CN105348345A - Prodrug containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition - Google Patents

Prodrug containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition Download PDF

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Publication number
CN105348345A
CN105348345A CN201510932904.2A CN201510932904A CN105348345A CN 105348345 A CN105348345 A CN 105348345A CN 201510932904 A CN201510932904 A CN 201510932904A CN 105348345 A CN105348345 A CN 105348345A
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general formula
definition
compound
pharmaceutically acceptable
prodrug
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周星露
董晓武
刘兴国
施雄伟
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HANGZHOU HERTZ PHARMACEUTICAL Co Ltd
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HANGZHOU HERTZ PHARMACEUTICAL Co Ltd
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Priority to CN201510932904.2A priority Critical patent/CN105348345A/en
Publication of CN105348345A publication Critical patent/CN105348345A/en
Priority to CN201611024004.9A priority patent/CN106883279B/en
Priority to PCT/CN2016/109913 priority patent/WO2017101785A1/en
Priority to CN201611158070.5A priority patent/CN106883280B/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention belongs to the field of medicinal chemistry. Specifically, the invention relates to a prodrug containing a tiopronin structure showed by the following general formula I or a tautomer and a stereisomer of the prodrug, a stereisomer mixture or pharmaceutically acceptable solvate of the stereisomer mixture, a preparation method of the prodrug, a pharmaceutical composition, and application of the pharmaceutical composition serving as an anti-hepatitis c drug. This type of compounds or pharmaceutical compositions thereof can be used for curing hepatitis c, and also has the effects of protecting hepatic tissues and hepatic cells, and improving hepatic function.

Description

A kind of prodrug, its preparation method, medical composition and its use containing tiopronin structure
Technical field
The invention belongs to medicinal chemistry art.Specifically, the present invention relates to the prodrug containing tiopronin structure shown in a kind of following general formula I or its tautomer, steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate, its preparation method, pharmaceutical composition and the purposes as anti-hepatitis C medicine thereof.This compounds or its pharmaceutical composition can be used for the treatment of hepatitis C, have protection hepatic tissue, liver cell simultaneously, improve the effect of liver function.
Background technology
Hepatitis C is the hepatic diseases of a kind of serious threat human health that hepatitis C virus (hepatitisCvirus, hereinafter referred to as HCV) causes.1978, hepatitis C virus was by Late Cambrian; 1989, complete gene sequencing, HCV is confirmed to be another main pathogens of non-A type, non-hepatitis B.According to the heterogeneous characteristic of HCV genome, 6 types can be divided at present, 30 hypotypes.The type infected has stronger region, and China is based on 1 type.The research of 2011 shows, in Chinese HCV infection person, 1 type accounts for 58.2%, and wherein gene 1a type is 1.4%, and genotype 1 b is 56.8%.At present, in global range, HCV infection person is more than 200,000,000, accounts for total world population's 3.3%.About there are 3,200,000 the infecteds in the U.S., and Chinese HCV patient has exceeded 4,000 ten thousand person-times, occupies first of the world, and a lot of HCV infection person is hepatitis B even AIDS patient simultaneously, which increases the complicacy for the treatment of.The hepatitis C vaccine also formally do not got the Green Light at present, still faces the challenge so prevent the third liver from propagating.Existing chronic infection's state of an illness develops, and estimates that following 10-20 will welcome onset peak.The standard scheme of clinical treatment third liver is that Peg-IFN alpha-2b α combines ribavirin, and criterion of cure is that 24 weeks inner bloods can't detect the RNA of HCV after the treatment.This therapeutic modality side effect is comparatively large, comprises depression, tired, influenza-like symptom and anemia etc.; Treatment cost is higher, and standard course for the treatment of needs 48 weeks, expense about 40,000 dollar.For solving the problem, the micromolecular compound medicament research and development in recent years for the anti-hepatitis C virus of HCVRNA gene order becomes focus rapidly, and antiviral will enter the small-molecule drug epoch from the Interferon, rabbit epoch.At present, existing many HCV protease inhibitor are extensively studied, wherein Telaprevir (TVR, VX-950, trade(brand)name Incivek) and Boceprevir (Bo Xipuwei, SCH-503034, trade(brand)name Victrelis) gone through in 2011 listing.The inhibitor of Nonstructural Protein NS5A is also a kind of specificity antivirus medicine acting on HCVRNA chain, and Multi-genotype HCV virus all has significant restraining effect.In addition, the medicine being target spot with NS5B polysaccharase is divided into ucleosides and non-nucleosides AG14361 two class.Sofosbuvir is wherein anti-HCV medicament the most efficiently up to now, can effectively infect HCV-Ab IgG genotype 1,2,3,4 and 6.
In addition, liver is as the maximum Metabolic activity center of human body, and be even more important to human body, liver protecting medicine mainly refers to promotion liver cell regeneration, and reduce the medicine of hepatocellular damage, Long-term clinical proves, in the treatment of hepatopathy, liver protection function seems particularly important.Therefore liver protecting medicine is applied clinically and is more and more come into one's own and approve, medication market scale remains steady growth, in all hepatopathy medications, be only second to antiviral and immunomodulator.Clinically, the treatment of anti-chronic hepatitis B virus generally can adopt there is protecting the liver, fall enzyme, the liver protecting medicine of the function such as amelioration of inflammation, immunity moderation and anti-hepatitis virus medicament coupling, to play the effect that virus, immunity moderation, recovery Hepatic function improvement hepatic pathology are removed in treatment, namely reach the therapeutic purpose of " sample is part-time ".But allow sufferer take antiviral and liver protecting medicine, not only patient's poor compliance, too increases the economical load of patient simultaneously simultaneously.Therefore, it is possible to research one had both had anti-hepatitis C virus activity, and the difunctional medicine with liver protecting activity is of great significance and value.
The object of the present invention is to provide a kind of new HCV-Ab IgG virus and protect the liver, protect the difunctional medicine of liver, make it play the effect of difunctional medicine, be used for the treatment of the diseases such as viral hepatitis.
Summary of the invention
An object of the present invention is to provide the prodrug containing tiopronin structure shown in a kind of general formula I or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate.
Another object of the present invention is to provide the preparation method of compound provided by the invention.
Another object of the present invention is to provide the prodrug containing tiopronin structure shown in general formula I or its steric isomer; stereoisomer mixture or its pharmaceutically acceptable solvate are as NS5B inhibitor; protection liver cell, liver organization; improve the purposes of liver function, and the application in preparation treatment viral hepatitis.
Another object of the present invention be to provide comprise shown in general formula I containing the prodrug of tiopronin structure or its steric isomer, one or more the pharmaceutical composition in stereoisomer mixture or its pharmaceutically acceptable solvate.
Another object of the present invention is to provide one and treats viral hepatitis, and the liver cell of protection protection simultaneously, liver organization, improve the method for liver function.
The present invention adopts technical scheme as described below:
According to an aspect of the present invention, the prodrug containing tiopronin structure shown in general formula I or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate:
Wherein,
X is hydroxyl or halogen (F, Cl, Br),
Linker is
Wherein, R 1for H, C1-C5 alkyl, n is the integer of 1-19.
In described general formula I, the compound shown in general formula I can be the compound shown in general formula I-A:
Wherein, X, R 1definition with its definition in general formula I.
In described general formula I, the compound shown in general formula I can be the compound shown in general formula I-B:
Wherein, X, R 1, n definition with its definition in general formula I.
In described general formula I, the compound shown in general formula I can be the compound shown in general formula I-C:
Wherein, the definition of X is with its definition in general formula I.
In described general formula I, the compound shown in general formula I is preferably the compound shown in general formula I I:
Wherein, Linker is r 1for H, C1-C3 alkyl, n is the integer of 1-5.
In described general formula I I, the compound shown in general formula I I can be the compound shown in general formula I I-A:
Wherein, R 1definition with its definition in general formula I I.
In described general formula I I, the compound shown in general formula I I can be the compound shown in general formula I I-B:
Wherein, R 1, n definition with its definition in general formula I I.
In described general formula I I, the compound shown in general formula I I can be the compound shown in II-C:
In described general formula I I, the compound shown in general formula I I can be the compound shown in general formula I I-D:
Wherein, the definition of n is with its definition in general formula I I.
In the compound shown in described general formula I, particularly preferred particular compound is one of following compounds:
Or the steric isomer of above-mentioned preferred compound, stereoisomer mixture or its pharmaceutically acceptable solvate
Compound shown in formula I can contain one or more chiral centre, therefore can there is steric isomer, i.e. enantiomer, diastereomer or its mixture.Therefore, the compound shown in formula I can be the mixture of single isomer or Isomers.
The present invention includes any prodrug forms of the compound shown in formula I.
The present invention also comprises the pharmaceutical acceptable solvates of the compound of formula I.
The present invention also comprises the pharmaceutically acceptable oxide compound of the compound shown in formula I, and pharmacologically acceptable salt and pharmaceutical acceptable solvates.
The present invention also comprises the multiple crystal formation of the compound shown in formula I.
Another object of the present invention is to provide the preparation method of general formula I-A compound, and described method comprises:
Obtain general formula V-A compound by compound of formula III and compound of Formula IV through alkylation reaction, then obtain through deprotection reaction.
Wherein, X, R 1definition with its definition in general formula I, Y is leavings group, and Z is thiol protecting group;
Another object of the present invention is to provide the preparation method of general formula I-B compound, and described method comprises:
Compound of formula III and general formula I V-B compound obtain general formula V-B compound through alkylation reaction, then obtain through deprotection reaction.
Wherein, X, R 1, n definition with its definition in general formula I, Y is leavings group, and Z is thiol protecting group;
Another object of the present invention is to provide the preparation method of general formula I-C compound, and described method comprises:
Obtain general formula V-C compound by compound of formula III and general formula I V-C compound through acylation reaction, then obtain through deprotection reaction.
Wherein, the definition of X is with its definition in general formula I, and Y is leavings group, and Z is thiol protecting group;
Another object of the present invention is to provide the preparation method of general formula I-D compound, and described method comprises:
Compound of formula III and general formula I V-D compound obtain general formula V-D compound through alkylation reaction, then obtain through deprotection reaction.
Wherein, the definition of X is with its definition in general formula I, and Y is leavings group, and Z is thiol protecting group;
According to another aspect of the invention; the invention provides the prodrug containing tiopronin structure shown in general formula I or its steric isomer; the purposes of stereoisomer mixture or its pharmaceutically acceptable solvate; it protects liver cell, liver organization as NS5B inhibitor simultaneously; improve the purposes of liver function, and the purposes in the medicine for the preparation of diseases such as treatment viral hepatitis.
In accordance with a further aspect of the present invention, present invention also offers the prodrug containing tiopronin structure shown in a kind of general formula I comprising treatment significant quantity or its steric isomer, one or more pharmaceutical composition in stereoisomer mixture or its pharmaceutically acceptable solvate, it can as NS5B inhibitor, and said composition can optionally comprise pharmaceutically acceptable carrier or vehicle.
According to a further aspect in the invention, present invention also offers a kind of NS5B inhibitor, it contains the prodrug containing tiopronin structure shown in the general formula I for the treatment of significant quantity or its steric isomer, one or more in stereoisomer mixture or its pharmaceutically acceptable solvate, and this inhibitor can optionally comprise pharmaceutically acceptable carrier or vehicle.
Said composition is by the prodrug containing tiopronin structure shown in one or more general formula Is for the treatment of significant quantity or its steric isomer, and stereoisomer mixture or its pharmaceutically acceptable solvate and at least one pharmaceutically acceptable auxiliaries form.The selection of pharmaceutical excipient is different because of route of administration and action character, normally weighting agent, thinner, tackiness agent, wetting agent, disintegrating agent, lubricant, emulsifying agent, suspending agent etc.Formula I, its steric isomer, stereoisomer mixture or the ratio of its pharmaceutically acceptable solvate shared by above-mentioned composition are 0.1% ~ 99.9% of gross weight, preferably 1% ~ 99%.
Described pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, such as: thinner, as water etc.; Weighting agent, as starch, sucrose etc.; Tackiness agent, as derivatived cellulose, alginate, gelatin, polyvinylpyrrolidone; Wetting agent, as glycerine; Disintegrating agent, as agar, calcium carbonate and sodium bicarbonate; Absorption enhancer, as quaternary ammonium compound; Tensio-active agent, as cetyl alcohol; Absorption carrier, as kaolin and soap clay; Lubricant, as talcum powder, calcium stearate and Magnesium Stearate and polyoxyethylene glycol etc.In addition, other assistant agent can also be added in described pharmaceutical composition, as flavouring agent and sweeting agent etc.
Present invention also offers the prodrug containing tiopronin structure shown in general formula I or its steric isomer, the preparation method of the pharmaceutically useful composition of stereoisomer mixture or its pharmaceutically acceptable solvate.Usually by the prodrug containing tiopronin structure shown in general formula I or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate mix mutually with pharmaceutically acceptable auxiliaries, and the preparation method through routine makes the form (formulation) being suitable for certain approach and using.Formulation comprises tablet, capsule, granule, pill, solution, suspensoid, emulsion, ointment, film, creme, aerosol, injection, suppository etc.Preferred tablet and capsule.
The using dosage of the compounds of this invention is generally 1 ~ 1000mg every day, and point single or multiple uses.But where necessary, can suitably depart from above-mentioned dosage.Professional as the case may be and expertise, can determine optimal dose.These situations comprise the severity of disease, the individual difference of patient, the characteristic of preparation and route of administration etc.
In addition, present invention also offers the prodrug containing tiopronin structure shown in general formula I or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate, or its pharmaceutically useful composition is as the purposes of people's medicine.
According to another aspect of the invention, present invention also offers the method for the diseases such as treatment viral hepatitis, the prodrug containing tiopronin structure shown in the general formula I that described method comprises administering therapeutic significant quantity or its steric isomer, one or more or described pharmaceutical composition of the present invention in stereoisomer mixture or its pharmaceutically acceptable solvate are to patient.
Compound provided by the invention or composition can oral, injection (in vein, muscle, subcutaneous and coronary artery), sublingual, use through cheek, per rectum, per urethra, transvaginal, intranasal, suction or topic route.Preferred approach is oral.For time oral, conventional solid preparation can be made into, as tablet, pulvis, granula, capsule etc., or make liquid preparation, as water or oil-suspending agent, or other liquid preparation, as syrup etc.; During for intestines external administration, the solution of injection, water or oleaginous suspension etc. can be made into.
Present invention also offers the prodrug containing tiopronin structure shown in general formula I or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate, the purposes in people's medicine of preparation NS5B inhibitor.
Activity experiment result shows: compound provided by the invention obviously reduces the activity of the copy number that hepatitis C virus copies under the prerequisite of propagation survival not affecting liver cell, significantly can alleviate the damage of tetracol phenixin to liver simultaneously, in blood plasma, ALT and AST level obviously declines, data show, compound provided by the invention possesses the effect for the treatment of third liver and liver protecting simultaneously, has possessed the application prospect of difunctional medicine.
Embodiment
Embodiment 1: the synthesis of Compound II per-A-1
Step one:
Be dissolved in 10mL anhydrous propanone by 529mg (1.0mmol) III-1, add 680mg (1.5mmol) IV-1 and salt of wormwood 414mg (3.0mmol) under room temperature, heated and stirred backflow 6h, TLC detection reaction is complete.Filter, filtrate is diluted with methylene dichloride (30mL), and use water (10mL) and saturated aqueous common salt (10mL) washing successively, be separated organic phase, filter after anhydrous sodium sulfate drying, concentrating under reduced pressure is except desolventizing.Residuum purification by silica gel column chromatography obtains 710mg white solid V-1, yield 75%. 1HNMR(400MHz,CDCl 3)δ8.90(s,1H),7.51–7.38(m,7H),7.35–7.25(m,9H),7.22(dd,J＝10.2,4.2Hz,5H),7.17(d,J＝7.6Hz,1H),6.41(dt,J＝72.5,5.3Hz,1H),6.15(d,J＝17.9Hz,1H),5.52(d,J＝8.2Hz,1H),5.17(dd,J＝19.9,8.7Hz,1H),4.97(dq,J＝12.6,6.3Hz,1H),4.49(dt,J＝5.4,4.7Hz,1H),4.23(ddd,J＝14.7,12.0,7.8Hz,2H),4.03–3.88(m,2H),3.83–3.69(m,1H),3.54(dd,J＝18.2,5.1Hz,1H),3.09(dq,J＝25.7,7.5Hz,1H),1.46(dd,J＝7.5,4.2Hz,3H),1.39–1.29(m,6H),1.20(d,J＝6.3Hz,6H).ESI-MS:m/z[M+H] +＝947
Step 2:
200mg (0.21mmol) V-1 is dissolved in 10mL anhydrous methylene chloride, 2mL (volume ratio: methylene dichloride/tri isopropyl silane/trifluoroacetic acid=5/1/1) solution is added under room temperature, react about 1h, TLC detection reaction is complete, carefully add saturated sodium bicarbonate solution, be separated organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure after filtering.Residuum purification by silica gel column chromatography obtains 96mg white solid II-A-1, yield 65%.
1HNMR(400MHz,CDCl3)δ9.62(s,1H),7.46(dd,J＝8.1,2.2Hz,1H),7.34(t,J＝7.8Hz,2H),7.29–7.22(m,3H),7.19(d,J＝7.4Hz,1H),6.16(d,J＝18.1Hz,1H),5.64–5.53(m,1H),5.37–5.17(m,1H),5.08–4.93(m,1H),4.53(dd,J＝11.4,5.5Hz,1H),4.38–4.20(m,3H),4.20–4.04(m,2H),3.97(tt,J＝11.7,5.9Hz,1H),3.57–3.43(m,1H),2.17(dd,J＝8.4,2.2Hz,1H),1.55(dd,J＝7.1,1.0Hz,3H),1.38(dd,J＝14.8,7.7Hz,6H),1.27(s,1H),1.24(d,J＝6.3Hz,6H). 13CNMR(100MHz,CDCl3)δ173.89,173.85,172.98,172.91,169.24,169.20,162.90,150.54,150.47,150.24,139.44,129.90,125.22,119.97,119.92,103.22,100.18,98.32,77.67,72.46,72.33,69.42,63.75,50.42,41.60,37.53,37.52,21.90,21.84,21.68,21.61,20.93,20.88,17.46,17.20. 19FNMR(376MHz,CDCl3)δ-75.76. 31PNMR(162MHz,CDCl3)δ2.85.ESI-MS:m/z[M+H] +＝705
Embodiment 2: the synthesis of Compound II per-A-2
Step one:
Be dissolved in 10mL anhydrous propanone by 529mg (1.0mmol) III-1, add 680mg (1.5mmol) IV-2 and salt of wormwood 414mg (3.0mmol) under room temperature, heated and stirred backflow 6h, TLC detection reaction is complete.Filter, filtrate is diluted with methylene dichloride (30mL), and use water (10mL) and saturated aqueous common salt (10mL) washing successively, be separated organic phase, filter after anhydrous sodium sulfate drying, concentrating under reduced pressure is except desolventizing.Residuum purification by silica gel column chromatography obtains 306mg white solid V-1, yield 38%.
1HNMR(400MHz,CDCl 3)δ8.90(s,1H),7.51-7.38(m,7H),7.35-7.25(m,9H),7.22(dd,J＝10.2,4.2Hz,5H),7.17(d,J＝7.6Hz,1H),6.65(q,J＝6.5Hz,1H)，6.19(d,J＝17.9Hz,1H),5.10-4.94(m,1H),4.52(dd,J＝11.4,5.7Hz,1H),4.39-4.21(m,3H),4.22-4.05(m,2H),3.98(tt,J＝11.5,5.8Hz,1H),3.57-3.45(m,1H),2.17(dd,J＝8.5,2.2Hz,1H),,1.86(d,J＝6.5Hz,3H),1.56(dd,J＝7.1,1.0Hz,3H),1.37(dd,J＝14.8,7.5Hz,6H),1.27(s,1H),1.20(d,J＝6.3Hz,6H).ESI-MS:m/z[M+H] +＝961.
Step 2:
200mg (0.21mmol) V-2 is dissolved in 10mL anhydrous methylene chloride, 2mL (volume ratio: methylene dichloride/tri isopropyl silane/trifluoroacetic acid=5/1/1) solution is added under room temperature, react about 1h, TLC detection reaction is complete, carefully add saturated sodium bicarbonate solution, be separated organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure after filtering.Residuum purification by silica gel column chromatography obtains 100mg white solid II-A-1, yield 67%.
1HNMR(400MHz,CDCl 3)δ9.64(s,1H),7.50(dd,J＝8.1,2.3Hz,1H),7.36(t,J＝7.8Hz,2H),7.30-7.22(m,3H),7.19(d,J＝7.6Hz,1H),6.65(q,J＝6.5Hz,1H)，6.19(d,J＝17.9Hz,1H),5.10-4.94(m,1H),4.52(dd,J＝11.4,5.7Hz,1H),4.39-4.21(m,3H),4.22-4.05(m,2H),3.98(tt,J＝11.5,5.8Hz,1H),3.57-3.45(m,1H),2.17(dd,J＝8.5,2.2Hz,1H),,1.86(d,J＝6.5Hz,3H),1.56(dd,J＝7.1,1.0Hz,3H),1.37(dd,J＝14.8,7.5Hz,6H),1.27(s,1H),1.25(d,J＝6.3Hz,6H). 13CNMR(100MHz,CDCl 3)δ173.82,173.75,172.83,172.61,169.27,169.20,162.76,150.51,150.27,150.21,139.42,129.93,125.12,119.87,118.92,103.52,99.88,98.02,72.56,72.31,71.69,69.40,63.72,49.92,41.63,37.43,37.55,21.93,21.74,21.62,21.51,20.83,20.78,18.33,17.43,17.10.ESI-MS:m/z[M+H] +＝719.
Embodiment 3: the synthesis of Compound II per-B-1
Step one:
Be dissolved in 10mL anhydrous propanone by 529mg (1.0mmol) III-1, add 690mgIV-3 and salt of wormwood 414mg (3.0mmol) under room temperature, heated and stirred backflow 6h, TLC detection reaction is complete.Filter, filtrate is diluted with methylene dichloride (30mL), and use water (10mL) and saturated aqueous common salt (10mL) washing successively, be separated organic phase, filter after anhydrous sodium sulfate drying, concentrating under reduced pressure is except desolventizing.Residuum purification by silica gel column chromatography obtains 300mgV-3, is directly used in next step reaction.
Step 2:
200mg (0.21mmol) V-3 is dissolved in 10mL anhydrous methylene chloride, 2mL (volume ratio: methylene dichloride/tri isopropyl silane/trifluoroacetic acid=5/1/1) solution is added under room temperature, react about 1h, TLC detection reaction is complete, carefully add saturated sodium bicarbonate solution, be separated organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure after filtering.Residuum purification by silica gel column chromatography obtains 100mg white solid II-B-1. 1HNMR(400MHz,CDCl3)δ9.62(s,1H),7.46(dd,J＝8.1,2.2Hz,1H),7.34(t,J＝7.8Hz,2H),7.29-7.22(m,3H),7.19(d,J＝7.4Hz,1H),6.16(d,J＝18.1Hz,1H),5.64-5.53(m,1H),5.37-5.17(m,1H),5.08-4.93(m,1H),4.53(dd,J＝11.4,5.5Hz,1H),4.38-4.20(m,3H),4.40-4.08(m,6H),3.97(tt,J＝11.7,5.9Hz,1H),3.57-3.43(m,1H),2.17(dd,J＝8.4,2.2Hz,1H),1.55(dd,J＝7.1,1.0Hz,3H),1.38(dd,J＝14.8,7.7Hz,6H),1.27(s,1H),1.24(d,J＝6.3Hz,6H).ESI-MS:749(M+1)
Embodiment 4: the synthesis of Compound II per-C
Step one:
Be dissolved in 10mL anhydrous propanone by 529mg (1.0mmol) III-1, add 800mgIV-4 and triethylamine 500mg under room temperature, stirring at room temperature 6h, TLC detection reaction is complete.Filter, filtrate is diluted with methylene dichloride (30mL), and use water (10mL) and saturated aqueous common salt (10mL) washing successively, be separated organic phase, filter after anhydrous sodium sulfate drying, concentrating under reduced pressure is except desolventizing.Residuum purification by silica gel column chromatography obtains 400mgV-4, is directly used in next step reaction.
Step 2:
200mg (0.21mmol) V-4 is dissolved in 10mL anhydrous methylene chloride, 2mL (volume ratio: methylene dichloride/tri isopropyl silane/trifluoroacetic acid=5/1/1) solution is added under room temperature, react about 1h, TLC detection reaction is complete, carefully add saturated sodium bicarbonate solution, be separated organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure after filtering.Residuum purification by silica gel column chromatography obtains 100mg white solid II-C. 1HNMR(400MHz,CDCl3)δ9.64(s,1H),7.53(dd,J＝8.1,2.2Hz,1H),7.33(t,J＝7.8Hz,2H),7.29-7.20(m,3H),7.21(d,J＝7.4Hz,1H),6.14(d,J＝18.1Hz,1H),5.67-5.51(m,1H),5.39-5.15(m,1H),5.03-4.92(m,1H),4.52(m,1H),4.33-4.20(m,3H),4.20-4.04(m,2H),3.97(tt,J＝11.7,5.9Hz,1H),3.57-3.43(m,1H),2.17(dd,J＝8.4,2.2Hz,1H),1.55(dd,J＝7.1,1.0Hz,3H),1.38(dd,J＝14.8,7.7Hz,6H),1.27(s,1H),1.24(d,J＝6.3Hz,6H).ESI-MS:749(M+1).
Embodiment 5: the synthesis of Compound II per-D-1
Step one:
Be dissolved in 10mL anhydrous propanone by 529mg (1.0mmol) III-1, add 800mgIV-5 and triethylamine 500mg under room temperature, stirring at room temperature 6h, TLC detection reaction is complete.Filter, filtrate is diluted with methylene dichloride (30mL), and use water (10mL) and saturated aqueous common salt (10mL) washing successively, be separated organic phase, filter after anhydrous sodium sulfate drying, concentrating under reduced pressure is except desolventizing.Residuum purification by silica gel column chromatography obtains 400mgV-5, is directly used in next step reaction.
Step 2:
200mg (0.21mmol) V-5 is dissolved in 10mL anhydrous methylene chloride, 2mL (volume ratio: methylene dichloride/tri isopropyl silane/trifluoroacetic acid=5/1/1) solution is added under room temperature, react about 1h, TLC detection reaction is complete, carefully add saturated sodium bicarbonate solution, be separated organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure after filtering.Residuum purification by silica gel column chromatography obtains 100mg white solid II-D-1. 1HNMR(400MHz,CDCl 3)δ9.66(s,1H),7.44(dd,J＝7.9,2.1Hz,1H),7.32(t,J＝7.8Hz,2H),7.28–7.20(m,3H),7.16(d,J＝7.5Hz,1H),6.13(d,J＝17.6Hz,1H),5.15–5.03(m,1H),4.60(t,J＝7.5Hz,2H),4.55(dd,J＝11.5,5.7Hz,1H),4.48–4.25(m,3H),4.23–4.09(m,2H),3.95(tt,J＝11.8,5.8Hz,1H),3.59–3.42(m,1H),3.25(t,J＝7.5Hz,2H),2.16(dd,J＝8.4,2.2Hz,1H),1.54(dd,J＝7.1,1.0Hz,3H),1.39(dd,J＝14.7,7.6Hz,6H),1.28(s,1H),1.25(d,J＝6.5Hz,6H). 13CNMR(100MHz,CDCl 3)δ174.81,174.55,173.54,172.89,169.87,169.23,161.79,150.97,150.51,150.01,140.37,131.81,125.72,119.88,118.62,102.52,99.48,98.03,72.76,72.15,69.19,63.68,59.55,49.84,40.99,39.16,36.95,36.55,21.93,21.65,21.42,20.90,20.45,17.48,16.88.ESI-MS:m/z[M+H] +＝719.
Embodiment 6: anti-hepatitis C virus activity (HCV, EC 50) and cytotoxicity (CC 50)
Owing to lacking desirable HCV Infection in Vitro cell and animal model, generally, the enzyme that the evaluation of HCV virus activity plays a crucial role during HCVRNA can be adopted to copy sets up extracellular molecular replication model.Wherein in compound on intracellular, the result of the inhibit activities (EC50) of HCV replicon is customary way in the world as its anti-hepatitis C virus activity of evaluation, and cytotoxic activity (CC simultaneously 50) synchronism detection for getting rid of the false positive results because cytotoxicity causes.Therapeutic index is higher, and representation compound more has application prospect.Result shows, compounds exhibit provided by the invention goes out the activity similar or more excellent to Sofosbuvir and therapeutic index, for II-A-2, its inhibit activities to intracellular HCV replicon (EC50) is obviously better than than positive control Sofosbuvir, show that this compound the form that can at rapid intracellular degradation become active metabolite the same as Sofosbuvir can play the effect of HCV-Ab IgG in liver cell, in addition, another one's share of expenses for a joint undertaking tiopronin obtained of degrading in molecule has certain gain effect for antiviral activity, and this synergistic effect makes compound provided by the invention, application prospect is had more in HCV-Ab IgG disease.
Anti-hepatitis C virus activity (HCV, the EC of table 1 the compounds of this invention 50) and cytotoxicity (CC 50)
Result
Embodiment 7:CCl4 liver damages the provide protection research of model
Before getting the male mice experiment of body weight 24 ~ 28g, fasting can't help water 6 hours, is divided into 3 groups at random by body weight, often organizes 5 mouse, sets up blank group, CCL separately 4group, compound group.The every 12h gastric infusion of compound group 1 time, each gavage capacity is 10mL/kg, altogether administration 4 times.Blank group and model control group such as to gavage at the physiological saline of capacity simultaneously.1h after third time administration, except blank group mouse, other two groups of mouse press the CCl of 2mg/kgb.w 4abdominal injection 50%CCl 4corn oil.After 12 hours, respectively organize administration again 1 time.After 24 hours, each mouse gets blood, measures Serum ALT and AST, gets liver and cut fritter, after formaldehyde is fixing, and paraffin section, with h and E dyeing, basis of microscopic observation liver cell situation.
As shown in the table, CCl 4aLT and AST of model group mouse is abnormal to be raised, and tiopronin (positive control) significantly can reverse and thisly rise enzyme effect, and compare down, Sofosbuvir does not then have the activity of this respect.And compound provided by the invention has obvious effect of reducing enzyme levels, active with tiopronin quite or more excellent.Tracing it to its cause, may be because after the carboxyl of tiopronin is made into prodrug, can improve its stability and by the ability of oral absorption, thus makes its activity obtain enhancing.For II-A-2, it causes ALT and AST rising effect to CCl4 induced liver injury, has obvious inhibit activities, and is better than positive control tiopronin.In addition, liver organization pathology section examination result is, CCl 4model group, central veins of liver extravasated blood, has centrilobular or peripheral necrosis around, and liver cell has swelling, the distortion of balloon sample, and II-A-2 administration group presents a small amount of point-like and piecemeal necrosis, and major part presents the distortion of balloon sample, shows by CCl 4the toxicity caused greatly reduces, illustrates that II-A-2 has protection CCl really 4the liver harm caused is used.Owing to lacking desirable HCV infection animal model; direct evaluation compound provided by the invention causes the provide protection of liver injury infeasible to HCV; but in theory and the angle of clinical application, the inflammatory reaction that the effect of the liver protecting of compound provided by the invention causes for HCV has provide protection equally.
The CCl4 liver of table 2 the compounds of this invention damages the provide protection result of study of model
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., be all included within protection scope of the present invention.

Claims (19)

1. the prodrug containing tiopronin structure shown in following general formula I or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate:
Wherein,
X is hydroxyl or halogen,
Linker is
Wherein, R 1for H or C1-C5 alkyl, n is the integer of 1-19.
2. the prodrug containing tiopronin structure shown in a kind of following general formula I-A according to claim 1 or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate:
Wherein, X, R 1definition with its definition in general formula I.
3. the prodrug containing tiopronin structure shown in a kind of following general formula I-B according to claim 1 or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate:
Wherein, X, R 1, n definition with its definition in general formula I.
4. the prodrug containing tiopronin structure shown in a kind of following general formula I-C according to claim 1 or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate:
Wherein, the definition of X is with its definition in general formula I.
5. the prodrug containing tiopronin structure shown in a kind of following general formula I-D according to claim 1 or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate:
Wherein, X, R 1definition with its definition in general formula I.
6. the prodrug containing tiopronin structure shown in a kind of following general formula I I according to claim 1 or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate:
Wherein, Linker is r 1for H or C1-C3 alkyl, n is the integer of 1-5.
7. the prodrug containing tiopronin structure shown in a kind of following general formula I I-A according to claim 6 or its tautomer, steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate:
Wherein, R 1definition with its definition in general formula I I.
8. the prodrug containing tiopronin structure shown in a kind of following general formula I I-B according to claim 6 or its tautomer, steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate:
Wherein, R 1, n definition with its definition in general formula I I.
9. the prodrug containing tiopronin structure shown in a kind of following II-C according to claim 6 or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate:
10. the prodrug containing tiopronin structure shown in a kind of following II-D according to claim 6 or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate:
Wherein, the definition of n is with its definition in general formula I I.
11. compounds according to claim 1 formula of I are selected from following compounds:
The preparation method of the compound shown in 12. 1 kinds of general formula I-A according to claim 2, can obtain general formula V-A compound by compound of formula III and compound of Formula IV through alkylation reaction, then obtain through deprotection reaction.
Wherein, X, R 1definition with its definition in general formula I, Y is leavings group, and Z is thiol protecting group.
The preparation method of the compound shown in 13. 1 kinds of general formula I-B according to claim 3, can obtain general formula V-B compound by compound of formula III and general formula I V-B compound through alkylation reaction, then obtain through deprotection reaction.
Wherein, X, R 1, n definition with its definition in general formula I, Y is leavings group, and Z is thiol protecting group.
The preparation method of the compound shown in 14. 1 kinds of general formula I-C according to claim 4, can obtain general formula V-C compound by compound of formula III and general formula I V-C compound through acylation reaction, then obtain through deprotection reaction.
Wherein, the definition of X is with its definition in general formula I, and Y is leavings group, and Z is thiol protecting group.
The preparation method of the compound shown in 15. 1 kinds of general formula I-D according to claim 5, can obtain general formula V-D compound by compound of formula III and general formula I V-D compound through alkylation reaction, then obtain through deprotection reaction.
Wherein, the definition of X is with its definition in general formula I, and Y is leavings group, and Z is thiol protecting group.
16. 1 kinds of one or more pharmaceutical compositions comprised in the prodrug containing tiopronin structure shown in general formula I or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate.
17. pharmaceutical compositions according to claim 16, wherein, shown in formula I containing tiopronin structure prodrug or its steric isomer, the dosage of one or more pharmaceutical composition in described pharmaceutical composition in stereoisomer mixture or its pharmaceutically acceptable solvate is 1 ~ 1000mg/ days.
According to any one of 18. claims 1 ~ 11 containing tiopronin structure prodrug or its steric isomer, stereoisomer mixture or its pharmaceutically acceptable solvate, in preparation as the purposes for the treatment of in hepatitis C medicine.
19. purposes according to claim 18, wherein, this compound or mixture further with the drug combination of other treatment hepatopathy.
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