertases, synthetases, and the like), substrates of enzymes, and the like.

(2) A small molecule drug. The types of small molecule drugs are not particularly limited, and include, but are not limited to, flavonoids, terpenoids, carotenoids, saponins, steroids, quinones, anthraquinones, fluoquinones, coumarins, alkaloids, porphyrins, polyphenols, macrolides, monobactams, phenylpropanoid phenols, anthracyclines, aminoglycosides, amino acids and their derivatives (natural and non-natural), and the like. The therapeutic field of small molecule drugs is not particularly limited and includes, but is not limited to, anticancer or antineoplastic drugs, antibiotics, antiviral agents, antifungal agents, other anticancer agents, antineoplastic agents, antibiotics, antiviral agents, antifungal agents, and other small molecule drugs. Preferably anticancer or antitumor drugs and antifungal drugs.

Anticancer or antineoplastic agents including, but not limited to, taxanes, paclitaxel and its derivatives, docetaxel, camptothecin and its derivatives (including, but not limited to, 7-ethyl-10-hydroxycamptothecin, 9-nitrocamptothecin, 9-aminocamptothecin, etc.), irinotecan, SN38, topotecan hydrochloride, topotecan, belotecan, irinotecan, rutotensin, ginekan, diflutecan, canetin, rubitecan, irinotecan, Karenitecin, gimatecan, gemecatecan, irinotecan, Aftecan, lurtotecan, cisplatin, oxaliplatin, hydroxycamptothecin (including, but not limited to, 10-hydroxycamptothecin, etc.), vinblastine, vincristine, emetine hydrochloride, colchicine, doxorubicin, epirubicin, pirarubicin, picorubicin, doxorubicin, and the like, Valrubicin, doxorubicin or doxorubicin hydrochloride, epirubicin, daunorubicin, daunomycin, mitomycin, aclarubicin, idarubicin, bleomycin, pelomycin, daunorubicin, mithramycin, rapamycin, bleomycin, streptozotocin, podophyllotoxin, actinomycin D (dactinomycin), maytansinoids, amikacin, mitoxantrone, all-trans tretinoin, vindesine, vinorelbine, gemcitabine, capecitabine, cladribine, pemetrexed disodium, tegasertibiazole, letrozole, anastrozole, fulvestrant, goserelin, triptorelin, leuprolide, buserelin, temozolomide, cyclophosphamide, ifosfamide, gefitinib, sunitinib malate, erlotinib hydrochloride, erlotinib, lapatinib, tolapartib tosylate, Sorafenib, imatinib mesylate, N-demethylimatinib, lenatinib, bosutinib, axitinib, Vanditinib, Secatinib, canertinib, Carnitinib dihydrochloride, canertinib, sunitinib, tandutinib, Rilinotinib, Tenidamole, Dovirtinib, lestatinib, octenidine, Octadine, baflutinib, Pafitinib, Tinosolol, pirtinid, Tenicic acid, Tenicitan, Afatinib, Moritinib, nilotinib, Brotinib, sunitinib mesylate, Tenitinib, Antertinide, Tenisanil, Tenisazoxan, soratinib tosylate, Tenonide, Dasatinib, Netinib (nilotinib), Tilapatinib, sirolimus, Everolimus, mercaptopurine, methotrexate, 5-Flubazine, Darbazine, Hydroxyurea, Trapatinib, Nenithine dihydrochloride, Netinib, Nepril, Nepridine, Tratinib, Tranetinib, Tradetinib, Vorinostat, ixabepilone, bortezomib, cytarabine, etoposide, azacytidine, teniposide, propranolol, procaine, tetracaine, lidocaine, bexarotene, carmustine (dichloroethylnitrosourea), chlorambucil, methylbenzyl hydrazine, thiotepa, topotecan, erlotinib, plitidipsin, ranimustine, genistein, bendamustine, and the like;

antibiotics, antivirals, antifungals including, but not limited to, macrolides, defensins, polymyxin E methanesulfonic acid, polymyxin B, capreomycin, bacitracin, gramicin, amphotericin B, aminoglycoside antibiotics, gentamicin, paramecium, tobramycin, kanamycin, aminobutylkanamycin A, neomycin, streptomycin, nystatin, echinomycin, carbenicillin, penicillin-sensitive agents, penicillin G, penicillin V, penicillinase counteractants (e.g., methicillin, benzazepine, cloxacillin, dicloxacillin, flucloxacillin, nafcillin, etc.), penems, amoxicillin, vancomycin, daptomycin, anthracyclines, chloramphenicol, erythromycin cydocarbonates, flavomycins, oleandomycin, clarithromycin, Daphne, erythromycin, dirithromycin, roxithromycin, azaerythromycin, azithromycin, fludromycin, josamycin, spiramycin, medemycin, mecamylin, leucomycin, miocamycin, rokitamycin, nettamycin, doxycycline, swinolide A, teicoplanin, lanoplanin, mediterranin, cleistanin, polymyxin E methanesulfonic acid, fluorocytosine, miconazole, econazole, fluconazole, itraconazole, ketoconazole, voriconazole, fluconazole, clotrimazole, bifonazole, netilmicin, amikacin, caspofungin, micafungin, terbinafine, fluoroquinolone, lomefloxacin, norfloxacin, ciprofloxacin, enoxacin, ofloxacin, levofloxacin, troxacin, moxifloxacin, ofloxacin, gatifloxacin, pafloxacin, temafloxacin, sparfloxacin, temafloxacin, doxafloxacin, doxorafloxacin, doxorabicin, doxorabicifloxacin, Aminofloxacin, fleroxacin, tosufloxacin, prulifloxacin, iloxacin, pazufloxacin, clinafloxacin, sitafloxacin, idarubicin, tosufloxacin, iloxacin, teicoplanin, rampolamin, daptomycin, colitimethate, nucleoside antiviral drugs, ribavirin, antihyperasporin, ticarcillin, azlocillin, mezlocillin, piperacillin, gram (stain) negative microbial active agents, ampicillin, hydaticillin, glatirocillin, amoxicillin, cephalosporins (such as cefpodoxime ester, cefprozil, ceftibuten, cefmenoxime, ceftriaxone, cefapirin, cephalexin, cefradine, cefoxitin, cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil, cefalexin, cefuroxime, ceforanide, ceftizoxime, ceftriaxone, thixone, ceftriaxone, thixone, thiflutria, Cefotaxime, cefepime, cefixime, cefonicid, cefoperazone, cefotetan, cefmetazole, ceftazidime, chlorocarbaceph, moxalactam, cefobutam, cephalosporin, cephalosporins II, cephalotriazines, cyanoacetyl cephalosporin, etc.), monobactal cycles, aztreonam, carbapenems, imipenem, pentamidine isethionate, imipenem, meropenem, pentamidine-artemethrin, salbutamol sulfate, lidocaine, metacinaline sulfate, beclomethasone dipropionate, metahydroxyisoprenaline sulfate, beclomethasone dipropionate, triamcinolone acetamide, budesonide acetonide, fluticasone propionate, ipratropium bromide, flunisolide, sodium cromoglycate, ergotamine tartrate, pentamidine isethionate, chlorogenic acid, and the like.

Other anti-cancer, anti-tumor, antibiotic, antiviral, antifungal and other small molecule drugs, including but not limited to cytochalasin B, aminomethylbenzoic acid, sodium p-carbamurite, aminoglutethimide, aminolevulinic acid, aminosalicylic acid, pamidronic acid, amsacrine, anagrelide, anastrozole, levamisole, busulfan, cabergoline, tilide, carboplatin, cilastatin sodium, disodium clodronate, amiodarone, ondansetron, descycloalprogesterone, megestrol, testosterone, estramustine, exemestane, fluoroxymethyltestosterone, diethylstilbestrol, fexofenadine, fludarabine, fludrocortisone, 16 α -methylhydrocortisone, fluticasone, deferoxamine, flutamide, bicalutamide, thalidomide, L-dopa, leucovorin, lisinopril, levothyroxine sodium, Azacitine, anglerin, metahydroxymethamphetamine ditartrate, metoclopramide, mitotane, nicotine tartrate, nilutamide, octreotide, pentostatin, pilampamycin, porphine, prednisone, procarbazine, praclonopiperazine, letrothiin, streptozotocin, sirolimus, tacrolimus, tamoxifen, teniposide, tetrahydrocannabinol, thioguanine, thiotepa, setipid, dolasetron, granisetron, formoterol fumarate, melphalan, midazolam, alprazan, podophyloxins, sumatriptan, low molecular weight heparin, amifostine, carmustine, gisitatin, lomustine, tebufotene, osteoarthritis treatment drugs (including but not limited to aspirin, salicylic acid, bazedoary, indomethacin, naproxen, diclofenac, naloxone, etodolorone, lomustine, etodolac, etc.) Sulindac, acemetacin, diacerein, etc.), amdoxovir, cyantraniliprole, aminoarone, aminocaproic acid, aminoglutethimide, aminolevulinic acid, butanediol mesylate, chloromethanediphosphonate, disodium chloromethanediphosphate, L-dihydroxyphenylalanine, lovatyroxine sodium, dichloromethyldiethane, metahydroxylamine bitartrate, o-dichlorophenylethane, prochlorperazine, ondansetron, ratrexed, tacrolimus, tamoxifen, tandioside, tetrahydrocannabinol, fluticasone, aroylhydrazone, sumatriptan, meocarcinomycin, spirotacamycin, milbemycin, isorhamnetin, myricetin, dicyanometricin, catechin, epicatechin, phloridzin, acarbose, salmeterol, naloxonone, opioids (e.g., mu-opium, etc.), phenytoin, etc.) Cinacalcet, diphenhydramine, and the like.

The amino acid may be a natural amino acid or an unnatural amino acid.

(3) A gene-related substance. Without particular limitation, the following may be mentioned: nucleosides, nucleotides, oligonucleotides, polynucleotides, antisense oligonucleotides, nucleic acids, DNA, RNA, aptamers, related aptamers or ligands, and the like.

(4) And (3) vitamins. Including but not limited to vitamin a (including but not limited to vitamin a, retinoic acid, isotretinoin, retinal, 3-dehydroretinol, 13-cis-retinoic acid, all-trans retinoic acid, alpha-carotene, beta-carotene, gamma-carotene, delta-carotene, cryptoxanthin, etretinate, eretin, etc.), vitamin B (such as folic acid, etc.), vitamin C, vitamin D, vitamin E, vitamin K, vitamin H, vitamin M, vitamin T, vitamin U, vitamin P, vitamin PP, etc.

(5) A saccharide. There are no particular restrictions, and glycolipids, glycoproteins, glycogen, and the like are mainly included. Glycolipids are widely distributed in organisms and mainly comprise two major classes of glycosyl acylglycerols and glycosphingolipids, specifically comprising ceramides, cerebrosides, sphingosines, gangliosides, glyceroglycolipids and the like; glycoproteins are complex carbohydrates consisting of branched oligosaccharide chains covalently linked to polypeptides, and are usually secreted into body fluids or are components of membrane proteins, including but not limited to transferrin, ceruloplasmin, membrane-bound proteins, histocompatibility antigens, hormones, carriers, lectins, heparin, and antibodies.

(6) A lipid. Lipids include mainly fatty acid esters and lipids.

Typical fatty acid esters are fats and oils, which refer to esters of fatty acids with glycerol. Fatty acid esters also include esters of non-glycerol alcohols with fatty acids, including but not limited to coconut oil fatty acid esters, polyglycerol fatty acid esters, sucrose fatty acid esters, and the like. Among them, the composition of the fatty acid is not particularly limited, but a fatty acid having 12 to 24 carbon atoms is preferable, and the fatty acid may be a saturated fatty acid or an unsaturated fatty acid.

The lipid comprises glycolipid, phospholipid, and cholesterol ester.

The glycolipid mainly comprises glyceroglycolipid, glycosphingolipid (glycosphingolipid), sophorolipid, cerebroside, acylsphingosyltrihexose, sphingosine-1-phosphate, rhamnolipid, and dirhamnolipid.

The phospholipid may be a natural phospholipid material, or a semisynthetic or synthetic phospholipid compound.

Natural phospholipids include, but are not limited to, phosphatidic acid, lecithin (belonging to phosphatidylcholine, derived from egg yolk, soybean, etc., e.g. egg yolk lecithin, soybean lecithin), cephalin (belonging to phosphatidylethanolamine, derived from brain, nerve, soybean, etc.), inositol phosphatide (phosphatidylinositol), phosphatidylserine, sphingomyelin, lysophospholipid, lysolecithin, lysocephalin, lysophosphatidic acid, myelin, cardiolipin (diphosphatidylglycerol), heparin, small molecular weight heparin, other phospholipids derived from soybean or egg yolk, and the like.

Semi-synthetic or synthetic phospholipid compounds include, but are not limited to, Phosphatidic Acid (PA), plasmalogens, Phosphatidylglycerol (PG), Phosphatidylcholine (PC), Phosphatidylethanolamine (PE), Phosphatidylserine (PS), Phosphatidylinositol (PI), ceramides, ceramide phospholipids (including, but not limited to, ceramide phosphatidylcholine, ceramide phosphatidylethanolamine, ceramide phosphatidylglycerol, ceramide phosphatidylserine, ceramide phosphatidylinositol, ceramide phosphatidylglycerol phosphate, and the like), lysoglycerophospholipid isomers, hydrogenated natural phospholipids, O-amino acid esters of phosphatidylglycerol, and the like. The number of fatty acyl groups in the synthetic phospholipid may be 1 or 2; when 2, the two fatty acyl groups may be the same or different. The fatty acyl group in the synthetic phospholipid may be derived from a saturated fatty acid or an unsaturated fatty acid. The source of the fatty acyl group is not particularly limited, and includes, but is not limited to, acyl groups derived from fatty acids such as butyric acid, t-butyric acid, valeric acid, heptanoic acid, 2-ethylhexanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, margaric acid, stearic acid, isostearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, arachidic acid, arachidonic acid, behenic acid, erucic acid, lignoceric acid, cerotic acid, octacosanoic acid, melissic acid, laccerotic acid, etc. By way of example, phosphatidic acids include, but are not limited to, dilauroyl phosphatidic acid, dimyristoyl phosphatidic acid, dipalmitoyl phosphatidic acid, and the like; phosphatidylglycerols include, but are not limited to, dihexanoylphosphatidylglycerol, dioctanoylphosphatidylglycerol, didecanoylphosphatidylglycerol, dilauroylphosphatidylglycerol, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol, and the like; phosphatidylcholines include, but are not limited to, dihexanoylphosphatidylcholine, dioctanoylphosphatidylcholine, didecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, hydrogenated soy phosphatidylcholine, and the like; phosphatidylethanolamines include, but are not limited to, N-glutaryl-phosphatidylethanolamine, dilauroyl phosphatidylethanolamine, dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, dioleoyl phosphatidylethanolamine, dilinoleoyl phosphatidylethanolamine, erucyl phosphatidylethanolamine, and the like; phosphatidylinositol kinases include, but are not limited to, dilauroyl phosphatidylinositol, dimyristoyl phosphatidylinositol, dipalmitoyl phosphatidylinositol, distearoyl phosphatidylinositol, dioleoyl phosphatidylinositol, lysophosphatidylinositol, and the like; hydrogenated natural phospholipids include, but are not limited to, hydrogenated soy lecithin, hydrogenated egg yolk lecithin, and the like; synthetic phospholipids containing two different acyl groups include, but are not limited to, 1-palmitoyl-2-oleoyl phosphatidylethanolamine, 1-palmitoyl-2-linoleoyl phosphatidylcholine, 1-stearoyl-2-oleoyl phosphatidylcholine, 1-stearoyl-2-arachidoylphosphatidylcholine, 1-palmitoyl-2-oleoyl phosphatidylcholine, 1-palmitoyl-2-stearoyl phosphatidylcholine, and the like.

Cholesterol and steroids (steroids ) include, but are not limited to, cholesterol, dihydrocholesterol, sitosterol, beta-sitosterol, lanosterol, anasterol, avenasterol, brassicasterol, ergosterol, ergocalciferol, dihydroergocalciferol, ergosterol, dihydroergosterol, campesterol, chalinosterol, chinasterol, cholestanol, coprosterol, cycloartenol, dehydrocholesterol, desmosterol, episterol, fucosterol, hexahydrosterol, hydroxycholesterol, photosterol, parkeol, porosterol, fucosterol, sitosterol, stigmastanol, stigmasterol, weinbasterol, zymosterol, bile alcohols, bile acids (including, but not limited to, cholic acid, chenocholic acid, taurocholic acid, deoxycholic acid, lithocholic acid, and the like), sex hormones, vitamin D, aldosterone, deoxycorticosterone, corticosterol, and the like, Clobetasol, fludrocortisone, cortisone, hydrocortisone, prednisone, medrysone, methylprednisolone, acalomethasone, beclomethasone, betamethasone, dexamethasone, diflorasone, difluminisone, triamcinolone, mometasone, desoximetasone, fluocinolone, flunisolide, paramethasone, halcinonide, amcinonide, desonide, prednisolone, methylprednisolone, clocortolone, fluorodrolone acetonide, etc.

(7) Neurotransmitters. And are classified into monoamines, polypeptides, amino acids, and the like. Wherein, the monoamines comprise dopamine, norepinephrine, epinephrine, 5-hydroxytryptamine (also called serotonin) and the like; peptides including neurotensin, cholecystokinin, vasoactive intestinal peptide, vasopressin, endogenous opioid peptide, somatostatin, neuropeptide y, neuregulin U, etc.; other classes include nucleotides, south-adamide, sigma receptors (sigma receptors), and the like. Related drugs include, but are not limited to, diphenhydramine bromide, doxylamine, carbinoxamine, clemastine, dimenhydrinate, tripelennamine, bimamine, mesalamine, azolamine, pheniramine, chlorpheniramine, dexchlorpheniramine, brompheniramine, dexbrompheniramine, piretamine, triprolidine, promethazine, alimemazine, methdilazine, cyclizine, clocyclazine, diphenyllene, phenindamine, indidine, minoxidil, buclizine, azazole, cyproheptadine, azatadine, terfenadine, fexofenadine, astemizole, cetirizine, azelastine, azatadine, loratadine, desloratadine, and the like.

(8) An extracellular matrix material. Including but not limited to collagen (e.g., type I collagen, type II collagen, etc.), hyaluronic acid, glycoproteins, proteoglycans, laminin, fibronectin, elastin, and other biological macromolecules.

(9) Dyes and fluorescent substances. Dyes include, but are not limited to, trypan blue, Coomassie Brilliant blue, crystal violet, pyrogallol red, cyclopentanone, and the like. The fluorescent substance can be used for fluorescent staining methods such as chemofluorescent staining, immunofluorescent staining and the like, and can also be used for fluorescent marking and tracing. Fluorescent substances include, but are not limited to: fluorescent proteins, rhodamines, phalloidin and derivatives thereof, rhodamines, cyanine dyes, indocyanine green, acridines, phycoerythrin, phycocyanin, methyl green, alizarin red, aniline blue, pyronin, fluorescein, aggregation-induced emission dyes, near infrared fluorescent dyes, fluorogenic carbacepacious nanodoot, hematoxylin, eosin, neutral red, basic fuchsin, Alexa Fluor series, Oregon green series, BODIPY series, Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Cy7.5, Hex, PerCP, DAPI, Hoechst series, Cascade blue, Astrazon series, SYTO series, stilbenes, naphthalimides, coumarins, pyrenes, phenanthridines, porphyrins, indole derivatives, chromomycin a, violaxanthin, erythromycin, and erythromycin. All fluorescent compounds disclosed in patents CN1969190A, CN101679849B, US14/526901 are incorporated herein by reference. The rhodamine derivatives described in the literature { Progress in Chemistry,2010,22(10):1929-1939} and the cited literature are all incorporated herein by reference. The coumarins also include, but are not limited to, 4,5, 7-trihydroxy coumarins. Functional groups of the general formula (1) which are J-like also belong to the biologically relevant substances here.

(10) A targeting factor. The targeting factor is not particularly limited. Can be in single target point class or multi-target point class. May be a single molecule or an aggregate of a plurality of molecules. Can be a targeting factor, and also comprises molecules, molecular aggregates, self-assemblies, nanoparticles, liposomes, vesicles, medicaments and the like modified with the targeting factor.

The site to be targeted is not particularly limited. Including but not limited to brain, lung, kidney, stomach, liver, pancreas, breast, prostate, thyroid, uterus, ovary, nasopharynx, esophagus, rectum, colon, small intestine, gallbladder, bladder, bone, sweat gland, skin, blood vessels, lymph, joints, soft tissues, etc.

The targeted tissue characteristics are not particularly limited and include, but are not limited to, tumor tissue, inflammatory tissue, diseased tissue, and the like.

Targeting factors include, but are not limited to, class I among the above functional groups, polypeptide ligands, small molecule ligands, other ligands and ligand variants that are recognized by cell surface receptors, tumor angiogenesis targeting ligands, tumor apoptosis targeting ligands, disease cell cycle targeting ligands, disease receptor targeting ligands, kinase inhibitors or proteasome inhibitors, PI3K/Akt/mTOR inhibitors, angiogenesis inhibitors, cytoskeletal signaling inhibitors, stem cell and Wnt gene inhibitors, protease inhibitors, protein tyrosine kinase inhibitors, apoptosis inhibitors, MAPK inhibitors, cell cycle regulation inhibitors, TGF-beta/Smad inhibitors, nerve signaling inhibitors, endocrine and hormone inhibitors, metabolic inhibitors, microbiological inhibitors, epigenetic inhibitors, JAK/STAT inhibitors, pro-and pro-inflammatory cytokines, pro-inflammatory, Any one of a DNA damage inhibitor, an NF-kB inhibitor, a GPCR & G Protein inhibitor, a transmembrane transporter inhibitor, an Autophagy inhibitor, a Ubiquitin inhibitor, a multi-target inhibitor, a receptor, an antibody, a gene targeting molecule, a virus, a vaccine, a biomolecular targeting factor, a vitamin, a targeting drug and the like.

Specifically, targeting factors include, but are not limited to: polypeptide ligands, small molecule ligands, other ligands and ligand variants that are recognized by cell surface receptors, tumor angiogenesis targeting ligands, disease cell cycle targeting ligands, tumor apoptosis targeting ligands, disease receptor targeting ligands, kinase inhibitors or proteasome inhibitors, PI3K/Akt/mTOR inhibitors, angiogenesis inhibitors, cytoskeletal signaling inhibitors, stem cell and Wnt gene inhibitors, protease inhibitors, Protein tyrosine kinase inhibitors, apoptosis inhibitors, MAPK inhibitors, cell cycle regulation inhibitors, TGF-beta/Smad inhibitors, nerve signaling inhibitors, endocrine and hormone inhibitors, metabolism inhibitors, microbiological inhibitors, epigenetic inhibitors, JAK/STAT inhibitors, DNA damage inhibitors, NF-kappa B inhibitors, GPCR & G Protein inhibitors, tumor angiogenesis targeting ligands, tumor cell cycle targeting ligands, tumor apoptosis targeting ligands, disease receptor targeting ligands, kinase inhibitors or proteasome inhibitors, PI3K/Akt/mTOR inhibitors, angiogenesis inhibitors, cytoskeletal signaling inhibitors, transmembrane transport protein inhibitor, Autophagy inhibitor, Ubiquitin inhibitor, multi-target inhibitor, receptor, antibody, targeted drug, gene targeted molecule, virus, vaccine, biomolecular targeted factor, vitamin and the like.

Targets for targeting factors include, but are not limited to, CD3, CD11, CD20, CD22, CD25, CD30, CD33, CD41, CD44, CD52, CD6, CD3, CD11a, Her2, GpIIb/IIIa, RANKL, CTLA-4, CO17-1A, IL-1 β, IL-12/23, IL6, IL13, IL-17, Blys, RSV, IgE-25, integrin- α 4, respiratory syncytial virus F protein, tumor necrosis factor α (TNF α), vascular endothelial growth factor, Epidermal Growth Factor Receptor (EGFR), FGR3, EGFL-7, interferon α, and the like.

Functional groups of the class I in the general formula (1) also belong to the biologically relevant substances here.

(11) Vesicles, liposomes, micelles, nanocarriers for drug delivery, cells (e.g., myeloblasts, etc.), viruses (e.g., cyanobacterial toxins), and the like, which are biologically relevant substances known to those skilled in the art.

(12) Plant or animal extract. Including but not limited to Tripterygium wilfordii hook F extract, Buxus sinica L extract, Mylabris extract and its derivatives, flavones or flavonoid drugs, Salvia miltiorrhiza extract, Silybum marianum extract, glycyrrhetinic acid, scopoletin, Tribulus terrestris extract, pollen extract, Ginkgo biloba extract, Couma chinensis leaf extract, honeysuckle extract, Schisandra chinensis extract, Veratrum plant extract, Cinobufagin, snake venom extract, leech extract, etc. Also comprises traditional Chinese medicine extracts and the like.

Tripterygium wilfordii hook F extract includes but is not limited to triptolide, tripdiolide, triptonide, begonia methyl ether, triptonide, triptolide, triptodipine, tripterygium wilfordii alkaloid, tripterygium wilfordii acid, hydroxyl tripterygium wilfordii acid, tripterygium wilfordii glycoside, etc. The buxus extract includes but is not limited to buxus alkali including but not limited to cyclovirobuxine, cyclonorbuxine, cyclovirobuxine C and the like. The cantharides extract and its derivatives include but are not limited to cantharidin, norcantharidin, methylcantharidimide, hydroxycantharimide, amino acid norcantharidin, etc.; the literature { aster red, synthesis of norcantharidin derivatives [ D ]. Zhongshan university, 2005.}, and cantharidin derivatives described in the cited literature are incorporated herein by reference. The flavone or flavonoid drugs also include, but are not limited to, puerarin, hydroxyisoflavone, homobaicalein, flavonone II, baicalein, baicalin, 4',5, 7-trihydroxyflavone, 3',4', 7-trihydroxyisoflavone, emodin anthrone, emodin, 5,7,4' -trihydroxyflavone, 3,5, 7-trihydroxyflavone, 4',6, 7-trihydroxyisoflavone, genistein, 4',5, 7-trihydroxyisoflavone-7-glycoside, and the like. The Saviae Miltiorrhizae radix extract can be tanshinone and its derivatives, including but not limited to tanshinone IIa, tanshinone IIb, tanshinone I, cryptotanshinone, Saviae Miltiorrhizae radix neoquinone A, Saviae Miltiorrhizae radix neoquinone B, and Saviae Miltiorrhizae radix neoquinone C, and water soluble Saviae Miltiorrhizae radix extract and its salts, including but not limited to tanshinol, protocatechualdehyde, rosmarinic acid, alkannic acid, salvianolic acid A, B, C, D, E, F, G, etc. The silybum marianum extract includes, but is not limited to, silybin, silychristin, silydianin, and the like. The pollen extract can be broken pollen or non-broken pollen. Ginkgo extracts include but are not limited to flavones, ginkgolides, and the like. Extracts of veratrum include, but are not limited to, resveratrol, cyclopamine, and the like. Snake venom extracts, such as thrombin, defibrase, etc. Hirudo extract such as hirudin.

(13) In addition, central nervous system inhibitors, central nervous system stimulants, psychotropic agents, respiratory tract agents, peripheral nervous system agents, agents acting at synaptic or neuroeffector junction sites, smooth muscle active agents, histaminergic agents, antihistaminic agents, cardiovascular agents, blood and hematopoietic system agents, gastrointestinal tract agents, steroid agents, cell growth inhibitors, antineoplastic agents, anti-infective agents, antibiotic agents, antifungal agents, anthelmintic agents, antimalarial agents, antiprotozoal agents, antimicrobial agents, anti-inflammatory agents, immunosuppressive agents, cytokines, enzymes, iminosugars, ceramide analogs, brain-acting hormones or neurotransmitters, neuropeptides or derivatives thereof, neurotrophic factors, antibodies or fragments thereof, Alzheimer's agents or compounds, as disclosed in patent 102316902A and the references cited therein, Nucleic acid-based compounds, imaging agents, (organophosphate) antidotes, and like biologically relevant substances are incorporated herein by reference. All biologically relevant substances in the classes of { biotech drugs (863 Biotechnology letters) } published in 2001 and the recombinant hormonal drugs, recombinant cytokine drugs, recombinant thrombolytic drugs, human blood substitutes, therapeutic antibodies, recombinant soluble receptor and adhesion molecule drugs, antisense oligonucleotide drugs, genetic drugs, genetically engineered viral vaccines, genetically engineered bacterins, genetically engineered parasite vaccines, therapeutic vaccines disclosed in the cited documents are also incorporated herein by reference. All anti-Cancer drugs listed in the literature { Macromolecular anticancer therapeutics and Development } (authors l. harivardhan Reddy and Patrick Couvreur, published 2010) are incorporated herein by reference.

(14) Also comprises phloretin, 2,4, 6-trihydroxy-3, 5-dimethyl acetophenone, etc.

The term "complex biologically relevant substance" refers to, for example, a combination of a lipid and another biologically relevant substance, such as a combination of a fluorescent substance and another biologically relevant substance, such as a combination of a targeting factor and another biologically relevant substance, such as a combination of a carbohydrate and another biologically relevant substance, and also includes any combination of two or more suitable biologically relevant substances.

6.2. Linking group L for connecting biologically relevant substance and polyethylene glycol branched chain

The structure of the covalent bond linking group L formed after the functional group in the functionalized eight-arm polyethylene glycol reacts with the reactive group in the bio-related substance is related to the reactive groups of the bio-related substance and the polyethylene glycol. Including but not limited to documents CN104877127A, CN104530413A, CN104530415A, CN 104530417A. For example, CN104530413A corresponds to paragraphs [0922] to [0935] and the examples section.

In general terms, the use of a single,

the reaction site in the bio-related substance is not particularly limited, and may be a naturally occurring reaction site, or a modified activated group or an introduced reactive group. For example, in the case of drug molecules, common naturally occurring reactive sites are amino, thiol, carboxyl, disulfide, N-amino, C-carboxyl, hydroxyl (alcoholic hydroxyl, phenolic hydroxyl, etc.), carbonyl, guanidino, and the like. The reactive sites of the amino acids described in the literature { Journal of Controlled Release,161(2012): 461-. Non-naturally occurring groups, modified to introduce reactive sites including, but not limited to, any of R in classes A through H as described above₀₁Examples thereof include aldehyde group, alkynyl group, azide group and the like.

The reactive group in the bio-related substance includes, but is not limited to, any one of an amino group, a thiol group, a disulfide group, a carboxyl group, a hydroxyl group, a carbonyl or aldehyde group, an unsaturated bond, and an introduced reactive group. For example: respectively reacting the amino-containing biologically-relevant substances with polyethylene glycol containing active ester, formic acid active ester, sulfonate, aldehyde, alpha, beta-unsaturated bonds, carboxylic acid groups, epoxide, isocyanate and isothiocyanate to obtain polyethylene glycol modifiers connected with groups such as amide groups, urethane groups, amino groups, imino groups (which can be further reduced into secondary amino groups), amino groups, amide groups, amino alcohols, urea bonds, thiourea bonds and the like; reacting a biological related substance containing sulfydryl with polyethylene glycol containing active ester, formic acid active ester, sulfonate, sulfydryl, maleimide, aldehyde, alpha, beta-unsaturated bonds, carboxylic acid groups, iodoacetamide and anhydride to obtain a polyethylene glycol modifier connected with groups such as thioester, thiocarbonate, thioether, disulfide, thioether, thiohemiacetal, thioether, thioester, thioether, imide and the like; reacting biologically-relevant substances containing unsaturated bonds with polyethylene glycol containing sulfydryl to obtain a polyethylene glycol modifier connected with a thioether group; respectively reacting biologically-relevant substances containing carboxylic acid with polyethylene glycol containing sulfydryl and amino to obtain polyethylene glycol modifiers connected with thioester groups, amide groups and other groups; respectively reacting biologically-relevant substances containing hydroxyl with polyethylene glycol containing carboxyl, isocyanate, epoxide and chloroformyl to obtain polyethylene glycol modifier with ester group, carbamate group, ether bond, carbonate group and other groups; respectively reacting biologically-relevant substances containing carbonyl or aldehyde groups with polyethylene glycol containing amino, hydrazine and hydrazide to obtain polyethylene glycol modifiers with imine bonds, hydrazone, acylhydrazone and other groups; reactive groups containing azide, alkynyl, alkenyl, sulfydryl, azide, diene, maleimide, 1,2, 4-triazoline-3, 5-diketone, dithioester, hydroxylamine, hydrazide, acrylate, allyloxy, isocyanate, tetrazole and the like are subjected to click chemistry reaction to generate various connecting groups containing structures such as triazole, isoxazole, thioether bonds and the like. Linkers produced by the click reaction reported in the document adv. funct. mater, 2014,24,2572 and cited therein are incorporated herein by reference.

The structure of L is not particularly limited, and includes, but is not limited to, a linear structure, a branched structure, or a cyclic-containing structure.

The valence of L is not particularly limited, and may be, for example, a divalent linking group, or a trivalent or higher covalent linking group. L is preferably a divalent linking group. Generally, a divalent linking group is formed. Trivalent linkers, such as those formed by reacting a thiol group with an alkynyl group, are exemplified. As another example, a reactive group of the type B5 can be reacted with a disulfide bond to provide a trivalent linking group

The stability of L is not particularly limited, and may be a linker that can exist stably or a degradable linker. The conditions which can be stably present, degradable conditions are in accordance with the term moiety. The L is preferably a linker that can stably exist under light, heat, low temperature, enzyme, redox, acidic, basic, physiological conditions or in vitro simulated environments, or a linker that can degrade under light, heat, low temperature, enzyme, redox, acidic, basic, physiological conditions or in vitro simulated environments. More preferably, L is a linker that is stable under light, heat, low temperature, enzyme, redox, acidic or basic conditions, or is a linker that is degradable under light, heat, low temperature, enzyme, redox, acidic or basic conditions.

When a linker group that can be stably present, L can contain a linker group including, but not limited to, an ether linkage, a thioether linkage, a urea linkage, a thiourea linkage, a carbamate group, a thiocarbamate group, a secondary amino group, a tertiary amino group, an amide group, an imide group, a thioamide group, a sulfonamide group, an enamine group, a triazole, an isoxazole, and the like.

When the position of L is degradable, the drug molecule can realize the polyethylene glycol removal, and the package of polyethylene glycol is released, so that the drug effect can be exerted to the maximum extent.

When degradable linking groups, L may contain a degradable linking group including, but not limited to, any of the degradable linking groups described above, specifically including, but not limited to, disulfide bonds, vinyl ether bonds, ester groups, thioester groups, dithioester groups, carbonate groups, thiocarbonate groups, dithiocarbonate groups, trithiocarbonate groups, carbamate groups, thiocarbamate groups, dithiocarbamate groups, acetals, cyclic acetals, mercaptals, azaacetals, azaheterocyclic acetals, dithioacetals, hemiacetals, thiohemiacetals, azahemiacetals, ketals, thioketals, azaheterocyclic ketals, thioketal, imine bonds, hydrazone bonds, acylhydrazone bonds, oxime bonds, thiooxime bonds, semicarbazone bonds, thiosemicarbazone bonds, hydrazine groups, hydrazide groups, thiocarbhydrazide groups, azohydrazide groups, thiohydrazide groups, thioazocarbohydrazide groups, thiohydrazide groups, Hydrazinoformate groups, hydrazinothiocarbamate groups, carbazide, thiocarbohydrazide, azo groups, isoureido groups, isothioureido groups, allophanate groups, thioallophanate groups, guanidino groups, amidino groups, aminoguanidino groups, amidino groups, imino groups, thioester groups, sulfonate groups, sulfinate groups, sulfonamide groups, sulfonyl hydrazide groups, sulfonyl urea groups, maleimide groups, orthoester groups, phosphate groups, phosphite groups, hypophosphite groups, phosphonate groups, phosphosilane groups, silane groups, carbonamide, thioamide, phosphoramide, phosphoramidite, pyrophosphoroamide, cyclophosphamide, ifosfamide, thiophosphoramide, aconityl groups, peptide bonds, thioamide bonds and the like.

L preferably contains any linking group such as triazole, 4, 5-dihydroisoxazole, ether bond, thioether group, amide bond, imide group, imide bond, secondary amine bond, tertiary amine bond, urea bond, ester group, thioester group, disulfide group, thioester group, dithioester group, thiocarbonate group, sulfonate group, sulfonamide group, carbamate group, thiocarbamate group, dithiocarbamate group, hemithioacetal, and carbonate group.

In addition to the degradable or non-degradable linking moieties described above, L may also contain any of the above stably present divalent linking groups STAG, or any combination of two or more of the above stably present divalent linking groups. For example, when modifying a hydroxyl group of a drug molecule, the drug may be modified to attach an amino acid molecule (glycine is the most common, and may be diglycine or polyglycine) to convert the hydroxyl group to an amino group, and the range of functional groups to be reacted with the amino group is wider.

6.3. Reaction between functionalized eight-armed polyethylene glycol and biologically-related substance

Including but not limited to documents CN104877127A, CN104530413A, CN104530415A, CN 104530417A. For example, CN104530413A corresponds to segments [0936] to [0939 ].

The type of reaction between the functionalized eight-arm polyethylene glycol and the biologically-relevant substance is not particularly limited, and may be a site-directed modification or an undefined site modification (also referred to as a random modification). By way of example, site-directed modifications such as commercial products

The site-directed reaction between the N-amino group and the aldehyde group of methionine, such as the site-directed reaction between thiol group and maleimide, vinylsulfone, 2-iodoacetamide, o-pyridyldisulfide, etc., and such as the site-directed reaction between amino group and cyano group and isocyanate, isothiocyanate, etc. By way of example, adventitious modifications such as reactions between amino groups and active esters, commercial products such as

And (3) performing indefinite-point modification during preparation. The fixed-point modification method and the variable-point modification method described in the literature { Pharm Sci Technol Today,1998,1(8): 352-.

When the functionalized eight-arm polyethylene glycol modifies the bio-related substance, 1 or more than 1 functionalized eight-arm polyethylene glycol molecule can be connected with one bio-related substance. For reference, e.g. commercial products

One molecule of polyethylene glycol reacts with only one reaction site in one drug molecule; to commercialize the product

In this case, one drug molecule may be linked to a plurality of polyethylene glycol molecules. It is preferred in the present invention that a biologically relevant substance is bound to only one functionalized eight-armed polyethylene glycol molecule.

When the functionalized eight-arm polyethylene glycol modifies the bio-related substance with two or more than two reaction sites, under the condition of no special description, the molecule of the bio-related substance modified by the functionalized eight-arm polyethylene glycol can react with any one or more reaction sites of the bio-related substance; preferably, 1 molecule of the biologically relevant substance reacts with only 1 functional group.

6.4. Eight-arm polyethylene glycol modified small molecule drug

The invention also discloses an eight-arm polyethylene glycol modified micromolecule drug, and D in the corresponding general formula (3) is residue (SD) of the micromolecule drug. The corresponding preferable structure comprises the general formula (4) and the general formula (5) in which D is the residue (SD) of the small molecule drug.

SD in the same molecule is derived from the same small molecule drug and can be residues formed after different reaction sites participate in the reaction.

The small molecule drug is a biological related substance with the molecular weight not more than 1000Da, or a small molecule mimicry or an active fragment of any biological related substance.

The small molecule drug may also be a derivative of any one, or a pharmaceutically acceptable salt of any one. The derivatives include, but are not limited to glycosides, nucleosides, amino acids, polypeptide derivatives, in addition to the molecularly modified derivatives.

The type of the small molecule drug is not particularly limited, and can be organic, inorganic, organic metal compound, oligopeptide or polypeptide and other biologically relevant substances with molecular weight not exceeding 1000 Da. Specifically, the drug composition comprises the small molecule drugs in the class (2), and also comprises the biologically relevant substances with the molecular weight not exceeding 1000Da in any one of the class (1) and the class (3) to the class (14), and small molecule mimicry or active fragments (including variants) of any biologically relevant substances.

The molecular weight of the small molecule drug is usually not more than 1000 Da. Any molecular weight in any one range of 0-300 Da, 300-350 Da, 350-400 Da, 400-450 Da, 450-500 Da, 500-550 Da, 550-600 Da, 600-650 Da, 650-700 Da, 700-750 Da, 750-800 Da, 800-850 Da, 850-900 Da, 900-950 Da and 950-1000 Da can be selected; the small value endpoints are not included but the large value endpoints are included in each interval.

The mode of obtaining the small molecule drug is not particularly limited, and includes, but is not limited to, natural extracts and derivatives thereof, degradation products of natural extracts, gene recombination products (molecular cloning products), chemically synthesized substances, and the like.

The hydrophilicity and hydrophobicity of the small molecule drug is not particularly limited, and the small molecule drug may be hydrophilic or water-soluble, or may be hydrophobic or fat-soluble. The charge properties of the small molecule drug are not particularly limited.

The small molecule drug can be the small molecule drug itself, and can also be a dimer or a polymer, a partial subunit or a fragment thereof and the like.

The small molecule drug can be the small molecule drug itself, or a precursor, an activated state, a derivative, an isomer, a mutant, an analog, a mimetic, a polymorph, a pharmaceutically acceptable salt, a fusion protein, a chemically modified substance, a gene recombinant substance, and the like thereof, or a corresponding agonist, activator, inhibitor, antagonist, modulator, receptor, ligand or ligand, antibody and a fragment thereof, and the like. The small molecule drug also allows for a target molecule, adjunct or delivery vehicle to be bound to it, either before or after it is bound to the functionalized polyethylene glycol.

The field of application of the small molecule drug is not particularly limited, including but not limited to any of the above-mentioned biologically relevant substances, including by way of example but not limited to anticancer drugs, antineoplastic drugs, anti-hepatitis drugs, diabetes treatment drugs, anti-infective drugs, antibiotics, antiviral agents, antifungal agents, vaccines, anti-respiratory drugs, anti-spasmodics, muscle relaxants, anti-inflammatory drugs, appetite suppressants, migraine treating agents, muscle contractants, antirheumatics, antimalarials, antiemetics, bronchodilators, antithrombotic agents, antihypertensive agents, cardiovascular agents, antiarrhythmic agents, antioxidants, anti-asthmatic agents, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitic agents, anticoagulants, anti-neoplastic agents, hypoglycemic agents, nutritional agents and additives, growth supplements, anti-enteritis agents, antibodies, diagnostic agents, anti-cancer drugs, anti-cancer, Contrast agents, and the like. Preferably anticancer, antitumor antibiotic, antiviral or antifungal medicine. Typical anti-cancer or anti-tumor drugs are in accordance with the above.

The small molecular drug is preferably selected from any one or any one derivative of SN38, irinotecan, resveratrol, cantharidin and derivatives thereof, chrysin, tripterygium wilfordii extract, flavone or flavonoid drug, salvia miltiorrhiza extract and silybum marianum extract or any one pharmaceutically acceptable salt; the pharmaceutically acceptable salt can be inorganic salt such as hydrochloride, or organic salt such as oxalate, malate, citrate, etc., preferably hydrochloride. The derivatives include, but are not limited to glycosides, nucleosides, amino acids, polypeptide derivatives, in addition to the molecularly modified derivatives. When the functionalized eight-arm polyethylene glycol is combined with the small-molecule drug through alcoholic hydroxyl or phenolic hydroxyl, the amino acid derivative of the small-molecule drug or the oligo-polyethylene glycol fragment with 2-10 EO units is preferred, the amino acid derivative of the small-molecule drug is more preferred, the glycine or alanine modified product of the small-molecule drug is more preferred, the glycine modified product of the small-molecule drug is most preferred, namely, the L preferably contains an amino acid derivative skeleton, the glycine skeleton or alanine skeleton is more preferred, and the glycine skeleton (-C (═ O) -CH is most preferred₂-NH-), when the reactive group in the amino acid derivative of the small molecule drug is converted to the amino group in the corresponding amino acid. The small molecule drug residue SD includes but is not limited to the fragment [1078 ] of CN104530413A]～[1113]Small molecule drug residues of the fragment.

7. Interpretation of terms

References CN104877127A (paragraphs [0032] - [0069 ]), and citations thereof, generally speaking, terms concerning compounds and structures include, but are not limited to, hydrocarbons, aliphatic hydrocarbons, aromatic alkanes, saturated hydrocarbons, alkanes, saturated aliphatic hydrocarbons, unsaturated aliphatic hydrocarbons, alkenes, alkynes, dienes, open-chain hydrocarbons, straight-chain structures (without pendant groups), straight-chain hydrocarbons, straight-chain aliphatic hydrocarbons, branched-chain structures (with pendant groups), branched-chain aliphatic hydrocarbons, cyclic structures, dendritic structures, comb structures, hyperbranched structures, ring atoms, ring skeletons, carbocyclics, alicyclic hydrocarbons, alicyclic rings, saturated alicyclic hydrocarbons (cycloalkanes), unsaturated alicyclic hydrocarbons, cycloalkynes, cycloalkadienes, benzene rings, aromatic rings, fused rings, structural units constituting ring skeletons, structures with or without nesting, cyclic structures, aromatic rings, fused rings, and aromatic rings, Heteroatoms, type of heteroatom, heterocycle, aliphatic heterocycle, aromatic heterocycle, alicyclic ring, heteroaromatic ring, oxa, aza, thia, phospha, number of heteroatoms, nitroxide, nitrogenthio, heteroatom position, number of ring structures, monocyclic ring, polycyclic compound, number of rings, bicyclic ring, tricyclic ring, tetracyclic ring, connection between ring structures, spiro ring, fused ring, bridged ring, rings in which any two of the rings are connected, heteromonocyclic ring (monocyclic), heterocyclic ring, heterospiro ring, heterobridged ring, heterofused ring, fused aromatic ring, fused heterocyclic ring (fused heterocyclic ring), fused aromatic ring (aromatic heterocycle), benzo heterocycle, fused heterocyclic ring, fused aromatic ring, monocyclic hydrocarbon, polycyclic hydrocarbon, spiro hydrocarbon, bridged hydrocarbon, fused aromatic hydrocarbon, saturated cyclic hydrocarbon (cyclic hydrocarbon), unsaturated cyclic hydrocarbon, unsaturated alicyclic hydrocarbon, aromatic hydrocarbon, oxa, aza, thia, phosph, polycyclic ring, heterocyclic ring structure, heterocyclic, Heterohydrocarbons, open-chain heterohydrocarbons, heterocyclics, aliphatic heterohydrocarbons, aromatic heterohydrocarbons, aliphatic heterocyclics, aliphatic heteroopen-chain hydrocarbons, saturated aliphatic heterohydrocarbons (heteroalkanes), heteroarenes, fused heterohydrocarbons, aromatic fused heterocyclics, fused heteroheterocyclics, heteroaromatic alkanes, open-chain heterohydrocarbons, heterocyclics, aromatic fused heterocyclics, and the like.

The heteroatom in the present invention is not particularly limited, but includes, but is not limited to, O, S, N, P, Si, F, Cl, Br, I, B and the like.

In the present invention, the hydrocarbon-derived ring includes, but is not limited to, any one of cyclic structures, any combination of two or more cyclic structures, and the number of cyclic structures in the combination is not particularly limited. In the present invention, two types are generally carried out depending on whether an aromatic ring or a heteroaromatic ring is contained.

In the present invention, a compound in which a carbon atom at any position of a hydrocarbon is substituted with a heteroatom is collectively referred to as a heterohydrocarbon.

With reference to CN104877127A and references cited therein, in general terms referring to groups include, but are not limited to, groups, residues, valences of the group, monovalent groups, divalent groups, trivalent groups, tetravalent groups, … …, one hundred valent groups, linkages, oxy groups, thio groups, hydrocarbyl groups, monovalent hydrocarbyl groups, divalent hydrocarbyl (alkylene) groups, trivalent hydrocarbyl groups, substituents, hydrocarbyl substituents, heteroatom-containing groups, heterohydrocarbyl groups, heteroatom-containing substituents, acyl groups, carbonyl groups, non-carbonyl groups, hydrocarbyloxy groups, hydrocarbylthio groups, acyloxy groups (acyloxy groups), oxyacyl groups, aminoacyl groups, acylamino groups, substituted hydrocarbyl groups, hydrocarbyl-substituted hydrocarbyl groups (still belonging to the group), saturated hydrocarbyl (alkyl) groups, unsaturated hydrocarbyl groups, alkenyl groups, alkynyl groups, dienyl groups, alkylene groups, alkynyl groups, dialkenyl groups, open-chain hydrocarbyl groups, straight-chain hydrocarbyl groups, branched-chain hydrocarbyl groups, Cycloalkyl, aliphatic hydrocarbon, alicyclic hydrocarbon, cycloalkane, unsaturated alicyclic hydrocarbon, monocyclic hydrocarbon, polycyclic hydrocarbon, aryl, arylalkyl, heteroalkyl-substituted hydrocarbon (which may be referred to as "heteroalkyl"), aliphatic heteroalkyl, open-chain heteroalkyl, aliphatic heterocycloalkyl, heterocycle-substituted hydrocarbon, heteroaromatic hydrocarbon, heteroaryl, heteroaromatic hydrocarbon, heteroaralkyl, fused cycloalkyl, fused heteroaryl, fused heterocycloalkyl, aromatic fused heterocycloalkyl, oxahydrocarbyl, azahydrocarbyl, thiahydrocarbyl, phosphalkyl, monoheterohydrocarbyl, diheterohydrocarbyl, polyheterohydrocarbyl, alkylene source, alkylene derived from unsaturated aliphatic hydrocarbon, cycloalkylene, alicyclic hydrocarbon, arylene, cyclic structure as a substituent, and alkylene which may or may not contain a substituent or a pendant group, Two positions in the alkylene group to which other groups are attached, a protecting group, a thiol protecting group, an alkynyl protecting group, a hydroxyl protecting group, an amino group, a divalent linking group, and the like.

One or more hydrogen atoms in the above hydrocarbons, aliphatic hydrocarbons, aromatic alkanes, saturated hydrocarbons, alkanes, unsaturated hydrocarbons, alkenes, alkynes, dienes, open-chain hydrocarbons, straight-chain hydrocarbons (straight-chain aliphatic hydrocarbons), branched-chain hydrocarbons (branched-chain aliphatic hydrocarbons), cyclic hydrocarbons, alicyclic hydrocarbons, cycloalkanes, unsaturated alicyclic hydrocarbons, cycloalkenes, cycloalkynes, cycloalkadienes, monocyclic hydrocarbons, polycyclic hydrocarbons, spiro hydrocarbons, bridged hydrocarbons, fused aromatics, hetero hydrocarbons, aliphatic hetero hydrocarbons, open-chain hetero hydrocarbons, heterocyclic hydrocarbons, aliphatic heterocyclic hydrocarbons, aromatic hetero hydrocarbons, hetero aromatics, hetero aralkyl alkanes, heterocyclic fused hydrocarbons, aryl fused heterocyclic hydrocarbons, hetero heterocyclic hydrocarbons and the like may be substituted with a hetero atom or any suitable group, and correspond in this order to the substituted hydrocarbons, substituted aliphatic hydrocarbons, substituted aromatic hydrocarbons, substituted aralkyl hydrocarbons, substituted saturated hydrocarbons, substituted alkanes, substituted unsaturated hydrocarbons, substituted alkenes, substituted alkynes, saturated hydrocarbons, substituted alkynes, straight-chain hydrocarbons, branched-chain hydrocarbons (branched-chain aliphatic hydrocarbons), branched-chain hydrocarbons, branched-, Substituted dienes, substituted open-chain hydrocarbons, substituted straight-chain hydrocarbons (substituted straight-chain aliphatic hydrocarbons), substituted branched-chain hydrocarbons (substituted branched-chain aliphatic hydrocarbons), substituted cyclic hydrocarbons, substituted alicyclic hydrocarbons, substituted cyclic hydrocarbons, substituted unsaturated alicyclic hydrocarbons, substituted cyclic olefins, substituted cycloalkynes, substituted cycloalkadienes, substituted monocyclic hydrocarbons, substituted polycyclic hydrocarbons, substituted spiro hydrocarbons, substituted bridged hydrocarbons, substituted fused cyclic hydrocarbons, substituted fused aromatic hydrocarbons, substituted heteroarenes, substituted lipoheteroarenes, substituted open-chain heteroarenes, substituted heterocyclics, substituted heteroaralkanes, substituted lipoheterocyclics, substituted arylheteroarenes, substituted heteroarenes, substituted fused heterocyclics, substituted aromatic fused heterocyclics, substituted fused heterocyclics, and the like. In the present invention, the heteroatom for substitution is referred to as "substituent atom", and any group for substitution is referred to as "substituent group".

In the present invention, the substituent containing a heteroatom, excluding the hydrocarbon group, includes, but is not limited to, a haloalkyl group, a nitro group, a silyl group (trimethylsilyl group, t-butyldimethylsilyl group, trimethoxysilyl group, etc.), a group in which a hydrocarbon group or a heterohydrocarbon group is directly connected to a heteroatom-containing linking group such as an oxy group, a thio group, an acyl group, an acyloxy group, an oxyacyl group, -NH — C (═ O) -, -C (═ O) -NH-, etc., and the like. Taking the hydrocarbyl group as an example, a hydrocarbyloxy group, a hydrocarbylthio group, an acyl group, an acyloxy group, a hydrocarbyloxyacyl group, an aminoacyl group, an acylamino group, and the like are formed in this order.

The acyl group in the present invention includes a carbonyl group and a non-carbonyl group, and examples include, but are not limited to, a carbonyl group, a sulfonyl group, a sulfinyl group, a phosphoryl group, a hypophosphoryl group, a nitroxyl group, a nitrosyl group, a thiocarbonyl group, an imidoyl group, a thiophosphoryl group, a dithiophosphoryl group, a trithiophosphoryl group, a thiophosphorous group, a dithiophosphoryl group, a thiophosphoryl group, a dithiophosphoryl group, and the like. And is preferably carbonyl, thiocarbonyl, sulfonyl or sulfinyl. Unless otherwise specified, acyl refers specifically to carbonyl.

For a compound, a group or an atom, both substituted and hybridized, e.g. nitrophenyl for a hydrogen atom, also e.g. -CH₂-CH₂-CH₂-is replaced by-CH₂-S-CH(CH₃)-。

The source of the alkylene group in the present invention is not particularly limited, and may be derived from, for example, an aliphatic hydrocarbon or an aromatic hydrocarbon, a saturated hydrocarbon or an unsaturated hydrocarbon, a linear hydrocarbon, a branched hydrocarbon or a cyclic hydrocarbon, a hydrocarbon or a hetero hydrocarbon, or the like. From a saturation point of view, for example, they may be derived from alkanes, alkenes, alkynes, dienes, and the like; for cyclic hydrocarbons, for example, they may be derived from alicyclic or aromatic hydrocarbons, monocyclic or polycyclic hydrocarbons; for heterocyclic hydrocarbons, for example, they may be derived from aliphatic or aromatic heterocyclic hydrocarbons.

The protecting groups referred to in the present invention, such as a mercapto protecting group, an alkynyl protecting group, a hydroxyl protecting group, an amino protecting group and the like, are not particularly limited. The protection groups described in the published patents and literature, including CN104877127A and the cited literature, are all incorporated herein by reference. The hydroxyl group protected by the hydroxyl protecting group is not particularly limited, and may be, for example, an alcoholic hydroxyl group, a phenolic hydroxyl group or the like. The amino group of the amino-protecting group is not particularly limited, and may be derived from, for example, a primary amine, a secondary amine, a diamine, an amide, or the like. The amino group in the present invention is not particularly limited, and includes, but is not limited to, primary amino group, secondary amino group, tertiary amino group, quaternary ammonium ion.

For simplicity, the range of carbon atoms in a group is also indicated herein by the subscript of C in the subscript form indicating the number of carbon atoms the group has, e.g., C_1-10Denotes "having 1 to 10 carbon atoms", C_3-20Means "having 3 to 20 carbon atoms". "substituted C_3-20Hydrocarbyl "means C_3-20A group obtained by substituting a hydrogen atom of a hydrocarbon group. "C_3-20The substituted hydrocarbon group "means a group having 3 to 20 carbon atoms in the group obtained by substituting the hydrogen atom of the hydrocarbon group. Also for example, when a group can be selected from C_1-10When a hydrocarbyl group is present, it may be selected from hydrocarbyl groups having any number of carbon atoms in the range indicated by the subscript, i.e., may be selected from C₁、C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀Any of hydrocarbon groups. In the present invention, unless otherwise specified, subscripts set forth as intervals each represent an integer selected from any one of the ranges, including both endpoints.

In the present invention, two or more objects "are independently preferred" and, when there are preferred cases of multiple stages, they are not required to be selected from the preferred groups of the same stage, but one may be selected from a wide range of preference, one may be selected from a narrow range of preference, one may be selected from a maximum range of preference, and the other may be selected from any of the preferred cases, and the other may be selected from the preferred cases of the same stage. For example, "R₈、R₉、R₁₀、R₁₁、R₁₂The number of carbon atoms of (a) is preferably 1 to 20, more preferably 1 to 10 ", and may be 1 to 20, 1 to 10, or 1 to 20, and the others may be 1 to 10.

Hair brushIn the present invention, the divalent linking group such as alkylene, arylene, amide bond and the like is not particularly limited, and any of the two linking ends may be selected when other groups are linked, for example, in A-CH₂CH₂-and-CH₂When an amide bond is used as a divalent linking group between-B, it may be A-CH₂CH₂-C(＝O)NH-CH₂-B or A-CH₂CH₂-NHC(＝O)-CH₂-B. Some of the structures are marked with asterisks as directional attachment points.

When the structure concerned has an isomer, any of the isomers may be used unless otherwise specified. For example, a cis-trans structure may be employed as the structure having cis-trans isomers. If not specifically stated, alkyl means a hydrocarbon group formed by losing a hydrogen atom at any position. Specifically, for example, propyl means any of n-propyl and isopropyl, and propylene means any of 1, 3-propylene, 1, 2-propylene and isopropylene.

In the formulae, when the terminal group of the linker is easily confused with the substituent protected by it, as in the formulaeIn (1), adopt

To mark the position of the divalent linking group to which the other group is attached. It may not be particularly marked when no ambiguity occurs, such as the phenylene structure

In the present invention, the ring structure is represented by a circle, and the ring structure is labeled differently according to the characteristics of the ring structure. For example,

represents an arbitrary cyclic structure;

represents an aliphatic cyclic structure and does not contain any aromatic or heteroaromatic ring, also known as an aliphatic ring;

represents an aromatic cyclic structure containing at least one aromatic or heteroaromatic ring, also called aromatic ring;

represents a skeleton of a saccharide or saccharide derivative having a cyclic monosaccharide skeleton, also referred to as a saccharide ring;

a ring having a chemical bond such as an amide bond, an ester bond, an imide, or an acid anhydride in the ring is referred to as a condensed ring;

is a cyclic backbone of a water-soluble polymer, also known as a polymer ring; the molecular weight of the water-soluble polymer is not particularly limited.

By way of example, such as

Respectively represent a cyclic structure containing nitrogen atoms, double bonds, azo groups, triple bonds, disulfide bonds, conjugated diene bonds, acid anhydrides, imide bonds and triazole.

Unless otherwise specified, the cyclic structures of the present invention include, but are not limited to, alicyclic rings

Aromatic ring

Sugar ring

Condensed ring

Polymer ring

CN104877127A and the relevant examples in the cited documents are all included in the present invention.

Aliphatic rings include alicyclic rings and alicyclic rings, and examples thereof include cyclopropane, oxirane, aziridine, cyclobutane, cyclobutene, squaric acid, cyclobutanedione, hemisquaric acid, cyclopentane, cyclopentadiene, tetrahydrofuran, pyrrolidine, thiazolidine, dihydroisoxazole, oxazolidine, cyclohexane, cyclohexene, tetrahydropyran, piperidine, 1, 4-dioxane, norbornane, norbornene, norbornadiene, 1,4, 7-triazacyclononane, cyclen, etc., and it is additionally noted that rings having weak aromaticity such as furan, thiophene, pyrrole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, etc., are also included in the aliphatic rings, and triazole is included in the same and classified as alicyclic rings.

Examples of sugar rings include, but are not limited to, furanose rings, pyranose rings, cyclodextrins, and the like.

Aromatic rings include aromatic rings and aromatic heterocycles, examples including, but not limited to, benzene, pyridine, pyridazine, pyrimidine, pyrazine, 1,3, 5-triazine, tetrazine (1,2,3,4-, 1,2,4, 5-and 1,2,3, 5-three isomers), indene, indane, indole, isoindole, purine, naphthalene, dihydroanthracene, xanthene, thioxanthene, dihydrophenanthrene, 10, 11-dihydro-5H-dibenzo [ a, d ] cycloheptane, dibenzocycloheptene, 5-dibenzocycloheptenone, quinoline, isoquinoline, fluorene, carbazole, iminodibenzyl, naphthylene, dibenzocyclooctyne, azadibenzocyclooctyne, and the like, substituted versions of either, or hybridized versions of either. Wherein the nitrogen atom of the ring is also allowed to exist in a cationic form. For example, pyridine, pyridazine, pyrimidine, pyrazine are aza forms of benzene, indole, isoindole are aza forms of indene, carbazole is aza form of fluorene, xanthene is oxa form of dihydroanthracene, thioxanthene is thia form of dihydroanthracene, 9H-thioxanthene-10, 10-dioxide is sulfone hybrid form of dihydroanthracene. Pyridinium is a substituted form of pyridine, in which case the nitrogen atom is present in a cationic form. The aromatic ring includes stages [0267] to [0284] in addition to stages [130] to [131] in CN 104530417A. In the trivalent biphenyl, the biphenyl is not a basic ring core structure, but is formed by combining a ring core structure of a trivalent phenyl group and a divalent phenyl group; trivalent diphenylmethane is similar to trivalent biphenyl.

The condensed rings include, but are not limited to, lactones (e.g., beta-lactide), lactides (e.g., lactide), lactams (e.g., beta-lactide), cyclic imides (e.g., maleimide, succinimide, 3H-1,2, 4-triazoline-3, 5-dione), cyclic anhydrides, cyclic peptides, and the like.

The term "substituted" as used herein means that any one or more hydrogen atoms at any position of the "hydrocarbon group" to be substituted may be substituted with any substituent atom or any substituent, for example, "substituted" or "hydrocarbon group". The substituent atom is not particularly limited, and a halogen atom is preferable. Without particular limitation, the substituents therein are not particularly limited, and include, but are not limited to, all substituents listed in the above term part, selected from any of the hydrocarbon-based substituents or heteroatom-containing substituents. When describing, optional substituent atoms and substituent groups can be directly illustrated, such as "the substituent atoms or substituent groups are selected from any one of halogen atoms, hydrocarbyl substituent groups and heteroatom-containing substituent groups. "

"Stable existence" and "degradable" of groups in the present invention are a pair of opposite concepts.

"degradable" means that cleavage of a chemical bond occurs and that the cleavage is at least two residues independently of each other. If the structure is altered by a chemical change, but the entire linker is still only one complete linker, the linker is still classified as "stably available". The degradable condition is not particularly limited, and may be an in vivo physiological condition, or an in vitro simulated physiological environment or other conditions, preferably an in vivo physiological condition and an in vitro simulated physiological condition. The physiological condition is not particularly limited, and includes, but is not limited to, serum, heart, liver, spleen, lung, kidney, bone, muscle, fat, brain, lymph node, small intestine, gonad, etc., and may refer to intracellular, extracellular matrix, normal physiological tissue, and pathological tissue (such as tumor, inflammation, etc.). The in vitro simulated environment is not particularly limited and includes, but is not limited to, physiological saline, buffer, culture medium, and the like. The degradation rate is not particularly limited, and may be, for example, rapid degradation by an enzyme, slow hydrolysis under physiological conditions, or the like. The physiological condition in vivo includes physiological condition during treatment, such as ultraviolet irradiation, thermotherapy, etc. Including but not limited to, degradable under conditions of light, heat, low temperature, enzymes, redox, acidic, basic, physiological conditions, in vitro simulated environments, and the like, preferably under conditions of light, heat, enzymes, redox, acidic, basic, and the like. Degradable refers to degradation under stimulation under any of the conditions described above. The light conditions include, but are not limited to, visible light, ultraviolet light, infrared light, near infrared light, mid-infrared light, and the like. The thermal conditions refer to temperature conditions above normal physiological temperature, typically above 37 ℃, and typically below 45 ℃, preferably below 42 ℃. Such as cryogenics in liquid nitrogen therapy. The enzyme conditions are not particularly limited, and enzymes that can be produced under physiological conditions are included, and examples thereof include peptidases, proteases, lyases and the like. The redox conditions are not particularly limited, such as redox transition between thiol group and disulfide bond, and hydrogenation reduction transition. The acidic and alkaline conditions mainly refer to the pH conditions of the internal body parts such as normal tissues, pathological tissues, organs or tissues in the treatment period, for example, the stomach is acidic, and the tumor part is often acidic. Degradable herein refers to degradation by metabolic action in vivo (e.g., physiological action, such as enzymes, such as redox, etc.), degradation at specific sites in the body by micro-environmental stimuli (e.g., acidic, basic), or degradation under clinical therapeutic stimuli (e.g., light, such as heat, such as hypothermia), etc. It should be noted that some extreme conditions in organic chemistry relative to organisms, such as bond cleavage under strong acid, strong base, high temperature (e.g., above 100 ℃), etc., are not included in the scope of the degradable conditions of the present invention. For another example, although ether linkages can be cleaved under strong acid conditions such as hydrobromic acid, they are always classified as stably available linkers in the present invention.

In contrast, a linker is defined as "stably present" as long as it remains present as an intact linker, wherein chemical changes that preserve the integrity of the linker are allowed to occur. The chemical changes are not particularly limited and include, but are not limited to, isomerization, oxidation, reduction, ionization, protonation, deprotonation, substitution reactions, and the like. The conditions that can be stably present are not particularly limited, and include, but are not limited to, light, heat, low temperature, enzymes, redox, neutral, acidic, basic, physiological conditions, in vitro simulated environments, and the like, and preferably, light, heat, enzymes, redox, acidic, basic, and the like. The stable existence here means that stable linkage can be maintained in the metabolic cycle in vivo without specific stimulation (e.g., pH condition at a specific site, light, heat, low temperature at the time of treatment, etc.) and the molecular weight is not lowered due to the occurrence of chain cleavage.

In addition, the term "stably exist" with respect to the same linker is not an absolute concept, for example, an amide bond is more stable under acidic or basic conditions than an ester bond, and the linker "stably exist" in the present invention includes an amide bond. Peptide bonds, however, may be cleaved when they encounter certain enzymatic actions, and are therefore also included in "degradable" linkers. Similarly, carbamate, thiocarbamate, and the like may be either a stably existing linker or a degradable linker. More generally, carbamate groups, thiocarbamate groups, and the like are more prone to slow degradation, while amide bonds other than peptide bonds may be stable during in vivo circulation. Also, for example, common ester bonds can be degraded under acid and alkali conditions, while ester bonds contained in a specific structure can also be degraded under ultraviolet light conditions.

The amino acid structure type in the present invention is not particularly limited unless otherwise specified, and may be any type as long as it is_LType-can also mean_D-type (II).

The definitions and examples of amino acid skeletons, amino acid derivative skeletons and cyclic monosaccharide skeletons in CN104877127A and the cited documents are also incorporated herein by reference. The amino acid skeleton refers to a residue having basic characteristics of an amino acid, and specifically refers to a residue formed by losing a carboxyl hydroxyl group (including all C-terminal carboxyl hydroxyl groups, and also including carboxyl hydroxyl groups on side groups such as aspartic acid and glutamic acid), a hydrogen atom on a hydroxyl group, a hydrogen atom on a phenolic hydroxyl group (a tyrosine), a hydrogen atom on a mercapto group (such as cysteine), a hydrogen atom on a nitrogen atom (including all N-terminal hydrogen atoms, and also including a hydrogen atom on an amino group in a side group such as an epsilon-amino group on lysine, a hydrogen atom on an amino group on a side ring of histidine and tryptophan, and the like), an amino group on an amide (such as asparagine, glutamine, and the like), an amino group in a side group of a guanidino group, or a hydrogen atom on an amino group. The amino acid derivative skeleton means an atom or group portion having its essential characteristics in addition to the amino acid skeleton. The monosaccharide skeleton refers to a residue formed by removing all hydroxyl groups from a monosaccharide having a cyclic structure, and includes an open chain monosaccharide skeleton and also includes a cyclic monosaccharide skeleton (such as a furanose ring and a pyranose ring).

The functionalized eight-arm polyethylene glycols and methods of making the same according to the present invention are further described below with reference to certain specific examples. The specific examples are intended to illustrate the present invention in further detail, and are not intended to limit the scope of the present invention. Among these, in the examples of preparing eight-arm polyethylene glycol, functionalized eight-arm polyethylene glycol, monodisperse starting materials, key intermediates and products were subjected to molecular weight confirmation by MALDI-TOF. For the determination of the attribution of the characteristic peaks in the nuclear magnetic tests, the analytical methods of CN104877127A, CN104530413A, CN104530415A, CN104530417A and the examples in each cited document were used. Yield in functionalized eight-armed polyethylene glycol modified bio-related substances refers to the percentage of the actual resulting product mass relative to the theoretical mass.