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WO2017101785A1 - Composé, son procédé de préparation, composition pharmaceutique associée, et utilisation correspondante - Google Patents

Composé, son procédé de préparation, composition pharmaceutique associée, et utilisation correspondante Download PDF

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Publication number
WO2017101785A1
WO2017101785A1 PCT/CN2016/109913 CN2016109913W WO2017101785A1 WO 2017101785 A1 WO2017101785 A1 WO 2017101785A1 CN 2016109913 W CN2016109913 W CN 2016109913W WO 2017101785 A1 WO2017101785 A1 WO 2017101785A1
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Prior art keywords
formula
compound
group
pharmaceutically acceptable
stereoisomer
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PCT/CN2016/109913
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English (en)
Chinese (zh)
Inventor
周星露
董晓武
刘兴国
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HANGZHOU HERTZ PHARMACEUTICAL Co Ltd
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HANGZHOU HERTZ PHARMACEUTICAL Co Ltd
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Priority claimed from CN201510932904.2A external-priority patent/CN105348345A/zh
Priority claimed from CN201610289337.8A external-priority patent/CN105777829B/zh
Application filed by HANGZHOU HERTZ PHARMACEUTICAL Co Ltd filed Critical HANGZHOU HERTZ PHARMACEUTICAL Co Ltd
Publication of WO2017101785A1 publication Critical patent/WO2017101785A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • 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
    • 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

Definitions

  • the invention belongs to the field of medicinal chemistry.
  • the present invention relates to a compound or a tautomer thereof, a stereoisomer, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a solvate thereof, a process for the preparation thereof, a pharmaceutical combination And its use as an anti-hepatitis C drug.
  • Hepatitis C is a liver disease caused by hepatitis C virus (HCV), which is a serious threat to human health.
  • HCV hepatitis C virus
  • HCV genome heterogeneity it can be divided into 6 types and 30 subtypes.
  • the type of infection has a strong regional nature, and China is mainly type 1.
  • type 1 accounted for 58.2%, of which gene type 1a was 1.4% and gene type 1b was 56.8%.
  • HCV-infected people there are more than 200 million HCV-infected people worldwide, accounting for 3.3% of the world's total population. There are about 3.2 million infected people in the United States. The number of HCV patients in China exceeds 40 million, ranking first in the world. Many HCV-infected patients are also hepatitis B and even AIDS patients, which increases the complexity of treatment. There is currently no officially approved hepatitis C vaccine, so preventing hepatitis C transmission remains a challenge. The existing chronically infected patients are developing, and it is expected that the peak incidence will be ushered in the next 10-20 years. The standard clinical regimen for the treatment of hepatitis C is peginterferon alfa combined with ribavirin.
  • the standard of cure is that the blood is not detected by HCV within 24 weeks after treatment.
  • This treatment has many side effects, including depression, fatigue, flu-like symptoms, and anemia; the cost of treatment is high, and the standard treatment takes 48 weeks and costs about $40,000.
  • the development of anti-hepatitis C virus small molecule compound drugs against the hepatitis C virus RNA gene sequence has rapidly become a hot spot, and antiviral drugs will enter the era of small molecule drugs from the interferon era.
  • HCV protease inhibitors have been extensively studied, among which Telaprevir (Terravir, VX-950, trade name Incivek) and Boceprevir (Bosipuvir, SCH-503034, trade name Victrelis) have been Approved for listing.
  • the inhibitor of the non-structural protein NS5A is also a specific antiviral drug acting on the hepatitis C virus RNA chain, and various genotypes of HCV virus have significant inhibitory effects.
  • drugs targeting NS5B polymerase are classified into two classes: nucleoside and non-nucleoside polymerase inhibitors. Among them, Sofosbuvir is by far the most potent anti-HCV drug, which is effective against HCV genotype 1, 2, 3, 4 and 6 infections.
  • the object of the present invention is to provide a novel anti-HCV virus and liver-protecting and liver-protecting bifunctional drugs, which can be used as a bifunctional drug, and has the characteristics of high oral bioavailability and good metabolic properties, and can be used for oral treatment. Viral hepatitis embolism.
  • Another object of the invention is to provide a process for the preparation of the compounds provided herein.
  • Still another object of the present invention is to provide a structural compound of the formula I or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof as an NS5B inhibitor, which protects liver cells, liver tissue, and improves The use of liver function and its application in the preparation of the treatment of viral hepatitis.
  • a further object of the present invention is to provide a pharmaceutical composition comprising one or more of the structural compounds of the formula I or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof.
  • X is hydroxy, F, Cl or Br
  • R, R' are independent of H, or And at least one of R and R' is Where Linker may or may not be present,
  • A is derived from a drug or derivative thereof for the treatment or adjuvant treatment of liver disease.
  • the drug or derivative thereof for treating or assisting in the treatment of liver disease may be a drug already on the market.
  • a group mentioned, such as the group I "from" the compound I generally means that the group I is obtained by reacting the compound I.
  • the invention protects a compound having the structure of formula I-1, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof Or a prodrug of the formula I-1:
  • X is a hydroxyl group or F, Cl, Br; R is Linker A is Or absent; G is derived from a drug or derivative thereof that has been marketed for the treatment or adjuvant treatment of liver disease; R 1 is H or C 1 -C 5 alkyl; n is an integer from 1 to 19.
  • a further preferred compound is a prodrug containing a nucleoside-like structure represented by the formula II-1A or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof.
  • X is a hydroxyl group or F, Cl, Br; Linker A is or Or absent; R 1 is H or C 1 -C 5 alkyl; n is 1, 2, 3 , 4 or 5; and R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group.
  • a further preferred compound is a structure represented by the formula II-1Aa or the formula II-1Ab or a tautomer, an optical isomer, a stereoisomer thereof, a stereoisomer Body mixture, prodrug, pharmaceutically acceptable salt or solvate:
  • X is a hydroxyl group or F, Cl, Br; Linker A is or Or absent; R 1 is H or C 1 -C 5 alkyl; n is 1, 2, 3 , 4 or 5; and R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group.
  • a further preferred compound is a structure represented by the formula II-1B or a tautomer, an optical isomer, a stereoisomer, a mixture of stereoisomers, and a former Drug, pharmaceutically acceptable salt or solvate:
  • X is a hydroxyl group or F, Cl, Br; Linker A is Or absent; R 1 is H or C 1 -C 5 alkyl; n is 1, 2, 3 , 4 or 5; and R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group.
  • X is a hydroxyl group or F, Cl, Br; Linker A is Or absent; R 1 is H or C 1 -C 5 alkyl; n is 1, 2, 3 , 4 or 5; and R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group.
  • a prodrug containing a tiopronin structure represented by the formula II-1A-A(1) or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable substance thereof is further preferred.
  • X is hydroxyl or F, Cl, Br, and Linker A is or R 1 is H or C 1 -C 5 alkyl, and n is an integer from 1 to 19.
  • the following prodrug containing a tiopronin structure or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable thereof is further preferred Solvate:
  • the following prodrug containing a tiopronin structure or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable thereof is further preferred Solvate:
  • R 1 is H or C 1 -C 5 alkyl, and n is 1, 2, 3, 4 or 5.
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula II-1A, which comprises: 1) reacting a compound of the formula III with a compound of the formula IV-1A to give a formula V-1A a compound represented by the formula V-1A is subjected to a deprotection reaction to obtain a compound of the formula II-1A;
  • X is a hydroxyl group or a halogen (F, Cl, Br); Linker A is Or absent; n is 1, 2, 3, 4 or 5; R 1 is H or C 1 -C 5 alkyl; R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group; The leaving group is preferably a halogen; Z is a mercapto protecting group, preferably trityl, 4-methoxytrityl, 4,4'-bismethoxytrityl.
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula II-1B, which comprises: 1) reacting a compound of the formula III with a compound of the formula IV-1B to give a formula V-1B a compound of the formula V-1B is subjected to a deprotection reaction to give a compound of the formula II-1B;
  • X hydroxyl or halogen (F, Cl, Br); Linker A is Or absent; n is 1, 2, 3, 4 or 5; R 1 is H or C 1 -C 5 alkyl; R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group;
  • the leaving group is preferably a halogen;
  • Z is a mercapto protecting group, preferably trityl, 4-methoxytrityl, 4,4'-bismethoxytrityl.
  • a method for preparing a compound represented by the formula II-1A-Aa can be obtained by subjecting a compound represented by the formula IIIm to a compound represented by the formula IV-1 to obtain a formula V-1A. The compound shown is then obtained by deprotection.
  • X is a hydroxyl group or F, Cl or Br
  • R 1 is H or a C 1 -C 5 alkyl group
  • Y is a leaving group, preferably a halogen, such as fluorine, chlorine, bromine, iodine, etc.
  • Z is The thiol protecting group is preferably trityl, 4-methoxytrityl, 4,4'-bismethoxytrityl.
  • a method for producing a compound represented by the formula II-1A-Ab which can be obtained by subjecting a compound represented by the formula IIIm to a compound represented by the formula IV-1B to give a compound represented by the formula V-1B. Then through the deprotection reaction to get:
  • X is a hydroxyl group or a halogen (F, Cl, Br); R 1 is H or a C 1 -C 5 alkyl group; n is an integer from 1 to 19; Y is a leaving group, preferably a halogen, such as may be Fluorine, chlorine, bromine, iodine, etc.; Z is a mercapto protecting group, preferably trityl, 4-methoxytrityl, 4,4'-bismethoxytrityl.
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula II-1A-B which can be subjected to a protective reaction by a compound represented by III and then reacted with an aldehyde to give a compound of the formula VII-1, and then Esterification or acylation with a compound represented by VIII-1A represented by the formula to give a compound of the formula IX-1A-B, followed by removal of a protecting group to give a compound of the formula II-1A-B .
  • the active site of the key intermediate of the preparation method is appropriately protected, which helps to reduce the occurrence of side reactions, has high reaction selectivity, and has high purity and easy purification of the obtained intermediate and final product.
  • the reaction involved in the method has the advantages of simple operation, convenient purification, and good controllability of the process, and is suitable for industrial production.
  • X is hydroxy or halogen (F, Cl, Br);
  • R 1 is H or C 1 -C 5 alkyl group;
  • R 3, R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group;
  • P 1 Is a hydroxy protecting group, preferably a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a triphenylsilyl group;
  • P 2 is an amide NH protecting group, preferably a tert-butoxycarbonyl group , benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl;
  • P 3 is a thiol protecting group, preferably trityl, 4-methoxytrityl, 4,4'-bismethoxytriphenyl methyl.
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula II-1B-B which may be esterified with a compound of the formula VII-1 and then with a compound of the formula VIII-1B or
  • the acylation reaction gives the compound of the formula IX-1B-B, and then the protecting group is removed to give the compound of the formula II-1B-B.
  • the active site of the key intermediate of the preparation method is appropriately protected, which helps to reduce the occurrence of side reactions, has high reaction selectivity, and has high purity and easy purification of the obtained intermediate and final product.
  • the reaction involved in the method has the advantages of simple operation, convenient purification, and good controllability of the process, and is suitable for industrial production.
  • X, R 1 , R 3 , R 4 are as defined in the formula II-1B, and P 1 is a hydroxy protecting group, preferably trimethylsilyl, triethylsilyl, tert-butyl a dimethylsilyl group, a triphenylsilyl group; P 2 is an amide NH protecting group, preferably a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group; and P 3 is a fluorenyl protecting group. Preferred is trityl, 4-methoxytrityl, and 4,4'-bismethoxytrityl.
  • Another object of the present invention is to provide an intermediate represented by the following VII-1 and its use for preparing an anti-hepatitis C virus drug:
  • X is a hydroxyl group or a halogen (F, Cl, Br); R 1 is H or a C 1 -C 5 alkyl group; and P 1 is a hydroxy protecting group, preferably a trimethylsilyl group, a triethylsilyl group, Tert-butyldimethylsilyl, triphenylsilyl.
  • Another object of the present invention is to provide an intermediate represented by the following VIII-1A or a stereoisomer thereof or a mixture of stereoisomers thereof:
  • P 2 is an NH protecting group, preferably tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl;
  • P 3 is a fluorenyl protecting group, preferably trityl, 4-methoxy Tritylmethyl, 4,4'-bismethoxytrityl and the like.
  • Another object of the present invention is to provide a prodrug of the following IX-1A-B or a stereoisomer thereof, a mixture of stereoisomers:
  • X is a hydroxyl group or a halogen (F, Cl, Br);
  • R 1 is H or a C 1 -C 5 alkyl group; and
  • P 1 is a hydroxy protecting group, preferably a trimethylsilyl group, a triethylsilyl group, Tert-butyldimethylsilyl, triphenylsilyl;
  • P 2 is an NH protecting group, preferably tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, etc.;
  • P 3 is a fluorenyl protecting group
  • the group is preferably a trityl group, a 4-methoxytrityl group, a 4,4'-bismethoxytrityl group or the like.
  • Another object of the present invention is to provide an intermediate represented by the following VIII-1B or a stereoisomer thereof or a mixture of stereoisomers thereof:
  • R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group
  • P 2 is an amide NH protecting group, preferably a tert-butoxycarbonyl group, a benzyloxycarbonyl group or a 4-methoxybenzyloxycarbonyl group.
  • P 3 is a thiol protecting group, preferably trityl, 4-methoxytrityl, 4,4'-bismethoxytrityl.
  • Another object of the present invention is to provide a prodrug of the following IX-1B-B or a stereoisomer thereof, a mixture of stereoisomers:
  • X is hydroxy or halogen (F, Cl, Br);
  • R 1 is H or C 1 -C 5 alkyl group;
  • R 3, R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group;
  • P 1 Is a hydroxy protecting group, preferably a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a triphenylsilyl group;
  • P 2 is an amide NH protecting group, preferably a tert-butoxycarbonyl group , benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl;
  • P 3 is a thiol protecting group, preferably trityl, 4-methoxytrityl, 4,4'-bismethoxytriphenyl methyl.
  • the present invention provides a prodrug of the formula I-2, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof.
  • X is a hydroxyl group, F, Cl or Br
  • R' is Where Linker B may or may not be present, B is derived from a drug or derivative thereof that has been marketed for the treatment or adjuvant treatment of liver disease, F is linked to Linker B via a covalent bond, and then Linker B is covalently bonded to the nucleoside 4 The hydroxyl group is bonded to a hydroxyl group.
  • Linker B is absent, F is directly bonded to the hydroxy atom of the nucleoside at the 4-position by a covalent bond.
  • R 1 , R 2 is H or C 1 -C 5 alkyl, further preferably methyl or ethyl or propyl .
  • X is F, Br or Cl
  • Linker B is Or absent, when Linker B is absent, tiopronin or its derivative is directly linked to the hydroxy atom of the nucleoside 4 through an ester bond;
  • R 1 , R 2 are respectively H or C 1 -C 5 alkyl, further Preferred is a C 1 -C 5 alkyl group, still more preferably a methyl group or an ethyl group or a propyl group;
  • R 3 , R 4 is a hydrogen atom or a C 1 -C 5 alkyl group, and still more preferably a methyl group or an ethyl group. Or propyl.
  • Linker B is Or absent, when Linker B is absent, tiopronin or its derivative is directly linked to the hydroxy atom of the nucleoside 4 via an ester bond, and R 1 and R 2 are respectively H or C 1 -C 5 alkyl, R 3 , R 4 is a hydrogen atom or a C 1 - C 5 alkyl group, and still more preferably a methyl group or an ethyl group or a propyl group.
  • Linker B is Or absent, when Linker B is absent, acetylcysteine or its derivative is directly linked to the hydroxy atom of the nucleoside 4 via an ester bond, and R 1 and R 2 are respectively H or C 1 -C 5 alkyl Further, it is preferably a C 1 - C 5 alkyl group, still more preferably a methyl group or an ethyl group or a propyl group, and R 3 and R 4 are a hydrogen atom or a C 1 - C 5 alkyl group, and still more preferably a methyl group. Or ethyl or propyl.
  • Linker B is Or absent, when Linker B is absent, acetylcysteine or its derivative is directly linked to the hydroxy atom of the nucleoside 4 via an ester bond, and R 1 and R 2 are respectively H or C 1 -C 5 alkyl Further, it is preferably a methyl group or an ethyl group or a propyl group, and R 3 and R 4 are a hydrogen atom or a C 1 - C 5 alkyl group, and still more preferably a methyl group or an ethyl group or a propyl group.
  • the compound of the formula II-2 may also be selected from the following compounds of the formula III-2C, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof:
  • Linker B is or R 3 and R 4 are a C 1 - C 5 hydrocarbon group, more preferably a C 1 - C 5 alkyl group, still more preferably a methyl group or an ethyl group or a propyl group.
  • the compounds of formula I may contain one or more chiral centers, as stereoisomers, ie, enantiomers, diastereomers or mixtures thereof, may be present.
  • the compounds of formula I- of the present invention may be individual isomers or mixtures of individual isomers.
  • the invention includes any prodrug form of the compound of Formula I.
  • the invention also includes pharmaceutically acceptable solvates of the compounds of formula I.
  • the invention also includes pharmaceutically acceptable oxides of the compounds of formula I, and pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof.
  • the invention also includes various crystalline forms of the compounds of formula I.
  • the present invention provides a compound of the formula I or a tautomer, a stereoisomer thereof, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a solvent thereof
  • a compound of the formula I or a tautomer, a stereoisomer thereof, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a solvent thereof Use of the compound as an NS5B inhibitor to simultaneously protect liver cells, liver tissue, improve liver function, and use in the preparation of a medicament for treating diseases such as viral hepatitis.
  • the present invention provides a therapeutically effective amount of a compound of the formula I or a tautomer thereof, a stereoisomer, a mixture of stereoisomers, a prodrug, a pharmacy
  • the present invention provides an NS5B inhibitor comprising a therapeutically effective amount of a compound of the formula I or a tautomer, a stereoisomer thereof, a mixture of stereoisomers
  • a prodrug a pharmaceutically acceptable salt or a solvate thereof
  • the inhibitor may optionally comprise a pharmaceutically acceptable carrier or excipient.
  • the composition consists of a therapeutically effective amount of one or more compounds of formula I or a tautomer, stereoisomer, stereoisomeric mixture, prodrug, pharmaceutically acceptable salt thereof or
  • the drug solvate is comprised of at least one pharmaceutically acceptable adjuvant.
  • the choice of pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and is usually a filler, a diluent, a binder, a wetting agent, a disintegrant, a lubricant, an emulsifier, a suspending agent, and the like.
  • the compound of the formula I, a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof, is present in the above composition in a proportion of from 0.1% to 99.9%, preferably from 1% to 99% by total weight. %.
  • the pharmaceutically acceptable carrier refers to a pharmaceutical carrier conventional in the pharmaceutical field, such as a diluent such as water; a filler such as starch, sucrose, etc.; a binder such as a cellulose derivative, an alginate, gelatin, Polyvinylpyrrolidone; wetting agent such as glycerin; disintegrants such as agar, calcium carbonate and sodium hydrogencarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and soap Clay; lubricants such as talc, calcium stearate and magnesium stearate, and polyethylene glycol.
  • a pharmaceutical carrier conventional in the pharmaceutical field, such as a diluent such as water; a filler such as starch, sucrose, etc.; a binder such as a cellulose derivative, an alginate, gelatin, Polyvinylpyrrolidone; wetting agent such as glycerin;
  • the present invention also provides a pharmaceutically acceptable compound of the formula I or a tautomer, a stereoisomer thereof, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
  • a method of preparing a composition A compound containing a tiopronin structure represented by Formula I or a tautomer thereof, a stereoisomer thereof, a mixture of stereoisomers, and a former
  • the drug, the pharmaceutically acceptable salt or the solvate thereof is mixed with a pharmaceutically acceptable adjuvant, and is prepared in a form suitable for administration by a conventional preparation method (dosage form).
  • Dosage forms include tablets, capsules, granules, pills, solutions, suspensions, emulsions, ointments, films, creams, aerosols, injections, suppositories, and the like. Preference is given to tablets and capsules.
  • the compound of the present invention is usually used in a dose of from 1 to 1000 mg per day, in single or multiple doses. However, if necessary, the above dosage can be appropriately deviated. Professionals can determine the optimal dose based on specific circumstances and expertise. These conditions include the severity of the disease, individual differences in the patient, characteristics of the formulation, and route of administration.
  • the present invention provides a compound of the formula I or a tautomer, a stereoisomer thereof, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a solvate thereof, or Use of a pharmaceutically acceptable composition as a human drug.
  • the present invention provides a method of treating viral hepatitis, the method comprising administering a therapeutically effective amount of a compound of the formula I or a tautomer thereof, a stereoisomer thereof One or more of a mixture of stereoisomers, prodrugs, pharmaceutically acceptable salts or solvates thereof or the pharmaceutical composition of the present invention is administered to a patient.
  • the compounds or compositions provided herein can be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, transurethral, vaginal, nasal, inhalation or topical routes.
  • the preferred route is oral.
  • it can be prepared into a conventional solid preparation such as a tablet, a powder, a granule, a capsule, etc., or as a liquid preparation, such as a water or oil suspension, or other liquid preparation, such as a syrup;
  • parenteral administration it may be prepared as a solution for injection, water or an oily suspension, or the like.
  • the present invention also provides a compound of the formula I or a tautomer, a stereoisomer thereof, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • a compound of the formula I or a tautomer, a stereoisomer thereof, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof Use in the preparation of a human NS5B inhibitor drug.
  • the present invention also provides a compound represented by Formula I, or a tautomer, a stereoisomer thereof, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a solvate thereof, and other therapeutic liver diseases.
  • a compound represented by Formula I or a tautomer, a stereoisomer thereof, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a solvate thereof, and other therapeutic liver diseases.
  • the combination of drugs is a compound represented by Formula I, or a tautomer, a stereoisomer thereof, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a solvate thereof, and other therapeutic liver diseases.
  • “Pharmaceutically acceptable” means a compound, material, composition, and/or dosage form that, within the scope of sound medical judgment, is suitable for contact with a patient's tissue without undue toxicity, irritation, allergies, or reasonable The benefits/risk ratios are commensurate with other problems and complications and are effectively used for the intended use.
  • halogen and “halo” are used interchangeably herein and refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • alkyl or "alkyl group” as used herein, denotes a saturated straight or branched monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally selected The ground is replaced by one or more substituents described herein.
  • the alkyl group contains from 1 to 6 carbon atoms; in another embodiment, the alkyl group contains from 1 to 4 carbon atoms; and in one embodiment, the alkyl group contains 1 - 3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), and the like.
  • the "pharmaceutically acceptable salt” as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art and are described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or by other methods described in the literature, such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid Salt, picrate, pi
  • Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -C 8 sulfonate and aromatic sulfonate.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -C 8 sulfonate and aromatic sulfonate.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or mixtures thereof.
  • hydrate means that the solvent molecule is an association formed by water.
  • hydrate can be used.
  • a molecule of the compound of the invention may be combined with a water molecule, such as a monohydrate; in another embodiment, a molecule of the invention may be combined with more than one water molecule, such as dihydrate. In yet another embodiment, a molecule of the compound of the invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the compounds in a non-hydrated form.
  • stereochemistry of any particular chiral atom when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the invention, and as disclosed herein are included in the present invention. .
  • stereochemistry is indicated by a solid wedge or dashed line indicating a particular configuration, then the stereoisomers of the structure are defined and defined herein.
  • the compound of formula I can exist in the form of a salt.
  • the salt refers to a pharmaceutically acceptable salt.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal treated therewith.
  • the salt is not necessarily a pharmaceutically acceptable salt, and may be an enantiomer for the preparation and/or purification of a compound of formula I and/or for isolation of a compound of formula I. Intermediates.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods.
  • such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • the free base form of these compounds is prepared by reaction with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched.
  • Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the invention relates to intermediates for the preparation of compounds of formula I.
  • the invention provides a pharmaceutical composition comprising a compound of the invention.
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or a combination thereof.
  • the pharmaceutical composition can be in the form of a liquid, solid, semi-solid, gel or spray.
  • the compound of the present invention or a pharmaceutical composition thereof can be used for the treatment of hepatitis C, and has the advantages of high oral bioavailability and good metabolic properties, and has the functions of protecting liver tissue, liver cells, and improving liver function.
  • the compounds of the present invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined in Formula I.
  • the following reaction schemes and examples are provided to further illustrate the contents of the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal.
  • Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.
  • reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe.
  • the glassware is dry.
  • the column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Plant.
  • MS mass spectrometry
  • Step 1 5.0 g (9.5 mmol) of compound III-1 was dissolved in 25 mL of anhydrous N,N-dimethylformamide (DMF), and 1.6 g (23.5 mmol) of imidazole, 0.12 g (stepwise) was added under Ar protection.
  • DMAP 4-dimethylaminopyridine
  • TLCl triethylchlorosilane
  • Step 2 The product VII-1 freshly obtained in the previous step was dissolved in 40 mL of anhydrous dichloromethane (DCM), cooled in an ice bath under argon atmosphere, and then added 62 mg (0.5 mmol) of 4-dimethylaminopyridine (DMAP). And 2.36 g (12.3 mmol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl), and 6.1 g (11.4 mmol) of compound VIII-A-1, The temperature was slowly raised to room temperature and the reaction was stirred for about 12 hours, and the reaction was completed by TLC. After adding 100 ml of dichloromethane, the mixture was washed with aq.
  • DCM anhydrous dichloromethane
  • Step 3 7.5 g (6.3 mmol) of compound IX-A-1 was dissolved in 50% water-acetone (20 mL) mixed solution, 30 mL of glacial acetic acid (HOAc) and 6 mL of trifluoroacetic acid (TFA) were added, and the reaction was stirred at room temperature. After about 6 hours, no remaining raw materials were detected by TLC.
  • HOAc glacial acetic acid
  • TFA trifluoroacetic acid
  • Compound VII-1 (3 mmol of compound III-1 was used as a starting material) was prepared by the method of Step B of Example 1, and dissolved in 12 mL of anhydrous dichloromethane (DCM), and cooled in an ice bath under argon atmosphere. 18 mg (0.15 mmol) of 4-dimethylaminopyridine (DMAP) and 0.75 g (3.9 mmol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl) were added in sequence.
  • DMAP 4-dimethylaminopyridine
  • EDC HCl 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • the formaldehyde is replaced by propionaldehyde, and 2 g of the intermediate IX-A-3 can be prepared with 2.65 g (5 mmol) of the compound III-1 in a yield of 33% (two steps).
  • ESI-MS: m/z [M+H] + 121.
  • Step 1 529 mg (1.0 mmol) of III-1 was dissolved in 10 mL of anhydrous acetone, and 690 mg of IV-A-3 and potassium carbonate 414 mg (3.0 mmol) were added at room temperature, and the mixture was stirred under reflux for 6 hours, and the reaction was completely confirmed by TLC. After filtration, the filtrate was diluted with methylene chloride (30 mL). The residue was purified by silica gel column chromatography eluting with EtOAc
  • Step 1 529 mg (1.0 mmol) of III-1 was dissolved in 10 mL of anhydrous acetone, and 800 mg of IV-A-4 and potassium carbonate 414 mg (3.0 mmol) were added at room temperature, and the mixture was stirred under reflux for 12 h. After filtration, the filtrate was diluted with methylene chloride (30 mL). The residue was purified by silica gel column chromatography to yield 400 mg of V-A-5.
  • the second step of the method B VIII-A-2 is substituted for VIII-A-1, and 1.29 g of the intermediate IX-A-8 can be prepared by using 1.6 g (3 mmol) of the compound III-1.
  • the rate is 65% (two steps).
  • ESI-MS: m/z [M+H] + 1219.
  • VIII-B-1 obtained from (DL)-N-acetylcysteine
  • VIII-1 2.1 g (4 mmol) of compound III-1
  • ESI-MS: m/z [M+H] + 1191.
  • VIII-B-1a prepared by L-acetylcysteine, chiral purity >99%
  • VIII-B-1a is substituted for VIII-1, and 2.65 g (5 mmol) of compound III-1 is used.
  • Intermediate IX-B-1a can be prepared in a yield of 67% (two steps).
  • ESI-MS: m/z [M+H] + 1191.
  • the second step of the method of the first embodiment the VIII-B-2 (prepared by L-acetylcysteine, chiral purity >99%) is substituted for VIII-1, thereby giving 1.6 g (3 mmol) of the compound.
  • Intermediate IX-B-3 can be prepared in III-1 in a yield of 76% (two steps).
  • ESI-MS: m/z [M+H] + 1205.
  • the second step in the method B of the first embodiment the III-1 is replaced by III-2, and the VIII-B-1a (prepared by L-acetylcysteine, the chiral purity is >99%) is substituted for VIII.
  • III-1 2.64 g of Intermediate IX-B-4 can be obtained in 1.6 g (3 mmol) of compound III-2 in a yield of 72% (two steps).
  • Step 1 529 mg (1.0 mmol) of III-1 was dissolved in 10 mL of anhydrous dichloromethane, and 405 mg (1.0 mmol) of XA-1 was added at room temperature (preparation method refers to Polymer Chemistry, 2011, 2, 906-913) cyclohexyl carbon two
  • the imine 412 mg (2.0 mmol) and DMAP 12.2 mg (0.1 mmol) were stirred for 6 h, and the reaction was confirmed by TLC.
  • the solvent was removed by concentration under reduced pressure.
  • the residue was purified by silica gel column chromatography to give white solid XI-A-1, a yield of 43%, LC-ESI-MS : [M + H] + 916, was used directly in the next reaction.
  • Step 1 5.4 g (10 mmol) of compound III-1 was dissolved in 50 mL of anhydrous dichloromethane (DCM), cooled in an ice bath under Ar protection, and 61 mg (0.5 mmol) of 4-dimethylaminopyridine (DMAP) and 2.3 g (12 mmol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl), after stirring for 5 minutes, 4.5 g (8.5 mmol) of compound VIII-A-1 was added. The reaction was stirred for about 6 hours and the reaction was complete by TLC. After adding 50 ml of dichloromethane, the mixture was washed with EtOAc EtOAc.
  • Step 2 4.7 g (4.5 mmol) of compound XII-A-1 was dissolved in 50 mL of dichloromethane, and 3.5 mL of trifluoroacetic acid (TFA) and 3.5 mL of triisopropylsilane ( i- Pr 3 SiH) were added at room temperature. After the reaction for 15 minutes, 3.5 mL of trifluoroacetic acid (TFA) was further added, and the reaction was continued for about 10 to 20 minutes. The reaction was completely confirmed by TLC, and the reaction was cautiously added with a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated and dried over anhydrous sodium The residue was purified by silica gel column chromatography to give 2.5g white solid, yield 82%, LC-ESI-MS : [M + H] + 675.
  • TFA trifluoroacetic acid
  • i- Pr 3 SiH triisopropylsilane
  • Step 1 Dissolve 529 mg (1.0 mmol) of III-1 in 5 mL of dimethyl sulfoxide, add 4 mL of acetic anhydride and 1.5 mL of acetic acid, stir at room temperature for 48 hours, carefully add saturated brine and ethyl acetate, and separate the organic phase. The extract was washed with aq. The solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography to give a pale yellow gum XIII-1, a yield of 25%, LC-ESI-MS : [M + H] + 590.
  • Step 2 118 mg (0.2 mmol) of XIII-1 was dissolved in anhydrous dichloromethane, and 0.3 mL of dichloromethane (1 M) of thionyl chloride was added thereto under ice-cooling. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. The solvent was concentrated under reduced pressure to give a yellow gum. The above-mentioned gum XIII-1 was dissolved in 1 mL of anhydrous tetrahydrofuran, and 93 mg (0.2 mmol) of IX-A-1 and potassium carbonate 55 mg (0.4 mmol) were added at room temperature, and stirred for 6 hours, and the reaction was completely confirmed by TLC. The solvent was removed by concentration under reduced pressure.
  • Step 2 VIII-A-2 is substituted for VIII-A-1, and 5.3 g (10 mmol) of compound III-1 is used as a raw material to prepare 4.9 g of white solid product III-2A- 5, yield 71% (two steps).
  • ESI-MS: m/z [M+H] + 702.
  • Step 1 529 mg (1.0 mmol) of III-1 was dissolved in 10 mL of anhydrous dichloromethane, and 405 mg of XB-1 (1.0 mmol), cyclohexylcarbodiimide 412 mg (2.0 mmol) and DMAP 12.2 mg ( 0.1 mmol), stirred for 12 h, and the reaction was complete by TLC. The solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography to give white solid XI-B-1, LC- ESI-MS: [M + H] + 916, was used directly in the next reaction.
  • VIII-B-1a prepared from L-acetylcysteine, L-form chiral purity 99%
  • VIII-A-1 was substituted for VIII-A-1 at 5.3 g (10 mmol).
  • Compound III-1 was used as a starting material to obtain 3.6 g of a white solid product II-A-1b in a yield of 51%.
  • Step 1 529 mg (1.0 mmol) of III-1 was dissolved in 10 mL of anhydrous dichloromethane, and 452 mg (1.0 mmol) of XV-1 was added under ice bath (preparation method refers to Chemistry-A European Journal, 2014, 20, 6526- 6531) and DMAP 122 mg (1.0 mmol), stirred for 1 h, filtered, EtOAc EtOAc (EtOAc)EtOAc. The solvent was concentrated under reduced pressure.
  • Example 28 Anti-hepatitis C virus activity (HCV, EC 50 ) and cytotoxicity (CC 50 )
  • HCV viral activity evaluation uses an enzyme that plays a key role in HCV RNA replication to establish an extracellular molecular replication model.
  • Huh7 cells containing HCV-replicon (1b genotype) were cultured in DMEM medium containing 10% fetal calf serum, 1X non-essential amino acid, Pen-Strep-Glu, G418. Antiviral screening tests were performed in different media without G418.
  • the cells were seeded in 96-well plates, and the test compounds were added immediately after inoculation of the cells, and incubated at 37 ° C in an incubator. The medium is then removed and the cells are used for whole nucleic acid extraction (including replicon RNA and host RNA).
  • the replicon RNA can be amplified in the Q-RT-PCR protocol and quantified accordingly.
  • the difference in the level of the observed replicon HCV RNA from the untreated control group was used as the manner of antiviral efficacy of the test compound, and the results are shown in Table 1.
  • the results of the inhibitory activity of the compound of intracellular replicon 1b of HCV (EC 50) was evaluated as an anti-hepatitis C virus activity, while cytotoxic activity (CC 50) for excluding a synchronization test false positive results due to the cytotoxicity caused.
  • inhibitory activity on intracellular HCV replicon (EC 50) was stronger than that in the positive control Sofosbuvir, indicating that the compound may be rapidly Sofosbuvir as intracellular degradation in the liver cells
  • the form that becomes an active metabolite exerts an anti-HCV effect.
  • another sub-thiopronin obtained by degradation in the molecule has a certain gain effect on antiviral activity, and this synergistic effect enables the compound provided by the present invention to be resistant to HCV.
  • the disease aspect has more application prospects.
  • Example 29 Study on the protective effect of mouse CCl 4 liver damage model
  • mice Male mice were taken before the experiment body weight of 24 ⁇ 28g, water, fasted 6 hours, were randomly divided into 3 groups, 5 mice per group, divided into blank control group, CCl 4 group, compound group (thio general Ning 50mg/kg, test compound 200mg/kg). The drug was administered once every 12 hours, and the perfusion volume was 10 mL/kg, which was administered 4 times. The blank control group and the model control group were simultaneously administered with an equal volume of physiological saline. One hour after the third administration, the other two groups of mice were intraperitoneally injected with 50% CCl 4 corn oil solution at 2 mg/kg bw of CCl 4 except for the blank control group. After 12 hours, each group was administered once more.
  • liver was cut into small pieces, fixed in formaldehyde, paraffin-embedded, stained with hematoxylin and eosin, and the liver cells were observed under a microscope.
  • III-2A-1 617.5 690.2 II-A-1a 596.3 672 II-A-1b 620.5 701.5 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 II-B-1a 699.1 795.3 III-2A-1a 663.5 701.5 III-2A-1b 682.3 679.2 III-2B-1a 710.3 695.8 III-2C-1 505.2 609.3
  • ALT and AST were abnormally elevated in the CCl 4 model group, and tiopronin significantly reversed the effect of this enzyme.
  • Sofosbuvir did not have this activity.
  • the compounds provided by the present invention have a significant enzyme-lowering effect, and the activity is comparable to or superior to that of tiopronin.
  • the reason may be that the thiopronin's carboxyl group is made into a prodrug, which improves its stability and its ability to be absorbed orally, thereby enhancing its activity.
  • the CCl4-induced liver injury leads to an increase in ALT and AST, and has significant inhibitory activity. And superior to the positive control tiopronin.
  • CCl 4 model group the central hepatic venous congestion, around lobular central or peripheral necrosis, liver cell swelling, ballooning deformation, II-A-1, II -Aa, II -A-2, II-A-5, III-2A-1a and other administration groups showed a small amount of punctate and fragmented necrosis, most of which showed balloon-like deformation, indicating that the toxicity caused by CCl 4 has been greatly reduced, indicating the present invention
  • the compounds involved do have a protective effect on liver damage caused by CCl 4 .
  • the compound provided by the present invention Due to the lack of an ideal animal model of HCV infection, it is not feasible to directly evaluate the protective effect of the compounds provided by the present invention on HCV-induced liver injury, but in theory and clinical application, the compound provided by the present invention has the function of protecting liver and protecting liver It also has a protective effect on the inflammatory response caused by HCV.
  • Example 30 Study on pharmacokinetic properties
  • the compounds of the present invention prepared using the above examples II-A-1, II-A-1a, II-A-1b, II-A-2, II-B-1, III-2A-1, III-2A- 1a (30mg/kg, the molar mass of the nucleoside moiety is consistent with the Sophie group), the positive control drug is Sophibuvir (25mg/kg), and each compound is added to 5% DMSO + 60% PEG400 + 35% physiological Saline was prepared by vortexing to a 10 mg/ml suspension for intragastric administration.
  • GS331007 was purchased from Shunyuan Technology (Shanghai) Co., Ltd.
  • SD rats were used as experimental animals (body weight 180-220 g), and 6 SD rats per test compound were randomly divided into 2 groups (gavage group and intravenous injection group), 3 in each group.
  • the time of blood collection from the tail vein of the intragastric administration was 0.17, 0.33, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours; the time of blood collection by intravenous administration was 0.05, 0.1, 0.17, 0.5. 1,2,4,6,8,12,24 hours.
  • 0.3 ml of whole blood was taken, and 0.1 ml of plasma was taken after centrifugation and analyzed by LC-MS.
  • liver homogenate sample or standard curve sample was added to 100 ⁇ l of acetonitrile containing internal standard (100 ng/ml), vortexed for 2 min, centrifuged for 10 min (6000 rpm), and the supernatant was transferred to a sample vial;
  • GS331007 is the final metabolite and is a marker for studying the metabolic behavior of Sofosbuvir in vivo.
  • the blood concentration and metabolic behavior of GS331007 in rats II-A-1, II-A-1a, II-A-1b, II-A-2, II-B-1 and III-2A-1a were investigated.
  • the results showed that the blood concentration of GS331007 and the area under the curve of the test compound were significantly improved compared with the blood concentration of GS331007 in the sofosbuvir group. Oral bioavailability improved significantly.
  • the oral bioavailability was 3.38, 2.75, and 2.25 times of Soofibvir, respectively.
  • the half-lives of II-A-1 and II-A-2 reached 6.14 and 6.23 hours, respectively, which were 2.95 and 2.51 times that of Sophibuvir, respectively, and the drug-time curve was more moderate. Therefore, the compounds of the present invention are superior in pharmacokinetic properties and can be administered by oral absorption for the treatment of hepatitis C diseases.
  • Test compound III-2A-1 (1 mg/mL) was tested for stability in human simulated gastric juice, simulated intestinal fluid, human plasma, and human liver microsomes. The results showed that III-2A-1 has high stability in simulated gastric fluid (1 hour metabolic rate ⁇ 5%), III-2A-1 in simulated intestinal fluid (5 minutes metabolic rate is greater than 90%), plasma (5 minutes metabolism) Both rates are greater than 99%) and liver microsomes (more than 99% in 5 minutes) can rapidly degrade and release sofosbuvir and tiopronin. This result demonstrates that the test compound can be rapidly metabolized by the intestine, plasma, and liver by oral administration, and the prototype drug is released.
  • the absorption of the drug mainly occurs in the small intestine, it is derived from the nucleoside hydroxyl group of Sophibruvir compared to the pyrimidine nitrogen atom derivative of Sophibruvir (CN201510932904.2), and the resulting compound III-2A-
  • the PK properties of 1 and its analogues in vitro are more favorable for its in vivo transformation and absorption, and it is expected to be more effective as a bifunctional prodrug molecule for anti-hepatitis C "speculation and treatment".
  • test compound III-2A-1 test (100 mg) was taken and placed in a stable container of 40 ⁇ 2 ° C and 75 ⁇ 5% to carry out an accelerated stability test.
  • a one-month experiment showed that the degradation rate of III-2 was ⁇ 1% (new impurity content), and similar compound II-A-1 was derivatized with the pyrimidine nitrogen atom of Sofibvir previously found (CN201510932904.2). Compared with its chemical stability, it has obvious advantages (the degradation rate of II-A-1 is 4.5% under the same conditions).
  • the chemical stability of the obtained compound is higher by derivatization from the nucleoside hydroxyl group of Sophibuvir, which facilitates its further development into a dual function.
  • Anti-HC candidate drugs compared with a similar compound derivatized with the pyrimidine nitrogen atom of Sophibruvir, the chemical stability of the obtained compound is higher by derivatization from the nucleoside hydroxyl group of Sophibuvir, which facilitates its further development into a dual function.

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Abstract

La présente invention concerne un promédicament comprenant une structure d'analogue nucléosidique comme représenté dans la formule I, un tautomère de celui-ci, un stéréo-isomère de celui-ci, un mélange de stéréo-isomères de celui-ci ou un solvate pharmaceutiquement acceptable de celui-ci. L'invention concerne également un procédé de préparation associé, une composition pharmaceutique formée à partir de celui-ci et une utilisation de celle-ci en tant que médicament contre l'hépatite C. Le composé ou la composition pharmaceutique de celui-ci peut être utilisé pour le traitement de l'hépatite C, et a également des fonctions telles que la protection du tissu hépatique et des cellules hépatiques, l'amélioration de la fonction hépatique et la réduction des aminotransférases.
PCT/CN2016/109913 2015-12-15 2016-12-14 Composé, son procédé de préparation, composition pharmaceutique associée, et utilisation correspondante Ceased WO2017101785A1 (fr)

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CN201510932904.2A CN105348345A (zh) 2015-12-15 2015-12-15 一种含有硫普罗宁结构的前药、其制备方法、药物组合物及其用途
CN201610289337.8A CN105777829B (zh) 2016-05-05 2016-05-05 一种含有类核苷结构的前药、其制备方法、药物组合物及其用途
CN201610289337.8 2016-05-05
CN201611024004.9A CN106883279B (zh) 2015-12-15 2016-11-18 一种前药、其制备方法、药物组合物及其用途
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US12215121B2 (en) 2020-12-29 2025-02-04 Microsoft Technology Licensing, Llc Linker structures with minimal scar for enzymatic synthesis

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