Salt forms, polycrystalline forms of allopregnanolone derivatives, and methods for their preparation and use

Abstract

The present invention provides multiple salt forms of allopregnanolone derivatives, including hydrochloride, phosphate, L-malate, maleate, p-toluenesulfonate, and benzoate. The present invention also provides multiple crystalline and amorphous forms of allopregnanolone derivative hydrochloride, including crystalline form I, crystalline form II, crystalline form III, and crystalline form IV. Both the hydrochloride and phosphate salts of allopregnanolone derivatives have good stability, are simple to prepare, are easy to operate, and are suitable for scale-up production, making them of good industrial applicability. [Formula 1] JPEG2026507720000023.jpg41169

Description

Detailed Description of the Invention

[0001] This application claims priority from a prior patent application bearing patent application number 2023102302217 and entitled "Salt forms and polycrystalline forms of allopregnanolone derivatives, and preparation and use thereof," filed with the State Intellectual Property Administration of China on March 10, 2023, the entire text of which is incorporated herein by reference.

[0002] [Technical field] The present invention relates to the field of medicinal chemistry, specifically to the salt form, polycrystalline form, and method for preparation and use of the allopregnanolone derivative L-valine-3-tritium, (3α,5α)-3-hydroxy-pregnan-20-one ester (1).

[0003] [Background technology] In the human body, gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter. Many neurological disorders are caused by alterations in the signal transduction of the neurotransmitter GABA receptor. Mental stress makes it abnormally difficult for GABA to accumulate in the brain, and a deficiency of GABA can cause symptoms such as anxiety, fatigue, and insomnia. GABA activates two types of receptors: the GABA-A receptor subtype and the GABA-B receptor subtype. The GABA-A receptor subtype can regulate rapid changes in neuronal excitability and mood, such as anxiety, panic, and stress responses.

[0004] GABA-A receptor subtype-positive allosteric modulators (GABA-APAMs), especially the neuroactive steroid GABA-APAMs, have shown clinical therapeutic effects in anesthesia, epilepsy, postpartum depression, and severe depression. Currently, neuroactive steroids that alter the activity of GABA-A receptor subtypes are being systematically investigated as candidate drugs for various nervous system disorders.

[0005] Allopregnanolone (3α-OH-5α-pregnan-20-one, brexanolone) is an endogenous pregnane neurosteroid and a positive allosteric modulator of the GABA-A receptor subtype. Studies have shown that allopregnanolone primarily binds to the α and β subunits of the GABA-A receptor subtype, increasing the frequency of chloride signaling channel opening on the receptor and reducing neuronal excitability, potentially producing sedative and anxiolytic effects. However, allopregnanolone has poor aqueous solubility, poor oral availability, a half-life in human plasma of approximately 45 minutes, and rapid metabolism, making it difficult to formulate as an oral formulation. In 2019, the US Food and Drug Administration (FDA) approved an intravenous formulation of brexanolone (trade name: Zulresso, SAGE Therapeutics) for the treatment of postpartum depression. This is the first and currently only drug approved for the treatment of postpartum depression. However, brexanolone injection requires intravenous infusion for up to 60 hours before it can exert its therapeutic effect, during which time specialized medical staff must be on-site to continuously monitor and intervene as needed, causing significant inconvenience to patients and medical staff.

[0006] To overcome this problem, the present applicant developed Compound 1 shown below (chemical name in Japanese: L-valine-3-deuterium, (3α,5α)-3-hydroxy-pregnan-20-one ester; chemical name in English: L-Valine-3-d,(3α,5α)-3-hydroxy-pregnan-20-one-3-ylester).

[0007] [ka]

[0008] This compound has high oral bioavailability, rapid onset of effect, long duration of action, minimal toxicity and side effects, and excellent metabolic stability. When formulated into an appropriate oral formulation, it can improve drug safety, patient compliance, and administration convenience.

[0009] Even if the same drug has different salt forms or crystalline forms, its appearance, solubility, melting point, dissolution rate, bioavailability, etc. may be significantly different, which affects the stability, bioavailability, and therapeutic effect of the drug.This phenomenon is particularly noticeable in oral preparations (e.g., tablets, oral suspensions, etc.).Therefore, further research on the pharmaceutically acceptable salt forms and crystalline forms of the compound is very important for improving the druggability of the drug.

[0010] [Summary of the Invention] [Problem to be solved by the invention] To solve the above technical problems, the present invention provides a pharmaceutically acceptable salt of L-valine-3-deuterium, (3α,5α)-3-hydroxy-pregnan-20-one ester (Compound 1). Converting the compound into a salt improves druggability, such as solubility, stability, hygroscopicity, and bioavailability, and is advantageous for the development of solid oral formulations.

[0011] The present invention also provides polycrystalline forms of the hydrochloride salt of Compound 1.

[0012] The present invention also provides a method for preparing polycrystalline forms of the hydrochloride salt of Compound 1.

[0013] The present invention also provides a pharmaceutical composition, which comprises a pharmaceutically acceptable salt of Compound 1 or a crystalline form thereof, and a pharmaceutically acceptable carrier.

[0014] The present invention also provides the use of a pharmaceutically acceptable salt of Compound 1 or a crystalline form thereof, or a pharmaceutical composition comprising said pharmaceutically acceptable salt or crystalline form, in the preparation of a medicament for the prevention and / or treatment of central nervous system diseases, for sedation and hypnosis, Alzheimer's disease, epilepsy or depression, in particular postpartum depression.

[0015] The present invention provides a pharmaceutically acceptable salt of Compound 1, which is a salt formed with Compound 1 and any organic or inorganic acid.

[0016] [ka]

[0017] Preferably, the pharmaceutically acceptable salt of Compound 1 is selected from hydrochloride, phosphate, benzoate, p-toluenesulfonate, malate, acetate, benzenesulfonate, and maleate salts. More preferably, the pharmaceutically acceptable salt is selected from hydrochloride, phosphate, benzoate, and p-toluenesulfonate salts of Compound 1, and even more preferably, hydrochloride and phosphate salts.

[0018] In the hydrochloride, benzoate, p-toluenesulfonate, acetate, and benzenesulfonate salts, the molar ratio of Compound 1 to acid is (1±0.1):1, for example, (1±0.05):1, such as about 1:1.

[0019] For the phosphate, malate, maleate salts, the molar ratio of Compound 1 to acid is (2±0.2):1, such as (2±0.1):1, for example, about 2:1.

[0020] In the present invention, the acid includes any optical isomer, racemic form, or meso form thereof. For example, malic acid may be L-malic acid, D-malic acid, or DL-malic acid.

[0021] The present invention also provides crystalline polymorphs of the hydrochloride salt of Compound 1, including amorphous forms, and crystalline forms I, II, III, and IV, the structural formula of which is represented by the following formula (2):

[0022] [ka]

[0023] In one embodiment, crystalline Form I of Compound 2 has characteristic peaks in an X-ray powder diffraction pattern expressed in 2θ angles at one or more of 6.3±0.2°, 10.9±0.2°, 13.3±0.2°, 13.5±0.2°, 15.1±0.2°, and 17.8±0.2°.

[0024] In one embodiment, crystalline Form I of Compound 2 has an X-ray powder diffraction pattern expressed in 2θ angles, with characteristic peaks at one or more of 6.3±0.2°, 10.9±0.2°, 13.3±0.2°, 13.5±0.2°, 14.2±0.2°, 15.1±0.2°, 15.8±0.2°, 17.4±0.2°, 17.8±0.2°, 20.9±0.2°, and 24.0±0.2°.

[0025] In one embodiment, the crystalline form I has absorption peaks at the following positions in the X-ray powder diffraction pattern shown in 2θ angles:

[0026] [Table 1]

[0027] In one embodiment, the crystalline Form I has an XRPD spectrum approximately as shown in FIG.

[0028] In one embodiment, the DSC spectrum of the crystalline form I has an endothermic peak in the range of about 154 to 158°C, for example, an endothermic peak at about 156°C.

[0029] In one embodiment, the crystalline form I has a DSC spectrum approximately as shown in FIG.

[0030] In one embodiment, the crystalline Form I has a TGA spectrum approximately as shown in FIG.

[0031] In one embodiment, the crystalline form I has a DVS spectrum approximately as shown in FIG.

[0032] In one embodiment, crystalline Form II of Compound 2 has characteristic peaks in an X-ray powder diffraction pattern expressed in 2θ angles at one or more of 4.0±0.2°, 10.6±0.2°, 13.9±0.2°, 14.5±0.2°, 18.4±0.2°, and 21.3±0.2°.

[0033] In one embodiment, crystalline Form II of Compound 2 has characteristic peaks in an X-ray powder diffraction pattern expressed in 2θ angles at one or more of 4.0±0.2°, 10.6±0.2°, 13.0±0.2°, 13.9±0.2°, 14.5±0.2°, 18.4±0.2°, and 21.3±0.2°.

[0034] In one embodiment, the crystalline form II has absorption peaks at the following positions in the X-ray powder diffraction pattern shown at 2θ angles:

[0035] [Table 2]

[0036] In one embodiment, the crystalline Form II has an XRPD spectrum approximately as shown in FIG.

[0037] In one embodiment, the DSC spectrum of the crystalline form II has endothermic peaks at about 78 to 90°C and about 160 to 162°C, for example, at about 82 to 86°C and about 160 to 162°C, for example, at about 84°C and about 161°C.

[0038] In one embodiment, the crystalline form II has a DSC spectrum approximately as shown in FIG.

[0039] In one embodiment, the crystalline Form II has a TGA spectrum approximately as shown in FIG.

[0040] In one embodiment, the crystalline form II is a hydrate, preferably the crystalline form II is a monohydrate.

[0041] In one embodiment, the crystalline form II has a DVS spectrum approximately as shown in FIG.

[0042] In one embodiment, crystalline Form III of Compound 2 has characteristic peaks in an X-ray powder diffraction pattern expressed in 2θ angles at one or more of 3.4±0.2°, 9.8±0.2°, 12.1±0.2°, 13.1±0.2°, 16.4±0.2°, and 21.9±0.2°.

[0043] In one embodiment, crystalline Form III of Compound 2 has an X-ray powder diffraction pattern expressed in 2θ angles, with characteristic peaks at one or more of 3.4±0.2°, 9.8±0.2°, 11.4±0.2°, 12.1±0.2°, 13.1±0.2°, 14.7±0.2°, 16.4±0.2°, 19.9±0.1°, and 21.9±0.2°.

[0044] In one embodiment, the crystalline form III has absorption peaks at the following positions in the X-ray powder diffraction pattern shown at 2θ angles:

[0045] [Table 3]

[0046] In one embodiment, the crystalline Form III has an XRPD spectrum approximately as shown in FIG.

[0047] In one embodiment, the DSC spectrum of the crystalline form III has an endothermic peak at about 100 to 109°C, for example, an endothermic peak at about 102 to 106°C, for example, an endothermic peak at about 104°C.

[0048] In one embodiment, the crystalline form III has a DSC spectrum approximately as shown in FIG.

[0049] In one embodiment, the crystalline Form III is a toluene solvate.

[0050] In one embodiment, crystalline Form IV of Compound 2 has characteristic peaks in an X-ray powder diffraction pattern expressed in 2θ angles at one or more of 10.7±0.2°, 11.4±0.2°, 12.9±0.2°, 13.3±0.2°, 16.1±0.2°, 17.6±0.2°, and 19.9±0.2°.

[0051] In one embodiment, crystalline Form IV of Compound 2 has characteristic peaks in an X-ray powder diffraction pattern expressed in 2θ angles at one or more of 10.7±0.2°, 11.4±0.2°, 12.1±0.2°, 12.9±0.2°, 13.3±0.2°, 16.1±0.2°, 17.6±0.2°, 19.1±0.2°, and 19.9±0.2°.

[0052] In one embodiment, the crystalline form IV has absorption peaks at the following positions in the X-ray powder diffraction pattern shown at 2θ angles:

[0053] [Table 4]

[0054] In one embodiment, the crystalline Form IV has an XRPD spectrum approximately as shown in FIG.

[0055] In one embodiment, the DSC spectrum of the crystalline form IV has an endothermic peak in the range of about 101 to 106°C, for example, at about 102°C.

[0056] In one embodiment, the crystalline form IV has a DSC spectrum approximately as shown in FIG.

[0057] In one embodiment, the crystalline form IV is a xylene solvate.

[0058] In one embodiment, the amorphous form of Compound 2 has an XRPD spectrum approximately as shown in FIG.

[0059] In one embodiment, the amorphous form has a DSC spectrum approximately as shown in FIG.

[0060] The present invention also provides methods for preparing Compound 2 polycrystalline forms.

[0061] In one embodiment, crystalline form I of compound 2 is prepared by the following method: Compound 2 is added to isopropyl acetate, heated and stirred, slurried, filtered, and dried to obtain crystalline form I. Preferably, the weight-volume ratio of compound 2 to isopropyl acetate is 1 g:(5 to 30) ml, for example, 1 g:(5 to 20) ml, for example, 1 g:10 ml. The heating temperature is 40 to 70°C, for example, 45 to 55°C, for example, 50°C.

[0062] In one embodiment, crystalline Form II of Compound 2 is prepared by the following method: Compound 2 is added to water, heated to dissolve, and cooled to crystallize, to obtain crystalline Form II. Preferably, the weight-volume ratio of Compound 2 to water is 1 g:(40-100) ml, for example, 1 g:(40-60) ml, for example, 1 g:50 ml.

[0063] In one embodiment, crystalline Form III of Compound 2 is prepared by the following method: Compound 2 is added to toluene, heated to dissolve, and cooled to crystallize, to obtain crystalline Form III. Preferably, the weight / volume ratio of Compound 2 to toluene is 1 g:(10-50) ml, for example, 1 g:(20-40) ml, for example, 1 g:25 ml.

[0064] In one embodiment, crystalline Form IV of Compound 2 is prepared by the following method: Compound 2 is added to xylene, stirred at room temperature to form a slurry, filtered, and dried to obtain crystalline Form IV. Preferably, the weight-volume ratio of Compound 2 to xylene is 1:(10-50) ml, for example, 1 g:(20-40) ml, for example, 1 g:25 ml. The drying temperature is 40-60°C, for example, 50°C.

[0065] In one embodiment, the amorphous form of compound 2 is prepared by the following method: Compound 2 is added to dichloromethane, stirred to dissolve, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain the amorphous form. Preferably, the weight / volume ratio of compound 2 to dichloromethane is 1 g:(10-30) ml, for example, 1 g:(10-15) ml, for example, 1 g:20 ml. The temperature for the concentration under reduced pressure is 30-45°C, for example, 35-40°C.

[0066] In the present invention, in the method for preparing the polycrystalline form, the cooling crystallization may be carried out at room temperature or below room temperature, for example, 0 to 25°C, for example, 0 to 10°C. The method may further include steps of filtration and drying, and may be carried out according to a conventional method. For example, vacuum drying is carried out at 40 to 70°C, for example, 50 to 60°C.

[0067] The purity of the crystals prepared in the present invention is greater than 95%, preferably greater than 97%, more preferably greater than 99%, and most preferably greater than 99.5%.

[0068] The present invention also provides a pharmaceutical composition comprising at least one of a pharmaceutically acceptable salt of Compound 1 according to the present invention, its crystalline form or amorphous form (e.g., a crystalline form of Compound 1 hydrochloride), and an optional pharmaceutically acceptable carrier.

[0069] According to an embodiment of the present invention, the crystalline form is at least one selected from crystalline forms I, II, III, and IV of Compound 2 above.

[0070] According to an embodiment of the present invention, the amorphous form is selected from amorphous forms of Compound 2.

[0071] The present invention also provides the use of a pharmaceutically acceptable salt of Compound 1, at least one of its crystalline or amorphous forms (e.g., a crystalline form of Compound 1 hydrochloride), or said pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of central nervous system diseases, for sedation and hypnosis, Alzheimer's disease, epilepsy or depression, particularly postpartum depression.

[0072] According to an embodiment of the present invention, the central nervous system disease is, for example, traumatic brain injury, essential tremor, epilepsy (including refractory persistent epilepsy), rare genetic epilepsy (e.g., Dravet syndrome and Rett syndrome), depression (including postpartum depression), and Alzheimer's disease. The central nervous system disease is, for example, selected from essential tremor, epilepsy, clinical depression, postpartum depression or postpartum depression, atypical depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysphoria, bipolar disorder, depressive personality disorder, recurrent brief depression, mild depression, bipolar disorder or manic depression, posttraumatic stress disorder, chronic medical illness-induced depression, treatment-resistant depression, treatment-refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior.

[0073] The present invention provides multiple salt forms of allopregnanolone derivatives, including hydrochloride, phosphate, L-malate, maleate, p-toluenesulfonate, and benzoate, and also provides multiple crystalline and amorphous forms of allopregnanolone derivative hydrochloride, including crystalline Form I, crystalline Form II, crystalline Form III, and crystalline Form IV. Both the hydrochloride salt of allopregnanolone derivative and its crystalline Form I and phosphate salt have good stability, are simple to prepare, are easy to operate, and are suitable for scale-up production, making them of good industrial applicability.

[0074] [Brief description of the drawing] FIG. 1 is an XRPD spectrum of crystalline form I of compound 2 of the present invention.

[0075] FIG. 2 is a DSC spectrum of crystalline form I of compound 2 of the present invention.

[0076] FIG. 3 is a TGA spectrum of crystalline form I of compound 2 of the present invention.

[0077] [Figure 4] DVS spectrum of crystalline form I of compound 2 of the present invention.

[0078] [Figure 5] XRPD spectrum of crystalline form II of compound 2 of the present invention.

[0079] [Figure 6] DSC spectrum of crystalline form II of compound 2 of the present invention.

[0080] [Figure 7] TGA spectrum of crystalline form II of compound 2 of the present invention.

[0081] [Figure 8] DVS spectrum of crystalline form II of compound 2 of the present invention.

[0082] [Figure 9] XRPD spectrum of crystalline form III of compound 2 of the present invention.

[0083] FIG. 10 is a DSC spectrum of crystalline form III of compound 2 of the present invention.

[0084] [Figure 11] XRPD spectrum of crystalline form IV of compound 2 of the present invention.

[0085] FIG. 12 is a DSC spectrum of crystalline form IV of compound 2 of the present invention.

[0086] [Figure 13] XRPD spectrum of the amorphous form of Compound 2 of the present invention.

[0087] FIG. 14 is a DSC spectrum of the amorphous form of Compound 2 of the present invention.

[0088] [Mode for Carrying Out the Invention] The present invention will be described in detail below with reference to examples. It should be understood that the methods in these examples are for illustrative purposes only and do not constitute any limitation of the present invention. Materials used in the examples may be commercially available or prepared by known or conventional methods unless otherwise specified. Unless otherwise specified, the experimental methods used are conventional methods.

[0089] Apparatus and Methods: XRPD (X-ray Powder Diffraction): Instrument: Bruker D8 ADVANCE X-ray Diffractometer; XRPD Parameters: Phototube: Cu, kα (λ=1.54056Å), Phototube Voltage: 40kV, Phototube Current: 40mA, Scan Range: 3-45°, Step Size: 0.02°, Step Scan Time: 0.12s. Test Method: Approximately 10-20mg of sample was used for XRPD detection.

[0090] DSC (Differential Scanning Calorimetry): Instrument: Mettler Toledo DSC3+ Differential Scanning Calorimeter. DSC Parameters: Temperature Range: 25-300°C, Heating Rate: 10°C / min, Nitrogen Purge Gas: 50ml / min. Test Method: Take a sample (3-5mg) and place it in a DSC aluminum pot for testing.

[0091] TGA (Thermogravimetric Analysis): Instrument: US TA TGA550, TGA parameters: Temperature range: 30-300°C, Heating rate: 10°C / min, Nitrogen purge gas: 25ml / min. Test method: Take a sample (5-10mg) and place it in a TGA platinum pot for testing.

[0092] Table 1 below shows the definition and range of hygroscopicity of drugs after equilibration at 25°C ± 1°C and 80% ± 2% RH in the "Guiding Principles for Drug Hygroscopicity Testing" (Chinese Pharmacopoeia 2020 Edition, Part 4, page 485).

[0093] [Table 5]

[0094] Test materials: As described below, Compound 1 or its hydrochloride salt (Compound 2) used in the Examples can be prepared according to the method described in Example 1 of Chinese Patent Application CN202211112060.3, the entire contents of which are incorporated herein by reference. Compound 2 can also be prepared by the salt formation method of the present invention.

[0095] [ka]

[0096] Synthesis of intermediate 1a: Boc-L-Val-OH-3-d (1.20 g, 5.5 mmol, see CN 113461573 A), MI001 (1.91 g, 6.0 mmol), and 4-dimethylaminopyridine (0.07 g, 0.6 mmol) were dissolved in dichloromethane (15 mL), and a solution of dicyclohexylcarbodiimide (1.24 g, 6.0 mmol) in dichloromethane (5 mL) was added dropwise at 20 °C and stirred overnight. Dicyclohexylurea was removed by filtration, and the filtrate was concentrated and purified by column chromatography (V 石油エーテル / 酢酸エチル The mixture was separated by a ratio of 20:1 to 7:1 to obtain intermediate 1a as a colorless oil in 80% yield. 1H NMR (400 MHz, CDCl3) δ 5.10 (m, 1H), 5.07 (d, J = 9.5 Hz, 1H), 4.23 (d, J = 9.1 Hz, 1H), 2.53 (t, J = 8.8 Hz, 1H), 2.26-2.08 (m, 1H), 2.11 (s, 3H), 2.06-1.95 (m, 1H), 1.85-0.71 (m, 20H), 1.46 (s, 9H), 0.98 (s, 3H), 0.90 (s, 3H), 0.80 (s, 3H), 0.61 (s, 3H). Synthesis of Compound 1: Intermediate 1a (2.3 g, 4.4 mmol) was dissolved in dichloromethane (15 mL) and stirred at 20°C. Trifluoroacetic acid (5.02 g, 44.0 mmol) was added dropwise, and the temperature was controlled at 15-25°C with stirring for 3-4 hours. After that, dichloromethane (20 mL) was added. The reaction mixture was slowly poured into aqueous sodium bicarbonate (15 g / 50 mL) with stirring, and after stirring for 5-15 minutes, the mixture was allowed to stand and the layers were separated. The organic phase was washed with pure water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.73 g of compound 1.

[0097] Synthesis of compound 2: Compound 1 (1.59 g, 3.8 mmol) was dissolved in ethyl acetate (20 mL) and isopropanol (1.3 mL), and hydrogen chloride in ethyl acetate (2.4 M, 1.6 mL, 3.8 mmol) was added dropwise. The mixture was stirred at 20 °C for 1 h, filtered, and the filter cake was washed with ethyl acetate (20 mL). The mixture was dried at 40 °C under oil pump vacuum (P ≦ −0.09 MPa) for 4 h to give compound 2 as a white solid in 68% yield.

[0098] Example 1 Preparation of various salt forms of Compound 1 Approximately 750 mg of compound 1 was added to 15 ml of solvent, stirred to dissolve, and filtered through a 0.22 μm PTFE filter membrane to obtain a clear solution of compound 1. 1 ml of each of the above solutions (containing approximately 50 mg of compound 1) was taken and a different acid was added to carry out a salt formation reaction. The precipitated solid was collected and dried under vacuum at 40°C to obtain different salt forms of compound 1. The salt formation reaction conditions are shown in Table 2.

[0099] [Table 6]

[0100] Various salt forms 1 The H-NMR data is as follows:

[0101] Compound 1 hydrochloride: 1 H NMR (400 MHz, CDCl3) δ 8.83 (brs, 3H), 5.23-5.14 (m, 1H), 4.00-3.88 (m, 1H), 2.52 (t, J = 8.7 Hz, 1H), 2.22-2.08 (m, 1H), 2.11 (s, 3H), 2.06-1.96 (m, 1H), 1.86-1.08 (m, 18H), 1.18 (s, 3H), 1.17 (s, 3H), 1.04-0.88 (m, 1H), 0.86-0.71 (m, 1H), 0.80 (s, 3H), 0.61 (s, 3H). Compound 1 Phosphate: 1 H NMR (400 MHz, DMSO-d6) δ 6.98 (brs, 5H), 5.13 (s, 1H), 3.97 (s, 1H), 2.52 (t, , 1H), 2.15 (d, 3H), 2.11(s, 2H), 2.01 (d, 1H), 1.76 (d, 1H), 1.66 (s, 3H), 1.54 (m, 7H), 1.45 (m, 2H), 1.28 (d, 1H), 1.12 (m, 8H), 0.98 (s, 3H), 0.79 (s, 3H), 0.61 (s, 3H). Compound 1 acetate: 1H NMR (400 MHz, CDCl3) δ 5.13-5.05 (m, 1H), 3.65 (brs, 3H), 3.35 (s, 1H), 2.52 (t, J = 8.9 Hz, 1H), 2.22-2.09 (m, 1H), 2.11 (s, 3H), 2.05-1.96 (m, 1H), 2.07 (s, 3H), 1.79-0.87 (m, 19H), 1.00 (s, 3H), 0.92 (s, 3H), 0.86-0.72 (m, 1H), 0.80 (s, 3H), 0.61 (s, 3H). Compound 1 L-リンゴ acid chloride: 1 H NMR (400 MHz, DMSO-d6) δ 6.24 (brs, 4H), 5.14 (s, 1H), 4.31 (t, 1H), 3.90 (s, , 1H), 2.77 (s, 2H), 2.52(d,1H)2.15(s, 1H), 2.11 (s, 3H), 2.04(s,2H),1.50 (d, 1H), 1.42 (m,1H), 1.24 (s, 3H), 1.19 (m, 6H), 1.07 (d, 6H), 0.96 (s, 3H), 0.80 (s, 3H).0.61(s,3H). Compound 1 malic acid chloride: 1 H NMR (400 MHz, CDCl3) δ 6.23 (s, 1H), 5.25-5.03 (m, 1H), 3.69 (s, 1H), 2.52 (t, J = 8.9 Hz, 1H), 2.23-2.09 (m, 1H), 2.11 (s, 3H), 2.04-1.97 (m, 1H), 1.82-0.90 (m, 19H), 1.06 (s, 3H), 1.02 (s, 3H), 0.86-0.72 (m, 1H), 0.80 (s, 3H), 0.61 (s, 3H). Compound 1p-Torotronic acid chloride: 1H NMR (400 MHz, CDCl3) δ 8.30-8.05 (m, 3H), 7.77 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 5.12-5.05 (m, 1H), 3.92-3.83 (m, 1H), 2.48 (t, J = 8.7 Hz, 1H), 2.35 (s, 3H), 2.22-2.06 (m, 1H), 2.10 (s, 3H), 2.01-1.91 (m, 1H), 1.77-0.82 (m, 19H), 1.01 (s, 3H), 0.98 (s, 3H), 0.81-0.69 (m, 1H), 0.76 (s, 3H), 0.59 (s, 3H). Compound 1 benzoic acid: 1 H NMR (400 MHz, CDCl3) δ 8.13-8.06 (m, 2H), 7.62-7.53 (m, 1H), 7.50-7.40 (m, 1H), 5.16-5.05 (m, 1H), 4.09 (brs, 3H), 3.41 (s, 1H), 2.51 (t, J = 8.9 Hz, 1H), 2.22-2.10 (m, 1H), 2.11 (s, 3H), 2.03-1.96 (m, 1H), 1.77-0.86 (m, 19H), 1.02 (s, 3H), 0.94 (s, 3H), 0.83-0.71 (m, 1H), 0.80 (s, 3H), 0.61 (s, 3H). Compound 1 ベンゼンスルホン acid chloride: 1 H NMR (400 MHz, CDCl3) δ 8.22-8.01 (m, 3H), 7.93-7.82 (m, 2H), 7.42-7.29 (m, 3H), 5.12-5.03 (m, 1H), 3.99-3.87 (m, 1H), 2.49 (t, J = 8.7 Hz, 1H), 2.22-2.06 (m, 1H), 2.10 (s, 3H), 2.02-1.96 (m, 1H), 1.76-0.82 (m, 19H), 1.02 (s, 3H), 1.00 (s, 3H), 0.81-0.68 (m, 1H), 0.76 (s, 3H), 0.59 (s, 3H). Example 2: Study of the properties of different salt forms In this example, the hygroscopicity, solubility, and chemical stability of various salt forms of Compound 1 obtained in Example 1 are investigated.

[0102] 2.1 Hygroscopicity Highly hygroscopic drugs can have a significant impact on the fluidity and even stability of the drug. Therefore, in this application, a hygroscopic weight gain test was conducted on various salt forms of Compound 1 according to the method described in the "Guiding Principles for Drug Hygroscopicity Testing (Chinese Pharmacopoeia, 2020 Edition, Part 4)." The results of the hygroscopic test are shown in Table 3.

[0103] [Table 7]

[0104] The hygroscopicity results showed that, except for the phosphate and L-malate salts, which are hygroscopic, the other salt forms are slightly or non-hygroscopic. Therefore, all of the above salt forms are suitable for drug research and development.

[0105] 2.2 Solubility Eight 4 ml portions of purified water were taken, and the free base of Compound 1 or its different salts were added until insoluble. The corresponding amounts used were recorded, and the system was placed in a water bath at 25°C and stirred. Separately, the same system was prepared in the same manner and stirred at 37°C. After 24 hours, the supernatant was collected and analyzed by HPLC. The results of the solubility of various salt forms in water are shown in Table 4.

[0106] [Table 8]

[0107] The solubility investigation results showed that the solubility of all salt forms of Compound 1 was improved compared to the free base, with the hydrochloride and phosphate salts having relatively high solubilities, and the hydrochloride salt having the highest solubility in water.

[0108] 2.3 Chemical stability Various salts of Compound 1 were collected in appropriate amounts and spread open to investigate the stability of the samples under conditions of high temperature (60°C), high humidity (RH 92.5%), and light exposure (4500±500 Lux). Samples were collected on days 0, 7, and 14, and their purity was detected by HPLC. The results are shown in Table 5.

[0109] [Table 9]

[0110] The experimental results showed that the hydrochloride salt of compound 1 had excellent stability, while the phosphate, benzoate, and p-toluenesulfonate salts had relatively good chemical stability, and that high temperatures had a certain effect on the stability of these three salt forms.

[0111] As described above, preferred pharmaceutically acceptable salts of Compound 1 include hydrochloride, phosphate, benzoate, and p-toluenesulfonate, with hydrochloride or phosphate being more preferred, and hydrochloride being most preferred.

[0112] Example 3 Scale-up preparation of the hydrochloride and phosphate salts of Compound 1 3.1 Preparation of Compound 1 Hydrochloride Under nitrogen protection, 14 g of compound 1, 210 ml of ethyl acetate (15V), and 14 ml of isopropanol (1V) were added to a three-necked flask and stirred to dissolve. A 2 mol / L solution of hydrogen chloride in ethyl acetate was added dropwise, the pH was adjusted to 3-4, and crystallization was allowed to proceed for 1 hour. The temperature was then lowered to 0-5°C and crystallization was allowed to continue for 2-3 hours. After filtration, the filter cake was washed with ethyl acetate and dried under reduced pressure at 50°C to obtain 9.5 g of compound 1 hydrochloride as a white solid.

[0113] 3.2 Preparation of Compound 1 Phosphate 10 g of compound 1 and 150 ml of ethyl acetate were added to a three-necked flask and dissolved by stirring at 40°C. A solution of ethyl acetate phosphoric acid was added dropwise, the pH was adjusted to 3-4, and crystallization was allowed to proceed for 1 hour. The temperature was then lowered to 0-5°C and crystallization was allowed to proceed for 2-3 hours. The mixture was then filtered, and the filter cake was washed with ethyl acetate and dried at 50°C under reduced pressure to obtain a white solid phosphate salt of compound 1.

[0114] Example 4 Preparation of Polycrystalline Forms of Compound 1 Hydrochloride (i.e., Compound 2) In order to develop a solid formulation of the compound, the present inventors further conducted polycrystalline form screening tests on Compound 2, and obtained four crystalline forms I, II, III and IV of Compound 2 and one amorphous form.

[0115] Below, exemplary preparations of polycrystalline forms of the compound are presented and the stability of the polycrystalline forms is tested.

[0116] 4.1 Preparation of Crystalline Form I of Compound 2 Approximately 5.0 g of Compound 2 was added to 50 ml of isopropyl acetate and stirred at 50°C for 12 hours to form a slurry, which was then filtered. The filter cake was washed with 10 ml of isopropyl acetate and dried under vacuum at 50°C to obtain crystalline Form I of Compound 2.

[0117] The XRPD spectrum of the resulting crystalline form I is shown approximately in Figure 1. The DSC spectrum is shown approximately in Figure 2. The TGA spectrum is shown approximately in Figure 3. The DVS spectrum is shown in Figure 4. The DSC spectrum of crystalline form I shows a single strong endothermic peak at approximately 156 °C, which is the melting peak, and no other thermal phenomena are observed in the spectrum. The TGA spectrum shows that crystalline form I does not show any obvious weight loss platform, and the weight loss is 1.40%, which is due to moisture adsorption, indicating that it is an anhydrous crystalline form. The DVS spectrum shows that as the humidity increases from 0% to 20%, the sample begins to absorb moisture and gain weight, with a weight gain of 1.2% at 90% relative humidity.

[0118] 4.2 Preparation of Crystalline Form II of Compound 2 Approximately 2.0 g of Compound 2 was added to 100 ml of purified water and dissolved by stirring at 60°C. The solution was filtered through a 0.22 μm PTFE filter membrane, and the filtrate was heated to 60°C and stirred, then cooled to room temperature to precipitate crystals. After filtration, the filter cake was dried under vacuum at 50°C to obtain Crystal Form II of Compound 2.

[0119] The XRPD spectrum of the resulting crystalline Form II is shown approximately in Figure 5. The DSC spectrum is shown approximately in Figure 6. The TGA spectrum is shown approximately in Figure 7. The DVS spectrum is shown in Figure 8. The DSC spectrum of crystalline Form II exhibited endothermic peaks at approximately 84.25 °C and 161.39 °C. The TGA spectrum showed that Form II had a clear thermal weight loss platform, with a weight loss of 3.829%, demonstrating that this crystalline form is a monohydrate. The DVS spectrum showed that as the humidity began to increase from 20%, the sample began to absorb moisture and gain weight, with a weight increase of approximately 4% at 50% relative humidity.

[0120] 4.3 Preparation of Crystalline Form III of Compound 2 Approximately 2.0 g of Compound 2 was added to 50 ml of toluene and dissolved by stirring. The mixture was filtered through a 0.22 μm PTFE filter membrane, and the filtrate was allowed to slowly evaporate at room temperature in the open state until a solid precipitated. The solid was then collected and dried under vacuum at 50° C. to obtain crystalline Form III of Compound 2.

[0121] The XRPD spectrum of the resulting crystalline Form III is approximately shown in Figure 9. The DSC spectrum is approximately shown in Figure 10. The DSC spectrum of crystalline Form III shows a single strong endothermic peak at 103.73°C, which is the desolvation peak, proving that the crystalline form is a toluene solvate.

[0122] 4.4 Preparation of Crystalline Form IV of Compound 2 2.0 g of Compound 2 was added to 50 ml of xylene, stirred at room temperature for 24 hours, filtered, the filter cake was rinsed with a small amount of xylene, and dried under vacuum at 50° C. to obtain crystalline Form IV of Compound 2.

[0123] The XRPD spectrum of the resulting crystalline Form IV is approximately shown in Figure 11. The DSC spectrum is approximately shown in Figure 12. The DSC spectrum of crystalline Form IV shows a single strong endothermic peak at 102.20°C, which is the desolvation peak and proves that the crystalline form is a xylene solvate.

[0124] 4.5 Preparation of the amorphous form of compound 2 Approximately 2.0 g of compound 2 was added to 40 ml of dichloromethane solvent, stirred to dissolve, and filtered through a 0.22 μm PTFE filter membrane. The filtrate was concentrated to dryness under reduced pressure at 35° C. to obtain a white solid. The obtained white solid was dried in vacuo to obtain an amorphous form of compound 2.

[0125] The XRPD spectrum of the resulting amorphous form is approximately shown in Figure 13. The spectrum shows diffuse peaks without any clear characteristic diffraction angles. The DSC spectrum is approximately as shown in Figure 14, and no obvious endothermic or exothermic events were observed.

[0126] Example 5: Studies on the conversion of polycrystalline forms of Compound 2 Even for the same compound, different crystalline forms may be converted into each other. Therefore, a drug made from one crystalline form may be converted into another crystalline form during storage, which may affect the efficacy of the drug or cause side effects. Therefore, in this example, the interconversion relationship of the crystalline form of compound 2 was studied to obtain a stable crystalline form.

[0127] Samples of the two different crystalline forms were mixed and dissolved in 5 ml of the corresponding solvent. The mixture was stirred at room temperature for 3 days, centrifuged, and the resulting solid was dried under vacuum at 40 °C. DSC measurements were performed on the dried product to determine the crystalline composition. The experimental design and results are shown in Table 6.

[0128] [Table 10]

[0129] The experimental results showed that Form II, Form III, and Form IV were easily converted to Form I through dehydration and desolvation in an isopropyl acetate solvent system, while Form III and Form IV were easily converted to Form II through dehydration and desolvation in an n-heptane solvent system. Overall, Form I and Form II were more stable than Form III and Form IV.

[0130] Example 6: Investigation of the stability of crystalline forms I and II of compound 2 In this example, the physicochemical stability of crystalline Form I and Form II of Compound 2 was further investigated. Approximately 50 mg of each sample of crystalline Form I and Form II of Compound 2 was taken and spread to investigate their stability under conditions of high temperature (60°C), high humidity (RH 92.5%), and light exposure. Samples were taken on days 0, 10, and 30, and their physical stability was evaluated by XRPD and DSC detection. Samples were also taken to detect purity by HPLC and evaluate their chemical stability. The results are shown in Table 7.

[0131] [Table 11]

[0132] The experimental results showed that after 30 days of exposure to high temperature (60°C), high humidity (RH 92.5%) and light irradiation, the spectrum of the crystal form was almost consistent with that on day 0, the purity of the sample remained essentially unchanged, and no obvious changes were observed in the related substances, indicating that the crystal form I possesses physical and chemical stability; after 30 days of exposure to high humidity (RH 92.5%) and light irradiation, no significant changes were observed in the purity of the sample and related substances, indicating that the crystal form II has relatively good chemical stability, but after 30 days of exposure to high temperature (60°C), the purity slightly decreased, and the crystal form II transformed into a mixed crystal, indicating that the stability of the crystal form I is superior to that of the crystal form II.

[0133] As described above, comparison of the polycrystalline forms demonstrated that Form I and Form II of Compound 2 are relatively stable and can be used in the development of drug formulations. Form I is an anhydrous compound with a melting point of approximately 154-158°C, is non-hygroscopic, and is resistant to interconversion between crystalline forms. Furthermore, it has good chemical and physical stability under different destructive test conditions and is easily scaled up for industrial production. Form I is the most preferred crystalline form. Although the amorphous form is less stable than Form I, it can be used to prepare solid dispersion formulations.

[0134] The above examples are only used to explain the technical solutions of the present invention, and are not intended to limit the same. Although the above examples have described the present invention in detail, it should be understood that those skilled in the art can modify the technical solutions described in the above examples or replace some of the technical features with equivalents based on the disclosure of the present invention. These modifications or substitutions do not deviate from the essence of the corresponding technical solutions from the present invention and still fall within the protection scope of the present invention. [Brief explanation of the drawings]

[0135] [Figure 1] 1 is an XRPD spectrum of crystalline form I of compound 2 of the present invention. [Figure 2] 1 is a DSC spectrum of crystalline form I of compound 2 of the present invention. [Figure 3] 1 is a TGA spectrum of crystalline form I of compound 2 of the present invention. [Figure 4] 1 is a DVS spectrum of crystalline form I of compound 2 of the present invention. [Figure 5] 1 is an XRPD spectrum of crystalline form II of compound 2 of the present invention. [Figure 6] 1 is a DSC spectrum of crystalline form II of compound 2 of the present invention. [Figure 7] 1 is a TGA spectrum of crystalline form II of Compound 2 of the present invention. [Figure 8] 1 is a DVS spectrum of crystalline form II of Compound 2 of the present invention. [Figure 9] 1 is an XRPD spectrum of crystalline form III of compound 2 of the present invention. [Figure 10] 1 is a DSC spectrum of crystalline form III of Compound 2 of the present invention. [Figure 11] 1 is an XRPD spectrum of crystalline form IV of compound 2 of the present invention. [Figure 12] 1 is a DSC spectrum of crystalline form IV of compound 2 of the present invention. [Figure 13] 1 is an XRPD spectrum of the amorphous form of Compound 2 of the present invention. [Figure 14] 1 is a DSC spectrum of the amorphous form of Compound 2 of the present invention.

Claims

1. A pharmaceutically acceptable salt of Compound 1 shown below: The pharmaceutically acceptable salt is a salt formed from Compound 1 with any organic or inorganic acid; 【Chemistry 1】 Preferably, the pharmaceutically acceptable salt is selected from hydrochloride, phosphate, benzoate, p-toluenesulfonate, malate, acetate, benzenesulfonate, and maleate salts.

2. The salt according to claim 1, wherein the molar ratio of compound 1 to acid is (1±0.1):1 in the hydrochloride, benzoate, and p-toluenesulfonate salts.

3. 2. The salt according to claim 1, wherein the molar ratio of compound 1 to acid is (2±0.2):1 for the phosphate, malate, and maleate salts.

4. Crystalline Form I of Compound 2, having an X-ray powder diffraction pattern expressed in 2θ angles with characteristic peaks at one or more of 6.3±0.2°, 10.9±0.2°, 13.3±0.2°, 13.5±0.2°, 15.1±0.2°, and 17.8±0.2°; Preferably, an X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at one or more of 6.3±0.2°, 10.9±0.2°, 13.3±0.2°, 13.5±0.2°, 14.2±0.2°, 15.1±0.2°, 15.8±0.2°, 17.4±0.2°, 17.8±0.2°, 20.9±0.2°, and 24.0±0.2°; More preferably, said crystalline form I of Compound 2 is characterized in that said crystalline form I has an XRPD spectrum substantially as shown in FIG. 【Chemistry 2】

5. Crystalline Form II of Compound 2, having an X-ray powder diffraction pattern expressed in 2θ angles with characteristic peaks at one or more of 4.0±0.2°, 10.6±0.2°, 13.9±0.2°, 14.5±0.2°, 18.4±0.2°, and 21.3±0.2°; Preferably, the X-ray powder diffraction pattern shown in 2θ angles has characteristic peaks at one or more of 4.0±0.2°, 10.6±0.2°, 13.0±0.2°, 13.9±0.2°, 14.5±0.2°, 18.4±0.2°, and 21.3±0.2°; More preferably, crystalline Form II of Compound 2 is characterized in that crystalline Form II has an XRPD spectrum approximately as shown in FIG. 【Transformation 3】

6. Crystalline Form III of Compound 2, having an X-ray powder diffraction pattern expressed in 2θ angles with characteristic peaks at one or more of 3.4±0.2°, 9.8±0.2°, 12.1±0.2°, 13.1±0.2°, 16.4±0.2°, and 21.9±0.2°; Preferably, crystalline Form III has an X-ray powder diffraction pattern expressed in 2θ angles, which has characteristic peaks at one or more of 3.4±0.2°, 9.8±0.2°, 11.4±0.2°, 12.1±0.2°, 13.1±0.2°, 14.7±0.2°, 16.4±0.2°, 19.9±0.2°, and 21.9±0.2°; More preferably, crystalline Form III of Compound 2, characterized in that crystalline Form III has an XRPD spectrum approximately as shown in Figure 9. 【Chemistry 4】

7. Crystalline Form IV of Compound 2, having an X-ray powder diffraction pattern expressed in 2θ angles with characteristic peaks at one or more of 10.7±0.2°, 11.4±0.2°, 12.9±0.2°, 13.3±0.2°, 16.1±0.2°, 17.6±0.2°, and 19.9±0.2°; Preferably, crystalline form IV has an X-ray powder diffraction pattern expressed in 2θ angles, which has characteristic peaks at one or more of 10.7±0.2°, 11.4±0.2°, 12.0±0.2°, 12.9±0.2°, 13.3±0.2°, 16.1±0.2°, 17.6±0.2°, 19.1±0.2°, and 19.9±0.2°; More preferably, crystalline Form IV of Compound 2 is characterized in that crystalline Form IV has an XRPD spectrum approximately as shown in FIG. 【Transformation 5】

8. 13. An amorphous form of Compound 2, characterized in that the amorphous form of Compound 2 has an XRPD spectrum substantially as shown in FIG. 【Transformation 6】

9. A pharmaceutical composition comprising at least one of a pharmaceutically acceptable salt form of compound 1 according to any one of claims 1 to 3, or a crystalline form according to claims 4 to 7, or an amorphous form according to claim 8, and an optional pharmaceutically acceptable carrier.

10. Use of a pharmaceutically acceptable salt form of compound 1 according to any one of claims 1 to 3, or a crystalline form according to claims 4 to 7, or an amorphous form according to claim 8, in the preparation of a drug for the prevention and / or treatment of central nervous system diseases, for use in sedation and hypnosis, Alzheimer's disease, epilepsy, or depression (e.g. postpartum depression).

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