Crystalline form of 3-hydroxy-5-pregnane-20-one derivatives, methods for producing the same, and uses

Abstract

The present invention provides crystals of the compound of formula I, which is a 3-hydroxy-5-pregnan-20-one derivative, and a method for producing the same. Specifically, the present invention provides new crystal forms A to C of the compound of formula I and a method for producing them. The new crystal forms of the compound of formula I of the present invention have excellent thermal stability and mechanical stability, and at the same time, the production process for these is simple, making them new crystal forms with excellent potential for industrialization. [Formula 1] JPEG2024505736000022.jpg2759

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry. Specifically, it relates to the crystal form of 3-hydroxy-5-pregnan-20-one derivatives, a method for producing the same, and use in the prevention or treatment of central nervous system disorders.

Background Art

[0002] Neuroactive steroids are steroids that have activity in nerve tissue. The neurosteroids that play important regulatory roles in the human body mainly include progesterone, pregnenolone, allopregnanolone, etc. Progesterone, pregnenolone, and allopregnanolone are all produced by the metabolism of cholesterol through different pathways. Cholesterol is transported from the outer membrane of mitochondria to the inner membrane via the 18 kDa translocator protein, and is metabolized by cytochrome P450 cholesterol side-chain cleavage enzyme to become pregnenolone, and then further metabolized by 3β-hydroxy cholesterol dehydrogenase to become progesterone, and subsequently metabolized by a series of enzyme-catalyzed reactions mediated by 5α-reductase and 3α-hydroxy cholesterol dehydrogenase to become allopregnanolone. Neuroactive steroids are useful as anesthetics, sedatives, sleep-inducing agents, anti-anxiety drugs, antidepressants, and anti-convulsants.

[0003] Allopregnanolone has been the focus of recent research, and it was already identified as a positive modulator of GABBA receptors in 1986. However, it was not until 2006 that it was discovered that allopregnanolone primarily binds to the α and β subunits of GABBA receptors, increasing the frequency of opening of chloride ion signaling channels in these receptors and reducing nerve excitability, thereby producing sedative and anxiolytic effects. One study reported that levels of progesterone and its metabolites in the body differ at different stages of the menstrual cycle. Before the onset of menstruation, levels of progesterone and its metabolites decrease, leading to premenstrual syndrome (PMS), that is, recurrent symptoms of stress, anxiety, and migraines may appear before the start of the menstrual cycle and disappear after menstruation. Postpartum depression is also associated with abnormal levels of progesterone and its metabolites, and the concentration of allopregnanolone in the plasma of healthy pregnant women increases as pregnancy progresses, and then drops sharply after delivery. Studies have shown that a decrease in allopregnanolone content is closely associated with the onset and development of many psychiatric disorders, including anxiety, depression, and tremor, and that external administration of allopregnanolone can significantly improve these psychiatric symptoms.

[0004] However, allopregnanolone has low water solubility, poor availability for oral administration, and is rapidly metabolized in human plasma with a half-life of approximately 45 minutes. Zulresso, already on the market, is a water-soluble allopregnanolone preparation based on sulfobutyl β-cyclodextrin, which generates stable physiological concentrations of allopregnanolone via intravenous injection. However, breakanolone requires long-term intravenous infusion of up to 60 hours, resulting in poor patient compliance.

[0005] Furthermore, as those skilled in the art will know, different crystalline forms of drugs can result in significant differences in bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, color, filterability, density, and fluidity. Research into drug crystalline polymorphism is beneficial in expanding the range of drug formulations, developing useful formulations, and making various groups more readily available by exploring drug forms with better physical and chemical properties or better processing modes.

[0006] Therefore, in this field, it is necessary to develop not only allopregnanolone derivatives that have improved solubility, shortened administration time, and maintain stable physiological concentrations in the body over a long period of time, but also different crystalline forms of such derivatives that possess superior properties. [Overview of the project] [Problems that the invention aims to solve]

[0007] The object of the present invention is to provide derivatives of 3-hydroxy-5-pregnan-20-one and their polymorphs that can be used in the manufacture of drugs for preventing or treating central nervous system failure disorders, and that have improved solubility, are stable in storage, are convenient to administer, and have high patient compliance during administration. Furthermore, an object of the present invention is to provide polymorphs of the 3-hydroxy-5-pregnane-20-one derivative that have excellent thermodynamic and mechanical stability. [Means for solving the problem]

[0008] In a first aspect, the present invention provides a crystalline form A of compound I, the powder X-ray diffraction spectrum of which has characteristic diffraction peaks at 2θ angles of 12.66±0.2°, 13.53±0.2°, 16.75±0.2°, and 25.39±0.2°. [ka]

[0009] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the above-mentioned A crystal form has characteristic diffraction peaks at 2θ angles of 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°.

[0010] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the above-mentioned A crystal form has characteristic diffraction peaks at 2θ angles of 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°.

[0011] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the above-mentioned A crystal form has characteristic diffraction peaks at 2θ angles of 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°.

[0012] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the above-mentioned A crystal form 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°.

[0013] In some embodiments of the present invention, the peak positions and intensities of the characteristic peaks in the powder X-ray diffraction spectrum of the above-mentioned crystal form A are as shown in Table 1. [Table 1]

[0014] In some embodiments of the present invention, the XRPD spectrum of the above crystal form A is as shown in Figure 1, that is, it has the characteristics represented by the XRPD spectrum shown in Figure 1. In some embodiments of the present invention, the analysis data of the XRPD spectrum of the above crystal form A are shown in Table 2. [Table 2]

[0015] In some embodiments of the present invention, the differential scanning calorimetry curve of the above crystal A has an endothermic peak at 216.85±3℃. In some embodiments of the present invention, the above-mentioned crystal form A has a DSC chart as shown in Figure 2, that is, it has the characteristics represented by the DSC chart shown in Figure 2.

[0016] In some embodiments of the present invention, the method for producing the A crystalline form of the above formula I compound is: (1) A step of mixing compound I with a solvent, (2) Including the steps of filtering and drying, Here, the solvent is one or more selected from methanol, ethanol, isopropanol, acetone, butanone, ethyl acetate, isopropyl acetate, methyl-t-butyl ether, n-heptane, and toluene, and is preferably ethanol, isopropanol, or ethyl acetate.

[0017] In some embodiments of the present invention, step (1) is carried out under heating conditions. In some embodiments of the present invention, the heating temperature in step (1) is about 60 to 70°C, preferably about 65°C. In some embodiments of the present invention, in step (1), after adding the compound of formula I, the mixture is stirred, and the stirring time may be 6 to 18 hours, preferably 12 hours.

[0018] In some embodiments of the present invention, step (2) may involve cooling before filtration, and the cooling may be to 0-30°C, preferably to 20°C. In some embodiments of the present invention, in step (2), if necessary, after cooling, stirring is carried out, and the stirring time may be 6 to 24 hours, preferably 18 hours. In some embodiments of the present invention, in step (2), before drying, it is optionally washed with a solvent, and the washing solvent is selected from methanol, ethanol, acetone, ethyl acetate, methyl ether, n-heptane, toluene, and preferably ethyl acetate.

[0019] On a second aspect, the present invention provides a B crystal form of the compound of formula I, and its powder X-ray diffraction spectrum has characteristic diffraction peaks at positions where the 2θ angle is 10.69 ± 0.2°, 13.17 ± 0.2°, 13.37 ± 0.2° and 15.22 ± 0.2°.

Chemical formula

[0020] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the above B crystal form has characteristic diffraction peaks at positions where the 2θ angle is 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°.

[0021] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the above B crystal form has characteristic diffraction peaks at positions where the 2θ angle is 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°.

[0022] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the above B crystal form has characteristic diffraction peaks at positions where the 2θ angle is 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°.

[0023] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the above-mentioned B crystal form has characteristic diffraction peaks at 2θ angles of 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°.

[0024] In some embodiments of the present invention, the peak positions and intensities of the characteristic peaks in the powder X-ray diffraction spectrum of the above-mentioned B crystal form are as shown in Table 3. [Table 3]

[0025] In some embodiments of the present invention, the XRPD spectrum of the above-mentioned B crystal form is as shown in Figure 3, that is, it has the characteristics represented by the XRPD spectrum shown in Figure 3. In some embodiments of the present invention, the analysis data of the XRPD spectrum of the above-mentioned B crystal form are shown in Table 4. [Table 4]

[0026] In some embodiments of the present invention, the differential scanning calorimetry curve of the above B crystal form has endothermic peaks near 120.67°C and 226.10°C. 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°C and 226.10±3°C.

[0027] In some embodiments of the present invention, the above-mentioned B crystal form has a DSC chart as shown in Figure 4, that is, it is characterized by being represented by the DSC chart shown in Figure 4. In some embodiments of the present invention, the above-mentioned B crystal form has a TGA chart as shown in Figure 5, that is, it is characterized by being represented by the TGA chart shown in Figure 5.

[0028] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned B crystal form has a single weight loss peak, with a weight loss of 6.475 ± 0.5%. Specifically, the thermogravimetric analysis curve of the B crystal form has a single weight loss peak in the range of 50°C to 125°C.

[0029] In some embodiments of the present invention, the method for producing the B crystalline form of the above compound I is: (1) A step of mixing compound I with a solvent, (2) Including the steps of filtering and drying, Here, the solvent is selected from water, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, a mixed solvent of acetone and water, or a mixed solvent of acetonitrile and water, and is preferably water or a mixed solvent of ethanol and water.

[0030] In some embodiments of the present invention, step (1) is carried out under heating conditions. In some embodiments of the present invention, the heating temperature in step (1) is about 65 to 75°C, preferably about 70°C. In some embodiments of the present invention, step (1) involves adding the compound of formula I and then stirring.

[0031] In some embodiments of the present invention, step (2) may involve cooling before filtration, and the cooling may be to 0-30°C, preferably 2-8°C. In some embodiments of the present invention, step (2) may, if necessary, be stirred after cooling, and the stirring time may be 15 to 22 hours, preferably 18 hours.

[0032] In some embodiments of the present invention, step (2) optionally involves washing with a solvent before drying, the solvent for washing being selected from water, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, a mixed solvent of acetone and water, or a mixed solvent of acetonitrile and water, preferably water or a mixed solvent of ethanol and water.

[0033] In a third aspect, the present invention provides a C crystalline form of compound I of formula, the powder X-ray diffraction spectrum of which has characteristic diffraction peaks at 2θ angles of 6.77±0.2°, 7.08±0.2°, 8.34±0.2°, and 12.46±0.2°. [ka]

[0034] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the above C crystal form has characteristic diffraction peaks at 2θ angles of 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°.

[0035] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the above C crystal form has characteristic diffraction peaks at 2θ angles of 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°.

[0036] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the above C crystal form has characteristic diffraction peaks at 2θ angles of 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°.

[0037] In some embodiments of the present invention, the powder X-ray diffraction spectrum of the above C crystal form has characteristic diffraction peaks at 2θ angles of 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°.

[0038] In some embodiments of the present invention, the peak positions and intensities of the characteristic peaks in the powder X-ray diffraction spectrum of the above C crystal form are as shown in Table 5. [Table 5]

[0039] In some embodiments of the present invention, the XRPD spectrum of the above C crystal form is as shown in Figure 6, that is, it has the characteristics represented by the XRPD spectrum shown in Figure 6. In some embodiments of the present invention, the analysis data of the XRPD spectrum of the above C crystal form are shown in Table 6. [Table 6]

[0040] In some embodiments of the present invention, the differential scanning calorimetry curve of the above C crystal form has an endothermic peak at 179.31±3°C. In some embodiments of the present invention, the above-mentioned C crystal form has a DSC chart as shown in Figure 7, that is, it has the characteristics represented by the DSC chart shown in Figure 7.

[0041] In some embodiments of the present invention, the method for producing the C crystalline form of the above formula I compound is: (1) A step of mixing compound I with solvent 1, (2) Step of adding solvent 2, (3) including the steps of filtering and drying, Here, solvent 1 is one or more selected from methanol, ethanol, isopropanol, n-propanol, and tetrahydrofuran, and solvent 2 is selected from acetone, ethyl acetate, methyl-t-butyl ether, n-heptane, and toluene.

[0042] In some embodiments of the present invention, step (1) is carried out under heating conditions. In some embodiments of the present invention, the heating temperature in step (1) is about 60 to 70°C, preferably about 65°C. In some embodiments of the present invention, in step (1), after adding the compound of formula I, the mixture is stirred, and the stirring time may be 6 to 18 hours, preferably 12 hours.

[0043] 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. In some embodiments of the present invention, step (3) may involve cooling before filtration, and the cooling may be to 0-30°C, preferably to 20°C. In some embodiments of the present invention, step (3) may, if necessary, be stirred after cooling, and the stirring time may be 15 to 22 hours, preferably 18 hours.

[0044] In some embodiments of the present invention, step (3) optionally involves washing with a solvent before drying, the solvent for washing being selected from methanol, ethanol, acetone, ethyl acetate, methyl-t-butyl ether, n-heptane, and toluene, preferably ethanol and methyl-t-butyl ether.

[0045] In a fourth aspect, the present invention provides a drug composition comprising the above-mentioned crystalline form A, the above-mentioned crystalline form B, or the above-mentioned crystalline form C, and optionally a pharmaceutically acceptable excipient. In some embodiments of the present invention, the drug composition comprises the above-mentioned crystalline form A and optionally a pharmaceutically acceptable excipient. In some embodiments of the present invention, the drug composition is for treating or preventing central nervous system dysfunction in mammals (for example, humans).

[0046] In a fifth aspect, the present invention provides the use of the above-mentioned crystalline form A, crystalline form B, or crystalline form C in the manufacture of a drug for treating or preventing central nervous system dysfunction in mammals (for example, humans). In some embodiments of the present invention, the present invention provides the use of the above-mentioned A crystalline form in the manufacture of a drug for treating or preventing central nervous system dysfunction in mammals (e.g., humans).

[0047] In a sixth aspect, the present invention provides a method for treating or preventing central nervous system dysfunction in a mammal (for example, a human), comprising the step of administering to a mammal (for example, a human) a therapeutically effective amount of a compound of formula (I), a crystalline form A of the compound of formula I, a drug composition comprising a crystalline form A of the compound of formula I, a crystalline form B of the compound of formula I, a drug composition comprising a crystalline form B of the compound of formula I, a crystalline form C of the compound of formula I, and a drug composition comprising a crystalline form C of the compound of formula I.

[0048] In some embodiments of the present invention, the method comprises administering to a mammal (for example, a human) a therapeutically effective amount of a drug composition comprising a compound of formula (I), a crystalline form A of the compound of formula I, and a crystalline form A of the compound of formula I.

[0049] In some embodiments of the present invention, the central nervous system dysfunction disorder includes, but is not limited to, tremor, sleep disorders, depression, psychotic depression, bipolar disorder, anxiety disorders, stress reactions, post-traumatic stress disorder, obsessive-compulsive disorder, schizophrenia, schizoaffective disorder, epilepsy, epileptic seizures, memory impairment and / or cognitive impairment, dementia, motor disorders, personality disorders, autism, monogenic autism, pain, traumatic brain injury, vascular disease, substance abuse disorder and / or withdrawal syndrome, or tinnitus.

[0050] The aforementioned central nervous system dysfunctions include, but are not limited to, tremors, epilepsy, clinical depression, postpartum or postnatal depression, atypical depression, severe psychotic depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent short-term depressive disorder, bipolar disorder or manic-depressive disorder, post-traumatic stress disorder, chronic medically induced depression, treatment-tolerant depression, refractory depression, suicidal tendencies, 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 syndromes, acute pain, chronic pain, stroke, ischemia, vascular malformations, opioid preparations, cocaine and / or alcoholism, or insomnia.

[0051] Of course, within the scope of the present invention, it is understood that the above-mentioned technical features of the present invention and the technical features specifically described below (for example, in the examples) can be combined to form new or preferred technical solutions. Due to space limitations, each will not be explained in detail here. [Brief explanation of the drawing]

[0052] [Figure 1] Figure 1 shows the XRPD spectrum of the A crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention. [Figure 2] Figure 2 shows the DSC chart of the A crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention. [Figure 3] Figure 3 shows the XRPD spectrum of the B crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention. [Figure 4] Figure 4 shows the DSC chart of the B crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention. [Figure 5] Figure 5 shows the TGA graph of the B crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention. [Figure 6] Figure 6 shows the XRPD chart of the 3-hydroxy-5-pregnane-20-one derivative of the present invention. [Figure 7] Figure 7 shows the DSC chart of the 3-hydroxy-5-pregnane-20-one derivative of the present invention. [Figure 8] Figure 8 shows the XRPD overlap spectra of the 3-hydroxy-5-pregnane-20-one derivative A of the present invention at room temperature for 1 month (191222 JS1M), 2 months (191222 JS2M), and 3 months (191222 JS3M). [Modes for carrying out the invention]

[0053] Through extensive and in-depth research, the inventor unexpectedly discovered a derivative of an allopregnanolone compound. This derivative significantly improves the water solubility of the allopregnanolone compound, exhibits a certain degree of storage stability in aqueous solutions, and allows for the creation of a sustained-release formulation with minimal individual variability after administration. The formulation made from this derivative maintains an effective physiological concentration of allopregnanolone in the body for an extended period and offers advantages such as improved patient compliance due to its convenient administration.

[0054] Based on this, the inventors discovered crystalline forms A, B, and C of the derivative, and each of these crystalline forms is superior in at least one aspect, such as physical stability, thermodynamic stability, and mechanical stability, thus completing the present invention.

[0055] term In this specification, "derivative of the present invention," "derivative of 3-hydroxy-5-pregnane-20-one," and "derivative of allopregnanolone compounds" have the same meaning and can be used interchangeably. All of these terms refer to the compound represented by the following formula I. [ka] In this specification, the chemical name of compound I is glycyl-L-valyl-3α-hydroxy-5α-pregnane-20-one hydrochloride.

[0056] polymorphism As is known to those skilled in the art, solids exist in amorphous or crystalline forms. In crystalline form, molecules are located at sites in a three-dimensional crystal lattice. When a compound crystallizes from a solution or thrilla, it can crystallize in different spatial lattices (this property is called "polymorphism"), forming crystals with different crystalline forms, each such crystalline form is called a "polymorph." Different polymorphs of a substance may differ from one another in one or more properties (e.g., solubility and dissolution rate, true specific gravity, crystalline form, deposition form, fluidity and / or solid stability).

[0057] The polymorphic forms of a compound exhibit different melting points, hygroscopicity, stability, solubility, bioavailability, bioactivity, and fluidity, all of which are factors that influence its medicinal properties. 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 is a crystal whose crystal form is crystal form A, or referred to as crystal A.

[0058] Furthermore, in this specification, "polymorph of the derivative of the present invention," "polymorph of the derivative of 3-hydroxy-5-pregnane-20-one," and "polymorph of the derivative of allopregnanolone compound" all refer to the crystalline form of the compound represented by formula I.

[0059] crystal Crystals of a compound of interest can be produced on a production scale by manipulating the solution and pushing its solubility beyond its limit. Many methods exist for this; for example, one method involves dissolving the compound at a relatively high temperature and then cooling the solution below its saturation limit. Alternatively, the volume of the liquid can be reduced by boiling, atmospheric evaporation, vacuum drying, or other methods. Another method involves lowering the solubility of the compound of interest by adding an antisolvent, a solvent with low solubility, or a mixture of such solvents. A third option is to lower solubility by adjusting the pH value. For further details on crystallization, see Crystallization, Third Edition, JW Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.

[0060] Crystal optimization involves introducing a crystal of the desired form as a seed crystal into the crystal medium. Many crystallization methods utilize a combination of these strategies. For example, after dissolving a compound of interest in a solvent at high temperature, an appropriate volume of antisolvent is added under controlled conditions to bring the system to a saturation level. At this point, a seed crystal of the desired form (while maintaining the seed crystal's integrity) is added, and the system is cooled to complete the crystal formation.

[0061] In this invention, after dissolving compound I in a solvent, crystals of compound I can be obtained by lowering the temperature of the resulting solution, slowly volatilizing the solution, or adding an antisolvent to the solution to precipitate the compound I. After obtaining the crystals of compound I, they can optionally be dried to obtain more crystals of compound I.

[0062] In specific embodiments, the solvent is one or more selected from water, methanol, ethanol, acetone, ethyl acetate, methyl ether, n-heptane, and toluene. In a preferred embodiment, step (1) may involve appropriately raising the temperature to promote the dissolution of the compound of formula I. In a preferred embodiment, the cooling involves cooling the solution of compound I to 20-30°C.

[0063] solvate During the process of a compound or drug molecule coming into contact with a solvent molecule, it is inevitable that the solvent and compound molecules will form cocrystals and remain in a solid substance due to a combination of external and internal conditions. The substance formed when a compound and solvent crystallize is called a solvate. Solvents that readily form solvates with active compounds include water, methanol, toluene, ethanol, ether, aromatic hydrocarbons, and heterocyclic aromatic hydrocarbons.

[0064] Hydrates are special solvates. In the pharmaceutical industry, hydrates are worth considering on their own due to their unique properties in all aspects of drug synthesis, drug formulation, drug storage, and drug activity evaluation. In the present invention, the crystals of the compound represented by formula I may be either a non-solvate or a solvate. For example, crystalline form B of the present invention is a hydrate.

[0065] Drug composition and administration form of the present invention Based on the polymorphs of the 3-hydroxy-5-pregnane-20-one derivative of the present invention, the present invention further provides a drug composition comprising the said polymorph. The drug composition has the effect of treating diseases caused by central nervous system abnormalities due to the 3-hydroxy-5-pregnane-20-one derivative contained therein, and also has excellent stability due to the 3-hydroxy-5-pregnane-20-one derivative contained therein, allowing for long-term storage, and in particular has further thermal and mechanical stability, and is easily formed into drug formulations.

[0066] In specific embodiments, the disorders due to central nervous system abnormalities include, but are not limited to, tremors, epilepsy, depression, or anxiety disorders. More specifically, the central nervous system dysfunction disorders include, but are not limited to, tremors, epilepsy, clinical depression, postpartum depression, atypical depression, severe psychotic depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent short-term depressive disorder, bipolar disorder or manic-depressive disorder, post-traumatic stress disorder, chronic medically induced depression, treatment-tolerant depression, refractory depression, suicidal tendencies, suicidal ideation, and suicidal behavior.

[0067] The drug compositions of the present invention may further include a pharmaceutically acceptable carrier. In this specification, the term “composition” encompasses products containing characteristic amounts of specific components, as well as any combination of specific components, directly or indirectly, in specific amounts. A pharmaceutically acceptable carrier is a carrier, diluent, or excipient that does not exhibit obvious irritation to the body 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 the recipient.

[0068] The drug compositions of the present invention can be prepared by 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 drug compositions. Furthermore, those skilled in the art can prepare the compounds or drug compositions of the present invention in a variety of suitable dosage forms, including, but not limited to, rectal, transdermal, intradermal, intrathin, subcutaneous, intravenous, intramuscular, intraarticular, oral mucosal, vaginal, and intranasal administration. Depending on the required dosage form, those skilled in the art can also select the appropriate pharmaceutically acceptable carriers, diluents, or excipients.

[0069] The drug composition of the present invention may contain a safe effective amount of a polymorph of a 3-hydroxy-5-pregnane-20-one derivative. The "safe effective amount" refers to an amount of the compound (crystalline form) that is sufficient for a significant improvement in the disease symptoms without causing severe side effects. Typically, the drug composition contains 30 to 800 mg / formulation of the crystalline form of the present invention, preferably 50 to 600 mg / formulation. Preferably, the "formulation" is a capsule or a tablet.

[0070] A "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gels that are applicable to humans and must be of sufficient purity and sufficiently low toxicity. "Compatible" means that each component in the composition can be mixed with the active ingredient of the present invention and with each other without significantly reducing the effect of the active ingredient. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Twin®), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogenic substance-removed distilled water, etc.

[0071] The mode of administration of the polymorph or drug composition of the present invention is not particularly limited, but typical modes of administration include, but are not limited to, oral administration, rectal administration, extra-gastrointestinal (intravenous, intramuscular, or subcutaneous) administration, and local administration.

[0072] Solid dosage forms used for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active ingredient is usually mixed with at least one inactive excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) a filler or phase solvent, such as starch, lactose, sucrose, glucose, mannitol, or silicic acid; (b) a binder, such as hydromethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, or gum arabic; (c) a humectant, such as glycerin; or (d) a disintegrant, such as agar or calcium carbonate. It is mixed with ingredients such as (e) a solution retarder, e.g., paraffin, (f) an absorption enhancer, e.g., an ammonium compound, (g) a wetting agent, e.g., cetanol, glycerin monostearate, (h) an adsorbent, e.g., kaolin, and (i) a lubricant, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or a mixture thereof. In capsules, tablets, and pills, the dosage form may include a buffer.

[0073] Solid dosage forms, such as tablets, pills, capsules, rounds, and granules, can be manufactured with coatings and shells, such as venous coatings and other materials known in the art. Opaque agents may be included, and in such compositions, the release of the active ingredient may be delayed and released in a portion of the gastrointestinal tract. Examples of usable embedding components include polymers and waxy substances. If necessary, the active ingredient may also be formed in the form of microcapsules with one or more of the above excipients.

[0074] Liquid dosage forms used for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, the liquid dosage forms may also contain inert diluents commonly used in this art, such as water or other solvents, phase solvents, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil, or mixtures thereof.

[0075] In addition to these inert diluents, the composition may also contain auxiliary agents, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and fragrances. In addition to the active ingredient, the suspension may also contain suspending agents, such as ethoxylated isooctadecanol, polyoxyethylene sorbitol or sorbitan ester, microcrystalline cellulose, methoxyaluminum or agar, or mixtures thereof.

[0076] Compositions for extra-gastrointestinal injection include physiologically acceptable sterile water-containing or water-free solutions, dispersions, suspensions, and emulsions, as well as sterile powders for redissolving into sterile, injectable solutions or dispersions. Suitable water-containing or water-non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyhydric alcohols, and suitable mixtures thereof. The polymorphic dosage forms of the present invention for topical administration include ointments, powders, poultices, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, an excipient.

[0077] Methods for preventing and treating diseases As described above, when the 3-hydroxy-5-pregnane-20-one derivative according to the present invention is administered to a subject, an active allopregnanolone is released under appropriate conditions. Those skilled in the art will know that polymorphs or drug compositions of the 3-hydroxy-5-pregnane-20-one derivative according to the present invention are useful for the prevention or treatment of central nervous system dysfunction disorders, including but not limited to the above-mentioned central nervous system dysfunction disorders. The present invention provides a method for preventing or treating central nervous system dysfunction, comprising administering a therapeutically effective amount of the above compound or drug composition to a target subject. The target subject includes, but is not limited to, humans.

[0078] Advantages of the present invention: 1. The present invention provides, for the first time, polymorphs of compounds of formula I. 2. Crystal forms A, B, and C of compound I exhibit good stability, low hygroscopicity, and good water solubility, making them promising candidates for drug development. 3. The crystalline form of the present invention has excellent industrialization potential because its manufacturing process is simple.

[0079] The present invention will be further described below with reference to specific examples. These examples are used solely to illustrate the present invention and are not intended to limit the scope of the invention. In the following examples, experimental methods where specific conditions are not described were typically carried out under normal conditions or conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts were calculated by weight.

[0080] Test method: XRPD (Powder X-ray Diffraction) Method 1: Approximately 10 mg of the sample is uniformly spread on a single-crystal silicon sample dish, and XRPD measurements are performed using the following parameters. Instrument model: X'Pert 3 Type X-ray diffractometer, target: Cu-Kα (40mA, 45kV), scanning range: 3° to 40° in a 2θ interval. XRPD (Powder X-ray Diffraction) Method 2: Approximately 10 mg of the sample is uniformly spread on a single-crystal silicon sample dish, and XRPD measurements are performed with the following parameters: Instrument model: BRUKER D8 X-ray diffractometer, Target: Cu-Kα (40 kV, 40 mA). Scanning range: 3° to 40° in a 2θ interval, Scanning speed: 8° / min.

[0081] Many factors contribute to the differences in measurements associated with such powder X-ray diffraction analysis results, including (a) errors in the sample's manufacture (e.g., sample height), (b) instrument errors, (c) calibration errors, (d) operator errors (including errors that occur when measuring peak positions), and (e) the properties of the material (e.g., preferred directional errors). Calibration errors and sample height errors often lead to a shift in all peaks toward the same method. When using a horizontal holder, small differences in sample height result in large shifts in XRPD peak positions. In system studies, a 1 mm difference in sample height can result in a 1° and high 2θ peak shift. These shifts can be identified from the X-ray diffraction spectrum and corrected for (by applying a system calibration factor to all peach position values), or the instrument can be recalibrated to eliminate the shifts. As described above, applying a system calibration factor can unify peak positions and calibrate measurement errors from different instruments.

[0082] TGA (Thermogravimetric Analysis) Method: Instrument Model: TA Q500 Thermogravimetric analyzer, N2 atmosphere, heating rate: 10°C / min. DSC (Differential Scanning Calorimetry) method: Instrument model: METTLER TOLEDO DSC3+, N2 atmosphere, heating rate: 10°C / min.

[0083] Example 1. Synthesis of the compound represented by formula I [ka]

[0084] Preparation of intermediate 2.1: Compound 1.3 (5.0 g, 12.0 mmol), Boc-Gly-OH (2.5 g, 14.3 mmol), and dichloromethane (50 mL) were placed in a 250 mL single-neck reaction bottle and magnetically stirred. 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 was allowed to proceed at room temperature for 4 hours, and the reaction mixture was washed with H2O (50 mL), 1N HCl (50 mL), saturated NaHCO3 aqueous solution, and pure water. The mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether (60-90):ethyl acetate = 10:1~3:1) to obtain an off-white solid (5.7 g, yield: 82.8%).

[0085] Preparation of intermediate 2.2: Compound 2.1 (5.5 g, 9.63 mmol, 1.0 eq) and dichloromethane (22 mL) were placed in a 250 mL three-necked reaction bottle. Under the protection of nitrogen gas, the mixture was magnetically stirred, and trifluoroacetic acid (10.9 g, 95.7 mmol) was added at 0°C. The reaction was then allowed to proceed at room temperature for 3 hours. The mixture was concentrated under reduced pressure, the solvent was evaporated and the mixture dried. Dichloromethane (50 mL) was added, and the mixture was washed with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with dichloromethane (30 mL). The organic phase was combined and further washed with 50 mL of pure water. The mixture was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and vacuum-dried using an oil pump to obtain an off-white solid (4.5 g, 99.0% yield).

[0086] Preparation of the compound represented by formula I: Compound 2.2 (4.5 g, 9.5 mmol, 1.0 eq) and ethyl acetate (27 mL) were placed in a 250 mL single-neck reaction bottle. Under the protection of nitrogen gas, the mixture was magnetically stirred, and ethyl acetate hydrogen chloride solution (3 M, 3.8 mL, 11.4 mmol) was added at room temperature, followed by stirring for 1 hour. The mixture was concentrated under reduced pressure, the solvent was evaporated and the mixture was dried, acetonitrile (70 mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the solid was washed with acetonitrile (15 mL). The mixture was vacuum-dried at 40°C for 2 hours using an oil pump to obtain a white solid (3.5 g, yield 72.2%).

[0087] 1 H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.5 Hz, 1H), 8.16 (bs, 3H), 5.14 - 5.03 (m, 1H), 4.55 (d, J = 4.1 Hz, 1H), 4.27 (d, J = 16.1 Hz, 1H), 4.09 (d, J = 16.0 Hz, 1H), 2.52 (t, J = 8.7 Hz, 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). MS: m / z [M+H]+ 475.3.

[0088] Example 2. Preparation of crystalline form A of compound I 60 ml of ethyl acetate and 10.0 g of compound I were placed in a 100 ml flask. The mixture was heated to 60-65°C, suspended, and stirred for 6-24 hours. After cooling to 20-30°C, the mixture was filtered and dried to obtain a white solid. The XRPD spectra (measured by XRPD Method 1) and DSC charts of the obtained crystal forms are basically as shown in Figures 1 and 2, respectively. The diffraction angle data for the XRPD spectra of all crystal forms are basically as shown in Table 7, where the error range of the 2θ value is ±0.2°. [Table 7]

[0089] Example 3. Preparation of crystalline form B of compound I 60 ml of purified water and 10.0 g of compound I were placed in a 100 ml flask, the temperature was raised to 65-75°C, and the mixture was stirred until the solid dissolved. Then, the temperature was lowered to 2-8°C to allow the crystals to precipitate completely, and the mixture was filtered and dried to obtain a white solid. The XRPD spectrum of crystal form B obtained by measurement is basically as shown in Figure 3 (measured by XRPD method 2). The diffraction angle data for the XRPD spectra of all crystal forms are basically as shown in Table 8, where the error range of the 2θ value is ±0.2°. [Table 8]

[0090] Measurements revealed that the DSC chart of the B crystal form was basically as shown in Figure 4, and the differential scanning calorimetry curve of the B crystal form showed endothermic peaks near 120.67°C and 226.10°C, suggesting that the B crystal form is likely a hydrate. Further measurements revealed that the TGA graph for the obtained crystal form B is essentially as shown in Figure 5. As can be seen from this figure, there was a weight loss of 6.475 ± 0.5%. Therefore, crystal form B is a dihydrate.

[0091] Example 4. Preparation of crystalline form C of compound I In a 250 ml flask, 40 ml of ethanol and 10.0 g of compound I were added, and the temperature was raised to 65-75°C. The mixture was stirred until the solid dissolved. Once completely dissolved, 80 ml of methyl-t-butyl ether was added, and the temperature was further reduced to 2-8°C to allow the crystals to precipitate completely. The mixture was then filtered and dried to obtain a white solid. The XRPD spectra (measured by XRPD method 2) and DSC charts of the obtained crystal forms are basically as shown in Figures 6 and 7, respectively. The diffraction angle data for the XRPD spectra of all crystal forms are basically as shown in Table 9, where the error range of the 2θ value is ±0.2°. [Table 9]

[0092] Example 5: Study of polymorphs of compound I The following are the results of detecting the A crystalline form of compound I by heating and suspending it in the appropriate solvent, stirring at 40°C away from light for 2 days, centrifuging the solution, discarding the precipitate, drying it, and then detecting it by XPRD. [Table 10] Analysis of the results in the table above indicates that crystal form A has good stability and maintains stability even in different solvent systems.

[0093] Example 6. Study of the mechanical stability of crystal form A. After treating crystalline form A of compound I under appropriate mechanical conditions, a portion of the sample was taken and detected by XRPD, with the following results. [Table 11] Analysis of the results in the table above indicates that polishing, mechanical grinding, and pressure do not cause a phase transition in crystal form A; in other words, polishing, mechanical grinding, and pressure do not affect the stability of crystal form A.

[0094] Example 7. Study of accelerated stability of crystal form A The crystal form A obtained in Example 1 was opened and laid flat, and left for 3 months under high temperature and high humidity conditions (40°C, RH 75%). Samples were taken at 1 month, 2 months, and 3 months, respectively, and the stability of crystal form A was evaluated by detecting the XRPD spectrum. From the experiments and XRPD spectra (measured by XRPD method 1), it can be seen that the XRPD spectra of crystal form A at 1 month (191222 JS1M), 2 months (191222 JS2M), and 3 months (191222 JS3M) are basically the same as the XRPD spectrum of crystal form A in Figure 1. This indicates that crystal form A is very stable and did not change even after a 3-month stability acceleration experiment. For specific spectra, please refer to Figure 8.

[0095] Example 8. Study of the physical stability of the crystal form. Crystal forms A, B, and C obtained in Example 1 were laid flat and open, and the stability of the samples under high temperature (60°C), high humidity (RH 92.5%), and light irradiation (4500 ± 500 Lux) conditions was investigated. The sampling times for the investigation were 5, 10, and 30 days, and the HPLC detection purity is shown in Table 10. [Table 12]

[0096] Analysis of the results in the table above indicates that crystal forms A, B, and C exhibit good stability under high temperature, high humidity, and light irradiation conditions, suggesting potential for future drug development. All documents relating to the present invention are cited herein by reference, so that each document may be cited independently. Furthermore, after reading the above, those skilled in the art will understand that various variations and modifications of the present invention may be made, and that equivalent forms thereof are included within the scope of the claims of the present invention.

Claims

1. A crystal of compound I, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 12.66±0.2°, 13.53±0.2°, 16.75±0.2°, and 25.39±0.2°. 【Chemistry 1】

2. The A crystal of compound I according to claim 1, characterized in that the powder X-ray diffraction spectrum of the A crystal has characteristic diffraction peaks at 2θ angles of 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. A B crystal of compound I, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 10.69±0.2°, 13.17±0.2°, 13.37±0.2°, and 15.22±0.2°. 【Chemistry 2】

4. The B crystal of the compound I of claim 3, characterized in that the powder X-ray diffraction spectrum of the B crystal has characteristic diffraction peaks at 2θ angles of 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°.

5. A C crystal of compound I of formula I, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 6.77±0.2°, 7.08±0.2°, 8.34±0.2°, and 12.46±0.2°. 【Transformation 3】

6. The C crystal of the compound of formula I according to claim 5, characterized in that the powder X-ray diffraction spectrum of the C crystal has characteristic diffraction peaks at 2θ angles of 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°.

7. A drug composition comprising the A crystal described in claim 1 or 2, the B crystal described in claim 3 or 4, or the C crystal described in claim 5 or 6, and optionally a pharmaceutically acceptable excipient.

8. The drug composition according to claim 7, characterized in that the drug composition comprises the A crystal described in claim 1 or 2, and optionally a pharmaceutically acceptable excipient.

9. Use of crystal A according to claim 1 or 2, crystal B according to claim 3 or 4, or crystal C according to claim 5 or 6 in the manufacture of a drug for treating or preventing a mammalian central nervous system disorder.

10. The use according to claim 9, wherein the mammal is a human.

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