Pharmaceutical composition for treating and preventing anhedonia

Abstract

The present invention provides a pharmaceutical composition for treating or preventing anhedonia, said composition comprising, as an active ingredient, a selective δ opioid receptor agonist, wherein preferably, the selective δ opioid receptor agonist further has a κ opioid receptor antagonist action and a μ opioid receptor antagonist action.

Description

Pharmaceutical composition for treating or preventing anhedonia

[0001] The present invention relates to a pharmaceutical composition for treating or preventing anhedonia, comprising a selective δ opioid receptor agonist as an active ingredient. This application claims priority to Japanese Patent Application No. 2024-042863 filed on March 18, 2024, and Japanese Patent Application No. 2024-134624 filed on August 9, 2024, the contents of which are incorporated herein by reference.

[0002] Opioids exert their effects by binding to opioid receptors, which have three subtypes: μ, δ, and κ. Compounds with similar activity to opioids are also known. Among these, for example, agonists that activate the δ opioid receptor (DOR) may also be agonists or antagonists of other receptors, such as the μ opioid receptor (MOR) or the κ opioid receptor (KOR), and compounds acting on opioid receptors may have a variety of activities. To date, various compounds have been reported as DOR agonists, and their analgesic, antidepressant, and anxiolytic effects, as well as effects on stress-related disorders, have been demonstrated (Patent Documents 1 to 8, and Non-Patent Documents 1 to 4).

[0003] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) stipulates that major depressive disorder (MD) requires the presence of five or more of the following nine depressive symptoms nearly every day during the same two-week period: "depressed mood," "marked decrease in interest or pleasure," "changes in weight or appetite," "insomnia or hypersomnia," "psychomotor agitation or retardation," "fatigue," "feelings of guilt or worthlessness," "decreased concentration or indecisiveness," and "recurrent thoughts of death." One of these symptoms must be "depressed mood" or "marked decrease in interest or pleasure." "Marked decrease in interest or pleasure" is synonymous with anhedonia, and is a component of substance-related disorders, psychotic disorders, and personality disorders in addition to depressive disorders. According to the Research Domain Criteria for Clinical Practice (RDocC) (non-patent document 5), anhedonia can be understood as a dysfunction of the positive valence system, and is described as a state that includes reduced motivation and effort for reward acquisition, reduced or difficulty sustaining pleasant emotions when reward is obtained, or difficulty learning about reward acquisition. Anhedonia is clearly distinguished from depressed mood, which is a core symptom of major depression. Previous treatments for depression have focused on alleviating depressed mood and negative symptoms, and little attention has been paid to the loss of positive emotions such as pleasure and enjoyment, known as anhedonia. Anhedonia in depression is refractory to treatment and is the last symptom to remain among depressive symptoms, and it has been reported that existing psychiatric treatments and psychological support methods do not sufficiently improve the condition (non-patent document 6). At least at present, there are no antidepressants on the market that are effective against anhedonia, both in Japan and overseas. Rather, it has been reported that anhedonia reduces the effect of selective serotonin reuptake inhibitors (SSRIs), which are the first-choice drugs for depression (Non-Patent Document 7), and that anhedonia most strongly predicts suicidal ideation among depressive symptoms (Non-Patent Document 8). Furthermore, anhedonia is a symptom that is not limited to depression but is also seen in diseases such as schizophrenia, Parkinson's disease, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD), and an effective therapeutic agent for anhedonia is anticipated.

[0004] Animal models for assessing anhedonia have been reported, including the female urinary sniffing test (FUST) (Non-Patent Document 9) and the sucrose preference test (Non-Patent Document 10). Attempts to treat anhedonia by modulating opioid receptors have also been reported, and evaluations have been conducted using a KOR agonist (Salvinolin A), a KOR antagonist (LY-2456302), a DOR agonist / MOR agonist / partial KOR agonist (Nalmefen), or a DOR agonist (SNC80) (Non-Patent Documents 9 to 12).

[0005] Patent Publication No. 2006-522775 International Publication No. 2001 / 046192 International Publication No. 2008 / 001859 International Publication No. 2013 / 035833 International Publication No. 2014 / 021273 International Publication No. 2014 / 136305 International Publication No. 2016 / 148232 International Publication No. 2022 / 181763

[0006] Hayashida et al. , Tetrahedron, 2011, 67, 6682 Kamei et al. ,E. J. Pharmacol. , 1995, 276, 131 Kamei et al. , E. J. Pharmacol. , 1997, 322, 27 Nagase et al. , Bioorg. Medic. Chem. Lett. , 2010, 20, 6302 Insel et al. , Am. J. Psychiatry. 2010, 167, 748 Dunn et al. , Clinic. Psychol. Sci. , 2020, 8, 36 Uher et al. ,Psychol. Med. , 2012, 42, 967. Ducasse et al. , Depress Anxiety. , 2018, 35, 382 Scheggi et al. , Int. J. Neuropsychopharmacol. , 2018, 21, 1049 Wu et al. ,E. J. Pharmacol. , 2023, 942, 175532 Harden et al. , Behav. Pharmacol. , 2012, 23, 710Page et al. , Int. J. Neuropsychopharmacol. ,2019,22,735

[0007] An object of the present invention is to provide a medicament useful for treating or preventing anhedonia.

[0008] The present inventors have conducted extensive research to achieve the above-mentioned object and have found that a pharmaceutical composition containing a selective DOR agonist as an active ingredient, preferably the selective DOR agonist having a morphinan skeleton and further having MOR antagonist activity and KOR antagonist activity, is useful for treating or preventing anhedonia, and have completed the present invention. That is, the present invention includes the following aspects.

[0009] [1] A pharmaceutical composition for treating or preventing anhedonia, comprising a selective δ opioid receptor agonist as an active ingredient. [2] The pharmaceutical composition for treating or preventing anhedonia according to [1], wherein the selective δ opioid receptor agonist further has κ opioid receptor antagonist activity. [3] The pharmaceutical composition for treating or preventing anhedonia according to [1] or [2], wherein the selective δ opioid receptor agonist further has μ opioid receptor antagonist activity and κ opioid receptor antagonist activity. [4] The pharmaceutical composition for treating or preventing anhedonia according to any one of [1] to [3], wherein the anhedonia is anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder (PTSD, etc.), autism spectrum disorder, or Alzheimer's disease. [5] The pharmaceutical composition for treatment or prevention according to any one of [1] to [4], wherein the anhedonia is anhedonia caused by mental stress or physical stress. [6] The pharmaceutical composition for treatment or prevention according to any one of [1] to [5], wherein the anhedonia is anhedonia caused by mental stress or physical stress. [7] The pharmaceutical composition for treatment or prevention according to any one of [1] to [6], wherein the anhedonia is a decreased responsiveness to pleasurable experiences related to money, food and drink, hobbies, entertainment, travel and recreation, and at least one selected from the desire for control, the desire for recognition, the desire for achievement, the desire for affiliation, and sexual desire. [8] The selective δ opioid receptor agonist is represented by the following general formula (I):

[0010] (In the formula, R １ is hydrogen; C １－１０ Alkyl; C ６－１０ Aryl; C ２－６ Alkenyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; C ３－６ cycloalkyl; or heteroarylalkyl in which the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and the alkylene portion has 1 to 5 carbon atoms, ２ represents a heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond and is further substituted with at least one oxo group, or pyridine 1-oxide, wherein R ２ is R ２ is bonded to Y through a carbon atom which is a ring-constituting atom of R ３ , R ４ and R ５ are the same or different and are hydrogen; hydroxy; halogen; cyano; carbamoyl; C １－６ Alkoxy; C ６－１０ Aryloxy; C １－６ Alkanoyloxy; Nitro; Amino; C １－８ Alkylamino; C ６－１０ represents an arylamino or an acylamino having 2 to 6 carbon atoms in the acyl moiety, ６ａ and R ６ｂ are the same or different and represent hydrogen; fluorine or hydroxy; or R ６ａ and R ６ｂ together represent =O, and R ７ and R ８ are the same or different and represent hydrogen, fluorine or hydroxy; R ９ and R １０ are the same or different and are hydrogen; C １－６ Alkyl; C ６－１０Aryl; heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms; aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; heteroarylalkyl having 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and 1 to 5 carbon atoms in the alkylene moiety; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; ２－６ represents alkenyl, and X is O or CH ２ and Y represents C(=O). １ C １－１０ alkyl; the alkylene and cycloalkyl portions of cycloalkylalkyl, in which the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; the alkylene portion of aralkyl, in which the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; and the alkylene portion of heteroarylalkyl, in which the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms and the alkylene portion has 1 to 5 carbon atoms, can each be selected from the group consisting of 1 to 6 halogens; hydroxy; C １－６ Alkoxy; C ６－１０ Aryloxy; C １－６ Alkanoyl; C １－６ Alkanoyloxy; carboxyl; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; alkylsulfonyl having 1 to 6 carbon atoms in the alkyl portion; aminosulfonyl; alkylsulfinyl having 1 to 6 carbon atoms in the alkyl portion; alkylthio having 1 to 6 carbon atoms in the alkyl portion; C substituted with 1 to 6 halogens １－６ alkoxy; and arylcarbonyl, the aryl portion of which has 6 to 10 carbon atoms; and R １ C ６－１０Aryl; an aryl portion of an aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; R ３ , R ４ and R ５ C ６－１０ the aryl portion of the aryloxy; and C ６－１０ the aryl portion of arylamino; and R ９ and R １０ C ６－１０ Aryl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; aryl moiety of aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and heteroaryl moiety of heteroarylalkyl having 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms and 1 to 5 carbon atoms in the alkylene moiety are C １－６ Alkyl; C １－６ Alkoxy; C １－６ Alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; halogen; nitro; cyano; C substituted with 1 to 3 halogens １－６ Alkyl; C substituted with 1 to 3 halogens １－６ R may be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl having 1 to 3 carbon atoms in the alkyl; and methylenedioxy; ２ The heterocycle of the formula (I) can be an oxo group or any of the above-mentioned R １ C ６－１０ The aryl may have a substituent, and R ２ The pyridine 1-oxide of the formula １ C ６－１０ The aryl may have a substituent, and R １ is C １－１０ In the case of alkyl, NR１１ R １２ where R １１ and R １２ are the same or different and are hydrogen; C １－１０ alkyl; or aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, or １１ and R １２ And, R １１ and R １２ may be joined together with the nitrogen atom to which R is attached and optionally one or two heteroatoms to form a 5- to 7-membered ring, and R １ The alkylene portion of the aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion is phenyl or C substituted with 1 to 3 halogens. １－６ [9] The pharmaceutical composition for treatment or prevention according to any one of [1] to [7], wherein the compound represented by general formula (I) is a compound represented by the formula: ５ , R ６ａ , R ６ｂ , R ７ , R ８ , R ９ and R １０ is hydrogen, and R １ is hydrogen; C １－６ Alkyl; C ２－６ alkenyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; or aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, ２ represents a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond, and further substituted with at least one oxo group, or a heterocycle in which a benzene ring is fused to the heterocycle, or pyridine 1-oxide, wherein R ２ is R ２ is bonded to Y through a carbon atom which is a ring-constituting atom of R３ and R ４ are the same or different and are hydrogen; hydroxy; halogen; cyano; carbamoyl; C １－６ Alkoxy; C ６－１０ Aryloxy; C １－６ Alkanoyloxy; amino; or acylamino having 2 to 6 carbon atoms in the acyl moiety, where X is CH ２ and Y is C(=O), provided that R １ C １－６ alkyl; the alkylene and cycloalkyl portions of cycloalkylalkyl, in which the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; or the alkylene portion of aralkyl, in which the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms, may each be selected from the group consisting of 1 to 6 halogens; hydroxy; １－６ Alkoxy; C ６－１０ Aryloxy; C １－６ Alkanoyl; C １－６ Alkanoyloxy; carboxyl; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; alkylsulfonyl having 1 to 6 carbon atoms in the alkyl portion; aminosulfonyl; alkylsulfinyl having 1 to 6 carbon atoms in the alkyl portion; alkylthio having 1 to 6 carbon atoms in the alkyl portion; C substituted with 1 to 6 halogens １－６ alkoxy; and arylcarbonyl, the aryl portion of which has 6 to 10 carbon atoms; and R １ an aralkyl aryl moiety having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and R ３ and R ４ C ６－１０ The aryl portion of the aryloxy is C １－６ Alkyl; C １－６ Alkoxy; C １－６Alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; halogen; nitro; cyano; C substituted with 1 to 3 halogens １－６ Alkyl; C substituted with 1 to 3 halogens １－６ R may be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl having 1 to 3 carbon atoms in the alkyl; and methylenedioxy; ２ The heterocycle of the formula (I) can be an oxo group or any of the above-mentioned R １ The aryl portion of the aralkyl may have a substituent that may be substituted, and the alkylene portion of the aralkyl may have a substituent that may be substituted, and the ... ２ The pyridine 1-oxide of the formula １ The aryl portion of the aralkyl may have a substituent that may be substituted, and the alkylene portion of the aralkyl may have a substituent that may be substituted, and R １ The alkylene portion of the aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion is phenyl or C substituted with 1 to 3 halogens. １－６

[10] The pharmaceutical composition for treatment or prevention according to any one of [1] to [8], wherein the compound represented by the general formula (I) is a compound optionally substituted with at least one substituent selected from R １ is C １－６

[11] The pharmaceutical composition for treatment or prevention according to any one of [1] to [9], wherein the compound represented by the general formula (I) is a compound selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety, and aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety. １

[12] The pharmaceutical composition for treatment or prevention according to any one of [1] to [9], wherein the compound represented by general formula (I) is a compound represented by formula (I) of which R １ is substituted with hydroxy ２－６ Alkyl; C substituted with 1 to 6 halogens １－６ alkyl; or C １－６ Alkoxy-substituted C ２－６

[13] The pharmaceutical composition for treatment or prevention according to any one of [1] to [9], wherein the compound represented by the general formula (I) is a compound represented by the general formula (I) １

[14] The pharmaceutical composition for treatment or prevention according to any one of [1] to [9], wherein R is a compound represented by general formula (I), ２ is a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond, and further substituted with at least one oxo group, or a heterocycle in which a benzene ring is fused to the heterocycle, or a compound represented by general formula (I), wherein R ２

[16] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[13] , wherein the compound represented by general formula (I) is a compound represented by R ２

[17] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[13] , wherein the compound represented by general formula (I) is a compound represented by the formula R ２

[18] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[13] , wherein the compound represented by general formula (I) is a compound represented by the formula: ２

[19] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[13] , wherein the compound represented by general formula (I) is a compound represented by the formula R ２

[20] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[13] , wherein the compound represented by general formula (I) is a compound represented by the formula: ２

[21] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[13] , wherein the compound represented by general formula (I) is a compound represented by the formula (I) ２

[22] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[13] , wherein the compound represented by general formula (I) is a compound represented by the formula: ２

[23] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[13] , wherein the compound represented by the general formula (I) is a compound in which X is CH ２

[24] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[22] , wherein the compound represented by general formula (I) is ３ and R ４

[25] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[23] , wherein the compound represented by general formula (I) is a compound represented by the formula (I) ３ is halogen; cyano; carbamoyl; C １－６ Alkoxy; C １－６ alkanoyloxy; amino; or acylamino having 2 to 6 carbon atoms in the acyl moiety, where R ４ is hydrogen or hydroxy, and R ５

[26] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[23] , wherein the compound represented by general formula (I) is a compound represented by formula (I) wherein R ３ is hydroxy; carbamoyl; or C １－６ Alkanoyloxy, R４ is hydrogen, and R ５

[27] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[23] , wherein the compound represented by general formula (I) is a compound represented by formula (I) wherein R ３ is hydroxy and R ４ is hydrogen, and R ５

[28] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[23] , wherein the compound represented by general formula (I) is a compound represented by formula (I) wherein R ３ , R ４ and R ５

[29] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[23] , wherein the compound represented by general formula (I) is a compound in which R ６ａ , R ６ｂ , R ７ , R ８ , R ９ and R １０

[30] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[28] , wherein the compound represented by general formula (I) is a compound in which R ３ is halogen; cyano; carbamoyl; C １－６ Alkoxy; C １－６ alkanoyloxy; amino; or acylamino having 2 to 6 carbon atoms in the acyl moiety, where R ４

[31] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[23] , wherein the compound represented by general formula (I) is a compound represented by R ３ is hydroxy; carbamoyl; or C １－６ Alkanoyloxy, R ４

[32] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[23] , wherein the compound represented by general formula (I) is a compound represented by formula (I) wherein R ３ is hydroxy and R ４

[33] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[23] , wherein R is hydrogen. ３ and R ４

[34] The pharmaceutical composition for treatment or prevention according to any one of [1] to

[23] , wherein the compound represented by general formula (I) is a compound represented by the following general formula (II):

[0011] (In the formula, R １ is hydrogen; C １－６ alkyl; or cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion, R ２ represents a 5- to 7-membered heterocycle containing one or two nitrogen atoms and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond and is further substituted with at least one oxo group, or pyridine 1-oxide, wherein R ２ is R ２ is bonded to Y through a carbon atom which is a ring-constituting atom of R ３ and R ４ are the same or different and are hydrogen; hydroxy; or C １－６ alkoxy, Y is C(=O), provided that R １ C １－６ alkyl; the alkylene and cycloalkyl portions of cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion are each independently selected from 1 to 6 halogen; hydroxy; and C １－６ and R ２ The heterocycle of the formula (I) can be an oxo group or a C １－６ Alkyl; C １－６ Alkoxy; C １－６ Alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; halogen; nitro; cyano; C substituted with 1 to 3 halogens １－６ Alkyl; C substituted with 1 to 3 halogens １－６alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl having 1 to 3 carbon atoms in the alkyl; and methylenedioxy, and R ２ The pyridine 1-oxide of C １－６ Alkyl; C １－６ Alkoxy; C １－６ Alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; halogen; nitro; cyano; C substituted with 1 to 3 halogens １－６ Alkyl; C substituted with 1 to 3 halogens １－６

[35] The pharmaceutical composition for treatment or prevention according to any one of [1] to [6], wherein the compound represented by general formula (II) is a compound represented by the formula (II) (which may have at least one substituent selected from the group consisting of alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl having 1 to 3 carbon atoms in the alkyl; and methylenedioxy). １

[36] The pharmaceutical composition for treatment or prevention according to any one of [1] to [6] and

[34] , wherein R is a cycloalkylalkyl compound having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety. ２ is represented by formula (III):

[0012] ;Formula (IV):

[0013] ;Formula (V):

[0014] or formula (VI):

[0015] (In Formulas III to VI, R ａ is hydrogen or C１－６

[37] The pharmaceutical composition for treatment or prevention according to any one of [1] to [6],

[34] and

[35] , wherein the compound represented by the general formula (II) is R ３

[38] The pharmaceutical composition for treatment or prevention according to any one of [1] to [6] and

[34] to

[36] , wherein the compound represented by general formula (II) is a compound represented by R ４The pharmaceutical composition for treatment or prevention according to any one of [1] to [6] and

[34] to

[37] , wherein the compound represented by general formula (I) is a compound represented by formula (I) of 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one and 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one The pharmaceutical composition for treatment or prevention according to any one of [1] to [6] and

[34] , wherein the compound represented by general formula (I) is at least one compound selected from the group consisting of 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide; 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one; 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one; 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one; 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one and 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one The pharmaceutical composition for treatment or prevention according to any one of [1] to [6] and

[34] , wherein the compound is at least one compound selected from the group consisting of:

[0016] The present invention provides a pharmaceutical composition useful for treating or preventing anhedonia.

[0017] FIG. 1 is a diagram showing the effect of a compound (Compound No. 7) on anhedonia caused by physical stress using a sucrose preference test (**: p<0.01 (Bonferroni's test after one-way analysis of variance)). FIG. 2 is a diagram showing the effect of KNT-127 on anhedonia caused by vicarious social defeat stress using a sucrose preference test (ns: not significant; **: p<0.01 (Bonferroni's test after one-way analysis of variance)). FIG. 3 is a diagram showing the effect of a compound (Compound No. 7) on anhedonia caused by vicarious social defeat stress using a sucrose preference test (ns: not significant; *: p<0.05 (Bonferroni's test after one-way analysis of variance)). Figure 4 shows the effect of a compound (Compound No. 7) on anhedonia caused by physical stress using a female urine sniffing test (ns: no significant difference; *: p<0.05 (Bonferroni's test after one-way analysis of variance)). Figure 5 shows the effect of a compound (Compound No. 7) on anhedonia caused by vicarious social defeat stress using a female urine sniffing test (ns: no significant difference; *: p<0.05; **: p<0.01 (Bonferroni's test after one-way analysis of variance)).

[0018] The present invention will now be described in more detail. All patent publications, published patent applications, non-patent publications, and other documents cited in this specification are hereby incorporated by reference in their entirety for all purposes.

[0019] 1. Anhedonia As used herein, "anhedonia" refers to a symptom of decreased responsiveness to rewards, recreation, or other enjoyable experiences. Anhedonia is also commonly referred to as decreased positive affect, decreased motivation, decreased sensitivity to rewards, loss of pleasure, etc. The Research Domain of Clinical Cognitive Assessment (RDoc) (non-patent document 5) describes anhedonia (loss of pleasure) as a disorder of the positive valence system, and as a condition that includes decreased motivation and effort to obtain rewards, decreased and difficulty sustaining pleasant feelings when obtaining rewards, and difficulty learning about obtaining rewards. Anhedonia can also be further classified into "motivational anhedonia," which refers to a decrease or disappearance of motivation to seek rewards; "consummatory anhedonia," which refers to a decrease or disappearance of the pleasant response once rewards are obtained; and "decisional anhedonia," which does not view anhedonia as a characteristic but as a problem in the dynamic decision-making process. One aspect of the present invention is a pharmaceutical composition for treating or preventing symptoms of anhedonia, comprising a selective DOR agonist as an active ingredient, more specifically a pharmaceutical composition for treating or preventing symptoms of motivational anhedonia, comprising a selective DOR agonist as an active ingredient, a pharmaceutical composition for treating or preventing symptoms of completion anhedonia, or a pharmaceutical composition for treating or preventing symptoms of decision-making anhedonia, wherein the selective DOR agonist is a compound having a morphinan skeleton, and preferably the selective DOR agonist is a compound that further has MOR antagonist activity and KOR antagonist activity.

[0020] As used herein, examples of rewards, recreation, or other enjoyable experiences related to "anhedonia" include money, food and drink, hobbies, entertainment (television programs, radio programs, reading, etc.), travel and outings, and enjoyable experiences related to at least one of the desire for control, the desire for recognition, the desire for achievement, the desire for affiliation, and sexual desire.

[0021] A questionnaire may be used to diagnose anhedonia according to the present invention. Examples of questionnaires include the Snaith-Hamilton Pleasure Scale (SHAPS) (Snaith et al., Br. J. Psychiatry, 1995, 167: 99), Chapman Scales for Physical and Social Anhedonia (Chapman et al., J. Abnorm. Psychol, 85: 374-382, 1976), and questionnaires specifically designed for various disorders associated with anhedonia (e.g., items 1 and 2 of the Edinburgh Postnatal Depression Scale; Cox JL, et al., Br. J. Psychiatry, 1987, 150, 782). SHAPS has 14 questions: 1) Do you enjoy your favorite television or radio programs? 2) Do you enjoy being with family or friends? 3) Do you enjoy spending time on your hobbies or recreational activities? 4) Can you enjoy eating your favorite meals? 5) Do you feel good after taking a warm bath or shower? 6) Do you find the scent of flowers, the sea breeze, or freshly baked bread pleasant? 7) Does someone's smile warm your heart? 8) Do you feel happy when you have properly groomed yourself? 9) Do you enjoy reading a book, magazine, or newspaper? 10) Do you enjoy drinking tea, coffee, or your favorite beverage? 11) Do you find joy in small things (such as sunny weather or a phone call from a friend)? 12) Does a beautiful view soothe your eyes? 13) Do you feel happy when you are able to help others? 14) Do you feel happy when others praise you? One aspect of the present invention is a pharmaceutical composition comprising a selective DOR agonist as an active ingredient, which improves scores on an anhedonia questionnaire.More specifically, one aspect of the present invention is a pharmaceutical composition comprising a selective DOR agonist as an active ingredient, which is capable of inducing, for example, the following states: finding a favorite television or radio program more enjoyable; feeling more enjoyable when spending time with family or friends; finding hobbies and leisure activities more enjoyable; being able to enjoy a favorite meal more; feeling more comfortable after a refreshing warm bath or shower; finding the scent of flowers, the sea breeze, and the smell of freshly baked bread more pleasant; being soothed by other people's smiles; feeling happier when properly groomed; finding more enjoyment in reading books, magazines, and newspapers; finding more enjoyment in drinking tea, coffee, or a favorite beverage; feeling joy in small things; finding a beautiful view more soothing; feeling happier when being helpful to others; feeling happier in romantic relationships with or liking a member of the opposite sex or being liked by a member of the opposite sex; or feeling happier when receiving praise from others. In another aspect of the present invention, the selective DOR agonist is a compound having a morphinan skeleton, and preferably the selective DOR agonist is a compound that further has MOR antagonist activity and KOR antagonist activity.

[0022] As a method for measuring anhedonia according to the present invention, the Effort-Expenditure for Rewards Task (EEfRT) (Treadway et al., PLoS One, 2009, 4, e65982009) task behavior may be used. In the EEfRT, participants are tasked with repeatedly pressing a button within a set time period, and if they complete the task, they receive a reward. In addition to the EEfRT, a method using the Progressive Ratio Task (PRT) (Wolf et al., Schizophrenia Bulletin, 2014, 40, 1328) task is also used. In the PRT, participants are tasked with selecting the larger of two numbers displayed on a screen a required number of times, and if they complete the task, they receive a reward. One aspect of the present invention is a pharmaceutical composition comprising a selective DOR agonist as an active ingredient, which enhances reward obtained through EEfTR or PRT. For example, administration of the pharmaceutical composition preferably enhances reward by 1% or more, 3% or more, 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 70% or more, 100% or more, or 200% or more, compared to when the pharmaceutical composition is not administered or before administration of the pharmaceutical composition. Also, in another aspect of the present invention, the selective DOR agonist is a compound having a morphinan skeleton, and preferably the selective DOR agonist is a compound that further has MOR antagonist activity and KOR antagonist activity.

[0023] The anhedonia of the present invention is a symptom associated with many diseases. Examples of diseases associated with anhedonia include diseases caused by dopamine system disorders, diseases caused by dysfunction of the reward system, and diseases caused by cognitive dysfunction. Specific examples include depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorders, alcohol dependence, nicotine dependence, eating disorders, neurotic disorders (e.g., PTSD), autism spectrum disorders, and Alzheimer's dementia. One aspect of the present invention is a pharmaceutical composition for treating or preventing anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorders, alcohol dependence, nicotine dependence, eating disorders, neurotic disorders (e.g., PTSD), autism spectrum disorders, or Alzheimer's dementia, which comprises a selective DOR agonist as an active ingredient.

[0013] In another aspect of the present invention, the selective DOR agonist is a compound having a morphinan skeleton, and preferably the selective DOR agonist is a compound further having MOR antagonist activity and KOR antagonist activity.

[0014] In another aspect of the present invention, the selective DOR agonist is a pharmaceutical composition for treating or preventing depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder (PTSD, etc.), autism spectrum disorder, or Alzheimer's dementia, comprising the selective DOR agonist as an active ingredient, and particularly for suppressing anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder (PTSD, etc.), autism spectrum disorder, or Alzheimer's dementia. Yet another aspect of the present invention is a pharmaceutical composition for treating or preventing depression, which comprises a selective DOR agonist as an active ingredient, and in particular suppresses anhedonia associated with depression.

[0024] Anhedonia according to the present invention is induced, for example, by stress. As used herein, "stress" (also referred to as "stressor") refers to external stimuli. Examples of stress include physical stress (high or low temperature, humidity, noise or vibration, violence, or electric shock), chemical stress (oxygen deficiency, drug-induced injury, or nutritional deficiency), biological stress (diseases such as pathogens or sleep deprivation), and mental stress (bullying, various forms of harassment such as power harassment or moral harassment, interpersonal issues such as bereavement, marriage, divorce, separation, or trouble with others, or mental distress associated with relocation, job change, trouble with others, or debt). As used herein, stress that directly affects the body, such as physical stress, chemical stress, or biological stress, is referred to as "physical stress." One aspect of the present invention is a pharmaceutical composition for treating or preventing anhedonia induced by mental or physical stress, comprising a selective DOR agonist as an active ingredient. In another aspect of the present invention, the selective DOR agonist is a compound having a morphinan skeleton, and preferably the selective DOR agonist is a compound that further has MOR antagonist activity and KOR antagonist activity.

[0025] The pharmaceutical composition for treating or preventing anhedonia according to the present invention can also be evaluated using animal models. Examples of animal models include the FUST (Non-Patent Document 9) and the sucrose preference test (Non-Patent Document 10). One aspect of the present invention is a pharmaceutical composition containing a selective DOR agonist as an active ingredient, which improves the decline in female urine sniffing behavior and / or improves the decline in sucrose preference. Another aspect of the present invention is a pharmaceutical composition containing a selective DOR agonist as an active ingredient, which improves sucrose preference by 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more compared to a non-administered control, or to a normal, non-stressed level. Another aspect of the present invention is a pharmaceutical composition containing a selective DOR agonist as an active ingredient, which improves the decline in female urine sniffing behavior by 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more compared to a non-administered control, or to a normal, non-stressed level.

[0026] As used herein, "suicidal ideation" refers to thoughts about suicide, a particular interest in suicide, or thoughts of ending one's life or not wanting to live anymore, without necessarily making any active efforts to do so. Among depressive symptoms, anhedonia is the strongest predictor of suicidal ideation. One aspect of the present invention is a pharmaceutical composition for suppressing, ameliorating, alleviating, treating, or preventing suicidal ideation, comprising a selective DOR agonist as an active ingredient. Another aspect of the present invention is a pharmaceutical composition for suppressing or preventing suicide, comprising a selective DOR agonist as an active ingredient. Another aspect of the present invention is a compound having a morphinan skeleton, and preferably the selective DOR agonist is a compound that further has MOR antagonist activity and KOR antagonist activity.

[0027] As used herein, the term "suppression" refers to stopping or slowing the worsening or progression of a symptom, condition, or disease, and to actions or means therefor, and also refers to improving the symptom, condition, or disease, or to actions or means therefor. The "worsening or progression of a symptom, condition, or disease" refers to the worsening or progression of a "pathological" or "abnormal" symptom, condition, or disease, and the worsening or progression from a "healthy" or "normal" state to a "pathological" or "abnormal" symptom, condition, or disease. In one embodiment, "suppression" refers to stopping or slowing the worsening or progression of a symptom, condition, or disease, or to actions or means therefor. In another embodiment, "suppression" refers to stopping or slowing the worsening or progression of a symptom, condition, or disease. Here, "improvement" refers to the concept of bringing a "pathological" or "abnormal" symptom, condition, or disease closer to a "healthy" or "normal" state, or to actions or means therefor. Therefore, in one embodiment, "improvement" includes a situation in which a numerical value indicating a "pathological" or "abnormal" symptom or condition becomes smaller or larger in accordance with the "improvement" and approaches a normal value or becomes a normal value. As used herein, "alleviation" can be a concept that includes the "improvement". As used herein, "treatment" includes eliminating, curing, curing, or remission of a "pathological" or "abnormal" symptom, condition, or disease, and actions or means therefor, "suppressing" the worsening of a "pathological" or "abnormal" symptom, condition, or disease, and actions or means therefor, and is also a concept that includes "improvement". In one embodiment, "treatment" refers to eliminating, curing, curing, or remission of a "pathological" or "abnormal" symptom, condition, or disease, and actions or means therefor. In another embodiment, "treatment" refers to eliminating, curing, curing, or remission of a "pathological" or "abnormal" symptom, condition, or disease. As used herein, the term "prevention" is a concept that includes preventing the onset of "pathological" or "abnormal" symptoms, conditions, or diseases, as well as actions or means for that purpose.

[0028] 2. δ Opioid Receptor Agonist (DOR Agonist) As used herein, "δ opioid receptor agonist" refers to a substance that, by binding to DOR, induces a biological response similar to or similar to that of an endogenous ligand. "Selective DOR agonist" refers to a substance that has a relatively strong DOR agonist effect compared to the μ opioid receptor agonist (MOR agonist) effect and the κ opioid receptor agonist (KOR agonist) effect. Among these, a substance that has DOR agonist effect and very weak or no MOR agonist effect or KOR agonist effect is preferred. Furthermore, a substance that has DOR agonist effect, no MOR agonist effect or KOR agonist effect, and a KOR antagonist effect is preferred. Furthermore, it is preferable that the substance has a DOR agonistic effect, no MOR agonistic effect and no KOR agonistic effect, and has a MOR antagonistic effect and a KOR antagonistic effect. Here, "MOR antagonist" or "KOR antagonist" means a substance that binds to MOR or KOR but does not induce a biological response reaction, unlike endogenous ligands, and that inhibits the binding of the endogenous ligand to the receptor by the binding, thereby not inducing a biological response reaction of the endogenous ligand.

[0029] The "selective DOR agonist" of the present invention can be produced by the method described in Patent Document 7. ５０ value is 30 nM or less, 10 nM or less, 3 nM or less, 1 nM or less, 0.3 nM or less, or 0.1 nM or less, and has an E ｍａｘ is 50% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or more.

[0030] It is preferable that the "selective DOR agonist" of the present invention further has a KOR antagonistic action. According to the method described in Patent Document 8, the "selective DOR agonist" of the present invention exhibits an IC ５０ The value is 100 nM or less, 30 nM or less, 20 nM or less, 15 nM or less, 10 nM or less, or 5 nM or less.

[0031] The "selective DOR agonist" of the present invention preferably also has an MOR antagonist activity. According to the method described in Patent Document 8, the "selective DOR agonist" of the present invention exhibits an IC ５０ The value is 100 nM or less, 30 nM or less, 20 nM or less, 15 nM or less, 10 nM or less, or 5 nM or less.

[0032] The "selective DOR agonist" of the present invention preferably further has KOR antagonistic activity and MOR antagonistic activity. According to the method described in Patent Document 8, the "selective DOR agonist" of the present invention exhibits an IC50 / IC10 inhibitory effect on the action of 100 nM U-69593 on KOR and the action of 30 nM DAMGO on MOR. ５０ The value is 100 nM or less, 30 nM or less, 20 nM or less, 15 nM or less, 10 nM or less, or 5 nM or less.

[0033] As used herein, the term "morphinan skeleton" refers to a fused ring structure of morphinan. The selective DOR agonist compounds of the present invention having a morphinan skeleton have a morphinan skeleton, to which a substituent may be further added, or to which another ring may be fused.

[0034] One embodiment of the pharmaceutical composition of the present invention contains, as an active ingredient, a selective DOR agonist which is a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.

[0035] In this specification, C １－６ Examples of alkyl include methyl, ethyl, propyl, i-propyl, butyl, tert-butyl, pentyl, neopentyl, and hexyl. １－１０ The alkyl includes the above C １－６ In addition to the alkyl groups exemplified above, heptyl, octyl, etc. are also included. C substituted with 1 to 3 halogen atoms １－６ Examples of alkyl include 2-chloroethyl, 2-fluoroethyl, 3-fluoropropyl, 2,2-difluoroethyl, trifluoromethyl, and 3,3,3-trifluoropropyl. ２－６Examples of alkenyl include 2-propenyl and 3-methyl-2-butenyl. Examples of cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion include C 1 alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. ３－６ Examples of aralkyl groups include methyl and ethyl substituted with cycloalkyl. Examples of aralkyl groups having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety include benzyl and phenethyl groups. ３－６ Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. ６－１０ Examples of aryl include phenyl and naphthyl. Preferred heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms are 5- or 6-membered heteroaryls, such as pyridyl, furyl, imidazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, and thiazolyl. As the heteroarylalkyl in which the heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and the alkylene portion has 1 to 5 carbon atoms, a heteroarylalkyl having a 5- or 6-membered heteroaryl is preferred, and examples thereof include (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl, (furan-2-yl)methyl, (furan-3-yl)methyl, (imidazol-2-yl)methyl, (imidazol-4-yl)methyl, (imidazol-5-yl)methyl, (thiazol-2-yl)methyl, (thiazol-4-yl)methyl, (thiazol-5-yl)methyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(pyrazol-1-yl)ethyl, 2-(thiophen-2-yl)ethyl, and 2-(thiophen-3-yl)ethyl.

[0036] C １－６ Examples of alkanoyl include acetyl and propionyl. １－６ Examples of alkoxy include methoxy, ethoxy, and propoxy.１－６ Examples of alkanoyloxy include acetoxy. Examples of alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety include methoxycarbonyl and ethoxycarbonyl. Examples of halogen include fluorine, chlorine, bromine, and iodine. Examples of C substituted with 1 to 3 halogens include methyl, ... １－６ Alkoxy includes fluoromethoxy and trifluoromethoxy. C substituted with 1 to 6 halogen atoms. １－６ The alkoxy includes the above C substituted with 1 to 3 halogen atoms. １－６ In addition to alkoxy, examples include tetrafluoroethoxy, etc. Examples of phenylalkyl in which the alkyl has 1 to 3 carbon atoms include benzyl, etc. ６－１０ Examples of aryloxy include phenoxy. １－８ Examples of alkylamino include methylamino and ethylamino. Examples of acylamino having 2 to 6 carbon atoms in the acyl moiety include acetylamino. ６－１０ Examples of arylamino include phenylamino. Examples of alkylcarbamoyl groups having 1 to 6 carbon atoms in the alkyl moiety include ethylcarbamoyl. Examples of dialkylcarbamoyl groups having 1 to 6 carbon atoms in the alkyl moiety include diethylcarbamoyl. Examples of alkylsulfonyl groups having 1 to 6 carbon atoms in the alkyl moiety include methylsulfonyl. Examples of alkylsulfinyl groups having 1 to 6 carbon atoms in the alkyl moiety include methylsulfinyl. Examples of alkylthio groups having 1 to 6 carbon atoms in the alkyl moiety include methylthio. Examples of arylcarbonyl groups having 6 to 10 carbon atoms in the aryl moiety include benzoyl.

[0037] In the above general formula (I), R １１ and R １２ And, R １１ and R １２Examples of the 5- to 7-membered ring which may be formed by combining with the nitrogen atom to which is bonded and, if desired, one or two heteroatoms include pyrrolidine, piperidine, and morpholine.

[0038] In the above general formula (I), R ２ (A) a heterocycle containing 1 to 4 heteroatoms selected from N, O and S and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond, and further substituted with at least one oxo group, or pyridine 1-oxide, such as (A) a C substituted with 1 to 3 fluorines, such as pyridine 1-oxide or 2-methylpyridine 1-oxide; １－１０ Alkyl and unsubstituted C １－１０ (B) pyridine 1-oxide optionally substituted by 1 to 4 substituents selected from alkyl, (C) pyridine 1-oxide optionally substituted by 1 to 3 fluorines, such as pyridin-2(1H)-one, 1-methylpyridin-2(1H)-one, 1-ethylpyridin-2(1H)-one, 6-methylpyridin-2(1H)-one, 6-ethylpyridin-2(1H)-one or 6-trifluoromethylpyridin-2(1H)-one １－１０ Alkyl and unsubstituted C １－１０ (C) pyridin-4(1H)-one, 1-methylpyridin-4(1H)-one, 1-ethylpyridin-4(1H)-one or 1-(fluoroethyl)pyridin-4(1H)-one, which may be substituted by 1 to 3 fluorines, such as pyridin-2(1H)-one, 1-methylpyridin-4(1H)-one, 1-ethylpyridin-4(1H)-one or 1-(fluoroethyl)pyridin-4(1H)-one; １－１０ Alkyl and unsubstituted C １－１０ (D) pyridazin-3(2H)-one or 2-methylpyridazin-3(2H)-one, each of which may be substituted by 1 to 4 substituents selected from alkyl; １－１０ Alkyl and unsubstituted C １－１０ pyridazin-3(2H)-one optionally substituted by 1 to 3 substituents selected from alkyl, (E) pyrazin-2(1H)-one, or C substituted by 1 to 3 fluorines such as 1-methylpyrazin-2(1H)-one;１－１０ Alkyl and unsubstituted C １－１０ (F) C substituted with 1 to 3 fluorines, such as 4H-pyran-4-one, 3-methyl-4H-pyran-4-one, 2H-pyran-2-one, or 5-methyl-2H-pyran-2-one; １－１０ Alkyl and unsubstituted C １－１０ (G) C substituted with 1 to 3 fluorines, such as quinolin-2(1H)-one, 6-methylquinolin-2(1H)-one, quinolin-1-oxide, or 4-methylquinolin-1-oxide, which may be substituted by 1 to 3 substituents selected from alkyl. １－１０ Alkyl and unsubstituted C １－１０ quinolin-2(1H)-one or quinolin-1-oxide, each of which may be substituted by 1 to 3 substituents selected from alkyl, C substituted by 1 to 3 fluorines, such as (H)pyrimidin-4(3H)-one or pyrimidine-2,4(1H,3H)-dione; １－１０ Alkyl and unsubstituted C １－１０ Examples thereof include pyrimidin-4(3H)-one and pyrimidine-2,4(1H,3H)-dione, each of which may be substituted with 1 to 3 substituents selected from alkyl.

[0039] One aspect of the present invention is a method for producing a compound of the formula (I) with a cyclopropylmethyl group, the compound being a cyclopropylmethyl group, and the compound being a cyclopropylmethyl group. 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,A pharmaceutical composition for treating or preventing anhedonia, comprising, as an active ingredient, 11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one, or 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one, or a pharmaceutically acceptable salt thereof.

[0040] The compound represented by the general formula (I) may exist as a tautomer, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof. The tautomer of the compound represented by the general formula (I) may be any of the above-mentioned R ２ and at least one carbon atom as ring-constituting atoms, and at least one pair of adjacent ring-constituting atoms has a double bond, and is further substituted with at least one oxo group, and examples thereof include tautomers in heterocycles such as R ２and the corresponding 2-hydroxypyridine (lactim type). Regarding the compound represented by the general formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or solvates thereof, the pharmaceutically acceptable salts are preferably acid addition salts, and examples of the acid addition salts include salts with organic or inorganic acids such as hydrochloride, sulfate, fumaric acid, oxalate, methanesulfonate, or camphorsulfonate. Regarding the compound represented by the general formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or solvates thereof, the stereoisomers include cis and trans isomers, racemates, and optically active forms. Regarding the compound represented by the general formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or solvates thereof, the solvates include pharmaceutically acceptable solvates of the compound of the present invention or a salt thereof, including hydrates. Furthermore, the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof may be a prodrug that is chemically modified so as to be converted into a pharmacologically active substance after reaching the body or a target site and to exert (activate) a pharmacological effect. Examples of such prodrugs include, for example, when the group constituting the prodrug is present on a hydroxyl group, a conventional hydroxyl-protecting group such as a lower acyl group or a lower alkoxycarbonyl group; when the group constituting the prodrug is present on a nitrogen atom, a conventional amino-protecting group such as a lower acyl group or a lower alkoxycarbonyl group; or a prodrug group introduced into a carboxylic acid moiety, for example, pivaloyloxymethyl (tBu-C(O)O-CH ２ - group, medoxomil group, cilextil group, etc. Furthermore, the compound represented by the above general formula (I), a tautomer of the compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof may be substituted with a stable isotope such as deuterium.

[0041] The compound represented by the above general formula (I), a tautomer of the compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof can be produced, for example, according to WO 2018 / 052114 or a method known per se.

[0042] The compound represented by the general formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or solvates thereof exhibit superior agonist activity and selectivity for DOR compared to μ and κ opioid receptors. Therefore, the compound represented by the general formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or solvates thereof can be used as active ingredients in pharmaceutical compositions that exhibit selective DOR agonist activity. Furthermore, the compound represented by the general formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or solvates thereof exhibit excellent stability against metabolism by human liver microsomes. Therefore, the compound represented by the general formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or solvates thereof can be used as active ingredients in pharmaceutical compositions for oral administration.

[0043] 3. Pharmaceutical Compositions The pharmaceutical compositions provided by the present invention are administered to humans or other mammals orally or parenterally. Examples of parenteral administration include intravenous administration, subcutaneous administration, intramuscular administration, intraarticular administration, transmucosal administration, transdermal administration, nasal administration, rectal administration, or intrathecal administration. The pharmaceutical compositions provided by the present invention may be prepared by mixing the selective DOR agonist, or the compound represented by general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or a solvate thereof, either as is or with a pharmaceutically acceptable carrier such as an excipient (e.g., lactose, D-mannitol, crystalline cellulose, or glucose), a binder (e.g., hydroxypropyl cellulose (HPC), gelatin, or polyvinylpyrrolidone (PVP)), a lubricant (e.g., magnesium stearate or talc), a disintegrant (e.g., starch or carboxymethylcellulose calcium (CMC-Ca)), a diluent (e.g., water for injection or physiological saline), or, if necessary, an additive (e.g., a pH adjuster, a surfactant, a solubilizer, a preservative, an emulsifier, an isotonic agent, or a stabilizer), and may be in the form of tablets, granules, powders, capsules, suspensions, injections, suppositories, or other formulations. For example, to prepare tablets, the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof may be mixed with an excipient (e.g., lactose, D-mannitol, crystalline cellulose, or glucose), a disintegrant (e.g., starch, or carboxymethylcellulose calcium (CMC-Ca)), a binder (e.g., hydroxypropyl cellulose (HPC), gelatin, or polyvinylpyrrolidone (PVP)), or a lubricant (e.g., magnesium stearate, or talc), and the like.For example, to prepare an injection, the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof may be mixed with a dispersing agent (e.g., a surfactant such as Tween 80, a polysaccharide such as carboxymethylcellulose, sodium alginate, or hyaluronic acid, or a polysorbate), a preservative (e.g., methylparaben or propylparaben), an isotonicity agent (e.g., sodium chloride, mannitol, sorbitol, or glucose), or a pH adjuster (e.g., sodium phosphate or potassium phosphate), etc.

[0044] The pharmaceutical composition provided by the present invention can comprise an amount effective for treating or preventing anhedonia of a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof. In one embodiment, the pharmaceutical composition provided by the present invention can comprise an amount effective for treating or preventing anhedonia of a compound represented by the above general formula (I), or a pharmaceutically acceptable solvate (e.g., a hydrate) thereof, or a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate (e.g., a hydrate) thereof. In one embodiment, the pharmaceutical composition provided by the present invention can comprise an amount effective for treating or preventing anhedonia of a compound represented by the above general formula (I), or a pharmaceutically acceptable salt of the compound.

[0045] The dosage of the compound represented by the general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof can be appropriately determined depending on the type of salt, the administration method, the symptoms and age of the subject, etc. For example, when the compound represented by the general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof is orally administered to a human, it may be administered at a dose of 1 μg to 10 g / day, preferably 0.01 to 2000 mg / day, and more preferably 0.1 to 100 mg / day, and when it is intravenously administered to a human, it may be administered at a dose of 0.1 μg to 1 g / day, preferably 0.001 to 200 mg / day. It may be administered in one to three divided doses per day.

[0046] The present invention also has the following aspects: <1a> A method for treating or preventing anhedonia, comprising administering a therapeutically effective amount of a selective δ opioid receptor agonist to a subject (e.g., a mammal including a human) in need thereof; <2a> The method according to <1a>, wherein the selective δ opioid receptor agonist further has κ opioid receptor antagonist activity; <3a> The method according to <1a> or <2a>, wherein the selective δ opioid receptor agonist further has μ opioid receptor antagonist activity and κ opioid receptor antagonist activity; <4a> The method according to any one of <1a> to <3a>, wherein the anhedonia is anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder, autism spectrum disorder, or Alzheimer's type dementia; <5a> The method according to any one of <1a> to <4a>, wherein the anhedonia is anhedonia caused by mental stress or physical stress; <6a> The method according to any one of <1a> to <5a>, wherein the anhedonia suppresses suicidal ideation; <7a> The method according to any one of <1a> to <6a>, wherein the anhedonia is decreased reactivity to pleasant experiences related to at least one selected from money, food and drink, hobbies, entertainment, travel and recreation, and the desire for control, recognition, achievement, affiliation, and sexual desire;

[0047] <1b> A pharmaceutical composition comprising a selective δ opioid receptor agonist or a selective δ opioid receptor agonist as an active ingredient for use in the treatment or prevention of anhedonia; <2b> A pharmaceutical composition comprising a selective δ opioid receptor agonist or a selective δ opioid receptor agonist as an active ingredient for the use according to <1b>, wherein the selective δ opioid receptor agonist further has a κ opioid receptor antagonistic effect; <3b> A pharmaceutical composition comprising a selective δ opioid receptor agonist or a selective δ opioid receptor agonist as an active ingredient for the use according to <1b> or <2b>, wherein the selective δ opioid receptor agonist further has a μ opioid receptor antagonistic effect and a κ opioid receptor antagonistic effect; <4b> A selective δ opioid receptor agonist or a pharmaceutical composition comprising a selective δ opioid receptor agonist as an active ingredient for the use according to any one of <1b> to <3b>, wherein the anhedonia is anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder, autism spectrum disorder, or Alzheimer's disease; <5b> A selective δ opioid receptor agonist or a pharmaceutical composition comprising a selective δ opioid receptor agonist as an active ingredient for the use according to any one of <1b> to <4b>, wherein the anhedonia is anhedonia caused by mental stress or physical stress; <6b> A selective δ opioid receptor agonist or a pharmaceutical composition comprising a selective δ opioid receptor agonist as an active ingredient for the use according to any one of <1b> to <5b>, which suppresses suicidal ideation; <7b> A selective δ opioid receptor agonist or a pharmaceutical composition comprising a selective δ opioid receptor agonist as an active ingredient for the use according to any one of <1b> to <6b>, wherein the anhedonia is decreased responsiveness to pleasurable experiences related to money, food and drink, hobbies, entertainment, travel and recreation, and at least one selected from the desire for control, the desire for recognition, the desire for achievement, the desire for affiliation, and sexual desire;

[0048] <1b'> A selective δ opioid receptor agonist or a pharmaceutical composition comprising a selective δ opioid receptor agonist as an active ingredient for use in the treatment or prevention of depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder (PTSD etc.), autism spectrum disorder or Alzheimer's dementia, in particular for suppressing anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder (PTSD etc.), autism spectrum disorder or Alzheimer's dementia; <2b'> A selective δ opioid receptor agonist or a pharmaceutical composition comprising a selective δ opioid receptor agonist as an active ingredient for the use according to <1b'>, wherein the selective δ opioid receptor agonist further has a κ opioid receptor antagonistic effect; <3b'> A selective δ opioid receptor agonist or a pharmaceutical composition comprising a selective δ opioid receptor agonist as an active ingredient for the use according to <1b'> or <2b'>, wherein the selective δ opioid receptor agonist further has a μ opioid receptor antagonistic effect and a κ opioid receptor antagonistic effect; <4b'> A selective δ opioid receptor agonist or a pharmaceutical composition comprising a selective δ opioid receptor agonist as an active ingredient for the use according to any one of <1b'> to <3b'>, wherein the anhedonia is anhedonia caused by mental stress or physical stress; <5b'> A selective δ opioid receptor agonist or a pharmaceutical composition comprising a selective δ opioid receptor agonist as an active ingredient for the use according to any one of <1b'> to <4b'>, wherein the anhedonia is anhedonia caused by mental stress or physical stress; <6b'> A selective δ opioid receptor agonist or a pharmaceutical composition comprising a selective δ opioid receptor agonist as an active ingredient for the use according to any one of <1b'> to <5b'>, wherein the anhedonia is a decreased responsiveness to pleasurable experiences related to at least one selected from money, food and drink, hobbies, entertainment, travel and recreation, and the desire for control, the desire for recognition, the desire for achievement, the desire for affiliation, and sexual desire;

[0049] <1c> Use of a selective δ opioid receptor agonist for producing a pharmaceutical composition for treating or preventing anhedonia; <2c> The use according to <1c>, wherein the selective δ opioid receptor agonist further has a κ opioid receptor antagonistic effect; <3c> The use according to <1c> or <2c>, wherein the selective δ opioid receptor agonist further has a μ opioid receptor antagonistic effect and a κ opioid receptor antagonistic effect; <4c> The use according to any one of <1c> to <3c>, wherein the anhedonia is anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder, autism spectrum disorder, or Alzheimer's type dementia; <5c> The use according to any one of <1c> to <4c>, wherein the anhedonia is anhedonia caused by mental stress or physical stress; <6c> The use according to any one of <1c> to <5c>, wherein the pharmaceutical composition for treating or preventing anhedonia suppresses suicidal ideation; <7c> The use according to any one of <1c> to <6c>, wherein the anhedonia is decreased reactivity to pleasant experiences related to money, food and drink, hobbies, entertainment, travel and recreation, and at least one selected from the desire for control, the desire for recognition, the desire for achievement, the desire for affiliation, and sexual desire;

[0050] <8d> The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the selective δ opioid receptor agonist is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof; <9d> The compound represented by general formula (I) according to <8d>, wherein, in the compound represented by general formula (I), R ５ , R ６ａ , R ６ｂ , R ７ , R ８ , R ９ and R １０ is hydrogen, and R １ is hydrogen; C １－６ Alkyl; C ２－６alkenyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; or aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, ２ represents a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond, and further substituted with at least one oxo group, or a heterocycle in which a benzene ring is fused to the heterocycle, or pyridine 1-oxide, wherein R ２ is R ２ is bonded to Y through a carbon atom which is a ring-constituting atom of R ３ and R ４ are the same or different and are hydrogen; hydroxy; halogen; cyano; carbamoyl; C １－６ Alkoxy; C ６－１０ Aryloxy; C １－６ Alkanoyloxy; amino; or acylamino having 2 to 6 carbon atoms in the acyl moiety, where X is CH ２ and Y is C(=O), provided that R １ C １－６ alkyl; the alkylene and cycloalkyl portions of cycloalkylalkyl, in which the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; or the alkylene portion of aralkyl, in which the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms, may each be selected from the group consisting of 1 to 6 halogens; hydroxy; １－６ Alkoxy; C ６－１０ Aryloxy; C １－６ Alkanoyl; C １－６Alkanoyloxy; carboxyl; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; alkylsulfonyl having 1 to 6 carbon atoms in the alkyl portion; aminosulfonyl; alkylsulfinyl having 1 to 6 carbon atoms in the alkyl portion; alkylthio having 1 to 6 carbon atoms in the alkyl portion; C substituted with 1 to 6 halogens １－６ alkoxy; and arylcarbonyl, the aryl portion of which has 6 to 10 carbon atoms; and R １ an aralkyl aryl moiety having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and R ３ and R ４ C ６－１０ The aryl portion of the aryloxy is C １－６ Alkyl; C １－６ Alkoxy; C １－６ Alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; halogen; nitro; cyano; C substituted with 1 to 3 halogens １－６ Alkyl; C substituted with 1 to 3 halogens １－６ R may be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl having 1 to 3 carbon atoms in the alkyl; and methylenedioxy; ２ The heterocycle of the formula (I) can be an oxo group or any of the above-mentioned R １ The aryl portion of the aralkyl may have a substituent that may be substituted, and the alkylene portion of the aralkyl may have a substituent that may be substituted, and the ... ２ The pyridine 1-oxide of the formula １The aryl portion of the aralkyl may have a substituent that may be substituted, and the alkylene portion of the aralkyl may have a substituent that may be substituted, and R １ The alkylene portion of the aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion is phenyl or C substituted with 1 to 3 halogens. １－６ The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the compound represented by general formula (I) according to <10d> or <8d> is a compound optionally substituted with at least one substituent selected from alkyl; １ is C １－６ <11d> The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'> and <1c> to <7c>, wherein the compound represented by general formula (I) according to any one of <8d> to <10d> is an alkyl; a cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or an aralkyl compound having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; <11d> The method, use or pharmaceutical composition according to any one of <8d> to <10d>, wherein the compound represented by general formula (I) is R １ is a cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; <12d> The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the compound represented by general formula (I) according to <8d> or <9d> is a compound represented by formula (I), １ is substituted with hydroxy ２－６ Alkyl; C substituted with 1 to 6 halogens １－６ alkyl; or C １－６ Alkoxy-substituted C ２－６ <13d> The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the compound represented by general formula (I) according to <8d> or <9d> is R１ is a compound which is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl;

[0051] <14d> The compound represented by general formula (I) according to any one of <8d> to <13d>, wherein R ２ is a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O and S and at least one carbon atom as ring-constituting atoms, and at least one pair of adjacent ring-constituting atoms has a double bond, and is further substituted with at least one oxo group, or a heterocycle in which a benzene ring is fused to the heterocycle, or a compound represented by general formula (I) according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>; <15d> The method, use, or pharmaceutical composition according to any one of <8d> to <14d>, wherein R ２ <16d> The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the compound represented by general formula (I) according to any one of <8d> to <14d> is a compound represented by R ２ The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the heterocycle is pyridin-2(1H)-one; <17d> The method, use or pharmaceutical composition according to any one of <8d> to <14d>, wherein the compound represented by general formula (I) is ２ <18d> The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the heterocycle is pyridin-4(1H)-one; <18d> The method, use or pharmaceutical composition according to any one of <8d> to <14d>, wherein the compound represented by general formula (I) is ２<19d> The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the heterocycle is pyridazin-3(2H)-one; <19d> The method, use or pharmaceutical composition according to any one of <8d> to <14d>, wherein the compound represented by general formula (I) is ２ <20d> The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the compound represented by general formula (I) according to any one of <8d> to <14d> is a compound represented by formula (I), wherein R ２ <21d> The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the heterocycle is 4H-pyran-4-one or 2H-pyran-2-one; <21d> The method, use or pharmaceutical composition according to any one of <8d> to <14d>, wherein the compound represented by general formula (I) is ２ <22d> The method, use or pharmaceutical composition according to any one of <8d> to <14d>, wherein the compound represented by general formula (I) is a compound represented by formula (I), wherein R ２ The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the heterocycle is a pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione;

[0052] <23d> The compound represented by formula (I) according to any one of <8d> and <10d> to <22d>, wherein X is CH ２ <24d> The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the compound represented by general formula (I) according to any one of <8d> to <23d> is a compound represented by R ３ and R ４<25d> The method, use or pharmaceutical composition according to any one of <8d> and <10d> to <23d>, wherein one of R is hydroxy and the other is hydrogen; ３ is halogen; cyano; carbamoyl; C １－６ Alkoxy; C １－６ alkanoyloxy; amino; or acylamino having 2 to 6 carbon atoms in the acyl moiety, where R ４ is hydrogen or hydroxy, and R ５ <26d> The method, use or pharmaceutical composition according to any one of <8d> and <10d> to <23d>, wherein the compound represented by formula (I) is a compound represented by formula (I), wherein R ３ is hydroxy; carbamoyl; or C １－６ Alkanoyloxy, R ４ is hydrogen, and R ５ <27d> The method, use or pharmaceutical composition according to any one of <8d> and <10d> to <23d>, wherein the compound represented by general formula (I) is a compound represented by formula (I), wherein R ３ is hydroxy and R ４ is hydrogen, and R ５ <28d> The method, use or pharmaceutical composition according to any one of <8d> and <10d> to <23d>, wherein R is a compound represented by formula (I); ３ , R ４ and R ５ The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein all of the

[0053] <29d> The compound represented by general formula (I) according to any one of <8d> and <10d> to <28d>, wherein R ６ａ , R ６ｂ , R ７ , R ８ , R ９ and R １０ <30d> The method, use or pharmaceutical composition according to any one of <9d> to <23d>, wherein R ３ is halogen; cyano; carbamoyl; C １－６ Alkoxy; C １－６ alkanoyloxy; amino; or acylamino having 2 to 6 carbon atoms in the acyl moiety, where R ４ <31d> The method, use or pharmaceutical composition according to any one of <9d> to <23d>, wherein R is a compound represented by formula (I), ３ is hydroxy; carbamoyl; or C １－６ Alkanoyloxy, R ４ <32d> The method, use or pharmaceutical composition according to any one of <9d> to <23d>, wherein R is a compound represented by formula (I); ３ is hydroxy and R ４ <33d> The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein R is hydrogen; <33d> The method, use or pharmaceutical composition according to any one of <9d> to <23d>, wherein R ３ and R ４is hydrogen; <34d> The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the compound represented by general formula (I) according to <8d> is a compound represented by the following general formula (II):

[0054] (In the formula, R １ is hydrogen; C １－６ alkyl; or cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion, R ２ represents a 5- to 7-membered heterocycle containing one or two nitrogen atoms and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond and is further substituted with at least one oxo group, or pyridine 1-oxide, wherein R ２ is R ２ is bonded to Y through a carbon atom which is a ring-constituting atom of R ３ and R ４ are the same or different and are hydrogen; hydroxy; or C １－６ alkoxy, Y is C(=O), provided that R １ C １－６ alkyl; the alkylene and cycloalkyl portions of cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion are each independently selected from 1 to 6 halogen; hydroxy; and C １－６ and R ２ The heterocycle of the formula (I) can be an oxo group or a C １－６ Alkyl; C １－６ Alkoxy; C １－６ Alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; halogen; nitro; cyano; C substituted with 1 to 3 halogens １－６ Alkyl; C substituted with 1 to 3 halogens １－６alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl having 1 to 3 carbon atoms in the alkyl; and methylenedioxy, and R ２ The pyridine 1-oxide of C １－６ Alkyl; C １－６ Alkoxy; C １－６ Alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; halogen; nitro; cyano; C substituted with 1 to 3 halogens １－６ Alkyl; C substituted with 1 to 3 halogens １－６ the method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the compound is represented by the formula (I), which optionally has at least one substituent selected from: alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms; phenoxy; phenylalkyl in which the alkyl has 1 to 3 carbon atoms; and methylenedioxy;

[0055] <35d> The compound represented by general formula (II) according to <34d> is R １ is a cycloalkylalkyl in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; <36d> The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the compound represented by general formula (II) according to <34d> or <35d> is a compound represented by formula (II), ２ is represented by formula (III):

[0056] ;Formula (IV):

[0057] ;Formula (V):

[0058] or formula (VI):

[0059] (In Formulas III to VI, R ａ is hydrogen or C １－６ <37d> The method, use or pharmaceutical composition according to any one of <34d> to <36d>, wherein the compound represented by general formula (II) is R ３ <38d> The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the compound represented by general formula (II) according to any one of <34d> to <37d> is a compound represented by formula (II), wherein R ４ is a compound in which is hydrogen;

[0060] <39d> The compound represented by general formula (I) according to <8d> is 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-Octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one and 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the compound is at least one compound selected from the group consisting of:

[0061] <40d> The compound represented by general formula (I) according to any one of <8d> and <34d> to <38d>, is 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide; 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one; 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one; 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one;6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, and The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the compound is at least one compound selected from 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one;

[0062] The present invention will now be described in more detail with reference to examples, but is not limited to these examples. The compounds of the examples were named by converting the structural formulas drawn using ChemDraw version 14 (CambridgeSoft) into English names using the naming algorithm built into the software, and then translating them into Japanese.

[0063] Example 1: Synthesis of compounds The following compounds Nos. 1 to 39 were synthesized according to the method described in Patent Document 7, and KNT-127 was synthesized according to the method described in Non-Patent Document 4.

[0064] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide (Compound No. 1, Example 1 of Patent Document 7); 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide (Compound No. 2, Example 2 of Patent Document 7); 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one (Compound No. 3, Example 3 of Patent Document 7); 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide (Compound No. 4, Example 4 of Patent Document 7); 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one (Compound No. 5, Example 5 of Patent Document 7); 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one (Compound No. 6, Example 6 of Patent Document 7);6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one (Compound No. 7, Example 7 of Patent Document 7); 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one (Compound No. 8, Example 8 of Patent Document 7); 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one (Compound No. 9, Example 9 of Patent Document 7); 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one (Compound No. 10, Example 10 of Patent Document 7); 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one (Compound No. 11, Example 11 of Patent Document 7);5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione (Compound No. 12, Example 12 of Patent Document 7); 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one (Compound No. 13, Example 13 of Patent Document 7); 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one (Compound No. 14, Example 14 of Patent Document 7); 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one (Compound No. 15, Example 15 of Patent Document 7); 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one (Compound No. 16, Example 16 of Patent Document 7);4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one (Compound No. 17, Example 17 of Patent Document 7); 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one (Compound No. 18, Example 18 of Patent Document 7); 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one (Compound No. 19, Example 19 of Patent Document 7); 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one (Compound No. 20, Example 20 of Patent Document 7); 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one (Compound No. 21, Example 21 of Patent Document 7);2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide (Compound No. 22, Example 22 of Patent Document 7); 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one (Compound No. 23, Example 23 of Patent Document 7); 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one (Compound No. 24, Example 24 of Patent Document 7); 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione (Compound No. 25, Example 25 of Patent Document 7); 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one (Compound No. 26, Example 26 of Patent Document 7);6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one (Compound No. 27, Example 27 of Patent Document 7); 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one (Compound No. 28, Example 28 of Patent Document 7); 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide hydrochloride (Compound No. 29, Example 29 of Patent Document 7); 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one hydrochloride (Compound No. 30, Example 30 of Patent Document 7); 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one hydrochloride (Compound No. 31, Example 31 of Patent Document 7);3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one hydrochloride (Compound No. 32, Example 32 of Patent Document 7); 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one hydrochloride (Compound No. 33, Example 33 of Patent Document 7); 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one hydrochloride (Compound No. 34, Example 34 of Patent Document 7); 6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one (Compound No. 35, Example 35 of Patent Document 7); 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one (Compound No. 36, Example 36 of Patent Document 7);5-chloro-3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one (Compound No. 37, Example 37 of Patent Document 7); 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Compound No. 38, Example 38 of Patent Document 7); 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one (Compound No. 39, Example 39 of Patent Document 7);

[0065] Example 2: Agonist activity of compounds against opioid receptors The agonist activity of the compounds synthesized in Example 1 against opioid receptors was as shown in Table 1 (Patent Document 7). KNT-127 also had similar agonist activity against DOR. It was confirmed that the compounds shown in Table 1 had strong agonist activity against DOR, and had no agonist activity or only very weak agonist activity against μ and κ receptors.

[0066]

[0067] N.C.: The maximum response was not reached at the highest concentration (10 μM), so ED ５０ The value was not calculated. ＊ : Because the maximum response was not achieved at the highest concentration, the response rate at the highest concentration is shown as a reference value.

[0068] Example 3: Antagonistic activity of compounds against opioid receptors The antagonistic activity of the compounds synthesized in Example 1 against opioid receptors is shown in Table 2 (Patent Document 8). The compounds shown in Table 2 were confirmed to have potent antagonistic activity against opioid μ and κ receptors.

[0069]

[0070] Example 4: Preparation of Social Defeat Stress (SDS) Model Mice To investigate whether the compounds of the present invention, which have a δ opioid receptor agonist, have an effect of improving anhedonia in depression, two types of SDS model mice suffering from depression were prepared. 1) Physical Stress (PS) Mice Physical stress-induced SDS model mice were prepared according to the report of Golden et al. (Nat Protoc (2011) 6:1183). Male C57BL / 6J mice (Sankyo Labo Service) were purchased and housed for at least 5 days for acclimation (4-6 mice / cage, 12-hour light-dark cycle (light period 8:00-20:00), room temperature 23±2°C). Highly aggressive male ICR mice (Sankyo Labo Service) were purchased and housed in individual cages (referred to as "home cages"). The home cages used were 225mm long x 338mm wide x 140mm high (manufactured by CLEA Japan). C57BL / 6J mice were randomly divided into two groups. One group was individually physically stressed (referred to as "PS mice"), while the other group was not physically stressed (referred to as "naive mice"). One C57BL / 6J mouse (6 weeks old) was challenged with an aggressor ICR mouse (retired age) for 10 minutes per day for 10 consecutive days in a home cage to induce physical stress. The PS mice were isolated and housed for 5 days starting the day after the final stressor, and then subjected to anhedonia testing. The aggressor challenge was performed between 4:00 PM and 8:00 PM to minimize the effects of circadian fluctuations in corticosterone levels.

[0071] 2) Chronic Vicarious Social Defeat Stress (cVSDS) Mice. A cVSDS model mouse without physical stress was generated according to the method of Sial et al. (J Neurosci Methods (2016) 258:94). Male C57BL / 6J mice (Sankyo Labo Service) were purchased and housed for at least 5 days for acclimation (4-6 mice / cage, 12-hour light-dark cycle (light period 8:00-20:00), room temperature 23±2°C). Highly aggressive male ICR mice (retired age) used as aggressors were individually housed in their home cages and then screened for 3 minutes per day for 3 days to select highly aggressive mice. Screening was performed by counting the number of attacks when male C57BL / 6J mice were exposed to the ICR mouse home cage. C57BL / 6J mice were randomly divided into two groups. One group was individually challenged with cVSDS (referred to as "cVSDS mice"), and the other group was not challenged with cVSDS (referred to as "naive mice"). One C57BL / 6J mouse was placed on one side of the home cage, separated from the ICR mouse by a transparent acrylic panel with a hole. Then, another C57BL / 6J mouse was placed in the home cage and challenged by the aggressor ICR mouse. This was repeated for 10 minutes per day for 10 consecutive days, thereby challenging the first C57BL / 6J mouse placed in the home cage with cVSDS. Different ICR and C57BL / 6J mice were used each day. The cVSDS mice were then isolated for 38 days after the initial stress challenge and then subjected to anhedonia testing. The stress was applied to the cVSDS mice between 16:00 and 20:00 in order to minimize the influence of the diurnal fluctuation of corticosterone in the body.

[0072] Example 5: Evaluation of Anhedonia: Sucrose Preference Test (SPT) The SPT was performed by providing normal drinking water and a 1% sucrose solution and measuring the proportion of sucrose solution consumed ad libitum. In a depressed state, consumption of sucrose solution, a reward response, is reduced. 1) Effects on PS Mice Compound No. 7, the present compound, was dissolved in a solvent (1% methylcellulose) and orally administered to the PS mice prepared in Example 4 twice daily (8:00 AM to 9:00 AM and 7:00 PM to 8:00 PM (except for 4:00 PM on the final day)) for 5 days starting the day after the final stress load (5 mg / kg / administration, n = 6). As a control group, PS mice or naive mice (C57BL / 6J mice) not subjected to physical stress were similarly administered vehicle alone (n = 6 each). From the second day after the start of drug administration, the mice were allowed to acclimate to normal drinking water and 1% sucrose solution ad libitum. From the fourth day of drug administration (22 hours before SPT), the mice were kept without water. On the fifth day, 2 hours after drug administration, normal drinking water and a 1% sucrose solution were provided and given free access. Sucrose preference (%) was calculated from the ratio of 1% sucrose consumption to total consumption (1% sucrose solution consumption + drinking water consumption) during the subsequent two-hour test period. As shown in Figure 1, PS mice showed a significantly reduced sucrose preference and anhedonia compared with naive mice not subjected to physical stress (p<0.01; Bonferroni's test after one-way ANOVA). Meanwhile, administration of the present compound to PS mice significantly improved the reduced sucrose preference (p<0.01; Bonferroni's test after one-way ANOVA). In PS mice, sucrose preference was reduced by 40%, and symptoms of anhedonia were severe, but 5 days of administration of the compound of the present application was found to have an ameliorative effect on anhedonia. The effect of the compound of the present application on anhedonia may be due to its antagonist activity against kappa and mu opioid receptors in addition to its agonist activity against delta opioid receptors.

[0073] 2) Effect on cVSDS Mice (KNT-127) KNT-127 synthesized in Example 1 was dissolved in physiological saline. Rapamycin (LC Laboratories), an mTOR inhibitor, was dissolved at 0.04 mM in 5% dimethyl sulfoxide / 95% physiological saline. LY294002 (Fujifilm Wako Pure Chemical Industries, Ltd.), a PI3K inhibitor, was dissolved at 4 mM in 10% dimethyl sulfoxide / 90% physiological saline. Starting 26 days after the final stress load, the cVSDS mice prepared in Example 4 were allowed to acclimate by ad libitum access to 1% sucrose solution in addition to normal drinking water. From 28 days after the final stress load (22 hours before SPT), the mice were kept without water. On the 29th day after the final stress load, rapamycin, LY294002, or their vehicle was administered intracerebroventricularly (5 μL) 60 minutes before the start of the test. Additionally, KNT-127 (10 mg / kg) or its vehicle was administered subcutaneously 30 minutes before the start of the test. After that, normal drinking water and a 1% sucrose solution were provided and given ad libitum. Sucrose preference (%) was calculated from the ratio of the amount of 1% sucrose solution consumed to the total amount consumed (1% sucrose solution consumption + drinking water consumption) over the subsequent 2-hour test period. The naive / drug vehicle / inhibitor vehicle group consisted of eight mice, the cVSDS / drug vehicle / inhibitor vehicle group consisted of eight mice, the cVSDS / KNT-127 / inhibitor vehicle group consisted of eight mice, the cVSDS / KNT-127 / rapamycin group consisted of seven mice, and the cVSDS / KNT-127 / LY294002 group consisted of seven mice. As shown in Figure 2, compared with naive mice not loaded with cVSDS, cVSDS mice exhibited significantly reduced sucrose preference and developed anhedonia (p<0.01; Bonferroni's test after one-way ANOVA). Meanwhile, administration of KNT-127 to cVSDS mice restored their sucrose preference to that of naive mice, demonstrating the ameliorative effect of KNT-127 on anhedonia. The effect of KNT-127 on anhedonia was inhibited by rapamycin and LY-294002, suggesting that mTOR and PI3K are involved in signal transduction.

[0074] 3) Effect on cVSDS Mice (Compound of the Present Application) Compound No. 7 of the present application was dissolved in a solvent (1% methylcellulose) and orally administered to the cVSDS mice prepared in Example 4 described above twice daily (8:00 AM to 9:00 AM and 4:00 PM to 5:00 PM on the final day only) for 5 days, starting from the 28th day after the final stress load (5 mg / kg / dose, n = 7). As a control group, cVSDS mice or naive mice (C57BL / 6J mice) not loaded with cVSDS were similarly administered the solvent alone (n = 6 for each). From the second day after the start of drug administration, the mice were allowed to freely consume a 1% sucrose solution in addition to regular drinking water for acclimatization. From the fourth day of drug administration (22 hours before SPT), the mice were kept without water. On the fifth day, 2 hours after drug administration, normal drinking water and a 1% sucrose solution were provided and given free access. Sucrose preference (%) was calculated as the ratio of the amount of 1% sucrose solution consumed to the total amount consumed (1% sucrose solution consumption + drinking water consumption) during the subsequent two-hour test period. As shown in Figure 3 , compared with naive mice not loaded with cVSDS, cVSDS mice showed a significantly reduced sucrose preference, indicating the development of anhedonia (p<0.05; Bonferroni's test after one-way ANOVA). Meanwhile, administration of the compound of the present invention tended to improve the reduced sucrose preference in cVSDS mice (p=0.075; Bonferroni's test after one-way ANOVA), demonstrating a similar level of sucrose preference to naive mice not loaded with stress.

[0075] Example 6: Evaluation of Anhedonia: Female Urine Sniffing Test (FUST) Next, the effects of the present compound on anhedonia, related to sexual desire, were examined using the FUST. In a depressed state, the time spent by male mice sniffing the urine of estrous female mice, a motivational / reward-seeking behavior based on sexual orientation as an innate desire, is reduced. 1) Effects on PS Mice Compound No. 7 of the present compound was dissolved in a solvent (1% methylcellulose) and orally administered to the PS mice prepared in Example 4 described above twice daily (8:00 AM to 9:00 AM and 4:00 PM to 5:00 PM, with a single administration on the final day) for five days (5 mg / kg / administration, n = 12) starting two days after the final stress load. As a control group, PS mice or naive mice (C57BL / 6J mice) not subjected to physical stress were similarly administered with the solvent alone (n = 9 and 10, respectively). Two hours after the final administration, the test was performed according to the following procedure. Mice were first presented with a cotton swab moistened with water for 3 minutes, and then 45 minutes later, with a cotton swab moistened with urine collected from an estrous female for another 3 minutes. The sniffing time for each mouse was measured. As shown in Figure 4, when presented with a cotton swab moistened with water, the sniffing time for all mice was approximately 2-5 seconds. However, when presented with a cotton swab moistened with female urine, the sniffing time for PS mice was only approximately 60% longer than that of naive mice that had not been physically stressed, indicating a decrease in sexual motivation / reward-seeking behavior (anhedonia) (p<0.05; Bonferroni's test after one-way ANOVA). On the other hand, in the group of PS mice administered with the compound of the present application, the sniffing time for female urine recovered to the same extent as that of naive mice (no significant difference compared to the naive mouse group; p<0.05 compared to the vehicle-administered cVSDS mouse group; Bonferroni's test after one-way analysis of variance).

[0076] 2) Effect on cVSDS Mice Compound No. 7 of the present invention was dissolved in a solvent (1% methylcellulose) and orally administered to the cVSDS mice prepared in Example 4 twice daily (8:00 AM to 9:00 AM and 4:00 PM to 5:00 PM (with a single administration on the final day)) for 5 days, starting from the 28th day after the final stress load (5 mg / kg / administration, n = 7). As a control group, cVSDS mice or naive mice (C57BL / 6J mice) not subjected to cVSDS load were similarly administered with the solvent alone (n = 6 for each group). Two hours after the final administration, the test was performed according to the following procedure. First, a cotton swab with the tip moistened with water was presented to the mice for 3 minutes, and then, 45 minutes later, a cotton swab with the tip moistened with urine collected from an estrous female was presented to the mice for another 3 minutes, and the duration of olfactory behavior for each group was measured. As shown in Figure 5, when presented with a cotton swab moistened with water, the sniffing time of all mice was approximately 2 to 5 seconds, whereas when presented with a cotton swab moistened with female urine, the sniffing time was extended. However, the sniffing time of the cVSDS mice was only approximately 50% longer than that of unstressed naive mice, indicating a decrease in sexual motivation / reward-seeking behavior (anhedonia) (p<0.05; Bonferroni's test after one-way ANOVA). On the other hand, in the group of cVSDS mice administered with the compound of the present application, the sniffing time for female urine recovered to the same level as that of unstressed naive mice (not significantly different from the naive mouse group; p<0.01 from the vehicle-administered cVSDS mouse group; Bonferroni's test after one-way ANOVA).

[0077] The pharmaceutical composition of the present invention is useful for treating or preventing anhedonia associated with depression.

Claims

1. A pharmaceutical composition for treating or preventing anhedonia, comprising a selective delta opioid receptor agonist as an active ingredient.

2. The pharmaceutical composition for treatment or prevention according to claim 1, wherein the selective delta opioid receptor agonist further has a kappa opioid receptor antagonist activity.

3. The pharmaceutical composition for treatment or prevention according to claim 1 or 2, wherein the selective delta opioid receptor agonist further has mu opioid receptor antagonist activity and kappa opioid receptor antagonist activity.

4. The pharmaceutical composition for treatment or prevention according to claim 1 or 2, wherein the anhedonia is anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder, autism spectrum disorder, or Alzheimer's disease.

5. The pharmaceutical composition for treatment or prevention according to claim 1 or 2, wherein the anhedonia is anhedonia caused by mental or physical stress.

6. A pharmaceutical composition for treatment or prevention according to claim 1 or 2, which suppresses suicidal thoughts.

7. The pharmaceutical composition for treatment or prevention according to claim 1 or 2, wherein the anhedonia is a decreased responsiveness to pleasurable experiences related to money, food and drink, hobbies, entertainment, travel and recreation, and at least one selected from the desire for control, the desire for recognition, the desire for achievement, the desire for affiliation, and sexual desire.

8. The selective delta opioid receptor agonist is represented by the following general formula (I): (In the formula, R １ is hydrogen; C １－１０ Alkyl; C ６－１０ Aryl; C ２－６ Alkenyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; C ３－６ cycloalkyl; or heteroarylalkyl in which the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and the alkylene portion has 1 to 5 carbon atoms, ２ represents a heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond and is further substituted with at least one oxo group, or pyridine 1-oxide, wherein R ２ is R ２ is bonded to Y through a carbon atom which is a ring-constituting atom of R ３ , R ４ and R ５ are the same or different and are hydrogen; hydroxy; halogen; cyano; carbamoyl; C １－６ Alkoxy; C ６－１０ Aryloxy; C １－６ Alkanoyloxy; Nitro; Amino; C １－８ Alkylamino; C ６－１０ represents an arylamino or an acylamino having 2 to 6 carbon atoms in the acyl moiety, ６ａ and R ６ｂ are the same or different and represent hydrogen; fluorine or hydroxy; or R ６ａ and R ６ｂ together represent =O, and R ７ and R ８ are the same or different and represent hydrogen, fluorine or hydroxy; R ９ and R １０ are the same or different and are hydrogen; C １－６ Alkyl; C ６－１０ Aryl; heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms; aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; heteroarylalkyl having 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and 1 to 5 carbon atoms in the alkylene moiety; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; ２－６ represents alkenyl, and X is O or CH ２ and Y represents C(=O). １ C １－１０ alkyl; the alkylene and cycloalkyl portions of cycloalkylalkyl, in which the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; the alkylene portion of aralkyl, in which the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; and the alkylene portion of heteroarylalkyl, in which the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and the alkylene portion has 1 to 5 carbon atoms, is substituted with 1 to 6 halogen atoms; hydroxy; C １－６ Alkoxy; C ６－１０ Aryloxy; C １－６ Alkanoyl; C １－６ Alkanoyloxy; carboxyl; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; alkylsulfonyl having 1 to 6 carbon atoms in the alkyl portion; aminosulfonyl; alkylsulfinyl having 1 to 6 carbon atoms in the alkyl portion; alkylthio having 1 to 6 carbon atoms in the alkyl portion; C substituted with 1 to 6 halogens １－６ alkoxy; and arylcarbonyl, the aryl portion of which has 6 to 10 carbon atoms; and R １ C ６－１０ Aryl; an aryl portion of an aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; R ３ , R ４ and R ５ C ６－１０ the aryl portion of the aryloxy; and C ６－１０ the aryl portion of arylamino; and R ９ and R １０ C ６－１０ Aryl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; aryl moiety of aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and heteroaryl moiety of heteroarylalkyl having 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms and 1 to 5 carbon atoms in the alkylene moiety are C １－６ Alkyl; C １－６ Alkoxy; C １－６ Alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; halogen; nitro; cyano; C substituted with 1 to 3 halogens １－６ Alkyl; C substituted with 1 to 3 halogens １－６ R may be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl having 1 to 3 carbon atoms in the alkyl; and methylenedioxy; ２ The heterocycle of the formula (I) can be an oxo group or any of the above-mentioned R １ C ６－１０ The aryl may have a substituent, and R ２ The pyridine 1-oxide of the formula １ C ６－１０ The aryl may have a substituent, and R １ is C １－１０ In the case of alkyl, NR １１ R １２ where R １１ and R １２ are the same or different and are hydrogen; C １－１０ alkyl; or aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, or １１ and R １２ And, R １１ and R １２ may be joined together with the nitrogen atom to which R is attached and optionally one or two heteroatoms to form a 5- to 7-membered ring, and R １ The alkylene portion of the aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion is phenyl or C substituted with 1 to 3 halogens. １－６ 2. The pharmaceutical composition for treatment or prevention according to claim 1, which is a compound represented by the following formula (I):

9. The compound represented by the general formula (I) is R ５ , R ６ａ , R ６ｂ , R ７ , R ８ , R ９ and R １０ is hydrogen, and R １ is hydrogen; C １－６ Alkyl; C ２－６ alkenyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; or aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, ２ represents a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond, and further substituted with at least one oxo group, or a heterocycle in which a benzene ring is fused to the heterocycle, or pyridine 1-oxide, wherein R ２ is R ２ is bonded to Y through a carbon atom which is a ring-constituting atom of R ３ and R ４ are the same or different and are hydrogen; hydroxy; halogen; cyano; carbamoyl; C １－６ Alkoxy; C ６－１０ Aryloxy; C １－６ Alkanoyloxy; amino; or acylamino having 2 to 6 carbon atoms in the acyl moiety, where X is CH ２ and Y is C(=O), provided that R １ C １－６ alkyl; the alkylene and cycloalkyl portions of cycloalkylalkyl, in which the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; or the alkylene portion of aralkyl, in which the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms, may each be selected from the group consisting of 1 to 6 halogens; hydroxy; １－６ Alkoxy; C ６－１０ Aryloxy; C １－６ Alkanoyl; C １－６ Alkanoyloxy; carboxyl; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; alkylsulfonyl having 1 to 6 carbon atoms in the alkyl portion; aminosulfonyl; alkylsulfinyl having 1 to 6 carbon atoms in the alkyl portion; alkylthio having 1 to 6 carbon atoms in the alkyl portion; C substituted with 1 to 6 halogens １－６ alkoxy; and arylcarbonyl, the aryl portion of which has 6 to 10 carbon atoms; and R １ an aralkyl aryl moiety having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and R ３ and R ４ C ６－１０ The aryl portion of the aryloxy is C １－６ Alkyl; C １－６ Alkoxy; C １－６ Alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; halogen; nitro; cyano; C substituted with 1 to 3 halogens １－６ Alkyl; C substituted with 1 to 3 halogens １－６ R may be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl having 1 to 3 carbon atoms in the alkyl; and methylenedioxy; ２ The heterocycle of the formula (I) can be an oxo group or any of the above-mentioned R １ The aryl portion of the aralkyl may have a substituent that may be substituted, and the alkylene portion of the aralkyl may have a substituent that may be substituted, and the ... ２ The pyridine 1-oxide of the formula １ The aryl portion of the aralkyl may have a substituent that may be substituted, and the alkylene portion of the aralkyl may have a substituent that may be substituted, and R １ The alkylene portion of the aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion is phenyl or C substituted with 1 to 3 halogens. １－６ 9. The pharmaceutical composition for treatment or prevention according to claim 8, which is a compound optionally substituted with at least one substituent selected from alkyl.

10. The compound represented by the general formula (I) is R １ is C １－６ The pharmaceutical composition for treatment or prevention according to claim 8 or 9, which is a compound which is alkyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; or aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion.

11. The compound represented by the general formula (I) is R １ The pharmaceutical composition for treatment or prevention according to claim 8 or 9, wherein the compound is a cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion.

12. The compound represented by the general formula (I) is R １ is substituted with hydroxy ２－６ Alkyl; C substituted with 1 to 6 halogens １－６ alkyl; or C １－６ Alkoxy-substituted C ２－６ The pharmaceutical composition for treatment or prevention according to claim 8 or 9, wherein the compound is alkyl.

13. The compound represented by the general formula (I) is R １ The pharmaceutical composition for treatment or prevention according to claim 8 or 9, wherein is a compound in which is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl.

14. The compound represented by the general formula (I) is R ２ is a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond, and is further substituted with at least one oxo group, or a heterocycle in which a benzene ring is fused to said heterocycle, or pyridine 1-oxide.

15. The compound represented by the general formula (I) is R ２ The pharmaceutical composition for treatment or prevention according to claim 8 or 9, wherein is a compound in which is pyridine 1-oxide.

16. The compound represented by the general formula (I) is R ２ 10. The pharmaceutical composition for treatment or prevention according to claim 8 or 9, wherein the heterocycle is pyridin-2(1H)-one.

17. The compound represented by the general formula (I) is R ２ 10. The pharmaceutical composition for treatment or prevention according to claim 8 or 9, wherein the heterocycle is pyridin-4(1H)-one.

18. The compound represented by the general formula (I) is R ２ 10. The pharmaceutical composition for treatment or prevention according to claim 8 or 9, wherein the heterocycle is pyridazin-3(2H)-one.

19. The compound represented by the general formula (I) is R ２ 10. The pharmaceutical composition for treatment or prevention according to claim 8 or 9, wherein the heterocycle is pyrazin-2(1H)-one.

20. The compound represented by the general formula (I) is R ２ 10. The pharmaceutical composition for treatment or prevention according to claim 8 or 9, wherein the heterocycle is 4H-pyran-4-one or 2H-pyran-2-one.

21. The compound represented by the general formula (I) is R ２ 10. The pharmaceutical composition for treatment or prevention according to claim 8 or 9, wherein the heterocycle is quinolin-2(1H)-one.

22. The compound represented by the general formula (I) is R ２ 10. The pharmaceutical composition for treatment or prevention according to claim 8 or 9, wherein the heterocycle is pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione.

23. The compound represented by the general formula (I) is ２ 9. The pharmaceutical composition for treatment or prevention according to claim 8, wherein the compound is 24. The compound represented by the general formula (I) is R ３ and R ４ 10. The pharmaceutical composition for treatment or prevention according to claim 8 or 9, wherein one of the following is hydroxy and the other is hydrogen:

25. The compound represented by the general formula (I) is R ３ is halogen; cyano; carbamoyl; C １－６ Alkoxy; C １－６ alkanoyloxy; amino; or acylamino having 2 to 6 carbon atoms in the acyl moiety, where R ４ is hydrogen or hydroxy, and R ５ The pharmaceutical composition for treatment or prevention according to claim 8, wherein is a compound in which is hydrogen.

26. The compound represented by the general formula (I) is R ３ is hydroxy; carbamoyl; or C １－６ Alkanoyloxy, R ４ is hydrogen, and R ５ The pharmaceutical composition for treatment or prevention according to claim 8, wherein is a compound in which is hydrogen.

27. The compound represented by the general formula (I) is R ３ is hydroxy and R ４ is hydrogen, and R ５ The pharmaceutical composition for treatment or prevention according to claim 8, wherein is a compound in which is hydrogen.

28. The compound represented by the general formula (I) is R ３ , R ４ and R ５ The pharmaceutical composition for treatment or prevention according to claim 8, wherein all of are hydrogen.

29. The compound represented by the general formula (I) is R ６ａ , R ６ｂ , R ７ , R ８ , R ９ and R １０ The pharmaceutical composition for treatment or prevention according to claim 8, wherein all of are hydrogen.

30. The compound represented by the general formula (I) is R ３ is halogen; cyano; carbamoyl; C １－６ Alkoxy; C １－６ alkanoyloxy; amino; or acylamino having 2 to 6 carbon atoms in the acyl moiety, where R ４ The pharmaceutical composition for treatment or prevention according to claim 9, wherein is a compound in which is hydrogen or hydroxy.

31. The compound represented by the general formula (I) is R ３ is hydroxy; carbamoyl; or C １－６ Alkanoyloxy, R ４ The pharmaceutical composition for treatment or prevention according to claim 9, wherein is a compound in which is hydrogen.

32. The compound represented by the general formula (I) is R ３ is hydroxy and R ４ The pharmaceutical composition for treatment or prevention according to claim 9, wherein is hydrogen.

33. The compound represented by the general formula (I) is R ３ and R ４ The pharmaceutical composition for treatment or prevention according to claim 9, wherein is a compound in which is hydrogen.

34. The compound represented by the general formula (I) is a compound represented by the following general formula (II): (In the formula, R １ is hydrogen; C １－６ alkyl; or cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion, R ２ represents a 5- to 7-membered heterocycle containing one or two nitrogen atoms and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond and is further substituted with at least one oxo group, or pyridine 1-oxide, wherein R ２ is R ２ is bonded to Y through a carbon atom which is a ring-constituting atom of R ３ and R ４ are the same or different and are hydrogen; hydroxy; or C １－６ alkoxy, Y is C(=O), provided that R １ C １－６ alkyl; the alkylene and cycloalkyl portions of cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion are each independently selected from 1 to 6 halogen; hydroxy; and C １－６ and R ２ The heterocycle of the formula (I) can be an oxo group or a C １－６ Alkyl; C １－６ Alkoxy; C １－６ Alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; halogen; nitro; cyano; C substituted with 1 to 3 halogens １－６ Alkyl; C substituted with 1 to 3 halogens １－６ alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl having 1 to 3 carbon atoms in the alkyl; and methylenedioxy, and R ２ The pyridine 1-oxide of C １－６ Alkyl; C １－６ Alkoxy; C １－６ Alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; halogen; nitro; cyano; C substituted with 1 to 3 halogens １－６ Alkyl; C substituted with 1 to 3 halogens １－６ 9. The pharmaceutical composition for treatment or prevention according to claim 8, wherein the compound is a compound represented by the formula (I), which optionally has at least one substituent selected from the group consisting of alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl in which the alkyl group has 1 to 3 carbon atoms; and methylenedioxy.

35. The compound represented by the general formula (II) is R １ The pharmaceutical composition for treatment or prevention according to claim 34, wherein is a compound which is cycloalkylalkyl, wherein the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms.

36. The compound represented by the general formula (II) is R ２ is represented by formula (III): ;Formula (IV): ;Formula (V): or formula (VI): (In Formulas III to VI, R ａ is hydrogen or C １－６ 36. The pharmaceutical composition for treatment or prevention according to claim 34 or 35, wherein the compound is:

37. The compound represented by the general formula (II) is R ３ The pharmaceutical composition for treatment or prevention according to claim 34 or 35, wherein is a compound in which is hydroxy.

38. The compound represented by the general formula (II) is R ４ The pharmaceutical composition for treatment or prevention according to claim 34 or 35, wherein is a compound in which is hydrogen.

39. The compound represented by the general formula (I) is 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide; 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide; 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one; 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide; 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one; 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one;6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one; 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one; 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one; 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one; 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one; 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione;3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one; 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one; 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one; 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one; 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one; 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one;2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one; 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one; 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one; 2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide; 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one; 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one;6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione; 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one; 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one; and The pharmaceutical composition for treatment or prevention according to claim 8, which is at least one compound selected from the group consisting of 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one; 40. The compound represented by the general formula (I) is 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide; 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one; 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one; 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one; 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one; and The pharmaceutical composition for treatment or prevention according to any one of claims 8, 34, and 35, wherein the compound is at least one compound selected from the group consisting of 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one.

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