WO2021104421A1 - 含氮三环化合物的无定形及其用途 - Google Patents
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Definitions
- the invention belongs to the technical field of medicines, and relates to the amorphous form of nitrogen-containing tricyclic compounds and uses thereof, in particular to 2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4- Yl)methoxy)-10H-spiro[benzo[6,7]oxazepine[3,2-b]pyridine-11,1'-cyclopropane]-7-carboxylic acid (compound represented by formula (I)
- the amorphous form of) and its use further relates to a pharmaceutical composition comprising the amorphous form.
- the amorphous form or the pharmaceutical composition is used to prevent, treat or alleviate a patient's disease mediated by FXR.
- Farnesoid X receptor is a member of the nuclear hormone receptor superfamily and is mainly expressed in the liver, kidney and intestine (Seol et al., Mol. Endocrinol (1995), 9:72-85; Forman et al., Cell (1995), 81:687-693). It functions as a heterodimer formed with the retinoic acid X receptor (RXR) and binds to the response element in the promoter of the target gene to regulate gene transcription.
- the FXR-RXR heterodimer binds to the inverted repeat-1 (IR-1) response element with the highest affinity, in which the hexamer that binds to the consensus receptor is separated by a single nucleotide.
- FXR can be activated by bile acids (the end product of cholesterol metabolism) (Makishima et al. Science (1999), 284: 1362-1365; Parks et al. Science (1999), 284: 1365-1368; Wang et al., MoI. Cell. (1999) , 3:543-553), and bile acids are used to inhibit the catabolism of cholesterol (Urizar et al., (2000) J. Biol. Chem. 275:39313-393170).
- FXR is a key regulator of cholesterol homeostasis, triglyceride synthesis and lipogenesis (Crawley, Expert Opinion Ther. Patents (2010), 20:1047-1057). In addition to being a target for the treatment of dyslipidemia, obesity, vitamin D-related diseases, intestinal diseases, drug-induced side effects, and hepatitis (Crawley, Expert Opinion Ther.
- FXR also It can be used for liver and gallbladder diseases, chronic hepatitis, non-alcoholic fatty liver (NAFLD), non-alcoholic steatohepatitis (NASH), cholestasis, liver fibrosis, liver cirrhosis, hepatitis B, metabolic diseases, lipid metabolism diseases, carbohydrates Targets for the treatment of compound metabolic diseases, cardiovascular metabolic diseases, atherosclerosis, type II diabetes and diabetic complications (Frank G. Schaap et al., Journal of Medicinal Chemistry (2005), 48:5383-5402).
- Patent applications WO 2018024224 and CN 107686486 disclose nitrogen-containing tricyclic compounds that can be used as FXR activity modifiers and preparation methods and applications thereof.
- 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-carboxylic acid (compound represented by formula (I)).
- the specific microstructure of the compound is not disclosed in the patent application.
- drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may be significantly different in appearance, solubility, melting point, dissolution, bioavailability, etc., and also have different effects on drug stability, bioavailability, and efficacy. Therefore, in drug research and development, the issue of drug polymorphism should be fully considered.
- Amorphous is a form of material polymorphism, which is an amorphous state.
- the various physical and chemical properties and clinical efficacy characteristics of amorphous drugs are often different from ordinary crystalline drugs. It is known in the art that the bioavailability of poorly water-soluble drugs can be improved by converting them into salts or amorphous forms. However, since the amorphous forms of many substances are unstable, few drugs are used in the amorphous state. Research on the use of drugs in a stable amorphous state is also of great significance.
- the present invention provides 2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-10H-spiro[benzo[6,7]
- the amorphous form of oxazepine [3,2-b]pyridine-11,1'-cyclopropane]-7-carboxylic acid and its pharmaceutical composition said amorphous or pharmaceutical composition having good pharmacological properties (for example, Good pharmacokinetic properties), and its stability and other properties have also been significantly improved, so it has excellent druggability.
- the present invention relates to the amorphous form of the compound represented by formula (I) and the pharmaceutical composition thereof, and the amorphous form or the pharmaceutical composition is prepared for the prevention, treatment or alleviation of FXR-mediated diseases in patients. Use in medicines.
- the amorphous form of the present invention may also be in the form of a solvate, such as a hydrate form.
- the present invention provides an amorphous form of the compound represented by formula (I),
- the amorphous shape has an X-ray powder diffraction pattern substantially as shown in FIG. 1.
- the amorphous has a glass transition temperature of 92.26°C ⁇ 3°C.
- the amorphous shape has a differential scanning calorimeter substantially as shown in FIG. 2.
- thermogravimetric analysis curve when the amorphous form is heated to 150°C, its thermogravimetric analysis curve includes a weight loss of 0.409%.
- the amorphous has a thermogravimetric analysis graph substantially as shown in FIG. 3.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the amorphous form of the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.
- the present invention also relates to the amorphous form of the compound of formula (I) or the use of the pharmaceutical composition in the preparation of a medicine, wherein the medicine is used to prevent, treat or alleviate a patient's disease mediated by FXR ; Further, the use includes the effective therapeutic dose of the amorphous or the pharmaceutical composition given to humans or animals of the present invention.
- the FXR-mediated diseases of 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 of the present invention are atherosclerosis, acute myocardial infarction, venous occlusive disease, portal hypertension, pulmonary hypertension, heart failure, peripheral tissue arterial obstructive disease, sex Dysfunction, stroke or thrombosis.
- the metabolic syndrome described in the present invention is insulin resistance, hyperglycemia, hyperinsulinemia, elevated fatty acid or triglyceride levels in the blood, hyperlipidemia, obesity, hyperglycerin Triesteremia, hypercholesterolemia, syndrome X, diabetic complications, atherosclerosis, hypertension, acute anemia, neutropenia, dyslipidemia, type II diabetes, diabetic nephropathy, diabetic neuropathy , Diabetic retinopathy, dyslipidemia or complications of diabetes and abnormally high body mass index.
- the hyperproliferative diseases of the present invention are hepatocellular carcinoma, colonic adenoma, polyposis, colon adenocarcinoma, breast cancer, pancreatic carcinoma, Bart’s esophageal carcinoma and other forms of gastrointestinal tract Or liver tumor disease.
- the fibrosis, inflammatory disease, or hepatobiliary-related disease of the present invention is non-alcoholic fatty liver, non-alcoholic steatohepatitis, cholestasis, liver fibrosis, primary biliary Liver cirrhosis, primary sclerosing cholangitis, progressive familial cholestasis, cystic fibrosis, drug-induced bile duct damage, gallstones, liver cirrhosis, hepatitis B, sebaceous gland disease, alcohol-induced liver cirrhosis, bile duct obstruction , Gallstone disease, colitis, neonatal xanthemia, nucleocapsid, or intestinal bacterial overgrowth.
- the present invention relates to a method for preventing, treating or alleviating a disease mediated by FXR in a patient, which includes administering to the patient a pharmaceutically acceptable effective dose of the amorphous form of the present invention or the pharmaceutical composition.
- the present invention relates to the use of the amorphous form of the compound of formula (I) or the pharmaceutical composition to prevent, treat or alleviate a patient's disease mediated by FXR.
- the present invention also relates to an amorphous preparation method of the compound represented by formula (I).
- the solvent used in the amorphous preparation method of 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 different ratios of solvents, solvent combinations, and solvent combinations described in the present invention are all deemed to be included in the scope of the present invention.
- the present invention provides preferable solvents used in each reaction step.
- the preparation experiment of the amorphous form of the present invention will be described in detail in the example section.
- the present invention provides the amorphous activity test experiment, such as pharmacokinetic experiment, stability experiment and moisture absorption experiment. It can be known from the experimental results that the amorphous form of the compound represented by formula (I) of the present invention has good biological activity and high stability, and is suitable for pharmaceutical use. Specifically, the amorphous form of the present invention has more excellent pharmacokinetic properties, for example, has a higher exposure.
- the amorphous shape of the present invention is not easily deliquescence under the influence of high humidity, and is convenient for long-term storage and placement of the medicine.
- Amorphous or “amorphous form” refers to a substance formed when the particles (molecules, atoms, ions) of a substance are arranged in a three-dimensional space without periodicity, and it is characterized by a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous is a special physical form of solid matter, and its local orderly structure features suggest that it is inextricably linked with crystalline matter.
- the amorphous form of the substance can be obtained by many methods known in the art. Such methods include, but are not limited to, quenching method, anti-solvent flocculation method, ball milling method, spray drying method, freeze drying method, wet granulation method, solid dispersion technology and so on.
- Solvent refers to a substance (typically a liquid) that can completely or partially dissolve 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, dichloromethane, 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, their mixtures, etc.
- Anti-solvent refers to a fluid that promotes the precipitation of a product (or product precursor) from a solvent.
- the anti-solvent may include 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 may be the same liquid as the solvent but at a different temperature, or it may be a liquid different from 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.
- 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-dimethylformaldehyde Amide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, Toluene, xylene and
- a specific example of a solvate is a hydrate, where the solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice is water.
- the hydrate On the surface of the substance, in the crystal lattice, or on the surface and in the crystal lattice, the hydrate may or may not have other solvents other than water.
- Amorphous can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy and scanning electron microscopy (SEM), etc.
- XRPD X-ray powder diffraction
- IR infrared absorption spectroscopy
- DSC differential scanning calorimetry
- TGA thermogravimetric analysis
- nuclear magnetic resonance Raman spectroscopy
- SEM scanning electron microscopy
- DSC Differential scanning calorimetry
- ⁇ -Al 2 O 3 inert reference material
- the amorphous of the present invention is characterized by a DSC chart with a glass transition, which is substantially as shown in the DSC chart provided in the accompanying drawings of the present invention.
- 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 the value of the peak value of the DSC endothermic peak cannot be regarded as absolute. According to the conditions of the instruments used in this experiment, the endothermic peak has an error tolerance of ⁇ 3°.
- the glass transition refers to the transition of an amorphous substance between the high elastic state and the glass state, which is an inherent property of the substance; its corresponding transition temperature is the glass transition temperature (Tg), which is an important part of the amorphous substance Physical properties.
- the glass transition is a phenomenon related to the movement of molecules. Therefore, the glass transition temperature (Tg) mainly depends on the structure of the substance, and is relatively insensitive to experimental details.
- the glass transition temperature (Tg) of the amorphous form of the present invention is measured by differential scanning calorimetry (DSC), and is characterized by having a glass transition temperature of 92.26°C. According to the condition of the instrument used in the experiment of the present invention, the glass transition temperature has an error tolerance of ⁇ 3°C
- Thermogravimetric analysis is a technique for measuring the quality of a substance with temperature changes under program control. It is suitable for checking the loss of solvent in the crystal or the process of sample sublimation and decomposition. It can be inferred that the crystal contains crystal water or crystal solvent. Case.
- the quality change displayed by the TGA curve depends on many factors such as sample preparation and instrument; the quality change of TGA detection varies slightly between different instruments and different samples. According to the condition of the instrument used in this experiment, there is an error tolerance of ⁇ 0.1% for the mass change.
- substantially as shown in the figure means at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95% in the X-ray powder diffraction pattern or DSC pattern, or At least 99% of the peaks are shown in the figure.
- peak refers to a feature that can be identified by those skilled in the art that will not be attributed to background noise.
- room temperature refers to a temperature ranging 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.
- the characteristics of the pharmaceutical composition of the present invention include the amorphous and pharmaceutically acceptable carrier, adjuvant, or excipient of the compound represented by formula (I).
- the amorphous amount of the compound in the pharmaceutical composition of the present invention can effectively and detectably treat or alleviate the disease mediated by FXR in the patient.
- the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable carriers, adjuvants, or excipients, which, like those used in the present invention, include any solvents, diluents, or other Liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for specific target dosage forms.
- pharmaceutically acceptable carriers, adjuvants, or excipients which, like those used in the present invention, include any solvents, diluents, or other Liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc.
- the amorphous form of the present invention can be used as the active ingredient and uniformly combined in the mixture together with the drug carrier according to the conventional drug compounding technology.
- the carrier can be in various forms.
- any conventional pharmaceutical medium can be used, for example, water, glycol, oil, alcohol, fragrance, preservative, etc. can be used when preparing oral liquid medicaments such as suspensions, elixirs and solutions.
- oral solid preparations such as powders, hard capsules, soft capsules and tablets, such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, Disintegrants and the like, among which solid oral preparations are more preferable than liquid medicines.
- tablets and capsules are easy to take, they represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously used. If necessary, the tablets can be coated with standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1% of active ingredient. Of course, the percentage of active ingredients in these compositions can be varied, and the percentage can conveniently vary from about 2% to about 60% of the unit weight.
- the active ingredient can be administered intranasally in the form of, for example, droplets or spray.
- the tablets, pills, capsules, etc. may also contain: binders (such as tragacanth, gum arabic, corn starch or gelatin); excipients (such as dicalcium phosphate); disintegrants (such as corn starch, Potato starch, alginic acid); lubricants (such as magnesium stearate); and sweeteners (such as sucrose, lactose, or saccharin).
- binders such as tragacanth, gum arabic, corn starch or gelatin
- excipients such as dicalcium phosphate
- disintegrants such as corn starch, Potato starch, alginic acid
- lubricants such as magnesium stearate
- sweeteners such as sucrose, lactose, or saccharin
- the dosage unit form may contain a liquid carrier (such as fatty oil) in addition to the above-mentioned types of materials.
- tablets can be coated with shellac, sugar, or both.
- syrups or elixirs may contain sucrose as a sweetener, methyl or propyl parabens as preservatives, dyes and flavoring agents (for example, cherry flavored or orange flavored).
- the scope of the present invention also includes ophthalmic preparations, ophthalmic ointments, powders, solutions and the like.
- the amorphous form of the present invention can also be administered parenterally.
- a solution or suspension of these active substances can be prepared by mixing appropriately with a surfactant (such as hydroxypropyl cellulose) in water.
- a surfactant such as hydroxypropyl cellulose
- glycerin liquid polyethylene glycol and mixtures thereof, and in oil, dispersants can also be prepared. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- compositions suitable for injection use include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions.
- the pharmaceutical form must be sterile and must be fluid in an easily syringable form. It must be stable under the conditions of manufacture and storage and must be preserved under conditions that resist 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 (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
- any suitable method of administration can be used to provide an effective dose of the amorphous form of the present invention to mammals, especially humans.
- oral, rectal, topical, parenteral, intraocular, pulmonary, and nasal administration methods can be used.
- Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, emulsions, ointments, aerosols, and the like.
- the therapeutically effective dose of the amorphous, pharmaceutical composition or combination of the present invention depends on the species, weight, age and individual condition of the individual, the disorder or disease to be treated or its severity. A physician, clinician or veterinarian of ordinary skill can easily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progress of the disorder or disease.
- the compound of the present invention or its amorphous form is used to treat or prevent the disease mediated by FXR of the present invention, at a daily dose of about 0.1 mg to about 100 mg/kg of animal body weight, preferably a single daily dose, Either the compound of the present invention or its amorphous form is administered in divided doses of 2 to 6 times a day, or in the form of continuous release, and substantially satisfactory effects are obtained.
- the total daily dose is about 1.0 mg to about 1000 mg, preferably about 1 mg to about 50 mg.
- the total daily dose is generally 7 mg to about 350 mg. This dosage method can be adjusted to provide the best therapeutic effect.
- the amorphous form of the present invention or the pharmaceutical composition thereof can be effectively used to prevent, treat, treat or alleviate the diseases mediated by FXR in patients, especially to effectively treat 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 damage, gallstones, cirrhosis, hepatitis B, sebaceous gland disease, alcohol-induced cirrhosis, cystic fibrosis, bile duct obstruction, gallstone disease, liver fibrosis, dyslipidemia , Atherosclerosis, type II diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, peripheral tissue arterial obstructive disease (PAOD),
- Figure 1 is an amorphous X-ray powder diffraction (XRPD) pattern of the compound represented by formula (I) prepared according to the method of Example 1 of the present invention.
- XRPD amorphous X-ray powder diffraction
- Fig. 2 is an amorphous differential scanning calorimetry (DSC) chart of the compound represented by formula (I) prepared according to the method of Example 1 of the present invention.
- Figure 3 is a thermogravimetric analysis (TGA) graph of the amorphous form of the compound represented by formula (I) prepared according to the method of Example 1 of the present invention.
- Figure 4 shows the X-ray powder diffraction pattern of the amorphous compound of formula (I) during the stability experiment under high temperature conditions according to the method (1) of Example 3 of the present invention.
- Figure 5 shows the X-ray powder diffraction pattern of the amorphous compound of formula (I) during the stability experiment under high humidity conditions according to the method (2) of Example 3 of the present invention.
- Figure 6 shows the X-ray powder diffraction pattern of the amorphous form of the compound represented by formula (I) during the stability experiment under illumination conditions according to the method (3) of Example 3 of the present invention.
- Figure 7 is an amorphous dynamic moisture adsorption (DVS) diagram 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 powdered sample is prepared into a thin layer on the single crystal silicon sample holder, placed on the rotating sample stage, and analyzed in 0.0167° steps in the range of 3°-60°.
- Use Data Collector software to collect data
- High Score Plus software to process the data
- Data Viewer software to read the data.
- the differential scanning calorimetry (DSC) analysis method used in the present invention is: using a TA Q2000 module with a thermal analysis controller to perform differential scanning calorimetry. Collect data and use TA Instruments Thermal Solutions software for analysis. Approximately 1-5 mg of the 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 of 10°C/min. During use, the DSC cell was purged with dry nitrogen.
- thermogravimetric analysis (TGA) analysis method used in the present invention is: using a TA Q500 module with a thermal analysis controller for thermogravimetric analysis. Collect data and use TA Instruments Thermal Solutions software for analysis. Put about 10-30 mg of the sample into a platinum crucible, and use a linear heating device of 10°C/min to analyze the sample from room temperature to about 300°C. During use, the DSC cell was purged with dry nitrogen.
- the amorphous differential scanning calorimeter prepared by the method of this embodiment is basically as shown in FIG. 2.
- thermogravimetric analysis chart prepared by the method of this embodiment is basically shown in FIG. 3.
- the compound represented by formula (I) of the present invention (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-carboxylic acid) amorphous filled capsules for oral administration.
- Illumination experiment Put an appropriate amount of the test sample into a flat weighing bottle, spread it into a thin layer ⁇ 5mm thick, and place it in an open light box (with ultraviolet) at an illuminance of 4500 ⁇ 500lx, ultraviolet light Place for 30 days under the condition of ⁇ 0.7w/m 2 and take samples on the 5th, 13th, and 30th days to observe the color change of the sample, the purity of the sample is checked by HPLC, and the structure is analyzed by X-ray powder diffraction.
- the X-ray powder diffraction change of the light experiment is basically as follows Shown in Figure 6.
- the experimental results are shown in Figure 7.
- the experimental results prove that the amorphous form of the present invention has a weight gain of less than 2% after equilibrium under the condition of a relative humidity of 80%, which is slightly hygroscopic according to the criterion for the weight gain of hygroscopicity. That is, the amorphous form of the present invention is not easily deliquescence under the influence of high humidity.
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Abstract
涉及含氮三环化合物的无定形及其用途，以及包含所述无定形的药物组合物，所述无定形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
本申请主张如下优先权：
CN 201911201723.7，申请日2019年11月29日。
本发明属于药物技术领域，涉及含氮三环化合物的无定形及其用途，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(式(I)所示化合物)的无定形及其用途，进一步涉及包含所述的无定形的药物组合物。所述的无定形或所述药物组合物用于预防、治疗或减轻患者由FXR介导的疾病。
法尼醇X受体(FXR)是核激素受体超家族中的一员，主要在肝脏、肾脏和肠中表达(Seol等，Mol.Endocrinol(1995),9:72-85；Forman等，Cell(1995),81:687-693)。它以与维甲酸X受体(RXR)形成的异源二聚体的形式发挥作用，与靶基因启动子中的应答元件结合来调节基因转录。FXR-RXR异源二聚体以最高亲合力与反向重复-1(IR-1)应答元件结合，其中结合共有受体(consensus receptor)的六聚物被一个核苷酸分开。FXR可被胆汁酸(胆固醇代谢的终产物)激活(Makishima等Science(1999),284:1362-1365；Parks等Science(1999),284:1365-1368；Wang等,MoI.Cell.(1999),3:543-553)，而胆汁酸用于抑制胆固醇的分解代谢(Urizar等,(2000)J.Biol.Chem.275:39313-393170)。
FXR是胆固醇动态平衡、甘油三酯合成以及脂肪生成的关键调节子(Crawley,Expert Opinion Ther.Patents(2010),20:1047-1057)。除了可作为治疗血脂异常、肥胖、维生素D-相关疾病、肠道疾病、药物导致的副作用以及肝炎的靶点外(Crawley,Expert Opinion Ther.Patents(2010),20:1047-1057)，FXR还可作为肝胆疾病、慢性肝炎、非酒精性脂肪肝(NAFLD)、非酒精性脂肪性肝炎(NASH)、胆汁淤积、肝纤维化、肝硬化、乙型肝炎、代谢性疾病、脂代谢疾病、碳水化合物代谢疾病、心血管代谢疾病、动脉粥样硬化、II型糖尿病和糖尿病并发症的治疗靶点(Frank G.Schaap等，Journal of Medicinal Chemistry(2005),48:5383-5402)。
专利申请WO 2018024224和CN 107686486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)。但该专利申请中并未公开该化合物的具体微观结构。
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，应全面考虑药物的多晶型问题。
无定形是物质多晶型现象中的一种形式，是一种非晶型状态。无定形药物的各种理化性质及临床药效特征常有别于一般的晶型药物。本领域公知水溶性差的药物的生物利用度可通过将其转化为盐或者无定形形式而提高，但是由于许多物质的无定形形式是不稳定的，很少药物以无定形状态被利用，因此药物以稳定的无定形状态被药物利用的研究同样有着重要意义。
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-甲酸的无定形及其药物组合物，所述无定形或药物组合物具有较好的药理性质(例如，良好的药代动力学性质)，并且其稳定性等性质也得到了明显改善，从而具有优良的成药性。
具体而言，本发明涉及式(I)所示化合物的无定形及其药物组合物，以及所述无定形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。本发明所述的无定形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)所示化合物的无定形，
在一些实施方案中，所述无定形具有基本上如图1所示的X射线粉末衍射图。
在一些实施方案中，所述无定形具有92.26℃±3℃的玻璃化转变温度。
在一些实施方案中，所述无定形具有基本上如图2所示的差示扫描量热图。
在一些实施方案中，所述无定形加热到150℃时，其热重分析曲线包含0.409％的重量损失。
在一些实施方案中，所述无定形具有基本上如图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无定形，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)化合物的无定形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无定形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无定形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)化合物的无定形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)所示化合物的无定形的制备方法。
本发明所述的无定形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。
本发明所述的无定形的制备实验将在实施例部分进行详细描述。同时，本发明提供了所述无定形的活性测试实验，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)所示化合物的无定形具有较好的生物活性，且稳定性高，适合制药用途。具体地，本发明所述的无定形具有更优异的药代动力学性质，例如，具有更高的暴露量。
其中，关于引湿性特征描述与引湿性增重的界定(中国药典2015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
本发明所述的无定形不易受高湿度影响而潮解，方便药物的长期贮存放置。
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。
“无定形”或“无定形形式”是指物质的质点(分子、原子、离子)在三维空间排列无周期性时形成的物质，其特征是具有漫射的不具尖峰的X射线粉末衍射图。无定形是固体物质的一种特殊的物理形式，其局部有序的结构特征，提示其与晶型物质有着千丝万缕的联系。物质的无定形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，骤冷法、反溶剂絮凝法、球磨法、喷雾干燥法、冷冻干燥法、湿法制粒法和固体分散体技术等等。
“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。
无定形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)、差示扫描量热法(DSC)、热重分析法(TGA)、核磁共振法、拉曼光谱和扫描电子显微镜(SEM)等等。
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，本发明所述无定形的特征在于具有玻璃态转变的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。
玻璃态转变是指非晶态物质在高弹态和玻璃态之间的转变，是该物质的固有性质；它所对应的转变温度为玻璃化转变温度(Tg)，是非晶态物质的一个重要物理性质。玻璃化转变是与分子运动有关的现象，因而，玻璃化转变温度(Tg)主要取决于物质的结构，而对实验细节等相对不敏感。在一些实施例中，本发明所述无定形的玻璃化转变温度(Tg)通过差示扫描量热法(DSC)测定，其特征在于具有92.26℃的玻璃化转变温度。根据本发明试验所用仪器状况，玻璃化转变温度存在±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。
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。
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。
本发明所述无定形的药物组合物，制剂，给药和用途
本发明的药物组合物的特点包括式(I)所示化合物的无定形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无定形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无定形不相容的范围，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。
本发明所述的无定形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。这样的组合物和制剂应当含有至少0.1％的活性成分。当然，可以改变在这些组合物中的活性成分的百分比，并且该百分比可以方便地在单位重量的约2％～约60％之间变化。可以以例如液滴或者喷雾剂的形式经鼻内给药该活性成分。
所述片剂、药丸、胶囊剂等也可以包含：粘合剂(比如黄蓍树胶、***胶、玉米淀粉或者明胶)；赋形剂(比如磷酸二钙)；崩解剂(比如玉米淀粉、马铃薯淀粉、藻酸)；滑润剂(比如硬脂酸镁)；和甜味剂(比如蔗糖、乳糖或者糖精)。当剂量单位形式是胶囊时，除了上述类型的材料以外，它可以包含液体载体(比如脂肪油)。
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)。
在本发明的范围内还包括眼科制剂、眼用软膏、散剂、溶液等。
本发明所述的无定形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无定形。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。
本发明的无定形、药物组合物或其组合的治疗有效剂量取决于个体的种属、体重、年龄和个体情况、待治疗的障碍或疾病或其严重程度。普通技术的医师、临床医师或兽医能容易地确定每种活性成分预防、治疗所述障碍或疾病或抑制所述障碍或疾病进展所需的有效量。
当使用本发明化合物或其无定形治疗或者预防本发明所述的由FXR介导的病症时，当以约0.1毫克～约100毫克/千克动物体重的每日剂量，优选以单次日剂量、或者以2次到6次每天的分剂量、或者以连续释放的形式施用给药本发明的化合物或其无定形时获得了大致满意的效果。对于大多数大型哺乳动物，总日剂量为约1.0毫克～约1000毫克，优选约1毫克～约50毫克。对于70公斤的成年人，总日剂量一般为7毫克～约350毫克。可以调整这个剂量方法以提供最佳治疗效果。
本发明涉及的无定形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、***功能障碍、胃肠道肿瘤性疾病和肝脏肿瘤性疾病等。
图1为按照本发明实施例1方法制备得到的式(I)所示化合物的无定形的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)所示化合物的无定形的差示扫描量热(DSC)图。
图3为按照本发明实施例1方法制备得到的式(I)所示化合物的无定形的热重分析(TGA)图。
图4显示的是式(I)所示化合物的无定形按照本发明实施例3第(1)个方法进行高温条件下的稳定性实验过程中的X射线粉末衍射变化图。
图5显示的是式(I)所示化合物的无定形按照本发明实施例3第(2)个方法进行高湿条件下的稳定性实验过程中的X射线粉末衍射变化图。
图6显示的是式(I)所示化合物的无定形按照本发明实施例3第(3)个方法进行光照条件下的稳定性实验过程中的X射线粉末衍射变化图。
图7为按照本发明实施例1方法制备得到的式(I)所示化合物的无定形的动态水分吸附(DVS)图。
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。
具体实施方法
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-甲酸的具体合成方法参照专利申请CN 107686486的实施例9。
实施例
实施例1 式(I)化合物的无定形
1.无定形的制备
室温下将化合物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(201.5mg)加入到100mL单口瓶中，然后加入自制的氢氧化钠(133.8mg,3.34mmol)的水(30.0mL)溶液，加热至65℃，待固体完全溶解，降温至40℃；滴入自制的稀盐酸(4.74mmol,15.0mL)溶液，加毕，测pH值在2-3之间，停止加热，自然冷却至室温并搅拌析晶3小时；抽滤，滤饼用水(3.0mL×3)洗涤，60℃真空干燥6小时，得到白色固体(1.41g,92.2％)。
2.无定形的鉴定
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，其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，所述无定形具有92.26℃的玻璃化转变温度，存在±3℃的误差容限。本实施例方法制备得到的无定形的差示扫描量热图基本上如图2所示。
(3)通过TA Q500进行热重分析(TGA)分析鉴定：升温速率为10℃/分钟，失重为0.409％，存在±0.1％的误差容限。本实施例方法制备得到的无定形的热重分析图基本上如图3所示。
实施例2 本发明所述无定形的药代动力学实验
将本发明所述的式(I)所示化合物(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)的无定形灌装胶囊，用于口服给药。
口服给予8-12kg雄性Beagle犬5mg/kg供试样品，每组3只动物。给药后按时间点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软件非房室模型计算药动学参数。实验结果如表1所示。
表1本发明所述无定形的药代动力学实验数据
| 供试样品 | 剂量(mg/kg) | AUC last(h*ng/ml) | C max(ng/ml) | T max(h) |
| 无定形 | 5 | 765 | 268 | 2 |
实验结论：
由表1可知，本发明所述的无定形在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 本发明所述无定形的稳定性实验
(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、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，其高温实验X射线粉末衍射变化基本上如图4所示。
(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、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，其高湿实验X射线粉末衍射变化基本上如图5所示。
(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，X射线粉末衍射分析结构，其光照实验X射线粉末衍射变化基本上如图6所示。
稳定性实验中供试品的外观和化学纯度变化情况如表2所示。
表2无定形的稳定性实验
实验结论：
在高温、高湿和光照条件下，本发明所述无定形的外观、化学纯度和晶型均无明显变化，稳定性效果好，适合制药用途。
实施例4 本发明所述无定形的引湿性实验
取供试品适量，采用动态水分吸附仪测试其引湿性。实验结果如图7所示。实验结果证明，本发明所述的无定形在相对湿度80％的条件下，平衡后增重小于2％，根据引湿性增重的界定标准，属于略有引湿性。即，本发明所述无定形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 (7)
- 式(I)所示化合物的无定形，
其中，所述无定形具有基本上如图1所示的X射线粉末衍射图。 - 式(I)所示化合物的无定形，
其中，所述无定形具有92.26℃±3℃的玻璃化转变温度。 - 根据权利要求2所述的无定形，所述无定形具有基本上如图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1-3任意一项所述的无定形，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1-3任意一项所述的无定形或权利要求4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5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6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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| WO2023061468A1 (zh) | 2021-10-15 | 2023-04-20 | 广东东阳光药业有限公司 | 含氮三环化合物的新晶型及其用途 |
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