Crystal form of steroid compound and application thereof

Abstract

The invention aims to provide a crystal form of a steroid compound, a pharmaceutical composition and application of the crystal form in preparation of a medicine for treating GABAA receptor related diseases. Compared with the prior art, the crystal form provided by the invention has one or more improved properties, and is of great significance to further development of the medicine.

Description

Technical Field

[0001] The present invention relates to the field of chemical medicine, and in particular to a crystal form of a steroid compound and a use thereof. Background Art

[0002] Neuropsychiatric diseases include anxiety, depression, schizophrenia, etc., which rank first in the total disease burden in my country, accounting for about 20% of the total disease burden. With the continuous development of social modernization, the accelerated pace of work and increased pressure in life have led to a significant increase in patients with various neuropsychiatric diseases, and the progression of symptoms has accelerated significantly, making it more urgent to develop, research and produce drugs against neuropsychiatric diseases.

[0003] GABA(A) receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand (GABA) exists in the central nervous system as an inhibitory neurotransmitter. The GABA system is the main inhibitory signaling pathway in the brain and central nervous system and is of great significance in regulating the function of the central nervous system. After GABA(A) receptor activation, it selectively allows Cl - Through its pores. - It flows out of neuronal cells when the internal voltage is less than the resting potential, and flows into neuronal cells when the internal voltage is greater than the resting potential (i.e. -75mv). This can successfully reduce the chance of action potentials occurring and have an inhibitory effect on neurotransmission. Research results have confirmed that the GABAergic system and GABA(A) receptors play an important role in the etiology and pathology of diseases such as anxiety, depression, and schizophrenia. The GABAergic system and GABA(A) receptors have been shown to be involved in the pathological processes of anxiety, depression, and schizophrenia at the molecular, preclinical, and clinical levels, and GABA(A) receptors have long been used as an important drug target for the treatment of these diseases.

[0004] Many studies are based on GABA(A) receptors in order to obtain drugs that can effectively treat related diseases. For example, WO2020143640A1 provides a class of steroid compounds that regulate brain excitability by regulating GABA(A) receptor modulators for the treatment of psychoneurological diseases.

[0005] Drug polymorphism refers to the different lattice arrangements formed by the orderly arrangement of chemical drug molecules in the microstructure, which is generally manifested as different existence forms of drug raw materials in the solid state. A drug can exist in multiple crystal forms. Different crystal forms of the same drug may show different physical or chemical properties. The study of drug polymorphism is of great significance for the development of crystal forms that are more suitable for pharmaceutical use. Summary of the invention

[0006] An object of the present invention is to provide a new crystalline form of the compound of the following formula I, named as crystalline form A.

[0007]

[0008] In some embodiments, the crystalline form A provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.1°±0.2°, 11.7°±0.2°, 13.5°±0.2°, 16.2°±0.2°, and 17.6°±0.2°.

[0009] In some embodiments, the crystalline form A provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.1°±0.2°, 11.7°±0.2°, 13.0°±0.2°, 13.5°±0.2°, 15.3°±0.2°, 16.2°±0.2°, 17.6°±0.2°, and 21.3°±0.2°.

[0010] In some embodiments, the present invention provides a crystalline form A, characterized in that its X-ray powder diffraction pattern is as follows Figure 1A shown.

[0011] In some embodiments, the present invention provides a method for preparing Form A, which comprises adding a compound of Formula I to an organic solvent to fully dissolve, then cooling and precipitating, and obtaining a solid after centrifugation. In some specific embodiments, the organic solvent is isopropanol, ethyl propyl acetate or acetonitrile, preferably isopropanol. In other specific embodiments, the organic solvent is a mixed solvent of isopropanol, ethanol or acetone and water; wherein the volume ratio of isopropanol, ethanol or acetone to water is 1:1 to 1:5, preferably 1:1 to 1:2. In other specific embodiments, the organic solvent is a mixed solvent of acetonitrile and 2-methyltetrahydrofuran, wherein the volume ratio of acetonitrile to 2-methyltetrahydrofuran is 1:1 to 1:5, preferably 1:1 to 1:2. In some preferred embodiments, the mass volume ratio of the compound of Formula I to the organic solvent is 100:1 to 5:1 (mg:ml), preferably 50:1 to 10:1, and more preferably 20:1.

[0012] In other embodiments, the preparation method of Form A provided by the present invention can also be prepared by slow volatilization, low temperature (4-8°C) slurry conversion, room temperature slurry conversion, high temperature (50°C) slurry conversion, anti-solvent addition, gas-solid diffusion, gas-liquid diffusion, water vapor stress, polymer induction, grinding, cyclic heating and cooling, rotary evaporation and other conventional methods in the art. For example, in the low temperature (4-8°C) slurry conversion preparation method, isopropanol, isopropyl acetate, methyl tert-butyl ether, acetonitrile and other organic solvents are added to the compound of formula I, and the obtained suspension is placed at a low temperature (e.g., 5°C) and magnetically stirred (e.g., after 3 days, 4 days, 5 days or even 6 days or more, the solid is collected by centrifugation). For example, in the anti-solvent addition preparation method, the positive solvent can be selected from acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, 2-methyltetrahydrofuran, isopropanol, dichloromethane, methyl tert-butyl ether, etc., and the anti-solvent is selected from water or n-heptane, etc. For example, in the rotary evaporation preparation method, the solvent can be selected from acetone or tetrahydrofuran.

[0013] Another object of the present invention is to provide a new crystalline form of the compound of formula I, named Form B.

[0014] In some embodiments, the crystalline form B provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.3°±0.2°, 9.0°±0.2°, 14.7°±0.2°, 15.6°±0.2°, and 18.0°±0.2°.

[0015] In some embodiments, the crystalline form B provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.3°±0.2°, 9.0°±0.2°, 11.0°±0.2°, 12.2°±0.2°, 14.7°±0.2°, 15.3°±0.2°, 15.6°±0.2°, and 18.0°±0.2°.

[0016] In some embodiments, the present invention provides Form B, characterized in that its X-ray powder diffraction pattern is as follows Figure 2A shown.

[0017] In some embodiments, the present invention provides a method for preparing Form B, which comprises adding the compound of Formula I to a mixed solvent of isopropyl acetate and toluene, or a mixed solvent of ethanol and toluene, and obtaining the resulting Form B after suspension and stirring at low temperature (e.g., 5° C.) or room temperature (e.g., 3 days, 4 days, 5 days, or even more than 6 days).

[0018] In other schemes, a crystal transformation experiment was conducted on Form B, and it was found that after Form B was left open at 50°C for 5 hours, XRPD was detected and the crystal was transformed into Form A. In another crystal transformation experiment, when Form B was heated to 110°C by DSC and kept at this temperature for 3 minutes and then cooled to room temperature, XRPD was detected and Form B was transformed into Form A + Form D.

[0019] Another object of the present invention is to provide a new crystalline form of the compound of formula I, named Form C.

[0020] In some embodiments, the crystalline form C provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.6°±0.2°, 8.6°±0.2°, 14.0°±0.2°, 16.7°±0.2°, and 17.4°±0.2°.

[0021] In some embodiments, the crystalline form C provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.6°±0.2°, 8.6°±0.2°, 9.9°±0.2°, 14.0°±0.2°, 14.9°±0.2°, 16.7°±0.2°, 17.4°±0.2°, and 18.5°±0.2°.

[0022] In some embodiments, the crystalline form C provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.6°±0.2°, 8.6°±0.2°, 9.9°±0.2°, 11.2°±0.2°, 11.8°±0.2°, 14.0°±0.2°, 14.9°±0.2°, 16.7°±0.2°, 17.4°±0.2°, 18.5°±0.2°, and 18.9°±0.2°.

[0023] In some embodiments, the present invention provides a crystalline form C, characterized in that its X-ray powder diffraction pattern is as follows Figure 3A shown.

[0024] In some embodiments, the present invention provides a method for preparing Form C, which comprises adding the compound of Formula I to methanol, ultrasonically dissolving, filtering, and allowing the filtrate to stand and evaporate to obtain Form C.

[0025] In a crystal transformation experiment, Form C was left open at 50°C for about 4 hours and tested by XRPD, showing that the crystal form remained unchanged. Form C was heated to 110°C using DSC and kept at this temperature for 3 minutes before being cooled to room temperature for XRPD testing, showing that the crystal was transformed into Form G.

[0026] Another object of the present invention is to provide a new crystalline form of the compound of formula I, named Form D.

[0027] In some embodiments, the crystal form D provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.1°±0.2°, 8.8°±0.2°, 12.2°±0.2°, 14.4°±0.2°, and 17.6°±0.2°.

[0028] In some embodiments, the crystalline form D provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.1°±0.2°, 8.8°±0.2°, 10.2°±0.2°, 12.2°±0.2°, 12.9°±0.2°, 13.5°±0.2°, 14.4°±0.2°, and 17.6°±0.2°.

[0029] In some embodiments, the crystalline form D provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.1°±0.2°, 7.6°±0.2°, 8.0°±0.2°, 8.8°±0.2°, 10.2°±0.2°, 11.0°±0.2°, 11.6°±0.2°, 12.2°±0.2°, 12.9°±0.2°, 13.5°±0.2°, 14.0°±0.2°, 14.4°±0.2°, 15.4°±0.2°, 17.6°±0.2°, and 18.2°±0.2°.

[0030] In some embodiments, the present invention provides a crystalline form D, characterized in that its X-ray powder diffraction pattern is as follows Figure 4A shown.

[0031] In some embodiments, the present invention provides a method for preparing Form D, comprising adding the compound of Formula I to dichloromethane, ultrasonically dissolving, filtering, and then rotary evaporating to obtain Form D.

[0032] In a crystal transformation experiment, Form D was heated to 160°C, kept at 160°C for 3 minutes, and then cooled to room temperature for XRPD detection. Form D was transformed into Form A + Form G after high temperature.

[0033] Another object of the present invention is to provide a new crystalline form of the compound of formula I, named Form E.

[0034] In some embodiments, the crystalline form E provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.1°±0.2°, 12.4°±0.2°, 13.8°±0.2°, 15.8°±0.2°, and 17.9°±0.2°.

[0035] In some embodiments, the crystalline form E provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.1°±0.2°, 12.4°±0.2°, 13.8°±0.2°, 14.6°±0.2°, 15.2°±0.2°, 15.8°±0.2°, 17.9°±0.2°, and 18.7°±0.2°.

[0036] In some embodiments, the crystalline form E provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.1°±0.2°, 10.1°±0.2°, 12.4°±0.2°, 13.8°±0.2°, 14.6°±0.2°, 15.2°±0.2°, 15.8°±0.2°, 17.6°±0.2°, 17.9°±0.2°, 18.7°±0.2°, 20.0°±0.2°, 21.6°±0.2°, and 22.9°±0.2°.

[0037] In some embodiments, the present invention provides a crystalline form E, characterized in that its X-ray powder diffraction pattern is as follows Figure 5A shown.

[0038] In some embodiments, the present invention provides a method for preparing Form E, comprising adding the compound of Formula I to methanol, ultrasonically dissolving, filtering to obtain a filtrate, slowly dripping the filtrate into a vial pre-filled with water, and precipitating a solid to obtain Form E.

[0039] In another embodiment, the present invention provides a method for preparing Form E, which comprises adding the compound of formula I to methanol, ultrasonically dissolving, filtering to obtain a filtrate, and then adding the filtrate to a container containing a certain volume of purified water to precipitate a solid, stirring at room temperature, filtering the solid, and drying in a high temperature (e.g., 50°C) oven overnight.

[0040] Another object of the present invention is to provide a new crystalline form of the compound of formula I, named Form F.

[0041] In some embodiments, the crystal form F provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.7°±0.2°, 14.9°±0.2°, 16.4°±0.2°, 17.5°±0.2°, and 20.4°±0.2°.

[0042] In some embodiments, the crystalline form F provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.7°±0.2°, 12.0°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 16.4°±0.2°, 17.5°±0.2°, 18.7°±0.2°, and 20.4°±0.2°.

[0043] In some embodiments, the present invention provides a crystalline form F, characterized in that its X-ray powder diffraction pattern is as follows Fig. 6A shown.

[0044] In some embodiments, the present invention provides a method for preparing Form F, comprising adding methanol to the compound of formula I, suspending and slurrying at room temperature overnight (about 18 hours), filtering, and drying the solid at 50°C overnight (about 18 hours) to obtain Form F.

[0045] Another object of the present invention is to provide a new crystalline form of the compound of formula I, named Form G.

[0046] In some embodiments, the crystalline form G provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.4°±0.2°, 10.1°±0.2°, 13.7°±0.2°, 16.8°±0.2°, and 17.6°±0.2°.

[0047] In some embodiments, the crystalline form G provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.4°±0.2°, 10.1°±0.2°, 13.7°±0.2°, 14.6°±0.2°, 15.2°±0.2°, 15.8°±0.2°, 16.8°±0.2°, and 17.6°±0.2°.

[0048] In some embodiments, the present invention provides a crystalline form G, characterized in that its X-ray powder diffraction pattern is as follows Fig. 7A shown.

[0049] In some embodiments, the present invention provides a method for preparing Form G, comprising placing Form F of the compound of Formula I on a hot stage, heating the temperature to 125° C. and maintaining the temperature for about 10 minutes to convert the crystal into Form G.

[0050] In some embodiments, the present invention provides a pharmaceutical composition comprising any crystalline form A, B, C, D, E, F or G of the compound of formula I described in the present invention, and a pharmaceutically acceptable excipient.

[0051] In some embodiments, the present invention provides use of any crystalline form A, B, C, D, E, F or G of the compound of formula I described in the present invention in the preparation of a medicament for a GABAA receptor-related disease.

[0052] In some embodiments, the GABAA receptor-related disease of the present invention is a nervous system disease or a metabolic disease.

[0053] In some embodiments, the neurological disease of the present invention is selected from: sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory disorders and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or truncation syndrome or tinnitus.

[0054] In some preferred embodiments, the mood disorder is depression; wherein the depression is disruptive mood dysregulation disorder, major depressive disorder, persistent depressive disorder, premenstrual dysphoric disorder, substance or medication-induced disorder, disorder caused by other medical illness, other specified depressive disorder and unspecified depressive disorder.

[0055] In some preferred embodiments, the depression is selected from mild depression, moderate depression, severe depression or postpartum depression.

[0056] In some preferred embodiments, the neurological disease of the present invention is major depression or postpartum depression.

[0057] In some embodiments, the metabolic disease described in the present invention is selected from the group consisting of obesity, hyperlipidemia, hypertension, etc.

[0058] The beneficial effects of the present invention are as follows: the present invention provides a type of crystal form of a compound of formula I suitable for pharmaceutical use, the crystal form does not contain solvent compounds or solvent residues, and has good thermal stability; in other preferred crystal forms, the crystal form of the present invention also has good storage stability (for example, resistance to high temperature, high humidity and light) and / or grinding stability, and is suitable for industrial production and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1A is the X-ray powder diffraction pattern of Form A according to Example 1 of the present invention;

[0060] Figure 1B This is a DSC graph of the crystal form A according to Example 1 of the present invention;

[0061] Figure 1C is a TGA diagram of the crystal form A according to Example 1 of the present invention;

[0062] Figure 1D According to the crystalline form A of Example 1 of the present invention 1 HNMR spectrum;

[0063] Figure 2A is the X-ray powder diffraction pattern of Form B according to Example 2 of the present invention;

[0064] Figure 2B This is a DSC graph of Form B according to Example 2 of the present invention;

[0065] Figure 2C According to the crystal form B of Example 2 of the present invention 1 HNMR spectrum;

[0066] Figure 3A is the X-ray powder diffraction pattern of Form C according to Example 3 of the present invention;

[0067] Figure 3B is a DSC graph of Form C according to Example 3 of the present invention;

[0068] Figure 3C According to the crystalline form C of Example 3 of the present invention 1 HNMR spectrum;

[0069] Figure 4A is the X-ray powder diffraction pattern of the crystal form D according to Example 4 of the present invention;

[0070] Figure 4B is a DSC graph of the crystal form D according to Example 4 of the present invention;

[0071] Figure 4C According to the crystal form D of Example 4 of the present invention 1 HNMR spectrum;

[0072] Figure 5A is the X-ray powder diffraction pattern of Form E according to Example 5 of the present invention;

[0073] Figure 5B is a DSC graph of Form E according to Example 5 of the present invention;

[0074] Figure 5C According to the crystalline form E of Example 5 of the present invention 1 HNMR spectrum;

[0075] Fig. 6A is the X-ray powder diffraction pattern of Form F according to Example 6 of the present invention;

[0076] Figure 6B is a DSC graph of Form F according to Example 6 of the present invention;

[0077] Figure 6C According to the crystal form F of Example 6 of the present invention 1 HNMR spectrum;

[0078] Fig. 7A is the X-ray powder diffraction pattern of Form G according to Example 7 of the present invention;

[0079] Figure 7B is a DSC graph of Form G according to Example 7 of the present invention;

[0080] Figure 7CAccording to the crystal form G of Example 7 of the present invention 1 HNMR spectrum;

[0081] Fig. 8A is the X-ray powder diffraction pattern of the crystal form H according to Example 8 of the present invention;

[0082] Figure 8B is a DSC graph of the crystal form H according to Example 8 of the present invention;

[0083] Fig.9A is the X-ray powder diffraction pattern of Form A according to Example 10 of the present invention;

[0084] Fig. 9B is the X-ray powder diffraction pattern of the crystal form G according to Example 10 of the present invention; DETAILED DESCRIPTION

[0085] The present invention is further described in detail by the following examples, which are not intended to limit the protection scope of the present invention.

[0086] Testing instruments and methods:

[0087] X-ray powder diffraction (XRPD) test method: instrument model: D8Advance, diffraction line: CuK (40KV, 40mA), step size 0.02°2θ, speed 0.1s / step, scanning range: 3°-40°(2θ).

[0088] Differential scanning calorimetry (DSC) test method: instrument model: DSC 3; parameters: N2 protection, gas flow rate 50mL / min, heating rate: 10℃ / min, temperature range: 30℃-300℃.

[0089] TGA: Instrument model: TGA2; Parameters: N2 protection, gas flow rate 50 mL / min, heating rate 10.0 k / min, temperature range: 30°C-350°C.

[0090] 1 HNMR: Instrument model: Bruker AVANCE III 400 MHz; Parameters: full-frequency excitation, spectral width 20 ppm single pulse, 30° angle excitation scan 8 times, digital orthogonal detection, temperature control 298 K; solvent is DMSO-d6

[0091] The compound of formula I ((1-((1S, 4aS, 4bR, 6aS, 8R, 10aS, 10bS, 12aS)-8-hydroxy-8, 10a, 12a-trimethyloctahydrobenzophenone-1-yl)-2-(2H-tetrazolyl-2-yl)ethane-1-one) can be obtained by commercial purchase or homemade. For example, it is prepared by the method described in Example 20 of the prior art patent CN202010015181.0 (WO2020143640A1).

[0092] Example 1 Preparation of Form A

[0093] About 20 mg of the compound of formula I was weighed and added to a 3 mL vial, 1 mL of isopropanol was added, sonicated at 50°C, and filtered into another 3 mL vial using a 0.45 μm PTFE filter. The clear filtrate was stirred at 50°C and cooled naturally to room temperature, solids precipitated, and the solids were collected by centrifugation and subjected to XRPD analysis.

[0094] Its XRPD powder diffraction pattern is as follows Figure 1A The XRPD data are shown in Table 1.

[0095] Table 1

[0096]

[0097]

[0098] DSC spectrum Figure 1B As shown, an endothermic peak is shown at around 170.14°C (onset value).

[0099] TGA spectrum Figure 1C As shown, Form A has no weight loss before 120°C and is an anorthite crystal form.

[0100] 1 HNMR spectrum Figure 1D As shown, 1 H NMR showed no residual solvent.

[0101] Example 2 Preparation of Form B

[0102] About 30 mg of the compound of formula I was weighed and added to a 3 mL vial. Then 0.5 mL of a mixed solvent of isopropyl acetate: toluene (1:4) was added to the vial. A stirring bar was added and the mixture was suspended and stirred at 5° C. for 5 days.

[0103] Powder diffraction pattern Figure 2A The XRPD data are shown in Table 2.

[0104] Table 2

[0105]

[0106]

[0107]

[0108] DSC spectrum Figure 2B As shown, there are two endothermic peaks, which are 91.88°C and 171.38°C (onset values).

[0109] 1 HNMR spectrum Figure 2C As shown, it can be seen from the figure that the sample has about 30.8% toluene (about 2 molecules of toluene) remaining.

[0110] Example 3 Preparation of Form C

[0111] About 20 mg of the compound of formula I was weighed and added to a 3 mL vial. 1 mL of methanol was added to the vial, and the solution was sonicated and filtered. The filtrate was allowed to stand for evaporation.

[0112] Powder diffraction pattern Figure 3A The XRPD data are shown in Table 3.

[0113] Table 3

[0114]

[0115]

[0116] DSC spectrum Figure 3B As shown, there are two endothermic peaks, which are 90.02°C and 174.69°C (onset values).

[0117] 1 HNMR spectrum Figure 3C As shown, it can be seen from the figure that the sample has about 3.09% methanol residue.

[0118] Example 4 Preparation of Form D

[0119] About 50 mg of the compound of formula I was weighed and added to a 5 mL vial. 1 mL of dichloromethane was added, and the solution was sonicated and then filtrated and rotary evaporated.

[0120] Its XRPD powder diffraction pattern is as follows Figure 4A The XRPD data are shown in Table 4.

[0121] Table 4

[0122]

[0123]

[0124] DSC spectrum Figure 4B As shown, there are two endothermic peaks, which are 155.68°C and 168.97°C (onset values). 1 HNMR spectrum Figure 4C As shown, it can be seen from the figure that the sample has about 1.02% of residual dichloromethane.

[0125] Example 5 Preparation of Form E

[0126] Weigh about 20 mg of the compound of formula I and add it to a 5 mL vial. Add 0.5 mL of methanol to the vial, sonicate and filter to obtain a filtrate. Slowly drop the filtrate into a vial pre-filled with 3 mL of water to precipitate a solid.

[0127] Its XRPD powder diffraction pattern is as follows Figure 5A The XRPD data are shown in Table 5.

[0128] Table 5

[0129]

[0130] DSC spectrum Figure 5B As shown, there is a single endothermic peak and the melting point is 170.16°C (onset value).

[0131] 1 HNMR spectrum Figure 5C As shown in the figure, it can be seen that there is no obvious solvent residue in the sample.

[0132] Example 6 Preparation of Form F

[0133] Preparation method: Weigh about 200 mg of the compound of formula I and add it to a 20 mL vial, then add 4 mL of methanol to the vial, add a magnetic bar, suspend and slurry at room temperature overnight (about 18 h), filter, and dry the solid at 50°C overnight (about 18 h).

[0134] Its XRPD powder diffraction pattern is as follows Fig. 6A The XRPD data are shown in Table 6.

[0135] Table 6

[0136]

[0137]

[0138] DSC spectrum Figure 6B As shown, two endothermic peaks can be seen from the figure, located at 83.04°C and 177.93°C (onset values) respectively.

[0139] 1 HNMR spectrum Figure 6C As shown, it can be seen from the figure that the sample has about 0.31% methanol residue.

[0140] Example 7 Preparation of Form G

[0141] Preparation method: Place the Form F compound on a hot plate, raise the temperature to 125°C and maintain for about 10 minutes to transform it into Form G.

[0142] Its XRPD powder diffraction pattern is as follows Fig. 7A The XRPD data are shown in Table 7.

[0143] Table 7

[0144]

[0145]

[0146] DSC spectrum Figure 7B As shown, the spectrum shows a single endothermic peak with a melting point at 177.75°C (onset value).

[0147] 1 HNMR spectrum Figure 7C As shown in the figure, it can be seen that there is no obvious solvent residue in the sample.

[0148] Example 8 Preparation of Form H

[0149] Preparation method: According to the method of Example 20 of WO2020143640A1, the KHC-8 compound is added to acetonitrile, cesium carbonate and 1H-tetrazole to react, water is added, and the mixture is extracted with ethyl acetate. The organic phases are combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure to obtain a crude compound of formula I.

[0150] 1) Weigh 1.370 g of the crude compound of formula I and dissolve it in 31 ml of a mixed solvent (DCM / MeOH=30 / 1), prepare a plate sample, develop the plate (developer DCM / MeOH=30 / 1, Rf=0.5), and after the prepared plate is completely dried, scrape the solid compound on the plate and perform XRPD detection. The powder diffraction pattern is as follows: Fig. 8A shown.

[0151] 2) Weigh 1.372 g of the crude compound of formula I and elute with 250 ml of a mixed solvent of DCM / MeOH = 30 / 1. Collect the eluate and concentrate under reduced pressure at 45°C to obtain a white solid. Its XRPD powder diffraction pattern is substantially the same as Fig. 8A Consistent.

[0152] The solid finally obtained in 1) or 2) is subjected to DSC test, and the DSC spectrum is as follows Figure 8BAs shown, it can be seen from the spectrum that there is a small endothermic peak near 64°C which may be a desolvation peak, the exothermic peak near 97°C is an amorphous recrystallization peak, and there are three endothermic peaks near 162°C, 170°C, and 179°C, indicating a mixed crystal.

[0153] Example 9 Anhydrous crystalline interconversion experiment

[0154] In order to confirm the stability relationship of anhydrous crystalline Form A / E / G under different temperature conditions, a suspension competition test in different solvents at 25°C and 50°C was set up. The specific steps are as follows: first, a saturated solution of the starting sample Formula I compound at the corresponding temperature and solvent was prepared, and equal weights of Form A / E were added to the filtered saturated solution to form a suspension, which was suspended and stirred at 25°C and 50°C for 4 days, and then samples were taken for XRPD detection; equal weights of Form A / G were added to the filtered saturated solution to form a suspension, which was suspended and stirred at 25°C and 50°C for 1 day, and then samples were taken for XRPD detection. The results are shown in Table 9.

[0155] Table 9

[0156]

[0157]

[0158] Example 10 Grinding stability experiment

[0159] After grinding Form A and Form G for 1 min, 3 min, and 10 min, respectively, PXRD was used to detect the changes in their crystal forms. Fig.9A and 9B The results showed that after grinding for 10 minutes, Form A remained unchanged, while Form G became semi-amorphous, indicating that Form A was more stable than Form G under grinding conditions.

[0160] Example 11 Storage stability test

[0161] Take appropriate amount of test sample and open container respectively, place under corresponding influencing factors (high temperature, high humidity, light) test conditions, take samples for 0 days, 5 days, 12 days, 30 days, and detect the crystal form and related substance content. Specific influencing factors test conditions are shown in the table below. Note: Constant humidity condition is made by placing saturated salt solution at the bottom of the dryer, and 92.5% RH is achieved by saturated KNO3 solution.

[0162] Table 10 Test condition parameters of influencing factors

[0163] Influencing factors Test condition parameters high temperature 60℃±2℃ High humidity 25℃±5℃, 92.5%±5%RH illumination 4500lx±500lx

[0164] The test results show that the maximum unknown single impurities and total impurities of crystal forms A and G stored under high temperature, high humidity and light conditions for 30 days did not increase significantly compared with 0 days, while the total impurities of crystal form H increased by 0.9% after 30 days of light exposure compared with 0 days. Crystal forms A and G remained relatively stable after being stored under high temperature, high humidity and light conditions for 30 days; however, crystal form H transformed after being stored under high temperature, high humidity and light conditions for 5 days, mainly transforming into a mixed crystal of crystal form A + a small amount of crystal form G.

Claims

1. A crystalline form A of a compound of formula I, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.1°±0.2°, 11.7°±0.2°, 13.5°±0.2°, 16.2°±0.2°, and 17.6°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ values ​​of 8.1°±0.2°, 11.7°±0.2°, 13.0°±0.2°, 13.5°±0.2°, 15.3°±0.2°, 16.2°±0.2°, 17.6°±0.2°, and 21.3°±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form A is substantially consistent with Figure 1A.

2. A crystalline form B of a compound of formula I, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.3°±0.2°, 9.0°±0.2°, 14.7°±0.2°, 15.6°±0.2°, and 18.0°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at 2θ values ​​of 7.3°±0.2°, 9.0°±0.2°, 11.0°±0.2°, 12.2°±0.2°, 14.7°±0.2°, 15.3°±0.2°, 15.6°±0.2°, and 18.0°±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form B is substantially consistent with Figure 2A.

3. A crystalline form C of a compound of formula I, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.6°±0.2°, 8.6°±0.2°, 14.0°±0.2°, 16.7°±0.2°, and 17.4°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 2θ values ​​of 5.6°±0.2°, 8.6°±0.2°, 9.9°±0.2°, 14.0°±0.2°, 14.9°±0.2°, 16.7°±0.2°, 17.4°±0.2°, 18.5°±0.2° having characteristic peaks; preferably, the X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 2θ values ​​of 5.6°±0.2°, 8.6°±0.2°, 9.9°±0.2°, 11.2°±0.2°, 11.8°±0.2°, 14.0°±0.2°, 14.9°±0.2°, 16.7°±0.2°, 17.4°±0.2°, 18.5°±0.2°, and 18.9°±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form C is substantially consistent with Figure 3A.

4. A crystalline form D of a compound of formula I, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.1°±0.2°, 8.8°±0.2°, 12.2°±0.2°, 14.4°±0.2°, and 17.6°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form D has characteristic peaks at 2θ values ​​of 7.1°±0.2°, 8.8°±0.2°, 10.2°±0.2°, 12.2°±0.2°, 12.9°±0.2°, 13.5°±0.2°, 14.4°±0.2°, and 17.6°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form D has characteristic peaks at 2θ values ​​of 7.1°±0.2°, 8.8°±0.2°, 10.2°±0.2°, 12.2°±0.2°, 12.9°±0.2°, 13.5°±0.2°, 14.4°±0.2°, and 17.6°±0.2°. The diffraction pattern has characteristic peaks at 2θ values ​​of 7.1°±0.2°, 7.6°±0.2°, 8.0°±0.2°, 8.8°±0.2°, 10.2°±0.2°, 11.0°±0.2°, 11.6°±0.2°, 12.2°±0.2°, 12.9°±0.2°, 13.5°±0.2°, 14.0°±0.2°, 14.4°±0.2°, 15.4°±0.2°, 17.6°±0.2°, and 18.2°±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form D is substantially consistent with Figure 4A.

5. A crystalline form E of a compound of formula I, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.1°±0.2°, 12.4°±0.2°, 13.8°±0.2°, 15.8°±0.2°, and 17.9°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at 2θ values ​​of 6.1°±0.2°, 12.4°±0.2°, 13.8°±0.2°, 14.6°±0.2°, 15.2°±0.2°, 15.8°±0.2°, 17.9°±0.2°, and 18.7°±0.2°; more preferably, The X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at 2θ values ​​of 6.1°±0.2°, 10.1°±0.2°, 12.4°±0.2°, 13.8°±0.2°, 14.6°±0.2°, 15.2°±0.2°, 15.8°±0.2°, 17.6°±0.2°, 17.9°±0.2°, 18.7°±0.2°, 20.0°±0.2°, 21.6°±0.2°, and 22.9°±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form E is substantially consistent with Figure 5A.

6. A crystalline form F of a compound of formula I, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.7°±0.2°, 14.9°±0.2°, 16.4°±0.2°, 17.5°±0.2°, and 20.4°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form F has characteristic peaks at 2θ values ​​of 8.7°±0.2°, 12.0°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 16.4°±0.2°, 17.5°±0.2°, 18.7°±0.2°, and 20.4°±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form F is substantially consistent with Figure 6A.

7. A crystalline form G of a compound of formula I, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.4°±0.2°, 10.1°±0.2°, 13.7°±0.2°, 16.8°±0.2°, and 17.6°±0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form G has characteristic peaks at 2θ values ​​of 8.4°±0.2°, 10.1°±0.2°, 13.7°±0.2°, 14.6°±0.2°, 15.2°±0.2°, 15.8°±0.2°, 16.8°±0.2°, and 17.6°±0.2°; more preferably, the X-ray powder diffraction pattern of the crystalline form G is substantially consistent with Figure 7A.

8. A method for preparing the crystalline form A according to claim 1, characterized in that: The compound of formula I is added into an organic solvent to be fully dissolved, then cooled to precipitate, and centrifuged to obtain a solid.

9. The preparation method according to claim 8, characterized in that: The organic solvent is isopropanol, ethyl propyl acetate or acetonitrile, preferably isopropanol.

10. The preparation method according to claim 8 or 9, characterized in that: The mass volume ratio of the compound of formula I to the organic solvent is 100:1 to 5:1, preferably 50:1 to 10:1, and more preferably 20:

1.

11. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the crystal form according to any one of claims 1 to 7, and a pharmaceutically acceptable excipient.

12. Use of the crystal form according to any one of claims 1 to 7 in the preparation of drugs for GABAA receptor-related diseases.

13. The use according to claim 12, characterized in that The GABAA receptor-related disease is a nervous system disease or a metabolic disease.

14. The use according to claim 12, characterized in that The nervous system disease is selected from: sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory disorders and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or truncation syndrome or tinnitus; preferably, the mood disorder is depression; wherein the depression is disruptive mood dysregulation disorder, major depressive disorder, persistent depressive disorder, premenstrual dysphoric disorder, disorders caused by substances or drugs, disorders caused by other physical diseases, other specific depressive disorders and unspecified depressive disorders; more preferably, the depression is selected from mild depression, moderate depression, severe depression or postpartum depression; more preferably, the nervous system disease is severe depression or postpartum depression.

15. The use according to claim 12, characterized in that The metabolic disease is selected from obesity, hyperlipidemia, and hypertension.

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