CN106883279A - A kind of prodrug, its preparation method, medical composition and its use - Google Patents

A kind of prodrug, its preparation method, medical composition and its use Download PDF

Info

Publication number
CN106883279A
CN106883279A CN201611024004.9A CN201611024004A CN106883279A CN 106883279 A CN106883279 A CN 106883279A CN 201611024004 A CN201611024004 A CN 201611024004A CN 106883279 A CN106883279 A CN 106883279A
Authority
CN
China
Prior art keywords
formula
compounds
compound
alkyl
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201611024004.9A
Other languages
Chinese (zh)
Other versions
CN106883279B (en
Inventor
周星露
刘兴国
董晓武
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong HEC Pharmaceutical
Original Assignee
HANGZHOU HERTZ PHARMACEUTICAL Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by HANGZHOU HERTZ PHARMACEUTICAL Co Ltd filed Critical HANGZHOU HERTZ PHARMACEUTICAL Co Ltd
Priority to PCT/CN2016/109913 priority Critical patent/WO2017101785A1/en
Publication of CN106883279A publication Critical patent/CN106883279A/en
Application granted granted Critical
Publication of CN106883279B publication Critical patent/CN106883279B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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 medicinal chemistry art.Specifically, the present invention relates to the prodrug containing Tiopronin structure or its dynamic isomer, stereoisomer shown in a kind of below formula I, stereoisomer mixture or its pharmaceutically acceptable solvate, its preparation method, pharmaceutical composition and its purposes as anti-hepatitis C medicine.Such compound or its pharmaceutical composition can be used for the treatment of hepatitis C, while the effect for having protection hepatic tissue, liver cell, improving liver function.

Description

A kind of prodrug, its preparation method, medical composition and its use
Technical field
The invention belongs to medicinal chemistry art.Specifically, the present invention relates to the compound shown in a kind of below formula I or Its dynamic isomer, stereoisomer, stereoisomer mixture, prodrug, pharmaceutically acceptable salt or its solvate, its Preparation method, pharmaceutical composition and its purposes as anti-hepatitis C medicine.
Background technology
Hepatitis C is a kind of serious prestige that HCV (hepatitis C virus, hereinafter referred to as HCV) causes Coerce the liver diseases of human health.1978, hepatitis C virus was found first；1989, complete gene sequencing, HCV quilts Confirm as non-A type, another main pathogens of non-hepatitis B.According to HCV genomes heterogeneity characteristic, can divide at present It is 6 types, 30 hypotypes.The type of infection has stronger region, and China is based on 1 type.The research of 2011 shows, in In state HCV infection person, 1 type accounts for 58.2%, and wherein gene 1a types are 1.4%, and genotype 1 b is 56.8%.At present, global range Interior HCV infection person accounts for the 3.3% of total world population more than 200,000,000.The U.S. there are about 3,200,000 the infecteds, and Chinese HCV patient exceedes 40000000 person-times, occupy first of the world, many HCV infection persons are simultaneously hepatitis B even AIDS patients, which increase answering for treatment Polygamy.There is presently no the hepatitis C vaccine for formally getting the Green Light, so prevent hepatitis from propagating still facing the challenge.Existing chronic sense Dye person's state of an illness develops, it is contemplated that following 10-20 will welcome onset peak.The standard scheme of clinical treatment hepatitis is Peg-IFN alpha-2b α combines Ribavirin, and criterion of cure is 24 weeks interior RNAs of the blood testing less than HCV after the treatment.It is this Therapeutic modality side effect is larger, including depressed, tired, influenza-like symptom and anemia etc.；Treatment cost is higher, and standard course for the treatment of is needed 48 weeks are wanted, expense about 40,000 dollar.To solve the above problems, in recent years for the anti-hepatitis of HCVRNA gene order The micromolecular compound medicament research and development of virus rapidly becomes focus, and antiviral drugs will enter small-molecule drug from the interferon epoch Epoch.At present, existing many HCV protease inhibitors are widely studied, wherein Telaprevir (TVR, VX-950, Trade name Incivek) and Boceprevir (Bo Xipuwei, SCH-503034, trade name Victrelis) criticized in 2011 years Quasi- listing.The inhibitor of non-structural protein NS5A is also a kind of specificity antivirus medicine for acting on HCVRNA chain, many Plant HCV genotype virus and be respectively provided with significant inhibitory action.Additionally, the medicine with NS5B polymerases as target spot be divided into ucleosides and The non-class of nucleosides AG14361 two.Sofosbuvir therein is anti-HCV medicament the most efficient so far, can be effectively right HCV-Ab IgG genotype 1,2,3,4 and 6 infects.According to the literature, its metabolic pathway in vivo is as shown below, wherein GS331007 is final metabolite, is to study the mark that Sofosbuvir is metabolized behavior in vivo.
In addition, liver is even more important as the maximum metabolic activity center of human body to human body, liver protecting medicine is primarily referred to as Promote liver cell regeneration, reduce the medicine of hepatocellular damage, Long-term clinical proves that liver protection function seems in the treatment of hepatopathy It is particularly important.Therefore clinically application is increasingly taken seriously and approves liver protecting medicine, and medication market scale remains Steady growth, antiviral and immunomodulator is only second in all hepatopathy medications.Clinically, anti-chronic hepatitis B virus treatment Typically can be using with liver protection, drop enzyme, the liver protecting medicine and anti-hepatitis virus medicament alleviating inflammation, adjust the function such as immune Combination, to play a part of, virus is removed in treatment, regulation is immune, recover Hepatic function improvement hepatic pathology, that is, reach " sample and The therapeutic purposes of duty ".However, allow sufferer while take antiviral drugs and liver protecting medicine, not only patient's poor compliance, together When also increase the financial burden of patient.It is a kind of both with anti-hepatitis C virus activity therefore, it is possible to study, and with liver protecting The difunctional medicine of activity is of great significance and value.
It is an object of the invention to provide a kind of new HCV-Ab IgG virus and liver protection, the difunctional medicine of protect liver, play it double The effect of function medicament, metabolisming property good advantage high with oral administration biaavailability can be used for treatment virus hepatitis etc. Disease.
The content of the invention
It is an object of the present invention to provide prodrug or its stereoisomer shown in a kind of formula I, stereoisomer is mixed Compound or its pharmaceutically acceptable solvate.
The preparation method of the compound provided it is a further object to provide the present invention.
A further object of the present invention is to provide prodrug or its stereoisomer shown in formula I, stereoisomer mixing , used as NS5B inhibitor, protection liver cell, liver organization improve the use of liver function for thing or its pharmaceutically acceptable solvate On the way, the application and in treatment virus hepatitis is prepared.
It is also another object of the present invention to provide comprising the prodrug shown in formula I or its stereoisomer, stereoisomer One or more in mixture or its pharmaceutically acceptable solvate of pharmaceutical composition.
Virus hepatitis is treated it is also another object of the present invention to provide one kind, while protecting liver cell, liver organization, is changed The method of kind liver function.
The present invention uses technical scheme as described below：
According to an aspect of the present invention, shown in formula I prodrug or its stereoisomer, stereoisomer mixture Or its pharmaceutically acceptable solvate：
Wherein, X is hydroxyl or halogen (F, Cl, Br)；
R is
Linker isOr do not exist, A is for Medicine for treatment or auxiliary treatment hepatopathy of listing or derivatives thereof；
R1It is H or C1-C5Alkyl；
N is the integer of 1-19.
In the formula I-A, formula I-A compounds be preferably the prodrug containing class nucleotide structure shown in formula II-A or Its stereoisomer, stereoisomer mixture or its pharmaceutically acceptable solvate：
Wherein, X is hydroxyl or halogen (F, Cl, Br)；
Linker isOr do not exist；
R1It is H or C1-C5Alkyl；
N is 1,2,3,4 or 5；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl.
In the formula II-A, formula II-A compounds be preferably structure shown in formula II-Aa or Formula II-Ab or Its dynamic isomer, optical isomer, stereoisomer, stereoisomer mixture, prodrug, pharmaceutically acceptable salt or molten Agent compound：
Wherein, X is hydroxyl or halogen (F, Cl, Br)；
Linker isOr do not exist；
R1It is H or C1-C5Alkyl；
N is 1,2,3,4 or 5；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl.
In the formula I, compound of Formula I is preferably structure or its dynamic isomer, optics shown in formula II-B Isomers, stereoisomer, stereoisomer mixture, prodrug, pharmaceutically acceptable salt or solvate：
Wherein, X is hydroxyl or halogen (F, Cl, Br)；
Linker isOr do not exist；
R1It is H or C1-C5Alkyl；
N is 1,2,3,4 or 5；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl.
In the formula II-A, formula II-A compounds be preferably structure shown in formula II-Ba or Formula II-Bb or its Optical isomer, pharmaceutically acceptable salt or solvate：
Wherein, X is hydroxyl or halogen (F, Cl, Br)；
Linker isOr do not exist；
R1It is H or C1-C5Alkyl；
N is 1,2,3,4 or 5；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl.
In the formula II-A, formula II-A compounds are preferably shown in formula II-A-A and contain Tiopronin structure Prodrug or its stereoisomer, stereoisomer mixture or its pharmaceutically acceptable solvate：
Wherein,
X be hydroxyl or halogen (F, Cl, Br),
Linker is
Wherein, R1It is H or C1-C5Alkyl, n is the integer of 1-19.
In the formula II-A-A, formula II-A-A compounds be preferably the following prodrug containing Tiopronin structure or Its stereoisomer, stereoisomer mixture or its pharmaceutically acceptable solvate：
Wherein,
X is hydroxyl or halogen (F, Cl, Br)；
R1It is H or C1-C5Alkyl,
N is 1,2,3,4 or 5.
In the formula II-A-A, formula II-A-A compounds be preferably the following prodrug containing Tiopronin structure or Its stereoisomer, stereoisomer mixture or its pharmaceutically acceptable solvate：
Wherein,
R1It is H or C1-C5Alkyl,
N is 1,2,3,4 or 5.
In the compound shown in the formula I, particularly preferred particular compound is one of following compounds：
Or the stereoisomer of above-mentioned preferred compound, stereoisomer mixture or its pharmaceutically acceptable solvent are closed Thing.
Compound shown in formula I can contain one or more chiral centres, different because there may be stereoisomer, i.e. mapping Structure body, diastereoisomer or its mixture.Therefore, the compound shown in formula I can be single isomers or different The mixture of structure body.
Any prodrug forms of the present invention including the compound shown in formula I.
Present invention additionally comprises the pharmaceutical acceptable solvates of the compound of formula I.
The present invention also includes the pharmaceutically acceptable oxide of the compound shown in formula I, and its officinal salt and acceptable solvent Compound.
Present invention additionally comprises various crystal formations of the compound shown in formula I.
It is a further object to provide the preparation method of formula II-A compounds, methods described includes：
1) formula III compound obtains Formula V-A compounds with the reaction of formula IV-A compounds,
2) Formula V-A compounds obtain Formula II-A compounds by deprotection reaction；
Wherein, X is hydroxyl or halogen (F, Cl, Br)；
Linker isOr do not exist；
N is 1,2,3,4 or 5；
R1It is H or C1-C5Alkyl；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl；
LG is leaving group, preferably halogen；
Z is thiol protecting group, preferably trityl, 4- Methoxytrityls, 4,4 '-bi-methoxy triphen first Base.
It is a further object to provide the preparation method of formula Ii-B compound, methods described includes：
1) formula III compound obtains Formula V-B compounds with the reaction of formula IV-B compounds；
2) Formula V-B compounds obtain Formula II-B compounds through deprotection reaction；
Wherein, X hydroxyls or halogen (F, Cl, Br)；
Linker isOr do not exist；
N is 1,2,3,4 or 5；
R1It is H or C1-C5Alkyl；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl；
LG is leaving group, preferably halogen；
Z is thiol protecting group, preferably trityl, 4- Methoxytrityls, 4,4 '-bi-methoxy triphen first Base.
Further, the preparation method of the compound shown in a kind of formula II-A-Aa, can be by compound of formula III Formula V-A compounds are obtained by alkylation reaction with compound of Formula IV, is then obtained by deprotection reaction.
Wherein, X is F, Cl or Br；
R1It is H or C1-C5Alkyl；
Y is leaving group,
Z is thiol protecting group.
A kind of preparation method of the compound shown in Formula II-A-Ab, can be by compound of formula III and formula IV-B chemical combination Thing obtains formula V-B compounds by alkylation reaction, is then obtained by deprotection reaction：
Wherein, X is hydroxyl or halogen (F, Cl, Br)；
R1It is H or C1-C5Alkyl；
N is the integer of 1-19；
Y is leaving group；
Z is thiol protecting group.
It is a further object to provide the preparation method of formula II-A-B, can be by III compounds through overprotection Reaction, then obtains Formula VII compound with aldehyde reaction, esterification then occurs with formula VIII-A compounds or acylation reaction is obtained To formula IX-A-B compounds, then slough protection group and obtain formula II-A-B compounds.The key intermediate of this preparation method The active site of reaction be suitably protected, help to reduce the generation of side reaction, reaction selectivity is high, the intermediate that obtains, most End-product purity is high, it is easy to purify.And the reaction that this method is related to has simple to operate, purifying convenient, and process controllability Good advantage, is adapted to industrialization production.
Wherein,
X is hydroxyl or halogen (F, Cl, Br)；
R1It is H or C1-C5Alkyl；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl；
P1It is hydroxy-protective group, preferably trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, triphenyl Silicon substrate；
P2It is amide NH blocking group, preferably tertbutyloxycarbonyl, benzyloxycarbonyl group, 4- methbxybenzyl-oxycarbonyls；
P3It is thiol protecting group, preferably trityl, 4- Methoxytrityls, 4,4 '-bi-methoxy triphen first Base.
It is a further object to provide shown in formula II-B-B, can by Formula VII compound, then with it is logical There is esterification in Formula VIII-B compounds or acylation reaction obtains formula IX-B-B compounds, then sloughs blocking group and obtains formula II-B-B compounds.The active site of reaction of the key intermediate of this preparation method is suitably protected, and helps to reduce side reaction Generation, reaction selectivity is high, and the intermediate that obtains, final product purity are high, it is easy to purify.And the reaction that this method is related to has There is simple to operate, purifying convenient, and the good advantage of process controllability, it is adapted to industrialization production.
Wherein, X, R1, R3, R4Definition with its definition in formula II-B,
P1It is hydroxy-protective group, preferably trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, triphenyl Silicon substrate；
P2It is amide NH blocking group, preferably tertbutyloxycarbonyl, benzyloxycarbonyl group, 4- methbxybenzyl-oxycarbonyls；
P3It is thiol protecting group, preferably trityl, 4- Methoxytrityls, 4,4 '-bi-methoxy triphen first Base.
It is a further object of the present invention to provide the intermediate shown in following VII and its for preparing anti-hepatitis C virus medicine Purposes：
Wherein,
X is hydroxyl or halogen (F, Cl, Br)；
R1It is H or C1-C5Alkyl；
P1It is hydroxy-protective group, preferably trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, triphenyl Silicon substrate.
It is a further object of the present invention to provide intermediate shown in following VIII-A or its stereoisomer or its alloisomerism Body mixture：
Wherein,
Wherein,
P2It is NH blocking groups, preferably tertbutyloxycarbonyl, benzyloxycarbonyl group, 4- methbxybenzyl-oxycarbonyls；
P3It is sulfydryl base blocking group, preferably trityl, 4- Methoxytrityls, 4,4 '-bi-methoxy triphen Methyl etc..
It is a further object of the present invention to provide the prodrug shown in following IX-A-B or its stereoisomer, stereoisomer is mixed Compound：
Wherein,
X is hydroxyl or halogen (F, Cl, Br)；
R1It is H or C1-C5Alkyl；
P1It is hydroxy-protective group, preferably trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, triphenyl Silicon substrate；
P2It is NH blocking groups, preferably tertbutyloxycarbonyl, benzyloxycarbonyl group, 4- methbxybenzyl-oxycarbonyls etc.；
P3It is thiol protecting group, preferably trityl, 4- Methoxytrityls, 4,4 '-bi-methoxy triphen first Base etc..
It is a further object of the present invention to provide intermediate shown in following VIII-B or its stereoisomer or its alloisomerism Body mixture：
Wherein,
R3、R4It is each independently hydrogen atom or C1-C5Alkyl；
P2It is amide NH blocking group, preferably tertbutyloxycarbonyl, benzyloxycarbonyl group, 4- methbxybenzyl-oxycarbonyls；
P3It is thiol protecting group, preferably trityl, 4- Methoxytrityls, 4,4 '-bi-methoxy triphen first Base.
It is a further object of the present invention to provide the prodrug shown in following IX-B-B or its stereoisomer, stereoisomer is mixed Compound：
Wherein,
X is hydroxyl or halogen (F, Cl, Br)；
R1It is H or C1-C5Alkyl；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl；
P1It is hydroxy-protective group, preferably trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, triphenyl Silicon substrate；
P2It is amide NH blocking group, preferably tertbutyloxycarbonyl, benzyloxycarbonyl group, 4- methbxybenzyl-oxycarbonyls；
P3It is thiol protecting group, preferably trityl, 4- Methoxytrityls, 4,4 '-bi-methoxy triphen first Base.
According to another aspect of the invention, the invention provides the compound shown in formula I or its dynamic isomer, solid Isomers, the purposes of stereoisomer mixture, prodrug, pharmaceutically acceptable salt or its solvate, it presses down as NS5B Preparation protects liver cell, liver organization simultaneously, improves the purposes of liver function, and preparing for treating virus hepatitis etc. Purposes in the medicine of disease.
In accordance with a further aspect of the present invention, present invention also offers the change shown in a kind of formula I comprising therapeutically effective amount Compound or its dynamic isomer, stereoisomer, stereoisomer mixture, prodrug, pharmaceutically acceptable salt or its solvent One or more in compound of pharmaceutical composition, it can optionally be included as NS5B inhibitor, and said composition Pharmaceutically acceptable carrier or excipient.
According to another aspect of the present invention, present invention also offers a kind of NS5B inhibitor, it contains the logical of therapeutically effective amount Compound or its dynamic isomer, stereoisomer shown in Formulas I, it is stereoisomer mixture, prodrug, pharmaceutically acceptable One or more in salt or its solvate, and the inhibitor can optionally include pharmaceutically acceptable carrier or figuration Agent.
Compound or its dynamic isomer, solid of the said composition as shown in one or more formula I of therapeutically effective amount Isomers, stereoisomer mixture, prodrug, pharmaceutically acceptable salt or its medicine solvate are pharmaceutically acceptable auxiliary with least one Material composition.The selection of pharmaceutic adjuvant is different because of route of administration and action character, typically filler, diluent, adhesive, wetting Agent, disintegrant, lubricant, emulsifying agent, suspending agent etc..Compound of formula I, its stereoisomer, stereoisomer mixture or its Ratio of the pharmaceutically acceptable solvate shared by the above-mentioned composition is the 0.1%~99.9% of gross weight, preferably 1%~99%.
The pharmaceutically acceptable carrier refers to the conventional pharmaceutical carrier of pharmaceutical field, for example：Diluent, such as water； Filler, such as starch, sucrose；Adhesive, such as cellulose derivative, alginates, gelatin, polyvinylpyrrolidone；Wetting agent, Such as glycerine；Disintegrant, such as agar, calcium carbonate and sodium acid carbonate；Sorbefacient, such as quaternary ammonium compound；Surfactant, such as ten Six alkanols；Absorption carrier, such as kaolin and soap clay；Lubricant, such as talcum powder, calcium stearate and magnesium stearate and poly- second two Alcohol etc..Furthermore it is also possible to add other assistant agents, such as flavouring agent and sweetener in described pharmaceutical composition.
Present invention also offers the compound shown in formula I or its dynamic isomer, stereoisomer, stereoisomer is mixed The preparation method of the pharmaceutically useful composition of compound, prodrug, pharmaceutically acceptable salt or its solvate.Generally by formula I The shown compound containing Tiopronin structure or its dynamic isomer, stereoisomer, it is stereoisomer mixture, preceding Medicine, pharmaceutically acceptable salt or its solvate and pharmaceutically acceptable auxiliaries are mixed, and are made through conventional preparation method and are suitable to one Determine the form (formulation) of approach administration.Formulation includes tablet, capsule, granule, pill, solution, supensoid agent, emulsion, soft Cream, film, creme, aerosol, injection, suppository etc..Preferred tablet and capsule.
The dosage of the compounds of this invention is generally daily 1~1000mg, divides single or multiple use.But in necessity When, can suitably deviate above-mentioned dosage.Professional can determine optimal dose as the case may be and professional knowledge.These situations The individual difference of the order of severity, patient, the characteristic of preparation and method of administration including disease etc..
Additionally, present invention also offers the compound shown in formula I or its dynamic isomer, stereoisomer, it is three-dimensional different Structure body mixture, prodrug, pharmaceutically acceptable salt or its solvate, or its pharmaceutically useful composition is used as human medicine Purposes.
According to another aspect of the invention, present invention also offers the method for the diseases such as treatment virus hepatitis, methods described Including compound or its dynamic isomer, stereoisomer shown in the formula I using therapeutically effective amount, stereoisomer mixing One or more in thing, prodrug, pharmaceutically acceptable salt or its solvate or described pharmaceutical composition of the invention To patient.
The present invention provide compound or composition can orally, inject (in vein, muscle, subcutaneous and coronary artery), Sublingual, buccal, per rectum, per urethra, Via vagina, intranasal, suction or topic route are applied.Preferred approach is oral.For When oral, conventional solid pharmaceutical preparation, such as tablet, pulvis, granula, capsule can be made into, or be made liquid preparation, such as water Or oil-suspending agent, or other liquid preparations, such as syrup；During for parenteral administration, can be made into the solution of injection, water or Oleaginous suspension etc..
Present invention also offers the compound shown in formula I or its dynamic isomer, stereoisomer, stereoisomer is mixed Compound, prodrug, pharmaceutically acceptable salt or its pharmaceutically acceptable solvate, are preparing people's medication of NS5B inhibitor Purposes in thing.
Present invention also offers the compound shown in formula I or its dynamic isomer, stereoisomer, stereoisomer is mixed Compound, prodrug, pharmaceutically acceptable salt or its solvate further with the drug combination of other treatment hepatopathy.It is at least one Selected from following treatment：Interferon, interferon beta, interferon gamma and interferon ω；Interleukin, including IL-10 and interleukin 12；Ribavirin；Interferon-' alpha ' or glycol interferon alpha are used in combination with Ribavirin or Levovirin；Left-handed Wei Woods；Protease inhibitors, including NS3 inhibitor, NS3/4A inhibitor；NS5A inhibitor；Helicase inhibitors；Polymerization enzyme level Agent, including HCV RNA polymerases and NS5B AG14361s；Gliotoxin；IRES inhibitor；ASON；Thiazole Alkane derivatives；N- benzanilides, ribozyme；Another nucleosides, nucleoside prodrugs or nucleoside derivates；1- amino-alkylcyclohexanes； Antioxidant, including vitamin E；Squalene；Amantadine；Bile acid；N- (phosphonoacetyl)-L-Aspartic acid；Benzene dicarboxyl Acid amides；Polyadenylic acid；Benzimidazole；Thymosin extrasin；Prevention vaccine；Immunomodulator, a kind of IMPDH inhibitor；Silymarin；Water Fly silibin-phosphatid ylcholine endosome；And Mycophenolate Mofetil.
" pharmaceutically acceptable " refers to such some compounds, raw material, composition and/or formulation, and they are cured rationally Learn judge in the range of, it is adaptable to patient tissue contacts and without excessive toxicity, excitant, allergy or with rational profit The symmetrical other problemses of benefit/Hazard ratio and complication, and effective for given application.
Term " halogen " and " halo " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I)。
Terminology used in the present invention " alkyl " or " alkyl group ", represent contain 1-20 carbon atom, the straight chain of saturation or Side chain univalent hydrocarbyl group, wherein, the alkyl group can optionally by the substitution base institute of one or more present invention descriptions Substitution.In one embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1-4 Individual carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group is included, but is not limited In methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), etc..
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of compound of the invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:Described in 1-19..The salt that pharmaceutically acceptable nontoxic acid is formed is included, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other method such as ion-exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, mesylate, 2- naphthalene sulfonates, nicotinic acid Salt, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, special penta Hydrochlorate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..By appropriate alkali The salt for obtaining includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any comprising N's The quaternary ammonium salt that the compound of group is formed.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Alkali Metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..It is appropriate, nontoxic that pharmaceutically acceptable salt is further included Ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid Compound, nitric acid compound, C1-C8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to the association that one or more solvent molecules are formed with compound of the invention Thing.The solvent for forming solvate is included, but is not limited to, water, isopropanol, ethanol, methyl alcohol, dimethyl sulfoxide, ethyl acetate, second Acid, monoethanolamine or its mixture.Term " hydrate " refers to that solvent molecule is associated matter that water is formed.
When the solvent is water, it is possible to use term " hydrate ".In one embodiment, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule Can be combined with more than one hydrone, such as dihydrate, in yet another embodiment, a compounds of this invention point Son can be combined with the hydrone less than, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non- The biological effectiveness of the compound of hydrated form.
Unless otherwise mentioned, all suitable isotope changes of compound of the invention, stereoisomer, tautomerism Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific is not indicated, then the structure All stereoisomers all consider within the present invention, and disclose compound and be included in the invention as the present invention.When Spatial chemistry is expressed when wedge shape line (solid wedge) or dotted line are indicated in fact of particular configuration, then the alloisomerism of the structure Body clearly and is defined with regard to this.
Compound shown in formula (I) can exist in a salt form.In one embodiment, the salt refers to that can pharmaceutically connect The salt received.Term " pharmaceutically acceptable " refer to material or composition must with other compositions comprising preparation and/or use it The mammal for the treatment of is compatible chemically and/or in toxicology.In another embodiment, the salt is not necessarily and pharmaceutically may be used The salt of receiving, can be for preparing and/or purifying compound shown in formula (I) and/or for separating compound shown in this formula (I) Enantiomer intermediate.
Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalescence or acidic moiety. In general, such salt can by make the free acid form of these compounds and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or by making the free alkali form of these compounds and chemistry The suitable acid reaction of metered amount is prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, it is necessary to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile in the case of appropriate. Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985)；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) in can find the list of the suitable salt of other.
Any structural formula that the present invention is given is also intended to expression these compounds not by the form of isotope enrichment and same The form of position element enrichment.The compound of isotope enrichment has the structure that the formula that the present invention is provided is described, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced into Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, the present invention relates to prepare the intermediate of compound shown in formula (I).
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention, further including pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or combinations thereof.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Type.
Such compound of the invention or its pharmaceutical composition can be used for the treatment of hepatitis C, with oral bioavailability The advantage that degree is high, metabolisming property is good, while the effect that there is protection hepatic tissue, liver cell, improve liver function.
Specific embodiment
It is the description present invention, is listed below embodiment.But it is to be understood that the invention is not restricted to these embodiments, simply The method of the present invention is put into practice in offer.
Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein substitution base definition such as formula (I) shown in.Following reaction scheme and embodiment are used to that this to be further illustrated The content of invention.
The professional of art will be recognized that：Chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds more of the invention, and be considered as in model of the invention for preparing other methods of compound of the invention Within enclosing.For example, the synthesis of the compound according to those non-illustrations of the invention can successfully by those skilled in the art Completed by method of modifying, such as appropriate protection interference group, by using other known reagents except described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all of temperature is set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company andAlfa Chemical Company, all not by being further purified when using, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Teng Long chemical reagent Co., Ltd, and Haiyang Chemical Plant, Qingdao's purchase Can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether is dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMA and N, N- Dimethylformamide is that drying is used in advance through anhydrous sodium sulfate.
Below reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb all suitable rubber stoppers beyond the Great Wall, substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1HNMR spectrums are recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.1H H NMR spectroscopies are with CDC13、DMSO- d6、CD3OD or acetone-d6It is solvent (in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) as reference standard.When When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), t (triplet, Triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, it is double double Peak), dt (doublet of triplets, double triplets).Coupling constant, is represented with hertz (Hz).
The condition determination of Algorithm (MS) data is：Level Four bar HPLC-M (the pillar models of Agilent 6120： Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Mobile phase：5%-95% (contains 0.1% The CH of formic acid3CN) in (H containing 0.1% formic acid2O the ratio in), using electron spray ionisation (ESI), under 210nm/254nm, Detected with UV.
Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar types Number：NOVASEP 50/80mm DAC), detected with UV in 210nm/254nm.
The use of brief word below is through the present invention：
CH2Cl2, DCM dichloromethane
CDC13Deuterochloroform
DMF N,N-dimethylformamides
DIPEA N, N- diisopropylethylamine
DMSO dimethyl sulfoxide (DMSO)s
MeOH methyl alcohol
MeCN、CH3CN acetonitriles
HCl hydrogen chloride
KI KIs
T-BuOK potassium tert-butoxides
NaHCO3Sodium acid carbonate
Na2S2O3Sodium thiosulfate
Na2SO4Sodium sulphate
The palladium carbons of Pd/C 10%
G grams
H hours
ML, ml milliliter
PE petroleum ethers (60-90 DEG C)
RT, rt, r.t. room temperature
Rt retention times
TFA trifluoroacetic acids
Embodiment 1：The synthesis of compound II-A-1
Method A：
Step one：529mg (1.0mmol) III-1 is dissolved in 10mL anhydrous propanones, 680mg is added at room temperature (1.5mmol) IV-A-1 and potassium carbonate 414mg (3.0mmol), heating stirring backflow 6h, TLC detection reaction is complete.Filtering, filter Liquid is diluted with dichloromethane (30mL), is washed with water (10mL) and saturated aqueous common salt (10mL) successively, separates organic phase, anhydrous sulphur Sour sodium is filtered after drying, and is concentrated under reduced pressure and is removed solvent.Residue silica gel column chromatography purifies to obtain 710mg white solid V-A-1, yield 75%, ESI-MS:m/z[M+H]+=947.
Step 2：200mg (0.21mmol) V-A-1 is dissolved in 10mL anhydrous methylene chlorides, 2mL (bodies are added at room temperature Product ratio：The solution of dichloromethane/tri isopropyl silane/trifluoroacetic acid=5/1/1), reacts about 1h, and TLC detection reactions are complete, carefully Saturated sodium bicarbonate solution is added, organic phase saturated common salt water washing is separated, anhydrous sodium sulfate drying depressurizes dense after filtering Contracting.The purifying of residue silica gel column chromatography obtains 96mg white solid II-A-1, yield 65%.1H NMR(400MHz,DMSO-d6)δ 8.43 (t, J=5.7Hz, 1H), 7.68 (d, J=7.2Hz, 1H), 7.39 (t, J=7.7Hz, 2H), 7.30-7.14 (m, 3H), 6.14-5.96 (m, 2H), 5.90 (d, J=4.9Hz, 1H), 5.84 (d, J=9.6Hz, 1H), 5.81 (d, J=9.6Hz, 1H), 5.74 (d, J=8.2Hz, 1H), 4.87 (dt, J=12.4,6.2Hz, 1H), 4.47-4.34 (m, 1H), 4.29-4.20 (m, 1H), 4.08-4.01 (m, 1H), 3.94-3.76 (m, 4H), 3.57-3.46 (m, 1H), 2.82 (d, J=8.3Hz, 1H), 1.35 (d, J=6.9Hz, 3H), 1.27 (t, J=15.0Hz, 6H), 1.16 (d, J=6.2Hz, 6H)13C NMR(100MHz,DMSO- d6)δ173.7,173.1,173.0,169.2,161.1,151.2,151.1,150.6,130.1,125.1,120.6,120.5, 101.9,101.6,99.8,80.2,72.1,71.9,68.5,65.1,64.9,50.3,41.0,36.3,22.4,22.3,21.9, 21.8,20.3,20.2,17.2,16.9.31P NMR(162MHz,DMSO)δ3.83(s)ESI-MS:m/z[M+H]+=705.
Method B:
Step one：5.0g (9.5mmol) compounds III-1 is dissolved in the anhydrous DMFs of 25mL (DMF), Sequentially add 1.6g (23.5mmol) imidazoles under Ar protections, 0.12g (1.0mmol) DMAP (DMAP) and 1.6mL (9.5mmol) chlorotriethyl silane (TESCl).Reaction about 10 hours is stirred at room temperature, TLC detection reactions are complete.So Afterwards toward 7mL 37%HCHO solution is added in reaction system, 80 degree of stirring reactions are heated to 1 hour.Room temperature is cooled to, is added 80mL ethyl acetate, successively with water, saturated common salt water washing, separates organic phase anhydrous sodium sulfate drying, is depressurized after filtering dense Contracting, obtains colorless oil VII-1, not purified to be directly used in next step.
Step 2：The product VII -1 of the fresh gained of previous step is dissolved in 40mL anhydrous methylene chlorides (DCM), in argon gas The lower ice bath cooling of protection, sequentially adds 62mg (0.5mmol) DMAP (DMAP) and 2.36g (12.3mmol) 1- second Base-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (EDC HCl), and 6.1g (11.4mmol) compounds VIII-A- 1, simultaneously stirring reaction about 12 hours are slowly warmed to room temperature, TLC detection reactions are complete.100mL dichloromethane is added, saturation is used successively Sodium bicarbonate aqueous solution, saturated common salt water washing, separate organic phase anhydrous sodium sulfate drying, are concentrated under reduced pressure after filtering.It is thick to produce Thing dichloromethane-normal heptane recrystallizes to obtain 8.5g white solid product IX-A-1, yield 70% (two steps).1H NMR (400MHz,CDCl3) δ 7.57 (d, J=8.1Hz, 1H), 7.35 (dd, J=17.2,7.6Hz, 6H), 7.31-7.12 (m, 12H), 6.77 (d, J=8.5Hz, 2H), 6.17 (d, J=18.4Hz, 1H), 6.04-5.87 (m, 2H), 5.68 (d, J= 8.2Hz, 1H), 5.00 (dt, J=12.3,6.2Hz, 1H), 4.60 (dd, J=11.4,6.4Hz, 1H), 4.35 (q, J= 6.9Hz,1H),4.29–4.20(m,2H),4.15–4.08(m,1H),4.02–3.85(m,3H),3.78(s,3H),3.71(t,J =10.0Hz, 1H), 1.39-1.32 (m, 6H), 1.35 (s, 9H), 1.27 (d, J=11.9Hz, 3H), 1.23 (d, J=6.2Hz, 6H),0.92(s,9H),0.15(s,6H).ESI-MS:m/z[M+H]+=1191.
Step 3：7.5g (6.3mmol) compounds IX-A-1 is dissolved in 50% boiling (20mL) mixed solution, plus Enter 30mL glacial acetic acid (HOAc) and 6mL trifluoroacetic acids (TFA), stirring reaction about 6 hours, residue is can't detect to TLC at room temperature Raw material.Vacuum rotary steam removes acetone, water, then sequentially adds 60mL dichloromethane, and 9ml trifluoroacetic acids (TFA), 6.5mL tri- is different Propyl silane (i-Pr3SiH), continue to react about 15 minutes at room temperature, TLC detection reactions are complete, are carefully added into unsaturated carbonate hydrogen Sodium water solution extracts reaction of going out.100mL dichloromethane is added, successively with water, saturated common salt water washing, the anhydrous sulphur of organic phase is separated Sour sodium is dried, and be concentrated under reduced pressure to obtain crude product after filtering.3.9g white solid II-A-1 are recrystallized to obtain with ethyl acetate-light petrol, Yield 88%.1H NMR (400MHz, DMSO) δ 8.43 (t, J=5.7Hz, 1H), 7.68 (d, J=7.2Hz, 1H), 7.39 (t, J =7.7Hz, 2H), 7.30-7.14 (m, 3H), 6.14-5.96 (m, 2H), 5.90 (d, J=4.9Hz, 1H), 5.84 (d, J= 9.6Hz, 1H), 5.81 (d, J=9.6Hz, 1H), 5.74 (d, J=8.2Hz, 1H), 4.87 (dt, J=12.4,6.2Hz, 1H), 4.47–4.34(m,1H),4.29–4.20(m,1H),4.08–4.01(m,1H),3.94–3.76(m,4H),3.57–3.46(m, 1H), 2.82 (d, J=8.3Hz, 1H), 1.35 (d, J=6.9Hz, 3H), 1.27 (t, J=15.0Hz, 6H), 1.16 (d, J= 6.2Hz,6H).ESI-MS:m/z[M+H]+=705.
Embodiment 2：The synthesis of compound II-A-1a
According to the fresh prepared compound VII-1 of method step B one in embodiment 1, (3mmol compounds III-1 is former for starting Material), it is dissolved in 12mL anhydrous methylene chlorides (DCM), ice bath cooling, sequentially adds 18mg (0.15mmol) 4- under argon gas protection Dimethylamino naphthyridine (DMAP) and 0.75g (3.9mmol) 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate , and 1.93g (3.6mmol) compounds VIII-A-1a (is prepared, S configuration chiral purities by chiral Tiopronin (EDCHCl) 97%, analysis method：AD-H column temperatures：25C；Detection wavelength：210nm；Flow velocity：1.0ml/min；Mobile phase：n-Hex:EtOH: TFA=90:10:0.1 isocratic elution), simultaneously stirring reaction about 12 hours are then slowly warmed to room temperature, TLC detection reactions are complete.Plus Enter 30mL dichloromethane, successively with saturated sodium bicarbonate aqueous solution, saturated common salt water washing, separate organic phase anhydrous sodium sulfate Dry, be concentrated under reduced pressure after filtering.Crude product dichloromethane-normal heptane recrystallizes to obtain 2.57g white solid product IX-A-1a, Yield 72%.
2.1g (1.76mmol) compounds IX-A-1a is dissolved in 50% boiling (5mL) mixed solution, 8mL ice is added Acetic acid (HOAc) and 2mL trifluoroacetic acids (TFA), stirring reaction about 6 hours, surplus stock is can't detect to TLC at room temperature.Decompression Revolving removes acetone, water, then sequentially adds 15mL dichloromethane, 3ml trifluoroacetic acids (TFA), 2.2mL tri isopropyl silanes (i-Pr3SiH), continue to react about 15 minutes at room temperature, TLC detection reactions are complete, are carefully added into saturated sodium bicarbonate water molten Liquid extracts reaction of going out.30mL dichloromethane is added, successively with water, saturated common salt water washing, organic phase anhydrous sodium sulfate is separated dry Dry, be concentrated under reduced pressure to obtain crude product after filtering.1.04g white solid II-A-1a, yield are recrystallized to obtain with ethyl acetate-light petrol 84%.ESI-MS:m/z[M+H]+=705.
Embodiment 3：The synthesis of compound II-A-1b
According to the step one of embodiment 2, step 2, (prepared by chiral Tiopronin, R configurations are chiral with VIII-A-1b Purity 95%, analysis method：AD-H column temperatures：25C；Detection wavelength：210nm；Flow velocity：1.0ml/min；Mobile phase：n-Hex: EtOH:TFA=90:10:0.1 isocratic elution) replace VIII-A-1a, can be prepared into 5.3g (10mmol) compounds III-1 8.7g intermediate compound I X-A-1b, yield 73% (two steps).
According to the step 3 of embodiment 2, compound IX-A-1b (2.9mmol) continues to slough protection group, can be prepared into 1.7g white Color solid product II-A-1b, yield 86%.ESI-MS:m/z[M+H]+=705.
Embodiment 4：The synthesis of compound II-A-2
Method A：
Step one：529mg (1.0mmol) III-1 is dissolved in 10mL anhydrous propanones, 680mg is added at room temperature (1.5mmol) IV-A-2 and potassium carbonate 414mg (3.0mmol), heating stirring backflow 6h, TLC detection reaction is complete.Filtering, filter Liquid is diluted with dichloromethane (30mL), is washed with water (10mL) and saturated aqueous common salt (10mL) successively, separates organic phase, anhydrous sulphur Sour sodium is filtered after drying, and is concentrated under reduced pressure and is removed solvent.Residue silica gel column chromatography purifies to obtain 306mg white solids V-A-2.ESI- MS:m/z[M+H]+=961.
Step 2：200mg (0.21mmol) V-A-2 is dissolved in 10mL anhydrous methylene chlorides, 2mL (bodies are added at room temperature Product ratio：The solution of dichloromethane/tri isopropyl silane/trifluoroacetic acid=5/1/1), reacts about 1h, and TLC detection reactions are complete, carefully Saturated sodium bicarbonate solution is added, organic phase saturated common salt water washing is separated, anhydrous sodium sulfate drying depressurizes dense after filtering Contracting.The purifying of residue silica gel column chromatography obtains 100mg white solid II-A-2, yield 67%.1HNMR(400MHz,CDCl3)δ 9.64 (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) .ESI- MS:m/z[M+H]+=719.
Method B：
According to the method step B one, step 2 of embodiment 1, formaldehyde is replaced with acetaldehyde, with 5.3g (10mmol) compounds III- 1 can be prepared into 4.6g intermediate compound I X-A-2, yield 38% (two steps).ESI-MS:m/z[M+H]+=1205.
According to the method step B three of embodiment 1, compound IX-A-2 (2.9mmol) continues to slough protection group, can be prepared into 1.7g white solid product II-A-2, yield 82%.ESI-MS:m/z[M+H]+=719.
Embodiment 5：The synthesis of compound II-A-3
According to the method step B one, step 2 of embodiment 1, formaldehyde is replaced with propionic aldehyde, with 2.65g (5mmol) compounds III- 1 can be prepared into 2g intermediate compound I X-A-3, yield 33% (two steps).ESI-MS:m/z[M+H]+=1219.
According to the method step B three of embodiment 1, compound IX-A-3 (0.8mmol) continues to slough protection group, can be prepared into 445mg white solid product II-A-3, yield 76%.ESI-MS:m/z[M+H]+=733.
Embodiment 6：The synthesis of compound II-A-4
Step one：529mg (1.0mmol) III-1 is dissolved in 10mL anhydrous propanones, 690mgIV-A-3 is added at room temperature And potassium carbonate 414mg (3.0mmol), heating stirring backflow 6h, TLC detection reaction is completely.Filtering, filtrate dichloromethane (30mL) dilutes, and is washed with water (10mL) and saturated aqueous common salt (10mL) successively, separates organic phase, mistake after anhydrous sodium sulfate drying Filter, is concentrated under reduced pressure and removes solvent.Residue silica gel column chromatography purifies to obtain 300mgV-A-4, is directly used in next step reaction.
Step 2：200mg (0.21mmol) V-A-4 is dissolved in 10mL anhydrous methylene chlorides, 2mL (bodies are added at room temperature Product ratio：The solution of dichloromethane/tri isopropyl silane/trifluoroacetic acid=5/1/1), reacts about 1h, and TLC detection reactions are complete, carefully Saturated sodium bicarbonate solution is added, organic phase saturated common salt water washing is separated, anhydrous sodium sulfate drying depressurizes dense after filtering Contracting.The purifying of residue silica gel column chromatography obtains 100mg white solids II-A-4.1HNMR(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), (d, J=6.3Hz, the 6H) .ESI-MS of 1.38 (dd, J=14.8,7.7Hz, 6H), 1.27 (s, 1H), 1.24:749(M+1).
Embodiment 7：The synthesis of compound II-A-5
Step one：529mg (1.0mmol) III-1 is dissolved in 10mL anhydrous propanones, 800mgIV-A-4 is added at room temperature And potassium carbonate 414mg (3.0mmol), heating stirring backflow 12h, TLC detection reaction is completely.Filtering, filtrate dichloromethane (30mL) dilutes, and is washed with water (10mL) and saturated aqueous common salt (10mL) successively, separates organic phase, mistake after anhydrous sodium sulfate drying Filter, is concentrated under reduced pressure and removes solvent.Residue silica gel column chromatography purifies to obtain 400mgV-A-5, is directly used in next step reaction.
Step 2：200mg (0.21mmol) V-A-5 is dissolved in 10mL anhydrous methylene chlorides, 2mL (bodies are added at room temperature Product ratio：The solution of dichloromethane/tri isopropyl silane/trifluoroacetic acid=5/1/1), reacts about 1h, and TLC detection reactions are complete, carefully Saturated sodium bicarbonate solution is added, organic phase saturated common salt water washing is separated, anhydrous sodium sulfate drying depressurizes dense after filtering Contracting.The purifying of residue silica gel column chromatography obtains 100mg white solids II-A-5.1HNMR(400MHz,CDCl3)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), (d, J=6.5Hz, the 6H) .ESI-MS of 1.39 (dd, J=14.7,7.6Hz, 6H), 1.28 (s, 1H), 1.25:m/z[M+H]+= 719.
Embodiment 8：The synthesis of compound II-A-7
According to the method step B one, step 2 of embodiment 1, III-1 is only replaced with III-2, changed with 1.1g (2mmol) Compound III-2 can be prepared into colorless oil IX-A-7, yield 71% (two steps).ESI-MS:m/z[M+H]+=1221.
According to the method step B three of embodiment 1,0.79g compounds IX-A-7 (0.65mmol) continue to slough protection group, can make It is standby to obtain white solid product II-A-7, yield 83%.ESI-MS:m/z[M+H]+=721.
Embodiment 9：The synthesis of compound II-A-8
According to the method step B one of embodiment 1, step 2 replaces VIII-A-1 with VIII-A-2, so as to 1.6g (3mmol) compound III-1 can be prepared into 1.29g intermediate compound I X-A-8, yield 65% (two steps).ESI-MS:m/z[M+H]+= 1219.
According to the method step B three of embodiment 1, compound IX-A-8 (0.8mmol) continues to slough protection group, can be prepared into 0.5g white solid product II-A-8, yield 83%.ESI-MS:m/z[M+H]+=733.
Embodiment 10：The synthesis of compound II-B-1
According to the method B of embodiment 1, with VIII-B-1 (being prepared by (DL)-N-acetylcystein) generations in step 2 For VIII-1,3.38g intermediate compound I X-B-1, yield 71% (two steps) can be prepared into 2.1g (4mmol) compounds III-1. ESI-MS:m/z[M+H]+=1191.
According to the method step B three of embodiment 1, compound IX-B-1 (2mmol) continues to slough protection group, can be prepared into 1.17g white solid product II-B-1, yield 83%.ESI-MS:m/z[M+H]+=705.
Embodiment 11：The synthesis of compound II-B-1a
According to the method B of embodiment 1, (prepared by L- acetylcysteines, chiral purity with VIII-B-1a in step 2 Degree>99%) replace VIII-1, intermediate compound I X-B-1a, yield 67% (two can be prepared into 2.65g (5mmol) compounds III-1 Step).ESI-MS:m/z[M+H]+=1191.
According to the method step B three of embodiment 1, compound IX-B-1a (2.1mmol) continues to slough protection group, can be prepared into 1.2g white solid product II-B-1a, yield 85%.ESI-MS:m/z[M+H]+=705.
Embodiment 12：The synthesis of compound II-B-1b
According to the method B of embodiment 1, (prepared by D-Cys, chiral purity with VIII-B-1b in step 2 95%) replace VIII-1,4.2g intermediate compound I X-B-1b, yield 70% can be prepared into 2.65g (5mmol) compounds III-1 (two steps).ESI-MS:m/z[M+H]+=1191.
According to the method step B three of embodiment 1, compound IX-B-1b (2.1mmol) continues to slough protection group, can be prepared into 1.2g white solid product II-B-1b, yield 81%.ESI-MS:m/z[M+H]+=705.
Embodiment 13：The synthesis of compound II-B-2
According to the method step B one of embodiment 1, formaldehyde is replaced with acetaldehyde, according to the method step B two of embodiment 1, with VIII- B-1a (is prepared, chiral purity by L- acetylcysteines>99%) VIII-1 is replaced, so as to 1.6g (3mmol) chemical combination Thing III-1 can be prepared into 1.3g intermediate compound I X-B-2, yield 36% (two steps).ESI-MS:m/z[M+H]+=1205.
According to the method step B three of embodiment 1, compound IX-B-2 (1mmol) continues to slough protection group, can be prepared into 0.57g white solid product II-B-2, yield 79%.ESI-MS:m/z[M+H]+=719.
Embodiment 14：The synthesis of compound II-B-3
According to the method step B one of embodiment 1, step 2 (is prepared, hand with VIII-B-2 by L- acetylcysteines Property purity>99%) VIII-1 is replaced, so as to intermediate compound I X-B-3, yield can be prepared into 1.6g (3mmol) compounds III-1 76% (two steps).ESI-MS:m/z[M+H]+=1205.
According to the method step B three of embodiment 1, compound IX-B-3 (1mmol) continues to slough protection group, can be prepared into 0.57g white solid product II-B-3, yield 82%.ESI-MS:m/z[M+H]+=719.
Embodiment 15：The synthesis of compound II-B-4
According to the step one of embodiment 1, step 2 replaces III-1 with III-2, and with VIII-B-1a (by the Guang of L- acetyl half Propylhomoserin is prepared, chiral purity>99%) replace VIII-1, can be prepared into 2.64g with 1.6g (3mmol) compounds III-2 Mesosome IX-B-4, yield 72% (two steps).ESI-MS:m/z[M+H]+=1207.
According to the step 3 of embodiment 6, compound IX-B-4 (1.5mmol) continues to slough protection group, can be prepared into 0.93g white Color solid product II-B-4, yield 84%.ESI-MS:m/z[M+H]+=721.
Embodiment 16:Anti- hepatitis C virus activity (HCV, EC50) and cytotoxicity (CC50)
Due to lacking preferable HCV Infection in Vitro cell and animal model, generally, HCV virus activity rating meeting The enzyme played a crucial role in being replicated using HCVRNA sets up extracellular molecule reconstructed model.
Experimental technique：
In containing 10% hyclone, 1X nonessential amino acid, the DMEM culture mediums of Pen-Strep-Glu, G418, training Support the Huh7 cells of replicon containing HCV- (1b genotype).Antiviral screening test is entered in the different culture media without G418 OK.Cell is inoculated in 96 orifice plates, adds the compound of experiment, and 37 DEG C of incubations in incubator after inoculating cell immediately.Then Culture medium is removed, cell is used for full nucleic acid extraction (including replicon rna and host RNA).Can amplify in Q-RT-PCR schemes Replicon rna, and it is accordingly quantitative.Observed replicon HCV RNA and the level difference of untreated control group are used as experiment The mode of compound antiviral efficacy, it the results are shown in Table 1.
Anti- hepatitis C virus activity (HCV, the EC of the compound of table 150) and cytotoxicity (CC50) result
Inhibitory activity (the EC of HCV replicons 1b in compound on intracellular50) result lived as its anti-hepatitis C virus is evaluated Property, and cytotoxic activity (CC simultaneously50) synchronism detection be used to exclude the false positive results caused due to cytotoxicity.Treatment refers to Number is higher, and representation compound has got over application prospect.Result shows that the compound that the present invention is provided shows and Sofosbuvir phases Like or more excellent activity and therapeutic index, by taking II-A-2 as an example, its inhibitory activity (EC50) to intracellular HCV replicon is bright It is aobvious to be better than than positive control Sofosbuvir, show that the compound can be in cell as Sofosbuvir in liver cell Interior fast degradation turns into the effect of the form performance HCV-Ab IgG of active metabolite, additionally, another one's share of expenses for a joint undertaking for obtaining of being degraded in molecule Tiopronin has certain gain effect for antiviral activity, and this cooperative effect makes the compound of present invention offer, HCV-Ab IgG disease aspect has more application prospect.
Embodiment 17:Mouse CCl4 livers damage the protective effect research of model
Experimental technique：Before taking the male mice experiment of 24~28g of body weight, fasting can't help water 6 hours, is randomly divided into by body weight 3 groups, every group of 5 mouse set up blank control group, CCL separately4Group, compound group (Tiopronin 50mg/kg, test compound 200mg/kg).Every 12h gastric infusions 1 time, each gavage capacity is 10mL/kg, is administered 4 times altogether.Blank control group and model Control group such as gavages at the physiological saline of capacity simultaneously.The 1h after third time is administered, in addition to blank control group mouse, other two groups small Mouse presses the CCl of 2mg/kg b.w4Intraperitoneal injection 50%CCl4Corn oil.In after 12 hours, each group is administered once again.It is small in 24 Shi Hou, each mouse takes blood, determines Serum ALT and AST (table 2), takes liver and cuts fritter, and after formaldehyde is fixed, paraffin section uses haematine And eosin stains, basis of microscopic observation liver cell situation.
The CCl4 livers of the compounds of this invention of table 2 damage the protective effect result of study of model
Group ALT(U/L) AST(U/L)
Blank 58.2 125.4
1423.2 1214.3
Sofosbuvir 1325.7 1185.2
Tiopronin 689.3 733.8
II-A-1 617.5 690.2
II-A-2 560.7 656.3
II-A-4 701.5 677.8
II-A-5 596.2 702.3
II-B-1 725.6 833.1
Result shows, CCl4The ALT and AST of model group mouse are raised extremely, and Tiopronin can significantly reverse this liter of enzyme Effect, under relatively, the Sofosbuvir then activity without this respect.And the compound that the present invention is provided has obvious drop enzyme Effect, activity is suitable with Tiopronin or more excellent.Trace it to its cause, it may be possible to because the carboxyl of Tiopronin is made into prodrug Afterwards, its stability and the ability by oral absorption can be improve, so that its activity is strengthened.By taking II-A-2 as an example, its Cause ALT and AST risings to act on to CCl4 induced liver injuries, there is obvious inhibitory activity, and better than positive control Tiopronin. Additionally, liver organization pathology section examination result is, CCl4Model group, central veins of liver extravasated blood, around have centrilobular or Peripheral necrosis, liver cell has swelling, balloon sample to deform, and II-A-2 administration groups are presented a small amount of point-like and piecemeal necrosis, big portion Divide and the deformation of balloon sample is presented, show by CCl4The toxicity for causing has greatly reduced, and illustrates that II-A-2 has protection CCl really4Cause Liver harm is used.
Due to lacking preferable HCV infection animal model, the compound for directly evaluating present invention offer causes liver to damage HCV The protective effect of wound is infeasible, but in theory and for the angle of clinical practice, the liver protection shield of the compound that the present invention is provided The effect of liver equally has protective effect for the inflammatory reaction that HCV causes.
Embodiment 18:Pharmacokinetic property is studied
Experimental technique:
With SD rats as experimental animal (body weight 180-220g), 6 SD rats of each test compound are randomly divided into 2 groups (gavage group and intravenous group), every group 3.The tail vein of gastric infusion takes blood time point for 0.17,0.33,0.5,1,1.5,2,4, 6,8,12,24 hours；Intravenously administrable took blood time point for 0.05,0.1,0.17,0.5,1,2,4,6,8,12,24 hours.Take complete Blood 0.3ml, is taken blood plasma 0.1ml and is analyzed using LC-MS after centrifugation.
Main pharmacokinetic parameters collect after the administration of the SD Oral Administration in Rats of table 3
With Suo Feibuwei references, the medicine generation of compound II-A-1, II-A-2 and II-B-1 in rat body has been investigated respectively Kinetic property, as a result shows, the oral administration biaavailability of compound II-A-1, II-A-2 and II-B-1 has clear improvement, with Suo Feibuwei is compared, and is respectively its 3.38,2.75,2.25 times.In addition, its half-life period of II-A-1 and II-A-2 respectively reach 6.14 and 6.23 hours, respectively the 2.95 and 2.51 of Suo Feibuwei times, its Drug-time curve more relaxed.Therefore, II-A-1, II-A-2 and II-B-1 are with the obvious advantage on pharmacokinetics, and the treatment of hepatitis disease can be administered for by oral absorption.
The foregoing is only presently preferred embodiments of the present invention, be not intended to limit the invention, it is all it is of the invention spirit and Any modification, equivalent and improvement for being made within principle etc., are all contained within protection scope of the present invention.

Claims (25)

1. a kind of compound, it has a structure shown in Formulas I, or structural compounds shown in Formulas I dynamic isomer, optical siomerism Body, stereoisomer, stereoisomer mixture, prodrug, pharmaceutically acceptable salt or solvate：
Wherein, X is hydroxyl or F, Cl, Br；
R is
Linker isOr do not exist, A is to have listed For treat or auxiliary treatment hepatopathy medicine or derivatives thereof；
R1It is H or C1-C5Alkyl；
N is the integer of 1-19.
2. compound according to claim 1, it has the structure or its dynamic isomer, optical siomerism shown in Formula II-A Body, stereoisomer, stereoisomer mixture, prodrug, pharmaceutically acceptable salt or solvate：
Wherein, X is hydroxyl or F, Cl, Br；
Linker isOr do not exist；
R1It is H or C1-C5Alkyl；
N is 1,2,3,4 or 5；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl.
3. compound according to claim 2, it has the structure or its mutual variation shown in Formula II-Aa or Formula II-Ab Structure body, optical isomer, stereoisomer, stereoisomer mixture, prodrug, pharmaceutically acceptable salt or solvate：
Wherein, X is hydroxyl or F, Cl, Br；
Linker isOr do not exist；
R1It is H or C1-C5Alkyl；
N is 1,2,3,4 or 5；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl.
4. compound according to claim 1, it has the structure or its dynamic isomer, optical siomerism shown in Formula II-B Body, stereoisomer, stereoisomer mixture, prodrug, pharmaceutically acceptable salt or solvate：
Wherein, X is hydroxyl or F, Cl, Br；
Linker isOr do not exist；
R1It is H or C1-C5Alkyl；
N is 1,2,3,4 or 5；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl.
5. compound according to claim 4, it has the structure or its optical siomerism shown in Formula II-Ba or Formula II-Bb Body, pharmaceutically acceptable salt or solvate：
Wherein, X is hydroxyl or F, Cl, Br；
Linker isOr do not exist；
R1It is H or C1-C5Alkyl；
N is 1,2,3,4 or 5；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl.
6. compound according to claim 1, it is the prodrug containing Tiopronin structure shown in Formula II-A-A or it is vertical Body isomers, stereoisomer mixture or its pharmaceutically acceptable solvate：
Wherein,
X be hydroxyl or F, Cl, Br,
Linker is
R1It is H or C1-C5Alkyl,
N is the integer of 1-19.
7. compound according to claim 6, it is that the prodrug containing Tiopronin structure as shown below or its solid are different Structure body, stereoisomer mixture or its pharmaceutically acceptable solvate：
Wherein,
X is hydroxyl or F, Cl, Br；
R1It is H or C1-C5Alkyl,
N is 1,2,3,4 or 5.
8. compound according to claim 7, it is the prodrug containing Tiopronin structure or its change as shown below Isomers, stereoisomer, stereoisomer mixture or its pharmaceutically acceptable solvate：
Wherein,
R1It is H or C1-C5Alkyl,
N is 1,2,3,4 or 5.
9. compound according to claim 1, it has the mutual of structure as shown below or structural compounds as shown below Tautomeric, stereoisomer, stereoisomer mixture, pharmaceutically acceptable salt or solvate：
10. the preparation method of the compound shown in a kind of Formula II-A, step is：
1) formula III compound obtains Formula V-A compounds with the reaction of formula IV-A compounds,
2) Formula V-A compounds obtain Formula II-A compounds by deprotection reaction；
Wherein, X is hydroxyl or F, Cl, Br；
Linker isOr do not exist；
N is 1,2,3,4 or 5；
R1It is H or C1-C5Alkyl；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl；
LG is leaving group, preferably halogen；
Z is thiol protecting group, preferably trityl, 4- Methoxytrityls, 4,4 '-dual-methoxy trityl.
The preparation method of the compound shown in a kind of 11. Formula II-B, step is：
1) formula III compound obtains Formula V-B compounds with the reaction of formula IV-B compounds；
2) Formula V-B compounds obtain Formula II-B compounds through deprotection reaction；
Wherein, X hydroxyls or F, Cl, Br；
Linker isOr do not exist；
N is 1,2,3,4 or 5；
R1It is H or C1-C5Alkyl；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl；
LG is leaving group, preferably halogen；
Z is thiol protecting group, preferably trityl, 4- Methoxytrityls, 4,4 '-dual-methoxy trityl.
The preparation method of the compound shown in a kind of 12. formula II-A-Aa, can be by compound of formula III and formula IV chemical combination Thing obtains formula V-A compounds by alkylation reaction, is then obtained by deprotection reaction.
Wherein, X be F, Cl or Br,
R1It is H or C1-C5Alkyl；
Y is leaving group,
Z is thiol protecting group.
The preparation method of the compound shown in a kind of 13. Formula II-A-Ab, can be by compound of formula III and formula IV-B chemical combination Thing obtains formula V-B compounds by alkylation reaction, is then obtained by deprotection reaction：
Wherein, X is hydroxyl or F, Cl, Br；
R1It is H or C1-C5Alkyl；
N is the integer of 1-19；
Y is leaving group；
Z is thiol protecting group.
A kind of 14. preparation methods of Formula II-A-B compounds, step is：
1) formula III compound is reacted through overprotection, and Formula VII compound is then obtained with aldehyde reaction；
2) Formula VII compound reacts with VIII-A compounds and obtains Formula IX-A-B compounds；
3) Formula IX-A-B compounds slough protection group and obtain Formula II-A-B compounds；
Wherein, X is hydroxyl or F, Cl, Br；
R1It is H or C1-C5Alkyl；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl；
P1It is hydroxy-protective group, preferably trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, triphenyl silicon substrate；
P2It is amide NH blocking group, preferably tertbutyloxycarbonyl, benzyloxycarbonyl group, 4- methbxybenzyl-oxycarbonyls；
P3It is thiol protecting group, preferably trityl, 4- Methoxytrityls, 4,4 '-dual-methoxy trityl.
A kind of 15. preparation methods of Formula II-B-B compounds, step is：
1) Formula VII compound reacts with VIII-B compounds and obtains Formula IX-B-B compounds；
2) Formula IX-B-B compounds slough protection group and obtain Formula II-B-B compounds；
Wherein, X is hydroxyl or F, Cl, Br；
R1It is H or C1-C5Alkyl；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl；
P1It is hydroxy-protective group, preferably trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, triphenyl silicon substrate；
P2It is amide NH blocking group, preferably tertbutyloxycarbonyl, benzyloxycarbonyl group, 4- methbxybenzyl-oxycarbonyls；
P3It is thiol protecting group, preferably trityl, 4- Methoxytrityls, 4,4 '-dual-methoxy trityl.
A kind of 16. compounds, it has Formula VII structure or its stereoisomer, stereoisomer mixture or salt：
Wherein,
X is hydroxyl or F, Cl, Br；
R1It is H or C1-C5Alkyl；
P1It is hydroxy-protective group, preferably trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, triphenyl silicon substrate.
A kind of 17. compounds, its have structure or its stereoisomer shown in Formula VIII-A, stereoisomer mixture or Salt：
Wherein,
P2It is NH blocking groups, preferably tertbutyloxycarbonyl, benzyloxycarbonyl group, 4- methbxybenzyl-oxycarbonyls；
P3It is sulfydryl base blocking group, preferably trityl, 4- Methoxytrityls, 4,4 '-dual-methoxy trityl Deng.
A kind of 18. compounds, its have structure or its stereoisomer shown in Formula IX-A-B, stereoisomer mixture or Salt：
Wherein X is hydroxyl or F, Cl, Br；
R1It is H or C1-C5Alkyl；
P1It is hydroxy-protective group, preferably trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, triphenyl silicon substrate；
P2It is NH blocking groups, preferably tertbutyloxycarbonyl, benzyloxycarbonyl group, 4- methbxybenzyl-oxycarbonyls；
P3It is thiol protecting group, preferably trityl, 4- Methoxytrityls, 4,4 '-dual-methoxy trityl.
A kind of 19. compounds, its have structure shown in Formula VIII-B or its stereoisomer, its stereoisomer mixture or Salt：
Wherein R3、R4It is each independently hydrogen atom or C1-C5Alkyl；
P2It is amide NH blocking group, preferably tertbutyloxycarbonyl, benzyloxycarbonyl group, 4- methbxybenzyl-oxycarbonyls；
P3It is thiol protecting group, preferably trityl, 4- Methoxytrityls, 4,4 '-dual-methoxy trityl.
A kind of 20. compounds, its have structure or its stereoisomer shown in Formula IX-B-B, stereoisomer mixture or Salt：
Wherein, X is hydroxyl or F, Cl, Br；
R1It is H or C1-C5Alkyl；
R3、R4It is each independently hydrogen atom or C1-C5Alkyl；
P1It is hydroxy-protective group, preferably trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl, triphenyl silicon substrate；
P2It is amide NH blocking group, preferably tertbutyloxycarbonyl, benzyloxycarbonyl group, 4- methbxybenzyl-oxycarbonyls；
P3It is thiol protecting group, preferably trityl, 4- Methoxytrityls, 4,4 '-dual-methoxy trityl.
21. a kind of one or more comprising in compound shown in claim any one of 1-9 of pharmaceutical compositions.
22. pharmaceutical compositions according to claim 21, wherein, compound or its dynamic isomer, solid shown in Formulas I The drug regimen of one or more of isomers, stereoisomer mixture, prodrug, pharmaceutically acceptable salt or solvate Dosage of the thing in described pharmaceutical composition is 1~1000mg/ days.
Compound any one of 23. claims 1~9 or the composition described in claim 21, are preparing as treatment Purposes in hepatitis C medicine.
24. purposes according to claim 23, wherein, the compound or composition further with the medicine of other treatment hepatopathy Internet of Things is used.
25. purposes according to claim 24, wherein the medicine in described drug combination is：Interferon, interferon beta, Interferon gamma and interferon ω；Interleukin, including IL-10 and interleukin 12；Ribavirin；Interferon-' alpha ' or Pegylation Interferon-' alpha ' is used in combination with Ribavirin or Levovirin；Levovirin；Protease inhibitors, including NS3 inhibitor, NS3/4A inhibitor；NS5A inhibitor；Helicase inhibitors；AG14361, including HCV RNA polymerases and NS5B polymerizations Enzyme inhibitor；Gliotoxin；IRES inhibitor；ASON；Tetrahydrothiazole derivates；N- benzanilides, ribozyme；It is another Plant nucleosides, nucleoside prodrugs or nucleoside derivates；1- amino-alkylcyclohexanes；Antioxidant, including vitamin E；Squalene；Gold Firm amine；Bile acid；N- (phosphonoacetyl)-L-Aspartic acid；Benzene dicarboxamide；Polyadenylic acid；Benzimidazole；Thymosin extrasin； Prevention vaccine；Immunomodulator, a kind of IMPDH inhibitor；Silymarin；Silymarin-phosphatid ylcholine endosome；Examined with wheat Phenols acids.
CN201611024004.9A 2015-12-15 2016-11-18 A kind of prodrug, preparation method, medical composition and its use Active CN106883279B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2016/109913 WO2017101785A1 (en) 2015-12-15 2016-12-14 Compound, preparation method therefor, pharmaceutical composition thereof and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2015109329042 2015-12-15
CN201510932904.2A CN105348345A (en) 2015-12-15 2015-12-15 Prodrug containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition

Publications (2)

Publication Number Publication Date
CN106883279A true CN106883279A (en) 2017-06-23
CN106883279B CN106883279B (en) 2019-12-03

Family

ID=55324426

Family Applications (3)

Application Number Title Priority Date Filing Date
CN201510932904.2A Pending CN105348345A (en) 2015-12-15 2015-12-15 Prodrug containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition
CN201611024004.9A Active CN106883279B (en) 2015-12-15 2016-11-18 A kind of prodrug, preparation method, medical composition and its use
CN201611158070.5A Active CN106883280B (en) 2015-12-15 2016-12-15 A kind of prodrug, preparation method, medical composition and its use

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201510932904.2A Pending CN105348345A (en) 2015-12-15 2015-12-15 Prodrug containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201611158070.5A Active CN106883280B (en) 2015-12-15 2016-12-15 A kind of prodrug, preparation method, medical composition and its use

Country Status (1)

Country Link
CN (3) CN105348345A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114190092A (en) * 2020-07-14 2022-03-15 四川大学 3-deoxy-2-ketonic acid nitrogenous derivative and preparation method and application thereof

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105777829B (en) * 2016-05-05 2019-01-22 杭州和正医药有限公司 A kind of prodrug containing class nucleotide structure, preparation method, medical composition and its use
CN105348345A (en) * 2015-12-15 2016-02-24 杭州和正医药有限公司 Prodrug containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition
WO2017101785A1 (en) * 2015-12-15 2017-06-22 杭州和正医药有限公司 Compound, preparation method therefor, pharmaceutical composition thereof and use thereof
CN108299532B (en) * 2016-12-29 2020-12-22 广东东阳光药业有限公司 Antiviral nucleoside analogue prodrug and composition and application thereof
CN117586329A (en) * 2022-08-11 2024-02-23 广东东阳光药业股份有限公司 Crystalline forms of hepatitis c inhibitors and their use in medicine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104470939A (en) * 2012-05-22 2015-03-25 埃迪尼克斯医药公司 D-amino acid compounds for liver disease
CN105348345A (en) * 2015-12-15 2016-02-24 杭州和正医药有限公司 Prodrug containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE20151318A1 (en) * 2012-10-08 2015-10-03 Idenix Pharmaceuticals Inc 2'-NUCLEOSIDE CHLORINE ANALOGS FOR HCV INFECTION

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104470939A (en) * 2012-05-22 2015-03-25 埃迪尼克斯医药公司 D-amino acid compounds for liver disease
CN105348345A (en) * 2015-12-15 2016-02-24 杭州和正医药有限公司 Prodrug containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
李竹轩: "射用硫普罗宁治疗慢性肝炎的临床观察", 《工企医刊》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114190092A (en) * 2020-07-14 2022-03-15 四川大学 3-deoxy-2-ketonic acid nitrogenous derivative and preparation method and application thereof
CN114190092B (en) * 2020-07-14 2023-07-18 四川大学 3-deoxy-2-ketonic acid nitrogenous derivative, preparation method and application thereof

Also Published As

Publication number Publication date
CN106883280B (en) 2019-05-21
CN106883280A (en) 2017-06-23
CN105348345A (en) 2016-02-24
CN106883279B (en) 2019-12-03

Similar Documents

Publication Publication Date Title
CN106883279B (en) A kind of prodrug, preparation method, medical composition and its use
CN102863428B (en) Spiro-compounds taken as hepatitis c virus (HCV) inhibitor
CN105829334B (en) Uracil nucleotides are like object and its preparation method and application
CN103827108B (en) Hepatitis c virus inhibitors
WO2017015451A1 (en) Hepatitis b antiviral agents
AU2014225052A1 (en) Novel nucleoside phosphoramidate compound and use thereof
US20090060874A1 (en) Bicyclic pyrrolidine derivatives
MX2014015846A (en) Inhibitors of hepatitis c virus.
KR20140048848A (en) Hepatitis c virus inhibitors
CN106543253B (en) Anti-viral nucleoside phosphoramidate and its pharmaceutical composition and purposes
CN104024249A (en) Hepatitis c virus inhibitors
CN103420991B (en) Application as the pyrrolidin derivatives of hepatitis c inhibitor and its in medicine
CN104725365A (en) Hepatitis c virus (HCV) inhibitor and application thereof
CN105294795B (en) Nucleoside phosphoramidate derivative and its application
JP2023145644A (en) Dihydroisoquinoline compounds
CN108129366B (en) Antiviral compounds, methods of preparation and uses thereof
WO2021047524A1 (en) Class of functional molecules targeting proteolysis pathways, preparation and application thereof
CN106699828A (en) Deuterated HCV NS5b inhibitor nucleotide derivative and application thereof
CN105777829B (en) A kind of prodrug containing class nucleotide structure, preparation method, medical composition and its use
CN110857285B (en) Substituted pyrazole compound, preparation method, pharmaceutical composition and application thereof
WO2017101785A1 (en) Compound, preparation method therefor, pharmaceutical composition thereof and use thereof
JP6958797B2 (en) Hepatitis C virus inhibitor and its use
CN105504007A (en) Phosphoramidate derivatives, preparation method, and applications thereof in pharmacy
US11008361B2 (en) Liver-specific delivery-based anti-hepatitis C prodrug nucleoside cyclo-phosphate compound and uses thereof
CN106967141A (en) Nucleoside phosphoramidate compound and its medical composition and purposes

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
EE01 Entry into force of recordation of patent licensing contract

Application publication date: 20170623

Assignee: DONGGUAN HEC PHARM R&D Co.,Ltd.

Assignor: HANGZHOU HERTZ PHARMACEUTICAL Co.,Ltd.

Contract record no.: 2017330000122

Denomination of invention: A kind of prodrug, its preparation method, medical composition and its use

License type: Exclusive License

Record date: 20170821

EE01 Entry into force of recordation of patent licensing contract
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20240116

Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province

Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd.

Address before: 310018 b1917, building 2, 452, No.6 street, Hangzhou Economic and Technological Development Zone, Zhejiang Province

Patentee before: HANGZHOU HERTZ PHARMACEUTICAL Co.,Ltd.

TR01 Transfer of patent right