N-containing derivative of substituted phenol hydroxy acid ester, preparation and application
阅读说明：本技术 一类取代苯酚羟基酸酯含n衍生物、制备和用途 (N-containing derivative of substituted phenol hydroxy acid ester, preparation and application ) 是由 杨俊� 刘进 张伟义 于 2020-10-16 设计创作，主要内容包括：本发明提供了一类取代苯酚羟基酸酯含N衍生物、制备和用途。所述的化合物如式(Ⅰ)所示。式(I)化合的盐具备良好的水溶性,且在体内可迅速、完全地释放出具有药理作用的取代苯酚类物质,在改善取代苯酚类物质水溶性的同时,迅速发挥取代苯酚在体内的药理作用,安全性好。上述化合物的制备方法和它们在制备对人和动物产生麻醉和/或镇静催眠作用的药物中的应用。(The invention provides N-containing derivatives of substituted phenol hydroxy acid esters, and preparation and application thereof. The compound is shown as a formula (I). The salt of the compound of the formula (I) has good water solubility, can quickly and completely release the substituted phenol substance with pharmacological action in vivo, improves the water solubility of the substituted phenol substance, quickly exerts the pharmacological action of the substituted phenol in vivo and has good safety. The preparation method of the compounds and the application of the compounds in preparing drugs for producing anesthesia and/or sedation hypnosis effects on human beings and animals.)
1. A compound having the structure of formula (I):
wherein R1-R5 are respectively H, C1-6 straight chain or branched chain or cyclic alkyl, halogen, C1-4 alkoxy, cyano, nitro, ester group and the like; r6-9 is H, C1-8 straight chain or branched chain or cyclic alkyl; when R6 and R7 are connected by a covalent bond, R6 and R7 can also be alkylene of C1-3; when R7 and R8 are connected by a covalent bond, R7 and R8 can also be alkylene of C1-3; h in the skeleton of R1-9 may be substituted by halogen, hydroxyl, mercapto, carbamoyl, guanidino, carboxyl, 4-imidazolyl, phenyl, hydroxyphenyl, beta-indolyl, etc., and the skeleton of R1-9 may contain hetero atoms such as O, S, N, etc.
2. Salts of compounds of formula (i) as claimed in claim 1, including but not limited to: acetate, adipate, alginate, 4-aminosalicylate, ascorbate, aspartate, glutamate, pyroglutamic acid, benzenesulfonate, benzoate, butyrate, camphorate, camphorsulfonate, carbonate, cinnamate, citrate, cyclamate, cyclopentanepropionate, caprate, 2-dichloroacetate, gluconate, dodecylsulfate, ethane-1, 2-disulfonate, ethanesulfonate, formate, fumarate, mucate, gentisate, glucoheptonate, gluconate, glucuronate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, isobutyrate, lactate, lactobionate, laurate, malate, pyroglutamate, isovalerate, lactate, lactobionate, laurate, malate, and malate, Maleate, malonate, mandelate, mesylate, naphthalene-1, 5-disulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, 2-oxoglutarate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, sebacate, stearate, succinate, sulfate, tannate, tartrate, bitartrate, thiocyanate, tosylate or undecanoate, hydrogen sulfide, sodium salt, ammonium salt.
3. A compound of formula (i) as claimed in claim 1, wherein: R1-R5 are respectively H, C1-6 straight chain or branched chain or cyclic alkyl; r6-9 is H, C1-8 straight chain or branched chain or cyclic alkyl; h in the skeleton of R1-9 may be substituted by hydroxyl, mercapto, carbamoyl, guanidino, carboxyl, 4-imidazolyl, phenyl, hydroxyphenyl, or β -indolyl, and the skeleton of R1-9 may contain hetero atoms such as O, S, and N.
4.A compound of formula (i) as claimed in claim 1, wherein: R1-R5 are respectively H, C1-6 straight chain or branched chain or cyclic alkyl; the R6 and the R7 are connected by a covalent bond, and R6 and R7 are alkylene groups of C1-3; r8 and R9 are H, C1-8 straight chain or branched chain or cyclic alkyl.
5. A compound of formula (i) as claimed in claim 1, wherein: R1-R5 are respectively H, C1-6 straight chain or branched chain or cyclic alkyl; the R7 and the R8 are connected by a covalent bond, and R7 and R8 are alkylene groups of C1-3; r6 and R9 are H, C1-8 straight chain or branched chain or cyclic alkyl.
6. A compound of formula (i) as claimed in claim 1, wherein: r1 and R5 are isopropyl; R2-R4 are H; r6-9 is H, C1-8 straight chain or branched chain or cyclic alkyl; when R6 and R7 are connected by a covalent bond, R6 and R7 can also be alkylene of C1-3; when R7 and R8 are connected by a covalent bond, R7 and R8 can also be alkylene of C1-3; h in the skeleton of R1-9 may be substituted with halogen, hydroxyl, mercapto, carbamoyl, guanidino, carboxyl, 4-imidazolyl, phenyl, hydroxyphenyl, β -indolyl or the like, and the skeleton may contain hetero atoms such as O, S, N or the like.
7.A compound of formula (i) as claimed in claim 1, wherein: r1 is isopropyl; r5 isR2-R4 are H; r6-9 is H, C1-8 straight chain or branched chain or cyclic alkyl; when R6 and R7 are connected by a covalent bond, R6 and R7 can also be alkylene of C1-3; when R7 and R8 are connected by a covalent bond, R7 and R8 can also be alkylene of C1-3; h in the skeleton of R1-9 may be substituted by halogen, hydroxyl, mercapto, carbamoyl, guanidino, carboxyl, 4-imidazolyl, phenyl, hydroxyphenyl, beta-indolyl, etc., and the skeleton of R1-9 may contain hetero atoms such as O, S, N, etc.
8. The compound of formula (i) as claimed in claims 1 to 5 and 7, wherein: preferred compounds are:
9.a compound of formula (I) as claimed in claims 1 to 6 wherein: preferred compounds are:
10. use of a compound of formula (i), or a stereoisomer, isotopic substituent, pharmaceutically acceptable salt, solvate, pharmaceutical composition, formulation with a pharmaceutically acceptable adjuvant/carrier/excipient, or the like, as claimed in any one of claims 1 to 9, in the manufacture of a medicament for use in producing a central sedative and/or anaesthetic effect in a human or animal.
Technical Field
The invention relates to a chemical structure, a preparation method and application of water-soluble prodrug molecules of substituted phenol, wherein the molecules can be rapidly decomposed in vivo to release active substituted phenol, and have the advantages of quick response, high utilization rate of the substituted phenol and small drug intake.
Background
The invention belongs to the field of prodrug research in chemical drugs. The prodrug is a medicine which has no activity and enters the body to release an active proto-drug through enzyme so as to play a curative effect. Compared with proto-drugs, due to the obvious change of chemical structure, the prodrug molecule obtains different physicochemical properties from proto-drugs, such as water solubility change, fat solubility change, stability change and the like. By utilizing the prodrug design, the defects of the proto-drug can be improved, and the curative effect, the tolerance, the industrial applicability and the like of the proto-drug can be improved. Propofol is a clinical first-line intravenous general anesthetic drug, is insoluble in water, and is an emulsion in the current clinical preparation. Emulsions are costly to prepare, susceptible to bacterial contamination, have a high incidence of pain on injection, and can cause disorders of lipid metabolism in individuals over prolonged periods of time (Macario, a., Weinger, m., Truong, p., Lee, m.,1999.anesth. analg.88, 1085-1091; Bennett, s.n., McNeil, m.m., Bland, l.a., Arduino, m.j., vilarino, m.e., perotta, d.m., et al, 1995.n.engl.j.med.333(3), 147. cotta 154; Kam, p.c., Cardone, d.,2007. anesia 62(7), 690. cotta 701; Wolf, a., p., Segar, p., stoj, sieve, 56 j., 357, 92357, and 357)). Therefore, propofol water-soluble prodrugs have been a hotspot in drug development. Prodrug molecules with improved water solubility can be obtained by covalent linkage of propofol to water-soluble molecules, such as propofol-amino acid conjugates (Gallop, Mark A., Xu, Feng, Cundy, Kenneth C., Sasikumar, Vivek, Wowode, Thomas W.,2005.US20050004381), propofol glycosyl conjugates (Brian, Shull, John, Baldwin, Ramesh, Gopalalswamy, Zishan, Haroon,2012 WO2012142141), propofol phosphate conjugates (Fechner, J., Ihmsen, H., Hatterscheid, D., Jeleazcov, C., Schissl, C., Vornov, J.J., Schwilden, H., Sch ttt, J.2004, Angeley 101, Young, Sha, C., Vornov, J.J.J., Schwilden, H., Sch, J.639, Young chemical, Young, Missin, Mitsuga, Mitsu, H., Mitsu, J., Mitsu, and attempts have been made to develop them into medicines. In 2008, the first propofol water-soluble prodrug, fosspofol, was marketed in the us, but later withdrawn from the market for an unknown reason, and no new propofol water-soluble prodrug was marketed by 2019.
The greatest clinical advantage of propofol is manifested by rapid onset of action and rapid recovery after withdrawal, which clinicians wish to retain. If a water-soluble prodrug of propofol cannot release propofol quickly in vivo, the advantage of rapid onset of action of the prodrug is lost; further, if the prodrug is released at a slow rate, the dosage of the prodrug has to be increased in order to maintain an effective plasma concentration of the proto-drug, and the remaining prodrug will release propofol continuously, resulting in a delay in awakening. Both the onset and maintenance of anesthesia were significantly longer than propofol due to its slow release of propofol in vivo. Therefore, the scholars have proposed: accelerating the release speed of a raw drug of a propofol prodrug in vivo and improving the molecular utilization rate of the raw drug are key for developing the prodrug, so that the clinical advantages of propofol can be retained, the intake of the prodrug can be reduced, the awakening quality is improved, and the safety is improved (Weiyi Zhang, Jun Yang, Jin Fan, Bin Wang, Yi Kang, Jin Liu, Wensheng Zhang, Tao Zhu. European Journal of Pharmaceutical Sciences,2019, 9-13.).
The foregoing requires that the water-soluble prodrug of propofol be sufficiently stable in vitro to be produced, transported and stored; the prodrug must release propofol as soon as possible after entry into the body in order to have a rapid onset of action and to ensure rapid recovery of the patient after withdrawal. The conflicting requirements make the development of the propofol water-soluble prodrug extremely difficult, and under the condition of ensuring safety, no propofol prodrug can simultaneously meet the requirements at present, and the research and development of the drug are limited under the condition.
In response to the above problems, the present invention provides a class of water-soluble prodrugs of substituted phenols, including propofol. The molecules are stable in vitro and have good water solubility; the substituted phenol carried in the molecule can be rapidly and completely released under the action of plasma after entering the body. The molecules are administered intravenously, and can produce anesthetic effect immediately after injection; because the release is rapid, the time required by the molecules to generate the anesthesia is equivalent to the time required by anesthesia caused by directly using propofol, the molar quantity of the prodrug under the effective dose is close to that of propofol of the effective dose, the awakening delay caused by slow release of the prodrug from the prodrug is avoided, the awakening speed of animals in an experiment is high, the awakening quality is good, and the difference is avoided compared with that of animals in a propofol control group. The molecule provided by the invention thoroughly solves the problem that the original drug of the propofol prodrug is slowly released, reduces the intake of the original drug to the maximum extent, has good safety and has good application prospect. In conclusion, the compounds of formula (I) and pharmaceutically acceptable salts thereof of the present invention are useful for the preparation of centrally inhibitory drugs that exert a sedative-hypnotic and/or anesthetic effect in animals or humans.
Disclosure of Invention
The invention provides water-soluble precursor molecules of substituted phenol including propofol, a preparation method and application. The molecule can be quickly decomposed to release the substituted phenol in an animal body under the effective dose, the drug effect is quickly generated, the accumulation effect caused by slow release of raw drugs is avoided, and the advantages of quick response and quick recovery of the substituted phenol are retained on the premise of improving the water solubility of the substituted phenol.
The substituted phenol hydroxy acid ester N-containing derivative has a structure shown in a formula (I):
wherein R1-R5 are respectively H, C1-6 straight chain or branched chain or cyclic alkyl, halogen, C1-4 alkoxy, cyano, nitro, ester group and the like; r6-9 is H, C1-8 straight chain or branched chain or cyclic alkyl; when R6 and R7 are connected by a covalent bond, R6 and R7 can also be alkylene of C1-3; when R7 and R8 are connected by a covalent bond, R7 and R8 can also be alkylene of C1-3; h in the skeleton of R1-9 may be substituted by halogen, hydroxyl, mercapto, carbamoyl, guanidino, carboxyl, 4-imidazolyl, phenyl, hydroxyphenyl, beta-indolyl, etc., and the skeleton of R1-9 may contain hetero atoms such as O, S, N, etc.
Salts of compounds of formula (i) include, but are not limited to: acetate, adipate, alginate, 4-aminosalicylate, ascorbate, aspartate, glutamate, pyroglutamic acid, benzenesulfonate, benzoate, butyrate, camphorate, camphorsulfonate, carbonate, cinnamate, citrate, cyclamate, cyclopentanepropionate, caprate, 2-dichloroacetate, gluconate, dodecylsulfate, ethane-1, 2-disulfonate, ethanesulfonate, formate, fumarate, mucate, gentisate, glucoheptonate, gluconate, glucuronate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, isobutyrate, lactate, lactobionate, laurate, malate, pyroglutamate, isovalerate, lactate, lactobionate, laurate, malate, and malate, Maleate, malonate, mandelate, mesylate, naphthalene-1, 5-disulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, 2-oxoglutarate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, sebacate, stearate, succinate, sulfate, tannate, tartrate, bitartrate, thiocyanate, tosylate or undecanoate, hydrogen sulfide, sodium salt, ammonium salt.
Further, the compound of formula (i) preferably has a range of substituents as follows: R1-R5 are respectively H, C1-6 straight chain or branched chain or cyclic alkyl; r6-9 is H, C1-8 straight chain or branched chain or cyclic alkyl; h on the skeleton of R1-9 can be substituted by hydroxyl, sulfydryl, carbamoyl, guanidino, carboxyl, 4-imidazolyl, phenyl, hydroxyphenyl, beta-indolyl and the like, and the skeleton of R1-9 can contain heteroatoms such as O, S, N and the like;
alternatively, the compound of formula (i) preferably has a range of substituents: R1-R5 are respectively H, C1-6 straight chain or branched chain or cyclic alkyl; the R6 and the R7 are connected by a covalent bond, and R6 and R7 are alkylene groups of C1-3; r8 and R9 are H, C1-8 straight chain or branched chain or cyclic alkyl.
Alternatively, the compound of formula (i) preferably has a range of substituents: R1-R5 are respectively H, C1-6 straight chain or branched chain or cyclic alkyl; the R7 and the R8 are connected by a covalent bond, and R7 and R8 are alkylene groups of C1-3; r6 and R9 are H, C1-8 straight chain or branched chain or cyclic alkyl.
Further, the compound of formula (I) preferably has a range of substituents as follows: r1 and R5 are isopropyl; R2-R4 are H; r6-9 is H, C1-8 straight chain or branched chain or cyclic alkyl; when R6 and R7 are connected by a covalent bond, R6 and R7 can also be alkylene of C1-3; when R7 and R8 are connected by a covalent bond, R7 and R8 can also be alkylene of C1-3; h in the skeleton of R1-9 may be substituted with halogen, hydroxyl, mercapto, carbamoyl, guanidino, carboxyl, 4-imidazolyl, phenyl, hydroxyphenyl, β -indolyl or the like, and the skeleton may contain hetero atoms such as O, S, N or the like. Preferred specific molecules of such compounds are:
or still further, the compound of formula (i) preferably has a range of substituents: r1 is isopropyl; r5 isR2-R4 are H; r6-9 is H, C1-8 straight chain or branched chain or cyclic alkyl; when R6 and R7 are connected by a covalent bond, R6 and R7 can also be alkylene of C1-3; when R7 and R8 are connected by a covalent bond, R7 and R8 can also be alkylene of C1-3; h in the skeleton of R1-9 may be substituted by halogen, hydroxyl, mercapto, carbamoyl, guanidino, carboxyl, 4-imidazolyl, phenyl, hydroxyphenyl, beta-indolyl, etc., and the skeleton of R1-9 may contain hetero atoms such as O, S, N, etc. Preferred specific molecules of such compounds are:
according to the general knowledge in the art, the compounds of formula (i), and stereoisomers, isotopically substituted forms, pharmaceutically acceptable salts, solvates, pharmaceutical compositions, formulations with pharmaceutically acceptable excipients/carriers/excipients, and the like thereof, are potentially useful in the preparation of a medicament for producing a central sedative and/or anaesthetic effect in a human or animal.
The compounds described in this patent can be prepared according to the following general method:
firstly, chloroacetyl chloride is used for forming ester with substituted phenol (a) to obtain chloroacetate compound (b) of the substituted phenol, and then (b) and nitrogen-containing carboxylic acid compound (c) are subjected to nucleophilic substitution reaction under alkaline condition to generate free base of the target compound (I), and the free base and different acids can form different salts. If the molecule of (I) contains carboxyl, (I) can also react with alkaline reagent such as sodium carbonate to obtain the salt of (I). Chloroacetyl chloride can also be replaced by bromoacetyl bromide with higher activity in the above synthetic general method.
In the above reaction process, if the N atom in the nitrogen-containing carboxylic acid compound (c) is a primary or secondary amine, the amino group thereof may be protected with a protecting group (e.g., BOC protection), and then reacted with (b) to obtain an intermediate containing a protecting group, followed by removal of the amino protecting group to obtain the target compound (i).
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
Carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the present invention all include isotopes thereof, and carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the present invention are optionally further replaced (i.e., isotopically substituted) by one or more of their corresponding isotopes, wherein isotopes of carbon include 12C, 13C and 14C, isotopes of hydrogen include protium (H), deuterium (D, also referred to as deuterium) and tritium (T, also referred to as deuterium), isotopes of oxygen include 16O, 17O and 18O, isotopes of sulfur include 32S, 33S, 34S and 36S, isotopes of nitrogen include 14N and 15N, isotopes of fluorine 19F, isotopes of chlorine 35Cl and 37Cl, and isotopes of bromine 79Br and 81 Br.
"hydrocarbyl" refers to a straight or branched chain or cyclic monovalent substituent containing only carbon and hydrogen atoms, the main chain comprising 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms. The hydrocarbyl group may be a linear or branched or cyclic alkyl/alkenyl/alkynyl group. Said hydrocarbyl group may optionally be further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl,Br, I, ═ O, hydroxy, -SR10, nitro, cyano, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, 3-to 8-membered heterocyclyl, - (CH)2)a-(C＝O)-SR10、-(CH2)a-(C＝O)-O-R10、-(CH2)a-(C＝O)-NR10R10a、-(CH2) a-S (C ═ O) b-R10, -O- (═ O) -O-R10, or-NR 10R10a, wherein R10 and R10a are each independently selected from H, hydroxy, amino, carboxy, C1-8 alkyl, C1-8 alkoxy, C2-8 alkenyl, C2-8 alkynyl, 3 to 10 membered carbocyclyl, 4 to 10 membered heterocyclyl, 3 to 10 membered carbocyclyloxy, or 4 to 10 membered heterocyclyloxy, a is selected from 0, 1, 2, 3, 4, or 5, and b is selected from 0, 1, or 2. Alkyl, a, b, R10 and R10a, as appearing herein, are defined as above.
"alkyl" refers to straight and branched chain monovalent saturated hydrocarbon radicals having a backbone comprising 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, even more preferably 1 to 4 carbon atoms, straight and branched chain groups, most preferably 1 to two carbon atoms, examples of alkyl including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl; said alkyl group may optionally be further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, ═ O, hydroxy, -SR10, nitro, cyano, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, 3 to 8 membered heterocyclyl, - (CH 3-8 carbocyclyl2)a-(C＝O)-SR10、-(CH2)a-(C＝O)-O-R10、-(CH2)a-(C＝O)-NR10R10a、-(CH2) a-S (C ═ O) b-R10, -O- (═ O) -O-R10, or-NR 10R10a, wherein R10 and R10a are each independently selected from H, hydroxy, amino, carboxy, C1-8 alkyl, C1-8 alkoxy, C2-8 alkenyl, C2-8 alkynyl, 3 to 10 membered carbocyclyl, 4 to 10 membered heterocyclyl, 3 to 10 membered carbocyclyloxy, or 4 to 10 membered heterocyclyloxy, a is selected from 0, 1, 2, 3, 4, or 5, and b is selected from 0, 1, or 2. Alkyl, a, b, R10 and R10a, as appearing herein, are defined as above.
"alkylene" refers to both straight and branched chain divalent saturated or unsaturated hydrocarbons. Wherein the saturated alkylene group is also called alkylene group and is represented as: - (CH)2) k- (k is an integer of 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene; said alkylene may optionally be further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of F, Cl, Br, I, ═ O, hydroxy, -SR10, nitro, cyano, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, 3 to 8 membered heterocyclyl, - (CH, Br, I, (-)2)a-(C＝O)-SR10、-(CH2)a-(C＝O)-O-R10、-(CH2)a-(C＝O)-NR10R10a、-(CH2) a-S (C ═ O) b-R10, -O- (═ O) -O-R10, or-NR 10R10a, and when the number of substituents in the alkylene group is 2 or more, the substituents may be fused together to form a cyclic structure. Alkylene, as used herein, is defined as above.
"alkoxy" refers to a monovalent radical of an O-alkyl group, where alkyl is as defined herein, and examples of alkoxy include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-1-butoxy, 2-methyl-1-butoxy, and the like. Alkoxy, as used herein, is defined as above.
"alkenyl" means a straight and branched chain monovalent unsaturated hydrocarbon group having at least one, and typically 1, 2 or 3 carbon double bond, the main chain comprising 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the main chain, examples of alkenyl include, but are not limited to, ethenyl, propenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, and the like; said alkenyl may optionally be further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, ═ O, hydroxy, -SR10, nitro, cyano, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, 3 to 8 membered heterocyclyl, - (CH 3-8 carbocyclyl2)a-(C＝O)-SR10、-(CH2)a-(C＝O)-O-R10、-(CH2)a-(C＝O)-NR10R10a、-(CH2) a-S (C ═ O) b-R10, -O- (═ O) -O-R10, or-NR 10R10 a. Alkenyl as used herein, is defined as above.
"alkynyl" refers to straight and branched chain monovalent unsaturated hydrocarbon radicals having at least one, and typically 1, 2 or 3 carbon-carbon triple bonds, and includes in the main chain, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-nonynyl, and the like; said alkynyl may optionally be further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, ═ O, hydroxy, -SR10, nitro, cyano, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, 3 to 8 membered heterocyclyl, - (CH, Br, I, (-O), -, O, -SR10, nitro, cyano, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C2-2)a-(C＝O)-SR10、-(CH2)a-(C＝O)-O-R10、-(CH2)a-(C＝O)-NR10R10a、-(CH2) a-S (C ═ O) b-R10, -O- (═ O) -O-R10, or-NR 10R10 a. Alkynyl, as found herein, is defined as above.
"cycloalkyl" refers to a monovalent saturated carbocyclic hydrocarbon group, typically of 3 to 10 carbon atoms, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the like. Said cycloalkyl group may optionally be further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, ═ O, hydroxy, -SR10, nitro, cyano, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, 3 to 8 membered heterocyclyl, - (CH 3-8 carbocyclyl2)a-(C＝O)-SR10、-(CH2)a-(C＝O)-O-R10、-(CH2)a-(C＝O)-NR10R10a、-(CH2) a-S (C ═ O) b-R10, -O- (═ O) -O-R10, or-NR 10R10 a. Cycloalkyl as found herein, is as defined above.
"carbocyclic" means a saturated or unsaturated aromatic or non-aromatic ring which may be a 3 to 10 membered monocyclic 4 to 12 membered bicyclic or 10 to 15 membered tricyclic ring system to which the carbocyclic group may be attached an endocyclic or spirocyclic ring, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, phenyl, or naphthyl. Said carbocyclyl may optionally be further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, ═ O, hydroxy, -SR10, nitro, cyano, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, 3 to 8 membered heterocyclyl, - (CH, Cl, Br, I2)a-(C＝O)-SR10、-(CH2)a-(C＝O)-O-R10、-(CH2)a-(C＝O)-NR10R10a、-(CH2) a-S (C ═ O) b-R10, -O- (═ O) -O-R10, or-NR 10R10 a. Carbocycle as used herein is defined as above.
"heterocyclic" means a saturated or unsaturated aromatic or non-aromatic ring which may be a 3-to 10-membered monocyclic, 4-to 10-membered bicyclic or 10-to 15-membered tricyclic ring system and contain 1 to 4 heteroatoms selected from N, O or S, preferably a 3-to 8-membered heterocyclic group, the optionally substituted N, S ring of which may be oxidized to various oxidation states. The heterocyclic group may be attached at a heteroatom or carbon atom, the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples of which include epoxyethyl, epoxypropyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1-3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepinyl, oxepinyl, thiepinyl, oxazepinyl, diazepinyl, thiazepinyl, pyridyl, piperidyl, homodiazepinyl, thiazepinyl, pyridyl, piperidyl, and the likePiperidinyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, perinyl, morpholinyl, thiomorpholinyl, thienylalkyl, 1, 3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiapentylyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, benzimidazolyl, benzopyridyl, pyrrolopyrrolyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, 3-azabicyclo [3.1.0 ] pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, piperidyl, tetrahydropyridinyl, tetrahydropyrazolyl, thiazolidinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, 3-azabicyclo [ 3.1.0.]Hexyl, 3-azabicyclo [4.1.0]Heptyl, azabicyclo [2.2.2]Hexyl, 3H-indolylquinozinyl, N-pyridylurea, 1-dioxothiomorpholinyl, azabicyclo [3.2.1]Octyl, azabicyclo [5.2.0 ] groups]Nonoalkyl oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl and oxaspiro [3.3 ]]A heptalkyl group. Said heterocycloalkyl may optionally be further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from F, Cl, Br, I, ═ O, hydroxy, -SR10, nitro, cyano, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, 3 to 8 membered heterocyclyl, - (CH 3-8 carbocyclyl2)a-(C＝O)-SR10、-(CH2)a-(C＝O)-O-R10、-(CH2)a-(C＝O)-NR10R10a、-(CH2) a-S (C ═ O) b-R10, -O- (═ O) -O-R10, or-NR 10R10 a. Heterocyclic rings, as found herein, are defined as above.
"optional" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not occur.
"pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt thereof with other ingredients, wherein the other ingredients comprise physiologically/pharmaceutically acceptable carriers and excipients.
"carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance added to a pharmaceutical composition to further depend on the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.
"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis, trans isomers, enantiomers and conformational isomers.
An "effective dose" refers to an amount of a compound that causes physiological or medical translation in a tissue, system, or subject that is sought, including an amount of the compound that is sufficient to prevent, or alleviate to some extent, one or more symptoms of the condition or disorder being treated when administered to a subject.
"solvate" refers to a compound of the invention or a salt thereof, which includes stoichiometric or non-stoichiometric amounts of solvent bound with intermolecular non-covalent forces. When the solvent is water, it is a hydrate.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. Various substitutions and alterations according to the general knowledge and conventional practice in the art are intended to be included within the scope of the present invention without departing from the technical spirit of the present invention as described above.
Detailed Description
Example 1
Propofol (178mg, 1mmoL) and chloroacetyl chloride (124mg, 1.1mmoL) were dissolved in 10mL of dichloromethane, pyridine (237mg, 3mmoL) was added in ice bath, stirred at room temperature for 2 hours, the solvent was evaporated to dryness, and the residue was chromatographed on silica gel column (cyclohexane/ethyl acetate. RTM. 20/1) to give 180mg of a colorless oil, intermediate b, in 70.6% yield.
Intermediate b (180mg, 71mmoL) and BOC-glycine (140mg, 80mmoL) were mixed in 10mL DMF, anhydrous potassium carbonate (290mg,210mmoL) was added, stirred at room temperature for 8 hours, filtered, the filtrate was washed into 100mL water, extracted with 50mL ethyl acetate, the organic layer was separated, dried over anhydrous sodium sulfate overnight, filtered the next day, the filtrate was evaporated under reduced pressure, and the residue was subjected to column chromatography (cyclohexane/ethyl acetate ═ 5/1) to give 183mg of white solid powder, i.e. intermediate c, in 66% yield. 183mg of intermediate c was dissolved in 10mL of ethyl acetate, an excess of dry hydrogen chloride gas was introduced, the mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure to obtain a crude product. And (3) rinsing the crude product with cyclohexane for 3 times, performing suction filtration, and drying a filter cake at 65 ℃ to obtain a white solid, namely 115mg of the target compound 1 with the yield of 75%.
1H NMR(400MHz,DMSO-d6)：δ8.52(s,3H),7.23～7.31(m,3H),5.29(s,2H),4.00(s,2H),2.94(hept,J＝6.9Hz,2H),1.13(d,J＝6.8Hz,12H).
Example 2
Intermediate b was prepared as described in example 1. Intermediate b (180mg, 71mmoL) and BOC-sarcosine (151mg, 80mmoL) were mixed in 10mL DMF, anhydrous potassium carbonate (290mg,210mmoL) was added, stirred at room temperature for 8 hours, filtered, the filtrate was washed into 100mL water, extracted with 50mL ethyl acetate, the organic layer was separated, dried over anhydrous sodium sulfate overnight, filtered the next day, the filtrate was evaporated under reduced pressure, and the residue was subjected to column chromatography (cyclohexane/ethyl acetate ═ 5/1) to give 186mg of white solid powder, i.e., intermediate c, in 64.5% yield. 186mg of intermediate c was dissolved in 10mL of ethyl acetate, an excess amount of dry hydrogen chloride gas was introduced, stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure to obtain a crude product. And (3) rinsing the crude product with cyclohexane for 3 times, performing suction filtration, and drying a filter cake at 65 ℃ to obtain a white solid, namely 113mg of the target compound 2, with the yield of 72%.
1H NMR(400MHz,DMSO-d6)：δ9.46(s,2H),7.23～7.31(m,3H),5.31(s,2H),4.17(s,2H),2.94(hept,J＝6.8Hz,2H),2.59(s,3H),1.13(d,J＝6.8Hz,12H).
Example 3
Intermediate b was prepared as described in example 1. Intermediate b (180mg, 71mmoL) and N, N-dimethylglycine (82.4mg, 80mmoL) were mixed in 10mL DMF, anhydrous potassium carbonate (290mg,210mmoL) was added, stirred at room temperature for 8 hours, filtered, the filtrate was washed with 100mL water, extracted with 50mL ethyl acetate, the organic layer was separated, dried over anhydrous sodium sulfate overnight, filtered the next day, the filtrate was evaporated to dryness under reduced pressure, and the residue was chromatographed (cyclohexane/ethyl acetate ═ 30:1) with 123mg of the free base of compound 3. Dissolving the free base 123mg of the compound 3 in 10mL of ethyl acetate, introducing dried hydrogen chloride gas for 1 hour, stirring at room temperature for 2 hours, and evaporating the solvent under reduced pressure to obtain a crude product. And (3) rinsing the crude product with cyclohexane for 3 times, performing suction filtration, and drying a filter cake at 65 ℃ to obtain a white solid, namely 87.6mg of the target compound 3 with the yield of 64%.
1H NMR(400MHz,DMSO-d6)：δ10.78(s,1H),7.23～7.31(m,3H),5.32(s,2H),4.42(s,2H),2.94(hept,J＝6.9Hz,2H),2.85(s,6H),1.13(d,J＝6.8Hz,12H).
Example 4
Boc-L-alanine (1.49g,7.87mmol) and propofol chloroacetate (2g,7.85mmol) were dissolved in DMF (10mL) and stirred at room temperature for 40 min. Then K is put2CO3(1.19g,8.6mmol) was added to the solution, and the reaction solution was stirred at 70 ℃ for 4 hours, filtered, the filtrate extracted the product with ethyl acetate (100mL) and water (50mL), and the organic layer was washed with water (3X 50mL) several times and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (cyclohexane/ethyl acetate from 40:1 to 20:1) to yield 2.18g of a white solidThe product, intermediate a, was obtained in 68% yield. Intermediate a (2.18g,5.35mmol) was dissolved in 50mL ethyl acetate and reacted with dry hydrogen chloride gas for 1 h with stirring at room temperature for 4 h. The ethyl acetate was evaporated under reduced pressure to give a crude product. And (3) rinsing the crude product with cyclohexane for 3 times, performing suction filtration, and drying a filter cake at 65 ℃ to obtain 1.28g of a white solid, namely the target compound 4, wherein the yield is 69.6%.
1H NMR(400MHz,DMSO-d6)：δ8.66(s,3H),7.23～7.31(m,3H),5.29(d,J＝2.4Hz,2H),4.26(q,J＝7.1Hz,1H),2.93(hept,J＝6.9Hz,2H),1.48(d,J＝7.2Hz,3H),1.13(d,J＝6.8Hz,12H).
Example 5
Boc-D-alanine (1.49g,7.87mmol) and propofol chloroacetate (2g,7.85mmol) were dissolved in DMF (10mL) and stirred at room temperature for 40 min. Then K is put2CO3(1.19g,8.6mmol) was added to the solution, and the reaction solution was stirred at 70 ℃ for 4 hours, filtered, the filtrate extracted the product with ethyl acetate (100mL) and water (50mL), and the organic layer was washed with water (3X 50mL) several times and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (cyclohexane/ethyl acetate from 40:1 to 20:1) to yield 2.01g of a white solid, intermediate a, in 62.8% yield. Intermediate a (2.01g,4.93mmol) was dissolved in 50mL ethyl acetate, and the reaction was stirred at room temperature for 4 hours with dry hydrogen chloride gas for 1 hour. The ethyl acetate was evaporated under reduced pressure to give a crude product. And (3) rinsing the crude product with cyclohexane for 3 times, performing suction filtration, and drying a filter cake at 65 ℃ to obtain 1.15g of a white solid, namely the target compound 5, with the yield of 62.5%.
1H NMR(400MHz,DMSO-d6)：δ8.69(s,3H),7.21～7.30(m,3H),5.24(d,J＝2.4Hz,2H),4.29(q,J＝7.2Hz,1H),2.91(hept,J＝6.9Hz,2H),1.44(d,J＝7.2Hz,3H),1.11(d,J＝6.8Hz,12H).
Example 6
(R) -2-cyclopropylethyl-6-isopropylphenol (CAS:1637741-58-2, 204mg, 1mmoL) and chloroacetyl chloride (124mg, 1.1mmoL) were dissolved in 10mL of dichloromethane, pyridine (237mg, 3mmoL) was added under ice-bath conditions, the mixture was stirred at room temperature for 2 hours, the solvent was evaporated to dryness, and the residue was chromatographed on silica gel column (cyclohexane/ethyl acetate 20/1) to give 186mg of a colorless oil, i.e., intermediate a, in 66% yield. Intermediate a (186mg,0.66mmoL) and morpholin-4-ylacetic acid (96mg,0.66mmoL) were dissolved in DMF (20mL) and stirred at room temperature for 40 min. Then K is put2CO3(97mg,0.7mmol) was added to the solution, and the reaction solution was stirred at 70 ℃ for 4 hours. The reaction solution was cooled, water (100mL) was added, the product was extracted with ethyl acetate (200mL), and the organic layer was washed with water (3X 100mL), separated and dried over anhydrous sodium sulfate. The next day, filtration was carried out, the solvent was evaporated to dryness to give a crude product, which was chromatographed on silica gel (cyclohexane/ethyl acetate from 30:1) to give 141mg of a colorless oil, intermediate b, in 55% yield. Dissolving 141mg of intermediate b in 3mL of trifluoroacetic acid, stirring at room temperature for 30 minutes, evaporating the redundant trifluoroacetic acid under reduced pressure, adding 20mL of cyclohexane into the residue, separating out a solid, filtering, rinsing the solid with cyclohexane for 3 times, carrying out suction filtration, and drying a filter cake at 65 ℃ to obtain 114.7mg of a white solid with the yield of 63%.
1H NMR(400MHz,DMSO-d6)：δ11.23(s,1H)，7.30～7.36(3H,m),5.36(2H,s),4.41(2H,s)，3.82～3.89(m,4H)，3.21～3.28(m,5H),2.55～2.58(m,1H),1.31(d,J＝7.2Hz,3H),1.26(d,J＝7.2Hz,6H),1.03～1.07(m,1H),0.42～0.52(m,2H),0.17～0.25(m,2H).
Example 7
Dissolving 4-methyl-1-piperazineacetic acid (CAS:54699-92-2) and propofol chloroacetate in DMF in equal mole, adding 2 times of excessive potassium carbonate, stirring at 40 ℃ for 6 hours, and preparing an intermediate a by following the post-treatment manner of example 3, wherein the yield is 46-68% of propofol chloroacetate.
And a is dissolved in ethyl acetate, dry hydrogen chloride gas is introduced, the mixture is stirred for 30 minutes at room temperature, ethyl acetate is removed by evaporation, residues are dispersed by cyclohexane, suction filtration is carried out, the solid is rinsed for three times, the suction filtration is carried out, a filter cake is dried at 65 ℃ to obtain a white solid, namely the target compound 7, and the yield is 71-84%.
1H NMR(400MHz,DMSO-d6)：δ11.07(s,1H),7.20～7.27(m,3H),5.19(s,2H),3.85(s,broad,2H),3.42–3.47(m,2H),3.14～3.23(m,4H),2.89～2.98(m,4H),2.75(s,3H),1.13(d,J＝6.9Hz,12H).
Example 8
And dissolving N, N-dimethylalanine (CAS:19701-89-4) and chloroacetic acid propofol ester in equal mol in DMF, adding 2 times of excessive potassium carbonate, stirring at 40 ℃ for 6 hours, and preparing an intermediate a by following the post-treatment mode of example 3, wherein the yield is 51-63% of propofol chloroacetate.
And a is dissolved in ethanol, 0.5 time of molar weight of sulfuric acid is added, the mixture is stirred at room temperature for 30 minutes, then the ethanol is evaporated, the residue is dispersed by cyclohexane, filtered, rinsed for three times, filtered, and dried at 65 ℃ to obtain a white solid, namely the target compound 8, with the yield of 61-71%.
1H NMR(400MHz,DMSO-d6)：δ8.91(s,1H),7.25～7.33(m,3H),5.21(s,2H),4.27(q,J＝7.2Hz,1H),2.95(hept,J＝6.8Hz,2H),2.83(s,6H),1.88(d,J＝7.2Hz,3H),1.13(d,J＝6.8Hz,12H).
Example 9
Equimolar 4-methyl-3-morpholinecarboxylic acid (CAS:1240518-88-0) and equimolar chloroacetic acid propofol ester are dissolved in DMF, 2 times excess potassium carbonate is added, and the mixture is stirred at 40 ℃ for 6 hours, so that an intermediate a is prepared by following the post-treatment manner of example 3, and the yield is 52-71% of propofol chloroacetate.
And a is dissolved in ethyl acetate, excessive dry hydrogen chloride gas is introduced, the mixture is stirred at room temperature for 30 minutes, then ethyl acetate is evaporated, residues are dispersed by cyclohexane, suction filtration is carried out, the solid is rinsed for three times, the suction filtration is carried out, and a filter cake is dried at 65 ℃ to obtain a white solid, namely the target compound 9, with the yield of 49-71%.
1H NMR(400MHz,DMSO-d6)：δ10.91(s,1H),7.31～7.36(m,3H),5.16(s,2H),4.61～4.64(m,1H),3.91～4.13(m,4H),3.32～3.41(m,2H),2.85(s,3H),1.15(d,J＝6.8Hz,12H).
Example 10
Equimolar 1-methylpiperidine-2-carboxylic acid (CAS:7730-87-2) and equimolar chloroacetic acid propofol ester are dissolved in DMF, 2 times of excessive potassium carbonate is added, and the mixture is stirred at 40 ℃ for 6 hours, so that an intermediate a is prepared by following the post-treatment manner of example 3, and the yield is 36-61%.
And a is dissolved in ethyl acetate, excessive dry hydrogen chloride gas is introduced, the mixture is stirred at room temperature for 30 minutes, then ethyl acetate is removed by evaporation, residues are dispersed by cyclohexane, suction filtration is carried out, the solid is rinsed for three times, the suction filtration is carried out, and a filter cake is dried at 65 ℃ to obtain a white solid, namely the target compound 10, with the yield of 45-68%.
1H NMR(400MHz,DMSO-d6)：δ11.21(s,1H),7.27～7.36(m,3H),5.28(s,1H),4.38～4.32(m,1H),3.13～3.25(m,2H),2.97(hept,J＝6.8Hz,2H),2.91(s,3H),2.01～2.18(m,2H),1.71～1.75(m,2H),1.13～1.35(m,14H).
Example 11
Dissolving equimolar 1-BOC-piperidine-2-carboxylic acid (CAS:98303-20-9) and equimolar chloroacetic acid propofol ester in DMF, adding 2 times of excessive potassium carbonate, stirring at 40 ℃ for 6 hours, and preparing an intermediate a by following the post-treatment mode of example 5, wherein the yield is 56-71%.
And a is dissolved in excessive trifluoroacetic acid, the solution is stirred for 6 hours at room temperature, then the trifluoroacetic acid is removed through reduced pressure evaporation, the residue is dispersed by cyclohexane, filtered, the solid is rinsed for three times, filtered, and the filter cake is dried at 65 ℃ to obtain a white solid, namely the target compound 11, with the yield of 55-63%.
1H NMR(400MHz,DMSO-d6)：δ10.83(s,2H),7.23～7.30(m,3H),5.23(s,1H),4.33～4.30(m,1H),3.14～3.26(m,2H),2.94(hept,J＝6.8Hz,2H),2.03～2.16(m,2H),1.72～1.77(m,2H),1.12～1.34(m,14H).
Example 12
The preparation method comprises the steps of dissolving 4-BOC-morpholine-3-carboxylic acid (CAS:212650-43-6) and propofol chloroacetate in DMF in equal moles, adding 2 times of excessive potassium carbonate, stirring at 40 ℃ for 6 hours, and preparing an intermediate a in an after-treatment mode similar to that of example 5, wherein the yield is 61-74%.
And a is dissolved in ethyl acetate, excessive dry hydrogen chloride gas is introduced, the mixture is stirred at room temperature for 30 minutes, then ethyl acetate is removed by evaporation, residues are dispersed by cyclohexane, suction filtration is carried out, the solid is rinsed for three times, the suction filtration is carried out, and a filter cake is dried at 65 ℃ to obtain a white solid, namely the target compound 12, with the yield of 55-78%.
1H NMR(400MHz,DMSO-d6)：δ10.45(s,2H),7.29～7.34(m,3H),5.19(s,2H),4.63～4.65(m,1H),3.92～4.15(m,4H),3.30～3.39(m,2H),2.95(hept,J＝6.8Hz,2H),1.13(d,J＝6.8Hz,12H).
Example 13
Equimolar N, N-bis (2-methoxyethyl) amine acetate (CAS:3235-71-0) and propofol chloroacetate are dissolved in DMF, 2 times of excessive potassium carbonate is added, and the mixture is stirred at 40 ℃ for 6 hours to obtain an intermediate a in a mode similar to the aftertreatment mode of example 3, wherein the yield is 41-61%.
And a is dissolved in ethyl acetate, excessive dry hydrogen chloride gas is introduced, the mixture is stirred at room temperature for 30 minutes, then ethyl acetate is evaporated, residues are dispersed by cyclohexane, the mixture is subjected to suction filtration, the solid is rinsed for three times by cyclohexane, the suction filtration is carried out, and a filter cake is dried at 65 ℃ to obtain a white solid, namely the target compound 13, with the yield of 65-69%.
1H NMR(400MHz,DMSO-d6)：δ8.95(s,1H),7.32～7.37(m,3H),5.22(s,2H),4.25(s,2H),3.73～3.81(m,4H),3.42～3.47(m,4H),3.24＝(s,6H),2.94(hept,J＝6.8Hz,2H),1.13(d,J＝6.8Hz,12H).
Example 14
The intermediate a is prepared by the way of imitating the aftertreatment mode of the example 5 by dissolving equal moles of BOC-L-valine (CAS:13734-41-3) and equal moles of chloroacetic acid propofol ester in DMF, adding 2 times of excessive potassium carbonate, stirring for 6 hours at 40 ℃, and obtaining the intermediate a with the yield of 54-61%.
And a is dissolved in ethyl acetate, excessive dry hydrogen chloride gas is introduced, the mixture is stirred at room temperature for 30 minutes, then ethyl acetate is evaporated, residues are dispersed by cyclohexane, suction filtration is carried out, the solid is rinsed for three times, the suction filtration is carried out, and a filter cake is dried at 65 ℃ to obtain a white solid, namely the target compound 14, wherein the yield is 51-68%.
1H NMR(400MHz,DMSO-d6)：δ8.91(s,3H),7.31～7.35(m,3H),5.22(s,2H),4.16(d,J＝6.8Hz,1H),2.96～3.04(m,3H),1.13(d,J＝7.2Hz,12H),0.96(d,J＝7.2Hz,6H).
Example 15
Dissolving equimolar BOC-L-cysteine (CAS:20887-95-0) and equimolar chloroacetic acid propofol ester in DMF, adding 2 times of excessive potassium carbonate, stirring at 40 ℃ for 6 hours, and preparing an intermediate a by following the post-treatment mode of example 5 with the yield of 49-72%.
And a is dissolved in ethyl acetate, excessive dry hydrogen chloride gas is introduced, the mixture is stirred at room temperature for 30 minutes, then ethyl acetate is evaporated, residues are dispersed by cyclohexane, suction filtration is carried out, the solid is rinsed for three times, the suction filtration is carried out, and a filter cake is dried at 65 ℃ to obtain a white solid, namely the target compound 15, wherein the yield is 67-73%.
1H NMR(400MHz,DMSO-d6)：δ8.56(s,3H),7.28～7.33(m,3H),5.26(s,2H),4.70(t,J＝6.8Hz,1H),3.46～3.64(m,3H),2.93(hept,J＝6.8Hz,2H),1.16(d,J＝7.2Hz,6H).
Example 16
The intermediate a is prepared by the following post-treatment manner of example 5 by dissolving equimolar BOC-N-methyl 2-aminopropionic acid (CAS:13734-31-1) and equimolar chloroacetic acid propofol ester in DMF, adding 2 times of excessive potassium carbonate, and stirring at 40 ℃ for 6 hours, wherein the yield is 52-66%.
And a is dissolved in ethyl acetate, excessive dry hydrogen chloride gas is introduced, the mixture is stirred at room temperature for 30 minutes, then ethyl acetate is evaporated, residues are dispersed by cyclohexane, suction filtration is carried out, the solid is rinsed for three times, the suction filtration is carried out, and a filter cake is dried at 65 ℃ to obtain a white solid, namely the target compound 16, with the yield of 61-69%.
1H NMR(400MHz,DMSO-d6)：δ8.71(s,2H),7.26～7.32(m,3H),5.25(s,2H),4.24(q,J＝7.2Hz,1H),2.95(hept,J＝6.8Hz,2H),2.84(s,3H),1.88(d,J＝7.2Hz,3H),1.13(d,J＝6.8Hz,12H).
Example 17
Dissolving the intermediate b in example 6 in ethyl acetate, introducing excessive dry hydrogen chloride gas, stirring at room temperature for 30 minutes, evaporating the solvent under reduced pressure, dispersing the residue with cyclohexane, filtering, rinsing the solid with cyclohexane for three times, performing suction filtration, and drying the filter cake at 65 ℃ to obtain a white solid, namely the target compound 17, wherein the yield is 51-64%.
1H NMR(400MHz,DMSO-d6)：δ10.91(s,1H)，7.28～7.33(3H,m),5.29(2H,s),4.44(2H,s)，3.78～3.85(m,4H)，3.22～3.27(m,5H),2.55～2.59(m,1H),1.34(d,J＝7.2Hz,3H),1.24(d,J＝7.2Hz,6H),1.01～1.06(m,1H),0.41～0.51(m,2H),0.18～0.24(m,2H)。
Example 18
Dissolving the intermediate b in example 6 in absolute ethanol, adding equimolar benzenesulfonic acid, stirring at room temperature for 30 minutes, evaporating the solvent under reduced pressure, dispersing the residue with cyclohexane, filtering, rinsing the solid with cyclohexane for three times, performing suction filtration, and drying the filter cake at 65 ℃ to obtain a white solid, namely the target compound 18, wherein the yield is 70-84%.
1H NMR(400MHz,DMSO-d6)：δ10.73(s,1H)，7.68～7.79(m,5H),7.31～7.35(3H,m),5.29(2H,s),4.44(2H,s)，3.81～3.89(m,4H)，3.22～3.26(m,5H),2.57～2.59(m,1H),1.32(d,J＝7.2Hz,3H),1.28(d,J＝7.2Hz,6H),1.04～1.07(m,1H),0.41～0.52(m,2H),0.16～0.23(m,2H)。
Example 19
Dissolving the intermediate b in example 6 in absolute ethanol, adding 0.5 molar equivalent of sulfuric acid, stirring at room temperature for 30 minutes, evaporating the solvent under reduced pressure, dispersing the residue with cyclohexane, filtering, rinsing the solid with cyclohexane for three times, performing suction filtration, and drying the filter cake at 65 ℃ to obtain a white solid, namely the target compound 19, with the yield of 80-88%.
1H NMR(400MHz,DMSO-d6)：δ11.24(s,1H)，7.31～7.35(3H,m),5.33(2H,s),4.43(2H,s)，3.83～3.89(m,4H)，3.19～3.26(m,5H),2.53～2.57(m,1H),1.29(d,J＝7.2Hz,3H),1.25(d,J＝7.2Hz,6H),1.02～1.07(m,1H),0.39～0.51(m,2H),0.18～0.26(m,2H)。
Example 20
Dissolving the intermediate b in example 6 in absolute ethanol, adding equimolar p-toluenesulfonic acid, stirring at room temperature for 30 minutes, evaporating the solvent under reduced pressure, dispersing the residue with cyclohexane, filtering, rinsing the solid with cyclohexane for three times, performing suction filtration, and drying the filter cake at 65 ℃ to obtain a white solid, namely the target compound 20, wherein the yield is 75-86%.
1H NMR(400MHz,DMSO-d6)：δ10.89(s,1H)，7.68～7.79(m,2H),7.45～7.49(m,2H),7.28～7.32(3H,m),5.24(2H,s),4.41(2H,s)，3.80～3.87(m,4H)，3.19～3.23(m,5H),2.53～2.55(m,1H),2.43(s,3H),1.33(d,J＝7.2Hz,3H),1.25(d,J＝7.2Hz,6H),1.02～1.05(m,1H),0.40～0.51(m,2H),0.17～0.23(m,2H)。
Example 21
Dissolving the intermediate b in example 6 in absolute ethanol, adding equimolar methanesulfonic acid, stirring at room temperature for 30 minutes, evaporating the solvent under reduced pressure, dispersing the residue with cyclohexane, filtering, rinsing the solid with cyclohexane for three times, performing suction filtration, and drying the filter cake at 65 ℃ to obtain a white solid, namely the target compound 21, with the yield of 75-86%.
1H NMR(400MHz,DMSO-d6)：δ11.21(s,1H),7.28～7.32(3H,m),5.25(2H,s),4.43(2H,s)，3.81～3.87(m,4H)，3.31(s,3H),3.15～3.22(m,5H),2.54～2.58(m,1H),2.42(s,3H),1.32(d,J＝7.2Hz,3H),1.26(d,J＝7.2Hz,6H),1.01～1.05(m,1H),0.40～0.51(m,2H),0.18～0.23(m,2H).
Example 22
Morpholin-4-ylacetic acid (2.29g,15.8mmol), NaI (1.18g,15.8mmol) and propofol chloroacetate (4g,15.8mmol) are dissolved in DMF (20mL) and K is added2CO3(2.25g,16.2mmol), stirring at 40 ℃ for 6 hours, cooling the reaction solution, extracting the product with ethyl acetate (200mL) and water (100mL), and washing the organic layer with water (3X 100mL) several times, separating the organic layer, and drying over anhydrous sodium sulfate. The next day, filtration, reduced pressure evaporation of the filtrate to dryness to obtain crude product, column chromatography (cyclohexane/ethyl acetate 30:1) purification to obtain 3.16g colorless oil, i.e. intermediate a, yield 55.34%.
Intermediate a (1.02g,2.8mmol) was dissolved in 30mL of ethyl acetate, dried hydrogen chloride gas was introduced for 30 minutes, stirred at room temperature for 1 hour, and ethyl acetate was evaporated under reduced pressure to give a crude product. After the crude product was rinsed with cyclohexane several times and filtered, it was dried at 65 ℃ to obtain 0.78g of a white solid, i.e., the target compound 22, with a yield of 70.91%.
1H NMR(400MHz,DMSO-d6)：δ11.29(s,1H),7.24～7.29(m,3H),5.32(s,2H),4.43(s,2H),3.86(s,broad,4H),3.25(s,broad,4H),2.93(hept,J＝6.8Hz,2H),1.13(d,J＝6.8Hz,12H).
Example 23
Dissolving the intermediate a described in example 22 in absolute ethanol, adding 0.5 molar equivalent of sulfuric acid, stirring at room temperature for 30 minutes, evaporating the solvent under reduced pressure, dispersing the residue with cyclohexane, filtering, rinsing the solid with cyclohexane for three times, performing suction filtration, and drying the filter cake at 65 ℃ to obtain a white solid, namely the target compound 23, with a yield of 70-85%.
1H NMR(400MHz,DMSO-d6):δ11.10(s,1H),7.25～7.31(m,3H),5.31(s,2H),4.41(s,2H),3.87(s,broad,4H),3.26(s,broad,4H),2.94(hept,J＝6.8Hz,2H),1.14(d,J＝6.8Hz,12H).
Example 24
Dissolving the intermediate a described in example 22 in absolute ethanol, adding equimolar benzenesulfonic acid, stirring at room temperature for 30 minutes, evaporating the solvent under reduced pressure, dispersing the residue with cyclohexane, filtering, rinsing the solid with cyclohexane for three times, performing suction filtration, and drying the filter cake at 65 ℃ to obtain a white solid, namely the target compound 24, wherein the yield is 71-79%.
1H NMR(400MHz,DMSO-d6)：δ11.32(s,1H),7.63～7.76(m,5H),7.28～7.32(m,3H),5.28(s,2H),4.37(s,2H),3.88(s,broad,4H),3.28(s,broad,4H),2.92(hept,J＝6.8Hz,2H),1.13(d,J＝6.8Hz,12H).
Example 25
Dissolving the intermediate a described in example 22 in absolute ethanol, adding equimolar p-toluenesulfonic acid, stirring at room temperature for 30 minutes, evaporating the solvent under reduced pressure, dispersing the residue with cyclohexane, filtering, rinsing the solid with cyclohexane for three times, performing suction filtration, and drying the filter cake at 65 ℃ to obtain a white solid, namely the target compound 25, with the yield of 75-89%.
1H NMR(400MHz,DMSO-d6)：δ11.04(s,1H),7.65～7.77(m,2H),7.46～7.51(m,2H),,7.27～7.30(m,3H),5.22(s,2H),4.38(s,2H),3.85(s,broad,4H),3.23(s,broad,4H),2.93(hept,J＝6.8Hz,2H),1.15(d,J＝6.8Hz,12H).
Example 26
Dissolving the intermediate a described in example 22 in absolute ethanol, adding equimolar methanesulfonic acid, stirring at room temperature for 30 minutes, evaporating the solvent under reduced pressure, dispersing the residue with cyclohexane, filtering, rinsing the solid with cyclohexane three times, performing suction filtration, and drying the filter cake at 65 ℃ to obtain a white solid, namely the target compound 26, with a yield of 72-88%.
1H NMR(400MHz,DMSO-d6)：δ11.16(s,1H),7.29～7.31(m,3H),5.22(s,2H),4.37(s,2H),3.84(s,broad,4H),3.25～3.35(m,7H),2.95(hept,J＝6.8Hz,2H),1.13(d,J＝6.8Hz,12H).
Example 27
Dissolving the intermediate a described in example 22 in excess trifluoroacetic acid, stirring at room temperature for 30 minutes, evaporating the solvent under reduced pressure, dispersing the residue with cyclohexane, filtering, rinsing the solid with cyclohexane three times, performing suction filtration, and drying the filter cake at 65 ℃ to obtain a white solid, namely the target compound 27, with a yield of 68-79%.
1H NMR(400MHz,DMSO-d6)：δ11.16(s,1H),7.27～7.33(m,3H),5.32(s,2H),4.43(s,2H),3.88(s,broad,4H),3.25(s,broad,4H),2.92(hept,J＝6.8Hz,2H),1.13(d,J＝6.8Hz,12H).
Example 28
(S) -2-cyclopropylethyl-6-isopropylphenol (CAS:1637741-59-3, 204mg, 1mmoL) and chloroacetyl chloride (124mg, 1.1mmoL) were dissolved in 10mL of dichloromethane, pyridine (237mg, 3mmoL) was added in an ice bath, the mixture was stirred at room temperature for 2 hours, the solvent was evaporated, and the residue was chromatographed on a silica gel column (cyclohexane/ethyl acetate 20/1) to give 176mg of a colorless oil, i.e., intermediate a. Intermediate a (176mg,0.62mmoL) and morpholin-4-ylacetic acid (90mg,0.66mmoL) were dissolved in DMF (20 mg,0.66mmoL)mL) and stirred at room temperature for 40 minutes. Then K is put2CO3(97mg,0.7mmol) was added to the solution, and the reaction solution was stirred at 70 ℃ for 4 hours. The reaction solution was cooled, water (100mL) was added, the product was extracted with ethyl acetate (200mL), and the organic layer was washed with water (3X 100mL), separated and dried over anhydrous sodium sulfate. The next day, filtration was carried out, the solvent was evaporated to dryness to give a crude product, and 138mg of a colorless oil, intermediate b, was obtained by silica gel column chromatography (cyclohexane/ethyl acetate from 30:1) in 54% yield. Dissolving 138mg of the intermediate b in 3mL of ethyl acetate, introducing excessive hydrogen chloride gas, stirring at room temperature for 30 minutes, evaporating the solvent under reduced pressure, adding 20mL of cyclohexane into the residue, separating out a solid, filtering, rinsing the solid with cyclohexane for 3 times, performing suction filtration, and drying a filter cake at 65 ℃ to obtain 101.2mg of a white solid with the yield of 55.6%.
1H NMR(400MHz,DMSO-d6)：δ11.61(s,1H),7.31～7.38(3H,m),5.32(2H,s)4.39(2H,s)，3.83～3.92(m,4H)，3.20～3.26(m,5H),2.57～2.59(m,1H),1.35(d,J＝7.2Hz,3H),1.28(d,J＝7.2Hz,6H),1.02～1.09(m,1H),0.41～0.53(m,2H),0.17～0.26(m,2H).
Example 29
Piperidine-1-acetic acid (2.26g,15.8mmol), NaI (1.18g,15.8mmol) and propofol chloroacetate (4g,15.8mmol) were dissolved in DMF (20mL) and K was added2CO3(2.25g,16.2mmol), stirring at 40 ℃ for 6 hours, cooling the reaction solution, extracting the product with ethyl acetate (200mL) and water (100mL), and washing the organic layer with water (3X 100mL) several times, separating the organic layer, and drying over anhydrous sodium sulfate. The next day, filtration, reduced pressure evaporation of the filtrate to dryness to obtain crude product, column chromatography (cyclohexane/ethyl acetate 30:1) purification to obtain 3.31g colorless oil, namely intermediate a, yield 58.1%.
Intermediate a (1.01g,2.8mmol) was dissolved in 30mL of ethyl acetate, dried hydrogen chloride gas was introduced for 30 minutes, stirred at room temperature for 1 hour, and ethyl acetate was evaporated under reduced pressure to give a crude product. After the crude product was rinsed with cyclohexane several times and filtered, it was dried at 65 ℃ to obtain 0.82g of a white solid, i.e., the target compound 29, in a yield of 73.6%.
1H NMR(400MHz,DMSO-d6):10.53(s,1H),7.2`～7.28(m,3H),5.33(s,2H),4.40(s,2H),3.45～3.48(m,2H),2.90～3.04(m,4H),1.68～1.80(m,5H),1.33～1.36(m,1H),1.13(d,J＝6.9Hz,12H)
Example 30
Intermediate a (176mg,0.62mmoL) and piperidine-1-acetic acid (89mg,0.66mmoL) were dissolved in DMF (20mL) and stirred at room temperature for 40 min. Then K is put2CO3(97mg,0.7mmol) was added to the solution, and the reaction solution was stirred at 70 ℃ for 4 hours. The reaction solution was cooled, water (100mL) was added, the product was extracted with ethyl acetate (200mL), and the organic layer was washed with water (3X 100mL), separated and dried over anhydrous sodium sulfate. The next day, filtration was carried out, the solvent was evaporated to dryness to give a crude product, which was chromatographed on silica gel (cyclohexane/ethyl acetate from 30:1) to give 145mg of a colorless oil, intermediate b, in 60.4% yield. Dissolving 145mg of the intermediate b in 3mL of ethyl acetate, introducing excessive hydrogen chloride gas, stirring at room temperature for 30 minutes, evaporating the solvent under reduced pressure, adding 20mL of cyclohexane into the residue, separating out a solid, filtering, rinsing the solid with cyclohexane for 3 times, carrying out suction filtration, and drying a filter cake at 65 ℃ to obtain 110.2mg of a white solid with the yield of 69.4%.
1H NMR(400MHz,DMSO-d6)：δ11.12(s,1H),7.29～7.37(3H,m),5.30(2H,s)4.35(2H,s)，3.81～3.91(m,4H)，3.15～3.19(m,1H),2.56～2.59(m,1H),1.55～1.71(m,6H)，1.34(d,J＝7.2Hz,3H),1.26(d,J＝7.2Hz,6H),1.01～1.07(m,1H),0.40～0.52(m,2H),0.18～0.25(m,2H).
Example 31
The general preparation of the target compounds of formula (I) according to the invention, according to the methods of examples 1 to 30, is in particular: mixing equimolar substituted phenol chloroacetate and N-BOC protected amino acid (amino hydrogen of which is completely substituted and amino group of which is not protected) in DMF, stirring and reacting for 4-12 hours at the temperature ranging from room temperature to 70 ℃ (equimolar sodium iodide can be added to promote reaction), cooling reaction liquid, adding water to dissolve inorganic salt and dilute DMF, extracting a product with ethyl acetate, washing an organic layer with water for three times, separating the organic layer, and drying with anhydrous sodium sulfate. Filtering the solution the next day, evaporating the solvent from the filtrate to obtain a crude product, and performing silica gel column chromatography to obtain the free alkali of the target compound shown in the formula (I), wherein the yield is 15-80%. Free alkali and organic acid or inorganic acid are salified in ethyl acetate or ethanol solution, and water-soluble salt of the compound (I) is obtained after the solvent is removed, wherein the yield is 35-85%. Salts of the target compounds of formula (i) (both main starting material and product molecular ion peaks) that may be prepared using the above methods include, but are not limited to:
table 1 structural and mass spectral data for some of the compounds
Example 32
The prodrug to be tested was formulated in a 10mg/mL physiological saline solution. mu.L of the drug-containing solution was added to 990. mu.L of mouse plasma, vortexed for 30 seconds, and incubated at 37 ℃. 50 mu L of blood plasma containing medicine is taken at 30s, 1min, 5min, 10min, 30min, 60min and 120min respectively, 150 mu L of acetonitrile is immediately added to stop the enzymatic reaction, then the mixture is centrifuged at 20000 r/min and 4 ℃ for 10min, 50 mu L of supernatant is taken for sample injection, and the propofol concentration is measured by an internal standard method. The decomposition rate of the prodrug is calculated according to the concentration of propofol or other substituted phenols. The chromatographic conditions are as follows: chromatography column Agilent Zorbax XDB C18 column (150mm × 4.6mm, 5 μm); the column temperature is 30 ℃; the mobile phase is pure water: acetonitrile (40: 60, v/v); fluorescence wavelength: excitation wavelength (Ex): 276nm, emission wavelength (Em): 310 nm; flow rate: 1.2 mL/min; retention time: internal standard (thymol) 3.9min, propofol 7.4 min. Linear range of propofol or other substituted phenols: 50-35000 ng/mL. The instrument comprises the following steps: a Waters 2695 model high performance liquid chromatograph, a Waters 2475 model fluorescence detector. The results of the plasma dissociation experiments for some of the prodrugs are shown in table 2.
TABLE 2 plasma decomposition rates of prodrug molecules
In vitro plasmapheresis experiments show that the prodrug molecules disclosed by the patent have extremely high decomposition speed in mouse plasma, the prodrug molecules are decomposed by 51-98% on average after being cultured with the plasma for 30 seconds, the marketed drug Fopropofol can not be decomposed obviously after being cultured with the plasma for 10 minutes, and only 38% is decomposed after 2 hours, which indicates that the Fospropofol is slowly decomposed in the plasma. The prodrug molecule prepared by the invention can be rapidly decomposed in plasma to obtain propofol or other substituted phenols.
Example 33
Each drug is tested by using 10 male Kunming mice, the weight of each drug is 20-35 g, and the dosage of each drug in the miceIn vivo 2-fold ED50. The compound and Fospropofol described in this patent were dissolved in physiological saline and injected via the tail vein of mice, propofol was injected via the tail vein using a commercially available glucose dilution of the emulsion, diprenia (5mg/mL), and another substituted phenol molecule (CAS:1637741-58-2) was formulated as a drug-containing emulsion using a 30% fat emulsion. The concentration of an injection solution of the compound is 10-15 mg/mL, the concentration of an injection solution of Fospropofol is 55mg/mL, and the concentration of an injection solution of another substituted phenol molecule (CAS:1637741-58-2) emulsion is 1 mg/mL. The time T1 for the disappearance of the righting reflex after injection of the drug, the duration T2 for the disappearance of the righting reflex (i.e., the time of anesthesia), and the time T3 required for the animal to recover fully after awakening were recorded. Complete recovery refers to the return of the animal's autonomic activity to pre-dose levels. In the experiment, animals are not given respiratory support such as oxygen inhalation or intubation.
TABLE 3 Anaesthetic Activity testing of drugs
T1, onset time after injection; t2: righting reflex disappearance duration; t3: time required for turning reflection to return to autonomous activity
Table 4 anesthetic activity testing of other substituted phenols and their prodrug molecules
T1, onset time after injection; t2: righting reflex disappearance duration; t3: time required for turning reflection to return to autonomous activity
The experimental result shows that the prodrug has extremely fast plasma decomposition speed, has the same onset time as propofol, and can immediately anaesthetize animals after injection. The compound of the patent has the advantages that at equivalent dose, animals take propofol in an amount equivalent to that of animals anesthetized by propofol directly, the dose of propofol carried by marketed drug Fospropofol is far higher than that of animals anesthetized by propofol directly, and the duration of animal anesthesia is obviously shorter than that of marketed drug Fospropofol due to the fact that the prodrug of the patent carries propofol at effective dose which is greatly reduced compared with Fospropofol; the time to complete recovery after awakening in animals of the prodrug group described in this patent is also significantly shorter than in animals of the fosspofol group. Similarly, the other substituted phenol prodrug molecules described in this patent also retain the fast onset and recovery characteristics of the original drug compared to the substituted phenol molecules carried by it.
In conclusion, the water-soluble prodrug molecule completely maintains the advantages of quick response and quick recovery after drug withdrawal of the substituted phenol anesthetic including propofol.
Example 34
Determination of prodrug molecular therapeutic index: reference method (Dixon, W.Staircase bioassay: the up-and-down method.Neurosci.Biobehav.Rev.1991,15,47-50), using Kunming mice as experimental animals (weight 25-30 g, half each female and half male), half Effective Dose (ED) of the molecule to be tested was determined50) And half the Lethal Dose (LD)50). The calculation method of the therapeutic index of each molecule comprises the following steps: TI ═ LD50/ED50. The results are shown in Table 5.
TABLE 5 therapeutic index of the Compounds
The therapeutic index reflects the distance between the effective dose and the lethal dose of a drug, and is one of the most basic safety indicators for drug molecules. The experimental result shows that the therapeutic index of the compound disclosed by the patent is similar to that of propofol, the safety of the compound is equivalent to that of propofol, and the compound is obviously superior to that of a marketed drug Fospropofol. Because the therapeutic index of general anesthetic drugs is generally low (3-5), the water-soluble prodrug of propofol with low treatment window cost can keep the similar therapeutic index, which indicates that the molecules have good safety.