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WO2017198102A1 - Composé quinoxaline macrocyclique substitué et composition pharmaceutique et son utilisation - Google Patents

Composé quinoxaline macrocyclique substitué et composition pharmaceutique et son utilisation Download PDF

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Publication number
WO2017198102A1
WO2017198102A1 PCT/CN2017/083870 CN2017083870W WO2017198102A1 WO 2017198102 A1 WO2017198102 A1 WO 2017198102A1 CN 2017083870 W CN2017083870 W CN 2017083870W WO 2017198102 A1 WO2017198102 A1 WO 2017198102A1
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Prior art keywords
compound
reaction
mmol
added
hydrogen
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Chinese (zh)
Inventor
王义汉
赵九洋
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Shenzhen Targetrx Inc
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Shenzhen Targetrx Inc
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Priority to CN201780004350.7A priority Critical patent/CN108368130B/zh
Publication of WO2017198102A1 publication Critical patent/WO2017198102A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a hepatitis C virus inhibitor, a pharmaceutical composition and application 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.
  • HCV infection is associated with progressive liver disease, including cirrhosis and hepatocellular carcinoma.
  • Grazoprevir is an NS3 inhibitor developed by Merck. In January 2016, the United States Food and Drug Administration (FDA) approved Merck & Co's combination drug elbasvir/grazoprevir (Zepatier) for the treatment of chronic hepatitis C (HCV) genotype 1 and 4 infections. The combination does not require the use of interferon at the same time, avoiding all serious adverse events of interferon therapy.
  • the present invention discloses a hepatitis C virus inhibitor, a pharmaceutical composition and use thereof, which have better hepatitis C virus protein NS5A inhibitory activity and/or have better pharmacodynamics/pharmacokinetics. performance.
  • a hepatitis C virus inhibitor such as a macrocyclic quinoxaline compound of formula (I), or a polymorph, pharmaceutically acceptable salt, prodrug, stereoisomer, isotopic variation, hydration thereof Compound or solvent compound,
  • 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 , 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 And 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 and R 47 are each independently hydrogen. , hydrazine, halogen or trifluoromethyl;
  • 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 , at least one of 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 and R 47 Modern or awkward.
  • 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 strontium isotope content of each of the 47 generations is at least 5%, preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, more preferably greater than 25%, and even more preferably greater than 30%.
  • the ground is greater than 70%, more preferably greater than 75%, more preferably greater than 80%, more preferably greater than 85%, more preferably greater than 90%, more preferably greater than 95%, and even more preferably greater than 99%.
  • R 1 , R 2 and R 3 are each independently hydrazine or hydrogen.
  • R 1 , R 2 , and R 3 are deuterium.
  • R 4 , R 5 and R 6 are each independently hydrazine or hydrogen.
  • R 4 , R 5 and R 6 are deuterium.
  • 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 and R 20 are each independently The ground is helium 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 are ⁇ .
  • R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 are each independently hydrazine or hydrogen.
  • R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 and R 30 are ⁇ .
  • R 31 , R 32 , R 33 , R 33 , R 34 , R 35 and R 36 are each independently hydrazine or hydrogen.
  • R 31 , R 32 , R 33 , R 33 , R 34 , R 35 and R 36 are ⁇ .
  • R 37 , R 38 and R 39 are each independently hydrazine or hydrogen.
  • R 37 , R 38 , and R 39 are deuterium.
  • R 40 , R 41 and R 42 are each independently hydrazine or hydrogen.
  • R 40 , R 41 , and R 42 are ⁇ .
  • R 43 , R 44 , R 45 , R 46 and R 47 are each independently hydrazine or hydrogen.
  • R 43 , R 44 , R 45 , R 46 and R 47 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 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 polymorphic form thereof, a pharmaceutically acceptable salt, a prodrug, Stereoisomers, isotopic variations, hydrates or solvates.
  • it further comprises other active compounds including, but not limited to, others HCV antiviral, anti-infective, immunomodulatory, antibiotic or vaccine combination.
  • the immunomodulator is an interferon drug compound.
  • the quinoxaline macrocycles of the invention may be used in combination therapies involving one or more additional therapeutic agents.
  • Additional therapeutic agents include those that also target HCV, target different pathogenic agents, or enhance the immune system.
  • Agents that enhance the immune system include those that normally enhance the function of the immune system and those that produce a specific immune response against HCV.
  • Additional therapeutic agents that target HCV include agents that target NS3 and agents that target other HCV activities, such as NS5A and NS5B, and agents that target host cell activity involved in HCV replication.
  • therapeutic agents that may be present in the combination include ribavirin, levovirin, viramidine, thymosin alpha-1, interferon-beta, interferon-alpha, PEGylated interferon-alpha (peg interferon-alpha) a combination of interferon-[alpha] and ribavirin, a combination of peg interferon-[alpha] and ribavirin, a combination of interferon-[alpha] and levovirin, and a combination of peg interferon-[alpha] and levovirin.
  • peg interferon-alpha a combination of interferon-[alpha] and ribavirin
  • peg interferon-[alpha] and ribavirin a combination of interferon-[alpha] and levovirin
  • peg interferon-[alpha] and levovirin a combination of peg interferon-[alpha] and levovirin.
  • Interferon- ⁇ includes recombinant interferon- ⁇ 2a (such as Roferon interferon available from Hoffmann-LaRoche, Nutley, NJ), PEGylated interferon- ⁇ 2a (Pegasys), interferon- ⁇ 2b (eg available from Schering Corp) .Kenilworth, NJ's Intron-A interferon), PEGylated interferon- ⁇ 2b (PegIntron), recombinant complex interferon (such as interferon alphacon-1), and purified interferon- ⁇ product.
  • the individual components of the combination may be administered separately at different times during the course of the treatment or simultaneously in separate or individual combinations.
  • the compounds of the invention may also be administered in combination with the antiviral agent amantadine (1-aminoadamantane).
  • amantadine 1-aminoadamantane
  • the compounds of the invention may also be administered in combination with the antiviral polymerase inhibitor R7128 (Roche).
  • the compounds of the invention may also be administered in combination with an HCV NS5B polymerase inhibitor.
  • HCV NS5B polymerase inhibitors that can be used as a combination therapy include, but are not limited to, International Patent Application Publication No. WO 02/057287, WO 02/057425, WO 03/068244, WO 2004/000858, WO 04/003138, and WO 2004 /007512; those disclosed in U.S. Patent No. 6,777,392, and U.S. Patent Application Publication No. 2004/0067901, the entire contents of each of which are hereby incorporated by reference.
  • Other such HCV polymerase inhibitors include, but are not limited to, valopicitabine (NM-283; Idenix) and 2'-F-2'-beta-methylcytidine (see also WO 2005/003147).
  • 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.
  • compositions of the present invention can be produced by methods well known in the art, such as conventional mixing methods, dissolution methods, Granulation method, sugar-coated pellet method, grinding method, emulsification method, freeze-drying method, and the like.
  • 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.
  • NS3 inhibitors can also be used in the preparation and implementation of screening assays for antiviral compounds.
  • such compounds can be used to isolate enzyme mutants, which are excellent screening tools for more potent antiviral compounds.
  • these compounds can be used to establish or measure binding sites for other antiviral agents to HCV protease, for example by competitive inhibition.
  • the compounds of the invention can be administered by contacting the active agent with the site of action of the drug. They can be administered as a separate therapeutic or combination of therapeutic agents by conventional means which can be used in combination with the drug. They can be administered alone, but are usually administered with a pharmaceutical carrier selected according to the chosen route of administration and standard pharmaceutical practice.
  • 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%).
  • the invention also includes isotopically labeled compounds (also referred to as "isotopic variants"), equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes. In addition, heavier isotopic substitutions such as guanidine, or 2 H, are preferred in certain therapies due to their good metabolic stability, such as increased half-life or reduced dosage in vivo, and therefore may be preferred in certain circumstances. Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • 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.
  • polymorph refers to a different arrangement of chemical drug molecules, generally expressed as the presence of a pharmaceutical material in a solid state.
  • a drug may exist in a plurality of crystalline forms, and different crystal forms of the same drug may have different dissolution and absorption in the body, thereby affecting the dissolution and release of the formulation.
  • 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.
  • prodrug refers to a compound that is converted in vivo to an active form having its medical effect by, for example, hydrolysis in blood.
  • a prodrug is any covalently bonded carrier which, when administered to a patient, releases the compound of the invention in vivo.
  • Prodrugs are typically prepared by modifying functional groups that cleave the prodrug in vivo to yield the parent compound.
  • Prodrugs include, for example, a compound of the invention wherein a hydroxy, amino or thiol group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amino or thiol group.
  • prodrugs include, but are not limited to, covalent derivatives of the compounds of the invention formed by the hydroxyl, amino or thiol functional groups thereof with acetic acid, formic acid or benzoic acid.
  • acetic acid formic acid or benzoic acid.
  • an ester such as a methyl ester, an ethyl ester or the like can be used.
  • the ester itself may be active and/or may hydrolyze under conditions in humans.
  • Suitable pharmaceutically acceptable in vivo hydrolysable esters include those which readily decompose in the human body to release the parent acid or its salt.
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of "stereoisomer" forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the beneficial effects of the present invention compared to the prior art are: First, the compound of the present invention has excellent inhibitory effect on the hepatitis C virus protein NS3. Second, by deuteration this technique changes the metabolism of the compound in the organism, giving the compound better pharmacokinetic parameter characteristics. In this case, the dosage can be changed and a long-acting preparation can be formed to improve the applicability. Third, replace it with ⁇ The hydrogen atom in the compound, due to its strontium isotope effect, increases the drug concentration of the compound in the animal and improves the drug efficacy. Fourth, replacing the hydrogen atom in the compound with hydrazine can inhibit certain metabolites and improve the safety of the compound.
  • 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.
  • Methyl magnesium chloride (16.9 mL, 50.94 mmol) was added to a three-necked reaction flask under nitrogen to heat to 60 ° C. At this temperature, a solution of compound 7 in dimethyltetrahydrofuran (4.16 g, 25.47 mmol, 20 mL) was slowly added dropwise.
  • 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 NS3 inhibitor MK-5172 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.
  • HCV GT1a EC 50 (nM) HCV GT1b EC 50 (nM) HCV CC 50 (nM) MK-5172 0.967 0.98 >1000 G-1 2.188 1.863 >1000
  • the compound of the present invention can be used for the inhibition of hepatitis C virus by inhibiting multiple genotypes of HCV.
  • 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 metabolic stability of human and rat liver microsomes was evaluated by simultaneously testing the compounds of the present invention and their compounds without deuteration.
  • the half-life and liver intrinsic clearance as indicators of metabolic stability are shown in Table 2.
  • the undeuterated compound MK-5172 was used as a control sample in Table 2.
  • the compound of the present invention, particularly G-4 can significantly improve metabolic stability by comparison with the compound KK-5172 which has not been deuterated, and is thus more suitable as a hepatitis C virus inhibitor.

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Abstract

La présente invention concerne un composé quinoxaline macrocyclique substitué et une composition pharmaceutique et son utilisation, le composé quinoxaline macrocyclique étant le composé tel que présenté dans la formule (I), ou un polymorphe, un sel de qualité pharmaceutique, un promédicament, un stéréoisomère, un variant isotope, un hydrate, ou un solvate de ce dernier. Le composé de la présente invention peut être utilisé comme inhibiteur du virus de l'hépatite C, et présente une meilleure activité d'inhibition de la protéine du virus de l'hépatite C NS3A et une meilleure efficacité pharmacodynamique/pharmacocinétique. Le composé présente une bonne applicabilité et une sécurité élevée, peut être utilisé de façon à préparer des médicaments destinés à traiter les infections par le virus de l'hépatite C, et présente de bonnes perspectives de développement sur le marché.
PCT/CN2017/083870 2016-05-16 2017-05-11 Composé quinoxaline macrocyclique substitué et composition pharmaceutique et son utilisation Ceased WO2017198102A1 (fr)

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CN112661775A (zh) 2021-04-16
CN108368130A (zh) 2018-08-03

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