Salts and crystalline forms of spiro ring-containing derivatives, and methods for their preparation and use

Abstract

The present invention relates to salts and crystalline forms of spiro ring-containing derivatives, as well as methods for preparing and using the same. In particular, the present invention relates to salts and crystalline forms of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine, as well as methods for preparing and using the same, pharmaceutical compositions containing therapeutically effective amounts of the salts and crystalline forms of the compound, and the use of the same in the manufacture of medicaments for preventing and / or treating neuropsychiatric disorders.

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 2022111813611, filed on September 27, 2022. This application cites the above Chinese patent application in its entirety.

[0002] The present invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to salts and crystalline forms of spiro ring-containing derivatives, as well as methods for their preparation and use. [Background technology]

[0003] Diseases related to the central nervous system affect many people to varying degrees. Generally, the primary features of such disorders include significant cognitive or memory impairments, resulting in a significant decline compared to the patient's previous level of functioning. Schizophrenia is a psychopathological disorder of unknown etiology that typically first manifests in early adulthood and is characterized by psychotic symptoms, gradual progression and development, and / or regression of social behavior and professional skills. Schizophrenia symptoms are generally categorized into three categories: positive, negative, and cognitive symptoms. Positive symptoms are those that represent an "excess" of normal experiences, such as hallucinations and delusions. Negative symptoms are those in which patients lose normal experiences, such as anhedonia and lack of social interaction. Cognitive symptoms are associated with the cognitive impairments of schizophrenia, such as a lack of sustained attention and impaired decision-making. While current antipsychotic medications are successful in treating positive symptoms, they are still less than ideal for treating negative and cognitive symptoms.

[0004] Biogenic amines play important roles as neurotransmitters in the central and peripheral nervous systems. Their synthesis and storage, as well as their release, degradation, and reabsorption, are tightly regulated. Imbalances in biogenic amine levels are known to be the primary cause of altered brain function in many pathological conditions. Serotonin, norepinephrine, epinephrine, dopamine, and histamine are classic biogenic amines that have been extensively studied. Among them, the 5-hydroxytryptamine system plays a key role in regulating functions in the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. Pyramidal neurons and GABAergic interneurons in the PFC contain several highly dense 5-hydroxytryptamine receptor subtypes, 5-HT1A and 5-HT2A. PFC and NMDA receptor channels have recently been shown to be targets of the 5-HT1AR, and these two receptors regulate excitatory neurons in the cerebral cortex, thereby affecting 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 and aripiprazole) for the 5-HT1AR and low EPS side effects suggest that the 5-hydroxytryptamine system plays a key role in regulating PFC functions, including emotional control, cognitive behavior, and working memory. Pyramidal neurons and GABAergic interneurons in the PFC contain several highly dense 5-hydroxytryptamine receptor subtypes, 5-HT1A and 5-HT2A. Recent studies have shown that 5-HT1A agonists, related to atypical antipsychotic treatments, can improve negative symptoms and cognitive impairment.

[0005] In recent years, as research on classical biogenic amines has gradually deepened, researchers have discovered a second class of endogenous amine compounds, the trace amines TAAR, including p-tyramine, β-phenylethylamine, tryptamine, and octopamine. Although their levels in the mammalian nervous system are generally lower than those of classical biogenic amines, they all share similar characteristics to classical biogenic amines in terms of structure, metabolism, and subcellular localization. As a new member of the GPCR family of G protein-coupled receptors, the trace amine-associated receptor (TAAR) shares a similar structure to the deep GPCR pharmacophore and consistent pharmacological data. Phylogenetic relationships of this receptor gene have shown that these receptors form three distinct subfamilies, of which TAAR1 is the first of four genes (TAAR1-4) highly conserved between humans and rodents. TAARs activate TAAR1 via Gαs and play a key role. Existing studies clearly show that dysregulation of trace amine-associated receptors, especially TAAR1, is closely associated with many psychiatric disorders such as schizophrenia and depression, as well as conditions such as attention deficit hyperactivity disorder, migraine, Parkinson's disease, substance abuse, and eating disorders, making it highly likely that TAAR ligands could be used to treat these diseases.

[0006] Although there are many anti-schizophrenia medications available, those currently in clinical use still suffer from a variety of side effects. Current anti-schizophrenia medications for negative symptoms have been clinically applied and have improved negative symptoms in some patients, but overall effectiveness is limited. Many patients still experience difficulties recovering or restoring normal social function due to negative symptoms, making it difficult for them to resume normal social activities. Furthermore, treating cognitive dysfunction is also a key focus of schizophrenia treatment. While verbal memory, verbal information processing ability, and attention function are affected in most schizophrenic patients, anti-schizophrenia medications currently under investigation or commercially available have only limited improvement in cognitive function. In addition, the treatment of refractory schizophrenia is still facing a dilemma. Such patients have been treated with three kinds of antipsychotic drugs with different active ingredients. However, even if they receive a sufficient course of treatment at a sufficient dose, they often do not respond well to treatment, or they cannot tolerate the side effects of antipsychotic drugs, or the disease still recurs or worsens despite appropriate maintenance or preventive treatment. Therefore, anti-refractory schizophrenia treatment drugs have always been a difficult problem in current clinical drug research and are a direction that must be overcome as soon as possible.

[0007] Sunovion's SEP-363856, a 5-hydroxytryptamine and / or trace amine-associated receptor agonist currently in Phase III clinical trials, has demonstrated significant activity at 5-HT1A and TAAR1 receptors and demonstrated favorable activity in existing clinical studies. Therefore, there is an urgent need to develop effective and sustained treatments for negative symptoms, improve cognitive function, and effectively treat refractory schizophrenia. Furthermore, there is a need for antipsychotic drugs with minimal side effects and that act on multiple targets to meet the huge market demand. Summary of the Invention [Problem to be solved by the invention]

[0008] International patent application PCT / CN2022 / 083485 describes the structures of a series of spiro ring-containing derivatives, and in subsequent research and development, the present invention has comprehensively studied the acid salts and crystalline forms of the above compounds in order to improve the solubility, stability, powder flow properties, and pharmacokinetics of the compounds, and / or to enhance the bioavailability, reduce storage costs, and extend the product cycle.

[0009] International Patent Application PCT / CN2022 / 083485 is incorporated herein by reference in its entirety.

[0010] The technical problem that the present invention aims to solve is to provide salts, crystalline forms of spiro ring-containing derivatives, as well as methods for their preparation and use. [Means for solving the problem]

[0011] It is an object of the present invention to provide an acid salt of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine. In a preferred embodiment of the invention, the acid salt is a hydrochloride salt.

[0012] In a preferred embodiment of the present invention, the number of acids in the acid salt is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5, or 3, more preferably 0.5, 1, 2, or 3, and even more preferably 1.

[0013] In a further preferred embodiment of the present invention, the molar ratio of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine to hydrochloride is 1:0.8-1.2.

[0014] In a further preferred embodiment of the present invention, the acid salt is unsolvated or solvated, and the solvent is one or more 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, and toluene.

[0015] In a further preferred embodiment of the present invention, the number of the above solvents is 0 to 3, preferably 0, 0.2, 0.5, 1, 1.5, 2, 2.5, or 3, and more preferably 0, 0.5, 1, 2, or 3.

[0016] In a further preferred embodiment of the present invention, the acid salts mentioned above are preferably anhydrous or monohydrate.

[0017] In a further preferred embodiment of the invention, the acid salt is in crystalline or amorphous form.

[0018] In a further preferred embodiment of the present invention, the acid salt of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is hydrochloride crystalline form I, hydrochloride crystalline form II, or hydrochloride crystalline form III; In the case of the hydrochloride crystalline form I, the acid number is 1, and its powder X-ray diffraction pattern shows diffraction peaks at 2θ positions of 12.03±0.2°, 16.08±0.2°, and 26.84±0.2°, Preferably, diffraction peaks at 2θ positions of 12.03±0.2°, 16.08±0.2°, 18.52±0.2°, 25.31±0.2°, and 26.84±0.2°; Preferably, diffraction peaks at 2θ positions of 12.03±0.2°, 16.08±0.2°, 18.52±0.2°, 20.94±0.2°, 22.06±0.2°, 23.10±0.2°, 24.72±0.2°, 25.31±0.2°, 26.84±0.2°, and 29.60±0.2°; More preferably, 2θ is 6.22±0.2°, 12.03±0.2°, 12.36±0.2°, 16.08±0.2°, 18.25±0.2°, 18.52±0.2°, 19.48±0.2°, 20.24±0.2°, 20.94±0.2°, 21.18±0.2°, 22.06±0.2°, 23.10±0.2°, 23.54±0.2°, 24.72±0.2°, 25.31±0.2°, 26. The diffraction peaks at the positions of 0.84±0.2°, 27.07±0.2°, 27.77±0.2°, 28.49±0.2°, 29.60±0.2°, 31.05±0.2°, 31.78±0.2°, 32.45±0.2°, 32.79±0.2°, 37.15±0.2°, 39.10±0.2°, 42.73±0.2°, 43.97±0.2°, 44.36±0.2°, and 45.23±0.2° are included. More preferably, X-ray diffraction peaks expressed by 2θ angles and d values ​​of crystal plane spacing are shown in Table 1 using Cu-Kα radiation.

[0019] [Table 1]

[0020] More preferably, for the hydrochloride salt crystalline Form I of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine, the powder X-ray diffraction pattern is approximately as shown in FIG. 1, the DSC pattern is approximately as shown in FIG. 2, and the TGA pattern is approximately as shown in FIG. 3.

[0021] In the case of the hydrochloride crystalline form II, the acid number is 1, and the powder X-ray diffraction pattern shows diffraction peaks at 2θ angles of 13.36±0.2°, 17.25±0.2°, and 27.74±0.2°. Preferably, diffraction peaks at 2θ positions of 10.30±0.2°, 13.36±0.2°, 17.25±0.2°, 22.77±0.2°, and 27.74±0.2°; Preferably, diffraction peaks at 2θ positions of 10.30±0.2°, 13.36±0.2°, 15.17±0.2°, 17.25±0.2°, 22.77±0.2°, 24.95±0.2°, 25.28±0.2°, 25.87±0.2°, 27.74±0.2°, and 30.99±0.2°; More preferably, 2θ is 8.55±0.2°, 9.96±0.2°, 10.30±0.2°, 11.23±0.2°, 12.49±0.2°, 13.36±0.2°, 15.17±0.2°, 15.99±0.2°, 17.25±0.2°, 18.25±0.2°, 18.83±0.2°, 19.20±0.2°, 20.04±0.2°, 21.11±0.2°, 21.72±0.2°, 22.04±0.2°, 23.02±0.2°, 24.02±0.2°, 25.02±0.2°, 26.02±0.2°, 27.02±0.2°, 28.02±0.2°, 29.02±0.2°, 30.02±0.2°, 31.02±0.2°, 32.02±0.2°, 33.02±0.2°, 34.02±0.2°, 35.02±0.2°, 36.02±0.2°, 37.02±0.2°, 38.02±0.2°, 39.02±0.2°, 40.02±0.2°, 41.02±0.2°, 42.02±0.2°, 43.02±0.2°, 44.02±0.2°, 45.02±0.2°, 46.02±0.2°, 47.02±0.2°, 48.02±0.2°, 4 The diffraction peaks at the positions of 0.77±0.2°, 24.13±0.2°, 24.95±0.2°, 25.28±0.2°, 25.87±0.2°, 26.39±0.2°, 27.11±0.2°, 27.74±0.2°, 28.57±0.2°, 29.23±0.2°, 30.99±0.2°, 32.26±0.2°, 34.85±0.2°, 38.72±0.2°, and 40.42±0.2° are included. More preferably, X-ray diffraction peaks expressed by 2θ angles and d values ​​of crystal plane spacing are shown in Table 2 using Cu-Kα radiation.

[0022] [Table 2]

[0023] More preferably, for the hydrochloride salt crystalline Form II of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine, the powder X-ray diffraction pattern is approximately as shown in FIG. 4, the DSC pattern is approximately as shown in FIG. 5, and the TGA pattern is approximately as shown in FIG. 6.

[0024] In the case of the hydrochloride crystalline form III, the acid number is 1, and the powder X-ray diffraction pattern shows diffraction peaks at 2θ angles of 8.86±0.2°, 17.71±0.2°, and 26.66±0.2°. Preferably, diffraction peaks at 2θ positions of 8.86±0.2°, 13.28±0.2°, 17.71±0.2°, 19.07±0.2°, and 26.66±0.2°; Preferably, diffraction peaks at 2θ positions of 8.86±0.2°, 13.28±0.2°, 15.75±0.2°, 16.22±0.2°, 17.71±0.2°, 19.07±0.2°, 22.75±0.2°, 23.70±0.2°, 26.66±0.2°, and 31.19±0.2°; More preferably, 2θ is 8.86±0.2°, 10.50±0.2°, 12.99±0.2°, 13.28±0.2°, 15.75±0.2°, 16.22±0.2°, 17.71±0.2°, 19.07±0.2°, 20.52±0.2°, 21.01±0.2°, 22.75±0.2°, 23.19±0.2°, 23.70±0.2°, 24.16±0.2°, 24.43±0.2°, 24.91±0.2°, 25. The diffraction peaks at the positions of .34±0.2°, 25.70±0.2°, 26.09±0.2°, 26.66±0.2°, 27.19±0.2°, 29.06±0.2°, 31.01±0.2°, 31.19±0.2°, 31.41±0.2°, 31.67±0.2°, 32.07±0.2°, 32.98±0.2°, 33.40±0.2°, 36.77±0.2°, 44.77±0.2°, and 49.93±0.2° are included. More preferably, X-ray diffraction peaks expressed by 2θ angles and d-values ​​of crystal plane spacing are shown in Table 3 using Cu-Kα radiation.

[0025] [Table 3]

[0026] More preferably, for the hydrochloride salt crystalline Form III of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine, the powder X-ray diffraction pattern is approximately as shown in Figure 7, the DSC pattern is approximately as shown in Figure 8, and the TGA pattern is approximately as shown in Figure 9.

[0027] In another aspect, the present invention also provides a method for preparing the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine acid salt, specifically comprising: Step (1) of weighing an appropriate amount of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine, which is a free base of the compound, and dissolving it in solvent 1; Step (2) of weighing an appropriate amount of hydrochloric acid, preferably 0.5 to 2.0 equivalents, and dissolving it in solvent 2; and (3) mixing both of the above, stirring at a predetermined temperature for a predetermined time to cause a reaction, filtering by suction, and drying to obtain the target product. or, Step (1) of weighing an appropriate amount of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine, which is a free base of the compound, and dissolving it in solvent 1; Step (2) of weighing an appropriate amount of hydrochloric acid, preferably 0.5 to 2.0 equivalents, and dissolving it in solvent 2; (3) mixing both of the above, stirring at a predetermined temperature for a predetermined time to allow the reaction, adding solvent 3, stirring for a further predetermined time to allow the reaction, suction filtering, and drying to obtain the target product; The reaction temperature is determined depending on the solvent of the system, and is preferably room temperature. wherein solvent 1, solvent 2, and solvent 3 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, and solvent 1 and solvent 2 must be compatible when used.

[0028] In another aspect, the present invention also provides a method for preparing the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine acid salt, specifically comprising: Step (1) of weighing an appropriate amount of the hydrochloride salt of the compound and dissolving or suspending it in a solvent 4; and step (2) refluxing the clear solution or suspension of step (1) at a predetermined temperature for a predetermined time to cause reaction, cooling to room temperature, suction filtering, and drying to obtain the target product; The reflux temperature is generally slightly higher than the boiling point of the solvent 4, and is preferably 70 to 90°C, more preferably 75 to 85°C, and even more preferably 80°C. wherein the solvent 4 is selected from water, absolute methanol, absolute ethanol, 95% 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.

[0029] The present invention further relates to pharmaceutical compositions comprising a therapeutically effective amount of an acid salt of any of the compounds or combinations thereof and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0030] The present invention further relates to the use of an acid salt of a compound according to any one of the above claims, or a pharmaceutical composition thereof, in the preparation of a medicament.

[0031] In a further preferred embodiment of the present invention, the medicament may be a medicament for preventing and / or treating a neuropsychiatric disorder in a mammal.

[0032] In a further preferred embodiment of the present invention, the neuropsychiatric disorder is a central nervous system disorder, preferably associated with 5-hydroxytryptamine receptors and / or trace amine-associated receptors and / or dopamine receptors.

[0033] In a further preferred embodiment of the present invention, the 5-hydroxytryptamine receptor is preferably 5-HT 1A It is a receptor.

[0034] In a further preferred embodiment of the present invention, said trace amine associated receptor is preferably the TAAR1 receptor.

[0035] In a further preferred embodiment of the present invention, the neuropsychiatric disorder is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, transient psychotic disorder, shared psychotic disorder, psychotic disorder due to somatic illness, drug-induced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, irritable psychosis, Tourette's syndrome, organic or NOS psychosis, epilepsy, agitation, post-traumatic stress disorder, behavioral disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, movement disorder, Huntington's disease, dementia, affective The condition may be one or more of: anxiety disorder, affective psychosis, depression, major depressive disorder, dysthymia, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, dizziness, epilepsy, pain, neuropathic pain, sensitization with neuropathic pain, inflammatory pain, fibromyalgia, migraine, cognitive impairment, movement disorder, restless legs syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, medication-induced sleepiness side effect, insomnia, substance abuse dependency, addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesch-Nyharn disease, Wilson's disease, autism, Huntington's chorea and premenstrual dysphoria. DETAILED DESCRIPTION OF THE INVENTION

[0036] 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", "X is A, B and C" convey the same meaning, i.e., X may be any one or more of A, B and C.

[0037] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the phrase includes both the occurrence and non-occurrence of the event or circumstance. For example, "cycloalkyl optionally substituted with alkyl" means that the alkyl group may be present, but does not have to be present; the description includes cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

[0038] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers, diluents, or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism and promote absorption of the active ingredients, thereby exerting their biological activity.

[0039] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is safe and effective when used in the mammalian body and that possesses the expected biological activity.

[0040] As used herein, "polymorphism" or "polymorphic form" refers to a crystalline form that has the same chemical composition but differs in the spatial arrangement of the molecules, atoms, and / or ions that make up the crystal. Polymorphs have the same chemical composition but differ in packing and geometric arrangement, and may exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and similar properties. The relative stability of the two solid phases is altered based on the relationship between temperature and stability. This phenomenon of a compound existing in different lattice structures is called drug polymorphism.

[0041] Crystal structures equivalent to those disclosed or claimed herein may exhibit similar, but not identical, analytical properties within reasonable error based on testing 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 scope of the present invention without departing from the scope and spirit of the invention. Other embodiments of the present invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. Applicants intend the specification and examples to be considered illustrative, not limiting, in scope.

[0042] "X-ray powder diffraction pattern or XRPD" refers to the Bragg equation, 2d sinθ=nλ (where λ is the wavelength of the X-ray, λ=1.54056A, and the diffraction order n is any positive integer, typically the first diffraction order peak, n=1). The "2θ or 2θ angle" refers to the diffraction angle, where θ is the Bragg angle, measured in ° or degrees. When X-rays are incident on an atomic plane of a crystal or part of a crystalline sample with an interplanar spacing of d at a glancing angle θ (complement to the angle of incidence, also called the Bragg angle), the Bragg equation is satisfied and a set of X-ray powder diffraction patterns can be measured.

[0043] It is well known to those skilled in the art that XRPD may produce certain deviations and intensity variations due to the spread thickness of the sample, the detection method, conditions, and the instrument. The same sample of the same crystalline form usually has the same main XRPD characteristic peak, but operational errors may occur. When a person skilled in the art detects the same crystalline form sample obtained using the corresponding method with the same instrument and detection method, the error of the characteristic peak is usually within ±0.2°. However, depending on the technician and the instrument used, there may be some characteristic peaks with errors outside this range. If the error is within ±0.5° or ±0.3°, it is considered that they belong to the XRPD characteristic peaks of the same crystalline form. Therefore, as a specific example of the crystalline form of the present invention, its XRPD is as shown in the pattern, but if the deviation of the important characteristic peak displacement 2θ is within ±0.5°, ±0.3°, or ±0.2°, especially if it is around ±0.2°, all can be identified as the same crystalline form and all can be considered to be within the protection scope of the present invention.

[0044] Additionally, the absolute and relative intensities of the peaks shown in the aforementioned tables and figures may vary due to various factors, such as the effect of the selected orientation of the crystalline solid relative to the X-ray beam, the effect of coarse particles, the purity of the analyte, or the crystallinity of the sample. Peak positions may also shift with changes in sample height. Furthermore, when different wavelengths are used for measurement, different shift values ​​are obtained based on the Bragg equation (nλ=2d sinθ). These different XRPD patterns obtained using different wavelengths are also within the scope of the present invention.

[0045] "Crystal plane spacing or crystal plane spacing (d value)" refers to the selection of three non-parallel unit vectors a, b, and c connecting two adjacent lattice points in a space lattice, which divide the lattice into juxtaposed parallelepiped units, which are the crystal plane spacings. The space lattice is divided according to the connecting lines of the defined parallelepiped units, resulting in a series of rectilinear grids called space lattices or crystal lattices. Lattice and crystal lattices use geometric points and lines, respectively, to reflect the periodicity of the crystal structure, and different crystal planes have different spacings (i.e., the distance between two adjacent parallel crystal planes), measured in Å or angstroms.

[0046] "Relative intensity (I%)" is the ratio of the intensity of the other peaks to the intensity of the most intense peak among all diffraction peaks in an X-ray powder diffraction pattern (XRPD), where the intensity of the most intense peak is taken as 100%.

[0047] Differential scanning calorimetry (DSC) measures the transition temperatures at which a crystal absorbs or releases heat due to changes in crystal structure or melting. For the same crystalline form of the same compound, the thermal transition temperatures and melting points vary within approximately 5°C, usually within approximately 3°C, in consecutive analyses. When describing a compound with a specific DSC peak or melting point, the deviation is typically ±5°C from the DSC peak or melting point, essentially accounting for this temperature variation. DSC provides a complementary method for distinguishing between various crystalline forms. Different crystalline forms can be identified based on their distinct transition temperature characteristics. For mixtures, the DSC peak or melting point may vary over a wider range. Furthermore, because decomposition occurs during the melting process, the melting temperature is related to the heating rate.

[0048] Thermogravimetric analysis (TGA) is a common method for measuring the thermal stability of a compound. In the present invention, TGA can also be used to measure the hydration state of a compound, and the heating rate during the test process will have a certain effect on the pattern. The error of TGA can be within about ±0.5% by mass.

[0049] "Amorphous," "non-crystalline," or "non-crystalline form" refers to a substance formed when material particles (molecules, atoms, ions) are arranged in three-dimensional space without periodicity, resulting in a diffuse, peakless X-ray powder diffraction pattern. Amorphous / non-crystalline is a special physical form of solid matter whose locally ordered structural characteristics suggest it is closely related to crystalline matter.

[0050] "Equivalent" or its abbreviation "eq" refers to the equivalent amount of a base material (1 equivalent) required in a chemical reaction.

[0051] "Substantially as shown in the figure" 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 powder X-ray diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum are shown in the figure.

[0052] In the context of the present invention, the words "approximately" or "about," when used or regardless of their use, mean within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, as will be apparent to one skilled in the art, the term "approximately" or "about" means within an acceptable standard error of the mean. When a numerical value having a value of N is disclosed, any numerical values ​​having a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8% are all expressly disclosed, where "+ / -" means plus or minus.

[0053] "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., and in other embodiments, "room temperature" refers to a temperature between 18° C. and 25° C.

[0054] Beneficial effects The hydrochloride salt crystalline form of the compound of the present invention not only exhibits superior product performance parameters such as melting point, solubility, solution stability and solid state stability, but also exhibits clear advantages in bioavailability. [Brief explanation of the drawings]

[0055] [Figure 1] 1 is an XRPD chart of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethylamine hydrochloride crystalline form I. [Figure 2] 1 is a DSC chart of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethylamine hydrochloride crystalline form I. [Figure 3] 1 is a TGA chart of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethylamine hydrochloride crystalline form I. [Figure 4] 1 is an XRPD chart of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethylamine hydrochloride crystalline form II. [Figure 5] 1 is a DSC chart of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethylamine hydrochloride crystalline form II. [Figure 6] 1 is a TGA chart of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethylamine hydrochloride crystalline form II. [Figure 7] 1 is an XRPD chart of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethylamine hydrochloride crystalline form III. [Figure 8]1 is a DSC chart of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethylamine hydrochloride crystalline form III. [Figure 9] 1 is a TGA chart of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethylamine hydrochloride crystalline form III.

[0056] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to explain the present invention and are not intended to limit the scope of the present invention. Furthermore, after reading the teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and it should be understood that these equivalent forms are also within the scope defined by the claims attached to this application.

[0057] The following SEP-363856 of the present invention is prepared with reference to the method described in Example 129 of patent document PCT / US2010 / 058884 as shown below. [ka]

[0058] The following Comparative Example 1 of the present invention is prepared with reference to the method described in Example 89 of patent document PCT / US2010 / 058884, as shown below. [ka]

[0059] 1. Preparation of compounds Example 1. Preparation of 1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine (Compound 1) Synthesis scheme: [ka]

[0060] Step a: Synthesis of 1-(thiophen-2-yl)cyclopropionitrile A solution of 2-(thiophen-2-yl)acetonitrile (2.0 g, 16.24 mmol) in N,N-dimethylformamide (30 mL) was added with sodium hydride (60%, 1.6 g, 40.59 mmol) under ice bath and nitrogen protection. After 1 hour, 1,2-dibromoethane (4.0 g, 21.3 mmol) was slowly added. The reaction mixture was slowly warmed to room temperature and stirred overnight. After completion of the reaction, the reaction was quenched by adding water (300 mL) in an ice bath. The mixture was extracted with ethyl acetate (300 mL x 3). The extract was washed with water (200 mL x 3) and saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate) to obtain the desired product (1.5 g, 61.9% yield). 1 H NMR (300 MHz, CDCl3) δ 7.17 (dd, J = 5.1, 0.6 Hz, 1 H), 7.07 - 7.02 (m, 1 H), 6.95 - 6.89 (m, 1 H), 1.78 - 1.67 (m, 2 H), 1.47 - 1.37 (m, 2 H).

[0061] Step b: Synthesis of 1-(thiophen-2-yl)cyclopropanal Under ice bath and nitrogen protection, a solution of 1-(thiophen-2-yl)cyclopropionitrile (1.4 g, 9.38 mmol) in tetrahydrofuran (100 mL) was slowly added with a n-hexane solution of diisobutylaluminum hydride (1 M in hexane, 18.8 mL, 18.8 mmol) and stirred at room temperature for 3 hours. After completion of the reaction, water (300 mL) was added to quench the reaction in an ice bath, followed by extraction with ethyl acetate (300 mL x 3). The extract was washed with water (300 mL x 3) and saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate) to obtain the desired product (632.0 mg, 44.3% yield). 1 H NMR (300 MHz, CDCl3) δ 9.34 (s, 1 H), 7.27 - 7.20 (m, 1 H), 7.03 - 6.96 (m, 2 H), 1.73 - 1.64 (m, 2 H), 1.55 - 1.47 (m, 2 H).

[0062] Step c: Synthesis of (1-(thiophen-2-yl)cyclopropyl)methanol Under ice bath and nitrogen protection, a solution of 1-(thiophen-2-yl)cyclopropanal (632.0 mg, 4.15 mmol) in tetrahydrofuran (20 mL) was slowly added with a solution of lithium aluminum hydride (2.5 M in THF, 3.3 mL, 8.30 mmol) in tetrahydrofuran, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction was quenched by adding water (200 mL) in an ice bath, extracted with ethyl acetate (300 mL x 3), washed with water (300 mL x 3) and saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the desired product (570.0 mg, 89.0% yield). 1H NMR (300 MHz, CDCl3) δ 7.17- 7.11 (m, 1 H), 6.97 - 6.90 (m, 2 H), 3.68 (s, 2 H), 1.96 (s, 1 H), 1.06 - 0.89 (m, 4 H).

[0063] Step d: Synthesis of 1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine To a solution of (1-(thiophen-2-yl)cyclopropyl)methanol (250 mg, 1.62 mmol) in 2-methyltetrahydrofuran (5 mL), 2,2-dimethoxy-N-methylethylamine (386.0 mg, 3.24 mmol) and trifluoromethanesulfonic acid (0.8 mL) were added and stirred at 80 °C for 20 minutes. After completion of the reaction, the pH of the reaction solution was adjusted to 13 with 15% aqueous sodium hydroxide in an ice bath, then diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The extract was concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate) to obtain the desired product (7.3 mg, yield 2.2%). 1 H NMR (400 MHz, CD3OD) δ 7.21 (d, J = 5.2 Hz, 1 H), 6.89 (d, J = 5.2 Hz, 1 H), 5.11 (d, J = 8.8 Hz, 1 H), 3.99 (d, J = 11.6 Hz, 1 H), 3.68 (d, J = 11.2 Hz, 1 H), 3.60 (dd, J = 12.8, 2.4 Hz, 1 H), 3.32-3.25 (m, 1 H), 2.77 (s, 3 H), 1.16 - 0.85 (m, 4 H). LC-MS [M+H] + : 210.1.

[0064] Example 2 Preparation of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine (Compound A) [ka] The compound of Example 1 was resolved on a chiral chromatography column to give optical enantiomer 1 (compound A) and optical enantiomer 2 (compound B). Liquid chromatography method: Chromatography column: DAICEL CHIRALPAK IG column; Mobile phase A: supercritical CO2, Mobile phase B: methanol (containing 0.1% dimethylamine); Detection wavelength: 214 nm; Flow rate: 1.5 mL / min, Column temperature: 35°C; Background column pressure: 1800 psi. Mobile phase gradient:

[0065] JPEG2025532281000009.jpg42170

[0066] Optical Enantiomer 1 (Compound A): RT: 3.62 min; [α]D 29 = -59.1 (c 0.163, MeOH); LC-MS [M+H] + : 210.1. 1 H NMR (CDCl3, 600 MHz): δ 7.00 (d, J = 5.4 Hz, 1 H), 6.75 (d, J = 4.8 Hz, 1 H), 4.93 (dd, J = 9.0, 3.0 Hz, 1 H), 3.92 (dd, J = 11.4, 1.2 Hz, 1 H), 3.56 (d, J = 11.4 Hz, 1 H), 3.02 (dd, J = 12.6, 3.0 Hz, 1 H), 2.92 (dd, J = 12.6, 9 Hz, 1 H), 2.51 (s, 3 H), 1.05 - 0.90 (m, 4 H). Optical Enantiomer 2 (Compound B): RT: 3.23 min; [α]D 29 = 65.1 (c 0.175, MeOH); LC-MS [M+H] + : 210.1. 1H NMR (CDCl3, 600 MHz): δ 7.00 (d, J = 5.4 Hz, 1 H), 6.75 (d, J = 4.8 Hz, 1 H), 4.98 (dd, J = 9.0, 2.4 Hz, 1 H), 3.92 (d, J = 11.4 Hz, 1 H), 3.57 (d, J = 11.4 Hz, 1 H), 3.07 (dd, J = 12.6, 2.4 Hz, 1 H), 2.95 (dd, J = 12.0, 9.0 Hz, 1H), 2.54 (s, 3 H), 1.08 - 0.90 (m, 4 H).

[0067] 2. Biological testing of compounds Test Example 1: Test method for TAAR1 receptor cAMP agonists 1.1 Experimental materials: The cAMP detection kit was purchased from Cisbio. The HE3K293 cell line stably expressing the TAAR1 receptor was constructed by Shanghai Shujing Biotechnology Co., Ltd. IBMX was purchased from Sigma. Phenethylamine (PEA) and ProxiPlate 384-well plates were purchased from PerkinElmer. HBSS was purchased from Thermo Fisher Scientific. A PerkinElmer Envision 2105 multifunction microplate reader, an Agilent Bravo liquid workstation, and a Countstar BioTech cell counter were used.

[0068] 1.2 Experimental Method: (1) Preparation of experimental buffer: 5x stimulation buffer was diluted to 1x with ddH2O, and IBMX was added to a final concentration of 0.5 mM and mixed evenly for subsequent use. (2) Thaw the cryopreserved cells quickly in a 37°C water bath, wash the cell suspension with HBSS buffer, and then centrifuge at 200 × g to remove the cryopreservation solution. Resuspend the pellet in an appropriate amount of experimental buffer, take 20 μL, and count using a cell counter to obtain a cell count of 1.5 × 10 cells. 6 cells / mL. (3) Add 5 μL of cell suspension (1.5 × 10 cells per well) to a ProxiPlate-384 well plate. 4 cells) were added. (4) Test compounds were serially diluted with experimental buffer and 5 μL was transferred to the reaction plate using a Bravo. 5 μL of experimental buffer was added to the negative control wells, and 5 μL of PEA (final concentration 10 μL) was added to the positive control wells. -2 M). (5) Incubated at 37°C for 1 hour. (6) 10 μL of detection reagent was added to the reaction plate and incubated in the dark at room temperature for 1 hour. (7) Detection was performed using an Envision 2105 multifunction microplate reader. The excitation light was 340 nm, and the emission light was 620 nm and 665 nm. The 665 nm / 620 nm ratio for each test well was calculated. Activity % = (negative control ratio - compound ratio) / (negative control ratio - positive control ratio) x 100% EC of the compound 50 Values ​​were calculated using the four-parameter fitting model log(agonist) vs. response-variable slope(four parameters) in GraphPad Prism.

[0069] 1.3 Experimental results: According to the above scheme, the specific results of the test of the agonist activity of the compounds of the present invention against the TAAR1 receptor are shown in Table 2-1.

[0070] [Table 2-1]

[0071] 1.4 Experimental conclusions: The results of in vitro experiments show that Compound A of the present invention has an agonistic effect on the TAAR1 receptor.

[0072] Test Example 2, 5-HT 1A Testing methods for receptor cAMP agonists 2.1 Experimental materials: The cAMP detection kit was purchased from Cisbio, and 5-HT 1A HEK293 cell lines stably expressing the receptor were constructed by Shanghai Pivoting Biotechnology Co., Ltd. Serotonin, forskolin, and IBMX were purchased from Sigma, ProxiPlate 384-well plates were purchased from PerkinElmer, and HBSS was purchased from Thermo Fisher Scientific. A PerkinElmer Envision 2105 multifunction microplate reader, a Tecan D300e picoliter micropipetter, an Agilent Bravo liquid workstation, and a Countstar BioTech cell counter were used.

[0073] 2.2 Experimental Method: (1) Preparation of experimental buffer: 5x stimulation buffer was diluted to 1x with ddH2O, and IBMX was added to a final concentration of 0.5 mM and mixed evenly for subsequent use. (2) Digest the cultured cells with trypsin. After digestion, wash the cell suspension with HBSS buffer, centrifuge at 200 × g to remove the medium, resuspend the pellet in an appropriate amount of experimental buffer, take 20 μL, and count using a cell counter to obtain a cell count of 0.4 × 10 6 cells / mL. (3) Add 5 μL of cell suspension (2 × 10 cells per well) to a ProxiPlate-384 well plate. 3 cells) were added. (4) Test compounds were serially diluted with the experimental buffer, and 5 μL was transferred to the reaction plate using a Bravo. 5 μL of experimental buffer was added to the negative control wells, and 5 μL of serotonin (final concentration 10 μL) was added to the positive control wells. -6 M). (5) Incubate at room temperature for 15 minutes. (6) Using a Tecan D300e picoliter micropipette, add forskolin (final concentration 1.5 × 10 -7 M) was added to the reaction plate. (7) Incubated at room temperature for 45 minutes. (8) 10 μL of detection reagent was added to the reaction plate and incubated in the dark at room temperature for 1 hour. (9) Detection was performed using an Envision 2105 multifunction microplate reader. The excitation light was 340 nm, and the emission light was 620 nm and 665 nm. The 665 nm / 620 nm ratio for each test well was calculated. Activity % = (negative control ratio - compound ratio) / (negative control ratio - positive control ratio) x 100% EC of the compound 50 Values ​​were calculated using the four-parameter fitting model log(agonist) vs. response-variable slope(four parameters) in GraphPad Prism.

[0074] 2.3 Experimental results: According to the above scheme, 5-HT 1A Specific results of the compounds of the present invention in the receptor agonist activity test are shown in Table 2-2.

[0075] [Table 2-2]

[0076] 2.4 Experimental conclusions: In vitro experiments have shown that Compound A of the present invention inhibits 5-HT 1A These results indicate that the compounds of the present invention have an agonistic effect on the receptor, suggesting that the compounds of the present invention can improve negative symptoms and cognitive impairment.

[0077] Test Example 3: Inhibitory effect of the compound of the present invention on MK-801-induced hyperlocomotion in mice 3.1 Experimental materials: Test compounds: self-made compounds of the examples of the present invention. (+)-MK-801 hydrogen maleate (also known as (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate, dizocilpine): purchased from Sigma-Aldrich Company, catalog number: M107-50MG. Experimental animals: 18-22g male C57Bl / 6J mice, purchased from SHANGHAI SLAC LABORATORY ANIMAL CO. LTD.

[0078] 3.2 Experimental Method: 3.2.1 Grouping of animals: Before the start of the experiment, the animals were randomly grouped according to their body weight. 3.2.2 Animal acclimatization: Before the experiment, mice were first acclimatized to the experimental environment for at least 1 hour, i.e., they were transferred from the breeding room to the experimental room and allowed to move freely within their cages. 3.2.3 Medication Administration: Preparation of the drug: The test compound was taken, pure water was added, and the mixture was sonicated. The animals were randomly divided into blank, model, and drug-administered groups according to their body weight, with 9 animals per group. Detailed drug administration information is shown in the table below.

[0079] JPEG2025532281000012.jpg78170

[0080] T-30 min: Oral administration of compound: The test compound or solvent (pure water) was orally administered by force. Immediately after administration, the mice were placed in a test box (test box size: length x width x height = 27 x 27 x 40 cm), and their spontaneous movement was recorded for 30 minutes. T0 min: Intraperitoneal injection of modeling drug: 30 min after compound administration, the mice were removed and intraperitoneally injected with MK-801 (0.3 mg / kg). A blank control group was injected with saline. Immediately after MK-801 administration, the animals were returned to the test chamber and recording was continued for 150 min. 3.2.4 Data recording and analysis. The animal's movement (distance traveled in the test box) was automatically recorded by a camera and analyzed with the ANY MAZE software. 50 was calculated.

[0081] 3.3 Experimental results: As shown in Table 2-3.

[0082] [Table 2-3]

[0083] 3.4 Experimental conclusions: From the above scheme, it can be concluded that compound A of the present invention can significantly inhibit the high spontaneous locomotion induced by MK-801 in mice, and with increasing compound dose, the inhibitory effect gradually increases, with a good dose-dependence relationship.Furthermore, compared with SEP-363856, the minimum effective dose of compound A of the present invention is lower, and the inhibitory effect is stronger.

[0084] Test Example 4: Inhibitory effect of the compound of the present invention on PCP-induced hyperlocomotion in mice 4.1 Experimental materials: Test compounds: self-made compounds of the examples of the present invention. Phencyclidine hydrochloride (PCP): Purchased from Shanghai Yuansi Material Technology Co., Ltd., specifications: 5g. Experimental animals: 18-22g male C57Bl / 6J mice, purchased from SHANGHAI SLAC LABORATORY ANIMAL CO. LTD.

[0085] 4.2 Experimental Method: 4.2.1 Grouping of animals: Before the start of the experiment, the animals were randomly grouped according to body weight. 4.2.2 Animal acclimatization: Before the experiment, mice were first acclimatized to the experimental environment for at least 1 hour, i.e., they were transferred from the breeding room to the experimental room and allowed to move freely within their cages. 4.2.3 Medication Administration: Preparation of the drug: The test compound was taken, pure water was added, and the mixture was sonicated. The animals were randomly divided into blank, model, and drug-administered groups according to their body weight, with 9 animals per group. Detailed drug administration information is shown in the table below.

[0086] JPEG2025532281000014.jpg83170

[0087] T-30 min: Oral administration of compound: The compound of the present invention or the solvent (pure water) was orally administered by force. Immediately after administration, the mice were placed in a test box (test box size: length x width x height = 27 x 27 x 40 cm), and their spontaneous movement activity was recorded for 30 minutes. T0 min: Intraperitoneal injection of modeling drug: 30 min after compound administration, the mice were removed and intraperitoneally injected with PCP (5 mg / kg). A blank control group was injected with ultrapure water. Immediately after PCP administration, the animals were returned to the test chamber and recording was continued for 60 min. 4.2.4 Data recording and analysis. The animal's activity (distance traveled in the test box) was automatically recorded by a camera and analyzed with the ANY MAZE software. 50 was calculated.

[0088] 4.3 Experimental results: As shown in Table 2-4.

[0089] [Table 2-4]

[0090] 4.4 Experimental conclusions: From the above scheme, it can be concluded that compound A of the present invention can clearly inhibit the PCP-induced hyperactivity in mice, and as the compound dose increases, the inhibitory effect gradually increases, and there is a good dose-dependence relationship.Furthermore, compared with SEP-363856, the minimum effective dose of compound A of the present invention is lower, and the inhibitory effect is stronger.

[0091] 3. Research on the salt crystal forms of compounds The free base of Compound A is an oil, and since the oil is not useful for further development of a pharmaceutical product, an attempt was made to form a salt of Compound A in its free state and further study the salt crystalline form of Compound A.

[0092] JPEG2025532281000016.jpg214170

[0093] 1. Preparation of a salt crystalline form of Compound A 1.1 Preparation of Crystalline Form I of the Hydrochloride Salt of Compound A The free alkali compound A (130.7 mg, 0.63 mmol) prepared in Example 2 and ethyl acetate (2.0 mL) were added to a 25 mL round-bottom flask and stirred at room temperature until the mixture became clear. Then, a 2 M HCl-ethyl acetate solution (0.32 mL, 0.64 mmol) was added and stirred at room temperature for 3 hours. The mixture was then suction filtered and the solid material was blow-dried at 50° C. for 3 hours to obtain a white solid identified as the hydrochloride crystalline form I of compound A (93.2 mg). As a result of detection and analysis, it has the XRPD pattern shown in Figure 1, the DSC pattern shown in Figure 2, and the TGA pattern shown in Figure 3. Analysis of the combined DSC and TGA results showed that it is a non-solvated product.

[0094] 1.2 Preparation of Crystalline Form II of the Hydrochloride Salt of Compound A To a 25 mL round-bottom flask were added Compound A hydrochloride crystalline Form I (73 mg, 0.3 mmol) prepared in 1.1 above and ethanol (1.0 mL). The resulting suspension was heated to 80°C and refluxed with stirring for 1 hour, then naturally cooled to room temperature, suction filtered, and the solid material was blown dry at 50°C overnight to obtain a white solid identified as Compound A hydrochloride crystalline Form II (20 mg). As a result of detection and analysis, it has the XRPD pattern shown in Figure 4, the DSC pattern shown in Figure 5, and the TGA pattern shown in Figure 6. Analysis of the combined DSC and TGA results showed that it is a non-solvated product.

[0095] 1.3 Preparation of Crystalline Form III of the Hydrochloride Salt of Compound A In a 25 mL round-bottom flask, the free alkali compound A (102 mg, 0.49 mmol) prepared in Example 2 and ethyl acetate (2.0 mL) were added, and the mixture was stirred at room temperature to dissolve until clear. Then, 2 M HCl-ethyl acetate solution (0.25 mL, 0.5 mmol) was added, and the mixture was stirred for 30 minutes to react. Then, water (0.25 mL) was added, and the mixture was stirred at room temperature for 3 days. Then, the mixture was suction filtered, and the solid material was dried at room temperature for 3 hours. When the measured weight remained unchanged, a white solid was obtained, which was identified as the hydrochloride crystalline form III of compound A (45 mg). As a result of detection and analysis, it has the XRPD pattern shown in Figure 7, the DSC pattern shown in Figure 8, and the TGA pattern shown in Figure 9. When the DSC and TGA results were combined and analyzed, there was an obvious endothermic peak at around 84.92 °C, which corresponds to 6.73% crystal water, meaning that one molecule of water has been removed, indicating that it is a monohydrate.

[0096] 2. Solubility Experiment 2.1 Purpose of the experiment The equilibrium solubility of each crystalline form of the hydrochloride of Compound A in water was investigated for 24 hours.

[0097] 2.2 Experimental scheme Excess Compound A hydrochloride crystalline Form I and hydrochloride crystalline Form II samples were weighed and placed in separate 10 mL centrifuge tubes, each tube containing 1 mL of deionized water, sealed with a sealing film, shaken at 150 rpm on a thermostatic shaker at 37°C for 24 hours, and passed through a 0.45 μm organic filter, diluted, injected, and analyzed by HPLC. 2.2 Experimental Results: The solubility results are shown in Table 3.1 below.

[0098] [Table 3-1]

[0099] 2.4 Experimental Conclusions The data in the table show that the solubility of each crystalline form of Compound A in aqueous media after salt formation is significantly improved.

[0100] 3. Solution Stability Experiments 3.1 Purpose of the experiment The solution stability of each crystalline form of the hydrochloride salt of Compound A was investigated.

[0101] 3.2 Experimental scheme and results Hydrochloric acid, phosphoric acid, and sodium hydroxide were used to prepare solutions with pH values ​​of 1.0, 3.0, 5.0, and 7.0. Appropriate amounts of Compound A hydrochloride crystalline Form I and Form II were weighed and added to corresponding 20 mL volumetric flasks, labeled, and dissolved in different pH media. The solutions were then filled to volume, filtered through a 0.45 μm organic filter, and analyzed by HPLC. The changes in the content of the samples from 0 to 24 hours were monitored, and the results were calculated.

[0102] 3.3 Experimental results The hydrochloride crystalline Form I and Form II of Compound A showed good stability for 24 hours under different pH conditions (1.0, 3.0, 5.0, and 7.0).

[0103] 4. Solid Stability Experiments 4.1 Purpose of the experiment The chemical stability of each crystalline form of the hydrochloride salt of Compound A under conditions of high temperature, high humidity, and lighting was investigated.

[0104] 4.2 Experimental scheme: Appropriate amounts of Compound A hydrochloride crystalline Form I and Form II were weighed and placed in weighing dishes, respectively. Three samples of each salt were prepared and left open in a stability test box at 60°C, a drying dish at RH 92.5%, and a lighting condition of 5000lx for 85 days. All samples were mixed uniformly, sampled, dissolved in acetonitrile and water, and HPLC-related substance method was used to detect changes in content and impurities.

[0105] 4.3 Experimental Results: The chemical stability results are shown in Table 3.2 below.

[0106] [Table 3-2]

[0107] 4.4 Experimental Conclusions From the above data, it was found that Compound A hydrochloride crystalline Form I and Compound A hydrochloride crystalline Form II of the present invention show little increase in impurities even under high temperature, high humidity or lighting conditions and have good chemical stability.

[0108] 5. Pharmacokinetic Experiments 5.1 Purpose of the test The compound was orally administered to mice by force, and the blood concentrations of each crystalline form of Compound A hydrochloride in the mice were measured, and PK parameters were calculated to evaluate the pharmacokinetics.

[0109] 5.2 Test materials (1) Test samples: hydrochloride crystalline form I, crystalline form II, and crystalline form III (self-made) of Compound A of the present invention. (2) Experimental animals: ICR mice, SPF grade, male, Shanghai Slack Laboratory Animal Co., Ltd.

[0110] 5.3 Test Scheme The compounds were administered orally at a dose of 5 mg / kg by gavage. ICR mice were classified according to body weight and randomly divided into groups of three mice each. They were fasted overnight before the test. The drugs were administered at a set dose and time. At specific time points, 250 μL of blood was collected from the mandibular or saphenous vein of the mice by cross-bleeding into sample tubes containing the anticoagulant heparin sodium and placed in wet ice. The temperature was 4000 rpm. -1 The mixture was centrifuged at RT for 10 min at RT, and the plasma was separated and subjected to LC-MS analysis.

[0111] 5.4 Test Results and Analysis The measured blood drug concentration-time data was input into the Winnonlin 7.0 program to calculate the main pharmacokinetic parameters. The specific results are shown in Table 3.3 below.

[0112] [Table 3-3]

[0113] 5.5 Test Conclusion From the results of the pharmacokinetic experiments in mice shown in the table, each crystalline form of the hydrochloride salt of Compound A of the present invention is rapidly absorbed after administration, exhibits favorable metabolic properties, and exhibits high exposure AUC and maximum blood concentration C max It was found that it shows good performance in

Claims

1. The acid salt of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine, which is the hydrochloride salt.

2. 2. The acid salt according to claim 1, wherein the number of acids in the acid salt is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5, or 3, more preferably 0.5, 1, 2, or 3, and even more preferably 1.

3. The acid salt according to any one of claims 1 to 2, wherein the acid salt is an anhydrate or a hydrate, and when the acid salt is a hydrate, the number of water atoms is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5, or 3, more preferably 0.5, 1, 2, or 3, and even more preferably 1.

4. the acid salt is in a crystalline form, preferably hydrochloride crystalline form I, hydrochloride crystalline form II, or hydrochloride crystalline form III; The powder X-ray diffraction pattern of the hydrochloride crystalline form I has diffraction peaks at 2θ positions of 12.03±0.2°, 16.08±0.2°, and 26.84±0.2°, preferably 2θ positions of 12.03±0.2°, 16.08±0.2°, 18.52±0.2°, 25.31±0.2°, and 26.84±0.2°, more preferably 2θ positions of 12. Diffraction peaks at positions where 2θ is 6.22±0.2°, 12.03±0.2°, 16.08±0.2°, 18.52±0.2°, 20.94±0.2°, 22.06±0.2°, 23.10±0.2°, 24.72±0.2°, 25.31±0.2°, 26.84±0.2°, and 29.60±0.2°, and more preferably at positions where 2θ is 6.22±0.2°, 12.03±0.2°, 12.36±0.2°, 13.03±0.2°, 16.08±0.2°, 18.52±0.2°, 20.94±0.2°, 22.06±0.2°, 23.10±0.2°, 24.72±0.2°, 25.31±0.2°, 26.84±0.2°, and 29.60±0.2°. .2°, 16.08±0.2°, 18.25±0.2°, 18.52±0.2°, 19.48±0.2°, 20.24±0.2°, 20.94±0.2°, 21.18±0.2°, 22.06±0.2°, 23.10±0.2°, 23.54±0.2°, 24.72±0.2°, 25.31±0.2°, 26.84±0.2°, 27.07±0.2° , 27.77±0.2°, 28.49±0.2°, 29.60±0.2°, 31.05±0.2°, 31.78±0.2°, 32.45±0.2°, 32.79±0.2°, 37.15±0.2°, 39.10±0.2°, 42.73±0.2°, 43.97±0.2°, 44.36±0.2°, and 45.23±0.2°, The powder X-ray diffraction pattern of the hydrochloride crystalline form II exhibits diffraction peaks at 2θ positions of 13.36±0.2°, 17.25±0.2°, and 27.74±0.2°, preferably 10.30±0.2°, 13.36±0.2°, 17.25±0.2°, 22.77±0.2°, and 27.74±0.2°, more preferably 10. Diffraction peaks at positions 2θ of 8.55±0.2°, 9.96±0.2°, 10.30±0.2°, 13.36±0.2°, 15.17±0.2°, 17.25±0.2°, 22.77±0.2°, 24.95±0.2°, 25.28±0.2°, 25.87±0.2°, 27.74±0.2°, and 30.99±0.2°, and more preferably at positions 2θ of 8.55±0.2°, 9.96±0.2°, and 10.30±0.2°. 2°, 11.23±0.2°, 12.49±0.2°, 13.36±0.2°, 15.17±0.2°, 15.99±0.2°, 17.25±0.2°, 18.25±0.2°, 18.83±0.2°, 19.20±0.2°, 20.04±0.2°, 21.11±0.2°, 21.72±0.2°, 22.77±0.2°, 24.13±0.2°, The diffraction peaks are located at 24.95±0.2°, 25.28±0.2°, 25.87±0.2°, 26.39±0.2°, 27.11±0.2°, 27.74±0.2°, 28.57±0.2°, 29.23±0.2°, 30.99±0.2°, 32.26±0.2°, 34.85±0.2°, 38.72±0.2°, and 40.42±0.2°. The powder X-ray diffraction pattern of the hydrochloride crystalline Form III has diffraction peaks at 2θ positions of 8.86±0.2°, 17.71±0.2°, and 26.66±0.2°, preferably at 2θ positions of 8.86±0.2°, 13.28±0.2°, 17.71±0.2°, 19.07±0.2°, and 26.66±0.2°, more preferably at 2θ positions of 8.86±0.2°, 13.28±0.2°, 17.71±0.2°, 19.07±0.2°, and 26.66±0.2°. Diffraction peaks at 2θ positions of 8.86±0.2°, 10.50±0.2°, 12.99±0.2°, 13.28±0.2°, 15.75±0.2°, 16.22±0.2°, 17.71±0.2°, 19.07±0.2°, 22.75±0.2°, 23.70±0.2°, 26.66±0.2°, and 31.19±0.2°, and more preferably at 2θ positions of 8.86±0.2°, 10.50±0.2°, 12.99±0.2°, 13.28±0.2°, 15.75±0.2°, 1 6.22±0.2°, 17.71±0.2°, 19.07±0.2°, 20.52±0.2°, 21.01±0.2°, 22.75±0.2°, 23.19±0.2°, 23.70±0.2°, 24.16±0.2°, 24.43±0.2°, 24.91±0.2°, 25.34±0.2°, 25.70±0.2°, 26.09±0.2°, 26.66±0.2°, 27.19 4. The acid salt according to claim 1, wherein the acid salt comprises diffraction peaks at positions 29.06±0.2°, 31.01±0.2°, 31.19±0.2°, 31.41±0.2°, 31.67±0.2°, 32.07±0.2°, 32.98±0.2°, 33.40±0.2°, 36.77±0.2°, 44.77±0.2°, and 49.93±0.2°.

5. the acid salt is hydrochloride crystalline form I, hydrochloride crystalline form II, or hydrochloride crystalline form III; The powder X-ray diffraction pattern of the hydrochloride salt crystalline form I is substantially as shown in Figure 1; The powder X-ray diffraction pattern of the hydrochloride salt crystalline form II is substantially as shown in Figure 4; 5. The acid salt of any one of claims 1 to 4, wherein the X-ray powder diffraction pattern of the hydrochloride salt crystalline Form III is approximately as shown in Figure 7.

6. the acid salt is hydrochloride crystalline form I, hydrochloride crystalline form II, or hydrochloride crystalline form III; The hydrochloride crystalline form I has an endothermic peak at 248.07±5°C in a DSC pattern, preferably a DSC pattern shown in FIG. 2 or a TGA pattern shown in FIG. 3; The hydrochloride crystalline form II has an endothermic peak at 249.54±5°C in a DSC pattern, preferably a DSC pattern shown in FIG. 5 or a TGA pattern shown in FIG. 6; 6. The acid salt according to any one of claims 1 to 5, wherein the hydrochloride crystalline form III has endothermic peaks at 84.92±5°C and 245.23±5°C in a DSC pattern, preferably a DSC pattern shown in Figure 8 or a TGA pattern shown in Figure 9.

7. A method for preparing the acid salt of any one of claims 1 to 6, comprising the steps of: in particular, Step (1) of weighing an appropriate amount of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine, which is a free base of the compound, and dissolving it in solvent 1; Step (2) of weighing an appropriate amount of hydrochloric acid, preferably 0.5 to 2.0 equivalents, and dissolving it in solvent 2; The above two components are mixed and reacted by stirring at a predetermined temperature for a predetermined time, followed by suction filtration and drying to obtain the target product. Alternatively, the method includes a step (3) of mixing both of the above, stirring the mixture at a predetermined temperature for a predetermined time to cause a reaction, adding a solvent 3, stirring the mixture for a further predetermined time to cause a reaction, filtering the mixture by suction, and drying the mixture to obtain a target product; wherein Solvent 1, Solvent 2, and Solvent 3 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; and Solvent 1 and Solvent 2 must be compatible when used.

8. A method for preparing the acid salt of any one of claims 1 to 6, comprising the steps of: in particular, Step (1) of weighing an appropriate amount of compound hydrochloride and dissolving or suspending it in a solvent 4; and step (2) refluxing the clear solution or suspension of step (1) at a predetermined temperature for a predetermined time to cause reaction, cooling to room temperature, suction filtering, and drying to obtain the target product; the solvent 4 is selected from water, absolute methanol, absolute ethanol, 95% 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.

9. 10. A pharmaceutical composition comprising a therapeutically effective amount of an acid salt according to any one of claims 1 to 6 or a combination thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

10. Use of an acid salt according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 8 in the preparation of a medicament which may be a medicament for the prevention and / or treatment of a neuropsychiatric disorder in a mammal, preferably a central nervous system disorder associated with 5-hydroxytryptamine receptors and / or trace amine associated receptors and / or dopamine receptors.

11. The neuropsychiatric disease may be schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizophrenic personality disorder, delusional disorder, psychosis, psychotic disorder, transient psychotic disorder, shared psychotic disorder, psychotic disorder due to physical illness, drug-induced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, irritable psychosis, Tourette's syndrome, organic or NOS psychosis, epilepsy, agitation, post-traumatic stress disorder, behavioral disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, movement disorder, Huntington's disease, dementia, affective disorder, anxiety disorder, affective psychosis, depression, 11. The use according to claim 10, wherein the condition is one or more of major depressive disorder, dysthymia, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, dizziness, epilepsy, pain, neuropathic pain, sensitization associated with neuropathic pain, inflammatory pain, fibromyalgia, migraine, cognitive impairment, movement disorder, restless legs syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, medication-induced sleepiness side effect, insomnia, substance abuse dependency, addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesch-Nyharn disease, Wilson's disease, autism, Huntington's chorea and premenstrual dysphoria.

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