Gene expression regulating agent

Abstract

The present invention provides an agent for regulating the expression of at least one gene selected from the group consisting of, for example, (i) a Wnt signal-related gene group, (ii) a neurulation-related gene group, (iii) a gene group related to cell adhesion, cell substrate, and blood-brain barrier regulation, (iv) a gene group related to memory and learning, (v) an inflammation-related gene group, and (vi) a gene group classified as RESPONSE TO HORMONE and the like in the pathway classification in the Gene Ontology biological process, the agent containing a melatonin receptor agonist.

Description

Gene expression regulators

[0001] The present invention relates to melatonin receptor agonists, and is directed to (i) Wnt signaling-related genes, (ii) neurulation-related genes, (iii) genes related to cell adhesion, cell matrix, and blood-brain barrier regulation, (iv) genes related to memory and learning, and (v) inflammation-related genes, and (vi) genes classified in pathways of Gene Ontology biological processes (typically, MSigDB v2023.2.Hs (Oct 2023)) as RESPONSE TO HORMONE, REGULATION OF HORMONE LEVELS, TISSUE MIGRATION PROCESSING AND PRESENTATION, REGULATION OF VIRAL PROCESS, NEVATIVE REGULATION OF VIRAL PROCESS, POSITIVE REGULATION OF MESENCHYMAL CELL PROLIFERATION, MUSCLE ORGAN DEVELOPMENT, NEGATIVE REGULATION OF NOTCH SIGNALING PATHWAY, and POSITIVE REGULATION OF BLOOD. The present invention relates to an agent for regulating the expression of at least one gene selected from the group consisting of genes classified into CIRCULATION and RESPONSE TO OXYGEN LEVELS, etc. The present invention also relates to an agent for preventing or treating diseases caused by the expression of the above genes or symptoms associated with the diseases.

[0002] Melatonin receptors regulate circadian rhythms. Melatonin receptor agonists, such as melatonin, ramelteon, and tasimelteon, have high affinity for melatonin receptors and are known to improve sleep disorders at doses that regulate circadian rhythms. Therefore, compounds containing melatonin receptor affinity have been used clinically as sleep-promoting drugs for insomnia accompanied by difficulty falling asleep.

[0003] In addition to sleep-wake disorders such as insomnia, which is accompanied by difficulty falling asleep, circadian rhythm disorders have also been reported in various neurodevelopmental syndromes including attention-deficit hyperactivity disorder and Smith-McGinnis syndrome, schizophrenia spectrum disorders including schizophrenia, neurodementias such as dementia, mild cognitive impairment, and Alzheimer's disease, and psychiatric and neurological disorders including chronic fatigue syndrome, which is a sequela of COVID-19 infection, and neurodegenerative diseases.

[0004] For example, Alzheimer's disease is the main cause of dementia, accounting for 60-80% of cases, affecting 44 million people worldwide, and is estimated to reach more than 100 million by 2050. Currently, Alzheimer's disease patients are treated with medications targeting degenerated substances such as degenerated amyloid beta, but these are limited to patients who meet certain conditions, such as the extent of the degenerated substance. Meanwhile, sleep disorders have been reported in many Alzheimer's disease patients.

[0005] In addition to sleep disorders, patients with these various psychiatric and neurological disorders often exhibit a wide range of symptoms, including autistic-like symptoms such as stereotypic movements and obsessions, anxiety, stress, hyperactivity, aggression, social behavior disorders, and cognitive dysfunction. Furthermore, for example, patients with dementia are known to simultaneously develop a wide range of psychiatric and neurological disorders, including behavioral and psychological signs and symptoms of dementia (BPSD).

[0006] Many clinical trials have been reported in which melatonin receptor agonists were administered to such patients, and although most of these have confirmed their effectiveness against sleep disorders, to the best of the inventors' knowledge, no efficacy has been observed against symptoms other than sleep disorders (Non-Patent Documents 1 to 5).

[0007] Moon E et al., Curr Psychiatry Rep. 2022 Nov;24(11):623-634.Salanitro M et al., Neurosci Biobehav Rev. 2022 Aug;139:104723.Moon E et al., Neuropsychopharmacology. 2022 Jul;47(8):1523-1536.Yuge K et al., BMC Psychiatry. 2020 Sep 10;20(1):445.Duan C et al., World J Psychiatry. 2021 Aug 19;11(8):463-476.

[0008] An object of the present invention is to provide a melatonin receptor agonist-containing compound for (i) Wnt signaling-related genes, (ii) neurulation-related genes, (iii) cell adhesion, cell matrix, and blood-brain barrier regulation-related genes, (iv) memory and learning-related genes, (v) inflammation-related genes, and (vi) pathways classified in Gene Ontology biological processes (typically, MSigDB v2023.2.Hs (Oct 2023)) as RESPONSE TO HORMONE, REGULATION OF HORMONE LEVELS, TISSUE MIGRATION PROCESSING AND PRESENTATION, REGULATION OF VIRAL PROCESS, NEVATIVE REGULATION OF VIRAL PROCESS, POSITIVE REGULATION OF MESENCHYMAL CELL PROLIFERATION, MUSCLE ORGAN DEVELOPMENT, NEGATIVE REGULATION OF NOTCH SIGNALING PATHWAY, POSITIVE REGULATION OF BLOOD The present invention also provides an agent for regulating the expression of at least one gene selected from the group consisting of genes classified into CIRCULATION and RESPONSE TO OXYGEN LEVELS, etc. The present invention also provides an agent for preventing or treating diseases caused by the expression of the above genes or symptoms associated with the diseases.

[0009] The present inventors aimed to develop pharmaceuticals that are effective not only for sleep disorders but also for a wide range of other symptoms in psychiatric and neurological disorders. Surprisingly, the inventors found that melatonin receptor agonists induce large-scale changes in the expression of not only circadian rhythm-related genes but also genes involved in various physiological functions in the hippocampus of pathological mouse models of psychiatric and neurological disorders. The genes whose expression levels were statistically significantly altered were primarily classified into several physiological pathways. These include WNT signaling, cell adhesion, cell matrix, protection of the blood-brain barrier, inflammation suppression, M1 / M2 microglial polarity reversal (inhibition of inflammatory microglia), induction of neuroprotective factors, induction of catecholamines, and protection of neural structure and function (synapse formation, dendritic spine morphology). Many of the genes whose expression was altered are known to play important roles in a wide range of psychiatric and neurological disorders, including, but not limited to, ADHD, bipolar disorder, depression, anxiety, traumatic and stress-related disorders, addiction, schizophrenia, epilepsy, delirium, Alzheimer's disease, cognitive impairments such as dementia caused by various reasons such as Lewy body dementia, frontotemporal lobar degeneration, and cerebral ischemia, behavioral and psychological signs and symptoms of dementia (BPSD), addiction, and chronic fatigue syndrome caused by various infectious diseases and other factors. We found that many of the gene alterations induced by melatonin receptor agonists act to modify and improve diseases and symptoms. The inventors then conceived the concept that when melatonin receptor agonists are used in a way that causes large-scale changes in the expression of genes responsible for various physiological functions, they can be used as therapeutic agents to prevent or ameliorate such diseases and symptoms.Based on these findings, they conducted further research and surprisingly found that melatonin receptor agonists are effective not only for sleep disorders but also for a wide range of symptoms, leading to the completion of the present invention.

[0010] That is, the present invention is as follows: [1] (i) a group of Wnt signal-related genes, (ii) a group of neurulation-related genes, (iii) a group of genes related to cell adhesion, cell matrix, and blood-brain barrier regulation, (iv) a group of genes related to memory and learning, (v) a group of inflammation-related genes, and (vi) a group of genes classified as response to hormone, regulation of hormone levels, tissue migration processing and presentation, regulation of viral process, negative regulation of viral process, positive regulation of mesenchymal cell proliferation, muscle organ development, negative regulation of notch signaling pathway, positive regulation of blood circulation, and response to oxygen in the pathway classification of biological processes in Gene Ontology. [2] The agent according to [1], wherein the Wnt signaling-related gene group is a Wnt family gene or an Fzd family gene classified into at least one of the group consisting of NON-CANONICAL WNT SIGNALING PATHWAY, PRIMARY NEURAL TUBE FORMATION, ESTABLISHMENT OF PLANAR POLARITY INVOVED IN NEURAL TUBE CLOSURE, and NEURAL TUBE FORMATION in the pathway classification of biological processes in Gene Ontology.[3] The agent according to [1], wherein the neurulation-related gene group is a neurulation-related gene group classified into at least one of the group consisting of "PRIMARY NEURAL TUBE FORMATION," "ESTABLISHMENT OF PLANAR POLARITY INVOVED IN NEURAL TUBE CLOSURE," and "NEURAL TUBE FORMATION" in the Gene Ontology Biological Process Pathway Classification. [4] The agent according to [1], wherein the vesicle adhesion, cytosolic, and blood-brain barrier regulation-related gene group is a collagen family gene, matrix metalloproteinase family gene, endothelin receptor gene, or nuclear receptor family gene classified into at least one of the group consisting of "POSITIVE REGULATION OF CYTOSOLIC CALCIUM ION CONCENTRATION," "TUBE MORPHOGENESIS," and "BONE DEVELOPMENT" in the Gene Ontology Biological Process Pathway Classification, and "EXTRACELLULAR MATRIX" and "MATRISOME" in the Gene Ontology Cellular Component Classification. [5] The agent according to [1], wherein the group of genes related to memory and learning is Arg3.1 and / or an early fluctuating gene classified as RNA BINDING in the molecular function classification of Gene Ontology and / or SKELETAL MUSCLE CELL DIFFERENTIATION in the pathway classification of biological processes. [6] The agent according to [5], wherein the early fluctuating gene is an Egr family gene, a Fos family gene, or a Foxo family gene.[7] The agent according to [1], wherein the inflammation-related gene group is an inflammasome-related gene or a microglia marker gene group classified into at least one of the group consisting of INNATE IMMUNE RESPONSE, ANTIGEN PROCESSING AND PRESENTATION, PRORESPONSE TO INTERFERON BETA, RESPONSE TO TYPE II INTERFERON, and REGULATION of NLRP3 INFLAMMASOME COMPLEX ASSEMBLY in the classification of biological process pathways in Gene Ontology, and NRLP6 INFLAMMASOME COMPLEX in the classification of cellular components. [8] The agent according to any one of [1] to [7], wherein the melatonin receptor agonist is selected from the group consisting of melatonin, sustained-release melatonin, ramelteon, tasimelteon, agomelatine, piromelatine, LY-156735 (PD-6735), VEC-162, GEX-2018, GEX-2303, 8-M-PDOT, GR135531, GR196429, S20242, S20242, S24268, S25150, GW-290569, AH-001, AH-002, GG-012, enol-3-IPA, ML-23, SL-18.1616, IP-100-9, IP-101, AH-017, derivatives thereof, and metabolites thereof. [9] The agent according to [8], wherein the melatonin receptor agonist is selected from the group consisting of melatonin, sustained-release melatonin, ramelteon, tasimelteon, agomelatine, GEX-2018, GEX-2303, derivatives thereof, and metabolites thereof.

[10] The agent according to any one of [1] to [9], further comprising one or more drugs.

[11] A preventive or therapeutic agent for at least one disease selected from the group consisting of attention-deficit hyperactivity disorder, schizophrenia, trauma- and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome including sequelae of COVID-19 infection, and neurodementia (excluding delirium, other specified delirium, and unspecified delirium), comprising the agent according to any one of [1] to

[10] .

[12] (i) Wnt signaling-related genes, (ii) neurulation-related genes, (iii) cell adhesion, cell matrix, and blood-brain barrier regulation-related genes, (iv) memory and learning-related genes, (v) inflammation-related genes, and (vi) Gene Ontology pathway classifications of biological processes, including RESPONSE TO HORMONE, REGULATION OF HORMONE LEVELS, TISSUE MIGRATION PROCESSING AND PRESENTATION, REGULATION OF VIRAL PROCESS, NEVATIVE REGULATION OF VIRAL PROCESS, POSITIVE REGULATION OF MESENCHYMAL CELL PROLIFERATION, MUSCLE ORGAN DEVELOPMENT, NEGATIVE REGULATION OF NOTCH SIGNALING PATHWAY, POSITIVE REGULATION OF BLOOD CIRCULATION, and RESPONSE TO OXGEN. Use of a melatonin receptor agonist for the manufacture of an expression regulator for at least one gene selected from the group consisting of genes classified into LEVELS.

[13] The use according to

[12] , wherein the expression regulator is an agent for the prophylaxis or treatment of at least one disease selected from the group consisting of attention-deficit hyperactivity disorder, schizophrenia, trauma- and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome including sequelae of COVID-19 infection, and neurodementia (excluding delirium, other specified delirium, and unspecified delirium).

[14] Melatonin receptor agonists are included in (i) Wnt signaling-related genes, (ii) neurulation-related genes, (iii) cell adhesion, cell matrix, and blood-brain barrier regulation-related genes, (iv) memory and learning-related genes, (v) inflammation-related genes, and (vi) Gene Ontology pathway classifications of biological processes, including response to hormone, regulation of hormone levels, tissue migration processing and presentation, regulation of viral process, negative regulation of viral process, positive regulation of mesenchymal cell proliferation, muscle organ development, negative regulation of notch signaling pathway, positive regulation of blood circulation, and response to oxygen.

[14] A kit for use in regulating the expression of at least one gene selected from the group consisting of genes classified into LEVELS.

[15] A product comprising the agent according to any one of [1] to

[11] and instructions describing how to use the agent.

[16] A method for evaluating the effect of a melatonin receptor agonist on symptoms of a psychiatric / neurological disorder, comprising the following steps: (1) administering the melatonin receptor agonist to a mammal lacking the Fmr1 gene, and (2) evaluating a behavioral index representative of symptoms of the psychiatric / neurological disorder in the mammal and / or fluctuations in the expression of a predetermined gene.

[17] A method for improving the quality of life of a subject by administering an effective amount of a melatonin receptor agonist to the subject, the method comprising: administering to the subject an effective amount of a melatonin receptor agonist; and measuring the quality of life of a subject by administering to the subject an effective amount of a melatonin receptor agonist to the subject;

[18] A method for controlling the expression of at least one gene selected from the group consisting of genes classified into LEVELS.

[19] A method for preventing or treating in a subject at least one disease selected from the group consisting of attention-deficit hyperactivity disorder, schizophrenia, trauma- and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome including sequelae of COVID-19 infection, and neurodementia (excluding delirium, other specified delirium, and unspecified delirium), comprising administering to the subject an effective amount of a melatonin receptor agonist.

[0011] According to the present invention, (i) Wnt signal-related genes, (ii) neurulation-related genes, (iii) cell adhesion, cell matrix, and blood-brain barrier regulation-related genes, (iv) memory and learning-related genes, (v) inflammation-related genes, and (vi) pathways classified in the Gene Ontology biological process pathways, such as RESPONSE TO HORMONE, REGULATION OF HORMONE LEVELS, TISSUE MIGRATION PROCESSING AND PRESENTATION, REGULATION OF VIRAL PROCESS, NEVATIVE REGULATION OF VIRAL PROCESS, POSITIVE REGULATION OF MESENCHYMAL CELL PROLIFERATION, MUSCLE ORGAN DEVELOPMENT, NEGATIVE REGULATION OF NOTCH SIGNALING PATHWAY, POSITIVE REGULATION OF BLOOD CIRCULATION, and RESPONSE TO OXYGEN This may provide a new option for regulating the expression of at least one gene selected from the group consisting of genes classified into LEVELS, etc. Furthermore, the present invention may also provide a new option for preventing or treating diseases caused by the expression of the above genes or symptoms associated with the diseases.

[0012] 1. The present invention relates to a gene expression regulator and a preventive / therapeutic agent, which comprises a melatonin receptor agonist and is capable of controlling (i) Wnt signaling-related genes, (ii) neurulation-related genes, (iii) genes related to cell adhesion, cell matrix, and blood-brain barrier regulation, (iv) genes related to memory and learning, (v) inflammation-related genes, and (vi) genes classified in the pathways of Gene Ontology biological processes (typically, MSigDB v2023.2.Hs (Oct 2023)) as RESPONSE TO HORMONE, REGULATION OF HORMONE LEVELS, TISSUE MIGRATION PROCESSING AND PRESENTATION, REGULATION OF VIRAL PROCESS, NEVATIVE REGULATION OF VIRAL PROCESS, POSITIVE REGULATION OF MESENCHYMAL CELL PROLIFERATION, MUSCLE ORGAN DEVELOPMENT, NEGATIVE REGULATION OF NOTCH SIGNALING PATHWAY ... The present invention provides an agent for regulating the expression of at least one gene selected from the group consisting of genes classified as REGULATION OF BLOOD CIRCULATION and RESPONSIBILITY TO OXYGEN LEVELS. The present invention also provides an agent for preventing or treating diseases caused by the expression of the above genes or symptoms associated with the diseases. In the present invention, pathways of biological processes in Gene Ontology are typically classified using MSigDB (The Molecular Signatures Database) v2023.2.Hs (Oct 2023). However, for example, if future versions of the MSigDB are updated, these may also be used. The classification method is not particularly limited as long as the desired classification can be performed.Furthermore, even if, for example, in the future, a change occurs in the classification due to an update of the MSigDB version, etc., and as a result, changes occur in the genes, etc. included in the classification, the changed form will be included in the scope of the present invention as long as the relationship with the classification based on the MSigDB version used in the present invention can be understood.

[0013] As used herein, the term "melatonin receptor agonist" refers to a substance that binds to a melatonin receptor and activates signal transduction of the receptor. The receptor agonist that can be used in the present invention is not particularly limited as long as it can exert the desired gene expression control effect. Examples of the receptor agonist include those described in US 6,218,429 B1 (WO97 / 3287A1), US 5,856,529A, US 5981571A, US 6,060,506A (WO98 / 25606A1), US2009182023 A1 (WO2007 / 148808), US 5225442, US 6,235,789 B1 (WO96 / 08466), US 5,708,005 B (WO97 / 01539), US 5,922,771 B (WO97 / 05098), US 8,73,761 B2 (WO2008 / 069311), US No. 8,247,429 B2 (WO2008 / 084717), US Pat. No. 8,110,585 B2 (WO2008 / 136382), etc., the entire contents of which are incorporated herein by reference.

[0014] Specifically, ramelteon (ROZEREM®, Takeda Pharmaceutical Co., Ltd., Japan) and its derivatives refer to ramelteon itself and those disclosed in Japanese Patent Application Laid-Open No. 11-152281 (Patent No. 4358917). Similarly, the following melatonin receptor agonists and their derivatives refer to melatonin receptor agonists themselves and those disclosed in patents that claim them. For example, agomelatine (N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide) and its derivatives are disclosed in U.S. Patent No. 5,225,442 (Patent Application Laid-Open No. 7-48331), and tasimelteon ((1R, 2R)-N-[2-(2,3-dihydrobenzofuran-4-yl)cyclopropylmethyl]propanamide) and its derivatives are described in U.S. Pat. No. 5,856,529 (Patent No. 4,290,765, WO 1998 / 025606, JP 2001-505916), and GEX-2018 ((S)-N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide). GEX-2303 ((S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]acetamide) and its derivatives are disclosed in Japanese Patent No. 5222737 (WO2007 / 148808), GEX-2303 ((S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]acetamide) and its derivatives are disclosed in Japanese Patent Application Laid-Open No. 10-287665 (Patent No. 2884153) and Japanese Patent Application Laid-Open No. 11-152281 (Patent No. 4358917), and GR135531 (5-Methoxycarbonylamino-N-acetyltryptamine) refers to those disclosed in U.S. Patent Application Publication No. 20010047016, AH-001 (2-acetamido-8-methoxytetralin) refers to those disclosed in U.S. Patent No. 5,151,446, AH-002 (8-methoxy-2-propionamido-tetralin) refers to those disclosed in U.S. Patent No. 5,151,446, ML-23 (N-2,4-dinitrophenyl-5-methoxy-tryptamine) refers to those disclosed in U.S. Patent No. 4,880,826, IP-100-9 (U.S. Patent No. 5,580,878, and AH-017 (U.S. Patent No. 5,151,446).

[0015] In addition, the following compounds are also listed: LY-156735 (PD-6735) (Phase II Discovery), VEC-162 (Vanda Pharmaceuticals, Rockville, MD), CGP 52608 (1-(3-allyl-4-oxothiazolidin-2-ylidene)-4-methylthiosemicarbazone) (Missbach et al., J. Biol. Chem. 1996, 271, 13515-22), GR196429 (N-[2-[2,3,7,8-tetrahydro-1H-furo(2,3-g)indol-1-yl]ethyl]acetamide) (Beresford et al., J. Pharmacol. Exp. Ther. 1998, 285, 1239-1245), and S20242 (N-[2-(7-methoxynaphth-1-yl)ethyl]propionamide) (Depres-Brummer et al., Eur. J. Pharmacol. 1998, 347, 57-66), S-23478 (Neuropharmacology July 2000), S24268 (Naunyn Schmiedebergs Arch. June 2003), S25150 (Naunyn Schmiedebergs Arch. June 2003), GW-290569, N-[1-(2,3-dihydrobenzofuran-4-yl)pyrrolidin-3-yl]-N-ethylurea, melatonin, 2-phenylmelatonin, 8-M-PDOT, 2-iodomelatonin, 6-chloromelatonin, melatonin research compound A, literature (IMS World R&D Focus August Melatonin agonist A described in a literature (Pharmaprojects August 1998), melatonin agonist B described in a literature (Chem. Pharm. Bull. (Tokyo) January 2002), melatonin agonist C described in a literature (J. Pineal Research November 2000), melatonin agonist D described in a literature (Chem. Pharm. Bull.(Tokyo) February 2002), melatonin agonist E described in the literature (Reprod. Nutr. Dev. May 1999), melatonin agonist G described in the literature (J. Med. Chem. October 1993), melatonin agonist H described in the literature (Famaco March 2000), melatonin agonist I described in the literature (J. Med. Chem. March 2000), melatonin agonist J described in the literature (Bioorg. Med. Chem. Lett. March 2003), melatonin agonist K described in the literature (MedAd News September 2001), melatonin agonist L, GG-012 (4-methoxy-2-(methylenepropylamido)indan) (Drijfhout et al., Eur. J. Pharmacol. 1999, 382, Other known melatonin receptor agonists include, but are not limited to, SL-18.1616, sleep-inducing peptide A, and IP-101. Those skilled in the art can easily find patents and literature that do not mention the above melatonin receptor agonists. Metabolites, prodrugs, stereoisomers, polymorphs, hydrates, solvates, and salts of the above compounds that directly or indirectly exhibit melatonin receptor agonist activity can also be used in the practice of the present invention.

[0016] In one embodiment, ramelteon and its derivatives are compounds of the following formula (I), which are disclosed in Japanese Patent Application Laid-Open No. 10-287665 (Patent No. 2884153) and Japanese Patent Application Laid-Open No. 11-152281 (Patent No. 4358917) (US Pat. No. 6,218,429 B1):

[0017]

[0018] [In the formula, R 1 represents an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted heterocyclic group, R 2 is a hydrogen atom or a hydrocarbon group which may have a substituent, R3 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; X represents CHR 4 , N.R. 4 , O or S(R 4 represents a hydrogen atom or a hydrocarbon group which may have a substituent),

[0019] Y is C, CH or N (provided that when X is CH2, Y is C or CH);

[0020]

[0021] Ring A is an optionally substituted 5- to 7-membered heterocycle containing an oxygen atom, Ring B is an optionally substituted benzene ring, and m is an integer of 1 to 4, or a salt thereof.

[0022] In one embodiment, the compound of formula (I) is R 1 (i) a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, carboxyl group, C 1-6 Alkyl-carbonyl group, C 1-6 Alkoxy-carbonyl group, carbamoyl group, mono-C 1-6 Alkyl-carbamoyl group, di-C 1-6 Alkyl-carbamoyl group, C 6-10 Aryl-carbamoyl group, C 6-10 Aryl group, C 6-10 an aryloxy group or an optionally halogenated C 1-6 (a) C optionally substituted with 1 to 5 alkyl-carbonylamino groups 1-6 (b) alkyl group, 2-6 alkenyl group, (c) C 2-6 Alkynyl group, (d) C 3-6 cycloalkyl group or (e) C 6-14 (ii) an aryl group, a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated C 1-6 Alkyl group, C1-6 Alkoxy group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, carboxyl group, C 1-6 Alkyl-carbonyl group, C 1-6 Alkoxy-carbonyl group, carbamoyl group, mono-C 1-6 Alkyl-carbamoyl group, di-C 1-6 Alkyl-carbamoyl group, C 6-10 Aryl-carbamoyl group, C 6-10 Aryl group, C 6-10 an aryloxy group or an optionally halogenated C 1-6 (a) C optionally substituted with 1 to 5 alkyl-carbonylamino groups 1-6 (b) alkyl group, 2-6 alkenyl group, (c) C 2-6 Alkynyl group, (d) C 3-6 cycloalkyl group or (e) C 6-14 an amino group optionally having one or two aryl groups, or (iii) a halogen atom, C 1-6 Alkyl group, C 3-6 Cycloalkyl group, C 2-6 Alkynyl group, C 2-6 Alkenyl group, C 7-11 Aralkyl group, C 6-10 Aryl group, C 1-6 Alkoxy group, C 6-10 Aryloxy group, formyl group, C 1-6 Alkyl-carbonyl group, C 6-10 Aryl-carbonyl group, formyloxy group, C 1-6 Alkyl-carbonyloxy group, C 6-10 Aryl-carbonyloxy group, carboxyl group, C 1-6 Alkoxy-carbonyl group, C 7-11 Aralkyloxy-carbonyl group, carbamoyl group, optionally halogenated C 1-4 Alkyl group, oxo group, amidino group, imino group, amino group, mono-C 1-4 Alkylamino group, di-C 1-4 alkylamino group, 3- to 6-membered cyclic amino group, C 1-3Alkylenedioxy group, hydroxy group, nitro group, cyano group, mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, mono-C 1-6 Alkyl sulfamoyl group, di-C 1-6 Alkylsulfamoyl group, C 1-6 Alkylthio group, C 6-10 Arylthio group, C 1-6 Alkylsulfinyl group, C 6-10 Arylsulfinyl group, C 1-6 Alkylsulfonyl group or C 6-10 a 5- to 14-membered heterocyclic group containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may be substituted with 1 to 5 arylsulfonyl groups; R 2 is (i) a hydrogen atom or (ii) a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, carboxyl group, C 1-6 Alkyl-carbonyl group, C 1-6 Alkoxy-carbonyl group, carbamoyl group, mono-C 1-6 Alkyl-carbamoyl group, di-C 1-6 Alkyl-carbamoyl group, C 6-10 Aryl-carbamoyl group, C 6-10 Aryl group, C 6-10 an aryloxy group or an optionally halogenated C 1-6 (a) C optionally substituted with 1 to 5 alkyl-carbonylamino groups 1-6 (b) alkyl group, 2-6 alkenyl group, (c) C 2-6 Alkynyl group, (d) C 3-6 cycloalkyl group or (e) C 6-14 Aryl group; R 3 is (i) a hydrogen atom, (ii) a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, amino group, mono-C1-6 Alkylamino group, di-C 1-6 Alkylamino group, carboxyl group, C 1-6 Alkyl-carbonyl group, C 1-6 Alkoxy-carbonyl group, carbamoyl group, mono-C 1-6 Alkyl-carbamoyl group, di-C 1-6 Alkyl-carbamoyl group, C 6-10 Aryl-carbamoyl group, C 6-10 Aryl group, C 6-10 an aryloxy group or an optionally halogenated C 1-6 (a) C optionally substituted with 1 to 5 alkyl-carbonylamino groups 1-6 (b) alkyl group, 2-6 alkenyl group, (c) C 2-6 Alkynyl group, (d) C 3-6 cycloalkyl group or (e) C 6-14 an aryl group, or (iii) a halogen atom, C 1-6 Alkyl group, C 3-6 Cycloalkyl group, C 2-6 Alkynyl group, C 2-6 Alkenyl group, C 7-11 Aralkyl group, C 6-10 Aryl group, C 1-6 Alkoxy group, C 6-10 Aryloxy group, formyl group, C 1-6 Alkyl-carbonyl group, C 6-10 Aryl-carbonyl group, formyloxy group, C 1-6 Alkyl-carbonyloxy group, C 6-10 Aryl-carbonyloxy group, carboxyl group, C 1-6 Alkoxy-carbonyl group, C 7-11 Aralkyloxy-carbonyl group, carbamoyl group, optionally halogenated C 1-4 Alkyl group, oxo group, amidino group, imino group, amino group, mono-C 1-4 Alkylamino group, di-C 1-4 alkylamino group, 3- to 6-membered cyclic amino group, C 1-3Alkylenedioxy group, hydroxy group, nitro group, cyano group, mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, mono-C 1-6 Alkyl sulfamoyl group, di-C 1-6 Alkylsulfamoyl group, C 1-6 Alkylthio group, C 6-10 Arylthio group, C 1-6 Alkylsulfinyl group, C 6-10 Arylsulfinyl group, C 1-6 Alkylsulfonyl group or C 6-10 a 5- to 14-membered heterocyclic group containing, in addition to carbon atoms, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may be substituted with 1 to 5 arylsulfonyl groups; R 4 is (i) a hydrogen atom or (ii) a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, carboxyl group, C 1-6 Alkyl-carbonyl group, C 1-6 Alkoxy-carbonyl group, carbamoyl group, mono-C 1-6 Alkyl-carbamoyl group, di-C 1-6 Alkyl-carbamoyl group, C 6-10 Aryl-carbamoyl group, C 6-10 Aryl group, C 6-10 an aryloxy group or an optionally halogenated C 1-6 (a) C optionally substituted with 1 to 5 alkyl-carbonylamino groups 1-6 (b) alkyl group, 2-6 alkenyl group, (c) C 2-6 Alkynyl group, (d) C 3-6 cycloalkyl group or (e) C 6-14 aryl group; A ring is (i) a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, amino group, mono-C 1-6Alkylamino group, di-C 1-6 Alkylamino group, carboxyl group, C 1-6 Alkyl-carbonyl group, C 1-6 Alkoxy-carbonyl group, carbamoyl group, mono-C 1-6 Alkyl-carbamoyl group, di-C 1-6 Alkyl-carbamoyl group, C 6-10 Aryl-carbamoyl group, C 6-10 Aryl group, C 6-10 an aryloxy group or an optionally halogenated C 1-6 (a) C optionally substituted with 1 to 5 alkyl-carbonylamino groups 1-6 (b) alkyl group, 2-6 alkenyl group, (c) C 2-6 Alkynyl group, (d) C 3-6 cycloalkyl group or (e) C 6-14 (ii) an aryl group, (iii) a halogen atom, 1-6 an alkoxy group, (iv) C 6-10 (v) an aryloxy group, (vi) a formyl group, 1-6 (vii) an alkyl-carbonyl group; 6-10 (viii) formyloxy group, (ix) C 1-6 alkyl-carbonyloxy group, (x) C 6-10 (xi) an aryl-carbonyloxy group, (xii) a carboxyl group, 1-6 (xiii) an alkoxy-carbonyl group, 7-11 (xiv) an aralkyloxy-carbonyl group, (xv) an optionally halogenated C 1-4 (xvi) an alkyl group, (xvii) an oxo group, (xviii) an amidino group, (xix) an amino group, (xx) a mono-C 1-4 alkylamino group, (xxi) di-C 1-4 (xxii) an alkylamino group, (xxiii) a 3- to 6-membered cyclic amino group, 1-3an alkylenedioxy group, (xxiv) a hydroxy group, (xxv) a nitro group, (xxvi) a cyano group, (xxvii) a mercapto group, (xxviii) a sulfo group, (xxix) a sulfino group, (xxx) a phosphono group, (xxxi) a sulfamoyl group, (xxxii) a mono-C 1-6 (xxxiii) alkylsulfamoyl group, (xxxiii) di-C 1-6 (xxxiv) alkylsulfamoyl group, 1-6 alkylthio group, (xxxv) C 6-10 an arylthio group, (xxxvi) C 1-6 alkylsulfinyl group, (xxxvii) C 6-10 (xxxviii) an arylsulfinyl group, 1-6 an alkylsulfonyl group or (xxxix) C 6-10 a 5- to 7-membered heterocyclic ring which may contain, in addition to carbon and oxygen atoms, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and which may be substituted with 1 to 4 arylsulfonyl groups; and a ring B which is (i) a halogen atom, (ii) a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, carboxyl group, C 1-6 Alkyl-carbonyl group, C 1-6 Alkoxy-carbonyl group, carbamoyl group, mono-C 1-6 Alkyl-carbamoyl group, di-C 1-6 Alkyl-carbamoyl group, C 6-10 Aryl-carbamoyl group, C 6-10 Aryl group, C 6-10 an aryloxy group or an optionally halogenated C 1-6 (a) C may be substituted with 1 to 5 alkyl-carbonylamino groups 1-6 alkyl group, (b) C 2-6 alkenyl group, (c) C 2-6 Alkynyl group, (d) C 3-6 cycloalkyl group or (e) C 6-14(iii) a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, carboxyl group, C 1-6 Alkyl-carbonyl group, C 1-6 Alkoxy-carbonyl group, carbamoyl group, mono-C 1-6 Alkyl-carbamoyl group, di-C 1-6 Alkyl-carbamoyl group, C 6-10 Aryl-carbamoyl group, C 6-10 Aryl group, C 6-10 an aryloxy group or an optionally halogenated C 1-6 (a) C optionally substituted with 1 to 5 alkyl-carbonylamino groups 1-6 (b) alkyl group, 2-6 alkenyl group, (c) C 2-6 Alkynyl group, (d) C 3-6 cycloalkyl group or (e) C 6-14 (iv) an amino group optionally having one or two aryl groups; 1-6 (v) an alkanoylamino group, a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated C 1-6 Alkyl group, C 1-6 Alkoxy group, amino group, mono-C 1-6 Alkylamino group, di-C 1-6 Alkylamino group, carboxyl group, C 1-6 Alkyl-carbonyl group, C 1-6 Alkoxy-carbonyl group, carbamoyl group, mono-C 1-6 Alkyl-carbamoyl group, di-C 1-6 Alkyl-carbamoyl group, C 6-10 Aryl-carbamoyl group, C 6-10 Aryl group, C 6-10 an aryloxy group or an optionally halogenated C 1-6 C optionally substituted with 1 to 3 alkyl-carbonylamino groups 1-6 an alkoxy group or (vi) C1-3 The compound is a benzene ring which may be substituted with one or two alkylenedioxy groups.

[0023] In one embodiment, the compound of formula (I) is

[0024]

[0025] [R 4 represents a hydrocarbon group which may have a substituent, and the other symbols are as defined above.

[0026] In one embodiment, the compound of formula (I) has the formula:

[0027]

[0028] wherein ring A′ is a heterocycle containing an oxygen atom which may have a substituent; n is an integer of 0 to 2;

[0029]

[0030] are the same or different and represent a single bond or a double bond, and the other symbols have the same meanings as above.

[0031] In one embodiment, the compound of formula (I) is R 1 (i) optionally substituted C 1-6 (ii) an alkyl group optionally having a substituent; 3-6 (iii) a C group optionally having a substituent; 2-6 (iv) an alkenyl group optionally having a substituent; 6-14 (v) an aryl group, optionally having a substituent, mono- or di-C 1-6 (vi) an alkylamino group optionally having a substituent; 6-14 (vii) a compound which is an arylamino group, or (vii) a 5- or 6-membered nitrogen-containing heterocyclic group which may have a substituent.

[0032] In one embodiment, the compound of formula (I) is R 1 C, which may be halogenated 1-6 It is a compound that is an alkyl group.

[0033] In one embodiment, the compound of formula (I) is R2 is a hydrogen atom or an optionally substituted C 1-6 It is a compound that is an alkyl group.

[0034] In one embodiment, the compound of formula (I) is R 2 is a hydrogen atom.

[0035] In one embodiment, the compound of formula (I) is R 3 is a hydrogen atom or an optionally substituted hydrocarbon group.

[0036] In one embodiment, the compound of formula (I) is R 3 is a hydrogen atom.

[0037] In one embodiment, the compound of formula (I) is R 4 is a hydrogen atom or an optionally substituted C 1-6 It is a compound that is an alkyl group.

[0038] In one embodiment, compounds of formula (I) are those in which X is CHR 4 (R 4 is as defined above).

[0039] In one embodiment, compounds of formula (I) are those in which X is CHR 4 (R 4 has the same meaning as above) and the following

[0040]

[0041] is a single bond.

[0042] In one embodiment, the compounds of formula (I) are those in which X is CH2.

[0043] In one embodiment, compounds of formula (I) are those in which X is NR 4 (R 4 is as defined above).

[0044] In one embodiment, the compounds of formula (I) are those in which Y is C or CH.

[0045] In one embodiment, the compounds of formula (I) are those in which Y is CH.

[0046] In one embodiment, the compounds of formula (I) are those in which m is 2.

[0047] In one embodiment, the compound of formula (I) is a compound in which the A ring is a tetrahydrofuran ring.

[0048] In one embodiment, the compound of formula (I) is one in which the A ring is unsubstituted.

[0049] In one embodiment, the compounds of formula (I) are those in which the B ring is unsubstituted.

[0050] In one embodiment, the compounds of formula (I) are those in which n is 0 or 1.

[0051] In one embodiment, the compound of formula (I) is

[0052]

[0053] [In the formula, R １ｂ is C １－６ alkyl group, X' is CH ２ , NH or NCHO,

[0054]

[0055] is a single or double bond, R 3a is a hydrogen atom or a phenyl group, E a is CH2CH2, CH=CH, CH2O, CH=N, CONH or CH2NH, n a is 0 or 1, and the A″ ring is C optionally substituted with a hydroxy group. 1-6 a 5- or 6-membered heterocycle containing an oxygen atom which may have one or two alkyl groups, and ring B' is a benzene ring which may be substituted with a halogen atom.

[0056] In one embodiment, the compound of formula (I) is

[0057]

[0058] is a single bond and X' is NH.

[0059] In one aspect, the compound of formula (I) is N-[2-(1,6,7,8-tetrahydro-2H-furo[3,2-e]indol-8-yl)ethyl]propionamide, N-[2-(1,6,7,8-tetrahydro-2H-furo[3,2-e]indol-8-yl)ethyl]butyramide, N-[2-(7-phenyl-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, or N-[2-(7-phenyl-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]butyramide.

[0060] In one aspect,

[0061]

[0062] [wherein each symbol has the same meaning as above] or a salt thereof.

[0063] In one aspect,

[0064]

[0065] [In the formula, X a is CHR 4a , N.R. 4a , O or S(R 4a represents a hydrogen atom or a hydrocarbon group which may have a substituent), Y a is C, CH or N (where X a When represents NH, Y a is CH or N), and the other symbols are as defined above, or a salt thereof.

[0066] In one aspect, compounds of formula (I) include N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]acetamide, N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]butyramide, N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, N-[2-(3,7,8,9-tetrahydropyrano[3,2-e]indol-1-yl)ethyl]propionamide, N-[2-(5-fluoro-3,7,8,9-tetrahydrocyclopenta[f][l]benzopyran -9-yl)ethyl]propionamide, N-[2-(3,7,8,9-tetrahydropyrano[3,2-e]indol-1-yl)ethyl]butyramide, N-[2-(1,2,3,7,8,9-hexahydropyrano[3,2-e]indol-1-yl)ethyl]propionamide, N-[2-(1,2,3,7,8,9-hexahydropyrano[3,2-e]indol-1-yl)ethyl]butyramide, N-[2-(4-fluoro-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]butyramide, N-[2-(4-fluoro-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, (R)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]butyramide, N-[ 2-(1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]acetamide, N-[2-(1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, N-[2-(1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]butyramide, N-[2-(7,8-dihydro-6H-indeno[4,5-d]-1,3-dioxol-8-yl)ethyl]propionamide, N- [2-(7,8-dihydro-6H-indeno[4,5-d]-1,3-dioxol-8-yl)ethyl]butyramide, N-[2-(2,3,8,9-tetrahydro-7H-indeno[4,5-b]-1,4-dioxin-9-yl)ethyl]propionamide, N-[2-(2,3,8,9-tetrahydro-7H-indeno[4,5-b]-1,4-dioxin-9-yl)ethyl]butyramide, N-[2-(1,6,7,8-tetrahydro-2H-furo [3,2-e]indol-8-yl)ethyl]propionamide, N-[2-(1,6,7,8-tetrahydro-2H-furo[3,2-e]indol-8-yl)ethyl]butyramide, N-[2-(7-phenyl-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, N-[2-(7-phenyl-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]butyramide, and the like.

[0067] In one aspect, the compound of formula (I) is N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]acetamide, N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, N-[2-(5-fluoro-3,7,8,9-tetrahydrocyclopenta[f][1]benzopyran-9 ... (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, (R)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, N-[2-(1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]butyramide, N-[2-(1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]acetamide, N-[2-(1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, N-[2-(1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]butyramide, N-[2-(1,6,7,8-tetrahydro-2H-furan N-[2-(1,6,7,8-tetrahydro-2H-furo[3,2-e]indol-8-yl)ethyl]propionamide, N-[2-(1,6,7,8-tetrahydro-2H-furo[3,2-e]indol-8-yl)ethyl]butyramide, N-[2-(7-phenyl-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, N-[2-(7-phenyl-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]butyramide.Particularly preferred are (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, N-[2-(1,6,7,8-tetrahydro-2H-furo[3,2-e]indol-8-yl)ethyl]propionamide, N-[2-(1,6,7,8-tetrahydro-2H-furo[3,2-e]indol-8-yl)ethyl]butyramide, N-[2-(7-phenyl-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, and N-[2-(7-phenyl-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]butyramide.

[0068] In one embodiment, agomelatine and its derivatives are represented by the following general formula (I):

[0069]

[0070] In the formula, A is

[0071]

[0072] R represents a linear or branched lower alkyl group, R1 represents a hydrogen atom or a linear or branched lower alkyl group, R2 represents a hydrogen atom, a linear or branched lower alkyl group or a cycloalkyl group optionally substituted by a halogen atom, an aryl or heteroaryl or lower aryl alkyl group or a substituted aryl or substituted heteroaryl or substituted aryl alkyl group, where the heteroaryl group is understood to be an unsaturated monocyclic or bicyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, each ring containing 4 or 5 vertices, and the aryl group is understood to be phenyl or naphthyl, optionally reduced and / or substituted by an oxo group, an imidazolyl group of the formula

[0073]

[0074] wherein G represents a linear or branched lower alkyl group, R3 and R4 are the same or different and both represent a lower alkyl group or a hydrogen atom or a phenyl or lower phenylalkyl group, or R3 and R4 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic heterocyclic system which may or may not be aromatic, while each ring contains another heteroatom and optionally has 5 or 6 vertices substituted by one or more lower alkyl, or oxo, aryl or lower arylalkyl, or substituted aryl or substituted lower arylalkyl groups, and furthermore the term "substituted" in the definition of R2, R3 and R4 limiting the aryl and arylalkyl or heteroaryl groups is understood to mean that these groups are substituted by one or more groups selected from among lower alkyl, lower alkoxy, trifluoromethyl or halogen atoms, or R1 together with R2 and the N-CO group represents the formula

[0075]

[0076] where A is a linear or branched alkyl group having from 2 to 8 carbon atoms, as well as, if that occurs, its isomers, epimers and diastereoisomers and addition salts thereof with pharmaceutically acceptable acids, wherein the terms "lower alkyl and lower alkoxy" mean groups having from 1 to 6 carbon atoms and "cycloalkyl" means groups having from 3 to 8 carbon atoms.

[0077] In one embodiment, the compounds of general formula (I) are those in which the OR group is in position 7, as well as, if that occurs, their isomers, epimers and diastereoisomers and addition salts thereof with pharmaceutically acceptable acids.

[0078] In one embodiment, the compounds of general formula (I) are those in which R1 represents a hydrogen atom or together with R2 and the N-CO group form the system pyrrolidin-2-one, as well as, if that is the case, its isomers, epimers and diastereoisomers and addition salts thereof with pharmaceutically acceptable acids.

[0079] In one embodiment, the compounds of general formula (I) are those in which R is a linear or branched lower alkyl group or a cycloalkoxy group optionally substituted by a halogen atom, an aryl group or a monocyclic or bicyclic heteroaryl group or a lower arylalkyl group optionally substituted by one or more halogen atoms or a group selected from lower alkyl, lower alkoxy or trifluoromethyl, a group represented by the following formula:

[0080]

[0081] wherein G represents a linear or branched lower alkyl group, and R and R, together with the nitrogen atom to which they are attached, represent a group which forms a monocyclic or bicyclic heterocyclic system having 5 or 6 vertices, each ring optionally containing another heteroatom and optionally substituted by lower alkyl, or oxo, aryl or lower arylalkyl, or substituted aryl or substituted lower arylalkyl groups, and wherein the term "substituted" limiting the aryl and arylalkyl groups means that these groups can be substituted by one or more groups selected from among lower alkyl, lower alkoxy, trifluoromethyl, or halogen atoms, as well as the compounds, if this occurs, their isomers, epimers and diastereoisomers, and addition salts thereof with pharmaceutically acceptable acids.

[0082] In one embodiment, the compounds of general formula (I) are those in which the OR group is in position 7, R represents a hydrogen atom and R represents a linear or branched lower alkyl or cycloalkyl group optionally substituted by a halogen atom, as well as their isomers, epimers and diastereoisomers, if this occurs.

[0083] In one embodiment, the compounds of general formula (I) are those in which the OR group is in position 7, R represents a hydrogen atom and R is a monocyclic or bicyclic aryl or heteroaryl group optionally substituted by one or more halogen atoms, as well as their isomers, epimers and diastereoisomers, if this occurs.

[0084] In one embodiment, the compound of general formula (I) is N-[2-(7-methoxynaphth-1-yl)ethyl]cyclopropylcarboxamide, N-[2-(7-methoxynaphth-1-yl)ethyl]-(2-oxopyrrolidin-1-yl)acetamide, N-[2-(7-methoxynaphth-1-yl)ethyl]pyrrolidin-2-one, N-[2-(7-methoxynaphth-1-yl)ethyl] ... N-[2-(7-methoxynaphth-1-yl)ethyl]isobutyramide, N-[2-(7-methoxynaphth-1-yl)ethyl]butyramide, N-[2-(7-methoxynaphth-1-yl)ethyl]propionamide, N-[2-(7-methoxynaphth-1-yl)ethyl]-4-chlorobutyramide, N-[2-(7-methoxynaphth-1-yl)ethyl]-2-morpholinoacetamide, N-[2-(7-methoxynaphth-1-yl)ethyl]- )ethyl]-2-{4-[(2,3,4-trimethoxyphenyl]piperazin-1-yl}acetamide, as well as its addition salts with pharmaceutically acceptable acids, N-[2-(7-methoxynaphth-1-yl)ethyl]benzamide, N-[2-(7-methoxynaphth-1-yl)ethyl]3,5-dichlorobenzamide, N-[2-(7-methoxynaphth-1-yl)ethyl](indol-2-yl)carboxamide, N-[2-(7-methoxynaphth-1-yl)ethyl]pentanamide, N-[2-(7-methoxynaphth-1-yl)ethyl]cyclobutanecarboxamide, N-[2-(7-methoxynaphth-1-yl)ethyl]-2-iodoacetamide, N-[2-(7-methoxynaphth-1-yl)ethyl]-2-bromoacetamide, and N-[2-(7-methoxynaphth-1-yl)ethyl]-2-chloroacetamide.

[0085] In one embodiment, tasimelteon and its derivatives are compounds of formula (I) disclosed in U.S. Pat. No. 5,856,529 (Patent No. 4,290,765) (WO9825606 A1):

[0086]

[0087] [In the ceremony, Q 1 and Q 2are each independently hydrogen or halogen; X is CH, CH, or oxygen; Y is CR 3 , C.R. 3 R 4 or (CH2) n where n=1 to 4; Z is CH, CH or oxygen; R is in each case hydrogen, halogen or C 1-4 alkyl; m is 1 or 2; R 1 is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-3 Haloalkyl, C 1-6 Alkylamino, C 2-6 Alkenyl, C 1-4 Alkoxy (C 1-4 ) alkyl, C 1-4 Alkylthio (C 1-4 ) alkyl or C 1-4 trifluoromethylalkyl; R 2 is hydrogen or C 1-4 alkyl; and R 3 and R 4 are each independently hydrogen or C 1-4 or a pharmaceutically acceptable solvate thereof.

[0088] In one aspect, the compound of formula (I) is 1 and Q 2 are independently hydrogen or iodo, and m is 1.

[0089] In one aspect, the compound of formula (I) is R 1 is C 1-6 Alkyl, C 3-4 Cycloalkyl, C 1-3 Haloalkyl, C 2-3 Alkenyl, C 1-2 Alkoxy (C 1-2 ) alkyl or C 1-2 trifluoromethylalkyl, and R 2 is a compound where

[0090] In one embodiment, the compounds of formula (I) are those in which X is CH2 and Z is oxygen.

[0091] In one aspect, the compound of formula (I) is selected from the group consisting of -(+)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide; (-)-(trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]acetamide; (-)-(trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]butanamide; (-)-(trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]methoxyacetamide; (-)-(trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]cyclopropanecarboxamide; (-)-(trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]trifluoroacetamide; (trans)-N-[[2-(2,3-dihydro-2,2-dimethyl-benzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide; (trans)-N-[[2-(2,3-dihydro-2,2-dimethyl-benzofuran-4-yl)cyclopropan-1-yl]methyl]butanamide; (+)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]acetamide; (+)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide; (+)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]butanamide; (+)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]cyclopropanecarboxamide; (+)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]-2-methylpropanamide; (+)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]chloroacetamide;(-)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]-2-methylpropanamide; (-)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]acetamide; (-)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]methoxyacetamide; (-)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]butanamide; (trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]acetamide; (-)-(trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide; (trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide; (trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]butanamide; (trans)-N-[[2-(2,3-dihydro-5,7-iodobenzofuran-4-yl)cyclopropyl]methyl]propanamide; (trans)-N-[[2-(2,3-dihydro-5-iodobenzofuran-4-yl)cyclopropyl]methyl]propanamide; (trans)-N-[[2-(3,4-dihydro-2H-1-benzopyran-5-yl)cyclopropan-1-yl]methyl]propanamide; (trans)-N-[[2-(3,4-dihydro-2H-1-benzopyran-5-yl)cyclopropan-1-yl]methyl]cyclopropanecarboxamide; (trans)-N-[[2-(3,4-dihydro-2H-1-benzopyran-5-yl)cyclopropan-1-yl]methyl]butanamide; and (+)-(trans)-N-[[2-(3,4-dihydro-2H-1-benzopyran-5-yl)cyclopropan-1-yl]methyl]propanamide.

[0092] In one aspect, the compounds of formula (I) are -(+)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide; (-)-(trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]acetamide; (-)-(trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]butanamide; (-)-(trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]cyclopropanecarboxamide; (+)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]acetamide; (+)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide; (+)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]butanamide; (+)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]cyclopropanecarboxamide; (-)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide; (-)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]acetamide; (-)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]cyclopropanecarboxamide; (-)-(trans)-N-[[2-(2-methyl-2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]butanamide; (trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]acetamide; (-)-(trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide;(trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide; (trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]butanamide; (trans)-N-[[2-(2,3-dihydro-5,7-iodobenzofuran-4-yl)cyclopropyl]methyl]propanamide; and (trans)-N-[[2-(2,3-dihydro-5-iodobenzofuran-4-yl)cyclopropyl]methyl]propanamide.

[0093] In one embodiment, the compound of formula (I) is (trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide.

[0094] In one embodiment, the compound of formula (I) is (-)-(trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide.

[0095] In one embodiment, the compound of formula (I) is a compound wherein X is oxygen and Y is (CH2) n (where n is 1 or 2) and Z is oxygen.

[0096] In one aspect, the compounds of formula (I) are: (trans)-N-[[2-(1,3-benzodioxol-4-yl)cyclopropan-1-yl]methyl]acetamide; (-)-(trans)-N-[[2-(1,3-benzodioxol-4-yl)cyclopropan-1-yl]methyl]acetamide; (trans)-N-[[2-(1,3-benzodioxol-4-yl)cyclopropan-1-yl]methyl]propanamide; (-)-(trans)-N-[[2-(1,3-benzodioxol-4-yl)cyclopropan-1-yl]methyl]propanamide; (trans)-N-[[2-(1,3-benzodioxol-4-yl)cyclopropan-1-yl]methyl]butanamide; (-)-(trans)-N-[[2-(1,3-benzodioxol-4-yl)cyclopropan-1-yl]methyl]butanamide; (trans)-N-[[2-(1,3-benzodioxol-4-yl)cyclopropan-1-yl]methyl]cyclopropanecarboxamide; (-)-(trans)-N-[[2-(1,3-benzodioxol-4-yl)cyclopropan-1-yl]methyl]cyclopropanecarboxamide; (trans)-N-[[2-(1,3-benzodioxol-4-yl)cyclopropan-1-yl]methyl]-2-methylpropanamide; (-)-(trans)-N-[[2-(1,3-benzodioxol-4-yl)cyclopropan-1-yl]methyl]-2-methylpropanamide; (-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]propanamide; (-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]acetamide; (-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]cyclopropanecarboxamide; (-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]butanamide;(+)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]propenamide: (-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]trifluoroacetamide; (-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]-3,3,3-trifluoropropanamide; (+)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]propanamide; (trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]acetamide; (trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]propanamide; (trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]butanamide; (trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]-2-methylpropanamide; and (trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]cyclopropanecarboxamide.

[0097] In one aspect, the compounds of formula (I) are: (trans)-N-[[2-(1,3-benzodioxol-4-yl)cyclopropan-1-yl]methyl]acetamide; (-)-(trans)-N-[[2-(1,3-benzodioxol-4-yl)cyclopropan-1-yl]methyl]acetamide; (trans)-N-[[2-(1,3-benzodioxol-4-yl)cyclopropan-1-yl]methyl]propanamide; and (-)-(trans)-N-[[2-(1,3-benzodioxol-4-yl)cyclopropan-1-yl]methyl]propanamide.

[0098] In one aspect, the compounds of formula (I) are: (-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]propanamide; (-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]acetamide; (-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]cyclopropanecarboxamide; and (-)-(trans)-N-[[2-(2,3-dihydro-1,4-benzodioxin-5-yl)cyclopropan-1-yl]methyl]butanamide.

[0099] In one aspect, compounds of formula (I) are those wherein X is CH and Y is CR 3 and Z is oxygen.

[0100] In one aspect, the compounds of formula (I) are: (-)-(trans)-N-[[2-benzofuran-4-yl]cyclopropan-1-yl]methyl]cyclopropanecarboxamide; (trans)-N-[[2-(2-methylbenzofuran-4-yl)cyclopropan-1-yl]methyl]acetamide; (trans)-N-[[2-(2-methylbenzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide; (trans)-N-[[2-(2-methylbenzofuran-4-yl)cyclopropan-1-yl]methyl]butanamide; (trans)-N-[[2-(benzofuran-4-yl)cyclopropan-1-yl]methyl]acetamide; (trans)-N-[[2-(benzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide; (trans)-N-[[2-(benzofuran-4-yl)cyclopropan-1-yl]methyl]butanamide; (trans)-N-[[2-(benzofuran-4-yl)cyclopropan-1-yl]methyl]-2-methylpropanamide; and (trans)-N-[[2-(benzofuran-4-yl)cyclopropan-1-yl]methyl]cyclopropanecarboxamide.

[0101] In one aspect, the compounds of formula (I) are: (-)-(trans)-N-[[2-benzofuran-4-yl]cyclopropan-1-yl]methyl]cyclopropanecarboxamide; (-)-(trans)-N-[[2-benzofuran-4-yl]cyclopropan-1-yl]methyl]cyclopropanamide; (trans)-N-[[2-(2-methylbenzofuran-4-yl)cyclopropan-1-yl]methyl]acetamide; (trans)-N-[[2-(2-methylbenzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide; (trans)-N-[[2-(2-methylbenzofuran-4-yl)cyclopropan-1-yl]methyl]butanamide; and (trans)-N-[[2-(benzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide.

[0102] In one embodiment, GEX-2018 and its derivatives are compounds of formula (I) disclosed in Patent No. 5222737 (WO2007 / 148808, US2009182023 A1):

[0103]

[0104] [In the formula, R １ represents an optionally substituted hydrocarbon group, an optionally substituted amino group, an optionally substituted hydroxy group, or an optionally substituted heterocyclic group; R ５ represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino, an optionally substituted hydroxy, or an optionally substituted mercapto; R ６ represents a hydrogen atom or an optionally substituted hydrocarbon group; X represents an oxygen atom or a sulfur atom; m represents 0, 1 or 2; Ring A represents an optionally substituted 5-membered ring; Ring B represents an optionally substituted 6-membered ring; Ring C represents an optionally substituted 5-membered ring;

[0105]

[0106] represents a single bond or a double bond, or a salt thereof.

[0107] In one aspect, the compound of formula (I) has the formula

[0108]

[0109] [In the formula, R ２ represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; R ３ represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group, an optionally substituted hydroxy group, an optionally substituted mercapto group, or an optionally substituted heterocyclic group; R ４a and R ４b are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino, an optionally substituted hydroxy, or an optionally substituted mercapto; and other symbols are as defined above.

[0110] In one embodiment, the compound of formula (I) has the formula

[0111]

[0112] [In the formula, R ２ , R ３ , R ４a and R ４b and other symbols have the same meanings as above.

[0113] In one aspect, the compound of formula (I) is R １ C which may have a substituent １－６ alkyl, optionally substituted C ３－６ Cycloalkyl or optionally substituted C ２－６ The compound is alkenyl.

[0114] In one aspect, the compound of formula (I) is R ５ is a hydrogen atom or an optionally substituted C １－６ It is a compound that is alkyl.

[0115] In one aspect, the compound of formula (I) is R６ is a hydrogen atom or an optionally substituted C １－６ It is a compound that is alkyl.

[0116] In one embodiment, the compounds of formula (I) are those in which m is 1.

[0117] In one embodiment, the compound of formula (I) is a compound in which ring A is a 5-membered ring optionally having 1 or 2 substituents selected from a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino, an optionally substituted hydroxy, and an optionally substituted mercapto.

[0118] In one embodiment, the compound of formula (I) is a compound in which ring B is a 6-membered ring optionally having 1 or 2 substituents selected from a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino, an optionally substituted hydroxy, an optionally substituted mercapto, and an optionally substituted heterocyclic group.

[0119] In one embodiment, the compound of formula (I) is a compound in which ring C is a 5-membered ring optionally having 1 or 2 substituents selected from a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl, and an optionally substituted heterocyclic group.

[0120] In one aspect, the compound of formula (I) is R ２ is a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group.

[0121] In one aspect, the compound of formula (I) is R ３ is a hydrogen atom, optionally substituted C １－６ alkyl, optionally substituted C ２－６ The compound is an alkenyl or an amino which may have a substituent.

[0122] In one aspect, the compound of formula (I) is R ４a and R ４bare the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, or an optionally substituted C １－６ It is a compound that is alkyl.

[0123] In one aspect, the compound of formula (I) is R １ C which may have a substituent １－６ alkyl, optionally substituted C ３－６ Cycloalkyl or optionally substituted C ２－６ alkenyl; R ２ is a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; R ３ is a hydrogen atom, optionally substituted C １－６ alkyl, optionally substituted C ２－６ alkenyl or optionally substituted amino; R ４a and R ４b are the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, or an optionally substituted C １－６ alkyl; R ５ is a hydrogen atom or an optionally substituted C １－６ alkyl; and R ６ is a hydrogen atom or an optionally substituted C １－６ It is a compound that is alkyl.

[0124] In one aspect, the compound of formula (I) is R １ C which may have a substituent １－６ alkyl; R ２ is a hydrogen atom; R ３ is a hydrogen atom or an optionally substituted C １－６ alkyl; R ４a and R ４b are the same or different and each is a hydrogen atom or a halogen atom; R ５ is a hydrogen atom or an optionally substituted C １－６ alkyl; and R ６is a compound where the atom is a hydrogen atom.

[0125] In one aspect, the compound of formula (I) has the formula

[0126]

[0127] [In the formula, R １a is (a) C １－６ C optionally having 1 to 3 substituents selected from alkyl-carbonyloxy, hydroxy and halogen atoms １－６ Alkyl, (b) C ３－６ cycloalkyl, (c) phenyl or (d) mono- or di-C １－６ represents alkylamino; R ２ａ is a hydrogen atom or C １－６ represents alkyl; R ２ｂ represents a hydrogen atom or hydroxy; R ３a is (a) a hydrogen atom, (b) a phenyl, hydroxyl, halogen atom, C １－６ Alkyl-carbonyl, C ７－１３ C optionally having 1 to 3 substituents selected from aralkyloxy and pyridyl １－６ Alkyl, (c) C ３－６ cycloalkyl, (d) phenyl, (e) C １－６ Alkoxy, (f) mercapto, (g) C １－６ alkylthio or (h) mono- or di-C １－６ The compound is represented by the formula: wherein R represents an alkylamino group.

[0128] In one aspect, the compound of formula (I) is selected from the group consisting of N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]acetamide, N-[2-(2-methyl-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide, N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]propionamide, N-{2-[2-(4-phenylbutyl)-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene]ethyl}acetamide, N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]thiazol-8-ylidene)ethyl]acetamide, N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide, (R)-N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide, (S)-N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide, N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]propionamide, (R)-N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]propionamide, (S)-N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]propionamide, N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]acetamide, (R)-N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]acetamide, (S)-N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]acetamide, N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide, (R)-N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide, (S)-N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide, N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide, (R)-N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide, (S)-N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide, or a salt thereof.

[0129] In one aspect, the compound of formula (I) has the formula

[0130]

[0131] [wherein each symbol has the same meaning as above] or a salt thereof.

[0132] In one aspect, the compound of formula (I) has the formula

[0133]

[0134] [In the formula, R ２ , R ３ , R ４a and R ４b and other symbols have the same meanings as above.

[0135] Salts of the melatonin receptor agonist compounds described above include, for example, pharmacologically acceptable salts. Examples include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Suitable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, and ammonium salts. Suitable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like. Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. Among these, pharmaceutically acceptable salts are preferred. Examples of such salts include, when the melatonin receptor agonist compound has a basic functional group, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid; and, when the melatonin receptor agonist compound has an acidic functional group, salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and ammonium salt.

[0136] Salts of the melatonin receptor agonist (hereinafter also referred to as "the compound of the present invention") contained in the agent of the present invention include, for example, pharmacologically acceptable salts. Examples include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Suitable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, as well as aluminum salts and ammonium salts. Suitable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like. Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc., and suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0137] Among these, pharmaceutically acceptable salts are preferred, and examples thereof include, when the compound of the present invention has a basic functional group, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc., and when the compound of the present invention has an acidic functional group, examples thereof include alkali metal salts such as sodium salt, potassium salt, etc., alkaline earth metal salts such as calcium salt, magnesium salt, etc., ammonium salt, etc. In addition, the compound of the present invention may be a hydrate or a non-hydrate.

[0138] The melatonin receptor agonist used in the agent of the present invention can be prepared by a method known per se, for example, a method described in US Pat. No. 6,218,429 B1 (WO97 / 3287A1), US Pat. No. 5,856,529A, US Pat. No. 5,981571A, US Pat. No. 6,060,506A (WO98 / 25606A1), US Pat. No. 2009182023 A1 (WO2007 / 148808), US Pat. No. 5,225442, US Pat. No. 6,235,789 B1 (WO96 / 08466), US Pat. No. 5,708,005 B (WO97 / 01539), US Pat. No. 5,922,771 B (WO97 / 05098), US Pat. No. 8,73,761 B2 (WO2008 / 069311), US Pat. It can be produced according to the production method described in US Pat. No. 8,247,429 B2 (WO2008 / 084717), US Pat. No. 8,110,585 B2 (WO2008 / 136382), etc., or a method similar thereto.

[0139] The compound of the present invention may be crystalline, and both a single crystalline form and a mixture of crystalline forms are encompassed within the scope of the compound of the present invention. Crystals can be produced by crystallization using a crystallization method known per se. The compound of the present invention or a salt thereof may be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, a co-crystal or co-crystal salt refers to a crystalline substance composed of two or more distinct solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, stability, etc.). A co-crystal or co-crystal salt can be produced according to a co-crystallization method known per se.

[0140] The compound of the present invention includes within its scope solvates (e.g., hydrates) and non-solvates. The compound of the present invention may contain isotopes (e.g., ２ H. ３ H. １１ C. １４ C. １８ F. ３５ S. １２５The compound may be a compound labeled or substituted with an isotope, such as I. Compounds labeled or substituted with an isotope may be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and may be useful in fields such as medical diagnosis.

[0141] When the compound of the present invention has an asymmetric center, it may exist in the form of isomers such as enantiomers or diastereomers. All such isomers and mixtures thereof are included within the scope of the present invention. In addition, isomers may be produced due to conformation or tautomerism, and such isomers and mixtures thereof are also included in the compound of the present invention.

[0142] The compounds of the present invention may have stereoisomers depending on the type of substituents, and both the isomers alone and mixtures thereof are included in the present invention.

[0143] The compound of the present invention may be used as a prodrug. A prodrug of the compound of the present invention refers to a compound that is converted into the compound of the present invention by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is converted into the compound of the present invention by enzymatic oxidation, reduction, hydrolysis, or the like, or a compound that is converted into the compound of the present invention by hydrolysis, etc., with gastric acid, or the like.

[0144] The melatonin receptor agonist contained in the agent of the present invention acts on mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, horses, cows, sheep, monkeys, gorillas, humans, etc.) by activating i) Wnt signal-related genes, (ii) neurulation-related genes, (iii) genes related to cell adhesion, cell matrix, and blood-brain barrier regulation, (iv) genes related to memory and learning, (v) inflammation-related genes, and (vi) genes classified as RESPONSE TO HORMONE, REGULATION OF HORMONE LEVELS, TISSUE MIGRATION PROCESSING AND PRESENTATION, REGULATION OF VIRAL PROCESS, NEVATIVE REGULATION OF VIRAL PROCESS, POSITIVE REGULATION OF MESENCHYMAL CELL PROLIFERATION, MUSCLE ORGANIC REGULATION, and VEGF-related genes in the pathway classification of Gene Ontology biological processes (typically, MSigDB v2023.2.Hs (Oct 2023)). The gene expression inhibitors of the present invention can be used as agents for regulating the expression of at least one gene selected from the group consisting of genes classified into DEVELOPMENT, NEGATIVE REGULATION OF NOTCH SIGNALING PATHWAY, POSITIVE REGULATION OF BLOOD CIRCULATION, and RESPONSE TO OXYGEN LEVELS. The gene expression inhibitors of the present invention can also be used as agents for preventing or treating diseases caused by the expression of the above-mentioned genes or symptoms associated with the diseases. As used herein, "treatment" includes complete cure, healing, improvement, alleviation, etc. of diseases caused by the expression of a specific gene or symptoms associated with the diseases.

[0145] The genes to be regulated by the gene expression regulator of the present invention are derived from, for example, the above-mentioned mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, horse, cow, sheep, monkey, gorilla, human, etc.). Specific examples of the target genes include (i) Wnt signaling-related genes, (ii) neurulation-related genes, (iii) cell adhesion, cell matrix, and blood-brain barrier regulation-related genes, (iv) memory and learning-related genes, (v) inflammation-related genes, and (vi) pathways classified in the Gene Ontology (https: / / geneontology.org) as biological process pathways, such as RESPONSE TO HORMONE, REGULATION OF HORMONE LEVELS, TISSUE MIGRATION PROCESSING AND PRESENTATION, REGULATION OF VIRAL PROCESS, NEVATIVE REGULATION OF VIRAL PROCESS, POSITIVE REGULATION OF MESENCHYMAL CELL PROLIFERATION, MUSCLE ORGAN DEVELOPMENT, NEGATIVE REGULATION OF NOTCH SIGNALING PATHWAY, POSITIVE REGULATION OF BLOOD CIRCULATION, and RESPONSE TO Examples include a group of genes classified as OXGEN LEVELS.

[0146] Examples of Wnt signaling-related genes include Wnt family genes and Fzd family genes, which are classified as NON-CANONICAL WNT SIGNALING PATHWAY, PRIMARY NEURAL TUBE FORMATION, ESTABLISHMENT OF PLANAR POLARITY INVOVED IN NEURAL TUBE CLOSURE, or NEURAL TUBE FORMATION in the Gene Ontology classification of biological process pathways.

[0147] Examples of neurulation-related genes include those classified as PRIMARY NEURAL TUBE FORMATION, ESTABLISHMENT OF PLANAR POLARITY INVOVED IN NEURAL TUBE CLOSURE, or NEURAL TUBE FORMATION in the pathway classification of biological processes in Gene Ontology.

[0148] Examples of gene groups related to cytoplasmic adhesion, cell matrix, and blood-brain barrier regulation include collagen family genes, matrix metalloproteinase family genes, endothelin receptor genes, and nuclear receptor family genes, which are classified as POSITIVE REGULATION OF CYTOSOLICCALCIUM IONCONCENTRATION, TUBE MORPHOGENESIS, and BONE DEVELOPMENT in the Gene Ontology biological process pathways, and as EXTRACELLULAR MATRIX and MATRISOME in the Gene Ontology cell component classifications.

[0149] Examples of genes related to memory and learning include Arg3.1 and / or early fluctuating genes, which are classified as RNA BINDING in the molecular function classification of Gene Ontology, and SKELETAL MUSCLE CELL DIFFERENTIATION in the pathway classification of biological processes.

[0150] Examples of the early fluctuating genes include Egr family genes, Fos family genes, and Foxo family genes.

[0151] Examples of inflammation-related genes include inflammasome-related genes classified as INNATE IMMUNE RESPONSE, ANTIGEN PROCESSING AND PRESENTATION, PRORESPONSE TO INTERFERON BETA, RESPONSE TO TYPE II INTERFERON, REGULATION of NLRP3 INFLAMMASOME COMPLEX ASSEMBLY in the Gene Ontology biological process pathway classification, and NRLP6 INFLAMMASOME COMPLEX in the cellular component classification, as well as microglial marker genes.

[0152] In one embodiment, genes that can be regulated (altered) by the gene expression regulator of the present invention are genes shown in Table 1 below.

[0153]

[0154] These altered genes belong to biological pathways (typically, MSigDB v2023.2.Hs (Oct 2023)) whose expression can be controlled by the gene expression regulator of the present invention in the Gene Ontology classification. Typically, by controlling (changing) the genes shown in Table 1, for example, it is possible to prevent or treat diseases such as those described below.

[0155] Diseases that can be prevented or treated by regulating gene expression with the agent of the present invention include, firstly, diseases described in DSM-5 (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 2013) or DSM-5-TR (Text Revision of the DSM-5, 2022 / 3). Specific examples include the following diseases: (1) Neurodevelopmental disorders (intellectual disability disorders (e.g., intellectual developmental disorder, global developmental delay, intellectual disability not otherwise specified), communication disorders (e.g., language disorders, speech disorders, childhood developmental fluency disorder, social communication disorder, communication disorder not otherwise specified), attention deficit hyperactivity disorder, restricted learning disorder, movement disorders (e.g., developmental hyperkinesia, stereotypic movement disorder), tic disorders (e.g., Tourette's syndrome, persistent motor or vocal tic disorder, provisional tic disorder, other specified tic disorders), other neurodevelopmental disorders (e.g., other specified neurodevelopmental disorders, neurodevelopmental disorder not otherwise specified, etc.), (2) Schizophrenia spectrum disorders (schizotypal personality disorder, paranoia (e.g., endearing type, grandiose type, jealous type, victim type, somatic type, mixed type, unspecified type), brief psychosis (e.g., with / without stress, postpartum onset), schizophreniform disorder (e.g., with / without favorable prognostic features), schizophrenia, schizoaffective disorder (e.g., bipolar type, depressive type), substance- or medication-induced psychosis, psychosis due to other medical causes, catatonia due to other psychosis, catatonia due to other medical causes, other specified schizophrenia spectrum disorders, schizophrenia spectrum disorders not otherwise specified, attenuated psychotic syndrome, etc.), (3) Obsessive-compulsive disorders (obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania, excoriation disorder, substance- or medication-induced obsessive-compulsive disorder, obsessive-compulsive disorder due to other medical causes, other specified obsessive-compulsive disorders, unspecified obsessive-compulsive disorder, etc.), (4) Trauma- and stressor-related disorders (e.g., reactive attachment disorder, disinhibited interpersonal disorder, post-traumatic stress disorder (including post-traumatic stress disorder in children under 6 years of age), acute stress disorder, adjustment reaction disorder, other specified trauma- and stressor-related disorders, unspecified stressor-related disorders, etc.);(5) Eating behavior disorders (pica, rumination disorder, avoidant / restrictive food intake disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, other specified eating behavior disorders, eating behavior disorders not otherwise specified, etc.), (6) Neurodementia (excluding delirium, other specified delirium, and delirium not otherwise specified) (dementia, mild cognitive impairment (e.g., Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, dementia due to traumatic brain injury, dementia caused by damage to other parts of the body (e.g., dementia due to cardiac damage), substance- or medication-induced dementia, dementia due to HIV infection), dementia due to prion disease, dementia due to other medical diseases, dementia due to multiple etiologies, dementia not otherwise specified, etc.), Behavioral and Psychological Signs and Symptoms of Dementia associated with dementia (BPSD, Behavioral and Psychological Signs and Symptoms of Dementia)), and (7) Personality disorders (e.g., paranoid, schizoid, schizotypal, antisocial, borderline, histrionic, narcissistic, avoidant, dependent, obsessive-compulsive, due to other medical illnesses, other specified, unspecified), personality changes due to other illnesses, other specified and unspecified personality disorders, etc.). Also included are the following disorders: (8) Neurodegenerative diseases (excluding Parkinson's disease) (traumatic brain injury, prion disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome caused by viral infections such as COVID-19 or other factors, etc.), (9) Blood-brain barrier (BBB) ​​damage-related diseases (multiple sclerosis, amyotrophic lateral sclerosis (ALS), neuropathic pain, stroke, Gulf War syndrome, encephaloma, Long-COVID, bacterial meningitis, encephalitis, etc.), and various psychiatric and neurological diseases mentioned above, and (10) Arc (Activity-regulated Cytoskeleton-associated Protein)-related diseases (excluding depression, anxiety, bipolar disorder, and delirium) (schizophrenia, Alzheimer's disease, mood disorders, intellectual disability, epilepsy, etc.).

[0156] Among the above diseases, in one aspect, the symptoms associated with a wide range of psychiatric and neurological disorders include attention deficit hyperactivity disorder, schizophrenia, trauma- and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome including sequelae of COVID-19 infection, cognitive impairment such as Alzheimer's disease, dementia with Lewy bodies, frontotemporal lobar degeneration, dementia caused by various reasons such as ischemia, and behavioral and psychological signs and symptoms of dementia (BPSD). Among these, the symptoms include attention deficit hyperactivity disorder, schizophrenia, trauma- and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome including sequelae of COVID-19 infection, and neurodementia (excluding delirium, other specified delirium, and delirium unspecified).

[0157] The compound of the present invention can be said to have excellent properties as a pharmaceutical, such as excellent solubility in water, the Japanese Pharmacopoeia Dissolution Test Second Fluid, or the Japanese Pharmacopoeia Disintegration Test Second Fluid, excellent pharmacokinetics (e.g., blood drug half-life, brain transferability, metabolic stability, CYP inhibition), low toxicity (e.g., superior as a pharmaceutical in terms of acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interactions, carcinogenicity, phototoxicity, etc.), and few side effects, and can therefore be safely administered orally or parenterally to mammals such as those mentioned above (e.g., mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.). "Parenteral" includes intravenous, intramuscular, subcutaneous, intravisceral, intranasal, intradermal, ocular, intracerebral, rectal, intravaginal, intraperitoneal, intratumor, proximal to a tumor, etc., and administration directly to a lesion.

[0158] The agent of the present invention may be in any form, such as a solid preparation, such as a powder, granules, tablets, capsules, or orally disintegrating film, or a liquid preparation, such as a syrup, emulsion, or injection.

[0159] The agent of the present invention can be manufactured by conventional methods, such as blending, kneading, granulation, tableting, coating, sterilization, and emulsification, depending on the form of the agent. Regarding the manufacture of the formulation, reference may be made to the various sections of the General Provisions for Preparations of the Japanese Pharmacopoeia. The agent of the present invention may also be formed into a sustained-release agent containing an active ingredient and a biodegradable polymer compound. The sustained-release agent can be prepared, for example, according to the method described in JP-A-9-263545.

[0160] The content of the compound of the present invention in the agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight, in terms of the amount of the compound of the present invention or a salt thereof relative to the total preparation (total pharmaceutical).

[0161] The compound of the present invention may be administered orally or parenterally as it is, or mixed with an appropriate pharmacologically acceptable carrier, for example, an excipient (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate, other suspending agents, etc.), a binder (e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone, etc.), a lubricant (e.g., stearic acid, magnesium stearate, calcium stearate, talc, etc.), a disintegrant (e.g., carboxymethylcellulose calcium, talc, etc.), a diluent (e.g., water for injection, physiological saline, etc.), and, if necessary, an additive (e.g., stabilizer, preservative, colorant, flavoring, sweetener, bitterness masker, solubilizer, emulsifier, buffer, isotonicity agent, etc.), in a conventional manner, in the form of a solid preparation such as a powder, fine granules, granules, tablets, capsules, or a liquid preparation such as an injection. Furthermore, the compound of the present invention or a salt thereof can be directly administered to the affected area of ​​a joint disease or the like by forming it into a topical preparation and administering it. In this case, it is preferable to administer it as an injection. It can be administered as a parenteral preparation for topical administration (e.g., an injection into the muscle, subcutaneously, organ, or joint, etc., solid preparations such as implants, granules, or powders, liquid preparations such as suspensions, ointments, etc.).

[0162] For example, to prepare an injection, a practical injection preparation can be obtained by forming the compound of the present invention into an aqueous suspension together with a dispersing agent (e.g., a surfactant such as Tween 80 or HCO-60, a polysaccharide such as carboxymethylcellulose, sodium alginate or hyaluronic acid, polysorbate, etc.), a preservative (e.g., methylparaben, propylparaben, etc.), an isotonicity agent (e.g., sodium chloride, mannitol, sorbitol, glucose, etc.), a buffer (e.g., calcium carbonate, etc.), a pH adjuster (e.g., sodium phosphate, potassium phosphate, etc.), etc. Alternatively, the compound of the present invention can be dispersed together with a vegetable oil such as sesame oil or corn oil, or a mixture thereof with a phospholipid such as lecithin, or a medium-chain fatty acid triglyceride (e.g., Miglyol 812, etc.) to prepare an injection that can be actually used as an oily suspension.

[0163] The dosage of the compounds of the present invention is determined appropriately depending on the desired therapeutic effect, the route of administration, and the duration of treatment. The dosage may vary from patient to patient depending on the nature and severity of the disease, the patient's weight, the diet being followed by the patient, concomitant medications, and other factors that would be recognized by those skilled in the art. For example, the dosage of the compounds of the present invention may be the dosage normally used for treating sleep disorders for each melatonin receptor agonist or its derivative, but a higher dosage is preferred. However, a dosage that does not cause serious side effects is desirable. The total daily dosage can be administered in a single dose or in divided doses, and may be outside the range stated herein at the discretion of the physician.

[0164] The agent of the present invention can be used as a pharmaceutical composition comprising the compound of the present invention alone or a mixture of the compound of the present invention with a pharmacologically acceptable carrier, according to a method known per se as a method for producing pharmaceutical preparations (e.g., a method described in the Japanese Pharmacopoeia, etc.). The agent of the present invention can be used in the form of, for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules), troches, syrups, liquids, emulsions, suspensions, controlled-release preparations (e.g., immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (e.g., orally disintegrating films, oral mucosal patch films), or the like.

[0113] The compound can be safely administered orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously, intraviscerally, intranasally, intradermally, by instillation, intracerebral, rectally, vaginally, intraperitoneally, or into a lesion) as a pharmaceutical composition such as a pharmaceutical composition comprising ...

[0165] The "pharmacologically acceptable carrier" may be any of various organic or inorganic carriers commonly used as starting materials for formulations. For example, excipients, lubricants, binders, disintegrants, etc. may be used in solid formulations, while solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. may be used in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, coloring agents, sweeteners, and bitterness maskers may be used as needed.

[0166] Examples of excipients include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid.

[0167] Examples of lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, and the like.

[0168] Examples of binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, and sodium carboxymethyl cellulose.

[0169] Examples of disintegrants include starch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, and L-hydroxypropylcellulose.

[0170] Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.

[0171] Examples of solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.

[0172] Examples of suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

[0173] Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, and the like.

[0174] Examples of the buffering agent include buffer solutions such as phosphate, acetate, carbonate, and citrate.

[0175] An example of a soothing agent is benzyl alcohol.

[0176] Examples of preservatives include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, and sorbic acid.

[0177] Examples of antioxidants include sulfites, ascorbic acid, and α-tocopherol.

[0178] Although it varies depending on the administration method, carrier, etc., the compound of the present invention can be added generally in a proportion of 0.01 to 100% (w / w), preferably 0.1 to 95% (w / w), based on the total amount of the formulation, and can be produced according to a conventional method.

[0179] The compounds of the present invention can be said to have extremely low toxicity and can be used in combination with other drugs to prevent or treat a wide range of diseases and symptoms, including, but not limited to, attention-deficit hyperactivity disorder (ADHD), schizophrenia, trauma- and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome (including sequelae of COVID-19 infection), cognitive impairments such as Alzheimer's disease, dementia with Lewy bodies, frontotemporal lobar degeneration, and dementia caused by various reasons such as ischemia, and behavioral and psychological signs and symptoms of dementia (BPSD). These compounds can exhibit excellent preventive and therapeutic effects when used in combination with other drugs. Furthermore, such combination therapy can reduce the dose of other drugs, thereby reducing their side effects. Drugs that can be used in combination with the compounds of the present invention (hereinafter referred to as "combined drugs") include the following:

[0180] Benzodiazepines (chlordiazepoxide, diazepam, clorazepate potassium, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel blockers (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.), selective serotonin reuptake inhibitors (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitors (benla hydrochloride, Faxine, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), norepinephrine reuptake inhibitors (reboxetine mesylate, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT1A agonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT3 antagonists (cyamemazine, etc.), non-cardioselective beta-blockers (propranolol hydrochloride, oxyprenolol hydrochloride, etc.), histamine H1 antagonists (hydroxyzine hydrochloride, etc.), antipsychotic drugs (chlorpromazine, haloperidol, etc.) Dhol, Sulpuride, Clozapine, Trifluoperazine Hydrochloride, Fluphenazine Hydrochloride, Olanzapine, Quetiapine Fumarate, Risperidone, Aripiprazole, etc.), CRF antagonists, other antianxiety drugs (Meprobamate, etc.), Tachykinin antagonists (Aprepitant, Saredutant, etc.), drugs acting on metabotropic glutamate receptors, CCK antagonists, β3 adrenergic antagonists (Amibegron Hydrochloride, etc.), GAT-1 inhibitors (Tiagabine Hydrochloride, etc.), N-type calcium channel blockers, Type 2 carbonic anhydrase inhibitors, NMDA glycine site agonists drugs, NMDA antagonists (memantine, etc.), peripheral benzodiazepine receptor agonists, vasopressin antagonists, vasopressin V1b antagonists, vasopressin V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid receptor agonists, thyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), 5-HT2A antagonists, 5-HT2A inverse agonists, COMT inhibitors (entacapone, etc.), drugs for treating bipolar disorder (lithium carbonate, sodium valproate,lamotrigine, riluzole, felbamate, etc.), cannabinoid CB1 antagonists (rimonabant, etc.), FAAH inhibitors, sodium channel blockers, anti-ADHD drugs (methylphenidate hydrochloride, methamphetamine hydrochloride, etc.), drugs for treating alcoholism, drugs for treating autism, drugs for treating chronic fatigue syndrome, drugs for treating convulsions, drugs for treating fibromyalgia, drugs for treating headaches, drugs for treating insomnia (etizolam, zopiclone, triazolam, zolpidem, indiplon, orexin receptor modulators (suvorexant, lemborexant, etc.), melatonin receptor agonists (melatonin, ramelteon , tasimelteon, etc.), drugs for smoking cessation, drugs for myasthenia gravis, drugs for stroke, drugs for mania, drugs for hypersomnia, drugs for pain, drugs for dysthymia, drugs for autonomic nervous system disorders, drugs for male and female sexual dysfunction, drugs for migraine, drugs for pathological gambling, drugs for restless legs syndrome, drugs for substance dependence, drugs for alcohol-related disorders, drugs for irritable bowel syndrome, drugs for Alzheimer's disease (donepezil, galantamine, drugs for Alzheimer's disease that act on amyloid beta and other substances that degenerate neural tissue (donanemab, aducanumab, lecanemab, etc.), etc.), Drugs for treating Kinson's disease, drugs for treating Huntington's chorea, drugs for treating ALS (riluzole, etc., neurotrophic factors, etc.), drugs for treating dyslipidemia such as cholesterol-lowering drugs (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthesis inhibitors), drugs for treating abnormal behavior or drugs to suppress wanderlust caused by dementia (sedatives, anti-anxiety drugs, etc.), analgesics (alpha-2 adrenergic receptor agonists (dexmedetomidine, guanfacine, etc.)), apoptosis inhibitors, anti-obesity drugs, drugs for treating diabetes, drugs for treating hypertension Antihypertensive drugs, antihypertensive drugs, rheumatoid arthritis drugs (DMARDs), anticancer drugs, parathyroid drugs (PTH), calcium receptor antagonists, sex hormones or derivatives thereof (progesterone, estradiol, estradiol benzoate, etc.), neurodifferentiation promoters, neuroregeneration promoters, non-steroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.), steroids (dexamethasone, cortisone acetate, etc.), anti-cytokine drugs (TNF inhibitors, MAP kinase inhibitors, etc.), antibody drugs,Nucleic acids or nucleic acid derivatives, aptamer drugs, electrolyte infusions, plasma expanders, peripheral parenteral nutrition, total parenteral nutrition, enteral nutrition, and other various infusions used before, during, and after surgery and / or during hospitalization or home medical care. Hereinafter, the combined use of the compound of the present invention and a concomitant drug may be referred to as the "concomitant drug of the present invention."

[0181] The above-mentioned concomitant drugs may be used in combination of two or more kinds in an appropriate ratio. When the compound of the present invention is used in combination with a concomitant drug, the amount of each drug may be reduced within a safe range, taking into account the opposing effects of the drugs. Therefore, the opposing effects that may be caused by these drugs can be safely prevented. The compound of the present invention may be used in combination with a non-drug therapy. Specific examples of non-drug therapy include: (1) surgery; (2) hypertensive chemotherapy using angiotensin II or the like; (3) gene therapy; (4) hyperthermia; (5) cryotherapy; (6) laser ablation; (7) radiation therapy; (8) immunotherapy; (9) regenerative medicine; (10) cell therapy; (11) psychotherapy or psychosocial therapy; and (12) cognitive behavioral therapy.

[0182] These concomitant drugs may be in their free form or pharmaceutically acceptable salts. Examples of such salts include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.), and ammonium salts when the drug has an acidic functional group. Examples of such salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid when the drug has a basic functional group, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid. The concomitant drugs exemplified here are readily available commercially or can be prepared according to known methods.

[0183] The administration form of the combination drug of the present invention is not particularly limited, and the compound of the present invention and the concomitant drug can be combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, (2) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via the same administration route, (3) administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via the same administration route with a time lag, (4) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via different administration routes, and (5) administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via different administration routes with a time lag (e.g., administration of the compound of the present invention and the concomitant drug in the order of administration, or administration in the reverse order). The concomitant drug may be a single drug or a combination drug containing two or more drugs. Furthermore, the method for the formulation is not particularly limited, and for example, the compound may be formulated as a multi-component crystal, such as a (single) crystalline complex of the compound of the present invention and one or more concomitant drugs (active ingredients), or two or more concomitant drugs (active ingredients).

[0184] The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. The compounding ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the administration subject, administration route, symptoms, type of concomitant drug used, etc. Usually, it can be determined based on the general dosage of the concomitant drug used. When the administration subject is a human, for example, 0.01 to 100 parts by weight of the concomitant drug can be used per 1 part by weight of the compound of the present invention.

[0185] The combination drug of the present invention can be said to have low toxicity. For example, the compound of the present invention or (and) the combination drug described above can be mixed with a pharmacologically acceptable carrier according to known methods to prepare pharmaceutical compositions such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc. These compositions can be safely administered orally or parenterally (e.g., topically, rectally, intravenously, etc.). Injections can be administered intravenously, intramuscularly, subcutaneously, or intraorganically, or directly to the lesion.

[0186] Pharmacologically acceptable carriers that may be used in the preparation of the combination drug of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical ingredients. For example, excipients, lubricants, binders, and disintegrants may be used in solid preparations. Liquid preparations may contain solvents, solubilizers, suspending agents, isotonicity agents, buffers, and soothing agents. Conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents, and the like may also be used as needed.

[0187] Examples of excipients include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid.

[0188] Examples of lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, and the like.

[0189] Examples of binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, and sodium carboxymethyl cellulose.

[0190] Examples of disintegrants include starch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, and L-hydroxypropylcellulose.

[0191] Examples of solvents include water for injection, isotonic saline, 5% dextrose, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.

[0192] Examples of solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.

[0193] Examples of suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

[0194] Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, and the like.

[0195] Examples of the buffering agent include buffer solutions such as phosphate, acetate, carbonate, and citrate.

[0196] An example of a soothing agent is benzyl alcohol.

[0197] Examples of preservatives include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, and sorbic acid.

[0198] Examples of antioxidants include sulfites, ascorbic acid, and α-tocopherol.

[0199] The blending ratio of the compound of the present invention to the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the subject of administration, the administration route, the disease, etc. For example, the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the formulation, but is usually about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight, and more preferably about 0.5 to about 20% by weight relative to the weight of the formulation.

[0200] The content of the concomitant drug in the concomitant preparation of the present invention varies depending on the form of the preparation, but is usually about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight, and more preferably about 0.5 to about 20% by weight, based on the weight of the preparation.

[0201] The content of additives such as carriers in the combination drug of the present invention varies depending on the form of the preparation, but is usually about 1 to about 99.99% by weight, preferably about 10 to about 90% by weight, of the preparation.

[0202] When the compound of the present invention and the concomitant drug are formulated separately, the contents thereof are the same as those described above.

[0203] 2. Kits and Products of the Invention The present invention relates to kits and products of the invention that contain melatonin receptor agonists and are useful for the treatment of (i) Wnt signaling-related genes, (ii) neurulation-related genes, (iii) cell adhesion, cell matrix, and blood-brain barrier regulation-related genes, (iv) memory and learning-related genes, (v) inflammation-related genes, and (vi) genes classified in the Gene Ontology pathways of biological processes as RESPONSE TO HORMONE, REGULATION OF HORMONE LEVELS, TISSUE MIGRATION PROCESSING AND PRESENTATION, REGULATION OF VIRAL PROCESS, NEVATIVE REGULATION OF VIRAL PROCESS, POSITIVE REGULATION OF MESENCHYMAL CELL PROLIFERATION, MUSCLE ORGAN DEVELOPMENT, NEGATIVE REGULATION OF NOTCH SIGNALING PATHWAY, POSITIVE REGULATION OF BLOOD CIRCULATION, and RESPONSE TO OXYGEN. The present invention also provides a kit for use in regulating the expression of at least one gene selected from the group consisting of genes classified into LEVELS. The present invention also provides a product comprising the gene expression regulator or preventive or therapeutic agent of the present invention and instructions for using the agent. Examples of instructions describing such instructions include package inserts for products (drugs, reagents, etc.). For other matters, the contents of 1. The gene expression regulator and preventive / therapeutic agent of the present invention are incorporated herein by reference.

[0204] 3. Evaluation Method (Screening Method) of the Present Invention The present invention also provides a method (screening method) for evaluating the effect of a melatonin receptor agonist on symptoms of a psychiatric / neurological disorder, comprising the steps of (1) administering a melatonin receptor agonist to a mammal lacking the Fmr1 gene, and (2) evaluating behavioral indicators representative of the symptoms of the psychiatric / neurological disorder and / or changes in predetermined gene expression in the mammal. In the evaluation method of the present invention, the effect of the melatonin receptor agonist on symptoms of the psychiatric / neurological disorder may be evaluated by comparing behavioral indicators representative of the symptoms of the psychiatric / neurological disorder and / or changes in predetermined gene expression in the mammal lacking the Fmr1 gene before and after administration of the melatonin receptor agonist. Alternatively, the behavioral indicators and / or changes in predetermined gene expression obtained when a specific melatonin receptor agonist is administered to a mammal lacking the Fmr1 gene may be used as a standard, and the behavioral indicators and / or changes in predetermined gene expression obtained when the specific melatonin receptor agonist is administered to the mammal lacking the Fmr1 gene may be compared with the behavioral indicators and / or changes in predetermined gene expression obtained with a desired melatonin receptor agonist.

[0205] In one embodiment, the mammal in which the Fmr1 gene has been deleted is a model mouse in which the Fmr1 gene has been deleted, and in another embodiment, an Fmr1-KO2 model mouse.

[0206] Psychiatric and neurological disorders are not particularly limited, and examples thereof include the aforementioned diseases and symptoms that are targets of the preventive and therapeutic agents of the present invention.

[0207] Examples of behavioral indicators include open field, hyponeophagia, nesting, aggression, new object recognition, and sociability interaction, as used in the examples described below.

[0208] The alteration of gene expression is not particularly limited, but includes genes whose expression is controlled (altered) by the gene expression regulator of the present invention. Specifically, for example, the above-mentioned (i) Wnt signal-related gene group, (ii) neurulation-related gene group, (iii) cell adhesion, cell matrix, and blood-brain barrier regulation-related gene group, (iv) memory and learning-related gene group, (v) inflammation-related gene group, and (vi) pathways of biological processes in the Gene Ontology (https: / / geneontology.org) (typically, MSigDB v2023.2.Hs (Oct 2023)) classified as RESPONSE TO HORMONE, REGULATION OF HORMONE LEVELS, TISSUE MIGRATION PROCESSING AND PRESENTATION, REGULATION OF VIRAL PROCESS, NEVATIVE REGULATION OF VIRAL PROCESS, POSITIVE REGULATION OF MESENCHYMAL CELL PROLIFERATION, MUSCLE ORGAN DEVELOPMENT, and NEGATIVE REGULATION OF NOTCH SIGNALING. Examples include gene clusters classified into PATHWAY, POSITIVE REGULATION OF BLOOD CIRCULATION, and RESPONSE TO OXGEN LEVELS.

[0209] The evaluation method (screening method) of the present invention can appropriately evaluate the effects of melatonin receptor agonists on the symptoms of psychiatric and neurological disorders in mammals and on fluctuations in the expression of specific genes as described above, and is therefore useful in contract businesses (e.g., CRO businesses) using the evaluation method, such as the development of pharmaceuticals and clinical trials. For other matters, the contents of 1. The gene expression regulator and preventive / therapeutic agent of the present invention, and 2. The kit and product of the present invention are all incorporated by reference.

[0210] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples in any way.

[0211] Example 1: Gene Expression Analysis in the Hippocampus of Fmr1 KO2 Mice Fmr1 KO2 mice (e.g., Cogram P et al., Front Behav Neurosci. 2019 Jun 25;13:141) lack expression of both the Fmr1 gene and FMR1 protein and exhibit a wide range of symptoms common to psychiatric and neurological disorders, including attention-deficit hyperactivity disorder (ADHD), bipolar disorder, depression, anxiety, trauma- and stress-related disorders, addiction, schizophrenia, epilepsy, delirium, chronic fatigue syndrome (including COVID-19 sequelae), cognitive impairments such as Alzheimer's disease, dementia with Lewy bodies, frontotemporal lobar degeneration, and dementia caused by various conditions such as ischemia, and behavioral and psychological signs and symptoms of dementia (BPSD). Since the hippocampus plays an important role in these diseases, we analyzed gene expression changes in hippocampal tissue following melatonin receptor agonists.

[0212] In this study, 8-week-old Fmr1 KO2 mice were orally administered the melatonin receptor agonist GEX-2018 once daily between 6:00 PM and 7:00 PM for two weeks. Two weeks later, hippocampal tissue was collected for comprehensive gene expression analysis. Specifically, hippocampi were collected from GEX-2018-treated and vehicle-controlled mice. Total RNA was extracted from the hippocampus using the RNeasy Mini kit (QIAGEN). mRNA was extracted from the total RNA using polyA-selection, followed by library preparation and RNA-seq (NovaSeq6000, Illumina Inc.). The resulting sequence data was mapped to the mouse genome using the STAR mapping tool (https: / / github.com / alexdobin / STAR / releases), and gene expression quantification software tpmcalculator (https: / / github.com / ncbi / TPMCalculator) was used to calculate counts for each gene. The count data was normalized between samples using the Trimmed Mean of M values ​​(TMM) using the gene expression analysis package edgeR (https: / / bioconductor.org / packages / release / bioc / html / edgeR.html), and genes that were significantly different between the solvent control and compound-treated groups (p-value < 0.05 and |expression ratio| > 1.25-fold) were extracted using the voom function of limma (https: / / bioconductor.org / packages / release / bioc / html / limma.html), a linear model analysis method (Table 2). Analysis was performed by searching for related pathways using a Fisher test on the group of different genes and the pathway gene set in MSigDB v2023.2.Hs (Oct 2023).

[0213] The results of this experiment showed that the expression of many genes was altered in the GEX-2018-treated group (Table 2), suggesting that changes in gene expression may also contribute to the effects on behavioral indicators.

[0214] When the pathways associated with genes whose expression levels were significantly altered by GEX-2018 administration are ranked in order of statistical significance (Tables 3 to 6), it can be seen that they include pathways known to play important roles in a variety of diseases, including various psychiatric and neurological disorders, such as the WNT signaling pathway, circadian rhythm-related pathways, and neurulation-related pathways (Tables 3 and 4).

[0215] In addition, pathways related to genes whose expression was decreased by administration of GEX-2018 include pathways related to the degradation of extracellular matrix (ECM), and pathways related to the processing and presentation of IFN-β and antibodies (Tables 5 and 6).

[0216] Many of the genes whose expression was induced by GEX-2018 administration in Fmr1 KO2 mice were known to be regulated downstream of Gq / 11, Gs, or Gi signaling pathways. GEX-2018 is a melatonin receptor agonist with high target selectivity. Melatonin receptors are G protein-coupled receptors known to be coupled to Gq / 11, Gs, or Gi. Therefore, the gene expression changes induced by GEX-2018 administration are likely mediated by melatonin receptors. Therefore, the gene expression changes induced by GEX-2018 administration and the associated pharmacological effects are likely not limited to GEX-2018, but are common to substances with similar structures and substances that have agonistic effects on melatonin receptors. However, melatonin receptor agonists are known to have receptors within cells, and this does not rule out their effects via these intracellular receptors.

[0217] This is the first report to show that melatonin receptor agonists induce such large-scale gene expression changes in addition to circadian rhythm-related genes, and that the range of physiological functions of these genes is so wide. Even more surprising, we found that many of these gene changes are in the direction of improving the pathology of various diseases.

[0218] The pathways whose expression was altered by GEX-2018 include genes involved in WNT signaling, cell adhesion, cell matrix, protection of the blood-brain barrier, suppression of inflammation, polarity conversion of M1 / M2 microglia (suppression of inflammatory microglia), induction of neuroprotective factors, induction of catecholamines, and protection of neural structure and function (synapse formation, dendritic spine morphology). These altered gene expression patterns are commonly observed in a wide range of psychiatric and neurological disorders, including, but not limited to, attention-deficit hyperactivity disorder (ADHD), schizophrenia, trauma- and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome (including COVID-19 sequelae), cognitive impairments such as Alzheimer's disease, dementia with Lewy bodies, frontotemporal lobar degeneration, and dementia caused by various factors such as ischemia, and behavioral and psychological signs and symptoms of dementia (BPSD). Therefore, GEX-2018 may be useful as a therapeutic agent or to prevent the onset of these disorders. Furthermore, these altered genes can be used as biomarkers in translational research, such as for diagnosis, patient stratification, and confirmation of compound efficacy. Representative examples are summarized below.

[0219] - Wnt signaling-related genes: GEX-2018 was confirmed to induce the expression of multiple genes in the Wnt signaling pathway, including Wnt family genes (Wnt3, Wnt4, etc.) and Fzd family genes (Fzd1, Fzd2, Fzd4, etc.) in the hippocampus of Fmr1 KO2 mice. Therefore, it is thought that the restoration and enhancement of Wnt signaling function contributes to the improvement of pathological conditions by GEX-2018.

[0220] It is known that melatonin receptor agonists activate Wnt / β-catenin signaling in a manner that does not involve gene expression control. However, to the inventors' knowledge, this is the first report showing that administration of GEX-2018, a substance with a similar structure, or a melatonin receptor agonist enhances the expression of a group of Wnt family genes and Fzd family genes.

[0221] Abnormalities in Wnt signaling have been reported in a wide range of psychiatric and neurological disorders, including, but not limited to, attention deficit hyperactivity disorder (ADHD), schizophrenia, trauma and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome (CFS), including the aftereffects of COVID-19 infection, cognitive impairments such as Alzheimer's disease, dementia with Lewy bodies, frontotemporal lobar degeneration, and dementia caused by various reasons such as ischemia, and behavioral and psychological signs and symptoms of dementia (BPSD).

[0222] In particular, activation of Wnt signaling has been reported to repair destruction of the blood-brain barrier, restore memory and learning function, and improve hippocampus-dependent memory impairment in elderly people and in those with cognitive impairments caused by various reasons, such as delirium, chronic fatigue syndrome including sequelae of COVID-19 infection, Alzheimer's disease, dementia with Lewy bodies, frontotemporal lobar degeneration, and ischemia.

[0223] - Genes related to cell adhesion, cell matrix, and blood-brain barrier regulation GEX-2018 found changes in the expression of a group of genes involved in the extracellular matrix and cell adhesion in the hippocampus of Fmr1 KO2 mice (collagen family genes (Col3A1, Col4A1, etc.), matrix metalloproteinase (Mmp) family genes, endothelin receptor genes (genes encoding endothelin receptors), nuclear receptor family genes, etc.).

[0224] Fmr1 KO2 mice showed abnormal expression of extracellular matrix genes (such as collagen family genes), but administration of GEX-2018 restored this to normal levels.

[0225] GEX-2018 dose-dependently suppresses the expression of genes such as Mmp14, which is thought to contribute to the improvement of pathological conditions. To the best of our knowledge, this is the first report that GEX-2018 or a melatonin receptor agonist suppresses Mmp14 gene expression.

[0226] Administration of GEX-2018 reduces the expression of endothelin receptors, which is elevated in Fmr1 KO2 mice, to normal levels. Increased endothelin expression has been reported to cause memory and learning impairments in Alzheimer's disease and various brain dysfunctions, as described below. Fmr1 KO2 mice also exhibit memory and learning impairments, and to our knowledge, this is the first report of increased endothelin receptor expression in Fmr1 KO2 mice and of the suppression of endothelin receptor expression by GEX-2018 or melatonin receptor agonists.

[0227] In addition to the Wnt family genes mentioned above, GEX-2018 also induces the expression of Nr4a1 Nuclear Receptor subfamily member genes, which are known to protect against blood-brain barrier disruption. Expression of this gene is known to be regulated by Creb, and GEX-2018 suggests that GEX-2018 stimulates melatonin receptors, which then induce gene expression via Gs / CREB. To the inventors' knowledge, this is the first report showing that GEX-2018 or a melatonin receptor agonist induces the expression of this gene.

[0228] Abnormal expression of collagen family genes, matrix metalloproteinase (MMP) family genes, endothelin receptors, and nuclear receptor family genes reduces the brain's barrier function by disrupting the blood-brain barrier, triggers inflammation in central tissues, and causes abnormalities in the structure of nerve cells (such as dendritic spines), which has various effects such as memory impairment and increased sensitivity to changes in the external environment such as sound and stress.

[0229] Abnormal expression of genes related to cell adhesion, cell matrix, and blood-brain barrier regulation leads to the destruction of the blood-brain barrier and abnormalities in the crosstalk between neurons, vascular endothelial cells, microglia, and astrocytes in the microenvironment of central tissues, as well as the accompanying inflammation. This abnormality is commonly seen in a wide range of diseases and symptoms, including but not limited to attention-deficit hyperactivity disorder (ADHD), schizophrenia, trauma and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome (including the aftereffects of COVID-19 infection), cognitive dysfunction such as Alzheimer's disease, dementia with Lewy bodies, frontotemporal lobar degeneration, and dementia caused by various reasons such as ischemia, and behavioral and psychological signs and symptoms of dementia (BPSD).

[0230] This is the first report to suggest that Mmp14 expression fluctuates in various diseases, particularly those mentioned above, and that it contributes to the pathology.

[0231] - Memory and learning genes: GEX-2018 restores to normal levels the expression of Arc (an Arc family gene), a master regulator of memory and learning, and a group of early-phase genes (transcription factors such as Egr family genes and Fos family genes) known to co-fluctuate with Arc in the hippocampus of Fmr1 KO2 mice. These genes are known to play important roles in various physiological functions, including cognitive function and the protection of neural structure and function (synapse formation, dendritic spine morphology). To our knowledge, this is the first report of the induction of Arc expression by GEX-2018 and melatonin receptor agonists.

[0232] In addition, GEX-2018 also restores to normal levels genes such as the Foxo family genes, which have been reported to be decreased in various diseases, including but not limited to Alzheimer's disease and various psychiatric and neurological disorders.

[0233] Abnormal expression of these genes has also been reported in a wide range of psychiatric and neurological disorders, including, but not limited to, attention deficit hyperactivity disorder (ADHD), schizophrenia, trauma and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome (CFS), including the aftereffects of COVID-19 infection, cognitive impairments such as Alzheimer's disease, dementia with Lewy bodies, frontotemporal lobar degeneration, and dementia caused by various reasons such as ischemia, and behavioral and psychological signs and symptoms of dementia (BPSD).

[0234] Inflammation-related genes: GEX-2018 regulates the expression of inflammation-related genes and microglial marker genes (Nlrp3, Pycrd / ASC, Aif1 / Iba1, Nos2 / iNOS, C1qa, Trem2, Stat1, Ror family genes, etc.) in the hippocampus of Fmr1 KO2 mice. The changes in the expression of these genes suggest that GEX-2018 induces a M1 / M2 polarity shift in microglia, exerting neuroprotective effects through the induction of BDNF by M2 microglia, and that these changes contribute to the drug's efficacy.

[0235] GEX-2018 also restores the expression of the Keap1 and Nfe2l2 / Nrf2 genes, which are known to contribute to antioxidant and inflammatory effects, to normal levels.

[0236] Abnormal expression of these genes has been reported in a wide range of diseases and conditions, including but not limited to attention deficit hyperactivity disorder (ADHD), schizophrenia, trauma and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome (CFS) including sequelae of COVID-19 infection, cognitive impairments such as Alzheimer's disease, dementia with Lewy bodies, frontotemporal lobar degeneration, and dementia caused by various reasons such as ischemia, and behavioral and psychological signs and symptoms of dementia (BPSD). These abnormalities are known to be involved in the destruction of the blood-brain barrier caused by abnormalities in the crosstalk between vascular endothelial cells, microglia, and astrocytes in the central tissue, and the accompanying inflammatory response.

[0237] To the best of the inventors' knowledge, this is the first report to comprehensively capture the changes in multiple inflammation-related genes caused by GEX-2018 and melatonin receptor agonists.

[0238] Furthermore, from the results shown in Tables 3 to 6 below, it was understood that the melatonin receptor agonist GEX-2018 can also regulate neurulation-related genes and gene groups classified as RESPONSE TO HORMONE, REGULATION OF HORMONE LEVELS, TISSUE MIGRATION PROCESSING AND PRESENTATION, REGULATION OF VIRAL PROCESS, NEVATIVE REGULATION OF VIRAL PROCESS, POSITIVE REGULATION OF MESENCHYMAL CELL PROLIFERATION, MUSCLE ORGAN DEVELOPMENT, NEGATIVE REGULATION OF NOTCH SIGNALING PATHWAY, POSITIVE REGULATION OF BLOOD CIRCULATION, and RESPONSE TO OXGEN LEVELS in the pathway classification of Gene Ontology (https: / / geneontology.org) biological processes (MSigDB v2023.2.Hs (Oct 2023)).

[0239] Based on the above results, it can be concluded that GEX-2018, as well as substances with similar structures and substances that have agonistic effects on melatonin receptors, can be used as therapeutic agents or to suppress the onset of a wide range of diseases and symptoms, including but not limited to attention deficit hyperactivity disorder (ADHD), schizophrenia, trauma and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome (CFS) including sequelae of COVID-19 infection, cognitive dysfunction such as Alzheimer's disease, dementia with Lewy bodies, frontotemporal lobar degeneration, and dementia caused by various reasons such as ischemia, and behavioral and psychological signs and symptoms of dementia (BPSD).

[0240]

[0241]

[0242]

[0243]

[0244]

[0245] Among the genes whose expression was altered by administration of melatonin and GEX-2018, genes whose expression was statistically significant (p-value < 0.05 and |expression ratio| > 1.25-fold) are shown in Table 7. Genes whose expression is already known to be altered by melatonin receptor agonists are marked with an *, such as the group of genes involved in circadian rhythm control (Cry1, Per1, Per2) (Satyanarayanan et al., Brain Behav Immun. 2020 Mar:85:142-151).

[0246] These gene expression changes can be considered as positive controls in this analysis. The results shown in Table 7 demonstrate that the large-scale gene expression changes induced by melatonin and GEX-2018 were confirmed under experimental conditions that adequately detected a group of genes whose changes in response to stimulation by melatonin receptor agonists are known to be physiologically significant, i.e., the positive control gene group. This strongly suggests that the observed gene expression changes are not mere artifacts but are physiologically significant changes.

[0247] These altered genes were confirmed to belong to the biological pathways (MSigDB v2023.2.Hs (Oct 2023)) whose expression can be controlled by the gene expression regulators of the present invention in the Gene Ontology classification. These results indicate that the observed gene expression changes are physiologically significant in these biological functional areas, supporting the usefulness of melatonin and GEX-2018 in the prevention or treatment of diseases according to the present invention. Furthermore, these gene expression changes suggest their applicability as biomarkers for the prevention and treatment of the aforementioned diseases, as well as for the diagnosis and evaluation of therapeutic effects. Other melatonin receptor agonists with similar mechanisms of action, such as GEX-2303, may also demonstrate similar utility.

[0248]

[0249] The compounds of the present invention and pharmaceutically acceptable salts thereof produce favorable (desired) changes in gene expression, which may exhibit the above-mentioned utility.

[0250] Example 2: Behavioral Tests Using Fmr1 KO2 Mice From the results of Example 1, the inventors found that Fmr1 KO2 mice were responsive to GEX-2018. Because GEX-2018 is a substance that exhibits high selectivity for melatonin receptors, Fmr1 KO2 mice can be used to evaluate a wide range of substances that have agonistic effects on melatonin receptors, including GEX-2018. A wide range of symptoms can be observed in Fmr1 KO2 mice (e.g., Cogram P et al., Front Behav Neurosci. 2019 Jun 25;13:141).

[0251] The observed symptoms are common to a wide range of psychiatric and neurological disorders, regardless of the patient's genetic background, including, but not limited to, attention deficit hyperactivity disorder (ADHD), schizophrenia, trauma and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome (CFS) including sequelae of COVID-19 infection, cognitive impairments such as Alzheimer's disease, dementia with Lewy bodies, frontotemporal lobar degeneration, and dementia caused by various reasons such as ischemia, and behavioral and psychological signs and symptoms of dementia (BPSD).

[0252] It is believed that the mechanisms underlying these symptoms involve common factors, regardless of genetic background such as disease-causing genes. Therefore, substances that show significant pharmacological effects in Fmr1 KO2 mice could be used to suppress the onset of a wide range of diseases or as therapeutic agents.

[0253] The results of Example 1 suggest that GEX-2018 and other substances with melatonin receptor agonist activity may have effects on autism symptoms, stress, anxiety, aggression, social behavior, memory and learning, etc. in Fmr1 KO2 mice. Therefore, the effects of GEX-2018 on various behavioral indicators were examined. In this study, 8-week-old Fmr1 KO2 mice were orally administered GEX-2018 (1 or 3 mg / kg) once daily between 6:00 PM and 7:00 PM for two weeks, followed by the following seven behavioral tests over the next two weeks. GEX-2018 administration continued throughout the behavioral testing period.

[0254] The open-field apparatus consisted of a PVC cage (50 × 9 × 30 cm) divided into 10-cm squares. Mice were placed in a corner square facing the corner, and their movements within the field were recorded using a video device (NT4.0 version, Viewpoint) throughout the entire test period. Activity was assessed by the total distance traveled. Self-grooming mice were individually placed in a cage (46 × 23.5 × 20 cm) and allowed to acclimate to the environment for 5 minutes. After that, grooming behavior, such as licking and scratching of body parts, was observed and recorded for 3 minutes. This index can be used to measure anxiety, hyperactivity, stress sensitivity, cognitive function, and other conditions.

[0255] Hyponeophagia: Mice cannot vomit due to the tightness of their cardiac sphincter, so new substances are first ingested in very small amounts to determine whether they are safe. This behavior was used as a way to measure anxiety, with condensed milk placed in the mice's cages and the time it took them to consume a certain amount measured. This index can be used to measure cognitive function, general behavior, hyperactivity, anxiety, stress response, etc.

[0256] Nesting: Compressed cotton was placed in the home cage, and the condition of the nests created by tearing it apart overnight was evaluated on a 5-point scale. Score 1: The cotton remained intact (more than 90% intact). Score 2: The cotton was partially torn (50-90% intact). Score 3: More than 50% of the cotton was torn, but no obvious nest was formed. Score 4: More than 90% of the cotton was torn and gathered within one-quarter of the cage floor area, but the nest was flat and less than 50% of the walls were higher than the mouse's body height. Score 5: More than 90% of the cotton was torn, forming a nearly complete nest. The nest was crater-shaped, with more than 50% of the walls higher than the mouse's body height. This index can be used to measure cognitive function, general behavior, hyperactivity, obsession, anxiety, stress response, etc.

[0257] The aggression test was conducted in a cage the same size as the home cage, with an acrylic resin lid. After allowing the test mouse to acclimate to the environment for 25 minutes, a control mouse was placed in the same cage and the number of bites and climbs was measured for 3 minutes. This index can be used to measure stress, anxiety, aggression, hyperactivity, social behavior, cognitive function, conditioning, memory and learning ability, etc.

[0258] The new object recognition device consisted of an acrylic resin box (26 cm long x 20 cm wide x 16 cm high) containing two objects (4-6 cm diameter x 2-6 cm high). Mice were allowed to freely explore the object-free box for two days prior to testing to familiarize them with the experimental environment. The test began with placing one object 1 on each end of the box and allowing the mice to explore the objects for five minutes. Next, object 1 on one end was replaced with object 2, and the time spent exploring familiar object 1 and novel object 2 was measured. This index can be used to measure stress, anxiety, hyperactivity, cognitive function, conditioning, obsession, memory and learning ability, etc.

[0259] A three-chamber experimental apparatus (each chamber measured 20 cm long, 40.5 cm wide, and 22 cm high) was used for the sociability interaction test. Each chamber was divided by a transparent acrylic resin, with a 10 cm x 5 cm opening at the bottom, allowing mice to freely move between the compartments. The test mouse was placed in the center compartment and allowed to acclimate for 5 minutes. After 5 minutes, a previously undisturbed mouse was placed in a wire cage in one of the side compartments. The side door was opened, and the test mouse was allowed to freely move between the left and right compartments for 10 minutes. After 10 minutes, a second undisturbed mouse was placed in the same wire cage in the opposite compartment. The time spent in each compartment of the apparatus was measured over the next 10 minutes. This index can be used to measure cognitive function, general behavior, social behavior, hyperactivity, anxiety, stress response, and other factors.

[0260] The results showed that GEX-2018, GEX-2303, and melatonin demonstrated the greatest efficacy in all seven behavioral tests (Tables 8 and 9). This suggests that GEX-2018 may be effective in treating various psychiatric and neurological disorders, including hyperactivity, stereotypic movements, anxiety, abnormal daily behavior, memory and learning disorders, aggression, and social disorders. Other melatonin receptor agonists with similar mechanisms of action, such as GEX-2303, may also demonstrate similar utility. To our knowledge, this is the first report demonstrating the use of GEX-2018 or similar melatonin receptor agonists in a mouse model of psychiatric and neurological pathology, with such extensive genetic alterations and with such a wide range of behavioral improvements at maximum efficacy.

[0261]

[0262]

[0263]

[0264]

[0265] From the above results, it can be seen that at least the melatonin receptor agonists used in the present invention (compounds of the present invention) can exert preventive or therapeutic effects on specific diseases and symptoms such as those described in Section 1. Gene Expression Regulators and Preventive / Therapeutic Agents of the Present Invention. In particular, it can be seen that melatonin receptor agonists are effective against diseases and symptoms such as attention deficit hyperactivity disorder, schizophrenia, trauma and stressor-related disorders, addiction, epilepsy, chronic fatigue syndrome including sequelae of COVID-19 infection, and neurodementia (excluding delirium, other specified delirium, and unspecified delirium), and can prevent or treat these diseases and symptoms. The compounds of the present invention and their pharmaceutically acceptable salts exhibit favorable (desired) pharmacological effects, which can demonstrate the above-mentioned utility.

[0266] According to the present invention, (i) Wnt signal-related genes, (ii) neurulation-related genes, (iii) cell adhesion, cell matrix, and blood-brain barrier regulation-related genes, (iv) memory and learning-related genes, (v) inflammation-related genes, and (vi) pathway classifications of Gene Ontology biological processes (MSigDB v2023.2.Hs (Oct 2023)) including RESPONSE TO HORMONE, REGULATION OF HORMONE LEVELS, TISSUE MIGRATION PROCESSING AND PRESENTATION, REGULATION OF VIRAL PROCESS, NEVATIVE REGULATION OF VIRAL PROCESS, POSITIVE REGULATION OF MESENCHYMAL CELL PROLIFERATION, MUSCLE ORGAN DEVELOPMENT, NEGATIVE REGULATION OF NOTCH SIGNALING PATHWAY, POSITIVE REGULATION OF BLOOD CIRCULATION, and RESPONSE TO The present invention can provide a drug that can be a new option for regulating the expression of genes included in the gene cluster classified as OXGEN LEVELS, etc. Furthermore, the present invention can provide a drug that can be a new option for the prevention and treatment of various diseases and symptoms, including, but not limited to, a wide range of psychiatric and neurological disorders, such as attention-deficit hyperactivity disorder, schizophrenia, trauma- and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome including sequelae of COVID-19 infection, cognitive dysfunction such as Alzheimer's disease, dementia with Lewy bodies, frontotemporal lobar degeneration, and dementia caused by various reasons such as ischemia, and behavioral and psychological signs and symptoms of dementia (BPSD).

[0267] This application is based on patent application No. 2024-090279 filed in Japan (filing date: June 3, 2024), the contents of which are incorporated in their entirety herein.

Claims

1. (i) Wnt signaling-related genes, including melatonin receptor agonists; (ii) neurulation-related genes; (iii) genes related to cell adhesion, cell matrix, and blood-brain barrier regulation; (iv) memory and learning-related genes; (v) inflammation-related genes; and (vi) Gene Ontology pathway classifications of biological processes, including response to hormone, regulation of hormone levels, tissue migration processing and presentation, regulation of viral processing, negative regulation of viral processing, positive regulation of mesenchymal cell proliferation, muscle organ development, negative regulation of notch signaling pathway, positive regulation of blood circulation, and response to oxygen. An agent for regulating the expression of at least one gene selected from the group consisting of genes classified into LEVELS.

2. The agent according to claim 1, wherein the Wnt signaling-related gene group is a Wnt family gene or an Fzd family gene classified into at least one of the group consisting of NON-CANONICAL WNT SIGNALING PATHWAY, PRIMARY NEURAL TUBE FORMATION, ESTABLISHMENT OF PLANAR POLARITY INVOVED IN NEURAL TUBE CLOSURE, and NEURAL TUBE FORMATION in the pathway classification of biological processes in Gene Ontology.

3. The agent according to claim 1, wherein the neurulation-related gene group is a neurulation-related gene group classified into at least one of the group consisting of PRIMARY NEURAL TUBE FORMATION, ESTABLISHMENT OF PLANAR POLARITY INVOVED IN NEURAL TUBE CLOSURE, and NEURAL TUBE FORMATION in the pathway classification of biological processes in Gene Ontology.

4. The agent described in claim 1, wherein the group of genes related to cytosolic adhesion, cytosolic matrix, and blood-brain barrier regulation is a collagen family gene, matrix metalloproteinase family gene, endothelin receptor gene, or nuclear receptor family gene classified into at least one of the group consisting of POSITIVE REGULATION OF CYTOSOLIC CALCIUM ION CONCENTRATION, TUBE MORPHOGENESIS, and BONE DEVELOPMENT in the pathways of biological processes in Gene Ontology, and EXTRACELLULAR MATRIX and MATRISOME in the classification of cellular components in Gene Ontology.

5. The agent according to claim 1, wherein the group of genes related to memory and learning is Arg3.1 and / or early variation genes classified as RNA BINDING in the molecular function classification of Gene Ontology and / or SKELETAL MUSCLE CELL DIFFERENTIATION in the pathway classification of biological processes.

6. The agent according to claim 5, wherein the early variable gene is an Egr family gene, a Fos family gene, or a Foxo family gene.

7. The agent according to claim 1, wherein the inflammation-related gene group is an inflammasome-related gene or a microglia marker gene group classified into at least one of the group consisting of INNATE IMMUNE RESPONSE, ANTIGEN PROCESSING AND PRESENTATION, PRORESPONSE TO INTERFERON BETA, RESPONSE TO TYPE II INTERFERON, and REGULATION of NLRP3 INFLAMMASOME COMPLEX ASSEMBLY in the classification of biological process pathways in Gene Ontology, and NRLP6 INFLAMMASOME COMPLEX in the classification of cellular components.

8. The agent according to any one of claims 1 to 7, wherein the melatonin receptor agonist is selected from the group consisting of melatonin, sustained-release melatonin, ramelteon, tasimelteon, agomelatine, piromelatine, LY-156735 (PD-6735), VEC-162, GEX-2018, GEX-2303, 8-M-PDOT, GR135531, GR196429, S20242, S24268, S25150, GW-290569, AH-001, AH-002, GG-012, enol-3-IPA, ML-23, SL-18.1616, IP-100-9, IP-101, AH-017, derivatives thereof, and metabolites thereof.

9. The agent according to claim 8, wherein the melatonin receptor agonist is selected from the group consisting of melatonin, sustained-release melatonin, ramelteon, tasimelteon, agomelatine, GEX-2018, GEX-2303, derivatives thereof, and metabolites thereof.

10. The agent according to any one of claims 1 to 9, further comprising one or more drugs.

11. An agent for the prevention or treatment of at least one disease selected from the group consisting of attention-deficit hyperactivity disorder, schizophrenia, trauma- and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome including sequelae of COVID-19 infection, and neurodementia (excluding delirium, other specified delirium, and unspecified delirium), comprising the agent according to any one of claims 1 to 10.

12. (i) Wnt signaling-related genes, (ii) neurulation-related genes, (iii) cell adhesion, cell matrix, and blood-brain barrier regulation-related genes, (iv) memory and learning-related genes, (v) inflammation-related genes, and (vi) Gene Ontology biological process pathway classifications: RESPONSE TO HORMONE, REGULATION OF HORMONE LEVELS, TISSUE MIGRATION PROCESSING AND PRESENTATION, REGULATION OF VIRAL PROCESS, NEVATIVE REGULATION OF VIRAL PROCESS, POSITIVE REGULATION OF MESENCHYMAL CELL PROLIFERATION, MUSCLE ORGAN DEVELOPMENT, NEGATIVE REGULATION OF NOTCH SIGNALING PATHWAY, POSITIVE REGULATION OF BLOOD CIRCULATION, and RESPONSE TO OXGEN Use of a melatonin receptor agonist for the manufacture of an agent for regulating the expression of at least one gene selected from the group consisting of genes classified into LEVELS.

13. The use according to claim 12, wherein the expression regulator is an agent for preventing or treating at least one disease selected from the group consisting of attention-deficit hyperactivity disorder, schizophrenia, trauma- and stress-related disorders, addiction, epilepsy, chronic fatigue syndrome including sequelae of COVID-19 infection, and neurodementia (excluding delirium, other specified delirium, and unspecified delirium).

14. (i) Wnt signaling-related genes, (ii) neurulation-related genes, (iii) cell adhesion, cell matrix, and blood-brain barrier regulation-related genes, (iv) memory and learning-related genes, (v) inflammation-related genes, and (vi) Gene Ontology pathway classifications of biological processes including response to hormone, regulation of hormone levels, tissue migration processing and presentation, regulation of viral processing, negative regulation of viral processing, positive regulation of mesenchymal cell proliferation, muscle organ development, negative regulation of notch signaling pathway, positive regulation of blood circulation, and response to oxygen. A kit for use in regulating the expression of at least one gene selected from the group consisting of genes classified into LEVELS.

15. A product comprising the agent according to any one of claims 1 to 11 and instructions on how to use said agent.

16. A method for evaluating the effect of a melatonin receptor agonist on symptoms of a psychiatric / neurological disorder, comprising the following steps: (1) administering a melatonin receptor agonist to a mammal in which the Fmr1 gene has been deleted; and (2) evaluating behavioral indicators representative of symptoms of the psychiatric / neurological disorder in the mammal and / or fluctuations in the expression of a predetermined gene.

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