Salts, crystalline forms, and methods for preparing and using spiro ring-containing derivatives

Abstract

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

Description

[Technical Field]

[0001] This application claims priority to Chinese patent application 2022111813611, filed on 27 / 2022. This application quotes the entire text of the aforementioned Chinese patent application.

[0002] The present invention belongs to the field of pharmaceutical synthesis, and more particularly to salts, crystalline forms, and methods for preparing and using spiro ring-containing derivatives. [Background technology]

[0003] Disorders affecting the central nervous system affect many people to varying degrees. Generally, the main features of such disorders include marked impairment of cognition or memory, showing a significant decline compared to the original level of function. Schizophrenia is a psychopathological disorder of unknown cause, usually first appearing in early adulthood, and is characterized by psychotic symptoms, a stepwise progression and development, and / or regression of social behavior and professional abilities. The symptoms of schizophrenia are generally classified into three categories: positive symptoms, negative symptoms, and cognitive symptoms. Positive symptoms are those that represent an "excessive" normal experience, such as hallucinations and delusions. Negative symptoms are those in which the patient loses the normal experience, such as anesthesia and lack of social interaction. Cognitive symptoms are associated with cognitive impairment in schizophrenia, such as persistent lack of attention and impaired decision-making. Current antipsychotic medications have been successful in treating positive symptoms, but are not yet ideal for negative symptoms and cognitive symptoms.

[0004] Biogenic amines play a crucial role 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 strictly controlled. Imbalances in biogenic amine levels are known to be a major cause of altered brain function in many pathological conditions. Serotonin, norepinephrine, epinephrine, dopamine, and histamine have been widely studied as classic biogenic amines. Among these, the 5-hydroxytryptamine system plays a vital role in regulating the function of the prefrontal cortex (PFC), including emotion regulation, cognitive behavior, and working memory. PFC pyramidal neurons and GABAergic interneurons contain several very dense subtypes of 5-hydroxytryptamine receptors, 5-HT1A and 5-HT2A. PFC and NMDA receptor channels have recently been identified as targets of 5-HT1AR, and these two receptors modulate excitatory neurons in the cerebral cortex, thereby influencing cognitive function. Indeed, 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 the low incidence of EPS side effects suggest that the 5-hydroxytryptamine system plays a crucial role in modulating the function of the proximal and posterior collateral cortex (PFC), including emotion regulation, cognitive behavior, and working memory. PFC pyramidal neurons and GABAergic interneurons contain several very dense clusters of 5-hydroxytryptamine receptor subtypes, 5-HT1A and 5-HT2A. Recent studies have shown that 5-HT1A agonists are associated with atypical antipsychotics and can improve negative symptoms and cognitive impairments.

[0005] In recent years, as research into classical biogenic amines has gradually deepened, people have discovered a second class of endogenous amine compounds, namely trace amines (TA), including p-tyramine, β-phenylethylamine, tryptamine, and octopamine. While their levels in the mammalian nervous system are generally lower than those of classical biogenic amines, they all share similar characteristics in terms of structure, metabolism, and intracellular localization. Trace amine-associated receptors (TAARs), as novel members of the GPCR family of G protein-coupled receptors, possess a similar structure to deep GPCR pharmacophores, and their pharmacological data are consistent. Phylogenetic developmental relationships of these receptor genes have shown that these receptors form three distinct subfamilies, with TAAR1 being the first of four highly conserved genes (TAAR1-4) between humans and rodents. TAs activate TAAR1 via Gαs and play a key role in this process. Existing research has clearly shown that dysregulation of trace amine-related receptors, particularly TAAR1, is closely associated with many mental disorders such as schizophrenia and depression, as well as conditions like attention deficit hyperactivity disorder, migraines, Parkinson's disease, substance abuse, and eating disorders. Therefore, TAAR ligands have a high potential for use in treating these disorders.

[0006] While many anti-schizophrenic drugs exist, those currently used clinically still have various side effects. Furthermore, while current anti-negative symptom drugs are clinically applied and have improved negative symptoms in some patients, their overall effectiveness is limited. Many patients still cannot recover or restore normal social functioning due to negative symptoms, making it difficult to resume normal social activities. Additionally, treating cognitive impairment is now a crucial aspect of schizophrenia treatment, affecting most patients' verbal memory, verbal information processing abilities, and attention functions. However, currently researched or marketed anti-schizophrenic drugs offer very limited improvement in cognitive function. Furthermore, the treatment of treatment-resistant schizophrenia remains a dilemma. Although these patients have been treated with three different antipsychotic drugs containing different active ingredients, even with sufficient doses and courses of treatment, the treatment response is often poor, patients cannot tolerate the side effects of the antipsychotics, or the disease continues to relapse or worsen despite appropriate maintenance or preventive care. Therefore, the development of anti-refractory schizophrenia drugs is a persistent challenge in current clinical drug research and an area that urgently needs to be overcome.

[0007] Sunovion's SEP-363856, currently in Phase III clinical trials as a 5-hydroxytryptamine and / or trace amine-related receptor agonist, has shown remarkable efficacy against 5-HT1A and TAAR1 receptors and demonstrated favorable activity in existing clinical studies. Therefore, there is an urgent need to develop effective and sustained treatments for negative symptoms, improve patients' cognitive function, and effectively treat treatment-resistant schizophrenia. Furthermore, there is a demand for schizophrenia treatments with fewer side effects and that act on multiple targets to meet the enormous market demand. [Overview of the project] [Problems that the invention aims to solve]

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

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

[0010] The technical problem that this invention aims to solve is to provide salts, crystalline forms, and methods for preparing and using spiro ring-containing derivatives. [Means for solving the problem]

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

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

[0013] In a more 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 its hydrochloride salt is 1:0.8 to 1.2.

[0014] In a more preferred embodiment of the present invention, the acidic salt is an unsolvated or solvated product, and the solvent is one or more selected from water, methanol, ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene, or toluene.

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

[0016] In a more preferred embodiment of the present invention, the above acidic salt is preferably an anhydride or a monohydrate.

[0017] In a more preferred embodiment of the present invention, the acidic salt is crystalline or amorphous.

[0018] <op In a more preferred embodiment of the present invention, the acidic salt of the compound (R)-1-(4’H,6’H-spiro[cyclopropane-1,7’-thieno[3,2-c]pyran]-4’-yl)-N-methylmethylamine is hydrochloride crystal form I, hydrochloride crystal form II, or hydrochloride crystal form III. In the case of hydrochloride crystal form I, the number of acids is 1, and its powder X-ray diffraction pattern has diffraction peaks at positions where 2θ is 12.03±0.2°, 16.08±0.2°, and 26.84±0.2°. Preferably, diffraction peaks are located at positions where 2θ is 12.03 ± 0.2°, 16.08 ± 0.2°, 18.52 ± 0.2°, 25.31 ± 0.2°, 26.84 ± 0.2°; Preferably, diffraction peaks are located at positions where 2θ is 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°; More preferably, diffraction peaks include those located at positions where 2θ is 6.22 ± 0.2°, 12.03 ± 0.2°, 12.36 ± 0.2°, 16.08 ± 0.2°, 18.25 ± 0.2°, 18.52 ± 0.2°, 19.48 ± 0.2°, 20.24 ± 0.2°, 20.94 ± 0.2°, 21.18 ± 0.2°, 22.06 ± 0.2°, 23.10 ± 0.2°, 23.54 ± 0.2°, 24.72 ± 0.2°, 25.31 ± 0.2°, 26.84 ± 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°; Even more preferably, using Cu-Kα radiation, the X-ray diffraction peaks represented by 2θ angle and crystal plane spacing d value are shown in Table 1.

[0019]

Table 1

[0020] Even more preferably, in the case of the hydrochloride crystal form I of the compound (R)-1-(4’H,6’H-spiro[cyclopropane-1,7’-thieno[3,2-c]pyran]-4’-yl)-N-methylmethylamine, the powder X-ray diffraction pattern is substantially as shown in Figure 1, the DSC pattern is substantially as shown in Figure 2, and the TGA pattern is substantially as shown in Figure 3.

[0021] In the case of hydrochloride crystal form II, the number of acid atoms is 1, and the powder X-ray diffraction pattern shows diffraction peaks at 2θ positions of 13.36±0.2°, 17.25±0.2°, and 27.74±0.2°. Preferably, diffraction peaks located at 2θ positions of 10.30±0.2°, 13.36±0.2°, 17.25±0.2°, 22.77±0.2°, and 27.74±0.2°. Preferably, diffraction peaks located at positions 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° of 2θ. More preferably, 2θ is 8.55±0.2°, 9.96±0.2°, 10.30±0.2°, 11.23±0.2°, 12.49±0.2°, 13.36±0.2°, 15.17±0.2°, 15.99±0.2°, 17.25±0.2°, 18.25±0.2°, 18.83±0.2°, 19.20±0.2°, 20.04±0.2°, 21.11±0.2°, 21.72±0.2°, 22 It includes diffraction peaks located at 0.77±0.2°, 24.13±0.2°, 24.95±0.2°, 25.28±0.2°, 25.87±0.2°, 26.39±0.2°, 27.11±0.2°, 27.74±0.2°, 28.57±0.2°, 29.23±0.2°, 30.99±0.2°, 32.26±0.2°, 34.85±0.2°, 38.72±0.2°, and 40.42±0.2°. More preferably, using Cu-Kα radiation, the X-ray diffraction peaks represented by the 2θ angle and the interplanar spacing d value are shown in Table 2.

[0022] [Table 2]

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

[0024] In the case of hydrochloride crystalline form III, the number of acid atoms is 1, and the powder X-ray diffraction pattern shows diffraction peaks at 2θ positions of 8.86±0.2°, 17.71±0.2°, and 26.66±0.2°. Preferably, diffraction peaks located at 2θ at positions 8.86±0.2°, 13.28±0.2°, 17.71±0.2°, 19.07±0.2°, and 26.66±0.2°. Preferably, diffraction peaks located at 2θ at positions 8.86±0.2°, 13.28±0.2°, 15.75±0.2°, 16.22±0.2°, 17.71±0.2°, 19.07±0.2°, 22.75±0.2°, 23.70±0.2°, 26.66±0.2°, and 31.19±0.2°. More preferably, 2θ is 8.86±0.2°, 10.50±0.2°, 12.99±0.2°, 13.28±0.2°, 15.75±0.2°, 16.22±0.2°, 17.71±0.2°, 19.07±0.2°, 20.52±0.2°, 21.01±0.2°, 22.75±0.2°, 23.19±0.2°, 23.70±0.2°, 24.16±0.2°, 24.43±0.2°, 24.91±0.2°, 25 Includes diffraction peaks located at 0.34±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°. More preferably, using Cu-Kα radiation, the X-ray diffraction peaks represented by the 2θ angle and the interplanar spacing d value are shown in Table 3.

[0025] [Table 3]

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

[0027] In another embodiment, the present invention also provides a method for preparing the acidic salt of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine, specifically, Step (1) involves weighing an appropriate amount of the free alkali of the compound, (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine, and dissolving it in solvent 1. Step (2) involves weighing an appropriate amount of hydrochloric acid, preferably 0.5 to 2.0 equivalents, and dissolving it in solvent 2. The process includes (3) mixing both of the above, stirring and reacting them at a predetermined temperature for a predetermined time, filtering by suction, drying, and obtaining the target product. or, Step (1) involves weighing an appropriate amount of the free alkali of the compound, (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine, and dissolving it in solvent 1. Step (2) involves weighing an appropriate amount of hydrochloric acid, preferably 0.5 to 2.0 equivalents, and dissolving it in solvent 2. (3) The step of mixing both of the above, stirring and reacting at a predetermined temperature for a predetermined time, adding solvent 3, stirring and reacting for a further predetermined time, filtering by suction, drying, and obtaining the target product (3) is included. The reaction temperature is determined according to the solvent of the system, and is preferably room temperature. The present invention relates to a method wherein solvents 1, 2, and 3 are each independently selected from water, methanol, ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene, or toluene, and solvents 1 and 2 need to be compatible at the time of use.

[0028] In another embodiment, the present invention also provides a method for preparing the acidic salt of compound (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine, specifically, Step (1) involves weighing an appropriate amount of the hydrochloride salt of the compound and dissolving or suspending it in solvent 4, Step (2) involves refluxing the clear solution or suspension from step (1) at a predetermined temperature for a predetermined time to react, cooling to room temperature, filtering by suction, drying, and obtaining the target product. 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. The method relates to a method in which 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.

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

[0030] The present invention further relates to the use of an acidic salt of any of the compounds described in any one of the above claims, or a pharmaceutical composition thereof, in the preparation of a drug.

[0031] In a more preferred embodiment of the present invention, the agent may be an agent for preventing and / or treating neuropsychiatric disorders in mammals.

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

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

[0034] In a more preferred embodiment of the present invention, the trace amine-related receptor is preferably a TAAR1 receptor.

[0035] In more preferred embodiments of the present invention, the neuropsychiatric disorders include schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, transient psychotic disorder, shared psychotic disorder, psychotic disorder due to physical illness, drug-induced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, irritability psychosis, Tourette syndrome, organ or NOS psychosis, epilepsy, agitation, post-traumatic stress disorder, behavioral disorders, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, movement disorders, Huntington's disease, dementia, and emotional disorders. One or more of the following: disorders, anxiety disorders, affective psychosis, depression, major depressive disorder, dysthymia, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, dizziness, epilepsy, pain, neuropathic pain, sensitization with neuropathic pain, inflammatory pain, fibromyalgia, migraine, cognitive impairment, motor impairment, restless legs syndrome, multiple sclerosis, sleep disorders, sleep apnea syndrome, narcolepsy, excessive daytime sleepiness, jet lag, drowsiness as a side effect of medication, insomnia, substance abuse, addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesche-Neyhan disease, Wilson's disease, autism, Huntington's disease, and premenstrual dysphoric disorder. [Modes for carrying out the invention]

[0036] Different expressions such as "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C" all convey the same meaning, that is, X may be one or more of A, B, or C.

[0037] The terms “optional” or “optionally” mean that the event or situation described thereafter may or may not occur, and this expression includes both the occurrence and non-occurrence of such event or situation. For example, “a cycloalkyl that may optionally be substituted with an alkyl group” means that an alkyl group may be present but is not required, and this statement includes both cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

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

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

[0040] As used herein, "polymorph" or "polymorph" refers to a crystalline form having the same chemical composition but differing in the spatial arrangement of molecules, atoms, and / or ions constituting the crystal. Polymorphs, while having the same chemical composition, may 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 characteristics. The relative stability of two solid phases is exchanged based on the relationship between temperature and stability. This phenomenon, in which a compound exists in different lattice structures, is called drug polymorphism.

[0041] Crystal structures equivalent to those disclosed or claimed herein may exhibit similar but not identical analytical properties within a reasonable margin of error based on test conditions, purity, apparatus, and other common variables known to those skilled in the art. Therefore, it will be apparent to those skilled in the art that various modifications and variations can be made within the scope of the invention without departing from the scope and spirit of the invention. Other embodiments of the invention will become apparent to those skilled in the art by considering the specification and practices of the invention disclosed herein. The applicant intends that the specification and examples are illustrative and not limiting.

[0042] "Powder X-ray diffraction pattern or XRPD" refers to Bragg's equation 2d sinθ = nλ (where λ is the wavelength of the X-ray, λ = 1.54056 A, and the order of diffraction n is an arbitrary positive integer, usually taking the first order diffraction peak, so n = 1). The aforementioned "2θ or 2θ angle" refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degrees. When X-rays are incident on an atomic plane of a crystal or a portion of a crystal sample with a lattice spacing of d at an illumination angle θ (complementary angle of incidence, also called Bragg angle), the Bragg equation is satisfied, and a powder X-ray diffraction pattern of this set can be measured.

[0043] It is well known to those skilled in the art that XRPDs can exhibit certain displacements and intensity deviations due to sample spread thickness, detection method, conditions, and equipment. While identical samples of the same crystal form typically have the same major XRPD feature peaks, operational errors can occur. When identical crystal form samples obtained by those skilled in the art are detected using the same equipment and detection method, the error in the feature peaks is usually within ±0.2°. However, if the technician and the equipment used differ, some feature peaks may have errors outside this range. If the error is within ±0.5° or ±0.3°, they are considered to belong to the same crystal form's XRPD feature peaks. Therefore, as a specific example of the crystal form of the present invention, its XRPD is as shown in the pattern, but if the deviation of the major feature peak displacement 2θ is within ±0.5°, ±0.3°, or ±0.2°, especially around ±0.2°, they can all be identified as the same crystal form and interpreted as all being within the protected range of the present invention.

[0044] Furthermore, the absolute and relative intensities of the peaks shown in the aforementioned tables and figures may vary due to various factors, including the effect of the selected orientation of the crystalline solid relative to the X-ray beam, the effect of coarse particles, the purity of the analyte, or the crystallinity of the sample. The peak position may also shift depending on the change in sample height. Moreover, different displacement values ​​are obtained based on Bragg's equation (nλ = 2dsinθ) when different wavelengths are used for measurement. Such different XRPD patterns obtained by using different wavelengths are also within the scope of the present invention.

[0045] "Planar interplanar spacing, or d-value," refers to the spatial lattice, where three non-parallel unit vectors a, b, and c are selected to connect two adjacent lattice points. These vectors divide the lattice into juxtaposed parallelepiped units that constitute the plane interplanar spacing. The spatial lattice is divided according to the connecting lines of the defined parallelepiped units, resulting in a series of linear grids called a space lattice or crystal lattice. The lattice and crystal lattice, using geometric points and lines respectively, reflect the periodicity of the crystal structure, with different crystal planes having different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes), in units of Å or angstroms.

[0046] "Relative intensity (1%)" refers to the ratio of the intensities of all other peaks in a powder X-ray diffraction pattern (XRPD) to the intensity of the strongest peak, with the strongest peak being set to 100%.

[0047] Differential scanning calorimetry (DSC) measures the transition temperature at which a crystal absorbs or releases heat due to changes in its crystal structure or melting. For the same crystalline form of the same compound, the error between the thermal transition temperature and melting point in sequential analysis is within approximately 5°C, usually within approximately 3°C. When describing a compound with a specific DSC peak or melting point, it refers to the DSC peak or melting point ± 5°C, and this temperature variation is essentially considered. DSC provides an auxiliary method for distinguishing various crystalline forms. Different crystalline forms can be identified based on their different transition temperature characteristics. In the case of mixtures, their DSC peaks or melting points can vary over a wider range. Furthermore, since decomposition occurs during the melting process of a substance, the melting temperature is related to the heating rate.

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

[0049] "Amorphous," "non-crystalline," or "amorphous form" refers to a material formed when its mass points (molecules, atoms, ions) are arranged in three-dimensional space without periodicity, and is characterized by an X-ray powder diffraction pattern without diffuse peaks. Amorphous / non-crystalline is a special physical form of solid material, and its locally ordered structural features suggest a close relationship with crystalline materials.

[0050] "Equivalent weight" or its abbreviation "eq" refers to the equivalent weight of other raw materials required in each step of a chemical reaction, based on the basic raw material (1 equivalent weight) used in each step.

[0051] "Approximately as shown in the figure" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the powder X-ray diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum are shown in the figure.

[0052] In the context of this invention, where the words “approximately” or “about” are used, or notwithstanding their use, they mean within 10%, preferably within 5%, and especially within 1% of a given value or range. Alternatively, as will be apparent to those skilled in the art, the terms “approximately” or “about” mean within the acceptable standard error of the mean. Where a numerical value of N is disclosed, all numerical values ​​having N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, and N+ / -8% are explicitly disclosed, where “+ / -” means plus or minus.

[0053] "Room temperature" refers to a temperature between 10°C and 40°C. In some embodiments, "room temperature" refers to a temperature between 15°C and 30°C, and in other embodiments, "room temperature" refers to a temperature between 18°C ​​and 25°C.

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

[0055] [Figure 1] This is the XRPD chart for (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form I. [Figure 2] This is the DSC chart for (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form I. [Figure 3] This is the TGA chart for (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form I. [Figure 4] This is the XRPD chart for (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form II. [Figure 5] This is the DSC chart for (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form II. [Figure 6] This is the TGA chart for (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form II. [Figure 7] This is the XRPD chart for (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form III. [Figure 8]This is the DSC chart for (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form III. [Figure 9] This is the TGA chart for (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine hydrochloride crystal form III.

[0056] The present invention will be further described below by combining specific examples. It should be understood that these examples are used solely for illustrative purposes and are not intended to limit the scope of the invention. Furthermore, it should be understood that, after reading the teachings of the present invention, those skilled in the art may make various changes or modifications to the invention, and these equivalent forms are also limited by the claims attached to this application.

[0057] The following SEP-363856 of the present invention is prepared by referring to the method described in Example 129 of Patent Document PCT / US2010 / 058884, as shown below. [ka]

[0058] Comparative Example 1 of the present invention is prepared as shown below, by referring to the method described in Example 89 of Patent Document PCT / US2010 / 058884. [ka]

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

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

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

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

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

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

[0065] JPEG0007839371000008.jpg42170

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

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

[0068] 1.2 Experimental Method: (1) Preparation of experimental buffer: 5× stimulation buffer was diluted to 1× with ddH2O, IBMX to a final concentration of 0.5 mM was added, and the mixture was homogenized for subsequent use. (2) Thaw the cryopreserved cells quickly in a 37°C water bath, wash the cell suspension with HBSS buffer, centrifuge at 200xg to remove the cryopreservation solution, resuspend the pellet in an appropriate amount of laboratory buffer, take 20 μL, count using a cell counter, and obtain 1.5 × 10⁶ 6 Diluted to cells / mL. (3) Add 5 μL of cell suspension (1.5 × 10⁶ per well) to a ProxiPlate-38 4-well plate. 4 Cells were added. (4) The test compound was serially diluted with 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) (5) Incubated at 37°C for 1 hour. (6) Add 10 μL of detection reagent to the reaction plate and incubate in the dark at room temperature for 1 hour. (7) Detection was performed using an Envision 2105 multifunction microplate reader. The excitation light was 340 nm, and the emitted light was 620 nm and 665 nm. The 665 nm / 620 nm ratio for each test well was calculated. Activation rate (Activity%) = (Negative control ratio - Compound ratio) / (Negative control ratio - Positive control ratio) × 100% EC of compounds 50 The values ​​were calculated using the GraphPad Prism 4-parameter fitting model log(agonist) vs. response-Variable slope(four parameters).

[0069] 1.3 Experimental Results: Table 2-1 shows the specific results of the agonist activity test of the compound of the present invention against the TAAR1 receptor, based on the scheme described above.

[0070] [Table 2-1]

[0071] 1.4 Conclusions of the experiment: In vitro experimental results indicate that compound A of the present invention has an agonist effect on the TAAR1 receptor.

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

[0073] 2.2 Experimental Method: (1) Preparation of experimental buffer: 5× stimulation buffer was diluted to 1× with ddH2O, IBMX to a final concentration of 0.5 mM was added, and the mixture was homogenized for subsequent use. (2) Digest the cultured cells with trypsin. After digestion, wash the cell suspension with HBSS buffer, centrifuge at 200xg to remove the medium, resuspend the pellet in an appropriate amount of experimental buffer, take 20 μL, and count using a cell counter. 0.4 × 10⁶ 6 Diluted to cells / mL. (3) Add 5 μL of cell suspension (2 × 10 per well) to a ProxiPlate-38 4-well plate. 3 Cells were added. (4) The test compound was serially diluted with 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) (5) Incubated at room temperature for 15 minutes. (6) Using the Tecan D300e picoliter microdispenser, Forskolin (final concentration 1.5 × 10) -7 M) was added to the reaction plate. (7) Incubated at room temperature for 45 minutes. (8) Add 10 μL of detection reagent to the reaction plate and incubate in the dark at room temperature for 1 hour. (9) Detection was performed using an Envision 2105 multifunction microplate reader. The excitation light was 340 nm, and the emitted light was 620 nm and 665 nm. The 665 nm / 620 nm ratio for each test well was calculated. Activation rate (Activity%) = (Negative control ratio - Compound ratio) / (Negative control ratio - Positive control ratio) × 100% EC of compounds 50 The values ​​were calculated using the GraphPad Prism 4-parameter fitting model log(agonist) vs. response-Variable slope(four parameters).

[0074] 2.3 Experimental Results: According to the above scheme, 5-HT 1A Table 2-2 shows the specific results of the compounds of the present invention in receptor agonist activity tests.

[0075] [Table 2-2]

[0076] 2.4 Conclusions of the experiment: In vitro experimental results showed that compound A of the present invention is 5-HT 1A The compounds exhibit agonist effects on receptors, suggesting that the compounds of the present invention can improve negative symptoms and cognitive impairment.

[0077] Test Example 3: Inhibition experiment of the compound of the present invention on MK-801-induced hyperspontaneous movement in mice. 3.1 Experimental materials: Test compound: A compound from an example of the present invention, prepared by the user. (+)-MK-801 Hydrogen Maleate (also known as (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptene-5,10-imine hydrogen maleate, dizocilpine): Purchased from Sigma-Aldrich Company, catalog number: M107-50MG. Laboratory animals: 18-22g male C57Bl / 6J mice, purchased from SHANGHAI SLAC LABORATORY ANIMAL CO. LTD.

[0078] 3.2 Experimental Method: 3.2.1 Animal grouping: Before the start of the experiment, the animals were randomly grouped according to their body weight. 3.2.2 Animal Adaptation: Before the experiment, the mice were first allowed to adapt to the experimental environment for at least one hour. That is, the animals were moved from the breeding room to the laboratory and allowed to move freely within their cages. 3.2.3 Drug administration: Preparation of the drug: The test compound was taken, pure water was added, and sonication was performed. The animals were randomly divided into a blank group, a model group, and a drug-administered group according to their body weight, with 9 animals per group. Detailed drug administration information is shown in the table below.

[0079] JPEG0007839371000011.jpg78170

[0080] T-30-minute oral administration of compound: The test compound or solvent (pure water) was administered orally, and immediately after administration, the mouse was placed in a test box (test box size: length x width x height = 27 x 27 x 40 cm), and the spontaneous movement of the mouse was recorded for 30 minutes. Intraperitoneal injection of modeling agent at T0 minutes: Mice were removed 30 minutes after compound administration and MK-801 (0.3 mg / kg) was administered intraperitoneally. The blank control group was injected with physiological saline. Immediately after MK-801 administration, the animals were returned to the test chamber and recording continued for 150 minutes. 3.2.4 Data Recording and Analysis. Animal movement (distance traveled within the test chamber) is automatically recorded by camera and analyzed using ANY MAZE software. 50 I calculated it.

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

[0082] [Table 2-3]

[0083] 3.4 Conclusions of the experiment: Based on the above scheme, compound A of the present invention can significantly inhibit the high spontaneous movement induced by MK-801 in mice, and it can be concluded that the inhibitory effect gradually increases with increasing dose of the compound, demonstrating a good 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.

[0084] Test Example 4: Inhibition experiment of the compound of the present invention on PCP-induced hyperspontaneous movement in mice. 4.1 Experimental materials: Test compound: A compound from an example of the present invention, prepared by the user. Phencycliding hydrochloride (PCP): Purchased from Shanghai Yuansibiao Technology Co., Ltd., Specifications: 5g. Laboratory animals: 18-22g male C57Bl / 6J mice, purchased from SHANGHAI SLAC LABORATORY ANIMAL CO. LTD.

[0085] 4.2 Experimental Method: 4.2.1 Animal grouping: Before the start of the experiment, the animals were randomly grouped according to their body weight. 4.2.2 Animal Adaptation: Before the experiment, the mice were first allowed to adapt to the experimental environment for at least one hour. That is, the animals were moved from the breeding room to the laboratory and allowed to move freely within their cages. 4.2.3 Drug administration: Preparation of the drug: The test compound was taken, pure water was added, and sonication was performed. The animals were randomly divided into a blank group, a model group, and a drug-administered group according to their body weight, with 9 animals per group. Detailed drug administration information is shown in the table below.

[0086] JPEG0007839371000013.jpg83170

[0087] T-30-minute oral administration of compound: The compound of the present invention or a solvent (pure water) was administered orally by forced administration. Immediately after administration, the mice were placed in a test box (test box size: length x width x height = 27 x 27 x 40 cm) and their spontaneous movement was recorded for 30 minutes. Intraperitoneal injection of modeling agent at T0 minutes: Mice were removed 30 minutes after compound administration and PCP (5 mg / kg) was administered intraperitoneally. The blank control group was injected with ultrapure water. Immediately after PCP administration, the animals were returned to the test chamber and recording continued for 60 minutes. 4.2.4 Data Recording and Analysis. Animal activity (distance traveled within the test chamber) is automatically recorded by camera and analyzed using ANY MAZE software. 50 I calculated it.

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

[0089] [Table 2-4]

[0090] 4.4 Conclusions of the experiment: Based on the above scheme, it can be concluded that compound A of the present invention can clearly inhibit PCP-induced hyperspontaneous movement in mice, and that the inhibitory effect gradually increases as the dose of the compound increases, indicating a good 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.

[0091] III. Research on the salt crystal forms of compounds The free alkali of compound A is an oily substance, and since oily substances are not useful for further drug development, attempts were made to form a salt of compound A in its free state and to further study the salt crystal form of compound A.

[0092] JPEG0007839371000015.jpg214170

[0093] 1. Preparation of the salt crystal form of compound A 1.1 Preparation of crystalline form I of the hydrochloride salt of compound A In a 25 mL round-bottom flask, the free alkali compound A (130.7 mg, 0.63 mmol) prepared in Example 2 and ethyl acetate (2.0 mL) were added and stirred at room temperature until clear. Then, 2 M HCl-ethyl acetate solution (0.32 mL, 0.64 mmol) was added and stirred at room temperature for 3 hours. After stirring, the mixture was filtered by suction, and the solid was air-dried at 50°C for 3 hours to obtain a white solid identified as crystalline form I of the hydrochloride salt of compound A (93.2 mg). Detection and analysis revealed that the substance exhibits the XRPD pattern shown in Figure 1, the DSC pattern shown in Figure 2, and the TGA pattern shown in Figure 3. Combining the DSC and TGA results, it was determined to be a non-solvate.

[0094] 1.2 Preparation of the hydrochloride salt crystalline form II of compound A In a 25 mL round-bottom flask, 73 mg (0.3 mmol) of the hydrochloride salt form I of compound A prepared in 1.1 above and 1.0 mL of ethanol were added. The resulting suspension was heated to 80°C, stirred for 1 hour under reflux, then allowed to cool naturally to room temperature, filtered by suction, and the solid was air-dried overnight at 50°C to obtain a white solid identified as the hydrochloride salt form II of compound A (20 mg). Detection and analysis revealed that the substance exhibits the XRPD pattern shown in Figure 4, the DSC pattern shown in Figure 5, and the TGA pattern shown in Figure 6. Combining the DSC and TGA results, it was determined to be a non-solvate.

[0095] 1.3 Preparation of the hydrochloride salt crystalline form III of compound A In a 25 mL round-bottom flask, the free alkali compound A (102 mg, 0.49 mmol) prepared in Example 2 and ethyl acetate (2.0 mL) were added and stirred at room temperature until clear. Then, 2 M HCl-ethyl acetate solution (0.25 mL, 0.5 mmol) was added and stirred for 30 minutes to react. After that, water (0.25 mL) was added and stirring was continued at room temperature for 3 days. After that, the mixture was filtered by suction and the solid was dried at room temperature for 3 hours. When the measured weight no longer changed, a white solid identified as crystalline form III of compound A hydrochloride was obtained. The detection and analysis results show the XRPD pattern shown in Figure 7, the DSC pattern shown in Figure 8, and the TGA pattern shown in Figure 9. When the DSC and TGA results were combined, a clear endothermic peak was found around 84.92°C, which corresponds to 6.73% crystal water, indicating that one molecule of water has been removed, resulting in a monohydrate.

[0096] 2. Solubility experiment 2.1 Objective of the experiment The equilibrium solubility of each crystalline form of the hydrochloride salt of compound A in water over 24 hours was investigated.

[0097] 2.2 Experimental Scheme Excess samples of compound A hydrochloride crystalline form I and hydrochloride crystalline form II were weighed, placed in different 10 mL centrifuge tubes, 1 mL of deionized water was added, the tubes were sealed with sealing film, and the mixture was shaken at 150 rpm for 24 hours on a 37°C constant temperature shaker. After passing through a 0.45 μm organic filter, the samples were diluted and injected, and analyzed by HPLC. 2.2 Experimental Results: The solubility results are shown in Table 3.1 below.

[0098] [Table 3-1]

[0099] 2.4 Conclusions of the Experiment The data in the table shows that the solubility of each crystalline form of compound A in aqueous media significantly improves after salt formation.

[0100] 3. Solution Stability Experiment 3.1 Objective of the experiment The solution stability of each crystalline form of the hydrochloride salt of compound A was investigated.

[0101] 3.2 Experimental Scheme and Results 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 hydrochloride crystalline form I and hydrochloride crystalline form II of compound A were weighed, added to the corresponding 20 mL volumetric flasks, labeled, dissolved in the different pH media, made up, passed through a 0.45 μm organic filter, and analyzed by HPLC. The change in content of the sample over 0 to 24 hours was monitored, and the results were calculated.

[0102] 3.3 Experimental Results The hydrochloride salt crystalline forms I and II of compound A showed good stability over 24 hours under different pH conditions (1.0, 3.0, 5.0, and 7.0).

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

[0104] 4.2 Experimental Scheme: Appropriate amounts of compound A's hydrochloride crystalline form I and hydrochloride crystalline form II were weighed and placed in weighing dishes. Three samples were prepared for each salt, and each was left open in a stability test box under the conditions of a 60°C oven, a drying dish with 92.5% RH, and 5000 lx of light for 85 days. All samples were homogenized, sampled, dissolved in acetonitrile and water, and changes in content and impurities were detected using HPLC-related substance methods.

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

[0106] [Table 3-2]

[0107] 4.4 Conclusions of the Experiment From the above data, it was found that the hydrochloride salt crystal form I and the hydrochloride salt crystal form II of compound A of the present invention exhibit little increase in impurities and good chemical stability even under high temperature, high humidity, or lighting conditions.

[0108] 5. Pharmacokinetic experiments 5.1 Purpose of the Examination The compound A hydrochloride was administered orally to mice, and the blood concentrations of each crystalline form in the mice were measured. The PK parameters were then calculated to evaluate its pharmacokinetics.

[0109] 5.2 Test Materials (1) Test sample: Crystalline form I, crystalline form II, and crystalline form III of compound A of the present invention. (2) Laboratory animals: ICR mice, SPF grade, male, Shanghai Slack Laboratory Animals Co., Ltd.

[0110] 5.3 Examination Scheme The compound was administered orally at a dose of 5 mg / kg. ICR mice were classified according to body weight, then randomly divided into groups of three, and fasted overnight before the experiment. The drug was administered according to the set dose and time, and at a certain point in time, 250 μL of blood was collected from the mandibular or saphenous vein of the mice by cross-collection into a sample tube containing the anticoagulant heparin sodium, and placed in a wet ice bath. (4000 r.min) -1 The mixture was centrifuged for 10 minutes, and the plasma was separated and subjected to LC-MS analysis.

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

[0112] [Table 3-3]

[0113] 5.5 Examination Conclusions The results of pharmacokinetic experiments in mice shown in the table indicate that each crystalline form of the hydrochloride salt of compound A of the present invention was rapidly absorbed after administration, exhibiting good metabolic properties, exposure AUC, and maximum blood concentration C. max It was found to exhibit good performance in this area.

Claims

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

2. The acidic salt according to claim 1, characterized in that the number of acids in the acidic salt is 0.2 to 3.

3. The acidic salt according to claim 1, characterized in that the acidic salt is an anhydrous or hydrate, and when the acidic salt is a hydrate, the number of water molecules is 0.2 to 3.

4. The acidic salt is hydrochloride crystal I, hydrochloride crystal II, or hydrochloride crystal III. The powder X-ray diffraction pattern of the hydrochloride crystal I includes diffraction peaks at positions where 2θ is 12.03±0.2°, 16.08±0.2°, and 26.84±0.2°. The powder X-ray diffraction pattern of the hydrochloride crystal II includes diffraction peaks located at 2θ of 13.36±0.2°, 17.25±0.2°, and 27.74±0.2°. The acidic salt according to claim 1, characterized in that the powder X-ray diffraction pattern of the hydrochloride crystal III includes diffraction peaks located at 2θ of 8.86±0.2°, 17.71±0.2°, and 26.66±0.2°.

5. The powder X-ray diffraction pattern of the hydrochloride crystal I 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°. The powder X-ray diffraction pattern of the hydrochloride crystal II 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°. The powder X-ray diffraction pattern of the hydrochloride crystal III 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°. The acidic salt according to feature 4.

6. A method for preparing the acidic salt described in claim 4, in particular, Step (1) involves weighing an appropriate amount of the free alkali of the compound, (R)-1-(4'H,6'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyran]-4'-yl)-N-methylmethylamine, and dissolving it in solvent 1. Step (2) involves weighing an appropriate amount of hydrochloric acid and dissolving it in solvent 2, The above two components are mixed, stirred and reacted at a predetermined temperature for a predetermined time, filtered by suction, dried, and the desired product is obtained. Alternatively, the process includes (3) mixing both of the above, stirring and reacting them at a predetermined temperature for a predetermined time, adding solvent 3, stirring and reacting them for a further predetermined time, filtering by suction, drying, and obtaining the target product. A method characterized in that solvent 1 and solvent 2 are ethyl acetate, and solvent 3 is water.

7. A method for preparing the acidic salt described in claim 4, in particular, Step (1) involves weighing an appropriate amount of the compound hydrochloride and dissolving or suspending it in solvent 4, Step (2) involves refluxing the clear solution or suspension from step (1) at a predetermined temperature for a predetermined time to react, cooling to room temperature, filtering by suction, drying, and obtaining the target product. The method is characterized in that the solvent 4 is ethyl acetate or 95% ethanol.

8. A pharmaceutical composition comprising a therapeutically effective amount of an acidic salt or a combination thereof according to any one of claims 1 to 3, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

9. The pharmaceutical composition according to claim 8 for preventing and / or treating neuropsychiatric disorders in mammals.

10. The aforementioned neuropsychiatric disorders include schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, transient psychotic disorder, shared psychotic disorder, psychotic disorder due to physical illness, drug-induced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, irritability psychosis, Tourette syndrome, organ or NOS psychosis, epilepsy, agitation, post-traumatic stress disorder, behavioral disorders, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, movement disorders, Huntington's disease, dementia, affective disorders, anxiety disorders, affective psychosis, depression, and The pharmaceutical composition according to claim 9, characterized in that it is one or more of the following: depressive disorder, dysthymia, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, dizziness, epilepsy, pain, neuropathic pain, sensitization with neuropathic pain, inflammatory pain, fibromyalgia, migraine, cognitive impairment, motor impairment, restless legs syndrome, multiple sclerosis, sleep disorders, sleep apnea syndrome, narcolepsy, excessive daytime sleepiness, jet lag, drowsiness as a side effect of medication, insomnia, drug abuse addiction, addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesche-Neyhan disease, Wilson's disease, autism, Huntington's disease, and premenstrual dysphoric mood.

11. Use of an acidic salt according to any one of claims 1 to 3 in the preparation of a drug that may be a drug for preventing and / or treating neuropsychiatric disorders in mammals.

12. The aforementioned neuropsychiatric disorders include schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, transient psychotic disorder, shared psychotic disorder, psychotic disorder due to physical illness, drug-induced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, irritability psychosis, Tourette syndrome, organ or NOS psychosis, epilepsy, agitation, post-traumatic stress disorder, behavioral disorders, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, movement disorders, Huntington's disease, dementia, affective disorders, anxiety disorders, affective psychosis, depression, The use according to claim 11, characterized in that it is one or more of the following: major depressive disorder, dysthymia, bipolar disorder, mania, seasonal affective disorder, attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, dizziness, epilepsy, pain, neuropathic pain, sensitization with neuropathic pain, inflammatory pain, fibromyalgia, migraine, cognitive impairment, motor impairment, restless legs syndrome, multiple sclerosis, sleep disorders, sleep apnea syndrome, narcolepsy, excessive daytime sleepiness, jet lag, drug-induced drowsiness, insomnia, drug abuse addiction, addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesche-Neyhan disease, Wilson's disease, autism, Huntington's disease, and premenstrual dysphoric mood.

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