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WO2025157275A1 - 金属酶抑制剂化合物的固体形式 - Google Patents

金属酶抑制剂化合物的固体形式

Info

Publication number
WO2025157275A1
WO2025157275A1 PCT/CN2025/074828 CN2025074828W WO2025157275A1 WO 2025157275 A1 WO2025157275 A1 WO 2025157275A1 CN 2025074828 W CN2025074828 W CN 2025074828W WO 2025157275 A1 WO2025157275 A1 WO 2025157275A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
difluoromethyl
difluoro
benzo
cyclopropyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/074828
Other languages
English (en)
French (fr)
Inventor
周涛
董阳
阿诺德·苏珊
郭红星
金燕峰
王伟
梅波
杨艳兰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Corxel Pharmaceuticals Hong Kong Ltd
Original Assignee
Corxel Pharmaceuticals Hong Kong Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Corxel Pharmaceuticals Hong Kong Ltd filed Critical Corxel Pharmaceuticals Hong Kong Ltd
Publication of WO2025157275A1 publication Critical patent/WO2025157275A1/zh
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • 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

Definitions

  • the present disclosure relates to solid forms of the metalloenzyme inhibitor compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole, in particular to crystalline and amorphous solid forms, as well as preparation methods, pharmaceutical compositions, and uses thereof.
  • Compound A has a chemical formula of C 15 N 4 H 10 F 4 and a molecular weight of 322.3.
  • Compound A is a metalloenzyme inhibitor, specifically a selective inhibitor of aldosterone synthase CYP11B2.
  • the synthesis method and biological activity of Compound A can be found in, for example, WO 2018/125800, the entire contents of which are incorporated herein by reference.
  • At least one solid form of the compound is required, such as a crystalline form with superior physicochemical properties, or an amorphous solid form that can exist stably, so that it is conducive to use in drug processing and pharmaceutical compositions.
  • the present invention provides a variety of crystal forms and amorphous solids of a metalloenzyme inhibitor compound A, as well as preparation methods, pharmaceutical compositions and uses thereof.
  • One aspect of the present invention relates to Form I of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.9°, 12.4°, 17.6°, 25.0°, and 25.8° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • the present invention also relates to a crystalline form I of compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.9°, 12.4°, 17.6°, 18.2°, 19.6°, 24.2°, 25.0°, 25.8°, 26.7°, 28.0°, and 28.8° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • the present invention also relates to Form I of Compound A having an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG1 .
  • XRPD X-ray powder diffraction
  • Form I of Compound A is an anhydrous crystalline form.
  • Form I of Compound A has an endothermic peak at approximately 211.6°C ⁇ 2.0°C when thermally analyzed using differential scanning calorimetry (DSC).
  • Form I of Compound A has a DSC pattern substantially as shown in FIG2 , when subjected to thermal analysis using differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • Form I of Compound A has a TGA pattern substantially as shown in FIG3 , when subjected to thermal analysis using thermogravimetric analysis (TGA).
  • TGA thermogravimetric analysis
  • Form I of Compound A when analyzed using dynamic water sorption (DVS), has a DVS pattern substantially as shown in FIG6 .
  • the present invention also relates to a method for preparing the crystalline form I of compound A, comprising the following steps:
  • organic solvent is one or more selected from organic acids, amides, sulfones, alcohols, ethers, and nitriles, preferably selected from organic acids and amides;
  • the organic solvent is selected from formic acid, acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, C 1 -C 6 alcohol or polyol, tetrahydrofuran, anisole or acetonitrile.
  • Another aspect of the present invention relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 18.1°, 22.1°, 24.8°, and 25.7° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • the present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.4°, 10.2°, 12.4°, 14.0°, 15.8°, 16.7°, 17.5°, 18.1°, 20.2°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • the present invention also relates to Form III of Compound A, which has an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG7 .
  • XRPD X-ray powder diffraction
  • the crystalline form III of compound A is an acetic acid-containing crystalline form, preferably an acetic acid solvate (AcOH solvate) crystalline form.
  • Form III of Compound A has endothermic peaks at approximately 78.3°C ⁇ 2°C, 121.4°C ⁇ 2°C, and/or 212.2°C ⁇ 2°C when thermally analyzed using differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • Form III of Compound A has a DSC pattern substantially as shown in FIG8 , when subjected to thermal analysis using differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • Form III of Compound A has a TGA pattern substantially as shown in FIG9 , when subjected to thermal analysis using thermogravimetric analysis (TGA).
  • TGA thermogravimetric analysis
  • the present invention also relates to a method for preparing Form III of Compound A, comprising the following steps:
  • the temperature of the heating suspension is ⁇ 60°C, preferably ⁇ 55°C, more preferably ⁇ 50°C; the temperature of the cooling and standing is ⁇ 10°C, preferably ⁇ 5°C.
  • Another aspect of the present invention relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, and 24.5° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • the present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 9.7°, 13.0°, 15.6°, 17.2°, 17.9°, 19.1°, 20.4°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, 32.7°, and 34.3° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • the present invention also relates to Form IV of Compound A having an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG10 .
  • XRPD X-ray powder diffraction
  • the crystalline form IV of compound A is a hydrochloric acid-containing crystalline form, preferably a crystalline form of the hydrochloride salt of the compound, and more preferably an anhydrous crystalline form.
  • Form IV of Compound A has endothermic peaks at approximately 180.5°C ⁇ 2°C and 209.0°C ⁇ 2°C when thermally analyzed using differential scanning calorimetry (DSC).
  • Form IV of Compound A has a DSC pattern substantially as shown in FIG11 when subjected to thermal analysis using differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • Form IV of Compound A has a TGA pattern substantially as shown in FIG12 when subjected to thermal analysis using thermogravimetric analysis (TGA).
  • the present invention also relates to a method for preparing the crystalline form IV of compound A, comprising the following steps:
  • the molar number of HCl is 2 to 5 times the molar number of Compound A, preferably 3 to 4 times.
  • composition comprising:
  • At least one of the crystalline form III of compound A and the crystalline form IV of compound A is at least one of the crystalline form III of compound A and the crystalline form IV of compound A.
  • the above composition is a mixture of two or more crystal forms of Compound A, which is a mixed crystal form directly prepared from a solution or suspension of Compound A.
  • the composition comprises any ratio of Form I, Form III and/or Form IV of Compound A. In some preferred embodiments, the composition comprises any ratio of Form I and Form III of Compound A.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • the pharmaceutical composition further comprises an additional therapeutic agent.
  • the pharmaceutical composition comprises an additional therapeutic agent selected from the group consisting of an anticancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, an agent for treating metabolic diseases, an agent for treating ophthalmic diseases, an agent for treating central nervous system (CNS) diseases, an agent for treating urological diseases, and an agent for treating gastrointestinal diseases.
  • an additional therapeutic agent selected from the group consisting of an anticancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, an agent for treating metabolic diseases, an agent for treating ophthalmic diseases, an agent for treating central nervous system (CNS) diseases, an agent for treating urological diseases, and an agent for treating gastrointestinal diseases.
  • CNS central nervous system
  • Another aspect of the present invention relates to an amorphous solid of Compound A, which has no obvious crystal diffraction characteristic peaks in its X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • the amorphous solid of Compound A has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 15.
  • XRPD X-ray powder diffraction
  • the amorphous solid of Compound A further comprises a pharmaceutically acceptable polymer.
  • the amorphous solid of Compound A is a solid dispersion of the compound and a polymer.
  • the polymer in the amorphous solid of compound A, is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP) and acrylic acid resin copolymer (Eudragit).
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropyl methylcellulose
  • HPC hydroxypropyl methylcellulose acetate succinate
  • HPMCP hydroxypropyl methylcellulose phthalate
  • acrylic acid resin copolymer Eudragit
  • the hypromellose is selected from HPMC E3, HPMC E5 or HPMC E50LV;
  • the hydropropyl methylcellulose acetate succinate is selected from HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS MMP or HPMCAS MF;
  • the hydropropyl methylcellulose phthalate is selected from HPMCP HP50;
  • the acrylic resin copolymer is selected from methacrylic acid/methyl methacrylate copolymer (Eudragit L100) or butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer (Euragit EPO).
  • the polymer in the amorphous solid of compound A, is selected from one or more of HPMC E3, HPMC E5, HPMC E50LV, HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS MMP, HPMCAS MF, HPMCP HP50, Eudragit L100, and Euragit EPO, preferably one or more of HPMCAS MG, HPMCAS MMP, and HPMCAS MF.
  • the compound in the amorphous solid of compound A, accounts for about 5% to 25% by weight of the amorphous solid, preferably about 5% to 20%, more preferably about 10% to 20%, and particularly preferably about 10% to 15%.
  • the mass ratio of the compound to the polymer is about 1:3 to 1:20, preferably about 1:4 to 1:20, more preferably about 1:4 to 1:9, and particularly preferably about 1:5.6 to 1:9.
  • the amorphous solid of Compound A is prepared by spray drying or hot melt extrusion.
  • Another aspect of the present invention relates to a method for preparing an amorphous solid of compound A, comprising the following steps:
  • the solution is spray dried to form a solid dispersion, which is the amorphous solid.
  • the polymer in the method for preparing the amorphous solid of Compound A, is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP) and acrylic resin copolymer (Eudragit).
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropyl methylcellulose
  • HPMC hydroxypropyl methylcellulose acetate succinate
  • HPMCP hydroxypropyl methylcellulose phthalate
  • acrylic resin copolymer Eudragit
  • the solvent is one or more selected from alcohols, alkyl halides, ketones, ethers, esters, amides , sulfones, and nitriles.
  • the solvent is one or more selected from C1-C6 alcohols or polyols, dichloromethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, anisole, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, and acetonitrile.
  • the solvent is a mixture of dichloromethane and methanol, preferably a mixture of dichloromethane and methanol in a volume ratio of 2:1.
  • the concentration of the compound in the solution is about 3-15 mg/mL, preferably about 4-12 mg/mL, and more preferably about 5-10 mg/mL.
  • the present invention also relates to the amorphous solid of compound A prepared according to the above-mentioned spray drying method.
  • Another aspect of the present invention relates to a method for preparing an amorphous solid of compound A, comprising the following steps:
  • the compound is mixed evenly with a pharmaceutically acceptable polymer, and the mixture is extruded through a hot melt extruder to obtain the amorphous solid.
  • the polymer in the method for preparing the amorphous solid of Compound A, is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP) and acrylic resin copolymer (Eudragit).
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropyl methylcellulose
  • HPMC hydroxypropyl methylcellulose acetate succinate
  • HPMCP hydroxypropyl methylcellulose phthalate
  • acrylic resin copolymer Eudragit
  • the heating temperature of the hot melt extruder is 150-200°C, preferably 160-180°C.
  • the method for preparing the amorphous solid of Compound A further comprises the steps of crushing and screening the hot-melt extrudate.
  • the present invention also relates to the amorphous solid of compound A prepared according to the hot melt extrusion method.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • the pharmaceutical composition further comprises an additional therapeutic agent.
  • the pharmaceutical composition comprises an additional therapeutic agent selected from the group consisting of an anticancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, an agent for treating metabolic diseases, an agent for treating ophthalmic diseases, an agent for treating central nervous system (CNS) diseases, an agent for treating urological diseases, and an agent for treating gastrointestinal diseases.
  • an additional therapeutic agent selected from the group consisting of an anticancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, an agent for treating metabolic diseases, an agent for treating ophthalmic diseases, an agent for treating central nervous system (CNS) diseases, an agent for treating urological diseases, and an agent for treating gastrointestinal diseases.
  • CNS central nervous system
  • Another aspect of the present invention relates to the use of the crystalline form I, crystalline form III, crystalline form IV or amorphous solid of Compound A in the preparation of medicines.
  • the drug is used to modulate metalloenzyme activity.
  • the drug is used to regulate the activity of aldosterone synthase CYP11B2.
  • the medicament is used to treat a metalloenzyme-related disorder or disease, wherein the disorder or disease is cancer, cardiovascular disease, endocrine disease, fibrosis, kidney disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urological disease, or gastrointestinal disease.
  • the disorder or disease is cancer, cardiovascular disease, endocrine disease, fibrosis, kidney disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urological disease, or gastrointestinal disease.
  • the condition or disease is adrenal cancer, adrenal adenoma, leukemia, breast cancer, hypertension, resistant hypertension, pulmonary hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, post-myocardial infarction syndrome, coronary heart disease, myocardial necrotic lesions, atrial fibrillation, atherosclerosis, restenosis, endothelial dysfunction, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, vascular disease, diseases associated with primary or secondary aldosteronism and adrenal hyperplasia.
  • Hypertension diabetes mellitus, metabolic syndrome, insulin resistance, neuropathy, insulinopathy, diabetic nephropathy, diseases characterized by increased collagen formation, fibrosis, and matrix remodeling following hypertension, diseases characterized by fibrosis and matrix remodeling following endothelial cell dysfunction, myocardial fibrosis, vascular fibrosis, renal failure, chronic renal failure, nephropathy, renal dysfunction, kidney disease, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, hypokalemia, retinopathy, sleep apnea, obstructive sleep apnea, muscular dystrophy, stroke, liver disease, nonalcoholic steatohepatitis, cirrhosis, or nonalcoholic fatty liver disease.
  • condition or disease is hypertension, resistant hypertension, pulmonary hypertension, atherosclerosis or hypokalemia.
  • Another aspect of the present invention relates to a method for treating a condition or disease, comprising administering to a subject in need thereof an effective amount of Form I, Form III, or Form IV of Compound A, or a mixture of at least two of the above forms in any proportion.
  • the condition or disease is as described above.
  • FIG1 shows the X-ray powder diffraction (XRPD) pattern of Form I of Compound A.
  • FIG2 shows the differential scanning calorimetry (DSC) spectrum of Form I of Compound A.
  • FIG3 shows a thermogravimetric analysis (TGA) spectrum of Form I of Compound A.
  • FIG4 shows the 1 H NMR spectrum of Form I of Compound A.
  • FIG5 shows the 13 C NMR spectrum of Form I of Compound A.
  • FIG6 shows a dynamic water sorption (DVS) spectrum of Form I of Compound A.
  • FIG7 shows the X-ray powder diffraction (XRPD) pattern of Form III of Compound A.
  • FIG8 shows the differential scanning calorimetry (DSC) spectrum of Form III of Compound A.
  • FIG9 shows a thermogravimetric analysis (TGA) spectrum of Form III of Compound A.
  • FIG10 shows the X-ray powder diffraction (XRPD) pattern of Form IV of Compound A.
  • FIG11 shows the differential scanning calorimetry (DSC) spectrum of Form IV of Compound A.
  • FIG12 shows a thermogravimetric analysis (TGA) spectrum of Form IV of Compound A.
  • FIG13 shows the 1 H NMR spectrum of Form IV of Compound A.
  • FIG14 shows the XRPD pattern of a portion of the solid dispersion prepared in Example 22.
  • FIG15 shows the X-ray powder diffraction (XRPD) pattern of the amorphous solid of Compound A prepared in Example 24.
  • Figure 16 shows the modulated differential scanning calorimetry (mDSC) spectrum of the amorphous solid of Compound A prepared in Example 24.
  • the three curves from top to bottom in the figure are the reversible sample heat flow, the irreversible sample heat flow and the total heat flow, respectively.
  • FIG17 shows a thermogravimetric analysis (TGA) spectrum of the amorphous solid of Compound A prepared in Example 24.
  • FIG18 shows the X-ray powder diffraction (XRPD) pattern of the amorphous solid of Compound A prepared in Example 27.
  • Figure 19 shows the modulated differential scanning calorimetry (mDSC) spectrum of the amorphous solid of Compound A prepared in Example 27.
  • the three curves from top to bottom in the figure are the irreversible sample heat flow, the total heat flow, and the reversible sample heat flow.
  • FIG20 shows a thermogravimetric analysis (TGA) spectrum of the amorphous solid of Compound A prepared in Example 27.
  • treating includes preventing, ameliorating, alleviating, and/or managing the disease and/or conditions that may cause the disease.
  • the terms “treat” and “treating” refer to methods of alleviating or alleviating a disease and/or its associated symptoms. According to the present disclosure, “treating” includes preventing, blocking, inhibiting, attenuating, protecting, regulating, reversing, and reducing the effects of a disease, such as the harmful effects of a disease.
  • inhibitor includes preventing, reducing, and halting progression.
  • modulate refers to an increase or decrease in the activity of an enzyme in response to exposure to a compound of the present disclosure.
  • the metalloenzyme activity of the present invention is the metalloenzyme activity that is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the metalloenzyme activity of the present invention is suppressed.In some embodiments, the
  • administration includes a route of introducing a compound into a subject to achieve its intended function.
  • routes of administration include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal administration.
  • the term "effective amount" includes an amount effective to achieve the desired result at the dosage and time period necessary.
  • the effective amount of a compound may vary depending on factors such as the subject's disease state, age, and weight, as well as the compound's ability to elicit the desired response in the subject.
  • the dosage regimen may be adjusted to provide the optimal therapeutic response.
  • An effective amount is also an amount in which the therapeutic benefits outweigh any toxic or deleterious effects (e.g., side effects) of the inhibitor compound.
  • systemic administration refers to the administration of a compound, drug, or other substance so that it enters the patient's system and thereby undergoes metabolism and other similar processes.
  • terapéuticaally effective amount refers to that amount of the compound being administered which is sufficient to prevent or alleviate to some extent the development of one or more symptoms of the disease or condition being treated.
  • the therapeutically effective amount (i.e., effective dose) of the compound can be from about 0.005 ⁇ g/kg body weight to about 200 mg/kg body weight, preferably from about 0.01 mg/kg body weight to about 200 mg/kg body weight, more preferably from about 0.015 mg/kg body weight to about 30 mg/kg body weight. In other embodiments, the therapeutically effective amount can be from about 1.0 pM to about 10 ⁇ M. It will be understood by those skilled in the art that certain factors can affect the dosage required for the effective treatment of the subject, including but not limited to the severity of the disease or condition, previous treatment, the subject's overall health status and/or age, and other diseases present.
  • treating a subject with a therapeutically effective amount of the compound can include a single treatment or preferably can include a series of treatments.
  • a subject is treated with a compound of about 0.005 ⁇ g/kg body weight to about 200 mg/kg body weight, once a day, for about 1 to 10 weeks, preferably 2 to 8 weeks, more preferably about 3 to 7 weeks, and even more preferably about 4, 5, or 6 weeks.
  • the subject in the case of a chronic condition or disease, the subject can be treated every day for several years. It is also understood that the effective dosage of the compound used in therapy may be increased or decreased during the course of a particular treatment.
  • subject refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some embodiments, the subject is a human.
  • primates e.g., humans
  • the subject is a human.
  • the term "pharmaceutically acceptable” means the carrier, vehicle, diluent, excipient and/or salt must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the term "pharmaceutically acceptable carrier, diluent or excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or animals, and any carrier in various forms that has no side effects on the composition of the pharmaceutical composition.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • NMR nuclear magnetic resonance
  • X-ray powder diffraction X-ray powder diffraction
  • peak positions (2 ⁇ ) can exhibit some variability, typically as much as 0.1° to 0.2°, depending on the solvent used and the apparatus used to measure diffraction.
  • relative peak intensities can exhibit inter-instrument variability as well as variability due to crystallinity, preferred orientation, the surface of the sample being prepared, and other factors known to those skilled in the art, and should be considered only as qualitative measurements.
  • the term "2 ⁇ value” or “2 ⁇ ” refers to the peak position in degrees based on the experimental setup of an X-ray powder diffraction (XRPD) experiment and is a common unit of the abscissa of a diffraction pattern.
  • the experimental setup requires that if the incident light beam forms an angle ⁇ (theta) with a certain crystal plane, the reflection is recorded at an angle of 2 ⁇ (2theta).
  • references herein to a specific 2 ⁇ value for a specific crystalline form are intended to refer to the 2 ⁇ value (in degrees) measured using the X-ray powder diffraction (XRPD) experimental conditions described in this disclosure. For example, as described herein, using CuK ⁇ As a radiation source.
  • the term "amorphous" refers to a solid substance having an irregular microstructure, which may be referred to as a non-crystalline substance.
  • the amorphous solid herein may comprise only one substance or more than one substance.
  • the amorphous solid may be referred to as an amorphous solid of substance A, or as an amorphous solid of substance B.
  • the amorphous solid may be a solid dispersion formed of two or more substances.
  • substance A and substance B form a solid dispersion, it may be referred to as a solid dispersion or an amorphous solid of substance A, or as a solid dispersion or an amorphous solid of substance B.
  • a term not preceded by a quantifier means "one or more than one.”
  • reference to "a sample” includes a plurality of samples unless the context clearly indicates otherwise (e.g., a plurality of samples), and so forth.
  • the term "about" when referring to a value is intended to include variations based on the specified amount, in some embodiments within ⁇ 20%, in some embodiments within ⁇ 10%, in some embodiments within ⁇ 5%, in some embodiments within ⁇ 1%, in some embodiments within ⁇ 0.5%, and in some embodiments within ⁇ 0.1%, as such variations are suitable for performing the disclosed methods or using the disclosed compositions.
  • "about” can mean that the error in the value for the diffraction angle 2 ⁇ is within ⁇ 0.2°.
  • a pharmaceutical composition comprising "a pharmaceutically acceptable carrier, diluent, or excipient” includes one pharmaceutically acceptable carrier, diluent, or excipient, or two or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the present invention relates to crystalline and solid forms of the compound 1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H -benzo[d]imidazole ("Compound A") of formula (I).
  • Compound A has a chemical formula of C15N4H10F4 and a molecular weight of 322.3.
  • Compound A is a metalloenzyme inhibitor, specifically a selective inhibitor of aldosterone synthase CYP11B2.
  • the synthesis method and biological activity of Compound A can be found in, for example, WO2018/125800, the entire contents of which are incorporated herein by reference.
  • One aspect of the present invention relates to Form I of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.9°, 12.4°, 17.6°, 25.0°, and 25.8° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.9° ⁇ 0.2°, 12.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 25.0° ⁇ 0.2°, and 25.8° ⁇ 0.2°.
  • the present invention also relates to a crystalline form I of compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.9°, 12.4°, 17.6°, 24.2°, 25.0°, and 25.8° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.9° ⁇ 0.2°, 12.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 24.2° ⁇ 0.2°, 25.0° ⁇ 0.2°, and 25.8° ⁇ 0.2°.
  • the present invention also relates to a crystalline form I of compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.9°, 12.4°, 17.6°, 18.2°, 24.2°, 25.0°, and 25.8° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.9° ⁇ 0.2°, 12.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.2° ⁇ 0.2°, 24.2° ⁇ 0.2°, 25.0° ⁇ 0.2°, and 25.8° ⁇ 0.2°.
  • the present invention also relates to a crystalline form I of compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.9°, 12.4°, 17.6°, 18.2°, 24.2°, 25.0°, 25.8°, and 26.7° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.9° ⁇ 0.2°, 12.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.2° ⁇ 0.2°, 24.2° ⁇ 0.2°, 25.0° ⁇ 0.2°, 25.8° ⁇ 0.2°, and 26.7° ⁇ 0.2°.
  • the present invention also relates to a crystalline form I of compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.9°, 12.4°, 17.6°, 18.2°, 24.2°, 25.0°, 25.8°, 26.7°, and 28.0° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.9° ⁇ 0.2°, 12.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.2° ⁇ 0.2°, 24.2° ⁇ 0.2°, 25.0° ⁇ 0.2°, 25.8° ⁇ 0.2°, 26.7° ⁇ 0.2°, and 28.0° ⁇ 0.2°.
  • the present invention also relates to a crystalline form I of compound A, which has characteristic peaks at diffraction angles 2 ⁇ of about 8.9°, 12.4°, 17.6°, 18.2°, 19.6°, 24.2°, 25.0°, 25.8°, 26.7°, and 28.0° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.9° ⁇ 0.2°, 12.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.2° ⁇ 0.2°, 19.6° ⁇ 0.2°, 24.2° ⁇ 0.2°, 25.0° ⁇ 0.2°, 25.8° ⁇ 0.2°, 26.7° ⁇ 0.2°, and 28.0° ⁇ 0.2°.
  • the present invention also relates to a crystalline form I of compound A, which has characteristic peaks at diffraction angles 2 ⁇ of about 8.9°, 12.4°, 17.6°, 18.2°, 19.6°, 24.2°, 25.0°, 25.8°, 26.7°, 28.0°, and 28.8° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.9° ⁇ 0.2°, 12.4° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.2° ⁇ 0.2°, 19.6° ⁇ 0.2°, 24.2° ⁇ 0.2°, 25.0° ⁇ 0.2°, 25.8° ⁇ 0.2°, 26.7° ⁇ 0.2°, 28.0° ⁇ 0.2°, and 28.8° ⁇ 0.2°.
  • the present invention also relates to Form I of Compound A having an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG1 .
  • XRPD X-ray powder diffraction
  • Form I of Compound A is an anhydrous crystalline form.
  • Form I of Compound A has an endothermic peak at approximately 211.6°C ⁇ 2.0°C when thermally analyzed using differential scanning calorimetry (DSC).
  • Form I of Compound A when thermally analyzed using differential scanning calorimetry (DSC), Form I of Compound A has a DSC pattern substantially as shown in Figure 2. As shown in Figure 2, Form I of Compound A has only one endothermic peak, which corresponds to the melting point of Form I.
  • Form I of Compound A when thermally analyzed using thermogravimetric analysis (TGA), Form I of Compound A has a TGA pattern substantially as shown in Figure 3. As shown in Figure 3, Form I of Compound A loses only about 0.5% of its weight within the heating range of 110-180°C, indicating that Form I is an anhydrous crystalline form.
  • TGA thermogravimetric analysis
  • Form I of Compound A when analyzed using dynamic moisture sorption (DVS), Form I of Compound A has a DVS pattern substantially as shown in Figure 6. As shown in Figure 6, Form I of Compound A has a weight change of ⁇ 0.2% during a cycle of relative humidity of 0-90%, indicating that Form I is not hygroscopic.
  • DVS dynamic moisture sorption
  • the present invention also relates to a method for preparing the crystalline form I of compound A, comprising the following steps:
  • organic solvent is one or more selected from organic acids, amides, sulfones, alcohols, ethers, and nitriles, preferably selected from organic acids and amides;
  • the organic solvent is selected from formic acid, acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, C 1 -C 6 alcohol or polyol, tetrahydrofuran, anisole or acetonitrile.
  • the crystalline form I of compound A is a dominant crystalline form, which can remain stable under high temperature, high humidity, light conditions and when suspended in water.
  • Another aspect of the present invention relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 18.1°, 22.1°, 24.8°, and 25.7° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.4° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 16.7° ⁇ 0.2°, 18.1° ⁇ 0.2°, 22.1° ⁇ 0.2°, 24.8° ⁇ 0.2°, and 25.7° ⁇ 0.2°.
  • the present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 18.1°, 22.1°, 24.8°, 25.2°, and 25.7° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.4° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 16.7° ⁇ 0.2°, 18.1° ⁇ 0.2°, 22.1° ⁇ 0.2°, 24.8° ⁇ 0.2°, 25.2° ⁇ 0.2°, and 25.7° ⁇ 0.2°.
  • the present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 18.1°, 22.1°, 23.4°, 24.8°, 25.2°, and 25.7° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.4° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 16.7° ⁇ 0.2°, 18.1° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.4° ⁇ 0.2°, 24.8° ⁇ 0.2°, 25.2° ⁇ 0.2°, and 25.7° ⁇ 0.2°.
  • the present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of about 8.4°, 10.2°, 12.4°, 16.7°, 17.5°, 18.1°, 22.1°, 23.4°, 24.8°, 25.2°, and 25.7° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.4° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.4° ⁇ 0.2°, 24.8° ⁇ 0.2°, 25.2° ⁇ 0.2°, and 25.7° ⁇ 0.2°.
  • the present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 17.5°, 18.1°, 22.1°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.4° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.4° ⁇ 0.2°, 24.8° ⁇ 0.2°, 25.2° ⁇ 0.2°, 25.7° ⁇ 0.2°, and 28.2° ⁇ 0.2°.
  • the present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 17.5°, 18.1°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.4° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1° ⁇ 0.2°, 22.1° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.4° ⁇ 0.2°, 24.8° ⁇ 0.2°, 25.2° ⁇ 0.2°, 25.7° ⁇ 0.2°, and 28.2° ⁇ 0.2°.
  • the present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.4°, 10.2°, 12.4°, 16.7°, 17.5°, 18.1°, 20.2°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.4° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1° ⁇ 0.2°, 20.2° ⁇ 0.2°, 22.1° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.4° ⁇ 0.2°, 24.8° ⁇ 0.2°, 25.2° ⁇ 0.2°, 25.7° ⁇ 0.2°, and 28.2° ⁇ 0.2°.
  • the present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.4°, 10.2°, 12.4°, 15.8°, 16.7°, 17.5°, 18.1°, 20.2°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.4° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1° ⁇ 0.2°, 20.2° ⁇ 0.2°, 22.1° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.4° ⁇ 0.2°, 24.8° ⁇ 0.2°, 25.2° ⁇ 0.2°, 25.7° ⁇ 0.2°, and 28.2° ⁇ 0.2°.
  • the present invention also relates to Form III of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 8.4°, 10.2°, 12.4°, 14.0°, 15.8°, 16.7°, 17.5°, 18.1°, 20.2°, 22.1°, 22.6°, 23.4°, 24.8°, 25.2°, 25.7°, and 28.2° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 8.4° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.4° ⁇ 0.2°, 14.0° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1° ⁇ 0.2°, 20.2° ⁇ 0.2°, 22.1° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.4° ⁇ 0.2°, 24.8° ⁇ 0.2°, 25.2° ⁇ 0.2°, 25.7° ⁇ 0.2°, and 28.2° ⁇ 0.2°.
  • the present invention also relates to Form III of Compound A, which has an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG7 .
  • XRPD X-ray powder diffraction
  • the crystalline form III of compound A is an acetic acid-containing crystalline form, preferably an acetic acid solvate crystalline form.
  • Form III of Compound A has endothermic peaks at approximately 78.3, 121.4, and/or 212.2°C ⁇ 2°C when thermally analyzed using differential scanning calorimetry (DSC).
  • Form III of Compound A when thermally analyzed using differential scanning calorimetry (DSC), Form III of Compound A exhibits a DSC pattern substantially as shown in Figure 8.
  • the endothermic peak of Form III of Compound A at approximately 63-90°C corresponds to the decomposition of the acetic acid solvate; the endothermic peak at approximately 121°C corresponds to the boiling point of acetic acid; and the endothermic peak at approximately 212°C corresponds to the melting point of Compound A.
  • Form III of Compound A when thermally analyzed using thermogravimetric analysis (TGA), Form III of Compound A has a TGA pattern substantially as shown in Figure 9. As shown in Figure 9, Form III of Compound A loses approximately 15.2% weight in the heating range of 50-150°C, indicating that the stoichiometric ratio of Compound A to acetic acid in Form III of acetic acid solvate is 1:1, and Form III of Compound A is an anhydrous crystalline form.
  • TGA thermogravimetric analysis
  • the present invention also relates to a method for preparing Form III of Compound A, comprising the following steps:
  • the temperature of the heating suspension is ⁇ 60°C, preferably ⁇ 55°C, more preferably ⁇ 50°C; the temperature of the cooling and standing is ⁇ 10°C, preferably ⁇ 5°C.
  • Form III of Compound A is stable at room temperature.
  • Form III converts to Form I when heated to temperatures above 110°C in air.
  • Form III is stable in an anhydrous acetic acid solvent system at temperatures below 60°C, preferably ⁇ 55°C; at temperatures above 60°C, Form III spontaneously converts to Form I.
  • Form IV of Compound A which has characteristic peaks at diffraction angles 2 ⁇ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, and 24.5° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 9.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.6° ⁇ 0.2°, 19.1° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.1° ⁇ 0.2°, and 24.5° ⁇ 0.2°.
  • the present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, 24.5°, and 28.1° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 9.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.6° ⁇ 0.2°, 19.1° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.5° ⁇ 0.2°, and 28.1° ⁇ 0.2°.
  • the present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, 24.5°, 25.2°, and 28.1° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 9.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.6° ⁇ 0.2°, 19.1° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.2° ⁇ 0.2°, and 28.1° ⁇ 0.2°.
  • the present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, and 29.0° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 9.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.6° ⁇ 0.2°, 19.1° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.2° ⁇ 0.2°, 28.1° ⁇ 0.2°, and 29.0° ⁇ 0.2°.
  • the present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 9.7°, 13.0°, 15.6°, 19.1°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, and 32.7° in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 9.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.6° ⁇ 0.2°, 19.1° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.2° ⁇ 0.2°, 28.1° ⁇ 0.2°, 29.0° ⁇ 0.2°, and 32.7° ⁇ 0.2°.
  • the present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 9.7°, 13.0°, 15.6°, 17.2°, 19.1°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, and 32.7° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 9.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.2° ⁇ 0.2°, 19.1° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.2° ⁇ 0.2°, 28.1° ⁇ 0.2°, 29.0° ⁇ 0.2°, and 32.7° ⁇ 0.2°.
  • the present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 9.7°, 13.0°, 15.6°, 17.2°, 19.1°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, and 32.7° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 9.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.2° ⁇ 0.2°, 19.1° ⁇ 0.2°, 21.3° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.2° ⁇ 0.2°, 28.1° ⁇ 0.2°, 29.0° ⁇ 0.2°, and 32.7° ⁇ 0.2°.
  • the present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 9.7°, 13.0°, 15.6°, 17.2°, 19.1°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, 32.7°, and 34.3° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 9.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.2° ⁇ 0.2°, 19.1° ⁇ 0.2°, 21.3° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.2° ⁇ 0.2°, 28.1° ⁇ 0.2°, 29.0° ⁇ 0.2°, 32.7° ⁇ 0.2°, and 34.3° ⁇ 0.2°.
  • the present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 9.7°, 13.0°, 15.6°, 17.2°, 19.1°, 20.4°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, 32.7°, and 34.3° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of 9.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.2° ⁇ 0.2°, 19.1° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.3° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.2° ⁇ 0.2°, 28.1° ⁇ 0.2°, 29.0° ⁇ 0.2°, 32.7° ⁇ 0.2°, and 34.3° ⁇ 0.2°.
  • the present invention also relates to Form IV of Compound A, which has characteristic peaks at diffraction angles 2 ⁇ of approximately 9.7°, 13.0°, 15.6°, 17.2°, 17.9°, 19.1°, 20.4°, 21.3°, 23.0°, 24.1°, 24.5°, 25.2°, 28.1°, 29.0°, 32.7°, and 34.3° in the X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • it has characteristic peaks at diffraction angles 2 ⁇ of approximately 9.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.9° ⁇ 0.2°, 19.1° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.3° ⁇ 0.2°, 23.0° ⁇ 0.2°, 24.1° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.2° ⁇ 0.2°, 28.1° ⁇ 0.2°, 29.0° ⁇ 0.2°, 32.7° ⁇ 0.2°, and 34.3° ⁇ 0.2°.
  • the present invention also relates to Form IV of Compound A, which has an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG10 .
  • XRPD X-ray powder diffraction
  • the crystalline form IV of compound A is a hydrochloric acid-containing crystalline form, preferably a crystalline form of the hydrochloride salt of the compound, and more preferably an anhydrous crystalline form.
  • Form IV of Compound A has endothermic peaks at approximately 180.5°C and 209.0°C ⁇ 2°C when thermally analyzed using differential scanning calorimetry (DSC).
  • Form IV of Compound A when thermally analyzed using differential scanning calorimetry (DSC), Form IV of Compound A has a DSC spectrum substantially as shown in Figure 11. As shown in Figure 11, the endothermic peak of Form IV of Compound A at about 160-180°C corresponds to the decomposition of the hydrochloride salt, and the endothermic peak at about 209°C corresponds to the melting point of Compound A.
  • DSC differential scanning calorimetry
  • Form IV of Compound A when thermally analyzed using thermogravimetric analysis (TGA), Form IV of Compound A exhibits a TGA pattern substantially as shown in Figure 12. As shown in Figure 12, Form IV of Compound A exhibits a weight loss of approximately 10% within the heating range of 145-205°C, indicating that the stoichiometric ratio of Compound A to hydrochloric acid in the hydrochloride salt is 1:1, and Form IV of Compound A is an anhydrous crystalline form.
  • TGA thermogravimetric analysis
  • the present invention also relates to a method for preparing Form IV of Compound A, comprising the following steps:
  • the molar number of HCl is 2 to 5 times the molar number of Compound A, preferably 3 to 4 times.
  • the heating temperature in step (1) is about 65 ⁇ 5°C.
  • the crystalline form IV of compound A can remain stable at room temperature. Under high temperature conditions (for example, greater than 100° C.), the crystalline form IV will convert into the crystalline form I.
  • composition comprising:
  • At least one of the crystalline form III of compound A and the crystalline form IV of compound A is at least one of the crystalline form III of compound A and the crystalline form IV of compound A.
  • the above composition is a mixture of two or more crystal forms of Compound A, which is a mixed crystal form directly prepared from a solution or suspension of Compound A.
  • the composition comprises any ratio of Form I, Form III and/or Form IV of Compound A. In some preferred embodiments, the composition comprises any ratio of Form I and Form III of Compound A.
  • composition (crystal form)
  • the present invention also provides a pharmaceutical composition comprising one or more of the above-mentioned crystalline forms of Compound A.
  • composition comprising:
  • the pharmaceutical composition further comprises an additional therapeutic agent.
  • the pharmaceutical composition comprises an additional therapeutic agent selected from the group consisting of an anticancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, an agent for treating metabolic diseases, an agent for treating ophthalmic diseases, an agent for treating central nervous system (CNS) diseases, an agent for treating urological diseases, and an agent for treating gastrointestinal diseases.
  • an additional therapeutic agent selected from the group consisting of an anticancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, an agent for treating metabolic diseases, an agent for treating ophthalmic diseases, an agent for treating central nervous system (CNS) diseases, an agent for treating urological diseases, and an agent for treating gastrointestinal diseases.
  • CNS central nervous system
  • Another aspect of the present invention relates to an amorphous solid of Compound A, which has no obvious crystal diffraction characteristic peaks in its X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • the amorphous solid of Compound A has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 15.
  • XRPD X-ray powder diffraction
  • the amorphous solid of Compound A further comprises a pharmaceutically acceptable polymer.
  • the amorphous solid of Compound A is a solid dispersion of the compound and a polymer.
  • the polymer in the amorphous solid of compound A, is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP) and acrylic acid resin copolymer (Eudragit).
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropyl methylcellulose
  • HPC hydroxypropyl methylcellulose acetate succinate
  • HPMCP hydroxypropyl methylcellulose phthalate
  • acrylic acid resin copolymer Eudragit
  • the hypromellose is selected from HPMC E3, HPMC E5 or HPMC E50LV;
  • the hydropropyl methylcellulose acetate succinate is selected from HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS MMP or HPMCAS MF;
  • the hydropropyl methylcellulose phthalate is selected from HPMCP HP50;
  • the acrylic resin copolymer is selected from methacrylic acid/methyl methacrylate copolymer (Eudragit L100) or butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer (Euragit EPO).
  • HPMCAS Hydroxypropyl methylcellulose acetate succinate
  • HPMCAS Hydroxypropyl methylcellulose acetate succinate
  • HPMCAS can have different dissolution pHs, such as 5.5, 6.0, and 6.5, and their grades are designated as -L, -M, and -H, respectively.
  • HPMCAS can also be formulated into solid particles of varying particle sizes, such as 5 ⁇ m, 200 ⁇ m, and 1000 ⁇ m, resulting in grades designated as -F, -MP, and -G, respectively.
  • HPMCAS HG HPMCAS with a particle size of 1000 ⁇ m and a dissolution pH of 6.5
  • HPMCAS MMP HPMCAS MMP
  • the polymer in the amorphous solid of compound A, is selected from one or more of HPMC E3, HPMC E5, HPMC E50LV, HPMCAS LG, HPMCAS MG, HPMCAS HG, HPMCAS MMP, HPMCAS MF, HPMCP HP50, Eudragit L100, and Euragit EPO, preferably one or more of HPMCAS MG, HPMCAS MMP, and HPMCAS MF.
  • Compound A accounts for about 5% to 25% by weight of the amorphous solid, preferably about 5% to 20%, more preferably about 10% to 20%, and particularly preferably about 10% to 15%.
  • the mass ratio of Compound A to polymer is about 1:3 to 1:20, preferably about 1:4 to 1:20, more preferably about 1:4 to 1:9, and particularly preferably about 1:5.6 to 1:9.
  • the amorphous solid of Compound A is prepared by spray drying or hot melt extrusion.
  • the amorphous solid of Compound A of the present invention can significantly improve the aqueous solubility and bioavailability of Compound A, such as the solubility of Compound A in fasted simulated intestinal fluid (FaSSIF), fed simulated intestinal fluid (FeSSIF), and simulated gastric fluid (SGF).
  • the solubility of the amorphous solid of Compound A is more than three times, and preferably more than five times, that of Compound A crystals.
  • the amorphous solid of compound A of the present invention can remain stable under high temperature, high humidity and light conditions without undergoing crystal transformation, which is conducive to its application in pharmaceutical compositions, pharmaceutical dosage forms and drug preparation.
  • the present invention also provides a method for preparing the amorphous solid of compound A, comprising a spray drying method or a hot melt extrusion method.
  • Another aspect of the present invention relates to a method for preparing an amorphous solid of compound A, comprising the following steps:
  • the solution is spray dried to form a solid dispersion, which is an amorphous solid of Compound A.
  • the polymer in the method for preparing the amorphous solid of Compound A, is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP) and acrylic resin copolymer (Eudragit).
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropyl methylcellulose
  • HPMC hydroxypropyl methylcellulose acetate succinate
  • HPMCP hydroxypropyl methylcellulose phthalate
  • acrylic resin copolymer Eudragit
  • the solvent is one or more selected from alcohols, alkyl halides, ketones, ethers, esters, amides , sulfones, and nitriles.
  • the solvent is one or more selected from C1-C6 alcohols or polyols, dichloromethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, anisole, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, and acetonitrile.
  • the solvent is a mixture of dichloromethane and methanol, preferably a mixture of dichloromethane and methanol in a volume ratio of 2:1.
  • the concentration of Compound A in the solution is about 3-15 mg/mL, preferably about 4-12 mg/mL, and more preferably about 5-10 mg/mL.
  • the present invention also relates to the amorphous solid of compound A prepared according to the above-mentioned spray drying method.
  • Another aspect of the present invention relates to a method for preparing an amorphous solid of compound A, comprising the following steps:
  • Compound A is mixed evenly with a pharmaceutically acceptable polymer, and the mixture is extruded through a hot melt extruder to obtain an amorphous solid of Compound A.
  • the polymer in the method for preparing the amorphous solid of Compound A, is selected from one or more of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP) and acrylic resin copolymer (Eudragit).
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropyl methylcellulose
  • HPMC hydroxypropyl methylcellulose acetate succinate
  • HPMCP hydroxypropyl methylcellulose phthalate
  • acrylic resin copolymer Eudragit
  • the heating temperature of the hot melt extruder is 150-200°C, preferably 160-180°C.
  • the method for preparing the amorphous solid of Compound A further comprises the steps of crushing and screening the hot-melt extrudate.
  • the present invention also relates to the amorphous solid of compound A prepared according to the above hot melt extrusion method.
  • the present invention also provides a pharmaceutical composition comprising the amorphous solid of Compound A.
  • composition comprising:
  • the pharmaceutical composition further comprises an additional therapeutic agent.
  • the pharmaceutical composition comprises an additional therapeutic agent selected from the group consisting of an anticancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, an agent for treating metabolic diseases, an agent for treating ophthalmic diseases, an agent for treating central nervous system (CNS) diseases, an agent for treating urological diseases, and an agent for treating gastrointestinal diseases.
  • an additional therapeutic agent selected from the group consisting of an anticancer agent, an antifungal agent, a cardiovascular therapeutic agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, an agent for treating metabolic diseases, an agent for treating ophthalmic diseases, an agent for treating central nervous system (CNS) diseases, an agent for treating urological diseases, and an agent for treating gastrointestinal diseases.
  • CNS central nervous system
  • Another aspect of the present invention relates to the use of Form I, Form III, or Form IV of Compound A (1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole), or a mixture of any two or more of these forms in any proportion, or an amorphous solid of Compound A in the preparation of a drug.
  • the drug is used to modulate metalloenzyme activity.
  • the drug is used to modulate the activity of aldosterone synthase CYP11B2.
  • the medicament is used to treat a metalloenzyme-related disorder or disease, wherein the disorder or disease is cancer, cardiovascular disease, endocrine disease, fibrosis, kidney disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urological disease, or gastrointestinal disease.
  • the disorder or disease is cancer, cardiovascular disease, endocrine disease, fibrosis, kidney disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, central nervous system (CNS) disease, urological disease, or gastrointestinal disease.
  • the condition or disease is adrenal cancer, adrenal adenoma, leukemia, breast cancer, hypertension, resistant hypertension, pulmonary hypertension, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, systolic heart failure, post-myocardial infarction syndrome, coronary heart disease, myocardial necrotic lesions, atrial fibrillation, atherosclerosis, restenosis, endothelial dysfunction, vascular injury, myocardial infarction, left ventricular hypertrophy, vascular wall hypertrophy, endothelial thickening, arterial fibrinoid necrosis, vascular disease, diseases associated with primary or secondary aldosteronism and adrenal hyperplasia.
  • Hypertension diabetes mellitus, metabolic syndrome, insulin resistance, neuropathy, insulinopathy, diabetic nephropathy, diseases characterized by increased collagen formation, fibrosis, and matrix remodeling following hypertension, diseases characterized by fibrosis and matrix remodeling following endothelial cell dysfunction, myocardial fibrosis, vascular fibrosis, renal failure, chronic renal failure, nephropathy, renal dysfunction, kidney disease, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, hypokalemia, retinopathy, sleep apnea, obstructive sleep apnea, muscular dystrophy, stroke, liver disease, nonalcoholic steatohepatitis, cirrhosis, or nonalcoholic fatty liver disease.
  • condition or disease is hypertension, resistant hypertension, pulmonary hypertension, atherosclerosis or hypokalemia.
  • the various crystal forms and amorphous solids of Compound A of the present invention can act as regulators and inhibitors of aldosterone synthase CYP11B2 and can effectively and specifically target CYP11B2, and thus can be used to prevent or treat various conditions or diseases associated with CYP11B2.
  • the present invention also provides a method for treating a condition or disease, comprising administering to a subject in need thereof an effective amount of Form I, Form III, or Form IV of Compound A (1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole), or a mixture of any two or more of these forms in any ratio, or an amorphous solid of Compound A.
  • the condition or disease is as described above.
  • the solid of compound A was prepared according to the method described in WO2018/125800.
  • the solid of compound A is dissolved in an organic solvent selected from formic acid, acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, C1-C6 alcohol or polyol, tetrahydrofuran, anisole or acetonitrile, or suspended in the organic solvent, and heated appropriately if necessary to obtain a solution or suspension.
  • organic solvent selected from formic acid, acetic acid, propionic acid, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, C1-C6 alcohol or polyol, tetrahydrofuran, anisole or acetonitrile, or suspended in the organic solvent, and heated appropriately if necessary to obtain a solution or suspension.
  • the X-ray powder diffraction (XRPD) pattern was measured using a Bruker XRD-D2Phaser X-ray diffractometer at room temperature.
  • the specific information collected is as follows:
  • the radiation source is Cu-K ⁇ radiation.
  • the scanning range (2 ⁇ range) was from 3° to 40°, the rotation speed was 20 rpm, the scanning speed was 0.2 s/step, the scanning step size was 0.02°, and the slit width was 0.01.
  • the sample was processed by pressing a glass slide directly onto the test plate. Subsequent XRPD patterns were measured using a similar method.
  • the DSC spectrum of Form I of Compound A prepared according to Example 1 was measured using a TA Instrument (Discovery DSC 250) thermal analyzer.
  • the DSC test conditions were a heating rate of 10°C/min and a temperature range of room temperature (25°C) to 300°C.
  • the DSC spectrum obtained from the test is shown in Figure 2.
  • the crystal form I of compound A has only one endothermic peak in the DSC test, with an onset temperature of 210.87°C and a peak temperature of 211.60°C. That is, the melting point of the crystal form I of compound A is 211.60°C.
  • the TGA spectrum of Form I of Compound A prepared according to Example 1 was measured using a TA Instrument (Discovery TA 55) thermal analyzer.
  • the TGA test conditions were a heating rate of 10°C/min and a temperature range of room temperature (25°C) to 300°C.
  • the TGA spectrum obtained from the test is shown in Figure 3.
  • the weight loss of Form I of Compound A in the heating range of 110-180° C. is only about 0.5%, which means that Form I is an anhydrous crystalline form.
  • the crystalline form I of compound A prepared in Example 1 was subjected to 1 H NMR analysis using an AVANCE NEO 400 MHz instrument with a test frequency of 400 MHz and a solvent of DMSO-d 6 .
  • the crystalline form I of compound A prepared in Example 1 was subjected to 13 C NMR testing using an instrument model: AVANCE NEO 400 MHz. The testing frequency was 400 MHz and the solvent was DMSO-d 6 .
  • the crystalline form I of Compound A contains only molecules of Compound A and does not contain water or other solvents.
  • the dynamic moisture adsorption spectrum of the crystalline form I of compound A prepared according to Example 1 was detected using a ProUmid (instrument model: Vsorp-Enhanced) dynamic moisture adsorption instrument.
  • the sample was first dried at 40°C/0% RH for 3 hours. The experiment was then carried out at 25°C with equilibrium conditions of 0.01%/45min.
  • the relative humidity (RH) was increased by 10% in each step (maximum 2 hours, minimum 50 minutes, the same below), and the test range was from RH 0% to 90%; after a maximum equilibrium of 2 hours at RH 90%, the relative humidity was reduced by 10% in each step (maximum 2 hours, minimum 50 minutes) until RH 0%.
  • the weight change of the sample was recorded during the process and reported as the percentage of deviation relative to the lowest weight of the sample.
  • the resulting dynamic moisture adsorption spectrum is shown in Figure 6.
  • Form I of Compound A prepared according to Example 1 was placed in a 60°C oven. Samples were removed after 5 and 10 days for XRPD analysis to investigate the temperature stability of the crystal form. The results showed that Form I was stable under high-temperature conditions.
  • Form I of Compound A prepared according to Example 1 was placed in 92.5% humidity. Samples were removed after 5 and 10 days for XRPD analysis to investigate the humidity stability of the crystal form. The results showed that Form I was stable under high humidity conditions.
  • Form I of Compound A prepared according to Example 1 was placed in a laboratory chamber at 40°C and 75% relative humidity. After one month, the sample was removed and analyzed by XRPD to assess its stability under high temperature and humidity conditions. The results demonstrated that Form I is stable under these conditions, facilitating the preparation and storage of both the API and the pharmaceutical formulation.
  • Form I of Compound A prepared according to Example 1 was exposed to 4500 lux light intensity. Samples were removed after 5 and 10 days for XRPD analysis to investigate the stability of the sample under light exposure. The results showed that Form I was stable under light exposure.
  • the error range of the 2 ⁇ value was ⁇ 0.2°.
  • the DSC spectrum of the crystalline form III of compound A prepared according to Example 9 was measured in the same manner as in Example 3.
  • the DSC spectrum obtained by the measurement is shown in FIG8 .
  • Form III of Compound A exhibits three endothermic peaks at approximately 63°C, 121°C, and 212°C (onset temperatures) in DSC testing.
  • the endothermic peak with an onset temperature of 62.7°C and a peak temperature of 78.3°C corresponds to the decomposition of acetic acid solvate;
  • the endothermic peak with an onset temperature of 121°C and a peak temperature of 121.4°C corresponds to the boiling point of acetic acid;
  • the endothermic peak at 212°C corresponds to the melting point of Compound A.
  • the TGA spectrum of the crystalline form III of compound A prepared according to Example 9 was measured in the same manner as in Example 4.
  • the TGA spectrum obtained by the measurement is shown in FIG9 .
  • the weight loss of Form III of Compound A in the heating range of 50-150°C is about 15.2%, corresponding to the decomposition of the acetic acid solvate and the volatilization of acetic acid, which means that the stoichiometric ratio of Compound A to acetic acid in the Form III of the acetic acid solvate is 1:1, and the Form III of Compound A is an anhydrous crystalline form.
  • Form III of Compound A is a stable crystalline form in an acetic acid solvent system at temperatures ⁇ 60°C, preferably ⁇ 55°C. Under these conditions, Form I can spontaneously convert to Form III. When the temperature of the acetic acid solvent system is ⁇ 60°C, Form I is a stable crystalline form, and under these conditions, Form III can spontaneously convert to Form I. This phenomenon generally corresponds to the decomposition temperature of the acetic acid solvate observed in DSC testing.
  • Form III spontaneously converted to Form I, which remained a stable crystalline form, regardless of temperature.
  • the acetic acid molecules in Form III have a lower free energy of binding with water and spontaneously migrate into water in an aqueous solvent system, disrupting the structure of the acetic acid solvate.
  • Form I of Compound A remained a thermodynamically stable crystalline form throughout the crystallization process.
  • the error range of the 2 ⁇ value is ⁇ 0.2°.
  • the DSC spectrum of the crystalline form IV of compound A prepared according to Example 15 was measured in the same manner as in Example 3.
  • the DSC spectrum obtained by the measurement is shown in FIG11 .
  • the crystal form IV of compound A has a broad endothermic peak in the range of about 160-180°C in the DSC test, which corresponds to the decomposition of the hydrochloride salt; in addition, the endothermic peak with an onset temperature of 205.81°C and a peak temperature of 208.92°C corresponds to the melting point of compound A.
  • the TGA spectrum of the crystalline form IV of compound A prepared according to Example 15 was measured in the same manner as in Example 4.
  • the TGA spectrum obtained by the measurement is shown in FIG12 .
  • the weight loss of Form IV of Compound A in the heating range of 145-205°C is about 9.9%, corresponding to the decomposition of the hydrochloride and the volatilization of hydrochloric acid (HCl), which means that the stoichiometric ratio of Compound A to HCl in the hydrochloride is 1:1, and Form IV of Compound A is an anhydrous crystalline form.
  • Example 15 The crystalline form IV of compound A prepared in Example 15 was subjected to 1 H NMR analysis in the same manner as in Example 5. The 1 H NMR spectrum obtained from the analysis is shown in FIG13 .
  • Form IV of Compound A contains molecules of Compound A and HCl in a stoichiometric ratio of 1:1, and does not contain water or other solvents.
  • Form IV of Compound A prepared according to Example 15 was weighed and placed in 1 mL of anhydrous acetic acid. The suspension was allowed to suspend at room temperature for 3 days. A sample was collected and filtered to obtain a solid, which was immediately analyzed by XRPD. The XRPD pattern showed that the crystalline form was still Form IV.
  • the suspension was heated to 65°C and stirred until the solid was completely dissolved.
  • the suspension was stirred at 65° C. for 2 days, and a sample was taken and filtered to obtain a solid, which was immediately tested for its crystal form by XRPD.
  • the XRPD pattern showed that the crystal form was Form I.
  • Form IV is completely dissolved by heating, its crystallization behavior is the same as that of Form I and Form III described in Example 14, that is, Form I is a thermodynamically stable form in an aqueous system, and other forms of Compound A will eventually spontaneously convert into Form I.
  • the ability of the polymer to inhibit the crystallization of Compound A was first preliminarily screened by the rapid evaporation method, and then the spray drying method was used to determine whether the obtained solid dispersion was amorphous and the degree of crystallization of Compound A.
  • the polymers tested include: PVP (polyvinyl pyrrolidone) K30, PVP-VA64 (ethyl pyrrolidone/vinyl acetate (6:4) copolymer), SOLUPLUS (polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), HPMC E3 (molecular weight 20,000), HPMC E5, HPMC E50LV, HPMCAS MG (particle size 1000 ⁇ m, dissolution pH 6.0), HPMCAS (hydroxypropyl methylcellulose acetate succinate) LG (particle size 1000 ⁇ m, dissolution pH 5.5), HPMCPHP50 (dissolution pH 5.0), HPC SSL (molecular weight 40,000), Eudragit L100 (methacrylic acid/methacrylate (1:1) copolymer), Euragit EPO butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1) copoly
  • HPMC E3, HPMC E5, HPMCP HP50, HPMCAS MG, HPMCAS HG, HPMCAS LG, Eudragit EPO, and HPMC E5 were able to achieve a substantially amorphous solid structure when rapidly evaporated at drug loadings of 10%-15% or higher. Combinations of two or more polymers were also tested, and it was found that the use of HPMC E50LV favored the formation of amorphous solids at higher drug loadings.
  • XRPD patterns of a portion of these spray-dried dispersions are shown in Figure 14.
  • the spray-dried dispersion (SDD) prepared in Example 22 was added to an 8 mL glass vial containing 5 mL of FaSSIF at a target concentration of 0.5 mg/mL of Compound A.
  • the mixture was stirred magnetically at 150 rpm at 37°C.
  • 0.5 mL samples were collected at 15, 30, 60, and 120 minutes, centrifuged, and the supernatant was diluted appropriately before HPLC analysis to determine the solubility of Compound A.
  • the endpoint pH of the solution at 120 minutes was measured using a pH meter. The results are shown in Table 6.
  • a modulated differential scanning calorimetry (mDSC) spectrum of an amorphous solid of Compound A was measured using a TA Discovery Q2000 thermal analyzer.
  • the test conditions were a temperature range of room temperature to 200°C, a modulation amplitude of ⁇ 0.32°C/minute, a modulation cycle of 60 seconds, and a heating rate of 2°C/minute.
  • the resulting mDSC spectrum is shown in Figure 16 .
  • the three curves from top to bottom represent the reversible sample heat flow, the irreversible sample heat flow, and the total heat flow, respectively.
  • the amorphous solid of compound A obtained in this example does not have characteristic X-ray diffraction peaks, proving that it is an amorphous body.
  • the TGA spectrum shows that the weight loss is approximately 1.5% in the range of room temperature to 150°C.
  • the content of Compound A in the solid dispersion was determined to be approximately 14.93% by HPLC, which was highly consistent with the drug loading of 15%.
  • GC also confirmed that the solid dispersion did not contain any residual solvent.
  • the two-step dissolution test simulates the dissolution process of Compound A in gastric and intestinal fluids after oral administration.
  • 50 mg of the amorphous solid of Compound A prepared in Example 24 and 7.5 mg of the crystals of Compound A (Form I) were weighed and placed in a 40 mL glass bottle.
  • 5 mL of simulated gastric fluid (SGF, pH 1.3) was added and magnetically stirred at 150 rpm at 37°C for 30 minutes.
  • 0.5 mL of the sample was taken and the supernatant was centrifuged and appropriately diluted before HPLC analysis to determine the solubility of Compound A.
  • High-temperature stability The amorphous solid of Compound A prepared according to Example 24 was placed in a 40°C oven. Samples were removed for XRPD analysis after one, two, and four weeks to assess the temperature stability of the sample. The results showed that the amorphous solid of Compound A remained amorphous after four weeks at 40°C, demonstrating that the amorphous solid of Compound A can remain stable at temperatures above room temperature.
  • Ambient Stability The amorphous solid of Compound A prepared according to Example 24 was placed in a laboratory chamber at 25°C and 60% relative humidity. Samples were removed for XRPD analysis after one, two, and four weeks to assess the sample's stability under ambient conditions. The results demonstrated that the amorphous solid of Compound A remained amorphous after four weeks and was stable under ambient conditions.
  • the thermal stability of compound A was tested by TGA.
  • Compound A was placed in a TGA analyzer and heated to 150°C, 160°C, 170°C, 180°C, 190°C, 200°C, and 210°C for 30 minutes.
  • the results showed that when the heating temperature was 170°C or lower, compound A had essentially no weight change within 30 minutes, and no thermal degradation was found by HPLC testing; when the heating temperature was 180°C, 190°C, 200°C, and 210°C, the sample weights after 30 minutes were 97.9%, 95.3%, 95.5%, and 53.6%, respectively, but no thermal degradation was found by HPLC testing, indicating that compound A had good thermal stability and only sublimated when approaching the melting point.
  • the temperature of the hot melt extruder was set to below 200°C, specifically 150°C, 160°C, 170°C, 180°C, or 190°C.
  • the mDSC spectrum of the amorphous solid of Compound A extruded at 170°C was measured using the same method as in Example 24.
  • the TGA spectrum of the amorphous solid of Compound A extruded at 170°C was measured using the same method as in Example 4, and are shown in Figures 19 and 20, respectively.
  • Figure 19 the three curves from top to bottom represent the irreversible sample heat flow, the total heat flow, and the reversible sample heat flow, respectively.
  • the hot-melt extrudate of Compound A with a drug loading of 15% and HPMCAS MF can significantly improve the solubility and dissolution performance of Compound A in gastric and intestinal fluids.
  • the solubility in SGF increased by nearly 4 times
  • the solubility in FaSSIF increased by about 2 to 3 times.
  • the dissolution rate of the hot-melt extrudate is lower than that of the spray-dried solid dispersion, mainly because the particle size of the solid particles obtained by the two preparation methods is different.
  • the hot-melt extrudate with a larger particle size has a smaller specific surface area, which limits the dissolution rate of the drug.
  • High-temperature stability The amorphous solid of Compound A prepared according to Example 27 was placed in an oven at 40°C or 60°C. Samples were removed after one, two, and four weeks for XRPD analysis to assess the temperature stability of the samples. The results showed that the amorphous solid of Compound A remained amorphous after four weeks at both 40°C and 60°C, demonstrating its stability under high-temperature conditions.
  • Ambient Stability The amorphous solid of Compound A prepared according to Example 24 was placed in a laboratory chamber at 25°C and 60% relative humidity. Samples were removed for XRPD analysis after one, two, and four weeks to assess the sample's stability under ambient conditions. The results demonstrated that the amorphous solid of Compound A remained amorphous after four weeks and was stable under ambient conditions.
  • Accelerated stability The amorphous solid of Compound A prepared according to Example 24 was placed in a test chamber at 40°C and 75% relative humidity. Samples were removed for XRPD analysis after one, two, and four weeks to assess the sample's stability under high temperature and humidity. The results showed that the amorphous solid of Compound A remained amorphous after four weeks, demonstrating stability under accelerated conditions.

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Abstract

本发明提供了金属酶抑制剂化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的固体形式，尤其涉及晶型和无定型固体形式，以及其制备方法、药物组合物和用途。

Description

金属酶抑制剂化合物的固体形式 技术领域
本公开涉及金属酶抑制剂化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的固体形式，尤其涉及晶型和无定型固体形式，以及其制备方法、药物组合物和用途。
背景技术
具有如下式(I)的化合物，1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑(1-cyclopropyl-2-(6-(difluoromethyl)pyridazin-4-yl)-5,6-difluoro-1H-benzo[d]imidazole)是一种金属酶抑制剂，具体为醛固酮合酶CYP11B2的选择性抑制剂，在针对醛固酮相关疾病的治疗上具有良好的应用前景。在本文中，也被简称为“化合物A”。
化合物A的化学式为C15N4H10F4，分子量322.3。化合物A是一种金属酶抑制剂，具体为醛固酮合酶CYP11B2的选择性抑制剂。化合物A的合成方法和生物活性可参见例如WO2018/125800，其全部内容通过引用并入本文。
为了促进上述化合物作为固态药用物质的开发，在生产、包装、储存或使用过程中保证化合物的质量和药效，需要至少一种该化合物的固态形式，例如具有优越的物理化学特性的晶型，或者能够稳定存在的无定形固体形式，使其有利于在药物加工和药物组合物中使用。
发明内容
本发明提供了金属酶抑制剂化合物A的多种晶型和无定形固体，以及其制备方法、药物组合物和用途。
本发明一方面涉及化合物A的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.9°、12.4°、17.6°、25.0°、25.8°处具有特征峰。
本发明还涉及化合物A的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.9°、12.4°、17.6°、18.2°、19.6°、24.2°、25.0°、25.8°、26.7°、28.0°、28.8°处具有特征峰。
本发明还涉及化合物A的晶型I，其具有基本上如图1所示的X射线粉末衍射(XRPD)图谱。
在一些具体实施方式中，化合物A的晶型I是无水晶型。
在一些具体实施方式中，化合物A的晶型I在使用差示扫描量热法(DSC)进行热分析时，在约211.6℃±2.0℃处具有吸热峰。
在一些具体实施方式中，化合物A的晶型I在使用差示扫描量热法(DSC)进行热分析时，具有基本上如图2所示的DSC图谱。
在一些具体实施方式中，化合物A的晶型I在使用热重分析法(TGA)进行热分析时，具有基本上如图3所示的TGA图谱。
在一些具体实施方式中，化合物A的晶型I在使用动态水分吸附法(DVS)进行分析时，具有基本上如图6所示的DVS图谱。
本发明还涉及化合物A的晶型I的制备方法，包括以下步骤：
(1)将化合物A的固体溶解在有机溶剂中或者在有机溶剂中悬浮，所述有机溶剂为选自有机酸类、酰胺类、砜类、醇类、醚类、腈类中的一种或多种，优选为选自有机酸类和酰胺类；
(2)向上述溶液或悬液中加入水，使晶体析出，其中所述水的用量为所述有机溶剂的体积的0.1～100倍；
(3)过滤收集晶体并干燥，得到化合物A的晶型I。
在一些具体实施方式中，在化合物A的晶型I的制备方法中，所述有机溶剂选自甲酸、乙酸、丙酸、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、二乙基亚砜、C1-C6的醇或多元醇、四氢呋喃、苯甲醚或乙腈。
本发明另一方面涉及化合物A的晶型III，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.4°、10.2°、12.4°、16.7°、18.1°、22.1°、24.8°、25.7°处具有特征峰。
本发明还涉及化合物A的晶型III，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.4°、10.2°、12.4°、14.0°、15.8°、16.7°、17.5°、18.1°、20.2°、22.1°、22.6°、23.4°、24.8°、25.2°、25.7°、28.2°处具有特征峰。
本发明还涉及化合物A的晶型III，其具有基本上如图7所示的X射线粉末衍射(XRPD)图谱。
在一些具体实施方式中，化合物A的晶型III是含乙酸晶型，优选为乙酸溶剂化物(AcOH solvate)晶型。
在一些具体实施方式中，化合物A的晶型III在使用差示扫描量热法(DSC)进行热分析时，在约78.3℃±2℃、121.4℃±2℃和/或212.2℃±2℃处具有吸热峰。
在一些具体实施方式中，化合物A的晶型III在使用差示扫描量热法(DSC)进行热分析时，具有基本上如图8所示的DSC图谱。
在一些具体实施方式中，化合物A的晶型III在使用热重分析法(TGA)进行热分析时，具有基本上如图9所示的TGA图谱。
本发明还涉及化合物A的晶型III的制备方法，包括以下步骤：
(1)将化合物A的固体加入无水乙酸中，在加热条件下悬浮；
(2)过滤，滤液在冷却条件下静置沉淀；
(3)过滤收集晶体并干燥，得到化合物A的晶型III。
在一些具体实施方式中，在化合物A的晶型III的制备方法中，加热悬浮的温度<60℃，优选为≤55℃，更优选为≤50℃；冷却静置的温度≤10℃，优选为≤5℃。
本发明另一方面涉及化合物A的晶型IV，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为9.7°、13.0°、15.6°、19.1°、23.0°、24.1°、24.5°处具有特征峰。
本发明还涉及化合物A的晶型IV，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为9.7°、13.0°、15.6°、17.2°、17.9°、19.1°、20.4°、21.3°、23.0°、24.1°、24.5°、25.2°、28.1°、29.0°、32.7°、34.3°处具有特征峰。
本发明还涉及化合物A的晶型IV，其具有基本上如图10所示的X射线粉末衍射(XRPD)图谱。
在一些具体实施方式中，化合物A的晶型IV是含盐酸晶型，优选为所述化合物盐酸盐的晶型，更优选为无水晶型。
在一些具体实施方式中，化合物A的晶型IV在使用差示扫描量热法(DSC)进行热分析时，在约180.5℃±2℃、209.0℃±2℃处具有吸热峰。
在一些具体实施方式中，化合物A的晶型IV在使用差示扫描量热法(DSC)进行热分析时，具有基本上如图11所示的DSC图谱。
在一些具体实施方式中，化合物A的晶型IV在使用热重分析法(TGA)进行热分析时，具有基本上如图12所示的TGA图谱。
本发明还涉及化合物A的晶型IV的制备方法，包括以下步骤：
(1)将化合物A的固体溶解于加热的含有HCl的有机溶剂中，所述有机溶剂优选包含乙酸异丙酯和异丙醇；
(2)在惰性气氛下，将溶液冷却至室温并搅拌，使晶体析出；
(3)过滤，用乙酸异丙酯清洗湿滤饼并干燥，得到化合物A的晶型IV。
在一些具体实施方式中，在化合物A的晶型IV的制备方法中，HCl的摩尔数为化合物A的摩尔数的2至5倍，优选为3至4倍。
本发明另一方面涉及一种组合物，其包含：
化合物A的晶型I，以及
化合物A的晶型III和化合物A的晶型IV中的至少一种。
在一些具体实施方式中，上述组合物作为化合物A的两种或多种晶型的混合物，是从化合物A的溶液或悬液中直接制备而成的混合晶型。
在一些具体实施方式中，所述组合物包含任意比例的化合物A的晶型I、晶型III和/或晶型IV。在一些优选实施方式中，所述组合物包含任意比例的化合物A的晶型I和晶型III。
本发明另一方面涉及药物组合物，其包含：
(i)化合物A的晶型I，和/或
化合物A的晶型III，和/或
化合物A的晶型IV，以及
(ii)药学上可接受的载体、稀释剂或赋形剂。
在一些具体实施方式中，药物组合物还包含另外的治疗剂。
在一些具体实施方式中，药物组合物包含的另外的治疗剂选自抗癌剂、抗真菌剂、心血管治疗剂、抗炎剂、化学治疗剂、抗血管生成剂、细胞毒性剂、抗增殖剂、代谢疾病治疗剂、眼科疾病治疗剂、中枢神经系统(CNS)疾病治疗剂、泌尿疾病治疗剂和胃肠疾病治疗剂。
本发明另一方面涉及化合物A的无定形固体，其在X射线粉末衍射(XRPD)图谱中没有明显的晶体衍射特征峰。
在一些具体实施方式中，化合物A的无定形固体具有基本上如图15所示的X射线粉末衍射(XRPD)图谱。
在一些具体实施方式中，化合物A的无定形固体还包含药学上可接受的聚合物。
在一些具体实施方式中，化合物A的无定形固体是所述化合物与聚合物的固体分散体。
在一些具体实施方式中，在化合物A的无定形固体中，聚合物选自羟丙甲纤维素(HPMC)、醋酸琥珀酸羟丙甲纤维素酯(HPMCAS)、邻苯二甲酸羟丙甲纤维素酯(HPMCP)和丙烯酸树脂共聚物(Eudragit)中的一种或多种。
在一些具体实施方式中，在化合物A的无定形固体中，所述羟丙甲纤维素选自HPMC E3、HPMC E5或HPMC E50LV；
所述醋酸琥珀酸羟丙甲纤维素酯选自HPMCAS LG、HPMCAS MG、HPMCAS HG、HPMCAS MMP或HPMCAS MF；
所述邻苯二甲酸羟丙甲纤维素酯选自HPMCP HP50；
所述丙烯酸树脂共聚物选自甲基丙烯酸/甲基丙烯酸甲酯共聚物(Eudragit L100)或甲基丙烯酸丁酯、甲基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯共聚物(Euragit EPO)。
在一些具体实施方式中，在化合物A的无定形固体中，所述聚合物选自HPMC E3、HPMC E5、HPMC E50LV、HPMCAS LG、HPMCAS MG、HPMCAS HG、HPMCAS MMP、HPMCAS MF、HPMCP HP50、Eudragit L100、Euragit EPO中的一种或多种，优选为HPMCAS MG、HPMCAS MMP、HPMCAS MF中的一种或多种。
在一些具体实施方式中，在化合物A的无定形固体中，所述化合物占所述无定形固体重量的约5％～25％，优选为约5％～20％，更优选为约10％～20％，特别优选为约10％～15％。
在一些具体实施方式中，在化合物A的无定形固体中，所述化合物与所述聚合物的质量比为约1:3～1:20，优选为约1:4～1:20，更优选为约1:4～1:9，特别优选为约1:5.6～1:9。
在一些具体实施方式中，化合物A的无定形固体是通过喷雾干燥法或热熔挤出法制备的。
本发明另一方面涉及化合物A的无定形固体的制备方法，包括以下步骤：
将所述化合物与药学上可接受的聚合物溶解于溶剂中，形成溶液；
喷雾干燥所述溶液以形成固体分散体，即为所述无定形固体。
在一些具体实施方式中，在化合物A的无定形固体的制备方法中，所述聚合物选自羟丙甲纤维素(HPMC)、醋酸琥珀酸羟丙甲纤维素酯(HPMCAS)、邻苯二甲酸羟丙甲纤维素酯(HPMCP)和丙烯酸树脂共聚物(Eudragit)中的一种或多种。
在一些具体实施方式中，在化合物A的无定形固体的制备方法中，所述溶剂为选自醇类、卤代烷类、酮类、醚类、酯类、酰胺类、砜类、腈类中的一种或多种。在一些具体实施方式中，所述溶剂为选自C1-C6的醇或多元醇、二氯甲烷、三氯甲烷、丙酮、甲基乙基酮、四氢呋喃、苯甲醚、乙酸乙酯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、二乙基亚砜、乙腈中的一种或多种。
在一些具体实施方式中，在化合物A的无定形固体的制备方法中，所述溶剂为二氯甲烷和甲醇的混合物，优选为二氯甲烷和甲醇体积比2:1的混合物。
在一些具体实施方式中，在化合物A的无定形固体的制备方法中，所述化合物在所述溶液中的浓度为约3-15mg/mL，优选为约4-12mg/mL，更优选为约5-10mg/mL。
因此，本发明还涉及根据上述喷雾干燥法制得的化合物A的无定形固体。
本发明另一方面涉及化合物A的无定形固体的制备方法，包括以下步骤：
将所述化合物与药学上可接受的聚合物混合均匀，经热熔挤出机挤出，获得所述无定形固体。
在一些具体实施方式中，在化合物A的无定形固体的制备方法中，所述聚合物选自羟丙甲纤维素(HPMC)、醋酸琥珀酸羟丙甲纤维素酯(HPMCAS)、邻苯二甲酸羟丙甲纤维素酯(HPMCP)和丙烯酸树脂共聚物(Eudragit)中的一种或多种。
在一些具体实施方式中，在化合物A的无定形固体的制备方法中，热熔挤出机的加热温度为150-200℃，优选为160-180℃。
在一些具体实施方式中，化合物A的无定形固体的制备方法还包括将热熔挤出物粉碎、过筛的步骤。
本发明还涉及根据上述热熔挤出法制得的化合物A的无定形固体。
本发明另一方面涉及药物组合物，其包含：
(i)化合物A的无定形固体，以及
(ii)药学上可接受的载体、稀释剂或赋形剂。
在一些具体实施方式中，药物组合物还包含另外的治疗剂。
在一些具体实施方式中，药物组合物包含的另外的治疗剂选自抗癌剂、抗真菌剂、心血管治疗剂、抗炎剂、化学治疗剂、抗血管生成剂、细胞毒性剂、抗增殖剂、代谢疾病治疗剂、眼科疾病治疗剂、中枢神经系统(CNS)疾病治疗剂、泌尿疾病治疗剂和胃肠疾病治疗剂。
本发明另一方面涉及化合物A的晶型I、晶型III、晶型IV或无定形固体在药物制备中的用途。
在一些具体实施方式中，所述药物用于调节金属酶活性。
在一些具体实施方式中，所述药物用于调节醛固酮合酶CYP11B2的活性。
在一些具体实施方式中，所述药物用于治疗金属酶相关病症或疾病，其中所述病症或疾病是癌症、心血管疾病、内分泌疾病、纤维化、肾脏疾病、炎性疾病、传染病、妇科疾病、代谢疾病、眼科疾病、中枢神经系统(CNS)疾病、泌尿疾病、或胃肠疾病。
在一些具体实施方式中，所述病症或疾病是肾上腺癌、肾上腺瘤、白血病、乳腺癌、高血压、顽固性高血压、肺动脉高血压、心力衰竭、舒张功能障碍、左心室舒张功能障碍、舒张性心力衰竭、收缩功能障碍、收缩性心力衰竭、心肌梗塞后综合征、冠心病、心肌坏死病变、心房颤动、动脉粥样硬化、再狭窄、内皮功能障碍、血管损伤、心肌梗死、左心室肥厚，血管壁肥厚、内皮增厚、动脉纤维蛋白样坏死、血管疾病、与原发性或继发性醛固酮增多症和肾上腺增生相关的病症、糖尿病、代谢综合征、胰岛素抵抗、神经病变、胰岛素病变、糖尿病肾病、以高血压后胶原形成增加、纤维化和基质重塑为特征的疾病、以内皮细胞功能障碍后的纤维化和基质重塑为特征的疾病、心肌纤维化、血管纤维化、肾衰竭、慢性肾衰竭、肾病、肾功能障碍、肾脏疾病、肾小球硬化、肾小球肾炎、肾病综合征、多囊肾病、低钾血症、视网膜病变、睡眠呼吸暂停、阻塞性睡眠呼吸暂停、肌营养不良、中风、肝病、非酒精性脂肪性肝炎、肝硬化或非酒精性脂肪肝病。
在优选的实施方式中，所述病症或疾病是高血压、顽固性高血压、肺动脉高血压、动脉粥样硬化或低钾血症。
本发明另一方面涉及病症或疾病的治疗方法，包括向有需要的对象施用有效量的化合物A的晶型I、晶型III、或晶型IV，或者至少任意两种以上晶型的任意比例的混合。所述病症或疾病如前文所述。
附图说明
图1示出化合物A的晶型I的X射线粉末衍射(XRPD)图谱。
图2示出化合物A的晶型I的差示扫描量热法(DSC)图谱。
图3示出化合物A的晶型I的热重分析法(TGA)图谱。
图4示出化合物A的晶型I的1H NMR图谱。
图5示出化合物A的晶型I的13C NMR图谱。
图6示出化合物A的晶型I的动态水分吸附法(DVS)图谱。
图7示出化合物A的晶型III的X射线粉末衍射(XRPD)图谱。
图8示出化合物A的晶型III的差示扫描量热法(DSC)图谱。
图9示出化合物A的晶型III的热重分析法(TGA)图谱。
图10示出化合物A的晶型IV的X射线粉末衍射(XRPD)图谱。
图11示出化合物A的晶型IV的差示扫描量热法(DSC)图谱。
图12示出化合物A的晶型IV的热重分析法(TGA)图谱。
图13示出化合物A的晶型IV的1H NMR图谱。
图14示出实施例22制备的部分固体分散体的XRPD图谱。
图15示出实施例24制备的化合物A的无定形固体的X射线粉末衍射(XRPD)图谱。
图16示出实施例24制备的化合物A的无定形固体的调制差示扫描量热法(mDSC)图谱，图中从上到下的三条曲线依次为可逆样品热流、不可逆样品热流和总热流。
图17示出实施例24制备的化合物A的无定形固体的热重分析法(TGA)图谱。
图18示出实施例27制备的化合物A的无定形固体的X射线粉末衍射(XRPD)图谱。
图19示出实施例27制备的化合物A的无定形固体的调制差示扫描量热法(mDSC)图谱，图中从上到下的三条曲线依次为不可逆样品热流、总热流和可逆样品热流。
图20示出实施例27制备的化合物A的无定形固体的热重分析法(TGA)图谱。
具体实施方式
定义
为了更容易理解本发明，为方便起见，首先在此定义某些术语。
如本文所用，术语“治疗”疾病包括预防、改善、减轻和/或管理该疾病和/或可能导致该疾病的病症。术语“治疗”和“处理”是指减轻或减轻疾病和/或其伴随症状的方法。根据本公开，“治疗”包括预防、阻断、抑制、减弱、保护、调节、逆转并减少疾病的影响例如疾病的有害影响。
如本文所用，“抑制”包括预防、减少和停止进展。术语“调节”是指响应于对本公开的化合物的暴露，酶的活性增加或减少。
本文中“抑制剂”一词的使用意指表现出抑制金属酶活性的分子。本文中的“抑制”是指与不存在抑制剂时的金属酶活性相比，金属酶的活性降低。在一些实施方案中，术语“抑制”是指金属酶活性降低至少约5％、至少约10％、至少约20％、至少约25％、至少约50％、至少约60％、至少约70％、至少约80％、至少约90％、或至少约95％。在其他实施方案中，抑制是指金属酶活性降低约5％至约25％、约25％至约50％、约50％至约75％、或约75％至100％。在一些实施方案中，抑制指金属酶活性降低约95％至100％，例如活性降低95％、96％、97％、98％、99％或100％。可以使用本领域技术人员认可的各种技术来测量这种降低。
术语“给药”或“施用”包括将化合物引入对象以实现其预期功能的途径。可以使用的给药途径的实例包括注射(皮下、静脉内、肠胃外、腹膜内、鞘内)给药、局部给药、经口给药、吸入给药、经直肠给药和经皮给药。
术语“有效量”包括在必要的剂量和时间段内达到期望结果的有效量。化合物的有效量可根据诸如对象的疾病状况、年龄和体重等因素以及化合物在对象中引发期望反应的能力而变化。可以调整剂量方案以提供最佳治疗反应。有效量也是其中治疗有益效果胜过抑制剂化合物的任何毒性或有害作用(例如副作用)的量。
这里使用的短语“全身施用”、“全身给药”、“外周施用”和“外周给药”是指化合物、药物或其他物质的施用，使得其进入患者系统，并因此经历代谢和其他类似过程。
术语“治疗有效量”是指施用的化合物的量足以预防或在一定程度上减轻正在治疗的疾病或病症的一种或多于一种症状的发展。
化合物的治疗有效量(即有效剂量)可以为约0.005μg/kg体重至约200mg/kg体重，优选为约0.01mg/kg体重至约200mg/kg体重，更优选为约0.015mg/kg体重至约30mg/kg体重。在其他实施方案中，治疗有效量可以为约1.0pM至约10μM。本领域技术人员将理解，某些因素可以影响有效治疗对象所需的剂量，包括但不限于疾病或病症的严重性、先前的治疗、对象的综合健康状况和/或年龄以及存在的其他疾病。此外，用治疗有效量的化合物治疗对象可以包括单一治疗、或者优选地可以包括一系列治疗。在一个实例中，用约0.005μg/kg体重至约200mg/kg体重的化合物治疗对象，每天一次，持续约1周至10周，优选2周至8周，更优选约3周至7周，甚至更优选约4周、5周或6周。在另一个实例中，在慢性病症或疾病的情况下，可以每天对对象进行治疗，持续治疗数年。还应当理解，用于治疗的化合物的有效剂量可以在特定治疗过程中增加或减少。
术语“对象”指动物，例如哺乳动物，包括但不限于灵长类动物(例如人类)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠等。在一些实施方案中，对象为人类。
如本文所用，术语“药学上可接受的”意指必须与制剂的其它成分相容并且不会对其接受者有害的载体、载剂、稀释剂、赋形剂和/或盐。
如本文所用，术语“药学上可接受的载体、稀释剂或赋形剂”包括但不限于已经被美国食品与药品管理局认可的而可用于人类或动物的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、香味增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗压剂、溶剂或乳化剂等对组成药物组合物无副作用的各种形式的载体。
本文中，涉及X射线粉末衍射(XRPD)图谱、差示扫描量热法(DSC)图谱、热重分析法(TGA)图谱、1H和13C核磁共振(NMR)图谱，术语“基本上如……中所示的”表示不必定与本公开中描绘的那些相同的图谱，但由本领域普通技术人员考虑时，落入实验误差或偏差的限制内。
本文中，当提及X射线粉末衍射(XRPD)峰位置时，本公开所用的术语“基本上相同的”意指考虑典型峰位置及强度可变性。举例而言，本领域的技术人员理解，峰位置(2θ)会显示一定的可变性，通常，多达0.1°至0.2°，视所用溶剂以及用于量测衍射的装置而定。进而言之，本领域的技术人员理解，相对峰强度会显示仪器间的变异性以及由结晶度、优选定向、所制备的试样表面及本领域的技术人员已知的其它因素造成的变异性，且仅应视为定性测量。
本文中，术语“2θ数值”或“2θ”系指基于X射线粉末衍射(XRPD)实验的实验设置的以度计的峰位置且是衍射图谱的常见横坐标单位。所述试验设置要求如果在入射光束与某一晶面形成角θ(theta)时反射被衍射，则以角2θ(2theta)记录反射的光束。应当理解，本文所提及具体晶型的具体2θ数值意欲指使用本公开所述的X射线粉末衍射(XRPD)实验条件测量的2θ数值(以角度(°)计)。举例而言，如本文所述，使用CuKα作为辐射源。
本文中，术语“无定形”指代具有不规则的微观结构的固态物质，可以称为非晶体。本文中的无定形固体可以仅包含一种物质，也可以包含多于一种物质。例如，当无定形固体包含物质A和物质B时，该无定形固体可以称为物质A的无定形固体，也可以称为物质B的无定形固体。在一些实施方案中，无定形固体可以是两种或多种物质形成的固体分散体。例如，当物质A和物质B形成固体分散体时，其可以称为物质A的固体分散体或无定形固体，也可以称为物质B的固体分散体或无定形固体。
在本申请(包括权利要求)中使用的术语前无数量词限定是指“一个或多于一个”。因此，例如，提及“样本”则包括多个样本，除非上下文明显与此相反(例如，多个样本)，等等。
在整个说明书和权利要求书中，除非上下文另有要求，否则词语“包括”、“包含”和“含有”以非排他性的含义使用。
如本文所用，术语“约”在提及值时是指包括基于特定量的变化，在一些实施方案中为±20％以内、在一些实施方案中为±10％以内、在一些实施方案中为±5％以内、在一些实施方案中为±1％以内、在一些实施方案中为±0.5％以内、且在一些实施方案中为±0.1％以内，因为这种变化适于执行所公开的方法或使用所公开的组合物。当涉及衍射角2θ的数值时，“约”可以表示衍射角2θ的数值的误差在±0.2°以内。
应当理解，在本公开的说明书和所附的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。因此，例如提到的包含“药物可接受的载体、稀释剂或赋形剂”的药物组合物包括一种药物可接受的载体、稀释剂或赋形剂，或两种或多种药物可接受的载体、稀释剂或赋形剂。
本文陈述的数值极限或范围包括端点，具体包括在数值极限或范围内的所有值和子范围。
下面通过具体实施方式对本发明作进一步的说明。除非另有限定，本文中所使用的术语具有与本领域普通技术人员通常理解相同的含义。
本发明涉及式(I)的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑(“化合物A”)的晶型和固体形式。化合物A的化学式为C15N4H10F4，分子量322.3。化合物A是一种金属酶抑制剂，具体为醛固酮合酶CYP11B2的选择性抑制剂。化合物A的合成方法和生物活性可参见例如WO2018/125800，其全部内容通过引用并入本文。
化合物A的晶型I
本发明一方面涉及化合物A的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.9°、12.4°、17.6°、25.0°、25.8°处具有特征峰。优选地，其在衍射角2θ为8.9°±0.2°、12.4°±0.2°、17.6°±0.2°、25.0°±0.2°、25.8°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.9°、12.4°、17.6°、24.2°、25.0°、25.8°处具有特征峰。优选地，其在衍射角2θ为8.9°±0.2°、12.4°±0.2°、17.6°±0.2°、24.2°±0.2°、25.0°±0.2°、25.8°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.9°、12.4°、17.6°、18.2°、24.2°、25.0°、25.8°处具有特征峰。优选地，其在衍射角2θ为8.9°±0.2°、12.4°±0.2°、17.6°±0.2°、18.2°±0.2°、24.2°±0.2°、25.0°±0.2°、25.8°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.9°、12.4°、17.6°、18.2°、24.2°、25.0°、25.8°、26.7°处具有特征峰。优选地，其在衍射角2θ为8.9°±0.2°、12.4°±0.2°、17.6°±0.2°、18.2°±0.2°、24.2°±0.2°、25.0°±0.2°、25.8°±0.2°、26.7°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.9°、12.4°、17.6°、18.2°、24.2°、25.0°、25.8°、26.7°、28.0°处具有特征峰。优选地，其在衍射角2θ为8.9°±0.2°、12.4°±0.2°、17.6°±0.2°、18.2°±0.2°、24.2°±0.2°、25.0°±0.2°、25.8°±0.2°、26.7°±0.2°、28.0°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.9°、12.4°、17.6°、18.2°、19.6°、24.2°、25.0°、25.8°、26.7°、28.0°处具有特征峰。优选地，其在衍射角2θ为8.9°±0.2°、12.4°±0.2°、17.6°±0.2°、18.2°±0.2°、19.6°±0.2°、24.2°±0.2°、25.0°±0.2°、25.8°±0.2°、26.7°±0.2°、28.0°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型I，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.9°、12.4°、17.6°、18.2°、19.6°、24.2°、25.0°、25.8°、26.7°、28.0°、28.8°处具有特征峰。优选地，其在衍射角2θ为8.9°±0.2°、12.4°±0.2°、17.6°±0.2°、18.2°±0.2°、19.6°±0.2°、24.2°±0.2°、25.0°±0.2°、25.8°±0.2°、26.7°±0.2°、28.0°±0.2°、28.8°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型I，其具有基本上如图1所示的X射线粉末衍射(XRPD)图谱。
在一些具体实施方式中，化合物A的晶型I是无水晶型。
在一些具体实施方式中，化合物A的晶型I在使用差示扫描量热法(DSC)进行热分析时，在约211.6℃±2.0℃处具有吸热峰。
在一些具体实施方式中，化合物A的晶型I在使用差示扫描量热法(DSC)进行热分析时，具有基本上如图2所示的DSC图谱。如图2所示，化合物A的晶型I只存在一个吸热峰，其对应于晶型I的熔点。
在一些具体实施方式中，化合物A的晶型I在使用热重分析法(TGA)进行热分析时，具有基本上如图3所示的TGA图谱。如图3所示，化合物A的晶型I在110-180℃的加热区间内重量损失仅为约0.5％，意味着晶型I是无水晶型。
在一些具体实施方式中，化合物A的晶型I在使用动态水分吸附法(DVS)进行分析时，具有基本上如图6所示的DVS图谱。如图6所示，化合物A的晶型I在相对湿度0-90％的循环中，重量变化<0.2％，表明晶型I不具有吸湿性。
本发明还涉及化合物A的晶型I的制备方法，包括以下步骤：
(1)将化合物A的固体溶解在有机溶剂中或者在有机溶剂中悬浮，所述有机溶剂为选自有机酸类、酰胺类、砜类、醇类、醚类、腈类中的一种或多种，优选为选自有机酸类和酰胺类；
(2)向上述溶液或悬液中加入水，使晶体析出，其中所述水的用量为所述有机溶剂的体积的0.1～100倍；
(3)过滤收集晶体并干燥，得到化合物A的晶型I。
在一些具体实施方式中，在化合物A的晶型I的制备方法中，有机溶剂选自甲酸、乙酸、丙酸、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、二乙基亚砜、C1-C6的醇或多元醇、四氢呋喃、苯甲醚或乙腈。
在本发明中，化合物A的晶型I属于优势晶型，其在高温、高湿、光照条件下以及在水中悬浮情况下均能保持稳定。
化合物A的晶型III
本发明另一方面涉及化合物A的晶型III，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.4°、10.2°、12.4°、16.7°、18.1°、22.1°、24.8°、25.7°处具有特征峰。优选地，其在衍射角2θ为8.4°±0.2°、10.2°±0.2°、12.4°±0.2°、16.7°±0.2°、18.1°±0.2°、22.1°±0.2°、24.8°±0.2°、25.7°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型III，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.4°、10.2°、12.4°、16.7°、18.1°、22.1°、24.8°、25.2°、25.7°处具有特征峰。优选地，其在衍射角2θ为8.4°±0.2°、10.2°±0.2°、12.4°±0.2°、16.7°±0.2°、18.1°±0.2°、22.1°±0.2°、24.8°±0.2°、25.2°±0.2°、25.7°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型III，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.4°、10.2°、12.4°、16.7°、18.1°、22.1°、23.4°、24.8°、25.2°、25.7°处具有特征峰。优选地，其在衍射角2θ为8.4°±0.2°、10.2°±0.2°、12.4°±0.2°、16.7°±0.2°、18.1°±0.2°、22.1°±0.2°、23.4°±0.2°、24.8°±0.2°、25.2°±0.2°、25.7°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型III，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.4°、10.2°、12.4°、16.7°、17.5°、18.1°、22.1°、23.4°、24.8°、25.2°、25.7°处具有特征峰。优选地，其在衍射角2θ为8.4°±0.2°、10.2°±0.2°、12.4°±0.2°、16.7°±0.2°、17.5°±0.2°、18.1°±0.2°、22.1°±0.2°、23.4°±0.2°、24.8°±0.2°、25.2°±0.2°、25.7°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型III，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.4°、10.2°、12.4°、16.7°、17.5°、18.1°、22.1°、23.4°、24.8°、25.2°、25.7°、28.2°处具有特征峰。优选地，其在衍射角2θ为8.4°±0.2°、10.2°±0.2°、12.4°±0.2°、16.7°±0.2°、17.5°±0.2°、18.1°±0.2°、22.1°±0.2°、23.4°±0.2°、24.8°±0.2°、25.2°±0.2°、25.7°±0.2°、28.2°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型III，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.4°、10.2°、12.4°、16.7°、17.5°、18.1°、22.1°、22.6°、23.4°、24.8°、25.2°、25.7°、28.2°处具有特征峰。优选地，其在衍射角2θ为8.4°±0.2°、10.2°±0.2°、12.4°±0.2°、16.7°±0.2°、17.5°±0.2°、18.1°±0.2°、22.1°±0.2°、22.6°±0.2°、23.4°±0.2°、24.8°±0.2°、25.2°±0.2°、25.7°±0.2°、28.2°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型III，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.4°、10.2°、12.4°、16.7°、17.5°、18.1°、20.2°、22.1°、22.6°、23.4°、24.8°、25.2°、25.7°、28.2°处具有特征峰。优选地，其在衍射角2θ为8.4°±0.2°、10.2°±0.2°、12.4°±0.2°、16.7°±0.2°、17.5°±0.2°、18.1°±0.2°、20.2°±0.2°、22.1°±0.2°、22.6°±0.2°、23.4°±0.2°、24.8°±0.2°、25.2°±0.2°、25.7°±0.2°、28.2°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型III，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.4°、10.2°、12.4°、15.8°、16.7°、17.5°、18.1°、20.2°、22.1°、22.6°、23.4°、24.8°、25.2°、25.7°、28.2°处具有特征峰。优选地，其在衍射角2θ为8.4°±0.2°、10.2°±0.2°、12.4°±0.2°、15.8°±0.2°、16.7°±0.2°、17.5°±0.2°、18.1°±0.2°、20.2°±0.2°、22.1°±0.2°、22.6°±0.2°、23.4°±0.2°、24.8°±0.2°、25.2°±0.2°、25.7°±0.2°、28.2°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型III，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.4°、10.2°、12.4°、14.0°、15.8°、16.7°、17.5°、18.1°、20.2°、22.1°、22.6°、23.4°、24.8°、25.2°、25.7°、28.2°处具有特征峰。优选地，其在衍射角2θ为8.4°±0.2°、10.2°±0.2°、12.4°±0.2°、14.0°±0.2°、15.8°±0.2°、16.7°±0.2°、17.5°±0.2°、18.1°±0.2°、20.2°±0.2°、22.1°±0.2°、22.6°±0.2°、23.4°±0.2°、24.8°±0.2°、25.2°±0.2°、25.7°±0.2°、28.2°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型III，其具有基本上如图7所示的X射线粉末衍射(XRPD)图谱。
在一些具体实施方式中，化合物A的晶型III是含乙酸晶型，优选为乙酸溶剂化物晶型。
在一些具体实施方式中，化合物A的晶型III在使用差示扫描量热法(DSC)进行热分析时，在约78.3、121.4和/或212.2℃±2℃处具有吸热峰。
在一些具体实施方式中，化合物A的晶型III在使用差示扫描量热法(DSC)进行热分析时，具有基本上如图8所示的DSC图谱。如图8所示，化合物A的晶型III在63-90℃左右的吸热峰对应于乙酸溶剂化物的分解；121℃左右的吸热峰对应于乙酸的沸点；而212℃左右的吸热峰对应于化合物A的熔点。
在一些具体实施方式中，化合物A的晶型III在使用热重分析法(TGA)进行热分析时，具有基本上如图9所示的TGA图谱。如图9所示，化合物A的晶型III在50-150℃的加热区间内重量损失约为15.2％，意味着乙酸溶剂化物晶型III中化合物A与乙酸的化学计量比为1:1，并且化合物A的晶型III为无水晶型。
本发明还涉及化合物A的晶型III的制备方法，包括以下步骤：
(1)将化合物A的固体加入无水乙酸中，在加热条件下悬浮；
(2)过滤，滤液在冷却条件下静置沉淀；
(3)过滤收集晶体并干燥，得到化合物A的晶型III。
在一些具体实施方式中，在化合物A的晶型III的制备方法中，加热悬浮的温度<60℃，优选为≤55℃，更优选为≤50℃；冷却静置的温度≤10℃，优选为≤5℃。
在本发明中，化合物A的晶型III能够在室温条件下保持稳定。晶型III在高温条件下，例如在空气中加热至>110℃时，转化为晶型I。此外，晶型III能够在无水乙酸溶剂体系中，在<60℃、优选为≤55℃的条件下保持稳定；而在温度≥60℃时，晶型III会自发转化为晶型I。
化合物A的晶型IV
本发明另一方面涉及化合物A的晶型IV，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为9.7°、13.0°、15.6°、19.1°、23.0°、24.1°、24.5°处具有特征峰。优选地，其在衍射角2θ为9.7°±0.2°、13.0°±0.2°、15.6°±0.2°、19.1°±0.2°、23.0°±0.2°、24.1°±0.2°、24.5°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型IV，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为9.7°、13.0°、15.6°、19.1°、23.0°、24.1°、24.5°、28.1°处具有特征峰。优选地，其在衍射角2θ为9.7°±0.2°、13.0°±0.2°、15.6°±0.2°、19.1°±0.2°、23.0°±0.2°、24.1°±0.2°、24.5°±0.2°、28.1°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型IV，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为9.7°、13.0°、15.6°、19.1°、23.0°、24.1°、24.5°、25.2°、28.1°处具有特征峰。优选地，其在衍射角2θ为9.7°±0.2°、13.0°±0.2°、15.6°±0.2°、19.1°±0.2°、23.0°±0.2°、24.1°±0.2°、24.5°±0.2°、25.2°±0.2°、28.1°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型IV，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为9.7°、13.0°、15.6°、19.1°、23.0°、24.1°、24.5°、25.2°、28.1°、29.0°处具有特征峰。优选地，其在衍射角2θ为9.7°±0.2°、13.0°±0.2°、15.6°±0.2°、19.1°±0.2°、23.0°±0.2°、24.1°±0.2°、24.5°±0.2°、25.2°±0.2°、28.1°±0.2°、29.0°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型IV，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为9.7°、13.0°、15.6°、19.1°、23.0°、24.1°、24.5°、25.2°、28.1°、29.0°、32.7°处具有特征峰。优选地，其在衍射角2θ为9.7°±0.2°、13.0°±0.2°、15.6°±0.2°、19.1°±0.2°、23.0°±0.2°、24.1°±0.2°、24.5°±0.2°、25.2°±0.2°、28.1°±0.2°、29.0°±0.2°、32.7°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型IV，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为9.7°、13.0°、15.6°、17.2°、19.1°、23.0°、24.1°、24.5°、25.2°、28.1°、29.0°、32.7°处具有特征峰。优选地，其在衍射角2θ为9.7°±0.2°、13.0°±0.2°、15.6°±0.2°、17.2°±0.2°、19.1°±0.2°、23.0°±0.2°、24.1°±0.2°、24.5°±0.2°、25.2°±0.2°、28.1°±0.2°、29.0°±0.2°、32.7°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型IV，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为9.7°、13.0°、15.6°、17.2°、19.1°、21.3°、23.0°、24.1°、24.5°、25.2°、28.1°、29.0°、32.7°处具有特征峰。优选地，其在衍射角2θ为9.7°±0.2°、13.0°±0.2°、15.6°±0.2°、17.2°±0.2°、19.1°±0.2°、21.3°±0.2°、23.0°±0.2°、24.1°±0.2°、24.5°±0.2°、25.2°±0.2°、28.1°±0.2°、29.0°±0.2°、32.7°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型IV，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为9.7°、13.0°、15.6°、17.2°、19.1°、21.3°、23.0°、24.1°、24.5°、25.2°、28.1°、29.0°、32.7°、34.3°处具有特征峰。优选地，其在衍射角2θ为9.7°±0.2°、13.0°±0.2°、15.6°±0.2°、17.2°±0.2°、19.1°±0.2°、21.3°±0.2°、23.0°±0.2°、24.1°±0.2°、24.5°±0.2°、25.2°±0.2°、28.1°±0.2°、29.0°±0.2°、32.7°±0.2°、34.3°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型IV，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为9.7°、13.0°、15.6°、17.2°、19.1°、20.4°、21.3°、23.0°、24.1°、24.5°、25.2°、28.1°、29.0°、32.7°、34.3°处具有特征峰。优选地，其在衍射角2θ为9.7°±0.2°、13.0°±0.2°、15.6°±0.2°、17.2°±0.2°、19.1°±0.2°、20.4°±0.2°、21.3°±0.2°、23.0°±0.2°、24.1°±0.2°、24.5°±0.2°、25.2°±0.2°、28.1°±0.2°、29.0°±0.2°、32.7°±0.2°、34.3°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型IV，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为9.7°、13.0°、15.6°、17.2°、17.9°、19.1°、20.4°、21.3°、23.0°、24.1°、24.5°、25.2°、28.1°、29.0°、32.7°、34.3°处具有特征峰。优选地，其在衍射角2θ约为9.7°±0.2°、13.0°±0.2°、15.6°±0.2°、17.2°±0.2°、17.9°±0.2°、19.1°±0.2°、20.4°±0.2°、21.3°±0.2°、23.0°±0.2°、24.1°±0.2°、24.5°±0.2°、25.2°±0.2°、28.1°±0.2°、29.0°±0.2°、32.7°±0.2°、34.3°±0.2°处具有特征峰。
本发明还涉及化合物A的晶型IV，其具有基本上如图10所示的X射线粉末衍射(XRPD)图谱。
在一些具体实施方式中，化合物A的晶型IV是含盐酸晶型，优选为所述化合物盐酸盐的晶型，更优选为无水晶型。
在一些具体实施方式中，化合物A的晶型IV在使用差示扫描量热法(DSC)进行热分析时，在约180.5℃、209.0℃±2℃处具有吸热峰。
在一些具体实施方式中，化合物A的晶型IV在使用差示扫描量热法(DSC)进行热分析时，具有基本上如图11所示的DSC图谱。如图11所示，化合物A的晶型IV在160-180℃左右的吸热峰对应于盐酸盐的分解，而209℃左右的吸热峰对应于化合物A的熔点。
在一些具体实施方式中，化合物A的晶型IV在使用热重分析法(TGA)进行热分析时，具有基本上如图12所示的TGA图谱。如图12所示，化合物A的晶型IV在145-205℃的加热区间内重量损失约为10％，意味着盐酸盐中化合物A与盐酸的化学计量比为1:1，并且化合物A的晶型IV为无水晶型。
本发明还涉及化合物A的晶型IV的制备方法，包括以下步骤：
(1)将化合物A的固体溶解于加热的含有HCl的有机溶剂中，所述有机溶剂优选包含乙酸异丙酯和异丙醇；
(2)在惰性气氛下，将溶液冷却至室温并搅拌，使晶体析出；
(3)过滤，用乙酸异丙酯清洗湿滤饼并干燥，得到1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型IV。
在一些具体实施方式中，在化合物A的晶型IV的制备方法中，HCl的摩尔数为化合物A的摩尔数的2至5倍，优选为3至4倍。
在一些具体实施方式中，在化合物A的晶型IV的制备方法中，步骤(1)中加热的温度为约65±5℃。
在本发明中，化合物A的晶型IV能够在室温条件下保持稳定。在高温条件下(例如大于100℃时)，晶型IV会转化为晶型I。
组合物
本发明另一方面涉及一种组合物，其包含：
化合物A的晶型I，以及
化合物A的晶型III和化合物A的晶型IV中的至少一种。
在一些具体实施方式中，上述组合物作为化合物A的两种或多种晶型的混合物，是从化合物A的溶液或悬液中直接制备而成的混合晶型。
在一些具体实施方式中，所述组合物包含任意比例的化合物A的晶型I、晶型III和/或晶型IV。在一些优选实施方式中，所述组合物包含任意比例的化合物A的晶型I和晶型III。
药物组合物(晶型)
本发明还提供了包含化合物A的上述晶型中的一种或多种的药物组合物。
具体地，本发明另一方面涉及药物组合物，其包含：
(i)化合物A的晶型I，和/或
化合物A的晶型III，和/或
化合物A的晶型IV，以及
(ii)药学上可接受的载体、稀释剂或赋形剂。
在一些具体实施方式中，药物组合物还包含另外的治疗剂。
在一些具体实施方式中，药物组合物包含的另外的治疗剂选自抗癌剂、抗真菌剂、心血管治疗剂、抗炎剂、化学治疗剂、抗血管生成剂、细胞毒性剂、抗增殖剂、代谢疾病治疗剂、眼科疾病治疗剂、中枢神经系统(CNS)疾病治疗剂、泌尿疾病治疗剂和胃肠疾病治疗剂。
化合物A的无定形固体
本发明另一方面涉及化合物A的无定形固体，其在X射线粉末衍射(XRPD)图谱中没有明显的晶体衍射特征峰。
在一些具体实施方式中，化合物A的无定形固体具有基本上如图15所示的X射线粉末衍射(XRPD)图谱。
在一些具体实施方式中，化合物A的无定形固体还包含药学上可接受的聚合物。
在一些具体实施方式中，化合物A的无定形固体是所述化合物与聚合物的固体分散体。
在一些具体实施方式中，在化合物A的无定形固体中，聚合物选自羟丙甲纤维素(HPMC)、醋酸琥珀酸羟丙甲纤维素酯(HPMCAS)、邻苯二甲酸羟丙甲纤维素酯(HPMCP)和丙烯酸树脂共聚物(Eudragit)中的一种或多种。
在一些具体实施方式中，在化合物A的无定形固体中，所述羟丙甲纤维素选自HPMC E3、HPMC E5或HPMC E50LV；
所述醋酸琥珀酸羟丙甲纤维素酯选自HPMCAS LG、HPMCAS MG、HPMCAS HG、HPMCAS MMP或HPMCAS MF；
所述邻苯二甲酸羟丙甲纤维素酯选自HPMCP HP50；
所述丙烯酸树脂共聚物选自甲基丙烯酸/甲基丙烯酸甲酯共聚物(Eudragit L100)或甲基丙烯酸丁酯、甲基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯共聚物(Euragit EPO)。
醋酸琥珀酸羟丙甲纤维素酯(HPMCAS)是一种基于羟丙甲纤维素的可药用聚合物，其纤维素主链上的羟基部分地被乙酰基和琥珀酰基取代。在市售的HPMCAS商品中，通过调整乙酰基和琥珀酰基的化学取代水平，HPMCAS可以具有不同的溶解pH，例如5.5、6.0和6.5，其等级名称分别为-L、-M和-H；通过将HPMCAS制成不同粒径的固体颗粒，例如5μm、200μm和1000μm，其等级名称分别为-F、-MP和-G。因此，粒径为1000μm、溶解pH为6.5的HPMCAS可以称为HPMCAS HG；粒径为200μm、溶解pH为6.0的HPMCAS可以称为HPMCAS MMP，等等。
在一些具体实施方式中，在化合物A的无定形固体中，所述聚合物选自HPMC E3、HPMC E5、HPMC E50LV、HPMCAS LG、HPMCAS MG、HPMCAS HG、HPMCAS MMP、HPMCAS MF、HPMCP HP50、Eudragit L100、Euragit EPO中的一种或多种，优选为HPMCAS MG、HPMCAS MMP、HPMCAS MF中的一种或多种。
在一些具体实施方式中，在化合物A的无定形固体中，化合物A占所述无定形固体重量的约5％～25％，优选为约5％～20％，更优选为约10％～20％，特别优选为约10％～15％。
在一些具体实施方式中，在化合物A的无定形固体中，化合物A与聚合物的质量比为约1:3～1:20，优选为约1:4～1:20，更优选为约1:4～1:9，特别优选为约1:5.6～1:9。
在一些具体实施方式中，化合物A的无定形固体是通过喷雾干燥法或热熔挤出法制备的。
本发明的化合物A的无定形固体，特别是化合物A的无定形固体分散体，能够大幅提高化合物A的水溶解度和生物利用度，例如化合物A在禁食状态模拟肠液(FaSSIF)、饱腹状态模拟肠液(FeSSIF)和模拟胃液(SGF)中的溶解度。化合物A的无定形固体的溶解度是化合物A晶体溶解度的3倍以上，优选为5倍以上。
本发明的化合物A的无定形固体，特别是化合物A的无定形固体分散体，能够在高温、高湿、光照条件下保持稳定，不会发生转晶现象，有利于在药物组合物、药物剂型和药物制备中的应用。
本发明还提供了化合物A的无定形固体的制备方法，包括喷雾干燥法或热熔挤出法。
本发明另一方面涉及化合物A的无定形固体的制备方法，包括以下步骤：
将化合物A与药学上可接受的聚合物溶解于溶剂中，形成溶液；
喷雾干燥所述溶液以形成固体分散体，即为化合物A的无定形固体。
在一些具体实施方式中，在化合物A的无定形固体的制备方法中，所述聚合物选自羟丙甲纤维素(HPMC)、醋酸琥珀酸羟丙甲纤维素酯(HPMCAS)、邻苯二甲酸羟丙甲纤维素酯(HPMCP)和丙烯酸树脂共聚物(Eudragit)中的一种或多种。
在一些具体实施方式中，在化合物A的无定形固体的制备方法中，所述溶剂为选自醇类、卤代烷类、酮类、醚类、酯类、酰胺类、砜类、腈类中的一种或多种。在一些具体实施方式中，所述溶剂为选自C1-C6的醇或多元醇、二氯甲烷、三氯甲烷、丙酮、甲基乙基酮、四氢呋喃、苯甲醚、乙酸乙酯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、二乙基亚砜、乙腈中的一种或多种。
在一些具体实施方式中，在化合物A的无定形固体的制备方法中，所述溶剂为二氯甲烷和甲醇的混合物，优选为二氯甲烷和甲醇体积比2:1的混合物。
在一些具体实施方式中，在化合物A的制备方法中，化合物A在所述溶液中的浓度为约3-15mg/mL，优选为约4-12mg/mL，更优选为约5-10mg/mL。
因此，本发明还涉及根据上述喷雾干燥法制得的化合物A的无定形固体。
本发明另一方面涉及化合物A的无定形固体的制备方法，包括以下步骤：
将化合物A与药学上可接受的聚合物混合均匀，经热熔挤出机挤出，获得化合物A的无定形固体。
在一些具体实施方式中，在化合物A的无定形固体的制备方法中，所述聚合物选自羟丙甲纤维素(HPMC)、醋酸琥珀酸羟丙甲纤维素酯(HPMCAS)、邻苯二甲酸羟丙甲纤维素酯(HPMCP)和丙烯酸树脂共聚物(Eudragit)中的一种或多种。
在一些具体实施方式中，在化合物A的无定形固体的制备方法中，热熔挤出机的加热温度为150-200℃，优选为160-180℃。
在一些具体实施方式中，化合物A的无定形固体的制备方法还包括将热熔挤出物粉碎、过筛的步骤。
因此，本发明还涉及根据上述热熔挤出法制得的化合物A的无定形固体。
药物组合物(无定形)
本发明还提供了包含化合物A的无定形固体的药物组合物。
具体地，本发明另一方面涉及药物组合物，其包含：
(i)化合物A的无定形固体，以及
(ii)药学上可接受的载体、稀释剂或赋形剂。
在一些具体实施方式中，药物组合物还包含另外的治疗剂。
在一些具体实施方式中，药物组合物包含的另外的治疗剂选自抗癌剂、抗真菌剂、心血管治疗剂、抗炎剂、化学治疗剂、抗血管生成剂、细胞毒性剂、抗增殖剂、代谢疾病治疗剂、眼科疾病治疗剂、中枢神经系统(CNS)疾病治疗剂、泌尿疾病治疗剂和胃肠疾病治疗剂。
化合物A的晶型和无定形固体的制药用途
本发明另一方面涉及化合物A(1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑)的晶型I、晶型III、或晶型IV，或任意两种以上晶型的任意比例的混合物，或化合物A的无定形固体，在药物制备中的用途。
在一些具体实施方式中，所述药物用于调节金属酶活性。
在一些具体实施方式中，所述药物用于调节醛固酮合酶CYP11B2的活性。
在一些具体实施方式中，所述药物用于治疗金属酶相关病症或疾病，其中所述病症或疾病是癌症、心血管疾病、内分泌疾病、纤维化、肾脏疾病、炎性疾病、传染病、妇科疾病、代谢疾病、眼科疾病、中枢神经系统(CNS)疾病、泌尿疾病、或胃肠疾病。
在一些具体实施方式中，所述病症或疾病是肾上腺癌、肾上腺瘤、白血病、乳腺癌、高血压、顽固性高血压、肺动脉高血压、心力衰竭、舒张功能障碍、左心室舒张功能障碍、舒张性心力衰竭、收缩功能障碍、收缩性心力衰竭、心肌梗塞后综合征、冠心病、心肌坏死病变、心房颤动、动脉粥样硬化、再狭窄、内皮功能障碍、血管损伤、心肌梗死、左心室肥厚，血管壁肥厚、内皮增厚、动脉纤维蛋白样坏死、血管疾病、与原发性或继发性醛固酮增多症和肾上腺增生相关的病症、糖尿病、代谢综合征、胰岛素抵抗、神经病变、胰岛素病变、糖尿病肾病、以高血压后胶原形成增加、纤维化和基质重塑为特征的疾病、以内皮细胞功能障碍后的纤维化和基质重塑为特征的疾病、心肌纤维化、血管纤维化、肾衰竭、慢性肾衰竭、肾病、肾功能障碍、肾脏疾病、肾小球硬化、肾小球肾炎、肾病综合征、多囊肾病、低钾血症、视网膜病变、睡眠呼吸暂停、阻塞性睡眠呼吸暂停、肌营养不良、中风、肝病、非酒精性脂肪性肝炎、肝硬化或非酒精性脂肪肝病。
在优选的实施方式中，所述病症或疾病是高血压、顽固性高血压、肺动脉高血压、动脉粥样硬化或低钾血症。
本发明的化合物A的各种晶型和无定形固体作为醛固酮合酶CYP11B2的调节剂和抑制剂，能够有效地特异性靶向CYP11B2，因此能够用于预防或治疗与CYP11B2相关的各种病症或疾病。
治疗方法
本发明还提供了病症或疾病的治疗方法，包括向有需要的对象施用有效量的化合物A(1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑)的晶型I、晶型III、或晶型IV，或任意两种以上晶型的任意比例的混合物，或化合物A的无定形固体。所述病症或疾病如前文所述。
实施例
以下通过实施例对本发明进行详细说明，实施例不旨在限制本发明。下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中使用的各种试剂和设备均为市售产品，且无特殊要求。
实施例1化合物A的晶型I的制备
根据WO2018/125800记载的方法制备化合物A的固体。
将化合物A的固体溶解在选自甲酸、乙酸、丙酸、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、二乙基亚砜、C1-C6的醇或多元醇、四氢呋喃、苯甲醚或乙腈的有机溶剂中或在该有机溶剂中悬浮，必要时可适当加热，得到溶液或悬液。
向上述溶液或悬液中加入水，使晶体析出，在室温下搅拌约2小时。取决于水与所使用有机溶剂的互溶性质，水的用量为所使用有机溶剂的体积的0.1～100倍。
过滤，用水清洗湿滤饼。在50±5℃干燥16小时，获得化合物A的晶型I样品。
实施例2化合物A的晶型I的X射线粉末衍射(XRPD)测试
X射线粉末衍射(XRPD)图谱的测量，使用(Bruker XRD-D2Phaser)X射线衍射仪，在室温下进行检测，具体采集信息如下：射线源为Cu-Kα射线、扫描范围(2θ范围)从3°到40°、旋转速度20转/分、扫描速度为0.2秒/步、扫描步长0.02°、狭缝宽度0.01。采用载玻片直接在测试板压制对样品进行处理。其后的XRPD图谱均采用类似的测量方法。
测定根据实施例1制备的化合物A的晶型I的XRPD图谱，在2θ＝8.87°、12.41°、12.97°、13.92°、15.39°、17.61°、18.20°、19.64°、20.37°、24.17°、25.06°、25.84°、26.65°、28.00°、28.79°、31.96°、36.05°等处具有特征衍射峰，如图1所示。其中2θ值误差范围为±0.2°。
源于该谱图的特征X-射线衍射峰的具体列表在表1中列出。
表1图1中的XRPD衍射峰列表
本领域技术人员应理解，这些衍射峰不代表化合物A的晶型I所显示衍射峰的详尽情况。X射线粉末衍射图的2θ值是可以随着机器以及随着样品制备中的变化和批次间变化而轻微变化，所引用的值不视为绝对值。还应理解的是，峰的相对强度可能随取向效应而变，因此本发明所含的XRPD迹线中所示的强度是示例性的，并不用于绝对比较。
实施例3化合物A的晶型I的差示扫描量热法(DSC)测试
使用TA Instrument的(仪器型号:Discovery DSC 250)热分析仪测试根据实施例1制备的化合物A的晶型I的DSC图谱。DSC测试条件为升温速度10℃/分钟，温度范围室温(25℃)到300℃。测试得到的DSC图谱在图2中示出。
如图2所示，化合物A的晶型I在DSC测试中只存在一个吸热峰，起始温度为210.87℃，峰值温度为211.60℃。即，化合物A的晶型I的熔点为211.60℃。
实施例4化合物A的晶型I的热重分析法(TGA)测试
使用TA Instrument的(仪器型号：Discovery TA 55)热分析仪测试根据实施例1制备的化合物A的晶型I的TGA图谱。TGA测试条件为升温速度10℃/分钟，温度范围室温(25℃)到300℃。测试得到的TGA图谱在图3中示出。
如图3所示，化合物A的晶型I在110-180℃的加热区间内重量损失仅为约0.5％，意味着晶型I是无水晶型。
实施例5化合物A的晶型I的1H NMR测试
使用(仪器型号：AVANCE NEO 400MHz)对实施例1制备的化合物A的晶型I进行1H NMR测试，测试频率为：400MHz，溶剂为DMSO-d6。
测试得到的1H NMR图谱在图4中示出。
1H NMR(400MHz,DMSO-d6)δ10.00(d,J＝2.0Hz,1H),8.56(d,J＝2.0Hz,1H),7.93–7.85(m,2H),7.43(t,J＝54.0Hz,1H),4.03–3.97(m,1H),1.22–1.17(m,2H),0.83–0.79(m,2H).
实施例6化合物A的晶型I的13C NMR测试
使用(仪器型号：AVANCE NEO 400MHz)对实施例1制备的化合物A的晶型I进行13C NMR测试，测试频率为：400MHz，溶剂为DMSO-d6。
测试得到的13C NMR图谱在图5中示出。
13C NMR(100MHz,DMSO-d6)δ155.68,155.43,155.17,151.95,149.86,149.82,149.73,149.57,149.24,149.09,147.32,147.16,146.86,146.71,137.92,137.81,133.56,133.45,129.95,123.13,123.10,123.07,116.06,113.68,111.30,107.98,107.78,100.74,100.51,26.90,8.99.
根据实施例5和实施例6的NMR测试结果可知，化合物A的晶型I中仅包含化合物A的分子，不含水或其他溶剂。
实施例7化合物A的晶型I的动态水分吸附法(DVS)测试
使用ProUmid的(仪器型号：Vsorp-Enhanced)动态水分吸附仪，检测根据实施例1制备的化合物A的晶型I的动态水分吸附图谱。样品首先在40℃/0％ RH干燥3个小时。随后实验在25℃下进行，平衡条件：0.01％/45min。每步将相对湿度(RH)提高10％(最长2小时，最短50分钟，下同)，测试范围从RH 0％到90％；在RH 90％的条件下最长平衡2小时后，每步将相对湿度降低10％(最长2小时，最短50分钟)，直到RH 0％。过程中记录样品的重量变化，报告为相对于样品最低重量的偏移百分比。得到的动态水分吸附图谱在图6中示出。
如图6所示，化合物A的晶型I在相对湿度0-90％的循环中，重量变化<0.2％，表明晶型I不具有吸湿性，并且晶型I在各种湿度条件下稳定。
实施例8化合物A的晶型I的稳定性测试
高温稳定性：将根据实施例1制备的化合物A的晶型I放置在60℃烘箱内，5天和10天后将样品取出进行XRPD测试，以考察样品对温度的晶型稳定性。结果表明，晶型I在高温条件下稳定。
高湿稳定性：将根据实施例1制备的化合物A的晶型I置于92.5％湿度条件下，5天和10天后将样品取出进行XRPD测试，以考察样品对湿度的晶型稳定性。结果表明，晶型I在高湿度条件下稳定。
加速稳定性：将根据实施例1制备的化合物A的晶型I置于40℃、相对湿度75％的实验箱内，1个月后将样品取出进行XRPD测试，以考察样品对高温高湿的晶型稳定性。结果表明，晶型I在高温高湿条件下稳定，有利于原料药和药物制剂的制备和储存。
光照稳定性：将根据实施例1制备的化合物A的晶型I置于4500lux光照强度下，5天和10天后将样品取出进行XRPD测试，以考察样品对光照的晶型稳定性。结果表明，晶型I在光照条件下稳定。
实施例9化合物A的晶型III的制备
称取300mg实施例1制备的化合物A的晶型I，投入3mL无水乙酸中，混合加热至50℃，获得悬浮液。然后过滤，将滤液冷却至4℃，静置。一天后，观察到大颗粒的晶体沉淀。收集沉淀的晶体，用滤纸干燥，获得化合物A的晶型III样品。用偏光显微镜观察晶型III的晶体，颗粒尺寸约为100μm。
实施例10化合物A的晶型III的X射线粉末衍射(XRPD)测试
以与实施例2相同的方法，测定根据实施例9制备的化合物A的晶型III的XRPD图谱，在2θ＝8.39°、10.21°、12.40°、14.05°、15.75°、16.66°、17.53°、18.10°、20.22°、22.07°、22.55°、23.37°、25.84°、25.23°、25.70°、28.18°、29.34°、31.37°、31.92°、34.45°等处具有特征衍射峰，如图7所示。其中2θ值误差范围为±0.2°。
源于该谱图的特征X-射线衍射峰的具体列表在表2中列出。
表2图7中的XRPD衍射峰列表

本领域技术人员应理解，这些衍射峰不代表化合物A的晶型III所显示衍射峰的详尽情况。X射线粉末衍射图的2θ值是可以随着机器以及随着样品制备中的变化和批次间变化而轻微变化，所引用的值不视为绝对值。还应理解的是，峰的相对强度可能随取向效应而变，因此本发明所含的XRPD迹线中所示的强度是示例性的，并不用于绝对比较。
实施例11化合物A的晶型III的差示扫描量热法(DSC)测试
以与实施例3相同的方法，测试根据实施例9制备的化合物A的晶型III的DSC图谱。测试得到的DSC图谱在图8中示出。
如图8所示，化合物A的晶型III在DSC测试中在63℃、121℃和212℃左右(起始温度)存在三个吸热峰。其中，起始温度62.7℃、峰值温度78.3℃的吸热峰对应于乙酸溶剂化物的分解；起始温度121℃、峰值温度121.4℃的吸热峰对应于乙酸的沸点；而212℃的吸热峰对应于化合物A的熔点。
实施例12化合物A的晶型III的热重分析法(TGA)测试
以与实施例4相同的方法，测试根据实施例9制备的化合物A的晶型III的TGA图谱。测试得到的TGA图谱在图9中示出。
如图9所示，化合物A的晶型III在50-150℃的加热区间内重量损失约为15.2％，对应于乙酸溶剂化物的分解和乙酸的挥发，意味着乙酸溶剂化物晶型III中化合物A与乙酸的化学计量比为1:1，并且化合物A的晶型III为无水晶型。
实施例13化合物A的晶型III的热转化测试
取多个根据实施例9制备的化合物A的晶型III样品，分别加热至80℃、90℃、100℃、110℃、120℃、130℃、150℃，维持30分钟后，自然冷却至室温，然后分别测量上述样品的XRPD谱图。结果表明，当化合物A的晶型III加热至110℃或更高温度后，晶型III会自发转化为晶型I。
实施例14化合物A的晶型III和晶型I的浆液竞争实验
称取相同质量的根据实施例1制备的化合物A的晶型I和根据实施例9制备的化合物A的晶型III样品各10-15mg，投入0.5mL预先用晶型I饱和的溶液中，在室温(RT)、50℃、55℃、60℃或65℃的温度下悬浮，在一定时间之后过滤得到固体，立即通过XRPD测试其晶型。实验所使用的溶剂、悬浮温度、测试时间、XRPD结果和稳定的晶型在表3中列出。
表3化合物A的晶型III和晶型I的浆液竞争实验结果
如表3所示，化合物A的晶型III在<60℃、优选为≤55℃的乙酸溶剂体系中为稳定晶型，并且在此条件下，晶型I能够自发转化为晶型III。当乙酸溶剂体系的温度≥60℃时，晶型I为稳定晶型，并且在此条件下，晶型III能够自发转化为晶型I。这一现象与DSC测试中观察到的乙酸溶剂化物的分解温度基本对应。
此外，当溶剂从无水乙酸变为含水体系之后，无论在何种温度下，晶型III都会自发转化为晶型I，晶型I均为稳定晶型。这表明晶型III中的乙酸分子与水结合的自由能更低，在含水溶剂体系中会自发向水中迁移，破坏乙酸溶剂化物的结构。从另一方面而言，化合物A的晶型I在整个结晶过程中都是热力学稳定的晶型。
实施例15化合物A的晶型IV的制备
在N2气氛下，将化合物A的固体溶解于65±5℃的乙酸异丙酯中，并加入4MHCl的异丙醇溶液，使HCl的摩尔数为化合物A摩尔数的3倍，搅拌2小时。
在N2气氛下，将溶液冷却至25±5℃，搅拌2小时，使晶体析出。
过滤，用乙酸异丙酯清洗湿滤饼。在50±5℃干燥16小时，获得化合物A的晶型IV样品。
实施例16化合物A的晶型IV的X射线粉末衍射(XRPD)测试
以与实施例2相同的方法，测定根据实施例15制备的化合物A的晶型IV的XRPD图谱，在2θ＝9.70°、10.34°、12.97°、15.55°、17.18°、17.85°、19.13°、20.37°、21.31°、23.00°、24.06°、24.49°、25.15°、28.08°、28.54°、29.05°、32.71°、34.27°等处具有特征衍射峰，如图10所示。其中2θ值误差范围为±0.2°。
源于该谱图的特征X-射线衍射峰的具体列表在表4中列出。
表4图10中的XRPD衍射峰列表

本领域技术人员应理解，这些衍射峰不代表化合物A的晶型IV所显示衍射峰的详尽情况。X射线粉末衍射图的2θ值是可以随着机器以及随着样品制备中的变化和批次间变化而轻微变化，所引用的值不视为绝对值。还应理解的是，峰的相对强度可能随取向效应而变，因此本发明所含的XRPD迹线中所示的强度是示例性的，并不用于绝对比较。
实施例17化合物A的晶型IV的差示扫描量热法(DSC)测试
以与实施例3相同的方法，测试根据实施例15制备的化合物A的晶型IV的DSC图谱。测试得到的DSC图谱在图11中示出。
如图11所示，化合物A的晶型IV在DSC测试中在160-180℃左右的范围存在一个较宽的吸热峰，其对应于盐酸盐的分解；此外，起始温度为205.81℃、峰值温度为208.92℃的吸热峰，对应于化合物A的熔点。
实施例18化合物A的晶型IV的热重分析法(TGA)测试
以与实施例4相同的方法，测试根据实施例15制备的化合物A的晶型IV的TGA图谱。测试得到的TGA图谱在图12中示出。
如图12所示，化合物A的晶型IV在145-205℃的加热区间内重量损失约为9.9％，对应于盐酸盐的分解和盐酸(HCl)的挥发，意味着盐酸盐中化合物A与HCl的化学计量比为1:1，并且化合物A的晶型IV为无水晶型。
实施例19化合物A的晶型IV的1H NMR测试
以与实施例5相同的方法，对实施例15制备的化合物A的晶型IV进行1H NMR测试。测试得到的1H NMR图谱在图13中示出。
1H NMR(400MHz,DMSO-d6)δ10.00(d,J＝2.0Hz,1H),9.00(s,1H),8.58(d,J＝2.0Hz,1H),7.89(m,2H),7.46(t,J＝54.0Hz,1H),4.03–3.97(m,1H),1.22–1.17(m,2H),0.83–0.79(m,2H).
根据以上1H NMR测试结果可知，化合物A的晶型IV中包含计量比为1:1的化合物A的分子和HCl，不含水或其他溶剂。
实施例20化合物A的晶型IV的浆液竞争实验
称取根据实施例15制备的化合物A的晶型IV样品约200mg，投入1mL无水乙酸中，在室温下悬浮3天，取样过滤得到固体，立即通过XRPD测试其晶型。XRPD图谱显示，晶型仍为晶型IV。
将上述悬液加热至65℃，搅拌，固体完全溶解。
加入1mL水，观察到固体沉淀，然后在65℃下搅拌3小时，取样过滤得到固体，立即通过XRPD测试其晶型。XRPD图谱显示，晶型为晶型I+晶型III(少量)。
将上述悬液继续在65℃下搅拌2天，取样过滤得到固体，立即通过XRPD测试其晶型。XRPD图谱显示，晶型为晶型I。
以上实验表明，化合物A的晶型IV在室温下的乙酸溶剂体系或无水体系中为稳定晶型。
此外，晶型IV在加热完全溶解之后，其结晶行为与实施例14中叙述的晶型I和晶型III的情况相同，即晶型I作为含水体系下热力学稳定的晶型，化合物A的其他晶型最终会自发转化为晶型I。
实施例21化合物A的溶解度测试
测试化合物A的晶型I在FaSSIF中的平衡溶解度，将约2mg化合物A的样品加入到8mL玻璃瓶中，加入1mL FaSSIF，在25℃下搅拌24小时，然后将混悬液离心，通过HPLC测试上清液中化合物A的浓度为5.6μg/mL，将这一浓度作为化合物A在FaSSIF中的平衡溶解度。
进一步测试化合物A在有机溶剂中的溶解度。将约2mg化合物A的样品加入到2mL玻璃瓶中，以每次10μL的增量加入有机溶剂，直到固体完全溶解或已加入1mL的有机溶剂，然后通过HPLC测试溶液中化合物A的浓度。所使用的有机溶剂及化合物A的溶解度在表5中列出。
表5化合物A在有机溶剂中的溶解度测试
基于以上溶解度测试的结果，在通过溶剂法制备无定形固体的实验中，使用甲醇/DCM体积比为1:2的混合物作为溶剂。
实施例22可药用聚合物对化合物A结晶的抑制能力的测试
本实施例中，首先通过快速蒸发法对聚合物抑制化合物A结晶的能力进行初步筛选，然后通过喷雾干燥法确定所得固体分散体是否为无定形以及化合物A的结晶程度。
经测试的聚合物包括：PVP(聚乙烯吡咯烷酮)K30、PVP-VA64(乙基吡咯烷酮/醋酸乙烯酯(6:4)共聚物)、SOLUPLUS(聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物)、HPMC E3(分子量20000)、HPMC E5、HPMC E50LV、HPMCAS MG(粒径1000μm，溶解pH 6.0)、HPMCAS(醋酸琥珀酸羟丙甲纤维素酯)LG(粒径1000μm，溶解pH 5.5)、HPMCPHP50(溶解pH 5.0)、HPC SSL(分子量40000)、Eudragit L100(甲基丙烯酸/甲基丙烯酸酯(1:1)共聚物)、Euragit EPO甲基丙烯酸丁酯、甲基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯(1:2:1)共聚物。
通过快速蒸发法制备固体分散体时，将约10mg化合物A加入40mL玻璃瓶中，并以载药量10％-20％的比例加入聚合物，然后加入1mL甲醇/DCM(1:2)混合溶剂，溶解得到澄清溶液。用滤纸覆盖玻璃瓶口，在60℃真空烘箱中加热1小时，通过使溶剂快速蒸发获得固体分散体，通过偏光显微测试判断所得固体是否为晶体。
经测试，PVP K30、PVP VA64、SOLUPLUS、HPC SSL、Eudragit L100在载药量10％的情况下，通过快速蒸发法获得的固体仍能观察到明显的晶体结构。HPMC E3、HPMC E5、HPMCP HP50、HPMCAS MG、HPMCAS HG、HPMCAS LG、Eudragit EPO、HPMC E5在载药量10％-15％或更高的情况下，通过快速蒸发法能够获得基本为无定形的固态结构。此外，还测试了组合使用两种或更多种聚合物的情况，发现当使用HPMC E50LV时，有利于在更高的载药量下获得无定形固体。
通过喷雾干燥法制备喷雾干燥分散体(SDD)时，将约200mg化合物A加入100mL烧瓶中，并以载药量10％-20％的比例加入聚合物，然后加入40mL甲醇/DCM(1:2)混合溶剂，溶解得到澄清溶液。通过喷雾干燥法获得固体分散体，然后通过XRPD测试判断所得固体是否为晶体。
经测试，HPMC E3、HPMC E50LV、HPMCP HP50、HPMCAS MG、HPMCAS HG、HPMCAS LG、Eudragit L100、Eudragit EPO与化合物A形成的载药量为10％-20％的喷雾干燥分散体，具有无定形或基本上无定形的结构。一部分喷雾干燥分散体的XRPD图谱在图14中示出。
以上实验表明，当所使用聚合物选自HPMC E3、HPMC E5、HPMC E50LV、HPMCAS、HPMCP HP50、Eudragit L100、Euragit EPO等时，特别是当固体分散体的载药量为10％～15％时，能够通过喷雾干燥法获得基本没有X射线衍射特征峰的无定形固体分散体。
实施例23化合物A的无定形固体分散体的动力学溶解度测试
在动力学溶解度测试中，将实施例22中制备的喷雾干燥分散体(SDD)以化合物A的目标浓度为0.5mg/mL的量加入盛有5mL FaSSIF的8mL玻璃瓶中，在37℃的温度下150rpm磁力搅拌，分别在15、30、60和120分钟时各取样0.5mL，离心取上清液，适当稀释后进行HPLC分析以确定化合物A的溶解度。此外，还通过pH计测试120分钟时溶液的终点pH值。结果在表6中示出。
表6化合物A的无定形固体分散体的动力学溶解度测试
以上实验表明，当化合物A与聚合物混合制备成无定形固体分散体时，能够提高化合物A在FaSSIF中的动力学溶解度。对于大部分化合物A无定形固体分散体，与化合物A晶体(晶型I)相比，溶解度能够提高3～5倍。
实施例24通过喷雾干燥法制备化合物A的无定形固体
将1.5g化合物A、8.5g HPMCAS MG和200mL甲醇/DCM(1:2)混合溶剂加入200mL烧瓶中，溶解得到澄清溶液。通过喷雾干燥法制备化合物A的无定形固体。收集喷雾干燥所得固体，在真空下50℃干燥3小时，获得8.79g无定形固体样品。以与实施例2相同的方法测定化合物A的无定形固体的XRPD图谱，以与实施例4相同的方法测定其TGA图谱，分别在图15和图17中示出。
此外，使用TA Discovery Q2000热分析仪测试化合物A的无定形固体的调制差示扫描量热法(mDSC)图谱。测试条件为温度范围室温到200℃，调制幅度±0.32℃/分钟，调制周期60秒，升温速率2℃/分钟。测试得到的mDSC图谱在图16中示出。图16中，从上到下的三条曲线依次为可逆样品热流、不可逆样品热流和总热流。
如图15所示，本实施例获得的化合物A的无定形固体不具有X射线特征衍射峰，证明其为无定形体；如图16所示，mDSC图谱显示单一的玻璃转化温度Tg＝95.59℃，证明化合物A和聚合物HPMCAS MG在固体分散体中的均匀分布；如图17所示，TGA图谱显示在室温至150℃的范围内重量损失约为1.5％。
此外，通过HPLC测定固体分散体中化合物A的含量为约14.93％，与15％的载药量高度一致。还通过GC测定固体分散体中不含有残留的溶剂。
实施例25化合物A的无定形固体的两步溶出测试
两步溶出测试模拟化合物A在口服施用后在胃液和肠液中的溶出过程。分别称取50mg实施例24制备的化合物A的无定形固体和7.5mg化合物A的晶体(晶型I)，置于40mL玻璃瓶中，加入5mL模拟胃液(SGF，pH 1.3)，在37℃的温度下150rpm磁力搅拌30分钟，取样0.5mL，离心取上清液，适当稀释后进行HPLC分析以确定化合物A的溶解度。
取样后立即向玻璃瓶中加入10mL空腹状态模拟肠液(cFaSSIF，pH 12.1)，使化合物A的目标浓度为0.5mg/mL，继续搅拌并且分别在15、30、60和120分钟时各取样0.5mL，离心取上清液，适当稀释后进行HPLC分析以确定化合物A的溶解度。此外，还通过pH计测试120分钟时溶液的终点pH值。结果在表7中示出。
表7化合物A的无定形固体的两步溶出测试
以上结果表明，载药量15％的化合物A与HPMCAS MG的固体分散体能够显著提高化合物A在胃液和肠液中的溶解度和溶出性能。与化合物A晶体(晶型I)相比，在SGF中的溶解度提高约7倍，在FaSSIF中的溶解度提高约3～4倍。
实施例26喷雾干燥法制备的化合物A的无定形固体的稳定性测试
高温稳定性：将根据实施例24制备的化合物A的无定形固体放置在40℃烘箱内，1周、2周和4周时将样品取出进行XRPD测试，以考察样品对温度的稳定性。结果表明，化合物A的无定形固体在40℃下存放4周后仍为无定形，表明化合物A的无定形固体能够在高于室温的温度下保持稳定。
环境条件稳定性：将根据实施例24制备的化合物A的无定形固体置于25℃、相对湿度60％的实验箱内，1周、2周和4周时将样品取出进行XRPD测试，以考察样品在环境条件下的稳定性。结果表明，化合物A的无定形固体在4周后仍为无定形，在环境条件下稳定。
实施例27通过热熔挤出法制备化合物A的无定形固体
首先通过TGA测试化合物A的热稳定性。将化合物A置于TGA分析仪中，分别加热至150℃、160℃、170℃、180℃、190℃、200℃、210℃并保持30分钟。结果表明，在加热温度为170℃或更低温度时，化合物A在30分钟时间内基本没有重量变化，通过HPLC测试也没有发现热降解；当加热温度为180℃、190℃、200℃、210℃时，30分钟后的样品重量分别为97.9％、95.3％、95.5％和53.6％，但是通过HPLC测试仍然没有发现热降解，表明化合物A的热稳定性很好，只是在接近熔点时会发生升华。在以下热熔挤出实验中，热熔挤出机的温度设定为200℃以下，具体为150℃、160℃、170℃、180℃或190℃。
将3g化合物A与17g HPMCAS MF装入密封袋中，手动震荡混合10分钟，然后装入热熔挤出机(Three-Tec,Model:ZE 5HMI)，分别在150℃、160℃、170℃、180℃或190℃的设定温度下进行热熔挤出。将挤出物(HME)研磨成粉，通过XRPD测定晶体形态，在图18中示出，并通过HPLC测定纯度。
通过视觉观察挤出物发现，160℃-190℃下挤出的样品均为透明，而150℃下挤出的样品不透明，其可能由于化合物A未充分形成固溶体所致。如图18所示，以上制备的5个热熔挤出样品均为无定形。HPLC结果表明，挤出物纯度在99％以上。
以与实施例24相同的方法测定170℃下挤出的化合物A的无定形固体的mDSC图谱，以与实施例4相同的方法测定170℃下挤出的化合物A的无定形固体的TGA图谱，分别在图19-20中示出。图19中，从上到下的三条曲线依次为不可逆样品热流、总热流和可逆样品热流。
如图19所示，mDSC图谱显示单一的玻璃转化温度Tg＝95.64℃，证明化合物A和聚合物HPMCAS MF在固体分散体中的均匀分布；如图20所示，TGA图谱显示在室温至150℃的范围内重量损失约为2.0％。
实施例28化合物A的无定形固体的两步溶出测试
以与实施例25相同的方法测定实施例27制备的化合物A的无定形固体的两步溶出结果，如表8所示。
表8化合物A的无定形固体的两步溶出测试
以上结果表明，载药量15％的化合物A与HPMCAS MF的热熔挤出物能够显著提高化合物A在胃液和肠液中的溶解度和溶出性能。与化合物A晶体(晶型I)相比，在SGF中的溶解度提高接近4倍，在FaSSIF中的溶解度提高约2～3倍。在配方相同的情况下，热熔挤出物的溶出速率低于喷雾干燥的固体分散体，主要是因为两种制备方法得到的固体颗粒的粒径不同，粒径较大的热熔挤出物比表面积较小，限制了药物的溶出速率。
实施例29热熔挤出法制备的化合物A的无定形固体的稳定性测试
高温稳定性：将根据实施例27制备的化合物A的无定形固体放置在40℃或60℃烘箱内，1周、2周和4周时将样品取出进行XRPD测试，以考察样品对温度的稳定性。结果表明，化合物A的无定形固体在40℃和60℃下存放4周后仍为无定形，在高温条件下稳定。
环境条件稳定性：将根据实施例24制备的化合物A的无定形固体置于25℃、相对湿度60％的实验箱内，1周、2周和4周时将样品取出进行XRPD测试，以考察样品在环境条件下的稳定性。结果表明，化合物A的无定形固体在4周后仍为无定形，在环境条件下稳定。
加速稳定性：将根据实施例24制备的化合物A的无定形固体置于40℃、相对湿度75％的实验箱内，1周、2周和4周时将样品取出进行XRPD测试，以考察样品对高温高湿的稳定性。结果表明，化合物A的无定形固体在4周后仍为无定形，在加速条件下稳定。
以上通过实施例，对于本发明的示例性实施方式进行了描述，但本发明不限定于此。本领域的技术人员应当理解，以上实施例仅为示意性目的，本发明的具体实施方式和实施例不应当视为限制本发明的范围。实施例包含可被本公开在其多种实施例和等效物中实践采用的重要的额外信息、例证和指导。在本发明的主旨的范围内能够对实施方式进行改变和变更，这样的改变和变更的方式，理应属于本发明的保护范围。

Claims (51)

  1. 化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型I，其特征在于，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.9°、12.4°、17.6°、25.0°、25.8°处具有特征峰。
  2. 化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型I，其特征在于，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.9°、12.4°、17.6°、18.2°、19.6°、24.2°、25.0°、25.8°、26.7°、28.0°、28.8°处具有特征峰。
  3. 化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型I，其特征在于，具有基本上如图1所示的X射线粉末衍射(XRPD)图谱。
  4. 根据权利要求1至3的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型I，其特征在于，所述晶型I是无水晶型。
  5. 根据权利要求1至3的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型I，其特征在于，所述晶型I满足如下任意一项或多项：
    在使用差示扫描量热法(DSC)进行热分析时，其在约211.6℃±2.0℃处具有吸热峰，优选地，其具有基本上如图2所示的DSC图谱；
    在使用热重分析法(TGA)进行热分析时，其具有基本上如图3所示的TGA图谱；和
    在使用动态水分吸附法(DVS)进行分析时，其具有基本上如图6所示的DVS图谱。
  6. 权利要求1至5的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型I的制备方法，其特征在于，包括以下步骤：
    (1)将化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的固体溶解在有机溶剂中或者在有机溶剂中悬浮，所述有机溶剂为选自有机酸类、酰胺类、砜类、醇类、醚类、腈类中的一种或多种，优选为选自有机酸类和酰胺类；
    (2)向上述溶液或悬液中加入水，使晶体析出，其中所述水的用量为所述有机溶剂的体积的0.1～100倍；
    (3)过滤收集晶体并干燥，得到1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型I。
  7. 根据权利要求6所述的制备方法，其特征在于，所述有机溶剂选自甲酸、乙酸、丙酸、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、二乙基亚砜、C1-C6的醇或多元醇、四氢呋喃、苯甲醚或乙腈。
  8. 化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型III，其特征在于，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.4°、10.2°、12.4°、16.7°、18.1°、22.1°、24.8°、25.7°处具有特征峰。
  9. 化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型III，其特征在于，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为8.4°、10.2°、12.4°、14.0°、15.8°、16.7°、17.5°、18.1°、20.2°、22.1°、22.6°、23.4°、24.8°、25.2°、25.7°、28.2°处具有特征峰。
  10. 化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型III，其特征在于，具有基本上如图7所示的X射线粉末衍射(XRPD)图谱。
  11. 根据权利要求8至10的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型III，其特征在于，所述晶型III是含乙酸晶型，优选为乙酸溶剂化物晶型。
  12. 根据权利要求8至10的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型III，其特征在于，所述晶型III满足如下任意一项或多项：
    在使用差示扫描量热法(DSC)进行热分析时，其在约78.3℃±2℃、121.4℃±2℃和/或212.2℃±2℃处具有吸热峰，优选地，其具有基本上如图8所示的DSC图谱；和
    在使用热重分析法(TGA)进行热分析时，其具有基本上如图9所示的TGA图谱。
  13. 权利要求8至12的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型III的制备方法，其特征在于，包括以下步骤：
    (1)将化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的固体加入无水乙酸中，在加热条件下悬浮；
    (2)过滤，滤液在冷却条件下静置沉淀；
    (3)过滤收集晶体并干燥，得到1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型III。
  14. 根据权利要求13所述的制备方法，其特征在于，
    所述加热悬浮的温度<60℃，优选为≤55℃，更优选为≤50℃；和/或
    所述冷却静置的温度≤10℃，优选为≤5℃。
  15. 化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型IV，其特征在于，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为9.7°、13.0°、15.6°、19.1°、23.0°、24.1°、24.5°处具有特征峰。
  16. 化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型IV，其特征在于，在X射线粉末衍射(XRPD)图谱中，其在衍射角2θ约为9.7°、13.0°、15.6°、17.2°、17.9°、19.1°、20.4°、21.3°、23.0°、24.1°、24.5°、25.2°、28.1°、29.0°、32.7°、34.3°处具有特征峰。
  17. 化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型IV，其特征在于，具有基本上如图10所示的X射线粉末衍射(XRPD)图谱。
  18. 根据权利要求15至17的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型IV，其特征在于，所述晶型是含盐酸晶型，优选为所述化合物盐酸盐的晶型，更优选为无水晶型。
  19. 根据权利要求15至17的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型IV，其特征在于，所述晶型IV满足如下任意一项或多项：
    在使用差示扫描量热法(DSC)进行热分析时，其在约180.5℃±2℃和/或209℃±2℃处具有吸热峰，优选地，其具有基本上如图11所示的DSC图谱；和
    在使用热重分析法(TGA)进行热分析时，其具有基本上如图12所示的TGA图谱。
  20. 权利要求15至19的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型IV的制备方法，其特征在于，包括以下步骤：
    (1)将化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的固体溶解于加热的含有HCl的有机溶剂中，所述有机溶剂优选包含乙酸异丙酯和异丙醇；
    (2)在惰性气氛下，将溶液冷却至室温并搅拌，使晶体析出；
    (3)过滤，用乙酸异丙酯清洗湿滤饼并干燥，得到1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型IV。
  21. 根据权利要求20所述的制备方法，其特征在于，所述HCl的摩尔数为所述化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的摩尔数的2至5倍，优选为3至4倍。
  22. 一种组合物，其包含：
    权利要求1至5的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型I，以及
    权利要求8至12的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型III和权利要求15至19的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型IV中的至少一种。
  23. 一种药物组合物，其包含：
    (i)权利要求1至5的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型I，和/或
    权利要求8至12的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型III，和/或
    权利要求15至19的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型IV，以及
    (ii)药学上可接受的载体、稀释剂或赋形剂。
  24. 化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的无定形固体，其特征在于，在X射线粉末衍射(XRPD)图谱中没有明显的晶体衍射特征峰。
  25. 根据权利要求24所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的无定形固体，其特征在于，具有基本上如图15所示的X射线粉末衍射(XRPD)图谱。
  26. 根据权利要求24或25所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的无定形固体，其特征在于，所述无定形固体还包含药学上可接受的聚合物；优选地，所述无定形固体是所述化合物与所述聚合物的固体分散体。
  27. 根据权利要求26所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的无定形固体，其特征在于，所述聚合物选自羟丙甲纤维素(HPMC)、醋酸琥珀酸羟丙甲纤维素酯(HPMCAS)、邻苯二甲酸羟丙甲纤维素酯(HPMCP)和丙烯酸树脂共聚物(Eudragit)中的一种或多种。
  28. 根据权利要求26所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的无定形固体，其特征在于，所述聚合物选自HPMC E3、HPMC E5、HPMC E50LV、HPMCAS LG、HPMCAS MG、HPMCAS HG、HPMCAS MMP、HPMCAS MF、HPMCP HP50、Eudragit L100、Euragit EPO中的一种或多种，优选为HPMCAS MG、HPMCAS MMP、HPMCAS MF中的一种或多种。
  29. 根据权利要求26至28的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的无定形固体，其特征在于，所述化合物占所述无定形固体重量的约5％～25％，优选为约5％～20％，更优选为约10％～20％，特别优选为约10％～15％。
  30. 根据权利要求26至28的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的无定形固体，其特征在于，所述化合物与所述聚合物的质量比为约1:3～1:19，优选为约1:4～1:19，更优选为约1:4～1:9，特别优选为约1:5.6～1:9。
  31. 根据权利要求24至30的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的无定形固体，其特征在于，所述无定形固体是通过喷雾干燥法或热熔挤出法制备的。
  32. 一种化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的无定形固体的制备方法，其特征在于，包括以下步骤：
    将所述化合物与药学上可接受的聚合物溶解于溶剂中，形成溶液；
    喷雾干燥所述溶液以形成固体分散体，即为所述无定形固体。
  33. 根据权利要求32所述的制备方法，其特征在于，所述聚合物选自羟丙甲纤维素(HPMC)、醋酸琥珀酸羟丙甲纤维素酯(HPMCAS)、邻苯二甲酸羟丙甲纤维素酯(HPMCP)和丙烯酸树脂共聚物(Eudragit)中的一种或多种。
  34. 根据权利要求32或33所述的制备方法，其特征在于，所述溶剂为选自醇类、卤代烷类、酮类、醚类、酯类、酰胺类、砜类、腈类中的一种或多种；优选地，所述溶剂为选自C1-C6的醇或多元醇、二氯甲烷、三氯甲烷、丙酮、甲基乙基酮、四氢呋喃、苯甲醚、乙酸乙酯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜、二乙基亚砜、乙腈中的一种或多种。
  35. 根据权利要求32至34的任一项所述的制备方法，其特征在于，所述溶剂为二氯甲烷和甲醇的混合物，优选为二氯甲烷和甲醇体积比2:1的混合物。
  36. 根据权利要求32至35的任一项所述的制备方法，其特征在于，所述化合物在所述溶液中的浓度为约3-15mg/mL，优选为约4-12mg/mL，更优选为约5-10mg/mL。
  37. 一种根据权利要求32至36中任一项所述的制备方法制得的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的无定形固体。
  38. 一种化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的无定形固体的制备方法，其特征在于，包括以下步骤：
    将所述化合物与药学上可接受的聚合物混合均匀，经热熔挤出机挤出，获得所述无定形固体。
  39. 根据权利要求38所述的制备方法，其特征在于，所述聚合物选自羟丙甲纤维素(HPMC)、醋酸琥珀酸羟丙甲纤维素酯(HPMCAS)、邻苯二甲酸羟丙甲纤维素酯(HPMCP)和丙烯酸树脂共聚物(Eudragit)中的一种或多种。
  40. 根据权利要求38或39所述的制备方法，其特征在于，热熔挤出机的加热温度为150-200℃，优选为160-180℃。
  41. 根据权利要求38至40的任一项所述的制备方法，其特征在于，还包括将热熔挤出物粉碎、过筛的步骤。
  42. 一种根据权利要求38至41中任一项所述的制备方法制得的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的无定形固体。
  43. 一种药物组合物，其包含：
    (i)权利要求24至31、37和42的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的无定形固体，以及
    (ii)药学上可接受的载体、稀释剂或赋形剂。
  44. 根据权利要求23或43所述的药物组合物，其还包含另外的治疗剂。
  45. 根据权利要求44所述的药物组合物，所述另外的治疗剂选自抗癌剂、抗真菌剂、心血管治疗剂、抗炎剂、化学治疗剂、抗血管生成剂、细胞毒性剂、抗增殖剂、代谢疾病治疗剂、眼科疾病治疗剂、中枢神经系统(CNS)疾病治疗剂、泌尿疾病治疗剂和胃肠疾病治疗剂。
  46. 权利要求1至5的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型I、权利要求8至12的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型III、权利要求15至19的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的晶型IV、或任意两种以上晶型的任意比例的混合物、或权利要求24至31、37和42的任一项所述的化合物1-环丙基-2-(6-(二氟甲基)哒嗪-4-基)-5,6-二氟-1H-苯并[d]咪唑的无定形固体在药物制备中的用途。
  47. 根据权利要求46所述的用途，所述药物用于调节金属酶活性。
  48. 根据权利要求46所述的用途，所述药物用于调节醛固酮合酶CYP11B2的活性。
  49. 根据权利要求46所述的用途，所述药物用于治疗金属酶相关病症或疾病，其中所述病症或疾病是癌症、心血管疾病、内分泌疾病、纤维化、肾脏疾病、炎性疾病、传染病、妇科疾病、代谢疾病、眼科疾病、中枢神经系统(CNS)疾病、泌尿疾病、或胃肠疾病。
  50. 根据权利要求49所述的用途，其中所述病症或疾病是肾上腺癌、肾上腺瘤、白血病、乳腺癌、高血压、顽固性高血压、肺动脉高血压、心力衰竭、舒张功能障碍、左心室舒张功能障碍、舒张性心力衰竭、收缩功能障碍、收缩性心力衰竭、心肌梗塞后综合征、冠心病、心肌坏死病变、心房颤动、动脉粥样硬化、再狭窄、内皮功能障碍、血管损伤、心肌梗死、左心室肥厚，血管壁肥厚、内皮增厚、动脉纤维蛋白样坏死、血管疾病、与原发性或继发性醛固酮增多症和肾上腺增生相关的病症、糖尿病、代谢综合征、胰岛素抵抗、神经病变、胰岛素病变、糖尿病肾病、以高血压后胶原形成增加、纤维化和基质重塑为特征的疾病、以内皮细胞功能障碍后的纤维化和基质重塑为特征的疾病、心肌纤维化、血管纤维化、肾衰竭、慢性肾衰竭、肾病、肾功能障碍、肾脏疾病、肾小球硬化、肾小球肾炎、肾病综合征、多囊肾病、低钾血症、视网膜病变、睡眠呼吸暂停、阻塞性睡眠呼吸暂停、肌营养不良、中风、肝病、非酒精性脂肪性肝炎、肝硬化或非酒精性脂肪肝病。
  51. 根据权利要求50所述的用途，其中所述病症或疾病是高血压、顽固性高血压、肺动脉高血压、动脉粥样硬化或低钾血症。
PCT/CN2025/074828 2024-01-26 2025-01-24 金属酶抑制剂化合物的固体形式 Pending WO2025157275A1 (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018125799A2 (en) * 2016-12-29 2018-07-05 Viamet Pharmaceuticals (Bermuda), Ltd. Metalloenzyme inhibitor compounds
CN110691598A (zh) * 2016-12-29 2020-01-14 赛列尼蒂治疗(百慕大)有限公司 金属酶抑制剂化合物
CN114269383A (zh) * 2019-01-08 2022-04-01 菲斯生物制药公司 金属酶抑制剂化合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018125799A2 (en) * 2016-12-29 2018-07-05 Viamet Pharmaceuticals (Bermuda), Ltd. Metalloenzyme inhibitor compounds
CN110691598A (zh) * 2016-12-29 2020-01-14 赛列尼蒂治疗(百慕大)有限公司 金属酶抑制剂化合物
CN114269383A (zh) * 2019-01-08 2022-04-01 菲斯生物制药公司 金属酶抑制剂化合物

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