Crystal forms, preparation methods and uses of 3-hydroxy-5-pregnane-20-one derivatives

Abstract

This invention provides crystals of Formula I compounds as 3-hydroxy-5-pregnane-20-one derivatives and methods for their preparation. Specifically, this invention provides novel crystal forms A-C of Formula I compounds and methods for their preparation. The novel crystal forms of Formula I compounds of this invention possess excellent thermal and mechanical stability, and their preparation processes are simple, making them novel crystal forms with excellent potential for industrial implementation.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry; specifically, it relates to the crystal form of a 3-hydroxy-5-pregnane-20-one derivative, its preparation method, and its use in the prevention or treatment of central nervous system disorders. Background Technology

[0002] Neuroactive steroids are active steroids found in nerve tissue. Key neurosteroids playing important regulatory roles in the human body include progesterone, pregnenolone, and allogeneic alcoholone. Progesterone, pregnenolone, and allogeneic alcoholone are all produced from cholesterol through different metabolic pathways. Cholesterol is transferred from the outer mitochondrial membrane to the inner membrane under the mediation of an 18kDa transloin. It is then metabolized by cytochrome P450 cholesterol side-chain cleavage enzyme to pregnenolone, which is further metabolized back to progesterone by 3β-hydroxysteroid dehydrogenase. Progesterone is then further metabolized by a series of enzymatic reactions mediated by 5α-reductase and 3α-hydroxysteroid dehydrogenase to produce allogeneic alcoholone. Neuroactive steroids can be used as anesthetics, sedatives, hypnotics, anti-anxiety drugs, antidepressants, and anticonvulsants.

[0003] Allogenein has been a hot research topic in recent years. As early as 1986, it was pointed out that allogenein is a positive regulator of the GABAA receptor. However, it wasn't until 2006 that it was discovered that allogenein may primarily bind to the α and β subunits of the GABAA receptor, increasing the opening frequency of chloride ion signaling channels on this receptor, reducing nerve excitability, and thus producing sedative and anti-anxiety effects. Literature reports that the levels of progesterone and its metabolites vary at different stages of the menstrual cycle. Before menstruation begins, the levels of progesterone and its metabolites decrease, which can cause premenstrual syndrome (PMS), where symptoms recur before the start of the menstrual cycle but disappear after menstruation, such as stress, anxiety, and migraines. Postpartum depression is also associated with abnormal levels of progesterone and its metabolites. As pregnancy progresses, the concentration of allogenein in the plasma of healthy pregnant women increases, and after delivery, the concentration of allogenein drops sharply. Studies have shown that decreased levels of allogeneic alcoholone are closely associated with the occurrence and development of numerous mental disorders such as anxiety, depression, and tremor, and that exogenous administration of allogeneic alcoholone can significantly improve these mental symptoms.

[0004] However, allegeranolone has low water solubility, poor oral bioavailability, and a plasma half-life of approximately 45 minutes, indicating rapid metabolism. Zulresso, a marketed allegeranolone formulation based on sulfobutyl β-cyclodextrin, produces stable physiological concentrations of allegeranolone via intravenous injection. However, Brexanolone requires up to 60 hours of intravenous infusion, leading to poor patient compliance.

[0005] Furthermore, those skilled in the art also know that different crystal forms of drugs may exhibit significant differences in bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, color, filterability, density, and flowability. Research on drug polymorphism is beneficial for identifying drug forms with better physicochemical properties or processing options, thereby broadening the range of drug formulations, developing valuable formulations, and facilitating use by various population groups.

[0006] Therefore, there is a need in the field not only for a pregnanetanolone derivative that can improve solubility, reduce administration time, and maintain a stable physiological concentration in vivo for a long time, but also for the development of different crystal forms of such a derivative with excellent properties. Summary of the Invention

[0007] The purpose of this invention is to provide a derivative of 3-hydroxy-5-pregnane-20-one and its polymorphs, wherein the derivative can be used to prepare drugs for the prevention or treatment of central nervous system disorders, and the derivative has improved solubility, storage stability, convenient administration and high patient compliance.

[0008] Another objective of this invention is to provide a polymorph of the above-mentioned 3-hydroxy-5-pregnane-20-one derivative, which possesses excellent thermodynamic and mechanical stability.

[0009] In a first aspect, the present invention provides a crystal form A of the compound of formula I, the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2θ angles: 12.66±0.2°, 13.53±0.2°, 16.75±0.2° and 25.39±0.2°.

[0010]

[0011] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 11.96±0.2°, 12.66±0.2°, 13.53±0.2°, 14.51±0.2°, 16.75±0.2° and 25.39±0.2°.

[0012] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 11.96±0.2°, 12.66±0.2°, 13.53±0.2°, 14.51±0.2°, 16.75±0.2°, 19.27±0.2°, 22.19±0.2°, and 25.39±0.2°.

[0013] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 11.96±0.2°, 12.66±0.2°, 13.53±0.2°, 14.51±0.2°, 16.75±0.2°, 19.27±0.2°, 22.19±0.2°, 25.39±0.2°, 26.23±0.2°, 31.87±0.2°, and 35.34±0.2°.

[0014] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned A-type crystal has characteristic diffraction peaks at the following 2θ angles: 11.96±0.2°, 12.66±0.2°, 13.53±0.2°, 13.88±0.2°, 14.51±0.2°, 15.81±0.2°, 16.75±0.2°, 17.99±0.2°, 18.99±0.2°, 19.27±0.2°, 21.95±0.2°, 22.19±0.2°, 25.39±0.2°, 26.23±0.2°, 31.87±0.2°, and 35.34±0.2°.

[0015] In some embodiments of the present invention, the peak positions and intensities of the characteristic peaks in the X-ray powder diffraction patterns of the above-mentioned A-type crystal are shown in Table 1:

[0016] Table 1: Peak positions and intensities of characteristic peaks in X-ray powder diffraction patterns of crystal form A.

[0017] serial number 2θ angle (°) Relative strength (%) serial number 2θ angle (°) Relative strength (%) 1 11.96 21.12 9 18.99 13.44 2 12.66 23.74 10 19.27 16.18 3 13.53 49.52 11 21.95 12.16 4 13.88 8.31 12 22.19 58.99 5 14.51 19.45 13 25.39 100.00 6 15.81 11.30 14 26.23 18.60 7 16.75 53.89 15 31.87 58.49 8 17.99 13.11 16 35.34 20.81

[0018] In some embodiments of the present invention, the XRPD pattern of the above-mentioned A-type crystal is as follows: Figure 1 As shown, it has the following characteristics: Figure 1 The features represented by the XRPD map shown.

[0019] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned A-type crystal form are shown in Table 2:

[0020] Table 2: XRPD resolution data for crystal form A

[0021]

[0022] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned A crystal form has an endothermic peak at 216.85℃±3℃.

[0023] In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form A is as follows: Figure 2 As shown, it has the following characteristics: Figure 2 The features represented by the DSC spectrum shown.

[0024] In some embodiments of the present invention, the method for preparing the A crystal form of the compound of formula I above includes the following steps:

[0025] (1) Mix the compound of formula I with a solvent;

[0026] (2) Filter and dry;

[0027] The solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, butanone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, n-heptane, and toluene; preferably ethanol, isopropanol, or ethyl acetate.

[0028] In some embodiments of the present invention, step (1) is performed under heating conditions.

[0029] In some embodiments of the present invention, the heating temperature in step (1) is about 60 to 70°C, preferably about 65°C.

[0030] In some embodiments of the present invention, after adding the compound of formula I in step (1), the mixture is stirred for a period of 6 to 18 hours, preferably 12 hours.

[0031] In some embodiments of the present invention, step (2) involves cooling before filtration, wherein the cooling may be to 0–30°C, preferably to 20°C.

[0032] In some embodiments of the present invention, step (2) can be stirred after cooling as needed, and the stirring time can be 6 to 24 hours, preferably 18 hours.

[0033] In some embodiments of the present invention, step (2) is optionally washed with a solvent before drying, the washing solvent being selected from methanol, ethanol, acetone, ethyl acetate, methanol ether, n-heptane, toluene, and preferably ethyl acetate.

[0034] In a second aspect, the present invention provides a B crystal form of the compound of formula I, the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2θ angles: 10.69±0.2°, 13.17±0.2°, 13.37±0.2° and 15.22±0.2°.

[0035]

[0036] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.26±0.2°, 4.50±0.2°, 10.69±0.2°, 13.17±0.2°, 13.37±0.2°, and 15.22±0.2°.

[0037] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.26±0.2°, 4.50±0.2°, 10.69±0.2°, 12.88±0.2°, 13.17±0.2°, 13.37±0.2°, 15.22±0.2°, and 15.81±0.2°.

[0038] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.26±0.2°, 4.50±0.2°, 8.77±0.2°, 10.69±0.2°, 12.14±0.2°, 12.88±0.2°, 13.17±0.2°, 13.37±0.2°, 15.22±0.2°, 15.81±0.2°, 25.35±0.2°, and 29.04±0.2°.

[0039] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.26±0.2°, 4.50±0.2°, 8.77±0.2°, 10.69±0.2°, 12.14±0.2°, 12.88±0.2°, 13.17±0.2°, 13.37±0.2°, 15.22±0.2°, 15.81±0.2°, 17.37±0.2°, 21.47±0.2°, 23.19±0.2°, 25.35±0.2°, 26.83±0.2°, 29.04±0.2°, 30.52±0.2°, and 30.79±0.2°.

[0040] In some embodiments of the present invention, the peak positions and intensities of the characteristic peaks in the X-ray powder diffraction patterns of the B crystal form are shown in Table 3:

[0041] Table 3: Peak positions and intensities of characteristic peaks in X-ray powder diffraction patterns of B-type crystals

[0042] serial number 2θ angle (°) Relative strength (%) serial number 2θ angle (°) Relative strength (%) 1 4.260 17.6 10 15.813 27.2 2 4.497 14.7 11 17.371 10.1 3 8.773 7.6 12 21.469 20.5 4 10.686 11.5 13 23.186 12.1 5 12.143 6.7 14 25.351 21.4 6 12.876 27.9 15 26.831 15.4 7 13.171 62.5 16 29.038 15.0 8 13.366 100 17 30.518 11.2 9 15.223 47.6 18 30.792 13.1

[0043] In some embodiments of the present invention, the XRPD pattern of the B crystal form is as follows: Figure 3 As shown, it has the following characteristics: Figure 3 The features represented by the XRPD map shown.

[0044] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned B crystal form are shown in Table 4:

[0045] Table 4: XRPD analytical data for B-type crystals

[0046]

[0047] In some embodiments of the present invention, the differential scanning calorimetry curves of the B crystal form exhibit endothermic peaks near 120.67 °C and 226.10 °C.

[0048] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned B crystal form has endothermic peaks at 120.67±3℃ and 226.10±3℃.

[0049] In some embodiments of the present invention, the DSC spectrum of the above-mentioned B crystal form is as follows: Figure 4 As shown, it has the following characteristics: Figure 4 The features represented by the DSC spectrum shown.

[0050] In some embodiments of the present invention, the TGA spectrum of the above-mentioned B crystal form is as follows: Figure 5 As shown, it has the following characteristics: Figure 5 The TGA diagram shown represents the characteristics.

[0051] In some embodiments of the present invention, the thermogravimetric analysis curve of the B crystal form has a weight loss peak, with a weight loss of 6.475±0.5%; specifically, the thermogravimetric analysis curve of the B crystal form has a weight loss peak at 50℃-125℃.

[0052] In some embodiments of the present invention, the method for preparing the B crystal form of the compound of formula I above includes the following steps:

[0053] (1) Mix the compound of formula I with a solvent;

[0054] (2) Filter and dry;

[0055] The solvent is selected from water, a mixture of methanol and water, a mixture of ethanol and water, a mixture of acetone and water, or a mixture of acetonitrile and water, preferably water or a mixture of ethanol and water.

[0056] In some embodiments of the present invention, step (1) is performed under heating conditions.

[0057] In some embodiments of the present invention, the heating temperature in step (1) is about 65 to 75°C, preferably about 70°C.

[0058] In some embodiments of the present invention, the addition of compound I in step (1) is followed by stirring.

[0059] In some embodiments of the present invention, step (2) involves cooling before filtration, wherein the cooling may be to 0–30°C, preferably to 2–8°C.

[0060] In some embodiments of the present invention, step (2) can be stirred after cooling as needed, and the stirring time can be 15 to 22 hours, preferably 18 hours.

[0061] In some embodiments of the present invention, the washing is optionally performed with a solvent before drying in step (2), the washing solvent being selected from water, a mixture of methanol and water, a mixture of ethanol and water, a mixture of acetone and water, or a mixture of acetonitrile and water, preferably water or a mixture of ethanol and water.

[0062] Thirdly, the present invention provides the C crystal form of the compound of formula I, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.77±0.2°, 7.08±0.2°, 8.34±0.2° and 12.46±0.2°.

[0063]

[0064] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C-type crystal has characteristic diffraction peaks at the following 2θ angles: 6.77±0.2°, 7.08±0.2°, 8.34±0.2°, 12.46±0.2°, 17.60±0.2° and 17.92±0.2°.

[0065] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C-type crystal has characteristic diffraction peaks at the following 2θ angles: 6.77±0.2°, 7.08±0.2°, 8.34±0.2°, 12.46±0.2°, 13.21±0.2°, 16.52±0.2°, 17.60±0.2°, and 17.92±0.2°.

[0066] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C-type crystal has characteristic diffraction peaks at the following 2θ angles: 6.77±0.2°, 7.08±0.2°, 8.34±0.2°, 11.02±0.2°, 12.46±0.2°, 13.21±0.2°, 14.20±0.2°, 15.06±0.2°, 16.52±0.2°, 17.60±0.2°, 17.92±0.2°, and 20.86±0.2°.

[0067] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C-type crystal has characteristic diffraction peaks at the following 2θ angles: 6.77±0.2°, 7.08±0.2°, 8.34±0.2°, 10.61±0.2, 11.02±0.2, 12.46±0.2°, 13.21±0.2°, 13.76±0.2, 14.20±0.2, 14.63±0.2, 15.06±0.2, 15.75±0.2, 16.52±0.2°, 17.60±0.2°, 17.92±0.2, 19.14±0.2, 20.86±0.2, 24.76±0.2, and 26.46±0.2.

[0068] In some embodiments of the present invention, the peak positions and intensities of the characteristic peaks in the X-ray powder diffraction patterns of the C-type crystal are shown in Table 5:

[0069] Table 5: Peak positions and intensities of characteristic peaks in X-ray powder diffraction patterns of C-type crystals

[0070] serial number 2θ angle (°) Relative strength (%) serial number 2θ angle (°) Relative strength (%) 1 6.766 100.00 11 15.063 38.8 2 7.079 43.9 12 15.753 16.4 3 8.342 25.0 13 16.521 27.3 4 10.608 10.7 14 17.605 47.5 5 11.024 19.5 15 17.921 34.1 6 12.462 71.8 16 19.143 17.0 7 13.212 23.2 17 20.858 27.5 8 13.764 11.4 18 24.762 20.7 9 14.197 19.8 19 26.457 13.6 10 14.629 15.9

[0071] In some embodiments of the present invention, the XRPD pattern of the above-mentioned C-type crystal is as follows: Figure 6 As shown, it has the following characteristics: Figure 6 The features represented by the XRPD map shown.

[0072] In some embodiments of the present invention, the XRPD spectra analysis data of the above-mentioned C-type crystal are shown in Table 6:

[0073] Table 6: XRPD resolution data for C-type crystals

[0074]

[0075] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned C crystal form has an endothermic peak at 179.31℃±3℃.

[0076] In some embodiments of the present invention, the DSC spectrum of the above-mentioned C crystal form is as follows: Figure 7 As shown, it has the following characteristics: Figure 7 The features represented by the DSC spectrum shown.

[0077] In some embodiments of the present invention, the method for preparing the C crystal form of the compound of formula I above includes the following steps:

[0078] (1) Mix the compound of formula I with solvent 1;

[0079] (2) Add solvent 2;

[0080] (3) Filter and dry;

[0081] Solvent 1 is selected from one or more of methanol, ethanol, isopropanol, n-propanol, and tetrahydrofuran; solvent 2 is selected from acetone, ethyl acetate, methyl tert-butyl ether, n-heptane, and toluene.

[0082] In some embodiments of the present invention, step (1) is performed under heating conditions.

[0083] In some embodiments of the present invention, the heating temperature in step (1) is about 60 to 70°C, preferably about 65°C.

[0084] In some embodiments of the present invention, after adding the compound of formula I in step (1), the mixture is stirred for a period of 6 to 18 hours, preferably 12 hours.

[0085] In some embodiments of the present invention, the addition process in step (2) is carried out at a temperature of about 60 to 70°C, preferably about 65°C.

[0086] In some embodiments of the present invention, step (3) involves cooling before filtration, wherein the cooling may be to 0-30°C, preferably to 20°C.

[0087] In some embodiments of the present invention, step (3) can be stirred after cooling as needed, and the stirring time can be 15 to 22 hours, preferably 18 hours.

[0088] In some embodiments of the present invention, the washing is optionally performed with a solvent before drying in step (3), the washing solvent being selected from methanol, ethanol, acetone, ethyl acetate, methyl tert-butyl ether, n-heptane, toluene, and preferably ethanol and methyl tert-butyl ether.

[0089] Fourthly, the present invention provides a pharmaceutical composition comprising the above-described crystal form A, crystal form B, or crystal form C, and optionally a pharmaceutically acceptable excipient.

[0090] In some embodiments of the present invention, the pharmaceutical composition comprises the above-described crystal form A and optionally a pharmaceutically acceptable excipient.

[0091] In some embodiments of the present invention, the pharmaceutical composition is used to treat or prevent central nervous system disorders in mammals (e.g., humans).

[0092] Fifthly, the present invention provides the use of the above-described crystal form A, crystal form B, or crystal form C in the preparation of a medicament for treating or preventing central nervous system disorders in mammals (e.g., humans).

[0093] In some embodiments of the present invention, the present invention provides the use of the above-described crystal form A in the preparation of medicaments for the treatment or prevention of central nervous system disorders in mammals (e.g., humans).

[0094] In a sixth aspect, the present invention provides a method for treating or preventing central nervous system disorders in mammals (e.g., humans), the method comprising administering to the mammal (e.g., a human) a therapeutically effective amount of a compound of formula (I), a crystal form A of the compound of formula I, a pharmaceutical composition comprising the crystal form A of the compound of formula I, a crystal form B of the compound of formula I, a pharmaceutical composition comprising the crystal form B of the compound of formula I, a crystal form C of the compound of formula I, and a pharmaceutical composition comprising the crystal form C of the compound of formula I.

[0095] In some embodiments of the present invention, the method includes administering to a mammal (e.g., a human) a therapeutically effective amount of a compound of formula (I), a crystal form A of the compound of formula I, and a pharmaceutical composition comprising the crystal form A of the compound of formula I.

[0096] In some embodiments of the present invention, the central nervous system disorders include, but are not limited to, tremors, sleep disorders, depression, depressive disorder, bipolar disorder, anxiety disorder, stress response, post-traumatic stress disorder, obsessive-compulsive disorder, schizophrenia, schizophrenic affective disorder, epilepsy, epileptic seizures, memory impairment and / or cognitive impairment, dementia, motor disorders, personality disorders, autism, single-cause autism, pain, traumatic brain injury, vascular disease, substance abuse disorder and / or withdrawal syndrome, or tinnitus; or

[0097] The central nervous system disorders mentioned include, but are not limited to, essential tremor, epilepsy, clinical depression, postpartum depression, atypical depression, psychotic severe depression, catatonic depression, seasonal affective disorder, dysphoric mood, bipolar disorder, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder or manic-depressive disorder, post-traumatic stress disorder, depression due to chronic medical conditions, treatment-resistant depression, treatment-resistant depression, suicidal ideation, suicidal behavior, traumatic brain injury, generalized anxiety disorder, social anxiety disorder, attention deficit hyperactivity disorder, dementia, Huntington's disease, Parkinson's disease, neuropathic pain, injury-related pain syndrome, acute pain, chronic pain, stroke, ischemia, vascular malformation, addiction to opioids, cocaine and / or alcohol, or insomnia.

[0098] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0099] Figure 1 The XRPD pattern of the A crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention is shown;

[0100] Figure 2 The DSC spectrum of the A crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention is shown;

[0101] Figure 3 The XRPD pattern of the B crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention is shown;

[0102] Figure 4 The DSC spectrum of the B crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention is shown;

[0103] Figure 5 The TGA spectrum of the B crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention is shown;

[0104] Figure 6 The XRPD pattern of the C-crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention is shown;

[0105] Figure 7 The DSC spectrum of the C-crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention is shown;

[0106] Figure 8 The XRPD overlay patterns of the A crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention are shown at room temperature for 1 month (191222JS1M), 2 months (191222JS2M), and 3 months (191222JS3M). Detailed Implementation

[0107] Through extensive and in-depth research, the inventors unexpectedly discovered a derivative of allogeneic ketone compounds. This derivative significantly improves the water solubility of allogeneic ketone compounds, exhibits certain storage stability in aqueous solutions, and can be formulated into long-acting, sustained-release formulations with minimal individual variability after administration. Formulations made from this derivative can maintain effective physiological concentrations of allogeneic ketones in the body for a longer period and are convenient to administer, thus improving patient compliance.

[0108] Based on this, the inventors discovered crystal forms A, B, and C of the derivative, which have advantages in at least one aspect, such as physical stability, thermodynamic stability, and mechanical stability, thereby completing the present invention.

[0109] the term

[0110] In this document, "derivatives of the present invention," "derivatives of 3-hydroxy-5-pregnane-20-one," and "derivatives of allogeneic ketones" have the same meaning and can be used interchangeably. These terms all refer to compounds represented by Formula I:

[0111]

[0112] In this article, the chemical name of compound I is: glycine-L-valine 3α-hydroxy-5α-pregn-20-keto ester.

[0113] Polymorph

[0114] Those skilled in the art will understand that solids exist in either amorphous or crystalline forms. In the crystalline form, molecules are located within three-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it can crystallize with different spatial lattice arrangements (a property known as "polymorphism"), forming crystals with different crystalline forms, which are called "polymorphs." Different polymorphs of a given substance can differ from one another in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystal form, packing order, fluidity, and / or solid-state stability.

[0115] Polymorphic forms of compounds can exhibit different melting points, hygroscopicity, stability, solubility, bioavailability, biological activity, and flowability, which are important factors affecting drug properties.

[0116] The terms “crystal”, “crystal of the present invention”, “polymorph”, and “polymorph of the present invention” used herein are interchangeable. For example, the crystal described in the first aspect of the present invention has a crystal form A or is referred to as crystal A.

[0117] Furthermore, in this document, "polymorphs of the derivatives of the present invention", "polymorphs of the derivatives of 3-hydroxy-5-pregnane-20-one", and "polymorphs of the derivatives of allogeneic ketone compounds" all refer to the crystal form of the compound shown in Formula I.

[0118] crystallization

[0119] Production-scale crystallization can be achieved by manipulating the solution to exceed the solubility limit of the compound of interest. This can be done in several ways, such as dissolving the compound at a relatively high temperature and then cooling the solution below the saturation limit. Alternatively, the liquid volume can be reduced by boiling, evaporation at atmospheric pressure, vacuum drying, or other methods. The solubility of the compound of interest can also be reduced by adding an antisolvent or a solvent in which the compound has low solubility, or a mixture of such solvents. Another alternative method is to adjust the pH to reduce solubility. For a detailed description of crystallization, see Crystallization, 3rd Edition, JW Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.

[0120] Optimization of crystallization may include seeding the crystals in the desired form into the crystallization medium. Additionally, many crystallization methods utilize combinations of the strategies described above. For example, the compound of interest can be dissolved in a solvent at high temperature, followed by the controlled addition of an appropriate volume of antisolvent to bring the system just below saturation. At this point, seed crystals in the desired form can be added (while maintaining their integrity), and the system can be cooled to complete crystallization.

[0121] In this invention, the compound of formula I can be dissolved in a solvent; the resulting solution can then be cooled, or the resulting solution can be slowly evaporated, or an antisolvent can be added to the resulting solution to precipitate crystals of the compound of formula I, thereby obtaining crystals of the compound of formula I. After obtaining crystals of the compound of formula I, the crystals of the compound of formula I can optionally be dried.

[0122] In a specific embodiment, the solvent is selected from one or more of the following: water, methanol, ethanol, acetone, ethyl acetate, methanol ether, n-heptane, and toluene.

[0123] In a preferred embodiment, in step (1), the temperature may be appropriately increased to promote the dissolution of compound I.

[0124] In a preferred embodiment, the cooling is performed by cooling the solution of compound I to 20-30°C.

[0125] solvates

[0126] During the contact between compound or drug molecules and solvent molecules, it is difficult to avoid the formation of eutectic residues of solvent and compound molecules in the solid substance due to external and internal factors. The substance formed after the crystallization of the compound and solvent is called a solvate. Solvents that readily form solvates with organic compounds include water, methanol, benzene, ethanol, ethers, aromatic hydrocarbons, and heterocyclic aromatic hydrocarbons.

[0127] Hydrates are a special type of solvate. In the pharmaceutical industry, hydrates are worthy of separate discussion due to their unique characteristics, whether in the synthesis of active pharmaceutical ingredients, drug formulations, drug storage, or evaluation of drug activity.

[0128] In this invention, the crystals of the compounds represented by Formula I can be either nonsolvents or solvates. For example, crystal form B of this invention is a hydrate.

[0129] The pharmaceutical composition and administration method of the present invention

[0130] Based on the polymorphism of the 3-hydroxy-5-pregnane-20 one derivative of the present invention, the present invention further provides a pharmaceutical composition comprising the said polymorphism. The pharmaceutical composition possesses therapeutic effects on diseases caused by central nervous system abnormalities due to the 3-hydroxy-5-pregnane-20 one derivative therein, and also exhibits excellent stability and long-term storage capability due to the polymorphism of the 3-hydroxy-5-pregnane-20 one derivative therein; in particular, it also possesses thermal and mechanical stability, facilitating its preparation into pharmaceutical formulations.

[0131] In specific embodiments, the diseases caused by the central nervous system abnormalities include, but are not limited to, tremors, epilepsy, depression, or anxiety disorders. More specifically, the central nervous system disorders include, but are not limited to, essential tremor, epilepsy, clinical depression, postpartum depression, atypical depression, severe psychotic depression, catatonic depression, seasonal affective disorder, dysphoric mood, dual depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder or manic-depressive disorder, post-traumatic stress disorder, depression due to chronic medical conditions, treatment-resistant depression, treatment-resistant depression, suicidal tendencies, suicidal ideation, or suicidal behavior.

[0132] The pharmaceutical compositions of the present invention also include, optionally, a pharmaceutically acceptable carrier. Hereinafter, the term "composition" is intended to cover products containing specific amounts of specific ingredients, and any product produced directly or indirectly from a combination of specific amounts of specific ingredients; and a pharmaceutically acceptable carrier is a carrier, diluent, or excipient that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound; that is, the carrier, diluent, or excipient must be compatible with the other components of the formulation and harmless to its recipient.

[0133] The pharmaceutical compositions of the present invention can be prepared using methods known to those skilled in the art. For example, the compounds of the present invention can be mixed with pharmaceutically acceptable carriers, diluents, or excipients to prepare the corresponding pharmaceutical compositions. Furthermore, those skilled in the art can formulate the compounds or pharmaceutical compositions of the present invention into various suitable dosage forms, including but not limited to those suitable for rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous administration, intravenous administration, intramuscular administration, intra-articular administration, oral mucosal administration, vaginal administration, and intranasal administration, etc. Depending on the desired dosage form, those skilled in the art can also select appropriate pharmaceutically acceptable carriers, diluents, or excipients.

[0134] The pharmaceutical compositions of the present invention may contain a safe and effective amount of a polymorph of a 3-hydroxy-5-pregnane-20 one derivative. The term "safe and effective amount" refers to an amount of the compound (or polymorph) sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 30-800 mg of the polymorph of the present invention per dose, more preferably, 50-600 mg of the polymorph of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0135] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of the components in the composition to interact with and incorporate the active ingredient of the invention without significantly reducing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0136] There are no particular limitations on the administration of the polymorphs or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0137] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0138] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active ingredient may also be formed into microcapsules with one or more of the excipients described above.

[0139] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0140] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0141] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0142] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0143] Dosage forms of the polymorphs of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0144] Disease prevention and treatment methods

[0145] As described above, given that the 3-hydroxy-5-pregnane-20 one derivative of the present invention, upon administration to a subject, can release an active allogeneic one under suitable conditions, those skilled in the art will understand that the polymorphs or pharmaceutical compositions of the 3-hydroxy-5-pregnane-20 one derivative of the present invention can be used for the prevention or treatment of central nervous system disorders, including but not limited to the aforementioned central nervous system disorders.

[0146] The method of the present invention for preventing or treating central nervous system disorders includes administering a therapeutically effective amount of the above-described compound or pharmaceutical composition to a subject in need. The subject includes, but is not limited to, humans.

[0147] Advantages of this invention:

[0148] 1. This invention provides for the first time the polymorphism of the compound of Formula I;

[0149] 2. The A crystal form of compound I, the B crystal form of compound I, and the C crystal form of compound I have good stability, low hygroscopicity, good water solubility, and good prospects for drug development.

[0150] 3. The crystal form preparation process of the present invention is simple, thus possessing excellent potential for industrial implementation.

[0151] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0152] Test method:

[0153] XRPD (X-ray Powder Diffraction) Method 1: Approximately 10 mg of sample is evenly spread on a single-crystal silicon sample disk, and XRPD testing is performed using the following parameters. Instrument Model: X'Pert 3 X-ray diffractometer, target: Cu-Kα (40mA, 45kV), scanning range from 3° to 40° in the 2θ interval.

[0154] XRPD (X-ray Powder Diffraction) Method 2: Approximately 10 mg of sample was evenly spread on a single-crystal silicon sample disk, and XRPD testing was performed using the following parameters. Instrument model: BRUKER D8 X-ray diffractometer; target: Cu-Kα (40 kV, 40 mA); scanning range: 3° to 40° in the 2θ interval; scanning speed: 8° / minute.

[0155] Measurement discrepancies associated with these X-ray powder diffraction (XPD) analysis results are caused by a variety of factors, including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration discrepancies, (d) operator errors (including errors occurring when determining peak positions), and (e) the properties of the material (e.g., preferred orientation errors). Calibration errors and sample height errors often result in shifts in the same direction for all peaks. When using a flat support, small differences in sample height can lead to large shifts in XRPD peak positions. Systematic studies have shown that a 1 mm sample height difference can result in peak shifts as high as 1° 2θ. These shifts can be identified from the X-ray diffraction pattern and can be eliminated by compensating for the shifts (applying a systematic calibration factor to all peak position values) or by recalibrating the instrument. As mentioned above, measurement errors from different instruments can be corrected by applying a systematic calibration factor to ensure consistent peak positions.

[0156] TGA (Thermogravimetric Analysis) method: Instrument model: TA Q500 thermogravimetric analyzer, using N2 atmosphere, heating rate is 10℃ / min.

[0157] DSC (Differential Scanning Calorimetry) method: Instrument model: METTLER TOLEDO DSC3+, using N2 atmosphere, heating rate is 10℃ / min.

[0158] Example 1. Synthesis of the compound shown in Formula I

[0159]

[0160] Preparation of intermediate 2.1:

[0161] Compound 1.3 (5.0 g, 12.0 mmol), Boc-Gly-OH (2.5 g, 14.3 mmol), and dichloromethane (50 mL) were added to a 250 mL single-necked reaction flask and stirred magnetically. Then, N,N-diisopropylethylamine (3.1 g, 24.0 mmol), HOBT (342 mg, 2.4 mmol), and EDCI (2.8 g, 14.6 mmol) were added. The reaction mixture was allowed to react at room temperature for 4 hours. The reaction solution was washed with 50 mL of H₂O, 50 mL of 1N HCl, saturated NaHCO₃ aqueous solution, and pure water. The solution was concentrated under reduced pressure, and the crude product was subjected to column chromatography (petroleum ether (60-90) / ethyl acetate 10:1-3:1) to give an off-white solid (5.7 g, yield 82.8%).

[0162] Preparation of intermediate 2.2:

[0163] Compound 2.1 (5.5 g, 9.63 mmol, 1.0 eq) and dichloromethane (22 mL) were added to a 250 mL three-necked flask. Under nitrogen protection and with magnetic stirring, trifluoroacetic acid (10.9 g, 95.7 mmol) was added at 0 °C, followed by reaction at room temperature for 3 hours. The mixture was concentrated under reduced pressure, the solvent was evaporated to dryness, and dichloromethane (50 mL) was added. The mixture was washed with a saturated sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane (30 mL). The organic phases were combined, washed with 50 mL of pure water, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and dried under vacuum using an oil pump to give an off-white solid (4.5 g, 99.0% yield).

[0164] Preparation of the compound shown in Formula I:

[0165] Compound 2.2 (4.5 g, 9.5 mmol, 1.0 eq) and ethyl acetate (27 mL) were added to a 250 mL single-necked reaction flask. Under nitrogen protection and with magnetic stirring, ethyl hydrochloride solution (3 M, 3.8 mL, 11.4 mmol) was added at room temperature, and stirring continued for 1 hour. The mixture was concentrated under reduced pressure, the solvent was evaporated to dryness, and acetonitrile (70 mL) was added. The mixture was stirred at room temperature for 2 hours. The solid was filtered and washed with acetonitrile (15 mL). The solid was dried under vacuum at 40 °C for 2 hours using an oil pump to give a white solid (3.5 g, yield 72.2%).

[0166] 1 H NMR(400MHz, CDCl3)δ8.28(d,J=8.5Hz,1H),8.16(bs,3H),5.14–5.03(m,1H) ,4.55(d,J=4.1Hz,1H),4.27(d,J=16.1Hz,1H),4.09(d,J=16.0Hz,1H),2.52 (t,J=8.7Hz,1H),2.40–2.07(m,2H),2.11(s,3H),2.05–1.96(m,1H),1.82–1 .08(m,18H),1.08–0.89(m,7H),0.85–0.71(m,1H),0.79(s,3H),0.61(s,3H).

[0167] MS:m / z[M+H]+475.3.

[0168] Example 2. Preparation of crystal form A of compound of formula I

[0169] Add 60 ml of ethyl acetate and 10.0 g of compound I to a 100 ml flask. Heat to 60–65 °C, suspend and stir for 6–24 h, then cool to 20–30 °C, filter, and dry to obtain a white solid.

[0170] After testing, the XRPD pattern (obtained using XRPD method 1) and DSC pattern of the obtained crystal form are basically as follows: Figure 1 and 2 As shown in Table 7, the diffraction angle data of the XRPD patterns of the obtained crystal forms are basically as shown in Table 7, where the error range of 2θ values ​​is ±0.2°.

[0171] Table 7: XRPD resolution data for crystal form A

[0172]

[0173] Example 3. Preparation of crystal form B of compound of formula I

[0174] Add 60 ml of purified water and 10.0 g of compound I to a 100 ml flask, heat to 65-75 °C, stir until the solid dissolves, then cool to 2-8 °C until crystallization is complete, filter, and dry to obtain a white solid.

[0175] The XRPD pattern of crystal form B obtained by testing is basically as follows: Figure 3 As shown in Table 8 (measured using XRPD method 2), the diffraction angle data of the obtained crystal forms' XRPD patterns are basically as shown in Table 8, where the error range of the 2θ value is ±0.2°.

[0176] Table 8. XRPD resolution data for crystal form B

[0177]

[0178] The DSC spectrum of the obtained B crystal form was basically as shown in the test. Figure 4 As shown, the differential scanning calorimetry curve of crystal form B has endothermic peaks near 120.67℃ and 226.10℃, indicating that crystal form B may be a hydrate.

[0179] Further testing revealed that the TGA pattern of crystal form B was essentially as follows: Figure 5 As shown in the figure, there is a weight loss of 6.475 ± 0.5%. Therefore, crystal form B should be a dihydrate.

[0180] Example 4. Preparation of crystal form C of compound I

[0181] Add 40 ml of ethanol and 10.0 g of compound I to a 250 ml flask, heat to 65-75 °C, stir until the solid dissolves, add 80 ml of methyl tert-butyl ether after complete dissolution, then cool to 2-8 °C until crystallization is complete, filter, and dry to obtain a white solid.

[0182] After testing, the XRPD pattern (obtained using XRPD method 2) and DSC pattern of the obtained crystal form are basically as follows: Figure 6 and 7 As shown in Table 9, the diffraction angle data of the XRPD patterns of the obtained crystal forms are basically as shown in Table 9, where the error range of 2θ value is ±0.2°.

[0183] Table 9: XRPD resolution data for C-type crystals

[0184]

[0185] Example 5: Polymorphism Study of Compound I

[0186] Compound A of Formula I was suspended in the appropriate solvent by heating and stirring. The mixture was stirred at 40°C in the dark for 2 days. After centrifugation to remove the precipitate and drying, the solution was analyzed by XPRD. The results are as follows:

[0187] Serial Number solvent Crystal form 1 Ethyl acetate Crystal type A 2 ethanol Crystal type A 3 acetone Crystal type A 4 Methyl tert-butyl ether Crystal type A 5 n-Heptane Crystal type A 6 Toluene Crystal type A 7 methanol Crystal type A

[0188] The results in the table above show that crystal form A has good stability and can remain stable in different solvent systems.

[0189] Example 6. Study on the mechanical stability of crystal form A

[0190] After the crystal form A of compound I was subjected to appropriate mechanical treatment, a certain sample was taken and analyzed by XRPD. The results are as follows:

[0191] Serial Number Mechanical conditions Crystal form 1 Grind in an agate mortar for several minutes Crystal type A 2 Crushed in a mechanical pulverizer for several minutes Crystal type A 3 Tablets are compressed using a tablet press. Crystal type A

[0192] The analysis of the results in the table above shows that grinding, mechanical crushing, and pressure did not cause crystal transformation in crystal form A, meaning that grinding, mechanical crushing, and pressure had no effect on the stability of crystal form A.

[0193] Example 7. Accelerated experimental study on the stability of crystal form A

[0194] The crystal form A obtained in Example 1 was laid flat in the open and placed under high temperature and high humidity (40°C, RH75%) for 3 months. Samples were taken at 1 month, 2 months and 3 months to detect XRPD spectra to evaluate the stability of crystal form A.

[0195] Experiments and XRPD spectra (obtained using XRPD method 1) show that the XRPD spectra of crystal form A at 1 month (191222JS1M), 2 months (191222JS2M), and 3 months (191222JS3M) are consistent with the attached... Figure 1 The XRPD patterns of crystalline form A are basically the same, indicating good stability. After three months of accelerated stability testing, crystalline form A remained unchanged. See the attached image for the detailed patterns. Figure 8 .

[0196] Example 8. Study on the physical stability of the crystal form

[0197] Crystal forms A, B, and C obtained in Example 1 were laid out flat in the open to investigate their stability under high temperature (60°C), high humidity (RH 92.5%), and light irradiation (4500±500 Lux). Sampling times were 5, 10, and 30 days. The purity determined by HPLC is shown in Table 10.

[0198] Table 10 Stability Experiments of Crystal Forms

[0199]

[0200] Analysis of the results in the table above shows that crystal form A, crystal form B, and crystal form C exhibit good stability under high temperature, high humidity, and light conditions, and have promising prospects for drug development.

[0201] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. The A crystal form of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 12.66±0.2°, 13.53±0.2°, 16.75±0.2° and 25.39±0.2°; I。 2. The crystalline Form A of the compound of formula I according to claim 1, characterized in that, The X-ray powder diffraction pattern of the A-type crystal has characteristic diffraction peaks at the following 2θ angles: 11.96±0.2°, 12.66±0.2°, 13.53±0.2°, 14.51±0.2°, 16.75±0.2° and 25.39±0.2°.

3. The crystalline Form A of the compound of formula I according to claim 1, characterized in that, The X-ray powder diffraction pattern of the above-mentioned crystal type A has characteristic diffraction peaks at the following 2θ angles: 11.96±0.2°, 12.66±0.2°, 13.53±0.2°, 14.51±0.2°, 16.75±0.2°, 19.27±0.2°, 22.19±0.2° and 25.39±0.2°.

4. The crystalline Form A of the compound of Formula I according to claim 1, characterized in that, The X-ray powder diffraction pattern of the above-mentioned crystal type A has characteristic diffraction peaks at the following 2θ angles: 11.96±0.2°, 12.66±0.2°, 13.53±0.2°, 14.51±0.2°, 16.75±0.2°, 19.27±0.2°, 22.19±0.2°, 25.39±0.2°, 26.23±0.2°, 31.87±0.2°, and 35.34±0.2°.

5. The crystalline Form A of the compound of formula I according to claim 1, characterized in that, The X-ray powder diffraction pattern of the above-mentioned crystal type A has characteristic diffraction peaks at the following 2θ angles: 11.96±0.2°, 12.66±0.2°, 13.53±0.2°, 13.88±0.2°, 14.51±0.2°, 15.81±0.2°, 16.75±0.2°, 17.99±0.2°, 18.99±0.2°, 19.27±0.2°, 21.95±0.2°, 22.19±0.2°, 25.39±0.2°, 26.23±0.2°, 31.87±0.2°, and 35.34±0.2°.

6. The crystalline Form A of the compound of formula I according to claim 1, characterized in that, The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction pattern of crystal form A are shown below: 。 7. The A crystal form of the compound of formula I as described in claim 1, characterized in that, The XRPD pattern of the above-mentioned A crystal form is shown in Figure 1, which has the characteristics represented by the XRPD pattern shown in Figure 1.

8. The A crystal form of the compound of formula I as described in claim 1, characterized in that, The XRPD spectra analysis data of the above crystal form A are shown below: 。 9. The A crystal form of the compound of formula I as described in claim 1, characterized in that, The differential scanning calorimetry curve of the above-mentioned crystal form A has an endothermic peak at 216.85℃±3℃.

10. The A crystal form of the compound of formula I as described in claim 1, characterized in that, The DSC spectrum of the above-mentioned crystal form A is shown in Figure 2, which has the characteristics represented by the DSC spectrum shown in Figure 2.

11. The B crystal form of the compound of formula I has X-ray powder diffraction patterns with characteristic diffraction peaks at the following 2θ angles: 10.69±0.2°, 13.17±0.2°, 13.37±0.2° and 15.22±0.2°; I。 12. The B crystal form of the compound of formula I as described in claim 11, characterized in that, The X-ray powder diffraction pattern of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.26±0.2°, 4.50±0.2°, 10.69±0.2°, 13.17±0.2°, 13.37±0.2°, and 15.22±0.2°.

13. The B crystal form of the compound of formula I as described in claim 11, characterized in that, The X-ray powder diffraction pattern of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.26±0.2°, 4.50±0.2°, 10.69±0.2°, 12.88±0.2°, 13.17±0.2°, 13.37±0.2°, 15.22±0.2°, and 15.81±0.2°.

14. The B crystal form of the compound of formula I as described in claim 11, characterized in that, The X-ray powder diffraction pattern of the B crystal form exhibits characteristic diffraction peaks at the following 2θ angles: 4.26±0.2°, 4.50±0.2°, 8.77±0.2°, 10.69±0.2°, 12.14±0.2°, 12.88±0.2°, 13.17±0.2°, 13.37±0.2°, 15.22±0.2°, 15.81±0.2°, 25.35±0.2°, and 29.04±0.2°.

15. The B crystal form of the compound of formula I as described in claim 11, characterized in that, The X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.26±0.2°, 4.50±0.2°, 8.77±0.2°, 10.69±0.2°, 12.14±0.2°, 12.88±0.2°, 13.17±0.2°, 13.37±0.2°, 15.22±0.2°, 15.81±0.2°, 17.37±0.2°, 21.47±0.2°, 23.19±0.2°, 25.35±0.2°, 26.83±0.2°, 29.04±0.2°, 30.52±0.2°, and 30.79±0.2°.

16. The B crystal form of the compound of formula I as described in claim 11, characterized in that, The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction pattern of the B crystal form are shown below: 。 17. The B crystal form of the compound of formula I as described in claim 11, characterized in that, The XRPD pattern of the B crystal form is shown in Figure 3, which has the characteristics represented by the XRPD pattern shown in Figure 3.

18. The B crystal form of the compound of formula I as described in claim 11, characterized in that, The XRPD spectra analysis data of the B crystal form are shown below: 。 19. The B crystal form of the compound of formula I as described in claim 11, characterized in that, The differential scanning calorimetry curves of the B crystal form above show endothermic peaks at 120.67℃ and 226.10℃.

20. The B crystal form of the compound of formula I as described in claim 11, characterized in that, The differential scanning calorimetry curves of the B crystal form above show endothermic peaks at 120.67±3℃ and 226.10±3℃.

21. The B crystal form of the compound of formula I as described in claim 11, characterized in that, The DSC spectrum of the B crystal form mentioned above is shown in Figure 4, which has the characteristics represented by the DSC spectrum shown in Figure 4.

22. The B crystal form of the compound of formula I as described in claim 11, characterized in that, The TGA spectrum of the aforementioned B crystal form is shown in Figure 5, which exhibits the characteristics represented by the TGA spectrum shown in Figure 5.

23. The B crystal form of the compound of formula I as described in claim 11, characterized in that, The thermogravimetric analysis curve of the B crystal form shows a weight loss peak at 50℃-125℃, with a weight loss of 6.475 ± 0.5%.

24. The C crystal form of the compound of formula I has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 6.77±0.2°, 7.08±0.2°, 8.34±0.2° and 12.46±0.2°; I。 25. The C-crystal form of the compound of formula I as described in claim 24, characterized in that, The X-ray powder diffraction pattern of the C-type crystal has characteristic diffraction peaks at the following 2θ angles: 6.77±0.2°, 7.08±0.2°, 8.34±0.2°, 12.46±0.2°, 17.60±0.2° and 17.92±0.2°.

26. The C-crystal form of the compound of formula I as described in claim 24, characterized in that, The X-ray powder diffraction patterns of the C-type crystal above exhibit characteristic diffraction peaks at the following 2θ angles: 6.77±0.2°, 7.08±0.2°, 8.34±0.2°, 12.46±0.2°, 13.21±0.2°, 16.52±0.2°, 17.60±0.2°, and 17.92±0.2°.

27. The C-crystal form of the compound of formula I as described in claim 24, characterized in that, The X-ray powder diffraction pattern of the above-mentioned C-type crystal has characteristic diffraction peaks at the following 2θ angles: 6.77±0.2°, 7.08±0.2°, 8.34±0.2°, 11.02±0.2°, 12.46±0.2°, 13.21±0.2°, 14.20±0.2°, 15.06±0.2°, 16.52±0.2°, 17.60±0.2°, 17.92±0.2°, and 20.86±0.2°.

28. The C-crystal form of the compound of formula I as described in claim 24, characterized in that, The X-ray powder diffraction patterns of the C-type crystal above exhibit characteristic diffraction peaks at the following 2θ angles: 6.77±0.2°, 7.08±0.2°, 8.34±0.2°, 10.61±0.2°, 11.02±0.2°, 12.46±0.2°, 13.21±0.2°, 13.76±0.2°, 14.20±0.2°, 14.63±0.2°, 15.06±0.2°, 15.75±0.2°, 16.52±0.2°, 17.60±0.2°, 17.92±0.2°, 19.14±0.2°, 20.86±0.2°, 24.76±0.2°, and 26.46±0.2°.

29. The C-crystal form of the compound of formula I as described in claim 24, characterized in that, The peak positions and intensities of the characteristic peaks in the X-ray powder diffraction pattern of the C-type crystal are shown below: 。 30. The C-crystal form of the compound of formula I as described in claim 24, characterized in that, The XRPD pattern of the C crystal form is shown in Figure 6, which has the characteristics represented by the XRPD pattern shown in Figure 6.

31. The C-crystal form of the compound of formula I as described in claim 24, characterized in that, The XRPD spectra analysis data of the C-type crystal are shown below: 。 32. The C-crystal form of the compound of formula I as described in claim 24, characterized in that, The differential scanning calorimetry curve of the C crystal form above has an endothermic peak at 179.31℃±3℃.

33. The C-crystal form of the compound of formula I as described in claim 24, characterized in that, The DSC spectrum of the aforementioned C crystal form is shown in Figure 7, which exhibits the characteristics represented by the DSC spectrum shown in Figure 7.

34. A pharmaceutical composition comprising crystal form A according to any one of claims 1-10, crystal form B according to any one of claims 11-23 or crystal form C according to any one of claims 24-33 and optionally a pharmaceutically acceptable excipient.

35. The pharmaceutical composition according to claim 34, characterized in that, The pharmaceutical composition comprises crystal form A as described in any one of claims 1-10 and optionally a pharmaceutically acceptable excipient.

36. The pharmaceutical composition according to claim 34 or 35, characterized in that, The pharmaceutical composition is used to treat or prevent disorders of the central nervous system in mammals.

37. The pharmaceutical composition of claim 36, characterized in that, The mammal in question is a human.

38. Use of crystal form A according to any one of claims 1-10, crystal form B according to any one of claims 11-23, or crystal form C according to any one of claims 24-33 in the preparation of a medicament for the treatment or prevention of disorders of the central nervous system in mammals.

39. The use as described in claim 38, characterized in that, The mammal in question is a human.

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