Use of pyridine derivative which is trpv1 antagonist

Abstract

The present invention provides a novel pharmaceutical composition and a method for treating and / or preventing social impairment, such as autism spectrum disorder, fragile X syndrome, and / or autism spectrum-like symptoms. Specifically, provided is a pharmaceutical composition for the treatment and / or prevention of social impairment, the pharmaceutical composition comprising a compound represented by formula (I) (in the formula, R1 is a substituted or unsubstituted alkyl; R2 is a hydrogen atom or the like; A is N or the like; the dashed line represents the presence or absence of a bond; R3 is a substituted or unsubstituted alkyl or the like; m is 0 or 1; and R4 and R5 each independently represent a hydrogen atom or the like) or a pharmaceutically acceptable complex thereof.

Description

Use of pyridine derivatives that are TRPV1 antagonists

[0001] The present invention relates to new pharmaceutical compositions and methods for the treatment and / or prevention of social disorders, such as autism spectrum disorders, fragile X syndrome, autism spectrum disorder-like conditions, and / or disorders in social communication and / or social interaction, particularly preferably for the treatment of autism spectrum disorders.

[0002] Autism spectrum disorder (ASD) is a disorder characterized by persistent impairments in social communication and social interactions across multiple contexts, two or more restricted and repetitive patterns of behavior, interests, or activities (e.g., emotional and repetitive physical movements or speech, fixations and obsessions, extremely limited and persistent interests, and hyper- or hypo-sensitivity to sensory stimuli), and these symptoms are present from early developmental stage. There are an estimated 3.8 million patients worldwide (Non-Patent Document 1) and over 350,000 patients in Japan. The economic burden per patient is estimated to be more than 5 million yen per year (Non-Patent Document 2). Given that the illness often lasts a lifetime, the economic impact is significant. However, there are currently no effective treatments for the core symptoms of ASD. Behavioral therapy, such as applied behavior analysis, is the primary treatment for ASD. However, because behavioral therapy requires significant time and human resources and its effectiveness is known to decrease with age, only a very limited number of patients can benefit from it. Given these circumstances, there is a strong need for effective treatments for the core symptoms of ASD. Currently, molecules known to be associated with social behavior, such as oxytocin and vasopressin, and their receptors are attracting attention as target molecules for ASD therapeutics. In 2016, Ru-Rong Ji et al. reported that deficiency of SHANK3, one of the causative genes for hereditary ASD, reduces TRPV1 function (Non-Patent Document 3). Considering that many of the SHANK3 gene mutations observed in ASD patients result in loss or reduction of its function, and that SHANK3-deficient mice exhibit ASD-like symptoms, it is speculated that TRPV1 receptor function may be reduced in at least some ASD patients. However, there have yet to be any pharmacological reports demonstrating a relationship between the TRPV1 receptor and ASD.

[0003] It is known that patients with human fragile X syndrome (FXS), which is caused by an abnormality in the X chromosome, often exhibit social impairment symptoms similar to those seen in ASD (Non-Patent Documents 4 to 6).

[0004] Non-Patent Document 7 and Patent Documents 1 to 6 describe TRPV1 (transient receptor potential vanilloid type 1) antagonists, but do not describe or suggest their use in treating social disorders or ASD.

[0005] International Publication WO2005 / 009988 International Publication WO2008 / 132600 International Publication WO2011 / 162409 International Publication WO2012 / 158844 International Publication WO2012 / 176061 US Publication US2020 / 0197378A1

[0006] JAMA Pediatr. 2014;168(8):721-728. Pediatrics 2014;133:e520-e529Neuron. 2016 Dec 21;92(6):1279-1293. A neurochemical theory of autism. Trends Neurosci 2: 174-177. J Intellect Disabil Res. 2015 Apr;59(4):293-306. Br J Pharmacol. 2018 Jul; 175(14): 2750-2769. Biochemical Pharmacology 78 (2009) 211-216.

[0007] Provided are new pharmaceutical compositions and methods for treating and / or preventing social disorders, such as autism spectrum disorders, fragile X syndrome, autism spectrum disorder-like symptoms, and / or disorders in social communication and / or social interaction, particularly preferably for treating autism spectrum disorders.

[0008] The present inventors have conducted extensive research into pharmaceutical compositions and methods for treating and / or preventing social disorders, such as autism spectrum disorders, fragile X syndrome, autism spectrum disorder-like symptoms, and / or disorders in social communication and / or social interactions, particularly preferably for treating autism spectrum disorders, and have found suitable active ingredients.

[0009] The present invention relates to, for example, the following:

[0010] (1) Formula (I): (In the formula, R １ is substituted or unsubstituted alkyl; R ２ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; A is N, CH, or C; when A is N or CH, the dashed line indicates the absence of a bond; when A is C, the dashed line indicates the presence of a bond; R ３ is a substituted or unsubstituted alkyl or halogen; m is 0 or 1; and R ４ and R ５ (2) A pharmaceutical composition for treating and / or preventing a social disorder, comprising a compound represented by the formula (I) or a pharmaceutically acceptable complex thereof, wherein R is independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, or a substituted or unsubstituted alkyloxycarbonyl. １ is a C2-C3 alkyl substituted with one or more hydroxy; R ２ is a halogen; and R ３ is methyl; and R ４ and R ５ are each independently a hydrogen atom, halogen, or methyl. (3) The pharmaceutical composition of (1) or (2) above, wherein the social disorder is a disorder in social communication and / or social interaction. (4) The pharmaceutical composition of any of (1) to (3) above, wherein the social disorder is an autism spectrum disorder, fragile X syndrome, and / or an autism spectrum disorder-like symptom. (5) The pharmaceutical composition of any of (1) to (4) above, wherein the social disorder is an autism spectrum disorder. (6) The compound represented by formula (I) or a pharmaceutically acceptable complex thereof is selected from the group consisting of the following compounds: (6A) The pharmaceutical composition according to any one of the above (1) to (5), wherein the compound represented by formula (I) or a pharmaceutically acceptable complex thereof is the following compound: (7) The pharmaceutical composition according to any one of (1) to (6), wherein the compound represented by formula (I) or a pharmaceutically acceptable complex thereof is a compound represented by formula (IA): (8) The pharmaceutical composition according to any one of (1) to (6) above, wherein the compound represented by formula (I) or a pharmaceutically acceptable complex thereof is a compound represented by formula (IB): or a pharmaceutically acceptable complex thereof. (9) The pharmaceutical composition according to any of (1) to (8) and (6A) above, wherein the pharmaceutically acceptable complex is a complex with hydrochloric acid, tartaric acid, benzenesulfonic acid, p-toluenesulfonic acid, or fumaric acid. (10) The pharmaceutical composition according to any of (1) to (9) and (6A) above, wherein the pharmaceutically acceptable complex is a complex with fumaric acid. (11) The pharmaceutical composition according to any of (1) to (10) and (6A) above, wherein the pharmaceutically acceptable complex is a fumaric acid cocrystal. (12) The pharmaceutical composition according to any of (1) to (11) and (6A) above, wherein the pharmaceutically acceptable complex is a complex of the compound represented by formula (I) and fumaric acid in a molar ratio of about 1:about 0.5 (alternatively, about 2:about 1). (13) The pharmaceutical composition according to any one of (1) to (12) and (6A) above, wherein the pharmaceutically acceptable complex is a complex of the compound represented by formula (I) and fumaric acid in a molar ratio of 1:0.5±0.2. (14) The pharmaceutical composition according to any one of (1) to (13) and (6A) above, wherein the compound represented by formula (I) or its pharmaceutically acceptable complex is administered in a single dose of 1 mg to 1000 mg. (15) The pharmaceutical composition according to any one of (1) to (14) and (6A) above, for the treatment and / or prevention of core symptoms of autism spectrum disorder.

[0011] (101) administering to a patient in need thereof a dose of formula (I): (In the formula, R １ is substituted or unsubstituted alkyl; R ２is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; A is N, CH, or C; when A is N or CH, the dashed line indicates the absence of a bond; when A is C, the dashed line indicates the presence of a bond; R ３ is a substituted or unsubstituted alkyl or halogen; m is 0 or 1; and R ４ and R ５ (102) A method for treating and / or preventing a social disorder, comprising administering a compound represented by the formula (I) or a pharmaceutically acceptable complex thereof, wherein R is independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, or a substituted or unsubstituted alkyloxycarbonyl. １ is a C2-C3 alkyl substituted with one or more hydroxy; R ２ is a halogen; and R ３ is methyl; and R ４ and R ５ are each independently a hydrogen atom, halogen, or methyl. (103) The method according to the above (1) or (2), wherein the social disorder is a disorder in social communication and / or social interaction. (104) The method according to any of the above (101) to (103), wherein the social disorder is an autism spectrum disorder, fragile X syndrome, and / or an autism spectrum disorder-like symptom. (105) The method according to any of the above (101) to (104), wherein the social disorder is an autism spectrum disorder. (106) The compound represented by formula (I) or a pharmaceutically acceptable complex thereof is selected from the group consisting of the following compounds: (106A) The method according to any one of the above (101) to (105), wherein the compound represented by formula (I) or a pharmaceutically acceptable complex thereof is the following compound: (107) The method according to any one of the above (101) to (106), wherein the compound represented by formula (I) or a pharmaceutically acceptable complex thereof is a compound represented by formula (IA): (108) The method according to any one of the above (101) to (106), wherein the compound represented by formula (I) or a pharmaceutically acceptable complex thereof is a compound represented by formula (IB): or a pharmaceutically acceptable complex thereof. (109) The method according to any one of (101) to (108) and (106A) above, wherein the pharmaceutically acceptable complex is a complex with hydrochloric acid, tartaric acid, benzenesulfonic acid, p-toluenesulfonic acid, or fumaric acid. (110) The method according to any one of (101) to (109) and (106A) above, wherein the pharmaceutically acceptable complex is a complex with fumaric acid. (111) The method according to any one of (101) to (110) and (106A) above, wherein the pharmaceutically acceptable complex is a fumaric acid cocrystal. (112) The method according to any one of (101) to (111) and (106A) above, wherein the pharmaceutically acceptable complex is a complex of the compound represented by formula (I) and fumaric acid in a molar ratio of about 1:about 0.5 (alternatively about 2:about 1). (113) The method according to any one of the above (101) to (112) and (106A), wherein the pharmaceutically acceptable conjugate is a complex of the compound of formula (I) and fumaric acid in a molar ratio of 1:0.5±0.2. (114) The method according to any one of the above (101) to (113) and (106A), wherein the single dose of the compound of formula (I) or its pharmaceutically acceptable conjugate is 1 mg to 1000 mg. (115) The method according to any one of the above (101) to (114) and (106A), for the treatment and / or prevention of core symptoms of autism spectrum disorder.

[0012] (201) A compound of formula (I): (In the formula, R １ is substituted or unsubstituted alkyl; R ２ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; A is N, CH, or C; when A is N or CH, the dashed line indicates the absence of a bond; when A is C, the dashed line indicates the presence of a bond; R ３is a substituted or unsubstituted alkyl or halogen; m is 0 or 1; and R ４ and R ５ (202) R is a compound represented by the formula (I) or a pharmaceutically acceptable complex thereof, wherein R is independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, or a substituted or unsubstituted alkyloxycarbonyl. １ is a C2-C3 alkyl substituted with one or more hydroxy; R ２ is a halogen; and R ３ is methyl; and R ４ and R ５ are each independently a hydrogen atom, a halogen atom, or a methyl. (203) The compound according to the above (201) or (202) or a pharmaceutically acceptable complex thereof for use in the treatment and / or prevention of a disorder in social communication and / or social interaction. (204) The compound according to any of the above (201) to (203) or a pharmaceutically acceptable complex thereof for use in the treatment and / or prevention of autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms. (205) The compound according to any of the above (201) to (204) or a pharmaceutically acceptable complex thereof for use in the treatment and / or prevention of autism spectrum disorder. (206) The following compound: (206A) The compound according to any one of the above (201) to (205), or a pharmaceutically acceptable complex thereof. (207) The compound according to any one of the above (201) to (206), which is a compound of formula (IA): (208) The compound according to any one of (201) to (206) above, which is a compound represented by formula (IB) or a pharmaceutically acceptable complex thereof. or a pharmaceutically acceptable complex thereof. (209) The compound or a pharmaceutically acceptable complex thereof according to any of the above (201) to (208) and (206A), wherein the pharmaceutically acceptable complex is a complex with hydrochloric acid, tartaric acid, benzenesulfonic acid, p-toluenesulfonic acid, or fumaric acid. (210) The compound or a pharmaceutically acceptable complex thereof according to any of the above (201) to (209) and (206A), wherein the pharmaceutically acceptable complex is a complex with fumaric acid. (211) The compound or a pharmaceutically acceptable complex thereof according to any of the above (201) to (210) and (206A), wherein the pharmaceutically acceptable complex is a fumaric acid cocrystal. (212) The compound according to any one of the above (201) to (211) and (206A) or a pharmaceutically acceptable complex thereof, wherein the pharmaceutically acceptable complex is a complex of the compound represented by formula (I) and fumaric acid in a molar ratio of about 1:about 0.5 (alternatively, about 2:about 1). (213) The compound according to any one of the above (201) to (212) and (206A) or a pharmaceutically acceptable complex thereof, wherein the pharmaceutically acceptable complex is a complex of the compound represented by formula (I) and fumaric acid in a molar ratio of 1:0.5±0.2. (214) The compound according to any one of the above (201) to (213) and (206A) or a pharmaceutically acceptable complex thereof, wherein the single dose of the compound represented by formula (I) or a pharmaceutically acceptable complex thereof is 1 mg to 1000 mg. (215) The compound according to any one of the above (201) to (214) and (206A) or a pharmaceutically acceptable complex thereof for the treatment and / or prevention of core symptoms of autism spectrum disorder.

[0013] (301) A compound of formula (I): (In the formula, R １ is substituted or unsubstituted alkyl; R ２is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; A is N, CH, or C; when A is N or CH, the dashed line indicates the absence of a bond; when A is C, the dashed line indicates the presence of a bond; R ３ is a substituted or unsubstituted alkyl or halogen; m is 0 or 1; and R ４ and R ５ (302) R is a compound represented by the formula (I) or a pharmaceutically acceptable complex thereof, wherein R is independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, or a substituted or unsubstituted alkyloxycarbonyl. １ is a C2-C3 alkyl substituted with one or more hydroxy; R ２ is a halogen; and R ３ is methyl; and R ４ and R ５ are each independently a hydrogen atom, halogen, or methyl. (303) Use of the compound according to the above (301) or (302) or a pharmaceutically acceptable complex thereof for the manufacture of a pharmaceutical composition for the treatment and / or prevention of disorders in social communication and / or social interactions. (304) Use of the compound according to any of the above (301) to (303) or a pharmaceutically acceptable complex thereof for the manufacture of a pharmaceutical composition for the treatment and / or prevention of autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms. (305) Use of the compound according to any of the above (301) to (304) or a pharmaceutically acceptable complex thereof for the manufacture of a pharmaceutical composition for the treatment and / or prevention of autism spectrum disorder. (306) A compound represented by formula (I) or a pharmaceutically acceptable complex thereof is selected from the group consisting of the following compounds: (306A) The use according to any one of the above (301) to (305), wherein the compound represented by formula (I) or a pharmaceutically acceptable complex thereof is the following compound: (307) The use according to any one of the above (201) to (306), wherein the compound represented by formula (I) or a pharmaceutically acceptable complex thereof is a compound represented by formula (IA): (308) The use according to any one of the above (301) to (306), wherein the compound represented by formula (I) or a pharmaceutically acceptable complex thereof is a compound represented by formula (IB): or a pharmaceutically acceptable complex thereof. (309) The use according to any one of the above (301) to (308) and (306A), wherein the pharmaceutically acceptable complex is a complex with hydrochloric acid, tartaric acid, benzenesulfonic acid, p-toluenesulfonic acid, or fumaric acid. (310) The use according to any one of the above (301) to (309) and (306A), wherein the pharmaceutically acceptable complex is a complex with fumaric acid. (311) The use according to any one of the above (301) to (310) and (306A), wherein the pharmaceutically acceptable complex is a fumaric acid cocrystal. (312) The use according to any one of the above (301) to (311) and (306A), wherein the pharmaceutically acceptable complex is a complex of the compound represented by formula (I) and fumaric acid in a molar ratio of about 1:about 0.5 (or about 2:about 1). (313) The use according to any one of the above (301) to (312) and (306A), wherein the pharmaceutically acceptable complex is a complex of the compound represented by formula (I) and fumaric acid in a molar ratio of 1:0.5±0.2. (314) The use according to any one of the above (301) to (313) and (306A), wherein the dosage of the compound represented by formula (I) or its pharmaceutically acceptable complex is 1 mg to 1000 mg per administration. (315) The use according to any one of the above (301) to (314) and (306A), for the treatment and / or prevention of core symptoms of autism spectrum disorder.

[0014] The pharmaceutical compositions and methods of the present invention are useful for the treatment and / or prevention of various psychiatric disorders, in particular social disorders such as autism spectrum disorders, fragile X syndrome, autism spectrum disorder-like symptoms, and / or disorders in social communication and / or social interaction.

[0015] 1 shows the results of evaluating the social behavior-improving effect of the compound represented by formula (IB) using BTBR model mice, which are ASD model mice.

[0016] The term "consisting of" means having only the elements. The term "including" means being open-ended and not excluding unrecited elements.

[0017] The present invention will be described below with reference to embodiments. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning commonly used in the above-mentioned field unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0018] "Halogen" includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Fluorine and chlorine atoms are preferred, with a fluorine atom being particularly preferred. "Alkyl" includes a straight-chain or branched hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0019] Substituents for "substituted or unsubstituted alkyl," "substituted or unsubstituted alkyloxy," and "substituted or unsubstituted alkyloxycarbonyl" include Substituent Group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, sulfanyl, and cyano.

[0020] Examples of "social disorders" include disorders in social communication and / or social interactions, such as autism spectrum disorder, fragile X syndrome, and autism spectrum disorder-like conditions, such as autism spectrum disorder. "Autistic Spectrum Disorder (ASD)" is a type of neurodevelopmental disorder, including autistic disorder, Asperger's syndrome, and pervasive developmental disorder not otherwise specified. The term (definition), characteristics, and diagnostic criteria for ASD can be found in the International Classification of Diseases (ICD) 11th Edition by the World Health Organization (WHO) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-5®) by the American Psychiatric Association. Criteria for accurately diagnosing autism spectrum disorder are not limited to the ICD-11 and DSM-5. Core symptoms of autism spectrum disorder include "persistent impairment in social communication and / or social interaction" and "symptoms related to restricted and repetitive patterns of behavior, interests, or activities" in patients with autism spectrum disorder, for example, persistent impairment in social communication and / or social interaction. "Autism spectrum disorder-like symptoms" include cases where a patient does not meet the diagnostic criteria for autism spectrum disorder but exhibits autism spectrum disorder-like symptoms. "Autism spectrum disorder-like symptoms" also include autism spectrum disorder-like symptoms associated with other diseases (e.g., Fragile X syndrome, Rett syndrome, tuberous sclerosis complex (TSC), etc.). "Autism spectrum disorder-like symptoms" include, for example, "(persistent) impairment in social communication and / or social interaction" and "symptoms related to restricted and repetitive patterns of behavior, interests, or activities," preferably (persistent) impairment in social communication and / or social interaction.

[0021] The terms (definitions), characteristics of the disorders, and diagnostic criteria for "Fragile X syndrome" and "Rett syndrome" can be found in, for example, the 11th edition of the International Classification of Diseases (ICD) compiled by the World Health Organization (WHO).

[0022] In this specification, unless the context dictates otherwise, the use of "about" before a numerical value X includes a range of + / - 10% of the numerical value X and includes values ​​rounded to the nearest significant figure, taking into account the significant digits of the numerical value X. For example, about 1 mg includes 0.9 mg and 1.4 mg.

[0023] Preferred embodiments of each substituent in the compound represented by formula (I) are shown below. Examples of the compound represented by formula (I) include all combinations of the specific examples shown below.

[0024] R １ is a substituted or unsubstituted alkyl. １ is alkyl optionally substituted with one or more groups selected from the substituent group α. １ is alkyl substituted with one or more hydroxy groups. １ is a C2-C3 alkyl substituted with one or more hydroxy groups. １ is a C2-C3 alkyl substituted with two hydroxy groups.

[0025] R ２ is a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl. ２ is a hydrogen atom, a halogen atom, or an alkyl group optionally substituted with one or more halogen atoms. ２ is a halogen.

[0026] A is N, CH or C. A is N. A is CH. A is C. is.

[0027] R ３ is a substituted or unsubstituted alkyl or halogen.３ is a substituted or unsubstituted alkyl. ３ is alkyl optionally substituted with one or more groups selected from the substituent group α. ３ is a C1-C3 alkyl optionally substituted with one or more groups selected from Substituent Group α. ３ is methyl.

[0028] m is 0 or 1. m is 1. m is 0.

[0029] R ４ and R ５ are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, or a substituted or unsubstituted alkyloxycarbonyl. ４ and R ５ are each independently alkyl optionally substituted with one or more groups selected from Substituent Group α, alkyloxy optionally substituted with one or more groups selected from Substituent Group α, alkyloxycarbonyl optionally substituted with one or more groups selected from Substituent Group α, a hydrogen atom, or a halogen. ４ and R ５ are each independently a C1 to C3 alkyl optionally substituted with one or more groups selected from Substituent Group α, a hydrogen atom, or a halogen. ４ and R ５ are each independently a hydrogen atom, a halogen atom, or a methyl.

[0030] (wherein bond a is bonded to the pyridine ring and bond b is bonded to the carbonyl group) includes the following embodiments: When A is CH, the H is R ３ may be substituted with Preferably, The group represented by is.

[0031] The "pharmaceutically acceptable complex" includes a pharmaceutically acceptable salt, a pharmaceutically acceptable co-crystal, and a combination thereof. A pharmaceutically acceptable co-crystal is preferred. The "pharmaceutically acceptable complex" is preferably a complex with hydrochloric acid, tartaric acid, benzenesulfonic acid, p-toluenesulfonic acid, or fumaric acid. A complex with fumaric acid is particularly preferred. For example, a "complex with fumaric acid" includes a fumarate salt, a co-crystal with fumaric acid, or a combination thereof.

[0032] As used herein, examples of "pharmaceutically acceptable salts" include basic salts, for example, alkali metal salts such as lithium salts, sodium salts, potassium salts, etc.; alkaline earth metal salts such as calcium salts, barium salts, etc.; transition metal salts such as zinc salts, iron salts, etc.; magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, ethylenediamine salts, meglumine salts, procaine salts, etc.; aralkylamine salts such as N,N-dibenzylethylenediamine, etc.; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, isoquinoline salts, etc.; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts, tetrabutylammonium salts, etc.; Acid salts include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, hydrobromide, hydroiodide, and perchlorate; organic acid salts such as formate, acetate, propionate, trifluoroacetate, citrate, lactate, tartrate, oxalate, maleate, fumarate, succinate, mandelate, glutarate, malate, benzoate, phthalate, and ascorbate; sulfonate salts such as methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate; and acidic amino acid salts such as aspartate and glutamate. These salts can be formed by conventional methods. In another embodiment, the pharmaceutically acceptable salt is a fumarate salt. In another embodiment, the pharmaceutically acceptable fumarate salt contains about 1 equivalent of the compound of Formula (I) and about 0.5 equivalents of fumaric acid, for example, in one embodiment, about 0.3 to about 0.7 equivalents of fumaric acid, in another embodiment, about 0.4 to about 0.6 equivalents of fumaric acid, in another embodiment, about 0.44 to about 0.56 equivalents of fumaric acid, or in another embodiment, about 0.47 to about 0.53 equivalents of fumaric acid. In another embodiment, the pharmaceutically acceptable fumarate salt contains 1 equivalent of the compound of Formula (I) and 0.5 equivalents of fumaric acid.In one embodiment, the salt contains about 2 equivalents of the compound of formula (I) and about 1 equivalent of fumaric acid. Those skilled in the art can prepare acid addition salts of the compound of formula (I), for example, by reacting the compound with the appropriate acid using a variety of known methods.

[0033] Examples of a "pharmaceutically acceptable co-crystal" of the compound of formula (I) (including a compound of formula (IA) and a compound of formula (IB)); the same applies hereinafter) include co-crystals with inorganic acids such as hydrochloride, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hydrogencarbonate, hydrobromic acid, hydroiodic acid, and perchloric acid; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, and ascorbic acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid. Another aspect includes co-crystals with, for example, hydrochloric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, succinic acid, fumaric acid, citric acid, oxalic acid, benzoic acid, cinnamic acid, caproic acid, sorbic acid, etc. In one embodiment, the co-crystal with the compound of Formula (I) comprises hydrochloric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, succinic acid, fumaric acid, citric acid, oxalic acid, benzoic acid, or any mixture thereof. In another embodiment, the co-crystal with the compound of Formula (I) comprises hydrochloric acid, benzenesulfonic acid, toluenesulfonic acid, L-tartaric acid, fumaric acid, or any mixture thereof. In another embodiment, the co-crystal consists of the compound of Formula (I) and hydrochloric acid. In another embodiment, the co-crystal consists of the compound of Formula (I) and benzenesulfonic acid. In another embodiment, the co-crystal consists of the compound of Formula (I) and toluenesulfonic acid. In another embodiment, the co-crystal consists of the compound of Formula (I) and L-tartaric acid. In another embodiment, the co-crystal comprises a compound of Formula (I) and fumaric acid. In another embodiment, the co-crystal contains about 1 equivalent of the compound of Formula (I) and about 0.5 equivalents of fumaric acid, for example, in one embodiment, about 0.3 to about 0.7 equivalents of fumaric acid, in another embodiment, about 0.4 to about 0.6 equivalents of fumaric acid, in another embodiment, about 0.44 to about 0.56 equivalents of fumaric acid, or in another embodiment, about 0.47 to about 0.53 equivalents of fumaric acid. In another embodiment, the co-crystal contains 1 equivalent of the compound of Formula (I) and 0.5 equivalents of fumaric acid. In one aspect, the co-crystal contains about 2 equivalents of the compound of Formula (I) and about 1 equivalent of fumaric acid.

[0034] However, it is recognized in the art that "the precise classification of a compound as a salt or co-crystal can sometimes be somewhat ambiguous" (Aakeroy et al., "Co-crystal or Salt: Does it Really Matter?" Mol. Pharmaceutics 4(3):317-322 (2007)). The phrase "and combinations thereof," when used in the context of salts and / or co-crystals, should be understood to mean that in one embodiment, properties ascribed to a salt and other properties ascribed to a co-crystal are simultaneously present; and in other embodiments, intermediate properties between those ascribed to a salt and those ascribed to a co-crystal are present.

[0035] The compound of formula (I) or a pharmaceutically acceptable complex thereof may be a solvate, co-crystal, and / or crystalline polymorph. Solvates include organic solvates in which any number of organic solvent molecules are coordinated, and hydrates in which any number of water molecules are coordinated. As used herein, the term "solvate" refers to a solvate of the compound or a pharmaceutically acceptable salt thereof, and includes, for example, a monosolvate, a disolvate, a monohydrate, a dihydrate, and the like. Examples of the solvate include a hydrate, an ethanol solvate, a methyl acetate solvate, an ethyl acetate and 2-propanol solvate, an n-propyl acetate and 2-propanol solvate, an acetonitrile solvate, a 1,2-dimethoxyethane solvate, and a methyl isobutyl ketone solvate. Preferably, the solvate is a hydrate, such as a monohydrate, or a trihydrate.

[0036] The compound of formula (I) or a pharmaceutically acceptable complex thereof may be administered as a possible isomer of the compound of formula (I) (e.g., keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotamer, racemate or a mixture thereof), a prodrug or a pharmaceutically acceptable complex thereof.

[0037] The compound of formula (I) or a pharmaceutically acceptable complex thereof may form a prodrug, and the present invention also encompasses various such prodrugs. A prodrug is a derivative of a compound of the present invention having a chemically or metabolically decomposable group, and is a compound that becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to a compound of formula (I) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted to a compound of formula (I) by hydrolysis with gastric acid, etc. Methods for selecting and preparing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." Prodrugs may themselves be active.

[0038] One or more hydrogen, carbon and / or other atoms of the compounds of formula (I) may be replaced by isotopes of the respective hydrogen, carbon and / or other atoms. Examples of such isotopes include: ２ H. ３ H. １１ C. １３ C. １４ C. １５ N. １８ O. １７ O. ３１ P. ３２ P. ３５ S. １８ F. 123 I and ３６ The isotopes of the compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as Cl. The compounds of formula (I) also include compounds substituted with such isotopes. The isotope-substituted compounds are also useful as pharmaceuticals, and include all radiolabeled compounds of formula (I). Also included in the present invention is a "radiolabeling method" for producing the "radiolabeled compounds," which are useful as research and / or diagnostic tools in metabolism pharmacokinetic studies and binding assays.

[0039] Radiolabeled compounds of formula (I) can be prepared by methods well known in the art. For example, tritium-labeled compounds of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) via catalytic dehalogenation using tritium. This method involves reacting a suitable halogen-substituted precursor of formula (I) with tritium gas in the presence of a suitable catalyst, such as Pd / C, in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." １４ C-labeled compounds are １４ It can be prepared by using a raw material having C carbon.

[0040] A pharmaceutical composition can be prepared by mixing an effective amount of the compound used in the present invention with various pharmaceutical additives suitable for the dosage form, such as excipients, binders, disintegrants, lubricants, etc., as needed. Furthermore, by appropriately changing the effective amount of the compound, dosage form, and / or various pharmaceutical additives, the pharmaceutical composition can also be made into a pharmaceutical composition for children, the elderly, critically ill patients, or surgical patients.

[0041] The route of administration of the pharmaceutical composition of the present invention is not particularly limited, and it can be administered either orally or parenterally. Parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, otic, and vaginal administration.

[0042] For oral administration, the composition may be prepared and administered in any of the commonly used dosage forms, such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) and liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, perfumes, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0043] In the case of parenteral administration, any of the commonly used dosage forms such as injections, infusions, topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.) can be suitably administered. Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types. Pharmaceutical compositions for transdermal administration include, but are not limited to, solid preparations for topical use (e.g., powders for topical use), liquid preparations for topical use (e.g., liniments, lotions), sprays (aerosols for topical use, pump sprays), ointments, creams, gels, patches (e.g., tapes (e.g., plasters, plasters), poultices), etc.

[0044] The embodiments of the method, agent, and pharmaceutical composition of the present invention are not particularly limited and can be appropriately determined depending on the severity of symptoms, the patient's weight and age, the dosage form of the drug, and the like.

[0045] Pharmaceutical compositions can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives, such as excipients, binders, disintegrants, and lubricants, appropriate for the dosage form, as needed. Furthermore, by appropriately modifying the effective amount of the compound of the present invention, the dosage form, and / or the various pharmaceutical additives, the pharmaceutical compositions can also be prepared for pediatric, elderly, and critically ill patients. For example, pediatric pharmaceutical compositions can be administered to newborns (less than 4 weeks old), infants (4 weeks old to less than 1 year old), toddlers (1 year old to less than 7 years old), children (7 years old to less than 15 years old), or patients aged 15 to 18 years. For example, pharmaceutical compositions for the elderly can be administered to patients aged 65 years or older.

[0046] The dosage of the compound represented by formula (I) or its pharmaceutically acceptable conjugate in the pharmaceutical composition of the present invention is desirably determined taking into consideration the patient's age and body weight, the type and severity of the disease, the route of administration, and the like. The dosage per administration is, for example, 0.1 mg to 2000 mg, for example, 0.1 mg to 1000 mg, for example, 1 mg to 1000 mg, for example, 1 mg to 600 mg, preferably 1 mg to 300 mg, for example, 1 mg to 200 mg, for example, 1 mg to 100 mg. For example, it can be administered once a day. For example, it can be administered twice a day. The daily dosage is, for example, 0.1 mg to 2000 mg, for example, 0.1 mg to 1000 mg, for example, 1 mg to 600 mg, preferably 1 mg to 300 mg, for example, 1 mg to 200 mg, for example, 1 mg to 100 mg. For example, it can be administered orally at the above-mentioned doses. In another embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable conjugate thereof in the pharmaceutical composition of the present invention is, for example, 0.1 mg / kg to 1000 mg / kg, for example, 0.1 mg / kg to 500 mg / kg, for example, 0.1 mg / kg to 100 mg / kg, 0.1 mg / kg to 30 mg / kg, for example, 1 mg / kg to 30 mg / kg, for example, 1 mg / kg to 10 mg / kg, for example, 1 mg / kg to 5 mg / kg, for example, 2.5 mg / kg to 5 mg / kg. In the case of parenteral administration, the dosage varies greatly depending on the route of administration, but is, for example, 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This dosage may be administered once or in divided doses per day.

[0047] The methods, pharmaceutical compositions, etc. of the present invention may include package inserts or labels written to identify the patient or subject targeted by the present invention as a treatment target and to provide instructions to medical professionals, such as physicians, involved in the prevention or treatment of the disease, regarding guidelines for treatment and / or prevention, such as dosage and administration, precautions, etc. However, these official documents are not limited to paper media and can be provided via the Internet. Furthermore, guidelines for prevention or treatment can be provided to physicians and others based on various other information sources in addition to official documents. Therefore, it is understood that the present invention also encompasses embodiments in which the drug is used based on information other than package inserts or labels. The methods, agents, medicaments, and pharmaceutical compositions of the present invention may be used in combination with, or without, other psychiatric medications (including digital medications) and / or other therapies (including various non-drug therapies).

[0048] The pharmaceutical composition or method of the present invention preferably has one or more excellent features selected from the following: a) It is useful for the treatment and / or prevention of social disorders, such as autism spectrum disorder, fragile X syndrome, autism spectrum disorder-like symptoms, and / or disorders in social communication and / or interactions. Preferably, it is useful for the treatment and / or prevention of autism spectrum disorder. Particularly preferably, it is useful for the treatment and / or prevention of core symptoms of autism spectrum disorder. b) It is highly safe. For example, it can be a pharmaceutical product with a high safety margin due to its low effective therapeutic dose and concentration. It can also be a pharmaceutical product with a low risk of side effects. For example, it has a low risk of side effects such as elevated body temperature. For example, it has a low brain penetration rate, resulting in a low risk of central nervous system side effects.

[0049] The compound represented by formula (I) or a pharmaceutically acceptable conjugate thereof can be synthesized according to known methods. For example, Patent Documents 1 to 5 can be referenced. Patent Document 2 describes a method for preparing the compound represented by formula (I) of the present application or a pharmaceutically acceptable conjugate thereof, as well as the results of a binding assay with TRPV1. For example, Example 12 of Patent Document 2 describes the results of a TRPV1 binding assay for compounds represented by formula (I) of the present application (e.g., compounds L1, R1, W1, V2, W2, B3, P3, C4, H4, L4, Z4, F5, N5, O5, Z5, V6, etc. in Patent Document 2). Patent Document 3 describes a method for preparing the compound represented by formula (I) of the present application or a pharmaceutically acceptable conjugate thereof, as well as the results of a binding assay with TRPV1. For example, Table 4 of Patent Document 3 describes assay results for compounds represented by formula (I) of the present application (e.g., compounds ACU, ABD, ADF, and AAH in Patent Document 3). For example, Table 5 of Patent Document 3 describes assay results for compounds represented by formula (I) of the present application (e.g., compounds AEF and ADK in Patent Document 3). Patent Document 5 describes a method for preparing the compound represented by formula (I) or a pharmaceutically acceptable complex thereof, and test results for the compound represented by formula (I) or a pharmaceutically acceptable complex thereof. For example, Example 10 of Patent Document 5 describes a method for preparing a complex of the compound represented by formula (IB) of the present application (compound A155(a) in Patent Document 5) and fumaric acid in an average molar ratio of about 1:0.5±0.2, as well as powder X-ray analysis results. Furthermore, it is described that the complex exhibited cocrystalline properties based on NMR analysis and other data. Furthermore, Figure 2 and the like of Patent Document 5 discloses the dihydrochloride salt of the compound represented by formula (IB) of the present application (compound A155(a) of Patent Document 5). Examples 11, 12, 13, and 14 disclose combinations of the compound represented by formula (IB) of the present application (compound A155(a) of Patent Document 5) with hydrochloric acid, tartaric acid, benzenesulfonic acid, or toluenesulfonic acid, respectively.Example 15 describes the test results (TRPV1 binding assay) of the compounds represented by formula (I) of the present application (compounds A122(a), A122(b), A122(c), A122(e), A123(e), A125(b), A125(e), A126(a), A126(e), A155(a), A155(b), A155(d), A155(e), A158(a), B122(j), B122(k), and many others). Example 17 describes the results of an in vivo assay of body temperature elevation. (Examples).

[0050] The present invention will be described below based on examples, but the present invention is not limited to these examples in any way.

[0051] Example 1: Evaluation of Pharmacological Efficacy Using BTBR Mice BTBR T+tf / J (BTBR) mice are one of the commonly used ASD model mice because they exhibit ASD-like symptoms, such as social impairment and repetitive behaviors, consistent with the diagnostic criteria for ASD (Physiol Behav. 2012 Dec 5; 107(5):649-662. Doi: 10.1016 / j.physbeh.2011.12.025). Using these mice, the pharmacological efficacy of the compound represented by formula (IB) on social impairment was evaluated. A reciprocal social interaction test was used to evaluate sociality. In this test, two mice were placed in a cage, and the number of seconds that the test mouse (test mouse) engaged in sniffing, a social behavior, toward the intruder mouse was quantified as an index of sociality. As a control group, 0.5 w / v% methylcellulose 400 solution (vehicle) or 30 mg / kg of the fumaric acid cocrystal of the compound represented by formula (IB) (a complex having a molar ratio of the compound represented by formula (IB) to fumaric acid of approximately 1:approximately 0.5) was orally administered, and the amount of social behavior was quantified for 5 minutes starting 1 hour after administration. Note that 30 mg / kg of the fumaric acid cocrystal of the compound represented by formula (IB) corresponds to 26.57 mg / kg of the free form of the compound represented by formula (IB). The results are shown in Figure 1. Compared to the vehicle, administration of 30 mg / kg of the fumaric acid cocrystal of the compound represented by formula (IB) significantly increased the amount of social behavior. These results suggest that the compound represented by formula (IB) or a pharmaceutically acceptable complex thereof has the effect of improving social impairment in ASD and is therefore considered useful as a therapeutic agent for ASD. Similarly, the compound represented by formula (IB) or a pharmaceutically acceptable complex thereof (e.g., a cocrystal of the compound represented by formula (IB) with fumaric acid) can be administered to BTBR model mice at 1 mg / kg, 3 mg / kg, or 10 mg / kg, and the effect of improving social impairment can be evaluated.

[0052] (Formulation Examples) The formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention in any way.

[0053] The compound of formula (I) or a pharmaceutically acceptable complex thereof can be administered as a pharmaceutical composition by any conventional route, for example, orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of an injectable solution or suspension, or topically, e.g., in the form of a lotion, gel, ointment, or cream, or intranasally or in the form of a suppository. Pharmaceutical compositions containing the compound of formula (I) or a pharmaceutically acceptable complex thereof in free form or in the form of a pharmaceutically acceptable complex together with at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation, or coating methods. For example, oral compositions can be in the form of tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. Injectable compositions can be in the form of solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc.

[0054] The pharmaceutical composition of the present invention comprising the compound represented by formula (I) or a pharmaceutically acceptable conjugate thereof, and the method of administering the compound represented by formula (I) or a pharmaceutically acceptable conjugate thereof are useful for the treatment and / or prevention of social disorders, such as autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms.

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, R １ is a substituted or unsubstituted alkyl group; R ２ is a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl; A is N, CH, or C; When A is N or CH, the dashed line indicates the absence of a bond; When A is C, the dashed line indicates the existence of a connection; R ３ is a substituted or unsubstituted alkyl or halogen; m is 0 or 1; and, R ４ and R ５ A pharmaceutical composition for the treatment and / or prevention of social disorders comprising a compound or a pharmaceutically acceptable complex thereof, wherein each of the compounds is independently represented by a hydrogen atom, a halogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyloxy, or a substituted or unsubstituted alkyloxycarbonyl.

2. R １ However, it is a C2-C3 alkyl group substituted with one or more hydroxyls; R ２ However, it is a halogen; 【Chemistry 2】 And; R ３ However, it is methyl; and, R ４ and R ５ are each independently a hydrogen atom, halogen or methyl, the pharmaceutical composition according to claim 1.

3. The pharmaceutical composition according to claim 1, wherein the social disorder is a disorder in social communication and / or social interaction.

4. The pharmaceutical composition according to claim 1, wherein the social impairment is autism spectrum disorder, fragile X syndrome, and / or autism spectrum disorder-like symptoms.

5. The pharmaceutical composition according to claim 1, wherein the social disorder is autism spectrum disorder.

6. The compound represented by formula (I) or a pharmaceutically acceptable complex thereof is one of the following compounds: 【Transformation 3】 A pharmaceutical composition according to any one of claims 1 to 5, or a pharmaceutically acceptable complex thereof.

7. The compound represented by formula (I) or a pharmaceutically acceptable complex thereof is formula (I-A): 【Chemistry 4】 A pharmaceutical composition according to any one of claims 1 to 5, wherein the compound represented by or a pharmaceutically acceptable complex thereof.

8. The compound represented by formula (I) or a pharmaceutically acceptable complex thereof is formula (I-B): 【Transformation 5】 A pharmaceutical composition according to any one of claims 1 to 5, wherein the compound represented by or a pharmaceutically acceptable complex thereof.

9. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutically acceptable complex is a complex with hydrochloric acid, tartaric acid, benzenesulfonic acid, p-toluenesulfonic acid, or fumaric acid.

10. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutically acceptable complex is a complex with fumaric acid.

Images