WO2022237878A1 - 化合物的晶型、含晶型组合物及其制备方法和应用 - Google Patents

化合物的晶型、含晶型组合物及其制备方法和应用 Download PDF

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WO2022237878A1
WO2022237878A1 PCT/CN2022/092499 CN2022092499W WO2022237878A1 WO 2022237878 A1 WO2022237878 A1 WO 2022237878A1 CN 2022092499 W CN2022092499 W CN 2022092499W WO 2022237878 A1 WO2022237878 A1 WO 2022237878A1
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crystal form
compound
preparation
solvent
rock
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PCT/CN2022/092499
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French (fr)
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娄军
王亮
袁意
郭晓丹
陈永凯
张轶涵
洪华云
彭微
王朝东
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武汉朗来科技发展有限公司
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Priority to CN202280033941.8A priority Critical patent/CN117321047A/zh
Publication of WO2022237878A1 publication Critical patent/WO2022237878A1/zh

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a crystal form of a compound, a composition containing the crystal form, a preparation method and application thereof.
  • Idiopathic interstitial pulmonary fibrosis is a chronic, diffuse pulmonary interstitial disease of unknown cause characterized by common interstitial pneumonia.
  • IPF interstitial pulmonary fibrosis
  • the disease progresses irreversibly, and early diagnosis is difficult; after diagnosis, the survival rate of patients decreases significantly over time.
  • the 3-year survival rate is 50%, and the 5-year survival rate is only 20%, which is higher than most cancers (such as : Leukemia, breast cancer, colon cancer, uterine tumor, kidney cancer, etc.) have a low survival rate and are called "cancer that is not cancer".
  • cancers such as : Leukemia, breast cancer, colon cancer, uterine tumor, kidney cancer, etc.
  • drugs such as pirfenidone and nintedanib can be used as appropriate, and nintedanib is only recommended for IPF patients with mild to moderate pulmonary dysfunction
  • drugs such as pirfenidone and nintedanib can be used as appropriate, and nintedanib is only recommended for IPF patients with mild to moderate pulmonary dysfunction
  • nintedanib can benefit IPF patients with severe pulmonary dysfunction and the course of drug administration needs to be further explored.
  • Rho GTPase Rho GTPase
  • Rho GTPase Rho GTPase
  • ROCK Rho-associated protein kinase
  • Rho-associated kinase belongs to serine/threonine protein kinase with a molecular mass of about 160kD. It is the most detailed functional research of Rho downstream target effector molecules.
  • ROCK includes ROCK1 (ROK ⁇ , p160-ROCK) and ROCK2 (ROK ⁇ ) subtypes. The amino acid sequence identity of the two isoforms is 65%, and there is a high similarity (92% identity) in the kinase domain.
  • ROCK is distributed in tissues throughout the body. In comparison, ROCK1 has higher expression in non-nervous tissues (blood, small intestine, thymus, etc.), while ROCK2 has higher expression in brain, heart and colon.
  • ROCK is involved in a variety of cardiovascular and cerebrovascular diseases, including hypertension, atherosclerosis, ischemic stroke, heart disease, diabetic nephropathy, eye disease, tumor, nerve damage disease, radiation damage and autoimmune disease, etc. .
  • the Rho/ROCK signaling pathway is involved in NAD(P)H oxidase activation, inducing oxidative stress, inducing cardiac microvascular injury and C-reactive protein-induced atherosclerotic thrombosis; high glucose can activate the Rho/ROCK pathway, inducing visceral fat
  • the expression of procollagen and type I procollagen in cardiomyoblasts can cause hyperproliferation of cardiomyocytes and induce diabetic cardiomyopathy; the activation of Rho/ROCK signaling pathway can regulate NF- ⁇ B signaling pathway, up-regulate inflammatory genes and induce the occurrence of diabetic nephropathy; Rho The /ROCK signaling pathway changes biofilm permeability and affects the metastasis of cancer cells
  • Rho/ROCK signaling pathway is also involved in the occurrence and development of fibrotic diseases.
  • the activation of Rho/ROCK signaling pathway can increase the level of ischemic myocardial fibrosis, and the expressions of Rho and ROCK in the heart tissue of rats with acute myocardial fibrosis were significantly increased.
  • Activation of the Rho/ROCK signaling pathway can induce actin phosphorylation and trigger cell fibrosis. Both in vivo and in vitro results demonstrated that cardiopulmonary physiological and pathological damage after a period of exposure to radiation was associated with Rho/ROCK pathway-induced fibrosis.
  • Ionizing radiation-induced endothelial adhesion fibronectin and focal adhesion formation, decreased endothelial cell migration, and endothelial dysfunction were associated with actin cytoskeleton reorganization and stress fiber formation induced by activation of the Rho/ROCK signaling pathway.
  • the lung injury of IPF mainly targets alveolar epithelial cells (ACEs), and the death of ACEs triggers wound healing responses, including innate immune activation, vascular leakage and extravascular coagulation, fibroblast recruitment, proliferation and activation, extracellular matrix synthesis and Cross-linking, alveolar collapse and epithelial regeneration.
  • ROCK signaling can fundamentally regulate the activities of these cells involved in the healing response, especially epithelial cells, endothelial cells and fibroblasts. The critical role of ROCK in these responses further suggests the potential of ROCK inhibitors in the treatment of pulmonary fibrosis.
  • the present invention provides the crystal form of the compound of formula A:
  • the crystal form is selected from crystal form I or crystal form II.
  • the crystal form I of the compound of formula A uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angle has a characteristic peak at 13.4 ⁇ 0.2°;
  • the crystal form I uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angles is 4.4 ⁇ 0.2°, 8.9 ⁇ 0.2°, 13.4 ⁇ 0.2°, 22.3 ⁇ 0.2°, 24.3 ⁇ 0.2°, There is a characteristic peak at 25.5 ⁇ 0.2°;
  • the crystal form I uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angle is at 4.4 ⁇ 0.2°, 8.9 ⁇ 0.2°, 13.4 ⁇ 0.2°, 22.3 ⁇ 0.2°, 24.0 ⁇ 0.2° , 24.3 ⁇ 0.2°, 25.5 ⁇ 0.2°, 27.3 ⁇ 0.2° have characteristic peaks;
  • the crystal form I uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is at 4.4 ⁇ 0.2°, 8.9 ⁇ 0.2°, 13.4 ⁇ 0.2°, 19.0 ⁇ 0.2°, 20.4 ⁇ 0.2° , 22.3 ⁇ 0.2°, 24.0 ⁇ 0.2°, 24.3 ⁇ 0.2°, 25.5 ⁇ 0.2°, 27.1 ⁇ 0.2°, 27.3 ⁇ 0.2° have characteristic peaks;
  • the crystal form I uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angle is 4.4 ⁇ 0.2°, 8.9 ⁇ 0.2°, 10.1 ⁇ 0.2°, 10.8 ⁇ 0.2, 13.4 ⁇ 0.2°, 17.1 ⁇ 0.2°, 17.9 ⁇ 0.2°, 19.0 ⁇ 0.2°, 20.4 ⁇ 0.2°, 20.8 ⁇ 0.2°, 22.3 ⁇ 0.2°, 24.0 ⁇ 0.2°, 24.3 ⁇ 0.2°, 24.8 ⁇ 0.2°, 25.5 ⁇ 0.2°, There are characteristic peaks at 25.9 ⁇ 0.2°, 27.1 ⁇ 0.2°, and 27.3 ⁇ 0.2°.
  • the crystal form I has an X-ray powder diffraction pattern substantially as shown in (a) of FIG. 1 .
  • the crystal form I has the characteristic peaks of X-ray powder diffraction represented by 2 ⁇ angles as shown in Table 6', with an error range of ⁇ 0.2°.
  • the crystal form I uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angle is shown in (b) in Figure 1, with an error range of ⁇ 0.20°.
  • the crystal form I is an anhydrate.
  • the crystal form I loses about 2.4% in weight within the temperature range from room temperature to about 150°C.
  • the crystalline form I has a weight loss of 2.4 ⁇ 2% from room temperature to 150 ⁇ 5°C.
  • the melting point of the crystal form I is 157 ⁇ 5°C, for example, 157 ⁇ 2°C.
  • the crystal form I has an endothermic peak at a peak temperature of about 167 ⁇ 2°C.
  • the crystal form I has a DSC-TGA spectrum substantially as shown in FIG. 6 .
  • the crystal form I has a morphology substantially as shown in (a) in FIG. 8 .
  • the crystal form II of the compound of formula A uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angle has characteristic peaks at 5.1 ⁇ 0.2°, 13.6 ⁇ 0.2°, and 17.8 ⁇ 0.2°;
  • the crystal form II uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angles is 5.1 ⁇ 0.2°, 13.6 ⁇ 0.2°, 13.9 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.1 ⁇ 0.2°, There are characteristic peaks at 21.3 ⁇ 0.2°, 22.9 ⁇ 0.2°, 25.6 ⁇ 0.2°, 26.0 ⁇ 0.2°;
  • the crystal form II uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is at 5.1 ⁇ 0.2°, 13.6 ⁇ 0.2°, 13.9 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.1 ⁇ 0.2° , 19.8 ⁇ 0.2°, 21.3 ⁇ 0.2°, 22.9 ⁇ 0.2°, 23.3 ⁇ 0.2°, 25.6 ⁇ 0.2°, 26.0 ⁇ 0.2°, 27.8 ⁇ 0.2° have characteristic peaks;
  • the crystal form II uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle is at 5.1 ⁇ 0.2°, 10.3 ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.6 ⁇ 0.2°, 13.9 ⁇ 0.2° , 16.4 ⁇ 0.2°, 16.7 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.1 ⁇ 0.2°, 19.8 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.3 ⁇ 0.2°, 22.9 ⁇ 0.2°, 23.3 ⁇ 0.2°, 24.2 ⁇ 0.2° , 25.6 ⁇ 0.2°, 26.0 ⁇ 0.2°, 27.8 ⁇ 0.2°, 37.3 ⁇ 0.2° have characteristic peaks;
  • the crystal form II uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed in 2 ⁇ angle also has a characteristic peak at 26.3 ⁇ 0.2°.
  • the crystal form II has an X-ray powder diffraction pattern substantially as shown in (a) of FIG. 2 .
  • the crystal form II has X-ray powder diffraction characteristic peaks expressed in 2 ⁇ angles as shown in Table 7', with an error range of ⁇ 0.2°.
  • the crystal form II uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angle is shown in (b) in Figure 2, with an error range of ⁇ 0.20°.
  • the crystal form II is an anhydrate.
  • the weight loss of the crystal form II is about 0-1.0%, such as 0-0.7%, in the temperature range from room temperature to about 150 ⁇ 5°C.
  • the melting point of the crystal form II is 174 ⁇ 5°C, such as 174 ⁇ 2°C.
  • the crystal form II has an endothermic peak at a peak temperature of about 178 ⁇ 2°C.
  • the crystal form II has a DSC-TGA spectrum substantially as shown in FIG. 7 .
  • the crystal form II has a morphology substantially as shown in (b) in FIG. 8 .
  • the present invention also provides a preparation method of the above-mentioned crystal form, which is selected from any of the following methods:
  • Method 1 Mix the compound of formula A with solvent A to form a suspension, and stir to obtain the crystal form;
  • Method 2 Mix the compound of formula A with solvent B to form a clear solution, and add solvent C to the clear solution under stirring to obtain the crystal form;
  • the solvent B is a good solvent for the compound of formula A
  • the solvent C is an antisolvent
  • the solvent A can be selected from organic solvents, water, or a mixed solvent of organic solvents and water, for example, the organic solvent can be selected from methyl tert-butyl ether, isopropanol, ethyl acetate One, two or more of , methanol and ethanol; Exemplarily, the solvent A is selected from ethyl acetate, water, a mixed solvent of ethanol and water, or a mixed solvent of methanol and water.
  • the solvent A may be selected from ethyl acetate, water, or a mixed solvent of ethanol and water.
  • the solvent B is selected from one, two or more of methanol, ethanol, acetonitrile, n-butanol, dimethyl sulfoxide, methylene chloride and butanone.
  • the solvent C is selected from one or two of isopropanol, n-heptane, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, water and methylcyclohexane. one or more species.
  • the ratio of the mass of the compound of formula A to the volume of solvent A is (1-150) mg: 1 mL, such as (50-150) mg: 1 mL, such as 1 mg: 1 mL, 50 mg: 1mL, 150mg: 1mL.
  • the stirring time may be 3 hours to 5 days, such as 0.5 to 3 days, exemplarily 15 hours or 3 days.
  • the stirring temperature is 15-30°C, such as 20-25°C.
  • the crystal form is crystal form I
  • the preparation method of the crystal form I is selected from any of the following methods:
  • Method (1) Mix the compound of formula A with ethyl acetate to form a suspension, and stir to obtain the crystal form I; preferably, the stirring is at room temperature for 0.5-3 days; more preferably, stirring at room temperature for 15 Hour;
  • Method (2) The compound of formula A is mixed with solvent B to form a clear solution, and solvent C is added to the clear solution under stirring to obtain the crystal form I;
  • the solvent B is selected from methanol, ethanol, acetonitrile, n-butanol, dimethyl sulfoxide, methylene chloride or butanone;
  • the solvent C is selected from isopropanol, n-heptane, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, water or methylcyclohexane.
  • the crystal form is crystal form II
  • the preparation method of the crystal form II includes the following steps: mixing the compound of formula A with water to form a suspension, and stirring to obtain the crystal form II;
  • the stirring is at room temperature for 3 hours to 3 days; more preferably, stirring is at room temperature for 15 hours.
  • the crystal form is crystal form II
  • the preparation method of the crystal form II comprises the following steps: mixing the compound of formula A with a mixed solvent of ethanol and water (1:10 in volume ratio) to form The suspension was stirred to obtain the crystal form II;
  • the stirring is at room temperature for 3 hours to 3 days; more preferably, stirring at room temperature for 3 days.
  • the present invention also provides a pharmaceutical composition, which contains the above crystal form and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition contains the crystalline form I and/or crystalline form II, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier includes, but is not limited to, excipients, lubricants, binders, disintegrants, solvents, dissolution aids, suspending agents, isotonic agents, buffers, preservatives, antioxidants, One, two or more of agents, coloring agents, foaming agents and flavoring agents (such as sweeteners, sour agents) and the like.
  • the pharmaceutically acceptable carrier includes one, two or more of water-soluble polymers, inorganic salts and the like.
  • the pharmaceutical composition may further contain other active ingredients, such as other ROCK inhibitors, tyrosine kinase inhibitors, tyrosinase inhibitors, fibrosis-promoting cytokine inhibitors, serum One or more of amyloid P inhibitors, autolysin-lecithin pathway inhibitors, GPR40 agonists, GPR84 antagonists, antacids and antibiotics.
  • active ingredients such as other ROCK inhibitors, tyrosine kinase inhibitors, tyrosinase inhibitors, fibrosis-promoting cytokine inhibitors, serum One or more of amyloid P inhibitors, autolysin-lecithin pathway inhibitors, GPR40 agonists, GPR84 antagonists, antacids and antibiotics.
  • the present invention also provides the application of the above crystal form or pharmaceutical composition in the preparation of preparations.
  • the present invention also provides a preparation containing the above crystal form.
  • the preparation contains the above-mentioned pharmaceutical composition.
  • the preparation can be powder, tablet (such as coated tablet, slow-release or controlled-release tablet), lozenge, capsule (such as soft capsule or hard capsule), granule, pill , dispersible powder, suspension, solution, emulsion, elixir, syrup, aerosol, cream, ointment, gel, injection, freeze-dried powder injection or suppository and other dosage forms.
  • tablet such as coated tablet, slow-release or controlled-release tablet
  • capsule such as soft capsule or hard capsule
  • granule, pill dispersible powder, suspension, solution, emulsion, elixir, syrup, aerosol, cream, ointment, gel, injection, freeze-dried powder injection or suppository and other dosage forms.
  • the preparation can be administered in any of the following ways: oral administration, buccal administration, sublingual administration, inhalation, topical application, intravenous, subcutaneous, acupoint, or intramuscular administration via parenteral administration. Injection, rectal administration.
  • the preparation is a ROCK antagonist.
  • the ROCK antagonist is used to prevent and/or treat one or more diseases caused by high expression of ROCK or overactivation of ROCK.
  • the disease is selected from cardiovascular and cerebrovascular diseases, nervous system diseases, fibrotic diseases, eye diseases, tumors, arterial thrombosis disorders, radiation damage, respiratory diseases, metabolic diseases and autoimmune diseases, etc.
  • the above diseases include atherosclerosis, acute coronary syndrome, hypertension, cerebral vasospasm, cerebral ischemia, ischemic stroke, restenosis, heart disease, heart failure, myocardial hypertrophy, myocardial ischemia-reperfusion injury, Diabetes, diabetic nephropathy, cancer, neuronal degeneration, nerve damage disease, spinal cord injury, erectile dysfunction, platelet aggregation, leukocyte aggregation, glaucoma, ocular hypertension, asthma, osteoporosis, pulmonary fibrosis (such as idiopathic pulmonary fibrosis), liver fibrosis, renal fibrosis, COPD, renal dialysis, glomerulosclerosis, fatty liver disease, steatohepatitis, or neuro
  • the present invention also provides a method for preventing and/or treating diseases caused by high expression of ROCK or overactivation of ROCK, comprising administering a therapeutically effective amount of the crystal form, pharmaceutical composition or preparation of Compound A to a subject .
  • crystalline form refers to crystalline forms having the same chemical composition but differing in the spatial arrangement of the crystal-forming molecules and/or ions.
  • amorphous refers to a solid form of molecules and/or ions that is not crystalline. Amorphous solids do not show a defined X-ray powder diffraction pattern with sharp maxima.
  • X-ray powder diffraction pattern substantially as shown means at least 50%, or at least 60%, or at least 70%, or at least 80%, of the major peaks shown in the X-ray powder diffraction pattern, or At least 90%, or at least 95%, or at least 99% of the peaks appear in the X-ray powder diffraction pattern; the main peak refers to the highest peak as a reference (the relative intensity of the highest peak is designated as 100%), and the relative intensity is greater than 10 %, preferably greater than 30% of the peak.
  • Object in the present invention have the same meaning and refer to human or other warm-blooded mammals.
  • Humans as “subjects” of the present invention include adults and infants, children, other warm-blooded mammals including but not limited to non-human primates such as chimpanzees, other great apes or monkeys, and other zoo animals, domestic mammals or Laboratory animals such as cats, pigs, dogs, cows, sheep, mice, rats, and guinea pigs.
  • the "subject” of the present invention is a human being.
  • the crystalline forms of Compound A of the present invention include non-solvated (anhydrous) and solvated (solvated) crystalline forms of Compound A.
  • ⁇ ективное amount or "therapeutically effective amount” can be determined according to the methods mastered by doctors with clinical qualifications in this field, which is sufficient to achieve the intended application (including but not limited to the treatment of diseases defined above).
  • the specific administered dose will vary depending on the specific compound or crystal form selected, the dosing regimen used, whether it is co-administered with other compounds, the timing of administration, the tissue administered and the host. Physical delivery system.
  • weight loss means that the mass percentage of weight loss is less than 0.2%, preferably less than 0.1%.
  • plural means more than two kinds, and “more than two kinds” includes two kinds, and more than two kinds.
  • Fig. 1 is the X-ray powder diffraction diagram (a) and diagram analysis (b) of crystal form I;
  • Figure 2 is the X-ray powder diffraction pattern (a) and spectrum analysis (b) of crystal form II;
  • Fig. 3 is the X-ray powder diffraction pattern of formula A compound amorphous form
  • Fig. 4 is the DSC and TGA spectrogram of formula A compound amorphous form
  • Fig. 5 is the MDSC spectrogram of formula A compound
  • Figure 6 is the DSC-TGA spectrum of Form I
  • Figure 7 is the DSC-TGA spectrum of Form II
  • Figure 8 is the PLM spectrum (a) of crystal form I and the PLM spectrum (b) of crystal form II;
  • Figure 9 is the 1 H-NMR spectrum of Form I
  • Figure 10 is the XRPD pattern of the 7-day stability test of the crystal form II
  • Figure 11 is the XRPD pattern of the 14-day stability test of the crystal form II.
  • Figure 12 is the DSC and TGA spectrogram of the crystal form II enlarged and prepared in Example 4.
  • Fig. 13 is the 1 H-NMR spectrum of the crystal form II enlarged and prepared in Example 4.
  • the solid state analysis of the solid obtained in the experiment was carried out by using an X-ray powder diffractometer PANalytical Empyrean equipped with a PIXcel 1D detector.
  • the instrument X-ray tube target uses copper target (K-Alpha ).
  • the light tube voltage and current were 45kV and 40mA, respectively.
  • the sample scan range was from 3°2 ⁇ to 40°2 ⁇ with a step size of 0.013°2 ⁇ .
  • the sample disk rotation speed and test speed are 60 rpm and 0.164° 2 ⁇ /s, respectively.
  • the samples were thermally analyzed using a Discovery DSC 250 (TA Instruments, US). Weigh an appropriate amount of sample and place it in the DSC sample pan and punch holes. The sample was heated to the final temperature at a rate of 10°C/min after equilibrating at 25°C.
  • MDSC Modulated Differential Scanning Calorimetry
  • the instrument model for MDSC analysis is DSC 250 (TA Instruments, US). Accurately weigh 2.6 mg of sample and place it in the DSC sample pan and punch holes. The test parameters are shown in the table below. Data were analyzed with TRIOS software.
  • the samples were thermogravimetrically analyzed using TGA 55 (TA Instruments, US). The sample was placed in a peeled closed aluminum sample pan. After the sample mass was automatically weighed in the TGA heating furnace, the sample was heated from room temperature to the final temperature at a rate of 10°C/min.
  • the instrument used in PLM is Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN).
  • the hydrogen spectrum information of the sample was confirmed by 1 H-NMR.
  • the instrument used for 1 H-NMR analysis is a Bruker AVANCE III HD 300/400 equipped with a Sample XPress 60 automatic sampling system.
  • Vsorp ProUmid GmbH&Co.KG, Germany moisture adsorption analyzer was used to perform moisture adsorption/desorption test on samples. Put the sample in the peeled sample pan, and record the change of sample mass with humidity (0-90%RH) at 25°C.
  • the specific DVS test parameters are shown in Table 1 below.
  • balance condition 0.01%/45min cycle weighing time 10min minimum time interval 50min maximum time interval 2.0h balance condition 40°C@0%RH (relative humidity) 6h Sample temperature 25°C Absorbed humidity 0,10,20,30,40,50,60,70,80,90%RH Desorption humidity 80,70,60,50,40,30,20,10,0%RH
  • the instrument used for HPLC analysis is Agilent HPLC 1260 series. Solubility The HPLC method used is shown in Table 2. The HPLC method used in the stability test is shown in Table 3 and Table 4.
  • the instrument used for IC analysis was Thermo ICS-6000.
  • the methods used in the ion chromatography tests are shown in Table 5.
  • Embodiment 1 Compound 5-(3-amino-1H-pyrazol-4-yl)-6-fluoro-N-(3-methoxybenzyl)indoline-1-carboxamide (compound of formula A ) preparation
  • compound M009-1 (1500mg), pinacol diboronate (CAS: 73183-34-3, 2010mg), potassium acetate (AcOK, 1940mg) and (1,1'-bis(diphenyl Phosphino)ferrocene)palladium dichloride (Pd(dppf)Cl 2 , 579mg), was added to 1,4-dioxane (1,4-dioxane, 20mL), and the resulting reaction solution was placed in an oil bath for 90 °C and stirred for 5 hours.
  • Embodiment 2 the preparation of crystal form I
  • the XRPD detection pattern of the crystal form I is shown in (a) in Figure 1, and the analysis is shown in (b) in Figure 1 and Table 6'.
  • the DSC-TGA test of the crystal form I is shown in Figure 6. Its melting point is about 157.20°C; the weight loss in the temperature range from room temperature to about 150°C is about 2.4%, and the crystal form I is an anhydrate.
  • the 1 H NMR detection chart of the crystal form I is shown in FIG. 9 .
  • Embodiment 3 the preparation of crystal form II
  • the DSC-TGA test of the crystal form II is shown in Figure 7, its melting point is about 173.72°C; the weight loss in the temperature range from room temperature to about 150°C is about 0.669%, and the crystal form II is an anhydrate.
  • the obtained sample was detected as crystal form II by XRPD.
  • Embodiment 5 the performance detection of the formula A compound of embodiment 1
  • Example 1 The compound of formula A prepared in Example 1 was characterized by XRPD, DSC, MDSC, TGA and 1 H-NMR.
  • the XRPD detection pattern of the compound of formula A is shown in Figure 3, and the compound A is amorphous.
  • the DSC-TGA test of the compound of formula A is shown in Figure 4.
  • the TGA results show that the weight loss of the sample increases with the increase of temperature, and the DSC spectrum shows that there is no obvious thermodynamic event in the range of RT (room temperature)-160°C.
  • the MDSC test results of the compound of formula A are shown in Figure 5, and the glass transition temperature Tg of the sample is about 20°C.
  • Embodiment 6 Stability test of crystal form II
  • Stability test (up to 14 days) for Form II at 60°C/closed and 40°C/75%RH open: Take an appropriate amount of free base Form II and place it at 60°C/closed and 40°C/ Keep 1 week and 2 weeks under the two conditions of 75% RH opening, take samples of 0 days, 1 week and 2 weeks, dissolve them in the diluent and prepare a solution of about 1.0mg/mL for HPLC analysis of chemical stability, 1 week or 2 weeks The solid sample after week carries out XRPD test analysis physical stability.
  • the test results are shown in Table 10-11 and Figure 10-11.
  • the stability results showed that Form II was physically and chemically stable after being placed for 1 week and 2 weeks under the conditions of 60°C/closed and 40°C/75%RH.
  • Embodiment 7 the solubility test of crystal form II
  • Form II in relevant biological media SGF, FaSSIF and FeSSIF
  • 15 mg of Form II sample was weighed and dispersed in 5.0 mL of biologically relevant media to obtain a dispersion.
  • oscillate on a shaker with a rotating speed of 100rpm take out 1mL of the dispersion at 0.5h, 2h and 24h for filtration, the filtrate is tested for solubility by HPLC and the pH value with a pH meter, and the filter cake is characterized by XRPD for crystal form.
  • the solubility test results are specifically shown in Table 12.
  • the crystalline form II remains unchanged for 24 hours in biorelevant media.
  • the solubility of crystal form II in SGF is the highest, up to 1 mg/mL; the solubility in FeSSIF is second, and the solubility distribution in 0-24h is 33-49 ⁇ g/mL; and the solubility in FaSSIF is the lowest ,
  • the solubility within 24h is only 6 ⁇ 9 ⁇ g/mL.
  • Embodiment 8 Pharmacokinetic research experiment of crystal form II
  • mice purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • weighing 180-280 g were used, half male and half male. They were randomly divided into four groups, 3 rats in each group, the first group was female rats, and the second group was male rats.
  • Blood was collected from the orbital venous plexus of rats at different time points (0.167, 0.5, 1, 2, 3, 4, 6, 9, 12 and 24 hours) after administration, and blood samples were collected. Detect the concentration of compound A in plasma;
  • PK parameters C 0 , C max , T max , AUC 0-last , AUC inf , T 1/2 , CL, Vz and other parameters.
  • the inventors unexpectedly found that the crystal forms I and II provided by the present invention have stable chemical properties.

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Abstract

本发明公开一种化合物的晶型、含晶型组合物及其制备方法和应用。式A化合物的晶型：晶型I和晶型II，具有稳定的化学性质：相对于无定型物，它们放置后所产生杂质的含量均得以降低；相对于无定型物，本发明的晶型在高温或高湿条件下晶型均较稳定，更有利于药物的质量控制及成药性。

Description

化合物的晶型、含晶型组合物及其制备方法和应用
本申请要求享有2021年5月14日向中国国家知识产权局提交的，专利申请号为202110529753.1，发明名称为“化合物的晶型、含晶型组合物及其制备方法和应用”的在先申请的优先权权益。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于药物化学领域，具体涉及一种化合物的晶型、含晶型组合物及其制备方法和应用。
背景技术
特发性肺间质纤维化(Idiopathic interstitial pulmonary fibrosis，IPF)，是一种原因不明的以普通间质性肺炎为改变的慢性、弥漫性肺间质疾病，其组织病理学及影像学多显示为普通间质性肺炎的表现。因其发病机制复杂，病情呈不可逆性进展，早期诊断困难；确诊后患者生存率随时间推移显著下降，其3年生存率为50％，5年生存率仅为20％，比多数癌症(例如：白血病、乳腺癌、结肠癌、子宫瘤、肾癌等)的生存率都低，被称为“不是癌症的癌症”。目前，IPF尚无肯定显著有效的治疗药物。根据近年来的随机对照临床试验的结果，结合我国临床实际情况，可以酌情使用的药物如吡非尼酮、尼达尼布，仅推荐轻到中度肺功能障碍的IPF患者应用尼达尼布治疗，而重度肺功能障碍的IPF患者服用尼达尼布治疗能否获益，以及药物服用疗程尚需进一步探讨。
Rho GTP酶(Rho GTPase)于1985年被发现，属于Ras超家族，与Ras有25％的同源性。目前发现的分布在哺乳动物组织细胞中的Rho GTP酶成员主要有Rho(A、B、C)、Rac(1、2、3)、Cdc42(Cdc42Hs/G25K、TC10、Tcl)、Rho D、Rho G、Chp(1、2)、Rnd(Rho E/Rnd3、Rnd1/Rho6、Rnd2/Rho7)、Rho H/TTF、Rif、Wrch1和Rho BTB(1、2)，其中Rho(A、B、C)是Rho GTP酶最主要的成员之一。ROCK(Rho-associated protein kinase)又称Rho激酶(Rho-associated kinase)，属于丝氨酸/苏氨酸蛋白激酶，分子质量大约160kD，是目前功能研究最为详细的Rho下游靶效应分子。ROCK包括ROCK1(ROKβ，p160-ROCK)和ROCK2(ROKα)亚型。两种亚型的氨基酸序列一致性为65％，在激酶结构域有高度相似性(92％一致)。ROCK分布于全身组织，相比较而言，ROCK1在非神经组织(血液、小肠、胸腺等)中有更高表达，而ROCK2在脑、心脏和结肠中有更高表达。
ROCK参与多种心脑血管疾病，包括高血压、动脉粥样硬化、缺血性脑卒中、心脏病、糖尿病肾病、眼疾病、肿瘤、神经损伤性疾病、辐射损伤以及自身免疫性疾病等的发生。例如，Rho/ROCK信号通路参与NAD(P)H氧化酶激活，诱导氧化应激，诱发心脏微血管损伤和C反应蛋白诱导的动脉粥样硬化血栓；高糖可以激活Rho/ROCK通路，诱导内脏脂肪素和I型前胶原在成心肌细胞的表达，使成心肌细胞过增殖而诱发糖尿病心肌病；Rho/ROCK信号通路激活可以调节NF-κB信号通路，上调炎症基因并诱导糖尿病肾病的发生；Rho/ROCK信号通路改变生物膜通透性影响癌细胞的转移；脊髓损伤时，Rho活化，从而诱发生长锥萎缩导致轴突再生障碍，同时诱发硫酸软骨素蛋白聚糖对神经元生长的抑制作用。
另外，Rho/ROCK信号通路还参与了纤维化疾病的发生与发展。Rho/ROCK信号通路激活可以增加局部缺血心肌纤维化水平，且急性心肌纤维化大鼠心脏组织的Rho和ROCK表达明显增高。Rho/ROCK信号通路激活可以诱导肌动蛋白磷酸化，引发细胞纤维化。体内和体外实验结果均证明，暴露于辐射一段时间后造成的心肺生理和病理损伤与Rho/ROCK通路参与诱导的纤维化有关。电离辐射导致的内皮黏附纤连蛋白和焦点黏着形成、内皮细胞迁移减少、内皮功能障碍与Rho/ROCK信号通路激活诱导的肌动蛋白骨架重组和应力纤维形成有关。
IPF的肺损伤主要以肺泡上皮细胞(ACEs)为靶点，ACEs死亡触发创伤愈合反应，包括天然免疫激活、血管渗漏和血管外凝血、成纤维细胞募集、增殖和活化、细胞外基质合成和交联、肺泡塌陷和上皮细胞再生。ROCK信号可从根本上调节这些参与愈合反应的细胞的活动，尤其是上皮细胞、内皮细胞和成纤维细胞。而ROCK在这些反应中的关键作用，进一步提示了ROCK抑制剂治疗肺纤维化的潜力。
目前尚无ROCK抑制途径治疗包括纤维化在内的众多病症的药物上市。新药剂的发展要求将先导化合物的化学及生物学特性仔细地进行最佳化。进一步地，所述化合物必须具有所希望的药代动力学以及药效动力学特征。该艰巨的开发过程通常要求广泛的试验。在许多情况下，确定所述最佳化合物的过程常常需要制备数以千计的结构上相似的化合物。因此，改善ROCK激酶抑制剂，开发出具有ROCK1和/或ROCK2激酶抑制作用的新骨架化合物，对于上述疾病的治疗具有积极意义。同时，研发这些化合物适于成药的药物固体形式，例如使稳定性、吸湿性和/或药效等得到改善的固体形式，从而在制药及用药阶段取得良好效果，成为亟待解决的技术问题。
发明内容
本发明提供式A化合物的晶型：
Figure PCTCN2022092499-appb-000001
根据本发明的技术方案，所述晶型选自晶型I或晶型II。
根据本发明的技术方案，式A化合物的晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在13.4±0.2°处具有特征峰；
优选地，所述晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在4.4±0.2°、8.9±0.2°、13.4±0.2°、22.3±0.2°、24.3±0.2°、25.5±0.2°处具有特征峰；
还优选地，所述晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在4.4±0.2°、8.9±0.2°、13.4±0.2°、22.3±0.2°、24.0±0.2°、24.3±0.2°、25.5±0.2°、27.3±0.2°处具有特征峰；
进一步优选地，所述晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在4.4±0.2°、8.9±0.2°、13.4±0.2°、19.0±0.2°、20.4±0.2°、22.3±0.2°、24.0±0.2°、24.3±0.2°、25.5±0.2°、27.1±0.2°、27.3±0.2°处具有特征峰；
更优选地，所述晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在4.4±0.2°、8.9±0.2°、10.1±0.2°、10.8±0.2、13.4±0.2°、17.1±0.2°、17.9±0.2°、19.0±0.2°、20.4±0.2°、20.8±0.2°、22.3±0.2°、24.0±0.2°、24.3±0.2°、24.8±0.2°、25.5±0.2°、25.9±0.2°、27.1±0.2°、27.3±0.2°处具有特征峰。
根据本发明的技术方案，所述晶型I具有基本如图1中(a)所示的X-射线粉末衍射图谱。
根据本发明的技术方案，所述晶型I具有如表6’所示的以2θ角度表示的X-射线粉末衍射特征峰，误差范围±0.2°。
根据本发明的技术方案，所述晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射如图1中(b)所示，误差范围±0.20°。
优选地，所述晶型I为无水合物。
根据本发明的技术方案，所述晶型I在室温至约150℃温度区间内失重约2.4％。
在一些实施方案中，所述晶型I在室温至150±5℃有2.4±2％的失重。
根据本发明的技术方案，所述晶型I的熔点为157±5℃，例如157±2℃。
根据本发明的技术方案，所述晶型I在峰值温度约为167±2℃处具有吸热峰。
根据本发明的技术方案，所述晶型I具有基本如图6所示的DSC-TGA图谱。
根据本发明的技术方案，所述晶型I具有基本如图8中的(a)所示的形貌。
根据本发明的技术方案，式A化合物的晶型II使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在5.1±0.2°、13.6±0.2°、17.8±0.2°处具有特征峰；
优选地，所述晶型II使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在5.1±0.2°、13.6±0.2°、13.9±0.2°、17.8±0.2°、18.1±0.2°、21.3±0.2°、22.9±0.2°、25.6±0.2°、26.0±0.2°处具有特征峰；
进一步优选地，所述晶型II使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在5.1±0.2°、13.6±0.2°、13.9±0.2°、17.8±0.2°、18.1±0.2°、19.8±0.2°、21.3±0.2°、22.9±0.2°、23.3±0.2°、25.6±0.2°、26.0±0.2°、27.8±0.2°处具有特征峰；
更优选地，所述晶型II使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在5.1±0.2°、10.3±0.2°、12.7±0.2°、13.6±0.2°、13.9±0.2°、16.4±0.2°、16.7±0.2°、17.8±0.2°、18.1±0.2°、19.8±0.2°、20.7±0.2°、21.3±0.2°、22.9±0.2°、23.3±0.2°、24.2±0.2°、25.6±0.2°、26.0±0.2°、27.8±0.2°、37.3±0.2°处具有特征峰；
还进一步优选地，所述晶型II使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射还在26.3±0.2°处具有特征峰。
根据本发明的技术方案，所述晶型II具有基本如图2中(a)所示的X-射线粉末衍射图谱。
根据本发明的技术方案，所述晶型II具有如表7’所示的以2θ角度表示的X-射线粉末衍射特征峰，误差范围±0.2°。
根据本发明的技术方案，所述晶型II使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射如图2中(b)所示，误差范围±0.20°。
优选地，所述晶型II为无水合物。
根据本发明的技术方案，所述晶型II在室温至约150±5℃温度区间内失重约为0-1.0％，例如0-0.7％。
根据本发明的技术方案，所述晶型II的熔点为174±5℃，例如174±2℃。
根据本发明的技术方案，所述晶型II在峰值温度约为178±2℃处具有吸热峰。
根据本发明的技术方案，所述晶型II具有基本如图7所示的DSC-TGA图谱。
根据本发明的技术方案，所述晶型II具有基本如图8中的(b)所示的形貌。
本发明还提供上述晶型的制备方法，选自下述任一种方法：
方法一：将式A化合物与溶剂A混合形成悬浊液，搅拌，得到所述晶型；
方法二：将式A化合物与溶剂B混合形成澄清溶液，搅拌下向所述澄清溶液中加入溶剂C，得到所述晶型；
其中，所述溶剂B为式A化合物的良溶剂，所述溶剂C为抗溶剂。
根据本发明的技术方案，所述溶剂A可以选自有机溶剂、水、或有机溶剂与水的混合溶剂，例如所述有机溶剂可以选自甲基叔丁基醚、异丙醇、乙酸乙酯、甲醇和乙醇等中的一种、两种或更多种；示例性地，所述溶剂A选自乙酸乙酯、水、乙醇和水的混合溶剂、或甲醇和水的混合溶剂。
优选地，所述溶剂A可以选自乙酸乙酯、水、或乙醇和水的混合溶剂。
根据本发明的技术方案，所述溶剂B选自甲醇、乙醇、乙腈、正丁醇、二甲基亚砜、二氯甲烷和丁酮中的一种、两种或多种。
根据本发明的技术方案，所述溶剂C选自异丙醇、正庚烷、甲基叔丁基醚、乙酸乙酯、乙酸异丙酯、水和甲基环己烷中的一种、两种或多种。
根据本发明的技术方案，所述式A化合物的质量与溶剂A的体积之比为(1-150)mg:1mL，例如为(50-150)mg:1mL，例如为1mg:1mL、50mg:1mL、150mg:1mL。
根据本发明的技术方案，所述搅拌的时间可以为3小时-5天，例如为0.5-3天，示例性为15小时、3天。
根据本发明的技术方案，所述搅拌的温度为15-30℃，例如20-25℃。
根据本发明的一个实施方案，所述晶型为晶型I，所述晶型I的制备方法选自下述任一种方法：
方法(1)：将式A化合物与乙酸乙酯混合形成悬浊液，搅拌，得到所述晶型I；优选地，所述搅拌为室温搅拌0.5-3天；更优选地，在室温搅拌15小时；
方法(2)：将式A化合物与溶剂B混合形成澄清溶液，搅拌下向所述澄清溶液中加入溶剂C，得到所述晶型I；
所述溶剂B选自甲醇、乙醇、乙腈、正丁醇、二甲基亚砜、二氯甲烷或丁酮；
所述溶剂C选自异丙醇、正庚烷、甲基叔丁基醚、乙酸乙酯、乙酸异丙酯、水或甲基环己烷。
根据本发明的一个实施方案，所述晶型为晶型II，所述晶型II的制备方法包括如下步骤：将式A化合物与水混合形成悬浊液，搅拌，得到所述晶型II；
优选地，所述搅拌为室温搅拌3小时-3天；更优选地，在室温下搅拌15小时。
根据本发明的一个实施方案，所述晶型为晶型II，所述晶型II的制备方法包括如下步骤：将式A化合物与乙醇和水的混合溶剂(体积比为1:10)混合形成悬浊液，搅拌，得到所述晶型II；
优选地，所述搅拌为室温搅拌3小时-3天；更优选地，在室温下搅拌3天。
本发明还提供一种药物组合物，所述药物组合物含有上述晶型以及任选药学上可接受的载体。
在一种实施方式中，所述药物组合物含有所述的晶型I和/或晶型II、以及任选药学上可接受的载体。
例如，所述药学上可接受的载体包括但不限于赋形剂、润滑剂、粘合剂、崩解剂、溶剂、溶解助剂、悬浮剂、等渗剂、缓冲液、防腐剂、抗氧剂、着色剂、起泡剂和调味剂(例如甜味剂、酸味剂)等中的一种、两种或更多种。
又如，所述药学上可接受的载体包括水溶性聚合物、无机盐等中的一种、两种或更多种。
根据本发明的技术方案，所述药物组合物中还可以进一步含有其他活性成分，例如其他ROCK抑制剂、酪氨酸激酶抑制剂、酪氨酸酶抑制剂、促纤维化细胞因子抑制剂、血清淀粉样蛋白P抑制剂、自溶素-卵磷脂酸通路抑制剂、GPR40激动剂、GPR84拮抗剂、抗酸药物和抗生素中的一种或两种以上。
本发明还提供上述晶型或药物组合物在制剂制备中的应用。
本发明还提供一种制剂，含有上述晶型。
根据本发明的实施方案，所述制剂含有上述药物组合物。
根据本发明的技术方案，所述制剂可以为散剂、片剂(例如包衣片剂、缓释或控释片剂)、锭剂、胶囊剂(例如软胶囊或硬胶囊)、颗粒剂、丸剂、可分散粉末、混悬剂、溶液剂、乳剂、酏剂、糖浆剂、气雾剂、霜剂、软膏剂、凝胶、注射剂、冻干粉针剂或栓剂等剂型。
根据本发明的技术方案，所述制剂可以以下述任一种方式施用：口服、口腔给药、舌下、吸入、局部涂敷，经胃肠外给药的静脉内、皮下、穴位、或肌内注射，直肠给药。
根据本发明的技术方案，所述制剂为ROCK拮抗剂。优选地，所述ROCK拮抗剂用于预防和/或治疗一种或多种ROCK的高表达或ROCK的过度激活导致的疾病。
优选地，所述疾病选自心脑血管疾病、神经系统疾病、纤维化疾病、眼疾病、肿瘤、动脉血栓形成病症、辐射损伤、呼吸系统疾病、代谢性疾病以及自身免疫性疾病等，例如所述疾病包括动脉粥样硬化、急性冠脉综合征、高血压、脑血管痉挛、脑缺血、缺血性脑卒中、再狭窄、心脏病、心脏衰竭、心肌肥厚、心肌缺血再灌注损伤、糖尿病、糖尿病肾病、癌症、 神经元变性、神经损伤性疾病、脊髓损伤、勃起功能障碍、血小板凝聚、白细胞聚集、青光眼、眼部高血压、哮喘、骨质疏松症、肺纤维化(如特发性肺纤维化)、肝纤维化、肾脏纤维化、COPD、肾透析、肾小球硬化症、脂肪性肝病、脂肪性肝炎或神经元变性炎症。
本发明还提供一种预防和/或治疗ROCK的高表达或ROCK的过度激活导致的疾病的方法，包括将治疗有效量的所述化合物A的晶型、药物组合物或制剂施用于受试者。
术语说明
术语“晶型”指具有相同化学组成但有不同的形成结晶的分子和/或离子的空间排布的晶型。
术语“无定型”指不是结晶的分子和/或离子的固体形式。无定型固体不显示确定的具有清晰最大值的X-射线粉末衍射图形。
术语“基本上如图所示的X-射线粉末衍射图谱”是指X-射线粉末衍射图所示的主要峰中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰出现在X-射线粉末衍射图中；其主要峰指以最高峰作为参照(最高峰的相对强度指定为100％)，相对强度大于10％、优选大于30％的峰。
本发明的“对象”、“患者”、“受试者”具有相同含义，指具有人或其他温血哺乳动物。本发明作为“对象”的人包括成人和婴幼儿、儿童，其他温血哺乳动物包括但不限于非人类的灵长类动物、例如黑猩猩、其他类人猿或猴，以及其他动物园动物、家养哺乳动物或实验室动物，例如猫、猪、狗、牛、羊、小鼠、大鼠和豚鼠等。优选地，本发明的“对象”为人。
本发明的化合物A的晶型包括化合物A的非溶剂合物(无水合物)以及溶剂合物(含溶剂合物)的晶型形式。
本领域技术人员根据常规方法能够确定药物组合物中晶型I、II中的任一种、两种的任意比例的混合物以及各种药学上可接受的载体和/或其他活性成分的合适的量。
术语“有效量”或者“治疗有效量”可以根据本领域具有临床执业资格的医生所掌握的方法确定足以实现预期应用(包括但不限于上述定义的疾病治疗)的本发明所述晶型I、II中的任一种或两种的任意比例的混合物、药物组合物或制剂的量。确定治疗有效剂量是本领域临床医生或研究人员力所能及的，可以因以下因素而改变：预期应用(体外或者体内)，或者所治疗的受试者和疾病病症如受试者的体重和年龄、一般健康状况、疾病病症的严重性、给药方式以及其他影响疗效的因素例如药物过敏史等。具体施用剂量将取决于以下因素而改变：所选择的特定化合物或晶型、所依据的给药方案、是否与其它化合物联合给药、给药的时间 安排、所给药的组织和所承载的物理递送系统。
本文中用术语“约”来指大致上、粗略地、大约或在…区域。在术语“约”与数字范围结合使用时，它通过在所示数值之上和之下扩展边界来修饰该范围。通常，本文中用术语“约”来修饰所述值在该类参数按照本领域技术人员理解的合理浮动范围内变化。具体的，当“约”与温度的范围结合使用时，指温度在例如±5℃、±4℃、±3℃、±2℃、±1℃范围内浮动。当“约”与表示失重质量的范围结合使用时，视情况指质量在例如±5％、±4％、±3％、±2％、±1％、±0.4％范围内浮动。
本文中“几乎无失重”指失重质量百分比小于0.2％，优选小于0.1％。
术语“多种”表示两种以上，“两种以上”包括两种，以及大于两种。
本领域技术人员可以理解，本发明的“游离碱”或“式A化合物的游离碱”即指式A化合物(未成盐形式)。
附图说明
图1为晶型I的X-射线粉末衍射图(a)和图谱解析(b)；
图2为晶型II的X-射线粉末衍射图(a)和图谱解析(b)；
图3为式A化合物无定型形式的X-射线粉末衍射图谱；
图4为式A化合物无定型形式的DSC和TGA谱图；
图5为式A化合物的MDSC谱图；
图6为晶型I的DSC-TGA图谱；
图7为晶型II的DSC-TGA图谱；
图8为晶型I的PLM图谱(a)和晶型II的PLM图谱(b)；
图9为晶型I的 1H-NMR图谱；
图10为晶型II的7天稳定性测试的XRPD图谱；
图11为晶型II的14天稳定性测试的XRPD图谱；
图12为实施例4放大制备的晶型II的DSC和TGA谱图；
图13为实施例4放大制备的晶型II的 1H-NMR图谱。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
X射线粉末衍射仪(XRPD)
利用配备了PIXcel 1D检测器的X射线粉末衍射仪PANalytical Empyrean对实验中所得到的固体进行固体形态分析。仪器X射线管靶材采用的是铜靶(K-Alpha
Figure PCTCN2022092499-appb-000002
)。光管电压和电流分别为45kV和40mA。样品扫描范围从3°2θ到40°2θ，步长为0.013°2θ。样品盘转速和测试速度分别是60rpm和0.164°2θ/s。
示差扫描量热分析(DSC)
利用Discovery DSC 250(TA Instruments,US)对样品进行了热分析。称取适量样品置于DSC样品盘中并扎孔。将样品在25℃平衡后以10℃/min的速率加热至最终温度。
调制示差扫描量热法(MDSC)
MDSC分析的仪器型号为DSC 250(TA Instruments，US)。精确称取2.6mg样品置于DSC样品盘中并扎孔。测试参数见下表。数据用TRIOS软件分析。
MDSC测试方法参数
仪器 TA,Discovery DSC 250
样品盘 铝盘，扎孔
温度范围 -20～250℃
调制周期 60s
加热速率 3℃/min
吹扫气体 N 2
气体流速 50mL/min
热重分析(TGA)
利用TGA 55(TA Instruments,US)对样品进行了热重分析。将样品置于已去皮的闭口铝制样品盘中，样品质量在TGA加热炉内自动称量后，将样品以10℃/min的速率从室温加热至最终温度。
偏折光显微镜分析(PLM)
PLM所用到的仪器为Polarizing Microscope ECLIPSE LV100POL(Nikon,JPN)。
核磁共振氢谱分析( 1H-NMR)
样品的氢谱信息经 1H-NMR确认。 1H-NMR分析采用的仪器是配备有Sample Xpress 60自动进样系统的Bruker AVANCE III HD 300/400。
动态水分吸附脱附分析(DVS)
利用Vsorp(ProUmid GmbH&Co.KG,Germany)水分吸附分析仪对样品进行水分吸附/脱附测试。将样品置于去皮后的样品盘中，并记录25℃下样品质量随湿度的变化(0-90％RH)， 具体的DVS测试参数如下表1所示。
表1. DVS测试引湿性方法
平衡条件 0.01％/45min
循环称重时间 10min
最小时间间隔 50min
最大时间间隔 2.0h
平衡条件 40℃@0％RH(相对湿度)6h
测样温度 25℃
吸附湿度 0,10,20,30,40,50,60,70,80,90％RH
脱附湿度 80,70,60,50,40,30,20,10,0％RH
高效液相色谱分析(HPLC)
HPLC分析采用的仪器为Agilent HPLC 1260 series。溶解度所用的HPLC方法如表2所示。稳定性试验所用的HPLC方法如表3和表4所示。
表2. 溶解度测试的HPLC方法
Figure PCTCN2022092499-appb-000003
表3. 7天稳定性测试的HPLC方法
Figure PCTCN2022092499-appb-000004
Figure PCTCN2022092499-appb-000005
表4. 14天稳定性测试的HPLC方法
Figure PCTCN2022092499-appb-000006
离子色谱(IC)
IC分析采用的仪器为Thermo ICS-6000。离子色谱测试所用的方法如表5所示。
表5. 离子色谱测试方法参数(Cl -和C 2O 4 2)
仪器 Thermo ICS-6000
工作站 Chromeleon Workstation
淋洗液发生器 EGC 500 KOH
抑制器 Dionx ASRS 300 4mm
保护柱 Dionex IonPacTMAG11-HC(4*50mm)
色谱柱 Dionex IonPacTMAG11-HC(4*250mm)
电导池温度 35.0℃
淋洗液浓度 30mm
抑制器工作模式 外部模式(External Mode)
抑制器电流 75mA
柱温 30.0℃
流速 1.0mL/min
洗脱梯度 等度洗脱(Isocratic elution)
运行时间 10min
进样体积 25μL
外接水循环流速 1.5mL/min
实施例1：化合物5-(3-氨基-1H-吡唑-4-基)-6-氟-N-(3-甲氧基苄基)二氢吲哚-1-甲酰胺(式A化合物)的制备
Figure PCTCN2022092499-appb-000007
(1)4-溴-3-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑(M002)的制备
称取4-溴-3-硝基-1H-吡唑(CAS号:89717-64-6，40g)，溶于THF(四氢呋喃，400mL)；将所得溶液降温并保持温度0-5℃，分2-4批加入NaH(12.5g)；将混合物在0-5℃保温0.5h，滴加2-(三甲基硅烷基)乙氧甲基氯(SEM-Cl)(41.6g)。然后将反应液升至室温保温反应2h，停止反应。向反应液中加水(600mL)，用EA(乙酸乙酯，500mL)萃取1次，用EA(300mL)萃取两次；取有机相，用氯化铵溶液(300mL)、饱和食盐水(300mL)各洗一次，用无水硫酸钠干燥，浓缩至干得粗品70.2g。向粗品中加入正庚烷(50mL)室温打浆3h，PE(石油醚，50mL)漂洗得白色固体51.2g，记为化合物M002，收率76％，HPLC纯度为96.8％，LC-MS[M+H] +＝322.0。
(2)化合物4-硝基苯基5-溴-6-氟二氢吲哚-1-羧酸酯(M001)的制备
将4-硝基氯甲酸苯酯(CAS号:7693-46-1，6.21g)溶于二氯甲烷(40mL)中；将所得溶液降温至0℃，滴加5-溴-6-氟二氢吲哚(6.00g)和吡啶(8.86g)的二氯甲烷(50mL)溶液；将混合物升温至室温搅拌过夜(15h)。向反应液中加入二氯甲烷(100mL)稀释，然后用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，取滤液浓缩，所得粗品经硅胶柱层析分离(石油醚：二氯甲烷＝3:1，v/v)，得到灰色固体7.20g，记为化合物M001，收率68％。LC-MS[M+H] +＝380.9。
(3)化合物5-溴-6-氟-N-(3-甲氧基苄基)二氢吲哚-1-甲酰胺(M009-1)的制备
将化合物M001(1600mg)和3-甲氧基卞胺(1150mg)加入到THF(20mL)中，然后在室温搅拌下向所得溶液加入N,N-二异丙基乙胺(2714mg)，所得反应液油浴75℃搅拌15小时。反应完全后，反应液减压浓缩，所得粗品经硅胶柱层析(石油醚:乙酸乙酯，体积比3:1)纯化得到1500mg黄色固体，记为化合物M009-1，产率94.2％，LC-MS[M+H] +＝381.1。
(4)化合物6-氟-N-(3-甲氧基苄基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)二氢吲哚-1-甲酰胺(M009)的制备
氮气保护下，将化合物M009-1(1500mg)，联硼酸频那醇酯(CAS：73183-34-3，2010mg)，醋酸钾(AcOK，1940mg)和(1,1'-双(二苯基膦基)二茂铁)二氯化钯(Pd(dppf)Cl 2，579mg)，加入到1,4-二氧六环(1,4-dioxane，20mL)中，将所得反应液油浴90℃搅拌5小时。反应完全后，将反应液浓缩，所得粗品经硅胶柱层析纯化(二氯甲烷:甲醇，体积比50:1)得到黄色油状物800mg，记为化合物M009，产率47.4％，LC-MS[M+H] +＝427.1。
(5)化合物6-氟-N-(3-甲氧基苄基)-5-(3-硝基-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑-4-基)二氢吲哚-1-甲酰胺(A-1)的制备
氮气保护下，将化合物M009(800mg)，4-溴-3-硝基-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑(544mg)，无水碳酸钾(1040mg)和(1,1'-双(二苯基膦基)二茂铁)二氯化钯(137mg)加入到1,4-二氧六环:水＝体积比(20:1，10mL)的混合溶剂中。将所得反应液油浴80℃搅拌2小时。反应完全后向反应液中加水(50mL)稀释，用乙酸乙酯(30mL×3)萃取，合并有机相；所得有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩后的残留物经硅胶柱层析纯化(石油醚:乙酸乙酯，体积比20:1)得到黄色油状物650mg，记为化合物A-1，产率63.9％，LC-MS[M+H] +＝542.1。
(6)化合物6-氟-N-(3-甲氧基苄基)-5-(3-硝基-1H-吡唑-4-基)二氢吲哚-1-甲酰胺(A-2)的制备
将化合物A-1(650mg)溶于乙醇(10mL)中，向所得溶液中加入浓盐酸(1mL，38％)。将 所得反应液80℃油浴回流搅拌5h，反应完全后得到化合物A-2，不处理直接进行下一步。LC-MS[M+H] +＝412.1。
(7)化合物5-(3-氨基-1H-吡唑-4-基)-6-氟-N-(3-甲氧基苄基)二氢吲哚-1-甲酰胺(A)的制备
冰水浴下将活化后的锌粉(Zn，798mg)加入到步骤(6)所得的反应液中，后加入乙酸(AcOH，3mL)，将所得反应液恢复至室温搅拌2小时后减压浓缩，然后加入饱和碳酸氢钠(10mL)，所得混合物用乙酸乙酯(5mL×3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液浓缩，所得粗产物经硅胶柱层析(二氯甲烷:甲醇，体积比20:1)纯化。得到98mg式A化合物，为白色固体，两步产率21.4％，LC-MS[M+H] +＝382.2。
1H NMR(400MHz,DMSO-d 6)δ11.69(s,1H),7.61(d,J＝12.9Hz,1H),7.46(s,1H),7.31(dd,J＝11.5,6.1Hz,2H),7.24(t,J＝8.0Hz,1H),6.93–6.87(m,2H),6.80(dd,J＝7.3,1.9Hz,1H),4.59(s,2H),4.31(d,J＝5.8Hz,2H),3.99(t,J＝8.7Hz,2H),3.74(s,3H),3.12(t,J＝8.5Hz,2H).
实施例2：晶型I的制备
取30mg式A化合物，加入0.2mL乙酸乙酯，得悬浊液，室温搅拌约15小时，过滤，将过滤收集的样品在50℃下真空干燥3小时，得到晶型I。
晶型I的XRPD检测图谱如图1中(a)所示，解析如图1中(b)、表6’所示。
表6’式A化合物晶型I的XRPD解析
Figure PCTCN2022092499-appb-000008
晶型I的DSC-TGA测试如图6所示，其熔点约为157.20℃；室温至约150℃温度区间内失重 约为2.4％，晶型I为无水合物。
晶型I的 1H NMR检测图如图9所示。
晶型I的PLM图谱如图8中的(a)所示。
表6.式A化合物晶型I的固态表征结果
Figure PCTCN2022092499-appb-000009
实施例3：晶型II的制备
取30mg式A化合物，加入0.2mL水中，室温搅拌15小时，过滤，将过滤收集的样品在50℃下真空干燥3小时，得到晶型II。
所得晶型II的XRPD图谱如图2中(a)所示，解析如图2中(b)、表7’所示；
表7’式A化合物晶型II的XRPD解析
Figure PCTCN2022092499-appb-000010
晶型II的DSC-TGA测试如图7所示，其熔点约为173.72℃；室温至约150℃温度区间内失重约为0.669％，晶型II为无水合物。
晶型II的PLM图谱如图8中的(b)所示。
表7.式A化合物晶型II的固态表征结果
Figure PCTCN2022092499-appb-000011
实施例4：晶型II的放大制备
称取约300mg式A化合物，分散于2mL的混合溶剂(EtOH/水，v/v＝1/10)中，室温搅拌3天。过滤收集样品并在50℃下抽真空干燥约15小时，得约200mg的产品，收率约67％。对所得样品进行检测分析。
所得样品经XRPD检测为晶型II。
所得晶型II的DSC-TGA测试如图12所示，在DSC图谱上有一峰值温度为179℃的吸热峰，归结为样品熔融所致；TGA数据显示样品在150℃之前无失重，晶型II为无水合物。
所得晶型II的 1H-NMR检测图如图13所示，样品无EtOH残留。
表8.放大制备的式A化合物晶型II的固态表征结果
Figure PCTCN2022092499-appb-000012
实施例5：实施例1的式A化合物的性能检测
对实施例1制备的式A化合物进行XRPD，DSC，MDSC，TGA和 1H-NMR表征。
式A化合物的XRPD检测图谱如图3所示，化合物A为无定型。
式A化合物的DSC-TGA测试如图4所示，TGA结果显示样品随着温度的上升失重一直在增加，DSC图谱显示RT(室温)-160℃范围内无明显热力学事件。
式A化合物的MDSC测试结果如图5所示，样品的玻璃转化温度Tg为约20℃。
此外， 1H-NMR结果显示少量溶剂残留。
表9.实施例1式A化合物的表征结果
Figure PCTCN2022092499-appb-000013
实施例6：晶型II的稳定性测试
在60℃/闭口和40℃/75％RH开口两种条件下对晶型II进行稳定性测试(最长至14天)：取适量游离碱晶型II放置在60℃/闭口和40℃/75％RH开口两种条件下保持1周和2周，取0天、1周和2周的样品溶解于稀释剂中配成约1.0mg/mL溶液进行HPLC分析化学稳定性，1周或2周后的固体样品进行XRPD测试分析物理稳定性。
测试结果如表10-11和图10-11所示。稳定性结果显示晶型II在60℃/闭口和40℃/75％RH开口两种条件下放置1周、2周后物理和化学均稳定。
表10.稳定性评估结果(7天)
Figure PCTCN2022092499-appb-000014
表11.稳定性评估结果(14天)
Figure PCTCN2022092499-appb-000015
实施例7：晶型II的溶解度测试
在37℃下，测试了晶型II在相关生物介质(SGF、FaSSIF和FeSSIF)中的溶解度：称取15mg的晶型II样品分散于5.0mL生物相关介质中，得到分散液。在37℃下，转速为100rpm摇床上振荡，分别于0.5h、2h和24h取出1mL分散液进行过滤，滤液通过HPLC测试的溶解度和pH计测试pH值，滤饼通过XRPD表征晶型。
溶解度测试结果具体如表12所示。晶型II在生物相关介质中24小时晶型保持不变。三种生物介质中，晶型II在SGF中的溶解度最高，可达1mg/mL以上；在FeSSIF中的溶解度次之， 0～24h溶解度分布在33～49μg/mL；而在FaSSIF中的溶解度最低，24h内溶解度只有6～9μg/mL。
表12.晶型II的溶解度测试结果
Figure PCTCN2022092499-appb-000016
实施例8：晶型II的药代动力学研究实验
实验中用SD大鼠(购买于北京维通利华实验动物技术有限公司)6只，体重为180-280g，雌雄各半。随机分成四组，每组3只，第一组为雌鼠，第二组为雄鼠。
以5％TPGS溶解式A化合物晶型II，药物浓度20mg/ml(以式A化合物计)，灌胃给药，给药体积为10ml/kg，给药剂量为20mg/kg，给药频率QD(一天一次)。于给药后不同时间点(0.167、0.5、1、2、3、4、6、9、12和24h)从大鼠眼眶静脉丛采取血液，收集血样。检测血浆中的化合物A的浓度；
数据将使用WinNonlin(version 5.2.1 Pharsight,Mountain View,CA)通过非房室模型进行分析，得到PK参数(根据不同给药途径选择C 0，C max，T max，AUC 0-last，AUC inf，T 1/2，CL，Vz等参数)。
各项药代动力学参数参见表13。
表13
Figure PCTCN2022092499-appb-000017
发明人出人意料地发现，本发明提供的晶型I和II具有稳定的化学性质。其一，相对于无定型物，它们放置后所产生杂质的含量均得以降低。其二，相对于无定型物，本发明的晶型在高温或高湿条件下晶型均较稳定。因此，本发明的晶型更有利于药物的质量控制及成药性。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (12)

  1. 式A化合物的晶型：
    Figure PCTCN2022092499-appb-100001
  2. 根据权利要求1所述的晶型，其特征在于，所述晶型选自晶型I或晶型II。
    优选地，式A化合物的晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在13.4±0.2°处具有特征峰；
    优选地，所述晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在4.4±0.2°、8.9±0.2°、13.4±0.2°、22.3±0.2°、24.3±0.2°、25.5±0.2°处具有特征峰；
    优选地，式A化合物的晶型II使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在5.1±0.2°、13.6±0.2°、17.8±0.2°处具有特征峰；
    优选地，所述晶型II使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在5.1±0.2°、13.6±0.2°、13.9±0.2°、17.8±0.2°、18.1±0.2°、21.3±0.2°、22.9±0.2°、25.6±0.2°、26.0±0.2°处具有特征峰。
  3. 根据权利要求2所述的晶型，其特征在于，所述晶型I具有基本如图1中(a)所示的X-射线粉末衍射图谱；
    优选地，所述晶型I具有如表6’所示的以2θ角度表示的X-射线粉末衍射特征峰，误差范围±0.2°；
    优选地，所述晶型I使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射如图1中(b)所示，误差范围±0.20°；
    优选地，所述晶型I为无水合物；
    优选地，所述晶型I的熔点为157±5℃；
    优选地，所述晶型I在峰值温度为167±2℃处具有吸热峰；
    优选地，所述晶型I具有基本如图6所示的DSC-TGA图谱；
    优选地，所述晶型I具有基本如图8中的(a)所示的形貌。
  4. 根据权利要求2所述的晶型，其特征在于，所述晶型II具有基本如图2中(a)所示的X-射线粉末衍射图谱；
    优选地，所述晶型II具有如表7’所示的以2θ角度表示的X-射线粉末衍射特征峰，误差范围±0.2°；
    优选地，所述晶型II使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射如图2中(b)所示，误差范围±0.20°；
    优选地，所述晶型II为无水合物；
    优选地，所述晶型II在室温至150±5℃温度区间内失重为0-1.0％；
    优选地，所述晶型II的熔点为174±5℃；
    优选地，所述晶型II在峰值温度为178±2℃处具有吸热峰；
    优选地，所述晶型II具有基本如图7所示的DSC-TGA图谱；
    优选地，所述晶型II具有基本如图8中的(b)所示的形貌。
  5. 权利要求1-4任一项所述晶型的制备方法，其特征在于，选自下述任一种方法：
    方法一：将式A化合物与溶剂A混合形成悬浊液，搅拌，得到所述晶型；
    方法二：将式A化合物与溶剂B混合形成澄清溶液，搅拌下向所述澄清溶液中加入溶剂C，得到所述晶型；
    其中，所述溶剂B为式A化合物的良溶剂，所述溶剂C为抗溶剂。
  6. 根据权利要求5所述的制备方法，其特征在于，所述溶剂A选自有机溶剂、水、或有机溶剂和水的混合溶剂；
    优选地，所述有机溶剂选自甲基叔丁基醚、异丙醇、乙酸乙酯、甲醇和乙醇中的一种、两种或更多种；
    优选地，所述溶剂B选自甲醇、乙醇、乙腈、正丁醇、二甲基亚砜、二氯甲烷和丁酮中的一种、两种或多种；
    优选地，所述溶剂C选自异丙醇、正庚烷、甲基叔丁基醚、乙酸乙酯、乙酸异丙酯、水和甲基环己烷中的一种、两种或多种；
    优选地，所述搅拌的时间为3小时-5天；
    优选地，所述搅拌的温度为15-30℃。
  7. 一种药物组合物，其特征在于，所述药物组合物含有权利要求1-4任一项所述的晶型以及任选药学上可接受的载体；
    优选地，所述药物组合物含有权利要求2-4任一项所述的晶型I和/或晶型II、以及任选药学上可接受的载体。
  8. 根据权利要求7所述的药物组合物，其特征在于，所述药物组合物中还含有其他活性成分，例如其他ROCK抑制剂、酪氨酸激酶抑制剂、酪氨酸酶抑制剂、促纤维化细胞因子抑制剂、血清淀粉样蛋白P抑制剂、自溶素-卵磷脂酸通路抑制剂、GPR40激动剂、GPR84拮抗剂、抗酸药物和抗生素中的一种或两种以上。
  9. 权利要求1-4任一项所述的晶型或权利要求7或8所述的药物组合物在制剂制备中的应用。
  10. 根据权利要求9所述的应用，其特征在于，所述制剂为散剂、片剂、锭剂、胶囊剂、颗粒剂、丸剂、可分散粉末、混悬剂、溶液剂、乳剂、酏剂、糖浆剂、气雾剂、霜剂、软膏剂、凝胶、注射剂、冻干粉针剂或栓剂剂型；
    优选地，所述制剂为ROCK拮抗剂；优选地，所述ROCK拮抗剂用于预防和/或治疗一种或多种ROCK的高表达或ROCK的过度激活导致的疾病；
    优选地，所述疾病选自心脑血管疾病、神经系统疾病、纤维化疾病、眼疾病、肿瘤、动脉血栓形成病症、辐射损伤、呼吸系统疾病、代谢性疾病、以及自身免疫性疾病；
    优选地，所述疾病包括动脉粥样硬化、急性冠脉综合征、高血压、脑血管痉挛、脑缺血、缺血性脑卒中、再狭窄、心脏病、心脏衰竭、心肌肥厚、心肌缺血再灌注损伤、糖尿病、糖尿病肾病、癌症、神经元变性、神经损伤性疾病、脊髓损伤、勃起功能障碍、血小板凝聚、白细胞聚集、青光眼、眼部高血压、哮喘、骨质疏松症、肺纤维化(如特发性肺纤维化)、肝纤维化、肾脏纤维化、COPD、肾透析、肾小球硬化症、脂肪性肝病、脂肪性肝炎或神经元变性炎症。
  11. 一种制剂，其特征在于，所述制剂含有权利要求1-4任一项所述的晶型。
  12. 根据权利要求11所述的制剂，其特征在于，所述制剂含有权利要求7或8所述的药物组合物；
    优选地，所述制剂为散剂、片剂、锭剂、胶囊剂、颗粒剂、丸剂、可分散粉末、混悬剂、溶液剂、乳剂、酏剂、糖浆剂、气雾剂、霜剂、软膏剂、凝胶、注射剂、冻干粉针剂或栓剂剂型；
    优选地，所述制剂为ROCK拮抗剂；优选地，所述ROCK拮抗剂用于预防和/或治疗一种或多种ROCK的高表达或ROCK的过度激活导致的疾病。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101253152A (zh) * 2005-09-02 2008-08-27 安斯泰来制药株式会社 作为rock抑制剂的酰胺衍生物
WO2011050245A1 (en) * 2009-10-23 2011-04-28 Yangbo Feng Bicyclic heteroaryls as kinase inhibitors
CN106817899A (zh) * 2014-07-15 2017-06-09 百时美施贵宝公司 作为rock抑制剂的螺环庚烷
WO2021093795A1 (zh) * 2019-11-15 2021-05-20 武汉朗来科技发展有限公司 一种rock抑制剂及其制备方法和用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101253152A (zh) * 2005-09-02 2008-08-27 安斯泰来制药株式会社 作为rock抑制剂的酰胺衍生物
WO2011050245A1 (en) * 2009-10-23 2011-04-28 Yangbo Feng Bicyclic heteroaryls as kinase inhibitors
CN106817899A (zh) * 2014-07-15 2017-06-09 百时美施贵宝公司 作为rock抑制剂的螺环庚烷
WO2021093795A1 (zh) * 2019-11-15 2021-05-20 武汉朗来科技发展有限公司 一种rock抑制剂及其制备方法和用途

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