WO2023061473A1 - 含氮三环化合物的新晶型及其用途 - Google Patents

含氮三环化合物的新晶型及其用途 Download PDF

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WO2023061473A1
WO2023061473A1 PCT/CN2022/125324 CN2022125324W WO2023061473A1 WO 2023061473 A1 WO2023061473 A1 WO 2023061473A1 CN 2022125324 W CN2022125324 W CN 2022125324W WO 2023061473 A1 WO2023061473 A1 WO 2023061473A1
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crystal form
diseases
present
crystal
ray powder
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French (fr)
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单岳峰
陈亮
杨新业
林继华
马发城
陈小舟
王晓军
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广东东阳光药业有限公司
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • 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
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    • A—HUMAN NECESSITIES
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    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
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    • A—HUMAN NECESSITIES
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the invention belongs to the technical field of medicines, and relates to new crystal forms of nitrogen-containing tricyclic compounds and uses thereof, in particular to 2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4 New crystal form of -yl)methoxy)-10H-spiro[benzo[6,7]oxazepine[3,2-b]pyridine-11,1'-cyclopropane]-7-carboxylic acid and its medicine
  • the composition further relates to the use of the new crystal form or the pharmaceutical composition in the preparation of medicines, such as the preparation of the new crystal form or the pharmaceutical composition for preventing, treating or alleviating the FXR-mediated Use in medicine for disease.
  • Patent applications WO 2018024224A1 and CN107686486A disclose nitrogen-containing tricyclic compounds that can be used as FXR activity regulators and their preparation methods and applications.
  • compound 7 is specifically disclosed, that is, compound 2-((5-cyclopropyl-3 -(2,6-Dichlorophenyl)isoxazol-4-yl)methoxy)-10H-spiro[benzo[6,7]oxazepine[3,2-b]pyridine-11,1 '-cyclopropane]-7-formic acid (compound shown in formula (I)).
  • Patent applications WO2021104427A1, WO2021104421A1 and CN112876490A disclose the crystal form of the compound.
  • the present invention provides 2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-10H-spiro[benzo[6,7]
  • a new crystal form of oxaza[3,2-b]pyridine-11,1'-cyclopropane]-7-carboxylic acid (compound represented by formula (I)), which is the crystal form J of the compound, said
  • the crystalline form is stable in properties, not susceptible to deliquescence due to high humidity, and has good pharmacological properties (for example, good pharmacokinetic properties, etc.), thus having excellent druggability.
  • the present invention also provides a pharmaceutical composition comprising the crystal form J of the compound represented by formula (I).
  • the present invention relates to the crystal form J of the compound represented by formula (I) and its pharmaceutical composition, and the preparation of the crystal form J or the pharmaceutical composition for preventing, treating or alleviating the FXR-mediated use in medicines for diseases.
  • the crystal form J described in the present invention can also be in the form of a solvate, such as a hydrate.
  • the present invention provides a crystal form of the compound represented by formula (I), wherein the crystal form is crystal form J,
  • the X-ray powder diffraction pattern of the crystal form J has diffraction peaks at the following 2 ⁇ angles: 4.33° ⁇ 0.2°, 12.86° ⁇ 0.2°, 21.18° ⁇ 0.2°, 24.11° ⁇ 0.2°, 25.08° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form J has diffraction peaks at the following 2 ⁇ angles: 4.33° ⁇ 0.2°, 8.37° ⁇ 0.2°, 11.56° ⁇ 0.2°, 12.86° ⁇ 0.2°, 16.26° ⁇ 0.2°, 20.66° ⁇ 0.2°, 21.18° ⁇ 0.2°, 21.61° ⁇ 0.2°, 24.11° ⁇ 0.2°, 25.08° ⁇ 0.2°, 27.57° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form J has diffraction peaks at the following 2 ⁇ angles: 4.33° ⁇ 0.2°, 8.37° ⁇ 0.2°, 8.55° ⁇ 0.2°, 11.56° ⁇ 0.2°, 12.86° ⁇ 0.2°, 16.26° ⁇ 0.2°, 20.66° ⁇ 0.2°, 21.18° ⁇ 0.2°, 21.61° ⁇ 0.2°, 24.11° ⁇ 0.2°, 25.08° ⁇ 0.2°, 27.57° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form J has diffraction peaks at the following 2 ⁇ angles: 4.33° ⁇ 0.2°, 8.37° ⁇ 0.2°, 8.55° ⁇ 0.2°, 11.56 ° ⁇ 0.2°,12.86° ⁇ 0.2°,15.16° ⁇ 0.2°,15.64° ⁇ 0.2°,15.86° ⁇ 0.2°,16.26° ⁇ 0.2°,16.69° ⁇ 0.2°,17.33° ⁇ 0.2°,18.01° ⁇ 0.2°,18.79° ⁇ 0.2°,19.31° ⁇ 0.2°,19.65° ⁇ 0.2°,19.90° ⁇ 0.2°,20.66° ⁇ 0.2°,21.18° ⁇ 0.2°,21.61° ⁇ 0.2°,22.01° ⁇ 0.2° ,22.56° ⁇ 0.2°,23.16° ⁇ 0.2°,23.69° ⁇ 0.2°,24.11° ⁇ 0.2°,24.41° ⁇ 0.2°,25.08° ⁇ 0.2°,25.99° ⁇ 0.2°,26.33° ⁇ 0.2°,27
  • the X-ray powder diffraction pattern of Form J has diffraction peaks at the following 2 ⁇ angles: 4.33° ⁇ 0.2°, 5.81° ⁇ 0.2°, 8.37° ⁇ 0.2°, 8.55 ° ⁇ 0.2°,11.56° ⁇ 0.2°,12.86° ⁇ 0.2°,13.73° ⁇ 0.2°,15.16° ⁇ 0.2°,15.64° ⁇ 0.2°,15.86° ⁇ 0.2°,16.26° ⁇ 0.2°,16.69° ⁇ 0.2°,17.33° ⁇ 0.2°,18.01° ⁇ 0.2°,18.79° ⁇ 0.2°,19.31° ⁇ 0.2°,19.65° ⁇ 0.2°,19.90° ⁇ 0.2°,20.66° ⁇ 0.2°,21.18° ⁇ 0.2° ,21.61° ⁇ 0.2°,22.01° ⁇ 0.2°,22.56° ⁇ 0.2°,23.16° ⁇ 0.2°,23.69° ⁇ 0.2°,24.11° ⁇ 0.2°,24.41° ⁇ 0.2°,25.08° ⁇ 0.2°,25
  • the X-ray powder diffraction pattern of the crystal form J has diffraction peaks at the following 2 ⁇ angles: 4.33° ⁇ 0.2°, 5.81° ⁇ 0.2°, 8.37° ⁇ 0.2°, 8.55° ⁇ 0.2°, 11.56° ⁇ 0.2°,12.86° ⁇ 0.2°,13.73° ⁇ 0.2°,15.16° ⁇ 0.2°,15.64° ⁇ 0.2°,15.86° ⁇ 0.2°,16.26° ⁇ 0.2°,16.69° ⁇ 0.2°,17.33° ⁇ 0.2°,18.01° ⁇ 0.2°,18.79° ⁇ 0.2°,19.31° ⁇ 0.2°,19.65° ⁇ 0.2°,19.90° ⁇ 0.2°,20.66° ⁇ 0.2°,21.18° ⁇ 0.2°,21.61° ⁇ 0.2 °,22.01° ⁇ 0.2°,22.56° ⁇ 0.2°,23.16° ⁇ 0.2°,23.69° ⁇ 0.2°,24.11° ⁇ 0.2°,24.41° ⁇ 0.2°,25.08° ⁇ 0.2°,
  • the Form J has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the differential scanning calorimetry of Form J comprises endothermic peaks at 116.45°C ⁇ 3°C and 195.53°C ⁇ 3°C.
  • the Form J has a differential scanning calorimetry diagram substantially as shown in FIG. 2 .
  • the weight loss when the crystal form J is heated to about 150° C., the weight loss is about 1.795%, with an error tolerance of ⁇ 0.1%.
  • the Form J has a thermogravimetric analysis profile substantially as shown in FIG. 3 .
  • the present invention also provides a pharmaceutical composition, which comprises the crystal form described in the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.
  • the present invention also relates to the use of the crystal form of the compound of formula (I) or the pharmaceutical composition in the preparation of medicines, wherein the medicines are used to prevent, treat or alleviate diseases mediated by FXR in patients ; Further, the use includes administering to humans or animals an effective therapeutic dose of the crystal form of the present invention or the pharmaceutical composition.
  • the diseases mediated by FXR described in the present invention are cardiovascular and cerebrovascular diseases, diseases related to dyslipidemia, metabolic syndrome, hyperproliferative diseases, fibrosis, inflammatory diseases or diseases related to liver and gallbladder disease.
  • the cardiovascular and cerebrovascular diseases described in the present invention are atherosclerosis, acute myocardial infarction, veno-occlusive disease, portal hypertension, pulmonary hypertension, heart failure, peripheral tissue arterial obstructive disease, sexual Dysfunction, stroke, or blood clots.
  • the metabolic syndrome of the present invention is insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or triglycerides in the blood, hyperlipidemia, obesity, hyperglycerol Triesteremia, hypercholesterolemia, Syndrome X, diabetic complications, atherosclerosis, hypertension, acute anemia, neutropenia, dyslipidemia, type II diabetes, diabetic nephropathy, diabetic neuropathy , diabetic retinopathy, dyslipidemia, or comorbidities of diabetes and an abnormally high body mass index.
  • the hyperproliferative diseases described herein are hepatocellular carcinoma, colon adenoma, polyposis, colon adenocarcinoma, breast cancer, pancreatic adenocarcinoma, Barth's esophagus carcinoma, and other forms of gastrointestinal or liver neoplastic disease.
  • the fibrosis, inflammatory disease or hepatobiliary-related disease described in the present invention is non-alcoholic fatty liver, non-alcoholic steatohepatitis, cholestasis, liver fibrosis, primary biliary Cirrhosis, primary sclerosing cholangitis, progressive familial cholestasis, cystic fibrosis, drug-induced bile duct injury, gallstones, cirrhosis, hepatitis B, sebaceous disease, alcohol-induced cirrhosis, biliary obstruction , gallstone disease, colitis, jaundice newborns, nuclear jaundice, or intestinal bacterial overgrowth.
  • the present invention relates to a method for preventing, treating or alleviating a disease mediated by FXR in a patient, comprising administering to the patient a pharmaceutically acceptable effective dose of the crystal form or the pharmaceutical composition described in the present invention.
  • the present invention relates to using the crystalline form of the compound of formula (I) or the pharmaceutical composition to prevent, treat or alleviate diseases mediated by FXR in patients.
  • the present invention also relates to the preparation method of the crystal form of the compound represented by formula (I).
  • the solvent used in the preparation method of the crystal form described in the present invention is not particularly limited, and any solvent that can dissolve the starting material to a certain extent and does not affect its properties is included in the present invention.
  • many similar modifications, equivalent substitutions, or equivalent solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are considered to be within the scope of the present invention.
  • the present invention provides the preferred solvents used in each reaction step.
  • the preparation experiment of the crystal form described in the present invention will be described in detail in the example part.
  • the present invention provides property testing experiments of the crystal form, such as pharmacokinetic experiments, stability experiments, and hygroscopicity experiments.
  • the crystal form J of the compound represented by formula (I) described in the present invention has good biological activity and high stability, and is suitable for pharmaceutical use.
  • the crystal form J of the present invention has better pharmacokinetic properties, for example, has a higher exposure; at the same time, the crystal form J of the present invention is not easily affected by high humidity and deliquescence, which is convenient for drug long-term storage.
  • the crystal form of the present invention has better technical effects, such as better pharmacokinetic properties (such as higher exposure and/or higher Cmax value), and/or higher stability.
  • the effect of the crystal forms described in the present invention is better in all aspects; the inventors have found through research that among the crystal forms disclosed in CN112876490A, the crystal form E is the most stable crystal form, but The crystal structure changes after being placed at a high temperature of 60° C. for 5 days, while the crystal form described in the present invention is very stable under high temperature conditions, and the crystal structure basically remains unchanged.
  • Crystal 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, co-crystal, salt, solvate of salt, hydrate of salt. 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 confined spaces, e.g., in nanopores or capillaries, crystallization on surfaces or templates, e.g., on polymers, Crystallization in the presence of additives such as co-crystal anti-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling and solvent drop milling, etc.
  • additives such as co-crystal anti-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling and solvent drop milling, etc.
  • Solvent means 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, isopropanol, methanol, Methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and
  • Anti-solvent refers to a fluid that facilitates the precipitation of a product (or product precursor) from a solvent.
  • An anti-solvent can include a cold gas, or a fluid that promotes precipitation through a chemical reaction, or a fluid that reduces the solubility of a product in a 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 means a compound having a solvent on the surface, in the crystal lattice, or both, the 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-dimethylformamide Amide, formamide, formic acid, heptane, hexane, isopropanol, 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, wherein the solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice is water. Hydrates may or may not have other solvents besides water, on the surface of the substance, in the crystal lattice, or both.
  • the crystal form can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic 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 scanning electron microscopy
  • X-ray powder diffraction can detect information such as changes in crystal forms, crystallinity, crystal structure state, etc., and is a common method for identifying crystal forms.
  • the crystalline forms of the present invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the accompanying drawings of the present invention.
  • there may be experimental errors in the measurement of 2 ⁇ in the XRPD pattern and there may be slight differences in the measurement of 2 ⁇ in the XRPD pattern between different instruments and different samples, so the value of 2 ⁇ cannot be regarded as absolute. According to the condition of the instrument used in this test, there is an error tolerance of ⁇ 0.2° for the diffraction peaks.
  • DSC Differential Scanning Calorimetry
  • an inert reference usually ⁇ -Al 2 O 3
  • 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 accompanying drawings of the present invention.
  • the DSC spectrum may have experimental errors, and the peak position and peak value of the DSC spectrum may be slightly different between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. According to the condition of the instrument used in this test, there is an error tolerance of ⁇ 3° for the endothermic peak.
  • Thermogravimetric analysis is a technique for determining the quality of a substance as a function of temperature under program control. It is suitable for checking the loss of solvent in the crystal or the process of sublimation and decomposition of the sample. It can be speculated that the crystal contains crystal water or crystal solvent. Case.
  • the mass change shown by the TGA curve depends on many factors such as sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. There is a ⁇ 0.1% error margin for mass variation depending on the condition of the instrumentation used in this test.
  • 2 ⁇ values in X-ray powder diffraction patterns are all in degrees (°).
  • the term "substantially as shown” means that the X-ray powder diffraction pattern or DSC pattern is at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or At least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks are shown in its graph.
  • Pheak when referring to a spectrum and/or data appearing in a graph refers to a feature that one skilled in the art would recognize and would not attribute to background noise.
  • the present invention relates to said 2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-10H-spiro[benzo[6, 7]
  • a new crystal form of oxaza[3,2-b]pyridine-11,1'-cyclopropane]-7-carboxylic acid (compound represented by formula (I)), which exists in a substantially pure crystal form.
  • Essentially pure means that one crystalline form is substantially free of another crystalline form or forms, i.e. the crystalline form has a purity of at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 96%, or at least 97%, 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, and the percentage of the other crystal forms in the total volume or weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less 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%.
  • Essentially free means that the percentage of one or more other crystal forms in the total volume or weight of the crystal 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%.
  • Relative intensity (or “relative peak height”) in the XRPD figure means that when the intensity of the first strong peak in all diffraction peaks of the X-ray powder diffraction pattern (XRPD) is 100%, the intensity of other peaks is the same as that of the first strong peak. The ratio of the intensities of the peaks.
  • 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, or 27.5°C, etc.
  • the characteristics of the pharmaceutical composition of the present invention include the crystal form of the compound represented by formula (I) or any combination thereof and a pharmaceutically acceptable carrier, adjuvant, or excipient.
  • the amount of the crystalline form of the compound in the pharmaceutical composition of the present invention is effective to detectably treat or alleviate a disease mediated by FXR in a patient.
  • the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used in the present invention, includes any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, etc., are suitable for the specific target dosage form.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used in the present invention, includes any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, etc.
  • the crystal form of the present invention can be used as an active ingredient and uniformly combined in a mixture with a drug carrier according to conventional drug compounding technology.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration, eg, oral or parenteral (including intravenous).
  • any conventional pharmaceutical media may be used, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, and medicaments in the preparation of oral liquid dosage forms such as suspensions, elixirs and solutions.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. Tablets may be coated, if desired, using standard aqueous or non-aqueous techniques.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent methyl or propylparabens as preservatives, a dye and flavoring (eg, cherry or orange).
  • crystal forms described in the present invention can also be administered parenterally.
  • Solutions or suspensions of these active materials can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the pharmaceutical form must be sterile and must be fluid in a readily syringable form. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable method of administration can be used to provide effective doses of the crystalline forms of the present invention to mammals, especially humans.
  • oral, rectal, topical, parenteral, ophthalmic, pulmonary, nasal, etc. administration methods can be used.
  • Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, emulsions, ointments, aerosols, and the like.
  • the crystal form or pharmaceutical composition thereof involved in the present invention can be effectively used for preventing, treating, treating or alleviating diseases mediated by FXR in patients, especially for effectively treating non-alcoholic fatty liver (NAFLD) and non-alcoholic steatohepatitis (NASH), obesity, hypertriglyceridemia, atherosclerosis, chronic intrahepatic cholestasis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), progressive Familial cholestasis (PFIC), drug-induced bile duct injury, gallstones, cirrhosis, hepatitis B, sebaceous disease, alcohol-induced cirrhosis, cystic fibrosis, biliary obstruction, gallstone disease, liver fibrosis, dyslipidemia , atherosclerosis, type II diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, peripheral arterial occlusive disease (PAOD), colitis, neonatal ja
  • Fig. 1 is an X-ray powder diffraction (XRPD) pattern of crystal form J of the compound represented by formula (I) prepared according to the method of Example 1 of the present invention.
  • XRPD X-ray powder diffraction
  • Fig. 2 is a differential scanning calorimetry (DSC) diagram of the crystal form J of the compound represented by formula (I) prepared according to the method of Example 1 of the present invention.
  • Fig. 3 is a thermogravimetric analysis (TGA) diagram of crystal form J of the compound represented by formula (I) prepared according to the method of Example 1 of the present invention.
  • Fig. 4 is a dynamic moisture adsorption (DVS) diagram of crystal form J of the compound represented by formula (I) prepared according to the method of Example 1 of the present invention.
  • the X-ray powder diffraction analysis method used in the present invention is: an Empyrean diffractometer, using Cu-K ⁇ radiation (45KV, 40mA) to obtain an X-ray powder diffraction pattern.
  • the powder sample was prepared into a thin layer on the single crystal silicon sample holder, placed on the rotating sample stage, and analyzed in the range of 3°-60° with a step size of 0.0167°.
  • Use Data Collector software to collect data
  • High Score Plus software to process data
  • Data Viewer software to read data.
  • the differential scanning calorimetry (DSC) analysis method used in the present invention is: use the TA Q2000 module that has thermal analysis controller to carry out differential scanning calorimetry. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 1-5 mg of sample is accurately weighed into a special aluminum crucible with a lid, and the sample is analyzed from room temperature to about 300°C using a linear heating device at 10°C/min. During use, the DSC cell was purged with dry nitrogen.
  • thermogravimetric analysis (TGA) analysis method of the present invention is: use has thermal analysis controller TA Q500 module to carry out thermogravimetric analysis. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 10-30 mg of the sample was put into a platinum crucible, and the sample was analyzed from room temperature to about 300°C using a linear heating device at 10°C/min. During use, the DSC cell was purged with dry nitrogen.
  • the hygroscopicity of the present invention is measured by a DVS INT-Std dynamic moisture and gas adsorption analyzer from Surface Measurement Systems, UK.
  • Embodiment 1 The crystal form J of the compound of formula (I)
  • Method 1 Suspend the original sample (207.2mg) in dichloromethane (2.5mL), heat to reflux, the solid is completely dissolved, add n-heptane (5.0mL), a large amount of solid precipitates, keep stirring for 2 hours, then stop heating, Naturally cooled to room temperature, suction filtered, and pumped to near dryness, the filter cake was vacuum-dried at room temperature for 12 hours to obtain a white solid (148 mg, yield 72.5%).
  • Method 2 Suspend the original sample (194.6mg) in dichloromethane (1.0mL), heat to 45°C, the solid dissolves first, then precipitates out, add n-heptane (4.0mL), keep stirring for 1 hour, and cool naturally Return to room temperature, filter with suction, wash the filter cake with n-heptane (4.0 mL ⁇ 2), pump to near dryness, and vacuum dry at room temperature for 4 hours to obtain a white solid (162.1 mg, yield 84.2%).
  • Method 3 Suspend the original sample (199.8mg) in dichloromethane (2.5mL), stir and dissolve at room temperature, add n-heptane (5.0mL), stir for 24 hours, filter with suction, pump until nearly dry, and dry in vacuum at room temperature for 4 hours , to obtain a white solid (130.1 mg, yield 65.8%).
  • thermogravimetric analysis diagram of the crystal form J prepared by the method of this embodiment is basically shown in FIG. 3 .
  • Embodiment 2 The pharmacokinetic experiment of crystal form described in the present invention
  • the crystal form of the compound represented by the formula (I) described in the present invention is filled into capsules for oral administration.
  • Embodiment 3 The stability experiment of crystal form described in the present invention
  • Illumination experiment Take a batch of test samples and put them into a flat weighing bottle, spread them into a thin layer with a thickness of ⁇ 5mm, place them in a light box (with ultraviolet light), and place them in a light box with an illumination of 4500 ⁇ 500lx and ultraviolet light. Place it under the condition of ⁇ 0.7w/ m2 for 30 days, take samples on the 5th, 13th, and 30th day, observe the color change of the sample, and test the purity of the sample by HPLC.
  • the crystal form J of the present invention has no obvious change in appearance and chemical purity, has good stability and is suitable for pharmaceutical use.
  • the crystal structure of the crystal form J of the present invention is also very stable, and the crystal structure basically does not change under conditions of high temperature, high humidity and/or light.
  • Embodiment 4 The hygroscopicity experiment of the crystal form described in the present invention

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Abstract

公开化合物2-((5-环丙基-3-(2,6-二氯苯基)异恶唑-4-基)甲氧基)-10H-螺[苯并[6,7]氧杂卓[3,2-b]吡啶-11,1'-环丙烷]-7-甲酸的新晶型，所述新晶型为晶型J。还公开包含所述晶型J的药物组合物，以及所述晶型J或所述药物组合物在制备用于预防、治疗或减轻患者由FXR介导的疾病的药物中的用途。

Description

含氮三环化合物的新晶型及其用途 技术领域
本发明属于药物技术领域，涉及含氮三环化合物的新晶型及其用途，具体涉及2-((5-环丙基-3-(2,6-二氯苯基)异恶唑-4-基)甲氧基)-10H-螺[苯并[6,7]氧杂卓[3,2-b]吡啶-11,1'-环丙烷]-7-甲酸的新晶型及其药物组合物，进一步涉及所述新晶型或所述药物组合物在制备药物中的用途，如所述新晶型或所述药物组合物在制备用于预防、治疗或减轻患者由FXR介导的疾病的药物中的用途。
背景技术
专利申请WO 2018024224A1和CN107686486A公开了可以用作FXR活性调节剂的含氮三环化合物及其制备方法和应用，其中，具体公开了化合物7，即，化合物2-((5-环丙基-3-(2,6-二氯苯基)异恶唑-4-基)甲氧基)-10H-螺[苯并[6,7]氧杂卓[3,2-b]吡啶-11,1'-环丙烷]-7-甲酸(式(I)所示化合物)。
Figure PCTCN2022125324-appb-000001
专利申请WO2021104427A1、WO2021104421A1和CN112876490A公开了该化合物的晶型。
本领域公知，药物多晶型是药物研发中的常见现象，是影响药物质量的重要因素。同一药物的不同晶型在外观、溶解度、熔点、溶出度、生物有效性等方面可能会显著不同，也会对药物的稳定性、生物利用度及疗效等方面产生不同的影响。因此，在药物研发中，应对药物的晶型进行全面的考察研究。
发明内容
本发明提供了2-((5-环丙基-3-(2,6-二氯苯基)异恶唑-4-基)甲氧基)-10H-螺[苯并[6,7]氧杂卓[3,2-b]吡啶-11,1'-环丙烷]-7-甲酸(式(I)所示化合物)的一种新晶型，为该化合物的晶型J，所述晶型的性质稳定，不易受高湿度影响而潮解，且具有良好的药理性质(例如，具有良好的药代动力学性质等)，从而具有优良的成药性。本发明还提供了包含式(I)所示化合物的晶型J的药物组合物。
具体而言，本发明涉及式(I)所示化合物的晶型J及其药物组合物，以及所述晶型J或所述药物组合物在制备用于预防、治疗或减轻患者由FXR介导的疾病的药物中的用途。本发明所述的晶型J还可以为溶剂化物形式，例如水合物形式。
一方面，本发明提供了式(I)所示化合物的晶型，其中所述晶型为晶型J，
Figure PCTCN2022125324-appb-000002
在一些实施方案中，所述晶型J的X射线粉末衍射图在下列2θ角处具有衍射峰：4.33°±0.2°,12.86°±0.2°,21.18°±0.2°,24.11°±0.2°,25.08°±0.2°。
在一些实施方案中，所述晶型J的X射线粉末衍射图在下列2θ角处具有衍射峰：4.33°±0.2°,8.37°±0.2°,11.56°±0.2°,12.86°±0.2°,16.26°±0.2°,20.66°±0.2°,21.18°±0.2°,21.61°±0.2°,24.11°±0.2°,25.08°±0.2°,27.57°±0.2°。
在一些实施方案中，所述晶型J的X射线粉末衍射图在下列2θ角处具有衍射峰：4.33°±0.2°,8.37°±0.2°,8.55°±0.2°,11.56°±0.2°,12.86°±0.2°,16.26°±0.2°,20.66°±0.2°,21.18°±0.2°,21.61°±0.2°,24.11°±0.2°,25.08°±0.2°,27.57°±0.2°。
在一些实施方案中，所述晶型J的X射线粉末衍射图在下列2θ角处具有衍射峰：处具有衍射峰：4.33°±0.2°,8.37°±0.2°,8.55°±0.2°,11.56°±0.2°,12.86°±0.2°,15.16°±0.2°,15.64°±0.2°,15.86°±0.2°,16.26°±0.2°,16.69°±0.2°,17.33°±0.2°,18.01°±0.2°,18.79°±0.2°,19.31°±0.2°,19.65°±0.2°,19.90°±0.2°,20.66°±0.2°,21.18°±0.2°,21.61°±0.2°,22.01°±0.2°,22.56°±0.2°,23.16°±0.2°,23.69°±0.2°,24.11°±0.2°,24.41°±0.2°,25.08°±0.2°,25.99°±0.2°,26.33°±0.2°,27.57°±0.2°,28.07°±0.2°,28.36°±0.2°,28.92°±0.2°,30.02°±0.2°,30.45°±0.2°,31.28°±0.2°,33.67°±0.2°,34.68°±0.2°,36.06°±0.2°,37.01°±0.2°,39.92°±0.2°,40.36°±0.2°。
在一些实施方案中，所述晶型J的X射线粉末衍射图在下列2θ角处具有衍射峰：处具有衍射峰：4.33°±0.2°,5.81°±0.2°,8.37°±0.2°,8.55°±0.2°,11.56°±0.2°,12.86°±0.2°,13.73°±0.2°,15.16°±0.2°,15.64°±0.2°,15.86°±0.2°,16.26°±0.2°,16.69°±0.2°,17.33°±0.2°,18.01°±0.2°,18.79°±0.2°,19.31°±0.2°,19.65°±0.2°,19.90°±0.2°,20.66°±0.2°,21.18°±0.2°,21.61°±0.2°,22.01°±0.2°,22.56°±0.2°,23.16°±0.2°,23.69°±0.2°,24.11°±0.2°,24.41°±0.2°,25.08°±0.2°,25.99°±0.2°,26.33°±0.2°,27.57°±0.2°,28.07°±0.2°,28.36°±0.2°,28.92°±0.2°,29.50°±0.2°,30.02°±0.2°,30.45°±0.2°,31.28°±0.2°,32.09°±0.2°,32.73°±0.2°,33.67°±0.2°,34.68°±0.2°,36.06°±0.2°,37.01°±0.2°,38.29°±0.2°,39.15°±0.2°,39.92°±0.2°,40.36°±0.2°。
在一些实施方案中，所述晶型J的X射线粉末衍射图在下列2θ角处具有衍射峰：4.33°±0.2°,5.81°±0.2°,8.37°±0.2°,8.55°±0.2°,11.56°±0.2°,12.86°±0.2°,13.73°±0.2°,15.16°±0.2°,15.64°±0.2°,15.86°±0.2°,16.26°±0.2°,16.69°±0.2°,17.33°±0.2°,18.01°±0.2°,18.79°±0.2°,19.31°±0.2°,19.65°±0.2°,19.90°±0.2°,20.66°±0.2°,21.18°±0.2°,21.61°±0.2°,22.01°±0.2°,22.56°±0.2°,23.16°±0.2°,23.69°±0.2°,24.11°±0.2°,24.41°±0.2°,25.08°±0.2°,25.99°±0.2°,26.33°±0.2°,27.57°±0.2°,28.07°±0.2°,28.36°±0.2°,28.92°±0.2°, 29.50°±0.2°,30.02°±0.2°,30.45°±0.2°,31.28°±0.2°,32.09°±0.2°,32.73°±0.2°,33.67°±0.2°,34.68°±0.2°,36.06°±0.2°,37.01°±0.2°,38.29°±0.2°,39.15°±0.2°,39.92°±0.2°,40.36°±0.2°,43.43°±0.2°,44.83°±0.2°,45.70°±0.2°,47.65°±0.2°,49.44°±0.2°,50.66°±0.2°,53.77°±0.2°。
在一些实施方案中，所述晶型J具有基本上如图1所示的X射线粉末衍射图。
在一些实施方案中，所述晶型J的差示扫描量热图包含116.45℃±3℃和195.53℃±3℃的吸热峰。
在一些实施方案中，所述晶型J具有基本上如图2所示的差示扫描量热图。
在一些实施方案中，所述晶型J加热到150℃左右时，失重约为1.795％，存在±0.1％的误差容限。
在一些实施方案中，所述晶型J具有基本上如图3所示的热重分析曲线图。
一方面，本发明还提供一种药物组合物，其包含本发明所述的晶型，和药学上可接受的载体、赋形剂、稀释剂、辅剂或它们的组合。
另一方面，本发明还涉及所述式(I)化合物的晶型或所述药物组合物在制备药物中的用途，其中，所述药物用于预防、治疗或减轻患者由FXR介导的疾病；进一步地，所述用途包括给予人或动物本发明所述的晶型或所述的药物组合物的有效治疗剂量。
在一些实施方案中，本发明所述的由FXR介导的疾病为心脑血管疾病、与血脂异常相关的疾病、代谢综合征、过度增殖性疾病、纤维化、炎性疾病或与肝胆相关的疾病。
在另一些实施方案中，本发明所述的心脑血管疾病为动脉粥样硬化、急性心肌梗死、静脉闭塞性疾病、门静脉高血压、肺动脉高血压、心力衰竭、周围组织动脉阻塞性疾病、性功能障碍、中风或血栓形成。
在另一些实施方案中，本发明所述的代谢综合征为胰岛素抗性、高血糖、高胰岛素血症、血液中脂肪酸或甘油三酯水平的升高、高脂血症、肥胖症、高甘油三酯血症、高胆固醇血症、X综合症、糖尿病并发症、动脉粥样硬化、高血压、急性贫血、中性粒细胞减少、血脂异常、II型糖尿病、糖尿病性肾病、糖尿病性神经病变、糖尿病视网膜病变、血脂障碍或糖尿病和体重指数异常高的合并病症。
在另一些实施方案中，本发明所述的过度增殖性疾病为肝细胞癌、结肠腺瘤、息肉病、结肠腺癌、乳腺癌、膜腺癌、巴特氏食管癌和其它形式的胃肠道或肝脏肿瘤性疾病。
在另一些实施方案中，本发明所述的纤维化、炎性疾病或与肝胆相关的疾病为非酒精性脂肪肝、非酒精性脂肪性肝炎、胆汁淤积、肝纤维化、原发性胆汁性肝硬化、原发性硬化性胆管炎、进行性家族性胆汁淤积、囊性纤维化、药物引起的胆管损伤、胆结石、肝硬化、乙型肝炎、皮脂腺病、酒精导致的肝硬化、胆道阻塞、胆石病、结肠炎、新生儿黄症、核黄症或肠道细菌过度生长。
一方面，本发明涉及预防、治疗或减轻患者由FXR介导的疾病的方法，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，本发明涉及使用所述式(I)化合物的晶型或所述药物组合物来预防、治疗或减轻患者由FXR介导的疾病。
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详细描述。同时，本发明提供了所述晶型的性质测试实验，如药代动力学实验、稳定性实验和引湿性实验等。由实验结果可知，本发明所述的式(I)所示化合物的晶型J具有良好的生物活性，且稳定性高，适合制药用途。具体地，本发明所述的晶型J具有更优异的药代动力学性质，例如，具有更高的暴露量；同时，本发明所述的晶型J不易受高湿度影响而潮解，方便药物的长期贮存放置。
其中，关于引湿性特征描述与引湿性增重的界定(中国药典2020年版附录9103药物引湿性试验指导原则，实验条件：25℃±1℃，80％±2％相对湿度)如下表所述：
引湿性特征描述与引湿性增重的界定
Figure PCTCN2022125324-appb-000003
相对于现有技术，本发明所述晶型具有更优的技术效果，如具有更优药代动力学性质(例如更高的暴露量和/或更高的Cmax值)、和/或更高的稳定性。例如，相对现有技术CN112876490A公开的所有晶型，本发明所述晶型各方面的效果更佳；发明人经研究发现，CN112876490A公开的晶型中，晶型E是最稳定的晶型，但其在高温60℃条件下放置5天后晶体结构即发生变化，而本发明所述的晶型在高温条件下非常稳定，晶体结构基本不变。
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。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-Al 2O 3)之间的能量差随温度变化的一种技术。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96％，或至少97％，或至少98％，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。
本发明涉及所述的2-((5-环丙基-3-(2,6-二氯苯基)异恶唑-4-基)甲氧基)-10H-螺[苯并[6,7]氧杂卓[3,2-b]吡啶-11,1'-环丙烷]-7-甲酸(式(I)所示化合物)的新晶型，它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96％，或至少97％，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％。
“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℃，或27.5℃等等。
本发明所述晶型的药物组合物，制剂，给药和用途
本发明的药物组合物的特点包括式(I)所示化合物的晶型或其任意组合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患者由FXR介导的疾病。
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或其晶型不相容的范围，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。
本发明所述的晶型可以作为活性成分与根据常规药物复合技术的药物载体一起均匀结合在混合物中。根据给药所要求的制剂形式，例如口服或者胃肠外的(包括静脉内的)，载体可以为各式各样的形式。当制备用于口服剂型的组合物时，可以使用任何常规的药物介质，例如，在制备口服液体药剂例如悬浮液、酏剂和溶液时使用水、乙二醇、油、醇、芳香剂、防腐剂、着色剂等等；或者在制备口服固体制剂例如粉末、硬胶囊、软胶囊和片剂时使用例如淀粉、糖、微晶纤维素、稀释剂、成粒剂、滑润剂、粘合剂、崩解剂等等，其中固体口服制剂是比液体药剂更优选的。
因为片剂和胶囊剂容易服用，所以它们代表了最有利的口服剂量单位形式，在这种情况下明显使用固体药物载体。如果需要的话，可以用标准水溶液或者非水溶液技术将片剂包衣。
可以存在各种各样的其它材料作为包衣或者来改变所述剂量单位的外形。例如，片剂可以用虫胶、糖或者两者进行包衣。除了所述活性成分以外，糖浆剂或者酏剂可以包含作为甜味剂的蔗糖、作为防腐剂的对羟基苯甲酸甲酯或丙酯、染料和调味剂(例如樱桃味或者橙味的)。
本发明所述的晶型也可以经胃肠外给药。可以在水中与表面活性剂(比如羟丙基纤维素)适当地混合来制备这些活性物质的溶液或者悬浮液。在甘油、液体聚乙二醇及其混合物中，和在油中，也可以制备分散剂。在贮存和使用的常规条件下，这些制剂含有防腐剂以防止微生物的生长。
适于注射用途的药品形式包括无菌水溶液或者分散剂和用于即时制备无菌可注射溶液或者分散剂的无菌粉末。在所有的情况下，所述药品形式都必须是无菌的并且必须是以容易注射的形式存在的流体。它在制造和贮存的条件下必须是稳定的并且必须在抗微生物比如细菌和真菌的污染作用的条件下保存。载体可以是溶剂或者分散介质，其含有，例如：水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)、它们适合的混合物和植物油。
可以使用任何适合的给药方法来向哺乳动物，尤其是人提供有效剂量的本发明所述的晶型。例如，可以使用经口、经直肠、经局部、经胃肠外、经眼、经肺、经鼻等给药方法。剂型包括片剂、锭剂、分散剂、悬浮剂、溶液剂、胶囊剂、乳剂、软膏剂、气溶胶等。
本发明涉及的晶型或其药物组合物能有效用于预防、处理、治疗或减轻患者由FXR介导的疾病，特别是能有效治疗非酒精性脂肪肝(NAFLD)、非酒精性脂肪性肝炎(NASH)、肥胖症、高甘油三酯血症、动脉粥样硬化、慢性肝内胆汁淤积症、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)、进行性家族性胆汁淤积(PFIC)、药物引起的胆管损伤、胆结石、肝硬化、乙型肝炎、皮脂腺病、酒精导致的肝硬化、囊性纤维化、胆道阻塞、胆石病、肝纤维化、血脂异常、动脉粥样硬化症、II型糖尿病、糖尿病性肾病、糖尿病性神经病变、糖尿病视网膜病变、周围组织动脉阻塞性疾病(PAOD)、结肠炎、新生儿黄症、核黄症、静脉闭塞性疾病、门静脉高血压、代谢综合征、急性心肌梗塞、急性中风、血栓形成、高胆固醇血症、肠道细菌过度生长、勃起功能障碍、胃肠道肿瘤性疾病和肝脏肿瘤性疾病等。
附图说明
图1为按照本发明实施例1方法制备得到的式(I)所示化合物的晶型J的X射线粉末衍射(XRPD)图。
图2为按照本发明实施例1方法制备得到的式(I)所示化合物的晶型J的差示扫描量热(DSC)图。
图3为按照本发明实施例1方法制备得到的式(I)所示化合物的晶型J的热重分析(TGA)图。
图4为按照本发明实施例1方法制备得到的式(I)所示化合物的晶型J的动态水分吸附(DVS)图。
具体实施方式
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°-60°的范围内以0.0167°步长进行分析。使用Data Collector软件收集数据，High Score 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。
本发明所用热重分析(TGA)分析方法为：使用带有热分析控制器TA Q500模件进行热重分析。收集数据并使用TA Instruments Thermal Solutions软件进行分析。将约10-30mg样品放入铂坩埚中，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。
本发明引湿性采用英国Surface Measurement Systems公司DVS INT-Std型动态水分与气体吸附分析仪测定，湿度测试范围：0％-95％，气流：200mL/min，温度：25℃，测试点：每升5％湿度取一个测试点。
具体实施方法
原始样品：参照专利申请CN107686486A中实施例9的方法制备得到的式(I)所示化合物(2-((5-环 丙基-3-(2,6-二氯苯基)异恶唑-4-基)甲氧基)-10H-螺[苯并[6,7]氧杂卓[3,2-b]吡啶-11,1'-环丙烷]-7-甲酸)。
实施例
实施例1 式(I)化合物的晶型J
1.晶型J的制备
方法一：将原始样品(207.2mg)悬浮于二氯甲烷(2.5mL)中，加热回流，固体完全溶解，加入正庚烷(5.0mL)，析出大量固体，保温搅拌2小时，随后停止加热，自然冷却至室温，抽滤，抽至近干，滤饼室温真空干燥12小时，得到白色固体(148mg,收率72.5％)。
方法二：将原始样品(194.6mg)悬浮于二氯甲烷(1.0mL)中，加热至45℃，固体先溶解，随后析出固体，加入正庚烷(4.0mL)，保温搅拌1小时，自然冷却至室温，抽滤，滤饼用正庚烷(4.0mL×2)洗涤，抽至近干，室温真空干燥4小时，得白色固体(162.1mg,收率84.2％)。
方法三：将原始样品(199.8mg)悬浮于二氯甲烷(2.5mL)中，室温搅拌溶解，加入正庚烷(5.0mL)，搅拌24小时，抽滤，抽至近干，室温真空干燥4小时，得到白色固体(130.1mg,收率65.8％)。
2.晶型J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°,5.81°,8.37°,8.55°,11.56°,12.86°,13.73°,15.16°,15.64°,15.86°,16.26°,16.69°,17.33°,18.01°,18.79°,19.31°,19.65°,19.90°,20.66°,21.18°,21.61°,22.01°,22.56°,23.16°,23.69°,24.11°,24.41°,25.08°,25.99°,26.33°,27.57°,28.07°,28.36°,28.92°,29.50°,30.02°,30.45°,31.28°,32.09°,32.73°,33.67°,34.68°,36.06°,37.01°,38.29°,39.15°,39.92°,40.36°,43.43°,44.83°,45.70°,47.65°,49.44°,50.66°和53.77°,存在±0.2°的误差容限。本实施例方法制备得到的晶型J的X射线粉末衍射图基本上如图1所示。
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定：扫描速度为10℃/分钟，包含116.45℃和195.53℃的吸热峰，存在±3℃的误差容限。本实施例方法制备得到的晶型J的差示扫描量热图基本上如图2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，失重为1.795％，存在±0.1％的误差容限。本实施例方法制备得到的晶型J的热重分析图基本上如图3所示。
实施例2 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8-12kg雄性Beagle犬3只，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J的药代动力学实验数据
供试样品 AUC last(h*ng/ml) C max(ng/ml) T max(h)
晶型J 885 554 0.667
实验结论：
由表1可知，本发明所述的晶型J在Beagle犬体内的暴露量较大，具有良好的药代动力学性质。
实施例3 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≤5mm厚的薄层，60℃温度下放置30天，于第5、13、30天取样，观察样品颜色变化，HPLC检测样品纯度。
(2) 高湿实验：取一批供试品适量放入扁形称量瓶中，摊成≤5mm厚的薄层，25℃、RH 90％±5％条件下放置30天，于第5、13、30天取样，观察样品颜色变化，HPLC检测样品纯度。
(3) 光照实验：取一批供试品适量放入扁形称量瓶中，摊成≤5mm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/m 2条件下放置30天，于第5、13、30天取样，观察样品颜色变化，HPLC检测样品纯度。
实验结论：在高温、高湿和/或光照条件下，本发明所述晶型J的外观和化学纯度均无明显变化，稳定性效果好，适合制药用途。此外，本发明所述晶型J的晶体结构也非常稳定，在高温、高湿和/或光照条件下，晶体结构基本不变。
实施例4 本发明所述晶型的引湿性实验
取供试样品适量，采用动态水分吸附仪测试其引湿性，实验结果如图4所示。由图4可知，本发明所述的晶型J在相对湿度80％的条件下，平衡后增重大于0.2％但小于2％，根据引湿性增重的界定标准，属于略有引湿性。由实验结果可知，本发明所述晶型J不易受高湿度影响而潮解，方便药物的长期贮存放置。
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. 式(I)所示化合物的晶型，其中所述晶型为晶型J，
    Figure PCTCN2022125324-appb-100001
    其中，所述晶型J的X射线粉末衍射图在下列2θ角处具有衍射峰：4.33°±0.2°,12.86°±0.2°,21.18°±0.2°,24.11°±0.2°,25.08°±0.2°。
  2. 根据权利要求1所述的晶型，所述晶型J的X射线粉末衍射图在下列2θ角处具有衍射峰：4.33°±0.2°,8.37°±0.2°,11.56°±0.2°,12.86°±0.2°,16.26°±0.2°,20.66°±0.2°,21.18°±0.2°,21.61°±0.2°,24.11°±0.2°,25.08°±0.2°,27.57°±0.2°。
  3. 根据权利要求1或2所述的晶型，所述晶型J的X射线粉末衍射图在下列2θ角处具有衍射峰：4.33°±0.2°,5.81°±0.2°,8.37°±0.2°,8.55°±0.2°,11.56°±0.2°,12.86°±0.2°,13.73°±0.2°,15.16°±0.2°,15.64°±0.2°,15.86°±0.2°,16.26°±0.2°,16.69°±0.2°,17.33°±0.2°,18.01°±0.2°,18.79°±0.2°,19.31°±0.2°,19.65°±0.2°,19.90°±0.2°,20.66°±0.2°,21.18°±0.2°,21.61°±0.2°,22.01°±0.2°,22.56°±0.2°,23.16°±0.2°,23.69°±0.2°,24.11°±0.2°,24.41°±0.2°,25.08°±0.2°,25.99°±0.2°,26.33°±0.2°,27.57°±0.2°,28.07°±0.2°,28.36°±0.2°,28.92°±0.2°,29.50°±0.2°,30.02°±0.2°,30.45°±0.2°,31.28°±0.2°,32.09°±0.2°,32.73°±0.2°,33.67°±0.2°,34.68°±0.2°,36.06°±0.2°,37.01°±0.2°,38.29°±0.2°,39.15°±0.2°,39.92°±0.2°,40.36°±0.2°。
  4. 根据权利要求1-3任意一项所述的晶型，所述晶型J具有基本上如图1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，其中，所述晶型J的差示扫描量热图包含116.45℃±3℃和195.53℃±3℃的吸热峰。
  6. 根据权利要求1-5任意一项所述的晶型，所述晶型J具有基本上如图2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，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、治疗或减轻患者由FXR介导的疾病。
  9. 根据权利要求8所述的用途，其中，所述的由FXR介导的疾病为心脑血管疾病、与血脂异常相关的疾病、代谢综合征、过度增殖性疾病、纤维化、炎性疾病或与肝胆相关的疾病。
  10. 根据权利要求9所述的用途，其中，所述心脑血管疾病为动脉粥样硬化、急性心肌梗死、静脉闭塞性疾病、门静脉高血压、肺动脉高血压、心力衰竭、周围组织动脉阻塞性疾病、性功能障碍、中风或血栓形成；
    所述代谢综合征为胰岛素抗性、高血糖、高胰岛素血症、血液中脂肪酸或甘油水平的升高、高脂血症、肥胖症、高甘油三酯血症、高胆固醇血症、X综合症、糖尿病并发症、动脉粥样硬化、高血压、急性贫血、中性粒细胞减少、血脂异常、II型糖尿病、糖尿病性肾病、糖尿病性神经病变、糖尿病视网膜病变、血脂障碍或糖尿病和体重指数异常高的合并病症；
    所述过度增殖性疾病为肝细胞癌、结肠腺瘤、息肉病、结肠腺癌、乳腺癌、膜腺癌、巴特氏食管癌和其它形式的胃肠道或肝脏肿瘤性疾病；
    所述纤维化、炎性疾病或与肝胆相关的疾病为非酒精性脂肪肝、非酒精性脂肪性肝炎、胆汁淤积、肝纤维化、原发性胆汁性肝硬化、原发性硬化性胆管炎、进行性家族性胆汁淤积、囊性纤维化、药物引起的胆管损伤、胆结石、肝硬化、乙型肝炎、皮脂腺病、酒精导致的肝硬化、胆道阻塞、胆石病、结肠炎、新生儿黄症、核黄症或肠道细菌过度生长。
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