WO2023226958A1 - 噻吩并嘧啶类化合物的晶型及其用途 - Google Patents

噻吩并嘧啶类化合物的晶型及其用途 Download PDF

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WO2023226958A1
WO2023226958A1 PCT/CN2023/095698 CN2023095698W WO2023226958A1 WO 2023226958 A1 WO2023226958 A1 WO 2023226958A1 CN 2023095698 W CN2023095698 W CN 2023095698W WO 2023226958 A1 WO2023226958 A1 WO 2023226958A1
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crystal form
cancer
crystalline form
present
ray powder
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PCT/CN2023/095698
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English (en)
French (fr)
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单岳峰
陈亮
黄伟明
顾峥
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广东东阳光药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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 crystal forms of thienopyrimidine compounds and their uses, specifically 2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5, 6,6a-Hexahydro-1H-cyclopenta[c]furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxa
  • the crystal form of azole-2-yl-2,4-dioxo-thieno[2,3-d]pyrimidin-3-yl]-2-methyl-propionic acid and its use further relate to the Crystalline pharmaceutical compositions.
  • Acetyl-CoA carboxylase is the rate-limiting enzyme in the first step of fatty acid anabolism.
  • HCO 3 - is used as the carboxyl donor to convert acetyl-CoA into acetyl-CoA carboxylase.
  • A is carboxylated to malonyl coenzyme A, which is a biotin-dependent enzyme.
  • ACC1 In humans and other mammals, this enzyme is a tissue-specific enzyme. There are two subtypes, ACC1 and ACC2, which are different in tissue distribution and function. ACC1 is usually expressed in all tissues, but is not expressed in lipogenesis. Expressed most in tissues such as liver and adipose tissue, ACC2 is highly expressed in skeletal muscle and heart and less expressed in liver tissue. ACC1 catalyzes the biosynthesis of long-chain fatty acids. If acetyl-CoA is not carboxylated to form malonyl-CoA, it is metabolized through the citric acid cycle (Krebs cycle); ACC2 catalyzes the production on the cytoplasmic surface of mitochondria. Malonyl-CoA, and regulates the amount of fatty acids used for ⁇ -oxidation by inhibiting carnitine palmitoyl transferase-1 (CPT-1).
  • CPT-1 carnitine palmitoyl transferase-1
  • ACC inhibitors inhibit ACC1 to reduce the synthesis of fatty acids, while inhibiting ACC2 can promote the oxidation of fatty acids in the liver, thereby reducing the accumulation of lipids in the body, and can effectively treat obesity, hypertension, diabetes, tumors, dyslipidemia and Diseases related to hyperlipidemia and type II diabetes, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) due to accumulation of lipids in the liver causing hepatic insulin resistance.
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • Non-alcoholic steatohepatitis is a chronic progressive liver disease caused by the accumulation of fat in the liver, which can lead to cirrhosis, liver failure and hepatocellular carcinoma.
  • NASH Non-alcoholic steatohepatitis
  • ALT alanine aminotransferase
  • AST acid aminotransferase
  • Cirrhosis is another cause of liver cancer after viral hepatitis and alcoholic hepatitis. Cirrhosis is the leading cause of death from liver disease, directly leading to liver decompensation and an annual mortality rate of nearly 4%.
  • the present invention provides the crystal form of the compound represented by formula (I).
  • the crystal form especially the crystal form C, can significantly improve the stability, pharmacokinetics and other properties of the compound, thereby having better pharmaceutical properties.
  • the present invention relates to the crystalline form of the compound represented by formula (I), as well as pharmaceutical compositions containing the crystalline form, and also relates to their preparation for the treatment or prevention of diseases modulated by acetyl-CoA carboxylase. Uses in medicines.
  • the crystalline form described in the present invention may also be in the form of a solvate, such as a hydrate form.
  • the present invention provides a crystalline form or amorphous form of the compound represented by formula (I),
  • the crystal form of the compound represented by formula (I) of the present invention is crystal form B, C or D.
  • the crystal form B of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form B has diffraction peaks at the following 2 ⁇ angles: 5.07° ⁇ 0.2°, 10.93° ⁇ 0.2° ,16.61° ⁇ 0.2°, 17.11° ⁇ 0.2°, 19.82° ⁇ 0.2°, 25.76° ⁇ 0.2°.
  • the crystal form B of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form B has diffraction peaks at the following 2 ⁇ angles: 5.07° ⁇ 0.2°, 10.93° ⁇ 0.2° ,12.79° ⁇ 0.2°,15.83° ⁇ 0.2°,16.61° ⁇ 0.2°,17.11° ⁇ 0.2°,18.47° ⁇ 0.2°,19.59° ⁇ 0.2°,19.82° ⁇ 0.2°,25.76° ⁇ 0.2°,27.48 ° ⁇ 0.2°.
  • the crystal form B of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form B has diffraction peaks at the following 2 ⁇ angles: 5.07° ⁇ 0.2°, 9.19° ⁇ 0.2 °,9.98° ⁇ 0.2°,10.12° ⁇ 0.2°,10.67° ⁇ 0.2°,10.93° ⁇ 0.2°,11.35° ⁇ 0.2°,11.61° ⁇ 0.2°,11.96° ⁇ 0.2°,12.79° ⁇ 0.2°, 13.77° ⁇ 0.2°,14.39° ⁇ 0.2°,14.95° ⁇ 0.2°,15.14° ⁇ 0.2°,15.83° ⁇ 0.2°,16.61° ⁇ 0.2°,17.11° ⁇ 0.2°,17.56° ⁇ 0.2°,18.47° ⁇ 0.2°,19.09° ⁇ 0.2°,19.59° ⁇ 0.2°,19.82° ⁇ 0.2°, 20.19° ⁇ 0.2°,21.00° ⁇ 0.2°,22.07° ⁇ 0.2°,22.36° ⁇ 0.2°,22.76° ⁇ 0.2°,23
  • the crystalline Form B of the present invention is characterized in that the crystalline Form B has an X-ray powder diffraction pattern substantially as shown in Figure 4.
  • the crystalline form B of the present invention is characterized in that the differential scanning calorimetry diagram of the crystalline form B includes endothermic peaks of 84.14°C ⁇ 3°C and 161.75°C ⁇ 3°C.
  • the crystalline Form B of the present invention is characterized in that the crystalline Form B has a differential scanning calorimetry diagram substantially as shown in Figure 5.
  • the crystalline form B of the present invention is characterized in that when the crystalline form B is heated to about 150°C, the weight loss is about 2.819%, and there is an error tolerance of ⁇ 0.1%.
  • the crystalline form C of the present invention is characterized in that the X-ray powder diffraction pattern of the crystalline form C has diffraction peaks at the following 2 ⁇ angles: 5.61° ⁇ 0.2°, 14.31° ⁇ 0.2° ,17.28° ⁇ 0.2°, 18.68° ⁇ 0.2°, 20.15° ⁇ 0.2°, 23.63° ⁇ 0.2°.
  • the crystalline form C of the present invention is characterized in that the X-ray powder diffraction pattern of the crystalline form C has diffraction peaks at the following 2 ⁇ angles: 5.61° ⁇ 0.2°, 9.58° ⁇ 0.2° ,10.05° ⁇ 0.2°,10.27° ⁇ 0.2°,12.00° ⁇ 0.2°,14.31° ⁇ 0.2°,17.28° ⁇ 0.2°,18.68° ⁇ 0.2°,19.18° ⁇ 0.2°,19.33° ⁇ 0.2°,20.15 ° ⁇ 0.2°,23.63° ⁇ 0.2°.
  • the crystalline form C of the present invention is characterized in that the X-ray powder diffraction pattern of the crystalline form C has diffraction peaks at the following 2 ⁇ angles: 5.61° ⁇ 0.2°, 9.58° ⁇ 0.2 °,10.05° ⁇ 0.2°,10.27° ⁇ 0.2°,11.19° ⁇ 0.2°,12.00° ⁇ 0.2°,12.63° ⁇ 0.2°,13.23° ⁇ 0.2°,14.31° ⁇ 0.2°,16.13° ⁇ 0.2°, 17.28° ⁇ 0.2°,17.88° ⁇ 0.2°,18.68° ⁇ 0.2°,19.18° ⁇ 0.2°,19.33° ⁇ 0.2°,20.15° ⁇ 0.2°,20.93° ⁇ 0.2°,21.66° ⁇ 0.2°,22.73° ⁇ 0.2°,23.63° ⁇ 0.2°,25.39° ⁇ 0.2°,26.60° ⁇ 0.2°,27.87° ⁇ 0.2°,28.93° ⁇ 0.2°,29.62° ⁇ 0.2°,30.88° ⁇ 0.2°,32.61
  • the crystalline Form C of the present invention is characterized in that the crystalline Form C has an X-ray powder diffraction pattern substantially as shown in Figure 7.
  • the crystalline form C of the present invention is characterized in that the differential scanning calorimetry diagram of the crystalline form C includes an endothermic peak of 166.88°C ⁇ 3°C.
  • the crystalline Form C of the present invention is characterized in that the crystalline Form C has a differential scan substantially as shown in Figure 8 Trace the heat map.
  • the crystalline form C of the present invention is characterized in that when the crystalline form C is heated to about 150°C, the weight loss is about 0.008%, and there is an error tolerance of ⁇ 0.1%.
  • the crystalline form D of the present invention is characterized in that the X-ray powder diffraction pattern of the crystalline form D has diffraction peaks at the following 2 ⁇ angles: 6.08° ⁇ 0.2°, 8.58° ⁇ 0.2° ,9.62° ⁇ 0.2°, 13.60° ⁇ 0.2°, 15.52° ⁇ 0.2°, 22.01° ⁇ 0.2°.
  • the crystalline form D of the present invention is characterized in that the X-ray powder diffraction pattern of the crystalline form D has diffraction peaks at the following 2 ⁇ angles: 6.08° ⁇ 0.2°, 8.58° ⁇ 0.2° ,9.62° ⁇ 0.2°,12.17° ⁇ 0.2°,13.60° ⁇ 0.2°,15.52° ⁇ 0.2°,17.26° ⁇ 0.2°,17.74° ⁇ 0.2°,18.31° ⁇ 0.2°,22.01° ⁇ 0.2°,24.05 ° ⁇ 0.2°.
  • the crystalline form D of the present invention is characterized in that the X-ray powder diffraction pattern of the crystalline form D has diffraction peaks at the following 2 ⁇ angles: 4.33° ⁇ 0.2°, 6.08° ⁇ 0.2 °,8.58° ⁇ 0.2°,9.62° ⁇ 0.2°,12.17° ⁇ 0.2°,12.91° ⁇ 0.2°,13.60° ⁇ 0.2°,14.06° ⁇ 0.2°,14.75° ⁇ 0.2°,15.07° ⁇ 0.2°, 15.52° ⁇ 0.2°,16.04° ⁇ 0.2°,17.26° ⁇ 0.2°,17.74° ⁇ 0.2°,17.93° ⁇ 0.2°,18.31° ⁇ 0.2°,18.51° ⁇ 0.2°,18.86° ⁇ 0.2°,19.28° ⁇ 0.2°,20.45° ⁇ 0.2°,21.21° ⁇ 0.2°,21.68° ⁇ 0.2°,22.01° ⁇ 0.2°,22.43° ⁇ 0.2°,23.30° ⁇ 0.2°,23.66° ⁇ 0.2°,24.
  • the crystalline form D of the present invention is characterized in that the crystalline form D has an X-ray powder diffraction pattern substantially as shown in Figure 10.
  • the crystalline form D of the present invention is characterized in that the differential scanning calorimetry diagram of the crystalline form D includes an endothermic peak of 122.02°C ⁇ 3°C.
  • the crystalline Form D of the present invention is characterized in that the crystalline Form D has a differential scanning calorimetry diagram substantially as shown in Figure 11.
  • the crystalline form D of the present invention is characterized in that when the crystalline form D is heated to about 150°C, the weight loss is about 7.634%, and there is an error tolerance of ⁇ 0.1%.
  • the amorphous form of the present invention is characterized in that the amorphous form has an X-ray powder diffraction pattern substantially as shown in Figure 13.
  • the amorphous form of the present invention is characterized in that the amorphous form has a differential scanning calorimetry pattern substantially as shown in Figure 14.
  • the amorphous form of the present invention is characterized in that when the amorphous form is heated to about 150°C, the weight loss is about 2.423%, and there is an error tolerance of ⁇ 0.1%.
  • the present invention provides a salt of the compound represented by formula (I),
  • the salt of the compound represented by formula (I) of the present invention is a sodium salt or a potassium salt.
  • the sodium salt of the compound represented by formula (I) of the present invention is the amorphous form of the sodium salt of the compound represented by formula (I).
  • the amorphous form of the sodium salt of the present invention is characterized in that the amorphous form of the sodium salt has an X-ray powder diffraction pattern substantially as shown in Figure 16.
  • the potassium salt of the compound represented by formula (I) of the present invention is the amorphous form of the potassium salt of the compound represented by formula (I).
  • the amorphous form of the potassium salt of the present invention is characterized in that the amorphous form of the potassium salt has an X-ray powder diffraction pattern substantially as shown in Figure 17.
  • the present invention relates to a pharmaceutical composition, which contains any crystal form described in the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, auxiliary agent or their combination.
  • the present invention relates to the use of any of the crystalline forms or the pharmaceutical composition in the preparation of medicaments for preventing, treating or alleviating diseases regulated by acetyl-CoA carboxylase.
  • the diseases regulated by the acetyl-CoA carboxylase of the present invention are metabolic diseases and tumors.
  • the present invention relates to the use of any of the crystalline forms or the pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating the disease in patients, which is at least partially regulated by acetyl-CoA carboxylase. disease.
  • the metabolic diseases of the present invention include insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, hepatic steatosis, bullous vesicles steatosis, advanced fibrosis or cirrhosis;
  • the tumors include liver cancer, kidney cancer, lung cancer, breast cancer, melanoma, papillary thyroid tumors, cholangiocarcinoma, colon cancer, ovarian cancer, malignant lymphoma, bladder cancer, prostate cancer cancer, pancreatic cancer, skin cancer, or recurrent solid tumors.
  • One aspect of the present invention relates to a method for preventing, treating or alleviating diseases regulated by acetyl-CoA carboxylase, comprising administering to a patient a pharmaceutically acceptable effective dose of the crystalline form of the present invention or the pharmaceutical composition. medicine.
  • the present invention also relates to a method for preparing the crystal form of the compound represented by formula (I).
  • 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 crystalline forms of the present invention will be described in detail in the Examples section.
  • the present invention provides pharmacological testing experiments (such as pharmacokinetic experiments) and stability experiments of the crystal form. Experiments have proven that the crystal form of the present invention has good stability and pharmacokinetic properties.
  • 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, crystallization on a surface or template, e.g., on a polymer, Crystallization in the presence of additives such as co-crystallized antimolecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding and solvent drop milling, etc.
  • additives such as co-crystallized antimolecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding and solvent drop milling, 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, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, their mixtures,
  • 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.
  • Solvate refers to a compound that has a solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice, which solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, Dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylform Amide, formamide, formic acid, heptane, hexane, isopropyl alcohol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, Toluene, xylene and their mixtures, etc.
  • a specific example of a solvate is a hydrate, in which the solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice is water.
  • the hydrate may or may not have a solvent other than water on the surface of the substance, in the crystal lattice, or on the surface and in the crystal lattice.
  • 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 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 Scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • SEM scanning 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 ° 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 ⁇ 0.1% 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.
  • the present invention relates to said 2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c] Furan-5-yl]oxy]-2-(2-methoxyphenyl)ethyl]-5-methyl-6-oxazol-2-yl-2,4-dioxo-thieno[ Crystalline forms of 2,3-d]pyrimidin-3-yl]-2-methyl-propionic acid, for example, Form C, which exist in a substantially pure crystalline form.
  • 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.
  • Room temperature in the present invention refers to a temperature from about 10°C to about 40°C. In some embodiments, “room temperature” refers to a temperature from about 20°C to about 30°C; in other embodiments, “room temperature” refers to 20°C, 22.5°C, 25°C, 27.5°C, and so on.
  • 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 of the compound represented by formula (I) and pharmaceutically acceptable carriers, adjuvants, or excipients.
  • the pharmaceutical compositions of the invention contain the crystalline form of the compound in an amount effective to detectably treat or alleviate a disease mediated by acetyl-CoA carboxylase.
  • 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 effective dose of the active ingredient employed may vary depending on the crystalline form of the compound employed, the mode of administration and the severity of the disease to be treated. However, generally satisfactory effects can be obtained when the crystalline form of the compound of the present invention is administered at a dose of about 0.25-1000 mg/kg of animal body weight per day, preferably in 2-4 divided doses per day, or in Administer in extended release form. This dosage regimen can be adjusted to provide optimal therapeutic response. In addition, depending on the treatment situation, several divided doses may be administered per day, or the dose may be proportionally reduced.
  • the crystal form of the compound involved in the present invention and the pharmaceutical composition of the present invention can be used to inhibit the activity of acetyl-CoA carboxylase, thereby regulating the stability and/or activity of acetyl-CoA carboxylase.
  • the crystalline form of the compound or the pharmaceutical composition can be used in methods for treating, pre-treating or delaying the onset or progression of acetyl-CoA carboxylase-related disorders, including but not limited to non-alcoholic Steatohepatitis.
  • the crystalline form of the compound involved in the present invention can be used to inhibit the activity of acetyl-CoA carboxylase.
  • Crystalline forms of the compounds may be administered to prevent, pre-treat or treat conditions modulated by acetyl-CoA carboxylase, including, for example, insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic lipids sexual liver disease, non-alcoholic steatohepatitis, hepatic steatosis, bullous steatosis, advanced fibrosis or cirrhosis; the tumors include liver cancer, kidney cancer, lung cancer, breast cancer, melanoma, papillary thyroid tumors, cholangiocarcinoma , colon cancer, ovarian cancer, lymphoid neoplasms, bladder cancer, prostate cancer, pancreatic cancer, skin cancer, or recurrent solid tumors.
  • 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 (TGA) analysis chart of crystal form A of the compound represented by formula (I).
  • Figure 4 is an X-ray powder diffraction (XRPD) pattern of crystal form B of the compound represented by formula (I).
  • FIG. 5 is a differential scanning calorimetry (DSC) chart of crystal form B of the compound represented by formula (I).
  • FIG. 6 is a thermogravimetric (TGA) analysis chart of crystal form B of the compound represented by formula (I).
  • Figure 7 is an X-ray powder diffraction (XRPD) pattern of crystal form C of the compound represented by formula (I).
  • FIG 8 is a differential scanning calorimetry (DSC) chart of crystal form C of the compound represented by formula (I).
  • FIG. 9 is a thermogravimetric (TGA) analysis chart of crystal form C of the compound represented by formula (I).
  • Figure 10 is an X-ray powder diffraction (XRPD) pattern of crystal form D of the compound represented by formula (I).
  • Figure 11 is a differential scanning calorimetry (DSC) chart of crystalline form D of the compound represented by formula (I).
  • FIG 12 is a thermogravimetric (TGA) analysis chart of crystal form D of the compound represented by formula (I).
  • Figure 13 is an amorphous X-ray powder diffraction (XRPD) pattern of the compound represented by formula (I).
  • Figure 14 is a differential scanning calorimetry (DSC) chart of the amorphous form of the compound represented by formula (I).
  • Figure 15 is a thermogravimetric (TGA) analysis chart of the amorphous compound represented by formula (I).
  • Figure 16 is an amorphous X-ray powder diffraction (XRPD) pattern of the sodium salt of the compound represented by formula (I).
  • XRPD amorphous X-ray powder diffraction
  • Figure 17 is an amorphous X-ray powder diffraction (XRPD) pattern of the potassium salt of the compound represented by formula (I).
  • XRPD amorphous X-ray powder diffraction
  • Figure 18 is a dynamic moisture adsorption (DVS) diagram of crystal form A of the compound represented by formula (I).
  • Figure 19 is a dynamic moisture adsorption (DVS) diagram of crystal form C of the compound represented by formula (I).
  • the X-ray powder diffraction analysis method used in the present invention is: Empyrean diffractometer, using Cu-K ⁇ radiation (45KV, 40mA) to obtain the X-ray powder diffraction pattern.
  • the powdered sample was prepared into a thin layer on a single crystal silicon sample holder, placed on a rotating sample stage, and analyzed with a step size of 0.0168° in the range of 3°-40°.
  • Use Data Collector software to collect data
  • Data Viewer software to read data.
  • the differential scanning calorimetry (DSC) analysis method used in the present invention is: using the TA Q2000 module with a thermal analysis controller to perform differential scanning calorimetry. Data were collected and analyzed using TA Instruments Thermal Solutions software. Accurately weigh approximately 1-5 mg of the sample into a special aluminum crucible with a lid, and conduct sample analysis from room temperature to approximately 300°C using a linear heating device at 10°C/min. During use, the DSC chamber was purged with dry nitrogen.
  • Thermal weight loss (TGA) analysis method used in the present invention is: using the TA Q500 module with a thermal analysis controller to perform thermal weight loss. Data were collected and analyzed using TA Instruments Thermal Solutions software. Approximately 10 mg of sample was accurately weighed into a platinum sample pan, and the sample was analyzed from room temperature to approximately 300°C using a linear heating device at 10°C/min. During use, the TGA furnace chamber was purged with dry nitrogen.
  • Crystal Form A can be prepared by referring to Example 1 of WO2021000242, and can also be obtained by the following four preparation methods:
  • TGA Thermal weight loss
  • TGA Thermal weight loss
  • TGA Thermal weight loss
  • TGA Thermogravimetric
  • TGA Thermal weight loss
  • the crystal form of the compound represented by formula (I) of the present invention is filled into capsules for oral administration.
  • Illumination experiment Put an appropriate amount of a batch of test samples into a flat weighing bottle, spread it into a thin layer ⁇ 3mm thick, place it in a light box (with ultraviolet) with the mouth open, and place it under the illumination of 4500 ⁇ 500lx and ultraviolet light. Place it under the condition of ⁇ 0.7w/ m2 for 30 days, take samples on the 5th, 10th, and 30th days, observe the color changes of the samples, detect the purity of the samples by HPLC, and analyze the structure by X-ray powder diffraction.
  • test sample is packaged in a single-layer PE inner package, an aluminum foil bag outer package, a built-in KD-20 deoxidizer, vacuumed and filled with nitrogen, and then heat-sealed and packaged under low temperature 5°C ⁇ 3°C long-term test conditions , observe the color change of the sample, and detect the purity of the sample by HPLC.
  • the stability of the crystalline form C of the present invention is relatively good and suitable for pharmaceutical use.
  • test sample Take an appropriate amount of the test sample and use a dynamic moisture adsorption instrument to test its hygroscopicity.
  • the DVS diagrams of the hygroscopicity experiments of crystal form A and crystal form C of the present invention are basically as shown in Figures 18 and 19, and the specific experimental results are shown in Table 2. According to the description of hygroscopic characteristics and the definition standards of hygroscopic weight gain (Chinese Pharmacopoeia 2015 Edition General Chapter 9103 Guiding Principles for Drug Hygroscopic Tests, see Table 3 for details).
  • references to the terms “one embodiment,” “some embodiments,” “an example,” “specific examples,” or “some examples” or the like means that specific features are described in connection with the embodiment or example. , structures, materials or features are included in at least one embodiment or example of the invention. 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.

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Abstract

本发明涉及噻吩并嘧啶类化合物的晶型及其用途。具体地，本发明涉及2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸的晶型及包含所述的晶型的药物组合物，进一步涉及它们在制备用于治疗和预防由乙酰辅酶A羧化酶调节的疾病的药物中的用途。

Description

噻吩并嘧啶类化合物的晶型及其用途 技术领域
本发明属于医药技术领域，涉及噻吩并嘧啶类化合物的晶型及其用途，具体涉及2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸的晶型及其用途，进一步涉及包含所述的晶型的药物组合物。
背景技术
乙酰辅酶A羧化酶(Acetyl-CoA carboxylase,ACC)是脂肪酸合成代谢第一步反应的限速酶，在ATP供能、Mg2+存在下，以HCO3 -为羧基供体，将乙酰辅酶A羧化生成丙二酸单酰辅酶A，是生物素依赖性酶。
在人类和其他哺乳动物中该酶属于组织特异性酶，存在两种亚型，ACC1和ACC2，两者在组织分布及功能上有所差别；ACC1通常在所有组织中表达，但在脂肪生成的组织(例如肝脏和脂肪组织)中表达最多，ACC2在骨骼肌和心脏中高度表达，在肝脏组织中表达较少。ACC1催化长链脂肪酸的生物合成，如果乙酰辅酶A不被羧化以形成丙二酸单酰辅酶A时，则其通过柠檬酸循环(Krebs cycle)进行代谢；ACC2催化在线粒体的胞质表面产生丙二酸单酰辅酶A，且通过抑制肉碱棕榈酰基转移酶-1(carnitine palmityl transferase,CPT-1)调节用于β-氧化的脂肪酸的量。
研究表明，ACC抑制剂抑制ACC1能够减少脂肪酸的合成，抑制ACC2则可以促进肝脏中脂肪酸的氧化，从而减少脂质在体内的累积，可有效治疗与肥胖、高血压、糖尿病、肿瘤、血脂异常和高血脂症有关的疾病以及由于脂质在肝的累积引起肝脏胰岛素抗性且导致的II型糖尿病、非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)。
非酒精性脂肪性肝炎(NASH)是一种肝内脂肪积聚而导致的慢性进展性肝病，可导致肝硬化、肝衰竭及肝细胞癌。诱发NASH的原因有很多，比如年龄、肥胖、身体质量指数(Body Mass Index,BMI)，胰岛素敏感性、血脂异常、高血压以及肝功相关酶(比如丙氨酸转氨酶(ALT)或天冬氨酸转氨酶(AST))的异常活性等等。据报道，出现代谢综合征表现的患者(主要为向心性肥胖、高血压、胰岛素抵抗、高甘油三酯和低高密度脂蛋白)与NASH的发生风险正相关。在大于50岁的糖尿病或肥胖的患者中，66％肝活检提示NASH伴有严重的纤维化。在美国，约有12％的人们深受这种疾病的影响，在患有糖尿病的人群中比例会升高到22％，更值得注意的是NASH患者中约有15～25％的病人会发展成肝硬化，这是一种仅次于病毒性肝炎和酒精性肝炎的另一种导致肝癌的原因。肝硬化是因肝脏疾病导致死亡的主要原因，其直接导致了肝脏失代偿及每年将近4％的死亡率。
国际申请WO2021000242A1公开了化合物2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲 基-丙酸(即本发明式(I)所示化合物的晶型A)，其可以治疗或减轻由乙酰辅酶A羧化酶调节的疾病，如非酒精性脂肪肝炎等。该化合物存在溶解性差，动物体内吸收不理想、引湿性差以及稳定性差等问题，这些缺陷给后续的制剂开发带来诸多不便。
发明内容
本发明提供了式(I)所示化合物的晶型。其中，所述晶型，特别是晶型C，可以明显改善了化合物的稳定性和药代动力学等性质，从而具有更优良的成药性。
具体而言，本发明涉及式(I)所示化合物的晶型，以及包含所述晶型的药物组合物，还涉及它们在制备用于治疗或预防由乙酰辅酶A羧化酶调节的疾病的药物中的用途。本发明所述的晶型还可以为溶剂化物形式，例如水合物形式。
一方面，本发明提供了一种式(I)所示化合物的晶型或无定型，
在一些实施方案中，本发明所述的式(I)所示化合物的晶型为晶型B，C或D。
在一些实施方案中，本发明所述的晶型B，其特征在于，所述晶型B的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.07°±0.2°,10.93°±0.2°,16.61°±0.2°,17.11°±0.2°,19.82°±0.2°,25.76°±0.2°。
在一些实施方案中，本发明所述的晶型B，其特征在于，所述晶型B的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.07°±0.2°,10.93°±0.2°,12.79°±0.2°,15.83°±0.2°,16.61°±0.2°,17.11°±0.2°,18.47°±0.2°,19.59°±0.2°,19.82°±0.2°,25.76°±0.2°,27.48°±0.2°。
在另一些实施方案中，本发明所述的晶型B，其特征在于，所述晶型B的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.07°±0.2°,9.19°±0.2°,9.98°±0.2°,10.12°±0.2°,10.67°±0.2°,10.93°±0.2°,11.35°±0.2°,11.61°±0.2°,11.96°±0.2°,12.79°±0.2°,13.77°±0.2°,14.39°±0.2°,14.95°±0.2°,15.14°±0.2°,15.83°±0.2°,16.61°±0.2°,17.11°±0.2°,17.56°±0.2°,18.47°±0.2°,19.09°±0.2°,19.59°±0.2°,19.82°±0.2°, 20.19°±0.2°,21.00°±0.2°,22.07°±0.2°,22.36°±0.2°,22.76°±0.2°,23.21°±0.2°,23.48°±0.2°,23.97°±0.2°,24.84°±0.2°,25.20°±0.2°,25.76°±0.2°,26.43°±0.2°,26.70°±0.2°,26.89°±0.2°,27.48°±0.2°,28.17°±0.2°,28.49°±0.2°,29.14°±0.2°,29.89°±0.2°,30.38°±0.2°,30.94°±0.2°,31.43°±0.2°,31.85°±0.2°,32.27°±0.2°,33.13°±0.2°,33.65°±0.2°,34.36°±0.2°,35.60°±0.2°,36.76°±0.2°,37.62°±0.2°,38.80°±0.2°,40.04°±0.2°,40.44°±0.2°,40.85°±0.2°,42.73°±0.2°,44.09°±0.2°,45.69°±0.2°,47.23°±0.2°,48.36°±0.2°,51.23°±0.2°,54.44°±0.2°,56.20°±0.2°。
在一些实施方案中，本发明所述的晶型B，其特征在于，所述晶型B具有基本上如图4所示的X射线粉末衍射图。
在一些实施方案中，本发明所述的晶型B，其特征在于，所述晶型B的差示扫描量热图包含84.14℃±3℃和161.75℃±3℃的吸热峰。
在一些实施方案中，本发明所述的晶型B，其特征在于，所述晶型B具有基本上如图5所示的差示扫描量热图。
在一些实施方案中，本发明所述的晶型B，其特征在于，所述晶型B加热到150℃左右时，失重约为2.819％，存在±0.1％的误差容限。
在一些实施方案中，本发明所述的晶型C，其特征在于，所述晶型C的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.61°±0.2°,14.31°±0.2°,17.28°±0.2°,18.68°±0.2°,20.15°±0.2°,23.63°±0.2°。
在一些实施方案中，本发明所述的晶型C，其特征在于，所述晶型C的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.61°±0.2°,9.58°±0.2°,10.05°±0.2°,10.27°±0.2°,12.00°±0.2°,14.31°±0.2°,17.28°±0.2°,18.68°±0.2°,19.18°±0.2°,19.33°±0.2°,20.15°±0.2°,23.63°±0.2°。
在另一些实施方案中，本发明所述的晶型C，其特征在于，所述晶型C的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.61°±0.2°,9.58°±0.2°,10.05°±0.2°,10.27°±0.2°,11.19°±0.2°,12.00°±0.2°,12.63°±0.2°,13.23°±0.2°,14.31°±0.2°,16.13°±0.2°,17.28°±0.2°,17.88°±0.2°,18.68°±0.2°,19.18°±0.2°,19.33°±0.2°,20.15°±0.2°,20.93°±0.2°,21.66°±0.2°,22.73°±0.2°,23.63°±0.2°,25.39°±0.2°,26.60°±0.2°,27.87°±0.2°,28.93°±0.2°,29.62°±0.2°,30.88°±0.2°,32.61°±0.2°,33.16°±0.2°,33.85°±0.2°,35.65°±0.2°,36.68°±0.2°,38.82°±0.2°,39.72°±0.2°,40.52°±0.2°,42.64°±0.2°,46.90°±0.2°,48.43°±0.2°,50.86°±0.2°。
在一些实施方案中，本发明所述的晶型C，其特征在于，所述晶型C具有基本上如图7所示的X射线粉末衍射图。
在一些实施方案中，本发明所述的晶型C，其特征在于，所述晶型C的差示扫描量热图包含166.88℃±3℃的吸热峰。
在一些实施方案中，本发明所述的晶型C，其特征在于，所述晶型C具有基本上如图8所示的差示扫 描量热图。
在一些实施方案中，本发明所述的晶型C，其特征在于，所述晶型C加热到150℃左右时，失重约为0.008％，存在±0.1％的误差容限。
在一些实施方案中，本发明所述的晶型D，其特征在于，所述晶型D的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.08°±0.2°,8.58°±0.2°,9.62°±0.2°,13.60°±0.2°,15.52°±0.2°,22.01°±0.2°。
在一些实施方案中，本发明所述的晶型D，其特征在于，所述晶型D的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.08°±0.2°,8.58°±0.2°,9.62°±0.2°,12.17°±0.2°,13.60°±0.2°,15.52°±0.2°,17.26°±0.2°,17.74°±0.2°,18.31°±0.2°,22.01°±0.2°,24.05°±0.2°。
在另一些实施方案中，本发明所述的晶型D，其特征在于，所述晶型D的X射线粉末衍射图谱在下列2θ角处具有衍射峰：4.33°±0.2°,6.08°±0.2°,8.58°±0.2°,9.62°±0.2°,12.17°±0.2°,12.91°±0.2°,13.60°±0.2°,14.06°±0.2°,14.75°±0.2°,15.07°±0.2°,15.52°±0.2°,16.04°±0.2°,17.26°±0.2°,17.74°±0.2°,17.93°±0.2°,18.31°±0.2°,18.51°±0.2°,18.86°±0.2°,19.28°±0.2°,20.45°±0.2°,21.21°±0.2°,21.68°±0.2°,22.01°±0.2°,22.43°±0.2°,23.30°±0.2°,23.66°±0.2°,24.05°±0.2°,24.46°±0.2°,25.22°±0.2°,25.61°±0.2°,26.29°±0.2°,26.65°±0.2°,27.41°±0.2°,27.76°±0.2°,28.30°±0.2°,28.95°±0.2°,29.63°±0.2°,30.10°±0.2°,31.23°±0.2°,32.19°±0.2°,33.10°±0.2°,34.23°±0.2°,35.08°±0.2°,35.98°±0.2°,37.43°±0.2°,38.28°±0.2°,39.16°±0.2°,39.96°±0.2°,40.43°±0.2°,41.44°±0.2°,42.19°±0.2°,42.71°±0.2°,43.31°±0.2°,44.87°±0.2°,45.39°±0.2°,46.02°±0.2°,47.76°±0.2°,48.82°±0.2°,49.37°±0.2°。
在一些实施方案中，本发明所述的晶型D，其特征在于，所述晶型D具有基本上如图10所示的X射线粉末衍射图。
在一些实施方案中，本发明所述的晶型D，其特征在于，所述晶型D的差示扫描量热图包含122.02℃±3℃的吸热峰。
在一些实施方案中，本发明所述的晶型D，其特征在于，所述晶型D具有基本上如图11所示的差示扫描量热图。
在一些实施方案中，本发明所述的晶型D，其特征在于，所述晶型D加热到150℃左右时，失重约为7.634％，存在±0.1％的误差容限。
在一些实施方案中，本发明所述的无定型，其特征在于，所述无定型具有基本上如图13所示的X射线粉末衍射图。
在一些实施方案中，本发明所述的无定型，其特征在于，所述无定型具有基本上如图14所示的差示扫描量热图。
在一些实施方案中，本发明所述的无定型，其特征在于，所述无定型加热到150℃左右时，失重约为2.423％，存在±0.1％的误差容限。
另一方面，本发明提供了一种式(I)所示化合物的盐，
在一些实施方案中，本发明所述式(I)所示化合物的盐为钠盐或钾盐。
在一些实施方案中，本发明所述式(I)所示化合物的钠盐为式(I)所示化合物的钠盐的无定型。
在一些实施方案中，本发明所述的钠盐的无定型，其特征在于，所述钠盐的无定型具有基本上如图16所示的X射线粉末衍射图。
在一些实施方案中，本发明所述式(I)所示化合物的钾盐为式(I)所示化合物的钾盐的无定型。
在一些实施方案中，本发明所述的钾盐的无定型，其特征在于，所述钾盐的无定型具有基本上如图17所示的X射线粉末衍射图。
另一方面，本发明涉及一种药物组合物，其包含本发明所述的任一晶型，和药学上可接受的载体、赋形剂、稀释剂、辅剂或它们的组合。
一方面，本发明涉及所述的任一晶型或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、治疗或减轻由乙酰辅酶A羧化酶调节的疾病。
在一些实施方案中，本发明所述的乙酰辅酶A羧化酶调节的疾病为代谢性疾病和肿瘤。
另一方面，本发明涉及所述的任一晶型或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、治疗或减轻患者至少部分由乙酰辅酶A羧化酶调节的疾病。
在一些实施方案中，本发明所述代谢性疾病包括胰岛素抵抗、肥胖症、血脂异常、代谢综合征、II型糖尿病、非酒精性脂肪性肝病，非酒精性脂肪肝炎、肝脏脂肪变性、大泡性脂肪变性、晚期纤维化或肝硬化；所述肿瘤包括肝癌、肾癌、肺癌、乳腺癌、黑色素瘤、乳头状甲状腺肿瘤、胆管癌、结肠癌、卵巢癌、恶性淋巴肿瘤、膀胱癌、前列腺癌、胰腺癌、皮肤癌或复发性实体瘤。
本发明一方面涉及预防、治疗或减轻由乙酰辅酶A羧化酶调节的疾病的方法，包括使用本发明所述的晶型或所述的药物组合物药学上可接受的有效剂量对患者进行给药。
另一方面，本发明还涉及式(I)所示化合物的晶型的制备方法。
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。
本发明所述的晶型的制备实验将在实施例部分进行了详细描述。同时，本发明提供了所述晶型的药理测试实验(如药代动力学实验)和稳定性实验等。经实验证明，本发明所述的晶型具有良好的稳定性和药代性质。
定义和一般术语
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。
“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。
“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、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。
“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。
“溶剂化物”是指在表面上、在晶格中或者在表面上和在晶格中具有溶剂的化合物，所述溶剂可以是水、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、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、二甲苯以及它们的混合物等等。溶剂化物的一个具体例子是水合物，其中在表面上、在晶格中或者在表面上和在晶格中的溶剂是水。在物质的表面上、在晶格中或者在表面上和在晶格中，水合物可以具有或者不具有除了水以外的其它溶剂。
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。
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。
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。
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±0.1％的误差容限。
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。
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。
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。
本发明涉及所述2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸的晶型，例如，晶型C，它们以基本上纯净的结晶形态存在。
“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％。
“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％。
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。
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。
本发明中“室温”指的是温度由大约10℃到大约40℃。在一些实施例中，“室温”指的是温度由大约20℃到大约30℃；在另外一些实施例中，“室温”指的是20℃，22.5℃，25℃，27.5℃等等。
本发明所述化合物的晶型的药物组合物，制剂，给药和用途
本发明的药物组合物的特点包括式(I)所示化合物的晶型和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化合物的晶型的量能有效地可探测地治疗或减轻由乙酰辅酶A羧化酶调节的疾病。
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。
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。
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。
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。
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。
所用的活性成分的有效剂量可随所用的化合物的晶型、给药的模式和待治疗的疾病的严重程度而变化。然而，通常当本发明的化合物的晶型每天以约0.25-1000mg/kg动物体重的剂量给予时，能得到令人满意的效果，较佳地每天以2-4次分开的剂量给予，或以缓释形式给药。可调节此剂量方案以提供最佳治疗应答。另外，由于治疗状况的不同，可每天给予若干次分开的剂量，或将剂量按比例减少。
本发明涉及的化合物的晶型、本发明的药物组合物可用于抑制乙酰辅酶A羧化酶的活性，从而调节乙酰辅酶A羧化酶的稳定性和/或活性。所述化合物的晶型或所述的药物组合物可用于对乙酰辅酶A羧化酶相关的病症进行治疗、预治疗或延迟其发作或发展的方法中，所述疾病包括但不限于非酒精性脂肪肝炎。
具体地，本发明涉及的化合物的晶型可用于抑制乙酰辅酶A羧化酶的活性。可施以所述化合物的晶型来预防、预治疗或治疗由乙酰辅酶A羧化酶调节的病症，包括例如胰岛素抵抗、肥胖症、血脂异常、代谢综合征、II型糖尿病、非酒精性脂肪性肝病、非酒精性脂肪肝炎、肝脏脂肪变性、大泡性脂肪变性、晚期纤维化或肝硬化；所述肿瘤包括肝癌、肾癌、肺癌、乳腺癌、黑色素瘤、乳头状甲状腺肿瘤、胆管癌、结肠癌、卵巢癌、恶性淋巴肿瘤、膀胱癌、前列腺癌、胰腺癌、皮肤癌或复发性实体瘤。
附图说明
图1为式(I)所示化合物的晶型A的X射线粉末衍射(XRPD)图。
图2为式(I)所示化合物的晶型A的差示扫描量热(DSC)图。
图3为式(I)所示化合物的晶型A的热失重(TGA)分析图。
图4为式(I)所示化合物的晶型B的X射线粉末衍射(XRPD)图。
图5为式(I)所示化合物的晶型B的差示扫描量热(DSC)图。
图6为式(I)所示化合物的晶型B的热失重(TGA)分析图。
图7为式(I)所示化合物的晶型C的X射线粉末衍射(XRPD)图。
图8为式(I)所示化合物的晶型C的差示扫描量热(DSC)图。
图9为式(I)所示化合物的晶型C的热失重(TGA)分析图。
图10为式(I)所示化合物的晶型D的X射线粉末衍射(XRPD)图。
图11为式(I)所示化合物的晶型D的差示扫描量热(DSC)图。
图12为式(I)所示化合物的晶型D的热失重(TGA)分析图。
图13为式(I)所示化合物的无定型的X射线粉末衍射(XRPD)图。
图14为式(I)所示化合物的无定型的差示扫描量热(DSC)图。
图15为式(I)所示化合物的无定型的热失重(TGA)分析图。
图16为式(I)所示化合物的钠盐的无定型的X射线粉末衍射(XRPD)图。
图17为式(I)所示化合物的钾盐的无定型的X射线粉末衍射(XRPD)图。
图18为式(I)所示化合物的晶型A的动态水分吸附(DVS)图。
图19为式(I)所示化合物的晶型C的动态水分吸附(DVS)图。
一般制备和检测方法
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。
本发明所用X射线粉末衍射分析方法为：Empyrean衍射仪，使用Cu-Kα辐射(45KV,40mA)获得X射线粉末衍射图。在单晶硅样品架上将粉末状样品制备成薄层，放在旋转样品台上，在3°-40°的范围内以0.0168°步长进行分析。使用Data Collector软件收集数据，HighScore Plus软件处理数据，Data Viewer软件读取数据。
本发明所用差示扫描量热(DSC)分析方法为：使用带有热分析控制器的TA Q2000模件进行差示扫描量热。收集数据并使用TA Instruments Thermal Solutions软件进行分析。将约1-5mg样品准确地称重到带有盖子的特制铝坩埚中，使用10℃/分钟的线形加热装置，从室温至大约300℃进行样品分析。在使用期间，将DSC小室用干燥氮气吹扫。
本发明所用热失重(TGA)分析方法为：使用带有热分析控制器的TA Q500模件进行热失重。收集数据并使用TA Instruments Thermal Solutions软件进行分析。将约10mg样品准确地称重到铂金样品盘中，使用10℃/分钟的线形加热装置，从室温至大约300℃进行样品分析。在使用期间，将TGA炉室用干燥氮气吹扫。
具体实施方法
式(I)所示化合物2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸的具体合成 方法参照国际申请WO2021000242A1中的实施例1(即晶型A)得到。
实施例
实施例1式(I)化合物的晶型A
1.晶型A可参考WO2021000242实施例1的制备得到，并且还可以通过以下四种制备方法得到：
方法一：将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(50.0mg)悬浮于乙腈(0.5mL)中，室温搅拌过夜，补加水(0.5mL)，加完后析出较多的固体，搅拌12小时，抽滤，抽至近干，室温真空干燥4小时，得到白色固体(39.1mg,收率78.2％)。
方法二：将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(50.1mg)悬浮于乙二醇乙醚(0.5mL)中，室温搅拌溶解，加入水(1.0mL)，析出固体，室温搅拌12小时，抽滤，60℃真空干燥6小时，得到白色固体(28.1mg,收率56.1％)。
方法三：将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(8.72g)悬浮于乙酸(44.0mL)中，50℃搅拌溶解，保温0.5小时，缓慢加入水(52.0mL)，加完后，变黏，补加乙酸(10.0mL)，自然冷却至室温，补加水(26.0mL)，搅拌2小时，抽滤，滤饼用20mL水洗涤，抽至近干，60℃真空干燥12小时，得到白色固体(7.96g,收率91.3％)。
2.晶型A的鉴定
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，具有下列以角度2θ表示的特征峰：4.30°,6.09°,8.53°,9.68°,12.21°,12.82°,13.30°,13.53°,13.78°,14.15°,14.80°,15.11°,15.32°,15.53°,16.10°,16.41°,17.28°,17.52°,17.69°,18.03°,18.16°,18.38°,18.86°,19.35°,20.39°,20.80°,21.29°,21.90°,22.18°,22.75°,23.54°,23.91°,24.63°,25.21°,25.64°,26.03°,26.21°,26.60°,27.14°,27.85°,28.03°,28.55°,29.05°,29.41°,29.78°,30.36°,30.89°,31.48°,32.60°,33.50°,34.23°,34.87°,35.77°,37.64°,38.53°,39.35°,40.60°,41.45°,43.64°,44.68°,45.85°,46.56°,47.14°,51.14°,55.02°,存在±0.2°的误差容限。
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定：扫描速度为10℃/分钟，所得DSC曲线如图2所示，其包含95.44℃和135.65℃的吸热峰，存在±3℃的误差容限。
(3)通过TA Q500进行热失重(TGA)分析鉴定：升温速率为10℃/分钟，所得TGA曲线如图3所示，其包含4.157％的重量损失，存在±0.1％的误差容限。
实施例2式(I)化合物的晶型B
1.晶型B的制备
将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙 基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(10.01g)悬浮于丙酮(50.0mL)中，加热50℃搅拌溶解，保温0.5小时，缓慢加入水(40.0mL)，加完后保温0.5小时，加入晶种C(300.2mg)，保温0.5小时，自然降至室温，再补加水(20.0mL)，室温搅拌12小时，抽滤，抽至近干，得到白色固体(9.16g,收率91.5％)。
2.晶型B的鉴定
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，具有下列以角度2θ表示的特征峰：5.07°,9.19°,9.98°,10.12°,10.67°,10.93°,11.35°,11.61°,11.96°,12.79°,13.77°,14.39°,14.95°,15.14°,15.83°,16.61°,17.11°,17.56°,18.47°,19.09°,19.59°,19.82°,20.19°,21.00°,22.07°,22.36°,22.76°,23.21°,23.48°,23.97°,24.84°,25.20°,25.76°,26.43°,26.70°,26.89°,27.48°,28.17°,28.49°,29.14°,29.89°,30.38°,30.94°,31.43°,31.85°,32.27°,33.13°,33.65°,34.36°,35.60°,36.76°,37.62°,38.80°,40.04°,40.44°,40.85°,42.73°,44.09°,45.69°,47.23°,48.36°,51.23°,54.44°,56.20°,存在±0.2°的误差容限。
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定：扫描速度为10℃/分钟，所得DSC曲线如图5所示，其包含84.14℃和161.75℃的吸热峰，存在±3℃的误差容限。
(3)通过TA Q500进行热失重(TGA)分析鉴定：升温速率为10℃/分钟，所得TGA曲线如图6所示，其包含2.819％的重量损失，存在±0.1％的误差容限。
实施例3式(I)化合物的晶型C
1.晶型C的制备
方法一：将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(500.2mg)悬浮于丙酮(2.5mL)中，加热50℃搅拌溶解，保温0.5小时，缓慢加入水(2.0mL)，加完后保温0.5小时，加入晶种C(15.2mg)，保温搅拌0.5小时，自然降至室温，补加水(1.0mL)，搅拌12小时，抽滤，滤饼用5.0mL水洗，抽至近干，60℃真空干燥12小时，得到白色固体(460.5mg,收率92.1％)。
方法二：将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(500.0mg)悬浮于乙酸(2.5mL)中，加热至50℃搅拌溶解，保温搅拌0.5小时，缓慢加入水(2.5mL)，保温1小时，加入晶种C(15mg)，保温搅拌2小时，降至室温(10℃/h)，抽滤，60℃真空干燥8小时，得到白色固体(423.2mg,收率84.6％)。
方法三：将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(500.0mg)悬浮于丙酮(2.5mL)中，加热至50℃，缓慢加入水(2.0mL)，加完后保温0.5小时，加入晶种C(10.0mg)，保温搅拌0.5小时，自然降至室温，补加水(1.0mL)，搅拌5小时，抽滤，60℃真空干燥过夜，得到白色固体(451.0 mg,收率90.2％)。
方法四：将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸的无定型(1.01g)悬浮于乙酸(2.0mL)和水(10.0mL)混合溶剂中，室温打浆12小时，抽滤，60℃真空干燥12小时，得到白色固体(0.89g,收率88.1％)。
2.晶型C的鉴定
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，具有下列以角度2θ表示的特征峰：5.61°,9.58°,10.05°,10.27°,11.19°,12.00°,12.63°,13.23°,14.31°,16.13°,17.28°,17.88°,18.68°±0.2°,19.18°,19.33°,20.15°,20.93°,21.66°,22.73°,23.63°,25.39°,26.60°,27.87°,28.93°,29.62°,30.88°,32.61°,33.16°,33.85°,35.65°,36.68°,38.82°,39.72°,40.52°,42.64°,46.90°,48.43°,50.86°,存在±0.2°的误差容限。
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定：扫描速度为10℃/分钟，所得DSC曲线如图8所示，其包含166.88℃的吸热峰，存在±3℃的误差容限。
(3)通过TA Q500进行热失重(TGA)分析鉴定：升温速率为10℃/分钟，所得TGA曲线如图9所示，其包含0.008％的重量损失，存在±0.1％的误差容限。
实施例4式(I)化合物的晶型D
1.晶型D的制备
将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(101.2mg)悬浮于异丙醇(1.0mL)中，加热50℃搅拌溶解，保温0.5小时，自然降至室温，加入晶种C(50.0mg)，搅拌12小时，抽滤至近干，室温真空干燥2小时，得到白色固体(83.1mg,收率82.1％)。
2.晶型D的鉴定
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，具有下列以角度2θ表示的特征峰：4.33°,6.08°,8.58°,9.62°,12.17°,12.91°,13.60°,14.06°,14.75°,15.07°,15.52°,16.04°,17.26°,17.74°,17.93°,18.31°,18.51°,18.86°,19.28°,20.45°,21.21°,21.68°,22.01°,22.43°,23.30°,23.66°,24.05°,24.46°,25.22°,25.61°,26.29°,26.65°,27.41°,27.76°,28.30°,28.95°,29.63°,30.10°,31.23°,32.19°,33.10°,34.23°,35.08°,35.98°,37.43°,38.28°,39.16°,39.96°,40.43°,41.44°,42.19°,42.71°,43.31°,44.87°,45.39°,46.02°,47.76°,48.82°,49.37°,存在±0.2°的误差容限。
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定：扫描速度为10℃/分钟，所得DSC曲线如图11所示，其包含122.02℃的吸热峰，存在±3℃的误差容限。
(3)通过TA Q500进行热失重(TGA)分析鉴定：升温速率为10℃/分钟，所得TGA曲线如图12所示，其包含7.634％的重量损失，存在±0.1％的误差容限。
实施例5式(I)化合物的无定型
1.无定型的制备
方法一：将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(50.2mg)悬浮于N,N-二甲基乙酰胺(0.25mL)中，室温搅拌溶解，随后缓慢加入水(0.25mL)，析出少量固体，补加水(0.3mL)，室温搅拌2小时，抽滤，滤饼在60℃真空干燥6小时，得到白色固体(25.2mg,收率50.2％)。
方法二：将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(501.1mg)悬浮于丙酮(10.0mL)中，室温搅拌溶解，减压蒸除溶剂，室温真空干燥4小时，得到白色固体(492.6mg,收率98.3％)。
2.无定型的鉴定
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定：无定型的X射线粉末衍射图如图13所示，存在±0.2°的误差容限。
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定：扫描速度为10℃/分钟，所得DSC曲线如图14所示。
(3)通过TA Q500进行热失重(TGA)分析鉴定：升温速率为10℃/分钟，所得TGA曲线如图15所示，其包含2.423％的重量损失，存在±0.1％的误差容限。
实施例6式(I)化合物的钠盐的无定型
1.钠盐的无定型的制备
将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(50.3mg,0.08mmol)加入25mL单口瓶中，再加入氢氧化钠(4.1mg)的水(0.5mL)溶液，室温搅拌，为澄清状，加入乙腈(2.0mL)，搅拌2小时，减压蒸除溶剂，往其中加入乙酸乙酯(1.0mL)和正庚烷(1.0mL)混合溶剂进行打浆，抽滤后室温真空干燥2小时，得到淡黄色固体粉末(43.1mg,收率83.1％)。
2.钠盐的无定型的鉴定
通过Empyrean X射线粉末衍射(XRPD)分析鉴定：钠盐的无定型的X射线粉末衍射图如图16所示，存在±0.2°的误差容限。
实施例7式(I)化合物的钾盐的无定型
1.钾盐的无定型的制备
将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(101.4mg,0.17mmol)和氢氧化钾(9.5mg)加入25mL单口瓶中，悬浮于水(1.0mL)中，室温搅拌后固体完全溶解，有少量固体不溶， 补加乙腈(1.0mL)，室温搅拌6小时，减压蒸除溶剂，得到淡黄色固体粉末(87.9mg,收率81.5％)。
2.钾盐的无定型的鉴定
通过Empyrean X射线粉末衍射(XRPD)分析鉴定：钾盐的无定型的X射线粉末衍射图如图17所示，存在±0.2°的误差容限。
实施例8本发明所述晶型的药代动力学实验
将本发明所述的式(I)所示化合物的晶型灌装胶囊，用于口服给药。
取6-8kg雄性比格犬分2组，3只为一组，口服给予装有供试样品的胶囊，剂量为5mg/kg，按时间点0.25,0.5,1.0,2.0,4.0,6.0,8.0和24h采血。根据样品浓度建立合适范围的标准曲线，使用AB SCIEX API4000型LC-MS/MS，在MRM模式下测定血浆样品中供试样品的浓度，并进行定量分析。根据药物浓度-时间曲线，采用WinNonLin 6.3软件非房室模型法计算药动学参数。实验结果如表1所示。
表1本发明所述晶型的药代动力学实验数据
实验结论：由表1可知，相对晶型A，本发明所述晶型C具有较好的最大血药浓度(Cmax)，因此晶型C具有较好的药代动力学性质。
实施例9本发明所述晶型的稳定性实验
(1)高温实验：取一批供试品适量放入扁形称量瓶中，摊成≤3mm厚的薄层，分别于60℃、40℃两个温度下放置30天，于第5、10、30天取样，观察样品颜色变化，HPLC检测样品纯度，X射线粉末衍射分析结构。
(2)高湿实验：取一批供试品适量放入扁形称量瓶中，摊成≤3mm厚的薄层，分别于25℃，RH 90％±5％和25℃，RH 75％±5％两个条件下放置30天，于第5、10、30天取样，观察样品颜色变化，HPLC检测样品纯度，X射线粉末衍射分析结构。
(3)光照实验：取一批供试品适量放入扁形称量瓶中，摊成≤3mm厚的薄层，敞口置于光照箱内(带紫外)，于照度4500±500lx、紫外光≥0.7w/m2条件下放置30天，于第5、10、30天取样，观察样品颜色变化，HPLC检测样品纯度，X射线粉末衍射分析结构。
(4)长期稳定性试验：考察样品在单层PE内包装，铝箔袋外包装，内置KD-20脱氧剂，并抽真空充氮气后热封口包装条件下，低温5℃±3℃长期试验条件，观察样品颜色变化，HPLC检测样品纯度。
由实验结果可知，本发明所述的晶型C在高温高湿条件下稳定，尤其是本发明所述的晶型C的外观和 纯度均无明显变化。
在长期稳定性试验条件下，本发明所述的晶型C的外观、纯度和水含量均无明显变化。
综上，本发明所述的晶型C的稳定性较好，适合制药用途。
实施例10本发明所述晶型的引湿性实验
取供试品适量，采用动态水分吸附仪测试其引湿性。
其中，晶型A和本发明晶型C的引湿性实验DVS图基本上如图18和图19所示，具体实验结果如表2所示。根据引湿性特征描述与引湿性增重的界定标准(中国药典2015年版通则9103药物引湿性试验指导原则，详见表3)。
表2本发明晶型的引湿性实验
表3引湿性特征描述与引湿性增重的界定(25℃±1℃，80％±2％相对湿度)
由实验结果可知，晶型A在20％湿度下有引湿性，而本发明晶型C则是略有引湿性，说明晶型C不易受高湿度影响而潮解。
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。
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。
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。

Claims (10)

  1. 一种如式(I)所示的化合物的晶型C，其特征在于，所述晶型C的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.61°±0.2°,14.31°±0.2°,17.28°±0.2°,18.68°±0.2°,20.15°±0.2°,23.63°±0.2°,
  2. 根据权利要求1所述的晶型C，其特征在于，所述晶型C的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.61°±0.2°,9.58°±0.2°,10.05°±0.2°,10.27°±0.2°,12.00°±0.2°,14.31°±0.2°,17.28°±0.2°,18.68°±0.2°,19.18°±0.2°,19.33°±0.2°,20.15°±0.2°,23.63°±0.2°。
  3. 根据权利要求1或2所述的晶型C，其特征在于，所述晶型C的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.61°±0.2°,9.58°±0.2°,10.05°±0.2°,10.27°±0.2°,11.19°±0.2°,12.00°±0.2°,12.63°±0.2°,13.23°±0.2°,14.31°±0.2°,16.13°±0.2°,17.28°±0.2°,17.88°±0.2°,18.68°±0.2°,19.18°±0.2°,19.33°±0.2°,20.15°±0.2°,20.93°±0.2°,21.66°±0.2°,22.73°±0.2°,23.63°±0.2°,25.39°±0.2°,26.60°±0.2°,27.87°±0.2°,28.93°±0.2°,29.62°±0.2°,30.88°±0.2°,32.61°±0.2°,33.16°±0.2°,33.85°±0.2°,35.65°±0.2°,36.68°±0.2°,38.82°±0.2°,39.72°±0.2°,40.52°±0.2°,42.64°±0.2°,46.90°±0.2°,48.43°±0.2°,50.86°±0.2°。
  4. 根据权利要求1-3任意一项所述的晶型C，其特征在于，所述晶型C具有基本上如图7所示的X射线粉末衍射图。
  5. 根据权利要求1-4任意一项所述的晶型C，其特征在于，所述晶型C的差示扫描量热图包含166.88℃±3℃的吸热峰。
  6. 根据权利要求1-5任意一项所述的晶型C，其特征在于，所述晶型C具有基本上如图8所示的差示扫描量热图。
  7. 一种药物组合物，其包含权利要求1-6任意一项所述的晶型C，和药学上可接受的载体、赋形剂、稀释剂、辅剂或它们的组合。
  8. 权利要求1-6任意一项所述的晶型C或权利要求7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、治疗或减轻由乙酰辅酶A羧化酶调节的疾病。
  9. 根据权利要求8所述的用途，其中，所述的乙酰辅酶A羧化酶调节的疾病为代谢性疾病和肿瘤。
  10. 根据权利要求9所述的用途，其中，所述代谢性疾病包括胰岛素抵抗、肥胖症、血脂异常、代谢综合征、II型糖尿病、非酒精性脂肪性肝病、非酒精性脂肪肝炎、肝脏脂肪变性、大泡性脂肪变性、晚期纤维化或肝硬化；所述肿瘤包括肝癌、肾癌、肺癌、乳腺癌、黑色素瘤、乳头状甲状腺肿瘤、胆管癌、结肠癌、卵巢癌、恶性淋巴肿瘤、膀胱癌、前列腺癌、胰腺癌、皮肤癌或复发性实体瘤。
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Publication number Priority date Publication date Assignee Title
WO2018133858A1 (en) * 2017-01-22 2018-07-26 Sunshine Lake Pharma Co., Ltd. Thienopyrimidine derivative and use thereof in medicine
WO2021000242A1 (zh) * 2019-07-02 2021-01-07 广东东阳光药业有限公司 具有立体构型的噻吩并嘧啶衍生物及其在药物中的应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018133858A1 (en) * 2017-01-22 2018-07-26 Sunshine Lake Pharma Co., Ltd. Thienopyrimidine derivative and use thereof in medicine
WO2021000242A1 (zh) * 2019-07-02 2021-01-07 广东东阳光药业有限公司 具有立体构型的噻吩并嘧啶衍生物及其在药物中的应用

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