WO2024174931A1 - 化合物的新晶型及其制备方法与用途 - Google Patents

化合物的新晶型及其制备方法与用途 Download PDF

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WO2024174931A1
WO2024174931A1 PCT/CN2024/077350 CN2024077350W WO2024174931A1 WO 2024174931 A1 WO2024174931 A1 WO 2024174931A1 CN 2024077350 W CN2024077350 W CN 2024077350W WO 2024174931 A1 WO2024174931 A1 WO 2024174931A1
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crystalline form
disease
ray powder
compound
diffraction pattern
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PCT/CN2024/077350
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English (en)
French (fr)
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刘鹏飞
沈旺
高红军
丁师哲
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启元生物(杭州)有限公司
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Publication of WO2024174931A1 publication Critical patent/WO2024174931A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of chemical medicine technology, and in particular to a new crystal form of a compound, a method for preparing the crystal form, a pharmaceutical composition containing the crystal form, and uses of the crystal form and the pharmaceutical composition.
  • Organic compounds with pharmaceutical activity can crystallize in more than one three-dimensional crystal structure.
  • Polymorphs of a particular organic drug compound have different physical properties, such as solubility, hygroscopicity, and stability, due to their unique three-dimensional structures.
  • solubility solubility
  • hygroscopicity hygroscopicity
  • stability due to their unique three-dimensional structures.
  • New crystalline forms of certain pharmaceutically useful compounds can help improve the performance of the drug, such as improving stability, solubility, and hygroscopicity, and improving drugability.
  • the object of the present invention is to provide a new crystalline form of the compound of formula (I): (R, E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxyphenyl)-2,6-dimethylpyridin-4(1H)-one.
  • the present invention provides a crystalline form A of a compound of formula (I),
  • the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2 ⁇ angles of 8.3 ⁇ 0.2°, 13.1 ⁇ 0.2°, 15.8 ⁇ 0.2°, 19.7 ⁇ 0.2°, 20.5 ⁇ 0.2°, 23.5 ⁇ 0.2°, 25.0 ⁇ 0.2°, and 27.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2 ⁇ angles of 8.3 ⁇ 0.2°, 13.1 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.6 ⁇ 0.2°, 19.7 ⁇ 0.2°, 20.5 ⁇ 0.2°, 23.5 ⁇ 0.2°, 24.6 ⁇ 0.2°, 25.0 ⁇ 0.2°, 26.4 ⁇ 0.2°, 27.7 ⁇ 0.2°, and 33.8 ⁇ 0.2°.
  • the main data of the X-ray powder diffraction pattern of the crystalline form A are shown in Table 1.
  • the crystalline Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the crystalline Form A has a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 2 .
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the three-dimensional structure diagram of the crystal form A is shown in Figure 3.
  • the crystalline Form A has a dynamic gas phase adsorption spectrum substantially as shown in FIG. 4 .
  • the crystalline form A is an anhydrous crystalline form of the compound of formula (I).
  • the present invention further provides a crystalline form B of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form B is There are characteristic peaks at angles of 8.6 ⁇ 0.2°, 13.1 ⁇ 0.2°, 16.6 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.8 ⁇ 0.2°, 22.5 ⁇ 0.2°, 24.6 ⁇ 0.2°, and 28.2 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at 2 ⁇ angles of 8.6 ⁇ 0.2°, 13.1 ⁇ 0.2°, 14.0 ⁇ 0.2°, 15.3 ⁇ 0.2°, 16.6 ⁇ 0.2°, 19.0 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.8 ⁇ 0.2°, 22.5 ⁇ 0.2°, 24.6 ⁇ 0.2°, 25.8 ⁇ 0.2°, and 28.2 ⁇ 0.2°.
  • the main data of the X-ray powder diffraction pattern of the crystalline form B is shown in Table 2.
  • the Form B has an X-ray powder diffraction pattern substantially as shown in FIG. 5 .
  • the Form B has a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 6 .
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the crystalline form B is an anhydrous crystalline form of the compound of formula (I).
  • the present invention further provides a crystalline form C of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 2 ⁇ angles of 15.2 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.2 ⁇ 0.2°, 19.8 ⁇ 0.2°, 21.7 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.7 ⁇ 0.2°, and 24.9 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 2 ⁇ angles of 14.2 ⁇ 0.2°, 15.2 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.2 ⁇ 0.2°, 19.8 ⁇ 0.2°, 20.6 ⁇ 0.2°, 21.2 ⁇ 0.2°, 21.7 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.7 ⁇ 0.2°, 24.9 ⁇ 0.2°, and 29.0 ⁇ 0.2°.
  • the main data of the X-ray powder diffraction pattern of the crystalline form C are shown in Table 3.
  • the Form C has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .
  • the crystalline Form C has a polarizing microscope photograph substantially as shown in FIG. 8 .
  • the Form C has a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 9 .
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the Form C has a dynamic gas adsorption spectrum substantially as shown in FIG. 10 .
  • the crystalline form C is a hydrate crystalline form of the compound of formula (I).
  • the present invention further provides a crystalline form E of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at 2 ⁇ angles of 13.1 ⁇ 0.2°, 16.7 ⁇ 0.2°, 21.9 ⁇ 0.2°, 22.5 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.3 ⁇ 0.2°, 27.5 ⁇ 0.2°, and 28.4 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at 2 ⁇ angles of 11.7 ⁇ 0.2°, 13.1 ⁇ 0.2°, 13.8 ⁇ 0.2°, 16.7 ⁇ 0.2°, 19.7 ⁇ 0.2°, 20.2 ⁇ 0.2°, 21.9 ⁇ 0.2°, 22.5 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.3 ⁇ 0.2°, 27.5 ⁇ 0.2°, and 28.4 ⁇ 0.2°.
  • the main data of the X-ray powder diffraction pattern of the crystalline form E are shown in Table 4.
  • the Form E has an X-ray powder diffraction pattern substantially as shown in FIG. 11 .
  • the Form E has a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 12 .
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the crystalline Form E has a hydrogen nuclear magnetic resonance spectrum ( 1 H-NMR spectrum) substantially as shown in FIG. 13 .
  • the present invention further provides a crystalline form F of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form F has characteristic peaks at 2 ⁇ angles of 11.0 ⁇ 0.2°, 11.8 ⁇ 0.2°, 15.4 ⁇ 0.2°, 20.0 ⁇ 0.2°, 21.9 ⁇ 0.2°, 23.9 ⁇ 0.2°, 24.7 ⁇ 0.2°, and 27.1 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form F has characteristic peaks at 2 ⁇ angles of 11.0 ⁇ 0.2°, 11.8 ⁇ 0.2°, 15.4 ⁇ 0.2°, 16.7 ⁇ 0.2°, 20.0 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.9 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.5 ⁇ 0.2°, 23.9 ⁇ 0.2°, 24.7 ⁇ 0.2°, and 27.1 ⁇ 0.2°.
  • the main data of the X-ray powder diffraction pattern of the crystalline form F are shown in Table 5.
  • the Form F has an X-ray powder diffraction pattern substantially as shown in FIG. 14 .
  • the Form F has a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 15 .
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the crystalline Form F has a hydrogen nuclear magnetic resonance spectrum ( 1 H-NMR spectrum) substantially as shown in FIG. 16 .
  • the present invention further provides a crystalline form G of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form G has characteristic peaks at 2 ⁇ angles of 12.8 ⁇ 0.2°, 14.4 ⁇ 0.2°, 17.6 ⁇ 0.2°, 20.1 ⁇ 0.2°, 21.0 ⁇ 0.2°, 21.5 ⁇ 0.2°, 23.2 ⁇ 0.2°, and 25.9 ⁇ 0.2°.
  • the main data of the X-ray powder diffraction pattern of the crystalline form G are shown in Table 6.
  • the Form G has an X-ray powder diffraction pattern substantially as shown in FIG. 17 .
  • the present invention further provides a crystalline form H of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form H at a 2 ⁇ angle of 11.0 ⁇ 0.2°, 11.8 ⁇ 0.2°, 13.0 ⁇ 0.2°, 16.7 ⁇ 0.2°, 19.6 ⁇ 0.2°, 19.9 ⁇ 0.2°, 21.9 ⁇ 0.2°, 22.7 ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form H has characteristic peaks at 2 ⁇ angles of 11.0 ⁇ 0.2°, 11.8 ⁇ 0.2°, 13.0 ⁇ 0.2°, 13.7 ⁇ 0.2°, 16.7 ⁇ 0.2°, 19.0 ⁇ 0.2°, 19.6 ⁇ 0.2°, 19.9 ⁇ 0.2°, 21.9 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.8 ⁇ 0.2°, and 28.3 ⁇ 0.2°.
  • the main data of the X-ray powder diffraction pattern of the crystalline form H are shown in Table 7.
  • the Form H has an X-ray powder diffraction pattern substantially as shown in FIG. 18 .
  • the crystalline form H has a nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR atlas).
  • the present invention further provides a method for preparing the crystalline form A of the compound of the aforementioned formula (I), the method comprising the following steps:
  • the preparation method of the crystalline form A of the compound of formula (I) comprises the following steps:
  • the concentration temperature is 10-20°C.
  • the concentration is concentration under reduced pressure.
  • the raw material compound of formula (I) used in the present invention is a free base, and its form is not limited and can be selected from any crystalline form or amorphous form, all of which can be prepared into crystalline form A according to the method provided by the present invention.
  • the present invention does not limit the method for dissolving the compound of formula (I) in acetone, as long as the purpose of the present invention can be achieved.
  • the compound of formula (I) and acetone are mixed, heated, and stirred to dissolve; wherein the temperature after heating can be 50-55°C.
  • the present invention does not impose any limitation on the amount of acetone used, as long as the purpose of the present invention can be achieved.
  • the present invention does not limit the amount of the crystal form A seed crystals used and the temperature at which the crystal form A seed crystals are added, as long as the purpose of the present invention can be achieved.
  • the present invention does not limit the stirring time after adding the crystal form A seed crystals, as long as the purpose of the present invention can be achieved.
  • the stirring time can be 2-4 hours.
  • the present invention does not limit the temperature and method of adding methyl tert-butyl ether to the concentrated solution, as long as the purpose of the present invention can be achieved.
  • the temperature of the concentrated solution is adjusted to 15-25° C., and then methyl tert-butyl ether is added; the method of adding methyl tert-butyl ether can be slow addition.
  • the present invention does not impose any limitation on the amount of methyl tert-butyl ether used, as long as the purpose of the present invention can be achieved.
  • the amount of methyl tert-butyl ether used can be 2-5 times the volume of acetone in the concentrated solution.
  • the present invention does not limit the stirring time and method after adding methyl tert-butyl ether, as long as the purpose of the present invention can be achieved. For example, after adding methyl tert-butyl ether, stirring can be performed for 6-10 hours, and then the temperature is adjusted to -5°C to 5°C, and stirring is continued for 6-10 hours.
  • the present invention does not limit the drying time and temperature, as long as the purpose of the present invention can be achieved.
  • the present invention further provides a method for preparing the crystal form C of the compound of the formula (I), the method comprising the following steps: dissolving the crystal form A of the compound of the formula (I) in ethanol until it is clear; adding water and stirring; centrifuging and drying to obtain the crystal form C;
  • the crystalline form A of the compound of formula (I) is dissolved in ethanol until it is clear; water and crystalline form C seed crystals of the compound of formula (I) are added in sequence and stirred; centrifuged and dried to obtain the crystalline form C.
  • the volume ratio of ethanol to water is 1:(2-3).
  • the present invention does not limit the amount of ethanol used, as long as the purpose of the present invention can be achieved.
  • the amount ratio between the crystalline form A of the compound of formula (I) and ethanol can be 0.1-0.5 g/mL.
  • the present invention does not limit the amount of water used and the method of adding water, as long as the purpose of the present invention can be achieved.
  • the volume ratio of ethanol to water can be 1: (2-3).
  • the present invention does not limit the amount of the crystal form C seed crystals used, as long as the purpose of the present invention can be achieved.
  • the present invention does not limit the stirring time and stirring method after adding the crystal form C seed crystals, as long as the purpose of the present invention can be achieved.
  • the stirring time can be 3-23h
  • the stirring method can be magnetic stirring.
  • the present invention does not limit the drying time and temperature, as long as the purpose of the present invention can be achieved.
  • the drying may be carried out at a temperature range of 10-30° C. for 12-24 hours.
  • the present invention further provides a method for preparing the crystalline form C of the compound of the aforementioned formula (I), which comprises the following steps: magnetically stirring the crystalline form A of the compound of the aforementioned formula (I) in an acetonitrile/water solvent system at room temperature for 3-5 days, and separating the solid to obtain the crystalline form C.
  • the volume ratio of acetonitrile to water is 1:(2-3).
  • the present invention further provides a crystalline composition of the crystalline form of the present invention.
  • the crystal form A described in the present invention accounts for more than 50% by weight of the crystal composition, preferably more than 80%, more preferably more than 90%, and most preferably more than 95%.
  • the crystal form C of the present invention accounts for more than 50% by weight of the crystal composition, preferably more than 80%, more preferably more than 90%, and most preferably more than 95%.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective therapeutic amount of the crystal form A, crystal form C or a mixture thereof described in the present invention and a pharmaceutically acceptable carrier, diluent or excipient.
  • the crystalline form A, crystalline form C or a mixture thereof and the carrier, diluent or excipient The weight ratio range is 0.0001 ⁇ 10.
  • the pharmaceutical composition is for external administration.
  • the pharmaceutical composition is used for the preparation of an ointment.
  • the pharmaceutical composition contains 0.01 wt%-99 wt% of the crystalline form A, crystalline form C or a mixture thereof described in the present invention.
  • the pharmaceutical composition contains 0.05 wt%-50 wt% of the crystalline form A, crystalline form C or a mixture thereof according to the present invention.
  • the pharmaceutical composition contains 0.1 wt%-30 wt% of the crystalline form A, crystalline form C or a mixture thereof according to the present invention.
  • the present invention further provides the use of the crystalline form A, crystalline form C or a mixture thereof of the compound of formula (I) of the present invention in the preparation of medicines.
  • the use is to treat, prevent, delay or stop the occurrence or development of inflammation.
  • the application is for preparing a drug for treating or preventing a disease mediated by PDE4.
  • the disease is inflammation.
  • the inflammation is selected from inflammatory allergic diseases such as bronchial asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis or nephritis; autoimmune diseases such as atopic dermatitis, psoriasis, alopecia areata, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, vitiligo, lupus, systemic lupus erythematosus or discoid lupus erythematosus, ankylosing spondylitis; acute or chronic skin wound diseases; central nervous system diseases such as depression, amnesia or dementia; organ diseases associated with ischemic reflux caused by heart failure, shock or cerebrovascular disease, etc.; insulin-resistant diabetes; wounds.
  • inflammatory allergic diseases such as bronchial asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis or nephritis
  • the use is as a PDE4 inhibitor.
  • the present invention also provides a method for treating and/or preventing diseases mediated by PDE4 by administering a therapeutically effective amount of at least one crystalline form A, crystalline form C or a mixture thereof of the compound of formula (I) to a subject.
  • the disease mediated by PDE4 is inflammation.
  • the inflammation is selected from inflammatory allergic diseases such as bronchial asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis or nephritis; autoimmune diseases such as atopic dermatitis, psoriasis, alopecia areata, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, vitiligo, lupus, systemic lupus erythematosus or discoid lupus erythematosus, ankylosing spondylitis; acute or chronic skin wound diseases; central nervous system diseases such as depression, amnesia or dementia; organ diseases associated with ischemic reflux caused by heart failure, shock or cerebrovascular disease, etc.; insulin-resistant diabetes; wounds.
  • inflammatory allergic diseases such as bronchial asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis or nephritis
  • the present invention also provides a method for treating inflammation, comprising administering a therapeutically effective amount of at least one crystalline form A, crystalline form C or a mixture thereof of the compound of formula (I) described in the present invention to a treatment subject, wherein the inflammation is selected from inflammatory allergic diseases such as bronchial asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis or nephritis; autoimmune diseases such as atopic dermatitis, psoriasis, alopecia areata, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, vitiligo, lupus, systemic lupus erythematosus or discoid lupus erythematosus, ankylosing spondylitis; acute or chronic skin wound diseases; central nervous system diseases such as depression, amnesia or dementia; organ diseases associated with ischemic reflux caused by heart failure,
  • the subject to be treated is a human being.
  • the crystalline form of the compound (R, E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxyphenylvinyl)-2,6-dimethylpyridin-4(1H)-one provided by the present invention has good stability, hygroscopicity and other properties, especially the crystalline form A and the crystalline form C have particularly good effects and good application prospects.
  • the solid form of the compound prepared in Example 100 disclosed in paragraphs 0857 to 0862 of the specification of the prior art patent CN110407741A it has better properties.
  • the term "substantially” used in "having an X-ray powder diffraction pattern substantially as shown in Figure 1" or "its X-ray powder diffraction pattern is substantially as shown in Figure 1" means that the precise position of the peak in the figure should not be interpreted as an absolute value. Because it is known to those skilled in the art that the 2 ⁇ value of the X-ray powder diffraction pattern may produce errors due to different measurement conditions (such as the equipment and instruments used) and different samples, the measurement error of the diffraction angle of the X-ray powder diffraction pattern is 5% or less. Generally, a difference of ⁇ 0.2° of a given value is considered appropriate.
  • the relative intensity of the peak may fluctuate with experimental conditions and sample preparation such as the preferred orientation of particles in the sample.
  • sample preparation such as the preferred orientation of particles in the sample.
  • the use of automatic or fixed divergence slits will also affect the calculation of relative intensity.
  • the intensity shown in the XRPD curve included here are illustrative only and should not be used as absolute comparisons.
  • the therapeutically effective amount of the present invention refers to the amount of a drug that is sufficient to affect the treatment of a disease, or at least one clinical symptom of a disease or condition when used to treat a subject.
  • the therapeutically effective amount may vary with the drug, the symptoms of the disease or condition, the severity of the symptoms of the disease or condition, etc. Wherever possible, a suitable dosage may be apparent to those skilled in the art or may be determined by routine experimentation.
  • the pharmaceutically acceptable carrier, diluent or excipient of the present invention refers to a non-toxic carrier, diluent or excipient that does not adversely affect the pharmacological activity of the crystal form formulated with it and is safe for animal use.
  • the pharmaceutically acceptable carrier, diluent or excipient that can be used in the crystal form of the present invention includes but is not limited to ion exchangers, aluminum oxide, aluminum stearate, magnesium stearate, lecithin, serum protein, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid partial glyceride mixtures, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose substances (such as microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, sodium lauryl sulfate and cross-linked sodium carboxymethyl cellulose), polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polypropylene oxide block polymers, polyethylene glycol and lanolin, etc
  • the pharmaceutical composition comprising the crystal form of the present invention can be administered orally, by nasal inhalation, rectal administration, parenteral administration or topical administration.
  • the pharmaceutical composition can be prepared into conventional solid dosage forms such as tablets, powders, granules, capsules, etc., liquid dosage forms such as water or oil suspensions, or other liquid dosage forms such as syrups, solutions, suspensions, etc.; when used for parenteral administration, the pharmaceutical composition can be prepared into solutions, aqueous solutions, oily suspensions, lyophilized powder injections, etc.
  • FIG1 is an X-ray powder diffraction pattern of Form A
  • FIG2 is an overlay of a differential scanning calorimetry spectrum and a thermogravimetric analysis spectrum of Form A;
  • FIG3 is a three-dimensional structure diagram of Form A
  • FIG4 is a dynamic gas phase adsorption diagram of Form A
  • FIG5 is an X-ray powder diffraction pattern of Form B
  • FIG6 is an overlay of a differential scanning calorimetry spectrum and a thermogravimetric analysis spectrum of Form B;
  • FIG7 is an X-ray powder diffraction pattern of Form C
  • FIG8 is a polarizing microscope photograph of Form C
  • FIG9 is an overlay of a differential scanning calorimetry spectrum and a thermogravimetric analysis spectrum of Form C;
  • FIG10 is a dynamic gas phase adsorption diagram of Form C
  • FIG11 is an X-ray powder diffraction pattern of Form E
  • FIG12 is an overlay of a differential scanning calorimetry spectrum and a thermogravimetric analysis spectrum of Form E;
  • FIG13 is a hydrogen nuclear magnetic resonance spectrum of Form E
  • FIG14 is an X-ray powder diffraction pattern of Form F
  • FIG15 is an overlay of the differential scanning calorimetry spectrum and the thermogravimetric analysis spectrum of Form F;
  • FIG16 is a hydrogen nuclear magnetic resonance spectrum of Form F
  • FIG17 is an X-ray powder diffraction pattern of Form G
  • FIG18 is an X-ray powder diffraction pattern of Form H
  • FIG19 is a hydrogen nuclear magnetic resonance spectrum of Form H
  • FIG20 is an X-ray powder diffraction pattern of Form I
  • Figure 21 is a comparison of XRPD images of Form I before and after standing at room temperature.
  • XRPD X-ray powder diffraction
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimeter
  • 1 H-NMR nuclear magnetic resonance hydrogen spectrum
  • PLM polarizing microscope
  • DVS Dynamic Vapor Sorption Instrument
  • SXRD single crystal X-ray diffraction
  • HPLC high performance liquid chromatography
  • RH relative humidity
  • ACN acetonitrile
  • THF tetrahydrofuran
  • MeOH methanol
  • MTBE methyl tert-butyl ether
  • Acetone acetone
  • CPME cyclopentyl methyl ether
  • MEK butanone
  • EtOAc ethyl acetate
  • Toluene toluene
  • IPA isopropyl alcohol
  • a w water activity.
  • the detection instrument information and detection method used in the present invention are as follows:
  • the X-ray powder diffraction data of the samples were collected under ambient conditions using a Bruker D2 model X-ray powder diffractometer, with an X-ray emitter power of 300 W.
  • Thermogravimetric data of the samples were collected using a TA Discovery series thermogravimetric instrument TGA550. Several milligrams of sample were placed in a Tzero aluminum pan and heated from room temperature to 300.0°C under N2 protection, with a N2 flow rate of 25 mL/min and a heating rate of 10°C/min.
  • the thermal data of the samples were collected using a TA Discovery series differential scanning calorimeter DSC2500. Several milligrams of the sample were weighed in a Tzero aluminum pan and sealed with a Tzero sealing lid. The pan was heated to 300.0°C under N2 protection, with a N2 flow rate of 50 mL/min and a heating rate of 10°C/min.
  • the shape of the crystal was observed at room temperature using an Olympus BX3M-KMA-S polarizing microscope and PLM photographs were taken.
  • the hygroscopicity data of the samples were collected using an ADVENTURE series dynamic gas phase adsorption instrument under N2 protection.
  • the sample amount was about 30 mg.
  • the compound of formula (I) used in the examples of the present invention is prepared by the method described in Example 100 (paragraphs 0857 to 0862) in the specification of compound patent CN110407741A owned by the inventor.
  • the obtained solid is crystal form I as determined by XRPD spectrum, and its X-ray powder diffraction pattern is shown in FIG20 .
  • the temperature is adjusted to 40° C., 2 g of crystal form A seed crystals are added, and the mixture is stirred for 2 hours; the temperature is lowered to 10° C., and the mixture is concentrated under reduced pressure until the concentration of the concentrated solution is 10 L, and the concentration is stopped; the temperature is adjusted to 15° C., 40 L of methyl tert-butyl ether is slowly added to the concentrated solution, and the mixture is stirred for 6 hours; the temperature is lowered to -5° C., and the stirring is continued for 6 hours; the mixture is filtered, and the filter cake is washed with methyl tert-butyl ether to obtain 1.8 kg of solid, and after drying, the obtained solid is determined to be crystal form A by XRPD, TGA, DSC, etc.
  • Form A was heated to 180°C and then cooled to room temperature.
  • the obtained solid was subjected to XRPD, TGA, DSC and other measurements, and the obtained solid was Form B.
  • Form A 20 mg was added to 0.3 mL of ACN/H 2 O (1:3, v/v) solvent system and magnetically stirred at room temperature to obtain a suspension. After about 5 days, a solid was separated and dried at room temperature. The obtained solid was Form C as determined by XRPD, TGA, DSC, etc.
  • Form F was heated to 75°C and then cooled to room temperature.
  • the obtained solid was determined by XRPD, TGA, DSC, etc., and the obtained solid was Form H.
  • Form A monoclinic crystal
  • Figure 3 is a three-dimensional structure diagram of Form A.
  • Form A was heated to 180°C under N2 protection and then cooled to room temperature to measure the XRPD of the solid.
  • crystal form A and crystal form B are in an interconversion relationship, crystal form A is stable at low temperatures, and crystal form B is more stable at high temperatures.
  • the specific operation is as follows: weigh 4 portions of excess Form A into 4 HPLC vials, add 0.5 mL of the corresponding solvent to each vial, and separate Place at room temperature and 60°C for magnetic stirring for about 2 hours, filter with a nylon membrane (pore size 0.22 ⁇ m) to obtain a saturated solution; add about 5 mg of Form A and Form B to the saturated filtrate, stir magnetically at room temperature or 60°C for about 1 day, and centrifuge to separate the solid for XRPD testing.
  • Table 8 The results of the suspension competition experiment are shown in Table 8.
  • IPA/H 2 O mixed solvents with target water activities (A w is 0, 0.2, 0.4, 0.6, 0.8, 1.0, respectively) were prepared.
  • the water activities of the systems corresponding to the IPA/H 2 O volume ratios are shown in Table 9.
  • 15-30 mg of Form A was added to the above IPA/H 2 O solutions, and the suspension was obtained after stirring at room temperature for about 2 hours, and filtered with a nylon membrane (pore size 0.22 ⁇ m). About 5 mg of Form C and Form A were weighed into HPLC vials, and the above filtrates were added accordingly. After stirring at room temperature for about 3 days, XRPD testing was performed. The results of the water activity experiment are shown in Table 9.
  • the experimental results show that when the water activity (A w ) is 0 and 0.2, the obtained solid is Form A; when the water activity is 0.4, 0.6, 0.8 and 1.0, the obtained solid is Form C, indicating that at room temperature: when the water activity is 0-0.2, that is, at low water activity, Form A is more stable; when the water activity is 0.4-1.0, that is, at high water activity, Form C is more stable; the critical water activity of Form A and Form C is 0.2-0.4.
  • the weight gain of Form A at 80% RH is 0.5%, indicating that Form A is slightly hygroscopic; during the first adsorption process of Form C at 80% RH, the weight gain of the sample relative to the initial step value (3.0%) is about 0.1%, indicating that Form C is not hygroscopic.
  • the crystal form I prepared in the prior art CN110407741A was placed at room temperature (20°C/78% RH) for 5 hours. Upon detection, the XRPD spectrum of the solid changed, as shown in FIG21 .
  • the crystal forms A, B, C, E, F and H of the compound of formula (I) were placed in a 4500 Lux lighting environment, a 60 ° C high temperature environment and a 90% RH ⁇ 5% RH high humidity environment for stability testing, and samples were taken on the 0th day, the 5th day, the 10th day and the 30th day. The samples were recorded for appearance, moisture content, and total related substances, and compared with the initial data. The comparison results show that the crystal forms of the present invention have good stability, especially the crystal forms A and C have better stability.
  • the compound (R, E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoro discloses a new crystal form of (methoxyphenylvinyl)-2,6-dimethylpyridin-4(1H)-one, which has good stability; the preparation method is simple to operate and has good reproducibility, and can meet the requirements of large-scale industrial production.

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Abstract

本发明涉及化学医药技术领域，提供了式(I)化合物的晶型，所述晶型的制备方法，含有所述晶型的药物组合物，以及它们在制备治疗疾病、病症或病状的药物中的应用或用于治疗疾病、病症或病状的治疗方法。

Description

化合物的新晶型及其制备方法与用途 技术领域
本发明涉及化学医药技术领域，特别是涉及一种化合物的新晶型、晶型的制备方法、含有所述晶型的药物组合物以及所述晶型和药物组合物的用途。
背景技术
许多具有药物活性的有机化合物可以以一种以上的三维晶体结构进行结晶。特定有机药物化合物的多晶型物，由于各自的独特的三维结构，而具有不同的物理性质，如溶解性、吸湿性及稳定性等。但是，通常无法预测特定有机药物化合物是否会形成何种不同的结晶形式，更不可能预测晶型本身的结构和性质。某些药学上有用的化合物的新晶型可以帮助改善药物的性能，比如改善稳定性、溶解性及吸湿性等，提高成药性。
对于(R，E)-1-(3-(四氢噻吩-3-基)氧基-4-二氟甲氧基苯乙烯基)-2，6-二甲基吡啶-4(1H)-酮，其结构式如式(I)所示：
该化合物的晶型研究目前还处于空白状态。
发明内容
本发明的目的在于提供式(I)化合物(R，E)-1-(3-(四氢噻吩-3-基)氧基-4-二氟甲氧基苯乙烯基)-2，6-二甲基吡啶-4(1H)-酮的新的晶型。
本发明提供了式(I)化合物的晶型A，
所述晶型A的X射线粉末衍射图在2θ角为8.3±0.2°、13.1±0.2°、15.8±0.2°、19.7±0.2°、20.5±0.2°、23.5±0.2°、25.0±0.2°、27.7±0.2°处有特征峰。
在一些实施方式中，所述晶型A的X射线粉末衍射图在2θ角为8.3±0.2°、13.1±0.2°、15.8±0.2°、16.6±0.2°、19.7±0.2°、20.5±0.2°、23.5±0.2°、24.6±0.2°、25.0±0.2°、26.4±0.2°、27.7±0.2°、33.8±0.2°处有特征峰。
在一些实施方式中，所述晶型A的X射线粉末衍射图的主要数据如表1所示。
表1
在一些实施方式中，所述晶型A具有基本上如图1所示的X射线粉末衍射图。
在一些实施方式中，所述晶型A具有基本上如图2所示的差示扫描量热(DSC)图谱和热重分析(TGA)图谱的叠图。
在一些实施方式中，所述晶型A的立体结构图如图3所示。
在一些实施方式中，所述晶型A具有基本上如图4所示的动态气相吸附图谱。
在一些实施方式中，所述晶型A为式(I)化合物的无水晶型。
本发明进一步提供了式(I)化合物的晶型B，所述晶型B的X射线粉末衍射图在2θ 角为8.6±0.2°、13.1±0.2°、16.6±0.2°、20.1±0.2°、20.8±0.2°、22.5±0.2°、24.6±0.2°、28.2±0.2°处有特征峰。
在一些实施方式中，所述晶型B的X射线粉末衍射图在2θ角为8.6±0.2°、13.1±0.2°、14.0±0.2°、15.3±0.2°、16.6±0.2°、19.0±0.2°、20.1±0.2°、20.8±0.2°、22.5±0.2°、24.6±0.2°、25.8±0.2°、28.2±0.2°处有特征峰。
在一些实施方式中，所述晶型B的X射线粉末衍射图的主要数据如表2所示。
表2
在一些实施方式中，所述晶型B具有基本上如图5所示的X射线粉末衍射图。
在一些实施方式中，所述晶型B具有基本上如图6所示的差示扫描量热(DSC)图谱和热重分析(TGA)图谱的叠图。
在一些实施方式中，所述晶型B为式(I)化合物的无水晶型。
本发明进一步提供了式(I)化合物的晶型C，所述晶型C的X射线粉末衍射图在2θ角为15.2±0.2°、16.5±0.2°、17.2±0.2°、19.8±0.2°、21.7±0.2°、22.7±0.2°、23.7±0.2°、24.9±0.2°处有特征峰。
在一些实施方式中，所述晶型C的X射线粉末衍射图在2θ角为14.2±0.2°、15.2±0.2°、16.5±0.2°、17.2±0.2°、19.8±0.2°、20.6±0.2°、21.2±0.2°、21.7±0.2°、22.7±0.2°、23.7±0.2°、24.9±0.2°、29.0±0.2°处有特征峰。
在一些实施方式中，所述晶型C的X射线粉末衍射图的主要数据如表3所示。
表3

在一些实施方式中，所述晶型C具有基本上如图7所示的X射线粉末衍射图。
在一些实施方式中，所述晶型C具有基本上如图8所示的偏光显微镜照片。
在一些实施方式中，所述晶型C具有基本上如图9所示的差示扫描量热(DSC)图谱和热重分析(TGA)图谱的叠图。
在一些实施方式中，所述晶型C具有基本上如图10所示的动态气相吸附图谱。
在一些实施方式中，所述晶型C为式(I)化合物的水合物晶型。
本发明进一步提供了式(I)化合物的晶型E，所述晶型E的X射线粉末衍射图在2θ角为13.1±0.2°、16.7±0.2°、21.9±0.2°、22.5±0.2°、22.7±0.2°、23.3±0.2°、27.5±0.2°、28.4±0.2°处有特征峰。
在一些实施方式中，所述晶型E的X射线粉末衍射图在2θ角为11.7±0.2°、13.1±0.2°、13.8±0.2°、16.7±0.2°、19.7±0.2°、20.2±0.2°、21.9±0.2°、22.5±0.2°、22.7±0.2°、23.3±0.2°、27.5±0.2°、28.4±0.2°处有特征峰。
在一些实施方式中，所述晶型E的X射线粉末衍射图的主要数据如表4所示。
表4

在一些实施方式中，所述晶型E具有基本上如图11所示的X射线粉末衍射图。
在一些实施方式中，所述晶型E具有基本上如图12所示的差示扫描量热(DSC)图谱和热重分析(TGA)图谱的叠图。
在一些实施方式中，所述晶型E具有基本上如图13所示的核磁共振氢谱图(1H-NMR图谱)。
本发明进一步提供了式(I)化合物的晶型F，所述晶型F的X射线粉末衍射图在2θ角为11.0±0.2°、11.8±0.2°、15.4±0.2°、20.0±0.2°、21.9±0.2°、23.9±0.2°、24.7±0.2°、27.1±0.2°处有特征峰。
在一些实施方式中，所述晶型F的X射线粉末衍射图在2θ角为11.0±0.2°、11.8±0.2°、15.4±0.2°、16.7±0.2°、20.0±0.2°、20.9±0.2°、21.9±0.2°、22.7±0.2°、23.5±0.2°、23.9±0.2°、24.7±0.2°、27.1±0.2°处有特征峰。
在一些实施方式中，所述晶型F的X射线粉末衍射图的主要数据如表5所示。
表5
在一些实施方式中，所述晶型F具有基本上如图14所示的X射线粉末衍射图。
在一些实施方式中，所述晶型F具有基本上如图15所示的差示扫描量热(DSC)图谱和热重分析(TGA)图谱的叠图。
在一些实施方式中，所述晶型F具有基本上如图16所示的核磁共振氢谱图(1H-NMR图谱)。
本发明进一步提供了式(I)化合物的晶型G，所述晶型G的X射线粉末衍射图在2θ角为12.8±0.2°、14.4±0.2°、17.6±0.2°、20.1±0.2°、21.0±0.2°、21.5±0.2°、23.2±0.2°、25.9±0.2°处有特征峰。
在一些实施方式中，所述晶型G的X射线粉末衍射图的主要数据如表6所示。
表6
在一些实施方式中，所述晶型G具有基本上如图17所示的X射线粉末衍射图。
本发明进一步提供了式(I)化合物的晶型H，所述晶型H的X射线粉末衍射图在2θ角为11.0±0.2°、11.8±0.2°、13.0±0.2°、16.7±0.2°、19.6±0.2°、19.9±0.2°、21.9±0.2°、22.7±0.2° 处有特征峰。
在一些实施方式中，所述晶型H的X射线粉末衍射图在2θ角为11.0±0.2°、11.8±0.2°、13.0±0.2°、13.7±0.2°、16.7±0.2°、19.0±0.2°、19.6±0.2°、19.9±0.2°、21.9±0.2°、22.7±0.2°、23.8±0.2°、28.3±0.2°处有特征峰。
在一些实施方式中，所述晶型H的X射线粉末衍射图的主要数据如表7所示。
表7
在一些实施方式中，所述晶型H具有基本上如图18所示的X射线粉末衍射图。
在一些实施方式中，所述晶型H具有基本上如图19所示的核磁共振氢谱图(1H-NMR 图谱)。
本发明进一步提供了前述式(I)化合物的晶型A的制备方法，该方法包括以下步骤：
1)使式(I)化合物溶解于丙酮溶剂中；
2)浓缩，加入甲基叔丁基醚，过滤。
优选的，前述式(I)化合物的晶型A的制备方法包括以下步骤：
1)将式(I)化合物溶解在丙酮溶剂中；
2)加入式(I)化合物的晶型A晶种，搅拌；
3)浓缩，在得到的浓缩液中加入甲基叔丁基醚，调节温度为-5℃至5℃，搅拌；
4)过滤分离，得到所述晶型A。
在一些实施方式中，浓缩的温度为10-20℃。
在一些实施方式中，浓缩为减压浓缩。
本发明采用的原料式(I)化合物为游离碱，其形式不做限定，可以选自任意的晶型或无定型，它们均可以根据本发明提供的方法制备得到晶型A。
本发明对于式(I)化合物在丙酮中溶解的方式不做限定，只要能够实现本发明的目的即可，例如，将式(I)化合物和丙酮混合后，升温，搅拌溶解；其中，升温后的温度可以为50-55℃。
本发明对于丙酮的使用量不做限定，只要能够实现本发明的目的即可。
本发明对于晶型A晶种的使用量和加入晶型A晶种时的温度不做限定，只要能够实现本发明的目的即可。
本发明对于加入晶型A晶种后的搅拌时间不做限定，只要能够实现本发明的目的即可，例如，搅拌的时间可以为2-4小时。
本发明对于在浓缩液中加入甲基叔丁基醚时的温度和加入方式不做限定，只要能够实现本发明的目的即可，例如，调节浓缩液的温度为15-25℃，然后加入甲基叔丁基醚；加入甲基叔丁基醚的方式可以为缓慢加入。
本发明对于甲基叔丁基醚时的使用量不做限定，只要能够实现本发明的目的即可，例如，甲基叔丁基醚的使用量可以为浓缩液中丙酮体积的2-5倍。
本发明对于加入甲基叔丁基醚后的搅拌时间和方式不做限定，只要能够实现本发明的目的即可，例如，加入甲基叔丁基醚之后可以先搅拌6-10小时，再调节温度为-5℃至5℃，继续搅拌6-10小时。
本发明在干燥过滤得到的湿样固体之前，可以采用甲基叔丁基醚进行洗涤。
本发明对于干燥的时间和温度不做限定，只要能够实现本发明的目的即可。
本发明进一步提供了前述式(I)化合物的晶型C的制备方法，该方法包括以下步骤：将前述式(I)化合物的晶型A溶于乙醇中至澄清；加入水，搅拌；离心分离，干燥，得到所述晶型C；
优选地，将式(I)化合物的晶型A溶于乙醇中至澄清；依次加入水和式(I)化合物的晶型C晶种，搅拌；离心分离，干燥，得到所述晶型C。
在一些实施方式中，乙醇和水的体积比为1：(2-3)。
本发明对于乙醇的使用量不做限定，只要能够实现本发明的目的即可。例如，式(I)化合物的晶型A与乙醇之间的用量比可以为0.1-0.5g/mL。
本发明对于水的使用量和加入方式不做限定，只要能够实现本发明的目的即可。例如，乙醇和水的体积比可以为1：(2-3)。
本发明对于晶型C晶种的使用量不做限定，只要能够实现本发明的目的即可。
本发明对于加入晶型C晶种后的搅拌时间和搅拌方式不做限定，只要能够实现本发明的目的即可，例如，搅拌时间可以为3-23h，搅拌方式可以为磁力搅拌。
本发明对于干燥的时间和温度不做限定，只要能够实现本发明的目的即可，例如，可以是10-30℃温度范围内干燥12-24小时。
本发明进一步提供了前述式(I)化合物的晶型C的制备方法，该方法包括以下步骤：将前述式(I)化合物的晶型A在乙腈/水溶剂体系中室温磁力搅拌3-5天，分离得到的固体为晶型C。
在本发明的一些实施方式中，乙腈和水的体积比为1：(2-3)。
本发明进一步提供本发明所述晶型的晶型组合物。
在本发明的部分实施方式中，本发明所述的晶型A占晶型组合物重量50％以上，较好的是80％以上，更好的是90％以上，最好的是95％以上。
在本发明的部分实施方式中，本发明所述的晶型C占晶型组合物重量50％以上，较好的是80％以上，更好的是90％以上，最好的是95％以上。
本发明进一步提供了药物组合物，包含有效治疗量的本发明所述的晶型A、晶型C或其混合物及药学上可接受的载体、稀释剂或赋形剂。
在上述药物组合物中，所述晶型A、晶型C或其混合物与所述载体、稀释剂或赋形剂 的重量比范围是0.0001～10。
作为优选，所述药物组合物用于外用给药。
作为优选，所述药物组合物用于软膏剂的制备。
作为优选，所述药物组合物含有0.01重量％-99重量％的本发明所述的晶型A、晶型C或其混合物。
作为优选，所述药物组合物含有0.05重量％-50重量％的本发明所述的晶型A、晶型C或其混合物。
作为优选，所述药物组合物含有0.1重量％-30重量％的本发明所述的晶型A、晶型C或其混合物。
本发明进一步提供了本发明所述的式(I)化合物的晶型A、晶型C或其混合物在制备药物中的应用。
作为优选，所述应用为治疗、预防、延迟或阻止炎症的发生或发展。
作为优选，所述应用为制备治疗或预防由PDE4介导的疾病的药物。
作为优选，所述疾病是炎症。
作为优选，所述炎症选自炎症性过敏性疾病如支气管哮喘、慢性阻塞性肺疾病(COPD)、过敏性鼻炎或肾炎；自身免疫性疾病如特异性皮炎、银屑病、斑秃、类风湿性关节炎、银屑病性关节炎、多发性硬化症、克罗恩病、溃疡性结肠炎、白癜风、狼疮、系统性红斑狼疮或盘状红斑狼疮、强直性脊柱炎；急性或慢性皮肤伤口疾病；中枢神经系统疾病例如抑郁症、健忘症或痴呆症；与由心力衰竭、休克或脑血管疾病等引起的缺血性反流相关的器官疾病；胰岛素抵抗性糖尿病；伤口。
作为优选，所述应用为用作PDE4抑制剂。
本发明还提供了一种在治疗对象上施用治疗有效量的至少一种所述的式(I)化合物的晶型A、晶型C或其混合物治疗和/或预防由PDE4介导的疾病的方法。
作为优选，在上述方法中，所述由PDE4介导的疾病是炎症。
作为优选，在上述方法中，所述炎症选自炎症性过敏性疾病如支气管哮喘、慢性阻塞性肺疾病(COPD)、过敏性鼻炎或肾炎；自身免疫性疾病如特异性皮炎、银屑病、斑秃、类风湿性关节炎、银屑病性关节炎、多发性硬化症、克罗恩病、溃疡性结肠炎、白癜风、狼疮、系统性红斑狼疮或盘状红斑狼疮、强直性脊柱炎；急性或慢性皮肤伤口疾病；中枢神经系统疾病例如抑郁症、健忘症或痴呆症；与由心力衰竭、休克或脑血管疾病等引起的缺血性反流相关的器官疾病；胰岛素抵抗性糖尿病；伤口。
本发明还提供了一种治疗炎症的方法，包括向治疗对象施用治疗有效量的至少一种本发明所述的式(I)化合物的晶型A、晶型C或其混合物，所述炎症选自炎症性过敏性疾病如支气管哮喘、慢性阻塞性肺疾病(COPD)、过敏性鼻炎或肾炎；自身免疫性疾病如特异性皮炎、银屑病、斑秃、类风湿性关节炎、银屑病性关节炎、多发性硬化症、克罗恩病、溃疡性结肠炎、白癜风、狼疮、系统性红斑狼疮或盘状红斑狼疮、强直性脊柱炎；急性或慢性皮肤伤口疾病；中枢神经系统疾病例如抑郁症、健忘症或痴呆症；与由心力衰竭、休克或脑血管疾病等引起的缺血性反流相关的器官疾病；胰岛素抵抗性糖尿病；伤口。
作为优选，在上述方法中，所述的治疗对象为人类。
本发明提供的化合物(R，E)-1-(3-(四氢噻吩-3-基)氧基-4-二氟甲氧基苯乙烯基)-2，6-二甲基吡啶-4(1H)-酮的晶型具有较好的稳定性、吸湿性等性能，特别是晶型A和晶型C的效果尤佳，具有较好的应用前景，且相对于现有技术专利CN110407741A说明书中第0857段至第0862段公开的实施例100所制得的化合物的固体形态具有更好的性能。
当然，实施本发明的任一产品或方法并不一定需要同时达到以上所述的所有优点。
本发明中，“具有基本上如图1所示的X射线粉末衍射图”或“其X射线粉末衍射图基本上如图1所示”中所使用的术语“基本上”是表示附图中的峰的精确位置不应当被解释为绝对值。因为本领域技术人员可知，X射线粉末衍射图的2θ值可能会由于不同的测量条件(如所使用的设备和仪器)和不同的样品而产生误差，X射线粉末衍射图的衍射角的测量误差为5％或更小，通常，给定的值的±0.2°的差别会被认为是恰当的。还应理解，峰值的相对强度可能随实验条件和样品制备诸如颗粒在样品中的优选的取向而波动。自动或固定的发散狭缝的使用也将会影响相对强度的计算。在这里所包括的XRPD曲线所示强度 只是示例性的，不能被用作绝对比较。
本发明所述的治疗有效量，指一种药物用于治疗对象时对于治疗一种疾病、或一种疾病或病症的至少一种临床症状时，足以影响对疾病、病症或症状的这种治疗的量。治疗有效量可以随着药物、疾病或病症的症状，疾病或病症的症状的严重程度等变化。在任意可能的情况下，一个合适的剂量对那些本领域的技术人员可以是显而易见的，也可以是用常规实验确定的。
本发明所述的药学上可接受的载体、稀释剂或赋形剂，指不会不利地影响与其共同配制的晶型的药理活性的且对于动物使用也是安全的无毒性的载体、稀释剂或赋形剂。可以在本发明的晶型中使用的药学上可接受的载体、稀释剂或赋形剂包括但不限于离子交换剂、氧化铝、硬脂酸铝、硬脂酸镁、卵磷脂、血清蛋白、缓冲物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和的植物脂肪酸的偏甘油酯混合物、水、盐或电解质如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、纤维素类物质(例如微晶纤维素、羟丙基甲基纤维素、乳糖一水合物、月桂基硫酸钠和交联羧甲基纤维素钠)、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚环氧丙烷嵌段聚合物、聚乙二醇和羊毛脂等。
包括本发明的晶型的药物组合物可通过口服、鼻吸入、直肠、肠胃外或局部施用等方式进行给药。用于口服时，药物组合物可以制成诸如片剂、粉剂、颗粒剂、胶囊剂等的常规的固体剂型，诸如水或油悬浮剂的液体剂型或诸如糖浆、溶液、悬浮液等的其他液体剂型：用于肠胃外给药时，药物组合物可以制成溶液、水溶液、油性悬浮剂、冻干粉针等。
附图说明
为了更清楚地说明本发明实施例和现有技术的技术方案，下面对实施例和现有技术中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，还可以根据这些附图获得其它的附图。
图1为晶型A的X射线粉末衍射图；
图2为晶型A的差示扫描量热图谱和热重分析图谱的叠图；
图3为晶型A的立体结构图；
图4为晶型A的动态气相吸附图；
图5为晶型B的X射线粉末衍射图；
图6为晶型B的差示扫描量热图谱和热重分析图谱的叠图；
图7为晶型C的X射线粉末衍射图；
图8为晶型C的偏光显微镜照片；
图9为晶型C的差示扫描量热图谱和热重分析图谱的叠图；
图10为晶型C的动态气相吸附图；
图11为晶型E的X射线粉末衍射图；
图12为晶型E的差示扫描量热图谱和热重分析图谱的叠图；
图13为晶型E的核磁共振氢谱图；
图14为晶型F的X射线粉末衍射图；
图15为晶型F的差示扫描量热图谱和热重分析图谱的叠图；
图16为晶型F的核磁共振氢谱图；
图17为晶型G的X射线粉末衍射图；
图18为晶型H的X射线粉末衍射图；
图19为晶型H的核磁共振氢谱图；
图20为晶型I的X射线粉末衍射图；
图21为晶型I的室温放置前后XRPD对比图。
具体实施方式
为使本发明的目的、技术方案及优点更加清楚明白，以下参照附图并举实施例，对本发明进一步详细说明。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员所获得的所有其他实施例，都属于本发明保护的范围。
缩略语：
XRPD：X射线粉末衍射；
TGA：热重分析；
DSC：差示扫描量热仪；
1H-NMR：核磁共振氢谱；
PLM：偏光显微镜；
DVS：动态蒸汽吸附仪；
SXRD：单晶X射线衍射；
HPLC：高效液相色谱；
RH：相对湿度；
ACN：乙腈；
THF：四氢呋喃；
MeOH：甲醇；
MTBE：甲基叔丁基醚；
Acetone：丙酮；
CPME：环戊基甲醚；
MEK：丁酮；
EtOAc：乙酸乙酯；
Toluene：甲苯；
IPA：异丙醇；
Aw：水活度。
除非另有说明，本发明所用到的检测仪器信息和检测方法如下：
(1)X-射线粉末衍射分析
使用布鲁克D2型号X-射线粉末衍射仪，在环境条件下收集样品的X-射线粉末衍射数据，X-射线发射器功率为300W。样品台无背景信号，步速为0.15秒/步，总步数为1837步，步长为2θ＝0.02°，电压为30kV，电流为10mA。X-射线管采用Cu靶(Kα)，Kα2/Kα1强度比为0.50
(2)热重分析
使用TA Discovery系列的热重仪TGA550收集样品的热重数据。取若干毫克样品放入Tzero铝盘中，在N2保护下从室温加热到300.0℃，N2流速为25mL/分钟，升温速率为10℃/分钟。
(3)差示扫描量热分析
使用TA Discovery系列的差式扫描量热仪DSC2500收集样品的热数据。称量若干毫克样品在Tzero铝盘中，用Tzero密封盖密封。在N2保护下加热到300.0℃，N2流速为50mL/分钟，升温速率为10℃/分钟。
(4)偏光显微镜
使用Olympus的BX3M-KMA-S型号偏光显微镜，在室温条件下观察晶型的形状，拍摄得到PLM照片。
(5)动态气相吸附仪
使用ADVENTURE系列动态气相吸附仪在N2保护下收集样品的吸湿性数据。样品用量约30mg。
以下结合具体实施例对本发明进行详细说明。
本发明实施例中所采用的式(I)化合物，其通过发明人所拥有的化合物专利CN110407741A说明书中实施例100(第0857段-第0862段)所示的方法制备得到。经XRPD图谱测定，所得固体为晶型I，其X射线粉末衍射图如图20所示。
实施例1：晶型A的制备
在4mL玻璃瓶中称量15mg式(I)化合物，加入2mL二氯甲烷使其溶清。用封口膜封口，并扎4个针孔，在室温条件下缓慢挥发，分离析出的固体经XRPD、TGA、DSC等测定确定为晶型A。
实施例2：晶型A的制备
在第一反应釜中将2.20kg式(I)化合物和30L丙酮混合，升温至50℃，搅拌溶解；将溶解得到的混合溶液转移至第二反应釜中，用2L丙酮润洗，50℃搅拌至溶清；调节温度为40℃，加入2g晶型A晶种，搅拌2小时；降温至10℃，减压浓缩至浓缩液的浓度为10L时，停止浓缩；调节温度为15℃，在浓缩液中缓慢加入40L甲基叔丁基醚，搅拌6小时；降温至-5℃，继续搅拌6小时；过滤，滤饼用甲基叔丁基醚洗涤得到1.8kg固体，干燥后，经XRPD、TGA、DSC等测定，所得固体为晶型A。
实施例3：晶型B的制备
在氮气保护条件下，将晶型A加热到180℃，之后冷却到室温，将得到的固体进行XRPD、TGA、DSC等测定，所得固体为晶型B。
实施例4：晶型C的制备
将20mg晶型A加入到0.3mL ACN/H2O(1：3，v/v)溶剂体系中，在室温条件下进行磁力搅拌，得到悬浊液。约5天后，分离得到固体，室温干燥，经XRPD、TGA、DSC等测定，所得固体为晶型C。
实施例5：晶型C的制备
在200.8mg晶型A中加入2.0mL乙醇，得到澄清溶液；在磁力搅拌条件下，向澄清溶液中滴加水，加入4.0mL水后出现浑浊；加入2.0mg晶型C晶种，继续磁力搅拌23h；离 心，将收集的固体室温干燥，经XRPD、TGA、DSC等测定，所得固体为晶型C。
实施例6：晶型E的制备
在4mL玻璃瓶中称量15mg起始晶型A，加入2mL MEK使其溶清。用封口膜封口，并扎4个针孔，在室温条件下缓慢挥发。室温挥发约3天，分离得到固体，室温干燥，经XRPD、TGA、DSC等测定，所得固体为晶型E。
实施例7：晶型F的制备
在4mL玻璃瓶中称量15mg起始晶型A，加入0.5mL MeOH(正溶剂)中溶清样品，并将其放入装有3mL MTBE(反溶剂)的20mL玻璃瓶中。将20mL玻璃瓶盖紧，放置在室温条件下，直至有固体析出。分离的固体，室温干燥，经XRPD、TGA、DSC等测定，所得固体为晶型F。
实施例8：晶型G的制备
在20mL玻璃瓶中称取15mg晶型A样品，加入1mL Acetone(正溶剂)溶清样品，在磁力搅拌条件下，向玻璃瓶中逐步加入CPME(反溶剂)使总体积达到15.0mL。在5℃搅拌至有固体析出，分离得到固体，室温干燥，经XRPD等测定，所得固体为晶型G。
实施例9：晶型H的制备
在N2保护下，加热晶型F至75℃，之后冷却至室温，得到的固体经XRPD、TGA、DSC等测定，所得固体为晶型H。
实施例10：单晶X射线衍射(SXRD)实验
采用溶剂自然挥发的方法在二氯甲烷溶液中制备出晶型A单晶(单斜晶体)。使用Bruker D8 Venture衍射仪，利用GaKα(λ＝1.34139)射线衍射系统采集晶体数据，利用Bruker Apex3程序进行分析。图3为晶型A的立体结构图。
实施例11：热力学分析实验
将晶型A在N2保护下加热至180℃，冷却至室温后测定固体的XRPD。
结果：晶型A加热到180℃，冷却至室温后，晶型A转为晶型B。
分析：根据Burger-Ramberger规则，晶型A和晶型B为互变关系，晶型A在低温下稳定，晶型B在高温下更稳定。
实施例12：混悬竞争实验
在室温和60℃两个条件下，将晶型A和晶型B以MEK、EtOAc和Toluene为溶剂设置混悬竞争实验。
具体操作为：称量4份过量晶型A到4个HPLC小瓶中，分别加入0.5mL对应的溶剂，分 别放置在室温和60℃磁力搅拌约2小时，用尼龙膜(孔径0.22μm)过滤得到饱和溶液；向饱和滤液中加入晶型A和晶型B各约5mg，在室温或60℃磁力搅拌约1天，离心分离固体用于XRPD测试。混悬竞争实验结果如表8所示。
表8混悬竞争实验结果
结果表明，室温和60℃条件下两种溶剂中所得固体均为晶型A，可见，相比晶型B，晶型A在室温和60℃下均更稳定。
实施例13：水活度实验
在室温条件下，配制目标水活度(Aw分别为0、0.2、0.4、0.6、0.8、1.0)的IPA/H2O混合溶剂，IPA/H2O体积比对应的体系水活度如表9所示。向上述IPA/H2O溶液中分别加入15-30mg晶型A，室温搅拌约2h后得到悬浊液，用尼龙膜(孔径0.22μm)过滤。各称取约5mg晶型C和晶型A到HPLC小瓶中，对应加入上述滤液，室温搅拌约3天后进行XRPD测试。水活度实验结果如表9所示。
表9水活度实验结果
实验结果说明，水活度(Aw)为0和0.2时，所得固体为晶型A；水活度为0.4、0.6、0.8和1.0时，所得固体为晶型C，表明在室温条件下：水活度为0-0.2时，即在低水活度时，晶型A更为稳定；水活度为0.4-1.0时，即在高水活度时，晶型C更为稳定；晶型A和晶型C的临界水活度为0.2-0.4。
实施例14：吸湿性试验
晶型A和晶型C的动态水分吸附测定结果分别如图4和图10所示。
分析：晶型A在80％RH时增重为0.5％，表明晶型A具有轻微吸湿性；晶型C在第一个吸附过程中80％RH下，样品相对起始台阶值(3.0％)增重约为0.1％，表明晶型C不吸湿。
实施例15：晶型稳定性试验
将现有技术CN110407741A中制备得到的晶型I在室温(20℃/78％RH)放置5h，经检测，上述固体的XRPD图谱发生转变，如图21。
结果说明：放置过程中晶型I部分转变为晶型G。可见，晶型I在室温下不稳定。
实施例16：稳定性试验
测定本发明晶型的稳定性。将式(I)化合物晶型A、晶型B、晶型C、晶型E、晶型F、晶型H分别置于4500Lux光照环境、60℃高温环境和90％RH±5％RH高湿环境下进行稳定性测试，于第0天、第5天、第10天和第30天取样，所取样品记录外观性状、水分含量、总相关物质，并与初始数据比较。比较结果发现，本发明的晶型均具有较好的稳定性，尤其是晶型A和晶型C具有更好的稳定性。
实施例17加速稳定性试验
将式(I)化合物晶型A分别在25℃、60％RH和40℃、75％RH两种加速试验条件下放置6个月，分别于1月、3月、6月取样，HPLC检测纯度、进行XRPD表征，并与0天的结果进行对比，结果如表10所示：
表10
结果表明，晶型A在加速稳定性实验条件下在6个月内均保持稳定的含量，且没有发生晶型转变。
由上述内容可知，本发明提供的化合物(R，E)-1-(3-(四氢噻吩-3-基)氧基-4-二氟 甲氧基苯乙烯基)-2，6-二甲基吡啶-4(1H)-酮的新晶型，稳定性好；制备方法操作简单、重现性好，可满足大规模工业化生产。
本说明书中的各个实施例均采用相关的方式描述，各个实施例之间相同相似的部分互相参见即可，每个实施例重点说明的都是与其他实施例的不同之处。
以上所述仅为本发明的较佳实施例，并非用于限定本发明的保护范围。凡在本发明的精神和原则之内所作的任何修改、等同替换、改进等，均包含在本发明的保护范围内。

Claims (22)

  1. 一种式(I)化合物的晶型A，其特征在于，
    所述晶型A的X射线粉末衍射图在2θ角为8.3±0.2°、13.1±0.2°、15.8±0.2°、19.7±0.2°、20.5±0.2°、23.5±0.2°、25.0±0.2°、27.7±0.2°处有特征峰。
  2. 根据权利要求1所述的晶型A，其特征在于，X射线粉末衍射图在2θ角为8.3±0.2°、13.1±0.2°、15.8±0.2°、16.6±0.2°、19.7±0.2°、20.5±0.2°、23.5±0.2°、24.6±0.2°、25.0±0.2°、26.4±0.2°、27.7±0.2°、33.8±0.2°处有特征峰。
  3. 根据权利要求1或2所述的晶型A，其特征在于，所述晶型A的X射线粉末衍射图的数据基本上如表1所示。
  4. 根据权利要求1-3中任一项所述的晶型A，其特征在于，所述晶型A的X射线粉末衍射图基本上如图1所示。
  5. 一种式(I)化合物的晶型C，其特征在于，
    所述晶型C的X射线粉末衍射图在2θ角为15.2±0.2°、16.5±0.2°、17.2±0.2°、19.8±0.2°、21.7±0.2°、22.7±0.2°、23.7±0.2°、24.9±0.2°处有特征峰。
  6. 根据权利要求5所述的晶型C，其特征在于，所述晶型C的X射线粉末衍射图在2θ角为14.2±0.2°、15.2±0.2°、16.5±0.2°、17.2±0.2°、19.8±0.2°、20.6±0.2°、21.2±0.2°、21.7±0.2°、22.7±0.2°、23.7±0.2°、24.9±0.2°、29.0±0.2°处有特征峰。
  7. 根据权利要求5或6所述的晶型C，其特征在于，所述晶型C的X射线粉末衍射图的数据基本上如表3所示。
  8. 根据权利要求5-7中任一项所述的晶型C，其特征在于，所述晶型C的X射线粉末 衍射图基本上如图7所示。
  9. 一种药物组合物，其特征在于，包含有效治疗量的权利要求1-4中任一项所述的晶型A、权利要求5-8中任一项所述的晶型C或其混合物及药学上可接受的载体、稀释剂或赋形剂。
  10. 权利要求1-4任一项所述的晶型A的制备方法，其特征在于，包括如下步骤：将式(I)化合物溶解在丙酮中；浓缩，加入甲基叔丁基醚，过滤，得到所述晶型A；优选地，将式(I)化合物溶解在丙酮中；加入晶型A晶种，搅拌；浓缩，在得到的浓缩液中加入甲基叔丁基醚，调节温度为-5℃至5℃，搅拌；过滤分离，干燥，得到所述晶型A。
  11. 权利要求5-8任一项所述的晶型C的制备方法，其特征在于，包括如下步骤：将权利要求1-4中任一项所述的式(I)化合物的晶型A溶于乙醇中至澄清；加入水，搅拌；离心分离，干燥，得到所述晶型C；优选地，将式(I)化合物的晶型A溶于乙醇中至澄清；依次加入水和晶型C晶种，搅拌；离心分离，干燥，得到所述晶型C。
  12. 权利要求1-4中任一项所述的晶型A、权利要求5-8中任一项所述的晶型C或其混合物或权利要求9所述的药物组合物在制备药物中的用途。
  13. 根据权利要求12所述的用途，其特征在于，所述药物用于治疗、预防、延迟或阻止炎症的发生或发展。
  14. 根据权利要求12所述的用途，其特征在于，所述药物用于治疗由PDE4介导的疾病。
  15. 根据权利要求14所述的用途，其特征在于，所述疾病是炎症。
  16. 根据权利要求15所述的用途，其特征在于，所述炎症是炎症性过敏性疾病、自身免疫性疾病、急性或慢性皮肤伤口疾病、中枢神经系统疾病、与由心力衰竭、休克或脑血管疾病引起的缺血性反流相关的器官疾病、胰岛素抵抗性糖尿病或伤口。
  17. 权利要求1-4中任一项所述的晶型A、权利要求5-8中任一项所述的晶型C或其混合物或权利要求9所述的药物组合物在制备PDE4抑制剂中的用途。
  18. 一种用于治疗和/或预防由PDE4介导的疾病的方法，其特征在于，所述方法向有需要的患者施用权利要求1-4中任一项所述的晶型A、权利要求5-8中任一项所述的晶型C或其混合物或权利要求9所述的药物组合物。
  19. 根据权利要求18所述的方法，其特征在于，所述疾病是炎症。
  20. 根据权利要求19所述的方法，其特征在于，所述炎症是炎症性过敏性疾病、自身免疫性疾病、急性或慢性皮肤伤口疾病、中枢神经系统疾病、与由心力衰竭、休克或脑血管疾病引起的缺血性反流相关的器官疾病、胰岛素抵抗性糖尿病或伤口。
  21. 一种治疗炎症的方法，其特征在于，所述方法为向有需要的患者施用权利要求1-4中任一项所述的晶型A、权利要求5-8中任一项所述的晶型C或其混合物或权利要求9所述的药物组合物。
  22. 根据权利要求21所述的方法，其特征在于，所述炎症是炎症性过敏性疾病、自身免疫性疾病、急性或慢性皮肤伤口疾病、中枢神经系统疾病、与由心力衰竭、休克或脑血管疾病引起的缺血性反流相关的器官疾病、胰岛素抵抗性糖尿病或伤口。
PCT/CN2024/077350 2023-02-23 2024-02-18 化合物的新晶型及其制备方法与用途 WO2024174931A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110407741A (zh) * 2018-04-26 2019-11-05 嘉兴维眸生物科技有限公司 一种抗炎化合物及其制备和应用
CN113912593A (zh) * 2020-07-10 2022-01-11 启元生物(杭州)有限公司 一种氘代吡啶酮类化合物及其应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110407741A (zh) * 2018-04-26 2019-11-05 嘉兴维眸生物科技有限公司 一种抗炎化合物及其制备和应用
CN113912593A (zh) * 2020-07-10 2022-01-11 启元生物(杭州)有限公司 一种氘代吡啶酮类化合物及其应用

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