WO2023061468A1 - 含氮三环化合物的新晶型及其用途 - Google Patents
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- 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
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-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, specifically, the new crystal form or the pharmaceutical composition is used in the preparation of prevention, treatment or relief of patients Use in medicine for diseases mediated by FXR.
- 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 oxazepine [3,2-b]pyridine-11,1'-cyclopropane]-7-carboxylic acid (compound represented by formula (I)), which is the crystal form I of the compound, said The crystal form is stable in properties, has no or almost no hygroscopicity, has good pharmacological properties (for example, has good pharmacokinetic properties, etc.), and thus has excellent druggability.
- the present invention also provides a pharmaceutical composition comprising the crystal form I of the compound represented by formula (I).
- the present invention relates to the crystal form I of the compound represented by formula (I) and its pharmaceutical composition, and the preparation of the crystal form I or the pharmaceutical composition for preventing, treating or alleviating the FXR-mediated use in medicines for diseases.
- the crystal form I described in the present invention can also be in the form of solvates, such as hydrates.
- the present invention provides a crystal form of the compound represented by formula (I), wherein the crystal form is crystal form I,
- the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2 ⁇ angles: 4.43° ⁇ 0.2°, 11.59° ⁇ 0.2°, 19.54° ⁇ 0.2°, 21.65° ⁇ 0.2°, 24.25° ⁇ 0.2°, 25.59° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the crystalline form I has diffraction peaks at the following 2 ⁇ angles: 4.43° ⁇ 0.2°, 11.59° ⁇ 0.2°, 13.56° ⁇ 0.2°, 19.54° ⁇ 0.2°, 19.86° ⁇ 0.2°, 20.89° ⁇ 0.2°, 21.65° ⁇ 0.2°, 23.39° ⁇ 0.2°, 24.25° ⁇ 0.2°, 25.59° ⁇ 0.2°, 28.13° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2 ⁇ angles: 4.43° ⁇ 0.2°, 8.05° ⁇ 0.2°, 8.83° ⁇ 0.2°, 9.42° ⁇ 0.2°,11.59° ⁇ 0.2°,12.96° ⁇ 0.2°,13.56° ⁇ 0.2°,14.06° ⁇ 0.2°,14.70° ⁇ 0.2°,15.59° ⁇ 0.2°,17.06° ⁇ 0.2°,17.32° ⁇ 0.2 °,17.82° ⁇ 0.2°,18.52° ⁇ 0.2°,18.93° ⁇ 0.2°,19.54° ⁇ 0.2°,19.86° ⁇ 0.2°,20.30° ⁇ 0.2°,20.89° ⁇ 0.2°,21.65° ⁇ 0.2°, 22.18° ⁇ 0.2°, 22.60° ⁇ 0.2°, 23.39° ⁇ 0.2°, 24.25° ⁇ 0.2°, 24.79° ⁇ 0.2°, 25.59° ⁇ 0.2°, 25.99° ⁇ 0.2°, 26.69° ⁇ 0.2°, 27
- the X-ray powder diffraction pattern of the crystal form I also has diffraction peaks at the following 2 ⁇ angles: 34.36° ⁇ 0.2°, 34.99° ⁇ 0.2°, 35.98° ⁇ 0.2°, 37.40° ⁇ 0.2 °, 38.40° ⁇ 0.2°, 39.03° ⁇ 0.2°, 39.51° ⁇ 0.2°, 40.55° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2 ⁇ angles: 4.43° ⁇ 0.2°, 8.05° ⁇ 0.2°, 8.83° ⁇ 0.2°, 9.42° ⁇ 0.2°, 11.59° ⁇ 0.2°,12.96° ⁇ 0.2°,13.56° ⁇ 0.2°,14.06° ⁇ 0.2°,14.70° ⁇ 0.2°,15.59° ⁇ 0.2°,17.06° ⁇ 0.2°,17.32° ⁇ 0.2°,17.82° ⁇ 0.2°,18.52° ⁇ 0.2°,18.93° ⁇ 0.2°,19.54° ⁇ 0.2°,19.86° ⁇ 0.2°,20.30° ⁇ 0.2°,20.89° ⁇ 0.2°,21.65° ⁇ 0.2°,22.18° ⁇ 0.2 °,22.60° ⁇ 0.2°,23.39° ⁇ 0.2°,24.25° ⁇ 0.2°,24.79° ⁇ 0.2°,25.59° ⁇ 0.2°,25.99° ⁇ 0.2°,26.69° ⁇ 0.2°,27
- the Form I has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- the differential scanning calorimetry of the crystalline form I comprises endothermic peaks at 177.02°C ⁇ 3°C and 195.73°C ⁇ 3°C.
- the Form I has a differential scanning calorimeter substantially as shown in FIG. 2 .
- the weight loss when the crystal form I is heated to about 150° C., the weight loss is about 0.321%, and there is an error tolerance of ⁇ 0.1%.
- the Form I 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. It can be seen from the experimental results that the crystal form I of the compound represented by the formula (I) described in the present invention has good biological activity and high stability, and is suitable for pharmaceutical use. Specifically, the crystalline form I described in the present invention has better pharmacokinetic properties, for example, has a higher exposure; the crystalline form I described in the present invention is not easily affected by high humidity and deliquescence, which facilitates the long-term Store and place.
- 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 form described in the present invention is better in all aspects; the inventor found through research that among all 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.
- 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 the crystal form I 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 I 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 I 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 the crystal form I of the compound represented by formula (I) prepared according to the method of Example 1 of the present invention.
- DVS dynamic moisture adsorption
- 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 powdered 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 I of the compound of formula (I)
- thermogravimetric analysis diagram of the crystal form I 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 appearance and chemical purity of the crystal form I of the present invention have no significant change, the stability effect is good, and it is suitable for pharmaceutical use.
- the crystal structure of the crystalline form I of the present invention is also very stable, and the crystal structure remains basically unchanged 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
Description
供试样品 | AUC last(h*ng/ml) | C max(ng/ml) | T max(h) |
晶型I | 1020 | 389 | 1.67 |
Claims (10)
- 根据权利要求1所述的晶型,所述晶型I的X射线粉末衍射图在下列2θ角处具有衍射峰:4.43°±0.2°,11.59°±0.2°,13.56°±0.2°,19.54°±0.2°,19.86°±0.2°,20.89°±0.2°,21.65°±0.2°,23.39°±0.2°,24.25°±0.2°,25.59°±0.2°,28.13°±0.2°。
- 根据权利要求1或2所述的晶型,所述晶型I的X射线粉末衍射图在下列2θ角处具有衍射峰:4.43°±0.2°,8.05°±0.2°,8.83°±0.2°,9.42°±0.2°,11.59°±0.2°,12.96°±0.2°,13.56°±0.2°,14.06°±0.2°,14.70°±0.2°,15.59°±0.2°,17.06°±0.2°,17.32°±0.2°,17.82°±0.2°,18.52°±0.2°,18.93°±0.2°,19.54°±0.2°,19.86°±0.2°,20.30°±0.2°,20.89°±0.2°,21.65°±0.2°,22.18°±0.2°,22.60°±0.2°,23.39°±0.2°,24.25°±0.2°,24.79°±0.2°,25.59°±0.2°,25.99°±0.2°,26.69°±0.2°,27.26°±0.2°,28.13°±0.2°,28.56°±0.2°,29.77°±0.2°,30.41°±0.2°,30.75°±0.2°,31.23°±0.2°,33.08°±0.2°。
- 根据权利要求1-3任意一项所述的晶型,所述晶型I具有基本上如图1所示的X射线粉末衍射图。
- 根据权利要求1-4任意一项所述的晶型,其中,所述晶型I的差示扫描量热图包含177.02℃±3℃和195.73℃±3℃的吸热峰。
- 根据权利要求1-5任意一项所述的晶型,所述晶型I具有基本上如图2所示的差示扫描量热图。
- 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。
- 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。
- 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。
- 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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