Novel crystal form of compound and preparation method and application thereof

Abstract

The invention relates to the technical field of chemical medicines, and provides a crystal form of a compound of formula (I), a preparation method of the crystal form, a pharmaceutical composition containing the crystal form, and application of the crystal form and the pharmaceutical composition in preparation of medicines for treating diseases, symptoms or symptoms or a treatment method for treating the diseases, the symptoms or the symptoms.

Description

New crystal form of compound and preparation method and use thereof Technical Field

[0001] 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. Background Art

[0002] Many pharmaceutically active organic compounds can crystallize in more than one three-dimensional crystal structure. Polymorphs of a given organic pharmaceutical compound, due to their unique three-dimensional structures, exhibit distinct physical properties, such as solubility, hygroscopicity, and stability. However, it is generally impossible to predict which different crystalline forms a given organic pharmaceutical compound will form, let alone the structure and properties of the crystalline forms themselves. New crystalline forms of certain pharmaceutically useful compounds can help improve drug performance, such as stability, solubility, and hygroscopicity, thereby enhancing drugability.

[0003] For (R,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxyphenyl)-2,6-dimethylpyridin-4(1H)-one, its structural formula is shown in formula (I):

[0004] The research on the crystal form of this compound is still blank.

[0005] Summary of the Invention

[0006] 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.

[0007] The present invention provides a crystalline form A of a compound of formula (I),

[0008] The X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ 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°.

[0009] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ 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°.

[0010] In some embodiments, the main data of the X-ray powder diffraction pattern of the crystalline form A are shown in Table 1.

[0011] Table 1

[0012] In some embodiments, the Form A has an X-ray powder diffraction pattern substantially as shown in FIG1 .

[0013] In some embodiments, the Form A has a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern substantially as shown in FIG2 .

[0014] In some embodiments, the three-dimensional structure diagram of the crystalline form A is shown in Figure 3.

[0015] In some embodiments, the crystalline Form A has a dynamic gas adsorption profile substantially as shown in FIG. 4 .

[0016] In some embodiments, the crystalline form A is an anhydrous crystalline form of the compound of formula (I).

[0017] 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 has characteristic peaks at 2θ 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°.

[0018] In some embodiments, the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at 2θ 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°.

[0019] In some embodiments, the main data of the X-ray powder diffraction pattern of the crystalline form B are shown in Table 2.

[0020] Table 2

[0021] In some embodiments, the Form B has an X-ray powder diffraction pattern substantially as shown in FIG5 .

[0022] In some embodiments, the Form B has a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern substantially as shown in FIG6 .

[0023] In some embodiments, the crystalline Form B is an anhydrous crystalline form of the compound of formula (I).

[0024] 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 2θ 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°.

[0025] In some embodiments, the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 2θ 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°.

[0026] In some embodiments, the main data of the X-ray powder diffraction pattern of the crystalline form C are shown in Table 3.

[0027] Table 3

[0028] In some embodiments, the Form C has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .

[0029] In some embodiments, the Form C has a polarizing microscope photograph substantially as shown in FIG8 .

[0030] In some embodiments, the Form C has a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern substantially as shown in FIG. 9 .

[0031] In some embodiments, the Form C has a dynamic gas adsorption profile substantially as shown in FIG10 .

[0032] In some embodiments, the crystalline form C is a hydrate crystalline form of the compound of formula (I).

[0033] 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 2θ 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°.

[0034] In some embodiments, the X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at 2θ 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°.

[0035] In some embodiments, the main data of the X-ray powder diffraction pattern of the crystalline form E are shown in Table 4.

[0036] Table 4

[0037] In some embodiments, the Form E has an X-ray powder diffraction pattern substantially as shown in FIG11 .

[0038] In some embodiments, the Form E has a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern substantially as shown in FIG. 12 .

[0039] In some embodiments, the crystalline Form E has a hydrogen nuclear magnetic resonance spectrum substantially as shown in FIG13 ( 1 H-NMR spectrum).

[0040] 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 2θ 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°.

[0041] In some embodiments, the X-ray powder diffraction pattern of the crystalline form F has characteristic peaks at 2θ 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°.

[0042] In some embodiments, the main data of the X-ray powder diffraction pattern of the crystalline form F are shown in Table 5.

[0043] Table 5

[0044] In some embodiments, the Form F has an X-ray powder diffraction pattern substantially as shown in FIG14 .

[0045] In some embodiments, the Form F has a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern substantially as shown in FIG. 15 .

[0046] In some embodiments, the crystalline Form F has a hydrogen nuclear magnetic resonance spectrum substantially as shown in FIG16 ( 1 H-NMR spectrum).

[0047] 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 2θ 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°.

[0048] In some embodiments, the main data of the X-ray powder diffraction pattern of the crystalline form G are shown in Table 6.

[0049] Table 6

[0050] In some embodiments, the Form G has an X-ray powder diffraction pattern substantially as shown in FIG17 .

[0051] 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 has characteristic peaks at 2θ angles 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°, and 22.7±0.2°.

[0052] In some embodiments, the X-ray powder diffraction pattern of the crystalline form H has characteristic peaks at 2θ 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°.

[0053] In some embodiments, the main data of the X-ray powder diffraction pattern of the crystalline form H are shown in Table 7.

[0054] Table 7

[0055] In some embodiments, the Form H has an X-ray powder diffraction pattern substantially as shown in FIG18 .

[0056] In some embodiments, the crystalline form H has a hydrogen nuclear magnetic resonance spectrum substantially as shown in FIG. 19 ( 1 H-NMR spectrum).

[0057] The present invention further provides a method for preparing the crystalline form A of the compound of formula (I), comprising the following steps:

[0058] 1) dissolving the compound of formula (I) in acetone solvent;

[0059] 2) Concentrate, add methyl tert-butyl ether, and filter.

[0060] Preferably, the preparation method of the crystalline form A of the compound of formula (I) comprises the following steps:

[0061] 1) dissolving the compound of formula (I) in acetone solvent;

[0062] 2) adding seed crystals of Form A of the compound of formula (I) and stirring;

[0063] 3) Concentrating, adding methyl tert-butyl ether to the obtained concentrate, adjusting the temperature to -5°C to 5°C, and stirring;

[0064] 4) filtering and separating to obtain the crystal form A.

[0065] In some embodiments, the concentration temperature is 10-20°C.

[0066] In some embodiments, the concentration is concentration under reduced pressure.

[0067] 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. They can all be prepared into crystalline form A according to the method provided by the present invention.

[0068] 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. For example, the compound of formula (I) and acetone are mixed, heated, and stirred to dissolve; wherein the temperature after heating can be 50-55°C.

[0069] 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.

[0070] The present invention does not impose any limitation on the amount of Form A seed crystals used and the temperature at which Form A seed crystals are added, as long as the purpose of the present invention can be achieved.

[0071] The present invention does not impose a limitation on the stirring time after adding the Form A seed crystals, as long as the purpose of the present invention can be achieved. For example, the stirring time can be 2-4 hours.

[0072] The present invention does not impose any limitation on the temperature and method of adding methyl tert-butyl ether to the concentrate, as long as the purpose of the present invention can be achieved. For example, the temperature of the concentrate is adjusted to 15-25° C., and then methyl tert-butyl ether is added; the methyl tert-butyl ether can be added slowly.

[0073] 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. For example, the amount of methyl tert-butyl ether used can be 2-5 times the volume of acetone in the concentrate.

[0074] The present invention does not impose any limitation on 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 can be adjusted to -5°C to 5°C, and stirring can be continued for 6-10 hours.

[0075] In the present invention, before the wet solid obtained by drying and filtering is washed with methyl tert-butyl ether.

[0076] The present invention does not impose any limitation on the drying time and temperature, as long as the purpose of the present invention can be achieved.

[0077] The present invention further provides a method for preparing the crystalline form C of the compound of formula (I), comprising the following steps: dissolving the crystalline form A of the compound of formula (I) in ethanol until clear; adding water and stirring; centrifuging and drying to obtain the crystalline form C;

[0078] Preferably, the crystalline form A of the compound of formula (I) is dissolved in ethanol until clear; water and crystalline form C seed crystals of the compound of formula (I) are added in sequence and stirred; the mixture is centrifuged and dried to obtain the crystalline form C.

[0079] In some embodiments, the volume ratio of ethanol to water is 1:(2-3).

[0080] The present invention does not impose any limitation on the amount of ethanol used, as long as the purpose of the present invention can be achieved. For example, the amount ratio between Form A of the compound of formula (I) and ethanol can be 0.1-0.5 g / mL.

[0081] 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. For example, the volume ratio of ethanol to water can be 1: (2-3).

[0082] The present invention does not impose any limitation on the amount of Form C seed crystals used, as long as the purpose of the present invention can be achieved.

[0083] 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. For example, the stirring time can be 3-23 hours, and the stirring method can be magnetic stirring.

[0084] The present invention does not impose any limitation on the drying time and temperature, as long as the purpose of the present invention can be achieved. For example, the drying time and temperature can be within the range of 10-30° C. for 12-24 hours.

[0085] The present invention further provides a method for preparing the crystalline form C of the compound of the aforementioned formula (I), comprising 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 obtained as crystalline form C.

[0086] In some embodiments of the present invention, the volume ratio of acetonitrile to water is 1:(2-3).

[0087] The present invention further provides a crystalline composition of the crystalline form of the present invention.

[0088] In some embodiments of the present invention, the crystalline form A of the present invention accounts for more than 50% by weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, and most preferably more than 95%.

[0089] In some embodiments of the present invention, the crystalline form C of the present invention accounts for more than 50% by weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, and most preferably more than 95%.

[0090] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of Form A, Form C, or a mixture thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0091] In the above pharmaceutical composition, the weight ratio of the crystalline form A, crystalline form C or a mixture thereof to the carrier, diluent or excipient is in the range of 0.0001 to 10.

[0092] Preferably, the pharmaceutical composition is for external administration.

[0093] Preferably, the pharmaceutical composition is used for the preparation of an ointment.

[0094] Preferably, the pharmaceutical composition contains 0.01 wt% to 99 wt% of the crystalline form A, crystalline form C or a mixture thereof according to the present invention.

[0095] Preferably, the pharmaceutical composition contains 0.05 wt% to 50 wt% of the crystalline form A, crystalline form C or a mixture thereof according to the present invention.

[0096] Preferably, the pharmaceutical composition contains 0.1 wt% to 30 wt% of the crystalline form A, crystalline form C or a mixture thereof according to the present invention.

[0097] The present invention further provides 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.

[0098] Preferably, the application is to treat, prevent, delay or stop the occurrence or development of inflammation.

[0099] Preferably, the application is for preparing a drug for treating or preventing a disease mediated by PDE4.

[0100] Preferably, the disease is inflammation.

[0101] Preferably, 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.

[0102] Preferably, the use is as a PDE4 inhibitor.

[0103] 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.

[0104] Preferably, in the above method, the disease mediated by PDE4 is inflammation.

[0105] Preferably, in the above method, 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; insulin-resistant diabetes; wounds.

[0106] 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) according to the present invention to a 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, shock or cerebrovascular disease; insulin-resistant diabetes; wounds.

[0107] Preferably, in the above method, the subject to be treated is a human.

[0108] The crystalline forms of the compound (R,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxyphenyl)-2,6-dimethylpyridin-4(1H)-one provided by the present invention have good stability, hygroscopicity and other properties, especially the crystalline forms A and C, which have particularly good effects and good application prospects. In addition, the crystalline forms have better properties than 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.

[0109] Of course, it is not necessary to achieve all of the advantages described above simultaneously in order to implement any product or method of the present invention.

[0110] In the present invention, the term "substantially" as 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 peaks in the figure should not be interpreted as absolute values. Because it is known to those skilled in the art that the 2θ 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° from a given value is considered appropriate. It should also be understood that the relative intensity of the peaks may fluctuate with experimental conditions and 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 intensities. The intensities shown in the XRPD curves included here are only exemplary and cannot be used as absolute comparisons.

[0111] As used herein, a therapeutically effective amount refers to an amount of a drug sufficient to affect treatment of a disease, condition, or symptom in a subject. The therapeutically effective amount may vary depending on the drug, the symptoms of the disease or condition, and the severity of the symptoms of the disease or condition. Wherever possible, an appropriate dosage will be readily apparent to those skilled in the art or can be determined by routine experimentation.

[0112] 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 formation formulated therewith and is safe for animal use. Pharmaceutically acceptable carriers, diluents or excipients that can be used in the crystal formation of the present invention include, but are 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, cellulosic substances (e.g., 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.

[0113] The pharmaceutical composition comprising the crystalline form of the present invention can be administered orally, by nasal inhalation, rectally, parenterally, or topically. For oral administration, the pharmaceutical composition can be prepared into conventional solid dosage forms such as tablets, powders, granules, capsules, etc., or liquid dosage forms such as aqueous or oily suspensions, or other liquid dosage forms such as syrups, solutions, and suspensions. For parenteral administration, the pharmaceutical composition can be prepared into solutions, aqueous solutions, oily suspensions, lyophilized powder injections, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0114] In order to more clearly illustrate the embodiments of the present invention and the technical solutions of the prior art, the following briefly introduces the drawings required for use in the embodiments and the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can also be obtained based on these drawings.

[0115] FIG1 is an X-ray powder diffraction pattern of Form A;

[0116] FIG2 is an overlay of the differential scanning calorimetry spectrum and the thermogravimetric analysis spectrum of Form A;

[0117] Figure 3 is a three-dimensional structural diagram of Form A;

[0118] FIG4 is a dynamic gas phase adsorption diagram of Form A;

[0119] FIG5 is an X-ray powder diffraction pattern of Form B;

[0120] FIG6 is an overlay of the differential scanning calorimetry spectrum and the thermogravimetric analysis spectrum of Form B;

[0121] FIG7 is an X-ray powder diffraction pattern of Form C;

[0122] FIG8 is a polarizing microscope photograph of Form C;

[0123] FIG9 is an overlay of the differential scanning calorimetry spectrum and the thermogravimetric analysis spectrum of Form C;

[0124] Figure 10 is a dynamic gas phase adsorption diagram of Form C;

[0125] FIG11 is an X-ray powder diffraction pattern of Form E;

[0126] FIG12 is an overlay of the differential scanning calorimetry spectrum and the thermogravimetric analysis spectrum of Form E;

[0127] FIG13 is a hydrogen nuclear magnetic resonance spectrum of Form E;

[0128] FIG14 is an X-ray powder diffraction pattern of Form F;

[0129] FIG15 is an overlay of the differential scanning calorimetry spectrum and the thermogravimetric analysis spectrum of Form F;

[0130] FIG16 is a hydrogen nuclear magnetic resonance spectrum of Form F;

[0131] FIG17 is an X-ray powder diffraction pattern of Form G;

[0132] FIG18 is an X-ray powder diffraction pattern of Form H;

[0133] FIG19 is a hydrogen nuclear magnetic resonance spectrum of Form H;

[0134] FIG20 is an X-ray powder diffraction pattern of Form I;

[0135] FIG21 is a comparison of XRPD images of Form I before and after standing at room temperature. DETAILED DESCRIPTION

[0136] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention is further described below with reference to the accompanying drawings and examples. It should be understood that the described examples are only some of the embodiments of the present invention, and not all of them. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention are intended to fall within the scope of protection of the present invention.

[0137] Abbreviations: XRPD: X-ray powder diffraction; TGA: thermogravimetric analysis; DSC: differential scanning calorimetry; 1 H-NMR: proton nuclear magnetic resonance; PLM: polarizing microscope; DVS: dynamic vapor sorption; 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.

[0138] Unless otherwise specified, the detection instrument information and detection methods used in the present invention are as follows:

[0139] (1) X-ray powder diffraction analysis

[0140] X-ray powder diffraction data of the samples were collected under ambient conditions using a Bruker D2 X-ray powder diffractometer with an X-ray emitter power of 300 W. The sample stage had no background signal, the step rate was 0.15 s / step, the total number of steps was 1837, the step length was 2θ = 0.02°, the voltage was 30 kV, and the current was 10 mA. The X-ray tube used a Cu target (Kα) with a Kα2 / Kα1 intensity ratio of 0.50.

[0141] (2) Thermogravimetric analysis

[0142] Thermogravimetric data were collected using a TA Discovery TGA550 thermogravimetric analyzer. Several milligrams of sample were placed in a Tzero aluminum pan and heated from room temperature to 300°C under nitrogen at a flow rate of 25 mL / min and a heating rate of 10°C / min.

[0143] (3) Differential scanning calorimetry

[0144] Thermal data for the samples were collected using a TA Discovery DSC2500 differential scanning calorimeter. Several milligrams of sample were weighed into a Tzero aluminum pan, sealed with a Tzero seal lid. The pan was heated to 300.0°C under nitrogen at a flow rate of 50 mL / min and a heating rate of 10°C / min.

[0145] (4) Polarizing microscope

[0146] The crystal shape was observed at room temperature using an Olympus BX3M-KMA-S polarizing microscope and PLM photographs were taken.

[0147] (5) Dynamic gas adsorption instrument

[0148] Hygroscopicity data of the sample was collected using an ADVENTURE series dynamic gas phase adsorption instrument under N2 protection. The sample size was approximately 30 mg.

[0149] The present invention is described in detail below with reference to specific embodiments.

[0150] The compound of formula (I) used in the present examples was prepared by the method described in Example 100 (paragraphs 0857-0862) of the inventor's patent CN110407741A. XRPD analysis confirmed that the resulting solid was Form I, and its X-ray powder diffraction pattern is shown in Figure 20.

[0151] Example 1: Preparation of Form A

[0152] Weigh 15 mg of the compound of formula (I) in a 4 mL glass vial and dissolve in 2 mL of dichloromethane. Seal the vial with parafilm and poke four holes. Slowly evaporate at room temperature. The separated solid is confirmed to be Form A by XRPD, TGA, and DSC.

[0153] Example 2: Preparation of Form A

[0154] In a first reaction kettle, 2.20 kg of the compound of formula (I) and 30 L of acetone were mixed, the temperature was raised to 50° C., and stirring was performed to dissolve; the dissolved mixed solution was transferred to a second reaction kettle, rinsed with 2 L of acetone, and stirred at 50° C. until the solution became clear; the temperature was adjusted to 40° C., 2 g of Form A seed crystals were added, and the mixture was stirred for 2 hours; the temperature was lowered to 10° C., and the mixture was concentrated under reduced pressure until the concentration of the concentrate reached 10 L, and the concentration was stopped; the temperature was adjusted to 15° C., 40 L of methyl tert-butyl ether was slowly added to the concentrate, and the mixture was stirred for 6 hours; the temperature was lowered to -5° C., and stirring was continued for 6 hours; the mixture was filtered, and the filter cake was washed with methyl tert-butyl ether to obtain 1.8 kg of a solid. After drying, the obtained solid was determined to be Form A by XRPD, TGA, DSC, etc.

[0155] Example 3: Preparation of Form B

[0156] Under nitrogen protection, 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.

[0157] Example 4: Preparation of Form C

[0158] 20 mg of Form A was added to 0.3 mL of ACN / H₂O (1:3, v / v) and magnetically stirred at room temperature to obtain a suspension. After approximately 5 days, a solid was isolated and dried at room temperature. XRPD, TGA, and DSC analysis confirmed the solid to be Form C.

[0159] Example 5: Preparation of Form C

[0160] 2.0 mL of ethanol was added to 200.8 mg of Form A to obtain a clear solution; water was added dropwise to the clear solution under magnetic stirring, and turbidity appeared after adding 4.0 mL of water; 2.0 mg of Form C seed crystals were added, and magnetic stirring was continued for 23 h; centrifugation was performed, and the collected solid was dried at room temperature. XRPD, TGA, DSC, etc. determined that the obtained solid was Form C.

[0161] Example 6: Preparation of Form E

[0162] Weigh 15 mg of Form A into a 4 mL glass vial and add 2 mL of MEK to dissolve. Seal the vial with parafilm and poke four holes. Slowly evaporate the solution at room temperature. Allow to evaporate for approximately 3 days. Isolate the solid, dry it at room temperature, and analyze it using XRPD, TGA, and DSC to determine that the resulting solid is Form E.

[0163] Example 7: Preparation of Form F

[0164] 15 mg of Form A was weighed into a 4 mL glass vial. The sample was dissolved in 0.5 mL of MeOH (positive solvent) and placed into a 20 mL glass vial containing 3 mL of MTBE (antisolvent). The 20 mL glass vial was tightly capped and left at room temperature until solid precipitated. The isolated solid was dried at room temperature and analyzed by XRPD, TGA, and DSC, confirming it to be Form F.

[0165] Example 8: Preparation of Form G

[0166] Weigh 15 mg of Form A sample into a 20 mL glass vial. Add 1 mL of Acetone (positive solvent) to dissolve the sample. Under magnetic stirring, gradually add CPME (antisolvent) to the vial until the total volume reaches 15.0 mL. Stir at 5°C until solid precipitates. Isolate the solid, dry it at room temperature, and determine it as Form G using XRPD and other methods.

[0167] Example 9: Preparation of Form H

[0168] Under N2 protection, Form F was heated to 75°C and then cooled to room temperature. The obtained solid was determined to be Form H by XRPD, TGA, DSC, etc.

[0169] Example 10: Single crystal X-ray diffraction (SXRD) experiment

[0170] Form A single crystal (monoclinic) was prepared in dichloromethane by natural solvent evaporation. Crystal data were collected using a Bruker D8 Venture diffractometer with a GaKα (λ=1.34139) diffraction system and analyzed using the Bruker Apex3 program. Figure 3 shows the three-dimensional structure of Form A.

[0171] Example 11: Thermodynamic analysis experiment

[0172] Form A was heated to 180° C. under N 2 protection and then cooled to room temperature before XRPD analysis of the solid was performed.

[0173] Results: After heating Form A to 180°C and cooling to room temperature, Form A transformed into Form B.

[0174] Analysis: According to the Burger-Ramberger rule, 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.

[0175] Example 12: Suspension competition experiment

[0176] At room temperature and 60°C, suspension competition experiments were performed using Form A and Form B using MEK, EtOAc, and Toluene as solvents.

[0177] The specific procedure was as follows: 4 portions of excess Form A were weighed into four HPLC vials, 0.5 mL of the corresponding solvent was added to each vial, and the mixture was magnetically stirred at room temperature and 60°C for approximately 2 hours. Saturated solutions were then filtered through a nylon membrane (pore size 0.22 μm) to obtain saturated solutions. Approximately 5 mg each of Form A and Form B were added to the saturated filtrates, and the mixture was magnetically stirred at room temperature or 60°C for approximately 1 day. The solids were then centrifuged and isolated for XRPD analysis. The results of the suspension competition experiment are shown in Table 8.

[0178] Table 8 Suspension competition experiment results

[0179] The results showed that the solids obtained in both solvents at room temperature and 60°C were all Form A. It can be seen that compared with Form B, Form A is more stable at both room temperature and 60°C.

[0180] Example 13: Water activity experiment

[0181] At room temperature, prepare the target water activity (A w The water activities of the systems corresponding to the IPA / H2O volume ratios (0, 0.2, 0.4, 0.6, 0.8, and 1.0, respectively) were reported in Table 9. 15-30 mg of Form A was added to the above IPA / H2O solutions, stirred at room temperature for approximately 2 hours to obtain a suspension, which was then filtered through a nylon membrane (pore size 0.22 μm). Approximately 5 mg of Form C and Form A were weighed into HPLC vials, and the corresponding filtrates were added. After stirring at room temperature for approximately 3 days, XRPD analysis was performed. The water activity test results are shown in Table 9.

[0182] Table 9 Water activity test results

[0183] The experimental results show that 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, i.e., at low water activity, Form A is more stable; when the water activity is 0.4-1.0, i.e., at high water activity, Form C is more stable; the critical water activity of Form A and Form C is 0.2-0.4.

[0184] Example 14: Hygroscopicity Test

[0185] The dynamic moisture adsorption measurement results of Form A and Form C are shown in Figures 4 and 10, respectively.

[0186] Analysis: 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 approximately 0.1%, indicating that Form C is not hygroscopic.

[0187] Example 15: Crystal stability test

[0188] 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 pattern of the solid changed, as shown in Figure 21.

[0189] The results show that during the storage process, the crystal form I partially transformed into the crystal form G. It can be seen that the crystal form I is unstable at room temperature.

[0190] Example 16: Stability Test

[0191] The stability of the crystal forms of the present invention was determined. The crystal forms A, B, C, E, F, and H of the compound of formula (I) were placed in a 4500 Lux illumination environment, a 60°C high temperature environment, and a 90% RH ± 5% RH high humidity environment for stability testing. Samples were taken on the 0th day, the 5th day, the 10th day, and the 30th day. The appearance, moisture content, and total related substances of the samples were recorded and compared with the initial data. The comparison results showed that the crystal forms of the present invention all had good stability, especially the crystal forms A and C had better stability.

[0192] Example 17 Accelerated stability test

[0193] The crystalline form A of the compound of formula (I) was placed under two accelerated test conditions, 25°C, 60% RH and 40°C, 75% RH, for 6 months. Samples were taken at 1 month, 3 months, and 6 months, respectively. The purity was tested by HPLC and characterized by XRPD. The results were compared with the results at day 0. The results are shown in Table 10:

[0194] Table 10

[0195] The results showed that Form A maintained a stable content within 6 months under accelerated stability test conditions and no crystal form transformation occurred.

[0196] From the above content, it can be seen that the new crystalline form of the compound (R, E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxyphenyl)-2,6-dimethylpyridin-4(1H)-one provided by the present invention has good stability; the preparation method is simple to operate and has good reproducibility, which can meet the needs of large-scale industrial production.

[0197] Each embodiment in this specification is described in a related manner. The same or similar parts between the embodiments can be referred to each other. Each embodiment focuses on the differences from other embodiments.

[0198] The above description is only a preferred embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention are included in the scope of protection of the present invention.

Claims

1. A crystalline form A of a compound of formula (I), It is characterized in that The X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ 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°.

2. The crystalline form A according to claim 1, It is characterized in that The X-ray powder diffraction pattern has characteristic peaks at 2θ 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°.

3. The crystalline form A according to claim 1 or 2, It is characterized in that The data of the X-ray powder diffraction pattern of the crystalline form A are basically as shown in Table 1.

4. The crystalline form A according to any one of claims 1 to 3, It is characterized in that The X-ray powder diffraction pattern of the crystalline form A is substantially as shown in FIG1 .

5. A crystalline form C of a compound of formula (I), It is characterized in that The X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 2θ 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°.

6. The crystalline form C according to claim 5, It is characterized in that The X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 2θ 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°.

7. The crystalline form C according to claim 5 or 6, It is characterized in that The data of the X-ray powder diffraction pattern of the crystalline form C are basically as shown in Table 3.

8. The crystalline form C according to any one of claims 5 to 7, It is characterized in that The X-ray powder diffraction pattern of the crystalline form C is substantially as shown in FIG7 .

9. A pharmaceutical composition, It is characterized in that Comprising an effective therapeutic amount of the crystalline form A according to any one of claims 1 to 4, the crystalline form C according to any one of claims 5 to 8, or a mixture thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

10. A method for preparing the crystalline form A according to any one of claims 1 to 4, It is characterized in that The method comprises the following steps: dissolving the compound of formula (I) in acetone; concentrating, adding methyl tert-butyl ether, filtering, and obtaining the crystalline form A; preferably, dissolving the compound of formula (I) in acetone; Add crystal form A seed crystals and stir; concentrate, add methyl tert-butyl ether to the obtained concentrated solution, adjust the temperature to -5°C to 5°C, and stir; filter, separate, and dry to obtain the crystal form A.

11. A method for preparing the crystalline form C according to any one of claims 5 to 8, It is characterized in that The method comprises the following steps: dissolving the crystalline form A of the compound of formula (I) according to any one of claims 1 to 4 in ethanol until it is clear; adding water and stirring; centrifuging and drying to obtain the crystalline form C; preferably, dissolving the crystalline form A of the compound of formula (I) in ethanol until it is clear; adding water and crystalline form C seed crystals in sequence and stirring; centrifuging and drying to obtain the crystalline form C.

12. Use of the crystalline form A according to any one of claims 1 to 4, the crystalline form C according to any one of claims 5 to 8 or a mixture thereof, or the pharmaceutical composition according to claim 9 in the preparation of a drug.

13. The use according to claim 12, It is characterized in that The drug is used to treat, prevent, delay or stop the occurrence or development of inflammation.

14. The use according to claim 12, It is characterized in that The medicament is used for treating diseases mediated by PDE4.

15. The use according to claim 14, It is characterized in that The disease is inflammation.

16. The use according to claim 15, It is characterized in that The inflammation is an inflammatory allergic disease, an autoimmune disease, an acute or chronic skin wound disease, a central nervous system disease, an organ disease associated with ischemic reflux caused by heart failure, shock or cerebrovascular disease, insulin-resistant diabetes or a wound.

17. Use of the crystalline form A according to any one of claims 1 to 4, the crystalline form C according to any one of claims 5 to 8 or a mixture thereof, or the pharmaceutical composition according to claim 9 in the preparation of a PDE4 inhibitor.

18. A method for treating and / or preventing diseases mediated by PDE4, It is characterized in that The method administers the crystalline form A according to any one of claims 1 to 4, the crystalline form C according to any one of claims 5 to 8, or a mixture thereof, or the pharmaceutical composition according to claim 9 to a patient in need thereof.

19. The method according to claim 18, It is characterized in that The disease is inflammation.

20. The method according to claim 19, It is characterized in that The inflammation is an inflammatory allergic disease, an autoimmune disease, an acute or chronic skin wound disease, a central nervous system disease, an organ disease associated with ischemic reflux caused by heart failure, shock or cerebrovascular disease, insulin-resistant diabetes or a wound.

21. A method for treating inflammation, It is characterized in that The method comprises administering the crystalline form A according to any one of claims 1 to 4, the crystalline form C according to any one of claims 5 to 8, or a mixture thereof, or the pharmaceutical composition according to claim 9 to a patient in need thereof.

22. The method according to claim 21, It is characterized in that The inflammation is an inflammatory allergic disease, an autoimmune disease, an acute or chronic skin wound disease, a central nervous system disease, an organ disease associated with ischemic reflux caused by heart failure, shock or cerebrovascular disease, insulin-resistant diabetes or a wound.