WO2024153165A1 - 一种抗抑郁化合物的盐、其制备方法、包含其的药物组合物及其用途 - Google Patents

一种抗抑郁化合物的盐、其制备方法、包含其的药物组合物及其用途 Download PDF

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WO2024153165A1
WO2024153165A1 PCT/CN2024/072942 CN2024072942W WO2024153165A1 WO 2024153165 A1 WO2024153165 A1 WO 2024153165A1 CN 2024072942 W CN2024072942 W CN 2024072942W WO 2024153165 A1 WO2024153165 A1 WO 2024153165A1
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acid
compound
formula
salt
crystalline form
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English (en)
French (fr)
Inventor
田广辉
程勇
张岩
杨飞瀑
何洋
吴春晖
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Shanghai Institute of Materia Medica of CAS
Vigonvita Life Sciences Co Ltd
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Shanghai Institute of Materia Medica of CAS
Vigonvita Life Sciences Co Ltd
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Priority to EP24744339.3A priority Critical patent/EP4653441A1/en
Priority to JP2025542227A priority patent/JP2026508826A/ja
Publication of WO2024153165A1 publication Critical patent/WO2024153165A1/zh
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/25—Sulfonic acids having sulfo groups bound to carbon atoms of rings other than six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medical technology, and specifically relates to an acid addition salt of an antidepressant compound 2-methyl-5-(naphthalene-2-yl)octahydropyrrole[3,4-c]pyrrole, a method for preparing the salt, a pharmaceutical composition containing the salt, and use of the salt or the pharmaceutical composition in preparing a drug for treating and/or alleviating depression.
  • Depression has become the fourth largest disease in the world. According to the "Depression and Other Common Mental Disorders Global Health Estimates” released by WHO in 2017, the total number of people suffering from depression in the world is 322 million, and nearly half of these people live in Southeast Asia and the Western Pacific region (including India and China). In China, the lifetime prevalence of depression is 6.9%, and the 12-month prevalence is 3.6%. With the acceleration of the pace of society, people are under increasing pressure in life, spirit and society, and the incidence of depression is on the rise. Depression is characterized by high incidence, high recurrence and high disability. There are significant emotional, cognitive and physical symptoms during the onset period, which brings serious troubles to patients' study, work and life, and brings heavy economic burdens to society and families.
  • antidepressants have various side effects, especially gastrointestinal side effects, such as nausea, vomiting, indigestion, diarrhea, headache, insomnia, drowsiness and anxiety. At the same time, antidepressants generally need to be taken continuously for 2-4 weeks to take effect, so they have a high discontinuation rate.
  • cognitive symptoms are also one of the main clinical manifestations of depression. Cognitive symptoms are mostly manifested as slow thinking, inattention, distraction and decreased information processing ability. This symptom group is not only a common symptom in the acute phase of depression, but also an important residual symptom that affects function. If it is not fully relieved, the patient's work, housework, and academic ability cannot be restored to the previous level, thereby reducing the quality of life.
  • Residual cognitive symptoms are also one of the influencing factors of depression relapse. Therefore, it is of great significance to reduce the gastrointestinal side effects of antidepressants, increase patient compliance with medication, thereby reducing the discontinuation rate, and relieve cognitive symptoms that are easily overlooked in clinical practice to promote the full recovery of function in patients with depression.
  • WO2020239073A1 discloses a class of drugs that can inhibit the reuptake of endogenous monoamines such as dopamine, serotonin and norepinephrine (e.g., from the synaptic cleft) by regulating one or more monoamine transporters, and/or regulate 5-HT3
  • endogenous monoamines such as dopamine, serotonin and norepinephrine (e.g., from the synaptic cleft)
  • 5-HT3 5-HT3
  • the compound shows a serotonin reuptake inhibition concentration of less than 10nM (IC 50 ) and has a high affinity for 5-HT3 receptors.
  • the compound is not only highly active, but also has the characteristics of low effective dose and small toxic side effects. It is effective for diseases in the field of central nervous system, especially for depression and other diseases. However, the compound has a low solubility, which limits its application in the pharmaceutical process to a certain extent.
  • the purpose of the present invention is to provide an acid addition salt of 2-methyl-5-(naphthalene-2-yl)octahydropyrrole[3,4-c]pyrrole with stable properties, high solubility and good drugability, a crystal form of the salt, and a pharmaceutical composition containing the salt or the crystal form, and to provide a corresponding preparation method and pharmaceutical use.
  • the present invention provides a salt of a compound of formula (I), wherein the acid for forming the salt is selected from maleic acid, succinic acid, citric acid, tartaric acid, fumaric acid, formic acid, acetic acid, propionic acid, malonic acid, oxalic acid, benzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, camphoric acid, camphorsulfonic acid, salicylic acid, acetylsalicylic acid, aspartic acid, glutamic acid, lactic acid, gluconic acid, ascorbic acid, gallic acid, mandelic acid, malic acid, citric acid, fumaric acid, succinic acid, sorbic acid, trifluoroacetic acid, taurine, homot
  • the salt-forming acid is selected from hydrochloric acid, maleic acid, sulfuric acid, hydrogen bromide, phosphoric acid, methanesulfonic acid, citric acid, and fumaric acid;
  • the salt-forming acid is selected from hydrochloric acid, maleic acid, hydrogen bromide, phosphoric acid, and sulfuric acid;
  • the hydrochloric acid is hydrochloric acid or maleic acid.
  • the salt of the compound of formula (I) according to the present invention is a crystalline form, including: crystalline form A of the hydrochloride salt of the compound of formula (I), crystalline form B of the maleate salt of the compound of formula (I), and crystalline form C of the hydrobromide salt of the compound of formula (I);
  • the XRPD spectrum of the crystalline form A of the hydrochloride salt of the compound of formula (I) has characteristic peaks at the following 2 ⁇ diffraction angles: 8.74, 17.53, 17.99, 19.38, 20.70, 22.68, 24.44, 26.42 ⁇ 0.20°; in particular, the XRPD spectrum of the crystalline form A has characteristic peaks at the following 2 ⁇ diffraction angles: 8.74, 14.88, 17.53, 17.99, 19.38, 20.70, 22.18, 22.68, 24.44, 26.42 ⁇ 0.20°; More particularly, the XRPD pattern of the crystalline form A has characteristic peaks at the following 2 ⁇ diffraction angles: 4.38, 8.74, 14.88, 16.52, 17.53, 17.99, 19.38, 20.17, 20.70, 22.18, 22.68, 24.44, 26.42, 27.29, 28.34, 29.08, 30.14, 30.94, 31.72, 32.46, 33.48, 34.
  • the XRPD spectrum of the crystalline form B of the maleate salt of the compound of formula (I) has characteristic peaks at the following 2 ⁇ diffraction angles: 11.07, 14.52, 16.70, 17.60, 20.12, 22.28, 24.10, 28.01 ⁇ 0.20°; in particular, the XRPD spectrum of the crystalline form B has characteristic peaks at the following 2 ⁇ diffraction angles: 11.07, 14.52, 16.70, 17.60, 20.12, 22.28, 24.10, 25.18, 26.77, 28.01 ⁇ 0.20°; more particularly, the XRPD spectrum of the crystalline form B has characteristic peaks at the following 2 ⁇ diffraction angles: 11.07, 14.52, 16.70, 17.60, 20.12, 22.28, 24.10, 25.18, 26.77, 28.01 ⁇ 0.20°; more particularly, the XRPD spectrum of the crystalline form B The PD spectrum has characteristic peaks at the following 2 ⁇ diffraction angles: 9.33, 11.07, 12.06
  • the XRPD spectrum of the crystalline form C of the hydrobromide salt of the compound of formula (I) has characteristic peaks at the following 2 ⁇ diffraction angles: 4.47, 8.88, 16.58, 17.78, 20.96, 22.27, 22.94, 26.78 ⁇ 0.20°; in particular, the XRPD spectrum of the crystalline form C has characteristic peaks at the following 2 ⁇ diffraction angles: 4.47, 8.88, 16.58, 17.78, 20.96, 22.27, 22.94, 24.28, 26.7 8, 28.34 ⁇ 0.20 °; more particularly, the XRPD spectrum of the crystalline form C has characteristic peaks at the following 2 ⁇ diffraction angles: 4.47, 8.88, 13.32, 15.04, 16.58, 17.78, 19.61, 20.96, 22.27, 22.94, 24.28, 25.90, 26.78, 27.15, 27.70, 28.34, 29.56, 30.70, 31.14, 34.00 ⁇ 0.20 °;
  • the present invention provides a method for preparing a salt of the compound of formula (I) according to the first aspect of the present invention, comprising the following steps:
  • step 2) Cooling the mixture in step 1) to 0-30°C (e.g., 5°C, 10°C) and continuing stirring for 0.5-4h;
  • the solvent is selected from acetone, alcohol solvents (such as methanol, ethanol, isopropanol, etc.), acetonitrile, isopropyl acetate, ethyl acetate, dichloromethane, chloroform, toluene or a combination thereof; preferably, the solvent is selected from acetone, anhydrous ethanol, isopropanol, methanol, acetonitrile, isopropyl acetate, ethyl acetate or a combination thereof.
  • alcohol solvents such as methanol, ethanol, isopropanol, etc.
  • acetonitrile isopropyl acetate, ethyl acetate, dichloromethane, chloroform, toluene or a combination thereof
  • the solvent is selected from acetone, anhydrous ethanol, isopropanol, methanol, acetonitrile, isopropyl acetate, ethy
  • the usage ratio of the compound of formula (I) to the solvent is 1 g: 2 to 25 mL, preferably 1 g: 3 to 15 mL.
  • step 1) the molar ratio of the compound of formula (I) to the acid is 1:0.9-1.2.
  • step 1) the stirring is continued for 0.5 to 2 hours.
  • step 2) the stirring time is 0.5 to 2 hours.
  • the salt of the compound of formula (I) prepared according to the preparation method of the present invention is a crystalline form, for example, the crystalline form A of the hydrochloride salt of the compound of formula (I), the crystalline form B of the maleate salt of the compound of formula (I), and the crystalline form C of the hydrobromide salt of the compound of formula (I) as described above.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a salt of the compound of formula (I) described in the first aspect; and optional pharmaceutically acceptable excipients.
  • the pharmaceutical composition is an oral preparation or a non-oral preparation.
  • the oral preparation is selected from tablets, capsules, granules, powders and syrups;
  • the non-oral preparation is selected from injections, powder injections, sprays and suppositories.
  • the present invention provides use of a salt of the compound of formula (I) described in the first aspect of the present invention or a pharmaceutical composition described in the third aspect in the preparation of a medicament for treating and/or alleviating depression.
  • the present invention synthesizes, separates, and studies the related physical and chemical properties of the acid addition salt and crystal of the compound (2-methyl-5-(naphthalene-2-yl) octahydropyrrole [3,4-c] pyrrole) with antidepressant effect, and finds a salt (and its corresponding crystal form) with the advantages of good solid properties, good stability, high solubility, low hygroscopicity, etc.
  • the salt can be used to prepare a drug for treating and/or relieving depression.
  • FIG1 shows the XRPD spectrum of the hydrochloride crystal form A of the compound of formula (I) prepared in Example 1.
  • FIG2 shows the XRPD pattern of the maleate salt form B of the compound of formula (I) prepared in Example 7.
  • FIG3 shows the XRPD spectrum of the hydrogen bromide crystalline form C of the compound of formula (I) prepared in Example 2.
  • the "pharmaceutical composition” described in the present invention comprises at least one salt of the compound of the present invention (including the crystalline form of the salt), and optional pharmaceutically acceptable excipients.
  • excipients include (but are not limited to) excipients, binders, lubricants, disintegrants, colorants, flavoring agents, olfactory agents, emulsifiers, surfactants, solubilizers, suspending agents, isotonic agents, buffers, preservatives, antioxidants, stabilizers, absorption enhancers, etc. commonly used in the pharmaceutical field.
  • excipients can also be used in appropriate combinations as needed.
  • the salt of the compound of the present invention is mixed with at least one pharmaceutically acceptable excipient, and each unit dose contains 10 to 2000 mg of the active pharmaceutical ingredient (API).
  • the API is mixed and tableted with at least one pharmaceutical excipient (e.g., starch, lactose, magnesium stearate, etc.), and the tablet can be further coated with a sugar coating or other suitable substances, or treated so that the tablet has a sustained release or controlled release effect.
  • the oral pharmaceutical composition is a capsule
  • the API is mixed with at least one diluent (e.g., starch) and optionally granulated and granulated, and the resulting mixture is loaded into a capsule shell.
  • the “therapeutically effective amount” described in the present invention refers to the amount of the salt of the compound of the present invention and/or the crystalline form of the salt that can cause an individual biological or medical response or improve symptoms, slow down or delay disease progression or prevent disease, etc.
  • the “therapeutically effective amount” can be determined by the participating physician or veterinary practitioner, and will vary with factors such as the salt of the compound and/or the crystalline form of the salt, the disease state being treated, the severity of the disease being treated, the age and related health conditions of the individual, the route and form of administration, and the judgment of the attending physician or veterinary practitioner. Taking adults as an example, the drug can be administered 1 to 7 times every 1 to 7 days according to the symptoms, with an administration amount of about 0.01 to 1000 mg, and the administration method is not limited.
  • the salts or pharmaceutical compositions of the compounds of the present invention can be used to treat and/or alleviate depression-related symptoms, and the salts or pharmaceutical compositions of the compounds of the present invention can also be used to prepare drugs for treating and/or relieving depression.
  • the anhydrous ethanol and other reagents involved in the preparation method are all analytically pure and provided by Sinopharm Chemical Reagent Co., Ltd. Unless otherwise specified, the reagents used are not specially treated.
  • 2-Methyl-5-(naphthalene-2-yl) octahydropyrrole [3,4-c] pyrrole is prepared with reference to Example 2 in CN202010474768.8, with a purity greater than 99%.
  • Trifluoroacetic acid and acetonitrile involved in the HPLC experiment are chromatographically pure.
  • Instrument Bruker D8advance X-ray polycrystal diffractometer; target: Cu-K ⁇ (40 kV, 40 mA); distance from sample to detector: 30 cm; scanning type: two-axis linkage; scanning step width: 0.02°; scanning range: 3° ⁇ 40°; scanning step diameter: 0.1 s.
  • the diffraction angle (2 ⁇ value) in XRPD may have an error within the range of ⁇ 0.2°, so the numerical values related to the diffraction angle in the present invention should be understood as being also included in the range of about ⁇ 0.2°. Therefore, the present invention not only covers the crystal form that completely matches the characteristic signal peak in the specific XRPD spectrum, but also covers the crystal form that has an error of about ⁇ 0.2° with the characteristic signal peak in the specific XRPD spectrum.
  • the sample was placed at 25°C and 92.5% RH for 24 hours and then its moisture absorption and weight gain were measured.
  • test samples were placed in suitable clean containers under high temperature (60°C) and high humidity (40°C, relative humidity 75%) conditions for 14 days. Samples were taken on the 0th and 14th days to detect the purity and impurities of the test samples.
  • Acetone (5 ml) was added to the compound of formula (I) (0.5 g, 1.98 mmol, 1 eq), and the temperature was raised to 40°C and stirred to dissolve.
  • Concentrated hydrochloric acid (227 mg, 2.18 mmol, 1.1 eq) was added, and the mixture was stirred at 40°C for half an hour, and solid was precipitated.
  • the mixture was stirred at 40°C for 1 hour, and the temperature was lowered to 5°C and stirred for 1 hour, and the filter cake was collected by filtration and dried at normal pressure of 55 ⁇ 5°C to obtain the hydrochloride of the compound of formula (I) (0.45 g, molar yield 78.9%, purity 99.72%).
  • the hydrochloride of the compound of formula (I) prepared in Example 1 is in crystalline form, corresponding to Form A, and its X-ray powder diffraction is shown in Table 2 and Figure 1.
  • the XRPD patterns of the hydrochloride of the compound of formula (I) prepared in Examples 8-12 are similar to Figure 1.
  • the maleate salt of the compound of formula (I) prepared in Example 7 is in crystalline form, corresponding to Form B, and its X-ray powder diffraction is shown in Table 3 and FIG. 2 .
  • the hydrogen bromide salt of the compound of formula (I) prepared in Example 2 is in crystalline form, corresponding to Form C, and its X-ray powder diffraction is shown in Table 4 and FIG. 3 .
  • the compounds of formula (I) prepared in Examples 1-7 have a certain degree of hygroscopicity after being salified. Through experimental screening, it was unexpectedly found that hydrochloride, hydrogen bromide, maleate, phosphate, and citrate have lower hygroscopicity than other salts, and are more conducive to storage and preparation into preparations.
  • solubility of the compound of formula (I) is significantly improved after being salified, especially after being salified into hydrochloride, hydrogen bromide and maleate, the solubility is improved more than that of other salts.
  • the improvement of solubility significantly improves the drugability of the compound of formula (I) and solves the problem of being unable to obtain a stable preparation due to solubility problems.
  • the stability test was performed on the preparations of different salt forms of the compound of formula (I).
  • the preparation stability test method and results are as follows:
  • Granulation The dried granules are granulated by a granulator with a 1.5 mm sieve;
  • Preparation stability test The samples of the preparation formula prepared above (double aluminum packaging) were placed under the test conditions of 40 ⁇ 2°C/RH75 ⁇ 5.0%, and samples were taken at 0 day, 1 month, 2 months and 3 months respectively to examine the changes in related substances. The results are shown in Table 9.

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Abstract

本发明涉及式(I)化合物的盐，所述盐的制备方法，包含所述盐的药物组合物及其用途。所述式(I)化合物的盐的成盐酸选自盐酸、马来酸、溴化氢、磷酸、硫酸等多种酸，所述式(I)化合物的盐具有稳定性好、溶解度高、引湿性小等优点，可用于制备治疗和/或缓解抑郁症的药物。

Description

一种抗抑郁化合物的盐、其制备方法、包含其的药物组合物及其用途
相关申请的交叉引用
本申请要求2023年1月18日提交的申请号为202310066877.X，发明名称为“一种抗抑郁化合物的盐、其制备方法、包含其的药物组合物及其用途”的中国专利申请的优先权，该申请的全部内容通过引用整体并入本文，其程度如同完全记载在本文中一样。
技术领域
本发明属于医药技术领域，具体涉及一种抗抑郁化合物2-甲基-5-(萘-2-基)八氢吡咯[3,4-c]吡咯的酸加成盐、所述盐的制备方法、包含所述盐的药物组合物，以及所述盐或药物组合物在制备用于治疗和/或缓解抑郁症的药物中的用途。
背景技术
抑郁症已成为全球第四大疾病，根据WHO 2017年发布的《Depression and Other Common Mental Disorders Global Health Estimates》，目前世界范围内患有抑郁症的总人数是3.22亿，这些人中有将近一半居住在东南亚地区和西太平洋地区(包括印度和中国)。在中国，抑郁症的终身患病率为6.9％，12个月患病率为3.6％。随着社会节奏的加快，人们经受的生活、精神及社会压力不断加大，抑郁症的发病率呈增长趋势。抑郁症具有高发病、高复发和高致残的特点，发作期存在显著的情感、认知和躯体症状，这给患者的学习、工作和生活带来严重的困扰，给社会和家庭带来沉重的经济负担。
目前已有的抗抑郁药物具有恶心、呕吐、消化不良、腹泻、头痛、失眠、困倦和焦虑等各种各样的副作用，特别是胃肠道副作用。同时抗抑郁药物一般都需要持续服药2-4周才能起效，因此具有较高的停药率。另外，除情感症状和躯体症状之外，认知症状也是抑郁症的主要临床表现之一。认知症状大多表现为思维迟缓、注意力不集中、分心及信息加工能力减退。该症状群不仅是抑郁症急性期常见的症状表现，也是影响功能的重要残留症状，若未得到全面缓解，则患者的工作、家务、学业能力无法恢复到既往水平，从而降低了生活质量。残留的认知症状还是抑郁症复燃的影响因素之一。因此，降低抗抑郁药物的胃肠道副作用、增加患者用药依从性从而降低停药率，缓解临床上易被忽视的认知症状促进抑郁症患者功能的全面恢复，具有重要意义。
WO2020239073A1公开了一类可通过调节一种或多种单胺转运蛋白，抑制内源性单胺例如多巴胺、5-羟色胺和去甲肾上腺素的再摄取(例如从突触间隙)，和/或调节5-HT3 受体的化合物，其结构通式如下所示：
其中，具体公开了如下式(I)结构的化合物2-甲基-5-(萘-2-基)八氢吡咯[3,4-c]吡咯：
该化合物显示出低于10nM(IC50)血清素再摄取抑制浓度，对5-HT3受体具有高亲和力。该化合物不仅活性强，具有药效剂量低、毒副作用小等特点，对中枢神经系统领域的疾病具有疗效，尤其对抑郁等疾病具有很好的成药前景。然而，该化合物溶解度较低，一定程度上限制了其在制药过程中的应用。
发明内容
发明要解决的问题
本发明的目的在于提供一种性质稳定、溶解度高、成药性好的2-甲基-5-(萘-2-基)八氢吡咯[3,4-c]吡咯的酸加成盐、该盐的晶型、包含该盐或晶型的药物组合物，并提供了相应的制备方法以及制药用途。
用于解决问题的方案
第一方面，本发明提供一种式(I)化合物的盐，所述盐的成盐酸选自马来酸、琥珀酸、柠檬酸、酒石酸、富马酸、甲酸、乙酸、丙酸、丙二酸、草酸、苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、萘磺酸、1,5-萘二磺酸、樟脑酸、樟脑磺酸、水杨酸、乙酰水杨酸、天门冬氨酸、谷氨酸、乳酸、葡萄糖酸、抗坏血酸、没食子酸、杏仁酸、苹果酸、柠檬酸、富马酸、丁二酸、山梨酸、三氟乙酸、牛磺酸、高牛磺酸、2-羟基乙磺酸、肉桂酸、粘酸、盐酸、溴化氢、碘化氢、硫酸、硝酸、磷酸、高氯酸或其组合，
在具体的实施方式中，所述成盐酸选自盐酸、马来酸、硫酸、溴化氢、磷酸、甲磺酸、柠檬酸、富马酸；
优选地，所述成盐酸选自盐酸、马来酸、溴化氢、磷酸、硫酸；
更优选地，所述成盐酸为盐酸、马来酸。
在一实施方式中，根据本发明的式(I)化合物的盐为晶型，包括：式(I)化合物盐酸盐的晶型A，式(I)化合物马来酸盐的晶型B，式(I)化合物氢溴酸盐的晶型C；
其中，所述式(I)化合物盐酸盐的晶型A的XRPD图谱在下列2θ衍射角处具有特征峰：8.74、17.53、17.99、19.38、20.70、22.68、24.44、26.42±0.20°；特别地，所述晶型A的XRPD图谱在下列2θ衍射角处具有特征峰：8.74、14.88、17.53、17.99、19.38、20.70、22.18、22.68、24.44、26.42±0.20°；更特别地，所述晶型A的XRPD图谱在下列2θ衍射角处具有特征峰：4.38、8.74、14.88、16.52、17.53、17.99、19.38、20.17、20.70、22.18、22.68、24.44、26.42、27.29、28.34、29.08、30.14、30.94、31.72、32.46、33.48、34.19±0.20°；更优选地，所述晶型A的XRPD图谱如图1所示；
所述式(I)化合物马来酸盐的晶型B的XRPD图谱在下列2θ衍射角处具有特征峰：11.07、14.52、16.70、17.60、20.12、22.28、24.10、28.01±0.20°；特别地，所述晶型B的XRPD图谱在下列2θ衍射角处具有特征峰：11.07、14.52、16.70、17.60、20.12、22.28、24.10、25.18、26.77、28.01±0.20°；更特别地，所述晶型B的XRPD图谱在下列2θ衍射角处具有特征峰：9.33、11.07、12.06、14.52、15.58、16.70、17.60、18.70、20.12、20.58、22.28、23.47、24.10、25.18、26.77、27.38、28.01、28.90、29.54、30.06、31.82、32.42、33.80、35.74、36.90、37.93±0.20°；更优选地，所述晶型B的XRPD图谱如图2所示；
所述式(I)化合物氢溴酸盐的晶型C的XRPD图谱在下列2θ衍射角处具有特征峰：4.47、8.88、16.58、17.78、20.96、22.27、22.94、26.78±0.20°；特别地，所述晶型C的XRPD图谱在下列2θ衍射角处具有特征峰：4.47、8.88、16.58、17.78、20.96、22.27、22.94、24.28、26.78、28.34±0.20°；更特别地，所述晶型C的XRPD图谱在下列2θ衍射角处具有特征峰：4.47、8.88、13.32、15.04、16.58、17.78、19.61、20.96、22.27、22.94、24.28、25.90、26.78、27.15、27.70、28.34、29.56、30.70、31.14、34.00±0.20°；更优选 地，所述晶型C的XRPD图谱如图3所示。
第二方面，本发明提供了本发明第一方面所述式(I)化合物的盐的制备方法，其包括下列步骤：
1)将式(I)化合物溶于溶剂中，升温至40-60℃(例如50℃，55℃)，搅拌后溶解得到溶液A，将成盐酸加入到溶液A中，搅拌，固体析出，继续搅拌0.5-4h；
2)将步骤1)中的混合物降温至0-30℃(例如5℃，10℃)，继续搅拌0.5-4h；
3)过滤，滤饼在常压、30-60℃(例如50℃，55℃)下烘干，即得式(I)化合物盐。
在具体的实施方式中，步骤1)中，所述溶剂选自丙酮、醇类溶剂(例如甲醇、乙醇、异丙醇等)、乙腈、乙酸异丙酯、乙酸乙酯、二氯甲烷、氯仿、甲苯或其组合；优选地，所述溶剂选自丙酮、无水乙醇、异丙醇、甲醇、乙腈、乙酸异丙酯、乙酸乙酯或其组合。
在具体的实施方式中，步骤1)中，所述式(I)化合物与所述溶剂的用量比为1g:2～25mL，优选1g:3～15mL。
在具体的实施方式中，步骤1)中，所述式(I)化合物与所述酸的摩尔比为1:0.9～1.2。
在具体的实施方式中，步骤1)中，所述继续搅拌的时间为0.5～2小时。
在具体的实施方式中，步骤2)中，所述继续搅拌的时间为0.5～2小时。
在具体的实施方式中，根据本发明的制备方法制备的式(I)化合物的盐为晶型，例如为如上所述的式(I)化合物盐酸盐的晶型A，式(I)化合物马来酸盐的晶型B，式(I)化合物氢溴酸盐的晶型C。
第三方面，本发明提供了一种药物组合物，其包含治疗有效量的第一方面所述式(I)化合物的盐；和任选的药学上可接受的辅料。
在具体的实施方式中，所述药物组合物为口服制剂或非口服制剂。优选地，所述口服制剂选自片剂、胶囊剂、颗粒剂、散剂和糖浆剂；所述非口服制剂选自注射剂、粉针剂、喷剂和栓剂。
第四方面，本发明提供了本发明第一方面所述的式(I)化合物的盐或第三方面所述的药物组合物在制备用于治疗和/或缓解抑郁症的药物中的用途。
有益效果
本发明对具有抗抑郁作用的化合物(2-甲基-5-(萘-2-基)八氢吡咯[3,4-c]吡咯)的酸加成盐及其晶体进行合成、分离，以及相关的理化性质研究，发现了具有固体性状好、稳定性好、溶解性高、吸湿性小等优点的盐(及其对应晶型)。可用于制备治疗和/或缓解抑郁症的药物。
附图说明
图1示出了实施例1制备的式(I)化合物的盐酸盐晶型A的XRPD图谱。
图2示出了实施例7制备的式(I)化合物的马来酸盐晶型B的XRPD图谱。
图3示出了实施例2制备的式(I)化合物的溴化氢晶型C的XRPD图谱。
具体实施方式
[术语定义]
药物组合物
除非另有说明，本发明中所述的“药物组合物”包含至少一种本发明中的化合物的盐(包括所述盐的晶型)，以及任选的药学上可接受的辅料。
除非另有说明，本发明中所述的“辅料”包括(但不限于)医药领域中常用的赋形剂、粘合剂、润滑剂、崩解剂、着色剂、矫味剂、矫嗅剂、乳化剂、表面活性剂、助溶剂、悬浮剂、等渗剂、缓冲剂、防腐剂、抗氧化剂、稳定剂、吸收促进剂等，也可根据需要将上述辅料进行适当组合后使用。
在口服药物组合物中，将本发明的化合物的盐与至少一种药学上可接受的辅料进行混合配制，每单位剂量中包含10～2000mg的药物活性成分(API)。例如，当该口服药物组合物为片剂时，将API与至少一种药用辅料(例如，淀粉、乳糖、硬脂酸镁等)进行混合和压片，还可以进一步给素片包裹糖衣或其他适宜的物质，或者将其进行处理，使得药片具有缓释或控释效果。又如，当该口服药物组合物为胶囊剂时，将API与至少一种稀释剂(例如，淀粉)进行混合和任选的制粒、整粒，并将所得混合物装入胶囊壳中。
治疗有效量
除非另有说明，本发明中所述“治疗有效量”指可以引起个体生物学或医学反应或改善症状、减慢或延缓疾病恶化或预防疾病等的本发明化合物的盐和/或所述盐的晶型的量。“治疗有效量”可以由参与医师或兽医执业者来确定，并且将随着化合物的盐和/或所述盐的晶型、所治疗的疾病状态、所治疗的疾病的严重程度、个体的年龄和相关健康状况、施用途径和形式、主治医师或兽医执业者的判断等因素而变化。以成年人为例，可以根据症状每1～7日给药1～7次，给药量约为0.01～1000mg，给药方式不限。
本发明的化合物的盐或药物组合物可用于治疗和/或缓解抑郁症相关症状，本发明的化合物的盐或药物组合物亦可用于制备治疗和/或缓解抑郁症的药物。
下面将结合具体实施例来进一步阐述本发明。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，本发明中的百分比和份数均按重量计算。
试剂和耗材说明
在本发明的实施例中，制备方法中涉及的无水乙醇等试剂均为分析纯，由国药集团化学试剂有限公司提供，除非特别说明，所用试剂均未经过特别处理。2-甲基-5-(萘-2-基)八氢吡咯[3,4-c]吡咯参照CN202010474768.8中的实施例2制备，纯度大于99％。高效液相色谱实验涉及的三氟醋酸、乙腈为色谱纯。
通用测试方法
1、X射线粉末衍射(XRPD)测试方法：
仪器：Bruker D8advance X射线多晶衍射仪；靶：Cu-Kα(40kV，40mA)；样品到检测器距离：30cm；扫描类型：两轴联动；扫描步宽：0.02°；扫描范围：3°～40°；扫描步径：0.1s。
一般情况下，XRPD中的衍射角度(2θ值)可以在±0.2°的范围内产生误差，因此本发明中涉及衍射角度的数值应当理解为也包含在约±0.2°的范围内的数值。所以，本发明不仅涵盖与具体XRPD图谱中的特征信号峰完全吻合的晶型，还涵盖与具体XRPD图谱中的特征信号峰存在±0.2°左右的误差的晶型。
2、溶解度测试方法：
取供试品约20mg置于1.5ml样品管中，加入1ml水后置于振荡器中，在37℃下振摇30分钟，取出样品管置于离心机中离心2分钟，取上清液用于HPLC分析。按外标法计算供试品在水(37℃)中的溶解度。
HPLC色谱色谱条件：
色谱柱：Waters Xselect CSH Phenyl-Hexyl 4.6×150mm 3.5μm
流速：1.0mL/min
检测波长：230nm
柱温箱：30℃
进样体积：10μL
稀释剂：乙腈-水＝1：1(v/v)
进样量：5ul
流动相：
流动相A：0.05％三氟醋酸水溶液
流动相B：0.05％三氟醋酸乙腈溶液
梯度洗脱程序见表1：
表1.HPLC梯度洗脱程序
3、吸湿性测定方法：
将供试品在25℃，92.5％RH的条件下，放置24小时后测定吸湿增重。
4、稳定性测试方法：
将供试品置于适宜的洁净容器中，分别放置于高温(60℃)，高湿(40℃，相对湿度75％)，条件下，放置14天，于第0、14天取样，检测供试品纯度和杂质情况。
实施例1：式(I)化合物盐酸盐的制备：
式(I)化合物(0.5g,1.98mmol,1eq)中加入丙酮(5ml)，升温至40℃搅拌溶清。加入浓盐酸(227mg,2.18mmol,1.1eq)，40℃搅拌半小时，有固体析出，继续40℃搅拌1小时，降温至5℃搅拌1小时，过滤，收集滤饼，常压55±5℃烘干得即得式(I)化合物盐酸盐(0.45g，摩尔收率78.9％，纯度99.72％)。
实施例2：式(I)化合物溴化氢盐的制备：
式(I)化合物(0.5g,1.98mmol,1eq)中加入无水乙醇(5ml)，升温至50℃搅拌溶清。加入溴化氢(440mg,2.18mmol,1.1eq)水溶液，50℃搅拌半小时，有固体析出，继续50℃搅拌1小时，降温至5℃搅拌1小时，过滤，收集滤饼，常压55±5℃烘干即得式(I)化合物溴化氢盐(0.6g，摩尔收率91.1％，纯度99.60％)。
实施例3：式(I)化合物甲磺酸盐的制备：
式(I)化合物(0.5g,1.98mmol,1eq)中加入无水乙醇(5ml)，升温至55℃搅拌溶清。加入甲磺酸(210mg,2.18mmol,1.1eq)，55℃搅拌半小时，有大量固体析出，继续 55℃搅拌1小时，降温至10℃搅拌1小时，过滤，收集滤饼，常压55±5℃烘干即得式(I)化合物甲磺酸盐(0.23，摩尔收率33.4％，纯度99.93％)。
实施例4：式(I)化合物硫酸盐的制备：
式(I)化合物(0.5g,1.98mmol,1eq)中加入无水乙醇(5ml)，升温至50℃搅拌溶清。加入浓硫酸(194mg,2.18mmol,1.1eq)，50℃搅拌半小时，有大量固体析出，继续50℃搅拌1小时，降温至10℃搅拌1小时，过滤，收集滤饼，常压55±5℃烘干即得式(I)化合物硫酸盐(0.64g，摩尔收率92％，纯度99.57％)。
实施例5：式(I)化合物磷酸盐的制备：
式(I)化合物(0.5g,1.98mmol,1eq)中加入无水乙醇(5ml)，升温至55℃搅拌溶清。加入磷酸(214mg,2.18mmol,1.1eq)，55℃搅拌半小时，有固体析出，继续55℃搅拌1小时，降温10℃搅拌1小时，过滤，收集滤饼，常压55±5℃烘干即得式(I)化合物磷酸盐(0.45g，摩尔收率78.9％，纯度99.72％)。
实施例6：式(I)化合物柠檬酸盐的制备：
式(I)化合物(0.5g,1.98mmol,1eq)中加入无水乙醇(5ml)，升温至50℃搅拌溶清。加入一水合柠檬酸(456mg,2.18mmol,1.1eq)，50℃搅拌半小时，有固体析出，继续50℃搅拌1小时，降温至10℃搅拌1小时，过滤，收集滤饼，常压55±5℃烘干即得式(I)化合物柠檬酸盐(0.89g，摩尔收率97.9％，纯度99.62％)。
实施例7：式(I)化合物马来酸盐的制备：
式(I)化合物(0.5g,1.98mmol,1eq)中加入无水乙醇(1.5ml)，升温至55℃搅拌溶清。加入马来酸(275mg,2.37mmol,1.2eq)，55℃搅拌半小时，有固体析出，继续55℃搅拌1小时，降温至10℃搅拌1小时，过滤，收集滤饼，常压55±5℃烘干即得式(I)化合物马来酸盐(0.6g，摩尔收率87％，纯度99.21％)。
实施例8：式(I)化合物盐酸盐的制备：
式(I)化合物(0.5g,1.98mmol,1eq)中加入无水乙醇(7ml)，升温至45℃搅拌溶清。加入浓盐酸(210mg,1.98mmol,1eq)，45℃搅拌半小时，有固体析出，继续45℃搅拌1小时，降温至5℃搅拌1小时，过滤，收集滤饼，常压50℃烘干即得式(I)化合物盐酸盐(0.42g，摩尔收率74％，纯度99.97％)。
实施例9：式(I)化合物盐酸盐的制备：
式(I)化合物(0.5g,1.98mmol,1eq)中加入异丙醇(5ml)，升温至50℃搅拌溶清。加入浓盐酸(227mg,2.18mmol,1.1eq)，50℃搅拌半小时，有固体析出，继续50℃搅拌1小时，降温至10℃搅拌1小时，过滤，收集滤饼，常压55±5℃烘干即得式(I)化合物盐酸盐(0.45g，摩尔收率78％，纯度99.73％)。
实施例10：式(I)化合物盐酸盐的制备：
式(I)化合物(0.5g,1.98mmol,1eq)中加入乙腈(5ml)，升温至55℃搅拌溶清。加入浓盐酸(227mg,2.18mmol,1.1eq)，55℃搅拌半小时，有固体析出，继续55℃搅拌1小时，降温至15℃搅拌1小时，过滤，收集滤饼，常压55±5℃烘干即得式(I)化合物盐酸盐(0.43g，摩尔收率74.5％，纯度99.95％)。
实施例11：式(I)化合物盐酸盐的制备：
式(I)化合物(0.5g,1.98mmol,1eq)中加入乙酸异丙酯(10ml)和无水乙醇(1.5ml)，升温至50℃搅拌溶清。加入浓盐酸(227mg,2.18mmol,1.1eq)，50℃搅拌半小时，有固体析出，继续50℃搅拌1小时，降温至10℃搅拌1小时，过滤，收集滤饼，常压55±5℃烘干即得式(I)化合物盐酸盐(0.56g，摩尔收率98.7％，纯度99.5％)。
实施例12：式(I)化合物盐酸盐的制备：
式(I)化合物(0.5g,1.98mmol,1eq)中加入乙酸乙酯(10ml)和无水乙醇(1.5ml)，升温至55℃搅拌溶清。加入浓盐酸(227mg,2.18mmol,1.1eq)，55℃搅拌半小时，有大量固体析出，继续55℃搅拌1小时，降温至15℃搅拌1小时，过滤，收集滤饼，常压55℃烘干即得式(I)化合物盐酸盐(0.55g，摩尔收率98.2％，纯度99.4％)。
对上述实施例制备得到式(I)化合物的盐按照前述方法进行X射线粉末衍射(XRPD)、吸湿性、溶解度、稳定性测试，结果如下：
X射线粉末衍射(XRPD)测试结果：
实施例1制备所得式(I)化合物盐酸盐为晶体形式，对应于晶型A，其X射线粉末衍射如表2及图1所示。实施例8-12制备的式(I)化合物盐酸盐的XRPD图谱与图1类似。
表2.式(I)化合物盐酸盐的晶型A的XRPD数据
实施例7制备的式(I)化合物马来酸盐为晶体形式，对应于晶型B，其X射线粉末衍射如表3及图2所示。
表3.式(I)化合物马来酸盐的晶型B的XRPD数据

实施例2制备的式(I)化合物溴化氢盐为晶体形式，对应于晶型C，其X射线粉末衍射如表4及图3所示。
表4.式(I)化合物溴化氢盐的晶型C的XRPD数据
吸湿性测试结果：
结果如表5所示：
表5.式(I)化合物盐的吸湿性
由于结构特点，实施例1-7制备的式(I)化合物成盐后都会有一定的吸湿性，通过试验筛选意外的发现，盐酸盐、溴化氢盐、马来酸盐、磷酸盐、柠檬酸盐相对于其他盐来说，具有更低的吸湿性，更有利于储存和制备成制剂。
溶解度测试结果：
结果如表6所示：
表6.式(I)化合物盐的溶解度(mg/mL)
从表6的数据可知，式(I)化合物成盐后，溶解度显著提高，特别是成盐酸盐、溴化氢盐和马来酸盐后，相较于其他的盐，溶解度的提升幅度更大。溶解度的提高显著的改善了式(I)化合物的成药性，解决了因溶解度问题而导致的无法获得稳定制剂的问题。
稳定性测试结果分析：
表7.式(I)化合物盐的稳定性

从表7长期稳定性数据可知，成盐后，式(I)化合物的稳定性得到的显著的提高，其盐在高温、高湿条件下总杂的增长都显著的低于未成盐的化合物。另外，盐酸盐和马来酸盐的稳定性优于其他盐型。稳定性的提高能显著改善制剂过程和最终制剂产品中API的稳定性。
对式(I)化合物不同盐型的制剂进行稳定性测试，制剂稳定性测试方法及结果如下：
表8.式(I)化合物不同盐型制剂处方

*注：式(I)化合物不同盐型的用量根据不同盐型的分子量进行了折算，使含有等量的游离碱。
处方1-3中的盐酸盐、硫酸盐、马来酸盐型分别按照实施例1、4、7的方法制备。
表8中各处方按以下制备步骤制备式(I)化合物不同盐型的组合物颗粒：
(1)原辅料准备：所有原辅料按理论用量称量，原料(式I化合物的不同盐型)过60目筛，辅料(EDTA-2Na除外)过20目筛；
(2)润湿剂准备：将配方量的EDTA-2Na加入适量纯化水中，搅拌至完全溶解；
(3)湿法制粒：将式(I)化合物的不同盐型和预胶化淀粉加入湿法制粒机中，搅拌下缓缓加入EDTA-2Na水溶液制湿颗粒；
(4)干燥：将湿颗粒加入流化床中干燥至干燥失重小于7％；
(5)整粒：将干燥后的颗粒通过1.5mm筛网的粉碎整粒机整粒；
(6)混合：在整粒后的干颗粒中加入硬脂富马酸钠，混合1min。
制剂稳定性测试试验：将上述制备的制剂处方的样品(双铝包装)放置于40±2℃/RH75±5.0％试验条件下，于0天、1个月、2个月和3个月分别取样，考察有关物质的变化情况，结果见表9。
表9.式(I)化合物不同盐型制剂处方稳定性结果
由制剂处方稳定性检测结果可知，式(I)化合物的马来酸盐和盐酸盐两种形式的制剂样品加速3个月后杂质增长较小。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献都被单独引用作为参考。此外应理解，在阅读本发明的上述内容之后，本领域技术人员可以对本发明做出各种调整或修改，这些等价形式同样落入本申请所附权利要求书所限定的范围之内。

Claims (10)

  1. 一种式(I)化合物的盐，所述盐的成盐酸选自马来酸、琥珀酸、柠檬酸、酒石酸、富马酸、甲酸、乙酸、丙酸、丙二酸、草酸、苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、萘磺酸、1,5-萘二磺酸、樟脑酸、樟脑磺酸、水杨酸、乙酰水杨酸、天门冬氨酸、谷氨酸、乳酸、葡萄糖酸、抗坏血酸、没食子酸、杏仁酸、苹果酸、柠檬酸、富马酸、丁二酸、山梨酸、三氟乙酸、牛磺酸、高牛磺酸、2-羟基乙磺酸、肉桂酸、粘酸、盐酸、溴化氢、碘化氢、硫酸、硝酸、磷酸、高氯酸，
  2. 根据权利要求1所述式(I)化合物的盐，其特征在于，所述盐的成盐酸选自盐酸、马来酸、硫酸、溴化氢、磷酸、甲磺酸、柠檬酸、富马酸；
    优选地，所述盐的成盐酸选自盐酸、马来酸、溴化氢、磷酸、硫酸；更优选为盐酸、马来酸。
  3. 根据权利要求1所述式(I)化合物的盐，其中，所述盐为式(I)化合物盐酸盐，其为晶型A；式(I)化合物马来酸盐，其为晶型B；或式(I)化合物氢溴酸盐，其为晶型C；
    其中，所述式(I)化合物盐酸盐的晶型A的XRPD图谱在下列2θ衍射角处具有特征峰：8.74、17.53、17.99、19.38、20.70、22.68、24.44、26.42±0.20°；优选地，所述晶型A的XRPD图谱在下列2θ衍射角处具有特征峰：8.74、14.88、17.53、17.99、19.38、20.70、22.18、22.68、24.44、26.42±0.20°；更优选地，所述晶型A的XRPD图谱在下列2θ衍射角处具有特征峰：4.38、8.74、14.88、16.52、17.53、17.99、19.38、20.17、20.70、22.18、22.68、24.44、26.42、27.29、28.34、29.08、30.14、30.94、31.72、32.46、33.48、34.19±0.20°；进一步优选地，所述晶型A的XRPD图谱如图1所示；
    所述式(I)化合物马来酸盐的晶型B的XRPD图谱在下列2θ衍射角处具有特征峰：11.07、14.52、16.70、17.60、20.12、22.28、24.10、28.01±0.20°；优选地，所述晶型B的XRPD图谱在下列2θ衍射角处具有特征峰：11.07、14.52、16.70、17.60、20.12、22.28、24.10、25.18、26.77、28.01±0.20°；更优选地，所述晶型B的XRPD图谱在下列2θ衍射角处具有特征峰：9.33、11.07、12.06、14.52、15.58、16.70、17.60、18.70、20.12、20.58、 22.28、23.47、24.10、25.18、26.77、27.38、28.01、28.90、29.54、30.06、31.82、32.42、33.80、35.74、36.90、37.93±0.20°；进一步优选地，所述晶型B的XRPD图谱如图2所示；
    所述式(I)化合物氢溴酸盐的晶型C的XRPD图谱在下列2θ衍射角处具有特征峰：4.47、8.88、16.58、17.78、20.96、22.27、22.94、26.78±0.20°；优选地，所述晶型C的XRPD图谱在下列2θ衍射角处具有特征峰：4.47、8.88、16.58、17.78、20.96、22.27、22.94、24.28、26.78、28.34±0.20°；更优选地，所述晶型C的XRPD图谱在下列2θ衍射角处具有特征峰：4.47、8.88、13.32、15.04、16.58、17.78、19.61、20.96、22.27、22.94、24.28、25.90、26.78、27.15、27.70、28.34、29.56、30.70、31.14、34.00±0.20°；进一步优选地，所述晶型C的XRPD图谱如图3所示。
  4. 权利要求1至3中任一项所述式(I)化合物的盐的制备方法，其包括下列步骤：
    1)将式(I)化合物溶于溶剂中，升温至40-60℃，搅拌后溶解得到溶液A，将成盐酸加入到溶液A中，搅拌，固体析出，继续搅拌0.5-4h；
    2)将步骤1)中的混合物降温至0-30℃，继续搅拌0.5-4h；
    3)过滤，滤饼在常压、30-60℃下烘干，即得式(I)化合物盐。
  5. 根据权利要求4所述的制备方法，其特征在于，步骤1)中，所述溶剂选自丙酮、醇类溶剂、乙腈、乙酸异丙酯、乙酸乙酯、二氯甲烷、氯仿、甲苯或其组合；优选地，所述溶剂选自丙酮、无水乙醇、异丙醇、甲醇、乙腈、乙酸异丙酯、乙酸乙酯或其组合。
  6. 根据权利要求4所述的制备方法，其特征在于，步骤1)中，所述式(I)化合物与所述溶剂的用量比为1g:2～25mL，优选1g:3～15mL；
    和/或，步骤1)中，所述式(I)化合物与所述酸的摩尔比为1:0.9～1.2。
  7. 根据权利要求4所述的制备方法，其特征在于，步骤1)中，所述继续搅拌的时间为0.5～2小时；
    和/或，步骤2)中，所述继续搅拌的时间为0.5～2小时。
  8. 一种药物组合物，其包含治疗有效量的权利要求1至3中任一项所述式(I)化合物的盐；和任选的药学上可接受的辅料。
  9. 根据权利要求8所述的药物组合物，其特征在于，所述药物组合物为口服制剂或非口服制剂；
    优选地，所述口服制剂选自片剂、胶囊剂、颗粒剂、散剂和糖浆剂；所述非口服制剂选自注射剂、粉针剂、喷剂和栓剂。
  10. 权利要求1至3中任一项所述式(I)化合物的盐或权利要求8所述药物组合物在制备用于治疗和/或缓解抑郁症的药物中的用途。
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