WO2024032718A1 - Forme cristalline d'un inhibiteur de l'hépatite c et son utilisation dans un médicament - Google Patents

Forme cristalline d'un inhibiteur de l'hépatite c et son utilisation dans un médicament 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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English (en)
Chinese (zh)
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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/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—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

La présente invention concerne une forme cristalline d'un inhibiteur de l'hépatite C et son utilisation dans un médicament, et concerne plus précisément une forme cristalline A d'un composé tel que représenté par la formule (I), une composition pharmaceutique de la forme cristalline A, et son utilisation dans la préparation d'un médicament pour prévenir, traiter, traiter ou atténuer des maladies liées aux infections par le VHC et/ou aux maladies de l'hépatite C. La forme cristalline du composé présente une bonne stabilité, de bonnes propriétés pharmacocinétiques, etc, ce qui permet d'obtenir une meilleure pharmacopotentialité.
PCT/CN2023/112232 2022-08-11 2023-08-10 Forme cristalline d'un inhibiteur de l'hépatite c et son utilisation dans un médicament WO2024032718A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016177300A1 (fr) * 2015-05-07 2016-11-10 苏州旺山旺水生物医药有限公司 Dérivé de (2'r)-2'-désoxy-2'-halo-2'-méthyl uridine et procédé de préparation et utilisation de celui-ci
CN106883280A (zh) * 2015-12-15 2017-06-23 杭州和正医药有限公司 一种前药、其制备方法、药物组合物及其用途
WO2018121678A1 (fr) * 2016-12-29 2018-07-05 广东东阳光药业有限公司 Promédicament d'analogues nucléosidiques antiviraux, composition et utilisation associées
CN110981910A (zh) * 2019-12-23 2020-04-10 南京正大天晴制药有限公司 一种用于治疗丙肝的无引湿性低变异性新晶型

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016177300A1 (fr) * 2015-05-07 2016-11-10 苏州旺山旺水生物医药有限公司 Dérivé de (2'r)-2'-désoxy-2'-halo-2'-méthyl uridine et procédé de préparation et utilisation de celui-ci
CN106883280A (zh) * 2015-12-15 2017-06-23 杭州和正医药有限公司 一种前药、其制备方法、药物组合物及其用途
WO2018121678A1 (fr) * 2016-12-29 2018-07-05 广东东阳光药业有限公司 Promédicament d'analogues nucléosidiques antiviraux, composition et utilisation associées
CN110981910A (zh) * 2019-12-23 2020-04-10 南京正大天晴制药有限公司 一种用于治疗丙肝的无引湿性低变异性新晶型

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