WO2017121188A1 - Inhibiteur du virus de l'hépatite c, composition pharmaceutique et application associées - Google Patents

Inhibiteur du virus de l'hépatite c, composition pharmaceutique et application associées Download PDF

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Publication number
WO2017121188A1
WO2017121188A1 PCT/CN2016/106875 CN2016106875W WO2017121188A1 WO 2017121188 A1 WO2017121188 A1 WO 2017121188A1 CN 2016106875 W CN2016106875 W CN 2016106875W WO 2017121188 A1 WO2017121188 A1 WO 2017121188A1
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compound
hepatitis
mmol
virus
virus inhibitor
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PCT/CN2016/106875
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English (en)
Chinese (zh)
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王义汉
赵九洋
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深圳市塔吉瑞生物医药有限公司
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Publication of WO2017121188A1 publication Critical patent/WO2017121188A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a hepatitis C virus inhibitor, a pharmaceutical composition and the use thereof.
  • HCV Hepatitis C Virus
  • the encapsulated HCV virion contains a positive-stranded RNA genome that encodes all known virus-specific proteins in a single uninterrupted open reading frame.
  • the open reading frame comprises approximately 9500 nucleotides and encodes a single large polyprotein of approximately 3000 amino acids.
  • Polyproteins include core proteins, envelope proteins E1 and E2, membrane-bound protein P7, and non-structural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B.
  • Sofabru is the first medicine in the world that can completely cure hepatitis C in the short term. It takes the oral route directly to the lesion, and the method has simple side effects and is highly sought after by patients. Sofibuvir is produced by Gilead, USA, and is marketed in the United States in 2013. It has been clinically proven to be effective in treating hepatitis C, type 1, 2, 3, and 4, including liver transplantation, liver cancer, and HCV/HIV-1 co-infection. Clinical Trials. This breakthrough has brought the gospel to hepatitis C patients around the world.
  • Odalasvir (Achillion's Hepatitis C Drug, also known as ACH-3102) is a new drug developed by Achillion for the potential treatment of hepatitis C. It works by inhibiting the hepatitis C virus protein NS5A and is currently pre-registered. status. Its hepatitis C cocktail therapy combined with sofosbuvir, in the trial of patients with type I genotype hepatitis C without ribavirin, obtained the ideal phase II clinical data, which can kill the virus found within six weeks. It is the shortest treatment time and highest response rate that can be achieved when all two drugs are combined.
  • the present invention discloses a substituted hepatitis C virus inhibitor, a pharmaceutical composition thereof and use thereof, which have better hepatitis C virus protein NS5A inhibitory activity and/or have better pharmacodynamics/pharmacokinetics. Power Learning performance.
  • a hepatitis C virus inhibitor such as a hepatitis C virus inhibitor represented by the formula (I), or a crystalline form thereof, a pharmaceutically acceptable salt, a hydrate or Solvent compound,
  • Additional conditions are R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 And R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 ,
  • the shape and volume of the ruthenium in the drug molecule are substantially the same as those of the hydrogen. If the hydrogen in the drug molecule is selectively replaced with hydrazine, the deuterated drug generally retains the original biological activity and selectivity. At the same time, the inventors have confirmed through experiments that the binding of carbon-germanium bonds is more stable than the combination of carbon-hydrogen bonds, which can directly affect the absorption, distribution, metabolism and excretion of some drugs, thereby improving the efficacy, safety and tolerability of the drugs.
  • the strontium isotope content of the cerium in the deuterated position is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, and even more preferably greater than 95. %, more preferably greater than 99%.
  • the compound of the formula (I) contains at least one deuterium atom, and the number of deuterium atoms may be any one of 1 to 68.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrazine or hydrogen.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are ⁇ .
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are each independently hydrazine or hydrogen.
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 is ⁇ .
  • R 7 and R 15 are ⁇ .
  • R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 are ⁇ .
  • R 14 and R 22 are ⁇ .
  • R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 and R 48 are each independently hydrazine or hydrogen.
  • R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 and R 48 are ⁇ .
  • R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , and R 45 are ⁇ .
  • R 33 , R 34 , R 35 , R 46 , R 47 and R 48 are fluorene.
  • R 49 , R 50 , R 51 , R 52 , R 53 and R 54 are each independently hydrazine or hydrogen.
  • R 49 , R 50 , R 51 , R 52 , R 53 and R 54 are ⁇ .
  • R 55 , R 56 , R 57 , R 58 , R 59 and R 60 are each independently hydrazine or hydrogen.
  • R 55 , R 56 , R 57 , R 58 , R 59 , R 60 are ⁇ .
  • R 61 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 and R 68 are each independently hydrazine or hydrogen.
  • R 61 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 are ⁇ .
  • the compound is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:
  • the compound does not include a non-deuterated compound.
  • the present invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the hepatitis C virus inhibitor as described above, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvent thereof
  • a pharmaceutical composition of a compound, stereoisomer, prodrug or isotopic variation comprising a pharmaceutically acceptable carrier and the hepatitis C virus inhibitor as described above, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvent thereof.
  • the pharmaceutically acceptable carrier includes a glidant, a sweetener, a diluent, a preservative, a dye/colorant, a flavor enhancer, a surfactant, a wetting agent, a dispersant At least one of a disintegrant, a suspending agent, a stabilizer, an isotonic agent, a solvent or an emulsifier.
  • the pharmaceutical composition is a tablet, a pill, a capsule, a powder, a granule, an ointment, an emulsion, a suspension, a solution, a suppository, an injection, an inhalant, a gel, a microsphere or Aerosol.
  • Typical routes of administration of the pharmaceutical compositions of the invention include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal , intramuscular, subcutaneous, intravenous administration. Oral administration or injection administration is preferred.
  • the pharmaceutical composition of the present invention can be produced by a method known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a pulverization method, an emulsification method, a freeze-drying method, and the like.
  • it further comprises other active compounds which are immunomodulatory or antiviral pharmaceutical compounds.
  • the immunomodulator is an interferon drug compound.
  • the antiviral drug compound is ribavirin, amantadine, other inhibitors of NS5A, helicase in the HCV life cycle, protease, polymerase, metalloproteinase or internal ribosome entry.
  • An inhibitor of a site target, wherein the other inhibitor of NS5A is Radipap or Dhakavir At least one.
  • the present invention also provides a method of preparing a pharmaceutical composition comprising the steps of: administering a pharmaceutically acceptable carrier to a hepatitis C virus inhibitor as described above, or a crystalline form thereof, a pharmaceutically acceptable salt, or a hydrate thereof Or the solvate is mixed to form a pharmaceutical composition.
  • the invention also discloses the use of a hepatitis C virus inhibitor as described above, characterized in that it is used for the preparation of a medicament for the treatment of hepatitis C virus infection.
  • the HCV includes a plurality of genotypes thereof and a plurality of gene subtypes, such as 1a, 1b, 2a, 2b, 3a, 3b, 4a, 5a, 6a.
  • halogen means F, Cl, Br, and I unless otherwise specified. More preferably, the halogen atom is selected from the group consisting of F, Cl and Br.
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid.
  • salts of the compounds of the invention with bases such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), ammonium salts (for example lower alkanolammonium).
  • bases such as alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), ammonium salts (for example lower alkanolammonium).
  • Salts and other pharmaceutically acceptable amine salts such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butyl
  • a base amine salt an ethylenediamine salt, a hydroxyethylamine salt, a dihydroxyethylamine salt, a trihydroxyethylamine salt, and an amine salt formed of morpholine, piperazine, and lysine, respectively.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • the compound of the present invention has excellent inhibitory properties against the hepatitis C virus protein NS5A.
  • this technique changes the metabolism of the compound in the organism, giving the compound better pharmacokinetic parameter characteristics.
  • the dosage can be changed and a long-acting preparation can be formed to improve the applicability.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • a hepatitis C virus inhibitor with the chemical name di-d3-methyl ((2S, 2'S)-((2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-2, 2'-(5, 5' -(tricyclo[8.8.2.24,7]hexa-4,6,10,12,13,15-hexene-5,11-diyl)di(1H-benzimidazole-5,2-di Base)) bis(octahydro-1hydro-indole-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate, ie Compound T-1, the molecular formula is as follows:
  • the compound 6 (460 mg, 0.518 mmol) was dissolved in a mixed solvent of 4 mL of dichloromethane and 1 mL of methanol, and 2.33 ml of hydrogen chloride dioxane was added at 0 ° C, and the mixture was allowed to react at room temperature for 1 hour. After the TLC test was completed, the solvent was removed by concentration. The crude compound 7 was obtained and was directly put to the next step without purification.
  • the triphosgene (2.67 g, 9 mmol) was dissolved in 20 ml of toluene, and deuterated methanol (1.08 g, 30) was added dropwise at 0 °C.
  • a solution of mmol and triethylamine (3.34 g, 33 mmol) in 20 ml of toluene was added and then allowed to react to room temperature for 1 hour.
  • the reaction liquid was washed three times with ice water, dried over anhydrous sodium sulfate, and filtered to give a toluene solution of compound 8 and directly to the next reaction.
  • the triphosgene (0.3 g, 1 mmol) was dissolved in 2 mL of toluene, and a solution of methanol (96.12 mg, 3 mmol) and triethylamine (334 mg, 3.3 mmol) in 2 mL of toluene was added dropwise at 0 ° C. hour.
  • the reaction liquid was washed three times with ice water, dried over anhydrous sodium sulfate, and filtered to give a toluene solution of compound 10, which was directly applied to the next reaction.
  • the compound 16 (480 mg, 0.537 mmol) was dissolved in a mixed solvent of 4 mL of dichloromethane and 1 mL of methanol, and 2.0 mL of hydrogen chloride dioxane was added at 0 ° C, and the mixture was allowed to react at room temperature for 1 hour. After the TLC was detected, the solvent was concentrated. The crude compound 17 was obtained and was directly taken to the next step without purification.
  • the compound 16 (480 mg, 0.537 mmol) was dissolved in a mixed solvent of 4 mL of dichloromethane and 1 mL of methanol, and 2.0 mL of hydrogen chloride dioxane was added at 0 ° C, and the mixture was allowed to react at room temperature for 1 hour. After the TLC was detected, the solvent was concentrated. The crude compound 20 was obtained and was directly taken to the next step without purification.
  • Moc-L-proline (98.53 mg, 0.553 mmol), HOBT (74.7 mg, 0.553 mmol) and EDCI (106.1 mg, 0.553 mmol) were added to the reaction flask, dissolved in 3 mL of acetonitrile, and reacted at room temperature for 5 minutes to obtain activation. After solution 1.
  • Compound 20 (200 mg, 0.24 mmol) was dissolved in 5 mL DMF and DIPEA (223.3 mg, 1. The solution 1 was added to the solution 2, and the reaction was stirred at room temperature for 3 hours.
  • the inventors used the HCV Replicon System as an evaluation model. Since its first report in Science in 1999, the HCV replication system has become one of the most important tools for studying HCV RNA replication, pathogenicity and viral persistence, for example, the use of replicons has successfully demonstrated the 5' required for HCV RNA replication. - NCR minimum region, and the HCV replication subsystem has been successfully used as an evaluation model for antiviral drugs. The inventors of the present invention verified according to the methods described in Science, 1999, 285 (5424), 110-3, and J. Virol, 2003, 77(5), 3007-19.
  • the inhibitory activities of the recombinant hepatitis C virus genotype 1a and 1b replicons were detected by stable transfection of replicon cells with HCV-1a and HCV-1b. This experiment will use the NS5A inhibitor BMS-790052 as a positive control compound.
  • Step 1 The compound was diluted 1:3 in 8 series points, double-replicated, and added to a 96-well plate.
  • the DMSO was set to no compound control.
  • the final concentration of DMSO in the cell culture was 0.5%.
  • Step 2 HCV-1a and 1b cells were separately suspended in a culture medium containing 10% FBS, and seeded into a 96-well plate containing the compound at a density of 8,000 cells per well. The cells were cultured for 3 days at 5% CO 2 at 37 °C.
  • Step 3 The cytotoxicity of the compound against GT1b replicon was determined using CellTiter-Fluor (Promega).
  • Step 4 Detection of luciferase assay by Bright-Glo (Promega) for anti-hepatitis C virus activity.
  • Step Five using GraphPad Prism data analysis software, the curve fitting and EC 50 values were calculated and the 50 value CC.
  • This infection model is referred to as A novel luciferase and GFP dual reporter virus for rapid and convenient evaluation of HCV replication.
  • the compound of the present invention can inhibit multiple genotypes of HCV and exerts superior anti-HCV action by inhibiting the mechanism of HCV NS5A protein.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • Preparation of the stock solution A certain amount of the powder of the compound examples 1-4 was accurately weighed and dissolved to 5 mM with DMSO, respectively.
  • phosphate buffer 100 mM, pH 7.4.
  • the pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the compounds of the present invention exhibited excellent metabolic stability in both human liver microsomes and rat liver microsome experiments.
  • OBJECTIVE To investigate the pharmacokinetic behavior of the compounds of the present invention after administration of Odalasvir and Compound T-1 to rats.
  • SD rat grade SPF grade
  • Weight range 180 ⁇ 220g (actual weight range is 187 ⁇ 197g)
  • the blood is taken from 100-200L, placed in a 0.5mL Eppendorf tube that is anticoagulated with EDTA-K2, and immediately mixed. After anticoagulation, gently invert the tube 5-6 times as soon as possible, after the blood is taken. Place in an ice box, centrifuge the blood sample at 4000 rpm, 10 min, 4 ° C for 30 min, collect all plasma and store at -20 ° C immediately. Plasma concentrations in plasma at each time point were determined after sample collection at all time points.
  • the present inventors found that the compound T-1 has superior activity to Odalasvir and has excellent pharmacokinetic properties as compared with Odalasvir, and thus is more suitable as a compound which inhibits the hepatitis C virus protein NS5A. It is further suitable for the preparation of a medicament for treating hepatitis C virus infection.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne un inhibiteur du virus de l'hépatite C, une composition pharmaceutique et une application associées. L'inhibiteur du virus de l'hépatite C est un composé de formule (I), ou sa forme cristalline, un sel, promédicament, hydrate ou solvate pharmaceutiquement acceptables correspondants. Le composé selon la présente invention inhibe plus fortement la protéine NS5A du virus de l'hépatite C, et ses performances pharmacodynamiques/pharmacocinétiques sont meilleures. Le composé est très utile et ne présente aucun danger, il peut être utilisé pour préparer un médicament destiné à traiter l'infection par le virus de l'hépatite C, et dispose d'un potentiel de commercialisation élevé.
PCT/CN2016/106875 2016-01-12 2016-11-23 Inhibiteur du virus de l'hépatite c, composition pharmaceutique et application associées WO2017121188A1 (fr)

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CN201610017674.1A CN106083829B (zh) 2016-01-12 2016-01-12 一种丙型肝炎病毒抑制剂、药物组合物及其应用
CN201610017674.1 2016-01-12

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CN106083829B (zh) * 2016-01-12 2019-01-22 深圳市塔吉瑞生物医药有限公司 一种丙型肝炎病毒抑制剂、药物组合物及其应用
CN110840969B (zh) * 2019-11-22 2021-04-16 南方医科大学 一种治疗丙型肝炎的中药组合物及其应用
CN115677595B (zh) * 2022-10-26 2024-06-14 江苏睿实生物科技有限公司 一种2,4,5-三氯嘧啶的制备方法

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CN103561739A (zh) * 2011-05-27 2014-02-05 艾其林医药公司 可用于治疗hcv感染的经取代的脂肪芬、环芬、异芬、杂芬、杂-异芬以及金属茂
CN106083829A (zh) * 2016-01-12 2016-11-09 深圳市塔吉瑞生物医药有限公司 一种丙型肝炎病毒抑制剂、药物组合物及其应用

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US8329159B2 (en) * 2006-08-11 2012-12-11 Bristol-Myers Squibb Company Hepatitis C virus inhibitors

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CN103561739A (zh) * 2011-05-27 2014-02-05 艾其林医药公司 可用于治疗hcv感染的经取代的脂肪芬、环芬、异芬、杂芬、杂-异芬以及金属茂
CN106083829A (zh) * 2016-01-12 2016-11-09 深圳市塔吉瑞生物医药有限公司 一种丙型肝炎病毒抑制剂、药物组合物及其应用

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