Pharmaceuticals for treating or preventing stress-related disorders.

Abstract

The invention relates to a pharmaceutical for the treatment or prevention of stress-related disorders, stress-induced anxiety disorders, or stress-related or anxiety-related disorders associated with depression, which contains a selective δ-opioid receptor agonist as the active ingredient, wherein the selective δ-opioid receptor agonist is better to also have µ-opioid receptor antagonist and κ-opioid receptor antagonist activity.

Description

Pharmaceutical composition for treating or preventing stress-related disorders

[0001] The present invention relates to a pharmaceutical composition for the treatment or prevention of stress-related disorders, stress-induced anxiety disorders, or stress-related disorders or anxiety disorders accompanied by depression, comprising a selective opioid δ receptor agonist as an active ingredient. This application claims priority to Japanese Patent Application No. 2021-030974 filed in Japan on February 26, 2021, and Japanese Patent Application No. 2021-117338 filed in Japan on July 15, 2021, 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. It is known that agonists of all three subtypes, μ, δ, and κ, have analgesic effects. Among these, agonists that selectively activate the opioid δ receptor are expected to have little or no side effects that manifest through activation of the opioid μ receptor or the opioid κ receptor. Various compounds have been reported as opioid δ receptor agonists, and their analgesic, antidepressant, and anxiolytic effects have been demonstrated (Patent Documents 1 to 6, Non-Patent Documents 1 to 3). Incidentally, the formation of fear memory is a defensive response to avoid danger or threat, and is an instinctive behavior possessed by all animals. Once acquired, fear memory is retained for a long period of time, but extinction occurs when an animal learns that it no longer needs to feel fear. For example, post-traumatic stress disorder (PTSD) is a disorder in which fear memories formed by a frightening experience are not erased even when there is no longer any need to feel fear, and abnormalities in fear memory control are thought to be related to its onset and pathology. PTSD's main symptoms include flashbacks or nightmares, repeated re-experiencing symptoms, avoidance of reminiscence stimuli, mental paralysis due to decreased mental activity, and hyperarousal symptoms such as irritability or insomnia. Conventionally, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-noradrenaline reuptake inhibitors (SNRIs) have been the first-line drug for PTSD, with atypical antipsychotics or benzodiazepines being considered second-line drugs. However, these are symptomatic treatments, and no drugs selective for the fear neural circuit have been put to practical use. On the other hand, the ability of opioid δ receptor agonists to promote the extinction of anxiety or fear memory has already been reported for SNC80 and KNT-127 (Non-Patent Documents 4 and 5). Using a contextual fear conditioning test as an animal model, these compounds exhibited anxiolytic effects by extinction of anxiety or fear memory, but only KNT-127 was observed to promote extinction learning of anxiety or fear memory.Furthermore, it has been suggested that the endogenous peptide dynorphin is released from the opioid kappa receptor (sometimes abbreviated as KOR) under stressful circumstances, and that KOR activation contributes to the formation and elimination of aversive memories (Non-Patent Document 6). However, although cognitive behavioral therapy is also used to treat PTSD and other conditions, the therapeutic effect is insufficient and the prognosis is poor, so new treatment methods are needed.

[0003] 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

[0004] Tetrahedron,2011,67,6682-6668European Journal of Pharmacology 276 (1995) 131-135European Journal of Pharmacology 322 (1997) 27-30Neuropharmacology, 160 (2019) 107792Journal of Pharmacological Sciences 139(3) (2019) 174-179Journal of Neuroscience 32(27) (2012) 9335-9343

[0005] An object of the present invention is to provide a medicament useful for treating or preventing stress-related disorders, stress-induced anxiety disorders, or stress-related disorders or anxiety disorders complicated with depression.

[0006] The present inventors have conducted extensive research to achieve the above-mentioned object and have found that a pharmaceutical composition comprising a selective opioid δ receptor agonist as an active ingredient, preferably wherein the selective opioid δ receptor agonist further has opioid μ receptor antagonist activity and opioid κ receptor antagonist activity, is useful for the treatment or prevention of stress-related disorders, stress-induced anxiety disorders, or stress-related disorders or anxiety disorders accompanied by depression, and have completed the present invention. That is, the present invention includes the following aspects.

[0007] [1] A pharmaceutical composition for treating or preventing stress-related disorders, stress-induced anxiety disorders, or stress-related disorders or anxiety disorders complicated with depression, comprising a selective opioid δ receptor agonist as an active ingredient; [2] The pharmaceutical composition for treating or preventing according to [1], wherein the selective opioid δ receptor agonist further has an opioid κ receptor antagonistic effect; [3] The pharmaceutical composition for treating or preventing according to [1] or [2], wherein the selective opioid δ receptor agonist further has an opioid μ receptor antagonistic effect and an opioid κ receptor antagonistic effect; [4] The pharmaceutical composition for treating or preventing according to any one of [1] to [3], wherein the stress-related disorder is acute stress disorder, post-traumatic stress disorder, or adjustment disorder; [5] The pharmaceutical composition for treating or preventing according to any one of [1] to [4], wherein the stress-related disorder is acute stress disorder or post-traumatic stress disorder; [6] A pharmaceutical composition for the treatment or prevention of post-traumatic stress disorder according to [4] or [5], which has an effect of suppressing intrusion symptoms associated with a traumatic event, suppressing persistent avoidance of stimuli associated with the traumatic event, or suppressing negative changes in cognition and mood associated with the traumatic event, which begin after the traumatic event;

[0008] [7] The pharmaceutical composition for treatment or prevention according to [6], wherein the intrusive symptoms related to a traumatic event that begin after the traumatic event are at least one of the following symptoms (1) to (5): (1) recurrent, involuntary, intrusive, and distressing memories of the traumatic event; (2) recurrent and distressing dreams, the content and / or emotions of which are related to the traumatic event; (3) dissociative symptoms, such as feeling or behaving as if the traumatic event is recurring; (4) intense or prolonged psychological distress when exposed to internal or external cues that symbolize or resemble aspects of the traumatic event; and (5) a pronounced physiological response to internal or external cues that symbolize or resemble aspects of the traumatic event; [8] The pharmaceutical composition for treatment or prevention according to any one of [1] to [7], which suppresses flashbacks; [9]

[10] The therapeutic or preventive pharmaceutical composition according to any one of [1] to [9], which suppresses avoidance of traumatic events and related matters;

[11] The therapeutic or preventive pharmaceutical composition according to

[10] , wherein the effect of promoting extinction of memories of traumatic events and / or the effect of inhibiting reconsolidation of memories of traumatic events is the effect of promoting extinction learning of memories of traumatic events;

[12] The therapeutic or preventive pharmaceutical composition according to any one of [1] to

[11] , which alleviates fear from fear memories;

[13] The selective opioid δ receptor agonist is a compound represented by the following general formula (I):

[0009] (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 ３－６cycloalkyl; 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; ２－６represents 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, contains 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 moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; alkylsulfonyl having 1 to 6 carbon atoms in the alkyl moiety; aminosulfonyl; alkylsulfinyl having 1 to 6 carbon atoms in the alkyl moiety; alkylthio having 1 to 6 carbon atoms in the alkyl moiety; C substituted with 1 to 6 halogens １－６ alkoxy; arylcarbonyl having 6 to 10 carbon atoms in the aryl portion; and 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 ６－１０Aryl; 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 moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; 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; 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 １２may 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 the pharmaceutical composition for treatment or prevention according to any one of [1] to

[12] , which is a compound represented by the formula (I), a tautomer, a stereoisomer, a pharmaceutically acceptable salt or a solvate of the compound,

[0010]

[14] The compound represented by the general formula (I) is R １ is C １－１０ The pharmaceutical composition for treatment or prevention according to

[13] , 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;

[15] The pharmaceutical composition for treatment or prevention according to

[13] , 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; or aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; １ is a cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety;

[16] the pharmaceutical composition for treatment or prevention according to

[13] or

[14] , wherein the compound represented by the general formula (I) is 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

[17] The pharmaceutical composition for treatment or prevention according to

[13] , wherein the compound represented by the general formula (I) is a compound represented by the general formula (I) １ is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl;

[18] The pharmaceutical composition for treatment or prevention according to

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

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

[13] to

[17] , wherein the compound represented by the general formula (I) is ２ C substituted with 1 to 3 fluorines １－１０ Alkyl and unsubstituted C １－１０ the pharmaceutical composition for treatment or prevention according to any one of

[13] to

[18] , which is a compound which is pyridine 1-oxide optionally substituted with 1 to 4 substituents selected from alkyl;

[0011]

[20] The compound represented by the general formula (I) is R ２

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

[13] to

[19] , wherein R is pyridine 1-oxide;

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

[13] to

[19] , wherein R is pyridine 1-oxide; ２ C substituted with 1 to 3 fluorines １－１０ Alkyl and unsubstituted C １－１０ The pharmaceutical composition for treatment or prevention according to any one of

[13] to

[18] , wherein the compound represented by the general formula (I) is pyridin-2(1H)-one optionally substituted with 1 to 4 substituents selected from alkyl;

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

[13] to

[18] , wherein the compound represented by the general formula (I) is pyridin-2(1H)-one optionally substituted with 1 to 4 substituents selected from alkyl; ２ is pyridin-2(1H)-one; 1-C １－６ Alkylpyridin-2(1H)-one; or 6-C １－６ The pharmaceutical composition for treatment or prevention according to any one of

[13] to

[18] and

[21] , wherein the compound represented by the general formula (I) is an alkylpyridin-2(1H)-one;

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

[13] to

[18] and

[21] , wherein the compound represented by the general formula (I) is R ２ C substituted with 1 to 3 fluorines １－１０ Alkyl and unsubstituted C １－１０The pharmaceutical composition for treatment or prevention according to any one of

[13] to

[18] , wherein the compound represented by the general formula (I) is pyridin-4(1H)-one optionally substituted with 1 to 4 substituents selected from alkyl;

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

[13] to

[18] , wherein the compound represented by the general formula (I) is pyridin-4(1H)-one optionally substituted with 1 to 4 substituents selected from alkyl; ２ is pyridin-4(1H)-one or 1-C １－６ The pharmaceutical composition for treatment or prevention according to any one of

[13] to

[18] and

[23] , wherein the compound represented by the general formula (I) is an alkylpyridin-4(1H)-one;

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

[13] to

[18] and

[23] , wherein the compound represented by the general formula (I) is R ２ C substituted with 1 to 3 fluorines １－１０ Alkyl and unsubstituted C １－１０ The pharmaceutical composition for treatment or prevention according to any one of

[13] to

[18] , wherein the compound is pyridazin-3(2H)-one optionally substituted with 1 to 3 substituents selected from alkyl;

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

[13] to

[18] , wherein the compound represented by general formula (I) is R ２ the pharmaceutical composition for treatment or prevention according to any one of

[13] to

[18] and

[25] , wherein

[0012]

[27] The compound represented by the general formula (I) is R ２ is C １－１０ C substituted with alkyl and 1 to 3 fluorines １－１０ The pharmaceutical composition for treatment or prevention according to any one of

[13] to

[18] , wherein the compound is pyrazin-2(1H)-one optionally substituted with 1 to 3 substituents selected from alkyl;

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

[13] to

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

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

[13] to

[18] and

[27] , wherein R is a compound represented by general formula (I); ２ C substituted with 1 to 3 fluorines １－１０ Alkyl and unsubstituted C １－１０The pharmaceutical composition for treatment or prevention according to any one of

[13] to

[18] , wherein the compound is 4H-pyran-4-one or 2H-pyran-2-one optionally substituted with 1 to 3 substituents selected from alkyl;

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

[13] to

[18] , wherein the compound represented by the general formula (I) is R ２ The pharmaceutical composition for treatment or prevention according to any one of

[13] to

[18] and

[29] , wherein R is 4H-pyran-4-one or 2H-pyran-2-one;

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

[13] to

[18] and

[29] , wherein R is 4H-pyran-4-one or 2H-pyran-2-one; ２ C substituted with 1 to 3 fluorines １－１０ Alkyl and unsubstituted C １－１０ The pharmaceutical composition for treatment or prevention according to any one of

[13] to

[18] , wherein the compound is quinolin-2(1H)-one optionally substituted with 1 to 3 substituents selected from alkyl;

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

[13] to

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

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

[13] to

[18] and

[31] , wherein the compound represented by general formula (I) is R ２ C substituted with 1 to 3 fluorines １－１０ Alkyl and unsubstituted C １－１０ The pharmaceutical composition for treatment or prevention according to any one of

[13] to

[18] , wherein the compound is pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione, optionally substituted with 1 to 3 substituents selected from alkyl;

[0013]

[34] The compound represented by the general formula (I) is R ２ The pharmaceutical composition for treatment or prevention according to any one of

[13] to

[18] and

[33] , wherein X is pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione;

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

[13] to

[18] and

[33] , wherein X is CH ２

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

[13] to

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

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

[13] to

[35] , wherein one of the groups is hydroxy and the other is hydrogen;

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

[13] to

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

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

[13] to

[35] , wherein the compound represented by the general formula (I) is a compound represented by R ３ is hydroxy; carbamoyl; or C １－６ Alkanoyloxy, R ４ is hydrogen, and R ５

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

[13] to

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

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

[13] to

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

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

[13] to

[35] , wherein the compound represented by the general formula (I) is a compound in which R ６ａ , R ６ｂ , R ７ , R ８ , R ９ and R １０ the pharmaceutical composition for treatment or prevention according to any one of

[13] to

[40] , wherein all of

[0014]

[42] The compound represented by the general formula (I) is R ５ , R ６ａ , R ６ｂ , R ７ , R ８ , R ９ and R １０is 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, R 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 in which the acyl moiety has 2 to 6 carbon atoms, and 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 substituted with 1 to 6 halogen; hydroxy; C 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 moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; alkylsulfonyl having 1 to 6 carbon atoms in the alkyl moiety; aminosulfonyl; alkylsulfinyl having 1 to 6 carbon atoms in the alkyl moiety; alkylthio having 1 to 6 carbon atoms in the alkyl moiety; C substituted with 1 to 6 halogens １－６ alkoxy; arylcarbonyl having 6 to 10 carbon atoms in the aryl portion; and １ an aralkyl aryl moiety in which the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; 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 moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; 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; 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 pharmaceutical composition for treatment or prevention according to

[13] , which is a compound optionally substituted with at least one substituent selected from alkyl;

[0015]

[43] The compound represented by the general formula (I) is R １ is C １－６ The pharmaceutical composition for treatment or prevention according to

[13] or

[42] , 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;

[44] The pharmaceutical composition for treatment or prevention according to

[13] or

[42] , 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 is a cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety;

[45] the pharmaceutical composition for treatment or prevention according to

[13] ,

[42] , or

[43] , wherein the compound represented by general formula (I) is 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

[46] The pharmaceutical composition for treatment or prevention according to

[13] or

[42] , wherein the compound represented by the general formula (I) is R １ is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl;

[47] The pharmaceutical composition for treatment or prevention according to

[13] or

[42] , wherein the compound represented by general formula (I) is ２ C substituted with 1 to 3 fluorines１－１０ Alkyl and unsubstituted C １－１０ The pharmaceutical composition for treatment or prevention according to any one of

[13] and

[42] to

[46] , wherein the compound represented by general formula (I) is pyridine 1-oxide, pyridin-2(1H)-one, pyridin-4(1H)-one, pyridazin-3(2H)-one, pyrazin-2(1H)-one, 4H-pyran-4-one, 2H-pyran-2-one, quinolin-2(1H)-one, pyrimidin-4(3H)-one, or pyrimidin-2,4(1H,3H)-dione, each of which may be substituted by a substituent selected from alkyl;

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

[13] and

[42] to

[46] , wherein the compound represented by general formula (I) is ２ is C １－１０ C substituted with alkyl and 1 to 3 fluorines １－１０ the pharmaceutical composition for treatment or prevention according to any one of

[13] and

[42] to

[47] , which is a compound which is pyridine 1-oxide optionally substituted with 1 to 4 substituents selected from alkyl;

[0016]

[49] The compound represented by the general formula (I) is R ２ The pharmaceutical composition for treatment or prevention according to any one of

[13] and

[42] to

[48] , wherein R is pyridine 1-oxide;

[50] The compound represented by the general formula (I) ２ is C １－１０ C substituted with alkyl and 1 to 3 fluorines １－１０ The pharmaceutical composition for treatment or prevention according to any one of

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is pyridin-2(1H)-one optionally substituted with 1 to 4 substituents selected from alkyl;

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

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is R ２ is pyridin-2(1H)-one; 1-C １－６ Alkylpyridin-2(1H)-one; or 6-C １－６ The pharmaceutical composition for treatment or prevention according to any one of

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is an alkylpyridin-2(1H)-one;

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

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is R ２ C substituted with 1 to 3 fluorines １－１０ Alkyl and unsubstituted C１－１０ The pharmaceutical composition for treatment or prevention according to any one of

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is pyridin-4(1H)-one optionally substituted with 1 to 4 substituents selected from alkyl;

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

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is R ２ is pyridin-4(1H)-one or 1-C １－６ The pharmaceutical composition for treatment or prevention according to any one of

[13] ,

[42] to

[47] and

[52] , wherein the compound represented by the general formula (I) is an alkylpyridin-4(1H)-one;

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

[13] ,

[42] to

[47] and

[52] , wherein the compound represented by the general formula (I) is R ２ C substituted with 1 to 3 fluorines １－１０ Alkyl and unsubstituted C １－１０ The pharmaceutical composition for treatment or prevention according to any one of

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is pyridazin-3(2H)-one optionally substituted with 1 to 3 substituents selected from alkyl;

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

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is R ２ The pharmaceutical composition for treatment or prevention according to any one of

[13] ,

[42] to

[47] and

[54] , wherein R is pyridazin-3(2H)-one;

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

[13] ,

[42] to

[47] and

[54] , wherein R is pyridazin-3(2H)-one; ２ C substituted with 1 to 3 fluorines １－１０ Alkyl and unsubstituted C １－１０ The pharmaceutical composition for treatment or prevention according to any one of

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is pyrazin-2(1H)-one optionally substituted with 1 to 3 substituents selected from alkyl;

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

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is R ２ the pharmaceutical composition for treatment or prevention according to any one of

[13] ,

[42] to

[47] , and

[56] , wherein

[0017]

[58] The compound represented by the general formula (I) is R ２ C substituted with 1 to 3 fluorines １－１０ Alkyl and unsubstituted C １－１０The pharmaceutical composition for treatment or prevention according to any one of

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is 4H-pyran-4-one or 2H-pyran-2-one, optionally substituted with 1 to 3 substituents selected from alkyl;

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

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is R ２ The pharmaceutical composition for treatment or prevention according to any one of

[13] ,

[42] to

[47] and

[58] , wherein R is 4H-pyran-4-one or 2H-pyran-2-one;

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

[13] ,

[42] to

[47] and

[58] , wherein R is 4H-pyran-4-one or 2H-pyran-2-one; ２ C substituted with 1 to 3 fluorines １－１０ Alkyl and unsubstituted C １－１０ The pharmaceutical composition for treatment or prevention according to any one of

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is quinolin-2(1H)-one optionally substituted with 1 to 3 substituents selected from alkyl;

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

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is ２ The pharmaceutical composition for treatment or prevention according to any one of

[13] ,

[42] to

[47] and

[60] , wherein R is quinolin-2(1H)-one;

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

[13] ,

[42] to

[47] and

[60] , wherein R is quinolin-2(1H)-one; ２ C substituted with 1 to 3 fluorines １－１０ Alkyl and unsubstituted C １－１０ The pharmaceutical composition for treatment or prevention according to any one of

[13] and

[42] to

[47] , wherein the compound is pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione, optionally substituted with 1 to 3 substituents selected from alkyl;

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

[13] and

[42] to

[47] , wherein the compound represented by the general formula (I) is ２ the pharmaceutical composition for treatment or prevention according to any one of

[13] ,

[42] to

[47] and

[62] , wherein

[0018]

[64] The compound represented by the general formula (I) is R ３ and R ４

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

[13] and

[42] to

[63] , wherein one of the groups is hydroxy and the other is hydrogen;

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

[13] and

[42] to

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

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

[13] and

[42] to

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

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

[13] and

[42] to

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

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

[13] and

[42] to

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

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

[13] and

[42] to

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

[0019] (In the formula, R １ is hydrogen; C １－６ alkyl; or cycloalkylalkyl, where the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; 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 ２is 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 or 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 the group consisting of 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 moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; 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, 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 moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; halogen; nitro; cyano; C substituted with 1 to 3 halogens １－６ Alkyl; C substituted with 1 to 3 halogens １－６the 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 group, and methylenedioxy);

[70] the compound represented by the 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 group, and methylenedioxy); １ is a cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety;

[71] The pharmaceutical composition for treatment or prevention according to

[69] , wherein the compound represented by the general formula (II) is ２ is represented by formula (III):

[0020] ;Formula (IV):

[0021] ;Formula (V):

[0022] or formula (VI):

[0023] (In Formulas III to VI, R ａ is hydrogen or C １－６

[72] The pharmaceutical composition for treatment or prevention according to

[69] or

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

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

[69] to

[71] , wherein the compound represented by the general formula (II) is R ４ the pharmaceutical composition for treatment or prevention according to any one of

[69] to

[72] , wherein R is a compound in which R is hydrogen;

[0024]

[74] 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)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,The pharmaceutical composition for treatment or prevention according to

[13] , which is at least one compound selected from 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;

[0025]

[75] The compound represented by the general formula (I) is 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, 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, 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, 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 and The pharmaceutical composition for treatment or prevention according to

[13] , wherein the compound is at least one compound selected from 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; or

[0026]

[76] 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

[13] and

[69] to

[73] , wherein the pharmaceutical composition 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.

[0027] The present invention also has the following aspects. <1> A pharmaceutical composition for treating or preventing stress-related disorders, stress-induced anxiety disorders, or stress-related disorders or anxiety disorders complicated with depression, comprising a selective opioid δ receptor agonist as an active ingredient; <2> The pharmaceutical composition for treating or preventing stress-related disorders or stress-induced anxiety disorders, or stress-related disorders or anxiety disorders complicated with depression, comprising a selective opioid δ receptor agonist as an active ingredient; <3> The pharmaceutical composition for treating or preventing stress-related disorders according to <1> or <2>, wherein the selective opioid δ receptor agonist further has an opioid κ receptor antagonistic action; <4> The pharmaceutical composition for treating or preventing stress-related disorders according to any one of <1> to <3>, wherein the stress-related disorder is acute stress disorder, post-traumatic stress disorder, or adjustment disorder; <5> The pharmaceutical composition for treating or preventing stress-related disorders according to any one of <1> to <4>, wherein the stress-related disorder is acute stress disorder or post-traumatic stress disorder; <6> <7> A pharmaceutical composition for treating or preventing post-traumatic stress disorder according to <4> or <5>, which has an effect of suppressing intrusion symptoms associated with a traumatic event, suppressing persistent avoidance of stimuli associated with the traumatic event, or suppressing negative changes in cognition and mood associated with the traumatic event, which begin after the traumatic event; <7> A pharmaceutical composition for treating or preventing post-traumatic stress disorder according to <6>, wherein the intrusion symptoms associated with the traumatic event, which begin after the traumatic event, are at least one of the following symptoms (1) to (5): (1) recurrent, involuntary, intrusive, and distressing memories of the traumatic event; (2) recurrent and distressing dreams, the content and / or emotions of which are related to the traumatic event; (3) dissociative symptoms, in which the patient feels as if the traumatic event is happening again or behaves in such a way; (4) Intense or prolonged psychological distress when exposed to internal or external cues that represent or resemble aspects of the traumatic event; and (5) A pronounced physiological response to internal or external cues that represent or resemble aspects of the traumatic event; <8> The therapeutic or preventive pharmaceutical composition according to any one of <1> to <7>, which suppresses flashbacks;<9> The therapeutic or preventive pharmaceutical composition according to any one of <1> to <8>, which suppresses avoidance of traumatic events and related matters; <10> The therapeutic or preventive pharmaceutical composition according to any one of <1> to <9>, which has an effect of promoting the extinction of memories of traumatic events and / or an effect of inhibiting the reconsolidation of memories of traumatic events; <11> The therapeutic or preventive pharmaceutical composition according to <10>, wherein the effect of promoting the extinction of memories of traumatic events is an effect of promoting extinction learning of memories of traumatic events; <12> The therapeutic or preventive pharmaceutical composition according to any one of <1> to <11>, which alleviates fear caused by fear memories; <13> The selective opioid δ receptor agonist is represented by the following general formula (I):

[0028] (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 １－６Alkanoyloxy; 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, contains 1 to 6 halogen atoms; hydroxy; C 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 moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; alkylsulfonyl having 1 to 6 carbon atoms in the alkyl moiety; aminosulfonyl; alkylsulfinyl having 1 to 6 carbon atoms in the alkyl moiety; alkylthio having 1 to 6 carbon atoms in the alkyl moiety; C substituted with 1 to 6 halogens １－６ alkoxy; arylcarbonyl having 6 to 10 carbon atoms in the aryl portion; and 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 moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; 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; 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 The pharmaceutical composition for treatment or prevention according to any one of <1> to <12>, which is a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof;

[0029] <14> 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; C１－６ 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, R 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 in which the acyl moiety has 2 to 6 carbon atoms, and 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 substituted with 1 to 6 halogen; hydroxy; C 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 moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; alkylsulfonyl having 1 to 6 carbon atoms in the alkyl moiety; aminosulfonyl; alkylsulfinyl having 1 to 6 carbon atoms in the alkyl moiety; alkylthio having 1 to 6 carbon atoms in the alkyl moiety; C substituted with 1 to 6 halogens １－６ alkoxy; arylcarbonyl having 6 to 10 carbon atoms in the aryl portion; and １ an aralkyl aryl moiety in which the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; 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 moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; 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; 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 pharmaceutical composition for treatment or prevention according to <13>, which is a compound optionally substituted with at least one substituent selected from alkyl;

[0030] <15> The compound represented by the general formula (I) is R １ is C １－６ <16> The pharmaceutical composition for treatment or prevention according to <13> or <14>, 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; <17> The pharmaceutical composition for treatment or prevention according to <17> or <18>, 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 <17> The pharmaceutical composition for treatment or prevention according to any one of <13> to <15>, wherein R is a compound represented by general 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 <18> The pharmaceutical composition for treatment or prevention according to <13> or <14>, wherein the compound represented by the general formula (I) is R １ The pharmaceutical composition for treatment or prevention according to <13> or <14>, wherein is a compound in which R is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl;

[0031] <19> The compound represented by the general formula (I) is R ２is 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 pyridine 1-oxide; <20> The pharmaceutical composition for treatment or prevention according to any one of <13> to <18>, wherein R ２ <21> The pharmaceutical composition for treatment or prevention according to any one of <13> to <19>, wherein R is pyridine 1-oxide; <22> The pharmaceutical composition for treatment or prevention according to any one of <13> to <19>, wherein R is pyridine 1-oxide; ２ <22> The pharmaceutical composition for treatment or prevention according to any one of <13> to <19>, wherein the compound represented by general formula (I) is a compound represented by the formula R ２ <23> The pharmaceutical composition for treatment or prevention according to any one of <13> to <19>, wherein the compound represented by general formula (I) is a compound represented by the formula R ２ <24> The pharmaceutical composition for treatment or prevention according to any one of <13> to <19>, wherein the compound represented by general formula (I) is a compound represented by the formula R ２ <25> The pharmaceutical composition for treatment or prevention according to any one of <13> to <19>, wherein the compound represented by general formula (I) is a compound represented by the formula R ２ <26> The pharmaceutical composition for treatment or prevention according to any one of <13> to <19>, wherein the compound represented by general formula (I) is a compound represented by the formula R ２ <27> The pharmaceutical composition for treatment or prevention according to any one of <13> to <19>, wherein the compound represented by general formula (I) is a compound represented by the formula R ２The pharmaceutical composition for treatment or prevention according to any one of <13> to <19>, wherein the heterocycle is pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione;

[0032] <28> The compound represented by the general formula (I) is ２ <29> The pharmaceutical composition for treatment or prevention according to any one of <13> and <15> to <27>, wherein the compound represented by general formula (I) is ３ and R ４ <30> The pharmaceutical composition for treatment or prevention according to any one of <13> to <28>, wherein one of R is hydroxy and the other is hydrogen; <31> The pharmaceutical composition for treatment or prevention according to any one of <13> to <28>, wherein the compound represented by the general formula (I) is ３ is halogen; cyano; carbamoyl; C １－６ Alkoxy; C １－６ alkanoyloxy; amino; or acylamino, where the acyl moiety has 2 to 6 carbon atoms; ４ is hydrogen or hydroxy, and R ５ <31> The pharmaceutical composition for treatment or prevention according to any one of <13> and <15> to <28>, wherein the compound represented by the general formula (I) is a compound represented by R ３ is hydroxy; carbamoyl; or C １－６ Alkanoyloxy, R ４ is hydrogen, and R ５ <32> The pharmaceutical composition for treatment or prevention according to any one of <13> and <15> to <28>, wherein the compound represented by the general formula (I) is a compound represented by R ３ is hydroxy and R ４ is hydrogen, and R ５ <33> The pharmaceutical composition for treatment or prevention according to any one of <13> and <15> to <28>, wherein the compound represented by the general formula (I) is a compound represented by R ３ , R ４ and R ５ The pharmaceutical composition for treatment or prevention according to any one of <13> and <15> to <28>, wherein all of

[0033] <34> The compound represented by the general formula (I) is R ６ａ , R ６ｂ , R ７ , R ８ , R ９ and R １０ <35> The pharmaceutical composition for treatment or prevention according to any one of <13> and <15> to <33>, wherein the compound represented by the 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, where the acyl moiety has 2 to 6 carbon atoms; ４ <36> The pharmaceutical composition for treatment or prevention according to any one of <14> to <28>, wherein the compound represented by the general formula (I) is a compound represented by R ３ is hydroxy; carbamoyl; or C １－６ Alkanoyloxy, R ４ <37> The pharmaceutical composition for treatment or prevention according to any one of <14> to <28>, wherein the compound represented by the general formula (I) is a compound represented by R ３ is hydroxy and R ４ <38> The pharmaceutical composition for treatment or prevention according to any one of <14> to <28>, wherein R is hydrogen; <39> The pharmaceutical composition for treatment or prevention according to any one of <16> to <28>, wherein R is hydrogen; ３ and R ４ <39> The pharmaceutical composition for treatment or prevention according to any one of <14> to <28>, wherein the compound represented by general formula (I) is a compound represented by the following general formula (II):

[0034] (In the formula, R １ is hydrogen; C １－６ alkyl; or cycloalkylalkyl, where the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; R ２represents 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 or 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 the group consisting of 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 moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; 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, ２ The pyridine 1-oxide of C １－６ Alkyl; C １－６ Alkoxy; C １－６Alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; halogen; nitro; cyano; C substituted with 1 to 3 halogens １－６ Alkyl; C substituted with 1 to 3 halogens １－６ the pharmaceutical composition for treatment or prevention according to <13>, which is a compound 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 having 1 to 3 carbon atoms in the alkyl; and methylenedioxy;

[0035] <40> The compound represented by the general formula (II) 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; <41> The pharmaceutical composition for treatment or prevention according to <39>, wherein the compound represented by the general formula (II) is ２ is represented by formula (III):

[0036] ;Formula (IV):

[0037] ;Formula (V):

[0038] or formula (VI):

[0039] (In Formulas III to VI, R ａ is hydrogen or C １－６ <42> The pharmaceutical composition for treatment or prevention according to <39> or <40>, wherein the compound represented by the general formula (II) is R ３ <43> The pharmaceutical composition for treatment or prevention according to any one of <39> to <41>, wherein the compound represented by the general formula (II) is R ４The pharmaceutical composition for treatment or prevention according to any one of <39> to <42>, wherein is a compound in which

[0040] <44> 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)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,The pharmaceutical composition for treatment or prevention according to <13>, which is at least one compound selected from 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; or

[0041] <45> 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 <13> and <39> to <43>, which 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.

[0042] The present invention provides a medicament useful for treating or preventing stress-related disorders, stress-induced anxiety disorders, or stress-related disorders or anxiety disorders complicated with depression.

[0043] Figure 1 shows the results of a test on the mechanism of action of emotion regulation for the compound of Example 7. Figure 2 shows the effect of the compound of Example 7 on the reconsolidation of fear memory. Figure 3 shows the effect of the compound of Example 7 on the reconsolidation of fear memory.

[0044] The present invention will now be described in more detail. As used herein, the term "opioid δ receptor agonist" refers to a substance that binds to an opioid δ receptor and thereby induces a biological response similar to or similar to that of an endogenous ligand. The term "selective opioid δ receptor agonist" refers to a substance that has a relatively stronger opioid δ receptor agonist effect than the opioid μ receptor agonist effect and the opioid κ receptor agonist effect. Among these, a substance that has an opioid δ receptor agonist effect and has very weak or no opioid μ receptor agonist effect and opioid κ receptor agonist effect is preferred. Furthermore, a substance that has an opioid δ receptor agonist effect, does not have an opioid μ receptor agonist effect and an opioid κ receptor agonist effect, and has an opioid κ receptor antagonist effect is preferred. Furthermore, it is preferable that the substance has an opioid δ receptor agonistic effect, but does not have an opioid μ receptor agonistic effect or an opioid κ receptor agonistic effect, and has an opioid μ receptor antagonistic effect and an opioid κ receptor antagonistic effect. Here, "opioid μ receptor antagonist" or "opioid κ receptor antagonist" means a substance that binds to the opioid μ receptor or the opioid κ receptor but does not induce a biological response, unlike endogenous ligands, and that inhibits the binding of the endogenous ligand to the receptor by the binding, thereby not inducing a biological response of the endogenous ligand.

[0045] "Stress-related disorders" are mental disorders primarily caused by acute or chronic psychosocial stress, and examples include acute stress disorder, post-traumatic stress disorder, and adjustment disorder. Here, the symptoms and diagnostic criteria for "acute stress disorder (also known as acute stress reaction)," "post-traumatic stress disorder," and "adjustment disorder" can be based on the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (sometimes abbreviated as DSM-5). Therefore, for example, post-traumatic stress disorder (sometimes abbreviated as PTSD) can be diagnosed in comparison with the following items A to H: A. Exposure to an event resulting in actual or threatened death, serious injury, or sexual violence, in any one (or more) of the following ways: (1) Directly experiencing the traumatic event; (2) Directly witnessing the event happening to another person; or (3) Hearing about a traumatic event happening to a close relative or close friend. If the event involved the actual or near death of a family member or friend, it must have been violent or accidental. (4) Experiencing repeated or extreme exposure to intensely disturbing details of the traumatic event (e.g., emergency responders collecting a body, police officers repeatedly exposed to details of child abuse).

[0046] B. The presence of one (or more) of the following intrusive symptoms related to the traumatic event, beginning after the traumatic event: (1) recurrent, involuntary, intrusive, and distressing memories of the traumatic event; (2) recurrent and distressing dreams, the content and / or emotions of which are related to the traumatic event; (3) dissociative symptoms (e.g., flashbacks) in which the individual feels or acts as if the traumatic event is recurring (these reactions occur on a continuum and, in extreme cases, may manifest as a complete loss of awareness of the reality of the situation); (4) intense or prolonged psychological distress when exposed to internal or external cues that symbolize or resemble aspects of the traumatic event; or (5) pronounced physiological responses to internal or external cues that symbolize or resemble aspects of the traumatic event.

[0047] C. Persistent avoidance of stimuli associated with the traumatic event. Beginning after the traumatic event and manifested by one or both of the following: (1) Avoidance or efforts to avoid distressing memories, thoughts, or feelings about or closely related to the traumatic event; or (2) Avoidance or efforts to avoid things (people, places, conversations, activities, objects, situations) associated with evoking distressing memories, thoughts, or feelings about or closely related to the traumatic event.

[0048] D. Negative changes in cognition and mood related to the traumatic event. These occur or worsen after the traumatic event and are manifested by any two (or more) of the following: (1) Inability to recall important aspects of the traumatic event (usually due to dissociative amnesia and not due to other factors such as head injury, alcohol, or drugs); (2) Persistent, excessively negative beliefs or expectations about oneself, others, or the world (e.g., "It's my fault," "No one can be trusted," "The world is completely dangerous," "My entire nervous system is permanently destroyed"); (3) Persistent, distorted perceptions of the causes and consequences of the traumatic event that lead to blame of oneself or others; (4) Persistent negative emotional states (e.g., fear, horror, anger, guilt, or shame); (5) Markedly reduced interest in or participation in important activities; (6) Feeling isolated or estranged from others; (7) Persistent inability to experience positive emotions (e.g., inability to feel happiness, contentment, or love).

[0049] E. Marked changes in arousal and reactivity associated with the traumatic event, which may develop or worsen after the traumatic event and are manifested by any two (or more) of the following: (1) Irritability and intense anger (with little or no provocation), usually manifested by verbal or physical aggression toward people or objects; (2) Reckless or self-destructive behavior; (3) Hypervigilance; (4) Exaggerated startle response; (5) Difficulty concentrating; or (6) Sleep disturbances (e.g., difficulty falling or staying asleep, or light sleep).

[0050] F. The disturbance (Criteria B, C, D, and E) persists for more than one month. G. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. H. The disturbance is not due to the physiological effects of a substance (e.g., drugs or alcohol) or another medical illness. Acute stress disorder is a transient disorder whose clinical symptoms are essentially the same as those of post-traumatic stress disorder, but do not persist for more than one month. For example, to be diagnosed with acute stress disorder, a person must have been directly or indirectly exposed to a traumatic event and experience any of the following symptoms: 1) recurrent, involuntary, intrusive, and distressing memories of the traumatic event; 2) recurrent, distressing dreams about the traumatic event; 3) dissociative reactions (e.g., flashbacks) that make it seem as if the traumatic event is happening again; 4) intense psychological or physiological distress when remembering the event (e.g., due to the anniversary, sounds similar to those heard at the time of the event); 5) a persistent inability to experience positive emotions (e.g., happiness, contentment, love); 6) an altered sense of reality (e.g., feeling spaced out, time slowing, changes in perspective); 7) an inability to recall significant parts of the traumatic event; 8) efforts to avoid distressing memories, thoughts, or feelings associated with the traumatic event; or 9) efforts to avoid external reminders (people, places, conversations, activities, objects, situations) associated with the traumatic event. At least nine of the following must be present for at least three days up to one month: 10) Sleep disturbances, 11) Irritability or outbursts of anger, 12) Hypervigilance, 13) Difficulty concentrating, and 14) Excessive startle response. Furthermore, the symptoms must be causing significant distress or significantly interfering with social or occupational functioning, and not be caused by the physiological effects of substances or other physical illnesses. Adjustment disorder is a condition in which a person is unable to cope well with the various stresses that arise in life, resulting in mental symptoms such as depression and anxiety that interfere with daily life.For example, to be diagnosed with adjustment disorder, all of the following criteria A to E must be met: A. Symptoms appear within three months of the onset of stress due to a clear stressor. B. Symptoms are accompanied by evidence of at least one of the following: - Symptoms or distress are disproportionate to the stressor - Significant impairment of functioning in important areas of life, such as social or occupational functioning. C. The symptoms cannot be explained by another psychiatric disorder. D. The symptoms cannot be explained by a normal bereavement response. E. Once the stressor or its consequences have ended, the symptoms do not persist for more than six months. The pharmaceutical composition of the present invention may be useful for suppressing symptoms of B above. The pharmaceutical composition of the present invention can suppress flashbacks. For example, flashbacks are suppressed by administering the pharmaceutical composition of the present invention to patients with acute stress disorder or post-traumatic stress disorder. The pharmaceutical composition of the present invention can suppress avoidance of traumatic events and related events. For example, administering the pharmaceutical composition of the present invention to a patient suffering from acute stress disorder or post-traumatic stress disorder suppresses the patient's tendency to avoid traumatic events or related events. One aspect of the present invention is the above-described pharmaceutical composition for treatment or prevention, which has the effect of promoting the extinction of memories of traumatic events or inhibiting the reconsolidation of memories of traumatic events. Here, reconsolidation of memories of traumatic events refers to a process in which once formed memories of traumatic events are stabilized or strengthened by re-exposure to the traumatic event, similar to extinction learning.

[0051] 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.

[0052] In this specification, C １－６Examples 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 halogens １－６ Examples of alkyl include 2-chloroethyl, 2-fluoroethyl, 3-fluoropropyl, 2,2-difluoroethyl, trifluoromethyl, and 3,3,3-trifluoropropyl. ２－６ Examples 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 in which the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms include benzyl and phenethyl groups. ３－６ Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. ６－１０Examples of aryl include phenyl and naphthyl. Examples of heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms include pyridyl, furyl, imidazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl and thiazolyl. Heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms, and heteroarylalkyl having 1 to 5 carbon atoms in the alkylene portion includes (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.

[0053] 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. ６－１０Examples 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 having 1 to 6 carbon atoms in the alkyl moiety include ethylcarbamoyl. Examples of dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety include diethylcarbamoyl. Examples of alkylsulfonyl having 1 to 6 carbon atoms in the alkyl moiety include methylsulfonyl. Examples of alkylsulfinyl having 1 to 6 carbon atoms in the alkyl moiety include methylsulfinyl. Examples of alkylthio having 1 to 6 carbon atoms in the alkyl moiety include methylthio. Examples of arylcarbonyl having 6 to 10 carbon atoms in the aryl moiety include benzoyl. R １１ and R １２ And, R １１ and R １２ Examples of the 5- to 7-membered ring which may be formed by combining the nitrogen atom to which is bonded and, if desired, one or two heteroatoms include pyrrolidine, piperidine, and morpholine.

[0054] 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, (B) a C substituted with 1 to 3 fluorines, such as pyridine 1-oxide and 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, 2-methylpyridazin-3(2H)-one, and the like, which may be substituted by 1 to 4 substituents selected from alkyl; １－１０ Alkyl and unsubstituted C １－１０ (E) C pyridazin-3(2H)-one, which may be substituted by 1 to 3 substituents selected from alkyl, such as pyrazin-2(1H)-one and 1-methylpyrazin-2(1H)-one, which may be substituted by 1 to 3 fluorines. １－１０ Alkyl and unsubstituted C １－１０ (F) C alkyl groups substituted with 1 to 3 fluorines, such as 4H-pyran-4-one, 3-methyl-4H-pyran-4-one, 2H-pyran-2-one, and 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, 4-methylquinolin-1-oxide, etc. １－１０Alkyl and unsubstituted C １－１０ C substituted with 1 to 3 fluorines, such as quinolin-2(1H)-one, quinolin-1-oxide, (H)pyrimidin-4(3H)-one, and pyrimidine-2,4(1H,3H)-dione, which may be substituted with 1 to 3 substituents selected from alkyl; １－１０ Alkyl and unsubstituted C １－１０ Examples thereof include pyrimidin-4(3H)-one and pyrimidin-2,4(1H,3H)-dione, each of which may be substituted with 1 to 3 substituents selected from alkyl.

[0055] The tautomers of the compound represented by the general formula (I) include the above 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, and 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 are 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, cilexityl group, etc. Furthermore, the compound represented by the above general formula (I), a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof may be substituted with a stable isotope such as deuterium.

[0056] 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.

[0057] The compound represented by the general formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts, or solvates thereof exhibit superior agonist activity and selectivity for the opioid δ receptor compared to the 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 in pharmaceutical compositions that exhibit selective opioid δ receptor agonism. 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 in pharmaceutical compositions for oral administration.

[0058] 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, and intrathecal administration. The pharmaceutical compositions provided by the present invention may be prepared by mixing the selective opioid δ receptor agonist, or the compound represented by the 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, glucose), a binder (e.g., hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), a lubricant (e.g., magnesium stearate, talc), a disintegrant (e.g., starch, carboxymethylcellulose calcium (CMC-Ca)), a diluent (e.g., water for injection, physiological saline), and, if necessary, an additive (e.g., pH adjuster, surfactant, solubilizer, preservative, emulsifier, isotonic agent, 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, glucose), a disintegrant (e.g., starch, carboxymethylcellulose calcium (CMC-Ca)), a binder (e.g., hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), a lubricant (e.g., magnesium stearate, talc), etc. 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, propylparaben), an isotonicity agent (e.g., sodium chloride, mannitol, sorbitol, glucose), a pH adjuster (e.g., sodium phosphate, potassium phosphate), or the like to be formulated.

[0059] The pharmaceutical composition provided by the present invention may comprise a compound represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt or solvate thereof, in an amount effective for the treatment or prevention of a stress-related disorder, a stress-induced anxiety disorder, or a stress-related disorder or anxiety disorder complicated with depression. In one embodiment, the pharmaceutical composition provided by the present invention may comprise a compound represented by the above general formula (I), a pharmaceutically acceptable solvate (e.g., hydrate) thereof, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate (e.g., hydrate) thereof, in an amount effective for the treatment or prevention of a stress-related disorder, a stress-induced anxiety disorder, or a stress-related disorder or anxiety disorder complicated with depression. In one embodiment, the pharmaceutical composition provided by the present invention may comprise a compound represented by the above general formula (I), or a pharmaceutically acceptable salt of the compound, in an amount effective for the treatment or prevention of a stress-related disorder, a stress-induced anxiety disorder, or a stress-related disorder or anxiety disorder complicated with depression.

[0060] 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.

[0061] The present invention also has the following aspects. <1a> A method for treating or preventing stress-related disorders, stress-induced anxiety disorders, or stress-related disorders or anxiety disorders complicated with depression, the method comprising administering a therapeutically effective amount of a selective opioid δ receptor agonist to a subject in need thereof (e.g., a mammal including a human); <2a> The method according to <1a>, wherein the selective opioid δ receptor agonist further has an opioid κ receptor antagonistic action; <3a> The method according to <1a> or <2a>, wherein the selective opioid δ receptor agonist further has an opioid μ receptor antagonistic action and an opioid κ receptor antagonistic action; <4a> The method according to any one of <1a> to <3a>, wherein the stress-related disorder is acute stress disorder, post-traumatic stress disorder, or adjustment disorder; <5a> The method according to any one of <1a> to <4a>, wherein the stress-related disorder is acute stress disorder or post-traumatic stress disorder; <6a> The method according to <4a> or <5a>, which is a method for treating or preventing post-traumatic stress disorder, comprising suppressing intrusion symptoms associated with a traumatic event, suppressing persistent avoidance of stimuli associated with the traumatic event, or suppressing negative changes in cognition and mood associated with the traumatic event, which begin after the traumatic event; <7a> The method according to <6a>, in which the intrusion symptoms associated with the traumatic event, which begin after the traumatic event, are at least one of the following symptoms (1) to (5): (1) recurrent, involuntary, intrusive, and distressing memories of the traumatic event; (2) recurrent and distressing dreams, the content and / or emotions of which are related to the traumatic event; (3) dissociative symptoms, in which the patient feels or behaves as if the traumatic event is happening again; (4) Intense or prolonged psychological distress when exposed to internal or external cues that represent or resemble aspects of the traumatic event; and (5) A pronounced physiological response to internal or external cues that represent or resemble aspects of the traumatic event; <8a> A method according to any one of <1a> to <7a>, which suppresses flashbacks;<9a> The method according to any one of <1a> to <8a>, which suppresses avoidance of traumatic events and related matters; <10a> The method according to any one of <1a> to <9a>, which comprises promoting the extinction of memories of traumatic events and / or inhibiting the reconsolidation of memories of traumatic events; <11a> The method according to <10a>, wherein promoting the extinction of memories of traumatic events is promoting extinction learning of memories of traumatic events; <12a> The method according to any one of <1a> to <11a>, which comprises alleviating fear from fear memories;

[0062] <1b> A selective opioid δ receptor agonist for use in the treatment or prevention of stress-related disorder, stress-induced anxiety disorder, or stress-related disorder or anxiety disorder complicated with depression; <2b> A selective opioid δ receptor agonist for use according to <1b>, wherein the selective opioid δ receptor agonist further has an opioid κ receptor antagonistic effect; <3b> A selective opioid δ receptor agonist for use according to <1b> or <2b>, wherein the selective opioid δ receptor agonist further has an opioid μ receptor antagonistic effect and an opioid κ receptor antagonistic effect; <4b> A selective opioid δ receptor agonist for use according to any one of <1b> to <3b>, wherein the stress-related disorder is acute stress disorder, post-traumatic stress disorder, or adjustment disorder; <5b> The selective opioid δ receptor agonist for use according to any one of <1b> to <4b>, wherein the stress-related disorder is acute stress disorder or post-traumatic stress disorder; <6b> The selective opioid δ receptor agonist for use according to <4b> or <5b>, for use in the treatment or prevention of post-traumatic stress disorder, comprising suppressing intrusion symptoms associated with a traumatic event, suppressing persistent avoidance of stimuli associated with the traumatic event, or suppressing negative changes in cognition and mood associated with the traumatic event, which begin after the traumatic event; <7b> The selective opioid δ receptor agonist for use according to <6b>, wherein the intrusion symptoms associated with the traumatic event, which begin after the traumatic event, are at least one of the following symptoms (1) to (5): (1) recurrent, involuntary, intrusive and distressing memories of the traumatic event; (2) recurrent and distressing dreams in which the content and / or emotions are related to the traumatic event; (3) dissociative symptoms in which the person feels or acts as if the traumatic event is recurring; (4) intense or prolonged psychological distress when exposed to internal or external cues that symbolize or resemble aspects of the traumatic event; and (5) marked physiological responses to internal or external cues that symbolize or resemble aspects of the traumatic event;<8b> A selective opioid δ receptor agonist for use according to any one of <1b> to <7b>, which suppresses flashbacks; <9b> A selective opioid δ receptor agonist for use according to any one of <1b> to <8b>, which suppresses avoidance of traumatic events and related matters; <10b> A selective opioid δ receptor agonist for use according to any one of <1b> to <9b>, which has an effect of promoting the extinction of memories of traumatic events and / or an effect of inhibiting the reconsolidation of memories of traumatic events; <11b> A selective opioid δ receptor agonist for use according to <10b>, wherein the effect of promoting the extinction of memories of traumatic events is an effect of promoting extinction learning of memories of traumatic events; <12b> A selective opioid δ receptor agonist for use according to any one of <1b> to <11b>, which alleviates fear from fear memory;

[0063] <1c> Use of a selective opioid δ receptor agonist for producing a pharmaceutical composition for the treatment or prevention of stress-related disorder, stress-induced anxiety disorder, or stress-related disorder or anxiety disorder complicated with depression; <2c> The use according to <1c>, wherein the selective opioid δ receptor agonist further has an opioid κ receptor antagonistic action; <3c> The use according to <1c> or <2c>, wherein the selective opioid δ receptor agonist further has an opioid μ receptor antagonistic action and an opioid κ receptor antagonistic action; <4c> The use according to any one of <1c> to <3c>, wherein the stress-related disorder is acute stress disorder, post-traumatic stress disorder, or adjustment disorder; <5c> The use according to any one of <1c> to <4c>, wherein the stress-related disorder is acute stress disorder or post-traumatic stress disorder; <6c> Use according to <4c> or <5c> for producing a pharmaceutical composition for treating or preventing post-traumatic stress disorder, which has an effect of suppressing intrusion symptoms associated with a traumatic event, suppressing persistent avoidance of stimuli associated with the traumatic event, or suppressing negative changes in cognition and mood associated with the traumatic event, which begin after the traumatic event; <7c> Use according to <6c>, in which the intrusion symptoms associated with the traumatic event, which begin after the traumatic event, are at least one of the following symptoms (1) to (5): (1) recurrent, involuntary, intrusive, and distressing memories of the traumatic event; (2) recurrent and distressing dreams, the content and / or emotions of which are related to the traumatic event; (3) dissociative symptoms, in which the patient feels as if the traumatic event is happening again or behaves in that way; (4) Intense or prolonged psychological distress when exposed to internal or external cues that represent or resemble aspects of the traumatic event; and (5) A pronounced physiological response to internal or external cues that represent or resemble aspects of the traumatic event; <8c> The use of any one of <1c> to <7c> to suppress flashbacks; <9c> The use of any one of <1c> to <8c> to suppress avoidance of traumatic events and related matters;<10c> The use according to any one of <1c> to <9c>, wherein the pharmaceutical composition has an effect of promoting the extinction of memories of a traumatic event and / or an effect of inhibiting the reconsolidation of memories of a traumatic event; <11c> The use according to <10c>, wherein the effect of promoting the extinction of memories of a traumatic event is an effect of promoting extinction learning of memories of a traumatic event; <12c> The use according to any one of <1c> to <11c>, wherein the pharmaceutical composition alleviates the sense of fear caused by fear memories;

[0064] <13d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the selective opioid δ receptor agonist is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof; <14d> The compound represented by the general formula (I) according to <13d>, wherein 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, R 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 ６－１０Aryloxy; C １－６ Alkanoyloxy; amino; or acylamino in which the acyl moiety has 2 to 6 carbon atoms, and 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 substituted with 1 to 6 halogen; 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 moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; alkylsulfonyl having 1 to 6 carbon atoms in the alkyl moiety; aminosulfonyl; alkylsulfinyl having 1 to 6 carbon atoms in the alkyl moiety; alkylthio having 1 to 6 carbon atoms in the alkyl moiety; C substituted with 1 to 6 halogens １－６ alkoxy; arylcarbonyl having 6 to 10 carbon atoms in the aryl portion; and １ an aralkyl aryl moiety in which the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; 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 moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; halogen; nitro; cyano; C substituted with 1 to 3 halogens１－６ 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; 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 The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the compound is optionally substituted with at least one substituent selected from alkyl;

[0065] <15d> The compound represented by general formula (I) according to <13d> or <14d>, wherein R １ is C １－６ <16d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the compound represented by general formula (I) according to any one of <13d> to <15d> is an alkyl; a cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; or an aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; <16d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the compound represented by general formula (I) according to any one of <13d> to <15d> is １is a cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; <17d> The method, use, or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b>, and <1c> to <12c>, wherein the compound represented by general formula (I) according to <13d> or <14d> 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 <18d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the compound represented by general formula (I) according to <13d> or <14d> is R １ is a compound which is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl;

[0066] <19d> The compound represented by general formula (I) according to any one of <13d> to <18d>, 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 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 <12a>, <1b> to <12b>, and <1c> to <12c>; <20d> The method, use, or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b>, and <1c> to <12c>, wherein R ２<21d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein R is pyridine 1-oxide; <21d> The method, use or pharmaceutical composition according to any one of <13d> to <19d>, wherein R is pyridine 1-oxide; ２ <22d> The method, use or pharmaceutical composition according to any one of <13d> to <19d>, wherein the compound represented by general formula (I) is a compound represented by formula (I), wherein R ２ <23d> The method, use or pharmaceutical composition according to any one of <13d> to <19d>, wherein the compound represented by general formula (I) is a compound represented by formula (I), wherein R ２ <24d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the heterocycle is pyridazin-3(2H)-one; <24d> The method, use or pharmaceutical composition according to any one of <13d> to <19d>, wherein the compound represented by general formula (I) is ２ <25d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the heterocycle is pyrazin-2(1H)-one; <25d> The method, use or pharmaceutical composition according to any one of <13d> to <19d>, wherein the compound represented by general formula (I) is ２ <26d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the heterocycle is 4H-pyran-4-one or 2H-pyran-2-one; <26d> The method, use or pharmaceutical composition according to any one of <13d> to <19d>, wherein the compound represented by general formula (I) is ２ <27d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the heterocycle is quinolin-2(1H)-one; <27d> The method, use or pharmaceutical composition according to any one of <13d> to <19d>, wherein the compound represented by general formula (I) is２ The method, use, or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b>, and <1c> to <12c>, wherein the heterocycle is a compound selected from the group consisting of pyrimidin-4(3H)-one and pyrimidin-2,4(1H,3H)-dione;

[0067] <28d> The compound represented by formula (I) according to any one of <13d> and <15d> to <27d>, wherein X is CH ２ <29d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the compound represented by general formula (I) according to any one of <13d> to <28d> is a compound represented by R ３ and R ４ <30d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein one of R is hydroxy and the other is hydrogen; <30d> The method, use or pharmaceutical composition according to any one of <13d> and <15d> to <28d>, wherein the compound represented by general formula (I) is ３ is halogen; cyano; carbamoyl; C １－６ Alkoxy; C １－６ alkanoyloxy; amino; or acylamino, where the acyl moiety has 2 to 6 carbon atoms; ４ is hydrogen or hydroxy, and R ５ <31d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the compound represented by general formula (I) according to any one of <13d> and <15d> to <28d> is a compound wherein R ３ is hydroxy; carbamoyl; or C １－６ Alkanoyloxy, R ４ is hydrogen, and R ５ <32d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the compound represented by general formula (I) according to any one of <13d> and <15d> to <28d> is a compound wherein R ３ is hydroxy and R ４is hydrogen, and R ５ <33d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the compound represented by general formula (I) according to any one of <13d> and <15d> to <28d> is a compound wherein R ３ , R ４ and R ５ The method, use, or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b>, and <1c> to <12c>, wherein all of the

[0068] <34d> The compound represented by formula (I) according to any one of <13d> and <15d> to <33d>, wherein R ６ａ , R ６ｂ , R ７ , R ８ , R ９ and R １０ <35d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the compound represented by general formula (I) according to any one of <14d> to <28d> is a compound in which R ３ is halogen; cyano; carbamoyl; C １－６ Alkoxy; C １－６ alkanoyloxy; amino; or acylamino, where the acyl moiety has 2 to 6 carbon atoms; ４ <36d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the compound represented by general formula (I) according to any one of <14d> to <28d> is a compound represented by R ３ is hydroxy; carbamoyl; or C １－６ Alkanoyloxy, R ４ <37d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the compound represented by general formula (I) according to any one of <14d> to <28d> is a compound wherein R ３ is hydroxy and R ４<38d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein R is hydrogen; <38d> The method, use or pharmaceutical composition according to any one of <14d> to <28d>, wherein R ３ and R ４ <39d> The method, use or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b> and <1c> to <12c>, wherein the compound represented by general formula (I) according to <13d> is a compound represented by the following general formula (II):

[0069] (In the formula, R １ is hydrogen; C １－６ alkyl; or cycloalkylalkyl, where the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; 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 or 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 the group consisting of 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 １－６Alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; 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, 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 moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; 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 <12a>, <1b> to <12b> and <1c> to <12c>, wherein the compound is represented by the formula (I), which may have 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;

[0070] <40d> The compound represented by general formula (II) according to <39d> is R １is a cycloalkylalkyl in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; <41d> The method, use, or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b>, and <1c> to <12c>, wherein the compound represented by general formula (II) according to <39d> or <40d> is a compound represented by formula (II), ２ is represented by formula (III):

[0071] ;Formula (IV):

[0072] ;Formula (V):

[0073] or formula (VI):

[0074] (In Formulas III to VI, R ａ is hydrogen or C １－６ <42d> The method, use or pharmaceutical composition according to any one of <39d> to <41d>, wherein the compound represented by general formula (II) is R ３ <43d> The method, use or pharmaceutical composition according to any one of <39d> to <42d>, wherein the compound represented by general formula (II) is a compound represented by R ４ The method, use, or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b>, and <1c> to <12c>, wherein is a compound in which

[0075] <44d> The compound represented by general formula (I) according to <13d> 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,The method, use, or pharmaceutical composition according to any one of <1a> to <12a>, <1b> to <12b>, and <1c> to <12c>, which is at least one compound selected from 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; or,

[0076] <45d> The compound represented by general formula (I) according to any one of <13d> and <39d> to <43d>, 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 <12a>, <1b> to <12b>, and <1c> to <12c>, 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.

[0077] Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. The example compounds were synthesized according to the method described in International Publication No. 2018 / 052114. The names of the example compounds were derived by converting the structural formula drawn using ChemDraw ver. 14 manufactured by CambridgeSoft into English names using the naming algorithm built into the software, and then translating them into Japanese.

[0078] Example 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)pyridine 1-oxide

[0079]

[0080] Example 2 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

[0081]

[0082] Example 3 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

[0083]

[0084] Example 4 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

[0085]

[0086] Example 5 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

[0087]

[0088] Example 6 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

[0089]

[0090] Example 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

[0091]

[0092] Example 8 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

[0093]

[0094] Example 9 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

[0095]

[0096] Example 10 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

[0097]

[0098] Example 11 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

[0099]

[0100] Example 12 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

[0101]

[0102] Example 13 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

[0103]

[0104] Example 14 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

[0105]

[0106] Example 15 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

[0107]

[0108] Example 16 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

[0109]

[0110] Example 17 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

[0111]

[0112] Example 18 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

[0113]

[0114] Example 19 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

[0115]

[0116] Example 20 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

[0117]

[0118] Example 21 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

[0119]

[0120] Example 22 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

[0121]

[0122] Example 23 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

[0123]

[0124] Example 24 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

[0125]

[0126] Example 25 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

[0127]

[0128] Example 26 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

[0129]

[0130] Example 27 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

[0131]

[0132] Example 28 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

[0133]

[0134] Example 29 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

[0135]

[0136] Example 30 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

[0137]

[0138] Example 31 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

[0139]

[0140] Example 32 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

[0141]

[0142] Example 33 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

[0143]

[0144] Example 34 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

[0145]

[0146] Example 35 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

[0147]

[0148] Example 36 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

[0149]

[0150] Example 37 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

[0151]

[0152] Example 38 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

[0153]

[0154] Example 39 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

[0155]

[0156] Example 40 (1) Opioid Receptor Functional Test (Evaluation of Agonist Activity) The functional activity of the compounds provided by the present invention at μ, δ, and κ opioid receptors was examined. Method: A Lance Ultra cAMP kit (PerkinElmer) was used, and the test was performed according to a prescribed method. To evaluate agonist activity, CHO cells expressing each human opioid receptor (δ, μ, and κ; accession numbers and catalog numbers are listed below) were reacted with the test compound in the presence of 10 μM forskolin in assay buffer (1×HBSS, 1 M HEPES, pH 7.4, 250 mM IBMX (Isobutylmethylxanthine), 7.5% BSA) for 30 minutes. Subsequently, the cAMP detection reagent included in the kit was added, and after 1 hour, time-resolved fluorescence measurement was performed using an EnVision plate reader (PerkinElmer). The test compound and each control drug (δ: SNC80, μ: DAMGO, κ: U-69593) were tested for 10 －１２ ~10 －５ The test compound was evaluated over a range of concentrations of 1000mg / mL, and a dose-response curve was calculated from the fluorescence value at 665 nm. ５０ value and E ｍａｘ The value was calculated. ｍａｘ The values ​​were calculated as the percentage of the maximum response of the test compound when the maximum response of each control drug was taken as 100%. SNC80: (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide DAMGO: [D-Ala ２ , N-MePhe ４,Gly-ol]enkephalin U-69593: (+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]decy-8-yl]benzeneacetamide <Accession Numbers and Catalog Numbers> δ: Catalog No. CT4607, accession No. NM_000911.2 μ: Catalog No. CT4605, accession No. NM_000914 κ: Catalog No. CT4606, accession No. NM_000912 (ChanTest Corporation)

[0157]

[0158] N.C.: The maximum response was not reached at the highest concentration (10 μM), so ED ５０ The value was not calculated. ＊ : Since the maximum response was not achieved at the highest concentration, the response rate at the highest concentration is shown as a reference value. As shown in Table 1, it was confirmed that the compounds of the present invention have strong agonist activity at the opioid δ receptor, and have no agonist activity or only very weak agonist activity at the μ and κ receptors. (2) Opioid Receptor Functional Test (Evaluation of Antagonist Activity) The antagonist activity at the μ and κ opioid receptors was evaluated using the same method as in (1). A fixed concentration of each control drug (μ: 30 nM DAMGO, κ: 100 nM U-69593) was reacted with the test compound and each human opioid receptor-expressing CHO cell in the presence of 10 μM forskolin in assay buffer for 30 minutes. The test compound and 10 －１２ ~10 －５ The evaluation was carried out over a range of concentrations of 100% and the subsequent procedures were carried out in the same manner as in the evaluation of agonist activity. The response of each control drug in the absence of the test substance was taken as 100%, and a dose-response curve in the presence of the test substance was calculated. The concentration at which the control drug response was inhibited by 50% (IC ５０ The values ​​were calculated.

[0159] As shown in Table 2, the compounds of the present invention were confirmed to have potent antagonist activity against opioid μ and κ receptors.

[0160] Example 41: Mouse Contextual Fear Conditioning Test (Effect on Extinction Learning of Fear Memory) The effect of the compound of Example 7 on extinction learning of fear memory in a mouse contextual fear conditioning test was examined. The test was performed according to Non-Patent Document 4. The compound of Example 7 (5, 10, 20 mg / kg, po) and vehicle were administered 2 hours before placing the mice in the experimental box on Day 2. The level of fear memory was assessed by measuring the time during which the fear response, known as freezing behavior, was exhibited and expressed as a percentage of the test time (6 minutes). This test revealed that the fear response on Days 2 and 3 was significantly reduced in the group treated with the compound of Example 7 compared to the vehicle-treated group (Figure 1). Previous studies have shown that extinction learning occurs upon re-exposure on Day 2, and these results indicate that the compound of Example 7 promotes extinction learning of fear memory.

[0161] Example 42: Mouse Contextual Fear Conditioning Test (Effect on Fear Memory Reconsolidation) Similar to Example 41, a fear conditioning test was used to examine the effect on fear memory reconsolidation. The test was conducted according to a method described in Non-Patent Document 4. The compound of Example 7 (20 mg / kg, po) and vehicle were administered 2 hours before placing the mice in the experimental box on Day 2. In this test, the test duration on Days 2 and 3 was 2 minutes. In this test, the group treated with the compound of Example 7 showed significantly reduced fear responses on Days 2 and 3 compared to the vehicle-treated group (Figure 2). Previous studies have shown that reconsolidation occurs after fear memory retrieval during re-exposure on Day 2. Therefore, these results suggest that the compound of Example 7 may inhibit the reconsolidation of fear memory.

[0162] Example 43 < Mouse contextual fear conditioning test (effect on reconsolidation of fear memory) > Immediately after the test on day 2 of Example 42, the compound of Example 7 was subcutaneously administered (1 mg / kg, 3 mg / kg, sc). The fear response on day 3 in the group administered with the compound of Example 7 was significantly reduced compared to the group administered with the vehicle ( Figure 3 ). This result suggests that the compound of Example 7 inhibits the reconsolidation of fear memory.

[0163] Example 44 <Metabolic Stability Test> (Test Method) Human liver microsomes were reacted with the test substance for a fixed time (0 to 60 min), and the amount of unchanged test substance remaining in the reaction sample was measured to determine the residual rate. The residual rate after incubation was plotted log-linearly against time, with the residual rate at 0 hour of reaction taken as 100%, and the regression line (y=100e －ｋｔ , k = linear slope: elimination rate constant) was calculated and metabolic clearance CL was calculated using the following formula: int (mL / min / kg) was calculated. int * = k (-min) × 52.5 (mg MS protein / g liver) × 26 (g liver / kg) / MS protein (mg MS protein / mL) *: Davies, B. and Morris, T.: Physiological parameters in laboratory animals and humans. Pharm. Res., 10(7): 1093-1095, 1993. (Test results) The test results are shown in Table 3.

[0164]

[0165] Comparative Compound 1: Example 93 (Compound 104) of WO 2013 / 35833 As is clear from Table 3, the compounds of the present invention have excellent metabolic stability. On the other hand, it was found that some of the compounds described in WO 2013 / 35833 (Patent Document 4) have poor metabolic stability.

[0166] The pharmaceutical compositions of the present invention are useful for treating or preventing stress-related disorders, stress-induced anxiety disorders, or stress-related disorders or anxiety disorders accompanied by depression.

Claims

1. A pharmaceutical composition for treating or preventing stress-related disorders, stress-induced anxiety disorders, or stress-related or anxiety disorders complicated by depression, comprising a selective opioid δ receptor agonist as an active ingredient.

2. The pharmaceutical composition for treatment or prevention according to claim 1, wherein the selective opioid δ receptor agonist further has an opioid κ receptor antagonist action.

3. The pharmaceutical composition for treatment or prevention according to claim 1 or 2, wherein the selective opioid δ receptor agonist further has an opioid μ receptor antagonist action and an opioid κ receptor antagonist action.

4. The pharmaceutical composition for treatment or prevention according to any one of claims 1 to 3, wherein the stress-related disorder is acute stress disorder, post-traumatic stress disorder, or adjustment disorder.

5. The pharmaceutical composition for treatment or prevention according to any one of claims 1 to 4, wherein the stress-related disorder is acute stress disorder or post-traumatic stress disorder.

6. A pharmaceutical composition for treating or preventing post-traumatic stress disorder, having an inhibitory effect on intrusive symptoms related to the traumatic event that begins after the traumatic event, an inhibitory effect on the persistent avoidance of stimuli related to the traumatic event, or an inhibitory effect on the negative changes in cognition and mood related to the traumatic event.

7. The pharmaceutical composition for treatment or prevention according to claim 6, wherein the intrusive symptoms related to the traumatic event that begins after the traumatic event are at least one of the following symptoms (1) to (5): (1) repetitive, involuntary, and intrusive and painful memories of the traumatic event; (2) repetitive and painful dreams in which the content and / or emotion of the dream is related to the traumatic event; (3) dissociative symptoms in which the traumatic event feels or acts as if it is happening again; (4) intense or prolonged psychological distress when exposed to internal or external cues that symbolize or are similar to aspects of the traumatic event; and (5) a marked physiological reaction to internal or external cues that symbolize or are similar to aspects of the traumatic event.

8. The pharmaceutical composition for treatment or prevention according to any one of claims 1 to 7, which suppresses flashbacks.

9. The pharmaceutical composition for treatment or prophylaxis according to any one of claims 1 to 8, which suppresses the avoidance of events related to mental trauma and related matters.

10. The pharmaceutical composition for treatment or prophylaxis according to any one of claims 1 to 9, which has an effect of promoting the erasure of memories of traumatic events and / or an effect of inhibiting the reconsolidation of memories of traumatic events.

11. The pharmaceutical composition for treatment or prophylaxis according to claim 10, wherein the effect of promoting the erasure of memories of the traumatic events is an effect of promoting the erasure learning of memories of the traumatic events.

12. The pharmaceutical composition for treatment or prophylaxis according to any one of claims 1 to 11, which alleviates the sense of fear from fear memories.

13. The selective opioid δ receptor agonist is represented by the following general formula (I): (wherein 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 moiety and 1 to 5 carbon atoms in the alkylene moiety; aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; C ３－６ cycloalkyl; or heteroarylalkyl having 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and having 1 to 5 carbon atoms in the alkylene moiety, R 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, and having at least one set of adjacent ring-constituting atoms having a double bond and being further substituted with at least one oxo group, or pyridine 1-oxide, wherein, R ２ is bonded to Y via a carbon atom which is a ring-constituting atom of R ２ , 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 arylamino or acylamino having 2 to 6 carbon atoms in the acyl moiety, R ６ａ and R ６ｂ are the same or different and are hydrogen; fluorine or hydroxy, or R ６ａ and R ６ｂ together represent =O, R ７ and R ８ are the same or different and are 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 in which the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; heteroarylalkyl in which the heteroaryl moiety contains 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms and the alkylene moiety has 1 to 5 carbon atoms; cycloalkylalkyl in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms or C ２－６ represents alkenyl, and X is O or CH ２ represents, and Y represents C(=O). However, R １ of C １－１０ alkyl; the alkylene moiety and cycloalkyl moiety of cycloalkylalkyl in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; the alkylene moiety of aralkyl in which the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; and the alkylene moiety of heteroarylalkyl in which the heteroaryl moiety contains 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms and the alkylene moiety has 1 to 5 carbon atoms may be substituted with at least one substituent selected from 1 to 6 halogens; hydroxy; C １－６ alkoxy; C 6－１０ aryloxy; C １－６ alkanoyl; C １－６ alkanoyloxy; carboxyl; alkoxycarbonyl in which the alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoyl in which the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl in which the alkyl moiety has 1 to 6 carbon atoms; alkylsulfonyl in which the alkyl moiety has 1 to 6 carbon atoms; aminosulfonyl; alkylsulfinyl in which the alkyl moiety has 1 to 6 carbon atoms; alkylthio in which the alkyl moiety has 1 to 6 carbon atoms; C １－６ alkoxy substituted with 1 to 6 halogens; arylcarbonyl in which the aryl moiety has 6 to 10 carbon atoms, and may be substituted with at least one substituent selected therefrom, and R １ of C ６－１０ Aryl; the aryl part of an aralkyl having 6 to 10 carbon atoms in the aryl part and 1 to 5 carbon atoms in the alkylene part; R ３ , R ４ and R ５ of C ６－１０ the aryl part of aryloxy; and C ６－１０ the aryl part of arylamino; and R ９ and R １０ of C ６－１０ aryl; heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms; the aryl part of an aralkyl having 6 to 10 carbon atoms in the aryl part and 1 to 5 carbon atoms in the alkylene part; and the heteroaryl part of a heteroarylalkyl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and having 1 to 5 carbon atoms in the alkylene part is C １－６ alkyl; C １－６ alkoxy; C １－６ alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy part; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl part; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl part; halogen; nitro; cyano; C １－６ alkyl substituted with 1 to 3 halogens; C １－６ alkoxy substituted with 1 to 3 halogens; 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; optionally substituted with at least one substituent selected from methylenedioxy, R ２ the heterocycle of may, in addition to an oxo group, have substituents that the above-mentioned C １ aryl of R ６－１０ may have, and also R ２ the pyridine 1-oxide of may have substituents that the above-mentioned C １ aryl of R ６－１０ may have, and further when R １ is C １－１０ alkyl, NR １１ R １２ may be replaced, 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 moiety and 1 to 5 carbon atoms in the alkylene moiety, or R １１ and R １２ and R １１ and R １２ may combine with the nitrogen atom to which they are attached and, optionally, one or two heteroatoms to form a 5- to 7-membered ring, and also the alkylene moiety of the aralkyl where the aryl moiety of R １ has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms may be substituted with at least one substituent selected from phenyl or C １－６ alkyl substituted with 1 to 3 halogens. ) A pharmaceutical composition for treatment or prevention according to any one of claims 1 to 12, which is a compound represented by or a pharmaceutically acceptable salt thereof.

14. The compound represented by the general formula (I) is such that R ５ , R ６ａ , R ６ｂ , R ７ , R ８ , R ９ and R １０ are hydrogen, and R １ is hydrogen; C １－６ alkyl; C ２－６ alkenyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety, and R ２ contains 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, a 5- to 7-membered heterocycle or a heterocycle condensed with a benzene ring to the heterocycle, or pyridine 1-oxide, where R ２ is bonded to Y via a carbon atom which is a ring-constituting atom of R ２ , and 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, X is CH ２ , and Y is C(=O), provided that the C １ of R １－６ alkyl; the alkylene moiety and cycloalkyl moiety of cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or the alkylene moiety of aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety has 1 to 6 of halogen; hydroxy; C １－６ alkoxy; C 6－１０ aryloxy; C １－６ alkanoyl; C １－６ Alkanoyloxy; carboxyl; alkoxycarbonyl in which the number of carbon atoms in the alkoxy moiety is 1 to 6; carbamoyl; alkylcarbamoyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; dialkylcarbamoyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; alkylsulfonyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; aminosulfonyl; alkylsulfinyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; alkylthio in which the number of carbon atoms in the alkyl moiety is 1 to 6; C substituted with 1 to 6 halogens １－６ Alkoxy; may be substituted with at least one substituent selected from arylcarbonyl in which the number of carbon atoms in the aryl moiety is 6 to 10, and R １ The aryl moiety of the aralkyl in which the number of carbon atoms in the aryl moiety is 6 to 10 and the number of carbon atoms in the alkylene moiety is 1 to 5; R ３ And R ４ The C of ６－１０ The aryl moiety of aryloxy is C １－６ Alkyl; C １－６ Alkoxy; C １－６ Alkanoyloxy; hydroxy; alkoxycarbonyl in which the number of carbon atoms in the alkoxy moiety is 1 to 6; carbamoyl; alkylcarbamoyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; dialkylcarbamoyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; 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 in which the number of carbon atoms in the alkyl is 1 to 3; may be substituted with at least one substituent selected from methylenedioxy, R ２ The heterocycle of R, in addition to the oxo group, may have the substituents that the aryl moiety of the above-mentioned R １ May have, in which the number of carbon atoms in the aryl moiety is 6 to 10 and the number of carbon atoms in the alkylene moiety is 1 to 5 of the aryl moiety of the aralkyl, and R ２ The pyridine 1-oxide of R is the above-mentioned R １ The aryl moiety of the aralkyl may have a substituent which the aryl moiety may have, the number of carbon atoms of the aryl moiety being 6 to 10 and the number of carbon atoms of the alkylene moiety being 1 to 5, and further R １ The alkylene moiety of the aralkyl in which the number of carbon atoms of the aryl moiety is 6 to 10 and the number of carbon atoms of the alkylene moiety is 1 to 5 is phenyl or C substituted with 1 to 3 halogen atoms １－６ The pharmaceutical composition for treatment or prophylaxis according to claim 13, which is a compound optionally substituted with at least one substituent selected from alkyls.

15. The compound represented by the general formula (I) is R １ is C １－６ alkyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety, The pharmaceutical composition for treatment or prevention according to claim 13 or 14.

16. The compound represented by the general formula (I) 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, and the pharmaceutical composition for treatment or prevention according to any one of claims 13 to 15.

17. The compound represented by the general formula (I) is R １ is C substituted with hydroxy ２－６ alkyl; C substituted with 1 to 6 halogens １－６ alkyl; or C １－６ alkyl substituted with alkoxy ２－６ The pharmaceutical composition for treatment or prophylaxis according to claim 13 or 14, which is a compound that is 18. The compound represented by the general formula (I) is R １ is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl or 2-(aminosulfonyl)ethyl, and the pharmaceutical composition for treatment or prevention according to claim 13 or 14.

19. The compound represented by the general formula (I) is R ２ contains 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, a 5- to 7-membered heterocycle or a heterocycle condensed with a benzene ring to the heterocycle, or pyridine 1-oxide, and the pharmaceutical composition for treatment or prevention according to any one of claims 13 to 18.

20. The compound represented by the general formula (I), wherein R ２ is a compound in which is pyridine 1-oxide, the pharmaceutical composition for treatment or prophylaxis according to any one of claims 13 to 19.

21. The compound represented by the general formula (I) is R ２ The pharmaceutical composition for treatment or prevention according to any one of claims 13 to 19, wherein the heterocyclic ring of is 2(1H)-pyridinone.

22. The compound represented by the general formula (I) is R ２ The pharmaceutical composition for treatment or prevention according to any one of claims 13 to 19, wherein the heterocyclic ring of is 4(1H)-pyridinone.

23. The compound represented by the general formula (I) is a compound in which the hetero ring of R ２ is pyridazin-3(2H)-one. The pharmaceutical composition for treatment or prevention according to any one of claims 13 to 19.

24. The compound represented by the general formula (I) is a compound in which the hetero ring of R ２ is pyrazin-2(1H)-one. The pharmaceutical composition for treatment or prevention according to any one of claims 13 to 19.

25. The compound represented by the general formula (I) is a compound in which the heterocycle of R ２ is 4H-pyran-4-one or 2H-pyran-2-one, and the pharmaceutical composition for treatment or prevention according to any one of claims 13 to 19.

26. The compound represented by the general formula (I) is a compound in which the hetero ring of R ２ is quinolin-2(1H)-one. The pharmaceutical composition for treatment or prevention according to any one of claims 13 to 19.

27. The compound represented by the general formula (I) is R ２ The pharmaceutical composition for treatment or prevention according to any one of claims 13 to 19, wherein the heterocyclic ring of is pyrimidin-4(3H)-one or pyrimidine-2,4(1H,3H)-dione.

28. The compound represented by the general formula (I), wherein X is CH ２ The pharmaceutical composition for treatment or prophylaxis according to any one of claims 13 and 15 to 27, which is a compound.

29. The compound represented by the general formula (I) is a compound in which one of R ３ and R ４ is hydroxy and the other is hydrogen. The pharmaceutical composition for treatment or prevention according to any one of claims 13 to 28.

30. The compound represented by the general formula (I) is such that R ３ is halogen; cyano; carbamoyl; C １－６ alkoxy; C １－６ alkanoyloxy; amino; or acylamino in which the acyl moiety has 2 to 6 carbon atoms, R ４ is hydrogen or hydroxy, and R ５ is hydrogen, and the pharmaceutical composition for treatment or prevention according to any one of claims 13 and 15 to 28.

31. The compound represented by the general formula (I), wherein R ３ is hydroxy; carbamoyl; or C １－６ alkanoyloxy, R ４ is hydrogen, and R ５ is hydrogen, which is a pharmaceutical composition for treatment or prevention according to any one of claims 13 and 15 to 28.

32. The compound represented by the general formula (I) is R ３ is hydroxy, R ４ is hydrogen, R ５ is hydrogen, and the pharmaceutical composition for treatment or prevention according to any one of claims 13 and 15 to 28.

33. The compound represented by the general formula (I) is R ３ , R ４ and R ５ are all hydrogen, and the pharmaceutical composition for treatment or prevention according to any one of claims 13 and 15 to 28.

34. The compound represented by the general formula (I) is R ６ａ , R ６ｂ , R ７ , R ８ , R ９ , and R １０ are all hydrogen, and the pharmaceutical composition for treatment or prevention according to any one of claims 13 and 15 to 33.

35. 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 in which the number of carbon atoms in the acyl moiety is 2 to 6, and R ４ is hydrogen or hydroxy, and the pharmaceutical composition for treatment or prevention according to any one of claims 14 to 28.

36. The compound represented by the general formula (I) is R ３ is hydroxy; carbamoyl; or C １－６ alkanoyloxy, and R ４ is hydrogen, and the pharmaceutical composition for treatment or prevention according to any one of claims 14 to 28.

37. The compound represented by the general formula (I) is R ３ is hydroxy and R ４ is hydrogen, and the pharmaceutical composition for treatment or prevention according to any one of claims 14 to 28.

38. The compound represented by the general formula (I) is a compound in which R ３ and R ４ are hydrogen. The pharmaceutical composition for treatment or prevention according to any one of claims 14 to 28.

39. The compound represented by the general formula (I) is the following general formula (II): (In the formula, R １ is hydrogen; C １－６ alkyl; or cycloalkylalkyl in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms, and R ２ contains 1 or 2 nitrogen atoms and at least 1 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, a 5- to 7-membered heterocycle, or pyridine 1-oxide, where R ２ is bonded to Y via a carbon atom that is a ring-constituting atom of R ２ , R ３ and R ４ are the same or different and are hydrogen or hydroxy; or C １－６ alkoxy, Y is C(=O), provided that the C １ of R １－６ [[ID=2!]] alkyl; the alkylene moiety and the cycloalkyl moiety of cycloalkylalkyl in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms may be substituted with at least one substituent selected from 1 to 6 halogen; hydroxy; and C １－６ alkoxy, and the heterocycle of R ２ , in addition to the oxo group, C １－６ alkyl; C １－６ alkoxy; C １－６ alkanoyloxy; hydroxy; alkoxycarbonyl in which the alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoyl in which the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl in which the alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C １－６ alkyl substituted with 1 to 3 halogen; C 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 group; may have at least one substituent selected from methylenedioxy, and R ２ The pyridine 1-oxide of １－６ alkyl; C １－６ alkoxy; C １－６ alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; halogen; nitro; cyano; C １－６ alkyl substituted with 1 to 3 halogens; C １－６ alkoxy substituted with 1 to 3 halogens; 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 group; may have at least one substituent selected from methylenedioxy), a pharmaceutical composition for treatment or prophylaxis according to claim 13, which is a compound represented by 40. The compound represented by the general formula (II) is R １ is cycloalkylalkyl, the cycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms, and the pharmaceutical composition for treatment or prevention according to claim 39, which is a cycloalkylalkyl compound.

41. The compound represented by the general formula (II) is R ２ wherein is the formula (III): ; the formula (IV): ; the formula (V): ; or the formula (VI): (in formulas III to VI, R ａ is hydrogen or C １－６ alkyl and is bonded to Y at the position of the arrow), the pharmaceutical composition for treatment or prevention according to claim 39 or 40.

42. The compound represented by the general formula (II) is R ３ The pharmaceutical composition for treatment or prevention according to any one of claims 39 to 41, which is a compound in which is hydroxy.

43. The compound represented by the general formula (II) is R ４ The pharmaceutical composition for treatment or prevention according to any one of claims 39 to 42, which is a compound in which is hydrogen.

44. 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[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)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-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,At least one compound selected from 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 claim 13., 45. 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 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, and is at least one compound selected therefrom, and the pharmaceutical composition for treatment or prevention according to any one of claims 13 and 39 to 43.

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