WO2022037580A1 - 化合物x7盐酸盐的晶体及其制备方法与应用 - Google Patents

化合物x7盐酸盐的晶体及其制备方法与应用 Download PDF

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WO2022037580A1
WO2022037580A1 PCT/CN2021/113018 CN2021113018W WO2022037580A1 WO 2022037580 A1 WO2022037580 A1 WO 2022037580A1 CN 2021113018 W CN2021113018 W CN 2021113018W WO 2022037580 A1 WO2022037580 A1 WO 2022037580A1
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crystal form
crystal
compound
hydrochloride
solvent
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PCT/CN2021/113018
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English (en)
French (fr)
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王朋
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沈阳海王生物技术有限公司
王朋
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Priority to JP2023512347A priority Critical patent/JP2023542816A/ja
Priority to EP21857672.6A priority patent/EP4201935A1/en
Priority to US18/042,108 priority patent/US20230322755A1/en
Publication of WO2022037580A1 publication Critical patent/WO2022037580A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the technical field of medicinal chemistry, in particular to a crystal of compound X7 hydrochloride and a preparation method and application thereof.
  • Compound X7 hydrochloride has a potent vasodilator effect, its antihypertensive effect is precise, the onset of action is fast, the blood pressure lowering is accompanied by mild heart rate slowdown, does not affect the cardiac conduction system, and has a favorable effect on hemodynamics.
  • Long-term medication has the advantage of having a protective effect on organ damage caused by hypertension.
  • the crystal structure of a medicinal active ingredient often affects the chemical and physical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the formation of other forms of crystal forms. Therefore, in-depth research is needed to find crystals with better physicochemical properties.
  • the purpose of the present invention is to propose a crystal of compound X7 hydrochloride, a preparation method and application thereof, and the crystal of compound X7 hydrochloride has better physicochemical properties.
  • one aspect of the present invention provides a crystal of Compound X7 hydrochloride, and the X-ray powder diffraction pattern of the crystal of Compound X7 hydrochloride has characteristic diffraction peaks at 5°-35° at a 2 ⁇ diffraction angle;
  • the crystal of the compound X7 hydrochloride comprises crystal form A, and the 2 ⁇ diffraction angles of the X-ray powder diffraction pattern of the crystal form A are 15.12 ⁇ 0.2°, 11.57 ⁇ 0.2° and 21.03° There are characteristic diffraction peaks at ⁇ 0.2°;
  • the 2 ⁇ diffraction angle of the X-ray powder diffraction pattern of the crystal form A also has characteristic diffraction peaks at 26.01 ⁇ 0.2°, 17.92 ⁇ 0.2° and 27.89 ⁇ 0.2° at the same time;
  • the 2 ⁇ diffraction angles of the X-ray powder diffraction pattern of the crystal form A are simultaneously at 25.34 ⁇ 0.2°, 19.96 ⁇ 0.2°, 12.49 ⁇ 0.2°, 30.64 ⁇ 0.2°, 7.57 ⁇ 0.2°, 31.11 ⁇ 0.2° and There is also a characteristic diffraction peak at 9.99 ⁇ 0.2°.
  • thermogravimetric analysis of Form A has a weight loss of 0.8 ⁇ 0.5% in the range of 30.0-155.0°C;
  • the differential scanning calorimetry of Form A has an endothermic peak in the range of 210.0-220.0°C;
  • Form A is an anhydrous form.
  • the crystal of Compound X7 hydrochloride comprises crystal form B, and the X-ray powder diffraction pattern of crystal form B has 2 ⁇ diffraction angles of 7.38 ⁇ 0.2°, 13.19 ⁇ 0.2° and 16.99 There are characteristic diffraction peaks at ⁇ 0.2°;
  • the 2 ⁇ diffraction angle of the X-ray powder diffraction pattern of the crystal form B also has characteristic diffraction peaks at 25.57 ⁇ 0.2°, 14.48 ⁇ 0.2° and 25.05 ⁇ 0.2° at the same time;
  • the 2 ⁇ diffraction angle of the X-ray powder diffraction pattern of the crystal form B also has characteristic diffraction peaks at 19.86 ⁇ 0.2°, 23.08 ⁇ 0.2° and 21.38 ⁇ 0.2° at the same time.
  • thermogravimetric analysis of Form B has a weight loss of 8.0-12.0% in the range of 29.0-72.0°C;
  • the differential scanning calorimetry of Form B has both endothermic peaks in the range of 60.0-80.0°C and 195.0-215.0°C, and an exothermic peak in the range of 125.0-145.0°C;
  • Form B is a hydrate.
  • the crystal of compound X7 hydrochloride comprises crystal form C, and the X-ray powder diffraction pattern of crystal form C has 2 ⁇ diffraction angles of 8.26 ⁇ 0.2°, 15.68 ⁇ 0.2° and 14.03° There are characteristic diffraction peaks at ⁇ 0.2°;
  • the 2 ⁇ diffraction angle of the X-ray powder diffraction pattern of the crystal form C also has characteristic diffraction peaks at 21.25 ⁇ 0.2°, 25.30 ⁇ 0.2° and 13.43 ⁇ 0.2°;
  • the 2 ⁇ diffraction angles of the X-ray powder diffraction pattern of the crystal form C are simultaneously at 15.91 ⁇ 0.2°, 20.59 ⁇ 0.2°, 23.64 ⁇ 0.2°, 28.70 ⁇ 0.2°, 16.59 ⁇ 0.2°, 21.73 ⁇ 0.2°, There are also characteristic diffraction peaks at 19.28 ⁇ 0.2°, 27.13 ⁇ 0.2°, 38.46 ⁇ 0.2°, 33.57 ⁇ 0.2°, 25.78 ⁇ 0.2°, 30.31 ⁇ 0.2° and 34.30 ⁇ 0.2°.
  • thermogravimetric analysis of Form C has a weight loss of 1.5-2.5% in the range of 27.0-190.0°C;
  • the differential scanning calorimetry of Form C has both an exothermic peak in the range of 128.0-160.0°C and an endothermic peak in the range of 201.0-210.0°C;
  • Form C is an anhydrous form.
  • the crystal of the compound X7 hydrochloride comprises crystal form D, and the 2 ⁇ diffraction angles of the X-ray powder diffraction pattern of the crystal form D are 15.69 ⁇ 0.2°, 24.98 ⁇ 0.2° and 8.69° There are characteristic diffraction peaks at ⁇ 0.2°;
  • the 2 ⁇ diffraction angle of the X-ray powder diffraction pattern of the crystal form D also has characteristic diffraction peaks at 15.12 ⁇ 0.2°, 12.67 ⁇ 0.2° and 22.11 ⁇ 0.2°;
  • the 2 ⁇ diffraction angles of the X-ray powder diffraction pattern of the crystal form D are simultaneously at 21.40 ⁇ 0.2°, 25.62 ⁇ 0.2°, 27.89 ⁇ 0.2°, 19.39 ⁇ 0.2°, 18.38 ⁇ 0.2°, 6.28 ⁇ 0.2°, There are also characteristic diffraction peaks at 13.85 ⁇ 0.2°, 27.39 ⁇ 0.2°, 28.94 ⁇ 0.2°, 18.88 ⁇ 0.2°, 35.84 ⁇ 0.2°, 33.36 ⁇ 0.2°, 31.68 ⁇ 0.2° and 30.65 ⁇ 0.2°.
  • thermogravimetric analysis diagram of crystal form D has a weight loss of 2.0-2.5% in the range of 30.0-190.0°C;
  • the differential scanning calorimetry of Form D has an endothermic peak in the range of 200.0-210.0°C;
  • Form D is an anhydrous form.
  • the crystal of compound X7 hydrochloride comprises crystal form E, and the X-ray powder diffraction pattern of said crystal form E has 2 ⁇ diffraction angles of 23.08 ⁇ 0.2°, 19.05 ⁇ 0.2° and 13.01° There are characteristic diffraction peaks at ⁇ 0.2°;
  • the 2 ⁇ diffraction angle of the X-ray powder diffraction pattern of the crystal form E also has characteristic diffraction peaks at 26.12 ⁇ 0.2°, 21.56 ⁇ 0.2° and 11.81 ⁇ 0.2°;
  • the 2 ⁇ diffraction angle of the X-ray powder diffraction pattern of the crystal form E also has characteristic diffraction peaks at 15.36 ⁇ 0.2°, 23.83 ⁇ 0.2° and 24.75 ⁇ 0.2°;
  • the 2 ⁇ diffraction angles of the X-ray powder diffraction pattern of the crystal form E are simultaneously 18.75 ⁇ 0.2°, 9.57 ⁇ 0.2°, 9.81 ⁇ 0.2°, 22.71 ⁇ 0.2°, 24.28 ⁇ 0.2°, 16.76 ⁇ 0.2° , 28.19 ⁇ 0.2°, 19.72 ⁇ 0.2°, 20.77 ⁇ 0.2° and 16.40 ⁇ 0.2° also have characteristic diffraction peaks.
  • the crystal of the compound X7 hydrochloride comprises crystal form F, and the 2 ⁇ diffraction angles of the X-ray powder diffraction pattern of the crystal form F are at 11.74 ⁇ 0.2°, 5.77 ⁇ 0.2° and 15.66° There are characteristic diffraction peaks at ⁇ 0.2°;
  • the 2 ⁇ diffraction angles of the X-ray powder diffraction pattern of the crystal form F are simultaneously at 23.79 ⁇ 0.2°, 26.51 ⁇ 0.2°, 13.81 ⁇ 0.2°, 28.49 ⁇ 0.2°, 30.11 ⁇ 0.2°, 20.25 ⁇ 0.2°, There are also characteristic diffraction peaks at 17.74 ⁇ 0.2°, 8.82 ⁇ 0.2°, 18.79 ⁇ 0.2° and 33.04 ⁇ 0.2°.
  • thermogravimetric analysis diagram of Form F has a weight loss of 8.0-8.5% in the range of 25.0-90.0°C;
  • the differential scanning calorimetry of Form F has endothermic peaks in the range of 50.0-80.0°C, 190.0-205.0°C and 206.0-215.0°C simultaneously;
  • Form F is a hydrate.
  • another aspect of the present invention provides a method for preparing the crystal of the above-mentioned compound X7 hydrochloride, (a) the preparation method of crystal form A comprises the following steps:
  • the first good solvent is selected from at least one of methanol, chloroform, dimethyl sulfoxide or N-methylpyrrolidone;
  • the first anti-solvent is selected from acetone, isopropyl acetate, 2-methyltetrahydrofuran, methyl isobutyl ketone, toluene, isopropanol, methyl tert-butyl ether, acetonitrile or At least one of ethyl acetate;
  • the preparation method of (b) crystal form A comprises the following steps:
  • the open container containing compound X7 hydrochloride is placed in a sealed container containing the first solvent, and the solid is collected to obtain the crystal form A;
  • the first solvent is selected from water, dichloromethane, ethanol, methanol, acetonitrile, tetrahydrofuran, chloroform, acetone, dimethyl sulfoxide, ethyl acetate, 1,4-dioxane or isotope at least one of propanol;
  • the standing is standing at room temperature for 6-10 days;
  • the preparation method of (c) crystal form A comprises the following steps:
  • the compound X7 hydrochloride is placed in a container, and a second solvent is added to dissolve the compound X7 hydrochloride in the second solvent to prepare a clear solution, which is then slowly volatilized, and the solid is collected to obtain the crystal form A;
  • the second solvent is selected from methanol, ethanol, dichloromethane, chloroform, a mixed solvent with a volume ratio of methanol to acetone of (0.5 ⁇ 1.5):1, and a volume ratio of ethanol to acetonitrile of (3.5 ⁇ 1.5) 4.5): 1 mixed solvent or at least one of the mixed solvents with a volume ratio of dichloromethane and tetrahydrofuran (3.5 to 4.5): 1;
  • the preparation method of (d) crystal form A comprises the following steps:
  • the third solvent is selected from methanol, trichloromethane, acetonitrile, a mixed solvent with a volume ratio of methanol to isopropyl acetate of (0.5-1.5):1, and a volume ratio of ethanol to methyl tert-butyl ether. at least one of a mixed solvent with a volume ratio of (3.5-4.5):1 or a mixed solvent with a volume ratio of chloroform and acetonitrile of (0.5-1.5):1;
  • the heating is heating at 40-60° C. for 1.5-2.5 h;
  • the slow cooling is to cool the filtrate from 40-60°C to 3-8°C at a cooling rate of 0.05-0.1°C/min;
  • the preparation method of (e) crystal form A comprises the following steps:
  • a fourth solvent is added to compound X7 hydrochloride to obtain a cloudy liquid, the cloudy liquid is stirred, and the solid is collected by centrifugation to obtain the crystal form A;
  • the fourth solvent is selected from ethanol, methyl isobutyl ketone, ethyl acetate, methyl tert-butyl ether, acetonitrile, toluene, ethanol and the volume ratio of 1,4-dioxane is (0.5 ⁇ 1.5): 1, the volume ratio of methyl isobutyl ketone and n-heptane is (0.5 ⁇ 1.5): 1, the volume ratio of isopropyl acetate and dichloromethane is (3.5 ⁇ 4.5 ): 1 mixed solvent, the volume ratio of tetrahydrofuran and acetonitrile is (0.5 ⁇ 1.5): 1 mixed solvent, the volume ratio of acetone and N-methylpyrrolidone is (3.5 ⁇ 4.5): 1 mixed solvent, isopropanol A mixed solvent with a volume ratio of ethyl acetate (0.5 to 1.5): 1, a mixed solvent with a volume ratio of methanol to methyl tert-butyl ether
  • the turbid solution is stirred at room temperature for 3 to 5 days;
  • the fifth solvent is added to compound X7 hydrochloride to obtain a cloudy liquid, the cloudy liquid is stirred at 45-55° C., and the solid is collected by centrifugation to obtain the crystal form A;
  • the fifth solvent is selected from the volume ratio of ethanol, isopropanol, acetone, isopropyl acetate, 1,4-dioxane, acetonitrile, n-heptane, isopropanol and 2-methyltetrahydrofuran (0.5 ⁇ 1.5): 1 mixed solvent, the volume ratio of methyl isobutyl ketone to ethyl acetate is (0.5 ⁇ 1.5): 1, the volume ratio of chloroform and n-heptane is (3.5 ⁇ 4.5): 1 mixed solvent, mixed solvent with the volume ratio of ethanol and acetone (0.5 ⁇ 1.5): 1, mixed solvent with the volume ratio of acetonitrile to water (0.5 ⁇ 1.5): 1, isopropyl acetate and A mixed solvent with a volume ratio of N,N-dimethylacetamide (8.5-9.5):1, a mixed solvent with a volume ratio of methyl tert-butyl ether and N-methylpyrrolidone (8.5
  • the turbid solution is stirred at 45 to 55°C for 3 to 5 days;
  • the preparation method of (g) crystal form A comprises the following steps:
  • the second good solvent is selected from at least one of methanol, dichloromethane or chloroform;
  • the second anti-solvent is selected from ethyl acetate, 1,4-dioxane, isopropyl acetate, toluene, methyl isobutyl ketone, acetonitrile, 2-methyltetrahydrofuran, At least one of n-heptane, isopropanol, ethyl acetate or methyl tert-butyl ether;
  • the preparation method of (h) crystal form A comprises the following steps:
  • the sixth solvent is selected from the group consisting of methanol, dichloromethane, a mixed solvent with a volume ratio of acetonitrile to chloroform (0.5 to 1.5): 1, chloroform, acetone and dichloromethane in a volume ratio of 1 : at least one of the mixed solvent of (1-3) or the mixed solvent of which the volume ratio of ethanol and water is (0.5-1.5): 1;
  • the high polymer includes mixed high polymer A and mixed high polymer B, and the mixed high polymer includes equal quality mixed polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyacetic acid Vinyl ester, hydroxypropyl methyl cellulose and methyl cellulose;
  • the mixed high polymer B includes polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate or Hydroxyethyl cellulose.
  • another aspect of the present invention provides a method for preparing the crystal of the above-mentioned compound X7 hydrochloride, (1) the preparation method of crystal form B comprises the following steps:
  • the compound X7 hydrochloride was placed in a container, and a mixed solvent with a volume ratio of acetonitrile to water (0.5-1.5): 1 was added to dissolve the compound X7 hydrochloride in the mixed solvent to prepare a clear solution, and then slowly volatilize, collect the solid to obtain the crystal form B;
  • the stirring is at 40-60° C. for 0.5-1.5 days;
  • the slow cooling is to cool the filtrate from 40-60°C to 3-8°C at a cooling rate of 0.05-0.1°C/min;
  • (3) the preparation method of crystal form B comprises the following steps:
  • the cloudy solution is stirred at room temperature for 3 to 5 days.
  • another aspect of the present invention provides a method for preparing the crystal of the above-mentioned compound X7 hydrochloride, and the preparation method of crystal form C comprises the following steps:
  • the stirring is at 40-60° C. for 2-4 hours;
  • the slow cooling is to cool the filtrate from 40-60°C to 3-8°C at a cooling rate of 0.05-0.1°C/min;
  • the vacuum drying time is 0.5-1.5 days.
  • another aspect of the present invention provides a method for preparing the crystal of the above-mentioned compound X7 hydrochloride, (i) the preparation method of crystal form D comprises the following steps:
  • the compound X7 hydrochloride is placed in a container, and a mixed solvent whose volume ratio of chloroform and n-heptane is (0.5 to 1.5): 1 is added to dissolve the compound X7 hydrochloride in the mixed solvent to prepare a clear solution , then slowly volatilized, and the solid was collected to obtain the crystal form D;
  • another aspect of the present invention provides a method for preparing the crystal of the above-mentioned compound X7 hydrochloride, and the preparation method of the crystal form E comprises the following steps:
  • the heating is heating at 40-60° C. for 1.5-2.5 h;
  • the slow cooling is cooling the filtrate from 40-60°C to 3-8°C at a cooling rate of 0.05-0.1°C/min.
  • another aspect of the present invention provides a method for preparing the crystal of the above-mentioned compound X7 hydrochloride, and the preparation method of the crystal form F comprises the following steps:
  • the ultrasonic time is 20-40s.
  • the crystal form F is dissolved in water, and is transformed into the crystal form B after stirring at room temperature;
  • the crystal form C is heated to 155-165° C. and cooled to room temperature and then transformed into the crystal form D;
  • the crystal form D or the crystal form C is stirred in at least one solvent selected from ethanol or chloroform for 2 to 4 days to transform into the crystal form A; preferably, the stirring temperature is room temperature or 45 to 55° C.;
  • the crystal form B or the crystal form F is converted into the crystal form A by stirring in acetone or a mixed solvent of acetone and water at room temperature.
  • the water activity of the mixed solvent of acetone and water a w ⁇ 0.8.
  • a further aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above crystal of Compound X7 hydrochloride and a pharmaceutically acceptable carrier or excipient.
  • another aspect of the present invention provides the crystals of the above-mentioned compound X7 hydrochloride or the above-mentioned pharmaceutical compositions in the preparation of drugs for preventing, treating and delaying hypertension, target organ damage caused by hypertension and hypertension-related diseases application in medicine.
  • Fig. 1 is the compound X7 hydrochloride polymorphic transformation relation diagram of the present invention
  • Fig. 2a is the XRPD figure of crystal form A of the present invention.
  • Figure 2b is a TGA/DSC chart of the crystal form A of the present invention; wherein, the A curve represents the TGA chart of the crystal form A, and the B curve represents the DSC chart of the crystal form A;
  • Fig. 2c is the 1 HNMR chart of the crystal form A of the present invention.
  • Fig. 3a is the XRPD pattern of crystal form B of the present invention.
  • Figure 3b is a TGA/DSC chart of the crystal form B of the present invention. wherein, curve A represents the TGA chart of crystal form B, and curve B represents the DSC chart of crystal form B;
  • Figure 3c is the 1 H NMR chart of the crystal form B of the present invention.
  • Fig. 4a is the XRPD pattern of crystal form C of the present invention.
  • Figure 4b is a TGA/DSC chart of the crystal form C of the present invention. wherein, curve A represents the TGA chart of crystal form C, and curve B represents the DSC chart of crystal form C;
  • Fig. 5a is the XRPD pattern of crystal form D of the present invention.
  • Figure 5b is a TGA/DSC chart of the crystal form D of the present invention. wherein, curve A represents the TGA chart of crystal form D, and curve B represents the DSC chart of crystal form D;
  • Fig. 6 is the XRPD figure of crystal form E of the present invention.
  • Fig. 7a is the XRPD pattern of crystal form F of the present invention.
  • Figure 7b is a TGA/DSC chart of the crystal form F of the present invention. wherein, curve A represents the TGA chart of crystal form F, and curve B represents the DSC chart of crystal form F;
  • Figure 7c is the 1 H NMR chart of the crystal form F of the present invention.
  • Figure 8a is a DVS diagram of the crystal form A of the present invention; wherein, represents cycle 1 adsorption, represents cycle 1 desorption;
  • Figure 8b is the DVS diagram of the crystal form B of the present invention; wherein, represents cycle 1 adsorption, represents cycle 1 desorption, represents cycle 2 adsorption;
  • Fig. 9a is the PLM diagram of crystal form A of the present invention.
  • Figure 9b is a PLM image of the crystal form B of the present invention.
  • room temperature refers to (25 ⁇ 2)°C
  • room humidity refers to a relative air humidity of 30-80%.
  • relative humidity is represented by RH, which represents the percentage of saturated water vapor content (saturated water vapor pressure) in the case of the same amount of water vapor (water vapor pressure) contained in the gas (usually in air).
  • the water activity is represented by a w , which is defined as the volume of free water currently available in the sample, which ranges from 0 (absolute dryness) to 1 (100% relative humidity).
  • the reagents in Table 1 can be purchased from Sinopharm Chemical Reagent Co., Ltd.
  • the crystal structure of a medicinal active ingredient often affects the chemical and physical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by Other crystal forms are produced. Therefore, in-depth research is needed to find crystals with better physicochemical properties.
  • the present invention aims to screen the polymorphic form of compound X7 hydrochloride, and by identifying and evaluating the found polymorphic form, a crystal form with better physical and chemical properties is recommended for subsequent research and development.
  • the present invention conducts a polymorphic screening test.
  • the polymorphic screening takes the starting sample compound X7 hydrochloride as a raw material, and adopts anti-solvent addition, gas-solid permeation, gas-liquid permeation, suspension stirring at room temperature/50°C, slow volatilization, slow More than 100 crystal form screening tests were set up by the method of cooling and polymer induction, and 6 new crystal forms of hydrochloride were found, which were named as crystal forms A, B, C, D, E and F respectively.
  • Table 2 The specific test methods and results are summarized in Table 2.
  • N/A No characterization and identification were performed due to the small amount of the obtained sample and the difficulty of repeated preparation.
  • the anhydrous crystal form A and the hydrate crystal form B were selected to test and evaluate the hygroscopicity, solid state stability, equilibrium solubility in H 2 O and crystal morphology.
  • the dynamic moisture adsorption (DVS) test results show that under the condition of 25°C/80%RH (relative humidity), the crystal form A absorbs 0.08% of water, indicating that it has no hygroscopicity (refer to the 2015 edition of the Chinese Pharmacopoeia (Guidelines for the hygroscopicity test of drugs).
  • anhydrous crystal form A is recommended as the preferred crystal form for further development.
  • the molecular weight of the polymer involved in the present invention is measured in terms of weight average molecular weight, which is measured by gel permeation chromatography (GPC) method, according to the "National Standard of the People's Republic of China GB/T 21863-2008” (equivalent to the German standard DIN55672-1:2007 “Gel Permeation Chromatography (GPC) Part 1: Tetrahydrofuran (THF) as Elution Solvent”).
  • GPC gel permeation chromatography
  • the weight-average molecular weight of polyvinylpyrrolidone is 8,000-700,000
  • the weight-average molecular weight of polyvinyl alcohol is 16,000-20,000
  • the weight-average molecular weight of polyvinyl chloride is 50,000-110,000
  • the weight-average molecular weight of polyvinyl acetate is 20,000-20,000- 30,000
  • the weight-average molecular weight of hydroxypropyl methylcellulose is 400,000-675,000
  • the weight-average molecular weight of methylcellulose is 18,000-200,000
  • the weight-average molecular weight of polycaprolactone is 50,000-70,000
  • the weight-average molecular weight of polyethylene glycol is 50,000-70,000.
  • the weight average molecular weight is 200 to 600
  • the weight average molecular weight of polymethyl methacrylate is 80,000 to 200,000
  • the weight average molecular weight of alginic acid is 300,000 to 400,000
  • the weight average molecular weight of hydroxyethyl cellulose is 700,000 to 800,000. Purchased from Ashland Chemical (Nanjing) Co., Ltd.
  • crystal form C can also be prepared by the following methods:
  • the slow cooling is to cool the filtrate from 40-60°C to 3-8°C at a cooling rate of 0.05-0.1°C/min;
  • the vacuum drying time is 0.5-1.5 days.
  • Form F can also be prepared by the following method:
  • Compound X7 hydrochloride is dissolved in a mixed solvent with a volume ratio of ethanol to water (4-6):2, filtered after ultrasonication, and the filtrate is volatilized at room temperature to obtain the crystal form F; preferably, the ultrasonic The time is 20 ⁇ 40s.
  • each crystal form can be transformed into each other.
  • the crystal form F is dissolved in water, and then transformed into crystal form B after stirring at room temperature;
  • the crystal form C is heated to 155-165° C. and cooled to room temperature, and then transformed into crystal form D; preferably, crystal form C is heated to 160° C. and cooled to room temperature, and then transformed into crystal form D;
  • the crystal form D or the crystal form C is stirred in at least one solvent selected from EtOH or CHCl 3 for 2-4 days to transform into the crystal form A; preferably, the stirring temperature is room temperature or 45-55°C; more Preferably, the stirring temperature is room temperature or 50°C;
  • the crystal form B or the crystal form F is stirred and transformed into the crystal form A in acetone or a mixed solvent of acetone and H 2 O at room temperature.
  • the water activity of the mixed solvent of acetone and H 2 O a w ⁇ 0.8 .
  • a further aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above crystal of Compound X7 hydrochloride and a pharmaceutically acceptable carrier or excipient.
  • pharmaceutically acceptable carrier refers to: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and low enough toxicity.
  • Cosmetic as used herein means that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting Agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • the dosage forms of the pharmaceutical composition of the present invention include tablets, capsules, granules, powders, pills or films.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch and sodium carbonate; (e) lubricants such as talc, calcium stearate, magnesium stearate or mixtures thereof.
  • inert excipient or carrier
  • fillers or compatibilizers for example, starch, lactose, sucrose, glucose
  • another aspect of the present invention provides the crystals of the above-mentioned compound X7 hydrochloride or the above-mentioned pharmaceutical compositions in the preparation of drugs for preventing, treating and delaying hypertension, target organ damage caused by hypertension and hypertension-related diseases application in medicine.
  • the target organ damage is heart, brain, kidney or blood vessel damage caused by hypertension;
  • the hypertension-related diseases include atherosclerosis, hyperlipidemia, obesity, coronary Heart disease, aortic dissection and hyperglycemia, impaired glucose tolerance, metabolic syndrome, diabetes.
  • the target organ damage is left ventricular hypertrophy, stroke, renal cortical atrophy or aortic thickening, angina pectoris, myocardial infarction, heart failure, renal failure, retinal arteriosclerosis, Hypertensive fundus lesions.
  • test methods of the present invention are general methods, and the test methods are as follows:
  • XRPD patterns were acquired on PANalytacal Empyrean and X'Pert3-ray powder diffraction analyzers, and the scan parameters are shown in Table 5.
  • TGA Thermogravimetric Analysis
  • DSC Differential Scanning Calorimetry
  • TGA and DSC graphs were collected on a TA Q500/5000 thermogravimetric analyzer and a TA Q200/2000 differential scanning calorimeter, respectively, and the test parameters are listed in Table 6.
  • Dynamic moisture sorption (DVS) curves were collected on the DVS Intrinsic of SMS (Surface Measurement Systems). The relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg( NO3 ) 2 and KCl. DVS test parameters are listed in Table 7.
  • Polarization microscopy data were acquired at room temperature with an Axio Lab.Al upright microscope.
  • a total of 16 anti-solvent addition experiments were set up with different solvents. Weigh about 15 mg/each of the initial sample (814802-05-A, prepared in Example 1), add it to a 20 mL vial, dissolve it with 0.8-4.0 mL of a good solvent (see Table 8), and add it to the clarifier. The anti-solvent in Table 8 was added to the solution, and the solution was stirred while adding dropwise until a solid was precipitated. If no solid was precipitated after adding about 10 mL of the anti-solvent, it was stopped. The precipitated solid was centrifuged and subjected to XRPD test. The results are shown in Table 8. In the anti-solvent addition test, crystal forms A, F and gel formation were obtained.
  • Test number Solvent (v/v) solid crystal form 814802-11-A1 EtOH Form A 814802-11-A2 MIBK Form A 814802-11-A3 EtOAc Form A 814802-11-A4 MTBE Form A 814802-11-A5 ACN Form A 814802-11-A6 toluene Form A 814802-11-A7 H 2 O Form B 814802-11-A8 EtOH/1,4-dioxane (1:1) Form A 814802-11-A9 MIBK/n-heptane (1:1) Form A
  • each starting sample (814802-05-A, prepared in Example 1) was weighed and dissolved in 1.0-3.0 mL of the solvent listed in Table 15, filtered to obtain the filtrate and transferred to a 3 mL vial containing ⁇ 2 mg of conjunct polymer , the vial containing the clear solution was sealed with parafilm and several small holes were made on it, and it was placed at room temperature to slowly evaporate, and the resulting solid was collected and tested by XRPD.
  • the test results are shown in Table 15, all of which were obtained in the polymer-induced crystallization test are Form A.
  • Hybrid Polymer A Polyvinylpyrrolidone, Polyvinyl Alcohol, Polyvinyl Chloride, Polyvinyl Acetate, Hydroxypropyl Methyl Cellulose and Methyl Cellulose (mixed in equal mass)
  • Mixed polymer B polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose (mixed in equal mass)
  • the preparation method of the crystal form B of compound X7 hydrochloride comprises the following steps:
  • the preparation method of the crystal form C of compound X7 hydrochloride comprises the following steps:
  • the crystal form D of compound X7 hydrochloride is obtained by heating the crystal form C, including the following steps:
  • the preparation method of the crystal form F of compound X7 hydrochloride comprises the following steps:
  • the crystal form A, crystal form B, crystal form C, crystal form D, crystal form E and crystal form F of the prepared compound X7 were characterized by XRPD, TGA, DSC and 1 H NMR, respectively.
  • characteristic peaks of crystal form A the main characteristic peaks: 15.12 ⁇ 0.2°, 11.57 ⁇ 0.2° and 21.03 ⁇ 0.2°; the secondary characteristic peaks: 26.01 ⁇ 0.2°, 17.92 ⁇ 0.2° and 27.89 ⁇ 0.2°.
  • the TGA/DSC characterization results of crystal form A (814802-11-A17, prepared in Example 6) are shown in Figure 2b.
  • the Type A sample lost 0.8% of its weight when heated to 150°C, and had a sharp endothermic peak at 211.7°C (onset temperature).
  • the 1 HNMR characterization results of the crystal form A (814802-11-A17, prepared in Example 6) are shown in Fig. 2c, and the 1 HNMR characterization results of the crystalline form A prepared in the other examples are consistent with Fig. 2c. According to the small TGA weight loss and a single endothermic peak, it is speculated that Form A is an anhydrous form.
  • the XRPD characterization results of the crystal form B (814802-09-A9, prepared in Example 4) are shown in Figure 3a.
  • the XRPD characterization results of the crystal form B prepared in the other examples are consistent with Figure 3a.
  • the XRPD characterization results of the crystal form B Diffraction peak data are shown in Table 17.
  • characteristic peaks of crystal form B the main characteristic peaks: 7.38 ⁇ 0.2°, 13.19 ⁇ 0.2° and 16.99 ⁇ 0.2°; the secondary characteristic peaks: 25.57 ⁇ 0.2°, 14.48 ⁇ 0.2° and 25.05 ⁇ 0.2°.
  • TGA/DSC characterization results of the crystal form B (814802-09-A9, prepared in Example 4) are shown in Figure 3b, and the TGA/DSC characterization results of the crystal form B prepared in the other examples are consistent with Figure 3b.
  • TGA results show that the sample loses 8.3% weight when heated to 70°C
  • DSC results show two endothermic peaks at 68.3°C (peak) and 201.3°C (onset), and a weak exotherm at 126.9°C (onset) peak.
  • the XRPD characterization results of crystal form C (prepared in Example 11) are shown in Figure 4a.
  • the XRPD characterization results of crystal form C prepared in other examples are consistent with Figure 4a.
  • the XRPD diffraction peak data of crystal form C are shown in Table 18. shown.
  • characteristic peaks of crystal form C the main characteristic peaks: 8.26 ⁇ 0.2°, 15.68 ⁇ 0.2° and 14.03 ⁇ 0.2°; the secondary characteristic peaks: 21.25 ⁇ 0.2°, 25.30 ⁇ 0.2° and 13.43 ⁇ 0.2°.
  • the TGA/DSC characterization results of the crystal form C are shown in Figure 4b.
  • the TGA/DSC characterization results of the crystal form C prepared in the other examples are consistent with Figure 4b, and the weight loss is 1.8% when heated to 180 °C. , with an exothermic peak at 134.8 °C (onset) and a sharp endothermic peak at 204.6 °C (onset).
  • the crystal form C has a relatively gentle weight loss and a single sharp endothermic peak, so it is speculated that the crystal form C is an anhydrous crystal.
  • the XRPD characterization results of the crystal form D (prepared in Example 12) are shown in Figure 5a.
  • the TGA/DSC characterization results of the crystal form D prepared in the other examples are consistent with Figure 5a.
  • the XRPD diffraction peak data of the crystal form D are as follows shown in Table 19.
  • characteristic peaks of crystal form D the main characteristic peaks: 15.69 ⁇ 0.2°, 24.98 ⁇ 0.2° and 8.69 ⁇ 0.2°; the secondary characteristic peaks: 15.12 ⁇ 0.2°, 12.67 ⁇ 0.2° and 22.11 ⁇ 0.2°.
  • the TGA/DSC characterization results of the crystal form D (prepared in Example 12) are shown in Fig. 5b, and the TGA/DSC characterization results of the crystal form D prepared in the other examples are consistent with Fig. 5b.
  • the sample of crystal form D loses 2.4% weight when heated to 180°C, and has a sharp endothermic peak at 204.5°C (onset). According to the relatively gentle TGA weight loss and a single DSC endothermic peak, it is speculated that the crystal form D is an anhydrous crystal form.
  • the XRPD characterization results of the crystal form E (814802-10-A5, prepared in Example 5) are shown in Figure 6.
  • the TGA/DSC characterization results of the crystal form E prepared in the other examples are consistent with Figure 6.
  • the crystal form E The XRPD diffraction peak data are shown in Table 20.
  • characteristic peaks of crystal form E the main characteristic peaks: 23.08 ⁇ 0.2°, 19.05 ⁇ 0.2° and 13.01 ⁇ 0.2°; the secondary characteristic peaks: 26.12 ⁇ 0.2°, 21.56 ⁇ 0.2° and 11.81 ⁇ 0.2°; again characteristic Peaks: 15.36 ⁇ 0.2°, 23.83 ⁇ 0.2°, 24.75 ⁇ 0.2°.
  • the XRPD characterization results of the crystal form F (prepared in Example 13) are shown in Figure 7a.
  • the TGA/DSC characterization results of the crystal form F prepared in the other examples are consistent with Figure 7a.
  • the XRPD diffraction peak data of the crystal form F are as follows shown in Table 21.
  • the main characteristic peaks are: 11.74 ⁇ 0.2°, 5.77 ⁇ 0.2° and 15.66 ⁇ 0.2°.
  • the TGA/DSC results of the crystal form F (prepared in Example 13) are shown in Fig. 7b, and the TGA/DSC characterization results of the crystal form F prepared in the other examples are consistent with Fig. 7b.
  • the sample of crystal form F loses 8.3% when heated to 80°C, and has three endothermic peaks at 71.2°C, 203.4°C and 208.9°C (peak).
  • the 1 HNMR results of the crystal form F (prepared in Example 13) (as shown in Figure 7c) show that no solvent EtOH remains in the sample, and the 1 HNMR characterization results of the crystal forms F prepared in other examples are consistent with Figure 7c. Combined with 1 HNMR results and TGA step weight loss, it is speculated that Form F is a hydrate.
  • a sample of Form A (814802-11-A17, prepared in Example 6) and a sample of Form B (814802-09-A9, prepared in Example 4) were tested for equilibrium solubility in water at room temperature.
  • the equilibrium solubility of Form C samples (prepared in Example 11), Form D samples (prepared in Example 12), and Form F samples (prepared in Example 13) was also tested under the same conditions.
  • the suspension of each crystal form ( ⁇ 10mg/mL) was prepared in the test, and the suspension was magnetically stirred at room temperature for 24 hours (speed ⁇ 800rpm), then centrifuged (10000rpm, 5min), and the supernatant was filtered (0.22 ⁇ m PTFE membrane).
  • the crystal form A sample absorbs 0.08% of water at 25°C/80% RH, indicating that the crystal form A has no hygroscopicity, and the crystal form does not change after the DVS test.
  • the sample of crystal form B absorbs 12.3% of water when the relative humidity is 50% RH.
  • the relative humidity decreases to 30% RH
  • the water absorption decreases rapidly, and when the relative humidity decreases to 30% RH, the water absorbs 0.4%.
  • the transformation of anhydrous crystal form during the adsorption process, the water absorption increased rapidly when the relative humidity increased to 80% RH, and the water absorbed 12.5% at 95% RH.
  • the crystal form A sample (814802-11-A17, prepared in Example 6) and the crystal form B sample (814802-09-A9, prepared in Example 4) were tested by PLM to evaluate the crystal morphology, and the results are shown in Figure 9a and Figure 9 9b.
  • the crystal form A is needle-like crystal
  • the crystal form B is a granular crystal with a particle size of less than 20 ⁇ m.
  • the thoracic cavity was quickly dissected, the descending aorta was peeled off, and the connective tissue and surrounding adipose tissue were removed (if the serotonin receptor antagonism experiment was performed, a smooth stainless steel rod should also be used to remove endothelial cells), cut into pieces.
  • 3-5mm vascular ring and then the wire hook is passed through the vascular ring, one end is fixed on the ventilation hook, the other end is connected to the tension transducer, placed in a bath tube filled with 20ml of nutrient solution, and the tension change is recorded by the recorder.
  • the temperature in the bath tube was kept at 37 ⁇ 0.5°C, and the mixed gas (95% O 2 +5% CO 2 ) was passed in at a speed of 1-2 bubbles per second.
  • the initial load of the specimen was 1.5 g, the nutrient solution was changed every 20 min, and the nutrient solution was equilibrated for 2 hours. The experiment was started after the baseline was stable.
  • X7 has a relaxing effect on the specimen contraction caused by AD vasopressin, and it has a dose-dependent effect on the relaxation of epinephrine.
  • the -logEC 50 value of the drug to relax the AD-contracted rabbit aorta is 8.07 ⁇ 0.09.
  • X7 is stable under various pH conditions and stable under high temperature conditions, and is suitable for development into a stomach-dissolving preparation; the crystal form A (814802-11-A17, prepared in Example 6) of this test example was prepared by conventional preparation methods. Dissolution test of tablets Data are as follows.
  • Dissolution medium 1000ml water, pH1.0 hydrochloric acid solution, pH4.5 acetate buffer, pH6.8 phosphate buffer were used as dissolution medium
  • Sampling point take the eluate at 5, 10, 15, 20, 30, 45, and 60 minutes, pass it through a 0.45 ⁇ m organic filter membrane, and take the subsequent filtrate directly into the high-performance liquid phase for detection.

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Abstract

本发明涉及式(I)化合物X7盐酸盐的晶体及其制备方法与应用，该化合物X7盐酸盐的晶体的X射线粉末衍射图2θ衍射角在5°～35°处具有特征衍射峰。该化合物X7盐酸盐的晶体具有较优的理化性质。

Description

化合物X7盐酸盐的晶体及其制备方法与应用 技术领域
本发明涉及药物化学技术领域，尤其涉及化合物X7盐酸盐的晶体及其制备方法与应用。
背景技术
化合物X7盐酸盐具有强效的舒张血管的作用，其降压效果确切、起效快、降压伴有轻度心率减慢、不影响心脏传导系统、对血流动力学产生有利的影响、长期用药对高血压引起的器官损伤有保护作用的优点。作为药用活性成分的晶型结构往往影响到该药物的化学和物理稳定性，结晶条件及储存条件的不同有可能导致化合物的晶体结构的变化，有时还会伴随着产生其他形态的晶型。因此，需要深入研究找到理化性质较优的晶体。
发明内容
有鉴于此，本发明的目的是提出化合物X7盐酸盐的晶体及其制备方法与应用，该化合物X7盐酸盐的晶体具有较优的理化性质。
基于上述目的，本发明的一个方面提供了化合物X7盐酸盐的晶体，所述化合物X7盐酸盐的晶体的X射线粉末衍射图2θ衍射角在5°～35°处具有特征衍射峰；
其中，所述化合物X7盐酸盐的结构式如式(I)所示：
Figure PCTCN2021113018-appb-000001
在本发明的优选的实施方案中，所述化合物X7盐酸盐的晶体包括晶型A，所述晶型A的X射线粉末衍射图2θ衍射角在15.12±0.2°、11.57±0.2°和21.03±0.2°处具有特征衍射峰；
更优选地，所述晶型A的X射线粉末衍射图2θ衍射角同时在26.01±0.2°、17.92±0.2°和27.89±0.2°处还具有特征衍射峰；
进一步优选地，所述晶型A的X射线粉末衍射图2θ衍射角同时在25.34±0.2°、19.96±0.2°、12.49±0.2°、30.64±0.2°、7.57±0.2°、31.11±0.2°和9.99±0.2°处还具有特征衍射峰。
在本发明的优选的实施方案中，晶型A的热重分析图在30.0～155.0℃范围内具有0.8±0.5％的失重；
和/或，晶型A的差示扫描量热图在210.0～220.0℃范围内具有吸热峰；
和/或，晶型A为无水晶型。
在本发明的优选的实施方案中，所述化合物X7盐酸盐的晶体包括晶型B，所述晶型B的X射线粉末衍射图2θ衍射角在7.38±0.2°、13.19±0.2°和16.99±0.2°处具有特征衍射峰；
更优选地，所述晶型B的X射线粉末衍射图2θ衍射角同时在25.57±0.2°、14.48±0.2°和25.05±0.2°处还具有特征衍射峰；
进一步优选地，所述晶型B的X射线粉末衍射图2θ衍射角同时在19.86±0.2°、23.08±0.2°和21.38±0.2°处还具有特征衍射峰。
在本发明的优选的实施方案中，晶型B的热重分析图在29.0～72.0℃范围内具有8.0～12.0％的失重；
和/或，晶型B的差示扫描量热图同时在60.0～80.0℃范围内和195.0～215.0℃范围内具有吸热峰，以及在125.0～145.0℃范围内具有放热峰；
和/或，晶型B为水合物。
在本发明的优选的实施方案中，所述化合物X7盐酸盐的晶体包括晶型C，所述晶型C的X射线粉末衍射图2θ衍射角在8.26±0.2°、15.68±0.2°和14.03±0.2°处具有特征衍射峰；
更优选地，所述晶型C的X射线粉末衍射图2θ衍射角同时在21.25±0.2°、25.30±0.2°和13.43±0.2°处还具有特征衍射峰；
进一步优选地，所述晶型C的X射线粉末衍射图2θ衍射角同时在15.91±0.2°、20.59±0.2°、23.64±0.2°、28.70±0.2°、16.59±0.2°、21.73±0.2°、19.28±0.2°、27.13±0.2°、38.46±0.2°、33.57±0.2°、25.78±0.2°、30.31±0.2°和34.30±0.2°处还具有特征衍射峰。
在本发明的优选的实施方案中，晶型C的热重分析图在27.0～190.0℃范围内具有1.5～2.5％的失重；
和/或，晶型C的差示扫描量热图同时在128.0～160.0℃范围内具有放热峰和201.0～210.0℃范围内具有吸热峰；
和/或，晶型C为无水晶型。
在本发明的优选的实施方案中，所述化合物X7盐酸盐的晶体包括晶型D，所述晶型D的X射线粉末衍射图2θ衍射角在15.69±0.2°、24.98±0.2°和8.69±0.2°处具有特征衍射峰；
更优选地，所述晶型D的X射线粉末衍射图2θ衍射角同时在15.12±0.2°、12.67±0.2°和22.11±0.2°处还具有特征衍射峰；
进一步优选地，所述晶型D的X射线粉末衍射图2θ衍射角同时在21.40±0.2°、25.62±0.2°、27.89±0.2°、19.39±0.2°、18.38±0.2°、6.28±0.2°、13.85±0.2°、27.39±0.2°、28.94±0.2°、18.88±0.2°、35.84±0.2°、33.36±0.2°、31.68±0.2°和30.65±0.2°处还具有特征衍射峰。
在本发明的优选的实施方案中，晶型D的热重分析图在30.0～190.0℃范围内具有2.0～2.5％的失重；
和/或，晶型D的差示扫描量热图在200.0～210.0℃范围内具有吸热峰；
和/或，晶型D为无水晶型。
在本发明的优选的实施方案中，所述化合物X7盐酸盐的晶体包括晶型E，所述晶型E的X射线粉末衍射图2θ衍射角在23.08±0.2°、19.05±0.2°和13.01±0.2°处具有特征衍射峰；
更优选地，所述晶型E的X射线粉末衍射图2θ衍射角同时在26.12±0.2°、21.56±0.2°和11.81±0.2°处还具有特征衍射峰；
进一步优选地，所述晶型E的X射线粉末衍射图2θ衍射角同时在15.36±0.2°、23.83±0.2°和24.75±0.2°处还具有特征衍射峰；
再进一步优选地，所述晶型E的X射线粉末衍射图2θ衍射角同时在18.75±0.2°、9.57±0.2°、9.81±0.2°、22.71±0.2°、24.28±0.2°、16.76±0.2°、28.19±0.2°、19.72±0.2°、20.77±0.2°和16.40±0.2°处还具有特征衍射峰。
在本发明的优选的实施方案中，所述化合物X7盐酸盐的晶体包括晶型F，所述晶型F的X射线粉末衍射图2θ衍射角在11.74±0.2°、5.77±0.2°和15.66±0.2°处具有特征衍射峰；
更优选地，所述晶型F的X射线粉末衍射图2θ衍射角同时在23.79±0.2°、26.51±0.2°、13.81±0.2°、28.49±0.2°、30.11±0.2°、20.25±0.2°、17.74±0.2°、8.82±0.2°、18.79±0.2°和33.04±0.2°处还具有特征衍射峰。
在本发明的优选的实施方案中，晶型F的热重分析图在25.0～90.0℃范围内具有8.0～8.5％的失重；
和/或，晶型F的差示扫描量热图同时在50.0～80.0℃、190.0～205.0℃和206.0～215.0℃范围内具有吸热峰；
和/或，晶型F为水合物。
基于相同的发明构思，本发明的另一个方面提供了制备上述化合物X7盐酸盐的晶体的方法，(a)晶型A的制备方法包括以下步骤：
将化合物X7盐酸盐溶解在第一良溶剂中，再逐滴滴加第一反溶剂，收集析出固体，得到所述晶型A；
优选地，所述第一良溶剂选自甲醇、三氯甲烷、二甲基亚砜或N-甲基 吡咯烷酮中的至少一种；
和/或，优选地，所述第一反溶剂选自丙酮、乙酸异丙酯、2-甲基四氢呋喃、甲基异丁基酮、甲苯、异丙醇、甲基叔丁基醚、乙腈或乙酸乙酯中的至少一种；
或者，(b)晶型A的制备方法包括以下步骤：
将装有化合物X7盐酸盐的敞口容器放置在装有第一溶剂的密封容器中，静置，收集固体，得到所述晶型A；
优选地，所述第一溶剂选自水、二氯甲烷、乙醇、甲醇、乙腈、四氢呋喃、三氯甲烷、丙酮、二甲基亚砜、乙酸乙酯、1,4-二氧六环或异丙醇中的至少一种；
优选地，所述静置为在室温下静置6～10天；
或者，(c)晶型A的制备方法包括以下步骤：
将化合物X7盐酸盐置于容器中，并加入第二溶剂使化合物X7盐酸盐溶解在第二溶剂中，配制成澄清溶液，随后缓慢挥发，收集固体，得到所述晶型A；
优选地，所述第二溶剂选自甲醇、乙醇、二氯甲烷、三氯甲烷、甲醇与丙酮体积比为(0.5～1.5)：1的的混合溶剂、乙醇与乙腈的体积比为(3.5～4.5)：1的混合溶剂或二氯甲烷与四氢呋喃的体积比为(3.5～4.5)：1的混合溶剂中的至少一种；
或者，(d)晶型A的制备方法包括以下步骤：
将化合物X7盐酸盐溶解在第三溶剂中，加热使溶液变澄清后过滤，将滤液缓慢降温，收集析出固体，得到所述晶型A；
优选地，所述第三溶剂选自甲醇、三氯甲烷、乙腈、甲醇与乙酸异丙酯的体积比为(0.5～1.5)：1的混合溶剂、乙醇与甲基叔丁基醚的体积比为(3.5～4.5)：1的混合溶剂或三氯甲烷与乙腈的体积比为(0.5～1.5)：1的混合溶剂中的至少一种；
和/或，优选地，所述加热为在40～60℃下加热1.5～2.5h；
和/或，优选地，所述缓慢降温为以0.05～0.1℃/分钟的降温速度将滤液从40～60℃降温至3～8℃；
或者，(e)晶型A的制备方法包括以下步骤：
在化合物X7盐酸盐中加入第四溶剂得到浑浊液，搅拌浑浊液，离心收集固体，得到所述晶型A；
优选地，所述第四溶剂选自乙醇、甲基异丁基酮、乙酸乙酯、甲基叔丁基醚、乙腈、甲苯、乙醇与1,4-二氧六环的体积比为(0.5～1.5)：1的混合溶剂、甲基异丁基酮与正庚烷的体积比为(0.5～1.5)：1的混合溶剂、乙 酸异丙酯与二氯甲烷的体积比为(3.5～4.5)：1的混合溶剂、四氢呋喃与乙腈的体积比为(0.5～1.5)：1的混合溶剂、丙酮与N-甲基吡咯烷酮的体积比为(3.5～4.5)：1的混合溶剂、异丙醇与乙酸乙酯的体积比为(0.5～1.5)：1的混合溶剂、甲醇与甲基叔丁基醚的体积比为(0.5～1.5)：1的混合溶剂、2-甲基四氢呋喃与三氯甲烷的体积比为(3.5～4.5)：1的混合溶剂、甲基异丁基酮与二甲基亚砜的体积比为(3.5～4.5)：1的混合溶剂或乙醇与水的体积比为(70～97)：(3～30)的混合溶剂中的至少一种；
和/或，优选地，室温下搅拌浑浊液3～5天；
或者，(f)晶型A的制备方法包括以下步骤：
在化合物X7盐酸盐中加入第五溶剂得到浑浊液，45～55℃下搅拌浑浊液，离心收集固体，得到所述晶型A；
优选地，所述第五溶剂选自乙醇、异丙醇、丙酮、乙酸异丙酯、1,4-二氧六环、乙腈、正庚烷、异丙醇与2-甲基四氢呋喃的体积比为(0.5～1.5)：1的混合溶剂、甲基异丁基酮与乙酸乙酯的体积比为(0.5～1.5)：1的混合溶剂、三氯甲烷与正庚烷的体积比为(3.5～4.5)：1的混合溶剂、乙醇与丙酮的体积比为(0.5～1.5)：1的混合溶剂、乙腈与水的体积比为(0.5～1.5)：1的混合溶剂、乙酸异丙酯与N,N-二甲基乙酰胺的体积比为(8.5～9.5)：1的混合溶剂、甲基叔丁基醚与N-甲基吡咯烷酮的体积比为(8.5～9.5)：1的混合溶剂、丙酮与乙腈的体积比为(0.5～1.5)：1的混合溶剂或2-甲基四氢呋喃与甲苯的体积比为(0.5～1.5)：1的混合溶剂中的至少一种；
和/或，优选地，45～55℃下搅拌浑浊液3～5天；
或者，(g)晶型A的制备方法包括以下步骤：
将化合物X7盐酸盐溶解在第二良溶剂中，制成澄清溶液，并将装有澄清溶液的容器敞口放置在装有第二反溶剂的密封容器中静置，收集析出固体，得到所述晶型A；
优选地，所述第二良溶剂选自甲醇、二氯甲烷或三氯甲烷中的至少一种；
和/或，优选地，所述第二反溶剂选自乙酸乙酯、1,4-二氧六环、乙酸异丙酯、甲苯、甲基异丁基酮、乙腈、2-甲基四氢呋喃、正庚烷、异丙醇、乙酸乙酯或甲基叔丁基醚中的至少一种；
或者，(h)晶型A的制备方法包括以下步骤：
将化合物X7盐酸盐溶解在第六溶剂中，并加入高聚物，缓慢挥发，收集固体，得到所述晶型A；
优选地，所述第六溶剂选自甲醇、二氯甲烷、乙腈与三氯甲烷的体积比为(0.5～1.5)：1的混合溶剂、三氯甲烷、丙酮与二氯甲烷的体积比为1： (1～3)的混合溶剂或乙醇与水的体积比为(0.5～1.5)：1的混合溶剂中的至少一种；
和/或，优选地，所述高聚物包括混合高聚物A和混合高聚物B，所述混合高聚物包括等质量混合的聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、聚醋酸乙烯酯、羟丙基甲基纤维素和甲基纤维素；所述混合高聚物B包括等质量混合的聚己酸内酯、聚乙二醇、聚甲基丙烯酸甲酯、海藻酸钠或羟乙基纤维素。
基于相同的发明构思，本发明的另一个方面提供了制备上述化合物X7盐酸盐的晶体的方法，(1)晶型B的制备方法包括以下步骤：
将化合物X7盐酸盐置于容器中，并加入乙腈与水的体积比为(0.5～1.5)：1的的混合溶剂使化合物X7盐酸盐溶解在混合溶剂中，配制成澄清溶液，随后缓慢挥发，收集固体，得到所述晶型B；
或者，(2)晶型B的制备方法包括以下步骤：
将化合物X7盐酸盐溶解在水或乙醇中，搅拌后过滤，将滤液缓慢降温，收集析出固体，室温室湿下干燥，得到所述晶型B；
优选地，所述搅拌为在40～60℃下搅拌0.5～1.5天；
和/或，优选地，所述缓慢降温为以0.05～0.1℃/分钟的降温速度将滤液从40～60℃降温至3～8℃；
或者，(3)晶型B的制备方法包括以下步骤：
在化合物X7盐酸盐中加入水得到浑浊液，搅拌浑浊液，离心收集固体，得到所述晶型B；
优选地，在室温下搅拌浑浊液3～5天。
基于相同的发明构思，本发明的另一个方面提供了制备上述化合物X7盐酸盐的晶体的方法，晶型C的制备方法包括以下步骤：
将化合物X7盐酸盐溶解在水中，搅拌后过滤，将滤液缓慢降温，收集析出固体，室温下真空干燥，得到所述晶型C；
优选地，所述搅拌为在40～60℃下搅拌2～4h；
和/或，优选地，所述缓慢降温为以0.05～0.1℃/分钟的降温速度将滤液从40～60℃降温至3～8℃；
和/或，优选地，所述真空干燥的时间为0.5～1.5天。
基于相同的发明构思，本发明的另一个方面提供了制备上述化合物X7盐酸盐的晶体的方法，(i)晶型D的制备方法包括以下步骤：
将化合物X7盐酸盐置于容器中，并加入三氯甲烷与正庚烷的体积比为(0.5～1.5)：1的混合溶剂使化合物X7盐酸盐溶解在混合溶剂中，配制成澄清溶液，随后缓慢挥发，收集固体，得到所述晶型D；
或者，(ii)晶型D的制备方法包括以下步骤：
将化合物X7盐酸盐溶解在水中，制成澄清溶液，并将装有澄清溶液的容器敞口放置在装有丙酮的密封容器中静置，收集析出固体，得到所述晶型D。
基于相同的发明构思，本发明的另一个方面提供了制备上述化合物X7盐酸盐的晶体的方法，晶型E的制备方法包括以下步骤：
将化合物X7盐酸盐溶解在水中，加热使溶液变澄清后过滤，将滤液缓慢降温，收集析出固体，得到所述晶型E；
优选地，所述加热为在40～60℃下加热1.5～2.5h；
和/或，优选地，所述缓慢降温为以0.05～0.1℃/分钟的降温速度将滤液从40～60℃降温至3～8℃。
基于相同的发明构思，本发明的另一个方面提供了制备上述化合物X7盐酸盐的晶体的方法，晶型F的制备方法包括以下步骤：
将化合物X7盐酸盐溶解在乙醇与水的体积比为(4～6)：2的混合溶剂中，超声后过滤，将滤液室温下挥发，得到所述晶型F；
优选地，所述超声的时间为20～40s。
在本发明的优选的实施方案中，晶型F溶解在水中，室温搅拌后转变为晶型B；
或者，晶型C加热至155～165℃并冷却至室温后转变为晶型D；
或者，晶型D或晶型C在选自乙醇或三氯甲烷的至少一种溶剂中搅拌2～4天转变为晶型A；优选地，所述搅拌的温度为室温或45～55℃；
或者，晶型B或晶型F在室温下在丙酮或丙酮与水的混合溶剂中搅拌转变为晶型A，优选地，所述丙酮与水的混合溶剂的水活度a w≤0.8。
基于相同的发明构思，本发明的再一个方面提供了一种药物组合物，包括上述化合物X7盐酸盐的晶体和药学上可接受的载体或赋形剂。
基于相同的发明构思，本发明的又一个方面提供了上述化合物X7盐酸盐的晶体或上述药物组合物在制备预防、治疗及延缓高血压、高血压引起的靶器官损伤及高血压相关疾病的药物中的应用。
附图说明
图1为本发明的化合物X7盐酸盐多晶型转化关系图；
图2a为本发明的晶型A的XRPD图；
图2b为本发明的晶型A的TGA/DSC图；其中，A曲线代表晶型A的TGA图，B曲线代表晶型A的DSC图；
图2c为本发明的晶型A的 1HNMR图；
图3a为本发明的晶型B的XRPD图；
图3b为本发明的晶型B的TGA/DSC图；其中，A曲线代表晶型B的TGA图，B曲线代表晶型B的DSC图；
图3c为本发明的晶型B的 1H NMR图；
图4a为本发明的晶型C的XRPD图；
图4b为本发明的晶型C的TGA/DSC图；其中，A曲线代表晶型C的TGA图，B曲线代表晶型C的DSC图；
图5a为本发明的晶型D的XRPD图；
图5b为本发明的晶型D的TGA/DSC图；其中，A曲线代表晶型D的TGA图，B曲线代表晶型D的DSC图；
图6为本发明的晶型E的XRPD图；
图7a为本发明的晶型F的XRPD图；
图7b为本发明的晶型F的TGA/DSC图；其中，A曲线代表晶型F的TGA图，B曲线代表晶型F的DSC图；
图7c为本发明的晶型F的 1H NMR图；
图8a为本发明的晶型A的DVS图；其中，
Figure PCTCN2021113018-appb-000002
代表周期1吸附，
Figure PCTCN2021113018-appb-000003
代表周期1脱附；
图8b为本发明的晶型B的DVS图；其中，
Figure PCTCN2021113018-appb-000004
代表周期1吸附，
Figure PCTCN2021113018-appb-000005
代表周期1脱附，
Figure PCTCN2021113018-appb-000006
代表周期2吸附；
图9a为本发明的晶型A的PLM图；
图9b为本发明的晶型B的PLM图。
具体实施方式
需要说明的是，除非另外定义，本说明书一个或多个实施例使用的技术术语或者科学术语应当为本公开所属领域内具有一般技能的人士所理解的通常意义。
在本发明中，如无相反说明，则所有操作在室温、常压条件实施。
在本发明中，“室温”指的是(25±2)℃，“室湿”指的是30～80％的相对空气湿度。
在本发明中，相对湿度用RH表示，表示气体中(通常为空气中)所含水蒸气量(水蒸气压)与其空气相同情况下饱和水蒸气量(饱和水蒸气压)的百分比。
在本发明中，水活度用a w表示，定义是样品中当前可被利用的游离水体积，其范围在0(绝对干燥)到1(相对湿度100％)之间。
以下实施例中涉及的溶剂的缩写与相应中文名称对照见下表1。
表1 溶剂名称对应表
英文 中文 英文 中文
MeOH 甲醇 1,4-dioxane 1,4-二氧六环
EtOH 乙醇 ACN 乙腈
IPA 异丙醇 DCM 二氯甲烷
acetone 丙酮 CHCl 3 三氯甲烷/氯仿
MIBK 甲基异丁基酮 n-heptane 正庚烷
EtOAc 乙酸乙酯 toluene 甲苯
IPAc 乙酸异丙酯 DMSO 二甲基亚砜
MTBE 甲基叔丁基醚 DMAc N,N-二甲基乙酰胺
THF 四氢呋喃 NMP N-甲基吡咯烷酮
2-MeTHF 2-甲基四氢呋喃 H 2O 水
表1中的试剂可购自国药集团化学试剂有限公司。
如背景技术部分所述，作为药用活性成分的晶型结构往往影响到该药物的化学和物理稳定性，结晶条件及储存条件的不同有可能导致化合物的晶体结构的变化，有时还会伴随着产生其他形态的晶型。因此，需要深入研究找到理化性质较优的晶体。本发明旨在对化合物X7盐酸盐展开多晶型筛选，通过对发现的多晶型进行鉴定和评估，推荐理化性质较优的晶型以供后续的研究开发。
本发明进行了多晶型筛选试验，多晶型筛选以起始样品化合物X7盐酸盐为原料，采用反溶剂添加、气固渗透、气液渗透、室温/50℃悬浮搅拌、缓慢挥发、缓慢降温、高聚物诱导的方法设置了100多个晶型筛选试验，共发现6种盐酸盐新晶型，分别命名为晶型A、B、C、D、E和F。具体试验方法及结果汇总于表2中。
表2 多晶型筛选试验总结
方法 试验数量 固体晶型
反溶剂添加 16 晶型A、F、成胶
气固渗透 12 晶型A
缓慢挥发 9 晶型A、B、D
缓慢降温 9 晶型A、B、E、成胶
室温悬浮搅拌 20 晶型A、B
50℃悬浮搅拌 16 晶型A
气液渗透 12 晶型A、D
高聚物诱导 6 晶型A
总计 100 晶型A、B、D、E、F、成胶
然后使用X射线粉末衍射(XRPD)、热重分析(TGA)和差示扫描量热(DSC)和高效液相色谱/离子色谱(HPLC/IC)等方法对所得新晶型的代表性样品进行了表征。具体表征结果汇总于表3中。
表3 化合物X7盐酸盐多晶型表征结果汇总
Figure PCTCN2021113018-appb-000007
#：峰值温度。 *：放热峰。
N/A：由于所得样品量较少且重复制备困难，没有进行表征和鉴定。
本发明中，化合物X7盐酸盐的结构式如式(I)所示：
Figure PCTCN2021113018-appb-000008
化合物X7盐酸盐的化学名称：3-(4-(4-(1H-苯并三唑-1-基)丁基)哌嗪-1-基)苯并异噻唑盐酸盐，分子式：C 21H 24SN 6·HCl，分子量：428.98，外观呈白色粉末状。
在本发明中，对筛选试验中获得的各晶型进行了相互转化关系研究，所得结果总结于图1中。为确定无水晶型及水合物之间的稳定性关系，对相关晶型进行了混悬竞争试验。结果显示，1)室温(25±2℃)及50℃下，无水晶型A、C和D的物理混合物在EtOH和CHCl 3中悬浮搅拌3天后均转变为晶型A。2)室温下，无水晶型A和水合物晶型B、F的物理混合物在acetone/H 2O中(a w≤0.8)悬浮搅拌后转变为晶型A，在H 2O中(a w＝1)悬浮搅拌后转变为晶型B。综合上述结果，在室温至50℃和室温下水活度a w≤0.8时，晶型A为热力学稳定的无水晶型；在室温下水活度a w＝1时，晶型B为更稳定的水合物。混悬竞争试验结果汇总于表4中。
表4 混悬竞争试验结果汇总
Figure PCTCN2021113018-appb-000009
根据上述表征结果，选择无水晶型A和水合物晶型B展开引湿性、固态稳定性、H 2O中平衡溶解度和晶体形貌的测试评估。1)动态水分吸附(DVS)试验结果显示在25℃/80％RH(相对湿度)条件下，晶型A吸水0.08％，表明其无引湿性(参考中国药典2015年版(药物引湿性试验指导原则))；晶型B在吸附过程中80％-95％RH及脱附过程中50％-30％RH时吸水量迅速变化，表明存在无水晶型和水合物间的转变。2)晶型A和B在80℃条件下闭口放置1天以及25℃/60％RH、40℃/75％RH条件下敞口放置1周后测定物理和化学稳定性。试验结果显示晶型A在三种条件下均未发生晶型转变和化学纯度降低；晶型B在三种条件下化学纯度未降低，在25℃/60％RH下放置1周后晶型不变。3)晶型A和B在H 2O中24小时的平衡溶解度分别为3.8、3.4mg/mL，溶解度测试后晶型均不变。4)PLM结果显示，晶型A为针状晶体，晶型B为粒径<20μm的颗粒状晶体。稳定性试验表明晶型A具有较好的物理和化学稳定性。
综合晶型间的稳定性关系以及固态性质的评估结果，推荐无水晶型A为进一步开发的优选晶型。
本发明涉及的聚合物分子量以重均分子量计，其测定采用凝胶渗透色谱(GPC)法，按照《中华人民共和国国家标准GB/T 21863-2008》测定(等同于德国标准DIN55672-1:2007《凝胶渗透色谱法(GPC)第1部分：用四氢呋喃(THF)作洗脱溶剂》)。具体的，聚乙烯吡咯烷酮的重均分子 量为8,000～700,000，聚乙烯醇的重均分子量为16,000～20,000，聚氯乙烯的重均分子量为50,000～110,000，聚醋酸乙烯酯的重均分子量为20,000～30,000，羟丙基甲基纤维素的重均分子量为400,000～675,000，甲基纤维素的重均分子量为18,000～200,000，聚己酸内酯的重均分子量为50,000～70,000，聚乙二醇的重均分子量为200～600，聚甲基丙烯酸甲酯的重均分子量为80,000～200,000，海藻酸的重均分子量为300,000～400,000，羟乙基纤维素的重均分子量为700,000～800,000，均可购自亚什兰化工(南京)有限公司。
需要说明的一点，除了表2中列出的晶型C的制备方法，晶型C还可采用以下方法制备得到：
将化合物X7盐酸盐溶解在水中，搅拌后过滤，将滤液缓慢降温，收集析出固体，室温下真空干燥，得到所述晶型C；优选地，所述搅拌为在40～60℃下搅拌2～4h；
和/或，优选地，所述缓慢降温为以0.05～0.1℃/分钟的降温速度将滤液从40～60℃降温至3～8℃；
和/或，优选地，所述真空干燥的时间为0.5～1.5天。
同样地，晶型F还可采用以下方法制备得到：
将化合物X7盐酸盐溶解在乙醇与水的体积比为(4～6)：2的混合溶剂中，超声后过滤，将滤液室温下挥发，得到所述晶型F；优选地，所述超声的时间为20～40s。
在本发明的优选的实施方案中，如图1所示，各晶型之间可以相互转变，具体的，所述晶型F溶解在水中，室温搅拌后转变为晶型B；
或者，晶型C加热至155～165℃并冷却至室温后转变为晶型D；优选地，晶型C加热至160℃并冷却至室温后转变为晶型D；
或者，晶型D或所述晶型C在选自EtOH或CHCl 3的至少一种溶剂中搅拌2～4天转变为晶型A；优选地，搅拌的温度为室温或45～55℃；更优选地，搅拌的温度为室温或50℃；
或者，晶型B或晶型F在室温下在丙酮或丙酮与H 2O的混合溶剂中搅拌转变为晶型A，优选地，丙酮与H 2O的混合溶剂的水活度a w≤0.8。
基于相同的发明构思，本发明的再一个方面提供了一种药物组合物，包括上述化合物X7盐酸盐的晶体和药学上可接受的载体或赋形剂。
在本发明中，“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受 的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂等。
本发明的药物组合物的剂型包括片剂、胶囊剂、颗粒剂、粉剂、丸剂或膜剂。在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉和碳酸钠；(e)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁或其混合物。
基于相同的发明构思，本发明的又一个方面提供了上述化合物X7盐酸盐的晶体或上述药物组合物在制备预防、治疗及延缓高血压、高血压引起的靶器官损伤及高血压相关疾病的药物中的应用。
在本发明的优选的实施方案中，所述的靶器官损伤是高血压引起的心、脑、肾或血管的损伤；所述高血压相关疾病，包括动脉粥样硬化、高血脂、肥胖、冠心病、主动脉夹层和高血糖、糖耐量异常、代谢综合征、糖尿病。
在本发明的优选的实施方案中，所述的靶器官损伤是左心室肥厚、脑卒中、肾皮质萎缩或主动脉增厚、心绞痛、心肌梗死、心功能衰竭、肾功能衰竭、视网膜动脉硬化、高血压眼底病变。
本发明所有的测试方法均为通用方法，测试方法如下：
1.X射线粉末衍射(XRPD)
XRPD图在PANalytacal Empyrean和X'Pert3射线粉末衍射分析仪上采集，扫描参数如表5所示。
表5 XRPD测试参数
Figure PCTCN2021113018-appb-000010
Figure PCTCN2021113018-appb-000011
2.热重分析(TGA)和差示扫描量热(DSC)
TGA和DSC图分别在TA Q500/5000热重分析仪和TA Q200/2000差示扫描量热仪上采集，表6列出了测试参数。
表6 TGA和DSC测试参数
参数 TGA DSC
方法 线性升温 线性升温
样品盘 铝盘，敞开 铝盘
温度范围 室温－设置终点温度 25℃-设置终点温度
扫描速率(℃/分钟) 10 10
保护气体 氮气 氮气
3.氢谱液态核磁( 1H Solution NMR)
氢谱液态核磁谱图在Bruker 400M核磁共振仪上采集，DMSO-d 6作为溶剂。
4.动态水分吸附(DVS)
动态水分吸附(DVS)曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。在25℃时的相对湿度用LiCl、Mg(NO 3) 2和KCl的潮解点校正。DVS测试参数列于表7中。
表7 DVS测试参数
Figure PCTCN2021113018-appb-000012
5.偏光显微镜(PLM)
偏光显微镜数据通过Axio Lab.Al正置式显微镜在室温下进行采集。
下面结合具体的实施例对本发明提供的技术方案做进一步的描述。下述实施例仅用于对本发明进行说明，并不会对本发明的保护范围进行限制。
实施例1 化合物X7的制备方法：
步骤1：4-氯丁基-取代苯并三氮唑(I)的制备
Figure PCTCN2021113018-appb-000013
在100mL反应瓶中加入24.0g纯化水，加入4.8g氢氧化钠溶解。称取3.0g苯并三氮唑、3.9g的1-溴-4-氯丁烷、四丁基溴化铵0.18g，混合搅拌。升至60℃，搅拌反应6小时。加入24.0g纯化水，搅拌降至室温；加入二氯甲烷31.8g，搅拌15分钟，静置15分钟，分液，水层弃去，得有机相(保留)；水相加入二氯甲烷31.8g，搅拌15分钟，静置15分钟，分液，水层弃去，得有机相(保留)，合并有机相；水层另行处理。将有机相减压浓缩得油状液体产物(I)。
步骤2：3-(4-(4-(1H-苯并三唑-1-基)丁基)哌嗪-1-基)苯并异噻唑游离碱(II)制备
Figure PCTCN2021113018-appb-000014
在100mL反应釜中加入15g乙腈、3-(1-哌嗪基)-1，2-苯并异噻唑1.9g、二异丙基乙胺3.3g、碘化钾1.4g、1-(4-氯丁基)-1H-苯并三氮唑1.8g。回流反应24小时。反应液降至室温，过滤，反应液浓缩得油状物，加入30mL乙酸乙酯溶解，纯化水萃取，有机相减压浓缩得油状产物(II)。
步骤3：3-(4-(4-(1H-苯并三唑-1-基)丁基)哌嗪-1-基)苯并异噻唑盐酸盐(III)制备
步骤二油状物(II)用15g无水乙醇溶解，转移至100mL反应瓶，滴加浓盐酸(约3mL)到反应瓶中，调pH＝1～2，析出黄白色固体，过滤得固体加入35g 95％乙醇混合均匀，加热溶解完全后过滤、析晶。将析出的晶体过滤，干燥得到X7盐酸盐2.23g。白色至类似白色固体，质谱测试[M+H] +＝393.2。
实施例2 反溶剂添加法制备化合物X7盐酸盐的晶型A和F
采用不同的溶剂共设置了16个反溶剂添加试验。分别称取约15mg/每份的起始样品(814802-05-A，实施例1制备)加至20mL的小瓶内，用 0.8～4.0mL的良溶剂(见表8)溶解后，向该澄清溶液中加入表8中的反溶剂，边滴加边搅拌至有固体析出，若加入约10mL反溶剂后仍无固体析出则停止。离心分离析出固体并进行XRPD测试，结果如表8所示，反溶剂添加试验中得到晶型A、F和成胶。
表8 反溶剂添加试验小结
Figure PCTCN2021113018-appb-000015
*：滴加10mL反溶剂后无固体析出，转移至5℃下搅拌。
#：滴加10mL反溶剂后无固体析出，转移至5℃下搅拌后澄清，转移至室温下挥发。
实施例3 气固渗透法制备化合物X7盐酸盐的晶型A
采用不同的溶剂共设置了12个气固扩散试验。称取约10mg每份的起始样品(814802-05-A，实施例1制备)于3mL小瓶中，另在20mL小瓶中加入约4mL溶剂，将3mL小瓶敞口置于20mL小瓶中后，将20mL小瓶密封。室温下静置8天后收集固体并进行XRPD测试。试验结果如表9所示，气固渗透试验中得到晶型A。
表9 气固渗透试验小结
试验编号 溶剂 固体晶型
814802-08-A1 H 2O 晶型A
8-l4802-08-A2 DCM 晶型A
814802-08-A3 EtOH 晶型A
814802-08-A4 MeOH 晶型A
814802-08-A5 ACN 晶型A
814802-08-A6 THF 晶型A
814802-08-A7 CHCl 3 晶型A
814802-08-A8 acetone 晶型A
814802-08-A9 DMSO 晶型A
814802-08-A10 EtOAc 晶型A
814802-08-A11 1,4-dioxane 晶型A
814802-08-A12 IPA 晶型A
实施例4 缓慢挥发法制备化合物X7盐酸盐的晶型A、B和D
采用不同的溶剂体系共设置了9个缓慢挥发试验。分别称取约15mg样品(814802-05-A，实施例1制备)至3mL小瓶中，分别加入1.0-3.0mL的表10中的溶剂，经震荡过滤后取其上清液，用封口膜封住装有澄清溶液的小瓶并在上面扎几个小孔，放置在室温下缓慢挥发。当溶剂完全挥干后，收集所得固体并进行XRPD测试。试验结果如表10所示，缓慢挥发试验中得到晶型A、B和D。
表10 缓慢挥发试验小结
试验编号 溶剂(v/v) 固体晶型
814802-09-A1 MeOH 晶型A
814802-09-A2 EtOH 晶型A
8l4802-09-A3 DCM 晶型A
814802-09-A4 CHCl 3 晶型A
814802-09-A5 MeOH/acetone(1:1) 晶型A
814802-09-A6 EtOH/ACN(4:1) 晶型A
814802-09-A7 DCM/THF(4:1) 晶型A
814802-09-A8 CHCl 3/n-heptane(1:1) 晶型D
814802-09-A9 ACN/H 2O(1:1) 晶型B
实施例5 缓慢降温法制备化合物X7盐酸盐的晶型A、B和E
称取约15mg每份的样品(814802-05-A，实施例1制备)于5mL小瓶中，加入0.6～4.0mL表11所示的溶剂，在50℃下搅拌约2小时后过滤 取滤液，将所得滤液放置在生化培养箱中，以0.1℃/分钟的降温速度从50℃降温至5℃，收集析出的固体并进行XRPD测试。试验结果见表11。缓慢降温试验得到晶型A、B、E和成胶。
表11 缓慢降温试验小结
试验编号 溶剂(v/v) 固体晶型
814802-10-Al & MeOH 晶型A #
814802-l0-A2 EtOH 晶型B #
814802-10-A3 CHCl 3 晶型A #
814802-10-A4 ACN 晶型A
814802-10-A5 H 2O 晶型E #
814802-10-A6 MeOH/IPAc(1:1) 晶型A *
814802-10-A7 EtOH/MTBE(4:1) 晶型A *
814802-1O-A8 CHCl 3/ACN(1:1) 晶型A
814802-10-A9 DMAc/toluene(1:1) 成胶 #
*：缓慢降温后澄清，转移至-20℃下析出固体。
#：缓慢降温后澄清，转移至-20℃下未析出固体，转移至室温下挥发。
&：加入34.3mg样品(814802-05-A)。
实施例6 室温悬浮搅拌法制备化合物X7盐酸盐的晶型A和B
称量约15mg每份的起始样品(814802-05-A，实施例1制备)至HPLC小瓶中，分别加入0.3mL表12中所列的溶剂，得到的浑浊液置于室温下磁力搅拌(～1000rpm)约4天后，离心分离固体并进行XRPD测试。试验结果见表12。室温悬浮搅拌试验得到晶型A和B。
表12 室温悬浮搅拌试验小结
试验编号 溶剂(v/v) 固体晶型
814802-11-A1 EtOH 晶型A
814802-11-A2 MIBK 晶型A
814802-11-A3 EtOAc 晶型A
814802-11-A4 MTBE 晶型A
814802-11-A5 ACN 晶型A
814802-11-A6 toluene 晶型A
814802-11-A7 H 2O 晶型B
814802-11-A8 EtOH/1,4-dioxane(1:1) 晶型A
814802-11-A9 MIBK/n-heptane(1:1) 晶型A
814802-11-Al0 IPAc/DCM(4:1) 晶型A
814802-11-A11 THF/ACN(1:1) 晶型A
814802-11-A12 acetone/NMP(4:1) 晶型A
814802-11-A13 IPA/EtOAc(1:1) 晶型A
814802-11-A14 MeOH/MTBE(1:1) 晶型A
814802-11-A15 2-MeTHF/CHCl 3(4:1) 晶型A
814802-11-A16 MIBK/DMSO(4:1) 晶型A
814802-11-A17 EtOH/H 2O(aw～0.2,97:3) 晶型A
814802-11-A18 EtOH/H 2O(aw～0.4,93:7) 晶型A
814802-11-A19 EtOH/H 2O(aw～0.6,86:14) 晶型A
814802-11-A20 EtOH/H 2O(aw～0.8,70:30) 晶型A *
＊：搅拌4天后澄清，加入20.3mg样品(814802-05-A)继续搅拌2天后测XRPD。
实施例7 50℃悬浮搅拌法制备化合物X7盐酸盐的晶型A
称量约20mg每份的起始样品(814802-05-A，实施例1制备)至HPLC小瓶中，分别加入0.3mL表13中所列的溶剂，得到的浑浊液置于50℃下磁力搅拌(～1000rpm)约4天后，离心分离固体并进行XRPD测试。试验结果见表13。悬浮搅拌试验得到晶型A。
表13 50℃悬浮搅拌试验小结
试验编号 溶剂(v/v) 固体晶型
814802-12-A1 EtOH 晶型A
814802-12-A2 IPA 晶型A
814802-12-A3 acetone 晶型A
814802-12-A4 IPAc 晶型A
814802-12-A5 1,4-dioxane 晶型A
814802-12-A6 ACN 晶型A
814802-12-A7 n-heptane 晶型A
814802-12-A8 IPA/2-MeTHF(1:1) 晶型A
814802-12-A9 MIBK/EtOAc(1:1) 晶型A
814802-12-A10 CHCl 3/n-heptane(1:4) 晶型A
814802-12-A11 EtOH/acetone(1:1) 晶型A
814802-12-A12 ACN/H 2O(1:1) 晶型A *
814802-12-A13 IPAc/DMAc(9:1) 晶型A
814802-12-A14 MTBE/NMP(9:1) 晶型A
814802-12-A15 acetone/ACN(1:1) 晶型A
814802-12-A16 2-MeTHF/toluene(1:1) 晶型A
＊：搅拌4天后澄清，加入40.3mg样品(814802-05-A)搅拌后仍澄清，转移至室温下挥发得到。
实施例8 气液渗透法制备化合物X7盐酸盐的晶型A和D
称取约15mg每份的起始样品(814802-05-A，实施例1制备)溶于1.2～2.4mL良溶剂中，过滤得滤液转移至3mL小瓶，另取20mL的小瓶向其中加入约4mL的反溶剂，将装有滤液的3mL小瓶敞口置于20mL小瓶后，密封20mL的小瓶并于室温下静置。当观察到有固体析出时，则分离固体测XRPD，收集得到的固体并进行XRPD测试。试验结果如表14所示，气液渗透试验得到晶型A和D。
表14 气液渗透试验小结
Figure PCTCN2021113018-appb-000016
*:6天后无固体析出，转移至室温下挥发。
实施例9 高聚物诱导法制备化合物X7盐酸盐的晶型A
称取约15mg每份的起始样品(814802-05-A，实施例1制备)溶于1.0～3.0mL表15中所列溶剂，过滤取得滤液转移至装有～2mg混合聚合物的3mL小瓶中，用封口膜封住装有澄清溶液的小瓶并在上面扎几个小孔，放置在室温下缓慢挥发，收集所得固体并进行XRPD测试。试验结果如表15所示，聚合物诱导析晶试验中得到的均为晶型A。
表15 高聚物诱导试验小结
Figure PCTCN2021113018-appb-000017
混合高聚物A:聚乙烯吡咯烷酮，聚乙烯醇，聚氯乙烯，聚醋酸乙烯酯，羟丙基甲基纤维素和甲基纤维素(等质量混合)
混合高聚物B:聚己酸内酯，聚乙二醇，聚甲基丙烯酸甲酯，海藻酸钠和羟乙基纤维素(等质量混合)
实施例10 制备化合物X7盐酸盐的晶型B
本实施例中，化合物X7盐酸盐的晶型B的制备方法包括以下步骤：
1.称取199.8mg起始样品(814802-05-A，实施例1制备)至20mL小瓶中，加入18.0mL水，50℃下磁力搅拌(～800rpm)约1天。
2.过滤(0.45m的PTFE滤头)，滤液以0.1℃/min的速率缓慢降温至5℃。
3.分离出固体室温室湿下干燥。
实施例11 制备化合物X7盐酸盐的晶型C
本实施例中，化合物X7盐酸盐的晶型C的制备方法包括以下步骤：
1.称取202.1mg起始样品(814802-05-A，实施例1制备)至20mL小瓶中，加入18.0mL水，50℃下磁力搅拌(～800rpm)约3小时。
2.过滤(0.45m的PTFE滤头)，滤液以0.1℃/min的速率缓慢降温至5℃。
3.分离出固体室温下真空干燥干燥1天。
实施例12 制备化合物X7盐酸盐的晶型D
本实施例中，化合物X7盐酸盐的晶型D通过加热晶型C得到，包括以下步骤：
1.称取100.4mg晶型C样品(8l4802-32-A2，实施例11制备)至20mL小瓶中。
2.在160℃烘箱中加热约5min。
3.室温下冷却。
实施例13 制备化合物X7盐酸盐的晶型F
本实施例中，化合物X7盐酸盐的晶型F的制备方法包括以下步骤：
1.称取102.4mg起始样品(814802-05-A，实施例1制备)至20mL小瓶中，加入14.0mL的EtOH/H 2O(5:2,v/v)。
2.超声约30s后过滤(0.45m的PTFE滤头)，滤液转移至新的20mL小瓶中。
3.室温下敞口挥发。
将制备得到的化合物X7的晶型A、晶型B、晶型C、晶型D、晶型E和晶型F分别用XRPD、TGA、DSC和 1H NMR进行表征。
(1)晶型A的表征结果
晶型A(814802-11-A17，实施例6制备)的XRPD表征结果如图2a所示，其余实施例制备得到的晶型A的XRPD表征结果经检测与图2a一致，晶型A的XRPD衍射峰数据如表16所示。
表16 晶型A的XRPD衍射峰数据
2theta d间隔 强度％
7.57 11.69 1.98
9.99 8.85 0.99
11.57 7.65 48.37
12.49 7.09 2.66
15.12 5.86 100.00
17.92 4.95 8.12
19.96 4.45 3.32
21.03 4.22 13.00
25.34 3.51 3.97
26.01 3.43 9.83
27.89 3.20 5.94
30.64 2.92 2.02
31.11 2.87 1.75
晶型A的特征峰选择中，主要特征峰：15.12±0.2°、11.57±0.2°和21.03±0.2°；次要特征峰：26.01±0.2°、17.92±0.2°和27.89±0.2°。
晶型A(814802-11-A17，实施例6制备)的TGA/DSC表征结果如图2b所示，其余实施例制备得到的晶型A的TGA/DSC表征结果经检测与图 2b一致，晶型A样品加热至150℃失重0.8％，在211.7℃(起始温度)处有一个尖锐的吸热峰。晶型A(814802-11-A17，实施例6制备)的 1HNMR表征结果如图2c所示，其余实施例制备得到的晶型A的 1HNMR表征结果经检测与图2c一致。根据较小的TGA失重和单一的吸热峰，推测晶型A为无水晶型。
(2)晶型B的表征结果
晶型B(814802-09-A9，实施例4制备)的XRPD表征结果如图3a所示，其余实施例制备得到的晶型B的XRPD表征结果经检测与图3a一致，晶型B的XRPD衍射峰数据如表17所示。
表17 晶型B的XRPD衍射峰数据
2theta d间隔 强度％
7.38 11.98 100.00
13.19 6.71 58.50
14.48 6.12 15.71
16.99 5.22 19.95
19.86 4.47 9.05
21.38 4.16 3.03
23.08 3.85 8.18
25.05 3.55 11.35
25.57 3.48 19.60
晶型B的特征峰选择中，主要特征峰：7.38±0.2°、13.19±0.2°和16.99±0.2°；次要特征峰：25.57±0.2°、14.48±0.2°和25.05±0.2°。
晶型B(814802-09-A9，实施例4制备)的TGA/DSC表征结果如图3b所示，其余实施例制备得到的晶型B的TGA/DSC表征结果经检测与图3b一致。TGA结果显示样品加热至70℃失重8.3％，DSC结果显示在68.3℃(峰值)和201.3℃(起始)处有两个吸热峰，在126.9℃(起始)处有一个微弱的放热峰。晶型B(814802-09-A9，实施例4制备)的 1HNMR表征结果(如图3c所示)显示晶型B样品中无溶剂ACN残留，其余实施例制备得到的晶型B的 1HNMR表征结果经检测与图3c一致。结合 1HNMR结果推测，晶型B为水合物，加热后脱水转变为无水晶型。
(3)晶型C的表征结果
晶型C(实施例11制备)的XRPD表征结果如图4a所示，其余实施例制备得到的晶型C的XRPD表征结果经检测与图4a一致，晶型C的XRPD衍射峰数据如表18所示。
表18 晶型C的XRPD衍射峰数据
2theta d间隔 强度％
8.26 10.71 100.00
13.43 6.59 11.43
14.03 6.31 33.63
15.68 5.65 90.14
15.91 5.57 25.61
16.59 5.34 5.72
19.28 4.60 4.57
20.59 4.31 8.64
21.25 4.18 28.11
21.73 4.09 4.77
23.64 3.76 6.87
25.30 3.52 14.35
25.78 3.46 3.39
27.13 3.29 4.22
28.70 3.11 6.84
30.31 2.95 1.69
33.57 2.67 3.45
34.30 2.61 1.31
38.46 2.34 3.91
晶型C的特征峰选择中，主要特征峰：8.26±0.2°、15.68±0.2°和14.03±0.2°；次要特征峰：21.25±0.2°、25.30±0.2°和13.43±0.2°。
晶型C(实施例11制备)的TGA/DSC表征结果如图4b所示，其余实施例制备得到的晶型C的TGA/DSC表征结果经检测与图4b一致，加热至180℃失重1.8％，在134.8℃(起始)处有一个放热峰，在204.6℃(起始)处有一个尖锐的吸热峰。晶型C失重较平缓且具有单一尖锐的吸热峰，推测晶型C为无水晶型。
(4)晶型D的表征结果
晶型D(实施例12制备)的XRPD表征结果如图5a所示，其余实施例制备得到的晶型D的TGA/DSC表征结果经检测与图5a一致，晶型D的XRPD衍射峰数据如表19所示。
表19 晶型D的XRPD衍射峰数据
2theta d间隔 强度％
6.28 14.08 5.12
8.69 10.17 49.97
12.67 6.99 16.49
13.85 6.39 4.99
15.12 5.86 25.63
15.69 5.65 100.00
18.38 4.83 6.07
18.88 4.70 3.60
19.39 4.58 6.83
21.40 4.15 11.14
22.11 4.02 15.40
24.98 3.56 63.49
25.62 3.48 8.36
27.39 3.26 4.96
27.89 3.20 6.90
28.94 3.08 3.90
30.65 2.92 1.77
31.68 2.82 2.18
33.36 2.69 2.32
35.84 2.51 3.22
晶型D的特征峰选择中，主要特征峰：15.69±0.2°、24.98±0.2°和8.69±0.2°；次要特征峰：15.12±0.2°、12.67±0.2°和22.11±0.2°。
晶型D(实施例12制备)的TGA/DSC表征结果如图5b所示，其余实施例制备得到的晶型D的TGA/DSC表征结果经检测与图5b一致。晶型D样品加热至180℃失重2.4％，在204.5℃(起始)处有一个尖锐的吸热峰。根据较平缓的TGA失重和单一的DSC吸热峰，推测晶型D为无水晶型。
(5)晶型E的表征结果
晶型E(814802-10-A5，实施例5制备)的XRPD表征结果如图6所示，其余实施例制备得到的晶型E的TGA/DSC表征结果经检测与图6一致，晶型E的XRPD衍射峰数据如表20所示。
表20 晶型E的XRPD衍射峰数据
2theta d间隔 强度％
9.57 9.24 40.00
9.81 9.02 33.15
11.81 7.50 35.10
13.01 6.80 83.29
15.36 5.77 29.03
16.40 5.41 7.38
16.76 5.29 19.14
18.75 4.73 60.18
19.05 4.66 87.86
19.72 4.50 11.93
20.77 4.28 9.96
21.56 4.12 35.94
22.71 3.92 26.29
23.08 3.85 100.00
23.83 3.73 24.60
24.28 3.67 19.51
24.75 3.60 21.74
26.12 3.41 52.84
28.19 3.17 12.12
晶型E的特征峰选择中，主要特征峰：23.08±0.2°、19.05±0.2°和13.01±0.2°；次要特征峰：26.12±0.2°、21.56±0.2°和11.81±0.2°；再次特征峰：15.36±0.2°、23.83±0.2°、24.75±0.2°。
(6)晶型F的表征结果
晶型F(实施例13制备)的XRPD表征结果如图7a所示，其余实施例制备得到的晶型F的TGA/DSC表征结果经检测与图7a一致，晶型F的XRPD衍射峰数据如表21所示。
表21 晶型F的XRPD衍射峰数据
2theta d间隔 强度％
5.77 15.31 30.71
8.82 10.03 0.57
11.74 7.54 100.00
13.81 6.41 1.82
15.66 5.66 4.04
17.74 5.00 0.69
18.79 4.72 0.41
20.25 4.39 0.73
23.79 3.74 1.99
26.51 3.36 1.91
28.49 3.13 1.07
30.11 2.97 0.89
33.04 2.71 0.13
晶型F的特征峰选择中，主要特征峰：11.74±0.2°、5.77±0.2°和15.66±0.2°。
晶型F(实施例13制备)的TGA/DSC结果如图7b所示，其余实施例制备得到的晶型F的TGA/DSC表征结果经检测与图7b一致。晶型F样品加热至80℃失重8.3％，在71.2℃、203.4℃和208.9℃(峰值)处有三个吸热峰。晶型F(实施例13制备)的 1HNMR结果(如图7c所示)表明样品中无溶剂EtOH残留，其余实施例制备得到的晶型F的 1HNMR表征结果经检测与图7c一致。结合 1HNMR结果和TGA台阶失重，推测晶型F为水合物。
试验例1 晶型间的转变关系研究
为了进一步研究无水晶型A、C、D和水合物晶型B、F的稳定性关系，设置了各晶型间的混悬竞争试验，包括室温和50℃下晶型A、C、D在EtOH和CHCl 3中的混悬竞争，以及室温下晶型A、B、F在acetone/H 2O(a w＝0～1)中的混悬试验。
1.1无水晶型A/C/D的混悬竞争
为了研究无水晶型A、C和D在不同温度及不同溶剂条件下的稳定性关系，设置了室温和50℃下在EtOH和CHCl 3中的混悬竞争试验。具体步骤如下：1)配制特定温度下起始样品(814802-05-A，实施例1制备)在不同溶剂中的饱和溶液；2)将等质量的晶型A(814802-11-A17，实施例6制备)、C(实施例11制备)和D样品(实施例12制备)(各约4mg)分别加入到0.5mL的饱和溶液中形成悬浊液；3)分别在室温和50℃条件下悬浮搅拌约2天(～800转/分)；4)分离出剩余固体(湿样)，测试XRPD(透射)。在所有试验中起始混合晶型最终均转变为无水晶型A，表明晶型A在室温至50℃范围内比晶型C和D更稳定。
1.2无水晶型A和水合物B/F的混悬竞争
为了研究无水晶型A与水合物晶型B/F在不同水活度条件下的稳定性关系，在室温下设置了不同水活度acetone/H 2O溶剂体系中的混悬竞争试验。具体步骤如下：1)配制室温下起始样品(814802-05-A，实施例1制备)在不同溶剂中的饱和溶液各0.5mL；2)将等质量的晶型A (814802-11-A17，实施例6制备)、B(814802-09-A9，实施例4制备)和F样品(实施例13制备)(各约5mg)分别加入到饱和溶液中形成悬浊液，在室温下磁力搅拌约2天(～800转/分) 2；3)分离出剩余固体，测试XRPD(透射)。结果显示当水活度a w≤0.8时，起始混合晶型最终均转变为无水晶型A；在H 2O中(a w＝1)悬浮搅拌后，起始混合晶型最终转变为水合物晶型B。上述结果表明，室温下无水晶型A在水活度a w＝0～0.8范围内更稳定，水合物晶型B在a w＝1时更稳定。
试验例2 晶型评估
结合试验例1中的混悬竞争的试验结果，晶型A在3种无水晶型中具有最高的热力学稳定性；水合物晶型B在a w＝1的条件下比其他晶型具有更好的稳定性。因此，选择晶型A和晶型B进行了进一步的评估，包括水中平衡溶解度、固态稳定性、引湿性和PLM形貌。
2.1水中平衡溶解度
室温下对晶型A样品(814802-11-A17，实施例6制备)和晶型B样品(814802-09-A9，实施例4制备)在水中的平衡溶解度进行了测试。作为对比，在相同条件下也测试了晶型C样品(实施例11制备)、晶型D样品(实施例12制备)和晶型F样品(实施例13制备)的平衡溶解度。试验中配置了各晶型的悬浊液(～10mg/mL)，室温下磁力搅拌24小时(转速～800rpm)后离心(10000rpm，5min)，上清液过滤(0.22μm的PTFE滤膜)后测溶解度和pH，固体测XRPD(透射)，试验结果汇总于下表22中。晶型A和晶型B在测试前后的晶型不变，水中24小时溶解度分别为3.8和3.4mg/mL；晶型C、D和F在水中平衡24小时后均转变为晶型B。
表22 晶型A/B/C/D/F的水中平衡溶解度结果汇总
起始晶型(编号) 溶解度(mg/mL) pH 晶型转变
晶型A 3.8 4.6 否
晶型B 3.4 4.9 否
晶型C 3.3 4.9 转变为晶型B
晶型D 3.1 4.9 转变为晶型B
晶型F 2.9 4.7 转变为晶型B
2.2固态稳定性
为了评估无水晶型A(814802-11-A17，实施例6制备)和水合物晶型B(814802-09-A9，实施例4制备)的固态稳定性，分别称取适量样品在80℃下闭口放置1天以及25℃/60％RH、40℃/75％RH条件下敞口放置一周。将不同条件下分离出的固体样品，分别通过HPLC测试纯度评估化学 稳定性，XRPD测试晶型评估物理稳定性。评估结果汇总于表23中：在三种测试条件下，晶型A均未发生晶型转变和HPLC纯度降低，表明晶型A具有较好的物理和化学稳定性；晶型B在25℃/60％RH下放置一周后晶型和HPLC纯度不变。
2.3引湿性
通过在25℃下的动态水分吸附试验对晶型A样品(814802-11-A17，实施例6制备)和晶型B样品(814802-09-A9，实施例4制备)的引湿性进行了评估，结果如图8a和图8b所示。
晶型A样品在25℃/80％RH时吸水0.08％，表明晶型A无引湿性，DVS测试后晶型未发生转变。
晶型B样品在脱附过程中，相对湿度50％RH时吸水12.3％，相对湿度降低至30％RH过程中吸水量迅速减少，30％RH时吸水0.4％，推测该过程发生了水合物向无水晶型的转变；吸附过程中，相对湿度增加至80％RH时吸水迅速增加，95％RH时吸水12.5％，推测该过程中由无水晶型向水合物转变。2.4PLM
对晶型A样品(814802-11-A17，实施例6制备)和晶型B样品(814802-09-A9，实施例4制备)进行了PLM测试以评估晶体形貌，结果如图9a和图9b所示。晶型A为针状晶体，晶型B为粒径＜20μm的颗粒状晶体。
试验例3 晶型A作为血管舒张药物的活性试验
(1)家兔离体血管平滑肌标本的制备
将家兔击晕后迅速剖开胸腔，剥离出降主动脉，将结缔组织及周围脂肪组织去除后(若进行五羟色胺受体拮抗实验，还应使用光滑的不锈钢钢棒去除内皮细胞)，切成3-5mm血管环，然后钢丝钩穿过血管环，一端固定在通气钩上，另一端连于张力换能器上，置于盛有20ml营养液的浴管中，通过记录仪记录张力变化。浴管内保持温度37±0.5℃，并以每秒1～2个气泡的速度通入混合气体(95％O 2+5％CO 2)。标本初始负荷1.5g，每20min换一次营养液，平衡2小时，待基线稳定后开始实验。
(2)晶型A(814802-11-A17，实施例6制备)对致痉剂AD引起收缩家兔离体血管平滑肌舒张作用
标本张力稳定后，记录一段波形，向浴管内加入致痉剂盐酸肾上腺素(AD)(10 -5mol/L)诱导收缩，当达到最大收缩后，充分冲洗标本，每20min换一次K-H液，平衡60min，待基线恢复平稳后，再次用同浓度致痉剂诱导收缩。当后一次收缩最大反应与前一次基本一致时，累积加入配制好的 X7溶液(1×10 -9～1×10 -6mol/L)，记录波形。以X7最大舒张反应为100％,分别计算各浓度X7舒张百分数,以此为纵坐标，各浓度对数为横坐标绘制量效曲线。X7对AD致痉剂引起的标本收缩有舒张作用，它对肾上腺素的舒张作用呈现一定的剂量依赖性，药物舒张AD收缩的家兔主动脉的-logEC 50值为8.07±0.09。
(3)晶型A(814802-11-A17，实施例6制备)对家兔血管平滑肌五羟色胺(5-HT)受体的拮抗作用
标本张力稳定之后，记录一段波形，向浴管内累积加入5-HT(10 -7～3×10 -4mol/L)直至达到最大反应，记录波形。然后用K-H液反复冲洗标本，平衡1.5h后，加入(10 -7mol/L)，20min后再以同法加入5-HT。以最大反应为100％，5-HT收缩百分数为纵坐标，5-HT各浓度负对数为横坐标绘制量效曲线，加入药物X7(10 -7mol/L)后，5-HT量效曲线明显平行右移，最大反应几乎不变，对各浓度反应百分数进行统计学检验后，P值<0.01，存在显著性差异。药物拮抗5-HT收缩家兔主动脉的PA 2值8.86±0.14。
(4)阳性对照药沙格雷酯对5-HT累积收缩量效曲线的影响
标本张力稳定之后，记录一段波形，向浴管内累积加入5-HT(10 -7～3×10 -4mol/L)直至达到最大反应，记录波形。然后用K-H液反复冲洗标本，平衡1.5h后，加入沙格雷酯(10 -6mol/L)，20min后再以同法加入5-HT。以最大反应为100％，5-HT收缩百分数为纵坐标，5-HT各浓度负对数为横坐标绘制量效曲线，加入药物沙格雷酯(10 -6mol/L)后，5-HT量效曲线明显平行右移，最大反应几乎不变，对各浓度反应百分数进行统计学检验后，P值<0.01，存在显著性差异。药物拮抗5-HT收缩家兔主动脉的PA 2值7.21±0.08。
(5)晶型A(814802-11-A17，实施例6制备)对家兔血管平滑肌α受体的拮抗作用
标本张力稳定之后，记录一段波形，向浴管内累积加入去甲肾上腺素(10 -8～6×10 -5mol/L)直至达到最大反应，记录波形。然后用K-H液反复冲洗标本，平衡1h后，加入(3×10 -8mol/L)，20min后再以同法加入苯肾上腺素。以最大反应为100％，苯肾上腺素收缩百分数为纵坐标，苯肾上腺素各浓度负对数为横坐标绘制量效曲线，加入药物X7(3×10 -8mol/L)后，去甲肾上腺素量效曲线明显平行右移，最大反应几乎不变，对各浓度反应百分数进行统计学t检验后，多数P值<0.01，存在显著性差异。药物拮抗去甲肾上腺素收缩家兔主动脉的PA 2值为7.98±0.04；
(6)阳性对照药多沙唑嗪对去甲肾上腺素累积收缩量效曲线的影响
标本张力稳定后，记录一段波形，向浴管内加入去甲肾上腺素(10 -8～3×10 -3mol/L)直到达到最大反应，记录波形。然后用K-H液反复冲洗标本，每20min换一次K-H液，平衡60min，待基线恢复平稳后，加入多沙唑嗪(10 -7mol/L)，15min后再以同法加入去甲上腺素(10 -6～10 -2mol/L)。以最大反应为100％，去甲上腺素收缩百分数为纵坐标，苯肾上腺素各浓度负对数为横坐标绘制量效曲线，加入多沙唑嗪(10 -7mol/L)后，苯肾上腺素量效曲线明显平行右移，最大反应几乎不变，对各浓度反应百分数进行统计学检验后，多数P值<0.01，存在显著性差异。阳性药多沙唑嗪拮抗NA收缩家兔主动脉的PA 2值为7.83±0.05。
试验例4 晶型A用于固体制剂的溶出试验数据
X7在各pH条件下稳定，在高温条件下稳定，适宜开发成胃溶型制剂；本试验例晶型A(814802-11-A17，实施例6制备)采用常规制剂方法制备片剂的溶出试验数据如下。
(1)溶出条件：
溶出介质：分别以1000ml水、pH1.0盐酸溶液、pH4.5醋酸盐缓冲液、pH6.8磷酸盐缓冲液作为溶出介质
方法：中国药典2015年版第四部通则0931溶出度与释放度测定法第二法。
转速：50r/min
温度：37℃
取样点：在5、10、15、20、30、45、60min取溶出液，过0.45μm有机滤膜，取续滤液直接进高效液相检测。
测定方法：中国药典2015年版第四部通则0512高效液相色谱法。
(2)检测结果：
表23 pH1.0盐酸溶液中X7的溶出曲线检测结果(n＝12)
Figure PCTCN2021113018-appb-000018
表24 水中X7的溶出曲线检测结果(n＝12)
Figure PCTCN2021113018-appb-000019
Figure PCTCN2021113018-appb-000020
表25 pH6.8磷酸盐缓冲液X7的溶出曲线检测结果(n＝12)
Figure PCTCN2021113018-appb-000021
表26 pH4.5醋酸盐缓冲液中X7的溶出曲线检测结果(n＝12)
Figure PCTCN2021113018-appb-000022
从四种介质的溶出曲线中可以看出，本试验例中晶型A研制的X7制剂片剂三批批间的溶出行为基本一致，自制样品批间重复性好，质量均一。

Claims (21)

  1. 化合物X7盐酸盐的晶体，其中，所述化合物X7盐酸盐的晶体的X射线粉末衍射图2θ衍射角在5°～35°处具有特征衍射峰；
    其中，所述化合物X7盐酸盐的结构式如式(I)所示：
    Figure PCTCN2021113018-appb-100001
  2. 根据权利要求1所述的化合物X7盐酸盐的晶体，其中，所述化合物X7盐酸盐的晶体包括晶型A，所述晶型A的X射线粉末衍射图2θ衍射角在15.12±0.2°、11.57±0.2°和21.03±0.2°处具有特征衍射峰；
    更优选地，所述晶型A的X射线粉末衍射图2θ衍射角同时在26.01±0.2°、17.92±0.2°和27.89±0.2°处还具有特征衍射峰；
    进一步优选地，所述晶型A的X射线粉末衍射图2θ衍射角同时在25.34±0.2°、19.96±0.2°、12.49±0.2°、30.64±0.2°、7.57±0.2°、31.11±0.2°和9.99±0.2°处还具有特征衍射峰。
  3. 根据权利要求1或2所述的化合物X7盐酸盐的晶体，其中，晶型A的热重分析图在30.0～155.0℃范围内具有0.8±0.5％的失重；
    和/或，晶型A的差示扫描量热图在210.0～220.0℃范围内具有吸热峰；
    和/或，晶型A为无水晶型。
  4. 根据权利要求1-3之一所述的化合物X7盐酸盐的晶体，其中，所述化合物X7盐酸盐的晶体包括晶型B，所述晶型B的X射线粉末衍射图2θ衍射角在7.38±0.2°、13.19±0.2°和16.99±0.2°处具有特征衍射峰；
    更优选地，所述晶型B的X射线粉末衍射图2θ衍射角同时在25.57±0.2°、14.48±0.2°和25.05±0.2°处还具有特征衍射峰；
    进一步优选地，所述晶型B的X射线粉末衍射图2θ衍射角同时在19.86±0.2°、23.08±0.2°和21.38±0.2°处还具有特征衍射峰。
  5. 根据权利要求1-4之一所述的化合物X7盐酸盐的晶体，其中，晶型B的热重分析图在29.0～72.0℃范围内具有8.0～12.0％的失重；
    和/或，晶型B的差示扫描量热图同时在60.0～80.0℃范围内和195.0～215.0℃范围内具有吸热峰，以及在125.0～145.0℃范围内具有放热峰；
    和/或，晶型B为水合物。
  6. 根据权利要求1-5之一所述的化合物X7盐酸盐的晶体，其中，所 述化合物X7盐酸盐的晶体包括晶型C，所述晶型C的X射线粉末衍射图2θ衍射角在8.26±0.2°、15.68±0.2°和14.03±0.2°处具有特征衍射峰；
    更优选地，所述晶型C的X射线粉末衍射图2θ衍射角同时在21.25±0.2°、25.30±0.2°和13.43±0.2°处还具有特征衍射峰；
    进一步优选地，所述晶型C的X射线粉末衍射图2θ衍射角同时在15.91±0.2°、20.59±0.2°、23.64±0.2°、28.70±0.2°、16.59±0.2°、21.73±0.2°、19.28±0.2°、27.13±0.2°、38.46±0.2°、33.57±0.2°、25.78±0.2°、30.31±0.2°和34.30±0.2°处还具有特征衍射峰。
  7. 根据权利要求1-6之一所述的化合物X7盐酸盐的晶体，其中，晶型C的热重分析图在27.0～190.0℃范围内具有1.5～2.5％的失重；
    和/或，晶型C的差示扫描量热图同时在128.0～160.0℃范围内具有放热峰和201.0～210.0℃范围内具有吸热峰；
    和/或，晶型C为无水晶型。
  8. 根据权利要求1-7之一所述的化合物X7盐酸盐的晶体，其中，所述化合物X7盐酸盐的晶体包括晶型D，所述晶型D的X射线粉末衍射图2θ衍射角在15.69±0.2°、24.98±0.2°和8.69±0.2°处具有特征衍射峰；
    更优选地，所述晶型D的X射线粉末衍射图2θ衍射角同时在15.12±0.2°、12.67±0.2°和22.11±0.2°处还具有特征衍射峰；
    进一步优选地，所述晶型D的X射线粉末衍射图2θ衍射角同时在21.40±0.2°、25.62±0.2°、27.89±0.2°、19.39±0.2°、18.38±0.2°、6.28±0.2°、13.85±0.2°、27.39±0.2°、28.94±0.2°、18.88±0.2°、35.84±0.2°、33.36±0.2°、31.68±0.2°和30.65±0.2°处还具有特征衍射峰。
  9. 根据权利要求1-8之一所述的化合物X7盐酸盐的晶体，其中，晶型D的热重分析图在30.0～190.0℃范围内具有2.0～2.5％的失重；
    和/或，晶型D的差示扫描量热图在200.0～210.0℃范围内具有吸热峰；
    和/或，晶型D为无水晶型。
  10. 根据权利要求1-9之一所述的化合物X7盐酸盐的晶体，其中，所述化合物X7盐酸盐的晶体包括晶型E，所述晶型E的X射线粉末衍射图2θ衍射角在23.08±0.2°、19.05±0.2°和13.01±0.2°处具有特征衍射峰；
    更优选地，所述晶型E的X射线粉末衍射图2θ衍射角同时在26.12±0.2°、21.56±0.2°和11.81±0.2°处还具有特征衍射峰；
    进一步优选地，所述晶型E的X射线粉末衍射图2θ衍射角同时在15.36±0.2°、23.83±0.2°和24.75±0.2°处还具有特征衍射峰；
    再进一步优选地，所述晶型E的X射线粉末衍射图2θ衍射角同时在18.75±0.2°、9.57±0.2°、9.81±0.2°、22.71±0.2°、24.28±0.2°、16.76±0.2 °、28.19±0.2°、19.72±0.2°、20.77±0.2°和16.40±0.2°处还具有特征衍射峰。
  11. 根据权利要求1-10之一所述的化合物X7盐酸盐的晶体，其中，所述化合物X7盐酸盐的晶体包括晶型F，所述晶型F的X射线粉末衍射图2θ衍射角在11.74±0.2°、5.77±0.2°和15.66±0.2°处具有特征衍射峰；
    更优选地，所述晶型F的X射线粉末衍射图2θ衍射角同时在23.79±0.2°、26.51±0.2°、13.81±0.2°、28.49±0.2°、30.11±0.2°、20.25±0.2°、17.74±0.2°、8.82±0.2°、18.79±0.2°和33.04±0.2°处还具有特征衍射峰。
  12. 根据权利要求1-11之一所述的化合物X7盐酸盐的晶体，其中，晶型F的热重分析图在25.0～90.0℃范围内具有8.0～8.5％的失重；
    和/或，晶型F的差示扫描量热图同时在50.0～80.0℃、190.0～205.0℃和206.0～215.0℃范围内具有吸热峰；
    和/或，晶型F为水合物。
  13. 一种制备如权利要求1-3任一项所述的化合物X7盐酸盐的晶体的方法，其中，(a)晶型A的制备方法包括以下步骤：
    将化合物X7盐酸盐溶解在第一良溶剂中，再逐滴滴加第一反溶剂，收集析出固体，得到所述晶型A；
    优选地，所述第一良溶剂选自甲醇、三氯甲烷、二甲基亚砜或N-甲基吡咯烷酮中的至少一种；
    和/或，优选地，所述第一反溶剂选自丙酮、乙酸异丙酯、2-甲基四氢呋喃、甲基异丁基酮、甲苯、异丙醇、甲基叔丁基醚、乙腈或乙酸乙酯中的至少一种；
    或者，(b)晶型A的制备方法包括以下步骤：
    将装有化合物X7盐酸盐的敞口容器放置在装有第一溶剂的密封容器中，静置，收集固体，得到所述晶型A；
    优选地，所述第一溶剂选自水、二氯甲烷、乙醇、甲醇、乙腈、四氢呋喃、三氯甲烷、丙酮、二甲基亚砜、乙酸乙酯、1,4-二氧六环或异丙醇中的至少一种；
    优选地，所述静置为在室温下静置6～10天；
    或者，(c)晶型A的制备方法包括以下步骤：
    将化合物X7盐酸盐置于容器中，并加入第二溶剂使化合物X7盐酸盐溶解在第二溶剂中，配制成澄清溶液，随后缓慢挥发，收集固体，得到所述晶型A；
    优选地，所述第二溶剂选自甲醇、乙醇、二氯甲烷、三氯甲烷、甲醇与丙酮的体积比为(0.5～1.5)：1的混合溶剂、乙醇与乙腈的体积比为 (3.5～4.5)：1的混合溶剂或二氯甲烷与四氢呋喃的体积比为(3.5～4.5)：1的混合溶剂中的至少一种；
    或者，(d)晶型A的制备方法包括以下步骤：
    将化合物X7盐酸盐溶解在第三溶剂中，加热使溶液变澄清后过滤，将滤液缓慢降温，收集析出固体，得到所述晶型A；
    优选地，所述第三溶剂选自甲醇、三氯甲烷、乙腈、甲醇与乙酸异丙酯的体积比为(0.5～1.5)：1的混合溶剂、乙醇与甲基叔丁基醚的体积比为(3.5～4.5)：1的混合溶剂或三氯甲烷与乙腈的体积比为(0.5～1.5)：1的混合溶剂中的至少一种；
    和/或，优选地，所述加热为在40～60℃下加热1.5～2.5h；
    和/或，优选地，所述缓慢降温为以0.05～0.1℃/分钟的降温速度将滤液从40～60℃降温至3～8℃；
    或者，(e)晶型A的制备方法包括以下步骤：
    在化合物X7盐酸盐中加入第四溶剂得到浑浊液，室温下搅拌浑浊液，离心收集固体，得到所述晶型A；
    优选地，所述第四溶剂选自乙醇、甲基异丁基酮、乙酸乙酯、甲基叔丁基醚、乙腈、甲苯、乙醇与1,4-二氧六环的体积比为(0.5～1.5)：1的混合溶剂、甲基异丁基酮与正庚烷的体积比为(0.5～1.5)：1的混合溶剂、乙酸异丙酯与二氯甲烷的体积比为(3.5～4.5)：1的混合溶剂、四氢呋喃与乙腈的体积比为(0.5～1.5)：1的混合溶剂、丙酮与N-甲基吡咯烷酮的体积比为(3.5～4.5)：1的混合溶剂、异丙醇与乙酸乙酯的体积比为(0.5～1.5)：1的混合溶剂、甲醇与甲基叔丁基醚的体积比为(0.5～1.5)：1的混合溶剂、2-甲基四氢呋喃与三氯甲烷的体积比为(3.5～4.5)：1的混合溶剂、甲基异丁基酮与二甲基亚砜的体积比为(3.5～4.5)：1的混合溶剂或乙醇与水的体积比为(70～97)：(3～30)的混合溶剂中的至少一种；
    和/或，优选地，室温下搅拌浑浊液3～5天；
    或者，(f)晶型A的制备方法包括以下步骤：
    在化合物X7盐酸盐中加入第五溶剂得到浑浊液，45～55℃下搅拌浑浊液，离心收集固体，得到所述晶型A；
    优选地，所述第五溶剂选自乙醇、异丙醇、丙酮、乙酸异丙酯、1,4-二氧六环、乙腈、正庚烷、异丙醇与2-甲基四氢呋喃的体积比为(0.5～1.5)：1的混合溶剂、甲基异丁基酮与乙酸乙酯的体积比为(0.5～1.5)：1的混合溶剂、三氯甲烷与正庚烷的体积比为(3.5～4.5)：1的混合溶剂、乙醇与丙酮的体积比为(0.5～1.5)：1的混合溶剂、乙腈与水的体积比为(0.5～1.5)：1的混合溶剂、乙酸异丙酯与N,N-二甲基乙酰胺的体积比为(8.5～9.5)：1 的混合溶剂、甲基叔丁基醚与N-甲基吡咯烷酮的体积比为(8.5～9.5)：1的混合溶剂、丙酮与乙腈的体积比为(0.5～1.5)：1的混合溶剂或2-甲基四氢呋喃与甲苯的体积比为(0.5～1.5)：1的混合溶剂中的至少一种；
    和/或，优选地，45～55℃下搅拌浑浊液3～5天；
    或者，(g)晶型A的制备方法包括以下步骤：
    将化合物X7盐酸盐溶解在第二良溶剂中，制成澄清溶液，并将装有澄清溶液的容器敞口放置在装有第二反溶剂的密封容器中静置，收集析出固体，得到所述晶型A；
    优选地，所述第二良溶剂选自甲醇、二氯甲烷或三氯甲烷中的至少一种；
    和/或，优选地，所述第二反溶剂选自乙酸乙酯、1,4-二氧六环、乙酸异丙酯、甲苯、甲基异丁基酮、乙腈、2-甲基四氢呋喃、正庚烷、异丙醇、乙酸乙酯或甲基叔丁基醚中的至少一种；
    或者，(h)晶型A的制备方法包括以下步骤：
    将化合物X7盐酸盐溶解在第六溶剂中，并加入高聚物，缓慢挥发，收集固体，得到所述晶型A；
    优选地，所述第六溶剂选自甲醇、二氯甲烷、乙腈与三氯甲烷的体积比为(0.5～1.5)：1的混合溶剂、三氯甲烷、丙酮与二氯甲烷的体积比为1：(1～3)的混合溶剂或乙醇与水的体积比为(0.5～1.5)：1的混合溶剂中的至少一种；
    和/或，优选地，所述高聚物包括混合高聚物A和混合高聚物B，所述混合高聚物包括等质量混合的聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、聚醋酸乙烯酯、羟丙基甲基纤维素和甲基纤维素；所述混合高聚物B包括等质量混合的聚己酸内酯、聚乙二醇、聚甲基丙烯酸甲酯、海藻酸钠或羟乙基纤维素。
  14. 一种制备如权利要求1和4-5任一项所述的化合物X7盐酸盐的晶体的方法，其中，(1)晶型B的制备方法包括以下步骤：
    将化合物X7盐酸盐置于容器中，并加入乙腈与水的体积比为(0.5～1.5)：1的混合溶剂使化合物X7盐酸盐溶解在混合溶剂中，配制成澄清溶液，随后缓慢挥发，收集固体，得到所述晶型B；
    或者，(2)晶型B的制备方法包括以下步骤：
    将化合物X7盐酸盐溶解在水或乙醇中，搅拌后过滤，将滤液缓慢降温，收集析出固体，室温室湿下干燥，得到所述晶型B；
    优选地，所述搅拌为在40～60℃下搅拌0.5～1.5天；
    和/或，优选地，所述缓慢降温为以0.05～0.1℃/分钟的降温速度将滤液 从40～60℃降温至3～8℃；
    或者，(3)晶型B的制备方法包括以下步骤：
    在化合物X7盐酸盐中加入水得到浑浊液，搅拌浑浊液，离心收集固体，得到所述晶型B；
    优选地，在室温下搅拌浑浊液3～5天。
  15. 一种制备如权利要求1和6-7任一项所述的化合物X7盐酸盐的晶体的方法，其中，晶型C的制备方法包括以下步骤：
    将化合物X7盐酸盐溶解在水中，搅拌后过滤，将滤液缓慢降温，收集析出固体，室温下真空干燥，得到所述晶型C；
    优选地，所述搅拌为在40～60℃下搅拌2～4h；
    和/或，优选地，所述缓慢降温为以0.05～0.1℃/分钟的降温速度将滤液从40～60℃降温至3～8℃；
    和/或，优选地，所述真空干燥的时间为0.5～1.5天。
  16. 一种制备如权利要求1和8-9任一项所述的化合物X7盐酸盐的晶体的方法，其中，(i)晶型D的制备方法包括以下步骤：
    将化合物X7盐酸盐置于容器中，并加入三氯甲烷与正庚烷的体积比为(0.5～1.5)：1的混合溶剂使化合物X7盐酸盐溶解在混合溶剂中，配制成澄清溶液，随后缓慢挥发，收集固体，得到所述晶型D；
    或者，(ii)晶型D的制备方法包括以下步骤：
    将化合物X7盐酸盐溶解在水中，制成澄清溶液，并将装有澄清溶液的容器敞口放置在装有丙酮的密封容器中静置，收集析出固体，得到所述晶型D。
  17. 一种制备如权利要求1或10所述的化合物X7盐酸盐的晶体的方法，其中，晶型E的制备方法包括以下步骤：
    将化合物X7盐酸盐溶解在水中，加热使溶液变澄清后过滤，将滤液缓慢降温，收集析出固体，得到所述晶型E；
    优选地，所述加热为在40～60℃下加热1.5～2.5h；
    和/或，优选地，所述缓慢降温为以0.05～0.1℃/分钟的降温速度将滤液从40～60℃降温至3～8℃。
  18. 一种制备如权利要求1和11-12任一项所述的化合物X7盐酸盐的晶体的方法，其中，晶型F的制备方法包括以下步骤：
    将化合物X7盐酸盐溶解在乙醇与水的体积比为(4～6)：2的混合溶剂中，超声后过滤，将滤液室温下挥发，得到所述晶型F；
    优选地，所述超声的时间为20～40s。
  19. 根据权利要求13-18之一所述的化合物X7盐酸盐的晶体的方法， 其中，晶型F溶解在水中，室温搅拌后转变为晶型B；
    或者，晶型C加热至155～165℃并冷却至室温后转变为晶型D；
    或者，晶型D或所述晶型C在选自乙醇或三氯甲烷的至少一种溶剂中搅拌2～4天转变为晶型A；优选地，所述搅拌的温度为室温或45～55℃；
    或者，晶型B或晶型F在室温下在丙酮或丙酮与水的混合溶剂中搅拌转变为晶型A，优选地，所述丙酮与水的混合溶剂的水活度a w≤0.8。
  20. 一种药物组合物，其中，包括权利要求1-12任一项所述的化合物X7盐酸盐的晶体和药学上可接受的载体或赋形剂。
  21. 权利要求1-12任一项所述的化合物X7盐酸盐的晶体或权利要求20所述的药物组合物在制备预防、治疗及延缓高血压、高血压引起的靶器官损伤及高血压相关疾病的药物中的应用。
PCT/CN2021/113018 2020-08-18 2021-08-17 化合物x7盐酸盐的晶体及其制备方法与应用 WO2022037580A1 (zh)

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