Crystalline forms of acrylic acid derivatives, their preparation methods and uses

Abstract

Crystalline forms A, B, C, D, E, F, G, and H of the compound of formula I and methods for their preparation, as well as the pharmaceutical uses and respective advantages of each crystalline form, are disclosed.

Description

cross reference

[0001] This application claims priority from Chinese Patent Application No. 201910438024.8, filed with the China Patent Office on May 24, 2019, entitled "Crystalline Form of Acrylic Acid Derivatives and Preparation Method and Use Thereof," the entire contents of which are incorporated herein by reference. [Technical Field]

[0002] The present invention belongs to the chemical and pharmaceutical field. Specifically, the present invention relates to novel crystalline forms A, B, C, D, E, F, G, and H of (E)-3-(3,5-difluoro-4-((1R,3R)-2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid, an acrylic acid derivative, and their preparation methods. Furthermore, the present invention relates to pharmaceutical compositions containing the novel crystalline forms and their medical uses. [Background technology]

[0003] Estrogen receptors (ERs) are ligand-activated transcriptional regulator proteins that mediate various biological effects through interaction with endogenous estrogens. Endogenous estrogens include 17β-estradiol and estrone. ERs have two subtypes: estrogen receptor α (ERα, ESR1, and NR3A) and estrogen receptor β (ERβ, ESR2 and NR3b). Estrogen receptor α and estrogen receptor β are members of the nuclear receptor family, a family of steroid hormone receptors. Similar to the mechanism of nuclear receptors, ERα is composed of six functional domains (designated AFs). After binding specific ligands (including the endogenous estrogen 17β-estradiol (E2)), ERα is a ligand-activated transcription factor that binds to genomic sequences to form complexes, i.e., estrogen receptor response elements (ERRs) and coregulators, which regulate the transcription of target genes. The ERα gene, located on 6q25.1, encodes a 595A protein, with distinct subtypes resulting from differences in splicing sites and transcription start sites. In addition to a DNA-binding motif (domain C) and a ligand-binding motif (domain E), the receptor also contains an N-terminal (A / B) domain, a hinge region (D connecting domains C and E), and a carbon terminal (F) domain. The C and E domains of ERα and ERβ are identical, while the A / B, D, and F domains are less identical. Both receptors are involved in the regulation and development of the female reproductive tract and also play important roles in the central nervous system, cardiovascular and cerebrovascular systems, and bone metabolism. Estrogen binding to the receptor can induce various cellular changes, and these regulatory mechanisms can be divided into two pathways: genomic and non-genomic. The ER-mediated genomic pathway involves the formation of estrogen receptor dimers, ERE binding to estrogen-regulated gene promoters, mediating the aggregation of other regulatory proteins to the promoters, and ultimately increasing or decreasing the mRNA levels of the gene.In the estrogen-mediated non-genomic pathway, estrogen can react with estrogen-binding proteins present in or adjacent to the plasma membrane of ERs, or even in the plasma membrane of cells lacking ERs. The cellular response triggered by estrogen via the non-genomic pathway increases intracellular calcium ion and NO levels, and activates various intracellular kinases, including MAPK, PI3K, PKA, and PKC, which can phosphorylate and activate nERs.

[0004] Approximately 70% of breast cancer patients express ER and / or progesterone receptors, indicating that the growth of these tumor cells is hormone-dependent. The growth of other tumors, such as ovarian and endometrial cancers, is also dependent on ERα. Treatment of these diseases can be achieved by inhibiting ER signaling in various ways, such as by antagonizing ligand binding to ER, antagonizing or downregulating ERα, or blocking estrogen synthesis. ERα and ERβ are also found in endocrine tumors, such as adrenocortical tumors, pancreatic cancer, prostate cancer, and thyroid cancer; digestive tumors, such as colon cancer, esophageal cancer, liver cancer, and pancreatic cancer; and lung cancer. While these treatments work to some extent in patients with ER-positive tumors, drug resistance can develop. Recently, mutations in ESR1 have been reported to be one of the reasons for drug resistance in patients with metastatic ER-positive breast cancer (Toyetal., Nat. Genetics 2013, 45:1439-1445; Li, S. et al. Cell Rep. 4, 1116-1130 (2013)). However, one possible mechanism of drug resistance under discussion is that tumor growth is dependent on ERα activity. Therefore, selective downregulation of ERα provides a promising approach to block ERα activity, which mediates early-stage, metastatic, and drug-resistant cancer.

[0005] Currently, many acrylic acid derivative drugs that can be used as selective estrogen receptor downregulators (degraders) have been disclosed, including Genentech's GDC-0810 and GDC-0927, which are in Phase II and Phase I clinical trials, respectively, and AstraZeneca's AZD-9496, which is in Phase I clinical trial. In addition, a series of patent applications for acrylic acid derivatives have been disclosed, including WO2011156518, WO2012037410, WO2015082990, etc. However, research and development of new estrogen receptor alpha downregulators is still needed.

[0006] WO2017080338A1 discloses an acrylic acid derivative having the structure of the following formula I, whose molecular formula is C 25 H 23 It is F3N2O2, and its chemical name is (E)-3-(3,5-difluoro-4-((1R,3R)-2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid. Furthermore, WO2017080338A1 discloses a method for preparing the compound represented by formula I and its use as an estrogen receptor antagonist or estrogen receptor α downregulator, and demonstrates that the compound has good ERα downregulation activity. JPEG0007736570000001.jpg67160

[0007] However, the compound of formula I disclosed in WO2017080338A1 is prepared in a yellow solid form in amorphous form, and its stability and particle size are still unsatisfactory. In particular, the amorphous particles disclosed in WO2017080338A1 have small particle size and poor flowability, making them unsuitable for molding into solid preparations (e.g., tablets, capsules, or granules).

[0008] Currently, the prior art has not disclosed any form of the compound of formula I that is suitable for formulation and has good stability, nor has there been any report on the crystalline form of the compound of formula I. The present inventors have obtained the crystalline form of the compound of formula I through numerous experiments. Summary of the Invention

[0009] In view of the problems in the prior art described above, the present invention provides a crystalline form of the compound (E)-3-(3,5-difluoro-4-((1R,3R)-2-((1-fluorocyclopropyl)methyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid having the structure represented by the following formula I, and a method for preparing the same. JPEG0007736570000002.jpg67160

[0010] In a first aspect, the present invention provides crystalline form A of the compound of formula I (hereinafter referred to as "crystalline form A").

[0011] The crystalline form A has characteristic peaks in its powder X-ray diffraction (XRPD) pattern using Cu-Kα radiation at 2θ degrees of 10.5±0.2°, 12.3±0.2°, 14.9±0.2°, 16.2±0.2°, 18.1±0.2°, 19.4±0.2°, 20.3±0.2°, and 24.4±0.2°.

[0012] Preferably, the crystalline form A has characteristic peaks in a powder X-ray diffraction pattern using Cu-Kα radiation at angles 2θ, expressed in degrees, of 10.5±0.2°, 12.3±0.2°, 13.6±0.2°, 14.2±0.2°, 14.9±0.2°, 16.2±0.2°, 17.1±0.2°, 18.1±0.2°, 19.4±0.2°, 20.3±0.2°, 22.8±0.2°, and 24.4±0.2°.

[0013] More preferably, the crystalline form A has characteristic peaks and relative intensities in a powder X-ray diffraction pattern using Cu-Kα radiation at 2θ degrees of the following positions: JPEG0007736570000003.jpg84161

[0014] More preferably, the crystalline form A has an X-ray powder diffraction pattern essentially as shown in FIG.

[0015] Furthermore, the crystalline form A has an endothermic peak at 110 to 150° C. in a differential scanning calorimetry (DSC) curve. The DSC curve is basically as shown in FIG.

[0016] Furthermore, the thermogravimetric analysis (TGA) curve of crystalline form A is essentially as shown in Figure 3. The water content of crystalline form A measured with a Karl Fischer moisture meter was 3.9%, and the TGA curve showed a weight loss of 3.9%, indicating that crystalline form A is a monohydrate of the compound of formula I.

[0017] Furthermore, the single crystal of the monohydrate of the compound of formula I has an orthorhombic crystal system, a P212121 space group, a = 7.33580(10) Å, b = 14.3722(2) Å, c = 41.3094(7) Å, and α = β = γ = 90°. The structural formula of the monohydrate of the compound of formula I is as follows: JPEG0007736570000004.jpg75160

[0018] Accordingly, the present invention provides a method for preparing crystalline form A, which is any one of the following methods:

[0019] Method (1): Adding a compound of formula I to a solvent, 、 Water or C1-C3 alcohols and water A suspension is obtained, and the suspension is stirred at 5 to 50°C for 1 to 7 days to form a crystal slurry. The solid is then separated and dried in vacuum at 20 to 60°C for 8 to 24 hours to obtain crystalline form A.

[0020] Preferably, in the method (1), the C1 to C3 alcohol is one or more selected from methanol, ethanol, n-propanol, and isopropanol.

[0021] Preferably, in the method (1), the weight / volume ratio of the compound represented by formula I to the solvent is 1:2 to 1:10 (g / mL).

[0022] Method (2): The compound of formula I is dissolved in a C1-C3 alcohol to obtain a clear liquid, and then water is added until a cloudy liquid precipitates. The solid is separated and dried at 20-60°C for 8-24 hours to obtain crystalline form A.

[0023] Preferably, in the method (2), the C1 to C3 alcohol is one or more selected from methanol, ethanol, n-propanol, and isopropanol.

[0024] Preferably, in the method (2), the weight-volume ratio of the compound represented by formula I to the C1-C3 alcohol is 1:5 to 1:20 (g / mL); Preferably, in the method (2), the weight-volume ratio of the compound represented by formula I to water is 1:3 to 1:100 (g / mL).

[0025] In another aspect, the present invention provides a pharmaceutical composition containing as an active ingredient a therapeutically effective amount of crystalline form A. Preferably, in said pharmaceutical composition, crystalline form A can be mixed with one or more pharmaceutically acceptable solid or liquid diluents and / or excipients to prepare a galenic formulation.

[0026] In another aspect, the present invention provides use of crystalline Form A or a pharmaceutical composition thereof in the manufacture of a medicament for treating an estrogen receptor-mediated disease, wherein the disease is cancer, preferably the cancer is breast cancer or gynecological cancer, preferably the gynecological cancer is ovarian cancer or endometrial cancer, and preferably the estrogen receptor is estrogen receptor alpha.

[0027] In another aspect, the present invention provides use of crystalline form A or a pharmaceutical composition thereof in the manufacture of a selective estrogen receptor downregulator, wherein the selective estrogen receptor downregulator is preferably an estrogen receptor alpha downregulator.

[0028] The present invention further provides a method for treating an estrogen receptor mediated disease comprising administering a therapeutically effective amount of crystalline form A to an individual in need thereof, wherein said disease is cancer, preferably said cancer is breast cancer or gynecological cancer, preferably said gynecological cancer is ovarian cancer or endometrial cancer, and preferably said estrogen receptor is estrogen receptor alpha.

[0029] The present invention further provides a method for selectively downregulating an estrogen receptor, which comprises contacting an estrogen receptor with crystalline form A or a pharmaceutical composition thereof, wherein the estrogen receptor is preferably estrogen receptor α.

[0030] In another embodiment, the present invention provides crystalline form B of the compound of formula I (hereinafter referred to as "crystalline form B").

[0031] The crystalline form B has characteristic peaks in its powder X-ray diffraction (XRPD) pattern using Cu-Kα radiation at 2θ degrees of 5.5±0.2°, 9.9±0.2°, 10.7±0.2°, 12.7±0.2°, 16.2±0.2°, 16.7±0.2°, and 23.0±0.2°.

[0032] Preferably, the crystalline form B has characteristic peaks in a powder X-ray diffraction pattern using Cu-Kα radiation at angles 2θ, expressed in degrees, of 5.5±0.2°, 9.9±0.2°, 10.7±0.2°, 12.7±0.2°, 14.5±0.2°, 16.2±0.2°, 16.7±0.2°, 19.7±0.2°, 23.0±0.2°, and 24.8±0.2°.

[0033] More preferably, the crystalline form B has characteristic peaks and relative intensities in a powder X-ray diffraction pattern using Cu-Kα radiation at 2θ degrees of the following positions: JPEG0007736570000005.jpg75161

[0034] More preferably, said crystalline form B has a powder X-ray diffraction pattern essentially as shown in FIG.

[0035] Furthermore, the DSC curve of the crystalline form B has an endothermic peak at 110 to 135° C. The DSC curve is basically as shown in FIG.

[0036] Furthermore, the TGA curve of crystalline form B is essentially as shown in Figure 6. The water content of crystalline form B measured by a Karl Fischer moisture meter was 3.9%, and the TGA curve showed a weight loss of 3.9%, indicating that crystalline form B is a monohydrate of compound of formula I.

[0037] In accordance with the above, the present invention provides: A method for preparing crystalline form B is provided, which comprises adding the compound of formula I to a water-saturated halogenated hydrocarbon solution to form a suspension, stirring the crystalline slurry at 5-40°C for 0.5-36 hours, separating the solid, and drying it under vacuum at 20-40°C for 8-24 hours to obtain crystalline form B.

[0038] Preferably, the halogenated hydrocarbon is one or more selected from dichloromethane, dichloroethane, trichloromethane, and dibromomethane; Preferably, the weight / volume ratio of the compound represented by formula I to the water-saturated halogenated hydrocarbon is 1:3 to 1:4 (g / mL).

[0039] In another aspect, the present invention provides a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of crystalline form B. Preferably, in said pharmaceutical composition, crystalline form B can be mixed with one or more pharmaceutically acceptable solid or liquid diluents and / or excipients to prepare a galenical formulation.

[0040] In another aspect, the present invention provides use of crystalline Form B or a pharmaceutical composition thereof in the manufacture of a medicament for treating an estrogen receptor-mediated disease, wherein the disease is cancer, preferably the cancer is breast cancer or gynecological cancer, preferably the gynecological cancer is ovarian cancer or endometrial cancer, and preferably the estrogen receptor is estrogen receptor alpha.

[0041] In another aspect, the present invention provides use of crystalline form B or a pharmaceutical composition thereof in the manufacture of a selective estrogen receptor downregulator, wherein the selective estrogen receptor downregulator is preferably an estrogen receptor alpha downregulator.

[0042] The present invention further provides a method for treating an estrogen receptor mediated disease comprising administering a therapeutically effective amount of crystalline form B to an individual in need thereof, wherein said disease is cancer, preferably said cancer is breast cancer or gynecological cancer, preferably said gynecological cancer is ovarian cancer or endometrial cancer, and preferably said estrogen receptor is estrogen receptor alpha.

[0043] Furthermore, the present invention provides a method for selectively downregulating an estrogen receptor, which method comprises contacting an estrogen receptor with crystalline form B or a pharmaceutical composition thereof, wherein the estrogen receptor is preferably estrogen receptor alpha.

[0044] In another embodiment, the present invention provides crystalline form C of the compound of formula I (hereinafter referred to as "crystalline form C").

[0045] The crystalline form C has characteristic peaks in its powder X-ray diffraction (XRPD) pattern using Cu-Kα radiation at 2θ degrees of 4.5±0.2°, 5.7±0.2°, 8.5±0.2°, 12.2±0.2°, 14.0±0.2°, 16.7±0.2°, and 23.0±0.2°.

[0046] Preferably, the crystalline form C has characteristic peaks and relative intensities in a powder X-ray diffraction pattern using Cu-Kα radiation at the following 2θ degrees: JPEG0007736570000006.jpg53161

[0047] More preferably, the crystalline form C has an X-ray powder diffraction pattern essentially as shown in FIG.

[0048] Furthermore, the DSC curve of crystalline form C has an endothermic peak at 100 to 140° C. The DSC curve is basically as shown in FIG.

[0049] Furthermore, the TGA curve of crystalline form C is essentially as shown in Figure 9. The water content of crystalline form C measured by a Karl Fischer moisture meter was 3.9%, and the TGA curve showed a weight loss of 3.9%, indicating that crystalline form C is a monohydrate of compound of formula I.

[0050] In accordance with the above, the present invention provides: A method for preparing crystalline form C is provided, which comprises adding the compound of formula I to a water-saturated halogenated hydrocarbon solution to form a suspension, stirring the crystalline slurry at 5-40°C for 2-7 days, isolating the solid, and drying it in vacuum at 20-40°C for 8-24 hours to obtain crystalline form C.

[0051] The halogenated hydrocarbon is one or more selected from the group consisting of dichloromethane, dichloroethane, trichloromethane, and dibromomethane.

[0052] Preferably, the halogenated hydrocarbon is one or more selected from dichloromethane, dichloroethane, trichloromethane, and dibromomethane, and the weight / volume ratio of the compound represented by formula I to the water-saturated halogenated hydrocarbon is preferably 1:15 to 1:50 (g / mL).

[0053] In another aspect, the present invention provides a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of crystalline form C. Preferably, in said pharmaceutical composition, crystalline form C can be mixed with one or more pharmaceutically acceptable solid or liquid diluents and / or excipients to prepare a galenic formulation.

[0054] In another aspect, the present invention provides the use of crystalline Form C or a pharmaceutical composition thereof in the manufacture of a medicament for treating an estrogen receptor-mediated disease, wherein the disease is cancer, preferably the cancer is breast cancer or gynecological cancer, preferably the gynecological cancer is ovarian cancer or endometrial cancer, and preferably the estrogen receptor is estrogen receptor alpha.

[0055] In another aspect, the present invention provides use of crystalline form C or a pharmaceutical composition thereof in the manufacture of a selective estrogen receptor downregulator, wherein the selective estrogen receptor downregulator is preferably an estrogen receptor alpha downregulator.

[0056] The present invention also provides a method for treating an estrogen receptor mediated disease, comprising administering a therapeutically effective amount of crystalline form C to an individual in need thereof, wherein the disease is cancer, preferably, the cancer is breast cancer or gynecological cancer, and the gynecological cancer is ovarian cancer or endometrial cancer, and preferably, the estrogen receptor is estrogen receptor alpha.

[0057] Furthermore, the present invention provides a method for selectively downregulating an estrogen receptor, which method comprises contacting an estrogen receptor with crystalline form C or a pharmaceutical composition thereof, wherein the estrogen receptor is preferably estrogen receptor alpha.

[0058] In another aspect, the present invention provides crystalline form D of the compound of formula I (hereinafter referred to as "crystalline form D"), which has characteristic peaks in degrees 2θ of 9.5±0.2°, 19.0±0.2°, 19.7±0.2°, 21.3±0.2°, and 21.8±0.2° in an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation.

[0059] In a specific embodiment, crystalline form D according to the present invention has characteristic peaks at angles 2θ, expressed in degrees, of 7.1±0.2°, 9.5±0.2°, 10.6±0.2°, 14.2±0.2°, 15.2±0.2°, 17.8±0.2°, 19.0±0.2°, 19.7±0.2°, 21.3±0.2°, and 21.8±0.2° in a powder X-ray diffraction pattern using Cu-Kα radiation.

[0060] In a more specific embodiment, the crystalline form D has characteristic peaks at 7.1±0.2°, 9.5±0.2°, 10.6±0.2°, 11.8±0.2°, 12.7±0.2°, 14.2±0.2°, 15.2±0.2°, 17.8±0.2°, 19.0±0.2°, 19.7±0.2°, 20.7±0.2°, 21.3±0.2°, 21.8±0.2°, 23.8±0.2°, 24.2±0.2°, and 27.7±0.2°, expressed in degrees, in an X-ray powder diffraction pattern using Cu-Kα radiation.

[0061] In one embodiment, the crystalline form D has an X-ray powder diffraction pattern essentially as shown in FIG.

[0062] In another embodiment, the DSC curve of the crystalline form D has an endothermic peak at 110 to 120° C. The DSC curve is essentially as shown in FIG.

[0063] In one embodiment, the crystalline form D is a butanone solvate, and its single crystal data indicates that it is orthorhombic, P212121 space group, a=8.4557(4) Å, b=16.7248(9) Å, c=18.6864(10) Å, α=β=γ=90°.

[0064] The present invention relates to a process for preparing crystalline form D, which is any one of the following processes: Method (1): The compound of formula I is added to butanone to form a clear solution, and then water is added until a cloudy liquid precipitates. The solid is solidified under stirring, separated, and dried in vacuum at 20-40°C for 8-24 hours to obtain crystalline form D.

[0065] Method (2): The compound of formula I is added to butanone to form a suspension, and the suspension is stirred at 20-40°C for 1-3 days. The solid is then separated and dried in vacuum at 20-40°C for 8-24 hours to obtain crystalline form D.

[0066] In one aspect, the present invention relates to a crystalline form E of the compound of formula I (hereinafter referred to as "crystalline form E"), having characteristic peaks in an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation at angles 2θ, expressed in degrees, of 9.1±0.2°, 10.6±0.2°, 11.1±0.2°, 11.9±0.2°, 14.4±0.2°, 18.2±0.2°, 19.0±0.2°, 20.3±0.2°, and 21.8±0.2°.

[0067] In a specific embodiment, the crystalline form E has characteristic peaks in a powder X-ray diffraction pattern using Cu-Kα radiation at angles 2θ, expressed in degrees, of 9.1±0.2°, 10.6±0.2°, 11.1±0.2°, 11.9±0.2°, 12.7±0.2°, 13.9±0.2°, 14.4±0.2°, 15.9±0.2°, 18.2±0.2°, 19.0±0.2°, 20.3±0.2°, 21.8±0.2°, 24.1±0.2°, 25.2±0.2°, and 25.8±0.2°.

[0068] In one embodiment, the crystalline form E has an X-ray powder diffraction pattern essentially as shown in FIG.

[0069] In another embodiment, the DSC curve of the crystalline form E has an endothermic peak at 110 to 130° C. The DSC curve is essentially as shown in FIG.

[0070] In one embodiment, the crystalline form E is an acetone solvate.

[0071] In another aspect, the present invention relates to a method for preparing crystalline form E, characterized in that it is any one of the following methods: Method (1): Add the compound of formula I to acetone to form a clear solution, add water or n-heptane until a cloudy liquid precipitates, and then add the solution to solidify the solution under stirring. The solid is separated and dried in vacuum at 20-40°C for 8-24 hours to obtain crystalline form E.

[0072] Method (2): The compound of formula I is added to acetone or a mixed solution of acetone and n-heptane to form a suspension, and the suspension is stirred at 20-40°C for 1-3 days. The solid is then separated and vacuum-dried at 20-40°C for 8-24 hours to obtain crystalline form E.

[0073] In one aspect, the present invention relates to crystalline form F of the compound of formula I (hereinafter referred to as "crystalline form F"), having characteristic peaks in an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation at angles 2θ, expressed in degrees, of 4.4±0.2°, 8.8±0.2°, 13.5±0.2°, 14.9±0.2°, 15.6±0.2°, 16.6±0.2°, 17.9±0.2°, 22.8±0.2°, and 30.1±0.2°.

[0074] In a specific embodiment, the crystalline form F has characteristic peaks at angles 2θ, expressed in degrees, of 4.4±0.2°, 8.8±0.2°, 11.6±0.2°, 13.5±0.2°, 14.9±0.2°, 15.6±0.2°, 16.6±0.2°, 17.9±0.2°, 18.6±0.2°, 19.7±0.2°, 21.1±0.2°, 22.0±0.2°, 22.8±0.2°, 23.9±0.2°, 24.4±0.2°, and 30.1±0.2° in a powder X-ray diffraction pattern using Cu-Kα radiation.

[0075] In one embodiment, the crystalline form F has an X-ray powder diffraction pattern essentially as shown in FIG.

[0076] In another embodiment, the DSC curve of crystalline form F has an endothermic peak at 90 to 110° C. The DSC curve is essentially as shown in FIG.

[0077] In one embodiment, the crystalline form F is a 1,4-dioxane solvate.

[0078] In another aspect, the present invention relates to a process for preparing crystalline form F, which comprises adding compound of formula I to 1,4-dioxane to form a clear solution, adding water until a cloudy solution precipitates, stirring to solidify, separating the solid, and drying it under vacuum at 20-40°C for 24 hours to obtain crystalline form F.

[0079] In one aspect, the present invention relates to a crystalline form G of the compound of formula I (hereinafter referred to as "crystalline form G"), which has characteristic peaks in an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation at angles 2θ, expressed in degrees, of 4.3±0.2°, 5.9±0.2°, 8.8±0.2°, 12.6±0.2°, 14.4±0.2°, 17.7±0.2°, and 21.0±0.2°.

[0080] In one embodiment, the crystalline form G has an X-ray powder diffraction pattern essentially as shown in FIG.

[0081] In another embodiment, the DSC curve of the crystalline form G has an endothermic peak at 100 to 130° C. The DSC curve is essentially as shown in FIG.

[0082] In one embodiment, the crystalline form G is a methyl tert-butyl ether solvate.

[0083] In another aspect, the present invention relates to a process for preparing crystalline form G, which comprises adding compound of formula I to methyl tert-butyl ether to form a suspension, stirring the crystalline slurry at 20-40°C for 1-3 days, and then isolating the solid and drying it under vacuum at 20-40°C for 8 hours to obtain crystalline form G.

[0084] In one aspect, the present invention relates to a crystalline form H of the compound of formula I (hereinafter referred to as "crystalline form H"), having characteristic peaks in an X-ray powder diffraction (XRPD) pattern using Cu-Kα radiation at angles 2θ, expressed in degrees, of 4.7±0.2°, 5.6±0.2°, 9.1±0.2°, 10.1±0.2°, 12.2±0.2°, 13.4±0.2°, 14.4±0.2°, and 23.5±0.2°.

[0085] In one embodiment, the crystalline form H has an X-ray powder diffraction pattern essentially as shown in FIG.

[0086] In another embodiment, the DSC curve of crystalline form H has an endothermic peak at 80 to 120° C. The DSC curve is essentially as shown in FIG.

[0087] In one embodiment, the crystalline form H is an n-heptane solvate.

[0088] In another aspect, the present invention relates to a method for preparing crystalline form H, comprising adding the compound of formula I to acetonitrile, tetrahydrofuran, ethanol, diethyl ether or a mixture thereof, dissolving the compound with stirring to obtain a transparent liquid, adding n-heptane until a cloudy liquid precipitates, solidifying the solid with stirring, separating the solid, and drying it under vacuum at 20-40°C for 8-24 hours to obtain crystalline form H. [Brief explanation of the drawings]

[0089] [Figure 1] FIG. 1 is a powder X-ray diffraction pattern of the crystalline form A prepared in Example 1. [Figure 2] FIG. 2 is a DSC curve of the crystalline form A prepared in Example 1. [Figure 3] FIG. 3 is a TGA curve of the crystalline form A prepared in Example 1. [Figure 4] FIG. 4 is a powder X-ray diffraction pattern of the crystalline form B prepared in Example 7. [Figure 5]FIG. 5 is a DSC curve of the crystalline form B prepared in Example 7. [Figure 6] FIG. 6 is a TGA curve of the crystalline form B prepared in Example 7. [Figure 7] FIG. 7 is a powder X-ray diffraction pattern of the crystalline form C prepared in Example 11. [Figure 8] FIG. 8 is a DSC curve of the crystalline form C prepared in Example 11. [Figure 9] FIG. 9 is a TGA curve of the crystalline form C prepared in Example 11. [Figure 10] FIG. 10 is a powder X-ray diffraction pattern of the crystalline form D prepared in Example 15. [Figure 11] FIG. 11 is a DSC curve of the crystalline form D prepared in Example 15. [Figure 12] FIG. 12 is a powder X-ray diffraction pattern of the crystalline form E prepared in Example 17. [Figure 13] FIG. 13 is a DSC curve of the crystalline form E prepared in Example 17. [Figure 14] FIG. 14 is a powder X-ray diffraction pattern of the crystalline form F prepared in Example 21. [Figure 15] FIG. 15 is a DSC curve of the crystalline form F prepared in Example 21. [Figure 16] FIG. 16 is a powder X-ray diffraction pattern of the crystalline form G prepared in Example 22. [Figure 17] FIG. 17 is a DSC curve of the crystalline form G prepared in Example 22. [Figure 18] FIG. 18 is a powder X-ray diffraction pattern of the crystalline form H prepared in Example 23. [Figure 19] FIG. 19 is a DSC curve of the crystalline form H prepared in Example 23. [Figure 20] FIG. 20 shows the powder X-ray diffraction pattern of the yellow amorphous solid obtained in the preparation example. DETAILED DESCRIPTION OF THE INVENTION

[0090] The present invention will now be described in more detail, with the understanding that these terms are used for descriptive purposes only and are not intended to limit the present invention.

[0091] General Definitions and Terminology Unless otherwise specified, the technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In the event of a conflict, the definitions provided herein shall prevail. When expressing a quantity, concentration, other value, or parameter in the form of a range, a preferred range, or a preferred upper and lower numerical limit, it should be understood that this is equivalent to specifically disclosing any range in combination with any pair of upper or preferred range limits and any lower or preferred range limits, regardless of whether the range is specifically disclosed. Unless otherwise specified, the numerical ranges described herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range.

[0092] The terms "about" and "approximately" when used in connection with a numerical variable generally mean that the numerical value of the variable and all numerical values ​​of the variable are within experimental error (e.g., within a 95% confidence interval of the mean), or within ±10% of the stated numerical value, or within a wider range.

[0093] The term "comprise" and its synonymous equivalents, such as "include," "contain," and "have," are open-ended and do not exclude other unspecified elements, steps, or ingredients. The term "consisting of" means excluding any unspecified element, step, or ingredient. The term "consisting essentially of" means limited to the specified elements, steps, or ingredients, plus any optional elements, steps, or ingredients that do not materially affect the basic and novel characteristics of the subject matter sought to be protected. The term "comprising" should be understood to encompass the terms "consisting essentially of" and "consisting of."

[0094] As used herein, the term "optionally" or "optionally" means that a described event or circumstance may or may not occur, and this expression includes the occurrence of said event or circumstance and the absence of said event or circumstance.

[0095] Unless otherwise specified, all percentages, parts, etc. stated herein are by weight.

[0096] As used herein, the term "crystalline form" or "crystal" refers to any solid material that has three-dimensional order and, unlike amorphous solid materials, produces a characteristic powder X-ray diffraction pattern with clearly defined peaks.

[0097] As used herein, the term "amorphous" refers to any solid material that lacks three-dimensional order.

[0098] As used herein, the term "hydrate" refers to a solvate that includes a pharmaceutical agent and a stoichiometric or non-stoichiometric amount of water.

[0099] As used herein, the term "solvate" refers to a solvate that includes a pharmaceutical agent and a stoichiometric or non-stoichiometric amount of something other than water.

[0100] As used herein, the term "X-ray powder diffraction (XRPD) pattern" refers to an experimentally observed diffraction pattern or parameters, data, or values ​​derived therefrom. XRPD patterns are typically characterized by peak positions (abscissa) and / or peak intensities (ordinate).

[0101] As used herein, the term "2θ" refers to the peak position, expressed in degrees (°), set in an X-ray diffraction experiment and is usually the unit of the horizontal axis in a diffraction pattern. When the incident beam forms a θ angle with a particular lattice plane, a reflection is diffracted, and the experimental setup is required to record the reflected beam at that 2θ angle. It should be understood that the specific 2θ values ​​associated with the specific crystalline forms referred to herein are intended to represent the 2θ values ​​(expressed in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, Cu-Kα (Kα1 is 1.5418 Å) is used as the radiation source. The XRPD patterns herein can be collected, for example, with a Rigaku D / max-2200 X-ray powder diffraction analyzer. Exemplary test conditions can be a scan rate of 10° / min and a scan step width of 0.01°.

[0102] As used herein, the term "essentially" with respect to X-ray diffraction peaks means that typical peak position and intensity variations are taken into account. For example, as will be understood by those skilled in the art, peak positions (2θ) may exhibit some variation, typically as large as 0.1 to 0.2 degrees (±0.1 to ±0.2 degrees), and the instrument used to measure the diffraction may also cause some variation. Furthermore, as will be understood by those skilled in the art, relative peak intensities should be considered only as qualitative measurements, with the understanding that they will vary depending on instrumental differences, crystallinity, preferred orientation, the surface of the sample as prepared, and other factors known to those skilled in the art.

[0103] As used herein, differential scanning calorimetry (DSC) measures the transition temperatures at which a crystal absorbs or releases heat due to a change in crystal structure or melting. For the same crystalline form of the same compound, the error between the thermal transition temperatures and the melting point is typically within about 5°C in consecutive analyses. When a compound is described as having a specific DSC peak or melting point, this means that the DSC peak or melting point is within ±5°C. The term "essentially" also takes into account temperature variations. DSC provides an auxiliary method for distinguishing between different crystalline forms. Different crystalline forms can be distinguished according to their different transition temperature characteristics. It should be noted that for mixtures, the DSC peak or melting point may vary over a wider range. Note that decomposition occurs as a substance melts, so the melting temperature is related to the heating rate. DSC curves can be measured, for example, using a NETZSCH DSC214 Polymer instrument. Exemplary test conditions include a heating rate of 10°C / min and a temperature range of 25-250°C.

[0104] Pharmaceutical Compositions and Dosages In one embodiment, the present invention provides a pharmaceutical composition comprising a crystalline form of a compound of Formula I and one or more pharmaceutically acceptable carriers.

[0105] As used herein, the term "pharmaceutically acceptable carrier" refers to a solid or liquid diluent, adjuvant, excipient, or vehicle with which a therapeutic is administered and which, within the scope of reasonable medical judgment, is suitable for contact with the tissues of humans and / or other animals and is free of undue toxicity, irritation, allergic response, or other problem or complication commensurate with reasonable benefit / risk.

[0106] Pharmaceutically acceptable carriers that can be used in pharmaceutical compositions of the present invention include sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as soybean oil, peanut oil, and mineral oil. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Saline and aqueous glucose and glycerin solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include glucose, starch, lactose, gelatin, maltose, sucrose, chalk, silica gel, glyceryl monostearate, sodium stearate, talc, sodium chloride, glycerin, propylene glycol, water, ethanol, and the like. The compositions can also contain small amounts of wetting agents, emulsifiers, or pH buffering agents, as needed. Oral formulations can also contain standard carriers, such as pharmaceutical levels of mannitol, lactose, starch, sodium stearate, cellulose, sodium saccharin, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described, for example, in Remington's Pharmaceutical Sciences (1990).

[0107] The compositions of the present invention can act systemically and / or locally, and therefore can be administered by any suitable route, such as, for example, injection, intraarterial, subcutaneous, intravenous, intraperitoneal, intramuscular or transdermal, or they can be administered orally, nasally, bucally, transmucosally, topically, in ophthalmic formulations, or by inhalation.

[0108] For these administration routes, the compositions of the present invention can be administered in appropriate dosage forms, including, but not limited to, tablets, drop pills, capsules, tablets, hard candies, powders, sprays, creams, ointments, suppositories, gels, aqueous suspensions, injections, elixirs, and syrups.

[0109] The pharmaceutical compositions of the present invention can be prepared by any method known in the art, such as by mixing, dissolving, granulating, sugar-coating, pulverizing, emulsifying, lyophilizing, etc. As used herein, the term "therapeutically effective amount" refers to the amount of a compound that, upon administration, is capable of alleviating to some extent one or more symptoms of the disease being treated.

[0110] Dosage regimens can be adjusted to provide the optimum desired response. For example, they can be administered as a single bolus shot, as several fractional doses administered over time, or the dosage can be proportionally reduced or increased depending on the exigencies of the therapeutic situation. It should be noted that dosages can vary depending on the type and severity of the condition to be alleviated and can include single or multiple administrations. Furthermore, it should be understood that for any particular individual, specific dosage regimens should be adjusted over time based on the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0111] Unless otherwise stated, the term "treatment" as used herein means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies or one or more symptoms of such disorder or condition, or preventing the progression of such disorder or condition or one or more symptoms of such disorder or condition.

[0112] As used herein, an "individual" includes a human or a non-human animal. Exemplary human individuals include individuals suffering from a disease (e.g., a disease of this description) (referred to as a patient) or normal individuals. "Non-human animals" in this invention include all vertebrates, including mammals such as non-mammals (e.g., amphibians, reptiles, birds, etc.), and non-human primates, and livestock and / or domesticated animals (e.g., dogs, cats, sheep, cows, pigs, etc.).

[0113] beneficial effects The crystalline form of the compound of formula I of the present invention has good solubility, a simple crystallization process, convenient operation, and low pollution, making it suitable for industrial production. Furthermore, the crystalline form of the drug of the present invention has advantages such as high product purity, excellent physical properties, good stability at high temperature and humidity, good chemical and physical stability, and excellent adaptability and reproducibility in processing (filtration, drying, dissolution, and tableting). It also has good solubility, dissolution rate, dissolution time, and biological release, and has good prospects for market application. [Example]

[0114] The present invention will be further illustrated by the following examples, which are intended to provide a better understanding of the present invention and are not intended to limit or restrict the scope of protection of the present invention.

[0115] Preparation of crystalline forms of the compound of formula I and Characterization Preparation example The compound of formula I described in the examples of the present invention was prepared according to Method 1 in Example 1 of Patent WO2017080338A1. The compound was dissolved in a dichloromethane / methanol mixed solvent until transparent, and then concentrated under reduced pressure to obtain a yellow solid. XRPD showed that the obtained yellow solid was amorphous, and its powder X-ray diffraction pattern is shown in Figure 20.

[0116] Measuring equipment information and methods The X-ray powder diffractometer and measurement conditions of the present invention are as follows: X-ray diffraction instrument model Rigaku D / max-2200 Cu target, operation method: scanning speed 10° / min, scanning step width 0.01°.

[0117] The DSC measurement conditions according to the present invention are as follows: the DSC detector model is NETZSCH DSC214 Polymer, the operating method is a temperature rise rate of 10°C / min or 2°C / min, and the temperature range is 25 to 250°C.

[0118] The TGA measurement conditions according to the present invention are as follows: the TGA detector model is PerkinElmer TGA4000, and the operation method is a temperature rise rate of 10°C / min and a temperature range of 25 to 250°C.

[0119] The measurement conditions for the high performance liquid chromatography (HPLC) according to the present invention are as follows: liquid chromatograph model: Agilent 1260; column: Agilent Eclipse XDB C-18 250 mm x 4.6 mm 5 um; detection wavelength: 280 nm; column temperature: 35°C.

[0120] The measurement conditions for the single crystal according to the present invention are as follows: the model of the single crystal X-ray diffraction device is Bruker APEX-II CCD, the target is GaKα, and the temperature is 169.97K.

[0121] The Karl Fischer moisture meter according to the present invention is a Mettler Toledo V20 Volumetric KF Tierator model, and the solvent is methanol. Example 1 Preparation of Crystalline Form A

[0122] 1 g of the compound of formula I was added to 5 mL of methanol and dissolved at 25°C with stirring until it became transparent. The solution was then added to 3 mL of water until a cloudy liquid precipitated, and stirred until it solidified. The solid was separated and dried in vacuum at 40°C for 8 hours to obtain 0.85 g of a solid, which was crystalline form A (purity 99.33%). Its powder X-ray diffraction pattern, DSC curve, and TGA curve are shown in Figures 1 to 3, respectively. Example 2 Preparation of Crystalline Form A

[0123] 1 g of the compound of formula I was added to 20 mL of ethanol and stirred at 20°C until it became transparent. The solution was then added to 100 mL of water and stirred until a cloudy liquid precipitated. The solid was separated and dried in vacuo at 20°C for 24 hours to obtain 0.82 g of a solid. The solid was identified as crystalline form A, and its powder X-ray diffraction pattern, DSC curve, and TGA curve were consistent with those shown in Figures 1 to 3, respectively. Example 3 Preparation of Crystalline Form A

[0124] 1 g of the compound of formula I was added to 15 mL of isopropanol and dissolved at 60°C with stirring until it became transparent. The solution was then added to 50 mL of water and stirred until it solidified. The solid was separated and dried in vacuo at 60°C for 16 hours to obtain 0.87 g of a solid, which is crystalline form A, and its powder X-ray diffraction pattern, DSC curve, and TGA curve are consistent with those shown in Figures 1 to 3, respectively. Example 4 Preparation of Crystalline Form A

[0125] 1 g of the compound of formula I was added to 10 mL of water to obtain a suspension, and the crystalline slurry was stirred at 50°C for 1 day. The solid was separated, and the filter cake was vacuum dried at 60°C for 24 hours to obtain 0.95 g of a solid, which is crystalline form A, and its powder X-ray diffraction pattern, DSC curve, and TGA curve are consistent with those shown in Figures 1 to 3, respectively. Example 5 Preparation of Crystalline Form A

[0126] 1 g of the compound of formula I was added to 2 mL of methanol to obtain a suspension, and the crystalline slurry was stirred at 5°C for 7 days. The solid was separated, and the filter cake was vacuum dried at 20°C for 8 hours to obtain 0.90 g of a solid, which is crystalline form A, and its powder X-ray diffraction pattern, DSC curve, and TGA curve are consistent with those shown in Figures 1 to 3, respectively. Example 6 Preparation of Crystalline Form A

[0127] 1 g of the compound of formula I was added to 4 mL of isopropanol to obtain a suspension, and the crystalline slurry was stirred at 25°C for 3 days. The solid was separated and the filter cake was dried under vacuum at 40°C for 16 hours to obtain 0.92 g of a solid, which is crystalline form A, and its powder X-ray diffraction pattern, DSC curve and TGA curve are consistent with those shown in Figures 1 to 3, respectively. Example 7 Preparation of Crystalline Form B

[0128] 1 g of the compound of formula I was added to 3 mL of water-saturated dichloromethane to form a suspension, and the crystalline slurry was stirred at 25°C for 24 hours. The solid was separated and dried under vacuum at 40°C for 8 hours to obtain 0.65 g of a solid, which was crystalline form B (purity 99.87%), and its powder X-ray diffraction pattern, DSC curve, and TGA curve are shown in Figures 4 to 6, respectively. Example 8 Preparation of Crystalline Form B

[0129] 1 g of the compound of formula I was added to 3 mL of water-saturated dichloroethane to form a suspension, which was stirred at 40°C for 0.5 hours. The solid was separated and dried under vacuum at 20°C for 8 hours to obtain 0.78 g of a solid, which is crystalline form B, and its powder X-ray diffraction pattern, DSC curve and TGA curve are consistent with those shown in Figures 4 to 6. Example 9 Preparation of Crystalline Form B

[0130] 1 g of the compound of formula I was added to 4 mL of water-saturated trichloromethane to form a suspension, which was stirred at 5°C for 12 hours. The solid was separated and dried under vacuum at 40°C for 16 hours to obtain 0.68 g of a solid, which is crystalline form B, and its powder X-ray diffraction pattern, DSC curve and TGA curve are consistent with those shown in Figures 4 to 6. Example 10 Preparation of Crystalline Form B

[0131] 1 g of the compound of formula I was added to 4 mL of water-saturated dibromomethane to form a suspension, which was stirred at 15°C for 36 hours. The solid was separated and dried under vacuum at 40°C for 24 hours to obtain 0.72 g of a solid, which is crystalline form B, and its powder X-ray diffraction pattern, DSC curve and TGA curve are consistent with those shown in Figures 4 to 6. Example 11 Preparation of Crystalline Form C

[0132] 1 g of the compound of formula I was added to 15 mL of water-saturated dichloromethane to form a suspension, which was stirred at 25°C for 3 days. The solid was separated and dried under vacuum at 40°C for 8 hours to obtain 0.80 g of a solid, which was crystalline form C (purity 99.78%), and its powder X-ray diffraction pattern, DSC curve and TGA curve are shown in Figures 7 to 9, respectively. Example 12 Preparation of Crystalline Form C

[0133] 1 g of the compound of formula I was added to 50 mL of water-saturated dibromomethane to form a suspension, which was stirred at 5°C for 7 days. The solid was separated and dried under vacuum at 40°C for 16 hours to obtain 0.68 g of a solid, which is crystalline form C, and its powder X-ray diffraction pattern, DSC curve and TGA curve are consistent with those shown in Figures 7 to 9, respectively. Example 13 Preparation of Crystalline Form C

[0134] 1 g of the compound of formula I was added to 25 mL of water-saturated dichloroethane to form a suspension, which was stirred at 15°C for 5 days. The solid was separated and dried under vacuum at 20°C for 24 hours to obtain 0.74 g of a solid, which is crystalline form C, and its powder X-ray diffraction pattern, DSC curve and TGA curve are consistent with those shown in Figures 7 to 9, respectively. Example 14 Preparation of Crystalline Form C

[0135] 1 g of the compound of formula I was added to 30 mL of water-saturated trichloromethane to form a suspension, which was stirred at 40°C for 3 days. The solid was separated and dried under vacuum at 30°C for 16 hours to obtain 0.71 g of a solid, which is crystalline form C, and its powder X-ray diffraction pattern, DSC curve and TGA curve are consistent with those shown in Figures 7 to 9, respectively. Example 15 Preparation of Crystalline Form D

[0136] 1 g of the compound of formula I was added to 10 mL of butanone and dissolved under stirring to form a clear liquid. 100 mL of water was added until a cloudy liquid precipitated, and the mixture was stirred until solidification occurred. The solid was separated and dried under vacuum at 40°C for 8 hours to obtain 0.81 g of a solid, which is crystalline form D. Its powder X-ray diffraction pattern and DSC curve are shown in Figures 10 and 11, respectively. Example 16 Preparation of Crystalline Form D

[0137] 1 g of the compound of formula I was added to 3 mL of butanone to form a suspension, which was then stirred at 25°C for 24 hours. The solid was separated and dried under vacuum at 40°C for 24 hours to obtain 0.91 g of a solid, which is crystalline form D, and its powder X-ray diffraction pattern and DSC curve are consistent with those shown in Figures 10 and 11, respectively. Example 17 Preparation of Crystalline Form E

[0138] 1 g of the compound of formula I was added to 3 mL of acetone to form a suspension, which was stirred at 25°C for 24 hours, filtered to separate the solid, and dried under vacuum at 40°C for 8 hours to obtain 0.55 g of a solid, which is crystalline form E, and its powder X-ray diffraction pattern and DSC curve are shown in Figures 12 and 13, respectively. Example 18 Preparation of Crystalline Form E

[0139] 1 g of the compound of formula I was added to 8 mL of acetone and dissolved under stirring to form a transparent solution. 6 mL of n-heptane was added until a cloudy precipitate appeared, and the solution was solidified under stirring. The solid was separated and dried under vacuum at 40°C for 24 hours to obtain 0.75 g of a solid. The solid was crystalline form E, and its powder X-ray diffraction pattern and DSC curve were consistent with those shown in Figures 12 and 13, respectively. Example 19 Preparation of Crystalline Form E

[0140] 1 g of the compound of formula I was added to 8 mL of acetone and dissolved under stirring to form a transparent solution. 8 mL of water was added until a cloudy precipitate appeared, followed by stirring to solidify. The solid was separated and dried under vacuum at 20°C for 16 hours to obtain 0.78 g of a solid, which is crystalline form E, and its powder X-ray diffraction pattern and DSC curve are consistent with those shown in Figures 12 and 13, respectively. Example 20 Preparation of Crystalline Form E

[0141] 1 g of the compound of formula I was added to 3 mL of acetone and 3 mL of n-heptane to form a suspension, which was stirred at 30°C for 3 days, filtered, and dried under vacuum at 25°C for 16 hours to obtain 0.82 g of a solid, which is crystalline form E, and its powder X-ray diffraction pattern and DSC curve are consistent with those shown in Figures 12 and 13, respectively. Example 21 Preparation of Crystalline Form F

[0142] 1 g of the compound of formula I was added to 5 mL of 1,4-dioxane and dissolved under stirring to form a clear solution. 200 mL of water was added to precipitate a solid, which was then solidified under stirring. The solid was separated and dried under vacuum at 40°C for 24 hours to obtain 0.94 g of a solid, which is crystalline form F. Its powder X-ray diffraction pattern and DSC curve are shown in Figures 14 and 15, respectively. Example 22 Preparation of Crystalline Form G

[0143] 1 g of the compound of formula I was added to 10 mL of methyl tert-butyl ether to form a suspension, which was stirred at 25°C for 24 hours. The solid was separated and dried under vacuum at 40°C for 8 hours to obtain 0.75 g of a solid, which is crystalline form G, and its powder X-ray diffraction pattern and DSC curve are shown in Figures 16 and 17, respectively. Example 23 Preparation of Crystalline Form H

[0144] 1 g of the compound of formula I was added to 15 mL of acetonitrile and dissolved with stirring until a clear solution was obtained. 95 mL of n-heptane was added until a cloudy precipitate appeared, and the mixture was stirred to solidify. The solid was separated and dried in vacuo at 40°C for 16 hours to obtain 0.70 g of a solid. This was crystalline form H, and its powder X-ray diffraction pattern and DSC curve are shown in Figures 18 and 19, respectively. Example 24 Preparation of Crystalline Form H

[0145] 1 g of the compound of formula I was added to 10 mL of ethanol and dissolved under stirring until a transparent solution was obtained. 100 mL of n-heptane was added until a cloudy liquid precipitated, and the mixture was stirred to solidify. The solid was separated and dried under vacuum at 20°C for 8 hours to obtain 0.74 g of a solid. The solid was crystalline form H, and its powder X-ray diffraction pattern and DSC curve were consistent with those shown in Figures 18 and 19, respectively. Example 25 Preparation of Crystalline Form H

[0146] 1 g of the compound of formula I was added to 150 mL of diethyl ether and dissolved with stirring until a transparent solution was obtained. 950 mL of n-heptane was added until a cloudy precipitate appeared, and the mixture was stirred to solidify. The solid was separated and dried in vacuo at 40°C for 8 hours to obtain 0.67 g of a solid. The solid was crystalline form H, and its powder X-ray diffraction pattern and DSC curve were consistent with those shown in Figures 18 and 19, respectively. Example 26 Preparation of Crystalline Form H

[0147] 1 g of the compound of formula I was added to 10 mL of tetrahydrofuran and dissolved with stirring until a clear solution was obtained. 75 mL of n-heptane was added until a cloudy precipitate appeared, and the mixture was stirred to solidify. The solid was separated and dried in vacuo at 30°C for 24 hours to obtain 0.63 g of a solid. The solid was crystalline form H, and its powder X-ray diffraction pattern and DSC curve were consistent with those shown in Figures 18 and 19, respectively. Preparation of Amorphous Forms of Compounds of Formula I

[0148] An amorphous form of the compound of formula I is prepared according to Example 1 of WO2017080338A1. Qualitative Experiments

[0149] The amorphous form of the compound of formula I prepared in the above Preparation Examples, crystalline form A of the compound of formula I prepared in Example 1, crystalline form B of the compound of formula I prepared in Example 7, and crystalline form C of the compound of formula I prepared in Example 11 were each left for 10 days under conditions of 75% RH, 92.5% RH, 40°C, 60°C, and light irradiation, and the powder X-ray diffraction patterns and purity of each crystalline form were measured. The results show that crystalline forms A, B, and C have good stability. Specific results are shown in the table below. JPEG0007736570000007.jpg94160 Particle size experiment

[0150] The amorphous form of the compound of formula I prepared in the above Preparation Examples, crystalline form A of the compound of formula I prepared in Example 1, crystalline form B of the compound of formula I prepared in Example 7, and crystalline form C of the compound of formula I prepared in Example 11 were taken and the particle size of each was measured. The specific results are shown in the table below. JPEG0007736570000008.jpg31161

[0151] The above results show that the amorphous particles are clearly small, significantly smaller than the particle sizes of crystalline forms A, B and C. Fluidity Test

[0152] The amorphous form of the compound of formula I prepared in the above Preparation Examples, crystalline form A of the compound of formula I prepared in Example 1, crystalline form B of the compound of formula I prepared in Example 7, and crystalline form C of the compound of formula I prepared in Example 11 were taken and the angle of repose of each was measured. The specific results are shown in the table below. JPEG0007736570000009.jpg37161

[0153] The above results show that the angle of repose of the amorphous form is significantly larger than that of crystalline forms A, B, and C, which indicates that crystalline forms A, B, and C are significantly superior to the amorphous form in terms of flowability.

[0154] Those skilled in the art will understand that the meaning or scope of protection of the numerical values ​​or numerical endpoints related to the technical solutions of the present invention is not limited to the numerical values ​​themselves, but includes tolerances widely accepted in the art, such as experimental error, measurement error, statistical error, and random error, and all of these tolerances are included in the scope of the present invention.

[0155] It will be apparent to those skilled in the art that many modifications and variations of the present invention can be made without departing from the spirit and scope of the present invention. The specific embodiments described herein are provided by way of example only and are not meant to be limiting in any way. The true scope and spirit of the invention are indicated by the following claims. The specification and examples are merely illustrative. The present invention includes the following aspects. 1. Crystalline form A of the compound of formula I below, characterized in that the powder X-ray diffraction pattern using Cu-Kα radiation has characteristic peaks at angles 2θ expressed in degrees of 10.5±0.2°, 12.3±0.2°, 14.9±0.2°, 16.2±0.2°, 18.1±0.2°, 19.4±0.2°, 20.3±0.2°, and 24.4±0.2°. JPEG0007736570000010.jpg67160 2. Crystalline form A according to item 1, characterized in that the powder X-ray diffraction pattern using Cu-Kα radiation has characteristic peaks at 2θ degrees of 10.5±0.2°, 12.3±0.2°, 13.6±0.2°, 14.2±0.2°, 14.9±0.2°, 16.2±0.2°, 17.1±0.2°, 18.1±0.2°, 19.4±0.2°, 20.3±0.2°, 22.8±0.2°, and 24.4±0.2°. 2. Crystalline form A according to item 1 or 2, characterized in that the powder X-ray diffraction pattern is essentially as shown in FIG. 1. 4. Crystalline form A according to any one of items 1 to 3, which is a monohydrate of the compound of formula I. 5. A method for preparing crystalline form A according to any one of items 1 to 4, comprising the steps of: In the method (1), the compound of formula I is added to a solvent which is a C1-C3 alcohol, water or a mixture thereof to obtain a suspension, and the suspension is stirred at 5-50°C to form a crystal slurry for 1-7 days, and then the solid is separated and vacuum dried at 20-60°C for 8-24 hours to obtain crystalline form A; Preferably, the C1-C3 alcohol according to the method (1) is one or more of methanol, ethanol, n-propanol, and isopropanol; Preferably, the weight / volume ratio of the compound represented by formula I to the solvent in method (1) is 1:2 to 1:10 (g / mL); and In the method (2), the compound of formula I is added to a C1-C3 alcohol, dissolved to obtain a transparent liquid, water is added until a cloudy liquid precipitates, the mixture is stirred until solidification occurs, the solid is separated, and the solid is vacuum-dried at 20-60°C for 8-24 hours to obtain crystalline form A. Preferably, the C1-C3 alcohol in the method (2) is one or more of methanol, ethanol, n-propanol, and isopropanol; Preferably, the weight / volume ratio of the compound represented by formula I to the C1-C3 alcohol in the method (2) is 1:5 to 1:20 (g / mL); Preferably, the weight-volume ratio of the compound represented by formula I to water in method (2) is 1:3 to 1:100 (g / mL). Item 5. The method for preparing crystalline form A according to any one of items 1 to 4, which is any one of the methods selected from the following: 6. Crystalline form B of the compound of formula I below, characterized in that the powder X-ray diffraction pattern using Cu-Kα radiation has characteristic peaks at angles 2θ expressed in degrees of 5.5±0.2°, 9.9±0.2°, 10.7±0.2°, 12.7±0.2°, 16.2±0.2°, 16.7±0.2°, and 23.0±0.2°. JPEG0007736570000011.jpg67160 7. Crystalline form B according to item 6, characterized in that the powder X-ray diffraction pattern using Cu-Kα radiation has characteristic peaks at angles 2θ expressed in degrees of 5.5±0.2°, 9.9±0.2°, 10.7±0.2°, 12.7±0.2°, 14.5±0.2°, 16.2±0.2°, 16.7±0.2°, 19.7±0.2°, 23.0±0.2°, and 24.8±0.2°. 8. Crystalline form B according to item 6 or 7, characterized in that the powder X-ray diffraction pattern is essentially as shown in FIG. 4. 9. Crystalline form B according to any one of items 6 to 8, which is a monohydrate of the compound of formula I. 10. A method for preparing crystalline form B according to any one of items 6 to 9, comprising adding the compound of formula I to a water-saturated halogenated hydrocarbon solution to form a suspension, stirring the crystalline slurry at 5 to 40°C for 0.5 to 36 hours, separating the solid, and drying it under vacuum at 20 to 40°C for 8 to 24 hours to obtain crystalline form B, Preferably, the halogenated hydrocarbon is one or more selected from dichloromethane, dichloroethane, trichloromethane, and dibromomethane; Preferably, the method is characterized in that the weight / volume ratio of the compound represented by formula I to the water-saturated halogenated hydrocarbon is 1:3 to 1:4 (g / mL). 11. Crystalline form C of the compound of formula I below, characterized in that the powder X-ray diffraction pattern using Cu-Kα radiation has characteristic peaks at 2θ degrees of 4.5±0.2°, 5.7±0.2°, 8.5±0.2°, 12.2±0.2°, 14.0±0.2°, 16.7±0.2°, and 23.0±0.2. JPEG0007736570000012.jpg67160 12. Crystalline form C according to item 11, characterized in that the powder X-ray diffraction pattern is essentially as shown in FIG. 7. 13. Crystalline form C according to any one of items 11 to 12, which is a monohydrate of the compound of formula I. 14. A method for preparing crystalline form C according to any one of items 11 to 13, comprising adding the compound of formula I to a water-saturated halogenated hydrocarbon solution to form a suspension, stirring the crystalline slurry at 5 to 40°C for 2 to 7 days, separating the solid, and drying it under vacuum at 20 to 40°C for 8 to 24 hours to obtain crystalline form C, Preferably, the halogenated hydrocarbon is one or more selected from dichloromethane, dichloroethane, trichloromethane, and dibromomethane; Preferably, the method is characterized in that the weight / volume ratio of the compound represented by formula I to the water-saturated halogenated hydrocarbon is 1:15 to 1:50 (g / mL). 15. A pharmaceutical composition comprising a therapeutically effective amount of crystalline form A described in any one of items 1 to 5, crystalline form B described in any one of items 6 to 10, or crystalline form C described in any one of items 11 to 14. 16. Use of crystalline form A described in any one of items 1 to 5, crystalline form B described in any one of items 6 to 10, crystalline form C described in any one of items 11 to 14, or the pharmaceutical composition described in item 15, in the manufacture of a medicament for treating an estrogen receptor-mediated disease, wherein the disease is cancer, preferably the carcinoma is breast cancer or gynecological cancer, preferably the gynecological cancer is ovarian cancer or endometrial cancer, and preferably the estrogen receptor is estrogen receptor α. 17. Use of crystalline form A described in any one of items 1 to 5, crystalline form B described in any one of items 6 to 10, crystalline form C described in any one of items 11 to 14, or the pharmaceutical composition described in item 15 in the manufacture of a selective estrogen receptor downregulator, wherein the selective estrogen receptor downregulator is preferably an estrogen receptor alpha downregulator.

Claims

1. A crystal of crystalline form A of the monohydrate of the compound of formula I below, which has characteristic peaks at 2θ degrees of 10.5±0.2°, 12.3±0.2°, 14.9±0.2°, 16.2±0.2°, 18.1±0.2°, 19.4±0.2°, 20.3±0.2°, and 24.4±0.2° in a powder X-ray diffraction pattern using Cu-Kα radiation.

2. 2. A crystal of crystalline form A according to claim 1, wherein the powder X-ray diffraction pattern using Cu-Kα radiation has characteristic peaks at 2θ degrees of 10.5±0.2°, 12.3±0.2°, 13.6±0.2°, 14.2±0.2°, 14.9±0.2°, 16.2±0.2°, 17.1±0.2°, 18.1±0.2°, 19.4±0.2°, 20.3±0.2°, 22.8±0.2°, and 24.4±0.2°.

3. The powder X-ray diffraction pattern is shown in Figure 1:

3. The crystal of crystalline form A according to claim 1 or 2, characterized in that it is as shown in

4. A method for preparing a crystal of crystalline form A according to any one of claims 1 to 3, comprising the steps of: In the method (1), the compound of formula I is added to a solvent which is water or a mixture of C1-C3 alcohol and water to obtain a suspension, and the suspension is stirred at 5-50°C to form a crystal slurry for 1-7 days, and then the solid is separated and dried in vacuum at 20-60°C for 8-24 hours to obtain crystals of crystalline form A. The C1 to C3 alcohol according to the method (1) is one or more of methanol, ethanol, n-propanol, and isopropanol; Method (1), wherein the weight-volume ratio of the compound represented by formula I to the solvent is 1:2 to 1:10 (g / mL); and In the method (2), the compound of formula I is added to a C1-C3 alcohol, dissolved to obtain a clear liquid, water is added until a cloudy liquid precipitates, the mixture is stirred until solidification occurs, the solid is separated, and the solid is vacuum dried at 20-60°C for 8-24 hours to obtain crystals of crystalline form A; The C1-C3 alcohol in the method (2) is one or more of methanol, ethanol, n-propanol, and isopropanol; In the method (2), the weight-volume ratio of the compound represented by formula I to the C1-C3 alcohol is 1:5 to 1:20 (g / mL); The method (2) wherein the weight-volume ratio of the compound represented by formula I to water is 1:3 to 1:100 (g / mL).

5. The method for preparing the crystal of crystalline form A according to claim 1, wherein the method is any one of the methods selected from the following:

5. A crystal of crystalline form B of the monohydrate of the compound of formula I below, which has characteristic peaks at 2θ degrees of 5.5±0.2°, 9.9±0.2°, 10.7±0.2°, 12.7±0.2°, 16.2±0.2°, 16.7±0.2°, and 23.0±0.2° in a powder X-ray diffraction pattern using Cu-Kα radiation.

6. 6. A crystal of crystalline form B according to claim 5, wherein the powder X-ray diffraction pattern using Cu-Kα radiation has characteristic peaks at 2θ degrees of 5.5±0.2°, 9.9±0.2°, 10.7±0.2°, 12.7±0.2°, 14.5±0.2°, 16.2±0.2°, 16.7±0.2°, 19.7±0.2°, 23.0±0.2°, and 24.8±0.2°.

7. The powder X-ray diffraction pattern is shown in Figure 4:

7. The crystal of crystalline form B according to claim 5 or 6, characterized in that it is as shown in

8. A method for preparing the crystals of crystalline form B according to any one of claims 5 to 7, comprising adding the compound of formula I to a water-saturated halogenated hydrocarbon solution to form a suspension, stirring the crystal slurry at 5 to 40°C for 0.5 to 36 hours, separating the solid, and drying it under vacuum at 20 to 40°C for 8 to 24 hours to obtain the crystals of crystalline form B, The halogenated hydrocarbon is one or more selected from the group consisting of dichloromethane, dichloroethane, trichloromethane, and dibromomethane; The weight-volume ratio of the compound represented by formula I to the water-saturated halogenated hydrocarbon is 1:3 to 1:4 (g / mL).

9. A crystal of crystalline form C of the monohydrate of the compound of formula I below, which has characteristic peaks at 2θ degrees of 4.5±0.2°, 5.7±0.2°, 8.5±0.2°, 12.2±0.2°, 14.0±0.2°, 16.7±0.2°, and 23.0±0.2 in a powder X-ray diffraction pattern using Cu-Kα radiation.

10. The powder X-ray diffraction pattern is shown in Figure 7:

10. The crystal of crystalline form C according to claim 9, wherein the crystal is as shown in

11. A method for preparing the crystals of crystalline form C according to any one of claims 9 to 10, comprising adding the compound of formula I to a water-saturated halogenated hydrocarbon solution to form a suspension, stirring the crystal slurry at 5 to 40°C for 2 to 7 days, separating the solid, and drying it under vacuum at 20 to 40°C for 8 to 24 hours to obtain the crystals of crystalline form C, The halogenated hydrocarbon is one or more selected from the group consisting of dichloromethane, dichloroethane, trichloromethane, and dibromomethane; The weight-volume ratio of the compound represented by formula I to the water-saturated halogenated hydrocarbon is 1:15 to 1:50 (g / mL).

12. A pharmaceutical composition comprising a therapeutically effective amount of a crystal of crystalline form A according to any one of claims 1 to 3, a crystal of crystalline form B according to any one of claims 5 to 7, or a crystal of crystalline form C according to any one of claims 9 to 10.

13. A pharmaceutical product for treating an estrogen receptor-mediated disease, comprising a crystal of crystalline form A according to any one of claims 1 to 3, a crystal of crystalline form B according to any one of claims 5 to 7, a crystal of crystalline form C according to any one of claims 9 to 10, or the pharmaceutical composition according to claim 12, wherein the disease is cancer, the carcinoma is breast cancer or gynecological cancer, the gynecological cancer is ovarian cancer or endometrial cancer, and the estrogen receptor is estrogen receptor α.

14. A selective estrogen receptor downregulator, comprising a crystal of crystalline form A described in any one of claims 1 to 3, a crystal of crystalline form B described in any one of claims 5 to 7, a crystal of crystalline form C described in any one of claims 9 to 10, or the pharmaceutical composition described in claim 12, wherein the selective estrogen receptor downregulator is an estrogen receptor alpha downregulator.

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