A salt containing a spiro derivative, a crystal form, and a preparation method and application thereof

Abstract

The present application relates to a kind of salt containing spiro derivative, crystal form and its preparation method and application.Specifically, the present application relates to the salt of compound (R) -1- (4' H, 6' H- spiro [cyclopropane-1, 7'-thieno [3, 2-c] pyran] -4'-yl) -N-methyl methylamine, crystal form and its preparation method and application and the pharmaceutical composition containing therapeutically effective amount of the salt of the compound, crystal form, and its use in the preparation of the drug for preventing and / or treating neuropsychiatric diseases.

Description

[0001] This application claims priority to Chinese Patent Application No. 2022111813611, filed on September 27, 2022. The entire contents of the aforementioned Chinese Patent Application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of drug synthesis technology, and specifically relates to a salt containing a spirocyclic derivative, its crystal form, preparation method, and application. Background Technology

[0003] Central nervous system disorders affect a wide range of people to varying degrees. Generally, these disorders are characterized by significant impairment in cognition or memory, and a marked deterioration in relatively primitive functional levels. Schizophrenia is a psychopathological disorder of unknown origin, typically first appearing in early adulthood, characterized by psychotic symptoms, progressive and developmental stages, and / or regression in social behavior and professional abilities. Symptoms of schizophrenia generally fall into three categories: positive symptoms, negative symptoms, and cognitive symptoms. Positive symptoms are those characterized by an "excessive" amount of normal experience, such as hallucinations and delusions. Negative symptoms are those characterized by a lack of normal experience, such as anhedonia and a lack of social interaction. Cognitive symptoms are associated with cognitive impairment in schizophrenia, such as a lack of sustained attention and impaired decision-making. Current antipsychotic medications are effective in treating positive symptoms, but are far from ideal for negative and cognitive symptoms.

[0004] Biogenic amines play important roles as neurotransmitters in the central and peripheral nervous systems. The synthesis and storage of biogenic amines, as well as their degradation and reabsorption after release, are tightly controlled. Imbalances in biogenic amine levels are known to be a major cause of brain function changes in many pathological conditions. Serotonin, norepinephrine, epinephrine, dopamine, and histamine, as classic biogenic amines, have been extensively studied. Among them, the serotonin system plays a crucial role in regulating the function of the prefrontal cortex (PFC), including emotion control, cognitive behavior, and working memory. PFC pyramidal neurons and GABA interneurons contain several serotonin receptor subtypes, 5-HT1A and 5-HT2A, with particularly high densities. Recently, it has been demonstrated that the PFC and NMDA receptor channels are targets of 5-HT1AR, both of which modulate excitatory neurons in the cerebral cortex, thereby affecting cognitive function. In fact, various preclinical data suggest that 5-HT1AR may be a novel target for antipsychotic drug development. The high affinity of atypical antipsychotics (such as olanzapine and aripiprazole) for 5-HT1AR and their low EPS side effects indicate that the serotonin system plays a crucial role in regulating PFC function, including mood control, cognitive behavior, and working memory. PFC pyramidal neurons and GABA interneurons contain several serotonin receptor subtypes, 5-HT1A and 5-HT2A, with particularly high density. Recent studies have shown that 5-HT1A agonists are associated with atypical antipsychotic treatment, improving negative symptoms and cognitive impairment.

[0005] In recent years, with the deepening research on classical biogenic amines, a second class of endogenous amine compounds, namely trace amines (TAs), has been discovered, including p-tyramine, β-phenylethylamine, tryptamine, and phenolethanolamine. Their levels in the mammalian nervous system are generally lower than those of classical biogenic amines, but they share similar characteristics with classical biogenic amines in terms of structure, metabolism, and subcellular localization. Trace amine-associated receptors (TAARs), as a new member of the G protein-coupled receptor (GPCR) family, have similar structures and pharmacological data to deep GPCR pharmacophores. Phylogenetic relationships of these receptor genes indicate that they form three distinct subfamilies, with TAAR1 being the first of four highly conserved genes (TAAR1-4) in humans and rodents. TAs activate TAAR1 through Gαs to exert their effects. Existing research shows that dysregulation of trace amine-associated receptors, particularly TAAR1, is closely linked to many psychiatric disorders such as schizophrenia and depression, as well as other conditions such as attention deficit hyperactivity disorder (ADHD), migraine, Parkinson's disease, substance abuse, and eating disorders. Therefore, TAAR ligands have high potential for treating these diseases.

[0006] Despite the availability of numerous medications for treating schizophrenia, a variety of adverse reactions persist in clinical use. Furthermore, while some antipsychotic drugs addressing negative symptoms have improved these symptoms in some patients, their overall effectiveness is limited. Many patients remain unable to fully recover and restore normal social functioning due to these negative symptoms, hindering their return to normal social work. Cognitive impairment is another key focus in schizophrenia treatment, affecting verbal memory, semantic processing, and attention in most patients. Currently available or marketed antipsychotic drugs offer limited improvement in cognitive function. Moreover, the treatment of treatment-resistant schizophrenia remains challenging. These patients have undergone treatment with three different antipsychotic drugs with varying active ingredients, receiving adequate dosage and duration, yet experiencing poor response or intolerance to the adverse effects of these drugs. Even with sufficient maintenance or preventative treatment, their condition may relapse or worsen. Therefore, developing effective treatments for treatment-resistant schizophrenia remains a significant challenge in clinical drug research and a direction that urgently needs to be addressed.

[0007] Currently, Sunovion's SEP-363856, which is in Phase III clinical trials, is a serotonin and / or trace amine-associated receptor agonist with significant activity against 5-HT1A and TAAR1 receptors, demonstrating good activity in existing clinical studies. Therefore, there is an urgent need to develop antipsychotic drugs that offer good and sustained efficacy in treating negative symptoms, improving patients' cognitive function, effectively treating treatment-resistant schizophrenia, and also have low adverse drug reactions and act on multiple targets to meet the huge market demand. Summary of the Invention

[0008] International patent application PCT / CN2022 / 083485 describes a series of structures containing spirocyclic derivatives. In subsequent research and development, in order to improve the solubility, stability, powder flow properties, pharmacokinetics and / or increase the bioavailability of the compounds, reduce storage costs, and extend the product cycle, this invention has conducted a comprehensive study on the acid salts and crystal forms of the above compounds.

[0009] All contents relating to international patent application PCT / CN2022 / 083485 are incorporated herein by reference.

[0010] The technical problem to be solved by the present invention is to provide a salt containing spirocyclic derivatives, its crystal form, preparation method and application.

[0011] The purpose of this invention is 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.

[0012] In a preferred embodiment of the present invention, the acid salt is a hydrochloride salt.

[0013] In a preferred embodiment of the present invention, the number of acids in the acid salt is 0.2-3, 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.

[0014] 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 the hydrochloride is 1:0.8-1.2.

[0015] In a further preferred embodiment of the present invention, the acid salt is a non-solvent or a solvate, wherein the solvent is selected from one or more of 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, trichloromethane, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene, or toluene.

[0016] In a further preferred embodiment of the present invention, the number of solvents is 0-3, preferably 0, 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0, 0.5, 1, 2 or 3.

[0017] In a further preferred embodiment of the present invention, the above-mentioned acid salt is preferably anhydrous or monohydrate.

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

[0019] In a further preferred embodiment of the present invention, the acid salt of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is hydrochloride crystal form I, hydrochloride crystal form II, or hydrochloride crystal form III, wherein:

[0020] The hydrochloride crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 12.03±0.2°, 16.08±0.2°, and 26.84±0.2°.

[0021] Preferably, it includes diffraction peaks located at 2θ of 12.03±0.2°, 16.08±0.2°, 18.52±0.2°, 25.31±0.2°, and 26.84±0.2°;

[0022] Preferably, it includes diffraction peaks located at 2θ 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°;

[0023] More preferably, the 2θ values ​​are 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°, and 25.31±0.2°. Diffraction peaks at 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°;

[0024] Further preferred, using Cu-Kα radiation, the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 1.

[0025] Table 1. XRPD diffraction data of the hydrochloride crystal form I of the compound.

[0026]

[0027]

[0028] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form I of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is essentially as follows:Figure 1 As shown; its DSC spectrum is basically as follows Figure 2 As shown; its TGA spectrum is basically as follows. Figure 3 As shown.

[0029] Hydrochloride crystal form II, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 13.36±0.2°, 17.25±0.2°, and 27.74±0.2°.

[0030] Preferably, it includes diffraction peaks located at 2θ of 10.30±0.2°, 13.36±0.2°, 17.25±0.2°, 22.77±0.2°, and 27.74±0.2°;

[0031] Preferably, it includes diffraction peaks located at 2θ 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°;

[0032] More preferably, the 2θ values ​​are 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°, and 21.72±0.2°. Diffraction peaks at 2°, 22.77±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°;

[0033] Further preferred, using Cu-Kα radiation, the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 2.

[0034] Table 2. XRPD diffraction data of the hydrochloride crystal form II of the compound.

[0035]

[0036] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form II of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is essentially as follows: Figure 4 As shown; its DSC spectrum is basically as follows Figure 5 As shown; its TGA spectrum is basically as follows. Figure 6 As shown.

[0037] Hydrochloride crystal form III, with one acid, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 8.86±0.2°, 17.71±0.2°, and 26.66±0.2°.

[0038] Preferably, it includes diffraction peaks located at 2θ of 8.86±0.2°, 13.28±0.2°, 17.71±0.2°, 19.07±0.2°, and 26.66±0.2°;

[0039] Preferably, the diffraction peaks include those located at 2θ 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°.

[0040] More preferably, the 2θ values ​​are 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°, and 24.91±0.2°. Diffraction peaks at 2°, 25.34±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°;

[0041] Further preferred, using Cu-Kα radiation, the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 3.

[0042] Table 3. XRPD diffraction data of the hydrochloride crystal form III of the compound.

[0043]

[0044] More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form III of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine is essentially as follows: Figure 7 As shown; its DSC spectrum is basically as follows Figure 8 As shown; its TGA spectrum is basically as follows. Figure 9 As shown.

[0045] On the other hand, the present invention also relates to a method for preparing the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamino acid salt, specifically comprising the following steps:

[0046] (1) Weigh an appropriate amount of the free base of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine and dissolve it in solvent 1;

[0047] (2) Weigh an appropriate amount of hydrochloric acid and dissolve it in solvent 2; the amount of hydrochloric acid is preferably 0.5-2.0 equivalents;

[0048] (3) Mix the two above, stir and react at a certain temperature for a certain time, filter and dry to obtain the target product;

[0049] or,

[0050] (1) Weigh an appropriate amount of the free base of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine and dissolve it in solvent 1;

[0051] (2) Weigh an appropriate amount of hydrochloric acid and dissolve it in solvent 2; the amount of hydrochloric acid is preferably 0.5-2.0 equivalents;

[0052] (3) Mix the two above, stir and react at a certain temperature for a certain time, add solvent 3 and continue stirring and reacting for a certain time, filter and dry to obtain the target product;

[0053] in:

[0054] The reaction temperature is determined based on the solvent in the system, and is preferably room temperature.

[0055] 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, trichloromethane, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene, or toluene; wherein Solvent 1 and Solvent 2 must be miscible when used.

[0056] On the other hand, the present invention also relates to a method for preparing the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamino acid salt, specifically comprising the following steps:

[0057] (1) Weigh an appropriate amount of the compound hydrochloride salt and dissolve or suspend it in solvent 4;

[0058] (2) Reflux the clear solution or suspension from step (1) at a certain temperature for a certain time, cool it to room temperature, filter it, and dry it to obtain the target product.

[0059] in:

[0060] The reflux temperature is generally slightly higher than the boiling point of solvent 4, preferably 70-90°C, more preferably 75-85°C, and even more preferably 80°C;

[0061] The solvent 4 is selected from water, anhydrous methanol, anhydrous 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.

[0062] The present invention further relates to a pharmaceutical composition comprising an acid salt or combination thereof of any of the compounds shown in a therapeutically effective dose, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0063] The present invention further relates to the use of any of the shown compounds, acid salts, or pharmaceutical compositions thereof, in the preparation of pharmaceuticals.

[0064] In a further preferred embodiment of the present invention, the drug may be a drug for the prevention and / or treatment of neuropsychiatric diseases in mammals.

[0065] In a further preferred embodiment of the present invention, the neuropsychiatric disease is preferably a central nervous system disease related to 5-hydroxytryptamine receptors and / or trace amine-related receptors and / or dopamine receptors.

[0066] In a further preferred embodiment of the present invention, the 5-hydroxytryptamine receptor is preferably 5-HT. 1A Receptors.

[0067] In a further preferred embodiment of the present invention, the trace amine-associated receptor is preferably the TAAR1 receptor.

[0068] In a further preferred embodiment of the present invention, the neuropsychiatric diseases include schizophrenia, schizophrenia spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizophrenia-like personality disorder, schizotypal personality disorder, paranoid personality disorder, psychosis, mental disorder, short-term mental disorder, sharing mental disorder, mental disorder caused by physical illness, drug-induced psychosis, psychotic disorders, aggressiveness, mental confusion, Parkinson's psychosis, irritative psychosis, Tourette syndrome, organ or NOS psychosis, epilepsy, agitation, post-traumatic stress disorder, behavioral disorder, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, movement disorders, Huntington's disease, dementia, affective disorders, anxiety disorders, and so on. Sensitive psychosis, depression, major depressive disorder, mood disorder, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, epilepsy, pain, neuropathic pain, neuropathic pain predisposition, inflammatory pain, fibromyalgia, migraine, cognitive impairment, movement disorder, restless limb syndrome, multiple sclerosis, sleep disorder, sleep apnea, hypersomnia, excessive daytime sleepiness, jet lag, drowsiness as a side effect of medication, insomnia, substance abuse dependence, addiction, eating disorder, sexual dysfunction, hypertension, vomiting, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's disease, and premenstrual anxiety.

[0069] Detailed description of the invention

[0070] The different terms "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.

[0071] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted cycloalkyl" means that alkyl may but does not have to be present, and the description includes cases where cycloalkyl is substituted with alkyl and cases where cycloalkyl is not substituted with alkyl.

[0072] "Pharmaceutical composition" refers to a mixture containing one or more compounds described in this invention, or their physiologically / pharmaceutical acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmaceutical acceptable carriers, diluents, or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0073] "Pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, which is safe and effective when used in mammals and has the intended biological activity.

[0074] The term "polymorph" or "polymorphic compound" as used in this article refers to a crystal form with the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions constituting 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 similar properties. The relative stability between the two solid phases is interchanged based on their temperature-stability relationship. This phenomenon of compounds existing in different lattice structures is called pharmaceutical polymorphism.

[0075] Crystal structures disclosed or claimed in this invention may exhibit similar but not identical analytical properties within a reasonable margin of error, depending on experimental conditions, purity, equipment, and other commonly used 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 and spirit of this invention without departing from its scope. Other embodiments of the invention will be apparent to those skilled in the art based on consideration of the specification and practice of the invention disclosed herein. The applicant expects this specification and examples to be considered exemplary and not limiting of its scope.

[0076] "X-ray powder diffraction pattern or XRPD" refers to the pattern obtained according to Bragg's formula 2d sinθ=nλ (where λ is the wavelength of the X-ray). The diffraction order n can be any positive integer, generally taking the first-order diffraction peak (n=1). The "2θ or 2θ angle" mentioned refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree. When X-rays are incident at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle) onto an atomic plane of a crystal or a partial crystal sample with a lattice spacing of d, the Bragg equation is satisfied, thus allowing the measurement of this set of X-ray powder diffraction patterns.

[0077] As is known to those skilled in the art, XRPD may exhibit certain displacement and intensity deviations due to sample tiling thickness, detection methods, conditions, and instruments. Samples of the same crystal form typically possess the same major XRPD characteristic peaks, but operational errors may exist. When samples of the same crystal form obtained by those skilled in the art using appropriate methods are detected using the same instruments and methods, the characteristic peak error is usually within ±0.2°. However, different technicians using different instruments may occasionally encounter a few characteristic peaks with errors exceeding this range. Errors within ±0.5° or ±0.3° should be considered as XRPD characteristic peaks of the same crystal form. Therefore, as a specific example of the crystal form of this invention, its XRPD is shown in spectrum X. However, those skilled in the art understand that when the 2θ displacement deviation of the key characteristic peak is within ±0.5°, ±0.3°, or ±0.2°, especially around ±0.2°, it can be considered as the same crystal form and can be interpreted as within the scope of protection of this invention.

[0078] 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 effect of the selective orientation of the crystalline solid on the X-ray beam, the influence of coarse particles, the purity of the analyzed substance, or the degree of crystallinity of the sample. Additionally, the peak positions may shift depending on variations in sample height. Moreover, if different wavelengths are used for measurement, different shift values ​​are obtained according to the Bragg formula (nλ = 2dsinθ), and these different XRPD patterns obtained by using different wavelengths are also within the scope of this invention.

[0079] "Interplanar spacing or interplanar spacing (d-value)" refers to the division of a space lattice into juxtaposed parallelepiped units by three non-parallel unit vectors a, b, and c, which connect adjacent points. The space lattice is then divided according to these defined parallelepiped unit vectors, resulting in a linear grid called a space lattice or crystal lattice. Lattice and crystal lattice represent the periodicity of crystal structure using geometric points and lines, respectively. Different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes); the unit is 1 / d. Or E.

[0080] "Relative intensity (I%)" refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak when the intensity of the first strongest peak in an X-ray powder diffraction pattern (XRPD) is 100%.

[0081] Differential scanning calorimetry (DSC) determines the transition temperatures of a crystal when it absorbs or releases heat due to changes in its crystal structure or melting. For the same crystal form of the same compound, the error in thermal transition temperature and melting point can be within about 5°C, typically within about 3°C, in consecutive analyses. When describing a compound as having a given DSC peak or melting point, this refers to ±5°C of that DSC peak or melting point, essentially taking this temperature variation into account. DSC provides an auxiliary method for distinguishing different crystal forms. Different crystal forms can be identified based on their different transition temperature characteristics. It should be noted that for mixtures, their DSC peaks or melting points may vary over a wider range. Furthermore, since decomposition occurs during the melting process, the melting temperature is related to the heating rate.

[0082] Thermogravimetric analysis (TGA) is a common method for determining the thermal stability of compounds. In this invention, TGA can also be used to determine the hydration state of compounds. 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.

[0083] "Amorphous," "amorphous form," or "amorphous structure" refers to matter formed when the particles (molecules, atoms, ions) are arranged non-periodically in three-dimensional space. Its characteristic feature is a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous / amorphous is a special physical form of solid matter, and its locally ordered structural features suggest a close connection with crystalline substances.

[0084] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalence relationship of a chemical reaction, using the basic raw materials used in each step as a reference (1 equivalent).

[0085] "Basically 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 X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum are shown in the figure.

[0086] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard error range of the average. Whenever a number with a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" means addition or subtraction.

[0087] "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.

[0088] Beneficial effects

[0089] The hydrochloride crystal form of the compound of the present invention not only exhibits excellent performance parameters in terms of melting point, solubility, solution stability and solid stability, but also shows significant advantages in terms of bioavailability. Attached Figure Description

[0090] Figure 1 XRPD illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form I.

[0091] Figure 2 DSC illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form I.

[0092] Figure 3 TGA illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form I.

[0093] Figure 4 XRPD illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form II.

[0094] Figure 5 DSC illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form II.

[0095] Figure 6 TGA illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form II.

[0096] Figure 7 XRPD illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form III.

[0097] Figure 8 DSC illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form III.

[0098] Figure 9 TGA illustration of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form III. Detailed Implementation

[0099] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0100] The present invention, SEP-363856, is shown below and was prepared according to the method of Example 129 in patent document PCT / US2010 / 058884.

[0101]

[0102] The following Comparative Example 1 of the present invention is shown below, prepared according to the method of Example 89 in Patent Document PCT / US2010 / 058884.

[0103]

[0104] I. Preparation of Compounds

[0105] Example 1: Preparation of 1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine (compound 1)

[0106] Synthesis route:

[0107]

[0108] Step a: Synthesis of 1-(thien-2-yl)cyclopropane nitrile

[0109] Under nitrogen protection and in an ice bath, sodium hydride (60%, 1.6 g, 40.59 mmol) was added to a solution of 2-(thiophene-2-yl)acetonitrile (2.0 g, 16.24 mmol) in N,N-dimethylformamide (30 mL), and the mixture was stirred for 1 hour. Then, 1,2-dibromoethane (4.0 g, 21.3 mmol) was slowly added, and the reaction mixture was slowly brought to room temperature and stirred overnight. After the reaction was complete, the reaction was quenched with water (300 mL) in an ice bath, and 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, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate) to obtain the target product (1.5 g, 61.9% yield).

[0110] 1 H NMR (300MHz, CDCl3) δ7.17 (dd, J = 5.1, 0.6Hz, 1H), 7.07-7.02 (m, 1H), 6.95-6.89 (m, 1H), 1.78-1.67 (m, 2H), 1.47-1.37 (m, 2H).

[0111] Step b: Synthesis of 1-(thiophen-2-yl)cyclopropanealdehyde

[0112] Under nitrogen protection and in an ice bath, diisobutylaluminum hydride (1M in hexane, 18.8mL, 18.8mmol) was slowly added dropwise to a tetrahydrofuran (100mL) solution of 1-(thiophene-2-yl)cyclopropanenitrile (1.4g, 9.38mmol), and the mixture was stirred for 3 hours at room temperature. After the reaction was complete, the reaction was quenched with water (300mL) in an ice bath, and the mixture was extracted with ethyl acetate (300mL x 3). The extract was washed with water (300mL x 3) and saturated brine (300mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate) to obtain the target product (632.0mg, 44.3% yield).

[0113] 1 H NMR (300MHz, CDCl3) δ9.34(s,1H),7.27-7.20(m,1H),7.03-6.96(m,2H),1.73-1.64(m,2H),1.55-1.47(m,2H).

[0114] Step c: Synthesis of (1-(thien-2-yl)cyclopropyl)methanol

[0115] Under nitrogen protection, a tetrahydrofuran solution of lithium aluminum hydride (2.5 M in THF, 3.3 mL, 8.30 mmol) was slowly added dropwise to a tetrahydrofuran solution of 1-(thiophene-2-yl)cyclopropanealdehyde (632.0 mg, 4.15 mmol) (20 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with water (200 mL) under ice bath conditions. The mixture was extracted with ethyl acetate (300 mL x 3), and the extract was washed with water (300 mL x 3) and saturated brine (300 mL x 3). After drying with anhydrous sodium sulfate, the extract was filtered and concentrated. The crude product was purified by column chromatography to obtain the target product (570.0 mg, 89.0% yield).

[0116] 1 H NMR (300MHz, CDCl3) δ7.17-7.11(m,1H),6.97-6.90(m,2H),3.68(s,2H),1.96(s,1H),1.06-0.89(m,4H).

[0117] Step d: Synthesis of 1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine

[0118] To a solution of (1-(thiophene-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 the mixture was stirred at 80 °C for 20 min. After the reaction was complete, the pH of the reaction solution was adjusted to 13 with 15% sodium hydroxide aqueous solution in an ice bath. Then, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL x 3). The crude product obtained after concentrating the extract was purified by column chromatography (petroleum ether / ethyl acetate) to obtain the target product (7.3 mg, 2.2% yield).

[0119] 1 H NMR (400MHz, CD3OD) δ7.21(d,J=5.2Hz,1H),6.89(d,J=5.2Hz,1H),5.11(d,J=8.8Hz,1H),3.99(d,J=11.6Hz, 1H),3.68(d,J=11.2Hz,1H),3.60(dd,J=12.8,2.4Hz,1H),3.32-3.25(m,1H),2.77(s,3H),1.16-0.85(m,4H).

[0120] LC-MS[M+H] +:210.1.

[0121] 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)

[0122]

[0123] The compound from Example 1 was separated by a chiral column to obtain optical enantiomer 1 (compound A) and optical enantiomer 2 (compound B). Liquid chromatography method: 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:

[0124]

[0125] Optical enantiomer 1 (compound A):

[0126] RT: 3.62 min; [α]D 29 =-59.1(c 0.163,MeOH); LC-MS[M+H] + :210.1.

[0127] 1 H NMR (CDCl3, 600MHz): δ7.00 (d, J = 5.4Hz, 1H), 6.75 (d, J = 4.8Hz, 1H), 4.93 (dd, J = 9.0, 3.0Hz, 1H), 3.92 (dd, J = 11.4, 1.2H z,1H),3.56(d,J=11.4Hz,1H),3.02(dd,J=12.6,3.0Hz,1H),2.92(dd,J=12.6,9Hz,1H),2.51(s,3H),1.05-0.90(m,4H).

[0128] Optical enantiomer 2 (compound B):

[0129] RT: 3.23 min; [α]D 29 =65.1(c 0.175,MeOH); LC-MS[M+H] + :210.1.

[0130] 1H NMR (CDCl3, 600MHz): δ7.00 (d, J = 5.4Hz, 1H), 6.75 (d, J = 4.8Hz, 1H), 4.98 (dd, J = 9.0, 2.4Hz, 1H), 3.92 (d, J = 11.4Hz, 1H ), 3.57 (d, J = 11.4Hz, 1H), 3.07 (dd, J = 12.6, 2.4Hz, 1H), 2.95 (dd, J = 12.0, 9.0Hz, 1H), 2.54 (s, 3H), 1.08-0.90 (m, 4H).

[0131] II. Compound Biological Testing

[0132] Test Example 1: TAAR1 receptor cAMP agonist assay method

[0133] 1.1 Experimental Materials:

[0134] cAMP assay 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-Aldrich; Phenethylamine (PEA); ProxiPlate-384-well plates were purchased from PerkinElmer; HBSS was purchased from Thermo Fisher Scientific. The equipment used included a PerkinElmer Envision 2105 multi-functional microplate reader, an Agilent Bravo liquid workstation, and a Countstar BioTech cell counter.

[0135] 1.2 Experimental Methods:

[0136] (1) Preparation of experimental buffer: Dilute 5×stimulation buffer to 1× with ddH2O, add IBMX to a final concentration of 0.5mM, mix well and set aside.

[0137] (2) Thaw the frozen cells rapidly in a 37°C water bath. Wash the cell suspension with HBSS buffer, centrifuge at 200×g to remove the cryopreservation solution, resuspend the pellet in an appropriate amount of experimental buffer, take 20 μL and count the cells using a cell counter, then dilute to 1.5×10⁻⁶. 6 per mL.

[0138] (3) Add 5 μL of cell suspension (1.5 × 10⁶ cells per well) to each ProxiPlate-38 4-well plate. 4 (cells).

[0139] (4) The test compound was serially diluted in experimental buffer, and 5 μL was transferred to the reaction plate using Bravo. 5 μL of experimental buffer was placed in the negative control well, and 5 μL of PEA (final concentration 10) was placed in the positive control well. -2 M).

[0140] (5) Incubate at 37℃ for 1 hour.

[0141] (6) Add 10 μL of the detection reagent to the reaction plate and incubate at room temperature in the dark for 1 hour.

[0142] (7) The Envision 2105 multi-mode microplate reader was used for detection. The excitation light was 340 nm, and the emission light was 620 nm and 665 nm. The ratio of 665 nm to 620 nm for each test well was calculated.

[0143] Activation rate (Activity%) = (Negative control ratio - Compound ratio) / (Negative control ratio - Positive control ratio) × 100%

[0144] The EC50 of the compound was calculated using the four-parameter fitting model log(agonist) vs. response--Variableslope(four parameters) in GraphPad Prism. 50 value.

[0145] 1.3 Experimental Results:

[0146] The specific results of the compounds of the present invention in the TAAR1 receptor agonist activity test obtained through the above scheme are shown in Table 2-1.

[0147] Table 2-1 Results of the agonistic activity of the compounds of the present invention on the TAAR1 receptor

[0148]

[0149] 1.4 Experimental Conclusions:

[0150] In vitro experimental results show that compound A of the present invention has an agonist effect on the TAAR1 receptor.

[0151] Test Example 2, 5-HT 1A Receptor cAMP agonist assay

[0152] 2.1 Experimental Materials:

[0153] cAMP assay kit purchased from CisBio; 5-HT stably expressed 1AThe HEK293 cell line for the recipient was constructed by Shanghai Shujing Biotechnology Co., Ltd.; Serotonin, Forskolin, and IBMX were purchased from Sigma-Aldrich; ProxiPlate-384-well plates were purchased from PerkinElmer; and HBSS was purchased from Thermo Fisher Scientific. The equipment used included a PerkinElmer Envision 2105 multi-mode microplate reader, a Tecan D300e skin-level microdispensing system, an Agilent Bravo liquid workstation, and a Countstar BioTech cell counter.

[0154] 2.2 Experimental Methods:

[0155] (1) Preparation of experimental buffer: Dilute 5×stimulation buffer to 1× with ddH2O, add IBMX to a final concentration of 0.5mM, mix well and set aside.

[0156] (2) Cultured cells were digested with trypsin. After digestion was terminated, the cell suspension was washed with HBSS buffer, centrifuged at 200×g to remove the culture medium, and the pellet was resuspended with an appropriate amount of experimental buffer. 20 μL of the pellet was used for cell counting and diluted to 0.4×10⁻⁶. 6 per mL.

[0157] (3) Add 5 μL of cell suspension to each ProxiPlate-38 4-well plate (2 × 10⁶ cells per well). 3 (cells).

[0158] (4) The test compound was serially diluted in experimental buffer, and 5 μL was transferred to the reaction plate using Bravo. 5 μL of experimental buffer was placed in the negative control well, and 5 μL of Serotonin (final concentration 10) was placed in the positive control well. -6 M).

[0159] (5) Incubate at room temperature for 15 minutes.

[0160] (6) Add Forskolin (final concentration 1.5 × 10⁻⁶) to the reaction plate using the Tecan D300e pill-lift micro-volume dosing system. -7 M).

[0161] (7) Incubate at room temperature for 45 minutes.

[0162] (8) Add 10 μL of the detection reagent to the reaction plate and incubate at room temperature in the dark for 1 hour.

[0163] (9) Detection was performed using an Envision 2105 multi-mode microplate reader. Excitation light was set at 340 nm, and emission light at 620 nm and 665 nm. The ratio of 665 nm to 620 nm was calculated for each test well.

[0164] Activation rate (Activity%) = (Negative control ratio - Compound ratio) / (Negative control ratio - Positive control ratio) × 100%

[0165] The EC50 of the compound was calculated using the four-parameter fitting model log(agonist) vs. response--Variableslope(four parameters) in GraphPad Prism. 50 value.

[0166] 2.3 Experimental Results:

[0167] The above methods demonstrate that the compound of the present invention is effective against 5-HT. 1A The specific results of the receptor agonist activity assay are shown in Table 2-2.

[0168] Table 2-2 Effects of the compounds of the present invention on 5-HT 1A Results of receptor agonistic activity

[0169]

[0170] 2.4 Experimental Conclusions:

[0171] In vitro experimental results show that compound A of the present invention has an effect on 5-HT 1A The receptors have agonistic effects, suggesting that the compounds of this invention can improve negative symptoms and cognitive impairment.

[0172] Test Example 3: Inhibition of MK-801-induced high spontaneous activity in mice by the compound of the present invention.

[0173] 3.1 Experimental Materials:

[0174] Test compound: The compound used in the embodiments of this invention was prepared in-house.

[0175] (+)-MK-801 maleate: purchased from Sigma-Aldrich, product number: M107-50MG.

[0176] Laboratory animals: 18-22g male C57Bl / 6J mice, purchased from Shanghai Slack Laboratory Animal Co., Ltd.

[0177] 3.2 Experimental Methods:

[0178] 3.2.1 Animal grouping: Before the experiment, the animals were randomly grouped according to their weight.

[0179] 3.2.2 Animal Adaptation: Before the experiment, the mice were acclimatized to the experimental environment for at least 1 hour. That is, the animals were transferred from the feeding room to the laboratory and allowed to move freely in their cages.

[0180] 3.2.3 Administration:

[0181] Drug preparation: Take the test compound, add pure water and sonicate.

[0182] After being grouped by body weight, the animals were randomly divided into a control group, a model group, and a drug-treated group, with 9 animals per group. Detailed drug treatment information is shown in the table below:

[0183]

[0184] T-30min Oral Administration of Compound: The test compound or solvent (pure water) was administered orally or by gavage. Immediately after administration, the mice were placed in a test chamber (test chamber dimensions: length × width × height = 27 × 27 × 40 cm), and spontaneous activity of the mice was recorded within 30 minutes.

[0185] T0min Modeling Drug Intraperitoneal Injection: 30 minutes after compound administration, mice were removed and administered MK-801 (0.3 mg / kg) via intraperitoneal injection. The blank control group was injected with physiological saline. After MK-801 administration, the animals were immediately returned to the test chamber, and the test continued for 150 minutes.

[0186] 3.2.4 Data Recording and Analysis. The animal's activities (distance traveled within the test chamber) will be automatically recorded using a camera and analyzed using ANY MAZE software to calculate ED. 50 .

[0187] 3.3 Experimental results: as shown in Table 2-3.

[0188] Table 2-3 Experimental results of the inhibitory effect of the compounds of the present invention on MK-801-induced high spontaneous activity in mice.

[0189]

[0190] Note: ED 50 The effective dose is half the effective dose, and MED is the minimum effective dose.

[0191] 3.4 Experimental Conclusions:

[0192] The above methods demonstrate that compound A of the present invention can significantly inhibit MK-801-induced high spontaneous activity in mice, and the inhibitory effect gradually increases with increasing compound dosage, exhibiting a strong dose-dependent relationship. Furthermore, compared to SEP-363856, compound A of the present invention has a lower minimum effective dose and a stronger inhibitory effect.

[0193] Test Example 4: Inhibition of PCP-induced high spontaneous activity in mice by the compound of this invention.

[0194] 4.1 Experimental Materials:

[0195] Test compound: The compound used in the embodiments of this invention was prepared in-house.

[0196] Phenylexin (PCP) hydrochloride: purchased from Shanghai Yuansi Biotechnology Co., Ltd., specification: 5g.

[0197] Laboratory animals: 18-22g male C57Bl / 6J mice, purchased from Shanghai Slack Laboratory Animal Co., Ltd.

[0198] 4.2 Experimental Methods:

[0199] 4.2.1 Animal grouping: Before the experiment, the animals were randomly grouped according to their weight.

[0200] 4.2.2 Animal Adaptation: Before the experiment, the mice were acclimatized to the experimental environment for at least 1 hour. That is, the animals were transferred from the feeding room to the laboratory and allowed to move freely in their cages.

[0201] 4.2.3 Administration:

[0202] Drug preparation: Take the test compound, add pure water and sonicate.

[0203] After being grouped by body weight, the animals were randomly divided into a control group, a model group, and a drug-treated group, with 9 animals per group. Detailed drug treatment information is shown in the table below:

[0204]

[0205] T-30min Compound Oral Administration: The compound of this invention or the solvent (pure water) was administered orally or by gavage. Immediately after administration, the mice were placed in a test chamber (test chamber dimensions: length × width × height = 27 × 27 × 40 cm), and the spontaneous activity of the mice was recorded within 30 minutes.

[0206] T0min Intraperitoneal Injection of Modeling Drug: 30 minutes after compound administration, mice were removed and administered PCP (5 mg / kg) via intraperitoneal injection. The blank control group was injected with ultrapure water. After PCP administration, the animals were immediately returned to the test chamber, and the test continued for 60 minutes.

[0207] 4.2.4 Data Recording and Analysis. The animal's activities (distance traveled within the test chamber) will be automatically recorded using a camera and analyzed using ANY MAZE software to calculate the ED. 50 .

[0208] 4.3 Experimental Results: As shown in Table 2-4

[0209] Table 2-4 Results of the inhibitory effects of the compounds of this invention on PCP-induced high spontaneous activity in mice.

[0210]

[0211] Note: ED 50 The effective dose is half the effective dose, and MED is the minimum effective dose.

[0212] 4.4 Experimental Conclusions:

[0213] The above methods demonstrate that compound A of the present invention can significantly inhibit PCP-induced hypersporadic activity in mice, and the inhibitory effect gradually increases with increasing compound dosage, exhibiting a strong dose-dependent relationship. Furthermore, compared to SEP-363856, compound A of the present invention has a lower minimum effective dose and a stronger inhibitory effect.

[0214] III. Study on the salt crystal form of the compound

[0215] The free base of compound A is an oily substance. Since the oily substance is not conducive to further drug development, we attempted to form a salt from the free state of compound A and further studied the salt crystal form of compound A.

[0216] Experimental apparatus:

[0217]

[0218]

[0219] 1. Preparation of the crystal form of compound A salt

[0220] 1.1 Preparation of Compound A Hydrochloride Crystal Form I

[0221] In a 25 mL round-bottom flask, add the free base compound A (130.7 mg, 0.63 mmol) prepared in Example 2 and ethyl acetate (2.0 mL), stir at room temperature until dissolved, then add 2 M HCl-ethyl acetate solution (0.32 mL, 0.64 mmol), stir at room temperature for 3 hours, filter, and dry the solid at 50 °C for 3 hours to obtain a white solid, which was identified as compound A hydrochloride crystal form I (93.2 mg).

[0222] After testing and analysis, it has the following properties: Figure 1 The XRPD diagram shown is as follows: Figure 2 The DSC diagram shown and as follows Figure 3 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0223] 1.2 Preparation of Compound A Hydrochloride Crystal Form II

[0224] Add 73 mg, 0.3 mmol of compound A hydrochloride crystal form I prepared in 1.1 above and 1.0 mL of ethanol to a 25 mL round-bottom flask. Heat the suspension to 80 °C and stir under reflux for 1 hour. Then cool naturally to room temperature, filter, and dry the solid at 50 °C overnight to obtain a white solid, which was identified as compound A hydrochloride crystal form II (20 mg).

[0225] After testing and analysis, it has the following properties: Figure 4 The XRPD diagram shown is as follows: Figure 5 The DSC diagram shown and as follows Figure 6 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0226] 1.3 Preparation of Compound A Hydrochloride Crystal Form III

[0227] In a 25 mL round-bottom flask, add the free base compound A (102 mg, 0.49 mmol) prepared in Example 2 and ethyl acetate (2.0 mL). Stir at room temperature until dissolved. Then add 2 M HCl-ethyl acetate solution (0.25 mL, 0.5 mmol). After stirring for half an hour, add water (0.25 mL). Continue stirring at room temperature for 3 days. Then filter and dry the solid at room temperature for 3 hours. The weight of the solid no longer changes, and a white solid is obtained. It is identified as compound A hydrochloride crystal form III (45 mg).

[0228] After testing and analysis, it has the following properties: Figure 7 The XRPD diagram shown is as follows: Figure 8 The DSC diagram shown and as follows Figure 9 The TGA graph shown is analyzed in conjunction with the DSC and TGA results. A significant endothermic peak is observed near 84.92℃, corresponding to 6.73% water of crystallization, indicating the loss of one molecule of water, thus classifying it as a monohydrate.

[0229] 2. Solubility Experiment

[0230] 2.1 Experimental Objective:

[0231] The equilibrium solubility of each crystal form of compound A hydrochloride in water over 24 hours was investigated.

[0232] 2.2 Experimental Scheme:

[0233] Excess amounts of compound A hydrochloride crystal form I and hydrochloride crystal form II samples 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 samples were shaken at 37 °C and 150 rpm for 24 h on a constant temperature shaker. After passing the samples through a 0.45 μm organic filter, the samples were diluted and injected for HPLC analysis.

[0234] 2.2 Experimental Results: The solubility results are shown in Table 3.1 below:

[0235] Table 3.1 Equilibrium solubility of various crystal forms of compound A hydrochloride in water after 24 h

[0236]

[0237] 2.4 Experimental Conclusions:

[0238] The data in the table show that the solubility of different crystal forms of compound A in aqueous medium is significantly improved after salt formation.

[0239] 3. Solution stability experiment

[0240] 3.1 Experimental Objective:

[0241] The solution stability of different crystal forms of compound A hydrochloride was investigated.

[0242] 3.2 Experimental Design and Results:

[0243] Solutions with pH values ​​of 1.0, 3.0, 5.0, and 7.0 were prepared using hydrochloric acid, phosphoric acid, and sodium hydroxide. Appropriate amounts of compound A hydrochloride crystal form I and hydrochloride crystal form II were weighed and added to corresponding 20 mL volumetric flasks, labeled, dissolved, and diluted to volume using different pH media. The solutions were then filtered through a 0.45 μm organic filter and analyzed by HPLC. The changes in the concentration of the compounds were monitored from 0 to 24 h, and the results were calculated.

[0244] 3.3 Experimental Results:

[0245] Compound A hydrochloride crystal form I and hydrochloride crystal form II both exhibited good stability for 24 hours under different pH conditions (1.0, 3.0, 5.0 and 7.0).

[0246] 4. Solid stability test

[0247] 4.1 Experimental Objective:

[0248] The chemical stability of different crystal forms of compound A hydrochloride under high temperature, high humidity and light conditions was investigated.

[0249] 4.2 Experimental Procedure:

[0250] Weigh appropriate amounts of compound A hydrochloride crystal form I and hydrochloride crystal form II, and place them separately in weighing dishes. Prepare three samples for each salt, and place them separately in an open oven at 60℃, a desiccator at RH 92.5%, and a stability test chamber under 5000 lx light conditions for 85 days. After mixing all samples thoroughly at 0, 10, 20, and 85 days, take samples, dissolve them in acetonitrile and water, and detect the content and impurity changes by HPLC related substances method.

[0251] 4.3 Experimental Results: The chemical stability results are shown in Table 3.2 below:

[0252] Table 3.2 Chemical stability results of various crystal forms of compound A hydrochloride

[0253]

[0254] 4.4 Experimental Conclusions:

[0255] The above data show that the impurity content of Compound A hydrochloride crystal form I and Compound A hydrochloride crystal form II of the present invention increases less under high temperature, high humidity or light conditions, and have good chemical stability.

[0256] 5. Pharmacokinetic experiments

[0257] 5.1 Experimental Objective:

[0258] Mice were administered the compound A hydrochloride orally via gavage, and the blood concentrations of each crystal form of the compound A hydrochloride were measured. PK parameters were calculated, and the pharmacokinetic profile was evaluated.

[0259] 5.2 Test Materials:

[0260] (1) Test samples: Compound A hydrochloride of the present invention, crystal form I, crystal form II and crystal form III, were prepared in-house.

[0261] (2) Experimental animals: ICR mice, SPF grade, male, Shanghai Slack Laboratory Animal Co., Ltd.

[0262] 5.3 Test Procedure:

[0263] The compound was administered orally via gavage at a dose of 5 mg / kg. ICR mice were stratified by body weight and randomly divided into groups of three mice each. Mice were fasted overnight before the experiment. The compound was administered at the prescribed dose and time. At fixed time points, 250 μL of blood was collected from the mandibular vein or saphenous vein of the mice using a cross-collection method and placed in sample tubes containing the anticoagulant sodium heparin. The tubes were then incubated on wet ice at 4000 rpm. -1 Centrifuge for 10 min, separate the plasma and perform LC-MS analysis.

[0264] 5.4 Experimental Results and Analysis:

[0265] The measured blood drug concentration-time data were substituted into the Winnonlin 7.0 program to calculate the main pharmacokinetic parameters. The specific results are shown in Table 3.3 below.

[0266] Table 3.3 Results of mouse pharmacokinetics experiment

[0267]

[0268] 5.5 Experimental Conclusions:

[0269] As can be seen from the pharmacokinetic results in mice, different crystal forms of compound A hydrochloride of this invention are rapidly absorbed after administration, exhibiting good metabolic properties, and the exposure AUC and maximum plasma concentration C are low. max They all performed well.

Claims

1. Acid salt of the compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethanamine, characterized in that, The acid salt is a hydrochloride salt.

2. Acid salt according to claim 1, characterized in that, The acid in the acid salt is present in an amount of 0.2 to 3.

3. The acid salt of claim 1, wherein, The acid in the acid salt is present in an amount of 0.2, 0.5, 1, 1.5, 2, 2.5 or 3.

4. The acid salt of claim 1, wherein, The acid in the acid salt is present in an amount of 0.5, 1, 2 or 3.

5. The acid salt of claim 1, wherein, The acid in the acid salt is present in an amount of 1.

6. Acid salt according to any one of claims 1 to 5, characterized in that, The acid salt is an anhydrate or a hydrate, and when the acid salt is a hydrate, the water is present in an amount of 1.

7. The acid salt of any one of claims 1-3, wherein, The acid salt is a crystalline form.

8. The acid salt of claim 7, wherein, The acid salt is a hydrochloride salt Form I, wherein: The X-ray powder diffraction pattern of the hydrochloride salt Form I comprises diffraction peaks at 2-theta values of 12.03±0.2°, 16.08±0.2°, 18.52±0.2°, 25.31±0.2°, 26.84±0.2°.

9. The acid salt of claim 8, wherein, The X-ray powder diffraction pattern of the hydrochloride salt Form I comprises diffraction peaks at 2-theta values 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°, 29.60±0.2°.

10. The acid salt of claim 8, wherein, The X-ray powder diffraction pattern of the hydrochloride salt Form I comprises diffraction peaks at 2-theta values of 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°, 26.84±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°, 45.23±0.2°.

11. Acid salt according to any one of claims 8-10, characterized in that, The X-ray powder diffraction pattern of the hydrochloride salt Form I is substantially as shown in Figure 1.

12. Acid salt according to any one of claims 8-10, characterized in that, The DSC pattern of the hydrochloride salt Form I has an endothermic peak at 248.07±5°C.

13. Acid salt according to any one of claims 8-10, characterized in that, The hydrochloride salt Form I has a DSC pattern as shown in Figure 2, or a TGA pattern as shown in Figure 3.

14. The acid salt of claim 7, wherein, The acid salt is a hydrochloride salt Form II, wherein: The X-ray powder diffraction pattern of the hydrochloride salt Form II comprises diffraction peaks at 2-theta values of 10.30±0.2°, 13.36±0.2°, 17.25±0.2°, 22.77±0.2°, 27.74±0.2°.

15. The acid salt of claim 14, wherein, The X-ray powder diffraction pattern of the hydrochloride salt Form II comprises diffraction peaks at 2-theta values 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°, 30.99±0.2°.

16. The acid salt of claim 14, wherein, The X-ray powder diffraction pattern of the hydrochloride salt Form II comprises diffraction peaks at 2-theta values of 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°, 22.77±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°, 40.42±0.2°.

17. The acid salt of any one of claims 14-16, wherein, The X-ray powder diffraction pattern of the hydrochloride salt Form II is substantially as shown in Figure 4.

18. The acid salt of any one of claims 14-16, wherein, The DSC pattern of the hydrochloride salt Form II has an endothermic peak at 249.54±5°C.

19. The acid salt of any one of claims 14-16, wherein, The hydrochloride salt Form II has a DSC pattern as shown in Figure 5, or a TGA pattern as shown in Figure 6.

20. The acid salt of claim 7, wherein, The acid salt is a hydrochloride salt Form III, wherein: The X-ray powder diffraction pattern of the hydrochloride salt Form III comprises diffraction peaks at 2-theta values of 8.86±0.2°, 13.28±0.2°, 17.71±0.2°, 19.07±0.2°, 26.66±0.2°.

21. The acid salt of claim 20, wherein, The X-ray powder diffraction pattern of the hydrochloride salt Form III comprises diffraction peaks at 2-theta values 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°, 31.19±0.2°.

22. The acid salt of claim 20, wherein, The X-ray powder diffraction pattern of the hydrochloride salt crystal form III comprises diffraction peaks at 2-theta 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°, 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±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°, 49.93±0.2°.

23. The acid salt of any one of claims 20-22, wherein, The X-ray powder diffraction pattern of the hydrochloride salt crystal form III is substantially as shown in Figure 7.

24. The acid salt of any one of claims 20-22, wherein, The DSC pattern of the hydrochloride salt crystal form III has endothermic peaks at 84.92±5℃ and 245.23±5℃.

25. The acid salt of any one of claims 20-22, wherein, The hydrochloride salt crystal form III has a DSC pattern as shown in Figure 8, or a TGA pattern as shown in Figure 9.

26. A process for the preparation of the acid salt of claim 1, characterized in that, Specifically comprising the following steps: (1) weigh an appropriate amount of compound free base (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethanamine, dissolve with solvent 1; (2) weigh an appropriate amount of hydrochloric acid, dissolve with solvent 2; (3) mix the above two, stir at a certain temperature for a certain time, suction filter, dry to obtain the target product; or mix the above two, stir at a certain temperature for a certain time, add solvent 3 to continue stirring for a certain time, suction filter, dry to obtain the target product; wherein: The solvent 1, solvent 2 and solvent 3 are each independently selected from water, methanol, ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutyl alcohol, tert-butyl alcohol, 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, trichloromethane, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene or toluene; wherein the solvent 1 and the solvent 2 need to be mutually soluble when used.

27. The method of claim 26, wherein the acid salt is formed by, The amount of hydrochloric acid is 0.5-2.0 equivalents.

28. A process for the preparation of the acid salt of claim 1, characterized in that, Specifically comprising the following steps: (1) weigh an appropriate amount of compound hydrochloride salt, dissolve or suspend with solvent 4; (2) refluxing the clear solution or suspension of step (1) at a certain temperature for a certain time, cooling to room temperature, suction filtration, and drying to obtain the target product; wherein: The solvent 4 is selected from water, anhydrous methanol, anhydrous 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, trichloromethane, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene, or toluene.

29. A pharmaceutical composition comprising a therapeutically effective amount of the acid salt as claimed in any one of claims 1-25 or a combination thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

30. Use of the acid salt as claimed in any one of claims 1-25 or the pharmaceutical composition of claim 29 in the manufacture of a medicament, which can be a medicament for preventing and / or treating a neuropsychiatric disorder in a mammal.

31. Use according to claim 30, characterized in that, The neuropsychiatric disorder is a central nervous system disorder associated with serotonin receptors and / or trace amine associated receptors and / or dopamine receptors.

32. The use according to claim 30, characterized in that, The neuropsychiatric disorder is one or more of schizophrenia spectrum disorders, psychoses, psychotic disorders, aggression, confusion, Tourette's syndrome, epilepsy, mania, conduct disorder, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, movement disorders, Huntington's disease, dementia, anxiety, depression, mood disorders, mania, attention deficit disorders, attention deficit hyperactivity disorder, obsessive-compulsive disorders, dizziness, pain, cognitive impairment, restless leg syndrome, multiple sclerosis, sleep disorders, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, drowsy side effects of drugs, insomnia, substance abuse dependency, addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesche-Nyhane disease, Wilson's disease, and autism.

33. Use according to claim 32, characterized in that, The schizophrenia spectrum disorder is schizophrenia; the psychosis is drug-induced psychosis, Parkinson's psychosis, stimulant-induced psychosis, organ- or NOS psychosis, or affective psychosis; the psychotic disorder is schizoid personality disorder, schizotypal personality disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, post-traumatic stress disorder, mood disorder, or bipolar disorder; the pain is neuropathic pain, inflammatory pain, fibromyalgia, or migraine; the depression is major depressive disorder; and the anxiety is premenstrual anxiety.

34. Use according to claim 33, characterized in that, The schizophrenia is acute schizophrenia, chronic schizophrenia, or NOS schizophrenia; the affective psychosis is seasonal affective psychosis; the mood disorder is psychological mood disorder; and the neuropathic pain is neuropathic pain susceptibility.

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