Pharmaceutical composition for the treatment or prevention of anhedonia

Abstract

The present invention provides a pharmaceutical composition for the treatment or prevention of anhedonia, comprising a selective delta opioid receptor agonist as an active ingredient, preferably wherein the selective delta opioid receptor agonist further has κ opioid receptor antagonistic activity and μ opioid receptor antagonistic activity.

Description

Technical Field

[0001] This invention relates to pharmaceutical compositions for the treatment or prevention of anhedonia, comprising a selective delta opioid receptor agonist as an active ingredient.

[0002] This application claims priority based on Japanese Patent Application No. 2024-042863 filed in Japan on March 18, 2024 and Japanese Patent Application No. 2024-134624 filed in Japan on August 9, 2024, the contents of which are incorporated herein by reference. Background Technology

[0003] Opioids exert their effects by binding to opioid receptors, which exist in three subtypes: μ, δ, and κ. Compounds with similar activities to opioids are also known. For example, agonists that activate δ opioid receptors (DOR) are sometimes agonists or antagonists of other receptors, namely μ opioid receptors (MOR) or κ opioid receptors (KOR), and compounds acting on opioid receptors sometimes exhibit multiple activities. To date, various compounds have been reported as DOR agonists, and their analgesic, antidepressant, anxiolytic, and stress-related disorder effects have been demonstrated (Patent Literature 1–8 and Non-Patent Literature 1–4).

[0004] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defines major depressive disorder as requiring five or more of the following nine symptoms: depressed mood, significant loss of interest or pleasure, changes in weight or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feelings of self-blame or worthlessness, decreased attention or indecisiveness, and recurrent thoughts of death. These symptoms must be present almost daily for two weeks, with at least one symptom being either depressed mood or significant loss of interest or pleasure. Significant loss of interest or pleasure is synonymous with anhedonia and, in addition to being a depressive disorder, is also a component of substance-related disorders, psychotic disorders, and personality disorders.

[0005] In the research field standard RDoC (non-patent literature 5), anhedonia can be regarded as a disorder of the positive valence system, and is described as a state including reduced motivation and effort to obtain rewards, reduced and difficult-to-maintain pleasure when obtaining rewards, or learning difficulties related to reward acquisition. Depressive mood, which is the core symptom of major depressive disorder, is clearly distinguished from anhedonia.

[0006] Previous treatments for depression have focused on alleviating depressive mood or negative symptoms, while paying insufficient attention to the loss of positive emotions such as pleasure or happiness, also known as anhedonia. It has been reported that anhedonia in depression is difficult to treat, being the last remaining symptom of depression, and existing psychiatric treatments and psychological support methods are insufficient to adequately improve it (Non-Patent Literature 6). At least currently, there are no antidepressants effective against anhedonia available domestically or internationally. Furthermore, reports indicate that anhedonia weakens the effects of selective serotonin reuptake inhibitors (SSRIs), a first-line treatment for depression (Non-Patent Literature 7), and that among depressive symptoms, anhedonia has the strongest predictive power for suicidal ideation (Non-Patent Literature 8). In addition, anhedonia is not only seen in depression but also in schizophrenia, Parkinson's disease, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), and other diseases; therefore, effective drugs for treating anhedonia are anticipated.

[0007] Animal models for evaluating anhedonia have been reported, such as the Female Urine Sniffing Test (FUST) (Non-Patent Literature 9) and the Sucrose Preference Test (Non-Patent Literature 10). Additionally, attempts to treat anhedonia by modulating opioid receptors have been reported, and these have been evaluated using KOR agonists (Salvinolin A), KOR antagonists (LY-2456302), DOR agonists / MOR agonists / partial KOR agonists (Nalmefene), or DOR agonists (SNC80) (Non-Patent Literatures 9–12).

[0008] Existing technical documents

[0009] Patent documents

[0010] Patent Document 1: Japanese Patent Publication No. 2006-522775

[0011] Patent Document 2: International Publication No. 2001 / 046192

[0012] Patent Document 3: International Publication No. 2008 / 001859

[0013] Patent Document 4: International Publication No. 2013 / 035833

[0014] Patent Document 5: International Publication No. 2014 / 021273

[0015] Patent Document 6: International Publication No. 2014 / 136305

[0016] Patent Document 7: International Publication No. 2016 / 148232

[0017] Patent Document 8: International Publication No. 2022 / 181763

[0018] Non-patent literature

[0019] Non-patent literature 1: Hayashida et al., Tetrahedron, 2011, 67, 6682

[0020] Non-patent literature 2: Kamei et al., EJ Pharmacol., 1995, 276, 131

[0021] Non-patent literature 3: Kamei et al., EJ Pharmacol., 1997, 322, 27

[0022] Non-patent literature 4: Nagase et al., Bioorg. Medic. Chem. Lett., 2010, 20, 6302

[0023] Non-patent literature 5: Insel et al., Am. J. Psychiatry. 2010, 167, 748

[0024] Non-patent literature 6: Dunn et al., Clinic. Psychol. Sci., 2020, 8, 36

[0025] Non-patent literature 7: Uher et al., Psychol. Med., 2012, 42, 967.

[0026] Non-patent literature 8: Ducasse et al., Depress Anxiety., 2018, 35, 382

[0027] Non-patent literature 9: Scheggi et al., Int. J. Neuropsychopharmacol., 2018, 21, 1049

[0028] Non-patent literature 10: Wu et al., EJ Pharmacol., 2023, 942, 175532

[0029] Non-patent literature 11: Harden et al., Behav. Pharmacol., 2012, 23, 710

[0030] Non-patent literature 12: Page et al., Int. J. Neuropsychopharmacol., 2019, 22, 735 Summary of the Invention

[0031] The subject of this invention is to provide a medicine useful for the treatment or prevention of anhedonia.

[0032] In order to solve the above-mentioned problems, the inventors conducted in-depth research and found that a pharmaceutical composition containing a selective DOR agonist as an active ingredient, preferably having a morphine skeleton, and further having MOR antagonistic and KOR antagonistic effects, is useful for the treatment or prevention of anhedonia, thus completing the present invention.

[0033] That is, the present invention includes the following solutions.

[0034] [1] A pharmaceutical composition for the treatment or prevention of anhedonia, comprising a selective delta opioid receptor agonist as an active ingredient.

[0035] [2] The therapeutic or preventive pharmaceutical composition according to [1], wherein the selective δ opioid receptor agonist further has κ opioid receptor antagonistic activity.

[0036] [3] The therapeutic or preventive pharmaceutical composition according to [1] or [2], wherein the selective δ opioid receptor agonist further has μ opioid receptor antagonistic activity and κ opioid receptor antagonistic activity.

[0037] [4] The therapeutic or preventive pharmaceutical composition according to any one of [1] to [3], wherein the anhedonia is anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder (PTSD, etc.), autism spectrum disorder or Alzheimer's disease.

[0038] [5] The therapeutic or preventive pharmaceutical composition according to any one of [1] to [4], wherein the anhedonia is caused by mental or physical stress.

[0039] [6] The therapeutic or preventive pharmaceutical composition according to any one of [1] to [5] suppresses suicidal ideation.

[0040] [7] The therapeutic or preventive pharmaceutical composition according to any one of [1] to [6], wherein the anhedonia is a reduced responsiveness to pleasurable experiences related to at least one of money, food, hobbies, entertainment, travel and leisure, and dominance, recognition, achievement, affinity and sexuality.

[0041] [8] A therapeutic or preventive pharmaceutical composition according to any one of [1] to [7], wherein the selective δ-opioid receptor agonist is a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[0042]

[0043] (where R) 1 Represents hydrogen, C 1-10 Alkyl, C 6-10 Aryl, C 2-6 Alkenyl, cycloalkyl groups with 3-6 carbon atoms in the cycloalkyl moiety and 1-5 carbon atoms in the alkylene moiety, and aralkyl groups with 6-10 carbon atoms in the aryl moiety and 1-5 carbon atoms in the alkylene moiety, C 3-6 The cycloalkyl or heteroaryl moiety comprises 1 to 4 heteroatoms selected from N, O, and S as ring-forming atoms, and the alkylene moiety has 1 to 5 carbon atoms.

[0044] R 2 This refers to a heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as a ring-forming atom, wherein at least one group of adjacent ring-forming atoms has a double bond and is subsequently substituted by at least one oxo group, or a pyridine 1-oxide.

[0045] Among them, R 2 Intermediate as R 2 The carbon atom of the ring-forming atom is bonded to Y.

[0046] R 3 R 4 and R 5 Same or different, indicating hydrogen, hydroxyl, halogen, cyano, carbamoyl, C 1-6 Alkoxy, C 6-10 aryloxy group, C 1-6 Alkyloxy, nitro, amino, C 1-8 Alkylamino, C 6-10 Acylamino groups with 2 to 6 carbon atoms in the arylamino or acyl moiety.

[0047] R 6a and R 6b Same or different, indicating hydrogen, fluorine or hydroxyl, or R 6a and R 6b Together means = 0,

[0048] R 7 and R 8 Same or different, indicating hydrogen, fluorine or hydroxyl.

[0049] R 9and R 10 Same or different, indicating hydrogen, C 1-6 Alkyl, C 6-10 Aryl, comprising 1 to 4 heteroatoms selected from N, O, and S as ring-forming atoms, aryl moiety having 6 to 10 carbon atoms and alkylene moiety having 1 to 5 carbon atoms, heteroaryl moiety comprising 1 to 4 heteroatoms selected from N, O, and S as ring-forming atoms and alkylene moiety having 1 to 5 carbon atoms, cycloalkyl moiety having 3 to 6 carbon atoms and alkylene moiety having 1 to 5 carbon atoms, or C 2-6 alkenyl,

[0050] X represents O or CH2.

[0051] Furthermore, Y represents C (=O).

[0052] Among them, R 1 C 1-10 Alkyl, cycloalkyl groups having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety, alkylene groups of aryl groups having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety, and heteroaryl alkyl groups having 1 to 4 heteroatoms selected from N, O, and S as ring-forming atoms and 1 to 5 carbon atoms in the alkylene moiety, the alkylene moiety of which may be selected from 1 to 6 halogens, hydroxyl groups, C 1-6 Alkoxy, C 6-10 aryloxy group, C 1-6 Alkyl group, C 1-6 Alkyloxy, carboxyl, alkoxycarbonyl with 1 to 6 carbon atoms in the alkoxy moiety, carbamoyl, alkylcarbamoyl with 1 to 6 carbon atoms in the alkyl moiety, dialkylcarbamoyl with 1 to 6 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 6 carbon atoms in the alkyl moiety, aminosulfonyl, alkylsulfinyl with 1 to 6 carbon atoms in the alkyl moiety, alkylthio with 1 to 6 carbon atoms in the alkyl moiety, and C groups substituted with 1 to 6 halogens. 1-6 The alkoxy group and at least one substituent in the aryl carbonyl group having 6 to 10 carbon atoms are substituted.

[0053] Moreover, R 1 C 6-10 aryl, the aryl moiety having 6 to 10 carbon atoms in the aryl group and 1 to 5 carbon atoms in the alkylene group, R 3 R 4 and R 5 C 6-10 The aryl moiety of the aryl group, and C 6-10 The aryl moiety of arylamino groups, and R9 and R 10 C 6-10 aryl, including a heteroaryl group comprising 1 to 4 heteroatoms selected from N, O, and S as ring-forming atoms, an aryl moiety having 6 to 10 carbon atoms and an aralkyl group having 1 to 5 carbon atoms in the alkylene moiety, and a heteroaryl moiety comprising 1 to 4 heteroatoms selected from N, O, and S as ring-forming atoms and an alkylene moiety having 1 to 5 carbon atoms in the alkylene moiety, wherein the heteroaryl moiety may be selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyloxy, hydroxyl, alkoxycarbonyl with 1-6 carbon atoms in the alkoxy moiety, carbamoyl, alkylcarbamoyl with 1-6 carbon atoms in the alkyl moiety, dialkylcarbamoyl with 1-6 carbon atoms in the alkyl moiety, halogen, nitro, cyano, C-terminal groups substituted with 1-3 halogens. 1-6 Alkyl groups, 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 constituent atoms, phenoxy, alkyl phenylalkyl having 1 to 3 carbon atoms, and at least one substituent selected from methylenedioxy.

[0054] R 2 In addition to the oxo group, the heterocycle may also have the aforementioned R. 1 C 6-10 Aryl groups may have substituents, or R 2 The pyridine 1-oxide can have the R 1 C 6-10 Aryl groups can have substituents.

[0055] Furthermore, in R 1 C 1-10 When alkyl, it can be NR 11 R 12 Replace, where R 11 and R 12 Same or different, is hydrogen, C 1-10 Alkyl, or an aryl group 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 Together with the nitrogen atoms they are bonded to, and one or two heteroatoms as needed, they form 5- to 7-membered rings. Furthermore, R... 1 The alkylene moiety having 6 to 10 carbon atoms in the aryl group and 1 to 5 carbon atoms in the alkylene moiety can be selected from phenyl or C6 groups substituted with 1 to 3 halogens. 1-6 At least one substituent in the alkyl group is substituted.

[0056] [9] A therapeutic or preventive pharmaceutical composition according to any one of [1] to [8], wherein, in the compound represented by the general formula (I), R 5 R 6a R 6b R 7 R 8 R 9 and R 10 It is hydrogen.

[0057] R 1 It is hydrogen; C 1-6 Alkyl; C 2-6 Alkenyl; cycloalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or aralkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety.

[0058] R 2 This refers to a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as a ring-forming atom, wherein at least one group of adjacent ring-forming atoms has a double bond and is subsequently substituted by at least one oxo group, or a heterocycle formed by fusion of the heterocycle with a benzene ring, or a pyridine 1-oxide.

[0059] Among them, R 2 Intermediate as R 2 The carbon atom of the ring-forming atom is bonded to Y.

[0060] R 3 and R 4 Same or different, indicating hydrogen; hydroxyl group; halogen; cyano group; carbamoyl group; C 1-6 Alkoxy; C 6-10 aryloxy group; C 1-6 Alkyloxy; amino; or acylamino with 2 to 6 carbon atoms in the acyl moiety.

[0061] X is CH2.

[0062] Moreover, Y is C (=O).

[0063] Among them, R 1 C 1-6 Alkyl; cycloalkyl moiety having 3 to 6 carbon atoms and alkylene moiety having 1 to 5 carbon atoms in cycloalkyl; or aryl moiety having 6 to 10 carbon atoms and alkylene moiety having 1 to 5 carbon atoms in aryl; the alkylene moiety may be selected from 1 to 6 halogens; hydroxyl group; C 1-6 Alkoxy; C 6-10 aryloxy group; C 1-6 Alkyl group; C 1-6Alkyloxy group; carboxyl group; alkoxycarbonyl group with 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl group; alkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; alkylsulfonyl group with 1 to 6 carbon atoms in the alkyl moiety; aminosulfonyl group; alkylsulfinyl group with 1 to 6 carbon atoms in the alkyl moiety; alkylthio group with 1 to 6 carbon atoms in the alkyl moiety; C substituted with 1 to 6 halogens 1-6 The alkoxy group; and at least one substituent in the aryl carbonyl group having 6 to 10 carbon atoms, are substituted.

[0064] Moreover, R 1 The aryl moiety of an aryl group having 6 to 10 carbon atoms and the alkylene moiety having 1 to 5 carbon atoms; and R 3 and R 4 C 6-10 The aryl moiety of the aryl group can be selected from C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxy group; hydroxyl group; alkoxycarbonyl group with 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl group; alkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; halogen; nitro group; cyano group; C atoms substituted with 1 to 3 halogens. 1-6 Alkyl group; C atoms substituted with 1 to 3 halogens 1-6 Alkoxy; phenyl; heteroaryl group comprising 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; phenoxy; phenylalkyl group having 1 to 3 carbon atoms; and at least one substituent selected from methylenedioxy.

[0065] R 2 In addition to oxo groups, the heterocycles can also have the aforementioned R groups. 1 The aryl moiety of an aryl group having 6 to 10 carbon atoms and the alkylene moiety having 1 to 5 carbon atoms may have substituents, and R 2 The 1-oxide of pyridine can have the above-mentioned R 1 The aryl moiety of an aryl group having 6 to 10 carbon atoms and the alkylene moiety having 1 to 5 carbon atoms may have substituents.

[0066] In addition, R 1 The alkylene moiety having 6 to 10 carbon atoms in the aryl group and 1 to 5 carbon atoms in the alkylene moiety can be selected from phenyl or C6 groups substituted with 1 to 3 halogens. 1-6 At least one substituent in the alkyl group is substituted.

[0067]

[10] A therapeutic or preventive pharmaceutical composition according to any one of [1] to [9], wherein, in the compound represented by the general formula (I), R 1 C 1-6 Alkyl; cycloalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or aralkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety.

[0068]

[11] A therapeutic or preventive pharmaceutical composition according to any one of [1] to [9], wherein, in the compound represented by the general formula (I), R 1 It is a cycloalkyl group in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms.

[0069]

[12] A therapeutic or preventive pharmaceutical composition according to any one of [1] to [9], wherein, in the compound represented by the general formula (I), R 1 C substituted with hydroxyl group 2-6 Alkyl group; C atoms substituted with 1 to 6 halogens 1-6 Alkyl; or C 1-6 alkoxy-substituted C 2-6 alkyl.

[0070]

[13] A therapeutic or preventive pharmaceutical composition according to any one of [1] to [9], wherein, in the compound represented by the general formula (I), R 1 It is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl or 2-(aminosulfonyl)ethyl.

[0071]

[14] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[13] , wherein, in the compound represented by general formula (I), R 2 It is a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O and S and at least 1 carbon atom as ring constituent atoms, and at least one group of adjacent ring constituent atoms having double bonds and being substituted by at least 1 oxo group, or a heterocycle or pyridine 1-oxide formed by fusion of the heterocycle with a benzene ring.

[0072]

[15] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[13] , wherein, in the compound represented by the general formula (I), R 2 It is a 1-oxide of pyridine.

[0073]

[16] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[13] , wherein, in the compound represented by general formula (I), R 2 The heterocycle is pyridine-2(1H)-one.

[0074]

[17] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[13] , wherein, in the compound represented by the general formula (I), R 2 The heterocycle is pyridine-4(1H)-one.

[0075]

[18] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[13] , wherein, in the compound represented by the general formula (I), R 2 The heterocycle is pyridazine-3(2H)-one.

[0076]

[19] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[13] , wherein, in the compound represented by the general formula (I), R 2 The heterocycle is pyrazine-2(1H)-one.

[0077]

[20] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[13] , wherein, in the compound represented by the general formula (I), R 2 The heterocycle is 4H-pyran-4-one or 2H-pyran-2-one.

[0078]

[21] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[13] , wherein, in the compound represented by the general formula (I), R 2 The heterocycle is quinoline-2(1H)-one.

[0079]

[22] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[13] , wherein, in the compound represented by the general formula (I), R 2 The heterocycle is either pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione.

[0080]

[23] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[22] , wherein X is CH2 in the compound represented by the general formula (I).

[0081]

[24] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[23] , wherein, in the compound represented by general formula (I), R 3 and R 4 One of them is a hydroxyl group, and the other is hydrogen.

[0082]

[25] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[23] , wherein, in the compound represented by general formula (I), R 3 Halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 1-6Alkyloxy; amino; or acylamino with 2 to 6 carbon atoms in the acyl moiety, R 4 For hydrogen or hydroxyl, R 5 It is hydrogen.

[0083]

[26] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[23] , wherein, in the compound represented by general formula (I), R 3 Hydroxyl; carbamoyl; or C 1-6 Alkyloxy, R 4 For hydrogen, R 5 It is hydrogen.

[0084]

[27] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[23] , wherein, in the compound represented by the general formula (I), R 3 For hydroxyl group, R 4 For hydrogen, R 5 It is hydrogen.

[0085]

[28] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[23] , wherein, in the compound represented by general formula (I), R 3 R 4 and R 5 It is all hydrogen.

[0086]

[29] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[28] , wherein, in the compound represented by general formula (I), R 6a R 6b R 7 R 8 R 9 and R 10 It is all hydrogen.

[0087]

[30] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[23] , wherein, in the compound represented by the general formula (I), R 3 Halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 1-6 Alkyloxy; amino; or acylamino with 2 to 6 carbon atoms in the acyl moiety, R 4 It can be hydrogen or hydroxyl.

[0088]

[31] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[23] , wherein, in the compound represented by the general formula (I), R 3 Hydroxyl; carbamoyl; or C 1-6 Alkyloxy, R 4 It is hydrogen.

[0089]

[32] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[23] , wherein, in the compound represented by general formula (I), R 3 For hydroxyl group, R 4 It is hydrogen.

[0090]

[33] A therapeutic or preventive pharmaceutical composition according to any one of [1] to

[23] , wherein, in the compound represented by general formula (I), R 3 and R 4 It is hydrogen.

[0091]

[34] A therapeutic or preventive pharmaceutical composition according to any one of [1] to [6], wherein the compound represented by general formula (I) is a compound represented by general formula (II) below.

[0092]

[0093] (where R) 1 It is hydrogen; C 1-6 Alkyl; or cycloalkyl groups having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety.

[0094] R 2 This refers to a 5- to 7-membered heterocycle or pyridine 1-oxide containing one or two nitrogen atoms and at least one carbon atom as ring-forming atoms, wherein at least one group of adjacent ring-forming atoms has a double bond and is subsequently substituted by at least one oxo group.

[0095] Among them, R 2 Intermediate as R 2 The carbon atom of the ring-forming atom is bonded to Y.

[0096] R 3 and R 4 Same or different, is hydrogen; hydroxyl; or C 1-6 Alkoxy

[0097] Y is C (=O).

[0098] Among them, R 1 C 1-6 Alkyl; cycloalkyl group having 3 to 6 carbon atoms in the alkyl group and 1 to 5 carbon atoms in the alkylene group; the alkylene group and cycloalkyl group can be selected from 1 to 6 halogens; hydroxyl groups; and C 1-6 At least one substituent in the alkoxy group is substituted.

[0099] Moreover, R 2 In addition to oxo groups, the heterocycles can also have groups selected from C. 1-6 Alkyl; C 1-6 Alkoxy; C 1-6Alkyloxy group; hydroxyl group; alkoxycarbonyl group with 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl group; alkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; halogen; nitro group; cyano group; C atoms substituted with 1 to 3 halogens. 1-6 Alkyl group; C atoms substituted with 1 to 3 halogens 1-6 Alkoxy; phenyl; heteroaryl group comprising 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; phenoxy; phenylalkyl group having 1 to 3 carbon atoms; and at least one substituent selected from methylenedioxy.

[0100] Additionally, R 2 1-Oxides of pyridine can have a composition selected from C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxy group; hydroxyl group; alkoxycarbonyl group with 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl group; alkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; halogen; nitro group; cyano group; C atoms substituted with 1 to 3 halogens. 1-6 Alkyl group; C atoms substituted with 1 to 3 halogens 1-6 Alkoxy; phenyl; heteroaryl group comprising 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; phenoxy; phenylalkyl group having 1 to 3 carbon atoms; and at least one substituent selected from methylenedioxy.

[0101]

[35] A therapeutic or preventive pharmaceutical composition according to any one of [1] to [6] and

[34] , wherein, in the compound represented by general formula (II), R 1 It is a cycloalkyl group, wherein the cycloalkyl group has 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion.

[0102]

[36] A therapeutic or preventive pharmaceutical composition according to any one of [1] to [6],

[34] and

[35] , wherein, in the compound represented by general formula (II), R 2 For example, Equation (III), Equation (IV), Equation (V), or Equation (VI).

[0103]

[0104]

[0105]

[0106]

[0107] (In formulas III to VI, R)a It is hydrogen or C 1-6 Alkyl group, bonded to Y at the position indicated by the arrow.

[0108]

[37] A therapeutic or preventive pharmaceutical composition according to any one of [1] to [6] and

[34] to

[36] , wherein, in the compound represented by general formula (II), R 3 It is a hydroxyl group.

[0109]

[38] A therapeutic or preventive pharmaceutical composition according to any one of [1] to [6] and

[34] to

[37] , wherein, in the compound represented by general formula (II), R 4 It is hydrogen.

[0110]

[39] A therapeutic or preventive pharmaceutical composition according to any one of [1] to [6] and

[34] , wherein the compound represented by the general formula (I) is at least one compound selected from the following compounds:

[0111] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide,

[0112] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide,

[0113] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0114] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide,

[0115] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0116] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,

[0117] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0118] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one,

[0119] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,

[0120] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,

[0121] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0122] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,

[0123] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-4(1H)-one,

[0124] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-4(1H)-one,

[0125] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,

[0126] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridazine-3(2H)-one,

[0127] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)quinoline-2(1H)-one,

[0128] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one,

[0129] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one,

[0130] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one,

[0131] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrazine-2(1H)-one,

[0132] 2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide,

[0133] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0134] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrazine-2(1H)-one,

[0135] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,

[0136] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-2(1H)-one,

[0137] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one, and

[0138] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-2(1H)-one.

[0139]

[40] A therapeutic or preventive pharmaceutical composition according to any one of [1] to [6] and

[34] , wherein the compound represented by the general formula (I) is at least one compound selected from the following compounds:

[0140] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide;

[0141] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one;

[0142] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one;

[0143] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one;

[0144] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, and

[0145] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-2(1H)-one.

[0146] This invention provides a pharmaceutical composition useful for the treatment or prevention of anhedonia. Attached Figure Description

[0147] Figure 1 This is a graph showing the effect of the compound (compound number 7) used in the sucrose preference test on anhedonia associated with physical stress (**: p < 0.01 (Bonferroni test after one-way ANOVA)).

[0148] Figure 2This is a graph showing the effect of KNT-127 on anhedonia associated with vicarious social frustration using a sucrose preference test (ns: no significant difference; **: p < 0.01 (Bonferroni test after one-way ANOVA)).

[0149] Figure 3 This is a graph showing the effect of the compound (compound number 7) in the sucrose preference test on anhedonia associated with vicarious social frustration (ns: no significant difference; *: p < 0.05 (Bonferroni test after one-way ANOVA)).

[0150] Figure 4 This is a graph showing the effect of the compound (compound number 7) in the female urine sniffing test on anhedonia accompanied by physical stress (ns: no significant difference; *: p < 0.05 (Bonferroni test after one-way ANOVA)).

[0151] Figure 5 This is a graph showing the effect of the compound (compound number 7) in the sniffing test using female urine on anhedonia associated with vicarious social frustration (ns: no significant difference; *: p < 0.05; **: p < 0.01 (Bonferroni test after one-way ANOVA)). Detailed Implementation

[0152] The present invention will now be described in more detail. It should be noted that all patent gazettes, patent application publications, and non-patent documents cited in this specification are incorporated herein by reference for all purposes.

[0153] 1. Anhedonia

[0154] In this specification, "anhedonia" refers to the symptom of reduced responsiveness to rewards, entertainment, or other pleasurable experiences. Anhedonia can also be described as decreased positive mood, reduced motivation, decreased sensitivity to rewards, and loss of pleasure. In the RDoC (Non-Patent Document 5), the research field standard, anhedonia (loss of pleasure) is considered a disorder of the positive valence system and is described as a state including reduced motivation and effort to obtain rewards, reduced or unsustainable pleasure when obtaining rewards, and learning difficulties related to reward acquisition. Anhedonia can be further subdivided into: "motivational anhedonia," which means a reduced or absent motivation to seek rewards; "consummatory anhedonia," which means a reduced or absent pleasurable response during the reward acquisition phase; and "decision anhedonia," which does not consider anhedonia as a trait but rather as a problem in the dynamic decision-making process.

[0155] One aspect of the present invention is a pharmaceutical composition containing a selective DOR agonist as an active ingredient for treating or preventing anhedonia symptoms. More specifically, it is a pharmaceutical composition containing a selective DOR agonist as an active ingredient for treating or preventing motivational anhedonia symptoms, a pharmaceutical composition containing a selective DOR agonist as an active ingredient for treating or preventing consumer anhedonia symptoms, or a pharmaceutical composition containing a selective DOR agonist as an active ingredient for treating or preventing decisional anhedonia symptoms. Furthermore, in another aspect of the present invention, the selective DOR agonist is a compound having a morphine skeleton, preferably a compound further having MOR antagonistic and KOR antagonistic effects.

[0156] In this specification, rewards, entertainment, or other pleasurable experiences associated with "anhedonia" include pleasurable experiences related to at least one of the following: money, food, hobbies, entertainment (television programs, radio programs, reading, etc.), travel and leisure, as well as desire for dominance, approval, achievement, affinity, and sexuality.

[0157] Questionnaires are sometimes used in the diagnosis of anhedonia, as described in this invention. Examples of questionnaires include the Snaith-Hamilton pleasure scale (SHAPS) (Snaith et al., Br J Psychiatry, 1995, 167:99), the Chapman scales for physical and social anhedonia (Chapman et al., J Abnorm Psychol 85: 374-382, 1976), and questionnaires specifically designed for various disorders accompanied by anhedonia (e.g., items 1 and 2 of the Edinburgh Self-Rating Postpartum Depression Scale; Cox JL, et al., Br. J. Psychiatry., 1987, 150, 782). SHAPS contains the following 14 questions.

[0158] 1) Can you enjoy your favorite TV or radio programs?

[0159] 2) Are you happy when you are with your family or friends?

[0160] 3) Do you enjoy your hobbies or leisure time?

[0161] 4) Can you enjoy your favorite dishes?

[0162] 5) Does it feel refreshing and comfortable after taking a hot bath or shower?

[0163] 6) Are the smells of flowers, sea breeze, and freshly baked bread pleasant?

[0164] 7) Do other people's smiles make you feel calm?

[0165] 8) Do you feel happy when you tidy yourself up?

[0166] 9) Are books, magazines, or newspapers interesting?

[0167] 10) Is drinking tea, coffee, or your favorite beverage enjoyable?

[0168] 11) Can you find joy in trivial things (such as a sunny day, a call from a friend, etc.)?

[0169] 12) Does seeing beautiful scenery soothe the eyes?

[0170] 13) Do you feel happy after helping others?

[0171] 14) Do you feel happy when you are praised?

[0172] One aspect of the present invention is a pharmaceutical composition containing a selective DOR agonist as an active ingredient that improves anhedonia-related questionnaire scores. More specifically, one aspect of the present invention is a pharmaceutical composition containing a selective DOR agonist as an active ingredient that, for example, enables individuals to enjoy their favorite TV programs or radio shows more, feel happier when with family or friends, enjoy their hobbies or leisure time more, enjoy their favorite dishes more, feel refreshed and comfortable after a hot bath or shower, feel more pleasant to the smell of flowers, sea breeze, or freshly baked bread, feel calmer when others smile, feel happier when grooming themselves, find reading, magazines, or newspapers more interesting, feel more pleasant when drinking tea, coffee, or their favorite beverages, feel more joy in trivial matters, feel more soothed by beautiful scenery, feel happier after helping others, feel happier when in love with or liking someone of the opposite sex, or be liked by someone of the opposite sex, or feel happier when praised. In another embodiment of the present invention, the selective DOR agonist is a compound having a morphine skeleton, and preferably the selective DOR agonist is a compound that further has MOR antagonistic and KOR antagonistic effects.

[0173] As a method for measuring anhedonia, as per this invention, the Effort-Expenditure for Rewards Task (EEfRT) (Treadway et al., PLoS One, 2009, 4, e65982009) is sometimes employed. In EEfRT, participants repeatedly press buttons within a specified time to complete a task, and receive a reward upon completion. Besides EEfRT, there is also the Progressive Ratio Task (PRT) (Wolf et al., Schizophrenia Bulletin, 2014, 40, 1328). PRT involves performing a required number of repetitions of the larger of two numbers displayed on a selection screen, and receiving a reward upon completion.

[0174] One aspect of the present invention is a pharmaceutical composition containing a selective DOR agonist as an active ingredient, which enhances the reward obtained through EEfRT or PRT. For example, compared with not administering the pharmaceutical composition or before administering the pharmaceutical composition, it is preferable that administering the pharmaceutical composition increases the reward by 1% or more, 3% or more, 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 70% or more, 100% or more, or 200% or more. Furthermore, in another aspect of the present invention, the selective DOR agonist is a compound having a morphine skeleton, preferably a compound that further has MOR antagonistic and KOR antagonistic effects.

[0175] The anhedonia involved in this invention is a symptom associated with various diseases. Diseases accompanied by anhedonia include those caused by dopamine system disorders, reward system dysfunction, and cognitive impairment. Specifically, examples include depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorders, alcohol dependence, nicotine dependence, eating disorders, neurotic disorders (PTSD, etc.), autism spectrum disorders, and Alzheimer's dementia. One aspect of this invention is a pharmaceutical composition containing a selective DOR agonist as an active ingredient, used for the treatment or prevention of anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorders, alcohol dependence, nicotine dependence, eating disorders, neurotic disorders (PTSD, etc.), autism spectrum disorders, or Alzheimer's dementia. Furthermore, in another aspect of this invention, the selective DOR agonist is a compound having a morphine skeleton, preferably a compound further having MOR antagonistic and KOR antagonistic effects.

[0176] Another aspect of the present invention is a pharmaceutical composition for the prevention or treatment of depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorders, alcohol dependence, nicotine dependence, eating disorders, neurotic disorders (PTSD, etc.), autism spectrum disorders, or Alzheimer's dementia, containing a selective DOR agonist as an active ingredient; particularly, a pharmaceutical composition that inhibits anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorders, alcohol dependence, nicotine dependence, eating disorders, neurotic disorders (PTSD, etc.), autism spectrum disorders, or Alzheimer's dementia. Yet another aspect of the present invention is a pharmaceutical composition for the treatment or prevention of depression, containing a selective DOR agonist as an active ingredient; particularly, a pharmaceutical composition that inhibits anhedonia associated with depression.

[0177] The anhedonia involved in this invention is caused, for example, by stress. In this specification, "stress" (also called "stressor") refers to stimuli from outside the body. Stress includes physical stress (high or low temperature, humidity, noise or vibration, violence, or electric shock, etc.), chemical stress (hypoxia, drug damage, or malnutrition, etc.), biological stress (diseases such as pathogens or sleep deprivation, etc.), and psychological stress (bullying, various forms of harassment such as workplace harassment / psychological harassment, death, marriage, divorce, separation, disputes with others, or the accompanying mental anguish such as moving, changing jobs, disputes with others, or debt, etc.). In this specification, stresses that directly affect the body, such as physical, chemical, or biological stresses, are described as "physical stress."

[0178] One aspect of the present invention is a pharmaceutical composition containing a selective DOR agonist as an active ingredient for treating or preventing anhedonia caused by mental or physical stress. In another aspect of the present invention, the selective DOR agonist is a compound having a morphine skeleton, preferably a compound further having MOR antagonistic and KOR antagonistic effects.

[0179] The pharmaceutical composition for the treatment or prevention of anhedonia according to the present invention can also be evaluated using animal models. Examples of animal models include the FUST (Non-Patent Document 9) and the sucrose preference test (Non-Patent Document 10).

[0180] One aspect of the present invention is a pharmaceutical composition containing a selective DOR agonist as an active ingredient, which improves reduced female urine snorting behavior and / or reduced sucrose preference. Another aspect of the present invention is a pharmaceutical composition containing a selective DOR agonist as an active ingredient, which, compared with a control group not given medication, improves sucrose preference by 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, or to the normal level without stress. A third aspect of the present invention is a pharmaceutical composition containing a selective DOR agonist as an active ingredient, which, compared with a control group not given medication, improves reduced female urine snorting behavior by 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, or to the normal level without stress.

[0181] In this specification, "suicidal ideation" refers to thoughts about suicide or a particular focus on suicide, or thoughts of ending one's life or not wanting to live anymore without necessarily actively attempting to do so. Anhedonia is the strongest predictor of suicidal ideation among depressive symptoms.

[0182] One aspect of the present invention is a pharmaceutical composition containing a selective DOR agonist as an active ingredient for inhibiting, improving, alleviating, treating, or preventing suicidal ideation. Furthermore, another aspect of the present invention is a pharmaceutical composition containing a selective DOR agonist as an active ingredient for inhibiting or preventing suicide.

[0183] In another embodiment of the present invention, the selective DOR agonist is a compound having a morphine skeleton, and preferably the selective DOR agonist is a compound that further has MOR antagonistic and KOR antagonistic effects.

[0184] In this specification, "inhibition" refers to the concept of stopping or slowing the worsening or progression of symptoms, states, or diseases, and the actions or means for doing so, as well as improving said symptoms, states, or diseases or the actions or means for doing so. The "worsening or progression of symptoms, states, or diseases" includes the worsening or progression of "pathological" or "abnormal" symptoms, states, or diseases, and the worsening or progression of symptoms, states, or diseases from a "healthy" or "normal" state to a "pathological" or "abnormal" state. In one embodiment, "inhibition" means stopping or slowing the worsening or progression of symptoms, states, or diseases, or the actions or means for doing so. In another embodiment, "inhibition" means stopping or slowing the worsening or progression of symptoms, states, or diseases. Here, "improvement" refers to the concept of bringing "pathological" or "abnormal" symptoms, states, or diseases closer to a "healthy" or "normal" state, or the actions or means for doing so, as well as bringing them to a "healthy" or "normal" state, or the actions or means for doing so. Therefore, in one embodiment, "improvement" includes causing the value of an indicator of a "pathological" or "abnormal" symptom or state to decrease or increase with said "improvement," approaching or reaching a normal value. In this specification, "relief" can be a concept that includes the aforementioned "improvement".

[0185] In this specification, "treatment" means the disappearance, eradication, cure, or relief of "pathological" or "abnormal" symptoms, states, or diseases, and the actions or means for doing so, including "suppressing" the worsening of "pathological" or "abnormal" symptoms, states, or diseases, and the actions or means for doing so, and also includes the concept of "improvement." In one embodiment, "treatment" means the disappearance, eradication, cure, or relief of "pathological" or "abnormal" symptoms, states, or diseases, and the actions or means for doing so. In another embodiment, "treatment" means the disappearance, eradication, cure, or relief of "pathological" or "abnormal" symptoms, states, or diseases.

[0186] In this specification, "prevention" refers to the concept of preventing the onset of "pathological" or "abnormal" symptoms, states, or diseases in advance, as well as the actions or means to do so.

[0187] 2. Delta opioid receptor agonists (DOR agonists)

[0188] In this specification, "δ-opioid receptor agonist" refers to a substance that, by binding to DOR, elicits a biological response that is the same as or similar to that of an endogenous ligand.

[0189] "Selective DOR agonist" refers to a substance with a relatively strong DOR agonist effect compared to the effects of μ-opioid receptor agonists (MOR agonists) and κ-opioid receptor agonists (KOR agonists). Preferably, it is a substance that has DOR agonist activity and very weak or no MOR and KOR agonist activity. More preferably, it is a substance that has DOR agonist activity, no MOR and KOR agonist activity, and KOR antagonist activity. Even more preferably, it is a substance that has DOR agonist activity, no MOR and KOR agonist activity, and MOR and KOR antagonist activities. Here, "MOR antagonist" or "KOR antagonist" refers to a substance that binds to MOR or KOR, but unlike the endogenous ligand, does not elicit a biological response, or, through its binding, prevents the binding of the endogenous ligand that would normally bind to the receptor, thereby preventing a biological response from the endogenous ligand.

[0190] The "selective DOR agonist" of the present invention, according to the method described in Patent Document 7, has EC 50 Values ​​below 30 nM, below 10 nM, below 3 nM, below 1 nM, below 0.3 nM, or below 0.1 nM, relative to the DOR agonist activity of SNC80, have an E max For 50% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or more.

[0191] The "selective DOR agonist" of the present invention preferably further possesses KOR antagonistic activity. According to the method described in Patent Document 8, the IC50 of the "selective DOR agonist" of the present invention relative to 100 nM U-69593 is... 50 Values ​​below 100nM, below 30nM, below 20nM, below 15nM, below 10nM, or below 5nM.

[0192] The "selective DOR agonist" of the present invention preferably further possesses MOR antagonistic activity. According to the method described in Patent Document 8, the IC50 of the "selective DOR agonist" of the present invention relative to 30 nM DAMGO... 50 Values ​​below 100nM, below 30nM, below 20nM, below 15nM, below 10nM, or below 5nM.

[0193] The "selective DOR agonist" of the present invention preferably further possesses KOR antagonistic and MOR antagonistic effects. According to the method described in Patent Document 8, relative to the effect of 100 nM U-69593 on KOR and the effect of 30 nM DAMGO on MOR, the IC50 of the "selective DOR agonist" of the present invention... 50 Values ​​below 100nM, below 30nM, below 20nM, below 15nM, below 10nM, or below 5nM.

[0194] In this specification, "morphinan skeleton" refers to a fused ring structure associated with morphinan. The selective DOR agonists of the present invention, having a morphinan skeleton, comprise compounds having a morphinan skeleton, which may be further substituented and fused with other rings.

[0195] One embodiment of the pharmaceutical composition of the present invention contains a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, i.e., a selective DOR agonist, as the active ingredient.

[0196] In this specification, as C 1-6 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, neopentyl, or hexyl.

[0197] As C 1-10 Alkyl groups, excluding the C groups mentioned above 1-6 In addition to alkyl groups, other examples include heptyl or octyl groups.

[0198] As C is replaced by 1 to 3 halogens 1-6 Alkyl groups, for example, include 2-chloroethyl, 2-fluoroethyl, 3-fluoropropyl, 2,2-difluoroethyl, trifluoromethyl, or 3,3,3-trifluoropropyl.

[0199] As C 2-6 Alkenyl groups, for example, include 2-propenyl or 3-methyl-2-butenyl.

[0200] Examples of cycloalkyl groups with 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety include those with carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3-6 Cycloalkyl-substituted methyl or ethyl compounds, etc.

[0201] Aryl groups having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety include benzyl or phenethyl.

[0202] As C 3-6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0203] As C 6-10Aryl groups can be exemplified by phenyl or naphthyl groups.

[0204] The heteroaryl group comprising 1 to 4 heteroatoms selected from N, O and S as ring constituent atoms is preferred, with 5 or 6-membered heteroaryl groups being examples, such as pyridyl, furanyl, imidazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl or thiazolyl.

[0205] The heteroaryl moiety comprises 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the alkylene moiety has 1 to 5 carbon atoms. Heteroaryl alkyl moieties having 5 or 6 members are preferred. Examples include (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl, (furan-2-yl)methyl, (furan-3-yl)methyl, (imidazol-2-yl)methyl, (imidazol-4-yl)methyl, (imidazol-5-yl)methyl, (thiazol-2-yl)methyl, (thiazol-4-yl)methyl, (thiazol-5-yl)methyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(pyridol-1-yl)ethyl, 2-(thiophen-2-yl)ethyl, or 2-(thiophen-3-yl)ethyl.

[0206] As C 1-6 Alkyl groups, such as acetyl or propionyl groups, can be examples.

[0207] As C 1-6 Alkoxy groups, such as methoxy, ethoxy, or propoxy, can be examples.

[0208] As C 1-6 Alkyloxy groups, such as acetoxy groups, can be cited as examples.

[0209] Examples of alkoxycarbonyl groups with 1 to 6 carbon atoms as the alkoxy moiety include methoxycarbonyl or ethoxycarbonyl.

[0210] Examples of halogens include fluorine, chlorine, bromine, and iodine.

[0211] As C is replaced by 1 to 3 halogens 1-6 Alkyl groups, for example, include fluoromethoxy or trifluoromethoxy.

[0212] C is replaced by 1 to 6 halogens. 1-6 Alkyl groups, except for those C groups substituted with 1 to 3 halogens as described above. 1-6 Besides alkoxy groups, tetrafluoroethoxy groups can also be cited.

[0213] Examples of phenylalkyl groups having 1 to 3 carbon atoms include benzyl groups.

[0214] As C 6-10 Aryloxy groups, such as phenoxy groups, can be cited as examples.

[0215] As C1-8 Alkylamino groups, such as methylamino or ethylamino, are examples.

[0216] Acylamino groups with 2 to 6 carbon atoms as the acyl group can be exemplified by acetamido groups.

[0217] As C 6-10 Arylamino groups, such as phenylamino groups, can be cited as examples.

[0218] Examples of alkyl carbamoyl groups with 1 to 6 carbon atoms as the alkyl moiety include ethyl carbamoyl groups.

[0219] Examples of dialkylcarbamoyl groups having 1 to 6 carbon atoms as the alkyl moiety include diethylcarbamoyl.

[0220] Alkyl sulfonyl groups having 1 to 6 carbon atoms as alkyl moiety can be exemplified by methyl sulfonyl groups.

[0221] Alkyl sulfinyl groups having 1 to 6 carbon atoms as alkyl moiety can be exemplified by methyl sulfinyl groups.

[0222] Examples of alkylthio groups with 1 to 6 carbon atoms as alkyl moiety include methylthio.

[0223] Examples of aryl carbonyl groups with 6 to 10 carbon atoms as the aryl moiety include benzoyl group.

[0224] R in the above general formula (I) 11 and R 12 Examples of 5- to 7-membered rings formed with the nitrogen atom bonded to them and, as needed, 1 to 2 heteroatoms include pyrrolidine, piperidine, or morpholine.

[0225] R in the above general formula (I) 2 Examples of heterocycles or pyridine 1-oxides comprising 1 to 4 heteroatoms selected from N, O, and S and at least 1 carbon atom as ring-forming atoms, wherein at least one group of adjacent ring-forming atoms has a double bond and is subsequently substituted by at least 1 oxo group include:

[0226] (A) Pyridine 1-oxide, or 2-methylpyridine 1-oxide, etc., can be made from C selected from those substituted with 1 to 3 fluorine atoms. 1-10 Alkyl groups and unsubstituted C 1-10 1-oxides of pyridine substituted with 1 to 4 substituents in the alkyl group,

[0227] (B) 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, etc., can be derived from C-type carbon atoms substituted with 1 to 3 fluorine atoms.1-10 Alkyl groups and unsubstituted C 1-10 pyridine-2(1H)-ones substituted with 1 to 4 substituents in the alkyl group,

[0228] (C) Pyridin-4(1H)-one, 1-methylpyridin-4(1H)-one, 1-ethylpyridin-4(1H)-one, or 1-(fluoroethyl)pyridin-4(1H)-one, etc., can be derived from C atoms substituted with 1 to 3 fluorine atoms. 1-10 Alkyl groups and unsubstituted C 1-10 pyridine-4(1H)-ones substituted with 1 to 4 substituents in the alkyl group,

[0229] (D) Pyridazin-3(2H)-one or 2-methylpyridazin-3(2H)-one, etc., can be derived from C-type carbon atoms substituted with 1 to 3 fluorine atoms. 1-10 Alkyl groups and unsubstituted C 1-10 pyridazine-3(2H)-ones with 1 to 3 substituents in the alkyl group,

[0230] (E) Pyrazin-2(1H)-one or 1-methylpyrazin-2(1H)-one, etc., can be derived from C-type carbon atoms substituted with 1 to 3 fluorine atoms. 1-10 Alkyl groups and unsubstituted C 1-10 Pyrazine-2(1H)-ones with 1 to 3 substituents in the alkyl group,

[0231] (F) 4H-pyran-4-one, 3-methyl-4H-pyran-4-one, 2H-pyran-2-one, or 5-methyl-2H-pyran-2-one, etc., can be derived from C atoms selected from those substituted with 1 to 3 fluorine atoms. 1-10 Alkyl groups and unsubstituted C 1-10 4H-pyran-4-one or 2H-pyran-2-one substituted with 1 to 3 substituents in the alkyl group,

[0232] (G) Quinoline-2(1H)-one, 6-methylquinoline-2(1H)-one, quinoline 1-oxide, or 4-methylquinoline 1-oxide, etc., can be derived from C atoms selected from those substituted with 1 to 3 fluorine atoms. 1-10 Alkyl groups and unsubstituted C 1-10 Quinoline-2(1H)-one or quinoline 1-oxide substituted with 1 to 3 substituents in the alkyl group,

[0233] (H) Pyrimidine-4(3H)-one or pyrimidine-2,4(1H,3H)-dione, etc., can be derived from C-type carbon atoms substituted with 1 to 3 fluorine atoms. 1-10 Alkyl groups and unsubstituted C 1-10 Pyrimidine-4(3H)-one or pyrimidine-2,4(1H,3H)-dione substituted with 1 to 3 substituents in the alkyl group.

[0234] One aspect of the present invention is a pharmaceutical composition for the treatment or prevention of anhedonia, comprising the following compounds or pharmaceutically acceptable salts thereof as active ingredients:

[0235] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide,

[0236] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide,

[0237] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0238] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide,

[0239] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0240] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,

[0241] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0242] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one,

[0243] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,

[0244] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,

[0245] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0246] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,

[0247] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-4(1H)-one,

[0248] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-4(1H)-one,

[0249] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,

[0250] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridazine-3(2H)-one,

[0251] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)quinoline-2(1H)-one,

[0252] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one,

[0253] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one,

[0254] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one,

[0255] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrazine-2(1H)-one,

[0256] 2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide,

[0257] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0258] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrazine-2(1H)-one,

[0259] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,

[0260] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-2(1H)-one,

[0261] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one, or

[0262] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-2(1H)-one.

[0263] The compounds represented by the above general formula (I) sometimes exist as tautomers, stereoisomers or pharmaceutically acceptable salts or solvates thereof.

[0264] Examples of tautomers of compounds represented by the above general formula (I) include the above-mentioned R. 2 The tautomer of a heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S as ring-forming atoms and at least one carbon atom, wherein at least one group of adjacent ring-forming atoms has a double bond and is subsequently substituted by at least one oxo group, for example, with R 2 The 2-hydroxypyridine (lactam type) corresponding to 2-pyridone (lactam type) belongs to this category.

[0265] Among the compounds represented by the above general formula (I), tautomers, stereoisomers of the compound, or pharmaceutically acceptable salts or solvates thereof, acid addition salts are preferably cited as pharmaceutically acceptable salts. Examples of acid addition salts include salts of hydrochloride, sulfate, fumarate, oxalate, methanesulfonate, or camphorsulfonate with organic or inorganic acids.

[0266] Among the compounds represented by the above general formula (I), tautomers, stereoisomers of the compound, or pharmaceutically acceptable salts or solvates thereof, cis-trans isomers, racemates, or optically active isomers may be cited as stereoisomers.

[0267] Among the compounds represented by the above general formula (I), tautomers, stereoisomers of the compounds, or pharmaceutically acceptable salts thereof, or solvates thereof, pharmaceutically acceptable solvates of the compounds of the present invention or their salts, including hydrates, can be cited as examples of pharmaceutically acceptable solvates.

[0268] In addition, the compounds represented by the above general formula (I), their tautomers, stereoisomers, or pharmaceutically acceptable salts or solvates thereof may also be prodrugs that are chemically modified to transform into pharmacologically active substances in vivo or upon reaching the target site, thereby exerting (activating) pharmacological effects.

[0269] As such prodrugs, for example, when the prodrug constitutive group is present in a hydroxyl group, common hydroxyl protecting groups such as lower acyl groups and lower alkoxycarbonyl groups can be cited; when it is present in a nitrogen atom, common amino protecting groups such as lower acyl groups and lower alkoxycarbonyl groups can be cited; or prodrug groups introduced into the carboxylic acid site can be cited, such as neopentyloxymethyl (tBu-C(O)O-CH2-), (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)methyl (Medoxomil), or 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl (Cilexetil), etc.

[0270] Furthermore, compounds represented by the above general formula (I), tautomers of the compound, stereoisomers of the compound, or pharmaceutically acceptable salts or solvates thereof may also be substituted with stable isotopes such as deuterium.

[0271] The compound represented by the above general formula (I), its tautomers, stereoisomers or pharmaceutically acceptable salts or solvates thereof can be manufactured, for example, by methods known per se, such as International Publication No. 2018 / 052114.

[0272] The compounds represented by the above general formula (I), their tautomers, stereoisomers, or pharmaceutically acceptable salts or solvates thereof, exhibit superior agonistic activity and selectivity for DOR compared to μ and κ opioid receptors.

[0273] Therefore, compounds represented by the above general formula (I), tautomers, stereoisomers of the compound, or pharmaceutically acceptable salts or solvates thereof may be used as active ingredients in pharmaceutical compositions that exert selective DOR agonist effects.

[0274] Furthermore, compounds represented by the above general formula (I), their tautomers, stereoisomers, or pharmaceutically acceptable salts or solvates thereof exhibit excellent stability to the metabolism of human liver microsomes.

[0275] Therefore, compounds represented by the above general formula (I), tautomers, stereoisomers of the compound, or pharmaceutically acceptable salts or solvates thereof may be used as active ingredients in oral pharmaceutical compositions.

[0276] 3. Pharmaceutical Composition

[0277] The pharmaceutical compositions provided by the present invention can be administered orally or non-orally to humans or other mammals. Examples of non-oral administration include intravenous administration, subcutaneous administration, intramuscular administration, intra-articular administration, mucosal administration, transdermal administration, nasal administration, rectal administration, or intrathecal administration.

[0278] The pharmaceutical compositions provided by the present invention can be prepared by directly using the above-mentioned selective DOR agonists or compounds represented by the above general formula (I), tautomers, stereoisomers of the compounds, or pharmaceutically acceptable salts or solvates thereof, or by mixing with pharmaceutically acceptable carriers, such as excipients (e.g., lactose, D-mannitol, crystalline cellulose, or glucose), binders (e.g., hydroxypropyl cellulose (HPC), gelatin, or polyvinylpyrrolidone (PVP)), lubricants (e.g., magnesium stearate or talc), disintegrants (e.g., starch or calcium carboxymethyl cellulose (CMC-Ca)), diluents (e.g., water for injection or physiological saline), or additives (e.g., pH adjusters, surfactants, solubilizers, preservatives, emulsifiers, isotonic agents, or stabilizers) as necessary, and can be in dosage forms such as tablets, granules, powders, capsules, suspensions, injections, or suppositories. For example, when formulating tablets, a compound represented by the above general formula (I), its tautomers, stereoisomers or pharmaceutically acceptable salts or solvates thereof may be mixed with excipients (e.g., lactose, D-mannitol, crystalline cellulose or glucose), disintegrants (e.g., starch or calcium carboxymethyl cellulose (CMC-Ca)), binders (e.g., hydroxypropyl cellulose (HPC), gelatin or polyvinylpyrrolidone (PVP)) or lubricants (e.g., magnesium stearate or talc) to form the tablet. For example, when preparing an injection, the compound represented by the above general formula (I), its tautomers, stereoisomers or pharmaceutically acceptable salts or solvates thereof can be mixed with a dispersant (e.g., surfactants such as Tween80, carboxymethyl cellulose, sodium alginate, hyaluronic acid or other polysaccharides or polysorbates), a preservative (e.g., methylparaben or propylparaben), an isotropic agent (e.g., sodium chloride, mannitol, sorbitol or glucose) or a pH adjuster (e.g., sodium phosphate or potassium phosphate) to form the preparation.

[0279] The pharmaceutical compositions provided by the present invention may contain an amount of the compound represented by the above general formula (I), a tautomer of the compound, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof or a solvate thereof that is effective in treating or preventing anhedonia.

[0280] In one embodiment, the pharmaceutical composition provided by the present invention may comprise an amount of the compound represented by the above general formula (I) or a pharmaceutically acceptable solvate (e.g., hydrate) thereof, or a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable solvate (e.g., hydrate) thereof, which is effective in treating or preventing anhedonia.

[0281] In one embodiment, the pharmaceutical composition provided by the present invention may comprise an amount of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt of the compound that is effective in treating or preventing anhedonia.

[0282] The dosage of the compound represented by the above general formula (I), its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or their solvates, may be appropriately determined according to the type of salt, the method of administration, the symptoms of the recipient, age, etc. For example, when the compound represented by the above general formula (I), its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or their solvates are administered orally to humans, the dosage may be 1 μg to 10 g / day, preferably 0.01 to 2000 mg / day, more preferably 0.1 to 100 mg / day; when administered intravenously to humans, the dosage may be 0.1 μg to 1 g / day, preferably 0.001 to 200 mg / day. It may be administered in 1 to 3 divided doses daily.

[0283] The present invention also has the following aspects.

[0284] <1a> A method for treating or preventing anhedonia, comprising administering a therapeutically effective amount of a selective delta opioid receptor agonist to a subject in need of such anhedonia (e.g., a mammal including a human);

[0285] <2a> According to the method of <1a>, wherein the selective δ-opioid receptor agonist further has κ-opioid receptor antagonistic activity;

[0286] <3a> According to the method of <1a> or <2a>, wherein the selective δ opioid receptor agonist further has μ opioid receptor antagonistic activity and κ opioid receptor antagonistic activity;

[0287] <4a> The method according to any one of <1a> to <3a>, wherein the anhedonia is anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder, autism spectrum disorder or Alzheimer's disease.

[0288] <5a>The method according to any one of <1a> to <4a>, wherein the anhedonia is caused by mental stress or physical stress;

[0289] <6a> The method according to any one of <1a> to <5a> suppresses suicidal ideation;

[0290] <7a>The method according to any one of <1a> to <6a>, wherein the loss of pleasure is a reduced responsiveness to pleasurable experiences related to at least one of the following: money, food, hobbies, entertainment, travel and leisure, and desire for dominance, desire for recognition, desire for achievement, desire for affiliation and sexual desire;

[0291] <1b> Selective delta opioid receptor agonists for the treatment or prevention of anhedonia, or pharmaceutical compositions containing a selective delta opioid receptor agonist as an active ingredient;

[0292] <2b> A selective delta opioid receptor agonist or a pharmaceutical composition containing a selective delta opioid receptor agonist as an active ingredient, according to the use described in <1b>, wherein the selective delta opioid receptor agonist further has κ opioid receptor antagonistic activity.

[0293] <3b> A selective delta opioid receptor agonist or a pharmaceutical composition containing a selective delta opioid receptor agonist as an active ingredient, according to the use described in <1b> or <2b>.

[0294] <4b> A selective delta opioid receptor agonist or a pharmaceutical composition containing a selective delta opioid receptor agonist as an active ingredient for the use according to any one of <1b> to <3b>, wherein the anhedonia is anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder, autism spectrum disorder or Alzheimer's disease;

[0295] <5b> A selective delta opioid receptor agonist or a pharmaceutical composition containing a selective delta opioid receptor agonist as an active ingredient for use according to any one of <1b> to <4b>, wherein the anhedonia is anhedonia caused by mental or physical stress;

[0296] <6b>A selective delta opioid receptor agonist or a pharmaceutical composition containing a selective delta opioid receptor agonist as an active ingredient, for use according to any one of <1b> to <5b>, which inhibits suicidal ideation;

[0297] <7b> A selective delta opioid receptor agonist or a pharmaceutical composition containing a selective delta opioid receptor agonist as an active ingredient for use according to any one of <1b> to <6b>, wherein the anhedonia is a reduced responsiveness to pleasurable experiences related to at least one of money, food, hobbies, entertainment, travel and leisure, and dominance, recognition, achievement, affinity and sexuality.

[0298] <1b'>A selective delta-opioid receptor agonist or a pharmaceutical composition containing a selective delta-opioid receptor agonist as an active ingredient for the treatment or prevention of depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder (PTSD, etc.), autism spectrum disorder or Alzheimer's disease, especially for the inhibition of anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder (PTSD, etc.), autism spectrum disorder or Alzheimer's disease;

[0299] <2b'>A selective delta opioid receptor agonist or a pharmaceutical composition containing a selective delta opioid receptor agonist as an active ingredient according to the use described in <1b'>, wherein the selective delta opioid receptor agonist further has κ opioid receptor antagonistic activity.

[0300] <3b'>A selective delta opioid receptor agonist or a pharmaceutical composition containing a selective delta opioid receptor agonist as an active ingredient, according to the use described in <1b'> or <2b'>.

[0301] <4b'>A selective delta opioid receptor agonist or a pharmaceutical composition containing a selective delta opioid receptor agonist as an active ingredient for use according to any one of <1b'> to <3b'>, wherein the anhedonia is anhedonia caused by mental or physical stress;

[0302] <5b'>A selective delta opioid receptor agonist or a pharmaceutical composition containing a selective delta opioid receptor agonist as an active ingredient, for use according to any one of <1b'> to <4b'>, which inhibits suicidal ideation;

[0303] <6b'>A selective delta opioid receptor agonist or a pharmaceutical composition containing a selective delta opioid receptor agonist as an active ingredient for the use according to any one of <1b'> to <5b'>, wherein the anhedonia is a reduced responsiveness to pleasurable experiences related to at least one of money, food, hobbies, entertainment, travel and leisure, and dominance, recognition, achievement, affinity and sexuality.

[0304] <1c> Use of selective delta opioid receptor agonists in the preparation of pharmaceutical compositions for the treatment or prevention of anhedonia;

[0305] <2c> According to the use described in <1c>, wherein the selective δ-opioid receptor agonist further has κ-opioid receptor antagonistic activity;

[0306] <3c> According to the use described in <1c> or <2c>, wherein the selective δ-opioid receptor agonist further has μ-opioid receptor antagonistic activity and κ-opioid receptor antagonistic activity;

[0307] <4c> The use according to any one of <1c> to <3c>, wherein the anhedonia is anhedonia associated with depression, Parkinson's disease, obsessive-compulsive disorder, schizophrenia, substance use disorder, alcohol dependence, nicotine dependence, eating disorder, neurotic disorder, autism spectrum disorder or Alzheimer's disease.

[0308] <5c> The use according to any one of <1c> to <4c>, wherein the anhedonia is anhedonia caused by mental stress or physical stress;

[0309] <6c>The use according to any one of <1c> to <5c>, wherein the pharmaceutical composition for the treatment or prevention of anhedonia inhibits suicidal ideation;

[0310] <7c> The use according to any one of <1c> to <6c>, wherein the anhedonia is a reduced responsiveness to pleasurable experiences related to at least one of the following: money, food, hobbies, entertainment, travel and leisure, and desire for dominance, desire for recognition, desire for achievement, desire for affiliation and sexual desire;

[0311] <8d>A method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'> and <1c> to <7c>, wherein the selective δ-opioid receptor agonist is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;

[0312] <9d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in the compound represented by general formula (I) described in <8d>, R 5 R 6a R 6b R 7 R 8 R 9 and R 10 It is hydrogen.

[0313] R 1 It is hydrogen; C 1-6 Alkyl; C 2-6 Alkenyl; cycloalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or aralkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety.

[0314] R 2 This refers to a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as a ring-forming atom, wherein at least one group of adjacent ring-forming atoms has a double bond and is subsequently substituted by at least one oxo group, or a heterocycle formed by fusion of the heterocycle with a benzene ring, or a pyridine 1-oxide.

[0315] Among them, R 2 Intermediate as R 2 The carbon atom of the ring-forming atom is bonded to Y.

[0316] R 3 and R 4 Same or different, is hydrogen; hydroxyl; halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 6-10 aryloxy group; C 1-6 Alkyloxy; amino; or acylamino with 2 to 6 carbon atoms in the acyl moiety.

[0317] X is CH2.

[0318] Moreover, Y is C (=O).

[0319] Among them, R 1 C 1-6 Alkyl; cycloalkyl moiety having 3 to 6 carbon atoms and alkylene moiety having 1 to 5 carbon atoms in cycloalkyl; or aryl moiety having 6 to 10 carbon atoms and alkylene moiety having 1 to 5 carbon atoms in aryl; the alkylene moiety may be selected from 1 to 6 halogens; hydroxyl group; C 1-6 Alkoxy; C 6-10 aryloxy group; C 1-6Alkyl group; C 1-6 Alkyloxy group; carboxyl group; alkoxycarbonyl group with 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl group; alkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; alkylsulfonyl group with 1 to 6 carbon atoms in the alkyl moiety; aminosulfonyl group; alkylsulfinyl group with 1 to 6 carbon atoms in the alkyl moiety; alkylthio group with 1 to 6 carbon atoms in the alkyl moiety; C substituted with 1 to 6 halogens 1-6 The alkoxy group; and at least one substituent in the aryl carbonyl group having 6 to 10 carbon atoms, are substituted.

[0320] Moreover, R 1 The aryl moiety of an aryl group having 6 to 10 carbon atoms and the alkylene moiety having 1 to 5 carbon atoms; and R 3 and R 4 C 6-10 The aryl moiety of the aryl group can be selected from C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxy group; hydroxyl group; alkoxycarbonyl group with 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl group; alkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; halogen; nitro group; cyano group; C atoms substituted with 1 to 3 halogens. 1-6 Alkyl group; C atoms substituted with 1 to 3 halogens 1-6 Alkoxy; phenyl; heteroaryl group comprising 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; phenoxy; phenylalkyl group having 1 to 3 carbon atoms; and at least one substituent selected from methylenedioxy.

[0321] R 2 In addition to oxo groups, the heterocycles can also have the aforementioned R groups. 1 The aryl moiety of an aryl group having 6 to 10 carbon atoms and the alkylene moiety having 1 to 5 carbon atoms may have substituents, and R 2 The 1-oxide of pyridine can have the above-mentioned R 1 The aryl moiety of an aryl group having 6 to 10 carbon atoms and the alkylene moiety having 1 to 5 carbon atoms may have substituents.

[0322] In addition, R 1 The alkylene moiety having 6 to 10 carbon atoms in the aryl group and 1 to 5 carbon atoms in the alkylene moiety can be selected from phenyl or C6 groups substituted with 1 to 3 halogens. 1-6 At least one substituent in the alkyl group is substituted;

[0323] <10d>The method, use, or pharmaceutical composition according to any one of <1a>~<7a>, <1b>~<7b>, <1b'>~<6b'>, and <1c>~<7c>, wherein, in the compound represented by general formula (I) described in <8d> or <9d>, R 1 C 1-6 Alkyl; cycloalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or aralkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety;

[0324] <11d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <8d> to <10d>, R is a compound of general formula (I). 1 It is a cycloalkyl group in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms;

[0325] <12d>The method, use, or pharmaceutical composition according to any one of <1a>~<7a>, <1b>~<7b>, <1b'>~<6b'>, and <1c>~<7c>, wherein, in the compound represented by general formula (I) described in <8d> or <9d>, R 1 C substituted with hydroxyl group 2-6 Alkyl group; C atoms substituted with 1 to 6 halogens 1-6 Alkyl; or C 1-6 alkoxy-substituted C 2-6 alkyl;

[0326] <13d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in the compound represented by general formula (I) described in <8d> or <9d>, R 1 It is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methanesulfonyl)ethyl or 2-(aminosulfonyl)ethyl;

[0327] <14d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <8d> to <13d>, R is a compound of general formula (I). 2It is a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O and S and at least 1 carbon atom as ring constituent atoms, and at least one group of adjacent ring constituent atoms having double bonds and being replaced by at least 1 oxo group, or a heterocycle or pyridine 1-oxide formed by fusion of the heterocycle with a benzene ring.

[0328] <15d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <8d> to <14d>, R 2 It is a 1-oxide of pyridine;

[0329] <16d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <8d> to <14d>, R is a compound of general formula (I). 2 The heterocycle is pyridine-2(1H)-one;

[0330] <17d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <8d> to <14d>, R 2 The heterocycle is pyridine-4(1H)-one;

[0331] <18d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <8d> to <14d>, R is a compound of general formula (I). 2 The heterocycle is pyridazine-3(2H)-one;

[0332] <19d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <8d> to <14d>, R is a compound of general formula (I). 2 The heterocycle is pyrazine-2(1H)-one;

[0333] <20d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <8d> to <14d>, R is a compound of general formula (I).2 The heterocycle is 4H-pyran-4-one or 2H-pyran-2-one;

[0334] <21d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <8d> to <14d>, R is a compound of general formula (I). 2 The heterocycle is quinoline-2(1H)-one;

[0335] <22d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <8d> to <14d>, R is a compound of general formula (I). 2 The heterocycle is pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione;

[0336] <23d>The method, use or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'> and <1c> to <7c>, wherein, in any one of <8d> and <10d> to <22d>, X is CH2 in the compound represented by general formula (I);

[0337] <24d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <8d> to <23d>, R 3 and R 4 One of them is a hydroxyl group, and the other is hydrogen.

[0338] <25d>The method, use, or pharmaceutical composition according to any one of <1a>~<7a>, <1b>~<7b>, <1b'>~<6b'>, and <1c>~<7c>, wherein, in the compound represented by general formula (I) according to any one of <8d> and <10d>~<23d>, R 3 Halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 1-6 Alkyloxy; amino; or acylamino with 2 to 6 carbon atoms in the acyl moiety, R 4 For hydrogen or hydroxyl, R 5 It is hydrogen;

[0339] <26d>The method, use, or pharmaceutical composition according to any one of <1a>~<7a>, <1b>~<7b>, <1b'>~<6b'>, and <1c>~<7c>, wherein, in the compound represented by general formula (I) according to any one of <8d> and <10d>~<23d>, R 3 Hydroxyl; carbamoyl; or C 1-6 Alkyloxy, R 4 For hydrogen, R 5 It is hydrogen;

[0340] <27d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in the compound represented by general formula (I) according to any one of <8d> and <10d> to <23d>, R 3 For hydroxyl group, R 4 For hydrogen, R 5 It is hydrogen;

[0341] <28d>The method, use, or pharmaceutical composition according to any one of <1a>~<7a>, <1b>~<7b>, <1b'>~<6b'>, and <1c>~<7c>, wherein, in the compound represented by general formula (I) according to any one of <8d> and <10d>~<23d>, R 3 R 4 and R 5 It is all hydrogen;

[0342] <29d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in the compound represented by general formula (I) according to any one of <8d> and <10d> to <28d>, R 6a R 6b R 7 R 8 R 9 and R 10 It is all hydrogen;

[0343] <30d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <9d> to <23d>, R is a compound of general formula (I). 3 Halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 1-6 Alkyloxy; amino; or acylamino with 2 to 6 carbon atoms in the acyl moiety, R 4It is hydrogen or hydroxyl;

[0344] <31d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <9d> to <23d>, R is a compound of general formula (I). 3 Hydroxyl; carbamoyl; or C 1-6 Alkyloxy, R 4 It is hydrogen;

[0345] <32d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <9d> to <23d>, R is a compound of general formula (I). 3 For hydroxyl group, R 4 It is hydrogen;

[0346] <33d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <9d> to <23d>, R is a compound of general formula (I). 3 and R 4 It is hydrogen;

[0347] <34d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, <8d>the compound represented by general formula (I) is a compound represented by the following general formula (II),

[0348]

[0349] (where R) 1 It is hydrogen; C 1-6 Alkyl; or cycloalkyl groups having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety.

[0350] R 2 This refers to a 5- to 7-membered heterocycle or pyridine 1-oxide containing one or two nitrogen atoms and at least one carbon atom as ring-forming atoms, wherein at least one group of adjacent ring-forming atoms has a double bond and is subsequently substituted by at least one oxo group.

[0351] Among them, R 2 By R 2 The carbon atom in the ring-forming atom is bonded to Y.

[0352] R3 and R 4 Same or different, is hydrogen; hydroxyl; or C 1-6 Alkoxy

[0353] Y is C (=O).

[0354] Among them, R 1 C 1-6 Alkyl; cycloalkyl group having 3 to 6 carbon atoms in the alkyl group and 1 to 5 carbon atoms in the alkylene group; the alkylene group and cycloalkyl group can be selected from 1 to 6 halogens; hydroxyl groups; and C 1-6 At least one substituent of the alkoxy group is substituted.

[0355] Moreover, R 2 In addition to oxo groups, the heterocycles can also have elements selected from C. 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxy group; hydroxyl group; alkoxycarbonyl group with 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl group; alkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; halogen; nitro group; cyano group; C atoms substituted with 1 to 3 halogens. 1-6 Alkyl group; C atoms substituted with 1 to 3 halogens 1-6 Alkoxy; phenyl; heteroaryl group comprising 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; phenoxy; phenylalkyl group having 1 to 3 carbon atoms; and at least one substituent selected from methylenedioxy.

[0356] Additionally, R 2 1-Oxides of pyridine can have a composition selected from C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyloxy group; hydroxyl group; alkoxycarbonyl group with 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl group; alkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl group with 1 to 6 carbon atoms in the alkyl moiety; halogen; nitro group; cyano group; C atoms substituted with 1 to 3 halogens. 1-6 Alkyl group; C atoms substituted with 1 to 3 halogens 1-6 Alkoxy; phenyl; heteroaryl group comprising 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; phenoxy; phenylalkyl group having 1 to 3 carbon atoms; and at least one substituent selected from methylenedioxy.

[0357] <35d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in the compound represented by general formula (II) described in <34d>, R 1 It is a cycloalkyl group, wherein the cycloalkyl group has 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety;

[0358] <36d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in the compound represented by general formula (II) described in <34d> or <35d>, R 2 For example, Equation (III), Equation (IV), Equation (V), or Equation (VI).

[0359]

[0360]

[0361]

[0362]

[0363] (In formulas III to VI, R) a It is hydrogen or C 1-6 Alkyl group (bonded to Y at the position indicated by the arrow).

[0364] <37d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <34d> to <36d>, R 3 It is a hydroxyl group;

[0365] <38d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, in any one of <34d> to <37d>, R is a compound of general formula (II). 4 It is hydrogen;

[0366] <39d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein, <8d>the compound represented by general formula (I) is at least one compound selected from the following compounds:

[0367] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide,

[0368] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide,

[0369] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0370] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide,

[0371] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0372] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,

[0373] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0374] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one,

[0375] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,

[0376] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,

[0377] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0378] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,

[0379] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-4(1H)-one,

[0380] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-4(1H)-one,

[0381] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,

[0382] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridazine-3(2H)-one,

[0383] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)quinoline-2(1H)-one,

[0384] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one,

[0385] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one,

[0386] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one,

[0387] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrazine-2(1H)-one,

[0388] 2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide,

[0389] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one,

[0390] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrazine-2(1H)-one,

[0391] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,

[0392] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-2(1H)-one,

[0393] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one, and

[0394] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-2(1H)-one;

[0395] <40d>The method, use, or pharmaceutical composition according to any one of <1a> to <7a>, <1b> to <7b>, <1b'> to <6b'>, and <1c> to <7c>, wherein the compound represented by general formula (I) in any one of <8d> and <34d> to <38d> is at least one compound selected from the following compounds:

[0396] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide;

[0397] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one;

[0398] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one;

[0399] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one;

[0400] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, and

[0401] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-2(1H)-one.

[0402] The present invention will now be described in more detail with reference to embodiments, but the invention is not limited thereto.

[0403] For the naming of the compounds in the examples, the structural formulas drawn using ChemDraw ver.14 (made by CambridgeSoft) were converted into English names using the naming algorithm built into the software, and then translated into Japanese.

[0404] Example

[0405] Example 1: Synthesis of the compound

[0406] The following compounds numbered 1 to 39 were synthesized according to the method described in Patent Document 7, and KNT-127 was synthesized according to the method described in Non-Patent Document 4.

[0407] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethbridged)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide (Example 1 of Compound No. 1 and Patent Document 7);

[0408] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethbridged)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide (Compound No. 2, Example 2 of Patent Document 7);

[0409] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one (Compound No. 3, Example 3 of Patent Document 7);

[0410] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethbridged)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide (Compound No. 4, Example 4 of Patent Document 7);

[0411] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one (Compound No. 5, Example 5 of Patent Document 7);

[0412] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one (Compound No. 6, Example 6 of Patent Document 7);

[0413] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one (Compound No. 7, Example 7 of Patent Document 7);

[0414] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one (Compound No. 8, Example 8 of Patent Document 7);

[0415] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one (Compound No. 9, Example 9 of Patent Document 7);

[0416] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one (Compound No. 10, Example 10 of Patent Document 7);

[0417] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one (Compound No. 11, Example 11 of Patent Document 7);

[0418] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione (Compound No. 12, Example 12 of Patent Document 7);

[0419] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-4(1H)-one (Compound No. 13, Example 13 of Patent Document 7);

[0420] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-4(1H)-one (Compound No. 14, Example 14 of Patent Document 7);

[0421] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one (Compound No. 15, Example 15 of Patent Document 7);

[0422] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridazine-3(2H)-one (Compound No. 16, Example 16 of Patent Document 7);

[0423] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)quinoline-2(1H)-one (Compound No. 17, Example 17 of Patent Document 7);

[0424] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one (Compound No. 18, Example 18 of Patent Document 7);

[0425] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one (Compound No. 19, Example 19 of Patent Document 7);

[0426] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one (Compound No. 20, Example 20 of Patent Document 7);

[0427] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrazine-2(1H)-one (Compound No. 21, Example 21 of Patent Document 7);

[0428] 2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethbridged)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide (Compound No. 22, Example 22 of Patent Document 7);

[0429] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one (Compound No. 23, Example 23 of Patent Document 7);

[0430] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrazine-2(1H)-one (Compound No. 24, Example 24 of Patent Document 7);

[0431] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione (Compound No. 25, Example 25 of Patent Document 7);

[0432] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one (Compound No. 26, Example 26 of Patent Document 7);

[0433] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one (Compound No. 27, Example 27 of Patent Document 7);

[0434] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one (Compound No. 28, Example 28 of Patent Document 7);

[0435] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethbridged)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide hydrochloride (Compound No. 29, Example 29 of Patent Document 7);

[0436] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-keto hydrochloride (Compound No. 30, Example 30 of Patent Document 7);

[0437] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-2(1H)-one hydrochloride (Compound No. 31, Example 31 of Patent Document 7);

[0438] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-6-methylpyridine-2(1H)-keto hydrochloride (Compound No. 32, Example 32 of Patent Document 7);

[0439] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-2(1H)-one hydrochloride (Compound No. 33, Example 33 of Patent Document 7);

[0440] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-2(1H)-one hydrochloride (Compound No. 34, Example 34 of Patent Document 7);

[0441] 6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one (Compound No. 35, Example 35 of Patent Document 7);

[0442] 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one (Compound No. 36, Example 36 of Patent Document 7);

[0443] 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-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one (Compound No. 37, Example 37 of Patent Document 7);

[0444] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Compound No. 38, Example 38 of Patent Document 7);

[0445] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethbridged)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one (Compound No. 39, Example 39 of Patent Document 7).

[0446] Example 2: Agonistaltic activity of the compound on opioid receptors

[0447] The agonistic activities of the compounds synthesized in Example 1 toward opioid receptors are shown in Table 1 (Patent Document 7). KNT-127 also exhibits the same agonistic activity toward DOR. The compounds shown in Table 1 were confirmed to have potent agonistic activity toward DOR, and no or only very weak agonistic activity toward μ and κ receptors.

[0448] [Table 1]

[0449]

[0450] NC: ED was not calculated because the maximum response was not reached at the highest concentration (10 μM). 50 value.

[0451] Since the maximum reaction was not achieved at the highest concentration, the reaction rate at the highest concentration is shown as a reference value.

[0452] Example 3: Antagonistic activity of the compound against opioid receptors

[0453] The antagonistic activities of the compounds synthesized in Example 1 against opioid receptors are shown in Table 2 (Patent Document 8). The compounds shown in Table 2 were confirmed to have potent antagonistic activity against opioid μ and κ receptors.

[0454] [Table 2]

[0455]

[0456] Example 4: Creation of a mouse model of Social Defeat Stress (SDS)

[0457] To investigate whether the compounds of this invention, which contain δ-opioid receptor agonists, can improve anhedonia in depression, two SDS mouse models with depression were created.

[0458] 1) Physical stress (PS) mice

[0459] Following the report by Golden et al. (Nat Protoc (2011) 6:1183), a mouse model of SDS (Solar Depression) under physical stress was created. Male C57BL / 6J mice (Sankyo Lab Service) were purchased and domesticated for more than 5 days (4–6 mice / cage, 12-hour light-dark cycle (8–20 o'clock light period), room temperature 23±2℃). Highly aggressive male ICR mice (Sankyo Lab Service) were purchased and isolated in separate cages (referred to as "home cages"). It should be noted that the home cages used were cages with dimensions of 225 mm (length) × 338 mm (width) × 140 mm (height) (manufactured by Clea Co., Ltd., Japan). The C57BL / 6J mice were randomly divided into two groups: one group was subjected to physical stress on each mouse (referred to as "PS mice"), and the other group was not subjected to physical stress (referred to as "Naive mice"). A 6-week-old C57BL / 6J mouse was subjected to physical stress by being exposed to an aggressor ICR mouse (retirement age) for 10 minutes daily in a home cage for 10 consecutive days. PS mice were isolated for 5 days starting the day after the last stress test for anhedonia testing. It should be noted that the aggressor attacks occurred between 4 PM and 8 PM to minimize the impact of circadian rhythm variations in corticosterone levels.

[0460] 2) Chronic vicarious social defeat stress (cVSDS) mice

[0461] A cVSDS model mouse without physical stress was created according to the method of Sial et al. (J Neurosci Methods (2016) 258:94). Male C57BL / 6J mice (Sankyo Lab Service) were purchased and domesticated for more than 5 days (4-6 mice / cage, 12-hour light-dark cycle (8-20 am), room temperature 23±2℃). Highly aggressive male ICR mice (retirement age) were housed separately in home cages, and highly aggressive mice were selected by screening for 3 minutes daily for 3 consecutive days. The number of attacks when male C57BL / 6J mice were exposed to ICR mice in their home cages was measured during screening. The C57BL / 6J mice were randomly divided into two groups: one group was subjected to cVSDS on each mouse (referred to as "cVSDS mice") as shown below, and the other group was not subjected to cVSDS (referred to as "Naive mice"). One C57BL / 6J mouse was moved to one side of the home cage while separated from the ICR mice by a perforated clear acrylic plate. Then, another C57BL / 6J mouse was placed in a home cage and subjected to attack by an ICR mouse acting as the aggressor. This was performed for 10 minutes daily for 10 consecutive days, thus subjecting the initially placed C57BL / 6J mouse to cVSDS. Different individuals were used daily for the attacking ICR mouse and the attacked C57BL / 6J mouse. The cVSDS mouse was isolated for 38 days after the initial stress load for anhedonia testing. It should be noted that the stress was applied to the cVSDS mouse between 4 PM and 8 PM to minimize the effects of circadian rhythm variability in corticosterone levels.

[0462] Example 5: Evaluation of anhedonia: Sucrose Preference Test (SPT)

[0463] SPT (Sugar Prophylaxis) is conducted by providing regular drinking water and a 1% sucrose solution for free consumption, and measuring the proportion of sucrose solution consumed. In a depressive state, sucrose solution consumption as a reward response decreases.

[0464] 1) Effects on PS mice

[0465] Compound No. 7 of this application was dissolved in a solvent (1% methylcellulose) and orally administered to PS mice prepared in Example 4 above twice daily (8:00-9:00 and 19:00-20:00, with only 16:00 on the last day) for 5 days (5 mg / kg / time, n=6). As a control group, PS mice or naive mice (C57BL / 6J mice) without physical stress were also given the solvent only (n=6 each). From the second day of administration, they were allowed free access to a 1% sucrose solution in addition to regular drinking water for acclimatization. From the fourth day of administration (22 hours before the SPT), they were kept in a water-deprived environment. On the fifth day of administration, 2 hours after administration, regular drinking water and a 1% sucrose solution were provided for free access. Then, during the 2-hour test period, the sucrose preference (%) was calculated based on the ratio of 1% sucrose solution consumption to total consumption (1% sucrose solution consumption + drinking water consumption).

[0466] like Figure 1 As shown, compared with naive mice that had not been subjected to physical stress, PS mice exhibited a significantly reduced sucrose preference, indicating that they had developed anhedonia (p < 0.01; Bonferroni test after one-way ANOVA). On the other hand, administration of the compound of this application to PS mice significantly improved the reduction in sucrose preference (p < 0.01; Bonferroni test after one-way ANOVA). PS mice had a sucrose preference reduced to 40%, indicating severe anhedonia symptoms, but an improvement in anhedonia was observed after 5 days of administration of the compound of this application. It is believed that the effect of the compound of this application on anhedonia may exert its effect not only through agonistic activity against δ-opioid receptors but also through antagonistic activity against κ-opioid or μ-opioid receptors.

[0467] 2) Effects on cVSDS mice (KNT-127)

[0468] KNT-127 synthesized in Example 1 was dissolved in physiological saline. The mTOR inhibitor rapamycin (manufactured by LC Laboratories) was dissolved at 0.04 mM in 5% dimethyl sulfoxide / 95% physiological saline. The PI3K inhibitor LY294002 (manufactured by Fujifilm and Koko Pure Chemical Industries, Ltd.) was dissolved at 4 mM in 10% dimethyl sulfoxide / 90% physiological saline. The cVSDS mice prepared in Example 4 were allowed free access to a 1% sucrose solution in addition to regular drinking water for acclimatization, starting on day 26 after the last stress. Water was withheld starting on day 28 after the last stress (22 hours before the SPT). On day 29 after the last stress, rapamycin or LY294002 or a solvent thereof was administered intracerebroventrally (5 μL) 60 minutes before the start of the experiment. Additionally, KNT-127 (10 mg / kg) or a solvent thereof was administered subcutaneously 30 minutes before the start of the experiment. Then, regular drinking water and a 1% sucrose solution were provided for free intake. The sucrose preference (%) was calculated based on the ratio of 1% sucrose solution consumption to total consumption (1% sucrose solution consumption + drinking water consumption) over the subsequent 2-hour test period. Eight mice were used in the Naive / drug solvent / inhibitor solvent group, eight mice in the cVSDS / drug solvent / inhibitor solvent group, eight mice in the cVSDS / KNT-127 / inhibitor solvent group, seven mice in the cVSDS / KNT-127 / rapamycin group, and seven mice in the cVSDS / KNT-127 / LY294002 group.

[0469] like Figure 2 As shown, compared with naive mice without cVSDS, cVSDS mice exhibited significantly reduced sucrose preference, indicating anhedonia (p < 0.01; Bonferroni test after one-way ANOVA). Conversely, administration of KNT-127 to cVSDS mice restored sucrose preference to naive mouse levels, demonstrating the ameliorative effect of KNT-127 on anhedonia. The anhedonia effect of KNT-127 was inhibited by rapamycin or LY-294002, suggesting that mTOR and PI3K are involved in signal transduction.

[0470] 3) Effects on cVSDS mice (compounds in this application)

[0471] Compound No. 7 of this application was dissolved in a solvent (1% methylcellulose) and orally administered to cVSDS mice prepared in Example 4 above for 5 days (5 mg / kg / dose, n=7) twice daily (8:00-9:00 and 16:00-17:00, with only 16:00 on the last day) starting 28 days after the last stress. As a control group, cVSDS mice or naive mice (C57BL / 6J mice) without cVSDS were also given the solvent only (n=6 each). From the second day of administration, they were allowed free access to a 1% sucrose solution in addition to regular drinking water for acclimatization. From the fourth day of administration (22 hours before the SPT), water was withheld. On the fifth day of administration, 2 hours after administration, regular drinking water and a 1% sucrose solution were provided for free access. Sucrose preference (%) was calculated based on the ratio of 1% sucrose solution consumption to total consumption (1% sucrose solution consumption + drinking water consumption) during the subsequent 2-hour test period.

[0472] like Figure 3 As shown, compared with unstressed naive mice, cVSDS mice exhibited significantly reduced sucrose preference, indicating anhedonia (p < 0.05; Bonferroni test after one-way ANOVA). On the other hand, administration of the compound of this application to cVSDS mice showed a trend towards improvement in reduced sucrose preference (p = 0.075; Bonferroni test after one-way ANOVA), demonstrating a similar level of sucrose preference to unstressed naive mice.

[0473] Example 6: Evaluation of anorgasmia: Female urine sniffing test (FUST)

[0474] Next, the effects of the compound of this application on anhedonia related to libido were investigated using FUST. In a depressive state, male mice exhibited reduced sniffing behavior towards the urine of female mice in estrus, a behavior motivated / reward-seeking based on the instinctive need for sexual orientation.

[0475] 1) Effects on PS mice

[0476] Compound No. 7 of this application was dissolved in a solvent (1% methylcellulose) and orally administered to PS mice prepared in Example 4 above for 5 days (5 mg / kg / dose, n=12) twice daily (8:00-9:00 and 16:00-17:00, with only one dose on the last day) starting from the second day after the last stress. As a control group, PS mice or naive mice (C57BL / 6J mice) without physical stress were also given the solvent only (n=9 and 10, respectively). The experiment was carried out 2 hours after the last administration, following these steps: First, the mice were prompted with a cotton swab moistened with water for 3 minutes. 45 minutes later, the mice were prompted again with a cotton swab moistened with urine collected from estrous females for 3 minutes, and the sniffing behavior time was measured.

[0477] like Figure 4 As shown, when prompted with a water-moistened cotton swab, the sniffing behavior time for all mice was approximately 2–5 seconds. In contrast, when prompted with a cotton swab moistened with female urine, a prolonged sniffing behavior time was observed. However, the sniffing behavior time of PS mice was only about 60% longer than that of naive mice without physical stress, indicating a decrease in sexual orientation-based motivational / reward exploration behavior (already suffering from anhedonia) (p < 0.05; Bonferroni test after one-way ANOVA). On the other hand, in the PS mouse group administered the compound of this application, the sniffing behavior time for female urine recovered to the same level as that of naive mice (no significant difference compared to the naive mouse group; p < 0.05 compared to the solvent-administered cVSDS mouse group; Bonferroni test after one-way ANOVA).

[0478] 2) Effects on cVSDS mice

[0479] Compound No. 7 of this application was dissolved in a solvent (1% methylcellulose) and orally administered to cVSDS mice prepared in Example 4 above for 5 days (5 mg / kg / dose, n=7) twice daily (8:00-9:00 and 16:00-17:00, with only one dose on the last day) starting on day 28 after the last stress. As a control group, cVSDS mice or naive mice (C57BL / 6J mice) without cVSDS were also given the solvent only (n=6 each). The experiment was carried out 2 hours after the last administration, following these steps: First, a cotton swab moistened with water was used to prompt the mice for 3 minutes. 45 minutes later, a cotton swab with urine collected from estrous females was used to prompt the mice again for 3 minutes, and the sniffing behavior time was measured.

[0480] like Figure 5As shown, when prompted with a water-moistened cotton swab, the sniffing behavior time for all mice was approximately 2–5 seconds. In contrast, when prompted with a cotton swab moistened with female urine, a prolonged sniffing behavior time was observed. However, the sniffing behavior time of cVSDS mice was only about 50% longer than that of unstressed naive mice, indicating a decrease in sexual orientation-based motivational / reward exploration behavior (already suffering from anhedonia) (p < 0.05; Bonferroni test after one-way ANOVA). On the other hand, the sniffing behavior time of the cVSDS mouse group administered the compound of this application recovered to the same level as that of the unstressed naive mice (no significant difference from the naive mouse group; p < 0.01 compared with the solvent-administered cVSDS mouse group; Bonferroni test after one-way ANOVA).

[0481] Industrial availability

[0482] The pharmaceutical compositions of the present invention can be used to treat or prevent anhedonia associated with depression.

Claims

1. A pharmaceutical composition for the treatment or prevention of anhedonia, comprising a selective delta opioid receptor agonist as the active ingredient.

2. The therapeutic or preventive pharmaceutical composition according to claim 1, wherein, The selective delta opioid receptor agonist further exhibits κ opioid receptor antagonism.

3. The therapeutic or preventive pharmaceutical composition according to claim 1 or 2, wherein, The selective delta opioid receptor agonist further exhibits μ opioid receptor antagonistic activity and κ opioid receptor antagonistic activity.

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

5. The therapeutic or preventive pharmaceutical composition according to claim 1 or 2, wherein, The anhedonia is anhedonia caused by mental or physical stress.

6. The therapeutic or preventive pharmaceutical composition according to claim 1 or 2, which inhibits suicidal ideation.

7. The pharmaceutical composition for treatment or prevention according to claim 1 or 2, wherein, The anhedonia is a reduced responsiveness to pleasurable experiences associated with at least one of the following: money, food, hobbies, entertainment, travel and leisure, and desire for dominance, approval, achievement, affinity and sexuality.

8. The pharmaceutical composition for treatment or prevention according to claim 1, wherein, The selective δ-opioid receptor agonist is a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. In equation (I), R 1 Represents hydrogen, C 1-10 Alkyl, C 6-10 Aryl, C 2-6 Alkenyl, cycloalkyl groups with 3-6 carbon atoms in the cycloalkyl moiety and 1-5 carbon atoms in the alkylene moiety, and aralkyl groups with 6-10 carbon atoms in the aryl moiety and 1-5 carbon atoms in the alkylene moiety, C 3-6 The cycloalkyl or heteroaryl moiety comprises 1 to 4 heteroatoms selected from N, O, and S as ring-forming atoms, and the alkylene moiety has 1 to 5 carbon atoms. R 2 This refers to a heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as a ring-forming atom, wherein at least one group of adjacent ring-forming atoms has a double bond and is subsequently substituted by at least one oxo group, or a pyridine 1-oxide. Here, R 2 Intermediate as R 2 The carbon atom of the ring-forming atom is bonded to Y. R 3 R 4 and R 5 Same or different, indicating hydrogen, hydroxyl, halogen, cyano, carbamoyl, C 1-6 Alkoxy, C 6-10 aryloxy group, C 1-6 Alkyloxy, nitro, amino, C 1-8 Alkylamino, C 6-10 Acylamino groups with 2 to 6 carbon atoms in the arylamino or acyl moiety. R 6a and R 6b Same or different, indicating hydrogen, fluorine or hydroxyl, or R 6a and R 6b Together means = 0, R 7 and R 8 Same or different, indicating hydrogen, fluorine or hydroxyl. R 9 and R 10 Same or different, indicating hydrogen, C 1-6 Alkyl, C 6-10 Aryl, comprising 1 to 4 heteroatoms selected from N, O, and S as ring-forming atoms, aryl moiety having 6 to 10 carbon atoms and alkylene moiety having 1 to 5 carbon atoms, heteroaryl moiety comprising 1 to 4 heteroatoms selected from N, O, and S as ring-forming atoms and alkylene moiety having 1 to 5 carbon atoms, cycloalkyl moiety having 3 to 6 carbon atoms and alkylene moiety having 1 to 5 carbon atoms, or C 2-6 alkenyl, X represents O or CH2. Moreover, Y represents C (=O). Among them, R 1 C 1-10 Alkyl, cycloalkyl groups having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety, alkylene groups of aryl groups having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety, and heteroaryl alkyl groups having 1 to 4 heteroatoms selected from N, O, and S as ring-forming atoms and 1 to 5 carbon atoms in the alkylene moiety, the alkylene moiety of which may be selected from 1 to 6 halogens, hydroxyl groups, C 1-6 Alkoxy, C 6-10 aryloxy group, C 1-6 Alkyl group, C 1-6 Alkyloxy, carboxyl, alkoxycarbonyl with 1 to 6 carbon atoms in the alkoxy moiety, carbamoyl, alkylcarbamoyl with 1 to 6 carbon atoms in the alkyl moiety, dialkylcarbamoyl with 1 to 6 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 6 carbon atoms in the alkyl moiety, aminosulfonyl, alkylsulfinyl with 1 to 6 carbon atoms in the alkyl moiety, alkylthio with 1 to 6 carbon atoms in the alkyl moiety, and C groups substituted with 1 to 6 halogens. 1-6 The alkoxy group and at least one substituent in the aryl carbonyl group having 6 to 10 carbon atoms are substituted. Moreover, R 1 C 6-10 Aryl group, aryl group of an aryl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety, R 3 R 4 and R 5 C 6-10 The aryl moiety of the aryl group and C 6-10 The aryl moiety of arylamino groups, and R 9 and R 10 C 6-10 Aryl, heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-forming atoms, aryl moieties of aryl moieties having 6 to 10 carbon atoms and aryl alkylene moieties having 1 to 5 carbon atoms, and heteroaryl moieties of heteroaryl alkylene moieties containing 1 to 4 heteroatoms selected from N, O, and S as ring-forming atoms and aryl alkylene moieties having 1 to 5 carbon atoms, may be selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyloxy, hydroxyl, alkoxycarbonyl with 1-6 carbon atoms in the alkoxy moiety, carbamoyl, alkylcarbamoyl with 1-6 carbon atoms in the alkyl moiety, dialkylcarbamoyl with 1-6 carbon atoms in the alkyl moiety, halogen, nitro, cyano, C-terminal groups substituted with 1-3 halogens. 1-6 Alkyl groups, 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 constituent atoms, phenoxy, alkyl phenylalkyl having 1 to 3 carbon atoms, and at least one substituent selected from methylenedioxy. R 2 In addition to the oxo group, the heterocycle may also have the aforementioned R. 1 C 6-10 Aryl groups may have substituents, or R 2 The pyridine 1-oxide can have the R 1 C 6-10 Aryl groups can have substituents. Furthermore, in R 1 C 1-10 When alkyl, it can be NR 11 R 12 Replace, where R 11 and R 12 Same or different, for hydrogen, C 1-10 Arylalkyl groups having 6 to 10 carbon atoms in the alkyl or aryl moiety and 1 to 5 carbon atoms in the alkylene moiety, or R 11 and R 12 Together with the nitrogen atoms they are bonded to, and one or two heteroatoms as needed, they form 5- to 7-membered rings. Furthermore, R... 1 The alkylene moiety having 6 to 10 carbon atoms in the aryl group and 1 to 5 carbon atoms in the alkylene moiety can be selected from phenyl or C6 groups substituted with 1 to 3 halogens. 1-6 At least one substituent in the alkyl group is substituted.

9. The pharmaceutical composition for treatment or prevention according to claim 8, wherein, The compounds represented by the general formula (I) are the following compounds: R 5 R 6a R 6b R 7 R 8 R 9 and R 10 It is hydrogen. R 1 For hydrogen, C 1-6 Alkyl, C 2-6 Cycloalkyl groups having 3 to 6 carbon atoms in the alkenyl or cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety, or aralkyl groups having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety, R 2 This refers to a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as a ring-forming atom, wherein at least one group of adjacent ring-forming atoms has a double bond and is subsequently substituted by at least one oxo group, or a heterocycle formed by fusion of the heterocycle with a benzene ring, or a pyridine 1-oxide. Among them, R 2 Intermediate as R 2 The carbon atom of the ring-forming atom is bonded to Y. R 3 and R 4 The same or different, is hydrogen, hydroxyl, halogen, cyano, carbamoyl, C 1-6 Alkoxy, C 6-10 aryloxy group, C 1-6 Acylamino groups with 2 to 6 carbon atoms in their alkyloxy, amino, or acyl moiety. X is CH2. Moreover, Y is C (=O). Among them, R 1 C 1-6 The alkyl or cycloalkyl moiety having 3 to 6 carbon atoms and the alkylene moiety having 1 to 5 carbon atoms, or the alkylene moiety having 6 to 10 carbon atoms and the alkylene moiety having 1 to 5 carbon atoms, can have its alkylene moiety selected from 1 to 6 halogens, hydroxyl groups, C... 1-6 Alkoxy, C 6-10 aryloxy group, C 1-6 Alkyl group, C 1-6 Alkyloxy, carboxyl, alkoxycarbonyl with 1 to 6 carbon atoms in the alkoxy moiety, carbamoyl, alkylcarbamoyl with 1 to 6 carbon atoms in the alkyl moiety, dialkylcarbamoyl with 1 to 6 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 6 carbon atoms in the alkyl moiety, aminosulfonyl, alkylsulfinyl with 1 to 6 carbon atoms in the alkyl moiety, alkylthio with 1 to 6 carbon atoms in the alkyl moiety, and C groups substituted with 1 to 6 halogens. 1-6 The alkoxy group and at least one substituent in the aryl carbonyl group having 6 to 10 carbon atoms are substituted. Moreover, R 1 The aryl moiety of an aryl group having 6 to 10 carbon atoms and the alkylene moiety having 1 to 5 carbon atoms, and R 3 and R 4 C 6-10 The aryl moiety of the aryl group can be selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyloxy, hydroxyl, alkoxycarbonyl with 1-6 carbon atoms in the alkoxy moiety, carbamoyl, alkylcarbamoyl with 1-6 carbon atoms in the alkyl moiety, dialkylcarbamoyl with 1-6 carbon atoms in the alkyl moiety, halogen, nitro, cyano, C-terminal groups substituted with 1-3 halogens. 1-6 Alkyl groups, 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 constituent atoms, phenoxy, alkyl phenylalkyl having 1 to 3 carbon atoms, and at least one substituent selected from methylenedioxy. R 2 In addition to the oxo group, the heterocycle may also have the aforementioned R. 1 The aryl moiety having 6 to 10 carbon atoms and the alkylene moiety having 1 to 5 carbon atoms may have substituents, or R... 2 The pyridine 1-oxide can have the R 1 The aryl moiety of an aryl group having 6 to 10 carbon atoms and the alkylene moiety having 1 to 5 carbon atoms may have substituents. In addition, R 1 The alkylene moiety having 6 to 10 carbon atoms in the aryl group and 1 to 5 carbon atoms in the alkylene moiety can be selected from phenyl and C atoms substituted with 1 to 3 halogens. 1-6 At least one of the alkyl groups is substituted.

10. The therapeutic or preventive pharmaceutical composition according to claim 8 or 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 1 C 1-6 Cycloalkyl groups having 3 to 6 carbon atoms in the alkyl or cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety, or aralkyl groups having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety.

11. The therapeutic or preventive pharmaceutical composition according to claim 8 or 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 1 It is a cycloalkyl group in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms.

12. The therapeutic or preventive pharmaceutical composition according to claim 8 or 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 1 C substituted with hydroxyl group 2-6 Alkyl groups, C atoms substituted with 1 to 6 halogens 1-6 Alkyl, or C 1-6 alkoxy-substituted C 2-6 alkyl.

13. The therapeutic or preventive pharmaceutical composition according to claim 8 or 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 1 It is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl or 2-(aminosulfonyl)ethyl.

14. The therapeutic or preventive pharmaceutical composition according to claim 8 or 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 2 It is a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O and S and at least 1 carbon atom as ring constituent atoms, and at least one group of adjacent ring constituent atoms having double bonds and being substituted by at least 1 oxo group, or a heterocycle formed by fusion of the heterocycle with a benzene ring, or pyridine 1-oxide.

15. The therapeutic or preventive pharmaceutical composition according to claim 8 or 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 2 It is a 1-oxide of pyridine.

16. The therapeutic or preventive pharmaceutical composition according to claim 8 or 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 2 The heterocycle is pyridine-2(1H)-one.

17. The therapeutic or preventive pharmaceutical composition according to claim 8 or 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 2 The heterocycle is pyridine-4(1H)-one.

18. The therapeutic or preventive pharmaceutical composition according to claim 8 or 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 2 The heterocycle is pyridazine-3(2H)-one.

19. The therapeutic or preventive pharmaceutical composition according to claim 8 or 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 2 The heterocycle is pyrazine-2(1H)-one.

20. The therapeutic or preventive pharmaceutical composition according to claim 8 or 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 2 The heterocycle is 4H-pyran-4-one or 2H-pyran-2-one.

21. The therapeutic or preventive pharmaceutical composition according to claim 8 or 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 2 The heterocycle is quinoline-2(1H)-one.

22. The therapeutic or preventive pharmaceutical composition according to claim 8 or 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 2 The heterocycle is either pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione.

23. The pharmaceutical composition for treatment or prevention according to claim 8, wherein, The compound represented by the general formula (I) is the following compound: X is CH2.

24. The therapeutic or preventive pharmaceutical composition according to claim 8 or 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 3 and R 4 One of them is a hydroxyl group, and the other is hydrogen.

25. The pharmaceutical composition for treatment or prevention according to claim 8, wherein, The compounds represented by the general formula (I) are the following compounds: R 3 Halogen, cyano, carbamoyl, C 1-6 Alkoxy, C 1-6 An acylamino group having 2 to 6 carbon atoms in its alkyloxy, amino, or acyl moiety, R 4 For hydrogen or hydroxyl, R 5 It is hydrogen.

26. The pharmaceutical composition for treatment or prevention according to claim 8, wherein, The compounds represented by the general formula (I) are the following compounds: R 3 It is hydroxyl, carbamoyl, or C 1-6 Alkyloxy, R 4 For hydrogen, R 5 It is hydrogen.

27. The pharmaceutical composition for treatment or prevention according to claim 8, wherein, The compounds represented by the general formula (I) are the following compounds: R 3 For hydroxyl group, R 4 For hydrogen, R 5 It is hydrogen.

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

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

30. The pharmaceutical composition for treatment or prevention according to claim 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 3 Halogen, cyano, carbamoyl, C 1-6 Alkoxy, C 1-6 An acylamino group having 2 to 6 carbon atoms in its alkyloxy, amino, or acyl moiety, R 4 It can be hydrogen or hydroxyl.

31. The pharmaceutical composition for treatment or prevention according to claim 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 3 It is hydroxyl, carbamoyl, or C 1-6 Alkyloxy, R 4 It is hydrogen.

32. The pharmaceutical composition for treatment or prevention according to claim 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 3 For hydroxyl group, R 4 It is hydrogen.

33. The pharmaceutical composition for treatment or prevention according to claim 9, wherein, The compounds represented by the general formula (I) are the following compounds: R 3 and R 4 It is hydrogen.

34. The pharmaceutical composition for treatment or prevention according to claim 8, wherein, The compound represented by general formula (I) is the compound represented by general formula (II) below. In equation (II), R 1 For hydrogen, C 1-6 Cycloalkyl groups having 3 to 6 carbon atoms in the alkyl or cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety. R 2 This refers to a 5- to 7-membered heterocycle containing one or two nitrogen atoms and at least one carbon atom as ring-forming atoms, wherein at least one group of adjacent ring-forming atoms has a double bond and is subsequently substituted by at least one oxo group, or a pyridine 1-oxide. Among them, R 2 Intermediate as R 2 The carbon atom of the ring-forming atom is bonded to Y. R 3 and R 4 Same or different, is hydrogen, hydroxyl, or C 1-6 Alkoxy Y is C (=O). Among them, R 1 C 1-6 In cycloalkyl groups, the alkylene and cycloalkyl moieties having 3 to 6 carbon atoms in the alkyl or cycloalkyl group and 1 to 5 carbon atoms in the alkylene moieties can be selected from 1 to 6 halogens, hydroxyl groups, and C. 1-6 At least one substituent in the alkoxy group is substituted. Moreover, R 2 In addition to oxo groups, the heterocycles can also have groups selected from C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyloxy, hydroxyl, alkoxycarbonyl with 1-6 carbon atoms in the alkoxy moiety, carbamoyl, alkylcarbamoyl with 1-6 carbon atoms in the alkyl moiety, dialkylcarbamoyl with 1-6 carbon atoms in the alkyl moiety, halogen, nitro, cyano, C-terminal groups substituted with 1-3 halogens. 1-6 Alkyl groups, 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-forming atoms, phenoxy, alkyl phenylalkyl having 1 to 3 carbon atoms, and at least one substituent selected from methylenedioxy. Or, R 2 1-Oxides of pyridine can have a composition selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyloxy, hydroxyl, alkoxycarbonyl with 1-6 carbon atoms in the alkoxy moiety, carbamoyl, alkylcarbamoyl with 1-6 carbon atoms in the alkyl moiety, dialkylcarbamoyl with 1-6 carbon atoms in the alkyl moiety, halogen, nitro, cyano, C-terminal groups substituted with 1-3 halogens. 1-6 Alkyl groups, 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 constituent atoms, phenoxy, alkyl phenylalkyl having 1 to 3 carbon atoms, and at least one substituent selected from methylenedioxy.

35. The therapeutic or preventative pharmaceutical composition according to claim 34, wherein, The compounds represented by general formula (II) are the following compounds: R 1 It is a cycloalkyl group, and the cycloalkyl group has 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety.

36. The therapeutic or preventative pharmaceutical composition according to claim 34 or 35, wherein, The compounds represented by general formula (II) are the following compounds: R 2 For example, Equation (III), Equation (IV), Equation (V), or Equation (VI). In equations III to VI, R a It is hydrogen or C 1-6 Alkyl group, bonded to Y at the position indicated by the arrow.

37. The therapeutic or preventive pharmaceutical composition according to claim 34 or 35, wherein, The compounds represented by general formula (II) are the following compounds: R 3 It is a hydroxyl group.

38. The therapeutic or preventive pharmaceutical composition according to claim 34 or 35, wherein, The compounds represented by general formula (II) are the following compounds: R 4 It is hydrogen.

39. The pharmaceutical composition for treatment or prevention according to claim 8, wherein, The compound represented by the general formula (I) is selected from at least one of the following compounds: 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridazine-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-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)quinoline-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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrazine-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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyrazine-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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-2(1H)-one.

40. The therapeutic or preventive pharmaceutical composition according to any one of claims 8, 34, and 35, wherein, The compound represented by the general formula (I) is selected from at least one of the following compounds: 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[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-(epiminoethionized)-1,5a-methylbridged naphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-2(1H)-one.

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