Polymorphic form of compound with anti-androgen receptor activity as well as preparation method and application of polymorphic form

Abstract

The invention provides a polymorphic form of a compound shown in a formula (I). The polymorphic form comprises a crystal form 1, a crystal form 2, a crystal form 3 and an amorphous form. The crystal form 1 has good stability, the preparation method is simple and easy to operate, the crystal form 1 is more suitable for large-scale production, and the crystal form 1 has good industrial application value and can be used for preparing drugs for preventing or treating symptoms or diseases related to male hormone disorder, such as androgenetic alopecia, acne and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a polymorph of a compound having anti-androgen receptor activity, a preparation method and use thereof. Background Art

[0002] Androgen receptor (AR) is a member of the large family of ligand-related transcription factors, among which ligand-related transcription factors are called steroid receptor superfamily. When androgen ligand binds to AR, AR originally in the cytoplasm dissociates from heat shock protein, changes conformation, exposes the nuclear localization signal region, and the ligand-AR complex translocates into the cell nucleus. The complex binds to the AR response element on the promoter of specific androgen-regulated genes and mediates transcription and translation in a DNA-dependent binding mode. AR is a member of the nuclear receptor superfamily. In addition to being highly expressed in the reproductive system, it is also distributed and expressed in adipose tissue, skeletal muscle, liver, spleen, and brain.

[0003] Literature reports that androgens and AR play an important role in the growth of normal prostate and prostate cancer, and anti-androgen drugs have been widely used in the treatment of prostate cancer. In addition, high serum androgen levels are associated with acne and androgenic alopecia, and anti-androgen therapy has a potential impact on acne and androgenic alopecia. However, androgens are involved in many biological processes. Blocking or inhibiting the binding of androgens to their corresponding receptors leads to an increase in the level of effective androgens in the surrounding environment. The increase in androgen levels in the surrounding environment affects other androgen-related biological processes and can cause undesirable side effects. Currently, inhibiting the production of androgen receptors has become a research hotspot, and compounds with anti-androgen receptor activity have been used as potential treatments for androgen receptor-related diseases.

[0004] Curcumin is the main component of the traditional Chinese medicine turmeric, which is a tautomer structure of dione and enol between benzene rings. It has anti-tumor, antibacterial, anti-inflammatory and antioxidant pharmacological effects. Dimethylcurcumin is a curcumin derivative that can inhibit the proliferation of prostate cancer cells. Its mechanism is related to the unique role of dimethylcurcumin in promoting the degradation of androgen receptors. So far, dimethylcurcumin has been studied in typical androgen receptor (AR)-related diseases such as prostate cancer, benign prostatic hypertrophy, bladder cancer, kidney disease, liver disease, cardiovascular disease, skin trauma, spinal cord and bulbar muscular atrophy, ovarian cancer and melanoma, showing strong disease control potential.

[0005] Patent application CN202310481798.5 filed by the present applicant on April 28, 2023 describes a curcumin derivative as shown in the following formula (I), which has good prostate tumor cell proliferation inhibition activity and anti-AR activity, as well as good in vivo metabolic properties, and can be used to prevent and / or treat diseases related to androgen disorders, such as androgenic alopecia, acne, etc.

[0006] Summary of the invention

[0007] The purpose of the present invention is to provide multiple crystal forms of the compound of formula (I) (2E, 2'E)-1,1'-(4,4-difluorocyclohexane-1,1-diyl)bis(3-(3,4-dimethoxyphenyl)prop-2-en-1-one) and preparation methods and uses thereof.

[0008] In a first aspect of the present invention, there is provided a polymorph and an amorphous form of a compound represented by the following formula (I), wherein the polymorph comprises: Form 1, Form 2 and Form 3:

[0009]

[0010] The present invention provides a crystalline form 1 of a compound represented by formula (I), wherein an X-ray powder diffraction pattern thereof has characteristic peaks at one or more of the following 2θ values: 14.51±0.2°, 15.02±0.2°, 15.26±0.2°, 20.68±0.2°, 21.17±0.2° and 21.57±0.2°.

[0011] In some embodiments of the present invention, the X-ray powder diffraction pattern (XRPD) of the crystalline form 1 has characteristic peaks at one or more of the following 2θ values: 14.51±0.2°, 15.02±0.2°, 15.26±0.2°, 15.71±0.2°, 19.06±0.2°, 20.68±0.2°, 21.17±0.2° and 21.57±0.2°.

[0012] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form 1 has characteristic peaks at the following 2θ values:

[0013] Serial number 2θ±0.2° d value Relative Strength Serial number 2θ±0.2° d value Relative Strength 1 7.57 11.66 2.6 7 19.06 4.65 18.7 2 14.51 6.10 31.7 8 19.54 4.54 14.0 3 15.02 5.89 100.0 9 20.68 4.29 41.6 4 15.26 5.80 36.9 10 21.17 4.19 25.8 5 15.71 5.63 16.7 11 21.57 4.12 47.6 6 18.12 4.89 4.1 12 25.23 3.53 9.3 .

[0014] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form 1 is substantially as follows Figure 1 Characterized by.

[0015] In some embodiments of the present invention, the DSC graph of the crystalline form 1 has an endothermic peak in the range of 115±3°C.

[0016] In some embodiments of the present invention, the DSC diagram of the crystalline form 1 is substantially as follows Figure 2 Characterized by.

[0017] In some embodiments of the present invention, the TGA graph of the crystalline form 1 shows a weight loss of about 0.2% in the range of 25-200°C.

[0018] In some embodiments of the present invention, the TGA diagram of the crystalline form 1 is substantially as follows Figure 3 Characterized by.

[0019] In some embodiments of the present invention, the DVS diagram of the crystal form 1 has no obvious hygroscopicity in the range of RH 0-90%, for example, its mass change is less than 0.07%.

[0020] In some embodiments of the present invention, the DVS diagram of the crystalline form 1 is substantially as follows Figure 4 Characterized by.

[0021] The present invention also provides a crystalline form 2 of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic peaks at one or more of the following 2θ values: 4.34±0.2°, 14.26±0.2°, 15.10±0.2°, 16.92±0.2°, 19.08±0.2° and 21.91±0.2°.

[0022] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form 2 has characteristic peaks at one or more of the following 2θ values: 4.34±0.2°, 14.26±0.2°, 15.10±0.2°, 16.34±0.2°, 16.92±0.2°, 18.45±0.2°, 19.08±0.2°, 21.91±0.2° and 25.47±0.2°.

[0023] In one embodiment, the X-ray powder diffraction pattern of the crystalline form 2 has characteristic peaks at the following 2θ values:

[0024] Serial number 2θ±0.2° d value Relative Strength Serial number 2θ±0.2° d value Relative Strength 1 4.34 20.33 68.4 7 16.92 5.24 100.0 2 11.04 8.00 15.8 8 18.45 4.80 39.6 3 12.98 6.82 13.4 9 19.08 4.65 52.4 4 14.26 6.21 66.3 10 21.91 4.05 58.1 5 15.10 5.86 54.2 11 23.40 3.80 37.7 6 16.34 5.42 44.4 12 25.47 3.49 43.1 .

[0025] In some embodiments of the present invention, the X-ray powder diffraction pattern of Form 2 is substantially as follows Figure 5 Characterized by.

[0026] In some embodiments of the present invention, the DSC graph of the crystalline form 2 has an endothermic peak in the range of 73±3°C.

[0027] In some embodiments of the present invention, the DSC diagram of Form 2 is substantially as follows Figure 6 Characterized by.

[0028] In some embodiments of the present invention, the TGA graph of Form 2 shows a weight loss of about 14% in the range of 25-175°C.

[0029] In some embodiments of the present invention, the TGA diagram of the crystalline form 2 is substantially as follows Figure 7 Characterized by.

[0030] In some embodiments of the present invention, the crystalline form 2 is a 1,4-dioxane solvate.

[0031] The present invention also provides a crystalline form 3 of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic peaks at one or more of the following 2θ values: 5.54±0.2°, 11.28±0.2°, 15.28±0.2°, 16.38±0.2°, 20.42±0.2° and 20.86±0.2°.

[0032] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form 3 has characteristic peaks at the following 2θ values:

[0033] Serial number 2θ±0.2° d value Relative Strength Serial number 2θ±0.2° d value Relative Strength 1 5.54 15.93 68.1 7 16.38 5.41 36.8 2 6.84 12.91 8.3 8 17.17 5.16 21.6 3 8.15 10.85 9.2 9 20.42 4.34 50.1 4 11.28 7.84 56.5 10 20.86 4.26 100.0 5 13.61 6.50 27.1 11 21.45 4.14 13.9 6 15.28 5.79 99.6 12 21.96 4.04 11.0 .

[0034] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form 3 is substantially as follows Figure 8 Characterized by.

[0035] In some embodiments of the present invention, the DSC graph of the crystalline form 3 has an endothermic peak in the range of 62±3°C.

[0036] In some embodiments of the present invention, the DSC diagram of the crystalline form 3 is substantially as follows Fig. 9 Characterized by.

[0037] In some embodiments of the present invention, the TGA graph of the crystalline form 3 shows a weight loss of about 6.85% in the range of 25-200°C.

[0038] In some embodiments of the present invention, the TGA diagram of the crystalline form 3 is substantially as follows Fig.10 Characterized by.

[0039] In some embodiments of the present invention, the crystalline form 3 is a 1,4-dioxane solvate.

[0040] The present invention also provides an amorphous form of the compound I, whose X-ray powder diffraction pattern shows diffuse peaks without obvious sharp peaks, which is basically Fig.11 Characterized by.

[0041] In some embodiments of the present invention, the amorphous DSC graph has no obvious endothermic or exothermic phenomenon.

[0042] In some embodiments of the present invention, the amorphous DSC pattern is substantially as follows Fig.12 Characterized by.

[0043] In the present invention, the purity of the crystalline form 1, 2 or 3, and the amorphous form is greater than 95%, preferably, the purity is greater than 97%, more preferably, the purity is greater than 99%, and most preferably, the purity is greater than 99.5%.

[0044] In a second aspect of the present invention, a method for preparing polymorphic and amorphous forms of Compound I is provided.

[0045] In some embodiments of the present invention, the method for preparing Compound I Form 1 comprises: heating and dissolving a crude Compound I in an organic solvent, cooling and crystallizing to obtain Compound I Form 1;

[0046] Preferably, the organic solvent is selected from methanol, ethanol, isopropanol, n-propanol, ethyl acetate, dichloromethane, and acetone.

[0047] Preferably, the weight-to-volume ratio of the compound I to the organic solvent is 1 g:(5-100) ml, more preferably 1 g:(5-35) ml.

[0048] Preferably, the dissolution temperature is 40-100°C, more preferably 60-85°C.

[0049] Preferably, the cooling crystallization is carried out at room temperature, such as 0 to 25°C, such as 0 to 10°C.

[0050] In some embodiments of the present invention, Form 1 is prepared in the following manner: Compound I is added to ethanol, heated to reflux to dissolve, and after the solution is clear, the temperature is slowly lowered to crystallize;

[0051] Alternatively, the crystal form 1 is prepared in the following manner: Compound I is dissolved in dichloromethane, and ethanol is added after the solution becomes clear to obtain a clear solution of Compound I; ethanol is heated to above 50° C., the clear solution of Compound I is added, and then the temperature is lowered for crystallization;

[0052] Alternatively, the crystal form 1 is prepared in the following manner: Compound I is added to isopropanol, the temperature is raised to reflux and stirred to dissolve; after the solution is clear, the temperature is slowly lowered to crystallize.

[0053] In some embodiments of the present invention, the preparation method of Compound I Form 2 includes: dissolving Compound I in a mixed solvent of 1,4-dioxane and n-heptane, stirring and crystallizing at room temperature to obtain Compound I Form 2.

[0054] Preferably, the volume ratio of 1,4-dioxane to n-heptane in the mixed solvent is 1:1.

[0055] Preferably, the total weight-to-volume ratio of the compound I to the organic solvent is 1 g:(1-50) ml, for example, 1 g:(3-20) ml.

[0056] In some embodiments of the present invention, the preparation method of Compound I Form 3 includes: dissolving Compound I in 1,4-dioxane, adding methyl tert-butyl ether solvent, cooling and crystallizing to obtain Compound I Form 3.

[0057] Preferably, the weight-to-volume ratio of the compound I to 1,4-dioxane is 1 g:(0.5-10) ml, more preferably 1 g:(1-5) ml.

[0058] Preferably, the volume ratio of 1,4-dioxane to methyl tert-butyl ether is 1:(5-20), more preferably 1:(8-15).

[0059] Preferably, the cooling crystallization is carried out at room temperature, such as 0-25°C, for example, at 0-10°C.

[0060] In the above method of the present invention, after crystallization, the crystallization further comprises filtering and drying steps, for example, vacuum drying at 40-50°C.

[0061] In some embodiments of the present invention, the method for preparing the amorphous form of Compound I comprises: dissolving Compound I in an organic solvent, and evaporating the solvent to obtain Compound I in an amorphous form.

[0062] Preferably, the organic solvent is selected from ethyl acetate, dichloromethane, acetone, acetonitrile and tetrahydrofuran.

[0063] Preferably, the temperature for evaporating and removing the solvent is 0 to 60°C, preferably 20 to 40°C.

[0064] The third aspect of the present invention provides a pharmaceutical composition comprising at least one of the crystalline forms (e.g., crystalline form 1, 2, or 3) or amorphous forms of Compound I described in the present invention, and optionally a pharmaceutically acceptable carrier.

[0065] The fourth aspect of the present invention also provides a use of at least one of the crystalline forms 1, 2, or 3 or amorphous forms of Compound I as described above, or the pharmaceutical composition as described above in the preparation of a medicament for preventing, treating or ameliorating the symptoms or diseases of androgen-related disorders.

[0066] The fifth aspect of the present invention also provides a method for treating, preventing or ameliorating the symptoms or diseases of androgen-related disorders, which comprises administering to an individual in need thereof a preventive or therapeutically effective amount of any crystalline or amorphous form of Compound I of the present invention, or the pharmaceutical composition as described above.

[0067] According to the present invention, non-limiting examples of symptoms or diseases of androgen-related disorders are: androgen-related inflammation, including trauma, acne, atopic dermatitis, rheumatoid arthritis, psoriasis and rosacea; Kennedy's disease (spinal and bulbar muscular atrophy or SBMA), polyglutamine-mediated motor neuron degeneration; androgen-related cancers, such as prostate cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, hepatocellular carcinoma, central nervous system cancer, skin cancer, lymphoma, leukemia, esophageal cancer, gastric cancer, colon cancer and pancreatic cancer; hair loss, including androgenic alopecia; acne and hirsutism.

[0068] The present invention provides a crystalline form and an amorphous form of a curcumin derivative as shown in formula I, wherein crystalline forms 1, 2 and the amorphous form have good reproducibility in the preparation process, and crystalline form 1 has excellent stability, and the preparation method is simple and easy to operate, more suitable for scale-up production, and has good industrial application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 is the XRPD pattern of Compound I Form 1 of the present invention;

[0070] Figure 2 is the DSC spectrum of Compound I Crystal Form 1 of the present invention;

[0071] Figure 3 is the TGA spectrum of Compound I Crystal Form 1 of the present invention;

[0072] Figure 4 is the DVS spectrum of Compound I Crystal Form 1 of the present invention;

[0073] Figure 5 is the XRPD pattern of Compound 1 Form 2 of the present invention;

[0074] Figure 6 is the DSC spectrum of Compound 1 Crystal Form 2 of the present invention;

[0075] Figure 7 is the TGA spectrum of Compound I Crystal Form 2 of the present invention;

[0076] Figure 8 is the XRPD pattern of Compound 1 Form 3 of the present invention;

[0077] Fig. 9 is the DSC spectrum of Compound I Crystal Form 3 of the present invention;

[0078] Fig.10 is the TGA spectrum of Compound I Crystal Form 3 of the present invention;

[0079] Fig.11 is the XRPD pattern of the amorphous form of Compound I of the present invention;

[0080] Fig.12 It is the DSC spectrum of the amorphous form of Compound I of the present invention. DETAILED DESCRIPTION

[0081] The present invention is described in detail below by way of examples. It should be understood that the methods in the examples are for illustration purposes only and do not constitute any limitation of the present invention. Unless otherwise specified, the materials used in the examples are commercially available. Unless otherwise specified, the experimental methods used are all conventional methods.

[0082] The solvate described in the present invention refers to a substance (solvate) formed after the crystallization of a compound and a solvent. During the contact between a compound or drug molecule and a solvent molecule, external and internal conditions may cause the solvent molecule and the compound molecule to form a eutectic and remain in the solid substance.

[0083] Instruments and methods:

[0084] XRPD (X-ray powder diffraction): Instrument: Bruker D8 ADVANCE X-ray diffractometer; XRPD parameters: Light tube: Cu, kα Light tube voltage: 40 kV, light tube current: 40 mA; scanning range: 3-45 degrees; step diameter: 0.02 degrees; step length: 0.12 seconds. Test method: About 10-20 mg of sample is used for XRPD detection.

[0085] DSC (Differential Scanning Calorimetry): Instrument: METTLER TOLEDO DSC3+ Differential Scanning Calorimeter; DSC parameters: Temperature range: 25-200°C; Heating rate: 10°C / min; Nitrogen purge gas: 50ml / min. Test method: Take a sample (1-5mg) and place it in a DSC aluminum pan for testing. The temperature range of the endothermic peak in this application refers to the Onset temperature range.

[0086] TGA (thermogravimetric analysis): Instrument: American TA TGA550; TGA parameters: temperature range: 30-300°C; heating rate: 10°C / min; nitrogen purge gas: 25ml / min. Test method: Take a sample (5-10mg) and place it in a TGA platinum pot for testing.

[0087] Compound I used in the present invention can be prepared in batches by referring to the method of Example 8 of Chinese patent application CN202310481798.5. The specific method is as follows:

[0088] 1. Synthesis of intermediate 7:

[0089]

[0090] Add dimethylcurcumin (100g, 252.2mmol, 1.0eq), 1,5-dichloropentanone (39.1g, 252.2mmol), KBr (120.1g, 100.9mmol), K2CO3 (104.6g, 756.7mmol) and DMF (3000mL) to the reaction bottle and stir at 50°C for 20 hours. After the reaction is completed, add water (7000mL) and ethyl acetate (4000mL), separate the liquids, and extract the aqueous phase with ethyl acetate (4000mL). Combine the organic phases, wash off the DMF with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue is subjected to column chromatography (petroleum ether / ethyl acetate 10:1~2:1) to obtain 40.1g of yellow foamy solid.

[0091] 1 H NMR(400MHz, CDCl3)7.75(d,J=15.5Hz,2H),7.15(dd,J=8.4,2.0Hz,2H),7.02(d,J=2.0H z,2H),6.85(d,J=8.4Hz,2H),6.74(d,J=15.4Hz,2H),3.91(s,12H),2.56–2.40(m,8H).MS m / z:479.29[M+H] + .

[0092] 2. Synthesis of Compound I:

[0093]

[0094] Under nitrogen protection, add intermediate compound 7 (40.0 g, 83.6 mmol), dichloromethane (400 mL), and 10 drops of pyridine hydrofluoride to the reaction bottle. Stir and cool to 0 ° C, add 4-tert-butyl-2,6-dimethylphenyl sulfur trifluoride (41.9 g, 167.4 mmol) at one time, and react at 10-15 ° C for 6 hours. The reaction solution is washed with water, dried over anhydrous sodium sulfate, concentrated, and column chromatography (petroleum ether / ethyl acetate 10:1-2:1) to obtain a crude product, and HPLC preparation (acetonitrile / water 10:90-80:20) to obtain 4.0 g of light yellow solid compound 1.

[0095] 1 H NMR (400MHz, CDCl3) δ7.71(d,J=15.4Hz,2H),7.14(d,J=8.3Hz,2H),7.09–6.96(m,2H),6.85( d,J=8.4Hz,2H),6.72(d,J=15.4Hz,2H),3.91(s,12H),2.45–2.18(m,4H),2.12–1.91(m,4H). 19F NMR(376MHz,CDCl3)δ-97.28.MS m / z:501.27[M+H] + .

[0096] Example 1. Preparation of Compound I Crystalline Form 1

[0097] About 2.0 g of compound I was added to 50 ml of ethanol solvent, heated to reflux to dissolve, and then slowly cooled to 0-10° C. for crystallization after the solution became clear. The filter cake was washed with ethanol and dried under vacuum at 40° C. to obtain a sample of compound I. DSC and XRPD measurements showed that the obtained sample was Form 1.

[0098] The XRPD pattern of the obtained crystal form 1 is basically as follows Figure 1 As shown, the diffraction angle data is shown in Table 1 below.

[0099] Table 1. XRPD data of Form 1

[0100] Serial number 2θ d value Relative Strength Serial number 2θ d value Relative Strength 1 7.57 11.66 2.6 7 19.06 4.65 18.7 2 14.51 6.10 31.7 8 19.54 4.54 14.0 3 15.02 5.89 100.0 9 20.68 4.29 41.6 4 15.26 5.80 36.9 10 21.17 4.19 25.8 5 15.71 5.63 16.7 11 21.57 4.12 47.6 6 18.12 4.89 4.1 12 25.23 3.53 9.3

[0101] The DSC spectrum of Form 1 is basically as follows Figure 2 It has an endothermic peak in the range of 115±3°C, for example, 113.91°C.

[0102] The TGA spectrum of Form 1 is basically as follows Figure 3 It loses about 0.2% of its weight in the range of 25-200°C.

[0103] The DVS spectrum of Form 1 is basically as follows Figure 4 It is non-hygroscopic in the RH range of 0-90%.

[0104] Example 2. Preparation of Compound I Crystalline Form 1

[0105] About 5.0 g of compound I was dissolved in 5 ml of dichloromethane, and 5 ml of ethanol solvent was added after the solution was clear to obtain a clear solution of compound I. 90 ml of ethanol solvent was heated to 70° C. and quickly added to the clear solution of compound I, then cooled to crystallize, filtered, and the filter cake was rinsed with ethanol and dried in vacuo at 40° C. to obtain a sample of compound I. DSC and XRPD measurements showed that the obtained sample was Form 1.

[0106] Example 3. Preparation of Compound I Crystalline Form 1

[0107] About 14.0 g of compound I was added to 80 ml of isopropanol, and the mixture was heated to reflux and stirred to dissolve. After the mixture was clear, the mixture was slowly cooled to 0-10°C for crystallization, filtered, and the filter cake was rinsed with isopropanol and dried under vacuum at 50°C to obtain a sample of compound I. DSC and XRPD measurements showed that the obtained sample was Form 1.

[0108] Example 4. Preparation of Compound I Crystalline Form 2

[0109] About 15.0 g of compound I was added to a mixed solvent of 25 ml of 1,4-dioxane and 25 ml of n-heptane, and the mixture was stirred to dissolve at room temperature. After the mixture was dissolved, the mixture was stirred to crystallize at room temperature. After a large amount of solid was precipitated, the mixture was filtered. The filter cake was rinsed with n-heptane and dried in vacuo at 40° C. to obtain Form 2 of compound I.

[0110] The XRPD pattern of the obtained crystal form 2 is as follows: Figure 5 As shown, the diffraction angle data is basically as shown in Table 2 below.

[0111] Table 2. XRPD data of Form 2

[0112] Serial number 2θ d value Relative Strength Serial number 2θ d value Relative Strength 1 4.34 20.33 68.4 7 16.92 5.24 100.0 2 11.04 8.00 15.8 8 18.45 4.80 39.6 3 12.98 6.82 13.4 9 19.08 4.65 52.4 4 14.26 6.21 66.3 10 21.91 4.05 58.1 5 15.10 5.86 54.2 11 23.40 3.80 37.7 6 16.34 5.42 44.4 12 25.47 3.49 43.1

[0113] The DSC spectrum of Form 2 is basically as follows Figure 6 It has an endothermic peak in the range of 73±3°C, for example, 73.43°C.

[0114] The TGA spectrum of Form 2 is basically as follows Figure 7 It loses about 14% of its weight in the range of 25-175°C. Nuclear magnetic resonance characterization confirms that the crystal form 2 is a 1,4-dioxane solvate.

[0115] Example 5. Preparation of Compound I Crystalline Form 3

[0116] About 0.3 g of compound I was dissolved in 0.6 ml of 1,4-dioxane solvent, 5.4 ml of methyl tert-butyl ether solvent was added, and the mixture was allowed to stand at 2-8° C. for crystallization. The solid was filtered and vacuum dried at 40° C. to obtain form 3 of compound I.

[0117] The XRPD pattern of the obtained crystal form 3 is as follows: Figure 8 As shown, the diffraction angle data is basically as shown in Table 3 below.

[0118] Table 3. XRPD data of Form 3

[0119] Serial number 2θ d value Relative Strength Serial number 2θ d value Relative Strength 1 5.54 15.93 68.1 7 16.38 5.41 36.8 2 6.84 12.91 8.3 8 17.17 5.16 21.6 3 8.15 10.85 9.2 9 20.42 4.34 50.1 4 11.28 7.84 56.5 10 20.86 4.26 100.0 5 13.61 6.50 27.1 11 21.45 4.14 13.9 6 15.28 5.79 99.6 12 21.96 4.04 11.0

[0120] The DSC spectrum of Form 3 is basically as follows Fig. 9 As shown, the DSC graph has an endothermic peak in the range of 62±3°C, for example, 61.49°C.

[0121] The TGA spectrum of Form 3 is basically as follows Fig.10 The weight loss was about 6.85% in the range of 25-200°C. Nuclear magnetic resonance characterization confirmed that the crystal form 3 was a 1,4-dioxane solvate.

[0122] Example 6. Preparation of Amorphous Form of Compound I

[0123] About 15 g of compound I was dissolved in 40 ml of dichloromethane solvent, and the solvent was quickly removed by concentrating under reduced pressure at 40° C. to obtain a foamy substance, which was then pumped dry with an oil pump to obtain an amorphous form of compound I.

[0124] The XRPD pattern of the obtained amorphous form is as follows: Fig.11 As shown, the XRPD spectrum shows diffuse peaks without obvious sharp peaks. The DSC diagram of the obtained amorphous form is basically as follows Fig.12 As shown, there is no obvious endothermic or exothermic phenomenon in the DSC graph.

[0125] Example 7. Thermodynamic Stability Study of Compound I Form 1 and Amorphous Form

[0126] In this example, the stability of Form 1 and the amorphous substance was studied.

[0127] About 150 mg of Compound I Form 1 sample was placed in 6 flasks, and 2 ml of the corresponding solvents in Table 5 were added, and stirred at 50° C. After stirring for 24 hours, the sample was filtered, and the filtered solid was vacuum dried at 40° C. to obtain a sample.

[0128] About 150 mg of amorphous form of Compound I was placed in two flasks, and 2 ml of the corresponding solvents in Table 5 were added, and stirred at room temperature. After stirring for 3 days, the sample was filtered, and the filtered solid was vacuum dried at 40° C. to obtain a sample.

[0129] The dried sample was subjected to DSC measurement, and the change of the crystal form was determined based on the DSC results.

[0130] The thermodynamic stability results of Compound I Form 1 and amorphous form are shown in Table 4.

[0131] Table 4. Thermodynamic stability of Form 1 and amorphous form of Compound 1

[0132] Serial number sample Solvents volume temperature time DSC determination 1 Crystal form 1 Methanol 2ml 50℃ 24h Crystal form 1 2 Crystal form 1 Ethanol 2ml 50℃ 24h Crystal form 1 3 Crystal form 1 Isopropyl alcohol 2ml 50℃ 24h Crystal form 1 4 Crystal form 1 water 2ml 50℃ 24h Crystal form 1 5 Crystal form 1 n-Heptane 2ml 50℃ 24h Crystal form 1 6 Crystal form 1 Methyl tert-butyl ether 2ml 50℃ 24h Crystal form 1 7 Amorphous form Isopropyl alcohol 2ml Room temperature 3 days Crystal form 1 8 Amorphous form Methyl tert-butyl ether 2ml Room temperature 3 days Crystal form 1

[0133] The experimental results show that the amorphous form of compound I is converted into Form 1 when stirred at room temperature in isopropanol (IPA) and methyl tert-butyl ether (MTBE) solvents; Form 1 remains stable in different solvents and conditions. In summary, Form 1 has excellent thermodynamic stability.

[0134] Example 8. Physical and chemical stability studies of Compound I Form 1 and amorphous form

[0135] The Compound I crystal form 1 sample and the amorphous form sample were laid open and placed flat to examine the physical stability of the samples under high temperature (60°C), high humidity (RH92.5%) and light conditions. Certain samples were taken at 0 days, 10 days and 30 days to test DSC and XRPD to evaluate the physical stability of the crystal form 1 and the amorphous form, and HPLC was used to evaluate the chemical stability of the crystal form 1 and the amorphous form. The stability results are shown in Table 5.

[0136] Table 5. Physicochemical stability of Form 1 and amorphous form of Compound I

[0137]

[0138] The results showed that the amorphous form of compound I was placed under high humidity (RH92.5%) and light conditions for 30 days, and the amorphous form underwent phase change; placed under high temperature (60°C) conditions for 10 days or 30 days, the amorphous form was transformed into crystalline form 1. In addition, the amorphous form was placed in a high temperature (60°C) and high humidity (RH92.5%) environment for 30 days, and the related substances did not change significantly, indicating that the amorphous form was chemically stable under these conditions; but it was placed under light conditions for 10 days or 30 days, and degradation occurred, indicating that the amorphous form was chemically unstable under light conditions, and storage under light conditions should be avoided. The amorphous form can be incorporated into the dosage form through formulation technology, and its stability can be maintained during the shelf life of the product, such as forming a co-amorphous or preparing a solid dispersion.

[0139] The crystal form 1 of compound I was placed under high temperature (60° C.), high humidity (RH92.5%) and light conditions for 30 days, and the DSC spectrum and XRPD spectrum were consistent with those at 0 days, indicating that the crystal form 1 of compound I did not change and had good physical stability. In addition, the crystal form 1 of compound I was placed under high temperature (60° C.), high humidity (RH92.5%) and light conditions for 30 days, and the related substances did not change significantly, indicating that the chemical stability of the crystal form 1 of compound I was good.

[0140] In summary, different crystal forms of the same drug can have different chemical and physical properties, which can directly affect the processing and production of raw materials and preparations, and affect the stability, solubility and bioavailability of preparations. The inventors obtained compound I crystal form 1, crystal form 2, crystal form 3 and amorphous form by screening compound I for polymorphs. Stability studies have found that crystal form 1 is the most thermodynamically stable crystal form. Compound I crystal form 1 is an anhydrous substance with a melting point of about 115±3°C, no hygroscopicity, and is not easy to convert between crystal forms, and still has good chemical stability and physical stability under different damage test conditions. In addition, crystal form 1 is easy to scale up and is suitable for industrial production. Therefore, crystal form 1 is a preferred crystal form suitable for the development of pharmaceutical preparations. Crystal forms 2 and 3 are 1,4-dioxane solvates with high solvent content, low melting point, and poor stability, and can be used as intermediates to further develop other crystal forms. Amorphous form is also a relatively stable form that can be used to develop solid dispersion preparations.

[0141] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them. A person skilled in the art should understand that the technical solutions recorded in the above embodiments may be modified based on the disclosure of the present invention, or some of the technical features therein may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the present invention, and they still fall within the protection scope of the present invention.

Claims

1. Crystalline form 1 of the compound represented by formula (I), characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at one or more of the following 2θ values: 14.51±0.2°, 15.02±0.2°, 15.26±0.2°, 20.68±0.2°, 21.17±0.2° and 21.57±0.2°, 2. The crystal form 1 according to claim 1, characterized in that The X-ray powder diffraction pattern of the crystalline form 1 has characteristic peaks at one or more of the following 2θ values: 14.51±0.2°, 15.02±0.2°, 15.26±0.2°, 15.71±0.2°, 19.06±0.2°, 20.68±0.2°, 21.17±0.2° and 21.57±0.2°.

3. The crystal form 1 according to claim 1, characterized in that The crystalline form 1 has an X-ray powder diffraction pattern substantially as shown in FIG1 .

4. The crystal form 1 according to claim 1, characterized in that The DSC graph of the crystal form 1 has an endothermic peak in the range of 115±3°C. Preferably, the crystal form 1 has a DSC graph substantially as shown in FIG2 ; Preferably, the TGA graph of the crystalline form 1 shows a weight loss of about 0.2% in the range of 25-200° C., and more preferably, the crystalline form 1 has a TGA graph substantially as shown in FIG. 3 .

5. The method for preparing the crystal form 1 according to any one of claims 1 to 4, characterized in that: The method comprises the following steps: heating and dissolving compound I in an organic solvent, cooling and crystallizing to obtain compound I crystal form 1; The organic solvent is selected from at least one of methanol, ethanol, isopropanol, n-propanol, ethyl acetate, dichloromethane and acetone.

6. Crystalline Form 2 of the compound represented by formula (I), characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at one or more of the following 2θ values: 4.34±0.2°, 14.26±0.2°, 15.10±0.2°, 16.34±0.2°, 16.92±0.2°, 18.45±0.2°, 19.08±0.2°, 21.91±0.2°, and 25.47±0.2°; Preferably, the crystalline form 2 has an X-ray powder diffraction pattern substantially as shown in FIG5 ; Preferably, the DSC graph of the crystalline form 2 has an endothermic peak in the range of 73±3°C. Preferably, the crystalline form 2 has a DSC graph substantially as shown in FIG. 6 ; Preferably, the TGA graph of the Form 2 shows a weight loss of about 14% in the range of 25-175° C. Preferably, the Form 2 has a TGA graph substantially as shown in FIG. 7 .

7. Crystalline form 3 of the compound represented by formula (I), characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at one or more of the following 2θ values: 5.54±0.2°, 11.28±0.2°, 15.28±0.2°, 16.38±0.2°, 20.42±0.2°, and 20.86±0.2°; Preferably, the crystalline form 3 has an X-ray powder diffraction pattern substantially as shown in FIG8 ; Preferably, the DSC graph of the crystalline form 3 has an endothermic peak in the range of 62±3°C; preferably, the crystalline form 3 has a DSC graph substantially as shown in FIG. 9; Preferably, the TGA graph of the Form 3 shows a weight loss of about 6.85% in the range of 25-200° C.; preferably, the Form 3 has a TGA graph substantially as shown in FIG. 10 .

8. An amorphous form of a compound of formula (I), characterized in that It has an X-ray powder diffraction pattern substantially as shown in FIG11 .

9. A pharmaceutical composition, characterized in that The invention comprises at least one of the crystal form 1 according to any one of claims 1 to 4, the crystal form 2 according to claim 6, the crystal form 3 according to claim 7, or the amorphous form according to claim 8, and a pharmaceutically acceptable carrier.

10. Use of the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating, preventing or ameliorating symptoms or diseases associated with androgen disorders. Preferably, the symptom or disease associated with androgen disorder is selected from: androgen-related inflammation, including trauma, acne, atopic dermatitis, rheumatoid arthritis, psoriasis and rosacea; Kennedy's disease (spinal and bulbar muscular atrophy or SBMA), polyglutamine-mediated motor neuron degeneration; androgen-related cancers, such as prostate cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, hepatocellular carcinoma, central nervous system cancer, skin cancer, lymphoma, leukemia, esophageal cancer, gastric cancer, colon cancer and pancreatic cancer; hair loss, including androgenic alopecia; acne and hirsutism.

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