WO2021233461A1 - 苯并噻唑类化合物的新晶型及其制备方法 - Google Patents

苯并噻唑类化合物的新晶型及其制备方法 Download PDF

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WO2021233461A1
WO2021233461A1 PCT/CN2021/098056 CN2021098056W WO2021233461A1 WO 2021233461 A1 WO2021233461 A1 WO 2021233461A1 CN 2021098056 W CN2021098056 W CN 2021098056W WO 2021233461 A1 WO2021233461 A1 WO 2021233461A1
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crystal form
solvent
compound
formula
preparation
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French (fr)
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鲁霞
张晓宇
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苏州晶云药物科技股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms

Definitions

  • the invention relates to the field of chemistry and medicine, in particular to a new crystal form of benzothiazole compounds and a preparation method thereof.
  • Farnesoid X receptor is a nuclear receptor encoded by the NR1H4 gene and is expressed at high levels in the liver and intestines. Similar to other nuclear receptors, when activated by chenodeoxycholic acid or other bile acid ligands, FXR will translocate to the nucleus to form dimers, and bind to hormone response elements on DNA, thereby up-regulating or down-regulating certain The expression of these genes.
  • One of the main functions activated by FXR is to inhibit cholesterol 7 ⁇ -hydroxylase (CYP7A1), which is the rate-limiting enzyme in the synthesis of cholesterol from bile acids. FXR does not directly bind to the CYP7A1 promoter.
  • CYP7A1 cholesterol 7 ⁇ -hydroxylase
  • FXR induces the expression of small heterodimer chaperone (SHP), and its function is then to inhibit the transcription of the CYP7A1 gene. In this way, a negative feedback pathway is established in which the synthesis of bile acids is inhibited when the cell level is already high.
  • FXR plays an important role in regulating liver triglyceride levels. Specifically, FXR activation can inhibit adipogenesis and promote free fatty acid oxidation through PPAR ⁇ activation. Studies have also shown that FXR can regulate the expression and activity of epithelial transporters involved in intestinal fluid homeostasis, such as cystic fibrosis transmembrane conductance regulator (CFTR).
  • CFTR cystic fibrosis transmembrane conductance regulator
  • FXR farnesoid X receptor
  • the activation of FXR can inhibit the synthesis of bile acids, increase the binding, transport and excretion of bile acids, thereby protecting the liver from the harmful effects of bile accumulation.
  • Research on FXR agonists is in the field of treatment of cholestasis and non-alcoholic steatohepatitis Research hotspots.
  • Patent WO2012087519A1 discloses the compound of formula (I) and its preparation method.
  • the oily phenomenon occurs during the product separation process.
  • the oily substance has poor fluidity and easily encapsulates impurities, which is not conducive to process control and quality control. It is required in the large-scale production of pharmaceutical products. Try to avoid it.
  • the preparation method has a cumbersome process and requires vacuum drying and repeated dissolution and separation in different solvents to obtain the final product. The introduction of multiple steps will lead to product loss in the post-processing process and reduce the yield.
  • the present invention provides the crystal form A of the compound of formula (I) and its preparation method and application.
  • the crystal form A described in 1 above has characteristic peaks in one or two or three of the 2 ⁇ values of 20.5° ⁇ 0.2°, 21.6° ⁇ 0.2°, 17.5° ⁇ 0.2° by X-ray powder diffraction .
  • the compound of formula (I) is dissolved in a positive solvent, and after filtration, an anti-solvent is added dropwise thereto to obtain crystal form A.
  • the compound of formula (I) is dissolved in the positive solvent, and after filtration, it is quickly added to the anti-solvent to obtain the crystal form A.
  • the compound of formula (I) is dissolved in a volatile solvent, volatilized and crystallized to obtain crystal form A.
  • the compound of formula (I) is dissolved in a positive solvent, and then placed in a sealed environment containing an anti-solvent for osmotic crystallization to obtain crystal form A.
  • a pharmaceutical composition comprising the crystal described in any one of 1 to 3 above and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition having FXR agonistic activity which contains the crystal described in any one of 1 to 3 above as an active ingredient.
  • a prophylactic or therapeutic drug for primary bile diarrhea, primary biliary cholangitis, and/or non-alcoholic steatohepatitis which contains the crystals described in any one of 1 to 3 above as an active ingredient.
  • the crystal form A of the compound of formula (I) provided by the invention has the advantages of solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability and processing performance, purification effect, There are advantages in at least one aspect of preparation production, safety, etc., which provides a new and better choice for the preparation of this novel selective non-bile acid Farnesoid X receptor (FXR) agonist pharmaceutical preparation. Drug development is of great significance.
  • Figure 8 X-ray powder diffraction comparison chart of crystal form A in Example 74 before and after being placed at 25°C/60% relative humidity
  • the compound represented by formula (I) 2-[((1R,5S)-3-][[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazole -4-yl]methoxy]-8-azabicyclo[3.2.1]octane-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid type A crystal, namely The crystal form A is characterized in that Cu-K ⁇ radiation is used, and the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 23.9° ⁇ 0.2°, 16.5° ⁇ 0.2°, and 23.2° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 20.5° ⁇ 0.2°, 21.6° ⁇ 0.2°, 17.5° ⁇ 0.2° at one or two or three places There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 20.5° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 17.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 9.1° ⁇ 0.2°, 12.0° ⁇ 0.2°, 25.4° ⁇ 0.2° at one or two or three locations. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 9.1° ⁇ 0.2°, 12.0° ⁇ 0.2°, and 25.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 23.9° ⁇ 0.2°, 16.5° ⁇ 0.2°, 23.2° ⁇ 0.2°, 20.5° ⁇ 0.2°, 21.6° ⁇ 0.2°, 17.5° ⁇ 0.2°, 9.1° ⁇ 0.2°, 12.0° ⁇ 0.2°, 25.4° ⁇ 0.2°Any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks everywhere.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 23.9° ⁇ 0.2°, 16.5° ⁇ 0.2°, 23.2° ⁇ 0.2°, 20.5° ⁇ 0.2°, 21.6° ⁇ There are characteristic peaks at 0.2°, 17.5° ⁇ 0.2°, 9.1° ⁇ 0.2°, 12.0° ⁇ 0.2°, 25.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A is shown in FIG. 1.
  • the preparation method of the crystal form A is characterized in that the compound of formula (I) is dissolved in a positive solvent, and after filtration, it is quickly added to the anti-solvent to obtain crystal form A, wherein the positive solvent is selected from ketones , Sulfoxides, ethers, halogenated hydrocarbons, amides, the anti-solvent is selected from isopropanol, methyl tert-butyl ether, toluene, n-heptane, water.
  • the positive solvent is selected from ketones , Sulfoxides, ethers, halogenated hydrocarbons, amides
  • the anti-solvent is selected from isopropanol, methyl tert-butyl ether, toluene, n-heptane, water.
  • the ketone solvent is acetone or methyl ethyl ketone
  • the sulfoxide solvent is dimethyl sulfoxide
  • the ether solvent is tetrahydrofuran, 1,4-dioxane.
  • Glycol dimethyl ether the halogenated hydrocarbon solvent is chloroform
  • the amide solvent is dimethylformamide.
  • the anti-solvent addition temperature is 20°C to 30°C.
  • the anti-solvent is added dropwise with stirring after filtration.
  • the stirring temperature is -25°C to 30°C, preferably -20°C to 28°C.
  • stirring is carried out for 1 to 5 days until solids are precipitated, for example, stirring is carried out for 2 days.
  • the above-mentioned stirring temperature is, for example, 22°C to 28°C. If there is no solid precipitation after adding excess anti-solvent, stop adding the anti-solvent, and stir at -25°C to 10°C, preferably -20°C to 5°C, for 1 day to 5 days, for example, 2 days.
  • the method for preparing the crystal form A is characterized in that the compound of formula (I) is dissolved in a positive solvent, and after filtration, it is quickly added to the anti-solvent to obtain crystal form A, wherein the positive solvent is selected from alcohols , Ketones, ethers, halogenated hydrocarbons, the anti-solvent is selected from methyl tert-butyl ether, dibromomethane, n-heptane, isopropanol, ethyl acetate, toluene, m-xylene, cyclohexane, water.
  • the positive solvent is selected from alcohols , Ketones, ethers, halogenated hydrocarbons
  • the anti-solvent is selected from methyl tert-butyl ether, dibromomethane, n-heptane, isopropanol, ethyl acetate, toluene, m-xylene, cyclohexane,
  • the alcohol solvent is ethanol
  • the ketone solvent is acetone
  • N-methylpyrrolidone methyl ethyl ketone
  • the cyclic ether solvent is tetrahydrofuran, ethylene glycol Methyl ether, 1,4-dioxane
  • the halogenated hydrocarbon solvent is chloroform
  • the dissolution temperature is 20°C to 50°C.
  • the stirring temperature is -20°C to 28°C.
  • the method for preparing the crystal form A is characterized in that the compound of formula (I) is dissolved in a volatile solvent at a certain temperature, and then volatilized and crystallized to obtain crystal form A, wherein the volatile solvent is alcohols, ketones, Single solvents or mixtures of nitriles, ethers, halogenated hydrocarbons, esters, amides, acids, alkanes, and aromatics.
  • the volatile solvent is alcohols, ketones, Single solvents or mixtures of nitriles, ethers, halogenated hydrocarbons, esters, amides, acids, alkanes, and aromatics.
  • the alcohol solvent is trifluoroethanol, methanol, ethanol, the ketone solvent is acetone, methyl isobutyl ketone, methyl ethyl ketone, and the nitrile solvent is Acetonitrile, the ether solvent is tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, anisole, cyclopentyl methyl ether, and the halogenated hydrocarbon solvent is chloroform, dichloromethane, chlorine Benzene, the ester solvent is ethyl acetate, methyl acetate, isopropyl acetate, the amide solvent is dimethylformamide, dimethylacetamide, the acidic solvent is acetic acid, and the alkane solvent It is n-heptane and cyclohexane, and the aromatic hydrocarbon solvent is m-xylene.
  • the ether solvent is tetrahydrofuran, 1,4-dioxane
  • the dissolution and volatilization temperature is 0°C to 60°C, preferably 5°C to 50°C.
  • the method for preparing the crystal form A is characterized in that the compound of formula (I) is dissolved in a positive solvent, and then placed in a sealed environment containing an anti-solvent, and osmosis crystallizes to obtain the crystal form A.
  • the normal solvent is selected from tetrahydrofuran, 1,4-dioxane, methyl ethyl ketone, dimethyl sulfoxide, and the anti-solvent is selected from n-hexane, isopropanol, water.
  • the dissolution and permeation temperature is 20°C to 30°C.
  • the compound of formula (I) as a raw material refers to its solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound as a raw material is in the form of a solid powder.
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, at a stirring speed of 50 to 1800 revolutions per minute, wherein the magnetic stirring is 200 to 1500 revolutions per minute, preferably 300 to 1000 revolutions. Per minute, mechanical stirring is preferably 100 to 300 revolutions per minute.
  • crystalline or “polymorphic form” refers to what is confirmed by the characterization of the X-ray diffraction pattern shown.
  • the physical and chemical properties discussed here can be characterized, and the experimental error depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern usually changes with the conditions of the instrument.
  • the relative intensity of the X-ray diffraction pattern may also change with changes in experimental conditions, so the order of peak intensities cannot be used as the only or decisive factor.
  • the relative intensity of the diffraction peaks in the XRPD spectrum is related to the preferred orientation of the crystal.
  • the peak intensities shown in this article are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and the error of ⁇ 0.2° is usually allowed.
  • the overall peak angle will be shifted, and a certain shift is usually allowed.
  • the X-ray diffraction pattern of a crystal form in the present invention does not have to be exactly the same as the X-ray diffraction pattern in the example referred to here, and the "XRPD pattern is the same" as used herein does not mean absolutely the same.
  • the same peak position can differ by ⁇ 0.2° and the peak intensity allows certain variability. Any crystal form having a pattern identical or similar to the characteristic peaks in these patterns falls within the scope of the present invention.
  • Those skilled in the art can compare the spectrum listed in the present invention with a spectrum of an unknown crystal form to confirm whether the two sets of maps reflect the same or different crystal forms.
  • the crystal form A of the present invention is pure and single, and substantially no other crystal forms are mixed.
  • substantially no when used to refer to a new crystal form means that this crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less. Other crystal forms that are less than 5% by weight, and even other crystal forms that are less than 1% by weight.
  • room temperature usually means 22-28°C unless otherwise specified.
  • PSD particle size distribution
  • the X-ray powder diffraction pattern of the present invention is collected on a PANalytacal X’Pert 3-ray powder diffractometer.
  • the parameters of the X-ray powder diffraction method of the present invention are as follows:
  • the differential scanning calorimetry (DSC) chart of the present invention is collected on TA Discovery Q2500.
  • the method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:
  • thermogravimetric analysis chart of the present invention is collected on the Discovery TGA 5500 and Q5000 thermogravimetric analyzers of TA Company.
  • the method parameters of the thermogravimetric analysis of the present invention are as follows:
  • the dynamic moisture adsorption map of the present invention is collected on the Intrinsic and Intrinsic Plus dynamic moisture adsorption instruments of SMS Company.
  • the method parameters of the dynamic moisture adsorption test described in the present invention are as follows:
  • Relative humidity gradient 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)
  • the particle size distribution results described in the present invention are collected on the S3500 laser particle size analyzer of Microtrac Company.
  • Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system.
  • SDC Sample Delivery Controller
  • This test uses the wet method, and the test dispersion medium is Isopar G (containing 0.2% lecithin).
  • the method parameters of the laser particle size analyzer are as follows:
  • Particle size distribution volume distribution Acquisition time: 10 seconds
  • the inherent dissolution rate data described in the present invention is collected on the Agilent 708DS dissolution apparatus of Agilent Company.
  • the inherent dissolution test conditions are as follows:
  • the polarizing microscope photos described in the present invention are collected by Zeiss microscope Axio Scope. A1 at room temperature, and the microscope is equipped with Axiocam 305 color camera and 5 ⁇ , 10 ⁇ , 20 ⁇ and 50 ⁇ objective lenses.
  • the starting material of the compound of formula (I) used in the following examples can be prepared according to the prior art, for example, according to the method described therein, but the starting crystal form is not a limiting condition for the preparation of the crystal form of the present invention.
  • the sample is at about 9.1° ⁇ 0.2°, about 11.1° ⁇ 0.2°, about 12.0° ⁇ 0.2°, about 14.7° ⁇ 0.2°, about 16.5° ⁇ 0.2°, about 17.5° ⁇ 0.2°, about 20.5° ⁇ 0.2 °, about 21.6° ⁇ 0.2°, about 23.2° ⁇ 0.2°, about 23.9° ⁇ 0.2°, about 25.4° ⁇ 0.2°, there are characteristic peaks, the X-ray powder diffraction data are shown in Table 1, and the XRPD pattern is As shown in Figure 1.
  • Examples 3-9 Dissolve about 15 mg of the compound of formula (I) in an appropriate volume of positive solvent at room temperature to obtain a clear solution, then slowly add 10 ml of the corresponding anti-solvent under magnetic stirring, and then place the samples in sequence After standing at 5°C and -20°C, no solid was precipitated, and then the solution was volatilized at room temperature to obtain the crystal form A of the compound of formula (I).
  • Examples 10-15 Dissolve about 15 mg of the compound of formula (I) in an appropriate volume of normal solvent at room temperature to obtain a clear solution, and then slowly add n-heptane to perform an anti-solvent addition test. It is observed that solids are precipitated. Form A of the compound of formula (I).
  • Examples 16-18 At room temperature, about 15 mg of the compound of formula (I) was dissolved in an appropriate volume of positive solvent to obtain a clear solution. Under magnetic stirring, the solution was added to 10 ml of methyl tert-butyl ether Or m-xylene. The sample was placed at 5° C. and -20° C. and allowed to stand still, and then the sample was volatilized openly at room temperature to obtain the crystal form A of the compound of formula (I).
  • Examples 19 and 20 At room temperature, about 15 mg of the compound of formula (I) was dissolved in an appropriate volume of a positive solvent to obtain a clear solution. Under magnetic stirring, the solution was added to 10 ml of cyclohexane. After that, the sample was placed at 5° C. to stand still, and a solid precipitated, and the crystal form A of the compound of formula (I) was obtained.
  • Example 21 Dissolve about 15 mg of the compound of formula (I) in an appropriate volume of N-methylpyrrolidone to obtain a clear solution. Under magnetic stirring, the solution was added to 10 ml of purified water. A solid was observed to precipitate, and the crystal form A of the compound of formula (I) was obtained.
  • Table 4 shows the quality of the compound of formula (I), the type and volume of the positive solvent and the anti-solvent added, and the test results in the above test. Taking Example 17 as an example, its sample X-ray powder diffraction data is shown in Table 5, and its XRPD pattern is shown in Figure 4.
  • Example 68 a solid precipitated, and the crystal form A of the compound of formula (I) was obtained. The remaining samples were still dissolved, and the clear sample was placed at -20°C to stand still, and no solid was found to precipitate. After that, the clear solution was volatilized in the open at room temperature to obtain the crystal form A of the compound of formula (I). Taking Example 63 as an example, its X-ray powder diffraction data are shown in Table 18.
  • Example 1 The method of Example 1 was used to prepare the crystal form A of the present invention and the prior art disclosed solid SGF (simulated artificial gastric fluid), FaSSIF (artificial intestinal fluid under fasting state) and FeSSIF (artificial intestinal fluid under fed state) were prepared into suspensions. After 1 hour, 2 hours, 4 hours and 24 hours of equilibrium, filter to obtain a saturated solution. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). It can be seen from the results that the crystal form A of the present invention has higher solubility in SGF, FaSSIF, FeSSIF and pure water, which is higher than that of the solid disclosed in the prior art.
  • HPLC high performance liquid chromatography
  • Example 1 Use a manual tablet press for tableting. When tableting, choose a round flat punch that can be compressed into a cylindrical tablet, and add a certain amount of it.
  • the method of Example 1 is used to prepare the crystal form A of the present invention and the solid disclosed in the prior art.
  • Use 10kN pressure to compress into round tablets place them in a desiccator for 24 hours, and use a tablet hardness tester to test the radial crushing force (hardness, H) after fully elastic recovery.
  • the results show that the crystal form of the present invention has greater tensile strength and better compressibility than the solid disclosed in the prior art.
  • Example 75 Comparative study on hygroscopicity
  • moisture-absorbing weight gain is not less than 15%
  • moisture absorption weight gain is less than 15% but not less than 2%
  • weight gain is less than 2% but not less than 0.2%
  • Example 76 Comparative study of crystal habits
  • Example 77 Comparative study on particle size distribution
  • the crystal form A of the present invention prepared by the method of Example 1 and the solid disclosed in the prior art, then add about 5 ml of Isopar G (containing 0.2% lecithin), mix the sample to be tested thoroughly and add it In the SDC sampling system, make the shading degree reach the appropriate range, start the experiment, and perform the particle size distribution test after 30 seconds of ultrasound.
  • the crystal form A of the present invention has a more uniform particle size distribution.

Abstract

本发明涉及苯并噻唑类化合物的新晶型及其制备方法。本发明提供了式(I)化合物的晶型A及其制备方法和用途。本发明提供的式(I)化合物晶型A，在溶解度、熔点、稳定性、溶出度、引湿性、黏附性、流动性、生物有效性以及加工性能、提纯作用、制剂生产、安全性等方面中的至少一方面上存在优势，为含式(I)化合物的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。

Description

苯并噻唑类化合物的新晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及苯并噻唑类化合物的新晶型及其制备方法。
背景技术
法尼醇X受体(FXR)是由NR1H4基因编码的核受体，在肝和肠中高水平表达。与其他核受体类似，当被鹅去氧胆酸或其他胆汁酸配体激活后，FXR会易位到细胞核，形成二聚体，并与DNA上的激素反应元件结合，从而上调或下调某些基因的表达。FXR激活的主要功能之一是抑制胆固醇7α-羟化酶(CYP7A1)，这是胆固醇从胆汁酸合成中的限速酶。FXR不直接与CYP7A1启动子结合。而是，FXR诱导小异二聚体伴侣(SHP)的表达，然后其功能是抑制CYP7A1基因的转录。以这种方式，建立了负反馈途径，其中当细胞水平已经很高时，胆汁酸的合成被抑制。此外，FXR在调节肝甘油三酯水平方面发挥重要作用。具体的，FXR激活可抑制脂肪生成，并通过PPARα激活促进游离脂肪酸氧化。研究还表明，FXR可以调节肠液动态平衡中涉及的上皮转运蛋白的表达和活性，例如囊性纤维化跨膜电导调节剂(CFTR)。
FXR的激活可抑制胆汁酸的合成，增加胆汁酸的结合、转运和排泄，从而保护肝脏免受胆汁积累的有害影响，针对FXR激动剂的研究是胆汁淤积和非酒精性脂肪性肝炎治疗领域的研究热点。
2-[((1R，5S)-3-][[5-环丙基-3-[2-(三氟甲氧基)苯基]-1,2-恶唑-4-基]甲氧基]-8-氮杂双环[3.2.1]辛烷-8-基]-4-氟-1,3-苯并噻唑-6-羧酸是一种新型、高效的FXR激动剂，用于治疗原发性胆汁腹泻、原发性胆汁胆管炎以及非酒精性脂肪性肝炎等，目前处于临床II期研究中，初步结果显示具有积极的疗效，其结构式如下所示：
Figure PCTCN2021098056-appb-000001
专利WO2012087519A1中公开了式(I)化合物及其制备方法，产物分离过程中出现成油现象，油状物流动性差，易包裹杂质，不利于于工艺控制与质量控制，是药物产品大规模生产中需要极力避免的。此外，该制备方法流程繁琐，需要经过真空干燥，在不同溶剂中反复多次的溶解分离，获得终产物。多个步骤的引入，会导致产品在后处理过程中的损耗，降低收率。同时，复杂的后处理过程需要使用大量有机溶剂(包括对生物体具有较大毒性，存在较大环境风险的2类溶剂)，增加工艺成本，也存在较大的环境风险，有必要开展该化合物的结晶条件研究，通过寻找满足大规模工业生产要求的晶型，为式(I)化合物的分离纯化提供更优的解决方案。
此外，同一药物的不同晶型在溶解度、熔点、密度、稳定性等方面有显著的差异，从而不同程度地影响药物的稳定性、均一性、生物利用度、疗效和安全性。因此，药物研发 中进行全面系统的多晶型筛选，选择最适合开发的晶型和方法，是不可忽视的重要研究内容之一。
发明内容
本发明提供了式(I)化合物的晶型A及其制备方法和用途。
1.式(I)所示化合物2-[((1R，5S)-3-][[5-环丙基-3-[2-(三氟甲氧基)苯基]-1,2-恶唑-4-基]甲氧基]-8-氮杂双环[3.2.1]辛烷-8-基]-4-氟-1,3-苯并噻唑-6-羧酸的A型晶体、即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为23.9°±0.2°,16.5°±0.2°,23.2°±0.2°处有特征峰，
Figure PCTCN2021098056-appb-000002
2.上述1所述的晶型A，其X射线粉末衍射在2θ值为20.5°±0.2°,21.6°±0.2°,17.5°±0.2°中的一处或两处或三处有特征峰。
3.根据上述1或2中任意一项所述的晶型A，其X射线粉末衍射在2θ值为20.5°±0.2°,21.6°±0.2°,17.5°±0.2°处有特征峰。
4.权利要求1～3中任意一项所述的晶型A的制备方法，其特征在于，
Figure PCTCN2021098056-appb-000003
将式(I)化合物溶解于正溶剂中，过滤后向其中逐滴加入反溶剂，得到晶型A。
5.上述1～3中任意一项所述的晶型A的制备方法，其特征在于，
Figure PCTCN2021098056-appb-000004
将式(I)化合物溶解于正溶剂中，过滤后将其快速加入反溶剂中，得到晶型A。
6.上述1～3中任意一项所述的晶型A的制备方法，其特征在于，
Figure PCTCN2021098056-appb-000005
一定温度下将式(I)化合物溶解于挥发性溶剂中，挥发析晶，得到晶型A。
7.上述1～3中任意一项所述的晶型A的制备方法，其特征在于，
Figure PCTCN2021098056-appb-000006
将式(I)化合物溶于正溶剂中，然后置于含有反溶剂的密封环境中，渗透析晶，得到晶型A。
8.药物组合物，其包含上述1～3中任一项所述的晶体和制药学可接受的载体。
9.具有FXR激动活性的药物组合物，其含有上述1～3中任一项所述的晶体作为有效成分。
10.原发性胆汁腹泻、原发性胆汁胆管炎和/或非酒精性脂肪性肝炎的预防药或治疗药，其含有上述1～3中任一项所述的晶体作为有效成分。
与现有技术相比，发明提供的式(I)化合物的晶型A，在溶解度、熔点、稳定性、溶出度、引湿性、黏附性、流动性、生物有效性以及加工性能、提纯作用、制剂生产、安全性等方面中的至少一方面上存在优势，为这种新型的选择性非胆汁酸Farnesoid X受体(FXR)激动剂的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。
附图说明
图1实施例1中所得晶型A的X射线粉末衍射图
图2实施例2中所得晶型A的热重分析图
图3实施例2中所得晶型A的差式扫描量热图
图4实施例17中所得晶型A的X射线粉末衍射图
图5实施例31中所得晶型A的X射线粉末衍射图
图6实施例45中所得晶型A的X射线粉末衍射图
图7实施例71中晶型A溶解度测试后X射线粉末衍射对比图
图8实施例74中晶型A在25℃/60％相对湿度放置前后X射线粉末衍射对比图
图9实施例74中晶型A在40℃/75％相对湿度放置前后X射线粉末衍射对比图
图10实施例75中晶型A的动态水分吸附脱附图
图11实施例75中晶型A在动态水分吸附脱附实验前后的X射线粉末衍射对比图
具体实施方式
式(I)所示化合物2-[((1R，5S)-3-][[5-环丙基-3-[2-(三氟甲氧基)苯基]-1,2-恶唑-4-基]甲氧基]-8-氮杂双环[3.2.1]辛烷-8-基]-4-氟-1,3-苯并噻唑-6-羧酸的A型晶体，即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为23.9°±0.2°,16.5°±0.2°,23.2°±0.2°处有特征峰，
Figure PCTCN2021098056-appb-000007
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为20.5°±0.2°,21.6°±0.2°,17.5°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为20.5°±0.2°,21.6°±0.2°,17.5°±0.2°处有特征峰。
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为9.1°±0.2°,12.0°±0.2°,25.4°±0.2°中的一处或两处或三处有特征峰。
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为9.1°±0.2°,12.0°±0.2°,25.4°±0.2°处有特征峰。
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为23.9°±0.2°,16.5°±0.2°,23.2°±0.2°,20.5°±0.2°,21.6°±0.2°,17.5°±0.2°,9.1°±0.2°,12.0°±0.2°,25.4°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为23.9°±0.2°,16.5°±0.2°,23.2°±0.2°,20.5°±0.2°,21.6°±0.2°,17.5°±0.2°,9.1°±0.2°,12.0°±0.2°,25.4°±0.2°处有特征峰。
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射图如图1所示。
所述晶型A的制备方法，其特征在于，将式(I)化合物溶解于正溶剂中，过滤后将其快速加入反溶剂中，得到晶型A，其中，所述正溶剂选自酮类、亚砜、醚类、卤代烃、酰胺类，所述反溶剂选自异丙醇、甲基叔丁基醚、甲苯、正庚烷、水。
在本发明的一个实施方式中，所述酮类溶剂为丙酮、甲基乙基酮，所述亚砜溶剂为二甲亚砜，所述醚类溶剂为四氢呋喃、1,4-二氧六环、乙二醇二甲醚，所述卤代烃溶剂为氯仿，所述酰胺类溶剂为二甲基甲酰胺。
在本发明的一个实施方式中，所述反溶剂添加温度为20℃到30℃。
在本发明的一个实施方式中，过滤后在搅拌下逐滴加入反溶剂。
在本发明的一个实施方式中，搅拌温度为-25℃至30℃，优选-20℃到28℃。
在本发明的一个实施方式中，搅拌1天到5天至有固体析出，例如搅拌2天。
当滴加反溶剂后有固体析出时，则离心分离所得固体，此时上述搅拌温度例如为22℃到28℃。如果加入过量反溶剂后无固体析出，则停止滴加反溶剂，在-25℃到10℃，优选-20℃到5℃，搅拌进行1天到5天，例如为2天。
所述晶型A的制备方法，其特征在于，将式(I)化合物溶解于正溶剂中，过滤后将其快速加入反溶剂中，得到晶型A，其中，所述正溶剂选自醇类、酮类、醚类、卤代烃，所述的反溶剂选自甲基叔丁基醚、二溴甲烷、正庚烷、异丙醇、乙酸乙酯、甲苯、间二甲苯、环己烷、水。
在本发明的一个实施方式中，所述醇类溶剂为乙醇，所述酮类溶剂为丙酮、N-甲基吡咯烷酮、甲基乙基酮，所述环醚类溶剂为四氢呋喃、乙二醇二甲醚、1,4-二氧六环，所述卤代烃溶剂为氯仿。
在本发明的一个实施方式中，所述溶解温度为20℃至50℃。
在本发明的一个实施方式中，过滤后在搅拌下快速加入反溶剂中。
在本发明的一个实施方式中，搅拌温度为-20℃到28℃。
在本发明的一个实施方式中，搅拌至有固体析出。
如果将正溶剂加入至反溶剂后无固体析出，则在-25℃到-10℃，优选-20℃到-15℃、例如为-20℃下进行搅拌，搅拌进行1天到5天，例如为2天。
所述晶型A的制备方法，其特征在于，一定温度下将式(I)化合物溶解于挥发性溶剂中，挥发析晶，得到晶型A，其中，挥发性溶剂为醇类、酮类、腈类、醚类、卤代烃类、酯类、酰胺类、酸、烷烃、芳烃的单一溶剂或混合物。
在本发明的一个实施方式中，所述醇类溶剂为三氟乙醇、甲醇、乙醇，所述酮类溶剂为丙酮、甲基异丁基酮、甲基乙基酮，所述腈类溶剂为乙腈，所述醚类溶剂为四氢呋喃、1,4-二氧六环、乙二醇二甲醚、苯甲醚、环戊基甲醚，所述卤代烃溶剂为氯仿、二氯甲烷、氯苯，所述酯类溶剂为乙酸乙酯、乙酸甲酯、乙酸异丙酯，所述酰胺类溶剂为二甲基甲酰胺、二甲基乙酰胺，所述酸性溶剂为乙酸，所述烷烃溶剂为正庚烷、环己烷，所述芳烃溶剂为间二甲苯。
在本发明的一个实施方式中，所述溶解与挥发温度为0℃至60℃，优选5℃至50℃。
所述晶型A的制备方法，其特征在于，将式(I)化合物溶于正溶剂中，然后置于含有反溶剂的密封环境中，渗透析晶，得到晶型A。
在本发明的一个实施方式中，所述正溶剂选自四氢呋喃、1,4-二氧六环、甲基乙基酮、二甲亚砜，所述反溶剂选自正己烷、异丙醇、水。
在本发明的一个实施方式中，所述溶解与渗透温度为20℃至30℃。
根据本发明，作为原料的所述式(I)化合物指其固体(晶体或无定形)、半固体、蜡或油形式。优选地，作为原料的化合物为固体粉末形式。所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50～1800转/分钟，其中，其中，磁力搅拌200～1500转/分钟，优选为300～1000转/分钟，机械搅拌优选为100～300转/分钟。
本发明中，“晶体”或“多晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、 样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品厚度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型A是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
本发明说明书中记载的数值范围的上限值和下限值可以任意地组合。
实施例
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
本发明中“室温”如无特别说明，通常是指22～28℃。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
1H NMR：核磁共振氢谱
DVS：动态水分吸附
PSD：粒径分布
PLM：偏光显微镜
HPLC：高效液相色谱
本发明所述的X射线粉末衍射图在PANalytacal X’Pert3射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Kα1
Figure PCTCN2021098056-appb-000008
1.540598；Kα2
Figure PCTCN2021098056-appb-000009
1.544426
Kα2/Kα1强度比例：0.50
电压：45千伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度(2θ角)
本发明所述的差示扫描量热分析(DSC)图在TA Discovery Q2500上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：N 2
本发明所述的热重分析图在TA公司的Discovery TGA 5500型及Q5000型热重分析仪上采集。本发明所述的热重分析的方法参数如下：
扫描速率：10℃/分钟
保护气体：氮气
本发明所述的动态水分吸附图在SMS公司的Intrinsic型及Intrinsic Plus型动态水分吸附仪上采集。本发明所述的动态水分吸附测试的方法参数如下：
温度：25℃
保护气体及流量：N 2，200毫升/分钟
dm/dt：0.002％/分钟
最小dm/dt平衡时间：10分钟
最大平衡时间：180分钟
相对湿度范围：0％RH-95％RH-0％RH
相对湿度梯度：10％(0％RH-90％RH-0％RH)、5％(90％RH-95％RH和95％RH-90％RH)
本发明中所述的粒径分布结果是在Microtrac公司的S3500型激光粒度分析仪上采集。Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。本测试采用湿法，测试分散介质为Isopar G(含0.2％卵磷脂)。所述的激光粒度分析仪的方法参数如下：
粒度分布：体积分布 采集时间：10秒
分散介质：Isopar G 粒度坐标：标准
采集次数：3次 分散介质折射率：1.42
透明度：透明 残差：启用
颗粒折射率：1.59 流速：60％*
颗粒形状：不规则 过滤：启用
超声功率：30瓦 超声时间：超声30秒
*：流速60％为65毫升/s的60％
本发明中所述的固有溶出速率数据是在Agilent公司的Agilent 708DS型溶出仪上采集。所述的固有溶出测试条件如下：
溶出仪 Agilent 708DS
方法 浆法
介质 pH 6.8磷酸盐缓冲液
介质体积 900毫升
转速 100转/分
介质温度 37℃
取样点 1,2,3,4,5,10,15,20,25,30分钟
补充介质 No
本发明中所述的偏光显微镜照片是通过蔡司显微镜Axio Scope.A1在室温条件下采集，显微镜配备Axiocam 305彩色相机以及5×、10×、20×和50×物镜。
下述实施例中所使用的式(I)化合物起始物可根据现有技术制备得到，例如根据中所记载的方法制备获得，但起始晶型并非制备本发明晶型的限定条件。
实施例1：晶型A的制备
室温条件下将15.1毫克式(I)化合物溶解于1毫升的甲基乙基酮中，得到澄清溶液，之后在磁力搅拌下缓慢添加10毫升甲苯进行反溶剂添加，之后将样品依次置于5℃和-20℃静置，无固体析出，之后将溶液室温下敞口挥发，得到式(I)化合物晶型A。该样品在约9.1°±0.2°、约11.1°±0.2°、约12.0°±0.2°、约14.7°±0.2°、约16.5°±0.2°、约17.5°±0.2°、约20.5°±0.2°、约21.6°±0.2°、约23.2°±0.2°、约23.9°±0.2°、约25.4°±0.2°处有特征峰，其X射线粉末衍射数据如表1所示，其XRPD图如图1所示。
表1
衍射角2θ d值 强度％
9.07 9.75 23.87
9.98 8.86 7.80
11.07 7.99 14.29
12.00 7.38 18.47
12.56 7.05 15.68
14.47 6.12 26.21
14.66 6.04 16.68
14.98 5.92 20.02
15.65 5.66 31.36
16.46 5.39 100.00
17.47 5.08 76.94
17.66 5.02 60.09
18.23 4.87 27.73
18.91 4.69 7.84
19.62 4.53 8.23
20.00 4.44 13.50
20.48 4.34 60.80
20.85 4.26 27.38
衍射角2θ d值 强度％
21.60 4.11 36.28
22.62 3.93 9.62
23.13 3.85 58.36
23.84 3.73 97.83
25.33 3.52 33.14
26.15 3.41 25.46
26.59 3.35 7.24
28.29 3.15 9.81
28.78 3.10 14.63
29.35 3.04 12.36
30.37 2.94 7.85
31.96 2.80 3.80
32.32 2.77 5.97
33.31 2.69 6.58
35.79 2.51 2.11
36.51 2.46 2.16
实施例2：晶型A的制备
将14.6毫克式(I)化合物加入0.5毫升苯甲醚/乙酸乙酯中，50℃下搅拌2小时，之后用0.45微米的聚四氟乙烯滤膜过滤，得到澄清滤液，之后将该滤液置于室温下挥发，得到式(I)化合物晶型A。其X射线粉末衍射数据如表2所示。晶型A的TGA如图2所示，晶型A的DSC如图3所示。
表2
衍射角2θ d值 强度％
9.09 9.73 11.00
9.99 8.85 12.69
11.03 8.02 4.72
12.01 7.37 22.49
12.60 7.03 27.52
14.70 6.03 21.69
15.66 5.66 18.82
16.47 5.38 77.79
17.47 5.08 27.19
17.66 5.02 44.03
18.25 4.86 11.73
衍射角2θ d值 强度％
19.64 4.52 9.46
20.50 4.33 62.00
20.84 4.26 35.83
21.62 4.11 18.61
23.15 3.84 60.24
23.86 3.73 100.00
25.36 3.51 70.85
25.79 3.45 33.52
26.17 3.41 34.70
28.32 3.15 8.91
28.81 3.10 8.54
29.38 3.04 25.33
30.39 2.94 8.64
32.11 2.79 3.03
33.36 2.69 6.56
实施例3～15：晶型A的制备(反溶剂添加法)
实施例3～9：室温条件下将约15毫克式(I)化合物溶解于适量体积的正溶剂中，得到澄清溶液，之后在磁力搅拌下缓慢添加10毫升相应反溶剂，之后将样品依次置于5℃和-20℃静置，无固体析出，之后将溶液室温下敞口挥发，得到式(I)化合物晶型A。
实施例10～15：室温条件下将约15毫克式(I)化合物溶解于适量体积的正溶剂中，得到澄清溶液，之后缓慢添加正庚烷进行反溶剂添加试验，观察到有固体析出，得到式(I)化合物晶型A。
上述实施例中加入的式(I)化合物质量、正溶剂和对应的反溶剂的种类和体积以及试验结果等见表3。
表3
Figure PCTCN2021098056-appb-000010
Figure PCTCN2021098056-appb-000011
实施例16～21：晶型A的制备(反向反溶剂添加法)
实施例16～18：室温条件下，将约15毫克式(I)化合物溶解于适量体积的正溶剂中，得到澄清溶液，在磁力搅拌下，将该溶液加入至10毫升甲基叔丁基醚或间二甲苯中。将该样品依次置于5℃和-20℃静置，之后将样品室温下敞口挥发，得到式(I)化合物晶型A。
实施例19、20：室温条件下，将约15毫克式(I)化合物溶解于适量体积的正溶剂中，得到澄清溶液，磁力搅拌下，将该溶液加入至10毫升环己烷中。之后将该样品置于5℃静置，有固体析出，得到式(I)化合物晶型A。
实施例21：将约15毫克式(I)化合物溶解于适量体积的N-甲基吡咯烷酮中，得到澄清溶液，磁力搅拌下，将该溶液加入至10毫升纯化水中。观察到有固体析出，得到式(I)化合物晶型A。
上述试验中的式(I)化合物质量、加入的正溶剂和反溶剂的种类和体积、以及试验结果见表4。以实施例17为例，其样品X射线粉末衍射数据如表5所示，其XRPD图如图4所示。
表4
Figure PCTCN2021098056-appb-000012
表5
衍射角2θ d值 强度％
5.75 15.36 6.77
9.09 9.73 26.98
10.04 8.81 11.86
11.10 7.97 16.48
12.01 7.37 23.16
12.60 7.03 15.89
14.52 6.10 35.82
14.69 6.03 33.58
14.99 5.91 22.22
15.67 5.65 31.64
16.48 5.38 85.56
17.01 5.21 10.02
17.47 5.08 70.70
17.67 5.02 32.06
18.25 4.86 25.38
18.91 4.69 7.66
19.65 4.52 8.71
20.01 4.44 8.37
20.49 4.33 37.32
20.88 4.25 27.36
21.67 4.10 34.60
22.64 3.93 10.53
23.16 3.84 49.55
23.87 3.73 100.00
24.71 3.60 6.40
24.96 3.57 6.28
25.36 3.51 25.48
26.17 3.41 21.90
26.60 3.35 8.29
27.49 3.24 3.81
28.30 3.15 6.21
28.82 3.10 11.60
29.38 3.04 8.55
30.41 2.94 9.13
31.99 2.80 4.03
衍射角2θ d值 强度％
33.34 2.69 4.31
34.86 2.57 1.43
35.84 2.51 2.37
36.55 2.46 2.76
37.59 2.39 2.22
实施例22～27：晶型A的制备(缓慢降温-挥发试验)
在50℃下，将约15毫克式(I)化合物溶解于适量体积的正溶剂中，采用0.45微米聚四氟乙烯膜过滤得到澄清溶液，之后将该溶液在静置状态下以0.1℃/min的速度降温至5℃，之后在5℃条件下放置约2天。样品依旧溶清，之后将该样品室温下敞口挥发，得到式(I)化合物晶型A。加入的式(I)化合物质量和对应的正溶剂的体积见表6。
表6
Figure PCTCN2021098056-appb-000013
实施例28～35：晶型A的制备(快速降温-挥发试验)
在50℃下，溶解约15毫克式(I)化合物于适量体积溶剂中，采用0.45微米聚四氟乙烯膜过滤得到澄清溶液，之后将该溶液迅速放入-20℃的环境中静置。约2天后样品依旧溶清，之后将该澄清样品室温下敞口挥发，得到式(I)化合物晶型A。加入的式(I)化合物质量和对应的正溶剂的体积见表7。以实施例31为例，样品的X射线粉末衍射数据如表8所示，其XRPD图如图5所示。
表7
Figure PCTCN2021098056-appb-000014
Figure PCTCN2021098056-appb-000015
表8
衍射角2θ d值 强度％
9.08 9.74 21.95
9.97 8.87 13.16
11.01 8.04 29.11
11.99 7.38 20.75
12.56 7.05 16.72
14.44 6.13 39.39
14.62 6.06 23.54
14.98 5.91 21.82
15.63 5.67 19.54
16.47 5.38 94.93
16.91 5.24 18.59
17.47 5.08 65.40
17.62 5.03 44.68
18.22 4.87 25.99
19.62 4.52 12.68
20.00 4.44 12.92
20.42 4.35 44.59
20.85 4.26 39.71
21.54 4.12 45.19
22.05 4.03 7.17
22.59 3.94 9.24
23.07 3.86 73.40
23.82 3.74 100.00
24.76 3.60 10.46
衍射角2θ d值 强度％
25.33 3.52 31.19
26.07 3.42 23.27
26.61 3.35 14.95
27.35 3.26 7.68
28.29 3.15 12.53
28.70 3.11 15.62
29.39 3.04 9.92
30.35 2.95 10.86
31.86 2.81 4.16
32.37 2.77 5.45
33.32 2.69 5.79
实施例35～38：晶型A的制备(气液扩散试验)
室温条件下，将约15毫克式(I)化合物溶解在适量体积的正溶剂中，采用0.45微米聚四氟乙烯膜过滤得到澄清溶液，之后将该溶液置于4毫升反溶剂的封闭环境中静置。约2周后观察到有固体析出，得到式(I)化合物晶型A。加入的式(I)化合物质量和对应的正反溶剂的种类和体积见表9。以实施例37为例，其样品的X射线粉末衍射数据如表10所示。
表9
Figure PCTCN2021098056-appb-000016
表10
衍射角2θ d值 强度％
5.71 15.48 5.35
9.09 9.73 14.13
9.99 8.85 2.64
11.10 7.97 23.95
12.00 7.38 14.88
12.64 7.00 37.29
14.48 6.12 16.87
衍射角2θ d值 强度％
14.70 6.03 25.41
15.01 5.90 9.23
15.67 5.66 9.71
16.49 5.38 42.90
16.98 5.22 4.67
17.47 5.08 100.00
17.68 5.02 34.24
18.25 4.86 24.23
18.86 4.71 12.15
19.18 4.63 6.97
19.63 4.52 7.22
20.01 4.44 4.85
20.50 4.33 31.44
20.89 4.25 15.14
21.63 4.11 35.56
21.74 4.09 55.77
22.19 4.01 3.71
22.61 3.93 14.18
23.15 3.84 61.88
23.88 3.73 47.08
24.53 3.63 8.07
24.73 3.60 5.04
24.95 3.57 4.79
25.38 3.51 65.88
26.17 3.40 24.41
26.59 3.35 7.97
26.94 3.31 4.90
27.44 3.25 4.62
28.33 3.15 3.90
28.80 3.10 17.93
29.36 3.04 6.15
30.40 2.94 7.62
30.88 2.90 1.75
31.82 2.81 4.59
32.37 2.77 1.59
衍射角2θ d值 强度％
33.35 2.69 3.93
33.91 2.64 1.52
34.60 2.59 4.04
35.82 2.51 2.29
36.58 2.46 4.46
37.30 2.41 2.71
37.57 2.39 1.59
实施例39～44：晶型A的制备(缓慢挥发试验)
室温条件下，称取约15毫克式(I)化合物于1.5毫升玻璃小瓶中，加入适量体积的溶剂，溶解，采用0.45微米聚四氟乙烯膜过滤，得澄清溶液，之后将该溶液用封口膜封口，膜上戳3-4个小孔，置于室温下缓慢挥发，挥干后得到式(I)化合物晶型A。加入的式(I)化合物质量和对应的正溶剂的种类和体积见表11。以实施例39为例，其样品的X射线粉末衍射数据如表12所示。
表11
Figure PCTCN2021098056-appb-000017
表12
衍射角2θ d值 强度％
5.77 15.32 14.10
9.08 9.74 15.45
9.99 8.85 3.08
11.06 8.00 6.54
11.54 7.67 1.66
11.99 7.38 5.11
12.08 7.33 4.73
12.61 7.02 6.51
12.79 6.92 3.56
衍射角2θ d值 强度％
13.20 6.71 1.26
14.41 6.15 11.48
14.65 6.05 9.37
14.99 5.91 11.41
15.68 5.65 37.59
16.47 5.38 37.81
16.95 5.23 3.62
17.33 5.12 26.45
17.47 5.08 43.60
17.67 5.02 16.74
18.23 4.87 15.58
18.67 4.75 3.04
18.91 4.69 7.35
19.24 4.61 7.16
19.63 4.52 4.02
20.03 4.43 9.61
20.50 4.33 100.00
20.93 4.24 24.63
21.60 4.11 13.13
21.78 4.08 21.37
22.62 3.93 5.18
23.18 3.84 42.65
23.86 3.73 43.46
24.32 3.66 6.82
24.69 3.61 2.90
24.97 3.57 3.55
25.38 3.51 18.44
25.80 3.45 3.33
26.17 3.41 31.10
26.62 3.35 6.46
27.03 3.30 6.62
27.49 3.24 2.18
28.34 3.15 3.79
28.81 3.10 5.31
29.11 3.07 3.09
衍射角2θ d值 强度％
29.40 3.04 1.91
30.23 2.96 2.96
30.42 2.94 3.66
30.86 2.90 1.06
31.98 2.80 2.75
32.39 2.76 1.71
实施例45～48：晶型A的制备(快速挥发试验)
室温条件下，将约15毫克式(I)化合物溶解在适量体积的正溶剂中，采用0.45微米聚四氟乙烯膜过滤，得到澄清溶液，之后将该溶液置于室温下敞口挥发，挥干后得到式(I)化合物晶型A。加入的式(I)化合物质量和对应的正溶剂的种类和体积见表13。实施例45样品为例，其X射线粉末衍射数据如表14所示，其XRPD图如图6所示。
表13
Figure PCTCN2021098056-appb-000018
表14
衍射角2θ d值 强度％
5.78 15.29 32.40
9.09 9.73 29.46
10.02 8.83 6.09
11.08 7.98 18.76
12.03 7.36 7.94
12.60 7.02 7.74
14.46 6.13 23.24
14.67 6.04 14.10
15.00 5.91 14.78
15.67 5.66 13.80
16.47 5.38 46.57
16.98 5.22 9.56
衍射角2θ d值 强度％
17.35 5.11 72.80
17.47 5.08 53.94
17.67 5.02 21.46
18.25 4.86 43.49
18.70 4.75 3.68
18.91 4.69 7.63
19.22 4.62 2.83
19.65 4.52 5.97
20.03 4.43 6.15
20.50 4.33 61.06
20.90 4.25 12.72
21.61 4.11 48.79
22.63 3.93 11.00
23.18 3.84 100.00
23.85 3.73 35.54
24.30 3.66 4.17
24.74 3.60 8.26
25.36 3.51 12.97
26.18 3.40 22.70
26.62 3.35 5.92
27.49 3.25 5.43
28.80 3.10 11.88
29.09 3.07 13.57
30.36 2.94 2.14
31.97 2.80 5.45
32.41 2.76 2.04
33.34 2.69 2.49
33.89 2.65 1.39
35.04 2.56 1.17
35.84 2.51 1.29
36.57 2.46 1.27
37.55 2.40 2.52
实施例49～57：晶型A的制备(50℃快速挥发试验)
将约15毫克式(I)化合物在50℃下溶解于适量体积的正溶剂中，采用0.45微米聚四 氟乙烯膜过滤得到澄清溶液，之后将该溶液置于50℃下敞口挥发，挥干后得到式(I)化合物晶型A。加入的式(I)化合物质量和对应的正溶剂的种类和体积见表15。
表15
Figure PCTCN2021098056-appb-000019
实施例58～62：晶型A的制备(5℃快速挥发试验)
室温条件下，将约15毫克式(I)化合物在5℃下溶解在适量体积的正溶剂中，采用0.45微米聚四氟乙烯膜过滤得到澄清溶液，之后将该溶液置于5℃下敞口挥发，挥干后得到式(I)化合物晶型A。加入的式(I)化合物质量和对应的正溶剂的种类和体积见表16。
表16
Figure PCTCN2021098056-appb-000020
实施例63～69：晶型A的制备(反向反溶剂添加试验)
将约15毫克式(I)化合物在50℃适量体积的正溶剂溶解，得到澄清溶液，之后将该溶液加入至4毫升预先-20℃条件下冷藏的反溶剂中进行反反溶剂添加试验。加入的API质量、正溶剂和对应的反溶剂的体积见表17。实施例68有固体析出，得到式(I)化合物晶型A。其余样品依旧溶清，随即将该澄清样品置于-20℃静置，未能发现固体析出，之后将澄清溶液室温下敞口挥发，得到式(I)化合物晶型A。以实施例63为例，其X射线粉末衍射数据如表18所示。
表17
Figure PCTCN2021098056-appb-000021
表18
衍射角2θ d值 强度％
5.78 15.29 17.22
9.10 9.72 64.41
10.00 8.84 9.34
11.08 7.99 13.27
11.98 7.39 13.32
12.61 7.02 15.60
12.80 6.92 24.43
14.47 6.12 30.87
14.69 6.03 14.27
15.01 5.90 21.07
15.67 5.65 15.78
16.49 5.37 100.00
17.37 5.10 42.13
17.47 5.08 59.29
17.69 5.01 47.46
18.26 4.86 37.76
18.93 4.69 16.74
19.25 4.61 36.23
19.66 4.52 9.69
20.04 4.43 14.74
20.50 4.33 48.70
20.93 4.24 37.64
21.63 4.11 47.23
衍射角2θ d值 强度％
23.18 3.84 67.24
23.88 3.73 92.64
25.39 3.51 27.22
26.18 3.40 19.61
26.63 3.35 5.65
28.85 3.10 25.62
30.45 2.94 8.80
33.39 2.68 5.36
实施例70：晶型A的溶液稳定性考察
为考核晶型A在不同温度下，不同常规工艺溶剂中的稳定性，分别将采用实施例1方法制备的一定量的式(I)化合物晶型A加入至一定体积的有机溶剂中，在5℃下搅拌7天、室温下搅拌5天、50℃下搅拌10天、120℃下搅拌约8小时后，分离固体测试XPRD，结果如表19所示。实验结果表明，晶型A在醇类、酮类、酯类、醚类、芳香烃、脂肪烃、烷基腈、水等单一或混合溶剂体系内，原料药合成以制剂生产过程中有可能涉及的温度范围内(5～120℃)，均表现出良好的固体稳定性，能够满足药品生产过程中对药物稳定性的要求，具有很好的应用前景。
表19
Figure PCTCN2021098056-appb-000022
Figure PCTCN2021098056-appb-000023
实施例71：晶型的溶解度
将采用实施例1方法制备本发明晶型A和现有技术中披露固体用SGF(模拟人工胃液)、FaSSIF(空腹状态下人工肠液)和FeSSIF(饱食状态下人工肠液)分别配制成悬浊液，在1小时、2小时、4小时和24小时平衡后过滤，得到饱和溶液。通过高效液相色谱法(HPLC)测定饱和溶液中样品的含量。由结果可知，本发明晶型A在SGF、FaSSIF、FeSSIF和纯水中的溶解度较高，高于现有技术中披露固体。采用XRPD检测溶解度测试后剩余固体的晶型，发现晶型A样品在生物介质中悬浮24小时后，晶型未发生改变(图7)，说明该晶型在生物介质中有较好的稳定性。
表20
Figure PCTCN2021098056-appb-000024
实施例72：晶型的可压性
采用手动压片机进行压片，压片时，选择可以压制成圆柱体片剂的圆形平冲，分别加入一定量的采用实施例1方法制备本发明晶型A和现有技术中披露固体，采用10kN压力压制成圆形片剂，放置于干燥器中24小时，待完全弹性复原后采用片剂硬度测定仪测试其径向破碎力(硬度，H)。采用游标卡尺测量片剂的直径(D)和厚度(L)，利用公式T＝2H/πDL计算出不同硬度下粉体的抗张强度。在一定的压力下，抗张强度越大的，表示其可压性越好。结果表明，本发明晶型较现有技术中披露固体的抗张强度更大，具有更优的可压性。
表19
Figure PCTCN2021098056-appb-000025
实施例73：晶型的固有溶出速率
称取采用实施例1方法制备本发明晶型A和现有技术中披露固体各约100毫克，倒入固有溶出模具，在5kN压力下持续1分钟，制成表面积0.5cm 2的薄片，取完整压片转移至溶出仪测试固有溶出速率，溶出条件如表20所示，根据10～30分钟之间的测定点计算斜率，以毫克/毫升表示，根据斜率进一步计算固有溶出速率(Intrinsic dissolution rate,IDR)，以毫克/分钟/cm 2表示。结果表明，本发明晶型的溶出速率较现有技术中披露固体更快。
表21
溶出仪 CSE-051 Agilent 708DS
方法 浆法
介质 pH 6.8磷酸盐缓冲液
介质体积 900毫升
转速 100转/分
介质温度 37℃
取样点 1,2,3,4,5,10,15,20,25,30min
补充介质 No
实施例74：稳定性对比研究
称取采用实施例1方法制备本发明晶型A(HPLC纯度99.17％)约15毫克，敞口放置于25℃/60％RH条件以及40℃/75％RH条件的稳定箱中，在1周、2周、5周、8周后取样测XRPD(图8、图9)。由结果可知，本发明晶型A在25℃/60％RH以及40℃/75％RH条件下放置，晶型与纯度未发生显著改变，具有良好的稳定性。
表22
Figure PCTCN2021098056-appb-000026
Figure PCTCN2021098056-appb-000027
*相对纯度＝测试样品HPLC纯度/起始样品HPLC纯度×100％
实施例75：引湿性对比研究
称取采用实施例1方法制备本发明晶型A和现有技术中披露固体各约10毫克进行动态水分吸附(DVS)测试，然后取样测XRPD。由结果可知(图7)，本发明晶型A在80％相对湿度下吸湿增重0.49％，属于略有引湿性，XRPD测试显示(图8)，DVS测试前后晶型未发生改变，说明晶型A具有较好的湿度稳定性。
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J药物引湿性试验指导原则)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
实施例76：晶习对比研究
称取采用实施例1方法制备本发明晶型和现有技术中披露固体各约10毫克，分别置于载玻片上，滴加少许真空硅油分散样品，然后盖上盖玻片，置于偏光显微镜下观察。本发明晶型A与现有技术相比具有更优的晶习。
实施例77：粒径分布对比研究
称取采用实施例1方法制备本发明晶型A和现有技术中披露固体约10-30毫克，然后加入约5毫升Isopar G(含有0.2％卵磷脂)，将待测样品充分混合均匀后加入SDC进样系统中，使遮光度达到合适范围，开始实验，超声30秒后进行粒径分布的测试。本发明晶型A与现有技术中披露固体相比具有更加均匀的粒径分布。
实施例78：黏附性对比研究
称取采用实施例1方法制备本发明晶型A和现有技术中披露固体各约100毫克，然后加入到10毫米圆形平冲中，采用10kN的压力进行压片处理，压片后停留约半分钟，称量冲头吸附的粉末量。本发明晶型A冲头吸附粉末量为1.5mg，黏附性优于现有技术中披露固体。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (10)

  1. 式(I)所示化合物2-[((1R，5S)-3-][[5-环丙基-3-[2-(三氟甲氧基)苯基]-1,2-恶唑-4-基]甲氧基]-8-氮杂双环[3.2.1]辛烷-8-基]-4-氟-1,3-苯并噻唑-6-羧酸的A型晶体、即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为23.9°±0.2°,16.5°±0.2°,23.2°±0.2°处有特征峰，
    Figure PCTCN2021098056-appb-100001
  2. 根据权利要求1所述的晶型A，其X射线粉末衍射在2θ值为20.5°±0.2°,21.6°±0.2°,17.5°±0.2°中的一处或两处或三处有特征峰。
  3. 根据权利要求1或2中任意一项所述的晶型A，其X射线粉末衍射在2θ值为20.5°±0.2°,21.6°±0.2°,17.5°±0.2°处有特征峰。
  4. 权利要求1～3中任意一项所述的晶型A的制备方法，其特征在于，
    Figure PCTCN2021098056-appb-100002
    将式(I)化合物溶解于正溶剂中，过滤后向其中逐滴加入反溶剂，得到晶型A。
  5. 权利要求1～3中任意一项所述的晶型A的制备方法，其特征在于，
    Figure PCTCN2021098056-appb-100003
    将式(I)化合物溶解于正溶剂中，过滤后将其快速加入反溶剂中，得到晶型A。
  6. 权利要求1～3中任意一项所述的晶型A的制备方法，其特征在于，
    Figure PCTCN2021098056-appb-100004
    一定温度下将式(I)化合物溶解于挥发性溶剂中，挥发析晶得到晶型A固体。
  7. 权利要求1～3中任意一项所述的晶型A的制备方法，其特征在于，
    Figure PCTCN2021098056-appb-100005
    将式(I)化合物溶于正溶剂中，然后置于含有反溶剂的密封环境中，渗透析晶，得到晶型A。
  8. 药物组合物，其包含权利要求1～3中任一项所述的晶体和制药学可接受的载体。
  9. 具有FXR激动活性的药物组合物，其含有权利要求1～3中任一项所述的晶体作为有效成分。
  10. 原发性胆汁腹泻、原发性胆汁胆管炎和/或非酒精性脂肪性肝炎的预防药或治疗药，其含有权利要求1～3中任一项所述的晶体作为有效成分。
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