WO2023040851A1 - 一种水溶性别孕烷醇酮衍生物及其制备方法和用途 - Google Patents

一种水溶性别孕烷醇酮衍生物及其制备方法和用途 Download PDF

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WO2023040851A1
WO2023040851A1 PCT/CN2022/118549 CN2022118549W WO2023040851A1 WO 2023040851 A1 WO2023040851 A1 WO 2023040851A1 CN 2022118549 W CN2022118549 W CN 2022118549W WO 2023040851 A1 WO2023040851 A1 WO 2023040851A1
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compound
formula
depression
acid
present
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PCT/CN2022/118549
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English (en)
French (fr)
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刘飞
吴刚
王晓波
林成刚
赵欣
陈庆
刘敏
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南京迈诺威医药科技有限公司
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    • 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
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the field of medicine, in particular to a water-soluble sex pregnanolone derivative suitable for oral administration, a preparation method and its use, a pharmaceutical composition containing it and its use for preventing or treating central nervous system disorders, sedative hypnosis , the use of treating Alzheimer's disease, treating epilepsy or treating depression, especially postpartum depression.
  • Neuroactive steroids are steroids that are active in nervous tissue and play an important regulatory role in the human body. Neurosteroids mainly include progesterone, pregnenolone, and progesterone metabolite pregnenolone. Neuroactive steroids play an important physiological role in the human body, and impaired synthesis in the body can lead to different neurological (CN 104736158 A) or psychiatric diseases (Expert Opin TherTargets.2014; 18(6):679-90).
  • pregnanolones are generally considered to include the following compounds: pregnanolone, allopregnolone, epipregnanolone, and isopregnolone (see Table 1).
  • Patent document CN1300219A discloses that different pregnanolone substances have different action mechanisms in the regulation of the central nervous system, and have different physiological effects on the central nervous system.
  • Pregnanolone (3 ⁇ -OH-5 ⁇ -pregnane-20-one) is an important GABAA ( ⁇ -aminobutyric acid A) receptor, which has anti-epileptic, hypnotic, anti-migraine and anti-anxiety effects.
  • GABAA ⁇ -aminobutyric acid A receptor
  • Pregnanolone (3 ⁇ -OH-5 ⁇ -pregnane-20-one) is a research hotspot in recent years. As early as 1986, it was pointed out that pregnanolone is a positive modulator of GABAA receptor. Pregnanolone may mainly bind to the ⁇ and ⁇ subunits of GABAA receptors, increase the opening frequency of chloride ion channels on the receptors, reduce nerve excitability, and thus produce sedative and anti-anxiety effects.
  • pregnanolone As pregnancy progresses, the plasma concentration of pregnanolone in healthy pregnant women increases, and after delivery, the concentration of pregnanolone decreases sharply. Studies have shown that the decline in the content of pregnanolone 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 pregnanolone can significantly improve the above mental symptoms.
  • the existing allopregnolone has low water solubility, poor oral bioavailability, human plasma half-life is about 45 minutes, and can be rapidly metabolized, which is not conducive to making oral preparations.
  • the patent document CN104736158A discloses a method of preparing a composition of pippregnanolone and cyclodextrin and infusing it intravenously to treat epilepsy or persistent epilepsy.
  • the composition of pippregnanolone and cyclodextrin Among them, the proportion of cyclodextrin is 1-30%, its blood concentration is 50-2300nM, and the treatment process lasts for more than 24 hours.
  • cyclodextrin is a high-molecular compound, which has a certain risk of nephrotoxicity (Study on the safety of cyclodextrin derivatives of medicinal supramolecular materials, China Materials Science and Technology and Equipment, No. 5, 2009, pages 1-3), Therefore, there is a potential safety hazard.
  • Piopregnolone Injection was approved for marketing in the United States. Injection preparation, which forms an inclusion complex of piagranolone and sulfobutyl ⁇ -cyclodextrin sodium to increase the solubility of pippregnanolone. Piespregnanolone injection produces stable and physiological concentration of piespregnanolone through intravenous injection to achieve the therapeutic effect, but it needs up to 60 hours of intravenous infusion, the infusion method is complicated, and professional treatment is required during the infusion. Continuous on-site monitoring by medical staff and necessary interventions. As a result, the patient's compliance with the piopregnanolone injection is poor, and it is extremely inconvenient for medical staff to use.
  • the infusion method of Pelpregnanolone Injection is as follows: 0-4h: infusion at a dose of 30 ⁇ g/kg/h; 4-24h: increase the dose to 60 ⁇ g/kg/h; 24-52h: increase the dose to 90 ⁇ g/kg/h (for patients who cannot tolerate 90 ⁇ g/kg/h, the dose can also be set to 60 ⁇ g/kg/h); 52-56h: reduce the dose to 60 ⁇ g/kg/h; 56- 60h: Reduce the dose to 30 ⁇ g/kg/h.
  • the purpose of the present invention is to provide an allopregnanolone derivative which is suitable for oral administration, has high bioavailability, can act quickly and maintain a stable physiological concentration in the body for a long time.
  • the object of the present invention is also to provide a composition containing the allopregnolone derivatives and the application of the above allopregnolone derivatives in the preparation of a medicament for treating diseases caused by abnormalities in the central nervous system.
  • the present invention provides a compound of general formula I, its racemate, stereoisomer, tautomer, solvate, polymorph or their pharmaceutically acceptable salt:
  • R 2 and R 4 are independently selected from H (hydrogen) or D (deuterium);
  • R 1 and R 3 are independently selected from CH 3 , CH 2 D, CHD 2 or CD 3 ;
  • the compound of formula I contains at least one deuterium atom.
  • the compound of formula I contains one to eight deuterium atoms, or the compound of formula I contains one to seven deuterium atoms, or the compound of formula I contains one to six deuterium atoms, specifically, the compound of formula I contains at least one , two, three, four, five, six, seven or eight deuterium atoms.
  • R is D.
  • R2 is D
  • R1 and R3 are CH3 .
  • R2 is D
  • R1 and R3 are CD3 .
  • the deuteration rate of each D is at least 3500 times (52.5%), preferably at least 4000 times (60%), preferably at least 4500 times (67.5%), more preferably , at least 5000 times (75%), more preferably at least 5500 times (82.5%), more preferably at least 6000 times (90%), more preferably at least 6333.3 times (95%), further Preferably, at least 6466.7 times (97%), more preferably, at least 6566.7 times (98.5%), more preferably, at least 6600 times (99%), further preferably, at least 6633.3 times (99.5%) .
  • any atoms not designated as deuterium are present in their natural isotopic abundance.
  • the compound of formula I is the compound shown in formula Ia or formula Ib:
  • R 1 , R 2 , R 3 , and R 4 have the above-mentioned definitions.
  • the present invention includes all tautomeric forms.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). Accordingly, the present invention includes enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and/or diastereoisomers, the stereoisomeric homogeneous components can be isolated in a known manner.
  • the present invention also provides a preparation method of the compound described in the above formula I, comprising the following steps:
  • R 1 -R 4 have the above definition
  • R 5 is a protecting group, such as an amino protecting group, such as tert-butoxycarbonyl (Boc);
  • the compound of formula II is reacted with the compound of formula III, and the protecting group is removed to obtain the compound of formula I.
  • the present invention also provides a pharmaceutical composition, including the compounds represented by formula I, their racemates, stereoisomers, tautomers, solvates, polymorphs or their pharmaceutically acceptable salts at least one of .
  • the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition is for oral administration, and the pharmaceutical composition can be tablets, pills, lozenges, sugar-coated agents, capsules and the like.
  • the pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, granulation methods, dragee-making methods and the like.
  • solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating.
  • Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • the present invention provides the compound of formula I of the present invention, its racemate, stereoisomer, tautomer, solvate, polymorph or their pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention Use in the preparation of drugs for preventing or treating central nervous system disorders, for sedation and hypnosis, for treating Alzheimer's disease, for treating epilepsy or for treating depression, especially postpartum depression.
  • the present invention provides methods for preventing or treating central nervous system disorders, sedative hypnosis, treating Alzheimer's disease, treating epilepsy or treating depression, especially postpartum depression, which comprises administering a preventive or therapeutically effective amount of the present invention to individuals in need.
  • the central nervous system diseases are, for example, traumatic brain injury, essential tremor, epilepsy (including refractory persistent epilepsy, rare genetic epilepsy (such as Dravet syndrome and Rett syndrome), depression, etc. (including postpartum depression) and Alzheimer's disease.
  • epilepsy including refractory persistent epilepsy, rare genetic epilepsy (such as Dravet syndrome and Rett syndrome), depression, etc. (including postpartum depression) and Alzheimer's disease.
  • the central nervous system disease is for example selected from essential tremor, epilepsy, clinical depression, postpartum or postpartum depression, atypical depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, bipolar depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar or manic-depressive disorder, post-traumatic stress disorder, chronic medical Depression caused by a medical condition, treatment-resistant depression, treatment-resistant depression, suicidal ideation, suicidal ideation, or suicidal behavior.
  • the daily dose administered is 0.01 to 200 mg/kg body weight.
  • Dosage regimens may be adjusted to provide the optimum desired response. For example, a single oral administration may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. It is further understood that for any given individual, the specific dosing regimen will be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • prevention or treatment means administering the compound or formulation of the present invention to prevent, improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • deuteration rate refers to the ratio of the amount of labeled synthetic isotope to the amount of naturally occurring isotope. Unless otherwise specified, when a position in a structure is defined as H, hydrogen (H-1), that position contains only the naturally occurring isotopic amount. When a position in the structure is defined as D, deuterium (H-2), the position contains an isotope at least 3340 times greater than the naturally occurring isotope (0.015%) (ie, at least 50.1% deuterium isotope).
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the invention for the onset of one or more symptoms of a particular disease, condition or disorder described herein.
  • the amount of a compound of the invention that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art according to its own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the pharmaceutically acceptable salts of the compounds of the present invention include their salts with pharmaceutically acceptable acids and their salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable acid refers to pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, formic acid, acetic acid, acetoacetic acid, trifluoroacetic acid, propionic acid, pyruvic acid , butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, stearic acid, palmitic acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 1, 5-naphthalene disulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, sulfamic acid, lactic acid, benzenesulfonic acid, p-toluenesulfonic acid, malonic acid, succinic acid, glutaric
  • pharmaceutically acceptable base refers to a pharmaceutically acceptable base such as an inorganic base (alkali metal hydroxide or alkaline earth metal hydroxide, etc.) or an organic base (such as an amine (primary, secondary or tertiary amines), etc.).
  • suitable salts include, but are not limited to, organic salts derived from amino acids, ammonia, primary, secondary and tertiary amines, and cyclic amines (e.g., diethylamine salts, piperidinium salts, morpholine salts, piperazine salts, choline salt, meglumine salt, tromethamine salt, etc.), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • organic salts derived from amino acids ammonia, primary, secondary and tertiary amines, and cyclic amines
  • diethylamine salts e.g., diethylamine salts, piperidinium salts, morpholine salts, piperazine salts, choline salt, meglumine salt, tromethamine salt, etc.
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,
  • solvate is a compound of the present invention which forms a complex in solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of solvates in which coordination is with water.
  • composition refers to a mixture of one or more compounds of the present invention or their salts and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the invention to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with suitable pharmaceutically acceptable excipients.
  • suitable pharmaceutically acceptable excipients for oral administration, it can be prepared by mixing the active compound with the well-known pharmaceutically acceptable excipients in the art.
  • the pharmaceutical composition enable the compounds of the present invention to be formulated into tablets, pills, lozenges, dragees, capsules, etc. for oral administration to patients.
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • the present invention provides a pippregnanolone derivative represented by formula I.
  • the pippregnanolone derivatives suitable for oral administration are obtained by modifying the structure of the pippregnanolone hydroxyl group. Alkanolone derivatives with good physical/chemical stability.
  • the active drug can be released in the body to exert a pharmacological effect.
  • the poppregnanolone derivatives of the present invention have stable metabolism, good oral bioavailability, small toxic and side effects, and can be made into a suitable pippregnanolone that can take effect quickly after oral administration and maintain a stable physiological concentration in the body for a long time. Oral preparations can improve drug safety, patient compliance and administration convenience.
  • Fig. 2 Pharmacokinetic curves of allopregnolone in beagle dog plasma after oral administration of the compound of the present invention.
  • the intermediate compound of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and the methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • aq stands for aqueous solution
  • DMSO dimethyl sulfoxide
  • EtOAc stands for ethyl acetate
  • EtOH stands for ethanol
  • TFA trifluoroacetic acid
  • i-PrOH stands for isopropanol
  • ECS stands for extracellular fluid
  • ICS represents intracellular fluid
  • MI001 represents allopregnolone.
  • Step 1 Add MI001 (50.0g, 157.0mmol, 1.0eq), Boc-L-Val-OH (tert-butoxycarbonyl L-valine) (40.9g, 188.2mmol) to a 1000mL three-neck round bottom reaction flask, 4-Dimethylaminopyridine (1.9g, 15.5mmol) and 500mL of dichloromethane were stirred, and the reaction system was cooled to -5 to 10°C under nitrogen protection, and dicyclohexylcarbodiimide (38.9g, 188.5mmol ) in dichloromethane (80mL) solution, then reacted at this temperature for 3 hours, TLC (Thin Layer Chromatography, thin layer chromatography) monitoring reaction was complete, stop the reaction.
  • TLC Thin Layer Chromatography, thin layer chromatography
  • reaction solution was filtered, and the filter cake was washed with dichloromethane (100 mL).
  • the filtrate was concentrated under reduced pressure, and the crude product was purified by 100-200 mesh silica gel sand column chromatography (petroleum ether (60-90)/ethyl acetate 20:1-10:1) to obtain an off-white waxy solid (78.2 g, yield 96.2%).
  • Step 2 Add the product of Step 1 (78g, 150.6mmol, 1.0eq) and dichloromethane (320mL) into a 1000mL three-neck round bottom reaction flask. Under nitrogen protection and magnetic stirring, the system was cooled to 0-10°C and trifluoroacetic acid (171.8g, 1506mmol) was quickly added dropwise, followed by reaction at 15-25°C for 3 hours to stop the reaction. The reaction solution was quenched by pouring it into a sodium bicarbonate (164.5 g, 1958 mmol) solution (780 mL of water), adding dichloromethane (700 mL), stirring, and standing for liquid separation to obtain an organic phase. The organic phase was washed with 500 mL of pure water and dried over anhydrous sodium sulfate. Filtration and concentration gave an off-white solid (59.5 g, yield 94.6%).
  • Step 3 Take 0.5g of the above product, add isopropanol (0.5mL), isopropyl acetate (7.5ml) to dissolve at room temperature, then add hydrochloric acid ethyl acetate solution (0.6ml, 2.0M hydrochloric acid ethyl acetate) dropwise, cool down A large amount of solid precipitated at 5-10°C, and was filtered and dried to obtain 0.36 g of the product, with a yield of 66.5% and a purity of 99.90% by HPLC.
  • Configuration of external standard solution Accurately weigh 50mg of the compound to be tested into a 10mL volumetric flask, add an appropriate amount of pure water for ultrasonic dissolution, dilute to the mark and mix well to obtain an external standard solution with a concentration of 5.0mg/mL.
  • Preparation of the solution to be tested Accurately weigh 1.0 g of the compound to be tested and dissolve it in 20 mL of pure water, stir and dissolve at 25°C for 24 hours, centrifuge, take the supernatant, and filter with a 0.45 ⁇ m filter membrane to obtain the filtrate. Precisely measure 1mL of the above filtrate into a 5mL measuring bottle, add pure water to dilute to the mark, and mix well to obtain the solution to be tested.
  • Chromatographic column Waters XBridge C8 3.5 ⁇ m 4.6*100mm NRT2019-21#, column temperature: 45°C, detection wavelength: 205nm;
  • Mobile phase A 10mM/L (NH 4 ) 2 HPO 4 solution
  • mobile phase B acetonitrile
  • isocratic elution A:B 40:60
  • the manual patch clamp method was used to detect the effect of the compound on the hERG potassium channel current stably expressed in Chinese hamster ovary cells.
  • the inhibition of the drug on the hERG potassium channel in the heart is the main reason for the prolonged myocardial repolarization.
  • experimental compound compound 1 prepared by the method of the present invention, comparative compound 1
  • dimethyl sulfoxide Sigma-Aldrich (Shanghai) Trading Co., Ltd.
  • cisapride positive reference substance, commercially available
  • CHO Chinese hamster ovary
  • CHO-hERG cells Sophion Biosciences
  • CHO-hERG cells in exponential growth phase were harvested and resuspended in ECS (extracellular fluid) for further use.
  • the cells are planted in the cell recording tank, placed on the stage of an inverted microscope, and a cell in the recording tank is randomly selected for the experiment.
  • the perfusion system was fixed on the inverted microscope stage and cells were continuously perfused with ECS.
  • Electrodes for manual patch clamp experiments were prepared from capillary glass tubes filled with intracellular fluid. On the day of the patch clamp test, electrodes were prepared using borosilicate glass tubes (GC150TF-10, Harvard Apparatus Co. UK). After the electrode is filled with ICS, the resistance is between 2-5M ⁇ .
  • the clamping voltage was -80mV, the first step depolarized to +60mV and maintained for 850ms to open the hERG channel. Then, the voltage is set to -50mV and maintained for 1275ms, resulting in rebound current or tail current, the peak value of tail current will be measured and used for analysis. Finally, the voltage returns to the clamping voltage (-80mV).
  • monitor the peak value of the tail current until more than 3 scanning curves are stabilized, then perfuse the test product/positive control working solution to be tested until the test product/positive control working solution has a positive effect on the hERG current. Inhibition of the peak reaches a steady state.
  • the hERG current was recorded under the whole-cell patch clamp technique, and the recording temperature was room temperature.
  • the output signal of the patch clamp amplifier was converted by digital-to-analog conversion and 2.9KHz low-pass filter, the data was collected and recorded by Patchmaster Pro software, and the data was processed by Origin 8E software to calculate the hERG IC 50 value.
  • the experimental data results are shown in Table 3:
  • Test product name hERGIC50 values Compound 1 1.93 ⁇ M Comparative compound 1 0.77 ⁇ M Cisapride ⁇ 0.10 ⁇ M
  • the drug's inhibition of cardiac hERG potassium channel is the main cause of prolonged myocardial repolarization, and the half inhibitory concentration (IC 50 ) value of compound 1 to hERG is 1.93 ⁇ M.
  • the compound 1 of the present invention has lower hERG inhibitory activity and less toxic side effects on the heart.
  • mice human liver microsomes (Corning Company, item number: 452117); testosterone (Jiuding Chemical Company) propafenone (Amp Company); diclofenac, tolidine urea, acetonitrile, DMSO from Sigma Company; NADPH (also Prototype coenzyme II) from Chem-Impex International; 0.1M pH7.4 PBS (phosphate buffer saline, self-prepared); other reagents were of analytical grade.
  • electrospray ionization ionization source spray voltage 4.8KV; capillary temperature (TEM) 300°C; sheath gas N 2 , flow rate 10psi; auxiliary gas N 2 , flow rate 1psi; collision gas (CID) Ar, pressure 1.5mTorr .
  • the mass spectrometry scanning method is mass spectrometry multiple reaction monitoring (MRM), and positive ion detection is adopted.
  • the internal standard is an acetonitrile solution containing 0.2 ⁇ g/mL of tolidine urea, the lowest limit of quantitation is 5 ng/mL, and the correlation coefficient is >0.99.
  • In vitro metabolism research method take testosterone, propafenone or diclofenac as a reference to verify the detection system, take allopregnolone (compound MI001) and comparative compound 1 as a reference, pass the in vitro test of the human liver microsome incubation system, and observe the examples
  • the reduction rate of the compound concentration and the generation rate of MI001 were used to evaluate the in vitro metabolic stability of the compounds of each example and the ability to maintain the concentration of MI001 in liver microsomes.
  • the metabolism of testosterone, propafenone or diclofenac proves that the detection system is normal; the results of comparing compound 1 and the example compound show that the compound of the present invention has good metabolic stability in human liver microsomes; the metabolism of the example compound in the liver microsome system
  • the concentration of poppregnanolone can quickly reach a stable level, while the comparative compound 1 has not been able to reach a steady state level.
  • the purpose of this experiment is to study the single oral administration of each compound solution of the present invention and pregnanolone solution to SD rats, detect the active ingredient in the plasma, and evaluate its pharmacokinetics in SD rats (PK) characteristics.
  • mice male SD rats (weight 180-220g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., production license number: SCXK (Beijing) 2016-0006), experimental compounds (prepared according to the method of the embodiment of the present invention ), purified water (homemade).
  • mice Male SD rats were randomly divided into groups (3 rats in each group), free to drink water during the test period, fasted for more than 12 hours before administration, and fed 4 hours after administration. Oral gavage administration, SD rats in each group were given a 5% Tween aqueous solution of the test compound at a dose of 20 mg/kg (calculated as the amount of prepregnanolone).
  • Plasma needs to be centrifuged within 60 minutes after blood collection (at 2-8°C, centrifuge at 8000rpm for 5min), after centrifugation, transfer the plasma to a 96-well plate or centrifuge tube, transport it in an ice box, and store it at ⁇ -15°C for LC-MS/MS detection.
  • LC-MS/MS bioanalysis method was used to detect the drug concentration in plasma of SD rats, using non-compartmental model, using WinNonlinTM (Version8.3, Certara, USA) to analyze the blood drug concentration-time data, and evaluate its effect in SD rats.
  • PK pharmacokinetic
  • the inventors of the present invention have found through experiments on the stability of liver microsomes of different species: the metabolism of the compound of the present invention in different species of liver microsomes is basically similar, and the metabolic behavior in beagle dog liver microsomes is similar to that of human liver microsomes. The metabolic behavior in the body is the closest.
  • the purpose of this experiment is to study the single oral administration of each compound solution of the present invention to Beagle dogs, detect the active ingredient pregnanolone in plasma, and evaluate its pharmacokinetic (PK) characteristics in Beagle dogs.
  • PK pharmacokinetic
  • mice male beagle dog (6-15kg in weight, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.), experimental compound (prepared according to the method of the embodiment of the present invention), purified water (self-made).
  • mice male beagle dogs were randomly divided into groups (3 in each group), free to drink water during the test period, fasted for more than 12 hours before administration, and fed 4 hours after administration. Oral gavage administration, each group of beagle dogs were given 5% Tween aqueous solution of the test compound at a dose of 10 mg/kg (based on the amount of pregnanolone).
  • Plasma needs to be centrifuged within 30 minutes after blood collection (at 2-8°C, centrifuge at 3200rpm for 10min), after centrifugation, transfer the plasma to a 96-well plate or centrifuge tube, transport it in an ice box, and store it at ⁇ -60°C for LC-MS/MS detection.
  • LC-MS/MS bioanalytical method was used to detect the drug concentration in Beagle dog plasma, using non-compartmental model, using WinNonlin (Version6.
  • PK pharmacokinetic
  • the compound of the present invention has significantly improved pharmacokinetic properties, particularly, after administration of the compound of the present invention, AUC and Cmax are all significantly improved, the compound of the present invention can be suitable for oral administration, and can greatly overcome The shortcomings of the long administration time of the pipregnanolone intravenous preparation and the need for continuous attention of medical staff can greatly improve the compliance of patients and the convenience of administration of medical staff.

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Abstract

本发明涉及医药领域，具体涉及一种式Ⅰ所示化合物、其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物或它们药学上可接受的盐：其中：R 2、R4分别独立的选自H或D；R1、R3分别独立的选自CH3、CH2D、CHD 2或CD 3；式Ⅰ化合物至少含有一个氘原子。本发明在保留别孕烷醇酮的药理活性的前提下，通过将别孕烷醇酮的羟基进行结构修饰得到适于口服的别孕烷醇酮衍生物，其具有良好的物理/化学稳定性。

Description

一种水溶性别孕烷醇酮衍生物及其制备方法和用途
本申请要求以下在先申请的优先权：2021年9月14日向中国国家知识产权局提交的专利申请号为202111084187.4，发明名称为“一种水溶性别孕烷酮衍生物及其制备方法和用途”的在先申请。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及医药领域，具体涉及一种适于口服的、水溶性别孕烷醇酮衍生物、制备方法及其用途，包含其的药物组合物及其用于预防或治疗中枢神经***病症、镇静催眠、治疗阿尔茨海默症、治疗癫痫或者治疗抑郁症特别是产后抑郁症的用途。
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，神经类固醇主要包括孕酮、孕烯醇酮和孕酮代谢物孕烷醇酮等。神经活性类固醇在人体中发挥着重要的生理作用，其在体内合成受损会导致不同的神经(CN 104736158 A)或精神疾病(Expert Opin TherTargets.2014；18(6):679-90)。
目前，通常认为孕烷醇酮类物质包括下列化合物：孕烷醇酮、别孕烷醇酮、表孕烷醇酮和等孕烷醇酮(见表1)。
表1：孕烷醇酮的名称
通用名称 IUPAC名称
孕烷醇酮 3α-OH-5β-孕烷-20-酮
别孕烷醇酮 3α-OH-5α-孕烷-20-酮
表孕烷醇酮 3β-OH-5β-孕烷-20-酮
等孕烷醇酮 3β-OH-5α-孕烷-20-酮
四氢脱氧皮质酮 3α-OH-5β-孕烷-21-醇-20-酮
别四氢脱氧皮质酮 3α-OH-5α-孕烷-21-醇-20-酮
专利文献CN1300219A公开了不同的孕烷醇酮类物质对中枢神经***的调控中具有不同的作用机制，且对中枢神经***具有不同生理作用。别孕烷醇酮(3α-OH-5α-孕烷-20-酮)是重要的GABAA(γ-氨基丁酸A)受体，具有抗癫痫、安眠、抗偏头疼及抗焦虑的作用。表别孕烷醇酮(3β-OH-5α-孕烷-20-酮)能够阻断并拮抗别孕烷醇酮的作用，适当地控制和终止别孕烷醇酮等引起的麻醉。
别孕烷醇酮(3α-OH-5α-孕烷-20-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。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道的开放频率，降低神经兴奋性，从而产生镇定、抗焦虑的作用。
有文献报道，在***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***开始前身体会重复出现一些症状，这些症状在经期后消失，例如应激，焦虑和偏头痛(Dalton,K.,Premenstrual Syndrome andProgesterone Therapy，第二版，Chicago Yearbook，Chicago(1984))。产后抑郁症也与异常的孕酮及其代谢产物的水平有关，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，别孕烷醇酮含量的下降被认为与焦虑，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，外源性给予别孕烷醇酮可以显著地改善上述精神症状。
但是，现有的别孕烷醇酮的水溶性低，口服生物利用度差，人体血浆半衰期大约为45分钟，可被快速代谢，不利于制成口服制剂。
专利文献CN104736158A公开了一种将别孕烷醇酮与环糊精配制形成组合物，并将其静脉输注以治疗癫痫或持续性癫痫的方法，别孕烷醇酮与环糊精的组合物中，环糊精所占比例为1～30％，其血药浓度为50～2300nM，治疗过程长达24小时以上。然而，环糊精为高分子化合物，具有一定肾毒性风险(药用超分子材料环糊精衍生物的安全性研究，中国材料科技与设备，2009年第5期，第1-3页)，因而存在安全隐患。
2019年，SAGE治疗公司的别孕烷醇酮注射液在美国获批上市，商品名为：ZULRESSO，别孕烷醇酮注射液是一种无菌、透明、无色且不含防腐剂的静脉注射制剂，其将别孕烷醇酮与磺丁基β-环糊精钠形成包合物，以提高别孕烷醇酮的溶解度。别孕烷醇酮注射液通过静脉注射产生稳定的、生理浓度的别孕烷醇酮以达到治疗效果，但其需要长达60个小时的静脉输注，输液方式复杂，在输注期间需要专业的医护人员进行持续的现场监测并进行必要的干预。导致别孕烷醇酮注射液患者依从性差，医护人员使用极其不便利。别孕烷醇酮注射液的输注方式如下：0-4h：以30μg/kg/h的剂量进行输注；4-24h：将剂量增加至60μg/kg/h；24-52h： 将剂量增加至90μg/kg/h(对于不能耐受90微克/公斤/小时的患者，也可考虑将剂量设为60μg/kg/h)；52-56h：将剂量减少至60μg/kg/h；56-60h：将剂量降低至30μg/kg/h。
发明内容
本发明目的在于提供了一种适用于口服给药的、生物利用度高的、又能快速起效且长时间维持体内稳定生理浓度的别孕烷醇酮类衍生物。
本发明的目的还在于提供包含别孕烷醇酮类衍生物的组合物及上述别孕烷醇酮类衍生物在制备用于治疗中枢神经***异常引起的疾病中的药物的应用。
本发明的目的是由以下技术方案来达到的，
第一个方面，本发明提供一种通式Ⅰ化合物、其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物或它们药学上可接受的盐：
Figure PCTCN2022118549-appb-000001
其中：
R 2、R 4分别独立的选自H(氢)或D(氘)；
R 1、R 3分别独立的选自CH 3、CH 2D、CHD 2或CD 3；
条件是式Ⅰ化合物至少含有一个氘原子。
在本发明的一些实施方案中，式Ⅰ化合物含有一至八个氘原子，或者式Ⅰ化合物含有一至七个氘原子，或者式Ⅰ化合物含有一至六个氘原子，具体的，式Ⅰ化合物至少含有一个、两个、三个、四个、五个、六个、七个或八个氘原子。
在本发明的一些实施方案中，R 2为D。
在本发明的一些实施方案中，R 2为D，且R 1和R 3为CH 3。
在本发明的一些实施方案中，R 2为D，且R 1和R 3为CD 3。
根据本发明的实施方案，每个D的氘代率至少为3500倍(52.5％)，优选地，至少为4000倍(60％)，优选地，至少为4500倍(67.5％)，更优选地，至少为5000倍(75％)，更优选地，至少为5500倍(82.5％)，更优选地，至少为6000倍(90％)，更优选地，至少为6333.3倍(95％)，进一步优选地，至少为6466.7倍(97％)，进一步优选地，至少为6566.7倍(98.5％)，进一步优选地，至 少为6600倍(99％)，进一步优选地，至少为6633.3倍(99.5％)。
优选地，任何未指定为氘的原子以其天然同位素丰度存在。
在本发明的具体实施方案中，式Ⅰ化合物为式Ⅰa或式Ⅰb所示化合物：
Figure PCTCN2022118549-appb-000002
其中，R 1、R 2、R 3、R 4具有如上所述的定义。
在本发明的一些优选实施方案中，式Ⅰ所示化合物的实例如下：
Figure PCTCN2022118549-appb-000003
如果本发明的化合物可以以互变异构体的形式存在，则本发明包括所有的互变异构体形式。
本发明的化合物可以以立体异构的形式(对映异构体，非对映异构体)存在。因此，本发明包括对映异构体或非对映异构体和它们各自的混合物。从这种对映异构体和/或非对映异构体的混合物，可以以已知的方式分离立体异构的均一组分。
本发明还提供上述式Ⅰ所述化合物的制备方法，包括以下步骤：
Figure PCTCN2022118549-appb-000004
其中，R 1-R 4具有如上所述的定义，R 5为保护基，例如氨基保护基，例如叔丁氧羰基(Boc)；
将式II化合物与式III化合物进行反应，再去保护基，得到式Ⅰ化合物。
本发明还提供一种药物组合物，包括式Ⅰ所示的化合物、其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物或它们药学上可接受的盐中的至少一种。
根据本发明，所述药物组合物还包括一种或多种药学上可接受的辅料。
根据本发明，所述药物组合物用于口服给药，所述药物组合物可为片剂、丸剂、锭剂、糖衣剂、胶囊剂等。
本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、制粒法、制糖衣药丸法等。如，可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
本发明提供本发明的式Ⅰ的化合物、其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物或它们药学上可接受的盐、或者本发明的药物组合物在制备用于预防或治疗中枢神经***病症、用于镇静催眠、用于治疗阿尔茨海默症、用于治疗癫痫或者用于治疗抑郁症特别是产后抑郁症的药物中的用途。
本发明提供预防或治疗中枢神经***病症、镇静催眠、治疗阿尔茨海默症、治疗癫痫或者治疗抑郁症特别是产后抑郁症的方法，其包括向有需要的个体给予预防或治疗有效量的本发明的式Ⅰ的化合物、其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物或它们药学上可接受的盐、或者本发明的药物组合物。
根据本发明，所述的中枢神经***疾病例如为外伤性脑损伤、特发性震颤、癫痫(包括难治性持续性癫痫、罕见基因性癫痫(例如Dravet综合征和Rett综合征)、抑郁症(包括产后抑郁症)和阿尔茨海默症。所述的中枢神经***疾病例如选自特发性震颤，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，***倾向，***观念或***行为。
本文所述的通式Ⅰ化合物的所有施用方法中，每天给药的剂量为0.01到200mg/kg体重。
可调整给药方案以提供最佳所需响应。例如，可给药单次口服，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
定义和说明
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明，应当应用本文所使用的下列定义。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
本文所用的术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
术语“预防或治疗”意为将本发明所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；
(ii)抑制疾病或疾病状态，即遏制其发展；
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“氘代率”指标记合成的同位素含量与天然存在的同位素量的比值。除非特别说明，当结构中某一位置被定义为H即氢(H-1)时，该位置仅含天然存在的同位素量。当结构中某一位置被定义为D即氘(H-2)时，该位置含同位素量至少比天然存在的同位素量(0.015％)大3340倍(即至少含50.1％氘同位素)。
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定 疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本发明化合物的用量。构成“治疗有效量”的本发明化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
本发明的化合物的药学可接受的盐包括其与药学可接受的酸形成的盐以及其与药学可接受的碱形成的盐。
本文所用的术语“药学可接受的酸”是指可药用的酸，例如盐酸、氢溴酸、硫酸、硝酸、磷酸、碳酸、甲酸、乙酸、乙酰乙酸、三氟乙酸、丙酸、丙酮酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、硬脂酸、棕榈酸、草酸、甲磺酸、三氟甲磺酸、乙二磺酸、羟乙基磺酸、1,5-萘二磺酸、2-萘磺酸、樟脑磺酸、氨基磺酸、乳酸、苯磺酸、对甲苯磺酸、丙二酸、丁二酸、戊二酸、己二酸、马来酸、富马酸、乳酸、酒石酸、枸橼酸、苹果酸、苯甲酸、水杨酸、肉桂酸、萘甲酸、扑酸、烟酸、乳清酸、甲基硫酸、十二烷基硫酸、谷氨酸、天冬氨酸、葡糖酸、葡糖醛酸或其任意组合。
本文所用的术语“药学可接受的碱”是指可药用的碱，例如无机碱(碱金属氢氧化物或碱土金属氢氧化物等)或有机碱(例如胺(伯胺、仲胺或叔胺)等)。适合的盐的实例包括但不限于得自氨基酸、氨、伯胺、仲胺和叔胺以及环胺的有机盐(例如二乙胺盐、哌啶盐、吗啉盐、哌嗪盐、胆碱盐、葡甲胺盐、氨丁三醇盐等)，以及得自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。
术语“溶剂化物”是本发明的化合物其以固体或液体的状态通过与溶剂分子的配位作用形成配合物。水合物是溶剂化物的特定形式，其中配位作用是与水进行。
术语“药物组合物”是指一种或多种本发明的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本发明的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
本发明的药物组合物可通过将本发明化合物与适宜的药学上可接受的辅料组合而制备， 对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂等，用于对患者的口服给药。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
有益效果
本发明提供一种式Ⅰ所示的别孕烷醇酮衍生物，在保留别孕烷醇酮药理活性的前提下，通过将别孕烷醇酮的羟基进行结构修饰得到适于口服的别孕烷醇酮衍生物，其具有良好的物理/化学稳定性。可以在体内释放出活性药物，从而发挥药理作用。本发明的别孕烷醇酮衍生物代谢稳定、口服生物利用度好、毒副作用小，口服后能够快速起效且长时间维持体内稳定生理浓度的别孕烷醇酮，可以被制成合适的口服制剂，提高药物安全性，改善患者依从性及给药便利性。
附图说明
图1口服给予本发明化合物后雄性大鼠血浆中别孕烷醇酮的药代动力学曲线；
图2口服给予本发明化合物后比格犬血浆中别孕烷醇酮的药代动力学曲线。
具体实施方式
下文将结合具体实施例对本发明的通式化合物及其制备方法和应用做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。
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。除非另有说明，否则百分比和份数按重量计算，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
本发明采用下述缩略词：aq代表水溶液；DMSO代表二甲基亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；TFA代表三氟乙酸；i-PrOH代表异丙醇；ECS代表细胞外液；ICS代表细胞内液；MI001代表别孕烷醇酮。
对比例1：对比化合物1(C1)盐酸盐的制备
Figure PCTCN2022118549-appb-000005
步骤1：向1000mL三口圆底反应瓶中加入MI001(50.0g，157.0mmol，1.0eq)，Boc-L-Val-OH(叔丁氧羰基L-缬氨酸)(40.9g，188.2mmol)，4-二甲氨基吡啶(1.9g，15.5mmol)和二氯甲烷500mL，搅拌，氮气保护下将反应体系冷却至-5至10℃，滴加二环己基碳二亚胺(38.9g，188.5mmol)的二氯甲烷(80mL)溶液，随后在此温度下反应3小时，TLC(Thin Layer Chromatography，薄层色谱)监测反应完全，停止反应。反应液过滤，滤饼用二氯甲烷(100mL)洗。减压浓缩滤液，粗品用100～200目硅胶制砂柱层析(石油醚(60～90)/乙酸乙酯20:1-10:1)纯化得类白色蜡状固体(78.2g，收率96.2％)。
步骤2：向1000mL三口圆底反应瓶中加入步骤1产物(78g，150.6mmol，1.0eq)和二氯甲烷(320mL)。氮气保护，磁力搅拌，将体系冷却至0～10℃下快速滴加三氟乙酸(171.8g，1506mmol)，随后在15～25℃下反应3小时，停止反应。反应液倒入碳酸氢钠(164.5g，1958mmol) 溶液中(水780mL)淬灭，加入二氯甲烷(700mL)，搅拌、静置分液，得到有机相。有机相再用500mL纯水洗，无水硫酸钠干燥。过滤，浓缩得类白色固体(59.5g，收率94.6％)。
步骤3：取上述产物0.5g，加入异丙醇(0.5mL)，醋酸异丙酯(7.5ml)室温溶清后滴加盐酸乙酸乙酯溶液(0.6ml，2.0M盐酸乙酸乙酯)，降温至5-10℃析出大量固体，抽滤干燥得产物0.36g，收率66.5％，纯度HPLC 99.90％。
1H NMR(400MHz,CDCl 3)δ8.83(brs,3H),5.23–5.14(m,1H),4.00–3.88(m,1H),2.52(t,J＝8.7Hz,2H),2.22–2.08(m,1H),2.11(s,3H),2.06–1.96(m,1H),1.86–1.08(m,18H),1.18(m,3H),1.17(m,3H),1.04–0.88(m,1H),0.86–0.71(m,1H),0.80(s,3H),0.61(s,3H).MS m/z:418.3[M+H] +.
实施例1化合物1及其盐酸盐的合成
Figure PCTCN2022118549-appb-000006
中间体1a的合成：
向100mL单口瓶中加入Boc-L-Val-OH-3-d(1.20g，5.5mmol)、MI001(1.91g，6.0mmol)、4-二甲氨基吡啶(0.07g，0.6mmol)和二氯甲烷(15mL)。20℃下滴加二环己基碳二亚胺(1.24g，6.0mmol)的二氯甲烷(5mL)溶液，搅拌过夜。过滤除去二环己基脲，将滤液浓缩，经柱层析(石油醚/乙酸乙酯20:1-7:1)得无色油状物2.3g中间体1a，收率80％。
1H NMR(400MHz,CDCl 3)δ5.10(m,1H),5.07(d,J＝9.5Hz,1H),4.23(d,J＝9.1Hz,1H),2.53(t,J＝8.8Hz,1H),2.26–2.08(m,1H),2.11(s,3H),2.06–1.95(m,1H),1.85–0.71(m,20H),1.46(s,9H),0.98(s,3H),0.90(s,3H),0.80(s,3H),0.61(s,3H).
化合物1的合成：
向100mL单口瓶中加入中间体1a(2.3g，4.4mmol)和二氯甲烷(15mL)，20℃下搅拌溶解，滴加三氟乙酸(5.02g，44.0mmol)。控温15～25℃下搅拌反应3～4小时后，加入二氯甲烷(20mL)。搅拌下将反应液缓慢倒入碳酸氢钠水溶液中(15g/50ml)，搅拌5～15分钟后静置分液。 有机相用纯水(50mL)洗涤分液、无水硫酸钠干燥。过滤，浓缩后得1.73g化合物1。
化合物1盐酸盐(1’)的合成：
用乙酸乙酯(20mL)和异丙醇(1.3mL)溶解得到的化合物1(1.59g，3.8mmol)，滴加氯化氢乙酸乙酯溶液(2.4M，1.6mL,3.8mmol)。20℃下搅拌1小时，过滤，滤饼用乙酸乙酯(20mL)洗。40℃下油泵真空(P≤-0.09MPa)干燥4小时，得白色固体1.18g，收率68％。
1H NMR(400MHz,CDCl 3)δ8.83(brs,3H),5.23–5.14(m,1H),4.00–3.88(m,1H),2.52(t,J＝8.7Hz,1H),2.22–2.08(m,1H),2.11(s,3H),2.06–1.96(m,1H),1.86–1.08(m,18H),1.18(s,3H),1.17(s,3H),1.04–0.88(m,1H),0.86–0.71(m,1H),0.80(s,3H),0.61(s,3H).MS m/z:419.28[M+H] +.
实施例2化合物2及其盐酸盐的的合成
Figure PCTCN2022118549-appb-000007
中间体2a的合成：
氮气保护下，100mL三口瓶中加入Boc-L-Val-OH-d6(2g，8.95mmol)，二氯甲烷(30g)，MI001(2.85g，8.95mmol)、4-二甲氨基吡啶(0.11g，0.90mmol)，搅拌降温至-5～5℃，滴加溶于二氯甲烷(7.5g)的二环己基碳二亚胺(2.1g，10mmol)溶液，15～25℃下反应3小时后，TLC反应完全，反应液经过水洗搅拌分液，得到有机相经过无水硫酸钠干燥浓缩后，柱层析分离(石油醚/乙酸乙酯＝20:1)得3.2g无色油状物中间体2a，收率68.5％。
化合物2的合成：
将上步得到的产物2a溶于二氯甲烷(16mL)，加入三氟乙酸(10.7g)，15～25℃下搅拌3～4小时，TLC，原料反应完全，将反应液加入碳酸氢钠水溶液(40mL)中，调节pH为7-8，再加 入二氯甲烷(10mL)，分液后保留有机相，水相再用二氯甲烷(20mL)萃取一次，合并有机相，水(5mL x 3)洗涤，有机相无水硫酸钠干燥后浓缩至干为固体，加入乙腈(8mL)打浆后过滤得1.2g化合物2。
化合物2盐酸盐(2’)的合成：
取化合物2(0.6g)，加入异丙醇(0.6mL)，醋酸异丙酯(9mL)室温溶解后滴加盐酸乙酸乙酯溶液(0.7mL，2.0M盐酸乙酸乙酯溶液)，降温至5-10℃析出大量固体，抽滤干燥得产物0.3g，收率46.2％，纯度HPLC 99.7％。
1H NMR(400MHz,CDCl 3)δ8.85(brs,3H),5.22(s,1H),3.95(brs,1H),2.54(t,J＝8.7Hz,1H),2.49(s,1H),2.19–2.14(m,1H),2.14(s,3H),2.05–2.02(m,1H),1.84–1.72(m,5H),1.61-1.41(m,7H),1.32-1.17(m,6H),1.04–0.88(m,1H),0.85(m,1H),0.82(s,3H),0.63(s,3H).MS m/z:424.39[M+H] +.
实施例3化合物3及其盐酸盐的合成：
Figure PCTCN2022118549-appb-000008
中间体3a的合成：
向100mL单口瓶中加入Boc-Val-OH-2-d(1.0g，4.6mmol)、MI001(1.46g，4.6mmol)、4-二甲氨基吡啶(0.06g，0.5mmol)和二氯甲烷(15mL)。20℃下滴加二环己基碳二亚胺(0.95g，4.6mmol)的二氯甲烷(5mL)溶液，搅拌过夜。过滤，将滤液浓缩。柱层析(石油醚/乙酸乙酯＝20:1-7:1)得无色油状物1.6g中间体3a，收率56％。
化合物3的合成：
将上步得到的产物中间体3a溶于二氯甲烷(8g)，加入三氟乙酸(4.5g)，15～25℃搅拌3～4 小时，TLC监测原料反应完全，将反应液加入20mL碳酸氢钠水溶液中，调节pH为7-8，再加入二氯甲烷(5mL)，分液后保留有机相，水相再用二氯甲烷(10mL)萃取一次，合并有机相，水(5mL x 3)洗涤，有机相无水硫酸钠干燥后浓缩至干为固体，加入乙腈4mL打浆后过滤得游离碱0.6g.
化合物3盐酸盐(3’)的合成：
取上述产物化合物3(0.5g)，加入异丙醇(0.5mL)，醋酸异丙酯(7.5ml)室温溶解后滴加氯化氢乙酸乙酯溶液(0.6mL，2.0M氯化氢乙酸乙酯溶液)，降温至5-10℃析出大量固体，抽滤干燥得产物0.36g，收率66.5％，纯度HPLC 99.70％。
1H NMR(400MHz,CDCl 3)δ8.84(brs,3H),5.21(s,1H),2.56-2.48(m,2H),2.21–2.17(m,1H),2.13(s,3H),2.05–2.02(m,1H),1.83–1.36(m,12H),1.32-1.19(m,12H),1.04–0.95(m,1H),0.90-0.84(m,1H),0.82(s,3H),0.63(s,3H).MS m/z:419.25[M+H] +.
实施例4化合物4及其盐酸盐的合成
Figure PCTCN2022118549-appb-000009
以MI001、Boc-D-Val-OH-3-d为原料，按照实施例1的合成方法，制备得到化合物4、化合物4的盐酸盐(4’)。
化合物4盐酸盐(4’)，白色固体， 1HNMR(400MHz,CDCl 3)δ8.76(brs,3H),5.16(brs,1H),4.00–3.88(m,1H),2.52(t,J＝8.7Hz,1H),2.22–2.08(m,1H),2.08(s,3H),2.06–1.96(m,1H),1.86–1.08(m,18H),1.18(s,3H),1.17(s,3H),1.04–0.88(m,1H),0.86–0.71(m,1H),0.79(s,3H),0.61(s,3H).MS m/z:419.35[M+H] +.
实施例5化合物5及其盐酸盐的合成
Figure PCTCN2022118549-appb-000010
以MI001、Boc-D-Val-OH-d7原料，按照实施例2的合成方法，制备得到化合物5、化合物5的盐酸盐(5’)。
化合物5盐酸盐(5’)，白色固体， 1H NMR(400MHz,CDCl 3)δ8.85(brs,3H),5.22(s,1H),3.95(brs,1H),2.54(t,J＝8.7Hz,1H),2.19–2.14(m,1H),2.14(s,3H),2.05–2.02(m,1H),1.84–1.72(m,5H),1.61-1.41(m,7H),1.32-1.17(m,6H),1.04–0.88(m,1H),0.85(m,1H),0.82(s,3H),0.63(s,3H).MS m/z:425.39[M+H] +.
测试例1化合物的溶解度实验
1.样品配置
外标溶液的配置：精密称取待测化合物50mg至10mL容量瓶中，加适量纯水超声溶解、稀释至刻度后混匀，得浓度为5.0mg/mL的外标溶液。
待测溶液的配置：精密称取待测化合物1.0g溶于20mL纯水中，25℃下搅拌溶解24h，离心、取上清液、0.45μm滤膜过滤，得滤液。精密量取1mL上述滤液至5mL量瓶中，加纯水稀释至刻度、混匀，得待测溶液。
2.外标法测定饱和溶解度
色谱条件：
色谱柱：Waters XBridge C8 3.5μm 4.6*100mm NRT2019-21#，柱温：45℃，检测波长：205nm；
流动相A：10mM/L(NH 4) 2HPO 4溶液，流动相B：乙腈，等度洗脱A:B＝40:60，流速：1.0mL/min；
进样量：10μL，运行时间：10min。
以纯水为空白对照溶液，通过带有UV检测器的高效液相色谱仪分别测定外标溶液、标准溶液的峰面积，分别记为A 外标、A 待测，通过如下公式计算出待测化合物的饱和溶解度C:C＝A 待测/A 外标*5mg/mL*5，具体结果如下表2。
表2各物质的饱和溶解度
Figure PCTCN2022118549-appb-000011
测试例2膜片钳实验结果
手动膜片钳方法用于检测化合物对稳定表达在中国仓鼠卵巢细胞的hERG钾通道电流的作用，药物对于心脏hERG钾离子通道的抑制是导致心肌复极化延长的主要原因，hERG IC 50值越大说明心脏毒性越低。
实验材料：实验化合物(通过本发明方法制备得到的化合物1、对比化合物1)、二甲基亚砜(西格玛奥德里奇(上海)贸易有限公司)、西沙必利(阳性对照品、市售)、中国仓鼠卵巢(CHO)细胞系，CHO-hERG细胞(Sophion生物科学公司)。
手动膜片钳试验方法：
将处于指数生长期的CHO-hERG细胞收集并重悬在ECS(细胞外液)中备用。细胞种在细胞记录槽中，放置在倒置显微镜载物台上，随机选择记录槽中的一个细胞进行试验。灌流***固定在倒置显微镜载物台上用ECS持续灌流细胞。
用毛细玻璃管制备手动膜片钳试验记录微电极，其中充灌细胞內液。在膜片钳试验当天，使用硼硅酸盐玻璃管(GC150TF-10,Harvard Apparatus Co.UK)制备电极。电极充灌ICS后电阻在2-5MΩ之间。
钳制电压为-80mV，第一步去极化至+60mV并维持850ms开放hERG通道。然后，电压设置为-50mV并维持1275ms，产生反弹电流或者称为尾电流，尾电流的峰值将被测量并用于分析。最后，电压恢复到钳制电压(-80mV)。在溶剂对照工作溶液灌流的记录开始阶段，监测尾电流峰值直至稳定3条以上扫描曲线后则可以灌流待测试的供试品/阳性对照工作溶液，直到供试品/阳性对照工作溶液对hERG电流峰值的抑制作用达到稳定状态。
全细胞膜片钳技术下记录hERG电流，记录温度为室温。膜片钳放大器输出信号通过数模转换以及2.9KHz低通滤波，数据用Patchmaster Pro软件采集并记录，使用Origin 8E软 件进行数据处理并计算出hERG IC 50值。实验数据结果如下表3：
表3各化合物的hERG活性
供试品名称 hERGIC 50值
化合物1 1.93μM
对比化合物1 0.77μM
西沙必利 <0.10μM
药物对于心脏hERG钾离子通道的抑制是导致心肌复极化延长的主要原因，化合物1对hERG的半数抑制浓度(IC 50)值为1.93μM。相对于对比化合物1，本发明化合物1具有更低的hERG抑制活性，心脏的毒副作用更小。
测试例3代谢研究
通过体外(人肝微粒体孵育体系)判断实施例化合物的代谢稳定性及生成活性物质别孕烷醇酮的速率。
实验材料与试剂：人肝微粒体(Corning公司，货号：452117)；睾酮(九鼎化学公司)普罗帕酮(安普公司)；双氯芬酸、甲苯环丁脲、乙腈、DMSO来自Sigma公司；NADPH(还原型辅酶II)来自Chem-Impex International公司；0.1M pH7.4 PBS(磷酸盐缓冲液，自配)；其他试剂均为分析纯。
仪器、条件及参数：液相色谱-质谱联用仪(LC/MS/MS，Shimadzu LC 30-AD,MS API 4000)，色谱柱为ACQUITY UPLC BEH C18柱(1.7um 2.1*50mm Column,Part No.186002350)；流动相为乙腈-水-甲酸(50:50:0.1)；流速0.7mL/min；进样量5μL；柱温为室温。采用电喷雾离子化电离源(ESI)，喷雾电压4.8KV；毛细管温度(TEM)300℃；鞘气N 2，流速10psi；辅助气N 2，流速1psi；碰撞气(CID)Ar，压力1.5mTorr。质谱扫描方式为质谱多反应监测(MRM)，采用正离子方式检测。内标为含甲苯环丁脲0.2μg/mL的乙腈溶液，最低定量下限5ng/mL，相关系数>0.99。
体外代谢研究方法：以睾酮、普罗帕酮或双氯芬酸作为参照验证检测体系，以别孕烷醇酮(化合物MI001)及对比化合物1作为参照，通过人肝微粒体孵育体系的体外试验，观察实施例化合物浓度的降低速率和MI001的生成速率，评价各实施例化合物体外代谢稳定性及维持肝微粒体中MI001浓度的能力。
精密称量各种待测样品约10mg，DMSO 0.1mL溶解，以纯净水逐级稀释成10μM、1μM 标准储备溶液。冰浴操作，按表3配制检测孵育体系。孵育体系(其组成见表4)中加NADPH启动反应，立即取50μL于150μL乙腈中，作为零时刻样品和1μM标准曲线样品。另取1μM标准储备溶液加入孵育体系中，立即取50μL于150μL乙腈中，作为0.1μM标准曲线样品。剩余体系在37℃水浴，分别于5min、15min、30min、1h、2h取50μL于150μL乙腈中。各样品经振荡，18000g离心10min，取上清液用LC/MS/MS进样测定。部分实施例化合物实验数据结果见下表5。
表4.孵育体系组成
成分 浓度
肝微粒体 0.5mg蛋白质/mL
Test Compound 1μΜ/10μΜ
Control Compound 1μΜ
MgCl 2 1mM
Acetonitrile 0.99％
DMSO 0.01％
MgCl 2 1mM
表5.待测化合物及MI001在各时间点测得浓度(μM)
Figure PCTCN2022118549-appb-000012
通过睾酮、普罗帕酮或双氯芬酸的代谢证明检测体系正常；对比化合物1及实施例化合物结果显示本发明化合物在人肝微粒体当中代谢稳定性良好；实施例化合物在肝微粒体体系中代谢出的别孕烷醇酮浓度能迅速达到稳定水平，而对比化合物1一直无法达到稳态水平。
测试例4药代动力学性质研究
1.SD大鼠药代动力学性质研究
本实验目的旨在研究SD大鼠单次口服给与本发明各化合物溶液，别孕烷醇酮溶液，检测血浆中活性成分别孕烷醇酮，并评估其在SD大鼠体内药物代谢动力学(PK)特性。
实验材料：雄性SD大鼠(体重180-220g，购自北京维通利华实验动物技术有限公司，生产许可证号：SCXK(京)2016-0006)、实验化合物(按本发明实施例方法制备)、纯化水(自制)。
实验方法：将雄性SD大鼠随机分组(每组3只)，试验期间自由饮水，给药前禁食12小时以上，给药后4小时喂食。经口灌胃给药，对各组SD大鼠分别按20mg/kg(以别孕烷醇酮量计)的剂量给予实验化合物的5％吐温水溶液。
给药前0min，给药后5min、15min、30min、1h、2h、3h、4h、6h、8h和12h各采集血样至K2EDTA抗凝管中，于冰上暂存至离心。
采血后60min内需离心出血浆(2-8℃条件下，以8000rpm离心5min)，离心后将血浆转移至96孔板或离心管中，冰盒转运，≤-15℃保存至LC-MS/MS检测。采用LC-MS/MS生物分析方法检测SD大鼠血浆中的药物浓度，采用非房室模型，使用WinNonlinTM(Version8.3,Certara,USA)对血药浓度-时间数据进行分析，评估其在SD大鼠体内药物代谢动力学(PK)特性，数据见表6，药代动力学曲线见图1。
表6.口服给予本发明化合物后雄性大鼠血浆中别孕烷醇酮的药代动力学参数
Figure PCTCN2022118549-appb-000013
注：“NA”表示无法计算。
2.比格犬药代动力学性质研究
本发明的发明人经过不同种属的肝微粒体稳定性实验发现：本发明化合物在不同种属肝微粒体中的代谢基本相似，在比格犬肝微粒体中的的代谢行为与人肝微粒体中的代谢行为最为接近。本实验目的旨在研究比格犬单次口服给与本发明各化合物溶液，检测血浆中活性成分别孕烷醇酮，并评估其在比格犬体内药物代谢动力学(PK)特性。
实验材料：雄性比格犬(体重6-15kg，购自北京维通利华实验动物技术有限公司)、实验化合物(按本发明实施例方法制备)、纯化水(自制)。
实验方法：将雄性比格犬随机分组(每组3只)，试验期间自由饮水，给药前禁食12小时以上，给药后4小时喂食。经口灌胃给药，对各组比格犬分别按10mg/kg(以别孕烷醇酮量计)的剂量给予实验化合物的5％吐温水溶液。
给药前0min，给药后5min、15min、30min、1h、2h、3h、4h、6h、8h和12h各采集血样至K2EDTA抗凝管中，于冰上暂存至离心。
采血后30min内需离心出血浆(2-8℃条件下，以3200rpm离心10min)，离心后将血浆转移至96孔板或离心管中，冰盒转运，≤-60℃保存至LC-MS/MS检测。采用LC-MS/MS生物分析方法检测比格犬血浆中的药物浓度，采用非房室模型，使用WinNonlin(Version6.3或更新版本)对血药浓度-时间数据进行分析，评估其在比格犬体内药物代谢动力学(PK)特性，数据见表7，药代动力学曲线见图2。
表7.口服给予本发明化合物后比格犬血浆中别孕烷醇酮的药代动力学参数
Figure PCTCN2022118549-appb-000014
上述结果表明，本发明的化合物具有显著改善的药代动力学性质，特别地，给药本发明化合物后，AUC和Cmax均极显著的提高，本发明化合物能适合口服给药，能够极大克服别孕烷醇酮静脉给药制剂的给药时间长、需要医护人员持续关注的缺点，能极大的提高患者的依从性及医护工作者的给药便利性。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种式Ⅰ所示化合物、其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物或它们药学上可接受的盐：
    Figure PCTCN2022118549-appb-100001
    其中：
    R 2、R 4分别独立的选自H或D(氘)；
    R 1、R 3分别独立的选自CH 3、CH 2D、CHD 2或CD 3；
    式Ⅰ化合物至少含有一个氘原子。
  2. 根据权利要求1所述的化合物，其特征在于：式Ⅰ所述化合物含有一个、两个、三个、四个、五个、六个、七个或八个氘原子。
  3. 根据权利要求1所述的化合物，其特征在于：R 2为D；
    优选地，R 2为D，且R 1和R 3为CH 3；
    优选地，R 2为D，且R 1和R 3为CD 3。
  4. 根据权利要求1-3任一项所述的化合物，其特征在于：式Ⅰ所述化合物为式Ⅰa或式Ⅰb所示化合物：
    Figure PCTCN2022118549-appb-100002
  5. 根据权利要求1-3任一项所述的化合物，其特征在于：式Ⅰ所述化合物选自如下结构：
    Figure PCTCN2022118549-appb-100003
  6. 一种权利要求1-5任一项所述化合物的制备方法，包括以下步骤：将式II化合物与式III化合物进行反应，再脱保护基，得到式Ⅰ化合物；
    Figure PCTCN2022118549-appb-100004
    其中，R 1-R 4如权利要求1-5任一项所定义，R 5为保护基，例如Boc。
  7. 一种药物组合物，包括权利要求1-5中任一项所述的式Ⅰ所示化合物、其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物或它们药学上可接受的盐中的至少一种。
  8. 如权利要求7所述的药物组合物，其中，所述药物组合物还包括一种或多种药学上可接受的辅料，所述辅料例如为粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
    优选地，所述药物组合物用于口服给药，所述药物组合物可为片剂、丸剂、锭剂、糖衣剂、胶囊剂等。
  9. 一种权利要求1-5中任一项所述式Ⅰ化合物、其消旋体、立体异构体、互变异构体、溶剂化物、多晶型物或它们药学上可接受的盐、或者权利要求7所述药物组合物在制备用于 预防或治疗中枢神经***病症、用于镇静催眠、用于治疗阿尔茨海默症、用于治疗癫痫或者用于治疗抑郁症特别是产后抑郁症的药物中的用途。
  10. 根据权利要求9所述的用途，其中，所述的中枢神经***疾病为外伤性脑损伤、特发性震颤、癫痫(包括难治性持续性癫痫、罕见基因性癫痫(例如Dravet综合征和Rett综合征))、抑郁症(包括产后抑郁症)和阿尔茨海默症；所述的中枢神经***疾病例如选自特发性震颤，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，***倾向，***观念或***行为。
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