A kind of N- furanonyl arylsulfonyl hydrazone compounds and its synthetic method and application
阅读说明：本技术 一种n-呋喃酮基芳基磺酰腙类化合物及其合成方法和应用 (A kind of N- furanonyl arylsulfonyl hydrazone compounds and its synthetic method and application ) 是由 杨凯 汪朝阳 罗时荷 于 2019-08-09 设计创作，主要内容包括：本发明公开了一种N-呋喃酮基芳基磺酰腙类化合物及其合成方法和应用。这种N-呋喃酮基芳基磺酰腙类化合物结构如通式(Ⅰ)所示：<Image he="387" wi="626" file="DDA0002160996380000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>这种N-呋喃酮基芳基磺酰腙类化合物是在有机碱和酸的催化作用下,将芳基磺酰肼类化合物、3,4-二卤-5-烃氧基-2(5H)-呋喃酮和醛酮类化合物混合反应,即可合成得到。同时也公开了其在制备抗肿瘤药物中的应用。本发明公开了一种同时具有2(5H)-呋喃酮结构单元和芳基磺酰腙结构单元的芳基磺酰腙类新化合物,其合成方法具有简单易行、反应周期短、原料易得、底物适用范围广、产率高等优点,这类化合物在抗肿瘤药物研究中具有非常好的应用前景。(The invention discloses a kind of N- furanonyl arylsulfonyl hydrazone compounds and its synthetic method and applications.Shown in this N- furanonyl arylsulfonyl hydrazone compounds structure such as general formula (I): This N- furanonyl arylsulfonyl hydrazone compounds are, by arylsulfonyl hydrazine class compound, -2 (5H)-furanone of 3,4- dihalo- -5- oxyl and group compounds of aldehydes and ketones hybrid reaction, can to synthesize to obtain under the catalytic action of organic base and acid.Its application in preparation of anti-tumor drugs is also disclosed simultaneously.The invention discloses a kind of arylsulfonyl hydrazone class noval chemical compounds simultaneously with 2 (5H)-furanone structure units and arylsulfonyl hydrazone structural unit, its synthetic method has many advantages, such as that simple and easy, reaction time is short, raw material is easy to get, wide application range of substrates, yield are high, and this kind of compound has extraordinary application prospect in anti-tumor drug research.)
1. a kind of N- furanonyl arylsulfonyl hydrazone compounds, shown in structure such as general formula (I):
In formula (I), R1Selected from the substituted or unsubstituted alkyl of C1~C10, the substituted or unsubstituted naphthenic base of C3~C6, substitution or Unsubstituted aryl, substituted or unsubstituted heteroaryl；R2、R3It is respectively and independently selected from the substituted or unsubstituted alkane of H, C1~C10 Base, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2And R3It is not simultaneously H；X is selected from halogen；Ar is selected from Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
2. a kind of N- furanonyl arylsulfonyl hydrazone compounds according to claim 1, it is characterised in that: the formula (I) in compound represented, R1One of alkyl, 6- chlorine hexyl, phenyl, benzyl or xenyl selected from C1~C6；R2、R3 It is respectively and independently selected from H, methyl, methoxyl group, trifluoromethyl, normal-butyl, isobutyl group, phenyl, 4- aminomethyl phenyl, 4- methoxybenzene Base, 4- nitrobenzophenone, 4- hydroxy phenyl, 2- hydroxy phenyl, 4- fluorophenyl, 4- chlorphenyl, 2- chlorphenyl, 3- hydroxyl -4- methoxy One of base phenyl, 4- phenyl, 4- ethenylphenyl, and R2And R3It is not simultaneously H；X is selected from Cl or Br；Ar is selected from 4- One of aminomethyl phenyl, 4- methoxyphenyl, 4- fluorophenyl, 4- phenyl, phenyl, 4- trifluoromethyl.
3. the synthetic method of N- furanonyl arylsulfonyl hydrazone compounds as claimed in claim 1 or 2, it is characterised in that: having Under the catalytic action of machine alkali and acid, by arylsulfonyl hydrazine class compound, -2 (5H)-furanone of 3,4- dihalo- -5- oxyl and aldehyde Ketone compounds hybrid reaction, synthesis obtain formula (I) compound represented.
4. synthetic method according to claim 3, it is characterised in that: the temperature of the reaction is room temperature, the time of reaction For 0.5h~38h.
5. synthetic method according to claim 3, it is characterised in that: the arylsulfonyl hydrazine class compound, 3,4- dihalo-- The molar ratio of 5- oxyl -2 (5H)-furanone and group compounds of aldehydes and ketones is (1~1.5): 1:(1.2~2).
6. synthetic method according to claim 3, it is characterised in that: the organic base is 4-dimethylaminopyridine；It is described Acid is hydrochloric acid.
7. N- furanonyl arylsulfonyl hydrazone compounds of any of claims 1 or 2 or its pharmaceutically acceptable salt, water Close object, solvate, polymorph, tautomer or prodrug application in preparation of anti-tumor drugs.
8. application according to claim 7, it is characterised in that: the tumour of the anti-tumor drug includes breast cancer, brain glue Matter tumor, lung cancer, histiocytic lymph cancer, cancer of pancreas, breast cancer, prostate cancer, liver cancer, gastric cancer, colon cancer, the carcinoma of the rectum, ovum Nest cancer, palace stem cancer, cancer of the esophagus, osteocarcinoma, carcinoma of testis, one of melanoma, cutaneum carcinoma, nasopharyngeal carcinoma, kidney or a variety of.
9. a kind of pharmaceutical composition, it is characterised in that: including N- furanonyl arylsulfonyl hydrazone class of any of claims 1 or 2 Compound or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer or prodrug.
10. pharmaceutical composition according to claim 9, it is characterised in that: described pharmaceutical composition further includes excipient substance.
Technical field
The present invention relates to a kind of arylsulfonyl hydrazone compounds, in particular to a kind of N- furanonyl arylsulfonyl hydrazone class Close object and its synthetic method and application.
Background technique
Many arylsulfonyl hydrazone compounds are with antitumor, antibacterial, antibacterium, treating tuberculosis, antianxiety, the anti-rhythm of the heart The potential medical value such as uneven, make the structural unit of hydrazone containing arylsulfonyl in the design and synthesis of drug molecule recently increasingly by To attention.But the arylsulfonyl hydrazone class bioactive molecule reported at present be usually 1- N- methyl replace (compound A) or The structure of unsubstituted (compound B, C, D).
Compound A~D structural formula is respectively:
The bibliography of compound A~D visible Kendall J D, Rewcastle G W, Frederick R, et al.Bioorg Med Chem.,2007,15(24),7677-7687；Loh W,Cosby L A,Sartorelli Alan C, et al.J.Med.Chem.,1980,23(6),631-634；Neumann D M,Cammarata A,Backes G,et al.Bioorg.Med.Chem.,2014,22(2),813-826；Arshia,Begum F,Almandil N B,et al.Bioorg Med Chem.,2019,6(27),1009-1022。
At the same time, 2 (5H)-furanone structure units are widely present in natural products, these natural products have mostly There is the bioactivity such as antitumor, antibacterial (bibliography: Wu Y-C, Luo S-H, Mei W-J, et al.Eur.J.Med.Chem.2017,139,84-94；Wu Y-C,Cao L,Mei W-J,et al.Chem.Biol.Drug Des.,2018,92,1232-1240；Wei M-X,Zhang J,Ma F-L,et al.Eur.J.Med.Chem.2018,155, 165-170).Therefore, based on simple 2 (5H)-Furanones intermediates using succinct reaction synthesis it is new there is antitumor work Property compound, find and exploitation high-efficiency low-toxicity anti-tumor drug, be always the effort target of Pharmaceutical Chemists.
In current document report, it is methyl substitution or not substituted base that relevant biological activity molecule, which usually has 1- N, Structure.2 (5H)-furanone structure units are introduced into sulfohydrazide, synthesizing aryl sulphur acylhydrazone by the present inventor's early period (referring to CN109651310A).However, replacing the conjunction for being coupled the arylsulfonyl hydrazone compounds of other pharmacophoric groups about 1- N At method, especially by NH2Continue to be coupled other pharmacophoric groups and generate N- [2 (5H)-furanonyl]-arylsulfonyl hydrazone class and spreads out The synthetic method of biology, and further its anti-tumor activity application study is had not been reported.So about N- [4- (3- halogen- 5- oxyl -2 (5H)-furanonyl]-arylsulfonyl hydrazone analog derivative synthetic method and its have in antitumor activity Certain research significance.
Summary of the invention
Of the existing technology in order to overcome the problems, such as, one of the objects of the present invention is to provide a kind of N- furanonyl aryl Sulphonyl hydrazone compounds, the second object of the present invention are to provide the synthesis of this N- furanonyl arylsulfonyl hydrazone compounds Method, the third object of the present invention are to provide the application of this N- furanonyl arylsulfonyl hydrazone compounds.
The present invention has synthesized while having had arylsulfonyl hydrazone and 2 (5H)-furanone structures by simple organic synthesis Medicine small molecule N- [4- (- 2 (5H)-furanonyl of 3- halogen -5- oxyl]-arylsulfonyl hydrazone analog derivative of unit, and study Its application in anti-tumor drug.
The technical solution used in the present invention is:
The present invention provides a kind of N- furanonyl arylsulfonyl hydrazone compounds, shown in structure such as general formula (I):
In formula (I), R1Selected from the substituted or unsubstituted alkyl of C1~C10, the substituted or unsubstituted naphthenic base of C3~C6, take Generation or unsubstituted aryl, substituted or unsubstituted heteroaryl；R2、R3It is substituted or unsubstituted to be respectively and independently selected from H, C1~C10 Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R2And R3It is not simultaneously H；X is selected from halogen；Ar choosing From substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
Preferably, in this formula (I) compound represented, R1Alkyl, 6- chlorine hexyl, phenyl, benzyl selected from C1~C6 Or one of xenyl；R2、R3It is respectively and independently selected from H, methyl, methoxyl group, trifluoromethyl, normal-butyl, isobutyl group, phenyl, 4- Aminomethyl phenyl, 4- methoxyphenyl, 4- nitrobenzophenone, 4- hydroxy phenyl, 2- hydroxy phenyl, 4- fluorophenyl, 4- chlorphenyl, 2- chlorine One of phenyl, 3- hydroxyl -4- methoxyphenyl, 4- phenyl, 4- ethenylphenyl, and R2And R3It is not simultaneously H；X choosing From Cl or Br；Ar is selected from 4- aminomethyl phenyl, 4- methoxyphenyl, 4- fluorophenyl, 4- phenyl, phenyl, 4- trifluoromethylbenzene One of base；Alkyl can be straight chained alkyl either branched alkyl.
It is further preferred that in this formula (I) compound represented, R1Selected from methyl, isopropyl, hexyl, phenyl, benzyl One of；R2、R3It is respectively and independently selected from H, methyl, isobutyl group, phenyl, 4- aminomethyl phenyl, 4- methoxyphenyl, 4- nitrobenzene Base, 4- hydroxy phenyl, 2- hydroxy phenyl, 4- fluorophenyl, 2- chlorphenyl, 3- hydroxyl -4- methoxyphenyl, 4- phenyl, 4- One of ethenylphenyl, and R2And R3It is not simultaneously H；X is selected from Cl or Br；Ar in 4- aminomethyl phenyl, phenyl one Kind.
The present invention also provides the synthetic method of above-mentioned N- furanonyl arylsulfonyl hydrazone compounds, the synthetic methods It is: under the catalytic action of organic base and acid, by arylsulfonyl hydrazine class compound, -2 (5H)-furans of 3,4- dihalo- -5- oxyl Ketone and group compounds of aldehydes and ketones hybrid reaction, synthesis obtain formula (I) compound represented.
Preferably, in the synthetic method of this N- furanonyl arylsulfonyl hydrazone compounds, the temperature of reaction is room temperature.
Preferably, in the synthetic method of this N- furanonyl arylsulfonyl hydrazone compounds, the time of reaction is 0.5h ~38h；It is further preferred that the time of reaction is 0.5h~36h.
Preferably, in the synthetic method of this N- furanonyl arylsulfonyl hydrazone compounds, arylsulfonyl hydrazine chemical combination The molar ratio of object, -2 (5H)-furanone of 3,4- dihalo- -5- oxyl and group compounds of aldehydes and ketones is (1~1.5): 1:(1.2~2)； It is further preferred that arylsulfonyl hydrazine class compound, -2 (5H)-furanone of 3,4- dihalo- -5- oxyl and group compounds of aldehydes and ketones Molar ratio be 1.2:1:1.5.
Preferably, in the synthetic method of this N- furanonyl arylsulfonyl hydrazone compounds, organic base is 4- diformazan ammonia Yl pyridines (DMAP)；Acid is hydrochloric acid, such as selects the concentrated hydrochloric acid of concentration 37%.
Preferably, in the synthetic method of this N- furanonyl arylsulfonyl hydrazone compounds, reaction is in organic solvent It carries out；Organic solvent in halogenated hydrocarbon solvent, ether solvent, alcohols solvent, esters solvent, amide solvent at least one Kind.
In the synthetic method of this N- furanonyl arylsulfonyl hydrazone compounds, the chemistry of arylsulfonyl hydrazine class compound Formula is ArSO2NHNH2；Wherein, Ar is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl；Preferably, Ar is selected From one of p-methylphenyl, p-methoxyphenyl, 4- fluorophenyl, 4- phenyl, phenyl, 4- trifluoromethyl；Into One step is preferred, and Ar is selected from one of 4- aminomethyl phenyl, phenyl；Still further preferably, arylsulfonyl hydrazine class compound selects From to one of Methyl benzenesulfonyl hydrazine, benzene sulfonyl hydrazide.
In the synthetic method of this N- furanonyl arylsulfonyl hydrazone compounds, 3,4- dihalo- -5- oxyls -2 (5H) - Shown in the structure of furanone such as formula (II):
In formula (II), R1Selected from the substituted or unsubstituted alkyl of C1~C10, the substituted or unsubstituted naphthenic base of C3~C6, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl；Preferably, R1Alkyl, 6- chlorine hexyl, benzene selected from C1~C6 One of base, benzyl or xenyl；It is further preferred that R1One in methyl, isopropyl, hexyl, phenyl, benzyl Kind.
In formula (II), X is selected from halogen；Preferably, X is selected from Cl or Br.
Still further preferably, -2 (5H)-furanone of 3,4- dihalo- -5- oxyl is selected from 5- methoxyl group -3,4- bis- bromo- 2 (5H)-furanone, bromo- 2 (the 5H)-furanone of 5- positive hexyloxy -3,4- two, bromo- 2 (the 5H)-furanone of 5- benzyloxy -3,4- two, Bromo- 2 (the 5H)-furanone of 5- phenoxy group -3,4- two, chloro- 2 (the 5H)-furanone of 5- positive hexyloxy -3,4- two, isopropoxy -3 5-, Bis- chloro- 2 (5H)-furanone of 4-, chloro- 2 (the 5H)-furanone of 5- methoxyl group -3,4- two, chloro- 2 (the 5H)-furan of 5- phenoxy group -3,4- two It mutters one of ketone.
In the synthetic method of this N- furanonyl arylsulfonyl hydrazone compounds, the structure of group compounds of aldehydes and ketones such as formula (III) shown in:
In formula (III), R2、R3It is respectively and independently selected from the substituted or unsubstituted alkyl of H, C1~C10, substituted or unsubstituted virtue Base, substituted or unsubstituted heteroaryl, and R2And R3It is not simultaneously H；Preferably, R2、R3It is respectively and independently selected from H, methyl, methoxy Base, trifluoromethyl, normal-butyl, isobutyl group, phenyl, 4- aminomethyl phenyl, 4- methoxyphenyl, 4- nitrobenzophenone, 4- hydroxy phenyl, 2- hydroxy phenyl, 4- fluorophenyl, 4- chlorphenyl, 2- chlorphenyl, 3- hydroxyl -4- methoxyphenyl, 4- phenyl, 4- vinyl One of phenyl, and R2And R3It is not simultaneously H；It is further preferred that R2、R3It is respectively and independently selected from H, methyl, isobutyl group, benzene Base, 4- aminomethyl phenyl, 4- methoxyphenyl, 4- nitrobenzophenone, 4- hydroxy phenyl, 2- hydroxy phenyl, 4- fluorophenyl, 2- chlorobenzene One of base, 3- hydroxyl -4- methoxyphenyl, 4- phenyl, 4- ethenylphenyl, and R2And R3It is not simultaneously H.
Still further preferably, group compounds of aldehydes and ketones is selected from benzaldehyde, parahydroxyben-zaldehyde, to phenyl benzaldehyde, adjacent chlorine Benzaldehyde, 4- methyl acetophenone, methyl iso-butyl ketone (MIBK), p-tolyl aldehyde, 4-methoxybenzaldehyde, 4- nitrobenzaldehyde, water One of poplar aldehyde, vanillic aldehyde, cinnamic acid, 4- fluoro acetophenone.
The present invention also provides the applications of this N- furanonyl arylsulfonyl hydrazone compounds.
Above-mentioned N- furanonyl arylsulfonyl hydrazone compounds or its pharmaceutically acceptable salt, hydrate, solvent Compound, polymorph, tautomer or prodrug application in preparation of anti-tumor drugs.
Preferably, in this application, the tumour of anti-tumor drug includes breast cancer, glioma, lung cancer, histiocytic Lymph cancer, cancer of pancreas, breast cancer, prostate cancer, liver cancer, gastric cancer, colon cancer, the carcinoma of the rectum, oophoroma, palace stem cancer, cancer of the esophagus, bone Cancer, carcinoma of testis, one of melanoma, cutaneum carcinoma, nasopharyngeal carcinoma, kidney or a variety of；It is further preferred that tumour is mammary gland One of cancer, glioma, lung cancer are a variety of.
The present invention also provides a kind of pharmaceutical composition, this pharmaceutical composition includes above-mentioned N- furanonyl aryl sulphur Acylhydrazone or its pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer or prodrug.
Preferably, this pharmaceutical composition further includes excipient substance；Auxiliary material includes at least one of following substance: molten Agent, propellant, solubilizer, stabilizer, glidant, corrigent, preservative, suspending agent, coating material, aromatic, anti-binder, Integrated agent, penetration enhancer, pH adjusting agent, buffer, plasticizer, cosolvent, emulsifier, colorant, binder, disintegration Agent, filler, lubricant, wetting agent, osmotic pressure regulator, surfactant, foaming agent, defoaming agent, thickener, inclusion agents, Moisturizer, absorbent, diluent, flocculant and deflocculant, filter aid, release retarding agent.
Pharmaceutical composition of the invention can be made into various dosage forms:
Classify according to the decentralized system of dosage form, specifically, following dosage form: solution-type, colloidal solution can be made Type, emulsion-type, suspension type, gas dispersing type, microdispersed form, solid dispersing；
According to typoiogical classification, specifically, following dosage form: liquid dosage form (such as aromatic waters, solution, note can be made Penetrate agent, mixture, lotion, liniment etc.), gas formulation (such as aerosol, spray), solid dosage forms (such as powder, pill, tablet, Film etc.), semisolid dosage form (such as ointment, suppository, paste)；
The administration route of pharmaceutical composition of the invention includes oral, vein, muscle or percutaneous drug delivery.
The beneficial effects of the present invention are:
The invention discloses a kind of virtues simultaneously with 2 (5H)-furanone structure units and arylsulfonyl hydrazone structural unit Base sulphonyl hydrazone class noval chemical compound, synthetic method have it is simple and easy, reaction time is short, raw material is easy to get, wide application range of substrates, The advantages that yield is high, this kind of compound have extraordinary application prospect in anti-tumor drug research.
Specifically:
The present invention synthesizes N- [4- (- 2 (5H)-furanonyl of 3- halogen -5- oxyl]-arylsulfonyl hydrazone compounds for the first time, And compound is carried out1H NMR、13C NMR, HRMS and X-ray single crystal diffraction analysis test method to the compound of synthesis into Structural characterization is gone, all noval chemical compounds enrich arylsulfonyl hydrazone micromolecular library.
The present invention provides a kind of simple and practical synthetic method, replaces -2 (5H)-furanones, sulphonyl with 3,4- dihalo- -5- Hydrazine and group compounds of aldehydes and ketones are raw material, and " one kettle way " synthesizes N- [4- (- 2 (5H)-furanonyl of 3- halogen -5- oxyl]-aryl sulphur Acylhydrazone.The synthetic method is with simple and easy, reaction time is short, raw material is easy to get, wide application range of substrates, yield are high The advantages that.Using the method provided by the present invention, tens kinds can be synthesized while there is arylsulfonyl hydrazone structural unit and 2 (5H)-furans The potential drug small molecule of ketone pharmacophoric group, i.e. serial new N- [4- (- 2 (5H)-furanonyl of 3- halogen -5- oxyl]-aryl Sulphur acylhydrazone.
The research of the invention finds that after the structural units such as sulfohydrazide and biphenyl class are coupled and generate sulphonyl hydrazone class, to some swollen The inhibitory activity of oncocyte greatly improves.N- of the invention [4- (- 2 (5H)-furanonyl of 3- halogen -5- oxyl]-aryl sulphur Acylhydrazone has inhibition to make the tumour cells such as breast cancer cell MCF-7, brain glioblastoma cell U87, lung cell A549 With, it is obvious to breast cancer cell MCF-7, brain glioblastoma cell U87, especially there is very strong inhibition to breast cancer cell MCF-7 Activity, IC50Value is up to 14.35 ± 0.21 μM.As it can be seen that this kind of N- furanonyl arylsulfonyl hydrazone compounds are in anti-tumor drug There is extraordinary application prospect in research.
Detailed description of the invention
Fig. 1 is the X-ray single crystal diffraction figure of the compounds of this invention 1.
Specific embodiment
The present invention provides the N- furanonyl arylsulfonyl hydrazone compounds of structure in detail below:
The synthetic method of these above-mentioned compounds can be found in following reaction equation:
Below in conjunction with the reaction equation of synthetic method, the contents of the present invention are made by specific embodiment further details of Explanation.Raw material used in embodiment unless otherwise specified, can be obtained from routine business approach.