Salts of antidepressant compounds, methods for producing the same, pharmaceutical compositions containing the same, and their uses

Abstract

This invention discloses salts of antidepressant compounds, methods for producing the same, pharmaceutical compositions containing the same, and their uses, and more specifically, salts of a compound of formula (I), methods for producing the salt, pharmaceutical compositions containing the salt, and their uses. The salt-forming acid of the salt of the compound of formula (I) is selected from the group consisting of multiple types of acids such as hydrochloric acid, maleic acid, hydrogen bromide, phosphoric acid, and sulfuric acid. The salt of the compound of formula (I) has advantages such as good stability, high solubility, and low hygroscopicity, and can be used in the manufacture of drugs for the treatment and / or alleviation of depression.

Description

Technical Field

[0001] (Cross - reference to related applications) This application claims the priority of a Chinese patent application with application number 202310066877.X, titled "Salt of an antidepressant compound, method for producing the same, pharmaceutical composition containing the same, and use thereof", filed on January 18, 2023, and the entire content of the said application is incorporated herein by reference to the same extent as if it were fully described herein.

[0002] The present invention relates to the field of pharmaceutical technology. Specifically, it relates to an acid addition salt of 2 - methyl - 5 - (naphthalen - 2 - yl) octahydropyrrolo[3,4 - c]pyrrole, which is an antidepressant compound, a method for producing the above salt, a pharmaceutical composition containing the above salt, and the use of the above salt or pharmaceutical composition in the manufacture of a medicament for treating and / or alleviating depression.

Background Art

[0003] Depression is the fourth most common disease in the world. According to the "World Health Estimates on Depression and Other Common Mental Disorders" published by the WHO in 2017, the total number of depression patients in the world is 322 million, and about half of them live in Southeast Asia and the Western Pacific region (including India and China). In China, the lifetime prevalence rate of depression is 6.9% and the 12 - month prevalence rate is 3.6%. As the social life rhythm accelerates, people are exposed to great pressures in life, spirit, and society, and the incidence rate of depression shows an upward trend. Depression is characterized by a high incidence rate, a high recurrence rate, and a high degree of disability. During the onset period, significant emotional, cognitive, and physical symptoms appear, seriously affecting the patient's study, work, and life, and bringing a heavy economic burden to society and family.

[0004] Antidepressants currently on the market have various side effects, particularly gastrointestinal side effects such as nausea, vomiting, indigestion, diarrhea, headache, insomnia, drowsiness, and anxiety. At the same time, because antidepressants typically require 2-4 weeks of continuous use to become effective, the discontinuation rate is high. Furthermore, in addition to emotional and physical symptoms, cognitive symptoms are also a major clinical symptom of depression. Cognitive symptoms primarily manifest as decreased thinking ability, inattention, distractibility, and impaired information processing ability. This group of symptoms is not only common in the acute phase of depression, but also represents significant residual symptoms that affect function. If not adequately alleviated, patients may not be able to recover their work, household, or academic abilities to previous levels, leading to a decline in their quality of life. Persistent cognitive symptoms are also a contributing factor to depression relapse. Therefore, it is crucial to reduce the gastrointestinal side effects of antidepressants, improve patient medication compliance and reduce discontinuation rates, and mitigate cognitive symptoms that are often overlooked in clinical practice, thereby promoting the full functional recovery of depressed patients.

[0005] Patent Document 1 discloses a compound that can modulate the 5-HT3 receptor by inhibiting the reuptake of endogenous monoamines such as dopamine, serotonin, and norepinephrine (e.g., from the synaptic cleft) and / or modulating one or more monoamine transporters, the general structural formula of which is shown below. [ka]

[0006] In particular, a compound having the following structure (I) was disclosed: 2-methyl-5-(naphthalene-2-yl)octahydropyrrolo[3,4-c]pyrrole. [ka] [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2020 / 239073 [Overview of the project] [Problems that the invention aims to solve]

[0008] The above compound is 10 nM (IC). 50 It exhibits serotonin reuptake inhibitory concentrations below 5 / 5 and shows high affinity for the 5-HT3 receptor. This compound not only has high activity but also features a low effective dose and few toxic side effects. It is effective for central nervous system disorders, particularly depression. However, its low solubility limits its application to pharmaceutical manufacturing processes to some extent.

[0009] The object of the present invention is to provide an acid addition salt of 2-methyl-5-(naphthalene-2-yl)octahydropyrrolo[3,4-c]pyrrole having stable properties, high solubility, and good pharmaceutically active properties, a crystalline form of this salt, and a pharmaceutical composition containing this salt or crystalline form, as well as a method for producing the same and pharmaceutical uses. [Means for solving the problem]

[0010] In a first aspect, the present invention provides a salt of a compound of formula (I), wherein the salt-forming acid of the salt is selected from the group consisting of 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, homotaurine, 2-hydroxyethanesulfonic acid, cinnamic acid, mucoic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, or a combination thereof.

[0011] [ka]

[0012] In specific embodiments, the salt-forming acid is selected from the group consisting of hydrochloric acid, maleic acid, sulfuric acid, hydrogen bromide, phosphoric acid, methanesulfonic acid, citric acid, and fumaric acid.

[0013] Preferably, the salt-forming acid is selected from the group consisting of hydrochloric acid, maleic acid, hydrogen bromide, phosphoric acid, and sulfuric acid.

[0014] More preferably, the salt-forming acid is hydrochloric acid or maleic acid.

[0015] In one embodiment, the salt of the compound of formula (I) according to the present invention is in crystalline form and includes 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); Among these, the XRPD pattern of crystalline form A of the hydrochloride salt of compound (I) has characteristic peaks at the following 2θ diffraction peaks: 8.74, 17.53, 17.99, 19.38, 20.70, 22.68, 24.44, 26.42±0.20°; in particular, the XRPD pattern of crystalline form A has characteristic peaks at the following 2θ diffraction peaks: 8.74, 14.88, 17.53, 17.99, 19.38, 20.70, 22.18, 22.68, 24.44, 26.42±0.20°; preferred More preferably, the XRPD pattern of crystal form A has characteristic peaks at the following 2θ diffraction peaks: 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°; more preferably, the XRPD pattern of crystal form A is as shown in Figure 1; The XRPD pattern of crystalline form B of the compound maleate of formula (I) has characteristic peaks at the following 2θ diffraction peaks: 11.07, 14.52, 16.70, 17.60, 20.12, 22.28, 24.10, 28.01±0.20°; in particular, the XRPD pattern of crystalline form B has characteristic peaks at the following 2θ diffraction peaks: 11.07, 14.52, 16.70, 17.60, 20.12, 22.28, 24.10, 25.18, 26.77, 28.01±0.20°; preferably, the XR The PD pattern has characteristic peaks at the following 2θ diffraction peaks: 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°; more preferably, the XRPD pattern of crystal form B is as shown in Figure 2; The XRPD pattern of the crystalline form C of the hydrobromide compound of formula (I) exhibits characteristic peaks at the following 2θ diffraction peaks: 4.47, 8.88, 16.58, 17.78, 20.96, 22.27, 22.94, and 26.78±0.20°. In particular, the XRPD pattern of the crystalline form C exhibits characteristic peaks at the following 2θ diffraction peaks: 4.47, 8.88, 16.58, 17.78, 20.96, 22.27, 22.94, 24.28, 26.78, and 28.34±0.20°. Preferably, the XRPD pattern of crystal form C has characteristic peaks at the following 2θ diffraction peaks: 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°; more preferably, the XRPD pattern of crystal form C is as shown in Figure 3.

[0016] In a second aspect, the present invention is 1) Dissolve the compound of formula (I) in a solvent, heat the temperature to 40 - 60 °C (for example, 50 °C, 55 °C), stir until dissolved, and obtain solution A. Add a salt-forming acid to solution A, stir, precipitate a solid, and continue to stir for 0.5 - 4 hours; 2) Cool the mixture in step 1) to 0 - 30 °C (for example, 5 °C, 10 °C), and continue to stir for 0.5 - 4 hours; 3) Filter, and dry the filter cake at normal pressure and 30 - 60 °C (for example, 50 °C, 55 °C) to obtain the salt of the compound of formula (I); Provided is a method for producing the salt of the compound of formula (I) according to the first aspect of the present invention, comprising the above steps.

[0017] In a specific embodiment, in step 1), the solvent is selected from the group consisting of acetone, alcohol solvents (for example, methanol, ethanol, isopropanol, etc.), acetonitrile, isopropyl acetate, ethyl acetate, dichloromethane, chloroform, toluene or a combination thereof; preferably, the solvent is selected from the group consisting of acetone, absolute ethanol, isopropanol, methanol, acetonitrile, isopropyl acetate, ethyl acetate or a combination thereof.

[0018] In a specific embodiment, in step 1), the dosage ratio of the compound of formula (I) to the solvent is 1 g : 2 - 25 mL, preferably 1 g : 3 - 15 mL.

[0019] In a specific embodiment, in step 1), the molar ratio of the compound of formula (I) to the acid is 1 : 0.9 - 1.2.

[0020] In a specific embodiment, in step 1), the time of the subsequent stirring is 0.5 - 2 hours.

[0021] In a specific embodiment, in step 2), the time of the subsequent stirring is 0.5 - 2 hours.

[0022] In specific embodiments, the salt of compound (I) produced by the manufacturing method according to the present invention is in crystalline form, for example, crystalline form A of the hydrochloride salt of compound (I), crystalline form B of the maleate salt of compound (I), and crystalline form C of the hydrobromide salt of compound (I).

[0023] In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a salt of the compound of formula (I) in a first aspect and an optional pharmaceutically acceptable additive.

[0024] In specific embodiments, the pharmaceutical composition is either an oral or parenteral preparation. Preferably, the oral preparation is selected from the group consisting of tablets, capsules, granules, powders, and syrups; and the parenteral preparation is selected from the group consisting of injections, powder injections, sprays, and suppositories.

[0025] In a fourth aspect, the present invention provides the use of a salt of the compound of formula (I) or a pharmaceutical composition according to the third aspect in the manufacture of a pharmaceutical for treating and / or alleviating depression, according to the first aspect of the present invention. [Effects of the Invention]

[0026] This invention involves the synthesis, separation, and study of the acid addition salt and its crystals of (2-methyl-5-(naphthalene-2-yl)octahydropyrrolo[3,4-c]pyrrole), a compound with antidepressant properties, resulting in the discovery of a salt (and its corresponding crystalline form) with advantages such as good solid characteristics, good stability, high solubility, and low hygroscopicity. This can be used in the manufacture of drugs for the treatment and / or alleviation of depression. [Brief explanation of the drawing]

[0027] [Figure 1] The XRPD pattern of crystalline form A of the hydrochloride salt of compound (I) produced in Example 1 is shown. [Figure 2] The XRPD pattern of crystalline form B of the maleate of the compound of formula (I) prepared in Example 7 is shown. [Figure 3]The XRPD pattern of crystalline form C of hydrogen bromide of the compound (I) produced in Example 2 is shown. [Modes for carrying out the invention]

[0028] [Term definition] Pharmaceutical composition Unless otherwise specified, the “pharmaceutical composition” described in the present invention comprises at least one salt of one of the compounds of the present invention (including the crystalline form of the salt) and any pharmaceutically acceptable additive.

[0029] Unless otherwise specified, the "additives" described in this invention include, but are not limited to, excipients, binders, lubricants, disintegrants, colorants, fragrances, olfactory agents, emulsifiers, surfactants, solubilizers, suspending agents, isotonic agents, buffering agents, preservatives, antioxidants, stabilizers, absorption enhancers, etc., which are commonly used in the pharmaceutical field. Furthermore, the above excipients may be used in appropriate combinations as needed.

[0030] In an oral pharmaceutical composition, a salt of the compound of the present invention is mixed with at least one pharmaceutically acceptable excipient, and the composition contains 10 to 2000 mg of the active pharmaceutical ingredient (API) per single dose. For example, if the oral pharmaceutical composition is a tablet, the API is mixed with at least one pharmaceutically acceptable excipient (e.g., starch, lactose, magnesium stearate, etc.) and compressed into a tablet, and the uncoated tablet may be further coated with a sugar coating or other suitable substance, or the tablet may be treated to have a sustained-release or controlled-release effect. In another example, if the oral pharmaceutical composition is a capsule, the API is mixed with at least one diluent (e.g., starch), granulated and sizing as necessary, and the resulting mixture is filled into a capsule shell.

[0031] Therapeutic effective dose Unless otherwise specified, the “therapeutic dose” as described in this invention refers to the amount of the salt of the compound of this invention and / or the crystalline form of the salt that can elicit a biological or medical response in an individual, improve symptoms, slow the progression of the disease, or prevent the disease. The “therapeutic dose” is determined by the attending physician or veterinarian and varies depending on factors such as the salt of the compound and / or the crystalline form of the salt, the state of the disease being treated, the severity of the disease being treated, the age and associated health status of the individual, the route and form of administration, and the judgment of the attending physician or veterinarian. For example, in adults, it can be administered 1 to 7 times every 1 to 7 days depending on the symptoms, with a dose of approximately 0.01 to 1000 mg, and the method of administration is not limited.

[0032] Salts or pharmaceutical compositions of the compounds of the present invention can be used to treat and / or alleviate depression-related symptoms, and salts or pharmaceutical compositions of the compounds of the present invention can also be used to manufacture pharmaceuticals for treating and / or alleviating depression.

[0033] The present invention will be further described below with reference to specific examples. It should be understood that these examples are illustrative of the present invention and do not limit its scope. In the following examples, experimental methods that do not specify concrete conditions are generally based on standard conditions or conditions recommended by the manufacturer. Unless otherwise specified, all percentages and parts in the present invention are by weight.

[0034] Description of reagents and consumables In the examples of the present invention, all anhydrous ethanol and other reagents used in the manufacturing method are analytically pure and provided by Sinopharm Chemical Reagents Co., Ltd. Unless otherwise specified, the reagents used have not undergone any special treatment. 2-Methyl-5-(naphthalene-2-yl)octahydropyrrolo[3,4-c]pyrrole was prepared with reference to Example 2 of Chinese Patent Application Publication No. 202010474768.8, and has a purity of 99% or higher. Trifluoroacetic acid and acetonitrile used in the HPLC experiment are chromatographically pure.

[0035] General measurement methods 1. X-ray powder diffraction (XRPD) measurement method: Instrument: Bruker D8 advance X-ray polycrystalline diffractometer, Target: Cu-Kα (40kV, 40mA), Distance from sample to detector: 30cm, Scan type: 2-axis linked, Scan step width: 0.02°, Scan range: 3°~40°, Scan step: 0.1 seconds.

[0036] Generally, the diffraction angle (2θ value) in XRPD can have an error of about ±0.2°, so the numerical values ​​related to the diffraction angle in this invention should be understood to be within a range of about ±0.2°. Accordingly, this invention applies not only to crystal forms that perfectly match the characteristic signal number peak in a specific XRPD spectrum, but also to crystal forms whose error with the characteristic signal number peak in a specific XRPD spectrum is about ±0.2°.

[0037] 2. Solubility measurement method: Take approximately 20 mg of the sample, place it in a 1.5 ml sample tube, add 1 ml of water, and shake in a shaker at 37°C for 30 minutes. Remove the sample tube and centrifuge for 2 minutes. Collect the supernatant and perform HPLC analysis. Calculate the solubility of the sample in water (37°C) using the external standard method.

[0038] HPLC chromatography conditions: Chromatography column: Waters Xselect CSH phenylhexyl 4.6 × 150 mm 3.5 μm Flow rate: 1.0mL / min Detection wavelength: 230nm Column oven: 30℃ Injection volume: 10μL Diluent: Acetonitrile - Water = 1:1 (v / v) Injection amount: 5ul Mobile phase: Mobile phase A: 0.05% trifluoroacetic acid aqueous solution Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile

[0039] The gradient elution program is shown in Table 1. Table 1. HPLC gradient elution programs [Table 1]

[0040] 3. Method for measuring hygroscopicity: The samples were placed in an environment of 25°C and 92.5% RH for 24 hours, and the amount of moisture absorbed and the weight increase were measured.

[0041] 4. Stability measurement method: Place the sample in a suitable, clean container and leave it for 14 days under high temperature (60°C) and high humidity (40°C, 75% relative humidity). Samples are taken on day 0 and day 14, and the purity and impurity levels of the sample are examined.

[0042] Example 1: Preparation of the hydrochloride salt of compound (I): 0.5 g, 1.98 mmol, 1 eq of compound (I) was mixed with 5 ml of acetone and heated to 40°C, stirring until clear. 227 mg, 2.18 mmol, 1.1 eq of concentrated hydrochloric acid was added and the mixture was stirred at 40°C for 30 minutes until a solid precipitate formed. The mixture was then stirred at 40°C for 1 hour, cooled to 5°C, and stirred for 1 hour. The mixture was filtered, the filter cake was collected, and dried at atmospheric pressure and 55±5°C to obtain the hydrochloride salt of compound (I) (0.45 g, molar yield 78.9%, purity 99.72%).

[0043] Example 2: Preparation of hydrobromide of compound (I): 0.5 g, 1.98 mmol, 1 eq of compound (I) was mixed with anhydrous ethanol (5 ml) and heated to 50°C, stirring until clear. An aqueous solution of hydrogen bromide (440 mg, 2.18 mmol, 1.1 eq) was added and stirred at 50°C for 30 minutes until a solid precipitate formed. The mixture was then stirred at 50°C for 1 hour, cooled to 5°C, stirred for 1 hour, filtered, and the filtered cake was collected. The mixture was dried at atmospheric pressure and 55 ± 5°C to obtain the hydrogen bromide salt of compound (I) (0.6 g, molar yield 91.1%, purity 99.60%).

[0044] Example 3: Preparation of compound (I) methanesulfonate: 0.5 g, 1.98 mmol, 1 eq of compound (I) was mixed with anhydrous ethanol (5 ml) and heated to 55°C, stirring until clear. 210 mg, 2.18 mmol, 1.1 eq of methanesulfonic acid was added and stirred at 55°C for 30 minutes, causing a large amount of solid to precipitate. The mixture was then stirred at 55°C for 1 hour, cooled to 10°C, stirred for 1 hour, filtered, and the filtered cake was collected. The mixture was dried at atmospheric pressure and 55±5°C to obtain methanesulfonate of compound (I) (0.23 ml, molar yield 33.4%, purity 99.93%).

[0045] Example 4: Preparation of compound (I) sulfate: 0.5 g, 1.98 mmol, 1 eq of compound (I) was mixed with anhydrous ethanol (5 ml) and heated to 50°C, stirring until clear. 194 mg, 2.18 mmol, 1.1 eq of concentrated sulfuric acid was added and the mixture was stirred at 50°C for 30 minutes, causing a large amount of solid to precipitate. The mixture was then stirred at 50°C for 1 hour, cooled to 10°C, stirred for 1 hour, filtered, and the filtered cake was collected. The mixture was dried at atmospheric pressure and 55±5°C to obtain the sulfate of compound (I) (0.64 g, molar yield 92%, purity 99.57%).

[0046] Example 5: Preparation of compound phosphate of formula (I): 0.5 g, 1.98 mmol, 1 eq of compound (I) was mixed with anhydrous ethanol (5 ml) and heated to 55°C, stirring until clear. 214 mg, 2.18 mmol, 1.1 eq of phosphoric acid was added and stirred at 55°C for 30 minutes until a solid precipitate formed. The mixture was then stirred at 55°C for 1 hour, cooled to 10°C, stirred for 1 hour, filtered, and the filtered cake was collected. The mixture was dried at atmospheric pressure and 55±5°C to obtain compound (I) phosphate (0.45 g, molar yield 78.9%, purity 99.72%).

[0047] Example 6: Preparation of the citrate of compound (I): 0.5 g, 1.98 mmol, 1 eq of compound (I) was mixed with anhydrous ethanol (5 ml) and heated to 50°C, stirring until clear. 456 mg, 2.18 mmol, 1.1 eq of citric acid monohydrate was added and stirred at 50°C for 30 minutes until a solid precipitate formed. The mixture was then stirred at 50°C for 1 hour, cooled to 10°C, stirred for 1 hour, filtered, and the filtered cake was collected. The mixture was dried at atmospheric pressure and 55±5°C to obtain the citrate of compound (I) (0.89 g, molar yield 97.9%, purity 99.62%).

[0048] Example 7: Preparation of maleate of compound (I): 0.5 g, 1.98 mmol, 1 eq of compound (I) was mixed with anhydrous ethanol (1.5 ml) and heated to 55°C, stirring until clear. 275 mg, 2.37 mmol, 1.2 eq of maleic acid was added and stirred at 55°C for 30 minutes until a solid precipitate formed. The mixture was then stirred at 55°C for 1 hour, cooled to 10°C, stirred for 1 hour, filtered, and the filtered cake was collected. The mixture was dried at atmospheric pressure and 55±5°C to obtain compound (I) maleate (0.6 g, molar yield 87%, purity 99.21%).

[0049] Example 8: Preparation of the hydrochloride salt of compound (I): 0.5 g, 1.98 mmol, 1 eq of compound (I) was mixed with anhydrous ethanol (7 ml) and heated to 45°C, stirring until clear. 210 mg, 1.98 mmol, 1 eq of concentrated hydrochloric acid was added and stirred at 45°C for 30 minutes until a solid precipitate formed. The mixture was then stirred at 45°C for 1 hour, cooled to 5°C, and stirred for 1 hour. The mixture was filtered, the filter cake was collected, and dried at atmospheric pressure and 50°C to obtain the hydrochloride salt of compound (I) (0.42 g, molar yield 74%, purity 99.97%).

[0050] Example 9: Preparation of the hydrochloride salt of compound (I): Isopropanol (5 ml) was added to compound (I) (0.5 g, 1.98 mmol, 1 eq), and the mixture was heated to 50°C and stirred until clear. Concentrated hydrochloric acid (227 mg, 2.18 mmol, 1.1 eq) was added, and the mixture was stirred at 50°C for 30 minutes until a solid precipitate formed. The mixture was then stirred at 50°C for 1 hour, cooled to 10°C, and stirred for 1 hour. The mixture was filtered, the filtered cake was collected, and dried at atmospheric pressure and 55±5°C to obtain the hydrochloride salt of compound (I) (0.45 g, molar yield 78%, purity 99.73%).

[0051] Example 10: Preparation of the hydrochloride salt of compound (I): 0.5 g, 1.98 mmol, 1 eq of compound (I) was mixed with 5 ml of acetonitrile and heated to 55°C, stirring until clear. 227 mg, 2.18 mmol, 1.1 eq of concentrated hydrochloric acid was added and the mixture was stirred at 55°C for 30 minutes until a solid precipitate formed. The mixture was then stirred at 55°C for 1 hour, cooled to 15°C, stirred for 1 hour, filtered, and the filtered cake was collected. The mixture was dried at atmospheric pressure and 55±5°C to obtain the hydrochloride salt of compound (I) (0.43 g, molar yield 74.5%, purity 99.95%).

[0052] Example 11: Preparation of the hydrochloride salt of compound (I): Compound (I) (0.5 g, 1.98 mmol, 1 eq) was mixed with isopropyl acetate (10 ml) and anhydrous ethanol (1.5 ml), and the mixture was heated to 50°C and stirred until clear. Concentrated hydrochloric acid (227 mg, 2.18 mmol, 1.1 eq) was added, and the mixture was stirred at 50°C for 30 minutes until a solid precipitate formed. The mixture was then stirred at 50°C for 1 hour, cooled to 10°C, and stirred for 1 hour. The mixture was filtered, the filtered cake was collected, and dried at atmospheric pressure and 55±5°C to obtain the hydrochloride salt of compound (I) (0.56 g, molar yield 98.7%, purity 99.5%).

[0053] Example 12: Preparation of the hydrochloride salt of compound (I): 0.5 g, 1.98 mmol, 1 eq of compound (I) was mixed with ethyl acetate (10 ml) and anhydrous ethanol (1.5 ml), and the mixture was heated to 55°C and stirred until clear. 227 mg, 2.18 mmol, 1.1 eq of concentrated hydrochloric acid was added, and the mixture was stirred at 55°C for 30 minutes, causing a large amount of solid to precipitate. The mixture was then stirred at 55°C for 1 hour, cooled to 15°C, and stirred for 1 hour. The mixture was filtered, the filtered cake was collected, and dried at atmospheric pressure and 55°C to obtain the hydrochloride salt of compound (I) (0.55 g, molar yield 98.2%, purity 99.4%).

[0054] The salts of the compound of formula (I) prepared in the above examples were subjected to X-ray powder diffraction (XRPD), hygroscopicity, solubility, and stability measurements according to the method described above. The results are as follows.

[0055] X-ray powder diffraction (XRPD) measurement results: The hydrochloride salt of compound (I) produced in Example 1 is in crystalline form, corresponding to crystal form A, and its X-ray powder diffraction pattern is shown in Table 2 and Figure 1. The XRPD pattern of the hydrochloride salt of compound (I) produced in Examples 8-12 is similar to that in Figure 1.

[0056] Table 2. XRPD data of crystalline form A of compound hydrochloride of formula (I). [Table 2]

[0057] The maleate of compound (I) produced in Example 7 is in crystalline form, corresponding to crystal form B, and its X-ray powder diffraction is shown in Table 3 and Figure 2.

[0058] Table 3. XRPD data of crystalline form B of compound (I) maleate. [Table 3]

[0059] The hydrobromide of compound (I) produced in Example 2 is in crystalline form, corresponding to crystal form C, and its X-ray powder diffraction is shown in Table 4 and Figure 3.

[0060] Table 4. XRPD data of crystalline form C of compound (I) hydrobromide [Table 4]

[0061] Hygroscopicity measurement results: The results are shown in Table 5.

[0062] Table 5. Hygroscopicity of compound salts of formula (I). [Table 5]

[0063] Due to their structural characteristics, the compounds of formula (I) prepared in Examples 1-7 exhibited some degree of hygroscopicity after salt formation. However, experimental screening unexpectedly revealed that the hydrochloride, hydrobromide, maleate, phosphate, and citrate salts were less hygroscopic than the other salts and were suitable for storage and preparation into formulations.

[0064] Solubility measurement results: The results are shown in Table 6.

[0065] Table 6. Solubility (mg / mL) of compound salt of formula (I) [Table 6]

[0066] The data in Table 6 shows that the solubility of the compound of formula (I) is significantly improved when it is converted to a hydrochloride salt, and in particular, the solubility is improved more when it is converted to hydrochloride, hydrobromide, or maleate compared to other salts. This improvement in solubility greatly enhances the formulation possibilities of the compound of formula (I) and solves the problem of not being able to obtain a stable formulation due to solubility issues.

[0067] Analysis of stability measurement results: Table 7. Stability of the compound salt of formula (I). [Table 7]

[0068] Table 7 shows that the long-term stability data significantly improves the stability of the compound of formula (I) after salt formation, and the increase in the total amount of impurities in the salt under high temperature and high humidity conditions is significantly lower than that of the compound without salt formation. Furthermore, the stability of the hydrochloride and maleate salts is superior to that of the other salt forms. This improvement in stability significantly enhances the stability of the API in the formulation process and in the final formulation.

[0069] Stability measurements were performed on different salt formulations of the compound of formula (I), and the measurement methods and results for formulation stability are shown below.

[0070] Table 8. Formulations of different salt formulations of formula (I) [Table 8] *Note: The amounts of different salt forms of the compound of formula (I) were converted to include an equivalent amount of free base, depending on the molecular weight of the different salt forms. The hydrochloride, sulfate, and maleate salts of formulations 1-3 were prepared according to the methods of Examples 1, 4, and 7, respectively.

[0071] The formulations in Table 8 were produced according to the following manufacturing procedure for producing composition particles of different salt forms of the compound of formula (I).

[0072] (1) Preparation of active ingredients and additives: All active ingredients and additives were weighed according to theoretical amounts. The active ingredients (different salts of the compound of formula I) were sieved through a 60-mesh sieve, and the additives (except EDTA-2Na) were sieved through a 20-mesh sieve.

[0073] (2) Preparation of the wetting agent: Add the specified amount of EDTA-2Na to an appropriate amount of purified water and stir until completely dissolved.

[0074] (3) Wet granulation: Different salt forms of the compound of formula (I) and pregelatinized starch were added to a wet granulator, and wet granules were produced by slowly adding an aqueous solution of EDTA-2Na while stirring.

[0075] (4) Drying: The moist granules were added to the fluidized bed and dried until the drying loss was less than 7%.

[0076] (5) Grain sizing: The dried granules were sized using a grinding and sizing machine equipped with a 1.5 mm sieve.

[0077] (6) Mixing: Sodium stearyl fumarate was added to the dried granules after granulation and mixed for 1 minute.

[0078] Formulation stability measurement test: Formulation samples (double aluminum packaging) prepared as described above were placed under measurement conditions of 40±2℃ / RH75±5.0%. Samples were taken at 0 days, 1 month, 2 months, and 3 months, and changes in the relevant substances were examined. The results are shown in Table 9.

[0079] Table 9. Stability results of different salt formulations of compound (I). [Table 9]

[0080] Results from formulation stability measurements showed that the increase in impurities in the maleate and hydrochloride salts of the compound (I) remained relatively small even after accelerated measurements over three months.

[0081] All documents referenced in this invention are cited as references in this application, just as each document is cited as a reference individually. Furthermore, after reading the above contents of this invention, those skilled in the art should understand that various adjustments and modifications can be made to the invention, and that these equivalent forms are also included within the scope defined in the claims attached to this application.

Claims

1. A salt of a compound of formula (I), wherein the salt-forming acid of the salt is selected from the group consisting of 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, homotaurine, 2-hydroxyethanesulfonic acid, cinnamic acid, mucoic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid. 【Chemistry 1】

2. The salt-forming acid of the salt is selected from the group consisting of hydrochloric acid, maleic acid, sulfuric acid, hydrogen bromide, phosphoric acid, methanesulfonic acid, citric acid, and fumaric acid; Preferably, the salt-forming acid of the salt is selected from the group consisting of hydrochloric acid, maleic acid, hydrogen bromide, phosphoric acid, and sulfuric acid; more preferably, it is hydrochloric acid or maleic acid. A salt of the compound of formula (I) according to claim 1, characterized in that it is a salt of the compound of formula (I) according to claim 1.

3. The salt is the hydrochloride salt of the compound of formula (I) in crystalline form A; or the maleate salt of the compound of formula (I) in crystalline form B; or the hydrobromide salt of the compound of formula (I) in crystalline form C; The XRPD pattern of crystalline form A of the hydrochloride salt of the compound of formula (I) has characteristic peaks at the following 2θ diffraction peaks: 8.74, 17.53, 17.99, 19.38, 20.70, 22.68, 24.44, 26.42±0.20°; preferably, the XRPD pattern of crystalline form A has characteristic peaks at the following 2θ diffraction peaks: 8.74, 14.88, 17.53, 17.99, 19.38, 20.70, 22.18, 22.68, 24.44, 26.42±0.20°; more preferably More preferably, the XRPD pattern of crystal form A has characteristic peaks at the following 2θ diffraction peaks: 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°; more preferably, the XRPD pattern of crystal form A is as shown in Figure 1; The XRPD pattern of crystalline form B of the maleate of the compound of formula (I) has characteristic peaks at the following 2θ diffraction peaks: 11.07, 14.52, 16.70, 17.60, 20.12, 22.28, 24.10, 28.01±0.20°; preferably, the XRPD pattern of crystalline form B has characteristic peaks at the following 2θ diffraction peaks: 11.07, 14.52, 16.70, 17.60, 20.12, 22.28, 24.10, 25.18, 26.77, 28.01±0.20°; more preferably, the crystalline form B The XRPD pattern has characteristic peaks at the following 2θ diffraction peaks: 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°; more preferably, the XRPD pattern of crystal form B is as shown in Figure 2; The XRPD pattern of the hydrobromide salt of the compound of formula (I) in crystalline form C has characteristic peaks at the following 2θ diffraction peaks: 4.47, 8.88, 16.58, 17.78, 20.96, 22.27, 22.94, 26.78 ± 0.20°; preferably, the XRPD pattern of the crystalline form C has characteristic peaks at the following 2θ diffraction peaks: 4.47, 8.88, 16.58, 17.78, 20.96, 22.27, 22.94, 24.28, 26.78, 28.34 ± 0.20°. °; More preferably, the XRPD pattern of the crystal form C has characteristic peaks at the following 2θ diffraction peaks: 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°; Even more preferably, the XRPD pattern of the crystal form C is as shown in Figure 3. A salt of the compound of formula (I) according to claim 1, characterized in that it is a salt of the compound of formula (I) according to claim 1.

4. A method for producing a salt of the compound of formula (I) according to any one of claims 1 to 3, 1) Dissolve the compound of formula (I) in a solvent, raise the temperature to 40-60°C, stir, and then dissolve to obtain solution A. Add the salt-forming acid to solution A, stir, and a solid precipitates. Continue stirring for 0.5-4 hours. 2) The mixture in step 1) is cooled to 0-30°C and then stirred for 0.5-4 hours. 3) Filter the mixture, dry the filtered cake at atmospheric pressure and 30-60°C to obtain a salt of compound (I), A manufacturing method that includes this.

5. In step 1), the solvent is selected from the group consisting of acetone, alcohol-based solvents, acetonitrile, isopropyl acetate, ethyl acetate, dichloromethane, chloroform, toluene, or a combination thereof; preferably, the solvent is selected from the group consisting of acetone, anhydrous ethanol, isopropanol, methanol, acetonitrile, isopropyl acetate, ethyl acetate, or a combination thereof. The manufacturing method according to claim 4, characterized in that

6. In step 1), the dose ratio of the compound of formula (I) to the solvent is 1 g: 2 to 25 mL, preferably 1 g: 3 to 15 mL; and / or, in step 1), the molar ratio of the compound of formula (I) to the acid is 1:0.9 to 1.

2. The manufacturing method according to claim 4, characterized in that

7. In step 1), the time for continued stirring is 0.5 to 2 hours; and / or, in step 2), the time for continued stirring is 0.5 to 2 hours. The manufacturing method according to claim 4, characterized in that

8. A pharmaceutical composition comprising a therapeutically effective amount of a salt of formula (I) compound according to any one of claims 1 to 3, and any pharmaceutically acceptable additive.

9. The pharmaceutical composition is an oral or parenteral preparation; Preferably, the oral formulation is selected from the group consisting of tablets, capsules, granules, powders, and syrups; the parenteral formulation is selected from the group consisting of injections, powder injections, sprays, and suppositories. The pharmaceutical composition according to claim 8, characterized in that...

10. Use of a salt of formula (I) compound according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 8 in the manufacture of a medicament for treating and / or alleviating depression.

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