New crystal form of 3-hydroxy-5-pregnane-20-ketone derivative as well as preparation method and application thereof

Abstract

The present invention provides a crystal of a compound of formula I as a 3-hydroxy-5-pregnane-20-one derivative and a preparation method thereof. Specifically, the invention provides a crystal form G of a compound shown as a formula I and a preparation method thereof. The crystal form G of the present invention has significantly improved solubility, excellent storage stability at various temperatures, and low hygroscopicity, thereby improving druggability, and bringing very excellent effects for production, sales and transportation of drugs.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry. Specifically, this invention relates to a novel crystalline 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 and play important regulatory roles in the human body. Therefore, neuroactive steroids can be used as anesthetics, sedatives, hypnotics, anxiolytics, antidepressants, and anticonvulsants.

[0003] Allogenein alcoholones have become a hot research topic in recent years. However, allogenein alcoholones have low water solubility and poor oral bioavailability. Currently marketed allogenein alcoholone formulations require intravenous injection to achieve stable physiological concentrations of allogenein alcoholone. Furthermore, this intravenous injection process can take up to 60 hours, resulting in poor patient compliance.

[0004] Furthermore, it is well known in the art that drugs may exhibit polymorphism. Different polymorphs can show significant differences in bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, color, filterability, density, and flowability. Therefore, 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.

[0005] 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 various excellent properties. Summary of the Invention

[0006] The purpose of this invention is to provide a new crystal form of a 3-hydroxy-5-pregnane-20-one derivative.

[0007] The present invention also aims to provide a method for preparing the new crystal form.

[0008] Another object of the present invention is to provide the use of the novel crystal form in the prevention or treatment of central nervous system disorders.

[0009] In a first aspect, the present invention provides a crystal form G of a compound of formula I, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 13.4±0.2°, 16.9±0.2°, and 17.8±0.2°.

[0010]

[0011] In a specific embodiment, its X-ray powder diffraction pattern also has some characteristic diffraction peaks at the following 2θ angles: 11.8±0.2°, 14.1±0.2°, and 16.1±0.2°.

[0012] In a specific embodiment, its X-ray powder diffraction pattern also has some characteristic diffraction peaks at the following 2θ angles: 14.4±0.2°, 16.6±0.2°, and 18.9±0.2°.

[0013] In a specific implementation, its X-ray powder diffraction pattern is as follows: Figure 1 As shown, it has the following characteristics: Figure 1 The features represented by the XRPD map shown.

[0014] In a preferred embodiment, the crystal structure of the crystal form G is as follows: Figure 2 As shown.

[0015] In a preferred embodiment, the differential scanning calorimetry curve of the crystal form G has an endothermic peak at 214.9℃±2℃.

[0016] In a preferred embodiment, the DSC spectrum of crystal form G is as follows: Figure 3 As shown, it has the following characteristics: Figure 3 The features represented by the DSC spectrum shown.

[0017] In a preferred embodiment, the TGA pattern of crystal form G is as follows: Figure 4 As shown, it has the following characteristics: Figure 4 The TGA diagram shown represents the characteristics.

[0018] In a preferred embodiment, the crystal form G does not exhibit significant weight loss before 200°C.

[0019] In a specific embodiment, the crystal form G is prepared by the following preparation method, which includes the following steps:

[0020] (1) Grind the compound shown in Formula I in an organic solvent;

[0021] (2) Keep the system obtained in step (1) at a constant temperature;

[0022] (3) Cool the system obtained in step (2) to obtain crystal form G.

[0023] In a preferred embodiment, in step (1), the organic solvent is an organic solvent selected from the group consisting of ethyl acetate, methyl acetate, propyl acetate, methanol, ethanol, propanol, isopropanol, butanol, and isobutanol; preferably, the composition is a mixture of ethyl acetate and ethanol.

[0024] In a preferred embodiment, the volume ratio of ethyl acetate to ethanol is 2-10:1, preferably 5-7:1.

[0025] In a preferred embodiment, in step (1), the organic solvent is first kept at 35-45°C, preferably 40°C; or, if the organic solvent is a mixture, it is stirred, for example at 300 rpm for 15-25 min, preferably 20 min, so that the mixture of organic solvents is fully mixed, and then the compound shown in Formula I is ground in the organic solvent.

[0026] In a preferred embodiment, the mass (g) ratio of the compound shown in Formula I to the volume (ml) of the organic solvent is 1:0.1-3; preferably 1:0.5-2.5; more preferably 1:1-1.5.

[0027] In a preferred embodiment, in step (2), the system obtained in step (1) is kept at 35-45°C, preferably 40°C; the heat preservation can be carried out for 4-6 hours, preferably 4.5-5.5 hours, and most preferably 5 hours.

[0028] In a preferred embodiment, in step (3), the system obtained in step (2) is cooled to 20-30°C at a rate of 10-15°C / h; preferably 25°C.

[0029] In a preferred embodiment, the preparation method further includes a step of drying the obtained crystal form G.

[0030] In a preferred embodiment, the drying is preferably carried out at 45-55°C, more preferably at 50°C.

[0031] In a preferred embodiment, the crystal form G is obtained by the following method:

[0032] (1) Stir 160 mL of ethyl acetate and 25 mL of ethanol at 40 °C and 300 rpm for 20 min.

[0033] (2) Add 20g of the compound shown in Formula I and grind until no obvious particles are visible;

[0034] (3) Keep warm at 40℃ for 5 hours, then cool down to 25℃ (room temperature 20℃) at 10-15℃ / h; filter, and dry at 50℃ to obtain crystal form G.

[0035] In a second aspect, the present invention provides a method for preparing the crystal form G described in the first aspect, the method comprising the following steps:

[0036] (1) Grind the compound shown in Formula I in an organic solvent;

[0037] (2) Keep the system obtained in step (1) at a constant temperature;

[0038] (3) Cool the system obtained in step (2) to obtain crystal form G.

[0039] In a specific embodiment, in step (1), the organic solvent is an organic solvent selected from the group consisting of ethyl acetate, methyl acetate, propyl acetate, methanol, ethanol, propanol, isopropanol, butanol, and isobutanol; preferably, the composition is a mixture of ethyl acetate and ethanol.

[0040] In a specific embodiment, the volume ratio of ethyl acetate to ethanol is 2-10:1, preferably 5-7:1.

[0041] In a preferred embodiment, in step (1), the organic solvent is first kept at 35-45°C, preferably 40°C; or, if the organic solvent is a mixture, it is stirred, for example at 300 rpm for 15-25 min, preferably 20 min, so that the mixture of organic solvents is fully mixed, and then the compound shown in Formula I is ground in the organic solvent.

[0042] In a preferred embodiment, the mass (g) ratio of the compound shown in Formula I to the volume (ml) of the organic solvent is 1:0.1-3; preferably 1:0.5-2.5; more preferably 1:1-1.5.

[0043] In a preferred embodiment, in step (2), the system obtained in step (1) is kept at 35-45°C, preferably 40°C; the heat preservation can be carried out for 4-6 hours, preferably 4.5-5.5 hours, and most preferably 5 hours.

[0044] In a preferred embodiment, in step (3), the system obtained in step (2) is cooled to 20-30°C at a rate of 10-15°C / h; preferably 25°C.

[0045] In a preferred embodiment, the preparation method further includes a step of drying the obtained crystal form G.

[0046] In a preferred embodiment, the drying is preferably carried out at 45-55°C, more preferably at 50°C.

[0047] In a preferred embodiment, the crystal form G is obtained by the following method:

[0048] (1) Stir 160 mL of ethyl acetate and 30 mL of ethanol at 40 °C and 300 rpm for 20 min;

[0049] (2) Add 20g of the compound shown in Formula I and grind until no obvious particles are visible;

[0050] (3) Keep warm at 40℃ for 5 hours, then cool down to 25℃ (room temperature 20℃) at 10-15℃ / h; filter, and dry at 50℃ to obtain crystal form G.

[0051] In a third aspect, the present invention provides a pharmaceutical composition comprising the crystal form G described in the first aspect and optionally a pharmaceutically acceptable excipient.

[0052] In a preferred embodiment, the pharmaceutical composition comprises the above-described crystal form A and optionally a pharmaceutically acceptable excipient.

[0053] In a preferred embodiment, the pharmaceutical composition is used to treat or prevent central nervous system disorders in mammals (e.g., humans).

[0054] In a fourth aspect, the present invention provides the use of the crystal form G described in the first aspect in the preparation of a medicament for treating or preventing disorders of the central nervous system in mammals (e.g., humans).

[0055] In a preferred embodiment, the present invention provides the use of the above-described crystal form A in the preparation of medicaments for treating or preventing central nervous system disorders in mammals (e.g., humans).

[0056] In a fifth 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., humans) a therapeutically effective amount of the crystal form G described in the first aspect or the pharmaceutical composition described in the third aspect.

[0057] In a preferred embodiment, 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.

[0058] In a preferred embodiment, the central nervous system disorder includes, but is not limited to, tremor, 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

[0059] 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.

[0060] 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

[0061] Figure 1 The XRPD pattern of the G crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention is shown;

[0062] Figure 2 The crystal structure of the G-form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention is shown;

[0063] Figure 3 The DSC spectrum of the G crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention is shown;

[0064] Figure 4 The TGA spectrum of the G crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention is shown;

[0065] Figure 5 The PXRD sampling results of the G crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention stored at 50°C are shown.

[0066] Figure 6 The PXRD sampling results of the G crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention stored at 40°C are shown.

[0067] Figure 7 The PXRD sampling results of the G crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention stored at 4–8 °C are shown; and

[0068] Figure 8The results of PXRD sampling of the G crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention stored at -15 to 20°C are shown. Detailed Implementation

[0069] Through extensive and in-depth research, the inventors discovered a specific polymorph based on a derivative of a eupregnaneolone compound. This specific polymorph of the present invention not only retains the advantages of eupregnaneolone derivatives, such as maintaining effective physiological concentrations of eupregnaneolone in vivo for a longer period and convenient administration, improving patient compliance, but also significantly improves solubility, exhibits excellent storage stability at various temperatures, and possesses low hygroscopicity, thus bringing excellent technical benefits to the production, sales, and transportation of drugs. The present invention was completed based on this.

[0070] the term

[0071] 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:

[0072]

[0073] In this article, the chemical name of compound I is: glycine-L-valine 3α-hydroxy-5α-pregn-20-keto ester.

[0074] Allogenein

[0075] 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.

[0076] 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.

[0077] 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.

[0078] Polymorph

[0079] 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.

[0080] Those skilled in the art also know that different crystal forms of drugs can exhibit significant differences in bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, color, filterability, density, and flowability. Polymorphic forms of compounds can exhibit different melting points, hygroscopicities, stability, solubility, bioavailability, biological activity, and flowability, all of which are important factors affecting drug development. Therefore, 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.

[0081] 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 this invention has a crystal form G or is referred to as crystal G.

[0082] 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 G of the compound shown in Formula I.

[0083] crystallization

[0084] Those skilled in the art will recognize that production-scale crystallization can be achieved by manipulating the solution to exceed the solubility limit of the compound of interest. This can be accomplished by various methods, 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.

[0085] 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.

[0086] In a specific embodiment, the crystal form G of the present invention is obtained by a method comprising the following steps:

[0087] (1) Grind the compound shown in Formula I in an organic solvent;

[0088] (2) Keep the system obtained in step (1) at a constant temperature;

[0089] (3) Cool the system obtained in step (2) to obtain crystal form G.

[0090] The organic solvent in step (1) may be an organic solvent selected from the group consisting of ethyl acetate, methyl acetate, propyl acetate, methanol, ethanol, propanol, isopropanol, butanol, and isobutanol; preferably, the composition is a mixture of ethyl acetate and ethanol. Preferably, the volume ratio of ethyl acetate to ethanol is 2-10:1, more preferably 5-7:1.

[0091] In a specific embodiment, in step (1), the organic solvent is first kept at 35-45°C, preferably 40°C; or, if the organic solvent is a mixture, it is stirred, for example at 300 rpm for 15-25 min, preferably 20 min, so that the mixture of organic solvents is fully mixed, and then the compound shown in Formula I is ground in the organic solvent.

[0092] During grinding, the ratio of the mass (g) of the compound shown in Formula I to the volume (ml) of the organic solvent is 1:0.1-3; preferably 1:0.5-2.5; more preferably 1:1-1.5.

[0093] In step (2), the system obtained in step (1) is kept at 35-45°C, preferably 40°C; the heat preservation can be carried out for 4-6 hours, preferably 4.5-5.5 hours, and most preferably 5 hours.

[0094] In step (3), the system obtained in step (2) is cooled to 20-30°C at a rate of 10-15°C / h; preferably 25°C.

[0095] Based on conventional practices in the art, the obtained crystal form G can also be dried. For example, drying can be carried out at 45-55°C, preferably at 50°C.

[0096] In a specific embodiment, the crystal form G of the present invention is obtained by the following method:

[0097] (1) Stir 160 mL of ethyl acetate and 30 mL of ethanol at 40 °C and 300 rpm for 20 min;

[0098] (2) Add 20g of the compound shown in Formula I and grind until no obvious particles are visible;

[0099] (3) Keep warm at 40℃ for 5 hours, then cool down to 25℃ (room temperature 20℃) at 10-15℃ / h; filter, and dry at 50℃ to obtain crystal form G.

[0100] The pharmaceutical composition and administration method of the present invention

[0101] Based on the polymorph of the 3-hydroxy-5-pregnane-20 one derivative of the present invention, the present invention further provides a pharmaceutical composition comprising the polymorph. The pharmaceutical composition, because the polymorph of the 3-hydroxy-5-pregnane-20 one derivative retains the characteristics of allogeneic ketone derivatives, such as maintaining an effective physiological concentration of allogeneic ketone in vivo for a longer period, convenient administration, and improved patient compliance, etc., also exhibits significantly improved solubility, thereby enhancing drugability. Simultaneously, the polymorph demonstrates excellent storage stability at various temperatures and possesses low hygroscopicity, enabling its formulation into pharmaceutical preparations and bringing significant technical advantages to drug production, sales, and transportation.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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 30-1200 mg of the polymorph of the present invention per dose, more preferably, 50-800 mg of the polymorph of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0106] "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.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] Disease prevention and treatment methods

[0116] 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.

[0117] 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.

[0118] Advantages of this invention:

[0119] 1. The crystal form G of the 3-hydroxy-5-pregnane-20 one derivative of the present invention retains the characteristics of allogeneic ketone derivatives, such as the ability to maintain an effective physiological concentration of allogeneic ketone in vivo for a longer period of time, convenient administration, and improved patient compliance.

[0120] 2. The solubility of crystal form G of the 3-hydroxy-5-pregnane-20 one derivative of the present invention is significantly improved, thereby enhancing its drug-likeness;

[0121] 3. The crystalline form G of the 3-hydroxy-5-pregnane-20 one derivative of the present invention exhibits excellent storage stability at various temperatures;

[0122] 4. The crystalline form G of the 3-hydroxy-5-pregnane-20 one derivative of the present invention has low hygroscopicity, thereby enabling it to be prepared into pharmaceutical formulations and bringing excellent technical benefits to the production, sale and transportation of drugs.

[0123] 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.

[0124] Test method:

[0125] XRPD (X-ray Powder Diffraction): Powder X-ray diffraction (PXRD) was performed on a Ultima IV instrument (Rigaku, Japan). The detection temperature was room temperature. Cu-Kα radiation was used. θ-2θ Bragg-Brentano configuration geometry and graphite monochromator. Measurement range: 3°–45° (2θ), step size: 0.02°, scan rate: 15° / min.

[0126] Single-crystal X-ray diffraction (SCXRD): Data were acquired using Cu-Kα radiation on a Bruker Photon III diffractometer (Bruker, Germany) and processed using APEX4 software. The structure was then solved using the intrinsic phase method in the XT program, and the F2 was improved using the full-matrix least-squares technique in the ShELXL-2018 program.

[0127] 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.

[0128] Thermogravimetric analysis (TGA) method: Performed on a TA Q500 thermogravimetric analyzer (TA, USA). Powder samples were placed in an aluminum sample tray. The analysis temperature ranged from room temperature to 400°C, the heating rate was 10°C / min, and the nitrogen flow rate was 60 mL / min.

[0129] DSC (Differential Scanning Calorimetry) method: Performed on a TA Q2000 instrument from TA Instruments, USA. The analysis temperature ranged from room temperature to decomposition temperature, the heating rate was 10℃ / min, the analysis was conducted in an aluminum sample pan, and the flow rate was 50mL / min.

[0130] Example 1. Synthesis of the compound shown in Formula I

[0131]

[0132] Preparation of intermediate 2.1:

[0133] 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%).

[0134] Preparation of intermediate 2.2:

[0135] 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).

[0136] Preparation of the compound shown in Formula I:

[0137] 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%).

[0138] 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).

[0139] MS:m / z[M+H]+475.3.

[0140] Example 2. Preparation of crystal form G of compound of formula I

[0141] 160 mL of ethyl acetate and 30 mL of ethanol were stirred at 300 rpm for 20 min at 40 °C. 20 g of the compound prepared in Example 1 was added. The mixture was ground until no obvious particles were present. The mixture was kept at 40 °C for 5 h. Subsequently, the mixture was cooled to 25 °C at a rate of 10-15 °C / h at room temperature (20 °C), filtered, and dried at 50 °C to obtain a white solid.

[0142] The XRPD pattern (obtained by X-ray powder diffraction) and DSC pattern of the obtained crystal form were basically as follows: Figure 1 and 3 As shown in the table below, the diffraction angle data of the XRPD pattern of crystal form G are basically as follows, where the error range of 2θ value is ±0.2°.

[0143]

[0144]

[0145] from Figure 1It can be seen that crystal form G has characteristic peaks at the following 2θ angles: 13.4±0.2°, 16.9±0.2°, and 17.8±0.2°. Furthermore, crystal form G also exhibits some characteristic diffraction peaks at the following 2θ angles: 11.8±0.2°, 14.1±0.2°, and 16.6±0.2°. In addition, crystal form G also exhibits some suboptimal characteristic diffraction peaks at the following 2θ angles: 14.4±0.2°, 16.1±0.2°, and 18.9±0.2°.

[0146] The DSC spectrum of the obtained crystal form G is basically as follows: Figure 3 As shown, the differential scanning calorimetry curve of crystal form G has an endothermic peak in its DSC spectrum, with an onset temperature of 214.9℃.

[0147] Further testing revealed that the TGA pattern of the obtained crystal form G was essentially as follows: Figure 4 As shown in the TGA spectrum, there was no significant weight loss before 200℃.

[0148] Example 3. Determination of the crystal structure of crystal form G

[0149] Single-crystal X-ray diffraction (SCXRD): Data were acquired using Cu-Kα radiation on a Bruker Photon III diffractometer (Bruker, Germany) and processed using APEX4 software. The structure was then solved using the intrinsic phase method in the XT program, and the F2 was improved using the full-matrix least-squares technique in the ShELXL-2018 program.

[0150] The crystal structure of Form G was determined to be as follows: Figure 2 As shown, it belongs to the orthorhombic crystal system, the space group is the non-centrosymmetric space group P212121, the cell parameters are a=6.2963(4), b=8.0861(5), c=56.515(3), α=β=γ=90°, and the cell volume is... Its smallest asymmetric unit comprises a compound cation of Formula I and a chloride ion.

[0151] Example 4. Comparison of solubility of crystal form G with other crystal forms of the compound shown in Formula I

[0152] The inventors prepared crystal forms A and B of the compound shown in Formula I according to WO2022 / 166774A1. The solubility of crystal form G, crystal form A, and crystal form B of the present invention were compared. Details are shown in the table below:

[0153]

[0154] The solubility comparison shows that, at both 37℃ and 25℃, the solubility of crystal form G is significantly better than that of crystal forms A and B.

[0155] Example 5. Storage stability experiment of crystal form G

[0156] The Form G sample was placed under four conditions: -20℃, 4-8℃, 40℃, and 50℃. The sample was taken out at the corresponding time point, and XRPD was used to detect whether its crystal form changed with different time and temperature.

[0157] The test results are shown in the table below:

[0158]

[0159] Figure 5 , 6 Images 7 and 8 show the PXRD sampling results of the G crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention stored at 50°C, 40°C, 4–8°C, and -15–20°C, respectively.

[0160] exist Figure 5 In the middle, from bottom to top, the spectra are as follows: 47-3-50-1107 is the spectrum of crystal form G placed in an environment of 50℃ on the 1st day; 47-3-50-1110 is the spectrum of the 4th day; 47-3-50-1118 is the spectrum of the 11th day; 47-3-50-1125 is the spectrum of the 18th day; 47-3-50-1201 is the spectrum of the 24th day; 47-3-50-1209 is the spectrum of the 31st day; 47-3-50-1216 is the spectrum of the 38th day; 47-3-50-1223 is the spectrum of the 45th day; and 47-3-50-1229 is the spectrum of the 51st day.

[0161] exist Figure 6 In the middle, from bottom to top, the patterns are as follows: 47-3-40-1108 is the spectrum of crystal form G placed in an environment of 40℃ on day 1; 47-3-40-1111 is the spectrum of day 4; 47-3-40-1118 is the spectrum of day 11; 47-3-40-1125 is the spectrum of day 18; 47-3-40-1201 is the spectrum of day 24; 47-3-40-1209 is the spectrum of day 31; 47-3-40-1216 is the spectrum of day 38; 47-3-40-1223 is the spectrum of day 45; and 47-3-40-1229 is the spectrum of day 51.

[0162] exist Figure 7In the middle, from bottom to top, the following are the spectra: 47-3-4-1108 is the spectrum of crystal form G placed in an environment of 4-8℃ on day 1; 47-3-4-1111 is the spectrum of day 4; 47-3-4-1118 is the spectrum of day 11; 47-3-4-1125 is the spectrum of day 18; 47-3-4-1201 is the spectrum of day 24; 47-3-4-1209 is the spectrum of day 31; 47-3-4-1216 is the spectrum of day 38; 47-3-4-1223 is the spectrum of day 45; and 47-3-4-1229 is the spectrum of day 51.

[0163] exist Figure 8 In the middle, from bottom to top, the following are the spectra: 47-3-20-1108 is the spectrum of crystal form G placed in an environment of -15 to -20℃ on day 1; 47-3-20-1111 is the spectrum of day 4; 47-3-20-1118 is the spectrum of day 11; 47-3-20-1127 is the spectrum of day 18; 47-3-20-1201 is the spectrum of day 24; 47-3-20-1209 is the spectrum of day 31; 47-3-20-1216 is the spectrum of day 38; and 47-3-20-1229 is the spectrum of day 51.

[0164] From the table above and Figure 5-8 It can be seen that crystal form G can maintain a stable crystal form G at -20℃, 4-8℃, 40℃ and 50℃.

[0165] Example 6. Determination of the hygroscopicity of crystal form G

[0166] DVS was measured using the DVS Intrinsic Plus instrument from SMS (Surface Measurement Systems).

[0167] The relative humidity at 25℃ was corrected for the deliquescence points of lithium chloride (LiCl), magnesium nitrate (Mg(NO3)2), and potassium chloride (KCl). Experimental parameters are shown in the table below:

[0168]

[0169]

[0170] Measurements showed that crystal form G has low hygroscopicity; according to the DVS test at 25℃ / 80%RH, it only absorbs 0.8983% moisture.

[0171] 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 crystal form G of compound I has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 13.4±0.2°, 16.9±0.2°, and 17.8±0.2°.

2. The crystal form G as described in claim 1, characterized in that, Its X-ray powder diffraction pattern also has some characteristic diffraction peaks at the following 2θ angles: 11.8±0.2°, 14.1±0.2°, and 16.1±0.2°.

3. The crystal form G as described in claim 2, characterized in that, Its X-ray powder diffraction pattern also has some characteristic diffraction peaks at the following 2θ angles: 14.4±0.2°, 16.6±0.2°, and 18.9±0.2°.

4. The crystal form G as described in claim 1, characterized in that, Its X-ray powder diffraction pattern is shown in Figure 1, which has the characteristics represented by the XRPD pattern shown in Figure 1.

5. The crystal form G according to any one of claims 1-4, characterized in that, The crystal form G is prepared by the following method, which includes the following steps: (1) Grind the compound shown in Formula I in an organic solvent; (2) Keep the system obtained in step (1) at a constant temperature; (3) Cool the system obtained in step (2) to obtain crystal form G.

6. The method for preparing crystal form G according to any one of claims 1-5, characterized in that, The preparation method includes the following steps: (1) Grind the compound shown in Formula I in an organic solvent; (2) Keep the system obtained in step (1) at a constant temperature; (3) Cool the system obtained in step (2) to obtain crystal form G.

7. The method as described in claim 6, characterized in that, In step (1), the organic solvent is an organic solvent selected from the group consisting of ethyl acetate, methyl acetate, propyl acetate, methanol, ethanol, propanol, isopropanol, butanol, and isobutanol; preferably, the composition is a mixture of ethyl acetate and ethanol.

8. The method as described in claim 7, characterized in that, The volume ratio of ethyl acetate to ethanol is 2-10:1, preferably 5-7:

1.

9. A pharmaceutical composition comprising crystal form G as described in any one of claims 1-5 and optionally a pharmaceutically acceptable excipient.

10. Use of crystal form G according to any one of claims 1-5 in the preparation of a medicament for treating or preventing central nervous system disorders in mammals (e.g., humans).

11. A method for treating or preventing a central nervous system disorder in a mammal (e.g., a human), the method comprising administering to the mammal (e.g., a human) a therapeutically effective amount of crystal form G according to any one of claims 1-5 or the pharmaceutical composition according to claim 9.

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