Crystal form of steroid compound and use thereof

Abstract

The purpose of the present invention is to provide a crystal form of a steroid compound, a pharmaceutical composition and the use thereof in the preparation of a drug for diseases related to a GABAA receptor. Compared with the prior art, the crystal form provided in the present invention has one or more improved properties, and has great significance in further development of the drug.

Description

A steroid compound crystal form and its use 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 its application. Background Art

[0002] Neuropsychiatric disorders, including anxiety, depression, and schizophrenia, rank first in my country's total disease burden, accounting for approximately 20%. With the continuous advancement of social modernization, the accelerated pace of work and increased stress in life have led to a significant increase in the number of patients with various neuropsychiatric disorders, and the progression of symptoms has significantly accelerated, making the development, research, and production of anti-neuropsychiatric drugs more urgent.

[0003] GABA(A) receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand (GABA) is present 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 plays an important role in regulating central nervous system function. After GABA(A) receptor activation, it selectively releases Cl - Through its pores. - It flows out of the neuronal cell when the internal voltage is less than the resting potential, and flows into the neuronal cell 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 confirmed to be involved in the pathological processes of anxiety, depression, and schizophrenia at the molecular, preclinical, and clinical levels, and the GABA (A) receptor has long been used as an important drug target for the treatment of these diseases.

[0004] Many studies are based on GABA(A) receptors in an attempt 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 neuropsychiatric diseases.

[0005] Drug polymorphism refers to the different crystal lattice arrangements formed by the orderly arrangement of chemical drug molecules within their microstructures. These typically manifest as different solid forms of a drug substance. A single drug can exist in multiple crystalline forms, and different crystalline forms of the same drug may exhibit distinct physical or chemical properties. The study of drug polymorphism is crucial for developing more suitable crystalline forms for pharmaceutical use.

[0006] Summary of the Invention

[0007] One object of the present invention is to provide a new crystalline form of the compound of formula I, named Form A.

[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 Form A, characterized in that its X-ray powder diffraction pattern is as shown in Figure 1A.

[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 and fully dissolving it, then cooling it to precipitate it, and centrifuging it to obtain a solid. 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 resulting 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 present invention provides Form B, 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 present invention provides Form B, 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 shown in Figure 2A.

[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 suspending and stirring at low temperature (e.g., 5°C) or room temperature (e.g., 3 days, 4 days, 5 days, or even 6 days or more) to obtain Form B.

[0018] In other schemes, a crystal transformation experiment was conducted on Form B, and it was found that after Form B was left unopened at 50°C for 5 hours, XRPD analysis revealed that Form B transformed into Form A. In another crystal transformation experiment, when Form B was heated to 110°C by DSC, held at this temperature for 3 minutes, and then cooled to room temperature, XRPD analysis revealed that Form B 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 present invention provides Form C, 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 present invention provides Form C, 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 Form C, characterized in that its X-ray powder diffraction pattern is shown in Figure 3A.

[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, which showed 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, which showed 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 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°, 12.2°±0.2°, 14.4°±0.2°, and 17.6°±0.2°.

[0028] In some embodiments, the present invention provides Form D, 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 present invention provides Form D, 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 Form D, characterized in that its X-ray powder diffraction pattern is shown in Figure 4A.

[0031] In some embodiments, the present invention provides a method for preparing Form D, comprising adding the compound of Formula I to dichloromethane, sonicating, filtering, and rotary evaporating to obtain the 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 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 present invention provides Form E, 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 Form E, characterized in that its X-ray powder diffraction pattern is shown in Figure 5A.

[0038] In some embodiments, the present invention provides a method for preparing Form E, comprising adding the compound of Formula I to methanol, sonicating, filtering to obtain a filtrate, slowly dropwise adding 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 the compound, filtering the filtrate, and then adding the filtrate to a container containing a certain volume of purified water to precipitate a solid. After stirring at room temperature, the solid is filtered and dried 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 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°, 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 Form F, characterized in that its X-ray powder diffraction pattern is shown in Figure 6A.

[0044] In some embodiments, the present invention provides a method for preparing Form F, which comprises adding the compound of Formula I to methanol, 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 present invention provides Form G, 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 Form G, characterized in that its X-ray powder diffraction pattern is shown in Figure 7A.

[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 plate, 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 one of crystalline forms 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 one of crystalline forms A, B, C, D, E, F or G of the compound of formula I of 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 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 of 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 class of crystalline forms of the compound of formula I suitable for pharmaceutical use, which do not contain solvent compounds or solvent residues and have good thermal stability; in other preferred crystalline forms, the crystalline forms of the present invention also have good storage stability (for example, resistance to high temperature, high humidity and light) and / or grinding stability, and are suitable for industrial production and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] FIG1A is an X-ray powder diffraction pattern of Form A according to Example 1 of the present invention;

[0060] FIG1B is a DSC diagram of Form A according to Example 1 of the present invention;

[0061] FIG1C is a TGA chart of Form A according to Example 1 of the present invention;

[0062] FIG1D is a diagram of Form A according to Example 1 of the present invention. 1 HNMR spectrum;

[0063] FIG2A is an X-ray powder diffraction pattern of Form B according to Example 2 of the present invention;

[0064] FIG2B is a DSC diagram of Form B according to Example 2 of the present invention;

[0065] FIG2C is a diagram of Form B according to Example 2 of the present invention. 1 HNMR spectrum;

[0066] FIG3A is an X-ray powder diffraction pattern of Form C according to Example 3 of the present invention;

[0067] FIG3B is a DSC diagram of Form C according to Example 3 of the present invention;

[0068] FIG3C is a diagram of Form C according to Example 3 of the present invention. 1 HNMR spectrum;

[0069] FIG4A is an X-ray powder diffraction pattern of Form D according to Example 4 of the present invention;

[0070] FIG4B is a DSC graph of Form D according to Example 4 of the present invention;

[0071] FIG4C is a diagram of Form D according to Example 4 of the present invention. 1 HNMR spectrum;

[0072] FIG5A is an X-ray powder diffraction pattern of Form E according to Example 5 of the present invention;

[0073] FIG5B is a DSC graph of Form E according to Example 5 of the present invention;

[0074] FIG5C is a diagram of Form E according to Example 5 of the present invention. 1 HNMR spectrum;

[0075] FIG6A is an X-ray powder diffraction pattern of Form F according to Example 6 of the present invention;

[0076] FIG6B is a DSC graph of Form F according to Example 6 of the present invention;

[0077] FIG6C is a diagram of Form F according to Example 6 of the present invention. 1 HNMR spectrum;

[0078] FIG7A is an X-ray powder diffraction pattern of Form G according to Example 7 of the present invention;

[0079] FIG7B is a DSC graph of Form G according to Example 7 of the present invention;

[0080] FIG. 7C is a diagram of Form G according to Example 7 of the present invention. 1 HNMR spectrum;

[0081] FIG8A is an X-ray powder diffraction pattern of Form H according to Example 8 of the present invention;

[0082] FIG8B is a DSC graph of Form H according to Example 8 of the present invention;

[0083] FIG9A is an X-ray powder diffraction pattern of Form A according to Example 10 of the present invention;

[0084] FIG9B is an X-ray powder diffraction pattern of 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 scope of protection of the present invention.

[0086] Testing instruments and methods:

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

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

[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° excitation scan 8 times, digital orthogonal detection, temperature control 298 K; solvent: DMSO-d6

[0091] The compound of formula I ((1-((1S, 4aS, 4bR, 6aS, 8R, 10aS, 10bS, 12aS)-8-hydroxy-8, 10a, 12a-trimethyloctahydrochrysene-1-yl)-2-(2H-tetrazol-2-yl)ethane-1-one) can be obtained commercially 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] Approximately 20 mg of the compound of Formula I was weighed and added to a 3 mL vial. 1 mL of isopropanol was added and sonicated at 50°C. The solution was then filtered through a 0.45 μm PTFE filter into another 3 mL vial. The clarified filtrate was stirred at 50°C and cooled naturally to room temperature. Solids precipitated and were collected by centrifugation for XRPD analysis.

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

[0095] Table 1

[0096] The DSC spectrum is shown in FIG1B , which shows an endothermic peak at around 170.14° C. (onset value).

[0097] As shown in the TGA spectrum of Figure 1C, Form A has no weight loss before 120°C and is an anhydrous crystalline form.

[0098] 1 The HNMR spectrum is shown in Figure 1D. 1 H NMR analysis revealed no residual solvent.

[0099] Example 2 Preparation of Form B

[0100] About 30 mg of the compound of formula I was weighed and added to a 3 mL vial. 0.5 mL of a mixed solvent of isopropyl acetate:toluene (1:4) was then added to the vial. A stirring bar was added, and the mixture was suspended and stirred at 5° C. for 5 days.

[0101] The powder diffraction pattern is shown in Figure 2A. The XRPD data are shown in Table 2.

[0102] Table 2

[0103] The DSC spectrum is shown in FIG2B , which shows two endothermic peaks at 91.88° C. and 171.38° C. (onset values).

[0104] 1 The HNMR spectrum is shown in FIG2C , from which it can be seen that the sample has about 30.8% of toluene (about 2 molecules of toluene) remaining.

[0105] Example 3 Preparation of Form C

[0106] 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.

[0107] The powder diffraction pattern is shown in Figure 3A. The XRPD data are shown in Table 3.

[0108] Table 3

[0109] The DSC spectrum is shown in FIG3B , which shows two endothermic peaks at 90.02° C. and 174.69° C. (onset values).

[0110] 1 The HNMR spectrum is shown in FIG3C , from which it can be seen that the sample has about 3.09% residual methanol.

[0111] Example 4 Preparation of Form D

[0112] 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, filtered, and then rotary evaporated.

[0113] Its XRPD powder diffraction pattern is shown in Figure 4A. The XRPD data are shown in Table 4.

[0114] Table 4

[0115] The DSC spectrum is shown in FIG4B , which shows two endothermic peaks at 155.68° C. and 168.97° C. (onset values).

[0116] 1 The HNMR spectrum is shown in FIG4C , from which it can be seen that the sample has about 1.02% of residual dichloromethane.

[0117] Example 5 Preparation of Form E

[0118] 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 add the filtrate dropwise to a vial pre-filled with 3 mL of water to precipitate a solid.

[0119] Its XRPD powder diffraction pattern is shown in Figure 5A. The XRPD data are shown in Table 5.

[0120] Table 5

[0121] The DSC spectrum is shown in FIG5B , which shows a single endothermic peak with a melting point of 170.16° C. (onset value).

[0122] 1 The HNMR spectrum is shown in Figure 5C, from which it can be seen that there is no obvious solvent residue in the sample.

[0123] Example 6 Preparation of Form F

[0124] 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 hours), filter, and dry the solid at 50°C overnight (about 18 hours).

[0125] Its XRPD powder diffraction pattern is shown in Figure 6A. The XRPD data are shown in Table 6.

[0126] Table 6

[0127] The DSC spectrum is shown in FIG6B , from which two endothermic peaks can be seen, located at 83.04° C. and 177.93° C. (onset values), respectively.

[0128] 1 The HNMR spectrum is shown in FIG6C , from which it can be seen that the sample has about 0.31% residual methanol.

[0129] Example 7 Preparation of Form G

[0130] Preparation method: Place the Form F compound on a hot plate, raise the temperature to 125°C and hold for about 10 minutes to transform it into Form G.

[0131] Its XRPD powder diffraction pattern is shown in Figure 7A. The XRPD data are shown in Table 7.

[0132] Table 7

[0133] The DSC spectrum is shown in FIG7B , which shows a single endothermic peak with a melting point at 177.75° C. (onset value).

[0134] 1 The HNMR spectrum is shown in FIG7C , from which it can be seen that there is no obvious solvent residue in the sample.

[0135] Example 8 Preparation of Form H

[0136] Preparation method: According to the method of Example 20 of WO2020143640A1, the KHC-8 compound was added to acetonitrile, cesium carbonate and 1H-tetrazole, and then water was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude compound of formula I.

[0137] 1) 1.370 g of the crude compound of Formula I was weighed and dissolved in 31 ml of a mixed solvent (DCM / MeOH = 30 / 1). A plate was prepared and developed (developing solvent: DCM / MeOH = 30 / 1, Rf = 0.5). After the plate was completely dried, the solid compound was scraped from the plate and analyzed by XRPD. The powder diffraction pattern is shown in Figure 8A.

[0138] 2) 1.372 g of the crude compound of Formula I was weighed and eluted with 250 ml of a 30 / 1 DCM / MeOH mixture. The eluate was collected and concentrated under reduced pressure at 45° C. to obtain a white solid. Its XRPD powder diffraction pattern was substantially consistent with that in FIG8A .

[0139] The solid finally obtained in 1) or 2) was subjected to DSC testing. The DSC spectrum is shown in Figure 8B. From the spectrum, it can be seen that there is a small endothermic peak near 64°C, which may be a desolvation peak, an exothermic peak near 97°C, an amorphous recrystallization peak, and three endothermic peaks near 162°C, 170°C, and 179°C, indicating mixed crystals.

[0140] Example 9 Anhydrous Crystalline Mutual Conversion Experiment

[0141] To confirm the stability relationship of anhydrous crystalline Forms A / E / G under different temperature conditions, suspension competition experiments were conducted in different solvents at 25°C and 50°C. The specific steps were as follows: First, saturated solutions of the starting sample, compound of Formula I, were prepared at the corresponding temperatures and solvents. Equal weights of Forms A / E were added to the filtered saturated solutions to form suspensions. The suspensions were then suspended and stirred at 25°C and 50°C for four days, respectively, before sampling for XRPD analysis. Equal weights of Forms A / G were added to the filtered saturated solutions to form suspensions. The suspensions were then suspended and stirred at 25°C and 50°C for one day, respectively, before sampling for XRPD analysis. The results are shown in Table 9.

[0142] Table 9

[0143] Example 10 Grinding stability experiment

[0144] Form A and Form G were ground for 1, 3, and 10 minutes, respectively, and their crystal forms were examined using PXRD. The results are shown in Figures 9A and 9B. The results show that after 10 minutes of grinding, Form A remained unchanged, while Form G became semi-amorphous, indicating that Form A is more stable than Form G under the grinding conditions.

[0145] Example 11 Storage stability test

[0146] Place an appropriate amount of test sample in an open container and place under the corresponding influencing factors (high temperature, high humidity, and light). Samples are taken after 0 days, 5 days, 12 days, and 30 days to test the crystal form and the content of related substances. Specific influencing factors and test conditions are shown in the table below. Note: Constant humidity is achieved by placing a saturated salt solution in the lower part of the desiccator. 92.5% RH is achieved by a saturated KNO3 solution.

[0147] Table 10 Test condition parameters of influencing factors

[0148] Test results showed that after 30 days of storage under high temperature, high humidity, and light conditions, the maximum unknown single impurities and total impurities in Forms A and G did not increase significantly compared to day 0. However, after 30 days of light exposure, the total impurities in Form H increased by 0.9% compared to day 0. Forms A and G remained relatively stable under these conditions for 30 days. However, Form H underwent crystal transformation after just five days of storage under these conditions, primarily transforming into a mixed crystal of Form A with a small amount of 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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