WO2024032718A1 - Crystal form of hepatitis c inhibitor and use thereof in drug - Google Patents

Crystal form of hepatitis c inhibitor and use thereof in drug Download PDF

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Publication number
WO2024032718A1
WO2024032718A1 PCT/CN2023/112232 CN2023112232W WO2024032718A1 WO 2024032718 A1 WO2024032718 A1 WO 2024032718A1 CN 2023112232 W CN2023112232 W CN 2023112232W WO 2024032718 A1 WO2024032718 A1 WO 2024032718A1
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Prior art keywords
crystal form
formula
compound represented
hcv
present
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PCT/CN2023/112232
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French (fr)
Chinese (zh)
Inventor
谢洪明
黎超
孙垚
谭敏
黄恩活
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广东东阳光药业股份有限公司
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Publication of WO2024032718A1 publication Critical patent/WO2024032718A1/en

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of medical technology and relates to a crystal form of a hepatitis C inhibitor compound, its pharmaceutical composition and their use in preparing drugs for preventing, treating, treating or alleviating HCV infection or diseases related to hepatitis C disease. the use of.
  • HCV infection is a major health problem leading to chronic liver diseases such as cirrhosis and hepatocellular carcinoma, with infected individuals estimated to account for 2-15% of the world's population. Once infected, about 20% of people clear the virus, but the remainder will carry HCV for the rest of their lives. This viral disease is transmitted parenterally through contaminated blood and blood products, contaminated needles, or sexual behavior, and vertically from infected mothers or carrier mothers to their offspring. HCV infection can lead to chronic inflammation, necrosis and fibrosis of the liver, and some patients may develop cirrhosis or even hepatocellular carcinoma. The mortality rate related to HCV infection will continue to increase, which is extremely harmful to the health and life of patients.
  • Example 3 of Chinese patent CN108299532A discloses the following compound of formula (I).
  • This compound is a nucleoside analog prodrug against hepatitis C virus infection.
  • This compound is an inhibitor of RNA-dependent RNA virus replication and can It is used as an inhibitor of HCV NS5B polymerase and as an inhibitor of HCV replication, and has significant effects in the treatment of hepatitis C virus (HCV) infection or hepatitis C disease.
  • HCV hepatitis C virus
  • the present invention provides crystal form A of the compound represented by formula (I), which has better stability, pharmacokinetics and other properties, and thus has better pharmaceutical properties.
  • the present invention relates to the crystalline form A of the compound represented by formula (I), as well as pharmaceutical compositions containing the crystalline form A, and also relates to their preparation for the treatment or prevention of HCV infection or/and hepatitis C disease. Use in medicines related to diseases.
  • the present invention provides a crystal form A of the compound represented by formula (I):
  • the X-ray powder diffraction pattern of the crystal form A includes the following diffraction peaks at 2 ⁇ angles: 10.35 ⁇ 0.2°, 10.56 ⁇ 0.2°, 13.39 ⁇ 0.2°, 15.68 ⁇ 0.2°, 15.82 ⁇ 0.2°, 20.42 ⁇ 0.2 °,20.84 ⁇ 0.2°,21.71 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of crystal form A of the compound represented by formula (I) of the present invention includes the following diffraction peaks at 2 ⁇ angles: 4.28 ⁇ 0.2°, 6.69 ⁇ 0.2°, 10.35 ⁇ 0.2 °,10.56 ⁇ 0.2°,11.83 ⁇ 0.2°,12.78 ⁇ 0.2°,13.39 ⁇ 0.2°,15.68 ⁇ 0.2°,15.82 ⁇ 0.2°,16.79 ⁇ 0.2°,17.59 ⁇ 0.2°,17.83 ⁇ 0.2°,20.00 ⁇ 0.2 °,20.42 ⁇ 0.2°,20.84 ⁇ 0.2°,21.71 ⁇ 0.2°,23.50 ⁇ 0.2°,24.73 ⁇ 0.2°,26.36 ⁇ 0.2°,26.52 ⁇ 0.2°,27.38 ⁇ 0.2°,28.18 ⁇ 0.2°,29.95 ⁇ 0.2 °,31.30 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of crystal form A of the compound represented by formula (I) of the present invention includes the following diffraction peaks at 2 ⁇ angles: 4.28 ⁇ 0.2°, 5.58 ⁇ 0.2°, 6.69 ⁇ 0.2°,8.23 ⁇ 0.2°,10.35 ⁇ 0.2°,10.56 ⁇ 0.2°,11.83 ⁇ 0.2°,12.78 ⁇ 0.2°,13.39 ⁇ 0.2°,15.68 ⁇ 0.2°,15.82 ⁇ 0.2°,16.45 ⁇ 0.2°,16.79 ⁇ 0.2°,17.59 ⁇ 0.2°,17.83 ⁇ 0.2°,18.93 ⁇ 0.2°,20.00 ⁇ 0.2°,20.42 ⁇ 0.2°,20.84 ⁇ 0.2°,21.71 ⁇ 0.2°,21.99 ⁇ 0.2°,23.17 ⁇ 0.2°,23.50 ⁇ 0.2°,23.78 ⁇ 0.2°,24.73 ⁇ 0.2°,25.71 ⁇ 0.2°,26.36 ⁇ 0.2°,26.52 ⁇ 0.2°,27.38 ⁇ 0.2°,28.18 ⁇ 0.2°,29.95 ⁇ 0.2
  • the X-ray powder diffraction pattern of crystal form A of the compound represented by formula (I) of the present invention includes the following diffraction peaks at 2 ⁇ angles: 4.28 ⁇ 0.2°, 5.58 ⁇ 0.2°, 6.69 ⁇ 0.2°,8.23 ⁇ 0.2°,8.52 ⁇ 0.2°,10.35 ⁇ 0.2°,10.56 ⁇ 0.2°,11.17 ⁇ 0.2°,11.83 ⁇ 0.2°,12.78 ⁇ 0.2°,13.39 ⁇ 0.2°,15.68 ⁇ 0.2°,15.82 ⁇ 0.2°,16.45 ⁇ 0.2°,16.79 ⁇ 0.2°,17.59 ⁇ 0.2°,17.83 ⁇ 0.2°,18.93 ⁇ 0.2°,20.00 ⁇ 0.2°,20.42 ⁇ 0.2°,20.84 ⁇ 0.2°,21.71 ⁇ 0.2°,21.99 ⁇ 0.2°,23.17 ⁇ 0.2°,23.50 ⁇ 0.2°,23.78 ⁇ 0.2°,24.10 ⁇ 0.2°,24.42 ⁇ 0.2°,24.73 ⁇ 0.2°,25.71 ⁇ 0.2°,26.36 ⁇ 0.2°
  • the crystal form A of the compound represented by formula (I) of the present invention has an X-ray powder diffraction pattern substantially as shown in Figure 1 .
  • the differential scanning calorimetry diagram of Form A of the compound represented by Formula (I) of the present invention includes an endothermic peak of 135°C ⁇ 3°C.
  • Form A of the compound represented by Formula (I) of the present invention has a differential scanning calorimetry pattern substantially as shown in Figure 2.
  • the crystal form A of the compound represented by formula (I) of the present invention has a TGA chart (thermogravimetric analysis chart) between 200°C and 200°C. No significant weight loss before.
  • the TGA chart (thermogravimetric analysis chart) of crystal form A of the compound represented by formula (I) of the present invention is as shown in Figure 3, and there is no significant weight loss before 200°C.
  • the present invention provides a pharmaceutical composition comprising crystalline form A of the compound represented by formula (I) of the present invention.
  • compositions of the present invention further comprise pharmaceutically acceptable carriers, excipients, diluents, adjuvants or combinations thereof.
  • compositions of the present invention further comprise other anti-HCV drugs.
  • other anti-HCV drugs described in the present invention are interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote the production of type 1 helper T cell responses, interfering RNA, Antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, baviliximab, hepatitis C immune globulin, civacir, boceprevir, Tilaprevir, daclatasvir, simeprevir, analprevir, silprevir, danoprevir, ledipasvir, nitazoxanide, nevirapine, alisporivir, imitasvir , vaniprevir, faldaprevir, paritaprevir, sovaprevir, grazoprevir, elbasvir, vedroprevir, narlaprevir, ombitasvir, ravidasvir
  • the present invention provides the use of crystal form A of the compound represented by formula (I) of the present invention or the pharmaceutical composition of the present invention in the preparation of medicines for prevention, treatment, treatment or Reduces illness associated with HCV infection or hepatitis C disease.
  • the present invention provides the use of a crystalline form A or a pharmaceutical composition of the compound represented by formula (I) of the present invention in the preparation of medicines for inhibiting the HCV replication process and/or inhibiting HCV Function of viral protein;
  • the HCV replication process includes HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV release;
  • the HCV viral protein is selected from metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, as well as the internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.
  • IRS internal ribosome entry point
  • IMPDH inosine monophosphate dehydrogenase
  • the present invention provides the use of crystal form A or a pharmaceutical composition of the compound represented by formula (I) of the present invention in the preparation of medicines, which are used to inhibit the function of HCV viral proteins;
  • the HCV viral protein is NS5B.
  • the present invention provides the use of crystal form A or a pharmaceutical composition of the compound represented by formula (I) of the present invention for preventing, treating, treating or alleviating HCV infection or hepatitis C disease in patients.
  • the present invention provides a crystal form A or a pharmaceutical composition of the compound represented by formula (I) of the present invention for inhibiting the HCV replication process and/or inhibiting the function of the HCV viral protein;
  • the HCV replication process Including HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV release;
  • the HCV viral protein is selected from metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and is required for HCV viral replication Internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH).
  • IRS Internal ribosome entry point
  • IMPDH inosine monophosphate dehydrogenase
  • the present invention provides a crystal form A or pharmaceutical composition of the compound represented by formula (I) of the present invention for inhibiting the function of HCV viral protein; the HCV viral protein is NS5B.
  • the present invention provides a method for preventing, treating, treating or alleviating HCV infection or hepatitis C disease in a patient, which includes administering to the patient an effective therapeutic amount of the crystal form of the compound represented by formula (I) of the present invention.
  • a or pharmaceutical composition is administered to the patient an effective therapeutic amount of the crystal form of the compound represented by formula (I) of the present invention.
  • the present invention provides a method for inhibiting the HCV replication process and/or inhibiting the function of HCV viral proteins, which includes administering to the patient an effective therapeutic amount of crystal form A or a drug of the compound represented by formula (I) of the present invention.
  • Composition; the HCV replication process includes HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV release; the HCV viral protein is selected from metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B , as well as the internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.
  • IRS internal ribosome entry point
  • IMPDH inosine monophosphate dehydrogenase
  • the present invention provides a method for inhibiting the function of HCV viral proteins, which includes administering to a patient an effective therapeutic amount of crystal form A or a pharmaceutical composition of the compound represented by formula (I) of the present invention;
  • the HCV viral protein is NS5B.
  • the solvent used in the preparation method of the crystalline form of the present invention is not particularly limited. Any solvent that can dissolve the starting materials to a certain extent and does not affect its properties is included in the present invention. In addition, many similar modifications, equivalent substitutions, or equivalent solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are deemed to be within the scope of the present invention.
  • the present invention provides preferred solvents used in each reaction step.
  • the preparation experiments of the crystal form A of the compound represented by formula (I) of the present invention are described in detail in the Examples section.
  • the present invention provides pharmacological testing experiments (such as pharmacokinetic experiments) of the crystal form A of the compound represented by formula (I).
  • pharmacological testing experiments such as pharmacokinetic experiments
  • the crystal form A of the compound represented by formula (I) of the present invention has good stability and pharmacokinetic properties.
  • Crystalline form refers to a solid with a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or polymorphs, solvates, hydrates, Clathrate, eutectic, salt, salt solvate, salt hydrate. Crystalline forms of substances can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, Crystallization in a defined space, e.g. in nanopores or capillaries, on a surface or template, e.g.
  • additives such as co-crystallized antimolecules, desolvation, dehydration, rapid evaporation, Rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, anti-solvent addition, grinding and solvent drop grinding, etc.
  • Solvent refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid).
  • Solvents used in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, ethanol , Ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropyl alcohol, methanol, Methyl ethyl ketone, N-methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene,
  • Antisolvent refers to a fluid that promotes the precipitation of a product (or product precursor) from a solvent.
  • the antisolvent can include a cold gas, or a fluid that promotes precipitation through a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid than the solvent.
  • Crystal forms can be identified through a variety of technical methods, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance Resonance method, Raman spectroscopy, X-ray single crystal diffraction, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • XRPD X-ray powder diffraction
  • IR infrared absorption spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Raman spectroscopy Raman spectroscopy
  • X-ray single crystal diffraction X-ray single crystal diffraction
  • solution calorimetry scanning electron microscopy (SEM)
  • SEM scanning electron microscopy
  • X-ray powder diffraction can detect changes in crystal form, crystallinity, crystal structure state and other information, and is a common method for identifying crystal forms.
  • the peak position of the XRPD spectrum mainly depends on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the Figures of the invention. At the same time, the measurement of 2 ⁇ of the XRPD spectrum may have experimental errors.
  • the measurement of 2 ⁇ of the XRPD spectrum may be slightly different between different instruments and different samples, so the value of 2 ⁇ cannot be regarded as absolute. According to the conditions of the instrument used in this test, there is an error tolerance of ⁇ 0.2 ° for the diffraction peak.
  • DSC Differential scanning calorimetry
  • ⁇ -Al 2 O 3 inert reference substance
  • the endothermic peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Accordingly, in some embodiments, the crystalline forms described herein are characterized by a DSC pattern having characteristic peak positions substantially as shown in the DSC patterns provided in the Figures herein. At the same time, the DSC spectrum may have experimental errors. The peak position and peak value of the DSC spectrum may be slightly different between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. According to the conditions of the instrument used in this test, there is an error tolerance of ⁇ 3°C for the endothermic peak.
  • Thermogravimetric analysis is a technique that measures the mass change of a substance with temperature under program control. It is suitable for checking the loss of solvent in crystals or the process of sample sublimation and decomposition. It can be inferred that the crystals contain crystal water or crystallization solvent. Case.
  • the mass change displayed by the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA is slightly different between different instruments and different samples. Depending on the condition of the instrument used in this test, there is an error tolerance of ⁇ 0.5% for mass changes.
  • 2 ⁇ values in X-ray powder diffraction patterns are all in degrees (°).
  • a peak refers to a feature that can be identified by a person skilled in the art and is not attributable to background noise.
  • substantially pure means that a crystalline form is substantially free of one or more other crystalline forms, that is, the purity of the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or At least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms, the The percentage of other crystal forms in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, Or less than 0.1%, or less than 0.01%.
  • substantially free means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4% , or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • the “relative intensity” (or “relative peak height”) in the XRPD pattern refers to the intensity of the first strongest peak among all diffraction peaks in the X-ray powder diffraction pattern (XRPD) when it is 100%.
  • the ratio of the intensity of strong peaks refers to the intensity of the first strongest peak among all diffraction peaks in the X-ray powder diffraction pattern (XRPD) when it is 100%. The ratio of the intensity of strong peaks.
  • the words "about” or “approximately” when or whether they are used mean within 10%, suitably within 5% and especially within 1% of a given value or range. .
  • the term “about” or “approximately” means within an acceptable standard error of the mean. Whenever a number with a value of N is disclosed, any number with N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+ Numbers within /-10% of the value are explicitly disclosed, where "+/-" means plus or minus.
  • Root temperature in the present invention refers to a temperature from about 20°C to about 30°C.
  • compositions, preparations, administration and uses of crystalline forms of the compounds of the present invention are provided.
  • the characteristics of the pharmaceutical composition of the present invention include the crystal form A of the compound represented by formula (I), optionally including a pharmaceutically acceptable carrier, adjuvant, or excipient.
  • the crystal form A of the compound represented by formula (I) in the pharmaceutical composition of the present invention can effectively and detectably treat or alleviate diseases related to HCV infection or hepatitis C disease in patients.
  • the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable carriers, adjuvants, or excipients, which include any solvents, diluents, or other as used in the present invention.
  • pharmaceutically acceptable carriers include any solvents, diluents, or other as used in the present invention.
  • Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc. suitable for the specific target dosage form.
  • Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphate; glycine; sorbic acid; sorbate Potassium acid; partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyethylene Pyrrolidone; polyacrylate; wax; polyethylene-polyoxypropylene-blocked polymer; lanolin; sugar, such as lactose, glucose and sucrose; starch, such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and
  • the pharmaceutical composition of the present invention can be capsules, tablets, pills, powders, granules and aqueous suspensions or solutions; it can be administered through the following routes: oral administration, injection administration, spray inhalation, topical administration, Administer rectally, nasally, bucally, vaginally or via an implantable cartridge.
  • Oral administration can be administered in the following forms: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, and elixirs; external administration can be administered in the following forms: ointments, gels , medicated tape, etc.
  • the crystalline form of the present invention is preferably prepared in dosage unit form according to the formulation to reduce dosage and uniformity of dosage.
  • dosage unit type refers to physically discrete units of drug required for appropriate treatment of a patient.
  • the crystalline form of the compound of formula (I) of the present invention, or the total daily usage of the pharmaceutical composition of the present invention will be determined by the attending physician based on reliable medical judgment.
  • the specific effective dosage level for any particular patient or organism will depend on many factors including the condition being treated and the severity of the condition, the activity of the specific crystalline form of the compound, the specific composition used, the age, weight, health of the patient. Condition, gender and dietary habits, timing of administration, route of administration and excretion rate of the specific compound used, duration of treatment, use of the drug in combination or with specific active forms of the compound, and others Factors well known in the pharmaceutical field.
  • the present invention provides the use of crystal form A or a pharmaceutical composition of the compound represented by formula (I) of the present invention in the preparation of medicines, which can be used to inhibit the HCV replication process and/or inhibit the function of HCV viral proteins;
  • the HCV replication process includes HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV release;
  • the HCV viral protein is selected from metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and HCV Internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for viral replication.
  • Any compound or pharmaceutical composition described in the present invention can be used to treat hepatitis C virus (HCV) infection or hepatitis C disease.
  • the treatment method comprising the administration of crystal form A or a pharmaceutical composition of the compound represented by formula (I) of the present invention further includes administering other HCV drugs to the patient, whereby the compound of the present invention can be combined with other anti-HCV drugs.
  • the anti-HCV drugs For interferons, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate desulfation Hydrogenase inhibitors, amantadine, rimantadine, baviliximab, hepatitis C immune globulin, civacir, boceprevir, telaprevir, daclatasvir, semeprevir, anaprevir Pivir, silprevir, danoprevir, ledipasvir, nitazoxanide, nevirapine, alisporivir, imitas
  • the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, complex alpha-interferon, interferon gamma or other combination.
  • the pharmaceutical composition further comprises at least one HCV inhibitor, which is used to inhibit the HCV replication process and/or inhibit the HCV viral protein function, wherein the HCV replication process is selected from the group consisting of HCV entry, uncoating, and translation. , the complete viral cycle of HCV that replicates, assembles and releases; the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and the internal ribosome entry point (IRES) required for HCV viral replication. ) and inosine monophosphate dehydrogenase (IMPDH).
  • HCV inhibitor is used to inhibit the HCV replication process and/or inhibit the HCV viral protein function
  • the HCV replication process is selected from the group consisting of HCV entry, uncoating, and translation. , the complete viral cycle of HCV that replicates, assembles and releases
  • the HCV viral protein is selected from the group consisting of metalloproteinases,
  • the treatment method comprising the administration of crystal form A or pharmaceutical composition of the compound represented by formula (I) of the present invention, further includes the administration of other anti-HCV drugs, wherein other anti-HCV drugs can be combined with the compound of the present invention or its drugs
  • the compounds or pharmaceutical compositions of the present invention may be administered in combination, as a single dosage form, or as separate compounds or pharmaceutical compositions as part of multiple dosage forms.
  • Other anti-HCV drugs may or may not be administered concurrently with the compounds of the present invention. In the latter case, administration can be staggered such as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.
  • the "effective amount” or “effective dosage” of the crystal form A of the compound represented by formula (I) or the pharmaceutically acceptable composition of the present invention refers to treating or reducing the severity of one or more of the conditions mentioned in the present invention. effective amount.
  • the crystalline form A and the composition of the compound represented by formula (I) can be effectively used to treat or reduce the severity of the disease in any dosage and by any route of administration.
  • the exact amount necessary will vary depending on the patient's condition, depending on race, age, general condition of the patient, severity of infection, special factors, mode of administration, etc.
  • Form A or compositions of the compound represented by Formula (I) may be administered in combination with one or more other therapeutic agents, as discussed herein.
  • Figure 1 is an X-ray powder diffraction (XRPD) pattern of crystal form A of the compound represented by formula (I).
  • FIG. 1 is a differential scanning calorimetry (DSC) chart of crystal form A of the compound represented by formula (I).
  • FIG. 3 is a thermogravimetric analysis (TGA) diagram of crystal form A of the compound represented by formula (I).
  • Figure 4 is an amorphous X-ray powder diffraction (XRPD) pattern of the compound represented by formula (I).
  • Figure 5 is a dynamic vapor adsorption (DVS) diagram of crystal form A of the compound represented by formula (I).
  • Figure 6 is an amorphous dynamic vapor adsorption (DVS) diagram of the compound represented by formula (I).
  • the X-ray powder diffraction analysis method used in the present invention is: collecting X-ray powder diffraction (XRPD) patterns on a Dutch PANalytical Empyrean X-ray diffractometer equipped with a transmission and reflection sample stage equipped with an automated 3*15 zero-background sample holder.
  • the radiation source used is (Cu, k ⁇ , K ⁇ 1 1.540598;K ⁇ 2 1.544426; K ⁇ 2/K ⁇ 1 intensity ratio: 0.50), where the voltage is set at 45KV and the current is set at 40mA.
  • the beam divergence of X-rays that is, the effective size of X-ray confinement on the sample, is 10mm using ⁇ - ⁇ continuous In scanning mode, an effective 2 ⁇ range of 3° to 40° is obtained.
  • the sample was scanned with a scan step of 0.0167° to produce a traditional XRPD pattern in the range of 2 ⁇ from 3 to 40° ⁇ 0.2°.
  • the software used for data collection was Data Collector, and the data was analyzed and displayed using Data Viewer and HighScore Plus.
  • the ordinate is the diffraction intensity expressed in counts (counts)
  • the abscissa is the diffraction angle 2 ⁇ expressed in degrees (°).
  • the differential scanning calorimetry (DSC) analysis method used in the present invention is: using TA Instruments differential scanning calorimeter Q2000 to perform differential scanning calorimetry (DSC). Place the sample (approximately 1 mg ⁇ 3 mg) into an aluminum pan and record the weight accurately. The pan is covered with a cap, then crimped, and the sample is transferred to the instrument for measurement. The sample cell was equilibrated at 30°C and heated to a final temperature of 300°C at a rate of 10°C/min under a nitrogen purge. In the DSC diagram, the abscissa represents the temperature (Temperature, °C), and the ordinate represents the heat flow (Heat Flow, W/g) released by the substance per unit mass.
  • DSC differential scanning calorimetry
  • thermogravimetric (TGA) analysis method used in the present invention is: use TA Instruments Thermogravimetric Analyzer Q500 to perform thermogravimetric analysis, place an appropriate amount of sample in a platinum sample plate, and heat it at a rate of 10°C/minute under a nitrogen atmosphere.
  • the temperature range is 30 to 300°C.
  • the abscissa represents temperature (Temperature, ° C), and the ordinate represents mass percentage (Weight, %).
  • the dynamic vapor adsorption analysis (DVS) analysis method used in the present invention is: DVS test isothermal adsorption equilibrium curve test method, using the British SMS dynamic vapor adsorption analyzer DVSINT-Std to test, with the relative humidity (0%-95.0%) under the condition of 25.0°C -0%), starting from 0% relative humidity, changing in steps of 10% relative humidity to 95% relative humidity, and then reaching 0% relative humidity in steps of 10% relative humidity. Under a certain relative humidity condition, when the absolute value of the sample weight change dm/dt per unit time is less than 0.1%, it is considered to have reached equilibrium and then enters the next relative humidity. Detect the changes in hygroscopicity of the product under (0%-95.0%-0%) relative humidity cycling conditions.
  • the compound represented by formula (I) was prepared by referring to the method of Example 3 in patent application CN108299532A, which was a white foamy solid, about 187.3 mg. It was analyzed by Empyrean X-ray powder diffraction (XRPD) as amorphous. The specific XRPD pattern is basically as shown in the attachment. As shown in Figure 4.
  • TGA Thermal weight loss
  • the DVS test isothermal adsorption equilibrium curve test method is as follows. Under the condition of 25.0°C, with the change of relative humidity (0%-95.0%-0%), starting from 0% relative humidity, with a step change of 10% relative humidity to reach 95% relative humidity. humidity and then in 10% relative humidity steps to up to 0% relative humidity. Under a certain relative humidity condition, when the absolute value of the sample weight change dm/dt per unit time is less than 0.1%, it is considered to have reached equilibrium and then enters the next relative humidity. Detect the changes in hygroscopicity of Dong'an strong crystal form A and amorphous products under (0%-95.0%-0%) relative humidity cycling conditions.
  • the DVS results of the crystal form A and the amorphous form of the compound represented by formula (I) are basically as shown in Figures 5 and 6. Among them, the weight gain of crystalline form A reached a maximum of 0.27% when the relative humidity was 95%, while the weight gain of the amorphous form reached 3.31% when the relative humidity was 95%. This shows that the crystalline form A has more advantages than the amorphous form. Significantly low hygroscopicity.
  • Table 2 Pharmacokinetic parameters of crystalline form A and amorphous form of the present invention in beagle dogs after oral administration

Abstract

The present invention relates to a crystal form of a hepatitis C inhibitor and the use thereof in a drug, and specifically relates to a crystal form A of a compound as represented by formula (I), a pharmaceutical composition of the crystal form A, and the use thereof in the preparation of a drug for preventing, processing, treating or alleviating diseases related to HCV infections or/and hepatitis C diseases. The crystal form of the compound has a good stability, good pharmacokinetic properties, etc., thereby having better druggability.

Description

丙型肝炎抑制剂的晶型及其在药物中的用途Crystalline forms of hepatitis C inhibitors and their use in medicines 技术领域Technical field
本发明属于医药技术领域，涉及一种丙型肝炎抑制剂化合物的晶型、其药物组合物及它们在制备用于预防、处理、治疗或减轻HCV感染或丙型肝炎疾病相关的疾病的药物中的用途。The invention belongs to the field of medical technology and relates to a crystal form of a hepatitis C inhibitor compound, its pharmaceutical composition and their use in preparing drugs for preventing, treating, treating or alleviating HCV infection or diseases related to hepatitis C disease. the use of.
背景技术Background technique
丙型肝炎病毒(HCV)感染是导致慢性肝病(如肝硬化和肝细胞癌)的主要健康问题，感染个体估计占世界人口的2-15％。一旦被感染，约20％的人可清除病毒，但其余的人在其余生中将携带HCV。通过污染的血液和血液制品、污染的针或性行为以及从受感染的母亲或携带者母亲垂直地到其后代，胃肠外地传播该病毒性疾病。HCV感染可导致肝脏慢性炎症坏死和纤维化，部分患者可发展为肝硬化甚至肝细胞癌。HCV感染相关的死亡率将继续增加，对患者的健康和生命危害极大。Hepatitis C virus (HCV) infection is a major health problem leading to chronic liver diseases such as cirrhosis and hepatocellular carcinoma, with infected individuals estimated to account for 2-15% of the world's population. Once infected, about 20% of people clear the virus, but the remainder will carry HCV for the rest of their lives. This viral disease is transmitted parenterally through contaminated blood and blood products, contaminated needles, or sexual behavior, and vertically from infected mothers or carrier mothers to their offspring. HCV infection can lead to chronic inflammation, necrosis and fibrosis of the liver, and some patients may develop cirrhosis or even hepatocellular carcinoma. The mortality rate related to HCV infection will continue to increase, which is extremely harmful to the health and life of patients.
中国专利CN108299532A中实施例3公开了以下式(I)化合物，该化合物为一种抗丙型肝炎病毒感染的核苷类似物前药，该化合物是RNA依赖性RNA病毒复制的抑制剂，并可用作HCV NS5B聚合酶的抑制剂、用作HCV复制的抑制剂，其用于治疗丙型肝炎病毒(HCV)感染或丙型肝炎疾病具有显著效果。
Example 3 of Chinese patent CN108299532A discloses the following compound of formula (I). This compound is a nucleoside analog prodrug against hepatitis C virus infection. This compound is an inhibitor of RNA-dependent RNA virus replication and can It is used as an inhibitor of HCV NS5B polymerase and as an inhibitor of HCV replication, and has significant effects in the treatment of hepatitis C virus (HCV) infection or hepatitis C disease.
然而，后续研究发现专利CN108299532A中制备得到的式(I)化合物为无定型，其稳定性、溶解性和药物动力学数据较差，影响药物的有效性。这些给后续的药物开发带来诸多不便。However, follow-up research found that the compound of formula (I) prepared in patent CN108299532A is amorphous, and its stability, solubility and pharmacokinetic data are poor, affecting the effectiveness of the drug. These bring a lot of inconvenience to subsequent drug development.
发明内容Contents of the invention
本发明提供了式(I)所示化合物的晶型A，其具有较好稳定性和药代动力学等性质，从而具有更优良的成药性。The present invention provides crystal form A of the compound represented by formula (I), which has better stability, pharmacokinetics and other properties, and thus has better pharmaceutical properties.
具体而言，本发明涉及式(I)所示化合物的晶型A，以及包含所述晶型A的药物组合物，还涉及它们在制备用于治疗或预防HCV感染或/和丙型肝炎疾病相关的疾病的药物中的用途。Specifically, the present invention relates to the crystalline form A of the compound represented by formula (I), as well as pharmaceutical compositions containing the crystalline form A, and also relates to their preparation for the treatment or prevention of HCV infection or/and hepatitis C disease. Use in medicines related to diseases.
一方面，本发明提供了一种式(I)所示化合物的晶型A：
On the one hand, the present invention provides a crystal form A of the compound represented by formula (I):
其中，所述晶型A的X射线粉末衍射图谱包含下列2θ角处的衍射峰：10.35±0.2°,10.56±0.2°,13.39±0.2°,15.68±0.2°,15.82±0.2°,20.42±0.2°,20.84±0.2°,21.71±0.2°。Wherein, the X-ray powder diffraction pattern of the crystal form A includes the following diffraction peaks at 2θ angles: 10.35±0.2°, 10.56±0.2°, 13.39±0.2°, 15.68±0.2°, 15.82±0.2°, 20.42±0.2 °,20.84±0.2°,21.71±0.2°.
在一些实施方案中，本发明所述的式(I)所示化合物的晶型A的X射线粉末衍射图谱包含下列2θ角处的衍射峰：4.28±0.2°,6.69±0.2°,10.35±0.2°,10.56±0.2°,11.83±0.2°,12.78±0.2°,13.39±0.2°,15.68±0.2°,15.82±0.2°,16.79±0.2°,17.59±0.2°,17.83±0.2°,20.00±0.2°,20.42±0.2°,20.84±0.2°,21.71±0.2°,23.50±0.2°,24.73±0.2°,26.36±0.2°,26.52±0.2°,27.38±0.2°,28.18±0.2°,29.95±0.2°,31.30±0.2°。In some embodiments, the X-ray powder diffraction pattern of crystal form A of the compound represented by formula (I) of the present invention includes the following diffraction peaks at 2θ angles: 4.28±0.2°, 6.69±0.2°, 10.35±0.2 °,10.56±0.2°,11.83±0.2°,12.78±0.2°,13.39±0.2°,15.68±0.2°,15.82±0.2°,16.79±0.2°,17.59±0.2°,17.83±0.2°,20.00±0.2 °,20.42±0.2°,20.84±0.2°,21.71±0.2°,23.50±0.2°,24.73±0.2°,26.36±0.2°,26.52±0.2°,27.38±0.2°,28.18±0.2°,29.95±0.2 °,31.30±0.2°.
在另一些实施方案中，本发明所述的式(I)所示化合物的晶型A的X射线粉末衍射图谱包含下列2θ角处的衍射峰：4.28±0.2°,5.58±0.2°,6.69±0.2°,8.23±0.2°,10.35±0.2°,10.56±0.2°,11.83±0.2°,12.78±0.2°,13.39±0.2°,15.68±0.2°,15.82±0.2°,16.45±0.2°,16.79±0.2°,17.59±0.2°,17.83±0.2°,18.93±0.2°,20.00±0.2°,20.42±0.2°,20.84±0.2°,21.71±0.2°,21.99±0.2°,23.17±0.2°,23.50±0.2°,23.78±0.2°,24.73±0.2°,25.71±0.2°,26.36±0.2°,26.52±0.2°,27.38±0.2°,28.18±0.2°,29.95±0.2°,31.30±0.2°,33.17±0.2°,34.80±0.2°。In other embodiments, the X-ray powder diffraction pattern of crystal form A of the compound represented by formula (I) of the present invention includes the following diffraction peaks at 2θ angles: 4.28±0.2°, 5.58±0.2°, 6.69± 0.2°,8.23±0.2°,10.35±0.2°,10.56±0.2°,11.83±0.2°,12.78±0.2°,13.39±0.2°,15.68±0.2°,15.82±0.2°,16.45±0.2°,16.79± 0.2°,17.59±0.2°,17.83±0.2°,18.93±0.2°,20.00±0.2°,20.42±0.2°,20.84±0.2°,21.71±0.2°,21.99±0.2°,23.17±0.2°,23.50± 0.2°,23.78±0.2°,24.73±0.2°,25.71±0.2°,26.36±0.2°,26.52±0.2°,27.38±0.2°,28.18±0.2°,29.95±0.2°,31.30±0.2°,33.17± 0.2°,34.80±0.2°.
在另一些实施方案中，本发明所述的式(I)所示化合物的晶型A的X射线粉末衍射图谱包含下列2θ角处的衍射峰：4.28±0.2°,5.58±0.2°,6.69±0.2°,8.23±0.2°,8.52±0.2°,10.35±0.2°,10.56±0.2°,11.17±0.2°,11.83±0.2°,12.78±0.2°,13.39±0.2°,15.68±0.2°,15.82±0.2°,16.45±0.2°,16.79±0.2°,17.59±0.2°,17.83±0.2°,18.93±0.2°,20.00±0.2°,20.42±0.2°,20.84±0.2°,21.71±0.2°,21.99±0.2°,23.17±0.2°,23.50±0.2°,23.78±0.2°,24.10±0.2°,24.42±0.2°,24.73±0.2°,25.71±0.2°,26.36±0.2°,26.52±0.2°,26.88±0.2°,27.38±0.2°,28.18±0.2°,29.00±0.2°,29.95±0.2°,31.30±0.2°,33.17±0.2°,33.95±0.2°,34.80±0.2°,36.50±0.2°。In other embodiments, the X-ray powder diffraction pattern of crystal form A of the compound represented by formula (I) of the present invention includes the following diffraction peaks at 2θ angles: 4.28±0.2°, 5.58±0.2°, 6.69± 0.2°,8.23±0.2°,8.52±0.2°,10.35±0.2°,10.56±0.2°,11.17±0.2°,11.83±0.2°,12.78±0.2°,13.39±0.2°,15.68±0.2°,15.82± 0.2°,16.45±0.2°,16.79±0.2°,17.59±0.2°,17.83±0.2°,18.93±0.2°,20.00±0.2°,20.42±0.2°,20.84±0.2°,21.71±0.2°,21.99± 0.2°,23.17±0.2°,23.50±0.2°,23.78±0.2°,24.10±0.2°,24.42±0.2°,24.73±0.2°,25.71±0.2°,26.36±0.2°,26.52±0.2°,26.88± 0.2°,27.38±0.2°,28.18±0.2°,29.00±0.2°,29.95±0.2°,31.30±0.2°,33.17±0.2°,33.95±0.2°,34.80±0.2°,36.50±0.2°.
在另一些实施方案中，本发明所述的式(I)所示化合物的晶型A基本上如图1所示的X射线粉末衍射图。In other embodiments, the crystal form A of the compound represented by formula (I) of the present invention has an X-ray powder diffraction pattern substantially as shown in Figure 1 .
在一些实施方案中，本发明所述的式(I)所示化合物的晶型A的差示扫描量热图包含135℃±3℃的吸热峰。In some embodiments, the differential scanning calorimetry diagram of Form A of the compound represented by Formula (I) of the present invention includes an endothermic peak of 135°C ± 3°C.
在一些实施方案中，本发明所述的式(I)所示化合物的晶型A具有基本上如图2所示的差示扫描量热图。In some embodiments, Form A of the compound represented by Formula (I) of the present invention has a differential scanning calorimetry pattern substantially as shown in Figure 2.
在一些实施方案中，本发明所述的式(I)所示化合物的晶型A在TGA图(热重分析图)在200℃之 前无显著失重。In some embodiments, the crystal form A of the compound represented by formula (I) of the present invention has a TGA chart (thermogravimetric analysis chart) between 200°C and 200°C. No significant weight loss before.
在一些实施方案中，本发明所述的式(I)所示化合物的晶型A在TGA图(热重分析图)如图3所示，在200℃之前无显著失重。In some embodiments, the TGA chart (thermogravimetric analysis chart) of crystal form A of the compound represented by formula (I) of the present invention is as shown in Figure 3, and there is no significant weight loss before 200°C.
另一方面，本发明提供了一种药物组合物，其包含本发明所述的式(I)所示化合物的晶型A。On the other hand, the present invention provides a pharmaceutical composition comprising crystalline form A of the compound represented by formula (I) of the present invention.
在一些实施方案中，本发明所述药物组合物进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂或它们的组合。In some embodiments, the pharmaceutical compositions of the present invention further comprise pharmaceutically acceptable carriers, excipients, diluents, adjuvants or combinations thereof.
在另一些实施方案中，本发明所述药物组合物进一步地包含其他的抗HCV的药物。In other embodiments, the pharmaceutical compositions of the present invention further comprise other anti-HCV drugs.
在一些实施方案中，本发明所述的其他的抗HCV的药物为干扰素、利巴韦林、白介素2、白介素6、白介素12、促进产生1型辅助性T细胞应答的化合物、干扰RNA、反义RNA、咪喹莫德、肌苷5’-单磷酸脱氢酶抑制剂、金刚烷胺、金刚乙胺、巴维昔单抗、丙型肝炎免疫球蛋白、civacir、波普瑞韦、替拉瑞韦、达卡他韦、司美匹韦、阿那匹韦、西鲁瑞韦、丹诺普韦、雷迪帕韦、硝唑尼特、奈韦拉平、阿拉泊韦、依米他韦、vaniprevir、faldaprevir、paritaprevir、sovaprevir、grazoprevir、elbasvir、vedroprevir、narlaprevir、ombitasvir、ravidasvir、velpatasvir、samatasvir、alisporivir、modithromycin、odalasvir、ritonavir、alloferon、nivolumab、multiferon、pibrentasvir、glecaprevir、procvax、miravirsen、EDP239、ANA975、MK-8325、BZF-961、GS-9256、GSK-2336805、PPI-461、ACH-1095、VX-985、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、VBY-376、INX-189、IDX-184、IDX102、R1479、UNX-08189、HCV-371、JKT-109、GL-60667、AZD-2795、TMC647055、WF-10、ACH-3422、MK-3682、MK-8408、GS-9857、CD-AdNS3、RG-101、INO-8000、MBL-HCV1、CIGB-230、TG-2349、CB-5300、chronvac-C、MK-1075、ACH-0143422、WS-007、MK-7680、MK-2248、IDX-21459、AV-4025、MK-8876、AL-335、JNJ-47910382、ABP-560、TD-6450、EDP-239、SB-9200、ITX-5061、ID-12，或其任意组合。In some embodiments, other anti-HCV drugs described in the present invention are interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote the production of type 1 helper T cell responses, interfering RNA, Antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, baviliximab, hepatitis C immune globulin, civacir, boceprevir, Tilaprevir, daclatasvir, simeprevir, analprevir, silprevir, danoprevir, ledipasvir, nitazoxanide, nevirapine, alisporivir, imitasvir , vaniprevir, faldaprevir, paritaprevir, sovaprevir, grazoprevir, elbasvir, vedroprevir, narlaprevir, ombitasvir, ravidasvir, velpatasvir, samatasvir, alisporivir, modithromycin, odalasvir, ritonavir, alloferon, nivolumab, multiferon, pibrentasvir, glecaprevir, procvax, miravirsen, EDP239, ANA975 , MK-8325, BZF-961, GS-9256, GSK-2336805, PPI-461, ACH-1095, VX-985, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX -316, VBY-376, INX-189, IDX-184, IDX102, R1479, UNX-08189, HCV-371, JKT-109, GL-60667, AZD-2795, TMC647055, WF-10, ACH-3422, MK -3682, MK-8408, GS-9857, CD-AdNS3, RG-101, INO-8000, MBL-HCV1, CIGB-230, TG-2349, CB-5300, chronvac-C, MK-1075, ACH-0143422 , WS-007, MK-7680, MK-2248, IDX-21459, AV-4025, MK-8876, AL-335, JNJ-47910382, ABP-560, TD-6450, EDP-239, SB-9200, ITX -5061, ID-12, or any combination thereof.
另一方面，本发明提供了本发明所述式(I)所示化合物的晶型A或本发明所述的药物组合物在制备药物中的用途，所述药物用于预防、处理、治疗或减轻HCV感染或丙型肝炎疾病相关的疾病。On the other hand, the present invention provides the use of crystal form A of the compound represented by formula (I) of the present invention or the pharmaceutical composition of the present invention in the preparation of medicines for prevention, treatment, treatment or Reduces illness associated with HCV infection or hepatitis C disease.
另一方面，本发明提供了一种本发明所述式(I)所示化合物的晶型A或药物组合物在制备药物中的用途，所述药物用于抑制HCV复制过程和/或抑制HCV病毒蛋白的功能；所述HCV复制过程包括HCV进入、HCV脱壳、HCV翻译、HCV复制、HCV组装或HCV释放；所述的HCV病毒蛋白选自金属蛋白酶、NS2、NS3、NS4A、NS4B、NS5A或NS5B，以及HCV病毒复制所需要的内部核糖体进入点(IRES)和肌苷单磷酸脱氢酶(IMPDH)。On the other hand, the present invention provides the use of a crystalline form A or a pharmaceutical composition of the compound represented by formula (I) of the present invention in the preparation of medicines for inhibiting the HCV replication process and/or inhibiting HCV Function of viral protein; the HCV replication process includes HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV release; the HCV viral protein is selected from metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, as well as the internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.
在一些实施例中，本发明提供了一种本发明所述式(I)所示化合物的晶型A或药物组合物在制备药物中的用途，所述药物用于抑制HCV病毒蛋白的功能；所述的HCV病毒蛋白为NS5B。In some embodiments, the present invention provides the use of crystal form A or a pharmaceutical composition of the compound represented by formula (I) of the present invention in the preparation of medicines, which are used to inhibit the function of HCV viral proteins; The HCV viral protein is NS5B.
另一方面，本发明提供了一种本发明所述式(I)所示化合物的晶型A或药物组合物用于预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病的用途。 On the other hand, the present invention provides the use of crystal form A or a pharmaceutical composition of the compound represented by formula (I) of the present invention for preventing, treating, treating or alleviating HCV infection or hepatitis C disease in patients.
另一方面，本发明提供了一种本发明所述式(I)所示化合物的晶型A或药物组合物用于抑制HCV复制过程和/或抑制HCV病毒蛋白的功能；所述HCV复制过程包括HCV进入、HCV脱壳、HCV翻译、HCV复制、HCV组装或HCV释放；所述的HCV病毒蛋白选自金属蛋白酶、NS2、NS3、NS4A、NS4B、NS5A或NS5B，以及HCV病毒复制所需要的内部核糖体进入点(IRES)和肌苷单磷酸脱氢酶(IMPDH)。On the other hand, the present invention provides a crystal form A or a pharmaceutical composition of the compound represented by formula (I) of the present invention for inhibiting the HCV replication process and/or inhibiting the function of the HCV viral protein; the HCV replication process Including HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV release; the HCV viral protein is selected from metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and is required for HCV viral replication Internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH).
在一些实施例中，本发明提供了一种本发明所述式(I)所示化合物的晶型A或药物组合物用于抑制HCV病毒蛋白的功能；所述的HCV病毒蛋白为NS5B。In some embodiments, the present invention provides a crystal form A or pharmaceutical composition of the compound represented by formula (I) of the present invention for inhibiting the function of HCV viral protein; the HCV viral protein is NS5B.
另一方面，本发明提供了一种预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病的方法，包括给予患者有效治疗量的本发明所述式(I)所示化合物的晶型A或药物组合物。On the other hand, the present invention provides a method for preventing, treating, treating or alleviating HCV infection or hepatitis C disease in a patient, which includes administering to the patient an effective therapeutic amount of the crystal form of the compound represented by formula (I) of the present invention. A or pharmaceutical composition.
另一方面，本发明提供了一种抑制HCV复制过程和/或抑制HCV病毒蛋白的功能的方法，包括给予患者有效治疗量的本发明所述式(I)所示化合物的晶型A或药物组合物；所述HCV复制过程包括HCV进入、HCV脱壳、HCV翻译、HCV复制、HCV组装或HCV释放；所述的HCV病毒蛋白选自金属蛋白酶、NS2、NS3、NS4A、NS4B、NS5A或NS5B，以及HCV病毒复制所需要的内部核糖体进入点(IRES)和肌苷单磷酸脱氢酶(IMPDH)。On the other hand, the present invention provides a method for inhibiting the HCV replication process and/or inhibiting the function of HCV viral proteins, which includes administering to the patient an effective therapeutic amount of crystal form A or a drug of the compound represented by formula (I) of the present invention. Composition; the HCV replication process includes HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV release; the HCV viral protein is selected from metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B , as well as the internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.
在一些实施例中，本发明提供了一种抑制HCV病毒蛋白的功能的方法，包括给予患者有效治疗量的本发明所述式(I)所示化合物的晶型A或药物组合物；所述的HCV病毒蛋白为NS5B。In some embodiments, the present invention provides a method for inhibiting the function of HCV viral proteins, which includes administering to a patient an effective therapeutic amount of crystal form A or a pharmaceutical composition of the compound represented by formula (I) of the present invention; The HCV viral protein is NS5B.
本发明所述的晶型的制备方法中所使用的溶剂没有特别限制，任何在程度上能溶解起始原料并且不影响其性质的溶剂均包含在本发明中。另外，本领域的许多类似改动，等同替换，或等同于本发明所描述的溶剂，溶剂组合，及溶剂组合的不同比例，均视为本发明的包含范围。本发明给出了各反应步骤所使用的较佳的溶剂。The solvent used in the preparation method of the crystalline form of the present invention is not particularly limited. Any solvent that can dissolve the starting materials to a certain extent and does not affect its properties is included in the present invention. In addition, many similar modifications, equivalent substitutions, or equivalent solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are deemed to be within the scope of the present invention. The present invention provides preferred solvents used in each reaction step.
本发明所述的式(I)所示化合物的晶型A的制备实验在实施例部分进行了详细描述。同时，本发明提供了所述式(I)所示化合物的晶型A的药理测试实验(如药代动力学实验)等。经实验证明，本发明所述的式(I)所示化合物的晶型A具有良好的稳定性和药代性质。The preparation experiments of the crystal form A of the compound represented by formula (I) of the present invention are described in detail in the Examples section. At the same time, the present invention provides pharmacological testing experiments (such as pharmacokinetic experiments) of the crystal form A of the compound represented by formula (I). Experiments have proven that the crystal form A of the compound represented by formula (I) of the present invention has good stability and pharmacokinetic properties.
定义和一般术语Definitions and general terms
除非另有说明，本发明使用的所有技术和科学术语与本发明所属领域的普通技术人员所通常理解的具有相同含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。尽管在本发明的实践或者测试中可以使用与本发明所述相似或者相同的任何方法和物质，但是本发明中描述的是优选的方法、设备和物质。Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, equipment, and materials are described herein.
“晶型”或“结晶形式”是指具有高度规则化学结构的固体，包括，但不限于，单组分或者多组分晶体，和/或化合物的多晶型物、溶剂化物、水合物、包合物、共晶、盐、盐的溶剂化物、盐的水合物。物质的结晶形式可通过本领域已知的许多方法得到。这种方法包括，但不限于，熔体结晶、熔体冷却、溶剂结晶、 在限定的空间中结晶，例如，在纳米孔或者毛细管中，在表面或者模板上结晶，例如，在聚合物上，在添加剂如共结晶反分子的存在下结晶、去溶剂、脱水、快速蒸发、快速冷却、缓慢冷却、蒸气扩散、升华、反应结晶、反溶剂添加、研磨和溶剂滴研磨等。"Crystalline form" or "crystalline form" refers to a solid with a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or polymorphs, solvates, hydrates, Clathrate, eutectic, salt, salt solvate, salt hydrate. Crystalline forms of substances can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, Crystallization in a defined space, e.g. in nanopores or capillaries, on a surface or template, e.g. on a polymer, in the presence of additives such as co-crystallized antimolecules, desolvation, dehydration, rapid evaporation, Rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, anti-solvent addition, grinding and solvent drop grinding, etc.
“溶剂”是指一种物质(典型地是一种液体)，该物质能够完全地或部分地溶解另一种物质(典型地是一种固体)。用于本发明实施的溶剂包括但并不限于，水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、N-甲基吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、吡啶、四氢呋喃、甲苯、二甲苯、它们的混合物等等。"Solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents used in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1,4-dioxane, ethanol , Ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropyl alcohol, methanol, Methyl ethyl ketone, N-methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, their mixtures, etc.
“反溶剂”是指促进产物(或产物前体)从溶剂中沉淀的流体。反溶剂可以包括冷气体、或通过化学反应促进沉淀的流体、或降低产物在溶剂中的溶解度的流体；其可以是与溶剂相同的液体但是处于不同温度，或者它可以是与溶剂不同的液体。"Antisolvent" refers to a fluid that promotes the precipitation of a product (or product precursor) from a solvent. The antisolvent can include a cold gas, or a fluid that promotes precipitation through a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid than the solvent.
晶型可以通过多种技术手段进行鉴别，例如X射线粉末衍射(XRPD)、红外吸收光谱法(IR)、熔点法、差示扫描量热法(DSC)、热重分析法(TGA)、核磁共振法、拉曼光谱、X射线单晶衍射、溶解量热法、扫描电子显微镜(SEM)、定量分析、溶解度和溶解速度等等。Crystal forms can be identified through a variety of technical methods, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance Resonance method, Raman spectroscopy, X-ray single crystal diffraction, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.
X射线粉末衍射(XRPD)可检测晶型的变化、结晶度、晶构状态等信息，是鉴别晶型的常用手段。XRPD图谱的峰位置主要取决于晶型的结构，对实验细节相对不敏感，而其相对峰高取决于与样品制备和仪器几何形状有关的许多因素。因此，在一些实施方案中，本发明的晶型的特征在于具有某些峰位置的XRPD图，其基本上如本发明附图中提供的XRPD图所示。同时，XRPD图谱的2θ的量度可以有实验误差，不同仪器以及不同样品之间，XRPD图谱的2θ的量度可能会略有差别，因此所述2θ的数值不能视为绝对的。根据本试验所用仪器状况，衍射峰存在±0.2°的误差容限。X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, crystal structure state and other information, and is a common method for identifying crystal forms. The peak position of the XRPD spectrum mainly depends on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the Figures of the invention. At the same time, the measurement of 2θ of the XRPD spectrum may have experimental errors. The measurement of 2θ of the XRPD spectrum may be slightly different between different instruments and different samples, so the value of 2θ cannot be regarded as absolute. According to the conditions of the instrument used in this test, there is an error tolerance of ±0.2 ° for the diffraction peak.
差示扫描量热(DSC)是在程序控制下，通过不断加热或降温，测量样品与惰性参比物(常用α-Al2O3)之间的能量差随温度变化的一种技术。DSC曲线的吸热峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施方案中，本发明所述晶型的特征在于具有特征峰位置的DSC图，其基本上如本发明附图中提供的DSC图所示。同时，DSC图谱可以有实验误差，不同仪器以及不同样品之间，DSC图谱的峰位置和峰值可能会略有差别，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。根据本试验所用仪器状况，吸热峰存在±3℃的误差容限。Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference substance (commonly used α-Al 2 O 3 ) as the temperature changes by continuously heating or cooling under program control. The endothermic peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Accordingly, in some embodiments, the crystalline forms described herein are characterized by a DSC pattern having characteristic peak positions substantially as shown in the DSC patterns provided in the Figures herein. At the same time, the DSC spectrum may have experimental errors. The peak position and peak value of the DSC spectrum may be slightly different between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. According to the conditions of the instrument used in this test, there is an error tolerance of ±3°C for the endothermic peak.
热重分析(TGA)是在程序控制下，测定物质的质量随温度变化的一种技术，适用于检查晶体中溶剂的丧失或样品升华、分解的过程，可推测晶体中含结晶水或结晶溶剂的情况。TGA曲线显示的质量变化取决于样品制备和仪器等许多因素；不同仪器以及不同样品之间，TGA检测的质量变化略有差别。根据本试验所用的仪器状况，质量变化存在±0.5％的误差容限。Thermogravimetric analysis (TGA) is a technique that measures the mass change of a substance with temperature under program control. It is suitable for checking the loss of solvent in crystals or the process of sample sublimation and decomposition. It can be inferred that the crystals contain crystal water or crystallization solvent. Case. The mass change displayed by the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA is slightly different between different instruments and different samples. Depending on the condition of the instrument used in this test, there is an error tolerance of ±0.5% for mass changes.
在本发明的上下文中，X-射线粉末衍射图中的2θ值均以度(°)为单位。 In the context of this invention, 2θ values in X-ray powder diffraction patterns are all in degrees (°).
术语“基本上如图所示”是指X-射线粉末衍射图或DSC图或拉曼光谱图或红外光谱图中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰显示在其图中。The term "substantially as shown in the drawings" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or At least 90%, or at least 95%, or at least 99% of the peaks are shown in its plot.
当提及谱图或/和出现在图中的数据时，“峰”指本领域技术人员能够识别的不会归属于背景噪音的一个特征。When referring to a spectrum or/and data appearing in a graph, a "peak" refers to a feature that can be identified by a person skilled in the art and is not attributable to background noise.
“基本上纯净的”是指一种晶型基本上不含另外一种或多种晶型，即晶型的纯度至少80％，或至少85％，或至少90％，或至少93％，或至少95％，或至少98％，或至少99％，或至少99.5％，或至少99.6％，或至少99.7％，或至少99.8％，或至少99.9％，或晶型中含有其它晶型，所述其它晶型在晶型的总体积或总重量中的百分比少于20％，或少于10％，或少于5％，或少于3％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。"Substantially pure" means that a crystalline form is substantially free of one or more other crystalline forms, that is, the purity of the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or At least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms, the The percentage of other crystal forms in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, Or less than 0.1%, or less than 0.01%.
“基本上不含”是指一种或多种其它晶型在晶型的总体积或总重量中的百分比少于20％，或少于10％，或少于5％，或少于4％，或少于3％，或少于2％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。"Substantially free" means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4% , or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
XRPD图中的“相对强度”(或“相对峰高”)是指X-射线粉末衍射图(XRPD)的所有衍射峰中第一强峰的强度为100％时，其它峰的强度与第一强峰的强度的比值。The "relative intensity" (or "relative peak height") in the XRPD pattern refers to the intensity of the first strongest peak among all diffraction peaks in the X-ray powder diffraction pattern (XRPD) when it is 100%. The ratio of the intensity of strong peaks.
在本发明的上下文中，当使用或者无论是否使用“大约”或“约”等字眼时，表示在给定的值或范围的10％以内，适当地在5％以内，特别是在1％以内。或者，对于本领域普通技术人员而言，术语“大约”或“约”表示在平均值的可接受的标准误差范围内。每当公开一个具有N值的数字时，任何具有N+/-1％，N+/-2％，N+/-3％，N+/-5％，N+/-7％，N+/-8％或N+/-10％值以内的数字会被明确地公开，其中“+/-”是指加或减。In the context of this invention, the words "about" or "approximately" when or whether they are used mean within 10%, suitably within 5% and especially within 1% of a given value or range. . Alternatively, to those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. Whenever a number with a value of N is disclosed, any number with N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+ Numbers within /-10% of the value are explicitly disclosed, where "+/-" means plus or minus.
本发明中“室温”指的是温度由大约20℃到大约30℃。"Room temperature" in the present invention refers to a temperature from about 20°C to about 30°C.
本发明所述化合物的晶型的药物组合物，制剂，给药和用途Pharmaceutical compositions, preparations, administration and uses of crystalline forms of the compounds of the present invention
本发明的药物组合物的特点包括式(I)所示化合物的晶型A，任选地包括药学上可接受的载体，辅剂，或赋形剂。本发明的药物组合物中式(I)所示化合物的晶型A能有效地可探测地治疗或减轻患者HCV感染或丙型肝炎疾病相关相关的疾病。The characteristics of the pharmaceutical composition of the present invention include the crystal form A of the compound represented by formula (I), optionally including a pharmaceutically acceptable carrier, adjuvant, or excipient. The crystal form A of the compound represented by formula (I) in the pharmaceutical composition of the present invention can effectively and detectably treat or alleviate diseases related to HCV infection or hepatitis C disease in patients.
像本发明所描述的，本发明药学上可接受的组合物进一步包含药学上可接受的载体，辅剂，或赋形剂，这些像本发明所应用的，包括任何溶剂，稀释剂，或其他液体赋形剂，分散剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的载体可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的载体媒介与本发明的化合物的晶型不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相 互作用，它们的用途也是本发明所考虑的范围。As described in the present invention, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable carriers, adjuvants, or excipients, which include any solvents, diluents, or other as used in the present invention. Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for the specific target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988-1999, Marcel Dekker, New York, review of the literature herein shows that various carriers may be used in the formulation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except to the extent that any conventional carrier medium is incompatible with the crystalline form of a compound of the invention, e.g., produces any adverse biological effects or interacts in a deleterious manner with any other component of a pharmaceutically acceptable composition. Interactions and their uses are also contemplated by the present invention.
可作为药学上可接受载体的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁；着色剂；释放剂；包衣衣料；甜味剂；调味剂；香料；防腐剂和抗氧化剂。Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphate; glycine; sorbic acid; sorbate Potassium acid; partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyethylene Pyrrolidone; polyacrylate; wax; polyethylene-polyoxypropylene-blocked polymer; lanolin; sugar, such as lactose, glucose and sucrose; starch, such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil, and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; seaweed Acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffered solution; and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; Coatings; sweeteners; flavorings; spices; preservatives and antioxidants.
本发明的药物组合物可以是胶囊，片剂，丸剂，粉剂，粒剂和水制悬浮液或溶液；可以通过如下途径给药：口服给药，注射给药，喷雾吸入法，局部给药，经直肠给药，经鼻给药，含服给药，阴道给药或通过植入性药盒给药。The pharmaceutical composition of the present invention can be capsules, tablets, pills, powders, granules and aqueous suspensions or solutions; it can be administered through the following routes: oral administration, injection administration, spray inhalation, topical administration, Administer rectally, nasally, bucally, vaginally or via an implantable cartridge.
口服给药可以用如下形式给药：片剂、丸剂、胶囊、可分散的粉末、颗粒或悬浮液、糖浆、和酏剂等；外用方式给药可以通过如下形式给药：软膏剂、凝胶、含药胶布等。Oral administration can be administered in the following forms: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, and elixirs; external administration can be administered in the following forms: ointments, gels , medicated tape, etc.
本发明的晶型优选地按制剂配方制备成剂量单位型以减轻给药量和剂量的均匀性。术语“剂量单位型”在此处是指患者得到适当治疗所需药物的物理分散单位。然而，应了解本发明式(I)化合物的晶型、或本发明的药物组合物每日总的用法将通过主治医生根据可靠的医学范围判断来确定。具体的有效剂量水平对于任何一个特殊的患者或有机体将取决于许多因素包括被治疗的病症和病症的严重性，具体化合物的晶型的活性，所用的具体组合物，患者的年龄、体重、健康状况、性别和饮食习惯，给药时间，给药途径和所用具体化合物的晶型的排泄速率，治疗的持续时间，药物应用于联合用药或与有特效的化合物的晶型联用，以及其他一些药学领域公知的因素。The crystalline form of the present invention is preferably prepared in dosage unit form according to the formulation to reduce dosage and uniformity of dosage. The term "dosage unit type" as used herein refers to physically discrete units of drug required for appropriate treatment of a patient. However, it should be understood that the crystalline form of the compound of formula (I) of the present invention, or the total daily usage of the pharmaceutical composition of the present invention will be determined by the attending physician based on reliable medical judgment. The specific effective dosage level for any particular patient or organism will depend on many factors including the condition being treated and the severity of the condition, the activity of the specific crystalline form of the compound, the specific composition used, the age, weight, health of the patient. Condition, gender and dietary habits, timing of administration, route of administration and excretion rate of the specific compound used, duration of treatment, use of the drug in combination or with specific active forms of the compound, and others Factors well known in the pharmaceutical field.
在本发明提供了本发明的式(I)所示化合物的晶型A或药物组合物在制备药物中的用途，所述药物可以用于抑制HCV复制过程和/或抑制HCV病毒蛋白的功能；所述HCV复制过程包括HCV进入、HCV脱壳、HCV翻译、HCV复制、HCV组装或HCV释放；所述的HCV病毒蛋白选自金属蛋白酶、NS2、NS3、NS4A、NS4B、NS5A或NS5B，以及HCV病毒复制所需要的内部核糖体进入点(IRES)和肌苷单磷酸脱氢酶(IMPDH)。本发明所述任一化合物或药物组合物可以用于治疗丙型肝炎病毒(HCV)感染或丙型肝炎疾病。The present invention provides the use of crystal form A or a pharmaceutical composition of the compound represented by formula (I) of the present invention in the preparation of medicines, which can be used to inhibit the HCV replication process and/or inhibit the function of HCV viral proteins; The HCV replication process includes HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV release; the HCV viral protein is selected from metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and HCV Internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for viral replication. Any compound or pharmaceutical composition described in the present invention can be used to treat hepatitis C virus (HCV) infection or hepatitis C disease.
包含本发明式(I)所示化合物的晶型A或药物组合物给药的治疗方法，进一步包括对患者给药其他HCV药物，由此，可以将本发明的化合物与其他抗HCV药物进行联合治疗，其中所述的抗HCV的药物 为干扰素、利巴韦林、白介素2、白介素6、白介素12、促进产生1型辅助性T细胞应答的化合物、干扰RNA、反义RNA、咪喹莫德、肌苷5’-单磷酸脱氢酶抑制剂、金刚烷胺、金刚乙胺、巴维昔单抗、丙型肝炎免疫球蛋白、civacir、波普瑞韦、替拉瑞韦、达卡他韦、司美匹韦、阿那匹韦、西鲁瑞韦、丹诺普韦、雷迪帕韦、硝唑尼特、奈韦拉平、阿拉泊韦、依米他韦、vaniprevir、faldaprevir、paritaprevir、sovaprevir、grazoprevir、elbasvir、vedroprevir、narlaprevir、ombitasvir、ravidasvir、velpatasvir、samatasvir、alisporivir、modithromycin、odalasvir、ritonavir、alloferon、nivolumab、multiferon、pibrentasvir、glecaprevir、procvax、miravirsen、EDP239、ANA975、MK-8325、BZF-961、GS-9256、GSK-2336805、PPI-461、ACH-1095、VX-985、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、VBY-376、INX-189、IDX-184、IDX102、R1479、UNX-08189、HCV-371、JKT-109、GL-60667、AZD-2795、TMC647055、WF-10、ACH-3422、MK-3682、MK-8408、GS-9857、CD-AdNS3、RG-101、INO-8000、MBL-HCV1、CIGB-230、TG-2349、CB-5300、chronvac-C、MK-1075、ACH-0143422、WS-007、MK-7680、MK-2248、IDX-21459、AV-4025、MK-8876、AL-335、JNJ-47910382、ABP-560、TD-6450、EDP-239、SB-9200、ITX-5061、ID-12，或其任意组合。其中，所述干扰素为干扰素α-2b、聚乙二醇化的干扰素α、干扰素α-2a、聚乙二醇化的干扰素α-2a、复合α-干扰素、干扰素γ或其组合。所述药物组合物，进一步包含至少一种HCV抑制剂，所述HCV抑制剂用于抑制HCV复制过程和/或抑制HCV病毒蛋白功能，其中所述HCV复制过程选自HCV进入、脱壳、翻译、复制、组装、释放的HCV的完整病毒周期；所述的HCV病毒蛋白选自金属蛋白酶、NS2、NS3、NS4A、NS4B、NS5A、NS5B；以及HCV病毒复制所需要的内部核糖体进入点(IRES)和肌苷单磷酸脱氢酶(IMPDH)。The treatment method comprising the administration of crystal form A or a pharmaceutical composition of the compound represented by formula (I) of the present invention further includes administering other HCV drugs to the patient, whereby the compound of the present invention can be combined with other anti-HCV drugs. Treatment, wherein the anti-HCV drugs For interferons, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate desulfation Hydrogenase inhibitors, amantadine, rimantadine, baviliximab, hepatitis C immune globulin, civacir, boceprevir, telaprevir, daclatasvir, semeprevir, anaprevir Pivir, silprevir, danoprevir, ledipasvir, nitazoxanide, nevirapine, alisporivir, imitasvir, vaniprevir, faldaprevir, paritaprevir, sovaprevir, grazoprevir, elbasvir, vedroprevir, narlaprevir, ombitasvir, ravidasvir, velpatasvir, samatasvir, alisporivir, modithromycin, odalasvir, ritonavir, alloferon, nivolumab, multiferon, pibrentasvir, glecaprevir, procvax, miravirsen, EDP239, ANA975, MK-8325, BZF-961, GS-9256, GSK-2336805, PPI-461, ACH-1095, VX-985, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, VBY-376, INX-189, IDX-184, IDX102, R1479, UNX-08189, HCV-371, JKT-109, GL-60667, AZD-2795, TMC647055, WF-10, ACH-3422, MK-3682, MK-8408, GS-9857, CD-AdNS3, RG- 101. INO-8000, MBL-HCV1, CIGB-230, TG-2349, CB-5300, chronvac-C, MK-1075, ACH-0143422, WS-007, MK-7680, MK-2248, IDX-21459, AV-4025, MK-8876, AL-335, JNJ-47910382, ABP-560, TD-6450, EDP-239, SB-9200, ITX-5061, ID-12, or any combination thereof. Wherein, the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, complex alpha-interferon, interferon gamma or other combination. The pharmaceutical composition further comprises at least one HCV inhibitor, which is used to inhibit the HCV replication process and/or inhibit the HCV viral protein function, wherein the HCV replication process is selected from the group consisting of HCV entry, uncoating, and translation. , the complete viral cycle of HCV that replicates, assembles and releases; the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and the internal ribosome entry point (IRES) required for HCV viral replication. ) and inosine monophosphate dehydrogenase (IMPDH).
并且包含本发明式(I)所示化合物的晶型A或药物组合物给药的治疗方法，进一步包含其他抗HCV药物的给药，其中，其他抗HCV药物可以和本发明化合物或其药物组合物联合给药，本发明化合物或药物组合物作为单个剂型，或分开的化合物或药物组合物作为多剂型的一部分。其他抗HCV药物可以与本发明化合物同时给药或不同时给药。后者的情况，给药可以错开进行如6h、12h、1天、2天、3天、1周、2周、3周、1个月或2个月进行。And the treatment method comprising the administration of crystal form A or pharmaceutical composition of the compound represented by formula (I) of the present invention, further includes the administration of other anti-HCV drugs, wherein other anti-HCV drugs can be combined with the compound of the present invention or its drugs The compounds or pharmaceutical compositions of the present invention may be administered in combination, as a single dosage form, or as separate compounds or pharmaceutical compositions as part of multiple dosage forms. Other anti-HCV drugs may or may not be administered concurrently with the compounds of the present invention. In the latter case, administration can be staggered such as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.
本发明的式(I)所示化合物的晶型A或药学上可接受的组合物的“有效量”或“有效剂量”是指处理或减轻一个或多个本发明所提到病症的严重度的有效量。根据本发明的方法，式(I)所示化合物的晶型A和组合物可以是任何给药量和任何给药途径来有效地用于处理或减轻疾病的严重程度。必需的准确的量将根据患者的情况而改变，这取决于种族，年龄，患者的一般条件，感染的严重程度、特殊的因素、给药方式，等等。式(I)所示化合物的晶型A或组合物可以和一个或多个其他治疗剂联合给药，如本发明所讨论的。The "effective amount" or "effective dosage" of the crystal form A of the compound represented by formula (I) or the pharmaceutically acceptable composition of the present invention refers to treating or reducing the severity of one or more of the conditions mentioned in the present invention. effective amount. According to the method of the present invention, the crystalline form A and the composition of the compound represented by formula (I) can be effectively used to treat or reduce the severity of the disease in any dosage and by any route of administration. The exact amount necessary will vary depending on the patient's condition, depending on race, age, general condition of the patient, severity of infection, special factors, mode of administration, etc. Form A or compositions of the compound represented by Formula (I) may be administered in combination with one or more other therapeutic agents, as discussed herein.
附图说明Description of drawings
图1为式(I)所示化合物的晶型A的X射线粉末衍射(XRPD)图。Figure 1 is an X-ray powder diffraction (XRPD) pattern of crystal form A of the compound represented by formula (I).
图2为式(I)所示化合物的晶型A的差示扫描量热(DSC)图。 Figure 2 is a differential scanning calorimetry (DSC) chart of crystal form A of the compound represented by formula (I).
图3为式(I)所示化合物的晶型A的热失重分析(TGA)图。Figure 3 is a thermogravimetric analysis (TGA) diagram of crystal form A of the compound represented by formula (I).
图4为式(I)所示化合物的无定型的X射线粉末衍射(XRPD)图。Figure 4 is an amorphous X-ray powder diffraction (XRPD) pattern of the compound represented by formula (I).
图5为式(I)所示化合物的晶型A的动态蒸汽吸附(DVS)图。Figure 5 is a dynamic vapor adsorption (DVS) diagram of crystal form A of the compound represented by formula (I).
图6为式(I)所示化合物的无定型的动态蒸汽吸附(DVS)图。Figure 6 is an amorphous dynamic vapor adsorption (DVS) diagram of the compound represented by formula (I).
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，并不因此将本发明限制在所述的实施例范围之中。The present invention will be further described below by means of examples, but the present invention is not limited to the scope of the described examples.
本发明所用X射线粉末衍射分析方法为：在装配有自动化3*15零背景样品架的透射反射样品台的荷兰PANalytical Empyrean X-射线衍射仪上收集X-射线粉末衍射(XRPD)图案。所用辐射源为(Cu，kα，Kα11.540598；Kα21.544426；Kα2/Kα1强度比例：0.50)，其中电压设定在45KV，电流设定在40mA.X-射线的束发散度，即样品上X-射线约束的有效尺寸，为10mm采用θ-θ连续扫描模式，得到3°～40°的有效2θ范围。取适量样品在环境条件(约18℃～32℃)下于零背景样品架圆形凹槽处，用洁净的载玻片轻压，得到一个平整的平面，并将零背景样品架固定。将样品以0.0167°的扫描步长在2θ为3～40°±0.2°范围内产生传统的XRPD图案。用于数据收集的软件为Data Collector，数据用Data Viewer和HighScore Plus分析和展示。在X-射线粉末衍射图中，纵坐标为用计数(counts)表示的衍射强度，横坐标为用度(°)表示的衍射角2θ。The X-ray powder diffraction analysis method used in the present invention is: collecting X-ray powder diffraction (XRPD) patterns on a Dutch PANalytical Empyrean X-ray diffractometer equipped with a transmission and reflection sample stage equipped with an automated 3*15 zero-background sample holder. The radiation source used is (Cu, kα, Kα1 1.540598;Kα2 1.544426; Kα2/Kα1 intensity ratio: 0.50), where the voltage is set at 45KV and the current is set at 40mA. The beam divergence of X-rays, that is, the effective size of X-ray confinement on the sample, is 10mm using θ-θ continuous In scanning mode, an effective 2θ range of 3° to 40° is obtained. Take an appropriate amount of sample and place it at the circular groove of the zero-background sample holder under ambient conditions (about 18°C ~ 32°C). Press it lightly with a clean glass slide to obtain a flat plane, and fix the zero-background sample holder. The sample was scanned with a scan step of 0.0167° to produce a traditional XRPD pattern in the range of 2θ from 3 to 40°±0.2°. The software used for data collection was Data Collector, and the data was analyzed and displayed using Data Viewer and HighScore Plus. In the X-ray powder diffraction pattern, the ordinate is the diffraction intensity expressed in counts (counts), and the abscissa is the diffraction angle 2θ expressed in degrees (°).
本发明所用差示扫描量热(DSC)分析方法为：使用TA Instruments差示扫描量热计Q2000进行差示扫描量热法(DSC)。将样品(约1mg～3mg)放入铝盘中并精确记录重量。该盘用盖子覆盖，然后压接，并将样品转移至仪器中进行测量。将样品池在30℃下平衡并在氮气吹扫下以10℃/min的速率加热至300℃的最终温度。在DSC图中，横坐标表示温度(Temperature,℃)，纵坐标表示单位质量的物质放出的热流量(Heat Flow,W/g)。The differential scanning calorimetry (DSC) analysis method used in the present invention is: using TA Instruments differential scanning calorimeter Q2000 to perform differential scanning calorimetry (DSC). Place the sample (approximately 1 mg ~ 3 mg) into an aluminum pan and record the weight accurately. The pan is covered with a cap, then crimped, and the sample is transferred to the instrument for measurement. The sample cell was equilibrated at 30°C and heated to a final temperature of 300°C at a rate of 10°C/min under a nitrogen purge. In the DSC diagram, the abscissa represents the temperature (Temperature, ℃), and the ordinate represents the heat flow (Heat Flow, W/g) released by the substance per unit mass.
本发明所用热失重(TGA)分析方法为：使用TA Instruments热重分析仪Q500进行热重分析，将适量样品放置在铂样品盘中，在氮气氛下，以10℃/分钟速率升温，温度范围为30至300℃。在TGA图中，横坐标表示温度(Temperature,℃)，纵坐标表示质量百分数(Weight,％)。The thermogravimetric (TGA) analysis method used in the present invention is: use TA Instruments Thermogravimetric Analyzer Q500 to perform thermogravimetric analysis, place an appropriate amount of sample in a platinum sample plate, and heat it at a rate of 10°C/minute under a nitrogen atmosphere. The temperature range is 30 to 300℃. In the TGA chart, the abscissa represents temperature (Temperature, ° C), and the ordinate represents mass percentage (Weight, %).
本发明所用动态蒸汽吸附分析(DVS)分析方法为：DVS测试等温吸附平衡曲线测试方法，使用英国SMS动态蒸汽吸附分析仪DVSINT-Std测试，25.0℃条件下随着相对湿度(0％-95.0％-0％)的变化，从0％相对湿度开始，以10％的相对湿度阶梯变化到达95％相对湿度，然后再以10％的相对湿度阶梯变化到达0％相对湿度。处于某一特定相对湿度条件下单位时间样品重量变化dm/dt的绝对值小于0.1％时认为达到平衡，则进入下一个相对湿度。检测产品在(0％-95.0％-0％)相对湿度循环条件下的引湿性变化情况。 The dynamic vapor adsorption analysis (DVS) analysis method used in the present invention is: DVS test isothermal adsorption equilibrium curve test method, using the British SMS dynamic vapor adsorption analyzer DVSINT-Std to test, with the relative humidity (0%-95.0%) under the condition of 25.0°C -0%), starting from 0% relative humidity, changing in steps of 10% relative humidity to 95% relative humidity, and then reaching 0% relative humidity in steps of 10% relative humidity. Under a certain relative humidity condition, when the absolute value of the sample weight change dm/dt per unit time is less than 0.1%, it is considered to have reached equilibrium and then enters the next relative humidity. Detect the changes in hygroscopicity of the product under (0%-95.0%-0%) relative humidity cycling conditions.
实施例Example
实施例1式(I)所示化合物的无定型的制备Example 1 Preparation of amorphous form of compound represented by formula (I)
参照专利申请CN108299532A中实施例3的方法制备得到式(I)所示化合物为白色泡沫状固体，约187.3mg，通过Empyrean X射线粉末衍射(XRPD)分析为无定型，具体XRPD图谱基本上如附图4所示。The compound represented by formula (I) was prepared by referring to the method of Example 3 in patent application CN108299532A, which was a white foamy solid, about 187.3 mg. It was analyzed by Empyrean X-ray powder diffraction (XRPD) as amorphous. The specific XRPD pattern is basically as shown in the attachment. As shown in Figure 4.
实施例2式(I)所示化合物的晶型A的制备
Example 2 Preparation of crystal form A of the compound represented by formula (I)
反应釜中投入43.35kg式(I-1)化合物(专利申请CN108299532A中实施例3的3-6)，加入91.4kg的冰乙酸和87.2kg饮用水，开启搅拌，控反应釜内温40±5℃，反应6h。反应液降温至20±5℃，加入75.0kg丙酮，缓缓滴加配制好的碳酸氢钠水溶液(91.04kg碳酸氢钠和867.0kg水)，搅拌下控釜内温度25±5℃，调pH＝5，继续搅拌8h大部分固体析出后，离心，50±5℃干燥16h，得到式(I)化合物粗品。反应釜中加入26.8kg丙酮，控制夹套温度30±5℃，缓缓加入式(I)化合物粗品，搅拌0.5h后加入15.2kg水，控制釜内温度45±5℃，溶清后加入250.6kg甲基叔丁基醚(控制釜内温度20±5℃)，搅拌降温至釜内温度-10±5℃，保温搅拌5h后离心，用预冷好的37.4kg甲基叔丁基醚淋洗得湿品，50±5℃干燥20h，得33.29kg白色固体粉末，经XRPD检测为晶型A。Put 43.35kg of the compound of formula (I-1) (3-6 of Example 3 in patent application CN108299532A) into the reaction kettle, add 91.4kg of glacial acetic acid and 87.2kg of drinking water, start stirring, and control the internal temperature of the reaction kettle to 40±5 ℃, reaction 6h. Cool the reaction solution to 20±5℃, add 75.0kg acetone, slowly add the prepared sodium bicarbonate aqueous solution (91.04kg sodium bicarbonate and 867.0kg water) dropwise, stir and control the temperature in the kettle to 25±5℃, and adjust the pH =5, continue stirring for 8 hours, and after most of the solid has precipitated, centrifuge and dry at 50±5°C for 16 hours to obtain a crude compound of formula (I). Add 26.8kg acetone to the reaction kettle, control the jacket temperature to 30±5°C, slowly add the crude compound of formula (I), stir for 0.5h and then add 15.2kg water, control the temperature inside the kettle to 45±5°C, and add 250.6 kg methyl tert-butyl ether (control the temperature in the kettle to 20±5℃), stir and cool down to -10±5℃, keep stirring for 5 hours, centrifuge, and rinse with 37.4kg of pre-cooled methyl tert-butyl ether. The wet product was obtained by washing and dried at 50±5°C for 20 hours to obtain 33.29kg of white solid powder, which was detected as crystal form A by XRPD.
式(I)所示化合物的晶型A的表征：Characterization of crystal form A of the compound represented by formula (I):
(1)通过Empyrean X射线粉末衍射(XRPD)分析：使用Cu-Kα辐射，具有下列以角度2θ表示的特征峰：4.28,5.58,6.69,8.23,8.52,10.35,10.56,11.17,11.83,12.78,13.39,15.68,15.82,16.45,16.79,17.59,17.83,18.93,20.00,20.42,20.84,21.71,21.99,23.17,23.50,23.78,24.10,24.42,24.73,25.71,26.36,26.52,26.88,27.38,28.18,29.00,29.95,31.30,33.17,33.95,34.80,36.50,存在±0.2°的误差容限，所得X射线粉末衍射图谱基本上如图1所示。(1) Analysis by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, it has the following characteristic peaks expressed in angle 2θ: 4.28, 5.58, 6.69, 8.23, 8.52, 10.35, 10.56, 11.17, 11.83, 12.78, 13.39,15.68,15.82,16.45,16.79,17.59,17.83,18.93,20.00,20.42,20.84,21.71,21.99,23.17,23.50,23.78,24.10,24.42,24.73,25.71,26. 36,26.52,26.88,27.38,28.18, 29.00, 29.95, 31.30, 33.17, 33.95, 34.80, 36.50, there is an error tolerance of ±0.2°, and the obtained X-ray powder diffraction pattern is basically as shown in Figure 1.
(2)通过TA Q2000差示扫描量热(DSC)分析：升温速率为10℃/分钟，所得DSC曲线基本上如图2所示，包含135℃的吸热峰，存在±3℃的误差容限。(2) Analysis by TA Q2000 differential scanning calorimetry (DSC): the heating rate is 10°C/minute, and the obtained DSC curve is basically as shown in Figure 2, including an endothermic peak of 135°C, and there is an error tolerance of ±3°C. limit.
(3)通过TA Q500进行热失重(TGA)分析：升温速率为10℃/分钟，所得TGA曲线基本上如图3所示，在200℃之前无显著失重，说明晶型A为无水晶型。(3) Thermal weight loss (TGA) analysis was performed by TA Q500: the heating rate was 10°C/min, and the obtained TGA curve was basically as shown in Figure 3. There was no significant weight loss before 200°C, indicating that the crystal form A was an amorphous form.
实施例3Example 3
DVS测试等温吸附平衡曲线测试方法如下，25.0℃条件下随着相对湿度(0％-95.0％-0％)的变化，从0％相对湿度开始，以10％的相对湿度阶梯变化到达95％相对湿度，然后再以10％的相对湿度阶梯变化到 达0％相对湿度。处于某一特定相对湿度条件下单位时间样品重量变化dm/dt的绝对值小于0.1％时认为达到平衡，则进入下一个相对湿度。检测东安强晶型A和无定型产品在(0％-95.0％-0％)相对湿度循环条件下的引湿性变化情况。The DVS test isothermal adsorption equilibrium curve test method is as follows. Under the condition of 25.0℃, with the change of relative humidity (0%-95.0%-0%), starting from 0% relative humidity, with a step change of 10% relative humidity to reach 95% relative humidity. humidity and then in 10% relative humidity steps to up to 0% relative humidity. Under a certain relative humidity condition, when the absolute value of the sample weight change dm/dt per unit time is less than 0.1%, it is considered to have reached equilibrium and then enters the next relative humidity. Detect the changes in hygroscopicity of Dong'an strong crystal form A and amorphous products under (0%-95.0%-0%) relative humidity cycling conditions.
式(I)所示化合物的晶型A和无定型的DVS结果基本上如附图5和附图6所示。其中，晶型A在相对湿度为95％时引湿增重达到最大为0.27％，而无定型在相对湿度为95％时引湿增重达到了3.31％，这表明晶型A对比无定型具有明显低的引湿性。The DVS results of the crystal form A and the amorphous form of the compound represented by formula (I) are basically as shown in Figures 5 and 6. Among them, the weight gain of crystalline form A reached a maximum of 0.27% when the relative humidity was 95%, while the weight gain of the amorphous form reached 3.31% when the relative humidity was 95%. This shows that the crystalline form A has more advantages than the amorphous form. Significantly low hygroscopicity.
实施例4Example 4
实验动物口服定量给予式(I)所示化合物晶型A和无定型后代谢产物的药代动力学评价Pharmacokinetic evaluation of crystalline form A and amorphous metabolites of the compound represented by formula (I) after oral administration to experimental animals
实验方法：比格犬(每组3只)经胶囊口服给予30mg/kg受试样品；给药后按时间点(0.25、0.5、1、2、4、6、8和24小时)前肢静脉采血，收集于加EDTA-K2的抗凝管内。血浆样品经液液萃取后，在高效液相串联质谱仪(超高效液相色谱仪(岛津LC30A)，质谱仪(AB SCIEX API 5500))上，以多重反应离子监测(MRM)方式进行定量分析代谢产物GS331007的血药浓度。采用WinNonlin 6.3软件用非房室模型法计算AUC和Cmax等药动学参数。试验结果如表2所示。
Experimental method: Beagle dogs (3 dogs in each group) were orally administered 30 mg/kg test sample via capsule; after administration, the forelimb veins were administered according to time points (0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours). Collect blood and collect it in anticoagulant tubes with EDTA-K 2 added. After liquid-liquid extraction, plasma samples were quantified using multiple reactive ion monitoring (MRM) on a high-performance liquid chromatography tandem mass spectrometer (ultra-performance liquid chromatography (Shimadzu LC30A), mass spectrometer (AB SCIEX API 5500)). Analyze the plasma concentration of metabolite GS331007. WinNonlin 6.3 software was used to calculate pharmacokinetic parameters such as AUC and C max using the non-compartmental model method. The test results are shown in Table 2.
表2：本发明所述晶型A和无定型口服给药后在比格犬体内的药代动力学参数
Table 2: Pharmacokinetic parameters of crystalline form A and amorphous form of the present invention in beagle dogs after oral administration
实验结果显示，相同剂量下，式(I)所示化合物的晶型A相比式(I)所示化合物的无定型，在比格犬体内药代动力学性质更好，体现在吸收更好，吸收后产生的代谢物GS331007的暴露量更高，血药浓度更高。Experimental results show that at the same dose, the crystal form A of the compound represented by formula (I) has better pharmacokinetic properties in beagle dogs than the amorphous form of the compound represented by formula (I), which is reflected in better absorption. , the exposure of the metabolite GS331007 produced after absorption is higher and the plasma concentration is higher.
以上所述内容仅为本发明构思下的基本说明，而依据本发明的技术方案所作的任何等效变换，均应属于本发明的保护范围。The above content is only a basic description of the concept of the present invention, and any equivalent transformation made based on the technical solution of the present invention shall fall within the protection scope of the present invention.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例 或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, reference to the terms "one embodiment,""someembodiments,""anexample,""specificexamples," or "some examples" or the like means that specific features are described in connection with the embodiment or example. , structures, materials or features included in at least one embodiment of the invention or example. In this specification, the schematic expressions of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the specific features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine different embodiments or examples and features of different embodiments or examples described in this specification unless they are inconsistent with each other.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。 Although the embodiments of the present invention have been shown and described above, it can be understood that the above-mentioned embodiments are illustrative and should not be construed as limitations of the present invention. Those of ordinary skill in the art can make modifications to the above-mentioned embodiments within the scope of the present invention. The embodiments are subject to changes, modifications, substitutions and variations.

Claims (10)

  1. 一种式(I)所示化合物的晶型A，
    A crystal form A of a compound represented by formula (I),
    其特征在于，所述晶型A的X射线粉末衍射图谱包含下列2θ角处的衍射峰：10.35±0.2°,10.56±0.2°,13.39±0.2°,15.68±0.2°,15.82±0.2°,20.42±0.2°,20.84±0.2°,21.71±0.2°。It is characterized in that the X-ray powder diffraction pattern of the crystal form A includes the following diffraction peaks at 2θ angles: 10.35±0.2°, 10.56±0.2°, 13.39±0.2°, 15.68±0.2°, 15.82±0.2°, 20.42 ±0.2°, 20.84±0.2°, 21.71±0.2°.
  2. 根据权利要求1所述的式(I)所示化合物的晶型A，其特征在于，所述晶型A的X射线粉末衍射图谱包含下列2θ角处的衍射峰：4.28±0.2°,6.69±0.2°,10.35±0.2°,10.56±0.2°,11.83±0.2°,12.78±0.2°,13.39±0.2°,15.68±0.2°,15.82±0.2°,16.79±0.2°,17.59±0.2°,17.83±0.2°,20.00±0.2°,20.42±0.2°,20.84±0.2°,21.71±0.2°,23.50±0.2°,24.73±0.2°,26.36±0.2°,26.52±0.2°,27.38±0.2°,28.18±0.2°,29.95±0.2°,31.30±0.2°。The crystal form A of the compound represented by formula (I) according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystal form A includes the following diffraction peaks at 2θ angles: 4.28±0.2°, 6.69± 0.2°,10.35±0.2°,10.56±0.2°,11.83±0.2°,12.78±0.2°,13.39±0.2°,15.68±0.2°,15.82±0.2°,16.79±0.2°,17.59±0.2°,17.83± 0.2°,20.00±0.2°,20.42±0.2°,20.84±0.2°,21.71±0.2°,23.50±0.2°,24.73±0.2°,26.36±0.2°,26.52±0.2°,27.38±0.2°,28.18± 0.2°,29.95±0.2°,31.30±0.2°.
  3. 根据权利要求1或2所述的式(I)所示化合物的晶型A，其特征在于，所述晶型A的X射线粉末衍射图谱包含下列2θ角处的衍射峰：4.28±0.2°,5.58±0.2°,6.69±0.2°,8.23±0.2°,10.35±0.2°,10.56±0.2°,11.83±0.2°,12.78±0.2°,13.39±0.2°,15.68±0.2°,15.82±0.2°,16.45±0.2°,16.79±0.2°,17.59±0.2°,17.83±0.2°,18.93±0.2°,20.00±0.2°,20.42±0.2°,20.84±0.2°,21.71±0.2°,21.99±0.2°,23.17±0.2°,23.50±0.2°,23.78±0.2°,24.73±0.2°,25.71±0.2°,26.36±0.2°,26.52±0.2°,27.38±0.2°,28.18±0.2°,29.95±0.2°,31.30±0.2°,33.17±0.2°,34.80±0.2°。The crystal form A of the compound represented by formula (I) according to claim 1 or 2, characterized in that the X-ray powder diffraction pattern of the crystal form A includes the following diffraction peaks at the 2θ angle: 4.28±0.2°, 5.58±0.2°,6.69±0.2°,8.23±0.2°,10.35±0.2°,10.56±0.2°,11.83±0.2°,12.78±0.2°,13.39±0.2°,15.68±0.2°,15.82±0.2°, 16.45±0.2°,16.79±0.2°,17.59±0.2°,17.83±0.2°,18.93±0.2°,20.00±0.2°,20.42±0.2°,20.84±0.2°,21.71±0.2°,21.99±0.2°, 23.17±0.2°,23.50±0.2°,23.78±0.2°,24.73±0.2°,25.71±0.2°,26.36±0.2°,26.52±0.2°,27.38±0.2°,28.18±0.2°,29.95±0.2°, 31.30±0.2°, 33.17±0.2°, 34.80±0.2°.
  4. 根据权利要求1-3任意一项所述的式(I)所示化合物的晶型A，其特征在于，所述晶型A的X射线粉末衍射图谱包含下列2θ角处的衍射峰：4.28±0.2°,5.58±0.2°,6.69±0.2°,8.23±0.2°,8.52±0.2°,10.35±0.2°,10.56±0.2°,11.17±0.2°,11.83±0.2°,12.78±0.2°,13.39±0.2°,15.68±0.2°,15.82±0.2°,16.45±0.2°,16.79±0.2°,17.59±0.2°,17.83±0.2°,18.93±0.2°,20.00±0.2°,20.42±0.2°,20.84±0.2°,21.71±0.2°,21.99±0.2°,23.17±0.2°,23.50±0.2°,23.78±0.2°,24.10±0.2°,24.42±0.2°,24.73±0.2°,25.71±0.2°,26.36±0.2°,26.52±0.2°,26.88±0.2°,27.38±0.2°,28.18±0.2°,29.00±0.2°,29.95±0.2°,31.30±0.2°,33.17±0.2°,33.95±0.2°,34.80±0.2°,36.50±0.2°。The crystal form A of the compound represented by formula (I) according to any one of claims 1 to 3, characterized in that the X-ray powder diffraction pattern of the crystal form A includes the following diffraction peaks at the 2θ angle: 4.28± 0.2°,5.58±0.2°,6.69±0.2°,8.23±0.2°,8.52±0.2°,10.35±0.2°,10.56±0.2°,11.17±0.2°,11.83±0.2°,12.78±0.2°,13.39± 0.2°,15.68±0.2°,15.82±0.2°,16.45±0.2°,16.79±0.2°,17.59±0.2°,17.83±0.2°,18.93±0.2°,20.00±0.2°,20.42±0.2°,20.84± 0.2°,21.71±0.2°,21.99±0.2°,23.17±0.2°,23.50±0.2°,23.78±0.2°,24.10±0.2°,24.42±0.2°,24.73±0.2°,25.71±0.2°,26.36± 0.2°,26.52±0.2°,26.88±0.2°,27.38±0.2°,28.18±0.2°,29.00±0.2°,29.95±0.2°,31.30±0.2°,33.17±0.2°,33.95±0.2°,34.80± 0.2°,36.50±0.2°.
  5. 根据权利要求1-4任意一项所述的式(I)所示化合物的晶型A，其特征在于，所述晶型A具有基本上如图1所示的X射线粉末衍射图。The crystal form A of the compound represented by formula (I) according to any one of claims 1 to 4, characterized in that the crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 1.
  6. 根据权利要求1-5任意一项所述的式(I)所示化合物的晶型A，其特征在于，所述晶型A的差示扫描量热图包含135℃±3℃的吸热峰。The crystal form A of the compound represented by formula (I) according to any one of claims 1 to 5, characterized in that the differential scanning calorimetry diagram of the crystal form A contains an endothermic peak of 135°C±3°C. .
  7. 根据权利要求1-6任意一项所述的式(I)所示化合物的晶型A，其特征在于，所述晶型A具有基本 上如图2所示的差示扫描量热图。The crystal form A of the compound represented by formula (I) according to any one of claims 1 to 6, characterized in that the crystal form A has basically The differential scanning calorimetry diagram shown in Figure 2 above.
  8. 一种药物组合物，其包含权利要求1-7任意一项所述的式(I)所示化合物的晶型A；任选地，所述药物组合物进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂或它们的组合。A pharmaceutical composition comprising the crystal form A of the compound represented by formula (I) according to any one of claims 1 to 7; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, an excipient excipients, diluents, auxiliaries or combinations thereof.
  9. 根据权利要求8所述的药物组合物，其进一步地包含其他的抗HCV的药物；任选地，所述其他的抗HCV的药物为干扰素、利巴韦林、白介素2、白介素6、白介素12、促进产生1型辅助性T细胞应答的化合物、干扰RNA、反义RNA、咪喹莫德、肌苷5’-单磷酸脱氢酶抑制剂、金刚烷胺、金刚乙胺、巴维昔单抗、丙型肝炎免疫球蛋白、civacir、波普瑞韦、替拉瑞韦、达卡他韦、司美匹韦、阿那匹韦、西鲁瑞韦、丹诺普韦、雷迪帕韦、硝唑尼特、奈韦拉平、阿拉泊韦、依米他韦、vaniprevir、faldaprevir、paritaprevir、sovaprevir、grazoprevir、elbasvir、vedroprevir、narlaprevir、ombitasvir、ravidasvir、velpatasvir、samatasvir、alisporivir、modithromycin、odalasvir、ritonavir、alloferon、nivolumab、multiferon、pibrentasvir、glecaprevir、procvax、miravirsen、EDP239、ANA975、MK-8325、BZF-961、GS-9256、GSK-2336805、PPI-461、ACH-1095、VX-985、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、VBY-376、INX-189、IDX-184、IDX102、R1479、UNX-08189、HCV-371、JKT-109、GL-60667、AZD-2795、TMC647055、WF-10、ACH-3422、MK-3682、MK-8408、GS-9857、CD-AdNS3、RG-101、INO-8000、MBL-HCV1、CIGB-230、TG-2349、CB-5300、chronvac-C、MK-1075、ACH-0143422、WS-007、MK-7680、MK-2248、IDX-21459、AV-4025、MK-8876、AL-335、JNJ-47910382、ABP-560、TD-6450、EDP-239、SB-9200、ITX-5061、ID-12，或其任意组合。The pharmaceutical composition according to claim 8, further comprising other anti-HCV drugs; optionally, the other anti-HCV drugs are interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12. Compounds that promote type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitors, amantadine, rimantadine, and bavixidine Monoclonal antibody, hepatitis C immunoglobulin, civacir, boceprevir, telaprevir, daclatasvir, semeprevir, anaprevir, silprevir, danoprevir, ledipavir We, nitazoxanide, nevirapine, alisporivir, emitasvir, vaniprevir, faldaprevir, paritaprevir, sovaprevir, grazoprevir, elbasvir, vedroprevir, narlaprevir, ombitasvir, ravidasvir, velpatasvir, samatasvir, alisporivir, modithromycin, odalasvir, ritonavir, alloferon, nivolumab, multiferon, pibrentasvir, glecaprevir, procvax, miravirsen, EDP239, ANA975, MK-8325, BZF-961, GS-9256, GSK-2336805, PPI-461, ACH-1095, VX-985, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, VBY-376, INX-189, IDX-184, IDX102, R1479, UNX-08189, HCV-371, JKT-109, GL- 60667, AZD-2795, TMC647055, WF-10, ACH-3422, MK-3682, MK-8408, GS-9857, CD-AdNS3, RG-101, INO-8000, MBL-HCV1, CIGB-230, TG- 2349, CB-5300, chronvac-C, MK-1075, ACH-0143422, WS-007, MK-7680, MK-2248, IDX-21459, AV-4025, MK-8876, AL-335, JNJ-47910382, ABP-560, TD-6450, EDP-239, SB-9200, ITX-5061, ID-12, or any combination thereof.
  10. 权利要求1-7任意一项所述的式(I)所示化合物的晶型A或权利要求8-9任意一项所述的药物组合物在制备药物中的用途，所述药物用于预防、处理、治疗或减轻HCV感染或丙型肝炎疾病相关的疾病。 The use of crystal form A of the compound represented by formula (I) according to any one of claims 1 to 7 or the pharmaceutical composition according to any one of claims 8 to 9 in the preparation of medicines for prevention , manage, treat or mitigate conditions associated with HCV infection or hepatitis C disease.
PCT/CN2023/112232 2022-08-11 2023-08-10 Crystal form of hepatitis c inhibitor and use thereof in drug WO2024032718A1 (en)

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