WO2022166774A1 - 3-羟基-5-孕烷-20-酮衍生物的晶型及其制备方法和用途 - Google Patents

3-羟基-5-孕烷-20-酮衍生物的晶型及其制备方法和用途 Download PDF

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WO2022166774A1
WO2022166774A1 PCT/CN2022/074412 CN2022074412W WO2022166774A1 WO 2022166774 A1 WO2022166774 A1 WO 2022166774A1 CN 2022074412 W CN2022074412 W CN 2022074412W WO 2022166774 A1 WO2022166774 A1 WO 2022166774A1
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crystal form
present
compound
formula
ray powder
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PCT/CN2022/074412
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English (en)
French (fr)
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刘飞
吴刚
李先朝
王晓波
刘金伟
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美商欢伯药业股份有限公司
南京诺瑞特医药科技有限公司
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Priority to JP2023547899A priority Critical patent/JP2024505736A/ja
Priority to US18/276,321 priority patent/US20240132536A1/en
Priority to EP22749053.9A priority patent/EP4289856A1/en
Publication of WO2022166774A1 publication Critical patent/WO2022166774A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the field of medicinal chemistry; in particular, the present invention relates to a crystal form of a 3-hydroxy-5-pregnane-20-one derivative, a preparation method thereof, and use in preventing or treating disorders of the central nervous system .
  • Neuroactive steroids are active steroids in nerve tissue.
  • Neurosteroids that play an important regulatory role in the human body mainly include progesterone, pregnenolone, and allopregnanolone.
  • Progesterone, pregnenolone and allopregnanolone are all metabolized from cholesterol through different pathways.
  • Cholesterol is transferred from the outer mitochondrial membrane to the inner membrane under the mediation of an 18kDa translocator protein, and undergoes cytochrome P450 cholesterol side chain lyase.
  • Neuroactive steroids are used as anesthetics, sedatives, hypnotics, anxiolytics, antidepressants, and anticonvulsants.
  • Allopregnanolone is a research hotspot in recent years. As early as 1986, it has been pointed out that allopregnanolone is a positive regulator of GABAA receptors. However, it was not discovered until 2006 that allopregnanolone may mainly bind to the ⁇ and ⁇ subunits of GABAA receptors, increase the opening frequency of chloride ion signal channels on the receptors, and reduce neural excitability, resulting in calming and anti-inflammatory effects. Anxiety effect. It has been reported in the literature that the levels of progesterone and its metabolites in the body vary during different phases of the menstrual cycle.
  • PMS premenstrual syndrome
  • symptoms such as stress, anxiety and migraines recur before the menstrual cycle begins but disappear after the period.
  • Postpartum depression is also associated with abnormal levels of progesterone and its metabolites, with plasma concentrations of allopreganolone increasing in healthy pregnant women as pregnancy progresses and sharply decreasing after delivery.
  • Studies have shown that the decrease in the content of allopregnanolone is considered to be closely related to the occurrence and development of many mental disorders such as anxiety, depression and tremor, and exogenous administration of allopregnanolone can significantly improve the above psychiatric symptoms.
  • allopregnanolone has low water solubility, poor oral availability, and a human plasma half-life of about 45 minutes, which can be rapidly metabolized.
  • Zulresso is marketed as a water-soluble, sulfobutyl beta-cyclodextrin-based formulation of allopregnanolone that produces stable physiological concentrations of allopregnanolone by intravenous injection.
  • Brexanolone requires up to 60 hours of intravenous fluids, and patient compliance is poor.
  • crystal forms of drugs may have significant differences in bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, color, filterability, density, fluidity, etc.
  • the study of drug polymorphs is helpful to find drug forms with better physical and chemical properties or better processing forms, thereby broadening the formulation forms of drugs, and developing valuable formulation forms, which are convenient for all kinds of people to use.
  • the object of the present invention is to provide a derivative of 3-hydroxy-5-pregnane-20-one and its polymorphic form, the derivative can be used for the preparation of a medicament for preventing or treating disorders of the central nervous system, and this
  • the derivatives have improved solubility, stable storage, convenient administration and high patient compliance during administration.
  • Another object of the present invention is to provide polymorphic forms of the above-mentioned 3-hydroxy-5-pregnane-20-one derivatives, which can have excellent thermodynamic and mechanical stability.
  • the present invention provides Form A of the compound of formula I, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 12.66 ⁇ 0.2°, 13.53 ⁇ 0.2°, 16.75 ⁇ 0.2° and 25.39 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 11.96 ⁇ 0.2°, 12.66 ⁇ 0.2°, 13.53 ⁇ 0.2°, 14.51 ⁇ 0.2°, 16.75 ⁇ 0.2 ° and 25.39 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 11.96 ⁇ 0.2°, 12.66 ⁇ 0.2°, 13.53 ⁇ 0.2°, 14.51 ⁇ 0.2°, 16.75 ⁇ 0.2 °, 19.27 ⁇ 0.2°, 22.19 ⁇ 0.2° and 25.39 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 11.96 ⁇ 0.2°, 12.66 ⁇ 0.2°, 13.53 ⁇ 0.2°, 14.51 ⁇ 0.2°, 16.75 ⁇ 0.2 °, 19.27 ⁇ 0.2°, 22.19 ⁇ 0.2°, 25.39 ⁇ 0.2°, 26.23 ⁇ 0.2°, 31.87 ⁇ 0.2° and 35.34 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 11.96 ⁇ 0.2°, 12.66 ⁇ 0.2°, 13.53 ⁇ 0.2°, 13.88 ⁇ 0.2°, 14.51 ⁇ 0.2 degrees ° and 35.34 ⁇ 0.2°.
  • Table 1 Peak positions and intensities of characteristic peaks in the X-ray powder diffraction pattern of Form A
  • the XRPD pattern of the above-mentioned A crystal form is shown in FIG. 1 , that is, it has the characteristics represented by the XRPD pattern shown in FIG. 1 .
  • the differential scanning calorimetry curve of the above-mentioned crystal form A has an endothermic peak at 216.85°C ⁇ 3°C.
  • the above-mentioned crystal form A the DSC spectrum of which is shown in FIG. 2 , that is, has the characteristics represented by the DSC spectrum as shown in FIG. 2 .
  • the preparation method of the A crystal form of the above-mentioned compound of formula I comprises the following steps:
  • the solvent is selected from one or more of methanol, ethanol, isopropanol, acetone, butanone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, n-heptane, and toluene; Preferred are ethanol, isopropanol, and ethyl acetate.
  • step (1) is carried out under heating.
  • the heating temperature of step (1) is about 60-70°C, preferably about 65°C.
  • the compound of formula I is added in step (1) and then stirred, and the stirring time may be 6 to 18 hours, preferably 12 hours.
  • step (2) is cooled before filtration, and the cooling can be cooling to 0-30°C, preferably cooling to 20°C.
  • step (2) can be stirred after cooling as required, and the stirring time can be 6 to 24 hours, preferably 18 hours.
  • the step (2) is optionally washed with a solvent before drying, and the washing solvent is selected from methanol, ethanol, acetone, ethyl acetate, methanol ether, n-heptane, toluene, preferably ethyl acetate .
  • the present invention provides Form B of the compound of formula I, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 10.69 ⁇ 0.2°, 13.17 ⁇ 0.2°, 13.37 ⁇ 0.2° and 15.22 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.26 ⁇ 0.2°, 4.50 ⁇ 0.2°, 10.69 ⁇ 0.2°, 13.17 ⁇ 0.2°, 13.37 ⁇ 0.2 °, and 15.22 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.26 ⁇ 0.2°, 4.50 ⁇ 0.2°, 10.69 ⁇ 0.2°, 12.88 ⁇ 0.2°, 13.17 ⁇ 0.2 °, 13.37 ⁇ 0.2°, 15.22 ⁇ 0.2° and 15.81 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.26 ⁇ 0.2°, 4.50 ⁇ 0.2°, 8.77 ⁇ 0.2°, 10.69 ⁇ 0.2°, 12.14 ⁇ 0.2 °, 12.88 ⁇ 0.2°, 13.17 ⁇ 0.2°, 13.37 ⁇ 0.2°, 15.22 ⁇ 0.2°, 15.81 ⁇ 0.2°, 25.35 ⁇ 0.2° and 29.04 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 4.26 ⁇ 0.2°, 4.50 ⁇ 0.2°, 8.77 ⁇ 0.2°, 10.69 ⁇ 0.2°, 12.14 ⁇ 0.2 degrees °, 29.04 ⁇ 0.2°, 30.52 ⁇ 0.2° and 30.79 ⁇ 0.2°.
  • Table 3 Peak positions and intensities of characteristic peaks in the X-ray powder diffraction pattern of crystal form B
  • the XRPD pattern of the above-mentioned crystal form B is shown in FIG. 3 , that is, it has the characteristics represented by the XRPD pattern shown in FIG. 3 .
  • the differential scanning calorimetry curve of the above-mentioned crystal form B has endothermic peaks around 120.67°C and 226.10°C.
  • the differential scanning calorimetry curve of the above-mentioned crystal form B has endothermic peaks at 120.67 ⁇ 3°C and 226.10 ⁇ 3°C.
  • the above-mentioned crystal form B the DSC spectrum of which is shown in FIG. 4 , that is, has the characteristics represented by the DSC spectrum as shown in FIG. 4 .
  • the above-mentioned crystal form B has a TGA spectrum as shown in FIG. 5 , that is, it has the characteristics represented by the TGA spectrum as shown in FIG. 5 .
  • thermogravimetric analysis curve of the above crystal form B has a weight loss peak, and the weight loss reaches 6.475 ⁇ 0.5%; specifically, the thermogravimetric analysis curve of the B crystal form has a weight loss at 50°C-125°C peak.
  • the preparation method of the B crystal form of the above-mentioned compound of formula I comprises the following steps:
  • 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, preferably water or a mixed solvent of ethanol and water.
  • step (1) is carried out under heating.
  • the heating temperature of step (1) is about 65-75°C, preferably about 70°C.
  • the compound of formula I is added in step (1) and then stirred.
  • step (2) is cooled before filtration, and the cooling can be cooling to 0-30°C, preferably cooling to 2-8°C.
  • step (2) may be stirred after cooling as required, and the stirring time may be 15-22 hours, preferably 18 hours.
  • the step (2) is optionally washed with a solvent before drying, and the washing solvent is selected from the group consisting of 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.
  • a solvent selected from the group consisting of 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.
  • Mixed solvent preferably water or mixed solvent of ethanol and water.
  • the present invention provides Form C of the compound of formula I, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.77 ⁇ 0.2°, 7.08 ⁇ 0.2°, 8.34 ⁇ 0.2° and 12.46 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 6.77 ⁇ 0.2°, 7.08 ⁇ 0.2°, 8.34 ⁇ 0.2°, 12.46 ⁇ 0.2°, 17.60 ⁇ 0.2 ° and 17.92 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 6.77 ⁇ 0.2°, 7.08 ⁇ 0.2°, 8.34 ⁇ 0.2°, 12.46 ⁇ 0.2°, 13.21 ⁇ 0.2 °, 16.52 ⁇ 0.2°, 17.60 ⁇ 0.2° and 17.92 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 6.77 ⁇ 0.2°, 7.08 ⁇ 0.2°, 8.34 ⁇ 0.2°, 11.02 ⁇ 0.2, 12.46 ⁇ 0.2° , 13.21 ⁇ 0.2°, 14.20 ⁇ 0.2, 15.06 ⁇ 0.2, 16.52 ⁇ 0.2°, 17.60 ⁇ 0.2°, 17.92 ⁇ 0.2 and 20.86 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 6.77 ⁇ 0.2°, 7.08 ⁇ 0.2°, 8.34 ⁇ 0.2°, 10.61 ⁇ 0.2, 11.02 ⁇ 0.2, 12.46 ⁇ 0.2°, 13.21 ⁇ 0.2°, 13.76 ⁇ 0.2, 14.20 ⁇ 0.2, 14.63 ⁇ 0.2, 15.06 ⁇ 0.2, 15.75 ⁇ 0.2, 16.52 ⁇ 0.2°, 17.60 ⁇ 0.2°, 17.92 ⁇ 0.2, 19.14 ⁇ 0.2, 20.86 ⁇ 0.2, 24.76 ⁇ 0.2 and 26.46 ⁇ 0.2.
  • the XRPD pattern of the above-mentioned crystal form C is shown in FIG. 6 , that is, it has the characteristics represented by the XRPD pattern shown in FIG. 6 .
  • the differential scanning calorimetry curve of the above crystal form C has an endothermic peak at 179.31°C ⁇ 3°C.
  • the above-mentioned crystal form C has the DSC spectrum shown in FIG. 7 , that is, the features represented by the DSC spectrum shown in FIG. 7 .
  • the preparation method of the C crystal form of the above-mentioned compound of formula I comprises the following steps:
  • the solvent 1 is selected from one or more of methanol, ethanol, isopropanol, n-propanol, and tetrahydrofuran;
  • the solvent 2 is selected from acetone, ethyl acetate, methyl tert-butyl ether, n-heptane , Toluene.
  • step (1) is carried out under heating.
  • the heating temperature of step (1) is about 60-70°C, preferably about 65°C.
  • the compound of formula I is added in step (1) and then stirred, and the stirring time may be 6 to 18 hours, preferably 12 hours.
  • the temperature of the addition process of step (2) is about 60-70°C, preferably about 65°C.
  • step (3) is cooled before filtration, and the cooling can be cooling to 0-30°C, preferably cooling to 20°C.
  • step (3) can be stirred after cooling as required, and the stirring time can be 15-22 hours, preferably 18 hours.
  • the step (3) is optionally washed with a solvent before drying, and the washing solvent is selected from methanol, ethanol, acetone, ethyl acetate, methyl tert-butyl ether, n-heptane, and toluene, preferably For ethanol and methyl tert-butyl ether.
  • the present invention provides a pharmaceutical composition comprising the above-mentioned crystal form A, the above-mentioned crystal form B or the above-mentioned crystal form C and optional pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprises the above-mentioned Form A and optional pharmaceutically acceptable excipients.
  • the pharmaceutical composition is used to treat or prevent central nervous system disorders in mammals (eg, humans).
  • the present invention provides the use of the above-mentioned crystal form A, the above-mentioned crystal form B or the above-mentioned crystal form C in the preparation of a medicament for the treatment or prevention of central nervous system disorders in mammals (eg, humans).
  • the present invention provides the use of the above-mentioned crystal form A in the preparation of a medicament for the treatment or prevention of central nervous system disorders in mammals (eg, humans).
  • the present invention provides a method for treating or preventing a central nervous system disorder in a mammal (eg, a human), the method comprising administering to the mammal (eg, a human) a therapeutically effective amount of a compound of formula (I), Form A of the compound of formula I, pharmaceutical composition comprising the crystalline form A of the compound of formula I, crystalline form B of the compound of formula I, pharmaceutical composition comprising the crystalline form B of the compound of formula I, crystalline form C of the compound of formula I and Pharmaceutical compositions of Form C of Compound I.
  • a mammal eg, a human
  • the methods comprise administering to a mammal (eg, a human) a therapeutically effective amount of a compound of formula (I), crystalline form A of a compound of formula I, a pharmaceutical composition comprising crystalline form A of a compound of formula I.
  • a mammal eg, a human
  • a therapeutically effective amount of a compound of formula (I), crystalline form A of a compound of formula I a pharmaceutical composition comprising crystalline form A of a compound of formula I.
  • the central nervous system disorders include, but are not limited to, tremors, sleep disorders, depression, depressive disorders, bipolar disorder, anxiety disorders, stress response, post-traumatic stress disorder, obsessive-compulsive disorder Sexual disorders, schizophrenia, schizoaffective disorder, epilepsy, seizures, memory impairment and/or cognitive impairment, dementia, movement disorders, personality disorders, autism, autism with single etiology, pain, traumatic Brain injury, vascular disease, substance use disorder and/or withdrawal syndrome or tinnitus; or
  • the central nervous system disorders include, but are not limited to, essential tremor, epilepsy, clinical depression, postpartum or postpartum depression, atypical depression, psychotic major depressive disorder, catatonic depression, seasonal affective disorder, dysthymia, Double depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar or manic-depressive disorder, post-traumatic stress disorder, depression due to chronic medical conditions, treatment-resistant depression, treatment-resistant Depression, suicidal ideation, 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 malformations, addiction to opiates, cocaine and/or alcohol, or insomnia.
  • Figure 1 shows the XRPD pattern of the A crystal form of the 3-hydroxy-5-pregnane-20-one derivatives of the present invention
  • Figure 2 shows the DSC spectrum of the A crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention
  • Figure 3 shows the XRPD pattern of the B crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention
  • Figure 4 shows the DSC spectrum of the B crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention
  • Figure 5 shows the TGA pattern of the B crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention
  • Figure 6 shows the XRPD pattern of the C crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention
  • Figure 7 shows the DSC spectrum of the C crystal form of the 3-hydroxy-5-pregnane-20-one derivative of the present invention
  • Figure 8 shows that the crystal form A of the 3-hydroxy-5-pregnane-20-one derivative of the present invention is placed at room temperature for 1 month (191222 JS1M), 2 months (191222 JS2M), and 3 months (191222 JS3M) XRPD overlays at time points.
  • the inventors unexpectedly found a derivative of allopregnanolones, which can significantly improve the water solubility of allopregnanolones, and has a certain amount of water in an aqueous solution. Storage stability, and can be made into long-acting, sustained-release preparations with little individual differences after administration.
  • the preparation prepared by the derivative can maintain the effective physiological concentration of allopregnanolone in the body for a long time and is convenient for administration, so that it can have the advantages of improving the compliance of patients and the like.
  • the inventors have discovered the crystal form A, crystal form B and crystal form C of the derivative, and the crystal forms have advantages in at least one aspect such as physical stability, thermodynamic stability and mechanical stability, thereby The present invention has been completed.
  • the chemical name of the compound of formula I is: glycine hydrochloride-L-valine 3 ⁇ -hydroxy-5 ⁇ -pregna-20-ketoester.
  • Polymorphic forms of compounds can exhibit different melting points, hygroscopicity, stability, solubility, bioavailability, biological activity and fluidity, etc., which are important factors affecting druggability.
  • crystal crystal of the present invention
  • polymorph polymorph of the present invention
  • polymorphs of derivatives of the present invention all refer to the crystalline forms of the compounds represented by formula I.
  • Production scale crystallization can be accomplished by manipulating the solution such that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, for example, dissolving the compound at a relatively high temperature and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying or by some other method to reduce the liquid volume. Alternatively, the solubility of the compound of interest can be reduced by adding an anti-solvent or solvent in which the compound has low solubility, or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of crystallisation see Crystallization, Third Edition, JW Mullens, Butterworth-Heineman Ltd., 1993, ISBN0750611294.
  • optimization of crystallization may include seeding the crystallization medium with crystals of the desired form as seeds. Additionally, many crystallization methods use a combination of the above strategies. For example, the compound of interest can be dissolved in a solvent at elevated temperature, followed by the controlled addition of an appropriate volume of antisolvent to bring the system just below saturation levels. At this point, the desired form of seed crystals can be added (and the integrity of the seed crystals maintained) and the system cooled to complete crystallization.
  • the compound of formula I can be dissolved in a solvent; then the obtained solution is cooled down, or the obtained solution is slowly volatilized, or an antisolvent is added to the obtained solution, so that the crystals of the compound of formula I are precipitated, thereby obtaining formula Crystals of Compound I.
  • the obtained crystals of the compound of formula I may also optionally be dried.
  • the solvent is selected from one or more of the following: water, methanol, ethanol, acetone, ethyl acetate, methanol ether, n-heptane, and toluene.
  • the temperature may be appropriately increased to facilitate the dissolution of the compound of formula I.
  • the cooling is to cool the solution of the compound of formula I to 20-30°C.
  • solvates Substances formed after crystallization of a compound and a solvent are called solvates.
  • the kinds of solvents that easily form solvates with organic compounds are water, methanol, benzene, ethanol, ether, aromatic hydrocarbons, heterocyclic aromatic hydrocarbons, and the like.
  • Hydrates are a special kind of solvates.
  • no matter in the synthesis of raw materials, pharmaceutical preparations, drug storage and drug activity evaluation, hydrates have the value of separate discussion because of their particularity.
  • the crystal of the compound represented by formula I may be an unsolvate or a solvate.
  • Form B of the present invention is a hydrate.
  • compositions and modes of administration of the present invention are provided.
  • the present invention further provides a pharmaceutical composition comprising the polymorphic form.
  • the pharmaceutical composition has the effect of treating diseases caused by abnormality of the central nervous system because of the 3-hydroxy-5-pregnane-20 ketone derivative therein, and also because of the 3-hydroxy-5-pregnane-20 ketone derivative therein.
  • the polymorph of the compound has excellent stability and can be stored for a long time; in particular, it also has thermal stability and mechanical stability, which is convenient for preparation into the form of pharmaceutical preparations.
  • the diseases caused by the abnormality of the central nervous system include, but are not limited to, tremor, epilepsy, depression or anxiety disorders.
  • the central nervous system disorders include, but are not limited to, essential tremor, epilepsy, clinical depression, postpartum or postpartum depression, atypical depression, psychotic major depressive disorder, catatonic depression, seasonal affective disorder , dysthymia, double 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 thoughts, suicidal ideation, or suicidal behavior.
  • compositions of the present invention also comprise an optional pharmaceutically acceptable carrier.
  • composition is intended to encompass a product comprising the specified ingredients in specified amounts, as well as any product that results, directly or indirectly, in combination with specified amounts of specified ingredients; and a pharmaceutically acceptable carrier refers to a pharmaceutically acceptable carrier for an organism.
  • compositions of the present invention can be prepared by methods known to those skilled in the art.
  • a compound of the present invention can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a corresponding pharmaceutical composition.
  • those skilled in the art can prepare the compounds or pharmaceutical compositions of the present invention into various suitable dosage forms, including but not limited to rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous administration Forms of administration, intravenous administration, intramuscular administration, intra-articular administration, oral mucosa administration, vaginal administration, intranasal administration, and the like.
  • those skilled in the art can also select corresponding pharmaceutically acceptable carriers, diluents or excipients.
  • a safe and effective amount of the polymorphic form of the 3-hydroxy-5-pregnane-20 ketone derivative can be included in the pharmaceutical composition of the present invention.
  • the "safe and effective amount” refers to: the amount of the compound (or crystal form) is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 30-800 mg of the crystal form/dose of the present invention, more preferably, 50-600 mg of the crystal form/dose of the present invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients.
  • Examples of pharmaceutically acceptable carrier moieties 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to: oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical medicine.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • 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, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • 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.
  • Dosage forms of the polymorphs of the invention for topical administration include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the 3-hydroxy-5-pregnane-20-one derivatives of the present invention can release active allopregnanolones under suitable conditions after administration to a subject.
  • the polymorphic forms or pharmaceutical compositions of the 3-hydroxy-5-pregnane-20 ketone derivatives of the present invention can be used to prevent or treat disorders of the central nervous system, including but not limited to the above-mentioned central nervous system Systemic disorders.
  • the method for preventing or treating disorders of the central nervous system of the present invention comprises administering a therapeutically effective amount of the above-mentioned compounds and pharmaceutical compositions to a subject in need thereof.
  • the subject includes, but is not limited to, humans.
  • the present invention provides the polymorphic form of the compound of formula I for the first time
  • the crystal form A of the compound of formula I, the crystal form B of the compound of formula I and the crystal form C of the compound of formula I have good stability, low hygroscopicity, good water solubility, and good drug prospects.
  • the preparation process of the crystal form of the present invention is simple, so that it has excellent potential for industrialization.
  • XRPD X-ray Powder Diffraction
  • XRPD X-ray Powder Diffraction
  • Measurement differences associated with the results of such X-ray powder diffraction analyses arise from a number of factors including: (a) errors in sample preparation (eg, sample height), (b) instrumental errors, (c) calibration differences, ( d) operator errors (including errors in determining peak positions), and (e) properties of the material (eg preferred orientation errors). Calibration errors and sample height errors often cause all peaks to shift in the same direction. When a flat holder is used, small differences in sample height will result in large shifts in the position of the XRPD peaks. Systematic studies have shown that a sample height difference of 1 mm can result in peak shifts of up to 1° in 2 ⁇ .
  • shifts can be identified from the X-ray diffractograms and can be eliminated by compensating for them (using a system calibration factor for all peak position values) or recalibrating the instrument. Measurement errors from different instruments can be corrected for by applying a system calibration factor to make the peak positions consistent, as described above.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • Instrument model METTLER TOLEDO DSC3+, using N2 atmosphere, the heating rate is 10°C/min.
  • Embodiment 1 the synthesis of compound shown in formula I
  • the XRPD pattern (measured by XRPD method 1) and DSC pattern of the obtained crystal form are basically as shown in Figures 1 and 2, respectively.
  • the diffraction angle data of the XRPD pattern of the obtained crystal form are basically as shown in Table 7, wherein the error range of the 2 ⁇ value is ⁇ 0.2°.
  • the XRPD pattern of the obtained crystal form B is basically as shown in Figure 3 (measured by XRPD method 2).
  • the diffraction angle data of the XRPD pattern of the obtained crystal form are basically as shown in Table 8, wherein the error range of the 2 ⁇ value is ⁇ 0.2°.
  • the DSC spectrum of the obtained crystal form B is basically shown in Figure 4, and the differential scanning calorimetry curve of the crystal form B has endothermic peaks around 120.67°C and 226.10°C, indicating that the crystal form B may be a hydrate.
  • the TGA diagram of the obtained crystal form B is basically as shown in FIG. 5 . As can be seen from this figure, there is a weight loss of 6.475 ⁇ 0.5%. Therefore, Form B should be a dihydrate.
  • the XRPD pattern (measured by XRPD method 2) and DSC pattern of the obtained crystal form are basically as shown in Figures 6 and 7, respectively.
  • the diffraction angle data of the XRPD pattern of the obtained crystal form are basically as shown in Table 9, wherein the error range of the 2 ⁇ value is ⁇ 0.2°.
  • Example 1 The crystal form A obtained in Example 1 was placed on an open side and placed under high temperature and high humidity (40°C, RH75%) for 3 months, and certain samples were taken in 1 month, 2 months and 3 months respectively.
  • the stability of Form A was evaluated by examining the XRPD pattern.
  • the crystal form A, crystal form B and crystal form C obtained in Example 1 were placed openly and flatly, and the samples were investigated under the conditions of high temperature (60°C), high humidity (RH92.5%), and light (4500 ⁇ 500Lux). stability.
  • the sampling time for investigation was 5 days, 10 days and 30 days, and the purity detected by HPLC was shown in Table 10.
  • the crystal form A, the crystal form B and the process C have good stability under high temperature, high humidity and light conditions, and have a good medicine prospect.

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Abstract

本发明提供了作为3-羟基-5-孕烷-20-酮衍生物的式I化合物的晶体及其制备方法。具体地，本发明提供了式I化合物的新晶型A-C以及它们的制备方法。本发明的式I化合物的新晶型具备优异的热稳定性和机械稳定性，同时它们的制备工艺简单，是具有优异工业化实施潜力的新晶型。

Description

3-羟基-5-孕烷-20-酮衍生物的晶型及其制备方法和用途 技术领域
本发明涉及药物化学领域；具体地说，本发明涉及一种3-羟基-5-孕烷-20-酮衍生物的晶型及其制备方法和在预防或治疗中枢神经系统紊乱疾病中的用途。
背景技术
神经活性类固醇是神经组织中具有活性的类固醇，在人体中起重要调节作用的神经类固醇主要包括孕酮，孕烯醇酮和别孕烷醇酮等。孕酮，孕烯醇酮和别孕烷醇酮都是胆固醇经过不同途径代谢生成，胆固醇在18kDa转位蛋白的介导下从线粒体外膜转至内膜，经过细胞色素P450胆固醇侧链裂解酶代谢生成孕烯醇酮，再经3β-羟基类固醇脱氢酶代谢成孕酮，继续被5α-还原酶和3α-羟基类固醇脱氢酶所介导的一系列酶促反应代谢生成别孕烷醇酮。神经活性类固醇可用作麻醉剂、镇静剂、安眠药、抗焦虑药、抗抑郁药和抗惊厥药。
别孕烷醇酮是近年来研究的热点，早在1986年就已经有人指出别孕烷醇酮是GABAA受体的正向调节剂。但直至2006年人们才发现，别孕烷醇酮可能主要与GABAA受体的α和β亚单位结合，增加该受体上氯离子信号通道的开放频率，降低神经兴奋性，从而产生镇定、抗焦虑作用。有文献报道，在月经周期的不同阶段，体内孕酮及其代谢物的水平不同。月经开始之前，孕酮及其代谢产物的水平降低，可以引起经前综合症(PMS)，即月经周期开始前身体会重复出现一些症状但在经期后消失，例如应激，焦虑和偏头痛。产后抑郁症也与异常的孕酮及其代谢产物水平有关，随着妊娠的发展，健康孕妇血浆中别孕烷醇酮浓度升高，分娩后，别孕烷醇酮的浓度会急剧下降。研究表明，别孕烷醇酮的含量下降被认为与焦虑，抑郁和震颤等众多精神障碍性疾病的发生和发展密切相关，且外源性给予别孕烷醇酮可以显著改善上述精神症状。
然而，别孕烷醇酮的水溶性低，口服利用度差，人体血浆半衰期大约为45分钟，可被快速代谢。已上市的Zulresso是一种水溶性、以磺丁基β环糊精为基础的别孕烷醇酮制剂，通过静脉注射产生稳定的生理浓度别孕烯烷醇酮。但Brexanolone需要长达60个小时的静脉输液，患者依从性差。
此外，本领域技术人员也知晓，药物的晶型不同，在生物利用度，溶解度，溶解速率，化学物理稳定性，熔点，颜色，可滤性，密度，流动性等方面可能存在显著差异。对药物多晶型的研究，有利于寻找具有更好的理化特性或具有更好加工形式的药物形态，从而拓宽药物的制剂形式，开发有利用价值的制剂形式，方便各类人群使用。
因此，本领域不仅需要一种能提高溶解能力，减少给药时间，又能长时间维持体内稳定生理浓度别孕烷醇酮衍生物；还需要开发出具备优异特性的这种衍生物的不同晶型。
发明内容
本发明的目的在于提供一种3-羟基-5-孕烷-20-酮的衍生物及其多晶型，所述衍生物能够用于制备预防或治疗中枢神经系统紊乱疾病的药物并且这种衍生物的溶解能力改善、储存稳定、给药方便并且给药时患者的依从度高。
本发明的目的还在于提供上述3-羟基-5-孕烷-20-酮衍生物的多晶型，所述多晶型能够具备优异的热力学稳定性和机械稳定性。
第一方面，本发明提供了式I化合物的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.66±0.2°、13.53±0.2°、16.75±0.2°和25.39±0.2°。
Figure PCTCN2022074412-appb-000001
本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：11.96±0.2°、12.66±0.2°、13.53±0.2°、14.51±0.2°、16.75±0.2°和25.39±0.2°。
本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°和25.39±0.2°。
本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°和35.34±0.2°。
本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°和35.34±0.2°。
本发明一些方案中，上述A晶型的X射线粉末衍射图谱中，特征峰的峰位置及强度如表1所示：
表1：A晶型的X射线粉末衍射图谱的特征峰的峰位置及强度
编号 2θ角(°) 相对强度(％) 编号 2θ角(°) 相对强度(％)
1 11.96 21.12 9 18.99 13.44
2 12.66 23.74 10 19.27 16.18
3 13.53 49.52 11 21.95 12.16
4 13.88 8.31 12 22.19 58.99
5 14.51 19.45 13 25.39 100.00
6 15.81 11.30 14 26.23 18.60
7 16.75 53.89 15 31.87 58.49
8 17.99 13.11 16 35.34 20.81
本发明的一些方案中，上述A晶型的XRPD图谱如图1所示，即具有如图1所示的XRPD图谱所代表的特征。
本发明的一些方案中，上述A晶型的XRPD图谱解析数据如表2所示：
表2：A晶型的XRPD解析数据
Figure PCTCN2022074412-appb-000002
本发明的一些方案中，上述A晶型的差示扫描量热曲线在216.85℃±3℃处具有吸热峰。
本发明的一些方案中，上述A晶型，其DSC图谱如图2所示，即具有如图2所示的DSC图谱所代表的特征。
本发明的一些方案中，上述式I化合物的A晶型的制备方法包括如下步骤：
(1)将式I化合物与溶剂混合；
(2)过滤，干燥；
其中，所述溶剂选自甲醇、乙醇、异丙醇、丙酮、丁酮、乙酸乙酯、醋酸异丙酯、甲基叔丁基醚、正庚烷、甲苯中的一种或一种以上；优选为乙醇、异丙醇、乙酸乙酯。
本发明的一些方案中，步骤(1)在加热的条件下进行。
本发明的一些方案中，步骤(1)的加热温度约为60～70℃，优选为约65℃。
本发明的一些方案中，步骤(1)中加入式I化合物后进行搅拌，所述搅拌时间可以是6～18小时，优选12小时。
本发明的一些方案中，步骤(2)在过滤前进行冷却，所述冷却可以是冷却至0～30℃，优选冷却至20℃。
本发明的一些方案中，步骤(2)可以根据需要在冷却后进行搅拌，所述搅拌的时间可以是6～24小时，优选18小时。
本发明的一些方案中，步骤(2)干燥之前任选地用溶剂洗涤，所述洗涤溶剂选自甲醇、乙醇、丙酮、乙酸乙酯、甲醇醚、正庚烷、甲苯，优选为乙酸乙酯。
第二方面，本发明提供了式I化合物的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.69±0.2°、13.17±0.2°、13.37±0.2°和15.22±0.2°。
Figure PCTCN2022074412-appb-000003
本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.26±0.2°、4.50±0.2°、10.69±0.2°、13.17±0.2°、13.37±0.2°、和15.22±0.2°。
本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°和15.81±0.2°。
本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°和29.04±0.2°。
本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°和30.79±0.2°。
本发明一些方案中，上述B晶型的X射线粉末衍射图谱中，特征峰的峰位置及强度如表3所示：
表3：B晶型的X射线粉末衍射图谱的特征峰的峰位置及强度
编号 2θ角(°) 相对强度(％) 编号 2θ角(°) 相对强度(％)
1 4.260 17.6 10 15.813 27.2
2 4.497 14.7 11 17.371 10.1
3 8.773 7.6 12 21.469 20.5
4 10.686 11.5 13 23.186 12.1
5 12.143 6.7 14 25.351 21.4
6 12.876 27.9 15 26.831 15.4
7 13.171 62.5 16 29.038 15.0
8 13.366 100 17 30.518 11.2
9 15.223 47.6 18 30.792 13.1
本发明的一些方案中，上述B晶型的XRPD图谱如图3所示，即具有如图3所示的XRPD图谱所代表的特征。
本发明的一些方案中，上述B晶型的XRPD图谱解析数据如表4所示：
表4：B晶型的XRPD解析数据
Figure PCTCN2022074412-appb-000004
本发明的一些方案中，上述B晶型的差示扫描量热曲线在120.67℃和226.10℃ 附近有吸热峰。
本发明的一些方案中，上述B晶型的差示扫描量热曲线在120.67±3℃和226.10±3℃处有吸热峰。
本发明的一些方案中，上述B晶型，其DSC图谱如图4所示，即具有如图4所示的DSC图谱所代表的特征。
本发明的一些方案中，上述B晶型，其TGA图谱如图5所示，即具有如图5所示的TGA图谱所代表的特征。
本发明的一些方案中，上述B晶型的热重分析曲线在有一失重峰，失重达6.475±0.5％；具体来说所述B晶型的热重分析曲线在50℃-125℃处有一失重峰。
本发明的一些方案中，上述式I化合物的B晶型的制备方法包括如下步骤：
(1)将式I化合物与溶剂混合；
(2)过滤，干燥；
其中，所述溶剂选自水、甲醇与水混合溶剂、乙醇与水混合溶剂、丙酮与水混合溶剂或乙腈与水混合溶剂，优选为水或乙醇与水混合溶剂。
本发明的一些方案中，步骤(1)在加热的条件下进行。
本发明的一些方案中，步骤(1)的加热温度约为65～75℃，优选为约70℃。
本发明的一些方案中，步骤(1)中加入式I化合物后进行搅拌。
本发明的一些方案中，步骤(2)在过滤前进行冷却，所述冷却可以是冷却至0～30℃，优选冷却至2～8℃。
本发明的一些方案中，步骤(2)可以根据需要在冷却后进行搅拌，所述搅拌的时间可以是15～22小时，优选18小时。
本发明的一些方案中，步骤(2)干燥之前任选地用溶剂洗涤，所述洗涤溶剂选自水、甲醇与水混合溶剂、乙醇与水混合溶剂、丙酮与水混合溶剂或乙腈与水的混合溶剂，优选水或乙醇与水混合溶剂。
第三方面，本发明提供了式I化合物的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.77±0.2°、7.08±0.2°、8.34±0.2°和12.46±0.2°。
Figure PCTCN2022074412-appb-000005
本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.77±0.2°、7.08±0.2°、8.34±0.2°、12.46±0.2°、17.60±0.2°和17.92±0.2°。
本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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°和17.92±0.2°。
本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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和20.86±0.2。
本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：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和26.46±0.2。
本发明一些方案中，上述C晶型的X射线粉末衍射图谱中，特征峰的峰位置及强度如表5所示：
表5：C晶型的X射线粉末衍射图谱的特征峰的峰位置及强度
编号 2θ角(°) 相对强度(％) 编号 2θ角(°) 相对强度(％)
1 6.766 100.00 11 15.063 38.8
2 7.079 43.9 12 15.753 16.4
3 8.342 25.0 13 16.521 27.3
4 10.608 10.7 14 17.605 47.5
5 11.024 19.5 15 17.921 34.1
6 12.462 71.8 16 19.143 17.0
7 13.212 23.2 17 20.858 27.5
8 13.764 11.4 18 24.762 20.7
9 14.197 19.8 19 26.457 13.6
10 14.629 15.9      
本发明的一些方案中，上述C晶型的XRPD图谱如图6所示，即具有如图6所示的XRPD图谱所代表的特征。
本发明的一些方案中，上述C晶型的XRPD图谱解析数据如表6所示：
表6：C晶型的XRPD解析数据
Figure PCTCN2022074412-appb-000006
本发明的一些方案中，上述C晶型的差示扫描量热曲线在179.31℃±3℃处具有吸热峰。
本发明的一些方案中，上述C晶型，其DSC图谱如图7所示，即具有如图7所示的DSC图谱所代表的特征。
本发明的一些方案中，上述式I化合物的C晶型的制备方法包括如下步骤：
(1)将式I化合物与溶剂1混合；
(2)添加溶剂2；
(3)过滤，干燥；
其中，所述溶剂1选自甲醇、乙醇、异丙醇、正丙醇、四氢呋喃中的一种或一种以上；溶剂2选自丙酮、乙酸乙酯、甲基叔丁基醚、正庚烷、甲苯。
本发明的一些方案中，步骤(1)在加热的条件下进行。
本发明的一些方案中，步骤(1)的加热温度约为60～70℃，优选为约65℃。
本发明的一些方案中，步骤(1)中加入式I化合物后进行搅拌，所述搅拌时间可以是6～18小时，优选12小时。
本发明的一些方案中，步骤(2)的添加过程在温度约为60～70℃，优选为约65℃。
本发明的一些方案中，步骤(3)在过滤前进行冷却，所述冷却可以是冷却至0～30℃，优选冷却至20℃。
本发明的一些方案中，步骤(3)可以根据需要在冷却后进行搅拌，所述搅拌的时间可以是15～22小时，优选18小时。
本发明的一些方案中，步骤(3)干燥之前任选地用溶剂洗涤，所述洗涤溶剂选自甲醇、乙醇、丙酮、乙酸乙酯、甲基叔丁基醚、正庚烷、甲苯，优选为乙醇和甲基叔丁基醚。
第四方面，本发明提供了一种药物组合物，所述药物组合物包含上述A晶型、上述B晶型或上述C晶型和任选的药学上可接受的赋形剂。
本发明的一些方案中，所述所述药物组合物包含上述A晶型和任选的药学上可接受的赋形剂。
本发明的一些方案中，所述药物组合物用于治疗或预防哺乳动物(例如人)的中枢神经系统紊乱疾病。
第五方面，本发明提供了上述A晶型、上述B晶型或上述C晶型在制备治疗或预防哺乳动物(例如人)的中枢神经系统紊乱疾病的药物中的用途。
本发明的一些方案中，本发明提供了上述A晶型在制备治疗或预防哺乳动物(例如人)的中枢神经系统紊乱疾病的药物中的用途。
第六方面，本发明提供了一种治疗或预防哺乳动物(例如人)的中枢神经系统紊乱疾病的方法，所述方法包括向哺乳动物(例如人)给予治疗有效量的式(I)化合物、式I化合物的A晶型、包含式I化合物的A晶型的药物组合物、式I化合物的B晶型、包含式I化合物B晶型的药物组合物、式I化合物的C晶型和包含I化合物的C晶型的药物组合物。
本发明的一些方案中，所述方法包括向哺乳动物(例如人)给予治疗有效量的式(I) 化合物、式I化合物的A晶型、包含式I化合物的A晶型的药物组合物。
本发明的一些方案中，所述中枢神经系统紊乱疾病包括但不限于震颤、睡眠障碍、抑郁症、精神抑郁病症、双相性精神障碍、焦虑症、应激反应、创伤后精神紧张性障碍、强制性障碍、精神分裂症、情感分裂性精神障碍、癫痫、癫痫发作、记忆障碍和/或认知障碍、痴呆、运动障碍、人格障碍、自闭症、单病因的自闭症、疼痛、外伤性脑损伤、血管疾病、物质滥用障碍和/或戒断综合征或耳鸣；或者
所述中枢神经系统紊乱疾病包括但不限于特发性震颤、癫痫、临床抑郁、分娩后或产后抑郁、非典型抑郁、精神病性严重抑郁症、紧张型抑郁、季节性情绪失调症、心境恶劣、双重抑郁、抑郁性人格障碍、复发性短暂抑郁、轻度抑郁障碍、双向性精神障碍或躁狂抑郁性障碍、创伤后应激障碍、因慢性医学病状引起的抑郁、耐治疗性抑郁、难治性抑郁、自杀倾向、自杀观念、自杀行为、外伤性脑损伤、广泛性焦虑症、社会焦虑症、注意缺陷多动障碍、痴呆、亨廷顿舞蹈症、帕金森氏症、神经性疼痛、损伤相关的疼痛综合征、急性疼痛、长期疼痛、中风、缺血、血管畸形、对阿片剂、可卡因和/或酒精成瘾或失眠。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了本发明的3-羟基-5-孕烷-20-酮衍生物的A晶型的XRPD图谱；
图2显示了本发明的3-羟基-5-孕烷-20-酮衍生物的A晶型的DSC图谱；
图3显示了本发明的3-羟基-5-孕烷-20-酮衍生物的B晶型的XRPD图谱；
图4显示了本发明的3-羟基-5-孕烷-20-酮衍生物的B晶型的DSC图谱；
图5显示了本发明的3-羟基-5-孕烷-20-酮衍生物的B晶型的TGA图谱；
图6显示了本发明的3-羟基-5-孕烷-20-酮衍生物的C晶型的XRPD图谱；
图7显示了本发明的3-羟基-5-孕烷-20-酮衍生物的C晶型的DSC图谱；
图8显示了本发明的3-羟基-5-孕烷-20-酮衍生物的A晶型室温放置1个月(191222 JS1M)、2个月(191222 JS2M)、3个月(191222 JS3M)时刻点的XRPD叠加图谱。
具体实施方式
发明人经过广泛而深入的研究，出乎意料地发现一种别孕烷醇酮类化合物的衍生物，该衍生物能够显著改善别孕烷醇酮类化合物的水溶性，在水溶液中具有一定的储存稳定性，并且可以制成长效、缓释且给药后个体差异小的制剂。该衍生物制成的制剂可以较长时间维持体内有效生理浓度的别孕烷醇酮并且给药方便，从而能够具备提 高患者的依从度等优点。
在此基础上，本发明人发现了该衍生物的晶型A、晶型B、晶型C，所述晶型在物理稳定性、热力学稳定性和机械稳定性等至少一个方面具备优势，从而完成了本发明。
术语
在本文中，“本发明的衍生物”、“3-羟基-5-孕烷-20-酮的衍生物”、“别孕烷醇酮类化合物的衍生物”具备相同的含义并且可以互换使用。这些术语均表示下式I所示化合物：
Figure PCTCN2022074412-appb-000007
本文中，式I化合物化学名称为：盐酸甘氨酸-L-缬氨酸3α-羟基-5α-孕甾-20-酮酯。
多晶型
本领域技术人员知晓，固体以无定形的形式或结晶的形式存在。在结晶形式的情况下，分子定位于三维晶格格位内。当化合物从溶液或浆液中结晶出来时，它可以不同的空间点阵排列结晶(这种性质被称作“多晶型现象”)，形成具有不同的结晶形式的晶体，这各种结晶形式被称作“多晶型物”。给定物质的不同多晶型物可在一个或多个物理属性方面(如溶解度和溶解速率、真比重、晶形、堆积方式、流动性和/或固态稳定性)彼此不同。
化合物的多晶型形式可以表现出不同的熔点、吸湿性、稳定性、溶解度、生物利用度、生物活性和流动性等，而这些是影响成药性的重要因素。
本文所用的“晶体”、“本发明晶体”、“多晶型”、“本发明的多晶型”等术语可互换使用，例如，本发明第一方面所述的晶体，其晶型为晶型A或称为晶体A。
进一步地，在本文中，“本发明的衍生物的多晶型”、“3-羟基-5-孕烷-20-酮的衍生物的多晶型”、“别孕烷醇酮类化合物的衍生物的多晶型”均是指式I所示化合物的晶型。
结晶
可以通过操作溶液，使得感兴趣化合物的溶解度极限被超过，从而完成生产规模的结晶。这可以通过多种方法来完成，例如，在相对高的温度下溶解化合物，然后冷却溶液至饱和极限以下。或者通过沸腾、常压蒸发、真空干燥或通过其它的一些方法来减小液体体积。或者可通过加入抗溶剂或化合物在其中具有低的溶解度的溶剂或这 样的溶剂的混合物，来降低感兴趣化合物的溶解度。另一种可选方法是调节pH值以降低溶解度。有关结晶方面的详细描述请参见Crystallization，第三版，J W Mullens,Butterworth-Heineman Ltd.，1993,ISBN0750611294。
结晶的优化可包括用所需形式的晶体作为晶种接种于结晶介质中。另外，许多结晶方法使用上述策略的组合。例如，可以在高温下将感兴趣的化合物溶解在溶剂中，随后通过受控方式加入适当体积的抗溶剂，以使体系正好在饱和水平之下。此时，可加入所需形式的晶种(并保持晶种的完整性)，将体系冷却以完成结晶。
在本发明中，可以采用将式I化合物溶解于溶剂中；随后将所得溶液降温，或者将所得溶液缓慢挥发，或者向所得溶液中加入抗溶剂，以使得式I化合物的晶体析出，从而获得式I化合物的晶体。在获得式I化合物的晶体后，还可任选干燥得到的式I化合物的晶体。
在具体的实施方式中，所述溶剂选自以下的一种或多种：水、甲醇、乙醇、丙酮、乙酸乙酯、甲醇醚、正庚烷、甲苯。
在优选的实施方式中，在步骤(1)中，可以适当升温以促进式I化合物的溶解。
在优选的实施方式中，所述的冷却是将式I化合物的溶液冷却至20-30℃。
溶剂合物
化合物或药物分子与溶剂分子接触过程中，外部条件与内部条件因素造成溶剂分子与化合物分子形成共晶而残留在固体物质中的情况难以避免。化合物与溶剂结晶后形成的物质称作溶剂合物(solvate)。容易与有机化合物形成溶剂合物的溶剂种类为水、甲醇、苯、乙醇、醚、芳烃、杂环芳烃等。
水合物是一种特殊的溶剂合物。在制药工业中，无论在原料药的合成、药物制剂、药物贮存和药物活性评价中，水合物都因为其特殊性而具有单独讨论的价值。
本发明中，式I所示化合物的晶体，可以为非溶剂合物，也可以为溶剂合物。例如，本发明的晶型B就是一种水合物。
本发明的药物组合物以及施用方式
在本发明的3-羟基-5-孕烷-20酮衍生物的多晶型的基础上，本发明进一步提供了包含所述多晶型的药物组合物。所述药物组合物因为其中的3-羟基-5-孕烷-20酮衍生物而具备治疗中枢神经系统异常引起的疾病的作用，还因为其中的3-羟基-5-孕烷-20酮衍生物的多晶型而具备优异的稳定性，能够长期储存；特别是其还具有热稳定性和机械稳定性，便于制备成药物制剂形式。
在具体的实施方式中，所述中枢神经系统异常引起的疾病包括但不限于震颤、癫痫、抑郁症或焦虑障碍。更详细地、所述中枢神经系统紊乱疾病包括但不限于特发性震颤、癫痫、临床抑郁、分娩后或产后抑郁、非典型抑郁、精神病性严重抑郁症、紧张型抑郁、季节性情绪失调症、心境恶劣、双重抑郁、抑郁性人格障碍、复发性短暂 抑郁、轻度抑郁障碍、双向性精神障碍或躁狂抑郁性障碍、创伤后应激障碍、因慢性医学病状引起的抑郁、耐治疗性抑郁、难治性抑郁、自杀倾向、自杀观念或自杀行为。
本发明的药物组合物还包含任选的药学上可接受的载体。在本文中，术语“组合物”旨在涵盖包含特定量的特定成分的产品，以及直接或间接地以特定量的特定成分的组合产生的任何产品；而药学上可接受的载体是指对有机体不引起明显的刺激性并且不干扰所给予化合物的生物活性和性质的载体、稀释剂或赋形剂；即，所述载体、稀释剂或赋形剂必须与制剂的其它成分相容并且对其接受者无害。
可以采用本领域技术人员公知的方法制备本发明的药物组合物。例如，可以将本发明的化合物与药学上可接受的载体、稀释剂或赋形剂混合来制备相应的药物组合物。进一步地，本领域技术人员可以将本发明的化合物或药物组合物制成各种合适的剂型，包括但不限于适合直肠给药、透皮给药、皮内给药、鞘内给药、皮下给药、静脉内给药、肌内给药、关节腔给药、口腔粘膜给药、阴道给药和鼻内给药等等的形式。根据所需的剂型，本领域技术人员也可以选择相应的药学上可接受的载体、稀释剂或赋形剂。
本发明的药物组合物中可以包含安全有效量的3-羟基-5-孕烷-20酮衍生物的多晶型。所述“安全有效量”指的是：化合物(或晶型)的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有30-800mg本发明的晶型/剂，更佳地，含有50-600mg本发明的晶型/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2022074412-appb-000008
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的多晶型物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙 二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明的多晶型物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
疾病的预防和治疗方法
如上所述，鉴于本发明的3-羟基-5-孕烷-20酮衍生物在给予受试者后，能够在合适的条件下释放出具备活性的别孕烷醇酮。本领域技术人员能够理解，本发明的3-羟基-5-孕烷-20酮衍生物的多晶型或药物组合物可以用于预防或治疗中枢神经系统紊乱疾病，包括但不限于上述中枢神经系统紊乱疾病。
本发明的预防或治疗中枢神经系统紊乱疾病的方法包括将治疗有效量的上述化合物、药物组合物给予有此需要的对象。所述对象包括但不限于人。
本发明的优点：
1.本发明首次提供了式Ⅰ化合物的多晶型；
2.式Ⅰ化合物的A晶型、式Ⅰ化合物的B晶和式Ⅰ化合物的C晶型稳定性好，吸湿性小，水溶性好，成药前景良好。
3.本发明的晶型制备工艺简单，从而具备优异的工业化实施潜力。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发 明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
测试方法：
XRPD(X-射线粉末衍射)方法1：将约10毫克样品均匀平铺在单晶硅样品盘上，用以下参数进行XRPD测试。仪器型号：X’Pert 3型X射线衍射仪，靶：Cu-Kα(40mA，45kV)，扫描范围在2θ区间自3°至40°。
XRPD(X-射线粉末衍射)方法2：将约10毫克样品均匀平铺在单晶硅样品盘上，用以下参数进行XRPD测试。仪器型号：BRUKER D8 X射线衍射仪，靶：Cu-Kα(40kV，40mA)。扫描范围在2θ区间自3°至40°，扫描速度为8°/分钟。
由包括以下的多种因素产生与这类X射线粉末衍射分析结果相关的测量差异：(a)样品制备物(例如样品高度)中的误差，(b)仪器误差，(c)校准差异，(d)操作人员误差(包括在测定峰位置时出现的误差)，和(e)物质的性质(例如优选的定向误差)。校准误差和样品高度误差经常导致所有峰在相同方向中的位移。当使用平的支架时，样品高度的小差异将导致XRPD峰位置的大位移。系统研究显示1mm的样品高度差异可以导致高至1°的2θ的峰位移。可以从X射线衍射图鉴定这些位移，并且可以通过针对所述位移进行补偿(将系统校准因子用于所有峰位置值)或再校准仪器消除所述位移。如上所述，通过应用系统校准因子使峰位置一致，可校正来自不同仪器的测量误差。
TGA(热重分析)方法：仪器型号：TA Q500热重分析仪，采用N 2气氛，升温速度为10℃/min。
DSC(差示扫描量热法)方法：仪器型号：METTLER TOLEDO DSC3+，采用N 2气氛，升温速度为10℃/min。
实施例1.式I所示化合物的合成
Figure PCTCN2022074412-appb-000009
中间体2.1的制备：
向250mL单口反应瓶中加入化合物1.3(5.0g，12.0mmol)，Boc-Gly-OH(2.5g，14.3mmol)和二氯甲烷(50mL)，磁力搅拌。随后加入N,N-二异丙基乙胺(3.1g，24.0mmol)，HOBT(342mg，2.4mmol)和EDCI(2.8g，14.6mmol)。室温下反应4小时，反应液用H 2O(50mL)洗，1N HCl(50mL)洗，饱和NaHCO 3水溶液洗涤、纯水洗涤。减压浓缩，粗品柱层析(石油醚(60-90)/乙酸乙酯10:1-3:1)得类白色固体(5.7g，收率82.8％)。
中间体2.2的制备：
向250mL三口反应瓶中加入化合物2.1(5.5g，9.63mmol，1.0eq)和二氯甲烷(22mL)。氮气保护，磁力搅拌，磁力搅拌，0℃下加入三氟乙酸(10.9g，95.7mmol)，随后室温反应3小时。减压浓缩，蒸干溶剂，加入二氯甲烷(50mL)，用饱和碳酸氢钠水溶液洗，水相用二氯甲烷(30mL)萃取。合并有机相，再用50mL纯水洗，无水硫酸钠干燥。过滤，减压浓缩，油泵真空干燥得类白色固体(4.5g，收率99.0％)。
式I所示化合物的制备：
向250mL单口反应瓶中加入化合物2.2(4.5g，9.5mmol，1.0eq)和乙酸乙酯(27mL)。氮气保护，磁力搅拌，磁力搅拌,室温下加氯化氢乙酸乙酯溶液(3M，3.8mL，11.4mmol)，继续搅拌1小时。减压浓缩，蒸干溶剂，加入乙腈(70mL)，室温下搅拌2小时。过滤，固体用乙腈(15mL)洗。40℃下用油泵抽真空干燥2小时,得白色固体(3.5g，收率72.2％)。
1H 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).
MS:m/z[M+H]+475.3.
实施例2.式I化合物晶型A的制备
向100ml烧瓶中加入乙酸乙酯60ml、式I化合物10.0g。升温至60～65℃，悬 浮搅拌6h-24h，然后降至20-30℃，过滤，干燥得白色固体。
经测试，所得晶型的XRPD图(采用XRPD方法1测得)和DSC图基本上分别如图1和2所示。所得晶型的XRPD图谱的衍射角数据基本如表7所示，其中2θ值误差范围为±0.2°。
表7：A晶型的XRPD解析数据
Figure PCTCN2022074412-appb-000010
实施例3.式I化合物晶型B的制备
向100ml烧瓶中加入纯化水60ml、式I化合物10.0g，升温至65～75℃，搅拌至固体溶解，然后降温至2～8℃至析晶完全，过滤，干燥得白色固体。
经测试，所得晶型B的XRPD图基本上如图3所示(采用XRPD方法2测得)。所得晶型的XRPD图谱的衍射角数据基本如表8所示，其中2θ值误差范围为±0.2°。
表8.晶型B的XRPD解析数据
Figure PCTCN2022074412-appb-000011
经测试，所得B晶型的DSC图谱基本如图4所示，B晶型的差示扫描量热曲线在120.67℃和226.10℃附近有吸热峰，说明B晶型可能为水合物。
进一步测试，所得晶型B的TGA图基本上如图5所示。从该图可以看出，存在6.475±0.5％的失重。因此，晶型B应是二水合物。
实施例4.式I化合物晶型C的制备
向250ml烧瓶中加入乙醇40ml、式I化合物10.0g，升温至65～75℃，搅拌至固体溶解，待溶解完全向其加入甲基叔丁基醚80ml，然后降温至2～8℃至析晶完全， 过滤，干燥得白色固体。
经测试，所得晶型的XRPD图(采用XRPD方法2测得)和DSC图基本上分别如图6和7所示。所得晶型的XRPD图谱的衍射角数据基本如表9所示，其中2θ值误差范围为±0.2°。
表9：C晶型的XRPD解析数据
Figure PCTCN2022074412-appb-000012
实施例5式I化合物的多晶型研究
将式I化合物A晶型在相应溶剂中加热悬浮打浆，在40℃下避光搅拌2天，将溶液离心去沉淀干燥后经XPRD检测，结果如下：
序号 溶剂 晶型
1 乙酸乙酯 A晶型
2 乙醇 A晶型
3 丙酮 A晶型
4 甲基叔丁基醚 A晶型
5 正庚烷 A晶型
6 甲苯 A晶型
7 甲醇 A晶型
经上表中的结果分析得出晶型A稳定性良好，在不同溶剂体系下仍然能保持稳定。
实施例6.晶型A的机械稳定性研究
将式Ⅰ化合物晶型A经过相应的机械条件处理后，取一定的样品经XRPD检测，结果如下：
序号 机械条件 晶型
1 玛瑙研钵中研磨数分钟 A晶型
2 机械粉碎机中粉碎数分钟 A晶型
3 经压片机压片 A晶型
经上表中的结果分析得出研磨、机械粉碎以及压力对晶型A未发生转晶，即研 磨、机械粉碎以及压力对晶型A的稳定性无影响。
实施例7.晶型A的稳定性加速实验研究
将实施例1中所得晶型A敞口平摊放置，在高温、高湿(40℃，RH75％)条件下放置3个月，分别在1个月、2个月、3个月取一定样品检测XRPD图谱来评价晶型A的稳定性。
经过实验及XRPD图谱(采用XRPD方法1测得)可知，A晶型在1个月(191222 JS1M)、2个月(191222 JS2M)、3个月(191222 JS3M)时刻点的XRPD图谱与附图1中晶型A的XRPD图谱基本相同，晶型A的稳定性良好，经过3个月的稳定性加速实验，晶型A没有发生改变，具体图谱见附图8。
实施例8.晶型的物理稳定性研究
将实施例1中所得晶型A、晶型B、晶型C分别敞口平摊放置，考察在高温(60℃)、高湿(RH92.5％)、光照(4500±500Lux)条件下样品的稳定性。考察取样时间为5天、10天、30天，HPLC检测纯度见表10。
表10晶型的稳定性实验
Figure PCTCN2022074412-appb-000013
经上表中的结果分析得出晶型A、晶型B及进行C在高温、高湿、及光照条件下稳定性好，具有良好的成药前景。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 式I化合物的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.66±0.2°、13.53±0.2°、16.75±0.2°和25.39±0.2°；
    Figure PCTCN2022074412-appb-100001
  2. 如权利要求1所述的式I化合物的A晶型，其特征在于，所述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：11.96±0.2°、12.66±0.2°、13.53±0.2°、14.51±0.2°、16.75±0.2°和25.39±0.2°。
  3. 式I化合物的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.69±0.2°、13.17±0.2°、13.37±0.2°和15.22±0.2°；
    Figure PCTCN2022074412-appb-100002
  4. 如权利要求3所述的式I化合物的B晶型，其特征在于，所述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：4.26±0.2°、4.50±0.2°、10.69±0.2°、13.17±0.2°、13.37±0.2°、和15.22±0.2°。
  5. 式I化合物的C晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.77±0.2°、7.08±0.2°、8.34±0.2°和12.46±0.2°；
    Figure PCTCN2022074412-appb-100003
  6. 如权利要求5所述的式I化合物的C晶型，其特征在于，所述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.77±0.2°、7.08±0.2°、8.34±0.2°、12.46±0.2°、17.60±0.2°和17.92±0.2°。
  7. 一种药物组合物，所述药物组合物包含权利要求1或2所述的A晶型、权利要求3或4所述的B晶型或权利要求5或6所述的C晶型和任选的药学上可接受的赋形剂。
  8. 如权利要求7所述的药物组合物，其特征在于，所述所述药物组合物包含权利要求1或2所述的A晶型和任选的药学上可接受的赋形剂。
  9. 权利要求1或2所述的A晶型、权利要求3或4所述的B晶型或权利要求5或6所述的C晶型在制备治疗或预防哺乳动物(例如人)的中枢神经系统紊乱疾病的药 物中的用途。
  10. 一种治疗或预防哺乳动物(例如人)的中枢神经系统紊乱疾病的方法，所述方法包括向哺乳动物(例如人)给予治疗有效量的式(I)化合物、权利要求1或2所述的A晶型、包含权利要求1或2所述的A晶型的药物组合物、权利要求3或4所述的B晶型、包含权利要求3或4所述的B晶型的药物组合物、权利要求5或6所述的C晶型和包含权利要求5或6所述的C晶型的药物组合物。
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