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WO2024088285A1 - 一种杂环取代的稠合γ-咔啉类衍生物的甲磺酸盐、晶型及其制备方法和应用 - Google Patents

一种杂环取代的稠合γ-咔啉类衍生物的甲磺酸盐、晶型及其制备方法和应用 Download PDF

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Publication number
WO2024088285A1
WO2024088285A1 PCT/CN2023/126353 CN2023126353W WO2024088285A1 WO 2024088285 A1 WO2024088285 A1 WO 2024088285A1 CN 2023126353 W CN2023126353 W CN 2023126353W WO 2024088285 A1 WO2024088285 A1 WO 2024088285A1
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acid salt
mesylate
preparation
compound
receptor
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English (en)
French (fr)
Inventor
王瑾
周炳城
胡志京
孔芒芒
冯子晋
梁小小
万泽红
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Nhwa Pharmaceutical Corp
Shujing Biopharma Co Ltd
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Nhwa Pharmaceutical Corp
Shujing Biopharma Co Ltd
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Priority to CN202380074728.6A priority Critical patent/CN120282964A/zh
Publication of WO2024088285A1 publication Critical patent/WO2024088285A1/zh
Anticipated expiration legal-status Critical
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems

Definitions

  • the invention belongs to the technical field of drug synthesis, and particularly relates to a mesylate salt, a crystal form, a preparation method and an application of a heterocyclic substituted fused gamma-carboline derivative.
  • Schizophrenia is a disease characterized by a profound split in cognition and emotion, affecting the most basic human behaviors, such as language, thought, perception, and self-perception.
  • the symptoms of the disease cover a wide range, with the most common being mental disorders such as hallucinations, delusions, and delusions.
  • schizophrenia often causes comorbidities such as anxiety disorders, depression or psychotropic drug abuse.
  • antipsychotic drugs that block dopamine D2 receptors are called first-generation antipsychotic drugs, or “typical” antipsychotic drugs (such as haloperidol). They have a breakthrough effect on the positive symptoms of schizophrenia, but fail to treat negative symptoms and cognitive impairment. Typical antipsychotic drugs generally have serious EPS side effects and are ineffective for one-third of schizophrenia patients.
  • the serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory.
  • PFC prefrontal cortex
  • the pyramidal neurons and GABA interneurons of the PFC contain several serotonin receptor subtypes 5-HT1A and 5-HT2A with particularly high densities.
  • 5-HT1AR serotonin receptor subtypes 5-HT1A and 5-HT2A with particularly high densities.
  • 5-HT1AR which regulate excitatory neurons in the cerebral cortex and thus affect cognitive functions.
  • various preclinical data suggest that 5-HT1AR may be a new target for the development of antipsychotic drugs.
  • atypical antipsychotic drugs such as olanzapine, aripiprazole, etc.
  • 5-HT1AR atypical antipsychotic drugs
  • EPS side effects indicate that the serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory.
  • the pyramidal neurons and GABA interneurons of the PFC contain several serotonin receptor subtypes 5-HT1A and 5-HT2A with particularly high densities. Recent studies have shown that 5-HT1A agonists are associated with atypical antipsychotic treatment and can improve negative symptoms and cognitive impairment.
  • 5-HT2A plays an important role in perception, emotion regulation, and motor control. Blocking 5-HT2A receptors It can normalize the release of dopamine and play an antipsychotic role. In addition, 5-HT2C receptors are closely related to weight gain.
  • D3 receptors in the brain are mainly selectively distributed in the limbic system.
  • This DA pathway is also the main pathway for reward effects in the brain.
  • D3R is distributed in both DA neural pathways and has complex interactions with other DA receptor subtypes. It may be a target for antipsychotic drug treatment.
  • Selective D3 receptor antagonism can reduce the negative and cognitive symptoms of schizophrenia. In addition, it can prevent extrapyramidal side effects, including tardive dyskinesia and Parkinson's disease. Therefore, finding an anti-schizophrenia drug with fewer side effects that binds multiple receptors is of great significance for clinical treatment.
  • Different salts and solid forms of active pharmaceutical ingredients may have different properties. Different salts and solid forms may have significant differences in appearance, solubility, melting point, hygroscopicity, stability, pharmacokinetics, etc., and may also have different effects on the stability, bioavailability and efficacy of the drug. Therefore, in drug development, the salt form and/or solid form of the drug should be fully considered.
  • the inventors found that the free base of the compound exists in an oily form, has poor solubility in water, and has low bioavailability, and is not a preferred form for clinical use. Therefore, it is necessary to further conduct comprehensive screening and research on the acid salt and its crystal form of the compound.
  • the technical problem to be solved by the present invention is to provide a mesylate salt, a crystal form and a preparation method and application of a heterocyclic substituted fused ⁇ -carboline derivative.
  • the object of the present invention is to provide an acid salt of a compound (6bR, 10aS)-8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one.
  • the acid salt is a methanesulfonate salt.
  • the number of acids in the acid salt is 0.5-2, preferably 0.8-1.2, and preferably 1.
  • the acid salt is in crystalline form.
  • the acid salt of the compound (6bR,10aS)-8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one is a mesylate salt form I, the number of acids is 1, and its X-ray powder diffraction pattern comprises diffraction peaks at 2 ⁇ of 5.83 ⁇ 0.2°, 12.75 ⁇ 0.2°, and 22.56 ⁇ 0.2°;
  • it comprises diffraction peaks at 2 ⁇ of 5.83 ⁇ 0.2°, 12.75 ⁇ 0.2°, 18.34 ⁇ 0.2°, 19.24 ⁇ 0.2°, and 22.56 ⁇ 0.2°;
  • it comprises diffraction peaks at 2 ⁇ of 5.83 ⁇ 0.2°, 8.29° ⁇ 0.2°, 12.75 ⁇ 0.2°, 14.43 ⁇ 0.2°, 16.76 ⁇ 0.2°, 17.64 ⁇ 0.2°, 18.34 ⁇ 0.2°, 19.24 ⁇ 0.2°, 19.71 ⁇ 0.2°, and 22.56 ⁇ 0.2°;
  • the 2 ⁇ values are 5.83 ⁇ 0.2°, 8.29 ⁇ 0.2°, 8.86 ⁇ 0.2°, 11.71 ⁇ 0.2°, 12.75 ⁇ 0.2°, 13.73 ⁇ 0.2°, 14.43 ⁇ 0.2°, 15.35 ⁇ 0.2°, 16.51 ⁇ 0.2°, 16.76 ⁇ 0.2°, 17.64 ⁇ 0.2°, 18.00 ⁇ 0.2°, 18.34 ⁇ 0.2°, 18.81 ⁇ 0.2°, 19.24 ⁇ 0.
  • Cu-K ⁇ radiation is used, and the X-ray diffraction peaks represented by 2 ⁇ angles and interplanar spacing d values are as shown in Table 1.
  • the X-ray powder diffraction pattern of the mesylate form I of the compound (6bR,10aS)-8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one is substantially as shown in Figure 1; its DSC pattern is substantially as shown in Figure 2; and its TGA pattern is substantially as shown in Figure 3.
  • the acid salt is anhydrous.
  • the present invention also relates to a method for preparing the compound (6bR, 10aS)-8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridinium[3',4':4,5]pyrrole[1,2,3-de]quinoxaline-2(3H)-one acid salt, which specifically comprises the following steps:
  • the solvent 1 and solvent 2 are each independently selected from water, methanol, ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of any acid salt of the compounds shown or a combination thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the present invention further relates to the use of an acid salt of any of the compounds shown, or a pharmaceutical composition thereof, in the preparation of a drug involving or regulating 5-hydroxytryptamine receptors, 5-hydroxytryptamine transporters and/or dopamine receptors; preferably, in the preparation of a drug involving or regulating 5-HT2A receptors, 5-hydroxytryptamine transporters, dopamine D1 receptors and/or dopamine D2 receptors, and more preferably, in the preparation of a drug involving or regulating 5-HT2A receptors and/or dopamine D2 receptors.
  • the present invention further relates to the use of an acid salt of any of the compounds shown, or a pharmaceutical composition thereof, in the preparation of a drug for treating neuropsychiatric diseases.
  • the neuropsychiatric disease is selected from one or more of depression, anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behavioral disorders in patients with dementia, Parkinson's disease, Alzheimer's disease, migraine, ADHD, obsessive-compulsive disorder, social phobia, neurodegenerative diseases, bipolar disorder, post-traumatic stress syndrome, addictive diseases, withdrawal syndrome or attention deficit, preferably any one or more of depression, anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behavioral disorders in patients with dementia, neurodegenerative diseases or bipolar disorder; the depression is, for example, major depressive disorder, and the ADHD is, for example, attention deficit hyperactivity disorder.
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur.
  • cycloalkyl optionally substituted with alkyl means that alkyl may but need not be present, and the description includes instances where cycloalkyl is substituted with alkyl and instances where cycloalkyl is not substituted with alkyl.
  • “Pharmaceutical composition” refers to a mixture containing one or more compounds described in the present invention or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers or excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.
  • polymorph or “polymorph” refers to a crystalline form having the same chemical composition but different spatial arrangements of the molecules, atoms and or ions that make up the crystal. Although polymorphs have the same chemical composition, they have different packing and geometric arrangements and may exhibit different physical properties, such as melting points, shapes, colors, densities, hardness, deformability, stability, solubility, dissolution rates and the like. Depending on their temperature-stability relationship, the relative stability of the two solid phases is swapped. This phenomenon of a compound existing in different lattice structures is called pharmaceutical polymorphism.
  • XRPD may produce certain displacement and intensity deviations due to detection methods, conditions and instruments.
  • the same sample of the same crystal form usually has the same main XRPD characteristic peak, but there may be certain operating errors.
  • the characteristic peak error is usually within ⁇ 0.2°.
  • different technicians using different instruments may occasionally have a few characteristic peaks with errors exceeding this range. For example, errors within ⁇ 0.5° or ⁇ 0.3° should be considered to belong to the XRPD characteristic peaks of the same crystal form.
  • the absolute intensity and relative intensity of the peaks shown in the above tables and figures may vary due to various factors, such as the effect of the selective orientation of the crystalline solid on the X-ray beam, the influence of coarse particles, the purity of the substance being analyzed, or the crystallinity of the sample.
  • the peak position may also shift according to the change in the sample height.
  • Interplanar spacing or interplanar spacing (d value) refers to the selection of three non-parallel unit vectors a, b, c connecting two adjacent lattice points in the space lattice. They divide the lattice into juxtaposed parallelepiped units, which are called interplanar spacing. The space lattice is divided according to the determined parallelepiped unit connection lines to obtain a set of straight line grids, called space grids or lattices. The lattice and lattice use geometric points and lines to reflect the periodicity of the crystal structure. Different crystal planes have different interplanar spacings (that is, the distance between two adjacent parallel crystal planes); the unit is Or Angstrom.
  • Relative intensity (I%) refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak among all diffraction peaks in an X-ray powder diffraction pattern (XRPD) when the intensity of the first strongest peak is 100%.
  • DSC Different Scanning Calorimetry or DSC measures the transition temperatures of a crystal when heat is absorbed or released as a result of changes in its crystal structure or melting of the crystal.
  • the thermal transition temperatures and melting points can be within about 5°C, usually within about 3°C, in consecutive analyses.
  • DSC peak or melting point ⁇ 5°C
  • this temperature variation is generally taken into account.
  • DSC provides an auxiliary method for distinguishing different crystalline forms. Different crystal forms can be identified by their different transition temperature characteristics. It should be noted that for mixtures, the DSC peak or melting point may vary over a wider range. In addition, since decomposition is associated with the melting of a substance, the melting temperature is related to the heating rate.
  • TGA Thermogravimetric analysis
  • Amorphous refers to the material formed when the particles (molecules, atoms, ions) of the material are arranged in three-dimensional space without periodicity, characterized by a diffuse X-ray powder diffraction pattern without peaks.
  • Amorphous/form is a special physical form of solid matter, and its locally ordered structural characteristics suggest that it is inextricably linked to crystalline substances.
  • “Substantially as shown” means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern, DSC pattern, Raman spectrum pattern, or infrared spectrum pattern are shown in the pattern.
  • Room temperature refers to a temperature from 10°C to 40°C. In some embodiments, “room temperature” refers to a temperature from 15°C to 30°C; in other embodiments, “room temperature” refers to a temperature from 18°C to 25°C.
  • the methanesulfonate crystal form I of the compound (6bR, 10aS)-8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one of the present invention not only performs well in product performance parameters such as solubility, hygroscopicity and stability, but also shows obvious advantages in pharmacokinetic studies, can be rapidly absorbed after administration, shows good metabolic properties, and has good exposure amount AUC and maximum blood drug concentration Cmax , has good oral absorption characteristics, and is of great significance in improving the efficacy of drugs, reducing dosage, saving costs, etc.
  • Figure 1 is an XRPD diagram of (6bR,10aS)-8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one methanesulfonate Form I.
  • Figure 2 is a DSC diagram of (6bR,10aS)-8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one methanesulfonate Form I.
  • Figure 3 is a TGA diagram of (6bR,10aS)-8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one methanesulfonate Form I.
  • Figure 4 is a DVS diagram of (6bR,10aS)-8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one methanesulfonate Form I.
  • compound A The compound of the present invention (6bR, 10aS)-8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one, hereinafter referred to as compound A, has a structural formula of
  • the DVS graph of Compound A mesylate Form I is shown in Figure 4, where the two curves represent the adsorption curve and the desorption curve, respectively. Due to the possible hysteresis during desorption, the two curves do not overlap.
  • Figure 4 shows that when the relative humidity (RH) of the sample is between 0% and 80%, as the humidity increases, the mass change ⁇ W% is less than 2%, indicating that the sample is slightly hygroscopic.
  • the moisture gain of Compound A methanesulfonate Form I at RH 80% and 25°C is between 0.2% and 2%, indicating that it is slightly hygroscopic, and the XRPD spectrum does not change, indicating that the crystal form is stable.
  • Test sample Compound A methanesulfonate Form I, prepared in-house.
  • Drug preparation Take the test sample, add physiological saline and perform ultrasound.
  • Administration route oral gavage; Dosage: 15 mg/kg; Frequency and duration of administration: single administration.
  • SD rats were stratified by body weight and randomly divided into groups, with 3 rats in each group. They were fasted overnight before the experiment.
  • the drugs were administered orally by gavage, and 250 ⁇ L of blood was collected from the jugular vein or orbital vein of the rats at 0, 0.167, 0.333, 0.5, 1, 2, 4, 7 and 10 hours into a sample tube containing sodium heparin, an anticoagulant, and placed in wet ice. The tube was centrifuged at 4000 r ⁇ min -1 for 10 min, and the plasma was separated for LC-MS analysis.
  • the measured blood drug concentration-time data were substituted into Winnonlin 8.2 program to calculate the main pharmacokinetic parameters.
  • Tmax and Cmax were measured values
  • AUC 0-t value and AUC inf value were calculated by trapezoidal method
  • t 1/2 was calculated from the terminal concentration point of the elimination phase by semi-logarithmic plotting method. The specific results are shown in Table 3.3 below.
  • the mesylate crystal form I of the compound A of the present invention can be rapidly absorbed after administration, showing good metabolic properties, and both the exposure amount AUC and the maximum blood drug concentration Cmax are good.

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Abstract

本发明涉及一种杂环取代的稠合γ-咔啉类衍生物的甲磺酸盐、晶型及其制备方法和应用。特别地，本发明涉及化合物(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮的甲磺酸盐、晶型及其制备方法和应用和含有治疗有效量的该化合物的甲磺酸盐、晶型的药物组合物，及其在制备预防和/或治疗神经精神类疾病药物中的用途。

Description

一种杂环取代的稠合γ-咔啉类衍生物的甲磺酸盐、晶型及其制备方法和应用
本申请要求申请日为2022年10月26日的中国专利申请2022113269716的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物合成技术领域，特别涉及一种杂环取代的稠合γ-咔啉类衍生物的甲磺酸盐、晶型及其制备方法和应用。
背景技术
精神分裂症是以认知力和情感深度分裂为特征的一种疾病，表现为最基本的人类行为受到影响，例如语言、思想、知觉和自我感知等。该疾病的症状所包含的范围较广，最常见的为精神方面的障碍，比如产生幻觉、妄想症和错觉等。
全球范围内约有1％的人患精神分裂症，而在所有接受治疗的患者中只有5％最终能够得以完全康复。此外，由于精神分裂症通常会引发合并症，例如焦虑障碍、抑郁或精神性药物滥用等。
传统上习惯把通过阻断多巴胺D2受体发挥药理作用的抗精神病药物称为第一代抗精神病药物，即“典型”抗精神病药物(如氟哌啶醇)，它们治疗精神分裂症阳性症状有突破性，但未能治疗阴性症状和认知障碍。典型抗精神病药物一般有严重的EPS副作用，并且对三分之一的精神分裂症病人无效。
20世纪60年代以后，又陆续开发了一系列新一代抗精神病药，包括齐拉西酮(Ziprasidone)、利培酮(Risperidone)等，被称为第二代抗精神病药物，即新型抗精神病药，虽然它们各自的药理作用不完全一致，但却具有共同的药理特征，即对5-羟色胺(5-HT)受体(5-HT1A、2A、2c)和去甲肾上腺素(NA)受体(α1、α2)的亲和力远比对D2受体的要高，导致D2/5-HT2A的比值较高。其临床效果与第一代抗精神病药物相比有更多优势，不但对阳性症状与传统抗精神病药同样有效，而且对阴性症状、认知缺陷症状有效，作用谱更广，但是这些药物有QT间隙延长，高泌乳素血症和体重增加等不良反应。因此寻找能对精神分裂症阳性、阴性症状和认知障碍有效，而且副作用小的药物是现在研究的热点。
5-羟色胺系统在调节前额叶皮层(PFC)的功能中起着重要作用，包括情绪控制，认知行为和工作记忆。PFC的锥体神经元和GABA中间神经元包含了几个具有特别高密度的5-羟色胺受体亚型5-HT1A和5-HT2A。最近得到证明PFC和NMDA受体通道是5-HT1AR的目标，这两个受体调节大脑皮层兴奋性神经元，从而影响认知功能。实际上，各种临床前数据表明5-HT1AR可能是抗精神病药发展药物的新目标。非典型抗精神药物(如olanzapine,aripiprazole等)对5-HT1AR的高亲和力及其低的EPS副作用均说明5-羟色胺系统在调节的前额叶皮层(PFC)的功能中起着重要作用，包括情绪控制、认知行为和工作记忆。PFC的锥体神经元和GABA中间神经元包含了几个具有特别高密度5-羟色胺受体亚型5-HT1A和5-HT2A。最近研究表明5-HT1A激动剂与非典型抗精神病药物治疗相关，能改善阴性症状和认知障碍。在应用非典型抗精神病药物氯氮平治疗精神分裂症中，人们发现5-HT2A在其中起着很重要的作用，涉及到感知、情绪调节以及运动控制的各个方面。阻断5-HT2A受体 可使多巴胺的释放正常化，而起到抗精神病作用。另外，5-HT2C受体与体重增加密切相关。
D3受体在脑内的分布情况主要选择性分布于边缘系统，脑内有两条主要DA神经通路，一条是黑质纹状体通路调控运动功能，另一条是中脑腹侧被盖区伏隔核前额叶皮层DA通路与学习认知和情感活动密切相关，其功能异常将导致精神分裂症，该DA通路也是脑内奖赏效应(reward efects)的主要通路，D3R在两条DA神经通路中都有分布，并和其他DA受体亚型间存在着复杂相互作用，可能作为抗精神病药物治疗的一个目标，选择性D3受体的拮抗作用能减少精神分裂症的消极和认知症状，此外能阻止锥体外系副作用，包括迟发性运动障碍，帕金森病。因此，寻找一个多受体结合副作用小的抗精神分裂症药物对临床治疗具有重要意义。
国际专利申请PCT/CN2021/122546中公开了一种作用于5-HT2A和D2受体的拮抗剂，其化学名称为(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮，对5-HT2A受体和D2(D2L、D2s)受体均具有良好的拮抗活性，且具有较高的D2/5-HT2A比值，即良好的选择性，具有良好的药代动力学性质，且具有良好的体内药效作用，能够有效治疗和改善精神分裂症。
药物活性成分的不同盐和固体形式可能具有不同的性质。不同盐和固体形式在外观、溶解度、熔点、吸湿性、稳定性、药代动力学等方面可能会有显著不同，也会对药物的稳定性、生物利用度及疗效等方面产生不同的影响。因此，在药物研发中，应全面考虑药物的盐型和/或固体形式问题。
发明人在对该化合物进行研究时发现，该化合物游离碱以油状物存在，在水中溶解性不佳，生物利用度低，不是临床用药的优选形式，故有必要进一步对该化合物的酸式盐及其晶型进行全面的筛选和研究。
发明内容
国际专利申请PCT/CN2021/122546中涉及的所有内容均以引证的方式添加到本发明中。
本发明所要解决的技术问题是提供一种杂环取代的稠合γ-咔啉类衍生物的甲磺酸盐、晶型及其制备方法和应用。
本发明的目的在于提供一种化合物(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮的酸式盐。
在本发明优选的实施方案中，所述酸式盐为甲磺酸盐。
在本发明优选的实施方式中，所述酸式盐中酸的个数为0.5-2，优选为0.8-1.2，优选为1。
在本发明进一步优选的实施方案中，所述酸式盐为晶型。
在本发明进一步优选的实施方案中，化合物(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮的酸式盐为甲磺酸盐晶型Ⅰ，酸的个数为1，其X射线粉末衍射图谱包含位于2θ为5.83±0.2°、12.75±0.2°、22.56±0.2°处的衍射峰；
优选的，包含位于2θ为5.83±0.2°、12.75±0.2°、18.34±0.2°、19.24±0.2°、22.56±0.2°处的衍射峰；
更优选的，包含位于2θ为5.83±0.2°、8.29°±0.2°、12.75±0.2°、14.43±0.2°、16.76±0.2°、17.64±0.2°、18.34±0.2°、19.24±0.2°、19.71±0.2°、22.56±0.2°处的衍射峰；
进一步优选的，包含位于2θ为5.83±0.2°、8.29±0.2°、8.86±0.2°、11.71±0.2°、12.75±0.2°、13.73±0.2°、14.43±0.2°、15.35±0.2°、16.51±0.2°、16.76±0.2°、17.64±0.2°、18.00±0.2°、18.34±0.2°、18.81±0.2°、19.24±0.2°、19.71±0.2°、19.98±0.2°、20.53±0.2°、21.85±0.2°、22.56±0.2°、23.05±0.2°、23.29±0.2°、23.82±0.2°、24.06±0.2°、24.99±0.2°、25.32±0.2°、26.70±0.2°、27.47±0.2°、29.67±0.2°、32.79±0.2°处的衍射峰；
更进一步优选的，使用Cu-Kα辐射，以2θ角和晶面间距d值表示的X-射线衍射峰如表1所示。
表1化合物的甲磺酸盐晶型Ⅰ的XRPD射线衍射数据
更进一步优选的，化合物(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮的甲磺酸盐晶型Ⅰ的X-射线粉末衍射图谱基本如图1所示；其DSC图谱基本如图2所示；其TGA图谱基本如图3所示。
在本发明进一步优选的实施例中，上述酸式盐为无水物。
另一方面，本发明还涉及一种制备化合物(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮酸式盐的方法，具体包括如下步骤：
(1)称取适量的化合物(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮游离碱，用溶剂1溶解；
(2)称取适量的甲磺酸，任选地，用溶剂2溶解；所述甲磺酸的量为0.5-2.0当量，优选0.5-1.0当量；
(3)将上述两者混合，搅拌析晶，抽滤，真空干燥得到目标产物；
其中：
所述的溶剂1和溶剂2各自独立地选自水、甲醇、乙醇、乙二醇、丙二醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、冰醋酸、丙酮、丁酮、3-戊酮、正己烷、环己烷、正庚烷、异丙醚、甲基叔丁基醚、石油醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、二氯甲烷、三氯甲烷、1,2-二氯乙烷、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙腈、四氢呋喃、1,4-二氧六环、1,2-二氧六环、苯或甲苯；上述溶剂1和溶剂2使用时需互溶。
本发明进一步涉及一种药物组合物，其包含治疗有效剂量的任一所示的化合物的酸式盐或其组合，以及一种或多种药学上可接受的载体或赋形剂。
本发明进一步涉及任一所示的化合物的酸式盐，或其药物组合物在制备涉及或调节5-羟色胺受体、5-羟色胺转运蛋白和/或多巴胺受体的药物中的用途；优选在制备涉及或调节5-HT2A受体、5-羟色胺转运蛋白、多巴胺D1受体和/或多巴胺D2受体的药物中的用途，更优选在制备涉及或调节5-HT2A受体和/或多巴胺D2受体的药物中的用途。
本发明进一步涉及任一所示的化合物的酸式盐，或其药物组合物在制备治疗神经精神类疾病的药物中的用途。
在本发明进一步优选的实施例中，所述神经精神类疾病选自抑郁症、焦虑症、痴呆症、精神分裂症、睡眠障碍、运动障碍、痴呆症患者的行为障碍、帕金森病、阿尔茨海默病、偏头痛、多动症、强迫症、社交恐惧症、神经退行性疾病、双相情感障碍、创伤后应激综合征、成瘾性疾病、戒断综合征或注意力缺陷中的一种或多种，优选抑郁症、焦虑症、痴呆症、精神分裂症、睡眠障碍、运动障碍、痴呆症患者的行为障碍、神经退行性疾病或双相情感障碍中的任意一种或多种；所述的抑郁症例如重度抑郁症，所述的多动症例如注意力缺陷多动症。
发明的详细说明
“X选自A、B或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选(的)被烷基取代的环烷基”意味着烷基可以但不必须存在，该说明包括环烷基被烷基取代的情形和环烷基不被烷基取代的情形。
“药物组合物”指含有一种或多种本发明所述的化合物或其生理学上/药学上可接受的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学上/药学上可接受的载体或赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“药学上可接受的盐”指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
本文所用的“多晶型”或“多晶型物”是指具有相同化学组成，但构成该晶体的分子、原子和或离子的不同空间排列的晶型。尽管多晶型物具有相同的化学组成，但它们的堆积和几何排列不同，并可能表现出不同的物理性质，如熔点、形状、颜色、密度、硬度、可形变性、稳定性、溶解度、溶出速率和类似性质。根据它们的温度-稳定性关系，两种固相之间的相对稳定性调换。这种化合物以不同晶格结构存在的现象被称作药物多晶型现象。
本发明公开或要求保护的晶体结构对等的晶体结构可能根据试验条件、纯度、设备和本领域技术人员已知的其他常用变量在合理误差范围内表现出类似但不完全相同的分析特性。相应地，本领域技术人员显而易见的是，可以在不背离本发明的范围和精神的情况下在本发明内做出各种修改和变动。在考虑本文公开的本发明的说明书和实践的基础上，本发明的其它实施方案是本领域技术人员显而易见的。申请人期望该说明书和实施例被视为示例性的，而非限制其范围。
“Ⅹ-射线粉末衍射图谱或XRPD”是指根据布拉格公式2d sinθ＝nλ(式中，λ为Ⅹ射线的波长，衍射的级数n为任何正整数，一般取一级衍射峰，n＝1)，所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度。当Ⅹ射线以掠角θ(入射角的余角，又称为布拉格角)入射到晶体或部分晶体样品的某一具有d点阵平面间距的原子面上时，就能满足布拉格方程，从而测得了这组Ⅹ射线粉末衍射图。
本领域普通技术人员公知，XRPD可能会因检测方法、条件和仪器的原因产生一定的位移和强度偏差。同一晶型的相同样品通常具有同样的主要XRPD特征峰，但可能存在一定操作误差，当由本领域普通技术人员，采用相应方法得到的同晶型样品采用相同的仪器和检测方法进行检测时，特征峰误差通常在±0.2°以内，然而不同技术人员使用不同仪器可能偶尔出现少数特征峰的误差超出该范围，如误差在±0.5°或±0.3°内均应认为属于相同晶型的XRPD特征峰。因此，作为本发明晶型的一个具体示例，其XRPD如图谱X所示，但普通技术人员了解的是，当关键特征峰位移2θ偏差在±0.5°、±0.3°或±0.2°以内，尤其在±0.2° 左右时，均可以被认定为同一晶型，都可被解释为本发明保护范围之内。
另外对于前述的表及图中所显示的峰的绝对强度及相对强度可能由于多种因素、例如结晶固体的选择取向对Ⅹ射线光束的效果、粗大粒子的影响、所分析的物质的纯度或样品的结晶化度而产生变动。另外，峰位置亦可根据样品高度的变动而发生移位。进而，若使用不同波长进行测定，则依据布拉格式(nλ＝2dsinθ)获得不同的位移值，此种通过使用不同波长所获得的不同的XRPD图案也包含于本发明的范围。
“晶面间距或晶面间距(d值)”是指空间点阵选择3个不相平行的连结相邻两个点阵点的单位矢量a，b，c，它们将点阵划分成并置的平行六面体单位，称为晶面间距。空间点阵按照确定的平行六面体单位连线划分，获得一套直线网格，称为空间格子或晶格。点阵和晶格是分别用几何的点和线反映晶体结构的周期性，不同的晶面，其面间距(即相邻的两个平行晶面之间的距离)各不相同；单位为或埃。
“相对强度(I％)”是指X‐射线粉末衍射图(XRPD)的所有衍射峰中第一强峰的强度为100％时，其它峰的强度与第一强峰的强度的比值。
“差示扫描量热分析或DSC”测定当晶体由于其晶体结构发生变化或晶体熔融而吸收或释放热时的转变温度。对于同种化合物的同种晶型，在连续的分析中，热转变温度和熔点误差可以是约5℃之内，通常在约3℃之内。当描述某个化合物具有某一给定的DSC峰或熔点时，指的是该DSC峰或熔点±5℃，基本上也将这种温度的变化考虑在内。DSC提供了一种辨别不同晶型的辅助方法。不同的晶体形态可根据其不同的转变温度特征而加以识别。需要指出的是对于混合物而言，其DSC峰或熔点可能会在更大的范围内变动。此外，由于在物质熔化的过程中伴有分解，因此熔化温度与升温速率相关。
“热重分析(TGA)”是测定化合物的热稳定性的常见方法。在本发明中，TGA还可用来测定化合物的水合状态，测试过程中升温速率会对图谱产生一定的影响。TGA的误差可以是约±0.5质量％以内。
“无定型”、“无定形”或“无定形形式”是指物质的质点(分子、原子、离子)在三维空间排列无周期性时形成的物质，其特征是具有漫射的不具尖峰的X射线粉末衍射图。无定型/形是固体物质的一种特殊的物理形式，其局部有序的结构特征，提示其与晶型物质有着千丝万缕的联系。
“当量”或其缩写“eq”，是按照化学反应的当量关系，以每步中所用基本原料为基准(1当量)，所需要的其他原材料的当量用量。
“基本上如图所示”是指X‐射线粉末衍射图或DSC图或拉曼光谱图或红外光谱图中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰显示在其图中。
在本发明的上下文中，当使用或者无论是否使用“大约”或“约”等字眼时，表示在给定的值或范围的10％以内，适当地在5％以内，特别是在1％以内。或者，对于本领域普通技术人员而言，术语“大约”或“约”表示在平均值的可接受的标准误差范围内。每当公开一个具有N值的数字时，任何具有N+/–1％，N+/–2％，N+/–3％，N+/–5％，N+/–7％，N+/–8％ 或N+/–10％值以内的数字会被明确地公开，其中“+/–”是指加或减。
“室温”指的是温度由10℃到40℃。在一些实施例中，“室温”指的是温度由15℃到30℃；在另一些实施例中，“室温”指的是温度由18℃到25℃。
有益效果
本发明化合物(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮的甲磺酸盐晶型I不仅在溶解度、吸湿性、稳定性等产品性能参数方面表现良好，且在药代动力学研究中也显示出明显的优势，给药后能迅速吸收，表现出良好的代谢性质，暴露量AUC和最大血药浓度Cmax都表现良好，具有较好的口服吸收特性，在提高药物的药效、减少用药剂量、节省成本等方面都具有重要的意义。
附图说明
图1为(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮甲磺酸盐晶型Ⅰ的XRPD图示。
图2为(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮甲磺酸盐晶型Ⅰ的DSC图示。
图3为(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮甲磺酸盐晶型Ⅰ的TGA图示。
图4为(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮甲磺酸盐晶型Ⅰ的DVS图示。
具体实施方式
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。此外应理解，在阅读了本发明讲授的内容之后，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。
本发明化合物(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮，以下简称化合物A，结构式为
其游离碱参照国际专利申请PCT/CN2021/122546中实施例1-A的制备方法制得。
化合物A的盐晶型研究
实验仪器：

1、化合物A酸式盐的制备
1.1化合物A甲磺酸盐晶型Ⅰ的制备
在25mL圆底烧瓶中加入化合物A游离碱(132mg，0.31mmol)，乙酸乙酯(1.0mL)， 通入氮气，于室温搅拌溶清。然后加入1M的甲磺酸-乙酸乙酯溶液(0.25mL，0.25mmol)，搅拌反应半小时。抽滤，滤饼室温真空干燥5小时，得到类白色固体，其被鉴定为化合物A甲磺酸盐晶型Ⅰ(68mg)。
经检测分析，其具有如图1所示的XRPD图，如图2所示的DSC图及如图3所示的TGA图。结合其DSC和TGA的结果分析可知其为非溶剂合物，且化合物A和甲磺酸盐的摩尔比例约为1:1。
2、溶解度实验
2.1实验目的：
考察化合物A游离碱和化合物A甲磺酸盐晶型I在水中的溶解度大小，为盐可成药性评估提供依据。
2.2实验方案：
称取过量化合物A游离碱和甲磺酸盐晶型I放置于不同10mL离心管中，加入1mL去离子水，封口膜密闭，恒温摇床37℃，150rpm摇晃24h后，过0.45μm有机滤头后稀释进样，HPLC分析。
2.3实验结果：溶解度结果如下表3.1所示。
2.4实验结论：
由上述数据可知化合物A甲磺酸盐晶型I在水介质中的溶解度相对化合物A游离碱显著提高。
3、固体稳定性实验
3.1实验目的：
考察化合物A甲磺酸盐晶型I在高温密闭条件下的物理化学稳定性。
3.2实验方案：
称取适量化合物A甲磺酸盐晶型I，置于称量皿中，密闭，放置在60℃稳定性试验箱中10天，在0天、3天、7天及10天时混合均匀后取样，甲醇溶解后，HPLC有关物质方法检测含量及杂质变化情况，另外，分别检测样品前后的XRPD图谱进行对比分析。
3.3实验结果：稳定性结果如下表3.2所示：
3.4实验结论：
以上数据表明，本发明的化合物A甲磺酸盐晶型I在高温密闭条件下均具有良好的稳定性，且XRPD图谱未发生改变。
4、引湿性实验
4.1实验目的：
考察化合物A甲磺酸盐晶型I的吸湿潮解性能。
4.2实验方案：
在室温25℃条件下，将化合物A甲磺酸盐晶型I 30.68mg置于DVS样品盘内进行测试。另外分别检测样品前后的XRPD图谱进行对比分析。
4.3实验结果：
化合物A甲磺酸盐晶型I的DVS图如图4所示，图中两条曲线分别代表吸附曲线和解吸曲线，由于解吸时可能存在滞后现象，导致两条曲线不重合。图4显示样品在相对湿度(RH)为0％-80％之间，随着湿度的增加，质量变化ΔW％小于2％，表明样品略有引湿性。
4.4实验结论：
化合物A甲磺酸盐晶型I在RH 80％，25℃条件下的引湿增重在0.2％-2％之间，略有引湿性，且XRPD图谱未发生改变，晶型稳定。
5、药代动力学实验
5.1试验目的：
对雌性SD大鼠进行经口灌胃给药，测定化合物A甲磺酸盐晶型I在大鼠中的血药浓度，计算PK参数，对其进行药代动力学评价。
5.2试验材料：
(1)试验样品：本发明化合物A甲磺酸盐晶型I，自制。
(2)试验动物：SD大鼠，SPF级，雌性，上海斯莱克实验动物有限责任公司。
5.3试验方案：
(1)给药信息：
药物配制：取受试样品，加入生理盐水并进行超声。给药途径：经口灌胃给药；给药剂量：15mg/kg；给药频率及期限：单次给药。
(2)试验方法：
将SD大鼠按体重分层后随机分组，每组3只大鼠，试验前过夜禁食。分别经口灌胃给药，在0、0.167、0.333、0.5、1、2、4、7和10小时，于大鼠颈静脉或眼眶静脉取血250μL至含有抗凝剂肝素钠的样品管并置于湿冰中，4000r·min-1离心10min，分离血浆进行LC-MS分析。
5.4试验结果与分析：
将所测得的血药浓度-时间数据代入Winnonlin 8.2程序计算主要药动学参数。Tmax和Cmax采用实测值，采用梯形法计算AUC0-t值和AUCinf值，以半对数作图法，由消除相末端浓度点计算t1/2。具体结果如下表3.3所示。
表3.3化合物A甲磺酸盐的大鼠药代实验结果
5.5试验结论：
从表中实验结果可以看出，本发明化合物A甲磺酸盐晶型I给药后能迅速吸收，表现出良好的代谢性质，暴露量AUC和最大血药浓度Cmax都表现良好。

Claims (9)

  1. 化合物(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮的酸式盐，其特征在于，所述酸式盐为甲磺酸盐。
  2. 根据权利要求1所述的酸式盐，其特征在于，所述酸式盐中甲磺酸的个数为0.5-2，优选为0.8-1.2，优选为1。
  3. 根据权利要求1或2所述的酸式盐，其特征在于，所述酸式盐为晶型，优选为甲磺酸盐晶型Ⅰ，其X-射线粉末衍射图谱包含位于2θ为5.83±0.2°、12.75±0.2°、22.56±0.2°处的衍射峰；优选其X-射线粉末衍射图谱包含位于2θ为5.83±0.2°、12.75±0.2°、18.34±0.2°、19.24±0.2°、22.56±0.2°处的衍射峰；优选其X-射线粉末衍射图谱包含位于2θ为5.83±0.2°、8.29°±0.2°、12.75±0.2°、14.43±0.2°、16.76±0.2°、17.64±0.2°、18.34±0.2°、19.24±0.2°、19.71±0.2°、22.56±0.2°处的衍射峰；优选其X-射线粉末衍射图谱包含位于2θ为5.83±0.2°、8.29±0.2°、8.86±0.2°、11.71±0.2°、12.75±0.2°、13.73±0.2°、14.43±0.2°、15.35±0.2°、16.51±0.2°、16.76±0.2°、17.64±0.2°、18.00±0.2°、18.34±0.2°、18.81±0.2°、19.24±0.2°、19.71±0.2°、19.98±0.2°、20.53±0.2°、21.85±0.2°、22.56±0.2°、23.05±0.2°、23.29±0.2°、23.82±0.2°、24.06±0.2°、24.99±0.2°、25.32±0.2°、26.70±0.2°、27.47±0.2°、29.67±0.2°、32.79±0.2°处的衍射峰。
  4. 根据权利要求1-3中任一项所述的酸式盐，其特征在于，所述酸式盐为甲磺酸盐晶型Ⅰ，其X-射线粉末衍射图谱基本如图1所示。
  5. 根据权利要求1-4中任一项所述的酸式盐，其特征在于，所述酸式盐为甲磺酸盐晶型Ⅰ，其DSC图谱在195.77±5℃有吸热峰，优选具有如图2所示的DSC图谱，和/或者具有如图3所示的TGA图谱。
  6. 制备权利要求1-5中任一项所述酸式盐的方法，其特征在于，具体包括如下步骤：
    (1)称取适量的化合物(6bR,10aS)-8-(4-(4-氟苯基)-4-氧代丁基)-3,6b-二甲基-6b,7,8,9,10,10a-六氢-1H-吡啶[3',4':4,5]吡咯[1,2,3-脱]喹喔啉-2(3H)-酮游离碱，用溶剂1溶解；
    (2)称取适量的甲磺酸，任选地，用溶剂2溶解；所述甲磺酸的量优选0.5-1.0当量；
    (3)将上述两者混合，搅拌析晶，抽滤，真空干燥得到目标产物；
    其中：
    所述的溶剂1和溶剂2各自独立地选自水、甲醇、乙醇、乙二醇、丙二醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、冰醋酸、丙酮、丁酮、3-戊酮、正己烷、环己烷、正 庚烷、异丙醚、甲基叔丁基醚、石油醚、N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、二氯甲烷、三氯甲烷、1,2-二氯乙烷、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙腈、四氢呋喃、1,4-二氧六环、1,2-二氧六环、苯或甲苯；上述溶剂1和溶剂2使用时需互溶。
  7. 一种药物组合物，其包含治疗有效剂量的权利要求1-5中任一项所示的酸式盐或其组合，以及一种或多种药学上可接受的载体或赋形剂。
  8. 根据权利要求1-5中任一项所示的酸式盐，或权利要求7所述的药物组合物在制备涉及或调节5-羟色胺受体、5-羟色胺转运蛋白和/或多巴胺受体的药物中的用途；优选在制备涉及或调节5-HT2A受体、5-羟色胺转运蛋白、多巴胺D1受体和/或多巴胺D2受体的药物中的用途，更优选在制备涉及或调节5-HT2A受体和/或多巴胺D2受体的药物中的用途。
  9. 根据权利要求1-5中任一项所示的酸式盐，或权利要求7所述的药物组合物在制备治疗神经精神类疾病的药物中的用途，所述神经精神类疾病选自抑郁症、焦虑症、痴呆症、精神分裂症、睡眠障碍、运动障碍、痴呆症患者的行为障碍、帕金森病、阿尔茨海默病、偏头痛、多动症、强迫症、社交恐惧症、神经退行性疾病、双相情感障碍、创伤后应激综合征、成瘾性疾病、戒断综合征或注意力缺陷中的一种或多种，优选抑郁症、焦虑症、痴呆症、精神分裂症、睡眠障碍、运动障碍、痴呆症患者的行为障碍、神经退行性疾病或双相情感障碍中的任意一种或多种；所述的抑郁症例如重度抑郁症，所述的多动症例如注意力缺陷多动症。
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