Mesylate of heterocyclic substituted fused gamma-carboline derivative, crystal form and preparation method and application of mesylate

Abstract

The invention relates to mesylate of a heterocyclic substituted fused gamma-carboline derivative, a crystal form and a preparation method and application thereof. In particular, the present invention relates to a mesylate and a crystal form of a compound (6bR, 10aS)-8-(4-(4-fluorophenyl)-4-oxobutyl)-3, 6b-dimethyl-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyridine [3 ', 4': 4, 5] pyrrole [1, 2, 3-dequinoxaline-2 (3H)-one, a preparation method and application thereof, and a pharmaceutical composition containing a therapeutically effective amount of the mesylate and the crystal form of the compound, the invention also relates to application of the compound in preparation of medicines for preventing and / or treating neuropsychiatric diseases.

Description

Methanesulfonate, crystal form, preparation method and application of heterocyclic substituted fused γ-carboline derivative

[0001] This application claims priority to Chinese patent application No. 2022113269716, filed on October 26, 2022. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present 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. Background Art

[0003] Schizophrenia is a disorder characterized by profound cognitive and emotional dissociations that affect basic human behaviors such as language, thought, perception, and self-awareness. The symptoms of the disease encompass a wide range of symptoms, with the most common being mental disorders such as hallucinations, delusions, and delusions.

[0004] Schizophrenia affects approximately 1% of the world's population, but only 5% of all patients who receive treatment ultimately fully recover. Furthermore, schizophrenia often presents with comorbidities such as anxiety disorders, depression, or psychotropic substance abuse.

[0005] Traditionally, antipsychotics that block dopamine D2 receptors are referred to as first-generation antipsychotics, or "typical" antipsychotics (such as haloperidol). These drugs have achieved breakthrough results in treating the positive symptoms of schizophrenia, but have failed to address negative symptoms and cognitive impairment. Typical antipsychotics generally have severe EPS side effects and are ineffective for one-third of schizophrenia patients.

[0006] Since the 1960s, a series of newer antipsychotics, including ziprasidone and risperidone, have been developed. These drugs are known as second-generation antipsychotics, or novel antipsychotics. Although their pharmacological actions vary, they share common pharmacological characteristics: a much higher affinity for serotonin (5-HT) receptors (5-HT1A, 2A, and 2c) and norepinephrine (NA) receptors (α1 and α2) than for D2 receptors, resulting in a higher D2 / 5-HT2A ratio. Their clinical efficacy offers advantages over first-generation antipsychotics. They are equally effective against positive symptoms as traditional antipsychotics, as well as negative symptoms and cognitive impairment, resulting in a broader spectrum of action. However, these drugs are associated with adverse effects such as QT prolongation, hyperprolactinemia, and weight gain. Therefore, the search for drugs that are effective against both positive and negative symptoms and cognitive impairment in schizophrenia, while also exhibiting minimal side effects, is a current research hotspot.

[0007] The serotonin system plays a crucial role in regulating prefrontal cortical (PFC) functions, including emotional control, cognitive behavior, and working memory. Pyramidal neurons and GABA interneurons in the PFC contain several serotonin receptor subtypes, 5-HT1A and 5-HT2A, with exceptionally high densities. Recently, it has been demonstrated that PFC and NMDA receptor channels are targets of 5-HT1AR, which regulates excitatory neurons in the cerebral cortex, thereby influencing cognitive function. Indeed, various preclinical data suggest that the 5-HT1AR may be a novel target for antipsychotic drug development. The high affinity of atypical antipsychotics (e.g., olanzapine, aripiprazole) for the 5-HT1AR and their low EPS side effects suggest that the serotonin system plays a crucial role in regulating prefrontal cortical (PFC) functions, including emotional control, cognitive behavior, and working memory. Pyramidal neurons and GABA interneurons in the PFC contain several serotonin receptor subtypes, 5-HT1A and 5-HT2A, with exceptionally high densities. Recent studies have shown that 5-HT1A agonists are associated with atypical antipsychotic treatment, improving negative symptoms and cognitive impairment. In the treatment of schizophrenia with the atypical antipsychotic clozapine, 5-HT2A has been found to play a crucial role, involved in various aspects of perception, emotion regulation, and motor control. Blocking 5-HT2A receptors can normalize dopamine release, leading to antipsychotic effects. Furthermore, 5-HT2C receptors are closely linked to weight gain.

[0008] D3 receptors are primarily distributed selectively in the limbic system. There are two major DA pathways in the brain: the nigrostriatal pathway, which regulates motor function, and the nucleus accumbens in the ventral tegmental area of ​​the midbrain, which is closely related to learning, cognition, and emotional activity. Dysfunction in this pathway can lead to schizophrenia and is also the primary pathway for reward effects in the brain. D3Rs are distributed in both pathways and interact in complex ways with other DA receptor subtypes. They may serve as a target for antipsychotic drug therapy. Selective D3 receptor antagonism can reduce the negative and cognitive symptoms of schizophrenia and prevent extrapyramidal side effects, including tardive dyskinesia and Parkinson's disease. Therefore, finding an antipsychotic drug with multiple receptor binding and minimal side effects is of great clinical significance.

[0009] International patent application PCT / CN2021 / 122546 discloses a method for treating 5-HT 2Aand D2 receptor antagonist, its chemical name is (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, which has a strong inhibitory effect on 5-HT 2A receptors and D2(D 2L 、D 2s ) receptors have good antagonist activity and have a high D2 / 5-HT 2A The invention has a high selectivity, good pharmacokinetic properties, and good in vivo pharmacodynamics, and can effectively treat and improve schizophrenia.

[0010] Different salts and solid forms of active pharmaceutical ingredients may exhibit distinct properties. These salts and solid forms can significantly differ in appearance, solubility, melting point, hygroscopicity, stability, and pharmacokinetics, and can also have varying effects on drug stability, bioavailability, and efficacy. Therefore, comprehensive consideration of the drug's salt form and / or solid form is crucial during drug development.

[0011] When studying the compound, the inventors found that the free base of the compound exists in the form of an oil, has poor solubility in water, and has low bioavailability, making it not a preferred form for clinical use. Therefore, it is necessary to further comprehensively screen and study the acid salt and its crystalline form of the compound.

[0012] Summary of the Invention

[0013] All contents involved in international patent application PCT / CN2021 / 122546 are added to the present invention by reference.

[0014] The technical problem to be solved by the present invention is to provide a mesylate salt, a crystal form, a preparation method and an application of a heterocyclic-substituted fused γ-carboline derivative.

[0015] The object of the present invention is to provide an acid salt of the 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]quinoxalin-2(3H)-one.

[0016] In a preferred embodiment of the present invention, the acid salt is methanesulfonate.

[0017] In a preferred embodiment of the present invention, the number of acids in the acid salt is 0.5-2, preferably 0.8-1.2, and preferably 1.

[0018] In a further preferred embodiment of the present invention, the acid salt is in crystalline form.

[0019] In a further preferred embodiment of the present invention, 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 methanesulfonate crystalline form I, the number of acids is 1, and its X-ray powder diffraction pattern comprises diffraction peaks at 2θ of 5.83±0.2°, 12.75±0.2°, and 22.56±0.2°;

[0020] Preferably, it comprises diffraction peaks at 2θ of 5.83±0.2°, 12.75±0.2°, 18.34±0.2°, 19.24±0.2°, and 22.56±0.2°;

[0021] More preferably, it comprises diffraction peaks located at 2θ 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°;

[0022] More preferably, the range of the 2θ values ​​is 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. diffraction peaks at 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°, and 32.79±0.2°;

[0023] More preferably, Cu-Kα radiation is used, and the X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are as shown in Table 1.

[0024] Table 1 XRPD diffraction data of mesylate salt form I of the compound

[0025] More preferably, the X-ray powder diffraction pattern of the mesylate salt form I of the 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 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.

[0026] In a further preferred embodiment of the present invention, the acid salt is anhydrous.

[0027] On the other hand, 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-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one acid salt, which specifically comprises the following steps:

[0028] (1) Weigh an appropriate amount 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]quinoxalin-2(3H)-one free base and dissolve it in solvent 1;

[0029] (2) Weighing an appropriate amount of methanesulfonic acid, and optionally dissolving it in solvent 2; the amount of methanesulfonic acid is 0.5-2.0 equivalents, preferably 0.5-1.0 equivalents;

[0030] (3) mixing the above two, stirring to crystallize, filtering, and vacuum drying to obtain the target product;

[0031] in:

[0032] 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, 1,2-dioxane, benzene or toluene; the solvent 1 and solvent 2 must be miscible when used.

[0033] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any one of the acid salts of the compounds shown or a combination thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0034] 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 medicament involving or regulating 5-hydroxytryptamine receptors, 5-hydroxytryptamine transporters and / or dopamine receptors; preferably, the use of the acid salt of any of the compounds shown, or a pharmaceutical composition thereof, in the preparation of a medicament involving or regulating 5-HT2A receptors, 5-hydroxytryptamine transporters, dopamine D1 receptors and / or dopamine D2 receptors, and more preferably, the use of the acid salt of any of the compounds shown, or a pharmaceutical composition thereof, in the preparation of a medicament involving or regulating 5-HT2A receptors and / or dopamine D2 receptors.

[0035] 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.

[0036] In a further preferred embodiment of the present invention, 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 disease, bipolar disorder, post-traumatic stress syndrome, addictive disease, 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 disease or bipolar disorder; the depression is, for example, major depressive disorder, and the ADHD is, for example, attention deficit hyperactivity disorder.

[0037] Detailed Description of the Invention

[0038] Different expressions such as “X is selected from A, B or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0039] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl may but need not be present, and that the description includes instances where the cycloalkyl is substituted with alkyl and instances where the cycloalkyl is not substituted with alkyl.

[0040] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, along with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0041] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0042] As used herein, "polymorph" or "polymorph" refers to a crystalline form having the same chemical composition but with different spatial arrangements of the molecules, atoms, and / or ions that make up the crystal. Although polymorphs have the same chemical composition, they differ in their packing and geometric arrangement and may exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, 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 crystal lattice structures is known as pharmaceutical polymorphism.

[0043] The crystal structures equivalent to the crystal structures disclosed or claimed in the present invention may show similar but not identical analytical characteristics within a reasonable error range according to experimental conditions, purity, equipment and other common variables known to those skilled in the art. Accordingly, it will be apparent to those skilled in the art that various modifications and variations can be made within the present invention without departing from the scope and spirit of the present invention. On the basis of considering the description and practice of the present invention disclosed herein, other embodiments of the present invention will be apparent to those skilled in the art. Applicants expect that these descriptions and examples are considered exemplary, rather than limiting their scope.

[0044] "X-ray powder diffraction pattern or XRPD" means the powder diffraction pattern of a substance according to the Bragg formula 2d sinθ = nλ (where λ is the wavelength of the X-rays, The diffraction order n is any positive integer, generally taking the first order diffraction peak as n=1. The "2θ or 2θ angle" mentioned herein refers to the diffraction angle, with θ being the Bragg angle, measured in degrees. When X-rays strike an atomic plane with a lattice spacing of d in a crystal or a portion of a crystalline sample at a grazing angle θ (the complementary angle to the incident angle, also known as the Bragg angle), the Bragg equation is satisfied, resulting in the measured X-ray powder diffraction pattern.

[0045] It is well known to those skilled in the art that XRPD may produce certain shifts and intensity deviations due to the detection method, conditions, and instrumentation. Identical samples of the same crystal form generally have the same main XRPD characteristic peaks, but there may be certain operating errors. When a person skilled in the art uses the same instrument and detection method to detect isomorphous samples obtained using the corresponding method, the characteristic peak error is generally within ±0.2°. However, different technicians using different instruments may occasionally have errors in a few characteristic peaks that exceed this range. For example, errors within ±0.5° or ±0.3° should all be considered to belong to the XRPD characteristic peaks of the same crystal form. Therefore, as a specific example of the crystal form of the present invention, its XRPD is shown in Figure X, but it is understood by those skilled in the art that when the 2θ deviation of the key characteristic peak shift is within ±0.5°, ±0.3°, or ±0.2°, especially around ±0.2°, it can be identified as the same crystal form and can be interpreted as being within the scope of protection of the present invention.

[0046] Furthermore, the absolute and relative intensities of the peaks shown in the aforementioned tables and figures may vary due to various factors, such as the effects 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. Furthermore, peak positions may shift due to variations in sample height. Furthermore, when measurements are performed using different wavelengths, different shift values ​​are obtained according to the Bragg formula (nλ = 2dsinθ). Such different XRPD patterns obtained using different wavelengths are also within the scope of the present invention.

[0047] "Interplanar spacing or interplanar spacing (d value)" refers to the selection of three non-parallel unit vectors a, b, and 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 lines connecting the parallelepiped units to obtain a set of straight line grids, which are called space grids or lattices. The lattice and lattice respectively 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.

[0048] “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%.

[0049] Differential Scanning Calorimetry (DSC) measures the transition temperatures of a crystal when heat is absorbed or released due to changes in its crystal structure or melting. For the same crystalline form of the same compound, the thermal transition temperatures and melting points can be within about 5°C, and typically within about 3°C, in consecutive analyses. When a compound is described as having a given DSC peak or melting point, this is referred to as ±5°C relative to that peak or melting point, essentially taking this temperature variation into account. DSC provides an auxiliary method for distinguishing between different crystalline forms. Different crystalline forms can be identified by their distinct transition temperature signatures. It should be noted that for mixtures, the DSC peak or melting point may vary over a wider range. Furthermore, because decomposition occurs during melting, the melting temperature is related to the heating rate.

[0050] Thermogravimetric analysis (TGA) is a common method for determining the thermal stability of compounds. In the present invention, TGA can also be used to determine the hydration state of a compound. The heating rate during the test will have a certain impact on the spectrum. The error of TGA can be within approximately ±0.5% by mass.

[0051] "Amorphous," "amorphous form," or "amorphous form" refers to a substance whose particles (molecules, atoms, ions) are arranged in a three-dimensional space without periodicity. This is characterized by a diffuse, non-peaked X-ray powder diffraction pattern. Amorphous is a specialized physical form of solid matter, and its locally ordered structure suggests a close relationship to crystalline forms.

[0052] "Equivalent" or its abbreviation "eq" refers to the equivalent amount of other raw materials required based on the equivalent relationship of chemical reactions, with the basic raw material used in each step as the benchmark (1 equivalent).

[0053] “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.

[0054] In the context of the present invention, when or whether the word "about" is used, it means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for a person of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. Whenever a number having a value of N is disclosed, any number having a value of N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8% or N + / - 10% is specifically disclosed, where "+ / -" means plus or minus.

[0055] "Room temperature" refers to a temperature between 10°C and 40°C. In some embodiments, "room temperature" refers to a temperature between 15°C and 30°C; in other embodiments, "room temperature" refers to a temperature between 18°C ​​and 25°C. Beneficial effects

[0056] The methanesulfonate crystalline 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 terms of product performance parameters such as solubility, hygroscopicity, and stability, but also shows obvious advantages in pharmacokinetic studies. It can be rapidly absorbed after administration and exhibits good metabolic properties. The exposure amount AUC and maximum blood concentration C max They all perform well and have good oral absorption characteristics, which are of great significance in improving the efficacy of drugs, reducing dosage, and saving costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] 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-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one methanesulfonate Form I.

[0058] 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-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one methanesulfonate Form I.

[0059] 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-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one methanesulfonate Form I.

[0060] 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-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one methanesulfonate Form I. DETAILED DESCRIPTION

[0061] Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiments are only used to illustrate the present invention and are not used in limiting the scope of the present invention.In addition, should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall equally within the scope limited by the appended claims of the application.

[0062] 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-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one, hereinafter referred to as Compound A, has the structural formula:

[0063] Its free base is prepared according to the preparation method of Example 1-A in international patent application PCT / CN2021 / 122546.

[0064] Study on the salt crystal form of compound A

[0065] Experimental instruments:

[0066] 1. Preparation of Compound A Acid Salt

[0067] 1.1 Preparation of Compound A Methanesulfonate Form I

[0068] Compound A free base (132 mg, 0.31 mmol) and ethyl acetate (1.0 mL) were added to a 25 mL round-bottom flask, purged with nitrogen, and stirred at room temperature until clear. A 1 M methanesulfonic acid-ethyl acetate solution (0.25 mL, 0.25 mmol) was then added and stirred for half an hour. The mixture was filtered and the filter cake was dried under vacuum at room temperature for 5 hours to yield an off-white solid identified as Compound A methanesulfonate Form I (68 mg).

[0069] After detection and analysis, it has an XRPD pattern as shown in Figure 1, a DSC pattern as shown in Figure 2, and a TGA pattern as shown in Figure 3. Combining the results of its DSC and TGA analysis, it can be seen that it is a non-solvate, and the molar ratio of compound A to mesylate is approximately 1:1.

[0070] 2. Solubility experiment

[0071] 2.1 Experimental Purpose:

[0072] The solubility of Compound A free base and Compound A mesylate salt form I in water was investigated to provide a basis for evaluating the drugability of the salt.

[0073] 2.2 Experimental plan:

[0074] Excess amounts of Compound A free base and mesylate salt Form I were weighed and placed in different 10 mL centrifuge tubes. 1 mL of deionized water was added, the tubes were sealed with a sealing film, and the tubes were shaken in a constant temperature shaker at 37°C and 150 rpm for 24 h. The tubes were then filtered through a 0.45 μm organic filter, diluted, and injected for HPLC analysis.

[0075] 2.3 Experimental results: The solubility results are shown in Table 3.1 below.

[0076] 2.4 Experimental Conclusions:

[0077] From the above data, it can be seen that the solubility of Compound A mesylate Form I in aqueous medium is significantly improved compared to Compound A free base.

[0078] 3. Solid stability test

[0079] 3.1 Experimental Purpose:

[0080] The physicochemical stability of Compound A mesylate salt Form I under high temperature and sealed conditions was investigated.

[0081] 3.2 Experimental plan:

[0082] An appropriate amount of Compound A mesylate salt Form I was weighed, placed in a weighing dish, sealed, and placed in a 60°C stability test chamber for 10 days. Samples were taken after mixing evenly at 0 days, 3 days, 7 days, and 10 days, and dissolved in methanol. The content and impurity changes were detected by HPLC related substance method. In addition, the XRPD patterns of the samples before and after testing were compared and analyzed.

[0083] 3.3 Experimental results: The stability results are shown in Table 3.2 below:

[0084] 3.4 Experimental Conclusions

[0085] The above data show that the mesylate salt form I of Compound A of the present invention has good stability under high temperature and sealed conditions, and the XRPD pattern does not change.

[0086] 4. Hygroscopicity test

[0087] 4.1 Experimental Purpose:

[0088] The hygroscopic and deliquescent properties of Compound A methanesulfonate Form I were investigated.

[0089] 4.2 Experimental plan:

[0090] At room temperature (25° C.), 30.68 mg of Compound A mesylate Form I was placed in a DVS sample tray for testing. XRPD patterns of the sample before and after testing were also compared and analyzed.

[0091] 4.3 Experimental Results

[0092] The DVS graph of Compound A mesylate Form I is shown in Figure 4. The two curves in the figure represent the adsorption and desorption curves, respectively. Due to possible hysteresis during desorption, the two curves do not overlap. Figure 4 shows that the mass change ΔW% of the sample is less than 2% with increasing relative humidity (RH) between 0% and 80%, indicating that the sample is slightly hygroscopic.

[0093] 4.4 Experimental Conclusions

[0094] The weight gain of Compound A methanesulfonate Form I under RH 80% and 25° C. due to moisture absorption is between 0.2% and 2%, indicating slight hygroscopicity. The XRPD pattern does not change, indicating that the form is stable.

[0095] 5. Pharmacokinetic experiments

[0096] 5.1 Test Purpose:

[0097] Female SD rats were orally administered with the drug, and the blood concentration of Compound A mesylate Form I in the rats was determined, the PK parameters were calculated, and the pharmacokinetic evaluation was performed.

[0098] 5.2 Test materials:

[0099] (1) Test sample: Compound A methanesulfonate Form I, prepared in-house.

[0100] (2) Experimental animals: SD rats, SPF grade, female, obtained from Shanghai Slake Laboratory Animal Co., Ltd.

[0101] 5.3 Test plan:

[0102] (1) Dosage information:

[0103] Drug preparation: Take the test sample, add physiological saline, and perform ultrasound. Administration route: Oral gavage; Dosage: 15 mg / kg; Dosing frequency and duration: Single administration.

[0104] (2) Test method:

[0105] SD rats were stratified by weight and randomly divided into groups of 3 rats per group. All rats were fasted overnight before the experiment. The drug was administered orally by gavage. At 0, 0.167, 0.333, 0.5, 1, 2, 4, 7, and 10 hours, 250 μL of blood was collected from the jugular vein or orbital vein of the rats into sample tubes containing sodium heparin, an anticoagulant, and placed on wet ice. The tubes were rotated at 4000 rpm. -1 After centrifugation for 10 min, plasma was separated and subjected to LC-MS analysis.

[0106] 5.4 Test results and analysis:

[0107] The measured blood drug concentration-time data were substituted into Winnonlin 8.2 program to calculate the main pharmacokinetic parameters. max and C max The AUC was calculated using the trapezoidal method using the measured values. 0-t Value and AUC inf The semi-logarithmic plot method was used to calculate the t value from the concentration point at the end of the elimination phase. 1 / 2 The specific results are shown in Table 3.3 below.

[0108] Table 3.3 Pharmacokinetic results of compound A methanesulfonate in rats

[0109] 5.5 Test conclusion:

[0110] It can be seen from the experimental results in the table that the mesylate salt form I of the compound A of the present invention can be rapidly absorbed after administration, showing good metabolic properties, exposure amount AUC and maximum blood concentration C max All performed well.

Claims

1. An acid salt of the 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]quinoxalin-2(3H)-one, characterized in that: The acid salt is methanesulfonate.

2. The acid salt according to claim 1, characterized in that The number of methanesulfonic acids in the acid salt is 0.5-2, preferably 0.8-1.2, and preferably 1.

3. The acid salt according to claim 1 or 2, characterized in that The acid salt is in a crystalline form, preferably a mesylate crystalline form I, and its X-ray powder diffraction pattern comprises diffraction peaks at 2θ of 5.83±0.2°, 12.75±0.2°, and 22.56±0.2°; preferably, its X-ray powder diffraction pattern comprises diffraction peaks at 2θ of 5.83±0.2°, 12.75±0.2°, 18.34±0.2°, 19.24±0.2°, and 22.56±0.2°; preferably, its X-ray powder diffraction pattern comprises diffraction peaks at 2θ of 5.83±0.2°, 12.75±0.2°, 18.34±0.2°, 19.24±0.2°, and 22.56±0.2°; The X-ray powder diffraction pattern comprises diffraction peaks at 2θ 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°; preferably, the X-ray powder diffraction pattern comprises diffraction peaks at 2θ 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°. 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° , diffraction peaks at 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°, and 32.79±0.2°.

4. The acid salt according to any one of claims 1 to 3, characterized in that The acid salt is mesylate crystal form I, and its X-ray powder diffraction pattern is substantially as shown in FIG1 .

5. The acid salt according to any one of claims 1 to 4, characterized in that The acid salt is a mesylate crystal form I, and its DSC spectrum has an endothermic peak at 195.77±5° C., preferably having a DSC spectrum as shown in FIG2 , and / or a TGA spectrum as shown in FIG3 .

6. A method for preparing the acid salt according to any one of claims 1 to 5, characterized in that: The specific steps include: (1) Weigh an appropriate amount 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]quinoxalin-2(3H)-one free base and dissolve it in solvent 1; (2) Weighing an appropriate amount of methanesulfonic acid, and optionally dissolving it in solvent 2; the amount of methanesulfonic acid is preferably 0.5-1.0 equivalents; (3) mixing the above two, stirring to crystallize, filtering, and vacuum drying to obtain the target product; in: 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, 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, 1,2-dioxane, benzene or toluene; the above solvent 1 and solvent 2 must be miscible when used.

7. A pharmaceutical composition comprising a therapeutically effective dose of the acid salt according to any one of claims 1 to 5 or a combination thereof, and one or more pharmaceutically acceptable carriers or excipients.

8. Use of the acid salt according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 7, in the preparation of a medicament involving or regulating 5-hydroxytryptamine receptors, 5-hydroxytryptamine transporters and / or dopamine receptors; preferably in the preparation of a medicament involving or regulating 5-HT2A receptors, 5-hydroxytryptamine transporters, dopamine D1 receptors and / or dopamine D2 receptors, more preferably in the preparation of a medicament involving or regulating 5-HT2A receptors and / or dopamine D2 receptors.

9. Use of the acid salt according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating a neuropsychiatric disease, wherein 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, attention deficit hyperactivity disorder, obsessive-compulsive disorder, social phobia, neurodegenerative disease, bipolar disorder, post-traumatic stress syndrome, addictive disease, withdrawal syndrome, or attention deficit disorder, preferably any one or more of depression, anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behavioral disorders in patients with dementia, neurodegenerative disease, or bipolar disorder; the depression is, for example, major depressive disorder, and the hyperactivity is, for example, attention deficit hyperactivity disorder.

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