Crystalline forms of steroid compounds and their uses

Abstract

The object of the present invention is to provide crystalline forms of steroid compounds, pharmaceutical compositions, and their use in the manufacture of drugs for GABAA receptor-related diseases. The crystalline forms described in the present invention have one or more improved properties compared to the prior art and are of great significance for the further development of the drugs.

Description

[Technical Field]

[0001] This invention relates to the field of chemical pharmaceuticals, and more specifically to the crystalline form of steroid compounds and their use. [Background technology]

[0002] Neuropsychiatric disorders, including anxiety disorders, depression, and schizophrenia, account for the largest share of the total disease burden in China, representing approximately 20% of the total disease burden. As society continues to modernize, people's work pace accelerates and life pressures increase, leading to a significant increase in the number of patients with various neuropsychiatric disorders and a remarkable acceleration in the progression of symptoms. Consequently, the development, research, and production of treatments for neuropsychiatric disorders are becoming increasingly urgent.

[0003] GABA(A) receptors (GABAARs) are ion channel receptors and ligand-gated ion channels. Their endogenous ligand (GABA) exists as an inhibitory neurotransmitter in the central nervous system. The GABAergic system is a major inhibitory signaling pathway in the brain and central nervous system and plays a crucial role in regulating central nervous system function. When GABA(A) receptors are activated, Cl - It selectively allows light to pass through that gap. - GABA(A) receptors flow out of neurons when their internal voltage falls below the resting potential and into neurons when their internal voltage rises above the resting potential (i.e., -75mV). This reduces the chance of action potential generation, resulting in an inhibitory effect on neurotransmission. Research has confirmed that the GABAergic system and GABA(A) receptors play important roles in both the etiology and pathogenesis of diseases such as anxiety, depression, and schizophrenia. The GABAergic system and GABA(A) receptors have been demonstrated 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 considered an important drug target in the treatment of these diseases.

[0004] Many studies based on GABA(A) receptors aim to obtain drugs that can effectively treat related diseases. For example, WO2020143640A1 provides a steroid compound that modulates brain excitability by regulating GABA(A) receptor modulators for the treatment of neuropsychiatric disorders.

[0005] Drug polymorphism refers to different lattice arrangements formed by the ordered arrangement of chemical drug molecules in the microstructure, and generally manifests as different forms of drug raw materials in the solid state. Drugs can exist in multiple crystalline forms, and even the same drug may exhibit different physical or chemical properties depending on its crystalline form. Therefore, the study of drug polymorphism is of great importance in developing crystalline forms more suitable for medicinal use. [Overview of the project] [Means for solving the problem]

[0006] One objective of the present invention is to provide a novel crystalline form of the following compound of formula I, which is named crystalline form A. JPEG2026524202000002.jpg2947

[0007] In some embodiments, crystal form A according to the present invention is characterized by having characteristic peaks in its X-ray powder diffraction pattern 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°.

[0008] In some embodiments, crystal form A according to the present invention is characterized by having characteristic peaks in its X-ray powder diffraction pattern 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°.

[0009] In some embodiments, the crystal form A according to the present invention is characterized in that its X-ray powder diffraction pattern is as shown in Figure 1A.

[0010] In some embodiments, the present invention provides a method for producing crystalline form A, comprising adding a compound of formula I to an organic solvent and dissolving it thoroughly, then cooling to precipitate it, and centrifugation to obtain a solid. In some specific embodiments, the organic solvent is isopropanol, ethylpropyl acetate, or acetonitrile, preferably isopropanol. In some other specific embodiments, the organic solvent is a mixed solvent of isopropanol, ethanol, or acetone and water, where the volume ratio of isopropanol, ethanol, or acetone to water is 1:1 to 1:5, preferably 1:1 to 1:2. In some other specific embodiments, the organic solvent is a mixed solvent of acetonitrile and 2-methyltetrahydrofuran, where 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, more preferably 20:1.

[0011] In some other embodiments, the method for producing crystalline form A according to the present invention can further be carried out by conventional methods in the art, such as slow volatilization, low-temperature (4-8°C) slurry conversion, room-temperature slurry conversion, high-temperature (50°C) slurry conversion, poor solvent addition, gas-solid diffusion, gas-liquid diffusion, water vapor stress, polymer induction, grinding, circulating heating and cooling, and rotary evaporation. For example, in the production method by low-temperature (4-8°C) slurry conversion, an organic solvent such as isopropanol, isopropyl acetate, methyl tert-butyl ether, or acetonitrile was added to the compound of formula I, and the resulting suspension was magnetically stirred at a low temperature (e.g., 5°C) (e.g., for 3, 4, 5, or even 6 days or more), and then the solid was collected by centrifugation. For example, in a production method using poor solvent addition, the good solvent may be selected from acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, acetone, 2-methyltetrahydrofuran, isopropanol, dichloromethane, methyl tert-butyl ether, etc., and the poor solvent may be selected from water or n-heptane, etc. For example, in a production method using rotary evaporation, the solvent may be selected from acetone or tetrahydrofuran, etc.

[0012] Another object of the present invention is to provide a novel crystalline form of a compound of formula I, which is named crystalline form B.

[0013] In some embodiments, crystal form B according to the present invention is characterized by having characteristic peaks in its X-ray powder diffraction pattern 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°.

[0014] In some embodiments, crystal form B according to the present invention is characterized by having characteristic peaks in its X-ray powder diffraction pattern 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°.

[0015] In some embodiments, the crystal form B according to the present invention is characterized in that its X-ray powder diffraction pattern is as shown in Figure 2A.

[0016] In some embodiments, the present invention provides a method for producing crystalline form B, the method comprising adding a 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 it at low temperature (e.g., 5°C) or room temperature (e.g., for 3, 4, 5, or even 6 days or more).

[0017] In several other forms, experiments to confirm the crystal form transition of crystal form B were conducted. After leaving crystal form B at 50°C in an open environment for 5 hours, XRPD detection revealed a transition to crystal form A. In another experiment to confirm the crystal form transition, crystal form B was heated to 110°C using DSC, held at this temperature for 3 minutes, and then cooled to room temperature. XRPD detection revealed that crystal form B had transitioned to crystal form A + crystal form D.

[0018] Another object of the present invention is to provide a novel crystalline form of a compound of formula I, named crystalline form C.

[0019] In some embodiments, the crystalline form C according to the present invention is characterized by having characteristic peaks in its X-ray powder diffraction pattern 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°.

[0020] In some embodiments, the crystalline form C according to the present invention is characterized by having characteristic peaks in its X-ray powder diffraction pattern 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°.

[0021] In some embodiments, the crystalline form C according to the present invention is characterized in that in its X-ray powder diffraction pattern, characteristic peaks are present at positions where the 2θ values are 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°, 18.9° ± 0.2°.

[0022] In some embodiments, the crystalline form C according to the present invention is characterized in that its X-ray powder diffraction pattern is as shown in FIG. 3A.

[0023] In some embodiments, the present invention provides a method for producing crystalline form C, the production method including adding a compound of formula I to methanol, promoting dissolution by ultrasonic waves, filtering, and allowing the filtrate to stand and volatilize to obtain.

[0024] In an experiment for confirming one crystal form transition, crystalline form C was left standing at 50 °C in an open state for about 4 h, and as a result of XRPD detection, the crystal form had not changed. Crystalline form C was heated to 110 °C by DSC, held at this temperature for 3 minutes, and then cooled to room temperature, and as a result of XRPD detection, a transition to crystalline form G was observed.

[0025] Another object of the present invention is to provide a novel crystalline form of a compound of formula I named crystalline form D.

[0026] In some embodiments, the crystalline form D according to the present invention is characterized in that in its X-ray powder diffraction pattern, characteristic peaks are present at positions where the 2θ values are 7.1° ± 0.2°, 8.8° ± 0.2°, 12.2° ± 0.2°, 14.4° ± 0.2°, 17.6° ± 0.2°.

[0027] In some embodiments, crystal form D according to the present invention is characterized by having characteristic peaks in its X-ray powder diffraction pattern 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°.

[0028] In some embodiments, crystal form D according to the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at the following 2θ values: 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°.

[0029] In some embodiments, the crystal form D according to the present invention is characterized in that its X-ray powder diffraction pattern is as shown in Figure 4A.

[0030] In some embodiments, the present invention provides a method for producing crystalline form D, the method comprising adding a compound of formula I to dichloromethane, promoting dissolution by ultrasound, filtering, and then performing rotary evaporation.

[0031] In one crystal form transition experiment, crystal form D was heated to 160°C, kept at 160°C for 3 minutes, and then cooled to room temperature. XRPD detection was performed, and the results showed that crystal form D transitions to crystal form A + crystal form G after reaching high temperatures.

[0032] Another object of the present invention is to provide a novel crystalline form of a compound of formula I, which is named crystalline form E.

[0033] In some embodiments, crystal form E according to the present invention is characterized by having characteristic peaks in its X-ray powder diffraction pattern 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°.

[0034] In some embodiments, crystal form E according to the present invention is characterized by having characteristic peaks in its X-ray powder diffraction pattern 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°.

[0035] In some embodiments, crystal form E according to 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°.

[0036] In some embodiments, the crystal form E according to the present invention is characterized in that its X-ray powder diffraction pattern is as shown in Figure 5A.

[0037] In some embodiments, the present invention provides a method for producing crystalline form E, the method comprising adding a compound of formula I to methanol, promoting dissolution by ultrasound, filtering to obtain a filtrate, placing the filtrate in a vial pre-filled with water, and precipitating a solid.

[0038] In another embodiment, the present invention provides a method for producing crystalline form E, the method comprising adding a compound of formula I to methanol, promoting dissolution by ultrasound, filtering to obtain a filtrate, then adding it to a container containing a certain volume of purified water to precipitate a solid, stirring at room temperature, filtering out the solid, and drying it overnight in a high-temperature (e.g., 50°C) oven.

[0039] Another object of the present invention is to provide a novel crystalline form of a compound of formula I, named crystalline form F.

[0040] In some embodiments, the crystal form F according to the present invention is characterized by having characteristic peaks in its X-ray powder diffraction pattern 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°.

[0041] In some embodiments, the crystal form F according to 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°.

[0042] In some embodiments, the crystalline form F according to the present invention is characterized in that its X-ray powder diffraction pattern is as shown in Figure 6A.

[0043] In some embodiments, the present invention provides a method for producing crystalline form F, the method comprising adding a compound of formula I to methanol, mixing the mixture at room temperature overnight (about 18 hours), filtering, and drying the solid at 50°C overnight (about 18 hours).

[0044] Another object of the present invention is to provide a novel crystalline form of a compound of formula I, named crystalline form G.

[0045] In some embodiments, the crystal form G according to 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°.

[0046] In some embodiments, the crystal form G according to the present invention is characterized by having characteristic peaks in its X-ray powder diffraction pattern 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°.

[0047] In some embodiments, the crystalline form G according to the present invention is characterized in that its X-ray powder diffraction pattern is as shown in Figure 7A.

[0048] In some embodiments, the present invention provides a method for producing crystalline form G, the method comprising placing crystalline form F of a compound of formula I on a hot stage, raising the temperature to 125°C and maintaining it for about 10 minutes to transform it into crystalline form G.

[0049] In some embodiments, the present invention provides a pharmaceutical composition comprising any crystalline form of a compound of formula I described in the present invention, A, B, C, D, E, F, or G, and a pharmaceutically acceptable excipient.

[0050] In some embodiments, the present invention provides the use of any of the crystalline forms A, B, C, D, E, F, or G of the Formula I compound described in the present invention in the manufacture of drugs for diseases related to GABAA receptors.

[0051] In some embodiments, the GABAA receptor-related diseases described in the present invention are neurological disorders or metabolic disorders.

[0052] In some embodiments, the neurological disorders described in the present invention are selected from sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory impairment and / or cognitive impairment, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or amputation syndromes or tinnitus.

[0053] In some preferred embodiments, the mood disorder is depression, and depression is severe dysthymia, major depressive disorder, persistent depressive disorder, premenstrual syndrome, substance or drug-induced disorder, disorder due to other physical illness, other specific depressive disorders, and non-specific depressive disorders.

[0054] In some preferred embodiments, the depression is selected from mild depression, moderate depression, severe depression, or postpartum depression.

[0055] In some preferred embodiments, the neurological disorder described in the present invention is severe depression or postpartum depression.

[0056] In some embodiments, the metabolic disease described in the present invention is selected from obesity, high cholesterol, high blood pressure, and the like. [Effects of the Invention]

[0057] The beneficial effects of the present invention are as follows: The present invention provides a crystalline form of a compound of formula I that is suitable for medicinal use, and the crystalline form is free of solvent compounds or solvent residues and has good thermal stability. In some other preferred crystalline forms, the crystalline forms described in the present invention also have good storage stability (e.g., resistance to high temperature, high humidity, and light) and / or grinding stability, making them suitable for industrial production and use. [Brief explanation of the drawing]

[0058] [Figure 1A] This is the X-ray powder diffraction pattern of crystal form A according to Example 1 of the present invention. [Figure 1B] This is a DSC chart of crystal form A according to Example 1 of the present invention. [Figure 1C] This is a TGA chart of crystal form A according to Example 1 of the present invention. [Figure 1D] This is the 1H NMR spectrum of crystal form A according to Example 1 of the present invention. [Figure 2A] This is the X-ray powder diffraction pattern of crystal form B according to Example 2 of the present invention. [Figure 2B] This is a DSC chart of crystal form B according to Example 2 of the present invention. [Figure 2C] This is the 1H NMR spectrum of crystal form B according to Example 2 of the present invention. [Figure 3A] This is the X-ray powder diffraction pattern of crystal form C according to Example 3 of the present invention. [Figure 3B] This is a DSC chart of crystal form C according to Example 3 of the present invention. [Figure 3C] This is the 1H NMR spectrum of crystalline form C according to Example 3 of the present invention. [Figure 4A] This is the X-ray powder diffraction pattern of crystal form D according to Example 4 of the present invention. [Figure 4B] This is a DSC chart of crystal form D according to Example 4 of the present invention. [Figure 4C] This is the 1H NMR spectrum of crystal form D according to Example 4 of the present invention. [Figure 5A] This is the X-ray powder diffraction pattern of crystal form E according to Example 5 of the present invention. [Figure 5B] This is a DSC chart of crystal form E according to Example 5 of the present invention. [Figure 5C] This is the 1H NMR spectrum of crystal form E according to Example 5 of the present invention. [Figure 6A] This is the X-ray powder diffraction pattern of crystal form F according to Example 6 of the present invention. [Figure 6B] This is a DSC chart of crystal form F according to Example 6 of the present invention. [Figure 6C] This is the 1H NMR spectrum of crystal form F according to Example 6 of the present invention. [Figure 7A] This is the X-ray powder diffraction pattern of crystal form G according to Example 7 of the present invention. [Figure 7B] This is a DSC chart of crystal form G according to Example 7 of the present invention. [Figure 7C] This is the 1H NMR spectrum of crystal form G according to Example 7 of the present invention. [Figure 8A] This is the X-ray powder diffraction pattern of crystalline form H according to Example 8 of the present invention. [Figure 8B] This is a DSC chart of crystalline form H according to Example 8 of the present invention. [Figure 9A] This is the X-ray powder diffraction pattern of crystal form A according to Example 10 of the present invention. [Figure 9B] This is the X-ray powder diffraction pattern of crystal form G according to Example 10 of the present invention. [Modes for carrying out the invention]

[0059] The present invention will be further described in detail by the following examples, but these examples are not intended to limit the scope of protection of the present invention.

[0060] Detection equipment and methods: X-ray powder diffraction (XRPD) test method: Instrument model: D8 Advance, diffraction line: CuK (40KV, 40mA), step size: 0.02° 2θ, speed: 0.1s / step, scan range: 3°~40°(2θ).

[0061] 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 to 300 °C.

[0062] TGA: Instrument model: TGA2, Parameters: N2 protection, Gas flow rate 50 mL / min, Heating rate 10.0 k / min, Temperature range: 30℃~350℃.

[0063] 1 1H NMR: Instrument model: BrukerAVANCE III 400MHz; Parameters: Full-frequency excitation, 20ppm spectral width single pulse, 8 excitation scans at 30° angles, digital quadrature detection, temperature control 298K; Solvent: DMSO-d6.

[0064] Compound I of formula ((1-((1S,4aS,4bR,6aS,8R,10aS,10bS,12aS)-8-hydroxy-8,10a,12a-trimethyloctadecahydrochrysen-1-yl)-2-(2H-tetrazole-2-yl)ethane-1-one) is commercially available or can be prepared in practice. For example, it can be prepared according to the method described in Example 20 of Prior Art Patent CN202010015181.0 (WO2020143640A1).

[0065] Example 1: Production of Crystal Form A Approximately 20 mg of compound I was weighed and added to a 3 mL vial. 1 mL of isopropanol was added, and dissolution was promoted by sonication at 50°C. The mixture was then filtered into another 3 mL vial using a 0.45 μm PTFE filter. This clear filtrate was stirred at 50°C, allowed to cool naturally to room temperature, and allowed to precipitate a solid. The solid was recovered by centrifugation, and the XRPD test was performed.

[0066] The XRPD powder diffraction pattern is shown in Figure 1A. The XRPD data is shown in Table 1.

[0067] TIFF2026524202000003.tif229157

[0068] The DSC chart shows a single endothermic peak around 170.14°C (onset value), as shown in Figure 1B.

[0069] In the TGA chart, as shown in Figure 1C, crystal form A shows no loss of weight before 120°C and is an anhydrous crystalline form.

[0070] 1 In the 1H NMR spectrum, as shown in Figure 1D, 1 According to the 1H NMR test, there is no solvent residue.

[0071] Example 2: Production of Crystal Form B Approximately 30 mg of compound I was weighed and added to a 3 mL vial. Then, 0.5 mL of a mixed solvent of isopropyl acetate and 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.

[0072] The powder diffraction pattern is shown in Figure 2A. The XRPD data is shown in Table 2.

[0073] TIFF2026524202000004.tif240157 TIFF2026524202000005.tif78157

[0074] The DSC chart shows two endothermic peaks at 91.88°C and 171.38°C (onset values), as shown in Figure 2B.

[0075] 1 The 1H NMR spectrum is shown in Figure 2C, and as can be seen from the figure, the sample contains approximately 30.8% toluene (about 2 molecules of toluene).

[0076] Example 3: Production of crystal form C Approximately 20 mg of compound I was weighed out and added to a 3 mL vial. Then, 1 mL of methanol was added to the vial, and dissolution was promoted by sonication. The mixture was filtered, and the filtrate was allowed to stand and volatilize.

[0077] The powder diffraction pattern is shown in Figure 3A. The XRPD data is shown in Table 3.

[0078] TIFF2026524202000006.tif235156 TIFF2026524202000007.tif40156

[0079] The DSC chart shows two endothermic peaks at 90.02°C and 174.69°C (onset value), as shown in Figure 3B.

[0080] 1The 1H NMR spectrum is shown in Figure 3C, and as can be seen from the figure, approximately 3.09% methanol remains in the sample.

[0081] Example 4: Production of crystal form D Approximately 50 mg of compound I was weighed and added to a 5 mL vial. 1 mL of dichloromethane was then added, and dissolution was promoted by sonication. After filtration, rotary evaporation was performed.

[0082] The XRPD powder diffraction pattern is shown in Figure 4A. The XRPD data is shown in Table 4.

[0083] TIFF2026524202000008.tif235156 TIFF2026524202000009.tif78156

[0084] The DSC chart shows two endothermic peaks at 155.68°C and 168.97°C (onset values), as shown in Figure 4B.

[0085] 1 The 1H NMR spectrum is shown in Figure 4C, and as can be seen from the figure, approximately 1.02% of dichloromethane remains in the sample.

[0086] Example 5: Production of crystal form E Approximately 20 mg of compound I was weighed and added to a 5 mL vial. 0.5 mL of methanol was added to the vial, and dissolution was promoted by sonication. The mixture was filtered to obtain a filtrate, and the filtrate was slowly added dropwise to a vial containing 3 mL of water to precipitate the solid.

[0087] The XRPD powder diffraction pattern is shown in Figure 5A. The XRPD data is shown in Table 5.

[0088] TIFF2026524202000010.tif215155

[0089] In the DSC chart, as shown in Figure 5B, there is a single endothermic peak, and the melting point is 170.16 °C (onset value).

[0090] 1 The 1H NMR spectrum is as shown in Figure 5C. As can be seen from the figure, no significant solvent residue was observed in the sample.

[0091] Example 6 Preparation of Crystal Form F Production method: Weigh about 200 mg of the compound of Formula I, add it to a 20 mL vial, then add 4 mL of methanol to the vial, add a magnon, suspend it at room temperature, slurry it overnight (about 18 h), filter it, and dry the solid at 50 °C overnight (about 18 h).

[0092] Its XRPD powder diffraction pattern is shown in Figure 6A. The XRPD data are shown in Table 6.

[0093] TIFF2026524202000011.tif234157

[0094] The DSC chart is as shown in Figure 6B. As can be seen from the figure, two endothermic peaks located at 83.04 °C and 177.93 °C (onset value), respectively, were observed.

[0095] 1 The 1H NMR spectrum is as shown in Figure 6C. As can be seen from the figure, about 0.31% of methanol remains in the sample.

[0096] Example 7 Preparation of Crystal Form G Production method: Place the crystal form F compound on a hot stage, heat it up to 125 °C, and maintain it for about 10 minutes to cause a crystal transition to crystal form G.

[0097] Its XRPD powder diffraction pattern is shown in Figure 7A. The XRPD data are shown in Table 7.

[0098] TIFF2026524202000012.tif202156

[0099] The DSC chart is shown in Figure 7B, which reveals a single endothermic peak and a melting point of 177.75°C (onset value).

[0100] 1 The 1H NMR spectrum is shown in Figure 7C, and as can be seen from the figure, no significant solvent residue was observed in the sample.

[0101] Example 8: Production of crystalline form H Preparation method: Following the method of Example 20 of WO2020143640A1, the KHC-8 compound was reacted with acetonitrile, cesium carbonate, and 1H-tetrazole, then water was added, the mixture was extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product of compound I.

[0102] 1) 1.370 g of the crude product of compound I was dissolved in 31 ml of a mixed solvent (DCM / MeOH=30 / 1), the sample was injected into a preparative plate, and the plate was developed (developing agent DCM / MeOH=30 / 1, Rf=0.5). After the preparative plate was completely dry, the solid compound on the plate was scraped off and detected by XRPD, and its powder diffraction pattern is shown in Figure 8A.

[0103] 2) 1.372 g of the crude product of compound I was weighed and eluted with 250 ml of a mixed solvent (DCM / MeOH = 30 / 1). The eluate was collected and concentrated under reduced pressure at 45°C to obtain a white solid. Its XRPD powder diffraction pattern was basically identical to that of Figure 8A.

[0104] A DSC test was performed on the solid finally obtained in 1) or 2), and the DSC chart is shown in Figure 8B. As can be seen from this chart, a small endothermic peak was observed around 64°C, which is thought to be a desolvation peak, an exothermic peak around 97°C is an amorphous recrystallization peak, and three endothermic peaks were observed around 162°C, 170°C, and 179°C, suggesting that it is a mixed crystal.

[0105] Example 9: Inter-transition experiment of anhydrous crystalline form To confirm the stability relationship of the anhydrous crystalline forms A / E / G under different temperature conditions, suspension competition tests were set up in different solvents at 25°C and 50°C. The specific steps were as follows: First, saturated solutions of the starting sample formula I compound were prepared at the corresponding temperature and solvent. Equal volumes of each of Form A / E were added to the filtered saturated solutions to create suspensions, which were then suspended and stirred for 4 days under the respective conditions of 25°C and 50°C. After that, samples were taken and XRPD detection was performed. Equal volumes of each of Form A / G were added to the filtered saturated solutions to create suspensions, which were then suspended and stirred for 1 day under the respective conditions of 25°C and 50°C. After that, samples were taken and XRPD detection was performed. The results are shown in Table 9.

[0106] TIFF2026524202000013.tif78154

[0107] Example 10 Experiment on grinding stability Crystal forms A and G were ground for 1 minute, 3 minutes, and 10 minutes, respectively, and the change in their crystal form was detected by PXRD. The results are shown in Figures 9A and 9B. As can be seen from the results, after 10 minutes of grinding, crystal form A remained unchanged, while crystal form G became semi-amorphous, indicating that crystal form A is more stable than crystal form G under grinding conditions.

[0108] Example 11: Experiment on storage stability Appropriate amounts of each test sample were taken and placed in open containers. These were then left under the corresponding influencing factors (high temperature, high humidity, light) for 0, 5, 12, and 30 days. Samples were taken, and the crystal form and the content of related substances were detected. The specific influencing factors and test conditions are shown in the table below. Note: Constant humidity conditions were created by placing saturated saline solution at the bottom of a desiccator, and 92.5% RH was achieved using a saturated KNO3 solution.

[0109] TIFF2026524202000014.tif38155

[0110] According to the test results, crystal forms A and G showed a significant increase in the largest unknown single impurity and total impurities compared to day 0 after 30 days of storage under high temperature, high humidity, and light conditions. On the other hand, crystal form H showed a 0.9% increase in total impurities compared to day 0 after 30 days of exposure to light. While crystal forms A and G remained relatively stable after 30 days of storage under high temperature, high humidity, and light conditions, crystal form H underwent a crystallization transition after only 5 days of storage under these conditions, mainly transforming into a mixed crystal of crystal form A + a small amount of crystal form G.

Claims

1. The crystalline form A of compound I is Crystal form A of the compound of formula I, characterized in that the 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 crystal 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°, and more preferably the X-ray powder diffraction pattern of crystal form A substantially matches that of Figure 1A.

2. The crystalline form B of compound I is Crystalline form B of the compound of formula I, characterized in that the 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 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°, and more preferably the X-ray powder diffraction pattern of crystalline form B substantially matches that of Figure 2A.

3. The crystalline form C of compound I is In the X-ray powder diffraction pattern, characteristic peaks are found 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°, and preferably, in the X-ray powder diffraction pattern of the crystal form C, characteristic peaks are found 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°, and preferably The crystalline form C of the compound of formula I is characterized in that, in the X-ray powder diffraction pattern of the crystalline form C, characteristic peaks are found 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°, and more preferably, the X-ray powder diffraction pattern of the crystalline form C substantially matches that of Figure 3A.

4. The crystalline form D of compound I is In the X-ray powder diffraction pattern, characteristic peaks are found 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 in the X-ray powder diffraction pattern of crystal form D, characteristic peaks are found 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 in the X-ray powder diffraction pattern of crystal form D The crystalline form D of the compound of formula I is characterized in that it 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°, and more preferably the X-ray powder diffraction pattern of the crystalline form D substantially matches that of Figure 4A.

5. The crystalline form E of the compound of formula I, In the X-ray powder diffraction pattern, characteristic peaks are found 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 in the X-ray powder diffraction pattern of crystal form E, characteristic peaks are found 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 in the crystal form E Crystal form E of compound I, characterized in that the 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°, and more preferably the X-ray powder diffraction pattern of crystal form E substantially matches that of Figure 5A.

6. The crystalline form F of compound I is The crystalline form F of the compound of formula I is characterized in that, in its X-ray powder diffraction pattern, it 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, in the X-ray powder diffraction pattern of the crystalline form F, it 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°, and more preferably, the X-ray powder diffraction pattern of the crystalline form F substantially matches that of 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 having 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°, and more preferably the X-ray powder diffraction pattern of the crystalline form G substantially matches that of Figure 7A.

8. A method for producing the crystalline form A described in claim 1, characterized by adding the compound of formula I to an organic solvent and dissolving it thoroughly, then lowering the temperature to precipitate it, and centrifuging it to obtain a solid.

9. The method for producing the product according to claim 8, characterized in that the organic solvent is isopropanol, ethylpropyl acetate, or acetonitrile, preferably isopropanol.

10. The manufacturing 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 a crystalline form described in any one of claims 1 to 7 and a pharmaceutically acceptable excipient.

12. Use of the crystalline form according to any one of claims 1 to 7 in the manufacture of a drug for a disease related to the GABAA receptor.

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

14. The neurological disorder is selected from sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory impairment and / or cognitive impairment, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or amputation syndrome or tinnitus, preferably the mood disorder is depression, and the depression is severe dysthymia, major depressive disorder, persistent depressive disorder, premenstrual syndrome, substance or drug-induced disorders, disorders due to other physical illnesses, other specific depressive disorders and nonspecific depressive disorders, more preferably the depression is selected from mild depression, moderate depression, severe depression or postpartum depression, and more preferably the neurological disorder is severe depression or postpartum depression, characterized in that the use according to 12.

15. The use according to claim 12, characterized in that the metabolic disease is selected from obesity, high cholesterol, and high blood pressure.

Images