Nothing Special   »   [go: up one dir, main page]

WO2021143811A1 - 四氮唑类化合物的可药用盐及其结晶形式、制备方法和用途 - Google Patents

四氮唑类化合物的可药用盐及其结晶形式、制备方法和用途 Download PDF

Info

Publication number
WO2021143811A1
WO2021143811A1 PCT/CN2021/072051 CN2021072051W WO2021143811A1 WO 2021143811 A1 WO2021143811 A1 WO 2021143811A1 CN 2021072051 W CN2021072051 W CN 2021072051W WO 2021143811 A1 WO2021143811 A1 WO 2021143811A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
difluorophenyl
difluoro
pyridin
Prior art date
Application number
PCT/CN2021/072051
Other languages
English (en)
French (fr)
Inventor
黄建
祝令建
李贝
唐应刚
尚婷婷
杜振兴
Original Assignee
上海森辉医药有限公司
上海盛迪医药有限公司
江苏恒瑞医药股份有限公司
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 上海森辉医药有限公司, 上海盛迪医药有限公司, 江苏恒瑞医药股份有限公司 filed Critical 上海森辉医药有限公司
Publication of WO2021143811A1 publication Critical patent/WO2021143811A1/zh

Links

Images

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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present disclosure belongs to the field of medical technology, and specifically relates to 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4- (2,2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl dihydrogen phosphate and its crystalline form, preparation method and application.
  • metalloenzymes The function of metalloenzymes is highly dependent on the presence of metal ions in the active site of the enzyme. It is recognized that reagents that bind to and inactivate metal ions at the active site greatly reduce the activity of the enzyme. Nature uses this same strategy to reduce the activity of certain metalloenzymes during periods when enzyme activity is not needed.
  • the protein TIMP tissue inhibitor of metalloproteinases
  • the pharmaceutical industry has used the same strategy in the design of therapeutic agents.
  • the azole antifungal agents fluconazole and voriconazole contain 1-(1,2,4-triazole) group, which exists in the active site of the target enzyme lanosterol demethylase The heme iron binds, thereby inactivating the enzyme.
  • Another example includes zinc-bound hydroxamic acid groups, which have been introduced into most of the published inhibitors of matrix metalloproteinases and histone deacetylases.
  • Another example is the zinc-binding carboxylic acid group, which has been introduced into most of the published angiotensin converting enzyme inhibitors.
  • the compound 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2, 2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol is an antifungal drug developed by VIAMET, currently in the clinical research stage. Its structure is as follows Shown:
  • This compound mainly acts on the CYP51 target of fungal cells. Compared with the previous triazole antifungal drugs, it has the advantages of wider antibacterial spectrum, low toxicity, high safety and good selectivity. However, this compound is not suitable for Liquid preparations (including or excluding the parenteral delivery carrier) are used to treat patients in need of such treatment.
  • 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoro Ethoxy)phenyl)pyridin-2-yl)propan-2-yl dihydrogen phosphate is a prodrug of VT-1161.
  • the present disclosure provides a new pharmaceutically acceptable salt form of a metalloenzyme inhibitor.
  • the present disclosure provides the compound 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4 -(2,2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl dihydrogen phosphate pharmaceutically acceptable salt selected from sodium salt and potassium Salt, magnesium salt, lithium salt, ammonium salt, ethanolamine salt and D/L-phenylglycinamide salt, preferably sodium salt.
  • the pharmaceutically acceptable salts of the present disclosure obtain base addition salts by contacting a neutral form of a compound with a base.
  • the chemical ratio of ions, D/L-phenylglycinamide ions is 1:1 or 1:2, preferably 1:2.
  • Some embodiments provide the compound 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2)
  • the pharmaceutically acceptable salt of ,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl dihydrogen phosphate is:
  • Some embodiments provide the compound 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2)
  • the pharmaceutically acceptable salt of ,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl dihydrogen phosphate is:
  • 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2 ,2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl dihydrogen phosphate is a chiral molecule with 1 chiral center and 2 configuration isomers, such as:
  • Some embodiments provide the compound 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2)
  • the pharmaceutically acceptable salt of ,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl dihydrogen phosphate is:
  • Some embodiments provide the compound 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2)
  • the pharmaceutically acceptable salt of ,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl dihydrogen phosphate is:
  • the present disclosure also relates to the preparation of 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,
  • the method for 2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl dihydrogen phosphate sodium salt comprising: compound 2-(2,4-difluorophenyl)-1 ,1-Difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propane
  • the molar ratio of 2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl dihydrogen phosphate and base is 1:1 or 1:2, preferably 1:2.
  • the aforementioned salt formation reaction is carried out in a solvent selected from at least one of ethanol, methanol, tert-butanol, isopropanol, tetrahydrofuran, and acetone.
  • the method for preparing the aforementioned pharmaceutically acceptable salt further includes the steps of concentration, filtration, drying, solvent volatilization, or stirring and crystallization.
  • the present disclosure also relates to (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-( 2,2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (the compound of formula Ia), crystalline form A, expressed by the diffraction angle 2 ⁇ angle X- X-ray powder diffraction pattern, there are characteristic peaks at 7.354, 9.280, 9.800, 18.398 and 19.628.
  • the crystalline form A of the compound of formula I-a has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.354, 9.280, 9.800, 11.075, 12.942, 18.398 and 19.628.
  • the crystalline form A of the compound of formula Ia has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles at 7.354, 9.280, 9.800, 11.075, 12.942, 14.701, 18.398, 19.628, 21.461 and 22.327 There are characteristic peaks.
  • the crystalline form A of the compound of formula I-a has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 1.
  • the present disclosure also relates to the preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5 -(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (compound of formula Ia), the method of crystal form A, including the following step:
  • the present disclosure also relates to (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5- (4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (formula Ia compound) crystal form B, with diffraction angle 2 ⁇
  • the indicated X-ray powder diffraction pattern has characteristic peaks at 9.461, 9.948, 12.168, 15.838, 17.146, 18.687 and 20.818.
  • the crystalline form B of the compound of formula Ia has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles, which are characterized at 9.461, 9.948, 12.168, 12.894, 13.674, 15.838, 17.146, 18.687 and 20.818 peak.
  • the crystalline form B of the compound of formula Ia has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles at 9.461, 9.948, 10.707, 12.168, 12.894, 13.674, 15.838, 16.579, 17.146, 18.687, There are characteristic peaks at 20.021 and 20.818.
  • the crystalline form B of the compound of formula I-a has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 2.
  • the present disclosure also relates to the preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5 -(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (compound of formula Ia), the method of crystal form B, including the following step:
  • the present disclosure also relates to (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5- (4-(2,2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (compound of formula Ia), crystalline form C, with a diffraction angle of 2 ⁇
  • the indicated X-ray powder diffraction pattern has characteristic peaks at 8.547, 9.008, 16.043, 22.966, 24.065 and 24.634.
  • the crystalline form C of the compound of formula Ia has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle, which is characterized at 7.997, 8.547, 9.008, 16.043, 22.465, 22.966, 24.065, 24.634, and 25.944 peak.
  • the crystalline form C of the compound of formula Ia has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ angle at 7.997, 8.547, 9.008, 16.043, 22.465, 22.966, 24.065, 24.634, 25.944, 29.826, There are characteristic peaks at 30.761 and 34.937.
  • the crystalline form C of the compound of formula I-a has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 3.
  • the present disclosure also provides the preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5 -(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (the compound of formula Ia), the method of crystal form C, including the following step:
  • solvent (V)-2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2 , 2-Trifluoroethoxy) phenyl) pyridin-2-yl) propan-2-yl phosphate disodium salt is added to solvent (V), the solvent (V) is selected from tetrahydrofuran, acetone, methanol, iso At least one of propanol and water,
  • the present disclosure also provides (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5- (4-(2,2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (the compound of formula Ia), crystalline form D, with a diffraction angle of 2 ⁇
  • the indicated X-ray powder diffraction pattern has characteristic peaks at 4.160, 8.388, 9.024, 10.618, 11.568, 20.429 and 22.042.
  • the crystalline form D of the compound of formula Ia has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles, which are characterized at 4.160, 8.388, 9.024, 10.618, 11.568, 14.918, 16.591, 20.429 and 22.042 peak.
  • the crystalline form D of the compound of formula Ia has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles at 4.160, 8.388, 9.024, 10.618, 11.568, 14.918, 16.591, 18.679, 20.429, 20.626, There are characteristic peaks at 22.042 and 22.346.
  • the crystalline form D of the compound of formula I-a has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 4.
  • the present disclosure also relates to the preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5 -(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (compound of formula Ia), the method of crystal form D, including the following step:
  • the present disclosure also relates to (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5- (4-(2,2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (the compound of formula Ia), crystalline form E, with a diffraction angle of 2 ⁇
  • the indicated X-ray powder diffraction pattern has characteristic peaks at 5.183, 5.801, 6.904, 7.684, 13.106 and 14.972.
  • the crystalline form E of the compound of formula Ia has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles, which are characterized at 5.183, 5.801, 6.904, 7.684, 13.106, 14.972, 17.177, 20.286, and 22.404 peak.
  • the crystalline form E of the compound of formula I-a has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 5.
  • the present disclosure also relates to the preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5 -(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (compound of formula Ia), the method of crystal form E, including the following step:
  • the present disclosure also relates to (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5- (4-(2,2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (the compound of formula Ia), crystalline form F, with a diffraction angle of 2 ⁇
  • the X-ray powder diffraction pattern shown has characteristic peaks at 6.649 and 9.90.
  • the crystalline form F of the compound of formula I-a has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 6.
  • the present disclosure also relates to the preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5 -(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (compound of formula Ia), the method of crystal form F, including the following step:
  • the present disclosure also relates to (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5- (4-(2,2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (formula Ia compound) crystal form G, with diffraction angle 2 ⁇
  • the indicated X-ray powder diffraction pattern has characteristic peaks at 8.886, 11.313, 12.060, 14.477, 15.433, 15.846 and 19.097.
  • the crystalline form G of the compound of formula Ia has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles, which are characterized at 8.886, 11.313, 12.060, 13.193, 14.477, 15.433, 15.846, 18.010 and 19.097 peak.
  • the crystalline form G of the compound of formula Ia has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles at 8.886, 11.313, 12.060, 13.193, 14.477, 15.433, 15.846, 18.010, 19.097, 20.210, There are characteristic peaks at 20.716 and 22.929.
  • the crystalline form G of the compound of formula I-a has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 7.
  • the present disclosure also relates to the preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5 -(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (compound of formula Ia), the method of crystalline form G, including the following step:
  • the present disclosure also provides (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5- (4-(2,2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (the compound of formula Ia), form H, with a diffraction angle of 2 ⁇
  • the indicated X-ray powder diffraction pattern has characteristic peaks at 9.466, 10.638, 12.947, 15.795, 17.053 and 18.653.
  • the crystalline form H of the compound of formula I-a has characteristic peaks at 9.466, 9.996, 10.638, 12.947, 15.795, 17.053, 18.653 and 20.113 in the X-ray powder diffraction pattern expressed by diffraction angle 2 ⁇ .
  • the crystalline form H of the compound of formula Ia has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles at 9.466, 9.996, 10.638, 12.125, 12.947, 15.795, 17.053, 18.653, 20.113 and 20.759 There are characteristic peaks.
  • the crystalline form H of the compound of formula I-a has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 8.
  • the present disclosure also relates to the preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5 -(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (the compound of formula Ia), the method of crystal form H, including the following step:
  • the present disclosure also provides (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5- (4-(2,2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (the compound of formula Ia), crystalline form I, with a diffraction angle of 2 ⁇
  • the indicated X-ray powder diffraction pattern has characteristic peaks at 7.768, 9.525, 10.021, 12.224, 12.982, 17.286 and 21.775.
  • the crystalline form I of the compound of formula Ia has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles, which are characterized at 7.768, 9.525, 10.021, 12.224, 12.982, 15.413, 15.906, 17.286 and 21.775 peak.
  • the crystalline form I of the compound of formula Ia has an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ angles at 7.768, 9.525, 10.021, 12.224, 12.982, 15.413, 15.906, 17.286, 18.849, 20.920, There are characteristic peaks at 21.775 and 22.318.
  • the crystalline form I of the compound of formula I-a has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 9.
  • the present disclosure also relates to the preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5 -(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (the compound of formula Ia), the method of crystal form I, including the following step:
  • the solvent volume (ml) used in the present disclosure is 1-50 times the compound weight (g), which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 , 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.
  • the preparation method of the crystal form in the present disclosure also includes steps such as filtration, washing or drying.
  • the drying temperature mentioned in the present disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and it can be dried under normal pressure or under reduced pressure. Preferably, drying is dried under reduced pressure.
  • the present disclosure also relates to a pharmaceutical composition, which contains the aforementioned pharmaceutically acceptable salt and a pharmaceutical excipient optionally selected from at least one of a pharmaceutically acceptable carrier, diluent or excipient, or is composed of the aforementioned pharmaceutically acceptable salt. It is prepared with a salt and a pharmaceutical excipient optionally selected from at least one of pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure also provides a pharmaceutical composition, which contains crystalline forms A to I of the compound of formula Ia and a pharmaceutical excipient optionally selected from at least one of a pharmaceutically acceptable carrier, diluent or excipient, or It is prepared from the aforementioned crystalline forms A to I of the compound of formula Ia and pharmaceutical excipients optionally selected from at least one of pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure also provides a method for preparing a pharmaceutical composition, which comprises combining the aforementioned pharmaceutically acceptable salt or crystalline form A to I of the compound of formula Ia and optionally selected from pharmaceutically acceptable carriers, diluents or excipients. At least one step of mixing to obtain a composition.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned pharmaceutically acceptable salt based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned pharmaceutically acceptable salts. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the aforementioned pharmaceutically acceptable salts. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned pharmaceutically acceptable salts. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned pharmaceutically acceptable salts.
  • the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable carrier, diluent or excipient based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable carrier, diluent or excipient.
  • the present disclosure also relates to the use of the aforementioned pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of a medicine for regulating the activity of Candida albicans in a subject.
  • the present disclosure also relates to the use of the aforementioned crystalline forms A to I of the compound of formula I-a in the preparation of a medicament for regulating the activity of Candida albicans in a subject.
  • the present disclosure also relates to the use of the aforementioned pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of a medicament for the treatment of Candida albicans-related disorders or diseases.
  • the disease or condition is systemic fungal infection or onychomycosis.
  • the present disclosure also relates to the use of the aforementioned crystalline forms A to I of the compound of formula I-a in the preparation of a medicament for the treatment of Candida albicans related disorders or diseases.
  • the disease or condition is systemic fungal infection or onychomycosis.
  • the present disclosure also relates to the use of the aforementioned pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of a medicine for inhibiting the activity of metalloenzymes.
  • the metalloenzyme is lanosterol demethylase (CYP51).
  • the present disclosure also relates to the use of the aforementioned crystal forms A to I of the compound of formula I-a in the preparation of a medicine for inhibiting the activity of metalloenzymes.
  • the metalloenzyme is lanosterol demethylase (CYP51).
  • the present disclosure also relates to the use of the aforementioned pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of a medicament for the treatment of a metalloenzyme-mediated disorder or disease, wherein the metalloenzyme-mediated disorder or disease is demethylated by lanosterol Enzyme (CYP51) mediated.
  • the disease or condition is an infectious disease.
  • the disease or condition is superficial fungal infection, mucosal fungal infection, systemic fungal infection, or onychomycosis.
  • the present disclosure also relates to the use of the aforementioned crystal forms A to I of the compound of formula Ia in the preparation of a medicament for the treatment of metalloenzyme-mediated disorders or diseases, wherein the metalloenzyme-mediated disorders or diseases are depleted by lanosterol. Methylase (CYP51) mediated.
  • the disease or condition is an infectious disease.
  • the disease or condition is superficial fungal infection, mucosal fungal infection, systemic fungal infection, or onychomycosis.
  • the present disclosure also relates to the aforementioned pharmaceutically acceptable salt or the aforementioned pharmaceutical composition, which is used to modulate the activity of Candida albicans in a subject.
  • the present disclosure also relates to the aforementioned crystalline forms A to I of the compound of formula I-a, which are used to modulate the activity of Candida albicans in a subject.
  • the present disclosure also relates to the aforementioned pharmaceutically acceptable salt or the aforementioned pharmaceutical composition, which is used for the treatment of Candida albicans-related disorders or diseases.
  • the disease or condition is systemic fungal infection or onychomycosis.
  • the present disclosure also relates to the aforementioned crystalline forms A to I of the compound of formula I-a, which are used for the treatment of Candida albicans-related disorders or diseases.
  • the disease or condition is systemic fungal infection or onychomycosis.
  • the present disclosure also relates to the aforementioned pharmaceutically acceptable salt or the aforementioned pharmaceutical composition, which is used to inhibit metalloenzyme activity.
  • the metalloenzyme is lanosterol demethylase (CYP51).
  • the present disclosure also relates to the aforementioned crystalline forms A to I of the compound of formula I-a, which are used to inhibit metalloenzyme activity.
  • the metalloenzyme is lanosterol demethylase (CYP51).
  • the present disclosure also relates to the aforementioned pharmaceutically acceptable salt or the aforementioned pharmaceutical composition for the treatment of metalloenzyme-mediated conditions or diseases, wherein the metalloenzyme-mediated conditions or diseases are mediated by lanosterol demethylase (CYP51) guide.
  • the disease or condition is an infectious disease.
  • the disease or condition is superficial fungal infection, mucosal fungal infection, systemic fungal infection, or onychomycosis.
  • the present disclosure also relates to the aforementioned crystalline forms A to I of the compound of formula Ia, which are used for the treatment of metalloenzyme-mediated conditions or diseases, wherein the metalloenzyme-mediated conditions or diseases are mediated by lanosterol demethylase (CYP51) guide.
  • the disease or condition is an infectious disease.
  • the disease or condition is superficial fungal infection, mucosal fungal infection, systemic fungal infection, or onychomycosis.
  • the present disclosure also relates to a method for regulating the activity of Candida albicans in a subject, which comprises administering to the subject a therapeutically effective amount of the aforementioned pharmaceutically acceptable salt or the aforementioned pharmaceutical composition or the aforementioned crystalline form A to I of the compound of formula Ia .
  • the present disclosure also relates to a method for treating Candida albicans-related disorders or diseases, which comprises administering to a subject in need thereof a therapeutically effective amount of the aforementioned pharmaceutically acceptable salt or the aforementioned pharmaceutical composition or the aforementioned pharmaceutical composition or the aforementioned formula Ia Compound crystalline forms A to I.
  • the disease or condition is systemic fungal infection or onychomycosis.
  • the present disclosure also relates to a method for treating Candida albicans-related disorders or diseases, which comprises administering to a subject in need thereof a therapeutically effective amount of the aforementioned pharmaceutically acceptable salt or the aforementioned pharmaceutical composition or the aforementioned crystalline form A of the compound of formula Ia To I.
  • the disease or condition is systemic fungal infection or onychomycosis.
  • the present disclosure also relates to a method for inhibiting metalloenzyme activity, which comprises administering a therapeutically effective amount of the aforementioned pharmaceutically acceptable salt or the aforementioned pharmaceutical composition or the aforementioned crystalline form A to I of the compound of formula I-a to a subject in need thereof.
  • the metalloenzyme is lanosterol demethylase (CYP51).
  • the present disclosure also relates to a treatment of a metalloenzyme-mediated disorder or disease, which comprises administering to a subject in need thereof a therapeutically effective amount of the aforementioned pharmaceutically acceptable salt or the aforementioned pharmaceutical composition or the aforementioned crystalline form A to of the compound of formula Ia I, wherein the metalloenzyme-mediated condition or disease is mediated by lanosterol demethylase (CYP51).
  • the disease or condition is an infectious disease.
  • the disease or condition is superficial fungal infection, mucosal fungal infection, systemic fungal infection, or onychomycosis.
  • the hydrogen in the functional group of the aforementioned pharmaceutically acceptable salt of the present disclosure is deuterated to obtain the corresponding deuterated compound.
  • the deuterated compound retains selectivity and potential comparable to hydrogen analogs; the deuterium bond is more stable, making “ADME” That is, the "toxic pharmacokinetics” are different, thereby providing clinically beneficial effects.
  • Toxic pharmacokinetics refers to the absorption, distribution, metabolism and excretion of foreign chemicals by the body. Examples of the deuterated compounds of the present disclosure are as follows:
  • XRPD is an X-ray powder diffraction test: the measurement is carried out using a BRUKER D8 X-ray diffractometer. The specific information collected: Cu anode (40kV, 40mA), Cu-K ⁇ 1 rays K ⁇ 2 rays K ⁇ rays Scanning range (2 ⁇ range): 3-50, scanning step length 0.02, slit width (collimator) 1.0mm.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present disclosure refers to the diffraction angle, and ⁇ is the Bragg angle, in degrees or degrees; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20, which can be -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01 , 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.
  • interplanar spacing or interplanar spacing (d value) means that the spatial lattice selects three non-parallel unit vectors a, b, and c connecting two adjacent lattice points.
  • the lattice is divided into juxtaposed parallelepiped units, called interplanar spacing.
  • the space lattice is divided according to the determined parallelepiped unit lines to obtain a set of linear grids, which are called spatial lattices or lattices.
  • Lattice and crystal lattice use geometric points and lines to reflect the periodicity of the crystal structure.
  • the interplanar spacing that is, the distance between two adjacent parallel crystal planes
  • the unit is Or angstrom.
  • the “differential scanning calorimetry or DSC” mentioned in the present disclosure refers to the measurement of the temperature difference and heat flow difference between the sample and the reference material during the temperature rise or constant temperature process of the sample to characterize all physical changes related to the thermal effect and Chemical changes to obtain the phase change information of the sample.
  • the "pharmaceutical composition” of the present disclosure means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable Carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • the crystalline forms described in the present disclosure include, but are not limited to, the solvate of the compound of formula I-a, and the complex formed by combining the compound of formula I-a with a solvent, and the solvent includes but is not limited to water.
  • the numerical values in this disclosure are measured by instruments, and there is a certain degree of error. Generally speaking, plus or minus 10% are within a reasonable error range. Of course, it is necessary to consider the context in which the value is used.
  • the chemical ratio of the compound to the acid or base molecule in the present disclosure is that the error after the measurement does not change by more than plus or minus 10%, and it can be plus or minus 9%, plus or minus. 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.
  • the drying temperature mentioned in the present disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and it can be dried under normal pressure or under reduced pressure. It is preferable to dry under reduced pressure.
  • the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or Or both and Two configurations.
  • the reagents used in this disclosure are commercially available.
  • the structure of the compound can be determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10-6 (ppm).
  • NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • HPLC High performance liquid chromatography analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.
  • Figure 1 XRPD spectrum of the crystalline form A of the compound of formula I-a.
  • Figure 2 XRPD spectrum of the crystalline form B of the compound of formula I-a.
  • Figure 3 XRPD spectrum of the crystalline form C of the compound of formula I-a.
  • Figure 4 XRPD spectrum of the crystalline form D of the compound of formula I-a.
  • Figure 5 XRPD spectrum of the crystalline form E of the compound of formula I-a.
  • Figure 7 XRPD spectrum of the crystalline form G of the compound of formula I-a.
  • Figure 8 XRPD spectrum of the crystalline form H of the compound of formula I-a.
  • Figure 10 Amorphous XRPD spectrum of the compound of formula I-a.
  • the X-ray powder diffraction test showed that there is no sharp diffraction peak in the XRPD spectrum, as shown in FIG. 10.
  • pH 7.0: Measure 39ml of 0.2mol/L NaH 2 PO 4 and 61ml of 0.2mol/L Na 2 HPO 4 and mix it, then finely adjust the pH;
  • the solution solubility of potassium salt or sodium salt is superior, and the solubility of compound 1 is better than that of compound 2, which provides solubility guarantee for the preparation of injections.
  • N.A is not detected; N.D is not detected.
  • Test Example 3 In vivo pharmacokinetic experiment in dogs
  • Preparation of administration formulation Compound 1, accurately weigh an appropriate amount of the test substance, add an appropriate volume of physiological saline, stir or sonicate uniformly to obtain a clear dosing solution with a concentration of 0.3 mg/mL for intravenous administration.
  • Blood is collected through the jugular vein or other suitable methods, and each sample is collected about 1 mL, K 2 EDTA is anticoagulated, and placed on ice after collection, and the plasma is separated by centrifugation within 1 hour (centrifugal force 2200 g, centrifugation 10 min, 2-8°C).
  • the collected plasma samples were stored in a refrigerator at -80°C before analysis.
  • Detect the concentration of compound 1 and VT-1161 in plasma samples evaluate the accuracy of quality control samples while analyzing the samples, and require more than 66% of the quality control samples to have an accuracy of 80-120%.
  • WinNonlin is used to calculate the pharmacokinetic parameters, such as AUC(0-t), T 1/2 , Cmax, Tmax and MRT.
  • Crystal form A prepared by referring to the method in Example 10 and add it to 0.5ml of 7% water/ethanol, stir insoluble at room temperature, raise and lower the temperature at 45-5°C, stir and crystallize at 5°C, filter, and dry to obtain a solid.
  • the crystal form D was detected by X-ray powder diffraction.
  • the humidity starts from 50%, the humidity range is 0%-95%, and the step is 10%.
  • the judgment standard is that the mass change dM/dT of each gradient is less than 0.002%,
  • the humidity gradient running time TMAX is 360min, and the cycle is two times.
  • Test Example 6 Take the compound of formula I-a crystal form C and compound 3 (prepared by the method in Example 2), respectively, and place them under the conditions of light, high temperature 40°C and 60°C, high humidity 75% and 92.5% to investigate the stability.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

涉及四氮唑类化合物的可药用盐及其结晶形式、制备方法和用途。具体而言，提供了2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯的可药用盐(式I)及其结晶形式、制备方法和抗真菌的用途。

Description

四氮唑类化合物的可药用盐及其结晶形式、制备方法和用途 技术领域
本公开属于医药技术领域，具体涉及2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯的可药用盐及其结晶形式、制备方法和用途。
背景技术
金属酶的功能高度依赖于酶的活性位点中金属离子的存在。人们公认，与活性位点金属离子结合并使其失活的试剂大大降低了酶的活性。大自然采用此相同的策略在不需要酶活性的时期降低某些金属酶的活性。例如，蛋白质TIMP(金属蛋白酶的组织抑制剂)在多种基质金属蛋白酶的活性位点中与锌离子结合，从而抑制酶活性。制药工业在治疗剂的设计中已经使用相同的策略。例如，唑类抗真菌剂氟康唑(fluconazole)和伏立康唑(voriconazole)含有1-(1,2,4-三唑)基团，其与目标酶羊毛甾醇脱甲基酶的活性位点中存在的血红素铁结合，从而使该酶失活。另一个实例包括锌结合氧肟酸基团，其已被引入到大多数已公开的基质金属蛋白酶和组蛋白脱乙酰基酶的抑制剂中。另一个实例是锌结合羧酸基团，其已被引入到大多数已公开的血管紧张素转化酶抑制剂中。
VT-1161，即化合物2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-醇，是由美国威尔金(VIAMET)公司开发的抗真菌药物，目前处于临床研究阶段，其结构如下所示：
Figure PCTCN2021072051-appb-000001
该化合物主要作用于真菌细胞的CYP51靶点，与以往的三氮唑类抗真菌药物相比具有抗菌谱更广，毒性低，安全性高及选择性好等优点，但是该化合物不适用于以液体制剂(包括或不包括所述胃肠外递药载体)形式治疗需要其治疗的患者。
2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯是VT-1161的一种前药。
另一方面，近一半药物分子都是以盐的形式存在，成盐可改善药物某一些不理想的物理化学或生物学性质。相对于2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯，开发出在理化性质或药学性质方面具有更优异的性质的盐是具有重要意义的。
为此，本公开提供一种新的金属酶抑制剂的可药用的盐形式。
发明内容
本公开(The disclosure)中提供了化合物2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯的可药用盐，所述可药用盐选自钠盐、钾盐、镁盐、锂盐、铵盐、乙醇胺盐和D/L-苯甘氨酰胺盐，优选钠盐。
本公开可药用盐通过使得中性形式的化合物与碱接触而获得碱加成盐。一些实施方案，2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯(根)与阳离子(包括但不限于钠离子、镁离子、钾离子、锂离子、铵离子如乙醇胺离子、D/L-苯甘氨酰胺离子)的化学配比为1:1或1:2，优选1:2。
一些实施方案提供化合物2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯的可药用盐为：
Figure PCTCN2021072051-appb-000002
一些实施方案提供化合物2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯的可药用盐为：
Figure PCTCN2021072051-appb-000003
另一方面，本公开化合物2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯含有1手性中心的手性分子，有2构型异构体，如：
Figure PCTCN2021072051-appb-000004
一些实施方案提供化合物2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯的可药用盐为：
Figure PCTCN2021072051-appb-000005
(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(化合物1)。
一些实施方案提供化合物2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯的可药用盐为：
Figure PCTCN2021072051-appb-000006
(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯单钠盐。
本公开中还涉及制备2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯钠盐的方法，包括：化合物2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯与碱反应的步骤，所述碱选自氢氧化钠、碳酸氢钠、乙醇钠和碳酸钠。
在一些实施方案中，2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯与碱的摩尔比为1:1或1:2，优选1:2。
在一些实施方案中，前述成盐反应在溶剂中进行，所述溶剂选自乙醇、甲醇、叔丁醇、异丙醇、四氢呋喃和丙酮中的至少一种。
进一步地，在可选实施方案中，制备前述可药用盐的方法还包括浓缩，过滤、干燥、挥发溶剂或搅拌析晶等步骤。
本公开还涉及(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.354、9.280、9.800、18.398和19.628处有特征峰。在可选实施方案中，式I-a化合物的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.354、9.280、9.800、11.075、12.942、18.398和19.628处有特征峰。
在可选实施方案中，式I-a化合物的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.354、9.280、9.800、11.075、12.942、14.701、18.398、19.628、21.461和22.327处有特征峰。
在另一可选实施方案中，式I-a化合物的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示。
另一方面，本公开还涉及制备(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型A的方法，包括以下步骤：
(a)将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐加入溶剂(I)中，搅拌溶解，所述溶剂(I)选自甲醇溶剂，
(b)挥发析晶。
另一方面，本公开还涉及(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型B，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.461、9.948、12.168、15.838、17.146、18.687和20.818处有特征峰。
在可选实施方案中，式I-a化合物的晶型B，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.461、9.948、12.168、12.894、13.674、15.838、17.146、18.687和20.818处有特征峰。
在可选实施方案中，式I-a化合物的晶型B，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.461、9.948、10.707、12.168、12.894、13.674、15.838、16.579、17.146、18.687、20.021和20.818处有特征峰。
在另一可选实施方案中，式I-a化合物的晶型B，以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
另一方面，本公开还涉及制备(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型B的方法，包括以下步骤：
(a)将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧 基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐加入溶剂(II)中，搅拌溶解，所述溶剂(II)为甲醇与四氢呋喃的混合溶剂，
(b)挥发析晶；
或者
(a)将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯溶于溶剂(III)，所述溶剂(III)为乙醇，
(b)加入氢氧化溶液，搅拌析晶。
另一方面，本公开还涉及(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型C，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.547、9.008、16.043、22.966、24.065和24.634处有特征峰。
在可选实施方案中，式I-a化合物的晶型C，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.997、8.547、9.008、16.043、22.465、22.966、24.065、24.634和25.944处有特征峰。
在可选实施方案中，式I-a化合物的晶型C，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.997、8.547、9.008、16.043、22.465、22.966、24.065、24.634、25.944、29.826、30.761和34.937处有特征峰。
在另一可选实施方案中，式I-a化合物的晶型C，以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
另一方面，本公开还提供制备(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型C的方法，包括以下步骤：
(a)将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐加入溶剂(IV)中，搅拌溶解或加热溶解，所述溶剂(IV)选自正庚烷、甲基叔丁醚、乙腈和异丙醇中的至少一种与水/丙酮混合溶液，
(b)静止析晶或搅拌析晶；
或者，
将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐加入溶剂(V)中，所述溶剂(V)选自四氢呋喃、丙酮、甲醇、异丙醇和水中的至少一种，
(b)挥发析晶；
或者，
(a)将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐晶型A加入水/异丙醇中，
(b)搅拌打浆。
另一方面，本公开还提供(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型D，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.160、8.388、9.024、10.618、11.568、20.429和22.042处有特征峰。
在可选实施方案中，式I-a化合物的晶型D，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.160、8.388、9.024、10.618、11.568、14.918、16.591、20.429和22.042处有特征峰。
在可选实施方案中，式I-a化合物的晶型D，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.160、8.388、9.024、10.618、11.568、14.918、16.591、18.679、20.429、20.626、22.042和22.346处有特征峰。
在另一可选实施方案中，式I-a化合物的晶型D，以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
另一方面，本公开还涉及制备(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型D的方法，包括以下步骤：
(a)将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐加入溶剂(VI)中，搅拌溶解，所述溶剂(VI)选自乙醇、乙醇/水、乙醇/乙酸乙酯混合溶液，
(b)挥发析晶。
另一方面，本公开还涉及(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型E，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.183、5.801、6.904、7.684、13.106和14.972处有特征峰。
在可选实施方案中，式I-a化合物的晶型E，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.183、5.801、6.904、7.684、13.106、14.972、17.177、20.286和22.404处有特征峰。
在另一可选实施方案中，式I-a化合物的晶型E，以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
另一方面，本公开还涉及制备(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型E的方法，包括以下步骤：
(a)将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐晶型A加入邻二甲苯中，
(b)搅拌打浆。
另一方面，本公开还涉及(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的 晶型F，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.649和9.990处有特征峰。
在另一可选实施方案中，式I-a化合物的晶型F，以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
另一方面，本公开还涉及制备(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型F的方法，包括以下步骤：
(a)将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐加入乙腈中，搅拌溶解，
(b)挥发析晶。
另一方面，本公开还涉及(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型G，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.886、11.313、12.060、14.477、15.433、15.846和19.097处有特征峰。
在可选实施方案中，式I-a化合物的晶型G，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.886、11.313、12.060、13.193、14.477、15.433、15.846、18.010和19.097处有特征峰。
在可选实施方案中，式I-a化合物的晶型G，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.886、11.313、12.060、13.193、14.477、15.433、15.846、18.010、19.097、20.210、20.716和22.929处有特征峰。
在另一可选实施方案中，式I-a化合物的晶型G，以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
另一方面，本公开还涉及制备(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型G的方法，包括以下步骤：
(a)将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐加入溶剂(VII)中，搅拌溶解或加热溶解，所述溶剂(VII)为丙二醇甲醚与甲基叔丁醚或异丙醚混合溶液，
(b)静止析晶或搅拌析晶；
或者，
将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐加入丙二醇甲醚/四氢呋喃中，
(b)挥发析晶。
另一方面，本公开还提供(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型H，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.466、10.638、12.947、 15.795、17.053和18.653处有特征峰。
在可选实施方案中，式I-a化合物的晶型H，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.466、9.996、10.638、12.947、15.795、17.053、18.653和20.113处有特征峰。
在可选实施方案中，式I-a化合物的晶型H，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.466、9.996、10.638、12.125、12.947、15.795、17.053、18.653、20.113和20.759处有特征峰。
在另一可选实施方案中，式I-a化合物的晶型H，以衍射角2θ角度表示的X-射线粉末衍射图谱如图8所示。
另一方面，本公开还涉及制备(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型H的方法，包括以下步骤：
(a)将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐加入乙腈/甲醇(1:1)中，搅拌溶解，
(b)挥发析晶；
或者，
(a)将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐晶型A加入四氢呋喃/乙醇(2:1)中，
(b)搅拌打浆。
另一方面，本公开还提供(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型I，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.768、9.525、10.021、12.224、12.982、17.286和21.775处有特征峰。
在可选实施方案中，式I-a化合物的晶型I，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.768、9.525、10.021、12.224、12.982、15.413、15.906、17.286和21.775处有特征峰。
在可选实施方案中，式I-a化合物的晶型I，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.768、9.525、10.021、12.224、12.982、15.413、15.906、17.286、18.849、20.920、21.775和22.318处有特征峰。
在另一可选实施方案中，式I-a化合物的晶型I，以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
另一方面，本公开还涉及制备(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(式I-a化合物)的晶型I的方法，包括以下步骤：
(a)将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐加入10％水/甲醇中，搅拌溶解，
(b)挥发析晶。
本公开中所用溶剂体积(ml)为化合物重量(g)的1～50倍，可以为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50倍。
进一步地，本公开中晶型的制备方法中还包括过滤，洗涤或干燥等步骤。本公开中所述干燥温度一般为25℃～100℃，优选40℃～70℃，可以常压干燥，也可以减压干燥。优选的，干燥在减压下干燥。
本公开还涉及了一种药物组合物，其含有前述可药用盐和任选自药学上可接受的载体、稀释剂或赋形剂中的至少一种的药用辅料，或者由前述可药用盐和任选自药学上可接受的载体、稀释剂或赋形剂中的至少一种的药用辅料制备获得。
本公开还提供了一种药物组合物，其含有式I-a化合物的晶型A至I和任选自药学上可接受的载体、稀释剂或赋形剂中的至少一种的药用辅料，或者由前述式I-a化合物的晶型A至I和任选自药学上可接受的载体、稀释剂或赋形剂中的至少一种的药用辅料制备获得。
本公开还提供了一种药物组合物的制备方法，包括将前述可药用盐或式I-a化合物的晶型A至I和任选自药学上可接受的载体、稀释剂或赋形剂中的至少一种混合得到组合物的步骤。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述可药用盐。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述可药用盐。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述可药用盐。在某些实施方案中，所述的药物组合物含有1％-99％的前述可药用盐。在某些实施方案中，所述的药物组合物含有2％-98％的前述可药用盐。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的载体、稀释剂或赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的载体、稀释剂或赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的载体、稀释剂或赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的载体、稀释剂或赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的载体、稀释剂或赋形剂。
本公开还涉及一种前述可药用盐或前述药物组合物在制备用于调节受试者中白色念珠菌活性的药物中的用途。
本公开还涉及一种前述式I-a化合物的晶型A至I在制备用于调节受试者中白色念珠菌活性的药物中的用途。
另一方面，本公开还涉及前述可药用盐或前述药物组合物在制备用于治疗白 色念珠菌相关病症或疾病的药物中的用途。在一些实施方案中，其中所述疾病或病症是全身性真菌感染或甲癣。
本公开还涉及一种前述式I-a化合物的晶型A至I在制备用于治疗白色念珠菌相关病症或疾病的药物中的用途。在一些实施方案中，其中所述疾病或病症是全身性真菌感染或甲癣。
本公开还涉及前述可药用盐或前述药物组合物在制备用于抑制金属酶活性的药物中的用途。在一些实施方案中，其中所述金属酶是羊毛甾醇脱甲基酶(CYP51)。
本公开还涉及一种前述式I-a化合物的晶型A至I在制备用于抑制金属酶活性的药物中的用途。在一些实施方案中，其中所述金属酶是羊毛甾醇脱甲基酶(CYP51)。
本公开还涉及前述可药用盐或前述药物组合物在制备用于治疗金属酶介导的病症或疾病的药物中的用途，其中所述金属酶介导的病症或疾病由羊毛甾醇脱甲基酶(CYP51)介导。在一些实施方案中，其中所述疾病或病症是传染病。在另一些实施方案中，其中所述疾病或病症是浅表性真菌感染、粘膜真菌感染、全身性真菌感染或甲癣。
本公开还涉及一种前述式I-a化合物的晶型A至I在制备用于治疗金属酶介导的病症或疾病的药物中的用途，其中所述金属酶介导的病症或疾病由羊毛甾醇脱甲基酶(CYP51)介导。在一些实施方案中，其中所述疾病或病症是传染病。在另一些实施方案中，其中所述疾病或病症是浅表性真菌感染、粘膜真菌感染、全身性真菌感染或甲癣。
本公开还涉及前述可药用盐或前述药物组合物，其用于调节受试者中白色念珠菌活性。
本公开还涉及前述式I-a化合物的晶型A至I，其用于调节受试者中白色念珠菌活性。
本公开还涉及前述可药用盐或前述药物组合物，其用于治疗白色念珠菌相关病症或疾病。在一些实施方案中，其中所述疾病或病症是全身性真菌感染或甲癣。
本公开还涉及前述式I-a化合物的晶型A至I，其用于治疗白色念珠菌相关病症或疾病。在一些实施方案中，其中所述疾病或病症是全身性真菌感染或甲癣。
本公开还涉及前述可药用盐或前述药物组合物，其用于抑制金属酶活性。在一些实施方案中，其中所述金属酶是羊毛甾醇脱甲基酶(CYP51)。
本公开还涉及前述式I-a化合物的晶型A至I，其用于抑制金属酶活性。在一些实施方案中，其中所述金属酶是羊毛甾醇脱甲基酶(CYP51)。
本公开还涉及前述可药用盐或前述药物组合物，其用于治疗金属酶介导的病症或疾病，其中所述金属酶介导的病症或疾病由羊毛甾醇脱甲基酶(CYP51)介导。在一些实施方案中，其中所述疾病或病症是传染病。在另一些实施方案中，其中所述疾病或病症是浅表性真菌感染、粘膜真菌感染、全身性真菌感染或甲癣。
本公开还涉及前述式I-a化合物的晶型A至I，其用于治疗金属酶介导的病症或疾病，其中所述金属酶介导的病症或疾病由羊毛甾醇脱甲基酶(CYP51)介导。在一些实施方案中，其中所述疾病或病症是传染病。在另一些实施方案中，其中所述疾病或病症是浅表性真菌感染、粘膜真菌感染、全身性真菌感染或甲癣。
本公开还涉及一种调节受试者中白色念珠菌活性，其包括向所述受试者施用治疗有效量的前述可药用盐或前述药物组合物或前述式I-a化合物的晶型A至I。
本公开还涉及一种治疗白色念珠菌相关病症或疾病的方法，其包括向需要其的受试者施用治疗有效量的前述可药用盐或前述药物组合物或前述药物组合物或前述式I-a化合物的晶型A至I。在一些实施方案中，其中所述疾病或病症是全身性真菌感染或甲癣。
本公开还涉及一种治疗白色念珠菌相关病症或疾病的方法，其包括向需要其的受试者施用治疗有效量的前述可药用盐或前述药物组合物或前述式I-a化合物的晶型A至I。在一些实施方案中，其中所述疾病或病症是全身性真菌感染或甲癣。
本公开还涉及一种抑制金属酶活性的方法，其包括向需要其的受试者施用治疗有效量的前述可药用盐或前述药物组合物或前述式I-a化合物的晶型A至I。在一些实施方案中，其中所述金属酶是羊毛甾醇脱甲基酶(CYP51)。
本公开还涉及一种治疗金属酶介导的病症或疾病，其包括向需要其的受试者施用治疗有效量的前述可药用盐或前述药物组合物或前述式I-a化合物的晶型A至I，其中所述金属酶介导的病症或疾病由羊毛甾醇脱甲基酶(CYP51)介导。在一些实施方案中，其中所述疾病或病症是传染病。在另一些实施方案中，其中所述疾病或病症是浅表性真菌感染、粘膜真菌感染、全身性真菌感染或甲癣。
另一方面，本公开前述可药用盐的官能团中氢被氘代，获得相应氘代化合物，氘代化合物保留了与氢类似物相当的选择性和潜力；氘键更稳定，使得“ADME”即“毒药物动力学”不同，从而提供临床上有益效果。毒药物动力学，指机体对外源化学物的吸收(absorption)、分布(distribution)、代谢(metabolism)及排泄(excretion)过程。本公开氘代化合物示例如下：
Figure PCTCN2021072051-appb-000007
XRPD为X射线粉末衍射检测：测定使用BRUKER D8型X射线衍射仪进行，具体采集信息：Cu阳极(40kV，40mA)，Cu-Kα1射线
Figure PCTCN2021072051-appb-000008
Kα2射线
Figure PCTCN2021072051-appb-000009
Kβ射线
Figure PCTCN2021072051-appb-000010
扫描范围(2θ范围)：3～50、扫描步长0.02、狭缝宽度(准直器)1.0mm。
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.20，可以为-0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20。
本公开中所述的“晶面间距或晶面间距(d值)”是指空间点阵选择3个不相平行的连结相邻两个点阵点的单位矢量a，b，c，它们将点阵划分成并置的平行六面体单位，称为晶面间距。空间点阵按照确定的平行六面体单位连线划分，获得一套直线网格，称为空间格子或晶格。点阵和晶格是分别用几何的点和线反映晶体结构的周期性，不同的晶面，其面间距(即相邻的两个平行晶面之间的距离)各不相同；单位为
Figure PCTCN2021072051-appb-000011
或埃。
本公开中所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本公开“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本公开所述的晶型包括但不限于式I-a化合物的溶剂合物，式I-a化合物与溶剂结合形成的络合物，所述溶剂包括但不限于水。
本公开中数值为仪器测量值，存在一定程度的误差，一般而言，正负10％均属于合理误差范围内。当然需要考虑该数值所用之处的上下文，例如，本公开中化合物与酸或碱分子的化学配比，该数值为测量后误差变化不超过正负10％，可以为正负9％、正负8％、正负7％、正负6％、正负5％、正负4％、正负3％、正负2％或正负1％，优选正负5％。本公开中所述干燥温度一般为25℃～100℃，优选40℃～70℃，可以常压干燥，也可以减压干燥。优选干燥在减压下干燥。
本公开所述化合物的化学结构中，键
Figure PCTCN2021072051-appb-000012
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2021072051-appb-000013
可以为
Figure PCTCN2021072051-appb-000014
或
Figure PCTCN2021072051-appb-000015
或者同时包含
Figure PCTCN2021072051-appb-000016
和
Figure PCTCN2021072051-appb-000017
两种构型。
本公开中所用试剂可通过商业途径获得。
本公开中实验所用仪器的测试条件：
X-射线粉末衍射谱(X-ray Powder Diffraction,XRPD)
(1)仪器型号：Bruker D8 Discover A25 X-射线粉末衍射仪
射线：单色Cu-Kα射线(λ＝1.5418)
扫描方式：θ/2θ，扫描范围：3-50 °
电压：40KV，电流：40mA
化合物的结构可通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo，型号：Finnigan LCQ advantage MAX)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高压液相色谱仪。
附图说明
图1：式I-a化合物的晶型A的XRPD谱图。
图2：式I-a化合物的晶型B的XRPD谱图。
图3：式I-a化合物的晶型C的XRPD谱图。
图4：式I-a化合物的晶型D的XRPD谱图。
图5：式I-a化合物的晶型E的XRPD谱图。
图6：式I-a化合物的晶型F的XRPD谱图。
图7：式I-a化合物的晶型G的XRPD谱图。
图8：式I-a化合物的晶型H的XRPD谱图。
图9：式I-a化合物的晶型I的XRPD谱图。
图10：式I-a化合物的无定型的XRPD谱图。
具体实施方式
以下将结合实施例或实验例更详细地解释本公开，本公开中的实施例或实验例仅用于说明本公开中的技术方案，并非限定本公开中的实质和范围。
实施例1：
(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐(化合物1)
Figure PCTCN2021072051-appb-000018
将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯(化合物1a，按照专利WO2013110002的方法制备获得，0.28g，0.46mmol，1.0eq)和乙醇(5mL)加入到反应瓶中，搅拌均匀。将溶于水(1mL)的NaOH(36.90mg，2.0eq)溶液滴加进上述反应瓶中，继续搅拌2h，浓缩得化合物1，白色固体300mg。
经X-射线粉末衍射检测，其XRPD谱图没有尖锐的衍射峰存在，如图10所示。
Ms:608.10[M-2Na+3H] +。
离子色谱检测，钠离子含量6.23％。
实施例2：(R)-((2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基)氧)甲基磷酸酯二钠盐(化合物2)
Figure PCTCN2021072051-appb-000019
冰浴冷却下，取NaH(58mg，0.87mmol)加入到反应瓶里，加入1.5mL的N,N-二甲基甲酰胺以及0.6mL的四氢呋喃，随后加入碘(38mg，0.15mmol)，再将化合物2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-醇(2b，按照专利WO2013110002的方法制备获得，158mg，0.3mmol)四氢呋喃(1ml)溶液加入反应液中，搅拌反应1-4h，再将化合物2a(519mg，2.01mmol)的四氢呋喃(1ml)溶剂，加入反应中，搅拌至反应完全，10％的氯化铵水溶液淬灭反应，萃取，浓缩抽干，粗品2c直接用于下一步反应，Ms:750.0[M+H] +。
Figure PCTCN2021072051-appb-000020
冰浴冷却下，向粗品2c(300mg)的二氯甲烷(2mL)溶液中加入三氟乙酸 (0.5mL)，搅拌至反应完全，浓缩后，经高效液相分离得目标化合物2d，82mg，Ms:638.0[M+H] +。
Figure PCTCN2021072051-appb-000021
将上步所得化合物2d(0.29g，0.46mmol，1.0eq)和乙醇(5mL)加入到反应瓶中，搅拌，将NaOH(36.90mg，2.0eq)水(1ml)溶液滴加至前述反应液中，搅拌2-5h，浓缩得目标化合物2，313mg。
Ms:638.10[M-2Na+3H] +。
实施例3：
参照实施例1方法，以氢氧化钾为碱制备(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钾盐(化合物3)
Figure PCTCN2021072051-appb-000022
离子色谱检测，钾离子含量9.57％。
经X-射线粉末衍射检测，其特征峰位置见表1
表1
Figure PCTCN2021072051-appb-000023
Figure PCTCN2021072051-appb-000024
实施例4：
参照实施例1方法，以氢氧化钙为碱制备(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯钙盐(化合物4)
Figure PCTCN2021072051-appb-000025
经X-射线粉末衍射检测，其特征峰位置见表2
表2
Figure PCTCN2021072051-appb-000026
实施例5：
参照实施例1方法制备(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1- 基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯镁盐(化合物5)
Figure PCTCN2021072051-appb-000027
实施例6：
参照实施例1方法制备(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯胺盐(化合物6)
Figure PCTCN2021072051-appb-000028
经X-射线粉末衍射检测，其特征峰位置见表3
表3
Figure PCTCN2021072051-appb-000029
测试例1：水溶性及溶液稳定性
1.配制试剂
(1)0.2mol/L的NaH 2PO 4·2H 2O溶液；称取31.2g的NaH 2PO 4·2H 2O(或27.6g的NaH 2PO 4·H 2O)加水至1000ml溶解。
(2)0.2mol/L的Na 2HPO 4溶液：称取71.632g的Na 2HPO 4·12H 2O(或53.6g的Na 2HPO 4·7H 2O或Na 2HPO 4·2H 2O 35.6g)加水至1000ml溶解。
pH＝4.0：用8.5％磷酸溶液调0.2mol/L的NaH 2PO 4的pH为4.0
pH＝7.0：量取39ml 0.2mol/L的NaH 2PO 4与61ml 0.2mol/L的Na 2HPO 4混合后，微调pH即得；
pH＝7.4：量取19ml 0.2mol/L的NaH 2PO 4与81ml 0.2mol/L的Na 2HPO 4混合后，微调pH即得；
pH＝9.0：用1M氢氧化钠溶液调0.2mol/L的Na 2HPO 4的pH为9.0
2.测试方法
精确称取适量待测化合物1和VT-1161少量多次加入溶液搅拌等待化合物溶解，测定溶液中化合物含量，
结论：
1)溶剂度方面：
化合物1在pH＝4条件下，溶解度大于4mg/ml；在pH＝7条件下，溶解度大于5mg/ml；在pH＝9条件下，溶解度大于6mg/ml。
化合物2在pH＝4条件下，溶解度1.0mg/ml；在pH＝7条件下，溶解度0.97mg/ml；在pH＝9条件下，溶解度0.99mg/ml。
化合物3在pH＝4条件下，溶解度大于4mg/ml；在pH＝7.4条件下，溶解度大于5mg/ml；在pH＝9条件下，溶解度大于6mg/ml。
化合物4在pH＝4条件下，溶解度为0.81mg/ml；在pH＝7.4条件下，溶解度为0.87mg/ml；在pH＝9条件下，溶解度为0.95mg/ml。
化合物5在pH＝4条件下，溶解度为1.67mg/ml；在pH＝7.4条件下，溶解度为1.89mg/ml；在pH＝9条件下，溶解度为1.78mg/ml。
化合物6在pH＝4条件下，溶解度为0.89mg/ml；在pH＝7.4条件下，溶解度为0.77mg/ml；在pH＝9条件下，溶解度为3.0mg/ml。
相比于其他盐而言，钾盐或钠盐的溶液溶解度比较优异，同时相比化合物2而言，化合物1溶解度更优异，为制备注射液提供溶解度保证。
2)溶液稳定性方面，分别将化合物1、3、4、5和6溶于不同pH溶液中，检测起始、1h、2h、4h和7h时溶液中有关物质含量，相关数据见表4至8。
表4：化合物1在不同pH溶液中溶液稳定性
Figure PCTCN2021072051-appb-000030
表5：化合物3在不同pH溶液中溶液稳定性
Figure PCTCN2021072051-appb-000031
表6：化合物4在不同pH溶液中溶液稳定性
Figure PCTCN2021072051-appb-000032
表7：化合物5在不同pH溶液中溶液稳定性
Figure PCTCN2021072051-appb-000033
表8：化合物6在不同pH溶液中溶液稳定性
Figure PCTCN2021072051-appb-000034
注：N.A未检测；N.D未检测到。
测试例2：固体稳定性
称取约1mg样品至小瓶中，放置真空袋中抽真空，再放入装有变色硅胶的容器内，密封，平行配制两份。按取样时间点配制足够的份数，分别放置在2-8℃度和室温下。化合物1和化合物3固体稳定数据分别见表9和10。从中不难看出，二钠盐(化合物1)不论在室温条件下还是2-8℃条件下，样品均表现出优异，其主要降解杂质的增幅较小，预期在后期成药过程中能保证药品无需苛刻储存条件下长期保质。
表9：化合物1固体稳定性数据
Figure PCTCN2021072051-appb-000035
表10：化合物3固体稳定性数据
Figure PCTCN2021072051-appb-000036
测试例3：犬体内药代动力学实验
给药制剂配制：化合物1，准确称取适宜量的受试物，加入适宜体积生理盐水，搅拌或超声均匀，得到浓度为0.3mg/mL澄清给药溶液，用于静脉注射给药。
实验设计：
Figure PCTCN2021072051-appb-000037
采血时间点：
给药前及给药后0.083h、0.25h、0.5h、1h、2h、4h、8h、24h、48h，共10个采血点。
样品采集和处置：
经颈静脉或其他合适方式采血，每个样品采集约1mL，K 2EDTA抗凝，采集后放置冰上，1小时内离心分离血浆(离心力2200g，离心10min，2-8℃)。采集的血浆样本在分析前存放于-80℃冰箱内。
生物分析和数据处理：
检测血浆样本中化合物1及VT-1161的浓度，分析样品的同时进行质控样品准确度评价，并要求超过66％的质控样品的准确度在80-120％之间。
通过不同时间点的血药浓度数据，运用WinNonlin计算药代动力学参数，如AUC(0-t)、T 1/2、Cmax、Tmax和MRT等。
表11
Figure PCTCN2021072051-appb-000038
结论：式I-a化合物在犬体内可有效转化成母药活性成份。
实施例7：
取参照实施例1方法制备获得式I-a化合物15mg加入0.15ml 10％水/丙酮溶液，搅拌溶解，加入0.75ml异丙醚，搅拌析晶，过滤，干燥得固体。经X-射线粉末衍射检测为无定型。
实施例8：
取参照实施例1方法制备获得式I-a化合物15mg加入0.15ml甲醇溶液，搅拌溶解，加入0.75ml甲基叔丁醚，搅拌析晶，过滤，干燥得固体。经X-射线粉末衍射检测为无定型。
实施例9：
取参照实施例1方法制备获得式I-a化合物15mg加入0.15ml 10％乙酸乙酯溶 液，搅拌溶解，加入0.75ml正庚烷，搅拌析晶，过滤，干燥得固体。经X-射线粉末衍射检测为无定型。
实施例10：
取参照实施例1方法制备获得式I-a化合物5mg加入0.02ml甲醇，搅拌溶解，于室温下缓慢挥发，得固体。经X-射线粉末衍射检测，XRPD谱图如图1所示，其特征峰位置见表12，将其定义为晶型A。
表12
Figure PCTCN2021072051-appb-000039
实施例11：
取参照实施例1方法制备获得式I-a化合物15mg加入0.15ml甲醇，搅拌溶解，加入0.75ml四氢呋喃，于室温下缓慢挥发，得固体。经X-射线粉末衍射检测，XRPD谱图如图2所示，其特征峰位置见表13，将其定义为晶型B。
表13
Figure PCTCN2021072051-appb-000040
Figure PCTCN2021072051-appb-000041
实施例12：
将化合物1a(按照专利WO2013110002的方法制备获得)15mg加入0.44ml乙醇中，搅拌溶解，加入56ul的1N氢氧化钠溶液，搅拌后析出固体，过滤，干燥得固体。经X-射线粉末衍射检测为晶型B。
实施例13：
取参照实施例10方法制备获得晶型A 5mg加入0.5ml 10％水/异丙醇溶液，室温打浆3天，过滤，干燥得固体。经X-射线粉末衍射检测，XRPD谱图如图3所示，其特征峰位置见表14，将其定义为晶型C。
表14
Figure PCTCN2021072051-appb-000042
Figure PCTCN2021072051-appb-000043
实施例14：
取参照实施例1方法制备获得式I-a化合物5mg加入0.02ml 10％水/丙酮，搅拌溶解，于室温下缓慢挥发，得固体。经X-射线粉末衍射检测为晶型C。
实施例15：
取参照实施例1方法制备获得式I-a化合物5mg加入0.24ml甲醇/水(1:1)，搅拌溶解，于室温下缓慢挥发，得固体。经X-射线粉末衍射检测为晶型C。
实施例16：
取参照实施例1方法制备获得式I-a化合物15mg加入0.15ml水，搅拌溶解，加入0.75ml异丙醇，于室温下缓慢挥发，得固体。经X-射线粉末衍射检测为晶型C。
实施例17：
取参照实施例1方法制备获得式I-a化合物15mg加入0.15ml 10％水/丙酮，搅拌溶解，加入0.75ml四氢呋喃，于室温下缓慢挥发，得固体。经X-射线粉末衍射检测为晶型C。
实施例18：
取参照实施例1方法制备获得式I-a化合物15mg加入0.15ml的10％水/丙酮中，搅拌溶解，加入0.75ml异丙醇，搅拌析晶，过滤，干燥得固体。经X-射线粉末衍射检测为晶型C。
实施例19：
取参照实施例1方法制备获得式I-a化合物15mg加入0.15ml的10％水/丙酮中，搅拌溶解，加入0.75ml乙腈，搅拌析晶，过滤，干燥得固体。经X-射线粉末衍射检测为晶型C。
实施例20：
取参照实施例1方法制备获得式I-a化合物15mg加入0.15ml的10％水/丙酮中，搅拌溶解，加入0.75ml甲基叔丁醚，搅拌析晶，过滤，干燥得固体。经X-射线粉末衍射检测为晶型C。
实施例21：
取参照实施例1方法制备获得式I-a化合物15mg加入0.15ml的10％水/丙酮中，搅拌溶解，加入0.75ml正庚烷，搅拌析晶，过滤，干燥得固体。经X-射线粉末衍射检测为晶型C。
实施例22：
取参照实施例1方法制备获得式I-a化合物5mg加入0.34ml乙醇，搅拌溶解，于室温下缓慢挥发，得固体。经X-射线粉末衍射检测，XRPD谱图如图4所示，其特征峰位置见表15，将其定义为晶型D。
表15
Figure PCTCN2021072051-appb-000044
Figure PCTCN2021072051-appb-000045
实施例23：
取参照实施例1方法制备获得式I-a化合物5mg加入0.26ml乙酸乙酯/乙醇(1:1)，搅拌溶解，于室温下缓慢挥发，得固体。经X-射线粉末衍射检测为晶型D。
实施例24：
取参照实施例10方法制备获得晶型A 5mg加入0.5ml的7％水/乙醇中，室温搅拌不溶，于45-5℃升降温，并于5℃搅拌析晶，过滤，干燥得固体。经X-射线粉末衍射检测为晶型D。
实施例25：
取参照实施例10方法制备获得晶型A 5mg加入0.5ml邻二甲苯中，室温打浆，过滤，干燥得固体。经X-射线粉末衍射检测，XRPD谱图如图5所示，其特征峰位置见表16，将其定义为晶型E。
表16
Figure PCTCN2021072051-appb-000046
实施例26：
取参照实施例10方法制备获得晶型A 5mg加入0.5ml乙腈中，搅拌过滤不溶物，滤液于室温下缓慢挥发，得固体。经X-射线粉末衍射检测，XRPD谱图如图6所示，其特征峰位置见表17，将其定义为晶型F。
表17
Figure PCTCN2021072051-appb-000047
实施例27：
取参照实施例1方法制备获得式I-a化合物5mg加入0.02ml的丙二醇甲醚中，搅拌溶解，于室温下缓慢挥发，得固体。经X-射线粉末衍射检测，XRPD谱图如图7所示，其特征峰位置见表18，将其定义为晶型G。
表18
Figure PCTCN2021072051-appb-000048
Figure PCTCN2021072051-appb-000049
实施例28：
取参照实施例1方法制备获得式I-a化合物15mg加入0.15ml丙二醇甲醚中，搅拌溶解，加入0.75ml四氢呋喃，于室温下缓慢挥发，得固体。经X-射线粉末衍射检测为晶型G。
实施例29：
取参照实施例1方法制备获得式I-a化合物15mg加入0.15ml丙二醇甲醚中，搅拌溶解，加入0.75ml甲基叔丁醚，搅拌析晶，过滤，干燥得固体。经X-射线粉末衍射检测为晶型G。
实施例30：
取参照实施例1方法制备获得式I-a化合物15mg加入0.15ml丙二醇甲醚中，搅拌溶解，加入0.75ml异丙醚，搅拌析晶，过滤，干燥得固体。经X-射线粉末衍射检测为晶型G。
实施例31：
取参照实施例1方法制备获得式I-a化合物15mg加入0.02ml的乙腈/甲醇(1:1)中，搅拌溶解，于室温下缓慢挥发，得固体。经X-射线粉末衍射检测，XRPD谱图如图8所示，其特征峰位置见表19，将其定义为晶型H。
表19
Figure PCTCN2021072051-appb-000050
Figure PCTCN2021072051-appb-000051
实施例32：
取参照实施例10方法制备获得晶型A 5mg加入0.5ml的四氢呋喃/乙醇(2:1)中，室温搅拌打浆，过滤，干燥得固体。经X-射线粉末衍射检测为晶型H。
实施例33：
取参照实施例1方法制备获得式I-a化合物5mg加入0.08ml的10％水/甲醇中，搅拌溶解，于室温下缓慢挥发，得固体。经X-射线粉末衍射检测，XRPD谱图如图9所示，其特征峰位置见表20，将其定义为晶型I。
表20
Figure PCTCN2021072051-appb-000052
Figure PCTCN2021072051-appb-000053
测试例4：引湿性研究
采用Surface Measurement Systems advantage 2，在25℃，湿度从50％起，考察湿度范围为0％-95％，步进为10％，判断标准为每个梯度质量变化dM/dT小于0.002％，每个湿度梯度运行时间TMAX为360min，循环两圈。
表21
Figure PCTCN2021072051-appb-000054
测试例5：晶型稳定性研究
1)将钠盐的晶型敞口平摊放置，分别考察在光照(4500Lux)、高温(40℃、60℃)、高湿(RH 75％、RH 92.5％)条件下样品的稳定性，取样考察期为30天。
表22
Figure PCTCN2021072051-appb-000055
Figure PCTCN2021072051-appb-000056
结论：影响因素实验表明：在光照、高温40℃和60℃、高湿75％和92.5％条件下30天，式I-a化合物晶型C具有较好的物理稳定性；在高湿和光照条件下，化学稳定性良好。
2)长期/加速稳定性：将式I-a化合物晶型A和晶型C分别放置-20℃、4℃、25℃/60％RH和40℃/75％RH条件考察稳定性。
表23
Figure PCTCN2021072051-appb-000057
结论：长期加速实验表明：在-20℃、4℃、25℃/60RH和40℃/75RH条件下3个月，式I-a化合物晶型C具有较好的物理稳定性，式I-a化合物晶型A物理稳定性差。长期加速实验3个月结果显示：式I-a化合物晶型A和C在-20℃和4℃条件下，化学稳定性良好。
测试例6：取式I-a化合物晶型C和化合物3(参照实施例2方法制备)分别置于在光照、高温40℃和60℃、高湿75％和92.5％条件下考察稳定性。
表24
Figure PCTCN2021072051-appb-000058
结论：影响因素实验表明，在光照、高温40℃和60℃、高湿75％和92.5％条件下30天，钠盐物理稳定性和化学稳定性良好，钾盐物理稳定性和化学稳定性稍差。

Claims (15)

  1. 化合物2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯的可药用盐，其特征在于，所述可药用盐为钠盐。
  2. 根据权利要求1所述的可药用盐，其特征在于，所述2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯与阳离子的化学配比为1:1或1:2，优选1:2。
  3. 根据权利要求1或2所述的可药用盐，其特征在于，其为(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐
    Figure PCTCN2021072051-appb-100001
  4. 一种制备权利要求1-3中任一项所述可药用盐的方法，包括化合物2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基二氢磷酸酯与碱反应的步骤，所述碱选自氢氧化钠、碳酸氢钠、碳酸钠和乙醇钠。
  5. 根据权利要求4所述的方法，其特征在于，所述反应在溶剂中进行，所述溶剂选自乙醇、甲醇、叔丁醇、异丙醇、四氢呋喃和丙酮中的至少一种。
  6. 一种药物组合物，含有权利要求1-3中任一项所述可药用盐和任选自药学上可接受的载体、稀释剂或赋形剂中的至少一种的药用辅料，或者由权利要求1-3中任一项所述可药用盐和任选自药学上可接受的载体、稀释剂或赋形剂中的至少一种的药用辅料制备获得。
  7. 根据权利要求1-3中任一项所述可药用盐或权利要求6所述药物组合物在制备用于调节受试者中白色念珠菌活性的药物中的用途。
  8. 根据权利要求1-3中任一项所述的可药用盐或权利要求6所述的药物组合物在制备用于治疗白色念珠菌相关病症或疾病的药物中的用途，所述疾病或病症优选为全身性真菌感染或甲癣。
  9. 根据权利要求3所述的可药用盐的晶型A，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.354、9.280、9.800、18.398和19.628处有特征峰，优选在7.354、9.280、9.800、11.075、12.942、18.398和19.628处有特征峰，更优选在7.354、9.280、9.800、11.075、12.942、14.701、18.398、19.628、21.461和22.327处有特征峰，最优以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示，其中，每个特征峰2θ的误差范围为±0.2。
  10. 根据权利要求3所述的可药用盐的晶型C，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.547、9.008、16.043、22.966、24.065和24.634处有特征峰，优选在7.997、8.547、9.008、16.043、22.465、22.966、24.065、24.634和25.944处有特征峰，更优选在7.997、8.547、9.008、16.043、22.465、22.966、24.065、24.634、25.944、29.826、30.761和34.937处有特征峰，最优以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示，其中，每个特征峰2θ的误差范围为±0.2。
  11. 一种制备根据权利要求10所述的晶型C的方法，选自：
    方法一：
    a)将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐加入溶剂(IV)中，搅拌溶解或加热溶解，所述溶剂(IV)选自正庚烷、甲基叔丁醚、乙腈和异丙醇中的至少一种与水/丙酮混合溶液，
    b)静止析晶或搅拌析晶；
    或，方法二：
    a)将(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐加入溶剂(V)中，所述溶剂(V)选自四氢呋喃、丙酮、甲醇、异丙醇和水中的至少一种，
    b)挥发析晶；
    或，方法三：
    a)将根据权利要求9所述的(R)-2-(2,4-二氟苯基)-1,1-二氟-3-(1H-四唑-1-基)-1-(5-(4-(2,2,2-三氟乙氧基)苯基)吡啶-2-基)丙-2-基磷酸酯二钠盐晶型A加入水/异丙醇中，
    b)搅拌打浆。
  12. 一种药物组合物，含有根据权利要求9所述的晶型A或根据权利要求10所述的晶型C和任选自药学上可接受的载体、稀释剂或赋形剂中的至少一种的药用辅料，或者由根据权利要求9所述的晶型A或根据权利要求10所述的晶型C和任选自药学上可接受的载体、稀释剂或赋形剂中的至少一种的药用辅料制备获得。
  13. 一种药物组合物的制备方法，包括权利要求9所述的晶型A或权利要求10所述的晶型C和任选自药学上可接受的载体、稀释剂或赋形剂中的至少一种混合得到组合物的步骤。
  14. 根据权利要求9所述的晶型A或根据权利要求10所述的晶型C或根据权利要求12所述药物组合物在制备用于调节受试者中白色念珠菌活性的药物中的用途。
  15. 根据权利要求9所述的晶型A或根据权利要求10所述的晶型C或根据权利要求12所述药物组合物在制备用于治疗白色念珠菌相关病症或疾病的药物中的用途，所述疾病或病症优选全身性真菌感染或甲癣。
PCT/CN2021/072051 2020-01-17 2021-01-15 四氮唑类化合物的可药用盐及其结晶形式、制备方法和用途 WO2021143811A1 (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202010054894 2020-01-17
CN202010054894.8 2020-01-17
CN202010065172 2020-01-20
CN202010065172.2 2020-01-20

Publications (1)

Publication Number Publication Date
WO2021143811A1 true WO2021143811A1 (zh) 2021-07-22

Family

ID=76863599

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/072051 WO2021143811A1 (zh) 2020-01-17 2021-01-15 四氮唑类化合物的可药用盐及其结晶形式、制备方法和用途

Country Status (2)

Country Link
TW (1) TW202140445A (zh)
WO (1) WO2021143811A1 (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103097374A (zh) * 2010-04-24 2013-05-08 威尔金制药有限公司 金属酶抑制剂化合物
CN104136427A (zh) * 2012-01-20 2014-11-05 威尔金制药有限公司 金属酶抑制剂化合物
CN104135861A (zh) * 2012-01-20 2014-11-05 威尔金制药有限公司 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
CN103097374A (zh) * 2010-04-24 2013-05-08 威尔金制药有限公司 金属酶抑制剂化合物
CN104136427A (zh) * 2012-01-20 2014-11-05 威尔金制药有限公司 金属酶抑制剂化合物
CN104135861A (zh) * 2012-01-20 2014-11-05 威尔金制药有限公司 金属酶抑制剂化合物

Also Published As

Publication number Publication date
TW202140445A (zh) 2021-11-01

Similar Documents

Publication Publication Date Title
EP2291345B1 (en) Co-crystals of duloxetine and naproxen
RU2663663C2 (ru) Соль омекамтива мекарбила и способ ее получения
US20060189682A1 (en) Water soluble prodrugs of COX-2 inhibitors
EP2603503B1 (en) Dabigatran etexilate bismesylate salt, solid state forms and process for preparation thereof
US10703724B2 (en) Crystalline forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino} acetic acid and processes for preparation thereof
KR20100003306A (ko) 미토콘드리아 표적화 산화방지제로서 사용되는 미토퀴논 유도체를 포함하는 약제학적 조성물
WO2022037647A1 (zh) 一种选择性Nav抑制剂的结晶形式及其制备方法
BR112019021447A2 (pt) sal fumarato, forma cristalina i do referido sal, métodos para preparação dos mesmos, composição farmacêutica compreendendo o sal e a forma cristalina i e uso do sal fumarato, da forma cristalina i e da composição farmacêutica
JP2018531280A (ja) 改善された特性を有するβ−グアニジノプロピオン酸の薬学的に許容される塩及びその使用
JP2018531280A6 (ja) 改善された特性を有するβ−グアニジノプロピオン酸の薬学的に許容される塩及びその使用
KR20110106355A (ko) 제니스테인의 결정성 형태
JP2015522037A (ja) ベムラフェニブコリン塩の固体形態
WO2015007073A1 (zh) 奎宁类化合物、其光学异构体及其制备方法和医药用途
KR20220107020A (ko) Erk 억제제로서 작용하는 스피로 화합물 및 이의 응용
TW201609717A (zh) Ｐｌｋ－４抑制劑之鹽和結晶形式
TWI540131B (zh) 阿瑞吡坦（ａｐｒｅｐｉｔａｎｔ）ｌ－脯胺酸組成物及共晶體
WO2017162157A1 (zh) 内磺酰胺化合物及其使用方法
WO2022109598A1 (en) Integrin inhibitor and uses thereof
EP4438613A1 (en) Mono-p-toluenesulfonate of axl kinase inhibitor and crystal form thereof
WO2021143811A1 (zh) 四氮唑类化合物的可药用盐及其结晶形式、制备方法和用途
JP2024517608A (ja) 結晶性カルバゾール誘導体
JP7252417B2 (ja) Ｒｈｏキナーゼ阻害剤としてのベンゾピラゾール化合物の塩形、結晶形及びその製造方法
CA3198831A1 (en) Polymorphs of an fxr agonist
EP3572399A1 (en) Crystal form of gft-505 and preparation method and use thereof
EP2551257A1 (en) Co-crystals of agomelatine with co-crystal-formers

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21741159

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21741159

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC, EPO FORM 1205A DATED 05.07.2023

122 Ep: pct application non-entry in european phase

Ref document number: 21741159

Country of ref document: EP

Kind code of ref document: A1