Salt containing spiro derivative, crystal form and preparation method and application of salt and crystal form

Abstract

The invention relates to a salt containing spiro derivatives, a crystal form and a preparation method and application of the salt and the crystal form. In particular, the invention relates to a salt and a crystal form of a compound (R)-1-(4 'H, 6' H-spiro [cyclopropane-1, 7 '-thieno [3, 2-c] pyran]-4'-yl)-N-methylmethylamine, a preparation method and application of the salt and the crystal form, a pharmaceutical composition containing a therapeutically effective amount of the salt and the crystal form of the compound, and application of the pharmaceutical composition in preparation of drugs for preventing and / or treating neuropsychiatric diseases.

Description

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

[0001] This application claims the benefit of Chinese patent application No. 2022111813611 filed on September 27, 2022. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention belongs to the technical field of drug synthesis, and particularly relates to a salt containing a spirocyclic derivative, a crystal form, and a preparation method and application thereof. Background Art

[0003] Diseases of the central nervous system affect a wide range of people to varying degrees. Generally speaking, the main features of such diseases include significant impairment of cognition or memory, and a marked deterioration from the original level of functioning. Schizophrenia is a psychopathological disorder of unknown origin that usually first appears in early adulthood and is characterized by psychotic symptoms, stage progression and development, and / or deterioration in social behavior and professional abilities. The symptoms of schizophrenia are generally manifested in three categories: positive symptoms, negative symptoms, and cognitive symptoms. Positive symptoms are symptoms that represent an "excess" of normal experiences, such as hallucinations and delusions. Negative symptoms are symptoms that represent a lack of normal experiences, such as lack of pleasure and social interaction. Cognitive symptoms are related to the cognitive impairment of schizophrenia, such as lack of sustained attention and poor decision-making ability. Current antipsychotic drugs can successfully treat positive symptoms, but are far from ideal for treating 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 primary cause of altered brain function 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 functions in the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. Pyramidal neurons and GABA interneurons in the PFC contain several serotonin receptor subtypes, 5-HT1A and 5-HT2A, with particularly high densities. Recently, it has been demonstrated that PFC and NMDA receptor channels are targets of 5-HT1A receptors, which regulate excitatory neurons in the cerebral cortex, thereby influencing cognitive function. Indeed, various preclinical data suggest that the 5-HT1A receptor may be a novel target for antipsychotic drug development. The high affinity of atypical antipsychotics (e.g., olanzapine, aripiprazole) for 5-HT1A receptors and their low EPS side effects suggest that the serotonin system plays a crucial role in regulating PFC functions, including mood control, cognitive behavior, and working memory. PFC pyramidal neurons and GABA interneurons contain several serotonin receptor subtypes with particularly high densities, including 5-HT1A and 5-HT2A. Recent studies have demonstrated that 5-HT1A agonists are associated with atypical antipsychotic treatment and can improve negative symptoms and cognitive impairment.

[0005] In recent years, as research on the classic biogenic amines has deepened, a second class of endogenous amine compounds, the trace amines (TAs), has been discovered. These include p-tyramine, β-phenylethylamine, tryptamine, and octopamine. While their levels in the mammalian nervous system are generally lower than those of the classic biogenic amines, they share similar structural, metabolic, and subcellular localization characteristics. Trace amine-associated receptors (TAARs), a new member of the G protein-coupled receptor (GPCR) family, share structural similarities with the GPCR pharmacophore and pharmacological data consistent with those of the GPCRs. The phylogenetic relationships of these receptor genes indicate that they form three distinct subfamilies, with TAAR1 being the first of four genes (TAAR1-4) that are highly conserved between humans and rodents. TAARs activate TAAR1 through Gαs to exert their effects. Existing studies have shown that dysregulation of trace amine-associated receptors, particularly TAAR1, is closely linked to numerous psychiatric disorders such as schizophrenia and depression, as well as other conditions such as attention deficit hyperactivity disorder, migraine, Parkinson's disease, substance abuse, and eating disorders. Therefore, TAAR ligands have high potential for treating these conditions.

[0006] Despite the availability of numerous medications for the treatment of schizophrenia, currently used schizophrenia medications still present a wide range of adverse reactions. Furthermore, while current antipsychotic drugs for the negative symptoms of schizophrenia have been used clinically and have improved negative symptoms in some patients, their overall effectiveness is limited. Many patients are still unable to recover and restore normal social function due to negative symptoms, making it difficult for them to resume normal social work. Furthermore, the treatment of cognitive impairment is currently a key focus of schizophrenia treatment, affecting verbal memory, semantic processing, and attention in most schizophrenia patients. However, currently developed or marketed antipsychotic drugs have very limited effects on cognitive function. Furthermore, the treatment of refractory schizophrenia remains a difficult problem. These patients have already received adequate doses and courses of treatment with three different antipsychotic drugs, but have not responded well to treatment or are unable to tolerate the adverse effects of antipsychotic drugs. Furthermore, even with adequate maintenance or preventive treatment, their condition relapses or worsens. Therefore, the development of drugs for the treatment of refractory schizophrenia remains a challenge in current clinical drug research and a direction that needs to be addressed urgently.

[0007] Currently in Phase III clinical trials, Sunovion's SEP-363856, a serotonin and / or trace amine-related receptor agonist, exhibits significant effects on 5-HT1A and TAAR1 receptors and has demonstrated promising activity in existing clinical studies. Therefore, there is an urgent need to develop antipsychotic drugs that demonstrate robust and sustained negative symptom treatment efficacy, improve cognitive function, and effectively treat refractory schizophrenia. Furthermore, these drugs must have a low adverse reaction profile and act on multiple targets to meet the enormous market demand.

[0008] Summary of the Invention

[0009] International patent application PCT / CN2022 / 083485 describes the structures of a series of spirocyclic derivatives. In subsequent research and development, in order to improve the solubility, stability, powder flow properties, pharmacokinetics and / or enhance the bioavailability of the compounds, reduce storage costs, and extend the product cycle, the present invention has conducted a comprehensive study of the acid salts and crystalline forms of the above-mentioned compounds.

[0010] All contents involved in international patent application PCT / CN2022 / 083485 are added to the present invention by reference.

[0011] The technical problem to be solved by the present invention is to provide a salt containing a spiro derivative, a crystal form, and a preparation method and application thereof.

[0012] The object of the present 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-methylmethanamine.

[0013] In a preferred embodiment of the present invention, the acid salt is hydrochloride.

[0014] 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 further preferably 1.

[0015] 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-methylmethanamine to the hydrochloride is 1:0.8-1.2.

[0016] In a further preferred embodiment of the present invention, the acid salt is a non-solvate 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, chloroform, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene or toluene.

[0017] In a further preferred embodiment of the present invention, the number of the above 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.

[0018] In a further preferred embodiment of the present invention, the acid salt is preferably an anhydrate or a monohydrate.

[0019] In a further preferred embodiment of the present invention, the acid salt is in crystalline or amorphous form.

[0020] 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-methylmethanamine is hydrochloride crystalline form I, hydrochloride crystalline form II or hydrochloride crystalline form III, wherein:

[0021] Hydrochloride Form I, the number of acids is 1, and its X-ray powder diffraction pattern includes diffraction peaks located at 2θ of 12.03±0.2°, 16.08±0.2°, and 26.84±0.2°;

[0022] Preferably, it comprises diffraction peaks at 2θ of 12.03±0.2°, 16.08±0.2°, 18.52±0.2°, 25.31±0.2°, and 26.84±0.2°;

[0023] Preferably, it comprises 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°;

[0024] More preferably, the range of the 2θ values ​​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°. 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°;

[0025] More preferably, Cu-Kα radiation is used, and the X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are as shown in Table 1.

[0026] Table 1 XRPD diffraction data of hydrochloride salt form I of the compound

[0027] More preferably, the X-ray powder diffraction pattern of the hydrochloride form I of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethanamine is substantially as shown in Figure 1; its DSC pattern is substantially as shown in Figure 2; and its TGA pattern is substantially as shown in Figure 3.

[0028] Hydrochloride Form II, the number of acids is 1, and its X-ray powder diffraction pattern includes diffraction peaks located at 2θ of 13.36±0.2°, 17.25±0.2°, and 27.74±0.2°;

[0029] Preferably, it comprises diffraction peaks at 2θ of 10.30±0.2°, 13.36±0.2°, 17.25±0.2°, 22.77±0.2°, and 27.74±0.2°;

[0030] Preferably, it comprises 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°;

[0031] More preferably, the range of the 2θ values ​​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°. 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°;

[0032] More preferably, Cu-Kα radiation is used, and the X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are as shown in Table 2.

[0033] Table 2 XRPD diffraction data of hydrochloride crystal form II of the compound

[0034] More preferably, the X-ray powder diffraction pattern of the hydrochloride form II of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethanamine is substantially as shown in Figure 4; its DSC pattern is substantially as shown in Figure 5; and its TGA pattern is substantially as shown in Figure 6.

[0035] Hydrochloride Form III, the number of acids is 1, and its X-ray powder diffraction pattern includes diffraction peaks at 2θ of 8.86±0.2°, 17.71±0.2°, and 26.66±0.2°;

[0036] Preferably, it comprises diffraction peaks at 2θ of 8.86±0.2°, 13.28±0.2°, 17.71±0.2°, 19.07±0.2°, and 26.66±0.2°;

[0037] Preferably, it comprises diffraction peaks 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°;

[0038] More preferably, the range of the 2θ values ​​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°. 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°;

[0039] More preferably, Cu-Kα radiation is used, and the X-ray diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are as shown in Table 3.

[0040] Table 3 XRPD diffraction data of hydrochloride salt form III of the compound

[0041] More preferably, the X-ray powder diffraction pattern of the hydrochloride form III of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethanamine is substantially as shown in Figure 7; its DSC pattern is substantially as shown in Figure 8; and its TGA pattern is substantially as shown in Figure 9.

[0042] 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-methylcarbamate acid salt, which specifically comprises the following steps:

[0043] (1) Weigh an appropriate amount of the compound free base (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethanamine and dissolve it in solvent 1;

[0044] (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;

[0045] (3) Mix the above two, stir and react at a certain temperature for a certain time, filter and dry to obtain the target product;

[0046] or,

[0047] (1) Weigh an appropriate amount of the compound free base (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethanamine and dissolve it in solvent 1;

[0048] (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;

[0049] (3) Mix the above two, 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;

[0050] in:

[0051] The reaction temperature is determined according to the system solvent, preferably room temperature;

[0052] 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, 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; wherein solvent 1 and solvent 2 need to be miscible when used.

[0053] 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-methylcarbamate acid salt, which specifically comprises the following steps:

[0054] (1) Weigh an appropriate amount of compound hydrochloride and dissolve or suspend it in solvent 4;

[0055] (2) reflux the clarified solution or suspension of step (1) at a certain temperature for a certain time, cool to room temperature, filter, and dry to obtain the target product;

[0056] in:

[0057] The reflux temperature is generally slightly higher than the boiling point of solvent 4, preferably 70-90°C, more preferably 75-85°C, and further preferably 80°C;

[0058] 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.

[0059] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any one of the acid salts of the compounds shown or a combination thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0060] The present invention further relates to the use of an acid salt of any of the compounds shown, or a pharmaceutical composition thereof, in preparing a drug.

[0061] In a further preferred embodiment of the present invention, the drug may be a drug for preventing and / or treating neuropsychiatric diseases in mammals.

[0062] In a further preferred embodiment of the present invention, the neuropsychiatric disease is preferably a central nervous system disease related to serotonin receptors and / or trace amine-related receptors and / or dopamine receptors.

[0063] In a further preferred embodiment of the present invention, the 5-hydroxytryptamine receptor is preferably 5-HT 1A receptor.

[0064] In a further preferred embodiment of the present invention, the trace amine-associated receptor is preferably a TAAR1 receptor.

[0065] In a further preferred embodiment of the present invention, the neuropsychiatric disease is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizophreniform personality disorder, schizotypal personality disorder, delusional mental disorder, psychosis, mental disorder, short-term mental disorder, shared mental disorder, mental disorder caused by physical disease, drug-induced psychosis, psychological affective disorder, aggression, mental disorder, Parkinson's psychosis, irritant psychosis, Tourette syndrome, organic or NOS psychosis, epilepsy, mental 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, mood disorder, One or more of psychotic disorder, depression, major depressive disorder, dysthymia, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, epilepsy, pain, neuropathic pain, neuropathic pain-prone states, inflammatory pain, fibromyalgia, migraine, cognitive impairment, movement disorders, restless legs syndrome, multiple sclerosis, sleep disorders, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, somnolence as a side effect of medication, insomnia, substance abuse dependence, addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesche-Nyhane disease, Wilson disease, autism, Huntington's disease, and premenstrual dysphoric disorder.

[0066] Detailed Description of the Invention

[0067] Different expressions such as “X is selected from A, B or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0068] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl may but need not be present, and that the description includes instances where the cycloalkyl is substituted with alkyl and instances where the cycloalkyl is not substituted with alkyl.

[0069] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, along with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers, diluents, or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0070] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0071] As used herein, "polymorph" or "polymorph" refers to a crystalline form having the same chemical composition but with different spatial arrangements of the molecules, atoms, and / or ions that make up the crystal. Although polymorphs have the same chemical composition, they differ in their packing and geometric arrangement and may exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and the like. Depending on their temperature-stability relationship, the relative stability of the two solid phases is swapped. This phenomenon of a compound existing in different crystal lattice structures is known as pharmaceutical polymorphism.

[0072] The crystal structures equivalent to the crystal structures disclosed or claimed in the present invention may show similar but not identical analytical characteristics within a reasonable error range according to experimental conditions, purity, equipment and other common variables known to those skilled in the art. Accordingly, it will be apparent to those skilled in the art that various modifications and variations can be made within the present invention without departing from the scope and spirit of the present invention. On the basis of considering the description and practice of the present invention disclosed herein, other embodiments of the present invention will be apparent to those skilled in the art. Applicants expect that these descriptions and examples are considered exemplary, rather than limiting their scope.

[0073] "X-ray powder diffraction pattern or XRPD" means the powder diffraction pattern of a substance according to the Bragg formula 2d sinθ = nλ (where λ is the wavelength of the X-rays, The diffraction order n is any positive integer, generally taking the first order diffraction peak as n=1. The "2θ or 2θ angle" mentioned herein refers to the diffraction angle, with θ being the Bragg angle, measured in degrees. When X-rays strike an atomic plane with a lattice spacing of d in a crystal or a portion of a crystalline sample at a grazing angle θ (the complementary angle to the incident angle, also known as the Bragg angle), the Bragg equation is satisfied, resulting in the measured X-ray powder diffraction pattern.

[0074] It is well known to those skilled in the art that XRPD may produce certain displacement and intensity deviations due to reasons such as sample tiling thickness, detection method, conditions, and instrumentation. The same sample of the same crystal form usually has the same main XRPD characteristic peak, but there may be certain operating errors. When a person skilled in the art uses the same instrument and detection method to detect an isomorphous sample obtained by a corresponding method, the characteristic peak error is usually within ±0.2°. However, different technicians using different instruments may occasionally have errors in a few characteristic peaks that exceed this range. For example, errors within ±0.5° or ±0.3° should all be considered to belong to the XRPD characteristic peaks of the same crystal form. Therefore, as a specific example of the crystal form of the present invention, its XRPD is shown in Figure X, but it is understood by those skilled in the art that when the 2θ deviation of the key characteristic peak shift is within ±0.5°, ±0.3°, or ±0.2°, especially around ±0.2°, it can be identified as the same crystal form and can be interpreted as being within the scope of protection of the present invention.

[0075] Furthermore, the absolute and relative intensities of the peaks shown in the aforementioned tables and figures may vary due to various factors, such as the effects of the selective orientation of the crystalline solid on the X-ray beam, the influence of coarse particles, the purity of the substance being analyzed, or the crystallinity of the sample. Furthermore, peak positions may shift due to variations in sample height. Furthermore, when measurements are performed using different wavelengths, different shift values ​​are obtained according to the Bragg formula (nλ = 2dsinθ). Such different XRPD patterns obtained using different wavelengths are also within the scope of the present invention.

[0076] "Interplanar spacing or interplanar spacing (d value)" refers to the selection of three non-parallel unit vectors a, b, and c connecting two adjacent lattice points in the space lattice. They divide the lattice into juxtaposed parallelepiped units, which are called interplanar spacing. The space lattice is divided according to the lines connecting the parallelepiped units to obtain a set of straight line grids, which are called space grids or lattices. The lattice and lattice respectively use geometric points and lines to reflect the periodicity of the crystal structure. Different crystal planes have different interplanar spacings (that is, the distance between two adjacent parallel crystal planes); the unit is Or angstrom.

[0077] “Relative intensity (I%)” refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak among all diffraction peaks in an X-ray powder diffraction pattern (XRPD) when the intensity of the first strongest peak is 100%.

[0078] Differential Scanning Calorimetry (DSC) measures the transition temperatures of a crystal when heat is absorbed or released due to changes in its crystal structure or melting. For the same crystalline form of the same compound, the thermal transition temperatures and melting points can be within about 5°C, and typically within about 3°C, in consecutive analyses. When a compound is described as having a given DSC peak or melting point, this is referred to as ±5°C relative to that peak or melting point, essentially taking this temperature variation into account. DSC provides an auxiliary method for distinguishing between different crystalline forms. Different crystalline forms can be identified by their distinct transition temperature signatures. It should be noted that for mixtures, the DSC peak or melting point may vary over a wider range. Furthermore, because decomposition occurs during melting, the melting temperature is related to the heating rate.

[0079] Thermogravimetric analysis (TGA) is a common method for determining the thermal stability of compounds. In the present invention, TGA can also be used to determine the hydration state of a compound. The heating rate during the test will have a certain impact on the spectrum. The error of TGA can be within approximately ±0.5% by mass.

[0080] "Amorphous," "amorphous form," or "amorphous form" refers to a substance whose particles (molecules, atoms, ions) are arranged in a three-dimensional space without periodicity. This is characterized by a diffuse, non-peaked X-ray powder diffraction pattern. Amorphous is a specialized physical form of solid matter, and its locally ordered structure suggests a close relationship to crystalline forms.

[0081] "Equivalent" or its abbreviation "eq" refers to the equivalent amount of other raw materials required based on the equivalent relationship of chemical reactions, with the basic raw material used in each step as the benchmark (1 equivalent).

[0082] “Substantially as shown” means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern, DSC pattern, Raman spectrum pattern, or infrared spectrum pattern are shown in the pattern.

[0083] In the context of the present invention, when or whether the word "about" or "approximately" is used, it means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. Whenever a number having a value of N is disclosed, any number having a value of N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8% or N + / - 10% is specifically disclosed, where "+ / -" means plus or minus.

[0084] "Room temperature" refers to a temperature between 10°C and 40°C. In some embodiments, "room temperature" refers to a temperature between 15°C and 30°C; in other embodiments, "room temperature" refers to a temperature between 18°C ​​and 25°C. Beneficial effects

[0085] The hydrochloride crystal form of the compound of the present invention not only performs well in terms of product performance parameters such as melting point, solubility, solution stability and solid stability, but also shows obvious advantages in terms of bioavailability. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] FIG1 is an XRPD diagram of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethanamine hydrochloride Form I.

[0087] FIG2 is a DSC diagram of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethanamine hydrochloride Form I.

[0088] FIG3 is a TGA diagram of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethanamine hydrochloride Form I.

[0089] FIG4 is an XRPD diagram of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethanamine hydrochloride Form II.

[0090] FIG5 is a DSC diagram of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethanamine hydrochloride Form II.

[0091] FIG6 is a TGA diagram of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethanamine hydrochloride Form II.

[0092] FIG7 is an XRPD diagram of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethanamine hydrochloride Form III.

[0093] FIG8 is a DSC diagram of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethanamine hydrochloride Form III.

[0094] FIG9 is a TGA chart of (R)-1-(4′H,6′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyran]-4′-yl)-N-methylmethanamine hydrochloride Form III. DETAILED DESCRIPTION

[0095] Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiments are only used to illustrate the present invention and are not used in limiting the scope of the present invention.In addition, should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall equally within the scope limited by the appended claims of the application.

[0096] The following SEP-363856 of the present invention is as follows, and is prepared according to the method of Example 129 of patent document PCT / US2010 / 058884.

[0097] The following comparative example 1 of the present invention is as follows, and is prepared according to the method of Example 89 of patent document PCT / US2010 / 058884.

[0098] 1. Preparation of Compounds

[0099] Example 1. Preparation of 1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethanamine (Compound 1)

[0100] Synthesis route:

[0101] Step a: Synthesis of 1-(thiophen-2-yl)cyclopropanecarbonitrile

[0102] To a solution of 2-(thiophen-2-yl)acetonitrile (2.0 g, 16.24 mmol) in N,N-dimethylformamide (30 mL) in an ice bath and under nitrogen, sodium hydride (60%, 1.6 g, 40.59 mmol) was added and stirred for 1 hour. 1,2-Dibromoethane (4.0 g, 21.3 mmol) was then slowly added, and the reaction solution was slowly warmed to room temperature and stirred overnight. After completion of the reaction, water (300 mL) was added to quench the reaction 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, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate) to obtain the desired product (1.5 g, 61.9% yield).

[0103] 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).

[0104] Step b: Synthesis of 1-(thiophen-2-yl)cyclopropane aldehyde

[0105] To a solution of 1-(thiophen-2-yl)cyclopropanecarbonitrile (1.4 g, 9.38 mmol) in tetrahydrofuran (100 mL) was slowly added diisobutylaluminum hydride (1 M in hexane, 18.8 mL, 18.8 mmol) dropwise in an ice bath under nitrogen. Stirring was continued at room temperature for 3 hours. After completion of the reaction, water (300 mL) was added to quench the reaction in an ice bath. The mixture was extracted 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, and concentrated. The crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain the desired product (632.0 mg, 44.3% yield).

[0106] 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).

[0107] Step c: Synthesis of (1-(thiophen-2-yl)cyclopropyl)methanol

[0108] To a solution of 1-(thiophen-2-yl)cyclopropanecarboxaldehyde (632.0 mg, 4.15 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise a solution of lithium aluminum tetrahydride in tetrahydrofuran (2.5 M in THF, 3.3 mL, 8.30 mmol) in an ice bath and under nitrogen protection. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (200 mL) was added to quench the reaction in an ice bath. The mixture was extracted 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, and concentrated. The crude product was separated and purified by column chromatography to obtain the desired product (570.0 mg, 89.0% yield).

[0109] 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).

[0110] Step d: Synthesis of 1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethanamine

[0111] To a solution of (1-(thiophen-2-yl)cyclopropyl)methanol (250 mg, 1.62 mmol) in 2-methyltetrahydrofuran (5 mL) were added 2,2-dimethoxy-N-methylethylamine (386.0 mg, 3.24 mmol) and trifluoromethanesulfonic acid (0.8 mL), and the mixture was stirred at 80°C for 20 minutes. After completion of the reaction, the pH of the reaction mixture was adjusted to 13 with 15% aqueous sodium hydroxide solution in an ice bath. The mixture was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The extract was concentrated, and the resulting crude product was isolated and purified by column chromatography (petroleum ether / ethyl acetate) to yield the desired product (7.3 mg, 2.2% yield).

[0112] 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).

[0113] LC-MS[M+H] + :210.1.

[0114] Example 2. Preparation of (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethanamine (Compound A)

[0115] The compound of Example 1 was separated by chiral chromatography to obtain optical antipodes 1 (Compound A) and 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:

[0116] Optical antipodes 1 (Compound A):

[0117] RT:3.62min; [α]D 29 =-59.1(c 0.163,MeOH); LC-MS[M+H] + :210.1.

[0118] 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).

[0119] Optical antipodes 2 (compound B):

[0120] RT:3.23min; [α]D 29 =65.1(c 0.175,MeOH); LC-MS[M+H] + :210.1.

[0121] 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).

[0122] 2. Biological Testing of Compounds

[0123] Test Example 1: TAAR1 receptor cAMP agonist test method

[0124] 1.1 Experimental Materials:

[0125] The cAMP assay kit was purchased from Cisbio; the HE3K293 cell line stably expressing the TAAR1 receptor was established by Shanghai Shujing Biotechnology Co., Ltd.; IBMX was purchased from Sigma; phenethylamine (PEA) and ProxiPlate-384-well plates were purchased from PerkinElmer; and HBSS was purchased from Thermo Fisher Scientific. A PerkinElmer Envision 2105 multi-function microplate reader, an Agilent Bravo liquid handling station, and a Countstar BioTech cell counter were used.

[0126] 1.2 Experimental methods:

[0127] (1) Experimental buffer preparation: Dilute 5× stimulation buffer to 1× with ddH2O, add IBMX to a final concentration of 0.5 mM, mix well and set aside.

[0128] (2) Take the frozen cells and thaw them quickly in a 37°C water bath. Wash the cell suspension with HBSS buffer and centrifuge at 200×g to remove the freezing solution. Resuspend the precipitate with an appropriate amount of experimental buffer and count 20 μL using a cell counter. Dilute to 1.5×10 6 pieces / mL.

[0129] (3) Add 5 μL of cell suspension (1.5×10 per well) to the ProxiPlate-384 well plate. 4 cells).

[0130] (4) The test compound was serially diluted in the assay buffer and 5 μL was transferred to the reaction plate using Bravo. 5 μL of assay buffer was added to the negative control wells and 5 μL of PEA (final concentration 10 -2 M).

[0131] (5) Incubate at 37°C for 1 hour.

[0132] (6) Add 10 μL of detection reagent to the reaction plate and incubate at room temperature in the dark for 1 hour.

[0133] (7) Detection was performed using an Envision 2105 multifunctional microplate reader. Excitation light was 340 nm, and emission light was 620 nm and 665 nm. The 665 nm / 620 nm ratio was calculated for each test well.

[0134] Activation rate (Activity%) = (negative control ratio - compound ratio) / (negative control ratio - positive control ratio) × 100%

[0135] The EC of the compound was calculated using the four-parameter fitting model log(agonist) vs. response--Variable slope (four parameters) in GraphPad Prism. 50 value.

[0136] 1.3 Experimental results:

[0137] The specific results of the compound of the present invention in the TAAR1 receptor agonist activity test obtained through the above scheme are shown in Table 2-1.

[0138] Table 2-1 Results of the agonist activity of the compounds of the present invention on TAAR1 receptor

[0139] 1.4 Experimental Conclusions:

[0140] The results of in vitro experiments show that compound A of the present invention has an agonist effect on TAAR1 receptor.

[0141] Test Example 2: 5-HT 1A cAMP receptor agonist test method

[0142] 2.1 Experimental Materials

[0143] cAMP detection kit was purchased from Cisbio; stable expression of 5-HT 1AThe recipient HEK293 cell line was established by Shanghai Shujing 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 multi-function microplate reader, a Tecan D300e picoliter microfluidics system, an Agilent Bravo liquid handling system, and a Countstar BioTech cell counter were used.

[0144] 2.2 Experimental methods:

[0145] (1) Experimental buffer preparation: Dilute 5× stimulation buffer to 1× with ddH2O, add IBMX to a final concentration of 0.5 mM, mix well and set aside.

[0146] (2) The cultured cells were digested with trypsin. After digestion, the cell suspension was washed with HBSS buffer and centrifuged at 200 × g to remove the culture medium. The precipitate was resuspended with an appropriate amount of experimental buffer and 20 μL was taken for counting using a cell counter and diluted to 0.4 × 10 6 pieces / mL.

[0147] (3) Add 5 μL of cell suspension (2×10 per well) to the ProxiPlate-384 well plate 3 cells).

[0148] (4) The test compound was serially diluted in the assay buffer and 5 μL was transferred to the reaction plate using Bravo. 5 μL of assay buffer was added to the negative control wells and 5 μL of Serotonin (final concentration 10 -6 M).

[0149] (5) Incubate at room temperature for 15 minutes.

[0150] (6) Forskolin (final concentration 1.5×10 -7 M).

[0151] (7) Incubate at room temperature for 45 minutes.

[0152] (8) Add 10 μL of detection reagent to the reaction plate and incubate at room temperature in the dark for 1 hour.

[0153] (9) Detection was performed using an Envision 2105 multifunctional microplate reader. Excitation light was 340 nm, and emission light was 620 nm and 665 nm. The 665 nm / 620 nm ratio was calculated for each test well.

[0154] Activation rate (Activity%) = (negative control ratio - compound ratio) / (negative control ratio - positive control ratio) × 100%

[0155] The EC of the compound was calculated using the four-parameter fitting model log(agonist) vs. response--Variable slope (four parameters) in GraphPad Prism. 50 value.

[0156] 2.3 Experimental results:

[0157] Through the above scheme, it is concluded that the compounds of the present invention have an effect on 5-HT 1A The specific results of the receptor agonist activity test are shown in Table 2-2.

[0158] Table 2-2 Effects of the compounds of the present invention on 5-HT 1A Receptor agonist activity results

[0159] 2.4 Experimental Conclusions:

[0160] The results of in vitro experiments showed that the compound A of the present invention has an effect on 5-HT 1A The receptor has an agonistic effect, suggesting that the compound of the present invention can improve negative symptoms and cognitive impairment.

[0161] Test Example 3: Inhibitory effect of the compounds of the present invention on MK-801-induced high spontaneous activity in mice

[0162] 3.1 Experimental Materials

[0163] Test compound: Compound of the present invention, homemade.

[0164] (+)-MK-801 hydrogen maleate: purchased from Sigma-Aldrich, product number: M107-50MG.

[0165] Experimental animals: 18-22 g male C57Bl / 6J mice were purchased from Shanghai Slake Laboratory Animal Co., Ltd.

[0166] 3.2 Experimental methods:

[0167] 3.2.1 Animal grouping: Before the start of the experiment, animals were randomly grouped according to their weight.

[0168] 3.2.2 Animal Acclimation: Before the experiment, mice were allowed to acclimate to the experimental environment for at least 1 hour. That is, the animals were transferred from the breeding room to the experimental room and allowed to move freely in their cages.

[0169] 3.2.3 Administration:

[0170] Drug preparation: Take the test compound, add pure water and perform sonication.

[0171] The animals were grouped according to body weight and randomly divided into a blank group, a model group, and a drug-treated group, with 9 animals in each group. Detailed drug administration information is shown in the table below:

[0172] T-30min Oral Administration of Compounds: The test compound or vehicle (pure water) was administered orally by gavage. After administration, the mice were immediately placed in a test box (dimensions of the test box: length × width × height = 27 × 27 × 40 cm) and their spontaneous activity was recorded for 30 minutes.

[0173] T0min Modeling Drug Intraperitoneal Injection: 30 minutes after compound administration, mice were removed and MK-801 (0.3 mg / kg) was administered intraperitoneally. A blank control group was injected with saline. Following MK-801 administration, animals were immediately returned to the testing chamber and monitored for an additional 150 minutes.

[0174] 3.2.4 Data recording and analysis. The animal's activities (movement distance in the test box) will be automatically recorded by a camera and analyzed using ANY MAZE software to calculate ED 50 .

[0175] 3.3 Experimental results: as shown in Table 2-3.

[0176] Table 2-3 Experimental results of the inhibition of MK-801-induced high spontaneous activity in mice by the compounds of the present invention

[0177] Note: ED 50 MED is the minimum effective dose.

[0178] 3.4 Experimental Conclusions

[0179] The above scheme demonstrates that Compound A of the present invention significantly inhibits MK-801-induced hyperlocomotion in mice. The inhibitory effect gradually increases with increasing compound dosage, demonstrating a well-defined dose-dependent relationship. Furthermore, compared to SEP-363856, Compound A of the present invention exhibits a lower minimum effective dose and a stronger inhibitory effect.

[0180] Test Example 4: Inhibitory effect of the compounds of the present invention on PCP-induced hyperlocomotor activity in mice

[0181] 4.1 Experimental Materials

[0182] Test compound: Compound of the present invention, homemade.

[0183] Phencyclidine (PCP) hydrochloride: purchased from Shanghai Yuansi Biaowu Technology Co., Ltd., specification: 5g.

[0184] Experimental animals: 18-22 g male C57Bl / 6J mice were purchased from Shanghai Slake Laboratory Animal Co., Ltd.

[0185] 4.2 Experimental methods:

[0186] 4.2.1 Animal grouping: Before the start of the experiment, animals were randomly grouped according to their weight.

[0187] 4.2.2 Animal Acclimation: Before the experiment, mice were allowed to acclimate to the experimental environment for at least 1 hour. That is, the animals were transferred from the breeding room to the experimental room and allowed to move freely in their cages.

[0188] 4.2.3 Administration:

[0189] Drug preparation: Take the test compound, add pure water and perform sonication.

[0190] The animals were grouped according to body weight and randomly divided into a blank group, a model group, and a drug-treated group, with 9 animals in each group. Detailed drug administration information is shown in the table below:

[0191] T-30min Oral Administration of Compounds: The compounds of the present invention or vehicle (pure water) were administered orally by gavage. After administration, the mice were immediately placed in a test box (dimensions L×W×H=27×27×40 cm) and their spontaneous activity was recorded for 30 minutes.

[0192] T0min Modeling Drug Intraperitoneal Injection: 30 minutes after compound administration, mice were removed and PCP (5 mg / kg) was administered intraperitoneally. A blank control group was injected with ultrapure water. Following PCP administration, animals were immediately returned to the testing chamber and monitored for an additional 60 minutes.

[0193] 4.2.4 Data recording and analysis. The animal's activities (movement distance in the test box) will be automatically recorded by a camera and analyzed using ANY MAZE software to calculate ED 50 .

[0194] 4.3 Experimental results: as shown in Table 2-4

[0195] Table 2-4 Inhibition results of the compounds of the present invention on PCP-induced high spontaneous activity in mice

[0196] Note: ED 50MED is the minimum effective dose.

[0197] 4.4 Experimental Conclusions

[0198] The above scheme demonstrates that Compound A of the present invention significantly inhibits PCP-induced hyperlocomotion in mice, with the inhibitory effect increasing with increasing compound dosage, demonstrating a well-defined dose-dependent relationship. Furthermore, compared to SEP-363856, Compound A of the present invention exhibits a lower minimum effective dose and a stronger inhibitory effect.

[0199] 3. Study on the salt crystal form of the compound

[0200] The free base of Compound A is an oily substance. Since the oily substance is not conducive to further development into a drug, attempts were made to salify the free base of Compound A and further study the salt-type crystal form of Compound A.

[0201] Experimental instruments:

[0202] 1. Preparation of Compound A Salt Crystalline Form

[0203] 1.1 Preparation of Compound A Hydrochloride Form I

[0204] The free base compound A (130.7 mg, 0.63 mmol) prepared in Example 2 was added to a 25 mL round-bottom flask, and ethyl acetate (2.0 mL) was stirred at room temperature to dissolve. Then, 2 M HCl-ethyl acetate solution (0.32 mL, 0.64 mmol) was added, and the reaction was stirred at room temperature for 3 hours. Then, the mixture was filtered and the solid was dried at 50 ° C for 3 hours to obtain a white solid, which was identified as Compound A hydrochloride Form I (93.2 mg).

[0205] After detection and analysis, it has an XRPD pattern as shown in Figure 1, a DSC pattern as shown in Figure 2, and a TGA pattern as shown in Figure 3. Combining the results of its DSC and TGA analysis, it can be seen that it is a non-solvate.

[0206] 1.2 Preparation of Compound A Hydrochloride Form II

[0207] Compound A hydrochloride Form I (73 mg, 0.3 mmol) prepared in 1.1 above and ethanol (1.0 mL) were added to a 25 mL round-bottom flask. The suspension was heated to 80°C with stirring and reflux for 1 hour, then naturally cooled to room temperature and filtered. The solid material was air-dried at 50°C overnight to obtain a white solid, which was identified as Compound A hydrochloride Form II (20 mg).

[0208] After detection and analysis, it has an XRPD pattern as shown in Figure 4, a DSC pattern as shown in Figure 5, and a TGA pattern as shown in Figure 6. Combining the results of its DSC and TGA analysis, it can be seen that it is a non-solvate.

[0209] 1.3 Preparation of Compound A Hydrochloride Form III

[0210] The free base compound A (102 mg, 0.49 mmol) prepared in Example 2 was added to a 25 mL round-bottom flask, and ethyl acetate (2.0 mL) was stirred at room temperature to dissolve, and then 2 M HCl-ethyl acetate solution (0.25 mL, 0.5 mmol) was added. After stirring for half an hour, water (0.25 mL) was added, and then stirring was continued at room temperature for 3 days. Then, the mixture was filtered and the solid material was dried at room temperature for 3 hours. It was found that its weight did not change, and a white solid was obtained, which was identified as Compound A hydrochloride Form III (45 mg).

[0211] After testing and analysis, it has an XRPD pattern as shown in Figure 7, a DSC pattern as shown in Figure 8, and a TGA pattern as shown in Figure 9. Combined analysis of the DSC and TGA results shows a clear endothermic peak near 84.92°C, corresponding to 6.73% crystalline water, i.e., the removal of one molecule of water, indicating that it is a monohydrate.

[0212] 2. Solubility experiment

[0213] 2.1 Experimental Purpose:

[0214] The equilibrium solubility of each crystalline form of Compound A hydrochloride in water for 24 hours was investigated.

[0215] 2.2 Experimental plan:

[0216] Excess amounts of Compound A hydrochloride Form I and Form II were weighed and placed in separate 10 mL centrifuge tubes. 1 mL of deionized water was added, the tubes were sealed with sealing film, and the tubes were shaken in a constant temperature shaker at 37°C and 150 rpm for 24 h. The tubes were then filtered through a 0.45 μm organic filter, diluted, and injected for HPLC analysis.

[0217] 2.2 Experimental results: The solubility results are shown in Table 3.1 below:

[0218] Table 3.1 Equilibrium solubility of each crystalline form of Compound A hydrochloride in water for 24 hours

[0219] 2.4 Experimental Conclusions:

[0220] It can be seen from the data in the table that the solubility of different crystalline forms of compound A after salt formation in aqueous media is significantly improved.

[0221] 3. Solution stability test

[0222] 3.1 Experimental Purpose:

[0223] The solution stability of each crystalline form of Compound A hydrochloride was investigated.

[0224] 3.2 Experimental plan and results:

[0225] Prepare solutions at pH 1.0, 3.0, 5.0, and 7.0 using hydrochloric acid, phosphoric acid, and sodium hydroxide. Weigh appropriate amounts of Compound A hydrochloride Form I and Form II into corresponding 20 mL volumetric flasks and label them. Dissolve in media of varying pH values, adjust to volume, and filter through a 0.45 μm organic filter. Analyze by HPLC. Monitor sample concentration changes over 0-24 hours and calculate the results.

[0226] 3.3 Experimental results:

[0227] Compound A hydrochloride Form I and Compound A hydrochloride Form II have good stability under different pH conditions (1.0, 3.0, 5.0 and 7.0) for 24 hours.

[0228] 4. Solid stability test

[0229] 4.1 Experimental Purpose:

[0230] The chemical stability of various crystalline forms of compound A hydrochloride under high temperature, high humidity and light conditions was investigated.

[0231] 4.2 Experimental plan:

[0232] Appropriate amounts of Compound A hydrochloride Form I and Form II were weighed and placed in weighing dishes. Three samples of each salt were prepared and placed in a 60°C oven, 92.5% RH, and a stability test chamber with 5000 lx illumination for 85 days. All samples were mixed and sampled at 0, 10, 20, and 85 days. After dissolution with acetonitrile and water, the content and impurity changes were determined using HPLC.

[0233] 4.3 Experimental results: The chemical stability results are shown in Table 3.2 below:

[0234] Table 3.2 Chemical stability results of various crystalline forms of Compound A hydrochloride

[0235] 4.4 Experimental Conclusions

[0236] The above data show that the impurity content of Compound A hydrochloride Form I and Compound A hydrochloride Form II of the present invention increases less under high temperature, high humidity or light conditions and has good chemical stability.

[0237] 5. Pharmacokinetic experiments

[0238] 5.1 Test Purpose:

[0239] The drugs were administered orally by gavage to mice, and the blood concentrations of various crystalline forms of Compound A hydrochloride in mice were measured. The PK parameters were calculated, and the pharmacokinetic evaluation was performed.

[0240] 5.2 Test materials:

[0241] (1) Test samples: Compound A hydrochloride crystalline form I, crystalline form II and crystalline form III, prepared in-house.

[0242] (2) Experimental animals: ICR mice, SPF grade, male, obtained from Shanghai Slake Laboratory Animal Co., Ltd.

[0243] 5.3 Test plan:

[0244] The compound was administered orally by gavage at a dose of 5 mg / kg. ICR mice were stratified by body weight and randomly divided into groups of 3 mice each. Mice were fasted overnight before the experiment. At the set dose and time of administration, 250 μL of blood was collected from the mandibular vein or saphenous vein of the mice at fixed time points using a cross-sampling method. The blood was placed in a sample tube containing sodium heparin, an anticoagulant, and placed on wet ice at 4000 rpm. -1 After centrifugation for 10 min, plasma was separated and subjected to LC-MS analysis.

[0245] 5.4 Test results and analysis:

[0246] The measured blood drug concentration-time data were entered into Winnonlin 7.0 to calculate the main pharmacokinetic parameters. The specific results are shown in Table 3.3 below.

[0247] Table 3.3 Results of mouse pharmacokinetic experiments

[0248] 5.5 Test conclusion:

[0249] From the results of the mouse pharmacokinetic experiment in the table, it can be seen that different crystalline forms of the hydrochloride of compound A of the present invention can be rapidly absorbed after administration, showing good metabolic properties, exposure AUC and maximum blood concentration C max All performed well.

Claims

1. An 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 hydrochloride.

2. The acid salt according to claim 1, characterized in that 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, further preferably 1.

3. The acid salt according to any one of claims 1 to 2, characterized in that The acid salt is an anhydrate or a hydrate. When the acid salt is a hydrate, the number of water 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 further preferably 1.

4. The acid salt according to any one of claims 1 to 3, characterized in that The acid salt is a crystalline form, preferably hydrochloride crystalline form I, hydrochloride crystalline form II or hydrochloride crystalline form III, wherein: The X-ray powder diffraction pattern of the hydrochloride crystalline form I comprises diffraction peaks at 2θ of 12.03±0.2°, 16.08±0.2°, and 26.84±0.2°; preferably comprises diffraction peaks at 2θ of 12.03±0.2°, 16.08±0.2°, 18.52±0.2°, 25.31±0.2°, and 26.84±0.2°; more preferably comprises diffraction peaks at 2θ of 12.03±0.2°, 16.08±0.2°, 18.52±0.2°, 25.31±0.2°, and 26.84±0.2°. 2θ is 6.22±0.2°, 12.03±0.2°, 12.36±0.2°, 13.70±0.2°, 14.72±0.2°, 15.11±0.2°, 16.90±0.2°, 17.96±0.2°, 18.70±0.2°, 19.90±0.2°, 20.90±0.2°, 21.70±0.2°, 23.10±0.2°, 24.72±0.2°, 25.31±0.2°, 26.84±0.2°, 29.60±0.2°; more preferably, the diffraction peaks are located at 2θ 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. diffraction peaks at 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 X-ray powder diffraction pattern of the hydrochloride crystalline form II comprises diffraction peaks at 2θ of 13.36±0.2°, 17.25±0.2°, and 27.74±0.2°; preferably comprises diffraction peaks at 2θ of 10.30±0.2°, 13.36±0.2°, 17.25±0.2°, 22.77±0.2°, and 27.74±0.2°; more preferably comprises diffraction peaks at 2θ of 10.30±0.2°, 13.36±0.2°, 17.25±0.2°, 22.77±0.2°, and 27.74±0.2°. .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°; further preferably, the diffraction peaks are located at 2θ 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. diffraction peaks at 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°; The X-ray powder diffraction pattern of the hydrochloride crystal form III comprises diffraction peaks at 2θ of 8.86±0.2°, 17.71±0.2°, and 26.66±0.2°; preferably comprises diffraction peaks at 2θ of 8.86±0.2°, 13.28±0.2°, 17.71±0.2°, 19.07±0.2°, and 26.66±0.2°; more preferably comprises diffraction peaks at 2θ of 8.86±0.2°, 13.28±0.2°, 15.75±0.2°, 16.22±0.2°, 17.71±0.2°, 19. 0.75 ± 0.2°, 19.07 ± 0.2°, 20.52 ± 0.2°, 21.01 ± 0.2°, 22.75 ± 0.2°, 23.70 ± 0.2°, 26.66 ± 0.2°, and 31.19 ± 0.2°; further preferably, the diffraction peaks are located at 2θ 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°, Diffraction peaks at 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°, and 49.93±0.2°.

5. The acid salt according to any one of claims 1 to 4, characterized in that The acid salt is hydrochloride crystal form I, hydrochloride crystal form II or hydrochloride crystal form III, wherein: The X-ray powder diffraction pattern of the hydrochloride salt form I is substantially as shown in FIG1 ; The X-ray powder diffraction pattern of the hydrochloride salt form II is substantially as shown in FIG4 ; The X-ray powder diffraction pattern of the hydrochloride salt form III is substantially as shown in FIG7 .

6. The acid salt according to any one of claims 1 to 5, characterized in that The acid salt is hydrochloride crystal form I, hydrochloride crystal form II or hydrochloride crystal form III, wherein: The DSC spectrum of the hydrochloride salt form I has an endothermic peak at 248.07±5°C, preferably having a DSC spectrum as shown in Figure 2, or a TGA spectrum as shown in Figure 3; The DSC spectrum of the hydrochloride salt form II has an endothermic peak at 249.54±5°C, preferably having a DSC spectrum as shown in Figure 5, or a TGA spectrum as shown in Figure 6; The DSC spectrum of the hydrochloride salt form III has endothermic peaks at 84.92±5°C and 245.23±5°C, preferably having a DSC spectrum as shown in FIG8 , or having a TGA spectrum as shown in FIG9 .

7. A method for preparing the acid salt according to any one of claims 1 to 6, characterized in that: The specific steps include: (1) Weigh an appropriate amount of the compound free base (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethanamine and dissolve it in solvent 1; (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; (3) Mix the above two, stir and react at a certain temperature for a certain time, filter and dry to obtain the target product; Alternatively, the above two are mixed, stirred and reacted at a certain temperature for a certain time, solvent 3 is added, and the stirring reaction is continued for a certain time, filtered, and dried to obtain the target product; in: 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, 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; wherein solvent 1 and solvent 2 need to be miscible when used.

8. A method for preparing the acid salt according to any one of claims 1 to 6, characterized in that: The specific steps include: (1) Weigh an appropriate amount of compound hydrochloride and dissolve or suspend it in solvent 4; (2) reflux the clarified solution or suspension of step (1) at a certain temperature for a certain time, cool to room temperature, filter, and dry to obtain the target product; in: 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.

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

10. Use of the acid salt according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 8 in the preparation of a medicament, wherein the medicament can be a medicament for preventing and / or treating neuropsychiatric diseases in mammals; the neuropsychiatric diseases are preferably central nervous system diseases related to serotonin receptors and / or trace amine-related receptors and / or dopamine receptors.

11. The use according to claim 10, characterized in that The neuropsychiatric diseases are schizophrenia, schizophrenia spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizophreniform personality disorder, schizotypal personality disorder, delusional mental disorder, psychosis, mental disorder, short-term mental disorder, shared mental disorder, mental disorder caused by physical disease, drug-induced psychosis, psychological affective disorder, aggression, mental disorder, Parkinson's psychosis, irritant psychosis, Tourette syndrome, organic or NOS psychosis, epilepsy, mental 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, mood disorder, One or more of psychotic disorder, depression, major depressive disorder, dysthymia, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, pain, neuropathic pain, neuropathic pain-prone states, inflammatory pain, fibromyalgia, migraine, cognitive impairment, restless legs syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, somnolence as a side effect of medication, insomnia, substance abuse dependence, addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesche-Nyhane disease, Wilson disease, autism, and premenstrual dysphoric disorder.

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