Title of invention: Cyclic amine derivative and its pharmaceutical use
Technical field
[0001]
　The present invention relates to a cyclic amine derivative and its pharmaceutical use.
Background technology
[0002]
　Autoimmune disease is a general term for diseases in which excessive immune reactions attack normal cells and tissues of self, and causes symptoms such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and inflammatory disease. These include enteropathy, ankylosing spondylitis, uveitis or polymyalgia rheumatica.
[0003]
　An allergic disease is a disease derived from an excessive immune reaction to a specific antigen, and includes, for example, allergic dermatitis, atopic dermatitis, allergic rhinitis (hay fever), allergic conjunctivitis, and allergies. Gastroenteritis, bronchial asthma, childhood asthma or food allergies.
[0004]
　Various mechanisms have been proposed for the onset and progress of autoimmune diseases and allergic diseases, one of which is Th17 cells, which is one of a subset of helper T cells, and inflammatory cytokines produced by them. It is known that IL-17 plays an important role in the onset and progression of autoimmune diseases (Non-patent documents 1 and 2).
[0005]
　IL-17 acts on various cells such as fibroblasts, epithelial cells, vascular endothelial cells, and macrophages, and is involved in the induction of inflammatory cytokines, chemokines, metalloproteases and other inflammatory mediators and migration of neutrophils. ing. Therefore, it is considered that if the production or function of IL-17 can be suppressed, a strong anti-inflammatory effect will be exerted, and clinical trials of anti-IL-17 antibody targeted for various autoimmune diseases will be conducted. Has been done.
[0006]
　In recent years, it has been clarified that a nuclear receptor, a retinoid-related orphan receptor γ (hereinafter, RORγ), functions as a transcription factor essential for the differentiation and proliferation of Th17 cells and the expression of IL-17 (non-patent document). Reference 3) has been shown to suppress the differentiation or activation of Th17 cells and the production of IL-17 by suppressing the expression or function of RORγ (Non-Patent Document 4).
[0007]
　In patients with autoimmune diseases (multiple sclerosis, psoriasis, systemic lupus erythematosus, etc.) and patients with allergic diseases (allergic dermatitis, etc.), the RORγ expression level in peripheral blood mononuclear cells or skin tissues was higher than that in healthy individuals. It has been reported to show a high value (Non-patent Documents 5, 6 and 10). In RORγ knockout mice, the pathology of mouse experimental autoimmune encephalomyelitis model, which is an animal model of multiple sclerosis, is suppressed, and symptoms of autoimmune diseases such as colitis and allergic diseases such as asthma It has been reported that the symptom is suppressed (Non-patent documents 3, 7 and 11).
[0008]
　Furthermore, it has been suggested that RORγ needs to bind to a coactivator in order for RORγ to function as a transcription factor (Non-Patent Document 8). Therefore, a RORγ antagonist, which is a compound that inhibits the binding between RORγ and coactivator, is expected to be useful as a therapeutic or prophylactic agent for autoimmune diseases.
[0009]
　On the other hand, as a RORγ antagonist, N-(5-(N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)sulfamoyl) has been used so far. -4-Methylthiazol-2-yl)acetamide (Non-Patent Document 9) and 6-(2-chloro-4-methylphenyl)-3-(4-cyclopropyl-5-(3-neopentylcyclobutyl) Substituted azole derivatives such as isoxazol-3-yl)-5-oxohexanoic acid (Patent Document 1) and N-(2-chloro-2′-(trifluoromethoxy)-[1,1′-biphenyl ]-4-yl)-2-(4-(methylsulfonyl)phenyl)acetamide (Patent Document 2) and (S)-1-isopropyl-N-((1-(methylsulfonyl)piperidin-4-yl) Methyl)-2-((trans-4-(trifluoromethyl)cyclohexyl)methyl)isoindoline-5-carboxamide (Patent Document 3) and other isoindoline derivatives, 1-acetyl-N-(2-chloro-2) Biaryl derivatives such as'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)piperidine-2-carboxamide have been reported (Patent Document 4).
[0010]
　In addition, as a compound having a cyclic amine structure such as 2-position-substituted 5,6,7,8-tetrahydro-1,6-naphthyridine, a histamine H3 receptor antagonist (2-((1-cyclobutylpiperidine- 4-yl)oxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(4-methoxyphenyl)methanone and the like have been reported (Patent Document 5), and 7-position substituted 2H-benzo[ Examples of the compound having a cyclic amine structure such as b][1,4]oxazin-3(4H)-one include 2-benzyl as a platelet aggregation inhibitor and a thrombin inhibitor and/or a blood coagulation factor factor Xa inhibitor. -3-((4-(4-carbamimidoylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)amino)-3-oxo Methyl propanoate and the like have been reported (Patent Document 6), but neither the action nor the action of these compounds on RORγ is disclosed or suggested.
Prior art documents
Patent literature
[0011]
Patent Document 1: Japanese Patent Laid-Open No. 2012-236822
Patent Document 2: International Publication No. 2013/0293338
Patent Document 3: US Patent Application Publication No. 2016/0122318
Patent Document 4: International Publication No. 2017/131156
Patent Document 5: International Publication No. 2010/026113
Patent Document 6: International Publication No. 2005/051934
Non-patent literature
[0012]
Non-Patent Document 1: Chen et al., International Immunopharmacology, 2011, Volume 11, p. 536-542
Non-Patent Document 2: Hofmann et al., Current Opinion in Allergy and Clinical Immunology, 2016, Vol. 16, p. 451-457
Non-Patent Document 3: Ivanov et al., Cell, 2006, Volume 126, p. 1121-1133
Non-Patent Document 4: Jetten, Nuclear Receptor Signaling, 2009, Volume 7, e003
Non-Patent Document 5: Hamzaoui et al., Medical Science Monitor, 2011, Volume 17, p. CR 227-234
Non-Patent Document 6: Ma et al., Journal of the Europe Academia of Dermatology and Venology, 2014, Vol. 28, p. 1079-1086
Non-Patent Document 7: Leppkes et al., Gastroenterology, 2009, Vol. 136, p. 257-267
Non-Patent Document 8: Jin et al., Molecular Endocrinology, 2010, Vol. 24, p. 923-929
Non-Patent Document 9: Solt et al., Nature, 2011, Volume 472, p. 491-494
Non-Patent Document 10: Zhao et al., British Journal of Dermatology, 2009, Volume 161, p. 1301-1306
Non-Patent Document 11: Jetten et al., The Journal of Immunology, 2007, Volume 178, p. 3208-3218
Summary of the invention
Problems to be Solved by the Invention
[0013]
　However, in the actual treatment of autoimmune diseases and allergic diseases, steroids or immunosuppressive agents that act on the entire immune system are used as internal medicines, which is sufficient from the fear of serious side effects such as infectious diseases. The current situation is that there are many cases in which administration must be discontinued before significant drug efficacy is observed. Therefore, there is a strong demand for the development of a new drug targeting a molecule that plays an important role in the onset and progression mechanism of autoimmune diseases and allergic diseases.
[0014]
　Therefore, an object of the present invention is to provide a novel compound having RORγ antagonist activity and exerting a therapeutic or preventive effect on autoimmune diseases such as psoriasis and allergic diseases such as allergic dermatitis. ..
Means for solving the problem
[0015]
　As a result of intensive studies to solve the above problems, the present inventors have found a novel cyclic amine derivative having RORγ antagonist activity, and completed the present invention.
[0016]
　That is, the present invention provides a cyclic amine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
[Chemical formula 1]

wherein, R 1 represents an alkyl group having 1 to 3 carbon atoms, A is represented by the following general formula (II-1), (II -2) or (II-3)
[Formula 2 ]

(wherein, R 2 represents a hydrogen atom or a halogen atom, R 3 represents an aryl group or a cycloalkyl group having a carbon number of 4-6 (where, R 3 above aryl groups and the cycloalkyl groups in the , Each independently one or two arbitrary hydrogen atoms may be substituted with an alkyl group having 1 to 3 carbon atoms or an alkyloxy group having 1 to 3 carbon atoms, the above aryl group and the above cycloalkyl group In the alkyl group having 1 to 3 carbon atoms and the alkyloxy group having 1 to 3 carbon atoms which can be substituted with, each independently 1 to 3 arbitrary hydrogen atoms may be substituted with a halogen atom.), n represents 1 or 2, and the wavy line represents a group represented by the bonding point with the general formula (I). ]
[0017]
　In the cyclic amine derivative represented by the above general formula (I), R 2 is a hydrogen atom, a fluorine atom or a chlorine atom, and R 3 is an aryl group or a cycloalkyl group having 4 to 6 carbon atoms (however, , The aryl group and the cycloalkyl group for R 3 may each independently have one or two arbitrary hydrogen atoms substituted with a methyl group or a methoxy group, and the aryl group and the cycloalkyl group may be substituted. In the methyl group and methoxy group which can be substituted with, each independently 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom).
[0018]
　In this case, higher RORγ antagonist activity can be expected.
[0019]
　In the cyclic amine derivative represented by the general formula (I), R 2 is a fluorine atom or a chlorine atom, R 3 is a phenyl group or a cyclohexyl group (provided that the phenyl group in R 3 and The cyclohexyl group may independently have 1 or 2 arbitrary hydrogen atoms substituted with a methyl group or a methoxy group, and the phenyl group and the cyclohexyl group-substitutable methyl group and methoxy group are , Each independently 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom.), and n is more preferably 1.
[0020]
　In this case, a higher RORγ antagonist activity can be expected, and further an excellent therapeutic effect or preventive effect on autoimmune diseases such as psoriasis or allergic diseases such as allergic dermatitis can be expected.
[0021]
　Further, the cyclic amine derivative represented by the above general formula (I), R 1 is methyl group, A is represented by the following general formula (II-1) or (II-2)
[Chemical formula 3]

[Formula In the formula, R 2 is a chlorine atom, R 3 is a phenyl group or a cyclohexyl group (provided that the phenyl group and the cyclohexyl group in R 3 each independently have one arbitrary hydrogen atom It may be substituted with a fluoromethyl group or a trifluoromethoxy group.) and n are 1 and the wavy line represents the point of attachment to the general formula (I). ] It is more preferable that it is a group shown by these.
[0022]
　In this case, a higher RORγ antagonist activity can be expected, and further an excellent therapeutic effect or preventive effect on autoimmune diseases such as psoriasis or allergic diseases such as allergic dermatitis can be expected.
[0023]
　The present invention also provides a drug and a RORγ antagonist, which contain the cyclic amine derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
[0024]
　The above-mentioned medicament is preferably a therapeutic agent or preventive agent for autoimmune disease or allergic disease, and the therapeutic agent or preventive agent for the above-mentioned autoimmune disease is a therapeutic agent or preventive agent for psoriasis or alopecia areata. More preferably, as the therapeutic agent or preventive agent for the above-mentioned allergic disease, more preferably a therapeutic agent or preventive agent for allergic dermatitis, as a therapeutic agent or preventive agent for allergic dermatitis, More preferably, it is a therapeutic or preventive agent for contact dermatitis or atopic dermatitis.
Effect of the invention
[0025]
　INDUSTRIAL APPLICABILITY The cyclic amine derivative of the present invention or a pharmacologically acceptable salt thereof has RORγ antagonist activity and therefore can effectively suppress the function of RORγ, and is used as a therapeutic or prophylactic agent for autoimmune disease or allergic disease. it can.
Brief description of the drawings
[0026]
FIG. 1 shows the inhibitory effect of the compound of Example 1 on the increase of auricle thickness in an imiquimod-induced mouse psoriasis model.
FIG. 2 is a graph showing the inhibitory effect of the compound of Example 4 on the increase in auricle thickness in an imiquimod-induced mouse psoriasis model.
FIG. 3 is a graph showing the inhibitory effect of the compound of Example 9 on the increase of auricle thickness in an imiquimod-induced mouse psoriasis model.
FIG. 4 is a graph showing the inhibitory effect of the compound of Example 1 on the ear swelling rate in a dinitrofluorobenzene-induced mouse allergic dermatitis model.
FIG. 5 is a graph showing the inhibitory effect of the compound of Example 4 on the ear swelling rate in a dinitrofluorobenzene-induced mouse allergic dermatitis model.
FIG. 6 shows the inhibitory effect of the compound of Example 9 on the ear swelling rate in a dinitrofluorobenzene-induced mouse allergic dermatitis model.
FIG. 7 is a graph showing the inhibitory effect of the compound of Example 1 on the increase in auricle thickness in an oxazolone-induced mouse atopic dermatitis model.
FIG. 8 is a graph showing the inhibitory effect of the compound of Example 4 on the increase in auricle thickness in an oxazolone-induced mouse atopic dermatitis model.
FIG. 9 is a graph showing the inhibitory effect of the compound of Example 9 on the increase of auricle thickness in an oxazolone-induced mouse atopic dermatitis model.
FIG. 10 is a graph showing the inhibitory effect of the compound of Example 4 on the increase in hair loss score in a mouse alopecia areata model.
MODE FOR CARRYING OUT THE INVENTION
[0027]
　The cyclic amine derivative of the present invention is characterized by being represented by the following general formula (I).
[Formula 4]

[wherein, R 1 represents an alkyl group having 1 to 3 carbon atoms, A is represented by the following general formula (II-1), (II -2) or (II-3)
[of 5 ]

(wherein, R 2 represents a hydrogen atom or a halogen atom, R 3 represents an aryl group or a cycloalkyl group having a carbon number of 4-6 (where, R 3 above aryl groups and the cycloalkyl groups in the , Each independently one or two arbitrary hydrogen atoms may be substituted with an alkyl group having 1 to 3 carbon atoms or an alkyloxy group having 1 to 3 carbon atoms, the above aryl group and the above cycloalkyl group In the alkyl group having 1 to 3 carbon atoms and the alkyloxy group having 1 to 3 carbon atoms that can be substituted with, each independently 1 to 3 arbitrary hydrogen atoms may be substituted with a halogen atom.), n represents 1 or 2, and the wavy line represents a group represented by the bonding point with the general formula (I). ]
[0028]
　The following terms as used herein are as defined below unless otherwise indicated.
[0029]
　“Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
[0030]
　The “alkyl group having 1 to 3 carbon atoms” means a methyl group, an ethyl group, a propyl group or an isopropyl group.
[0031]
　“In the alkyl group having 1 to 3 carbon atoms, 1 to 3 arbitrary hydrogen atoms may be independently substituted with a halogen atom.” means that the above alkyl group having 1 to 3 carbon atoms. 1 to 3 arbitrary hydrogen atoms each independently mean a group which may be substituted with the above halogen atom, in other words, an alkyl group having 1 to 3 carbon atoms (the alkyl group is 1 to 3 arbitrary hydrogen atoms may be each independently substituted with the above halogen atom), and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group and a fluoro group. Examples thereof include a methyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a trifluoroethyl group, a trichloromethyl group and a trichloroethyl group.
[0032]
　The "methyl group may have 1 to 3 arbitrary hydrogen atoms independently substituted with a fluorine atom or a chlorine atom." means 1 to 3 arbitrary hydrogen atoms of the methyl group. , Each independently represents a group which may be substituted with a fluorine atom or a chlorine atom, in other words, a methyl group (wherein 1 to 3 arbitrary hydrogen atoms are independently , Which may be substituted with a fluorine atom or a chlorine atom), and examples thereof include a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group or a trichloromethyl group.
[0033]
　The “alkyloxy group having 1 to 3 carbon atoms” means a methoxy group, an ethoxy group, a propyloxy group or an isopropyloxy group.
[0034]
　“In the alkyloxy group having 1 to 3 carbon atoms, 1 to 3 arbitrary hydrogen atoms may be independently substituted with halogen atoms.” means that the alkyloxy group having 1 to 3 carbon atoms described above. 1 to 3 arbitrary hydrogen atoms of the group each independently represent a group which may be substituted with the above halogen atom, in other words, an alkyloxy group having 1 to 3 carbon atoms (the alkyl group). The oxy group has the same meaning as 1 to 3 arbitrary hydrogen atoms each of which may be independently substituted with the above halogen atom.), for example, a methoxy group, an ethoxy group, a propyloxy group. , Isopropyloxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-fluoroethoxy group, trifluoroethoxy group, trichloromethoxy group or trichloroethoxy group.
[0035]
　"A methoxy group may independently have 1 to 3 arbitrary hydrogen atoms substituted with a fluorine atom or a chlorine atom." means 1 to 3 arbitrary hydrogen atoms of the methoxy group. , Each independently represents a group which may be substituted with a fluorine atom or a chlorine atom, in other words, a methoxy group (wherein the methoxy group has 1 to 3 arbitrary hydrogen atoms each independently , Which may be substituted with a fluorine atom or a chlorine atom), and means a methoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group or a trichloromethoxy group.
[0036]
　The “aryl group” means an aromatic hydrocarbon group, and examples thereof include a phenyl group, a 1-naphthyl group and a 2-naphthyl group.
[0037]
　The “cycloalkyl group having 4 to 6 carbon atoms” means a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
[0038]
　“Aryl group (provided that R 3In the above aryl group in 1, each independently one or two arbitrary hydrogen atoms may be substituted with an alkyl group having 1 to 3 carbon atoms or an alkyloxy group having 1 to 3 carbon atoms. In the alkyl group having 1 to 3 carbon atoms and the alkyloxy group having 1 to 3 carbon atoms that can be substituted with, each independently 1 to 3 arbitrary hydrogen atoms may be substituted with a halogen atom. )” means that one or two arbitrary hydrogen atoms in the above aryl group are each independently the above alkyl group having 1 to 3 carbon atoms (wherein the alkyl group is 1 to 3 Each of the hydrogen atoms of the above may be independently substituted with the above halogen atom) or the above alkyloxy group having 1 to 3 carbon atoms (wherein the alkyloxy group is any of 1 to 3). Hydrogen atoms each independently may be substituted with the above halogen atom), and a group optionally substituted with, for example, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, Tolyl group, dimethylphenyl group, ethylphenyl group, ethylmethylphenyl group, propylphenyl group, methylpropylphenyl group, isopropylphenyl group, isopropylmethylphenyl group, (fluoromethyl)phenyl group, (difluoromethyl)phenyl group, (tri Fluoromethyl)phenyl group, methyl(trifluoromethyl)phenyl group, ethyl(trifluoromethyl)phenyl group, propyl(trifluoromethyl)phenyl group, isopropyl(trifluoromethyl)phenyl group, (2-fluoroethyl)phenyl group , (Trifluoroethyl)phenyl group, (trichloromethyl)phenyl group, (trichloroethyl)phenyl group, methoxyphenyl group, methoxy(methyl)phenyl group, methoxy(trifluoromethyl)phenyl group, ethoxyphenyl group, ethoxy(methyl ) Phenyl group, ethoxy(trifluoromethyl)phenyl group, propyloxyphenyl group, methyl(propyloxy)phenyl group, trifluoromethyl(propyloxy)phenyl group, isopropyloxyphenyl group, isopropyloxy(methyl)phenyl group, isop
[0039]
　“Aryl group (provided that in the aryl group in R 3 , each independently one or two arbitrary hydrogen atoms may be substituted with a methyl group or a methoxy group, and a methyl group which can be substituted with the aryl group is substituted. The group and the methoxy group may each independently have 1 to 3 arbitrary hydrogen atoms substituted with a fluorine atom or a chlorine atom.)" means one or two of the above aryl groups. Independently of each other the above-mentioned methyl group (in the methyl group, 1 to 3 arbitrary hydrogen atoms may be each independently substituted with a fluorine atom or a chlorine atom). ) Or the above-mentioned methoxy group (wherein 1 to 3 arbitrary hydrogen atoms may be each independently substituted with a fluorine atom or a chlorine atom). Means a good group, for example, phenyl group, 1-naphthyl group, 2-naphthyl group, tolyl group, dimethylphenyl group, (fluoromethyl)phenyl group, (difluoromethyl)phenyl group, (trifluoromethyl)phenyl group, Methyl (trifluoromethyl)phenyl group, (trichloromethyl)phenyl group, methoxyphenyl group, methoxy(methyl)phenyl group, methoxy(trifluoromethyl)phenyl group, (fluoromethoxy)phenyl group, (difluoromethoxy)phenyl group, Examples thereof include a (trifluoromethoxy)phenyl group, a methyl(trifluoromethoxy)phenyl group, a trifluoromethoxy(trifluoromethyl)phenyl group, a methoxy(trifluoromethoxy)phenyl group or a (trichloromethoxy)phenyl group.
[0040]
　“Phenyl group (provided that each of the above phenyl groups in R 3 may independently have one or two arbitrary hydrogen atoms substituted with a methyl group or a methoxy group, and is a methyl group which can be substituted with the above phenyl group. The group and the methoxy group may each independently have 1 to 3 arbitrary hydrogen atoms substituted with a fluorine atom or a chlorine atom.)" means 1 or 2 arbitrary hydrogen atoms of a phenyl group. The atoms are each independently the above-mentioned methyl group (wherein 1 to 3 arbitrary hydrogen atoms may be independently substituted with a fluorine atom or a chlorine atom) or A group which may be substituted with the above-mentioned methoxy group (wherein 1 to 3 arbitrary hydrogen atoms may be independently substituted with a fluorine atom or a chlorine atom). Means, for example, phenyl group, tolyl group, dimethylphenyl group, (fluoromethyl)phenyl group, (difluoromethyl)phenyl group, (trifluoromethyl)phenyl group, methyl (trifluoromethyl)phenyl group, (trichloromethyl) ) Phenyl group, methoxyphenyl group, methoxy(methyl)phenyl group, methoxy(trifluoromethyl)phenyl group, (fluoromethoxy)phenyl group, (difluoromethoxy)phenyl group, (trifluoromethoxy)phenyl group, methyl (trifluoro) Examples thereof include a methoxy)phenyl group, a trifluoromethoxy(trifluoromethyl)phenyl group, a methoxy(trifluoromethoxy)phenyl group or a (trichloromethoxy)phenyl group.
[0041]
　"Phenyl group (however, in the above phenyl group in R 3 , each independently one arbitrary hydrogen atom may be substituted with a trifluoromethyl group or a trifluoromethoxy group)" is a phenyl group, It means a (trifluoromethyl)phenyl group or a (trifluoromethoxy)phenyl group.
[0042]
　“A cycloalkyl group having 4 to 6 carbon atoms (provided that R 3In the above cycloalkyl group in 1, each independently one or two arbitrary hydrogen atoms may be substituted with an alkyl group having 1 to 3 carbon atoms or an alkyloxy group having 1 to 3 carbon atoms. In the alkyl group having 1 to 3 carbon atoms and the alkyloxy group having 1 to 3 carbon atoms which can be substituted with an alkyl group, 1 to 3 arbitrary hydrogen atoms may be independently substituted with a halogen atom. )” means that one or two arbitrary hydrogen atoms of the cycloalkyl group having 4 to 6 carbon atoms are each independently the alkyl group having 1 to 3 carbon atoms (the alkyl group is 1 to 3 arbitrary hydrogen atoms may be each independently substituted with the above halogen atom) or the above alkyloxy group having 1 to 3 carbon atoms (wherein the alkyloxy group is 1 3 to 3 arbitrary hydrogen atoms each independently may be substituted with the above halogen atom)), and a group which may be substituted with, for example, a cyclobutyl group, a cyclopentyl group, Cyclohexyl group, methylcyclobutyl group, dimethylcyclobutyl group, (trifluoromethyl)cyclobutyl group, methyl(trifluoromethyl)cyclobutyl group, methoxycyclobutyl group, methoxy(methyl)cyclobutyl group, methoxy(trifluoromethyl)cyclobutyl group , (Trifluoromethoxy)cyclobutyl group, methyl(trifluoromethoxy)cyclobutyl group, trifluoromethoxy(trifluoromethyl)cyclobutyl group, methoxy(trifluoromethoxy)cyclobutyl group, methylcyclopentyl group, dimethylcyclopentyl group, (trifluoromethyl ) Cyclopentyl group, methyl(trifluoromethyl)cyclopentyl group, methoxycyclopentyl group, methoxy(methyl)cyclopentyl group, methoxy(trifluoromethyl)cyclopentyl group, (trifluoromethoxy)cyclopentyl group, methyl(trifluoromethoxy)cyclopentyl group, Trifluoromethoxy(trifluoromethyl)cyclopentyl group, methoxy(trifluoromethoxy)cyclopentyl group, methylcyclohexyl group, dime
[0043]
　“A cycloalkyl group having 4 to 6 carbon atoms (provided that R 3In the cycloalkyl group in 1, each independently one or two arbitrary hydrogen atoms may be substituted with a methyl group or a methoxy group, and the methyl group and the methoxy group which can be substituted with the cycloalkyl group are Each independently 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom. )” means that one or two arbitrary hydrogen atoms of the cycloalkyl group having 4 to 6 carbon atoms are each independently the above methyl group (the methyl group is 1 to 3 Any hydrogen atom may be independently substituted with a fluorine atom or a chlorine atom.) or the above methoxy group (wherein the methoxy group has 1 to 3 arbitrary hydrogen atoms, each independently , Which may be substituted with a fluorine atom or a chlorine atom), and a group which may be substituted with, for example, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a methylcyclobutyl group, a dimethylcyclobutyl group. , (Trifluoromethyl)cyclobutyl group, methyl(trifluoromethyl)cyclobutyl group, methoxycyclobutyl group, methoxy(methyl)cyclobutyl group, methoxy(trifluoromethyl)cyclobutyl group, (trifluoromethoxy)cyclobutyl group, methyl(tri Fluoromethoxy)cyclobutyl group, trifluoromethoxy(trifluoromethyl)cyclobutyl group, methoxy(trifluoromethoxy)cyclobutyl group, methylcyclopentyl group, dimethylcyclopentyl group, (trifluoromethyl)cyclopentyl group, methyl(trifluoromethyl)cyclopentyl group , Methoxycyclopentyl group, methoxy(methyl)cyclopentyl group, methoxy(trifluoromethyl)cyclopentyl group, (trifluoromethoxy)cyclopentyl group, methyl(trifluoromethoxy)cyclopentyl group, trifluoromethoxy(trifluoromethyl)cyclopentyl group, methoxy (Trifluoromethoxy)cyclopentyl group, methylcyclohexyl group, dimethylcyclohexyl group, (trifluoromethyl)cyclohexyl group, methyl(trifluoromethyl)cyclohexyl group
[0044]
　“Cyclohexyl group (provided that in the cyclohexyl group in R 3 , each independently one or two arbitrary hydrogen atoms may be substituted with a methyl group or a methoxy group, and the cyclohexyl group-substitutable methyl group may be substituted. The group and the methoxy group may each independently have 1 to 3 arbitrary hydrogen atoms substituted with a fluorine atom or a chlorine atom.)" means 1 or 2 arbitrary hydrogen atoms of a cyclohexyl group. The atoms are each independently the above-mentioned methyl group (wherein 1 to 3 arbitrary hydrogen atoms may be independently substituted with a fluorine atom or a chlorine atom) or A group which may be substituted with the above-mentioned methoxy group (in the methoxy group, 1 to 3 arbitrary hydrogen atoms may be independently substituted with a fluorine atom or a chlorine atom). Means, for example, cyclohexyl group, methylcyclohexyl group, dimethylcyclohexyl group, (trifluoromethyl)cyclohexyl group, methyl(trifluoromethyl)cyclohexyl group, methoxycyclohexyl group, methoxy(methyl)cyclohexyl group, methoxy(trifluoromethyl) ) Cyclohexyl group, (trifluoromethoxy)cyclohexyl group, methyl(trifluoromethoxy)cyclohexyl group, trifluoromethoxy(trifluoromethyl)cyclohexyl group or methoxy(trifluoromethoxy)cyclohexyl group.
[0045]
　A “cyclohexyl group (however, in the cyclohexyl group for R 3 each independently, one arbitrary hydrogen atom may be substituted with a trifluoromethyl group or a trifluoromethoxy group)” is a cyclohexyl group, It means a (trifluoromethyl)cyclohexyl group or a (trifluoromethoxy)cyclohexyl group.
[0046]
　“An aryl group or a cycloalkyl group having 4 to 6 carbon atoms (provided that R 3In the aryl group and the cycloalkyl group in, each independently one or two arbitrary hydrogen atoms may be substituted with an alkyl group having 1 to 3 carbon atoms or an alkyloxy group having 1 to 3 carbon atoms. Often, the alkyl group having 1 to 3 carbon atoms and the alkyloxy group having 1 to 3 carbon atoms which can be substituted with the aryl group and the cycloalkyl group each independently have 1 to 3 arbitrary hydrogen atoms as halogen atoms. May be substituted with. )” means, in the above aryl group or the above-mentioned cycloalkyl group having 4 to 6 carbon atoms, independently of one or two of the above aryl group or the above cycloalkyl group having 4 to 6 carbon atoms. Each arbitrary hydrogen atom is independently the above-mentioned alkyl group having 1 to 3 carbon atoms (in the alkyl group, each arbitrary hydrogen atom of 1 to 3 is independently substituted with the above halogen atom). Or an alkyloxy group having 1 to 3 carbon atoms (the alkyloxy group has 1 to 3 arbitrary hydrogen atoms each independently substituted with the halogen atom described above). Or a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a tolyl group, a dimethylphenyl group, an ethylphenyl group, an ethylmethylphenyl group, Propylphenyl group, methylpropylphenyl group, isopropylphenyl group, isopropylmethylphenyl group, (fluoromethyl)phenyl group, (difluoromethyl)phenyl group, (trifluoromethyl)phenyl group, methyl (trifluoromethyl)phenyl group, ethyl (Trifluoromethyl)phenyl group, propyl(trifluoromethyl)phenyl group, isopropyl(trifluoromethyl)phenyl group, (2-fluoroethyl)phenyl group, (trifluoroethyl)phenyl group, (trichloromethyl)phenyl group, (Trichloroethyl)phenyl group, methoxyphenyl group, methoxy(methyl)phenyl group, methoxy(trifluoromethyl)phenyl group, ethoxyphenyl group, ethoxy(methyl)phenyl group, ethoxy(trifluoromethyl)phenyl group, propyloxy group
[0047]
　“An aryl group or a cycloalkyl group having 4 to 6 carbon atoms (provided that R 3In the aryl group and the cycloalkyl group in, each independently one or two arbitrary hydrogen atoms may be substituted with a methyl group or a methoxy group, and the aryl group and the cycloalkyl group can be substituted. In the methyl group and methoxy group, 1 to 3 arbitrary hydrogen atoms may be independently substituted with a fluorine atom or a chlorine atom. )” means, in the above aryl group or the above cycloalkyl group having 4 to 6 carbon atoms, independently of one or two of the above aryl group or the above cycloalkyl group having 4 to 6 carbon atoms. Arbitrary hydrogen atoms are each independently the above methyl group (in the methyl group, 1 to 3 arbitrary hydrogen atoms may be each independently substituted with a fluorine atom or a chlorine atom). .) or the above-mentioned methoxy group (wherein 1 to 3 arbitrary hydrogen atoms may be each independently substituted with a fluorine atom or a chlorine atom). Means a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a tolyl group, a dimethylphenyl group, a (fluoromethyl)phenyl group, a (difluoromethyl)phenyl group, a (trifluoromethyl)phenyl group , Methyl(trifluoromethyl)phenyl group, (trichloromethyl)phenyl group, methoxyphenyl group, methoxy(methyl)phenyl group, methoxy(trifluoromethyl)phenyl group, (fluoromethoxy)phenyl group, (difluoromethoxy)phenyl group , (Trifluoromethoxy)phenyl group, methyl(trifluoromethoxy)phenyl group, trifluoromethoxy(trifluoromethyl)phenyl group, methoxy(trifluoromethoxy)phenyl group, (trichloromethoxy)phenyl group, cyclobutyl group, cyclopentyl group , Cyclohexyl group, methylcyclobutyl group, dimethylcyclobutyl group, (trifluoromethyl)cyclobutyl group, methyl (trifluoromethyl)cyclobutyl group, methoxycyclobutyl group, methoxy(methyl)cyclobutyl group, methoxy(trifluoromethyl)cyclobutyl group Group, (trifluorome
[0048]
　“Phenyl group or cyclohexyl group (provided that R 3In the above-mentioned phenyl group and the above-mentioned cyclohexyl group, 1 or 2 arbitrary hydrogen atoms may be independently substituted with a methyl group or a methoxy group, and the above-mentioned phenyl group and the above-mentioned cyclohexyl group may be substituted with methyl. The group and the methoxy group may each independently have 1 to 3 arbitrary hydrogen atoms substituted with a fluorine atom or a chlorine atom. )”, in a phenyl group or a cyclohexyl group, each independently one or two arbitrary hydrogen atoms of the phenyl group or the cyclohexyl group are independently the above-mentioned methyl group (the methyl group is 1 to 3 arbitrary hydrogen atoms may be each independently substituted with a fluorine atom or a chlorine atom) or the above methoxy group (wherein the methoxy group is 1 to 3 arbitrary). Hydrogen atoms of may each independently be substituted with a fluorine atom or a chlorine atom.), and a group which may be substituted with, for example, a phenyl group, a tolyl group, a dimethylphenyl group, ( Fluoromethyl)phenyl group, (difluoromethyl)phenyl group, (trifluoromethyl)phenyl group, methyl (trifluoromethyl)phenyl group, (trichloromethyl)phenyl group, methoxyphenyl group, methoxy(methyl)phenyl group, methoxy( Trifluoromethyl)phenyl group, (fluoromethoxy)phenyl group, (difluoromethoxy)phenyl group, (trifluoromethoxy)phenyl group, methyl (trifluoromethoxy)phenyl group, trifluoromethoxy (trifluoromethyl)phenyl group, methoxy (Trifluoromethoxy)phenyl group, (trichloromethoxy)phenyl group, cyclohexyl group, methylcyclohexyl group, dimethylcyclohexyl group, (trifluoromethyl)cyclohexyl group, methyl(trifluoromethyl)cyclohexyl group, methoxycyclohexyl group, methoxy(methyl ) Cyclohexyl group, methoxy(trifluoromethyl)cyclohexyl group, (trifluoromethoxy)cyclohexyl group, methyl(trifluoromethoxy)cyclohexyl group, trifluoromethoxy(tri
[0049]
　“Phenyl group or cyclohexyl group (however, in the phenyl group and the cyclohexyl group in R 3 , each independently one arbitrary hydrogen atom may be substituted with a trifluoromethyl group or a trifluoromethoxy group. )” means a phenyl group, a (trifluoromethyl)phenyl group, a (trifluoromethoxy)phenyl group, a cyclohexyl group, a (trifluoromethyl)cyclohexyl group or a (trifluoromethoxy)cyclohexyl group.
[0050]
　In the above cyclic amine derivative, in the above general formula (I), R 1 is preferably a methyl group.
[0051]
　A is preferably a group represented by the above general formula (II-1) or (II-2).
[0052]
　R 2 is preferably a hydrogen atom, a fluorine atom or a chlorine atom, more preferably a fluorine atom or a chlorine atom, and further preferably a chlorine atom.
[0053]
　R 3 is an aryl group or a cycloalkyl group having a carbon number of 4 to 6 (provided that the aryl group and the cycloalkyl group in R 3 each independently have 1 or 2 arbitrary hydrogen atoms represented by methyl). Or a methoxy group, which may be substituted with a group or a methoxy group, and which can be substituted with the above aryl group or the above cycloalkyl group, independently has 1 to 3 arbitrary hydrogen atoms each being a fluorine atom or a chlorine atom. Is preferably a phenyl group or a cyclohexyl group (provided that the phenyl group and the cyclohexyl group in R 3 each independently have 1 or 2 arbitrary hydrogen atoms, The methyl group and methoxy group, which may be substituted with a methyl group or a methoxy group, and which can be substituted with the phenyl group and the cyclohexyl group, each independently have 1 to 3 arbitrary hydrogen atoms, a fluorine atom or a chlorine atom. Is more preferably a phenyl group or a cyclohexyl group (provided that the phenyl group and the cyclohexyl group in R 3 each independently have one arbitrary hydrogen atom as trifluoro). It may be substituted with a methyl group or a trifluoromethoxy group).
[0054]
　Here, when the above cycloalkyl group, for example, a cyclohexyl group has a substituent, specific examples thereof include a cis-4-(trifluoromethyl)cyclohexyl group, a trans-4-(trifluoromethyl)cyclohexyl group, Examples thereof include a cis-4-(trifluoromethoxy)cyclohexyl group and a trans-4-(trifluoromethoxy)cyclohexyl group.
[0055]
　n is preferably 1.
[0056]
　The cyclic amine derivative represented by the above general formula (I) preferably has a steric configuration represented by the following general formula (Ia). That is, in the cyclic amine derivative represented by the above general formula (I), in the above general formula (I), the configuration of the carbon atom at the 2-position of the piperidinyl group is preferably the R configuration.
[Chemical 6]

[0057]
　In the cyclic amine derivative represented by the above general formula (I), the above preferred R 1 , the above preferred R 2 , the above preferred R 3 , the above preferred n, the above preferred general formula (I) and the above preferred R 1 Any aspect can be selected for A and they can be combined. For example, the following combinations may be mentioned, but not limited to these.
[0058]
　In the cyclic amine derivative represented by the general formula (I), R 1 is an alkyl group having 1 to 3 carbon atoms, R 2 is a hydrogen atom or a halogen atom, and R 3 is an aryl group or a carbon atom. A cycloalkyl group having a number of 4 to 6 (provided that the aryl group and the cycloalkyl group in R 3 each independently have 1 or 2 arbitrary hydrogen atoms, an alkyl group having a carbon number of 1 to 3 or It may be substituted with an alkyloxy group having 1 to 3 carbon atoms, and the alkyl group having 1 to 3 carbon atoms and the alkyloxy group having 1 to 3 carbon atoms which may be substituted with the aryl group or the cycloalkyl group are respectively Independently, 1 to 3 arbitrary hydrogen atoms may be substituted with a halogen atom.), n is 1 or 2, and the wavy line is a point of attachment to the general formula (Ia). The general formula (I) is the following general formula (Ia), and A is a group represented by the following general formula (II-1), (II-2) or (II-3). It is preferable.
[Chemical 7]

[Chemical 8]

[0059]
　In another embodiment, in the cyclic amine derivative represented by the above general formula (I), R 1 is a methyl group, R 2 is a chlorine atom, R 3 is a phenyl group or a cyclohexyl group ( However, in the phenyl group and the cyclohexyl group in R 3 , one arbitrary hydrogen atom may be independently substituted with a trifluoromethyl group or a trifluoromethoxy group.), and n is 1. It is more preferable that the general formula (I) is the above general formula (Ia) and A is a group represented by the above general formula (II-1) or (II-2).
[0060]
　Specific examples of preferable compounds of the cyclic amine derivative represented by the above general formula (I) are shown in Table 1, but the present invention is not limited thereto.
[0061]
[table 1]

[0062]
　The compounds described in Table 1 also include their stereoisomers and solvates thereof, and pharmacologically acceptable salts thereof and mixtures thereof.
[0063]
　In the cyclic amine derivative represented by the general formula (I), stereoisomers may exist, but not only a single stereoisomer but also a mixture of stereoisomers such as a racemate and a diastereomer mixture. (Eg, a mixture of enantiomers) is also included.
[0064]
　“Stereoisomer” refers to a compound having the same chemical structure but different arrangement in three-dimensional space, such as a conformer, a rotamer, a tautomer, an enantiomer or a diastereomer. Etc.
[0065]
　The cyclic amine derivative represented by the above general formula (I) may be labeled with one or more isotopes, and examples of the labeled isotope include 2 H, 3 H, 13 C, 14 C. , 15 N, 15 O, 18 O and/or 125 I.
[0066]
　Examples of the “pharmacologically acceptable salt” of the cyclic amine derivative represented by the above general formula (I) include salts with inorganic acids and salts with organic acids. Examples of the salt with an inorganic acid include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide or phosphate, and examples of the salt with an organic acid include oxalate. , Malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, ascorbate , Glutarate, mandelate, phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, aspartate, glutamate or cinnamic acid Examples include salt.
[0067]
　The cyclic amine derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof may be an anhydride or may form a solvate such as a hydrate. .. Here, the solvate is preferably a pharmaceutically acceptable solvate. The pharmaceutically acceptable solvate may be either a hydrate or a non-hydrate, but a hydrate is preferred. Examples of the solvent that constitutes the solvate include alcohol solvents such as methanol, ethanol, and n-propanol, N,N-dimethylformamide (hereinafter, DMF), dimethyl sulfoxide (hereinafter, DMSO), and water.
[0068]
　The cyclic amine derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof can be made into a solvate such as a hydrate by a known method. As a known method, for example, the cyclic amine derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof is treated with water or another solvent (for example, methanol, ethanol or n-propanol). Examples include a method of treating with an alcohol solvent, DMF, DMSO) or a mixed solvent thereof.
[0069]
　The cyclic amine derivative represented by the above general formula (I) (hereinafter, cyclic amine derivative (I)) can be produced by an appropriate method based on the characteristics derived from the basic skeleton and the kind of the substituent. The starting materials and reagents used for producing these compounds can be generally purchased or can be produced by known methods.
[0070]
　The cyclic amine derivative (I) and the intermediates and starting materials used for the production thereof can be isolated and purified by the known means. Known means for isolation and purification include, for example, solvent extraction, reprecipitation, recrystallization or chromatography.
[0071]
　When the cyclic amine derivative (I) contains a stereoisomer, each enantiomer, diastereomer and the like can be obtained as a single optically active substance by a known method. Known methods include, for example, crystallization, enzyme resolution or chiral chromatography.
[0072]
　Crystallization can be performed according to a known method (for example, Brittain, HG, “Polymorphism in Pharmaceutical Solids, Second Edition”, CRC Press Co.) or a method analogous thereto. Seed crystals may be used if necessary.
[0073]
　Examples of the solvent used for crystallization of the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof include tetrahydrofuran (hereinafter, THF), 1,4-dioxane, diethyl ether, tert-butyl methyl ether or anisole. Ether solvents such as methanol, ethanol, 2-methoxyethanol, 2-ethoxyethanol, n-propanol, 2-propanol, 2-methyl-1-propanol, n-butanol, 2-butanol, 3-methyl-1- Alcohol solvents such as butanol, n-pentanol or ethylene glycol, aromatic hydrocarbon solvents such as toluene, xylene, cumene or tetralin, DMF, N,N-dimethylacetamide, formamide, N-methylpyrrolidone, DMSO or sulfolane. Aprotic polar solvent such as acetonitrile, nitrile solvent such as acetonitrile or propionitrile, ester solvent such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate or ethyl formate, acetone, methyl ethyl ketone, methyl Ketone-based solvents such as butyl ketone or methyl isobutyl ketone, halogen-based solvents such as dichloromethane, chloroform, 1,2-dichloroethene, 1,1,2-trichloroethene or chlorobenzene, hexane, pentane, heptane, cyclohexane, methylcyclohexane, etc. A hydrocarbon solvent, a nitro solvent such as nitromethane, a pyridine solvent such as pyridine, a carboxylic acid solvent such as acetic acid or formic acid, water or a mixed solvent thereof, or a solvent thereof and a cyclic amine derivative (I). Examples thereof include a mixed solvent with a solvent containing a base or an acid which forms the above-mentioned pharmacologically acceptable salt.
[0074]
　In each reaction of the production methods described below, in the case where the starting compound has an amino group or a carboxyl group, a protecting group may be introduced into these groups, and the protecting group may be deprotected as necessary after the reaction. By doing so, the target compound can be obtained.
[0075]
　Examples of the amino group-protecting group include an alkylcarbonyl group having 2 to 6 carbon atoms (eg, acetyl group), benzoyl group, an alkyloxycarbonyl group having 2 to 8 carbon atoms (eg, tert-butoxycarbonyl group or benzyloxy group). Examples thereof include a carbonyl group), an aralkyl group having 7 to 10 carbon atoms (eg, benzyl group), and a phthaloyl group.
[0076]
　Examples of the protective group for the carboxyl group include an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group or tert-butyl group) or an aralkyl group having 7 to 10 carbon atoms (eg, benzyl group).
[0077]
　Deprotection of the protecting group depends on the type of the protecting group, but is performed according to a known method (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method analogous thereto. be able to.
[0078]
　The cyclic amine derivative (I) is, for example, as shown in Scheme 1, a deprotection reaction of the tert-butoxycarbonyl group of the N-tert-butoxycarbonylpipecolic amide derivative (III) in the presence of an acid (first step). Then, it can be obtained by the condensation reaction (second step-1) of the pipecolic acid amide derivative (IV) obtained in the first step and the organic acid chloride derivative (V) in the presence of a base. The cyclic amine derivative (I) can also be obtained by a condensation reaction (second step-2) between the pipecolic acid amide derivative (IV) and the organic acid anhydride derivative (VI). The optically active form of the cyclic amine derivative (I) can be obtained, for example, by using the optically active form of the N-tert-butoxycarbonylpipecolic amide derivative (III).
[In the

formula, A and R 1 are the same as defined above.] ]
[0079]
(First step)
　Examples of the acid used in the deprotection reaction include acids such as hydrochloric acid, trifluoroacetic acid and hydrofluoric acid, and hydrochloric acid and trifluoroacetic acid are preferable.
[0080]
　The amount of acid used in the deprotection reaction is preferably 0.5 to 100 equivalents, and more preferably 1 to 30 equivalents, based on the N-tert-butoxycarbonylpipecolic acid amide derivative (III).
[0081]
　The reaction solvent for the deprotection reaction is appropriately selected depending on the type of reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include diethyl ether, THF, dimethoxyethane or 1,4-dioxane. Etc., ether solvents such as, ester solvents such as ethyl acetate or propyl acetate, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, alcohol solvents such as methanol or ethanol, or mixed solvents thereof. An ester solvent such as ethyl acetate or propyl acetate or a halogen solvent such as dichloromethane, chloroform or 1,2-dichloroethane is preferable.
[0082]
　The reaction temperature for the deprotection reaction is preferably −78° C. to 200° C., more preferably −20° C. to 100° C.
[0083]
　The reaction time of the deprotection reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 50 hours.
[0084]
　The concentration of the N-tert-butoxycarbonylpipecolic acid amide derivative (III) used in the deprotection reaction at the start of the reaction is preferably 1 mmol/L to 1 mol/L.
[0085]
　The N-tert-butoxycarbonylpipecolic amide derivative (III) used in the deprotection reaction can be produced, for example, by the method described in Scheme 2 or Scheme 3 below.
[0086]
(Second Step-1, Second Step-2
　) The amount of the organic acid chloride derivative (V) or the organic acid anhydride derivative (VI) used in the condensation reaction is 0.5 with respect to the pipecolic amide derivative (IV). It is preferably to 10 equivalents, more preferably 1 to 3 equivalents.
[0087]
　Examples of the base used in the condensation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride, and methyl lithium. Alternatively, there may be mentioned alkyllithium such as butyllithium, lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof, but an organic base such as triethylamine or diisopropylethylamine is preferable.
[0088]
　The amount of the base used in the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents, based on the pipecolic acid amide derivative (IV).
[0089]
　The reaction solvent used in the condensation reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxy. Examples include ether solvents such as ethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, and nitrile solvents such as acetonitrile or propionitrile. A halogen-based solvent such as chloroform or 1,2-dichloroethane is preferable.
[0090]
　The reaction temperature of the condensation reaction is preferably −78° C. to 200° C., more preferably −20° C. to 100° C.
[0091]
　The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 0.5 to 30 hours.
[0092]
　The concentration of the pipecolic amide derivative (IV) used in the condensation reaction at the start of the reaction is preferably 1 mmol/L to 1 mol/L.
[0093]
　The pipecolic amide derivative (IV) used in the condensation reaction may be a free form or a salt such as a hydrochloride.
[0094]
　The organic acid chloride derivative (V) and the organic acid anhydride derivative (VI) used in the condensation reaction can be purchased or can be produced by a known method or a method analogous thereto.
[0095]
　In the N-tert-butoxycarbonylpipecolic amide derivative (III) shown in Scheme 1, N-tert-butoxy in which A is a group represented by the above general formula (II-1) or (II-2). The carbonylpipecolic acid amide derivative (III-a) is, for example, as shown in Scheme 2, in the presence of a reducing agent, a reductive amination reaction of a secondary amine derivative (VII-a) with an aldehyde derivative (VIII) (see 1 step-1), or in the presence of a base, an alkylation reaction of the secondary amine derivative (VII-a) and the alkyl halide derivative (IX) (first step-2), and then in the presence of a halogenating agent, Halogenation reaction of the tertiary amine derivative (X) obtained in the first step (second step), and then in the presence of a metal and an acid, the second step or the third step-1 or the third step-2 described later. Of the nitrophenyl derivative (XI) obtained in step (4th step), followed by the reaction between the aniline derivative (XII) obtained in the 4th step and the pipecolic acid derivative (XIII) in the presence of a condensing agent and a base. It can be obtained by a condensation reaction (fifth step). In addition, the reductive amination reaction of the secondary amine derivative (VII-b) and the aldehyde derivative (VIII) (3rd step-1), or in the presence of a base, the secondary amine derivative (VII-b) and an alkyl halide The nitrophenyl derivative (XI) can also be obtained by the alkylation reaction (third step-2) of the derivative (IX). Further, when R 2 is a hydrogen atom, the reduction reaction (fourth step) described above is performed without subjecting the tertiary amine derivative (X) obtained in the first step to the halogenation reaction (second step). And the condensation reaction (fifth step) described above. The N-tert-butoxycarbonylpipecolic acid amide derivative (III-a) can be obtained by using, for example, the optically active pipecolic acid derivative (XIII).
[Chemical 10]

[In the formula, m represents 1 or 2, X represents a halogen atom, A represents a group represented by the above general formula (II-1) or (II-2), and R 2 , R 3 And n are the same as defined above. ]
[0096]
(Step 1)
　The amount of the aldehyde derivative (VIII) used in the reductive amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the secondary amine derivative (VII-a). preferable.
[0097]
　Examples of the reducing agent used in the reductive amination reaction include sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride, with sodium triacetoxyborohydride being preferred.
[0098]
　The amount of the reducing agent used in the reductive amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the secondary amine derivative (VII-a).
[0099]
　The reaction solvent used for the reductive amination reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include alcohol solvents such as methanol or ethanol, diethyl ether. Examples include ether solvents such as THF, THF, dimethoxyethane, and 1,4-dioxane, halogen solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, and mixed solvents thereof, and dichloromethane, chloroform, and 1,2-dichloroethane. And the like halogen-based solvents are preferable.
[0100]
　The reaction temperature of the reductive amination reaction is preferably −78° C. to 200° C., more preferably −20° C. to 100° C.
[0101]
　The reaction time of the reductive amination reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
[0102]
　The concentration of the secondary amine derivative (VII-a) used in the reductive amination reaction at the start of the reaction is preferably 1 mmol/L to 1 mol/L.
[0103]
　The secondary amine derivative (VII-a) used in the reductive amination reaction may be in a free form or a salt such as hydrochloride.
[0104]
　The secondary amine derivative (VII-a) and the aldehyde derivative (VIII) used in the reductive amination reaction can be purchased or can be produced by a known method or a method analogous thereto.
[0105]
(First Step-2)
　The amount of the alkyl halide derivative (IX) used in the alkylation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents relative to the secondary amine derivative (VII-a). preferable.
[0106]
　Examples of the base used in the alkylation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride, and methyl. Examples thereof include alkyllithium such as lithium or butyllithium, lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof, but an inorganic base such as sodium hydrogen carbonate or potassium carbonate is preferable.
[0107]
　The amount of the base used in the alkylation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, based on the secondary amine derivative (VII-a).
[0108]
　The reaction solvent used for the alkylation reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxy. Examples include ether solvents such as ethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, and nitrile solvents such as acetonitrile or propionitrile. Aprotic polar solvents such as DMSO are preferred.
[0109]
　The reaction temperature of the alkylation reaction is preferably −78° C. to 200° C., more preferably −20° C. to 100° C.
[0110]
　The reaction time of the alkylation reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
[0111]
　The concentration of the secondary amine derivative (VII-a) used in the alkylation reaction at the start of the reaction is preferably 1 mmol/L to 1 mol/L.
[0112]
　The secondary amine derivative (VII-a) used in the alkylation reaction may be in a free form or a salt such as hydrochloride.
[0113]
　The secondary amine derivative (VII-a) and the halogenated alkyl derivative (IX) used in the alkylation reaction can be purchased or can be produced by a known method or a method analogous thereto.
[0114]
(Second step)
　Examples of the halogenating agent used in the halogenation reaction include N-chlorosuccinimide (hereinafter, NCS), N-bromosuccinimide (hereinafter, NBS) and N-iodosuccinimide (hereinafter, NIS) N- N-halogenated hydantoin derivative of halogenated succinimide derivative, 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin or 1,3-diiodo-5,5-dimethylhydantoin Examples of the halogen atom include chlorine, bromine, and iodine, and NCS-, NBS-, or NIS-halogenated succinimide derivatives are preferable.
[0115]
　The amount of the halogenating agent used in the halogenation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the tertiary amine derivative (X).
[0116]
　The reaction solvent used in the halogenation reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxy. Examples include ether solvents such as ethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, and nitrile solvents such as acetonitrile or propionitrile. Aprotic polar solvents such as DMSO are preferred.
[0117]
　The reaction temperature of the halogenation reaction is preferably −78° C. to 200° C., more preferably −20° C. to 100° C.
[0118]
　The reaction time of the halogenation reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
[0119]
　The concentration of the tertiary amine derivative (X) used in the halogenation reaction at the start of the reaction is preferably 1 mmol/L to 1 mol/L.
[0120]
　The tertiary amine derivative (X) used in the halogenation reaction may be a free form or a salt such as hydrochloride.
[0121]
(Third step-1)
　The amount of the aldehyde derivative (VIII), the reducing agent, the amount of the reducing agent, the reaction solvent, the reaction temperature, the reaction time and the concentration at the start of the reaction in the reductive amination reaction are the first step- The same as 1.
[0122]
　The secondary amine derivative (VII-b) used in the reductive amination reaction may be in a free form or a salt such as hydrochloride.
[0123]
　The secondary amine derivative (VII-b) and aldehyde derivative (VIII) used in the reductive amination reaction can be purchased or can be produced by a known method or a method analogous thereto.
[0124]
(Third step-2) In the
　alkylation reaction, the amount of the alkyl halide derivative (IX), the base, the amount of the base, the reaction solvent, the reaction temperature, the reaction time and the concentration at the start of the reaction are the same as those in the first step-2. The same is true.
[0125]
　The secondary amine derivative (VII-b) used in the alkylation reaction may be in a free form or a salt such as hydrochloride.
[0126]
　The secondary amine derivative (VII-b) and the halogenated alkyl derivative (IX) used in the alkylation reaction can be purchased or can be produced by a known method or a method analogous thereto.
[0127]
(Fourth step)
　Examples of the metal used in the reduction reaction include iron powder and tin (II) chloride, and iron powder is preferable.
[0128]
　The amount of metal used in the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, based on the nitrophenyl derivative (XI).
[0129]
　Examples of the acid used in the reduction reaction include acetic acid, hydrochloric acid, and an ammonium chloride aqueous solution, and acetic acid or an ammonium chloride aqueous solution is preferable.
[0130]
　The amount of the acid used in the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, based on the nitrophenyl derivative (XI).
[0131]
　The reaction solvent used for the reduction reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include alcohol solvents such as methanol or ethanol, diethyl ether, THF. Examples thereof include ether solvents such as dimethoxyethane and 1,4-dioxane, water and mixed solvents thereof, and alcohol solvents such as methanol and ethanol, diethyl ether, THF, dimethoxyethane and 1,4-dioxane. A mixed solvent of the ether solvent and the water is preferable.
[0132]
　The reaction temperature of the reduction reaction is preferably 0 to 200°C, more preferably 50 to 150°C.
[0133]
　The reaction time of the reduction reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
[0134]
　The concentration of the nitrophenyl derivative (XI) used in the reduction reaction at the start of the reaction is preferably 1 mmol/L to 1 mol/L.
[0135]
　The nitrophenyl derivative (XI) used in the reduction reaction may be a free form or a salt such as hydrochloride.
[0136]
(Fifth Step)
　The amount of the pipecolic acid derivative (XIII) used in the condensation reaction is preferably 0.1 to 10 equivalents, more preferably 0.5 to 3 equivalents, based on the aniline derivative (XII).
[0137]
　Examples of the condensing agent used in the condensation reaction include N,N′-dicyclohexylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride (hereinafter, EDC·HCl), N,N′-carbodiimidazole. , {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethylene}dimethylammonium hexafluorophosphate (hereinafter referred to as COMU), O-(7-azabenzotriazole- 1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (hereinafter HATU) or O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl Although uronium hexafluorophosphate (henceforth, HBTU) is mentioned, HATU or HBTU is preferable.
[0138]
　The amount of the condensing agent used in the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the aniline derivative (XII).
[0139]
　Examples of the base used in the condensation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride, and methyl lithium. Alternatively, there may be mentioned alkyllithium such as butyllithium, lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof, but an organic base such as triethylamine or diisopropylethylamine is preferable.
[0140]
　The amount of the base used in the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents, based on the aniline derivative (XII).
[0141]
　The reaction solvent used in the condensation reaction is appropriately selected depending on the type of reagent used and the like, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxy. Examples include ether solvents such as ethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, and nitrile solvents such as acetonitrile or propionitrile. A halogen-based solvent such as chloroform or 1,2-dichloroethane or an aprotic polar solvent such as DMF or DMSO is preferable.
[0142]
　The reaction temperature of the condensation reaction is preferably 0 to 200°C, more preferably 20 to 100°C.
[0143]
　The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
[0144]
　The concentration of the aniline derivative (XII) used in the condensation reaction at the start of the reaction is preferably 1 mmol/L to 1 mol/L.
[0145]
　The aniline derivative (XII) used in the condensation reaction may be a free form or a salt such as hydrochloride.
[0146]
　The pipecolic acid derivative (XIII) used in the condensation reaction can be purchased or can be produced by a known method or a method analogous thereto.
[0147]
　Among the N-tert-butoxycarbonylpipecolic amide derivatives (III) shown in Scheme 1, A is a group represented by the above general formula (II-3), and the N-tert-butoxycarbonylpipecolic amide derivative is (III-b) is, for example, as shown in Scheme 3, in the presence of NBS and a radical initiator, a bromination reaction of the methylphenyl derivative (XIV) (first step), and then in the presence of a cyanating agent. Cyanation reaction of benzyl bromide derivative (XV) obtained in 1 step (2nd step), followed by reduction-cyclization reaction of benzyl cyanide derivative (XVI) obtained in 2nd step in the presence of a reducing agent (3rd step), then, in the presence of a reducing agent, the reduction reaction of the lactam derivative (XVII) obtained in the 3rd step (4th step), and subsequently in the presence of a base, 2 obtained in the 4th step Alkylation reaction of a primary amine derivative (XVIII) with an alkyl halide derivative (IX) (step 5), followed by an aryl halide derivative obtained in the step 5 in the presence of a metal catalyst, a ligand and a base ( XIX) and a primary pipecolic acid amide derivative (XX) by a coupling reaction (sixth step). The optically active form of the N-tert-butoxycarbonylpipecolic acid amide derivative (III-b) can be obtained, for example, by using the optically active form of the primary pipecolic acid amide derivative (XX).
[

Wherein A represents a group represented by the above general formula (II-3), and R 2 , R 3 , n and X are the same as defined above.] ]
[0148]
(First step)
　The amount of NBS used in the bromination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the methylphenyl derivative (XIV).
[0149]
　Examples of the radical initiator used in the bromination reaction include 2,2′-azobis(isobutyronitrile) and benzoyl peroxide.
[0150]
　The amount of the radical initiator used in the bromination reaction is preferably 0.01 to 5 equivalents, more preferably 0.05 to 0.5 equivalents, relative to the methylphenyl derivative (XIV).
[0151]
　The reaction solvent used for the bromination reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and for example, a halogen-based solvent such as dichloromethane or carbon tetrachloride or acetonitrile. Alternatively, a nitrile solvent such as propionitrile can be used, but a halogen solvent such as dichloromethane or carbon tetrachloride is preferable.
[0152]
　The reaction temperature of the bromination reaction is preferably -78°C to 200°C, more preferably -20°C to 160°C.
[0153]
　The reaction time of the bromination reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
[0154]
　The concentration of the methylphenyl derivative (XIV) used in the bromination reaction at the start of the reaction is preferably 1 mmol/L to 1 mol/L.
[0155]
　The methylphenyl derivative (XIV) used in the bromination reaction can be purchased or can be produced by a known method or a method analogous thereto.
[0156]
(Second Step)
　Examples of the cyanating agent used in the cyanation reaction include sodium cyanide and potassium cyanide.
[0157]
　The amount of the cyanating agent used in the cyanation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the benzyl bromide derivative (XV).
[0158]
　The reaction solvent used for the cyanation reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, for example, an alcohol solvent such as methanol or ethanol, diethyl ether, Ether solvent such as THF, dimethoxyethane or 1,4-dioxane, halogen solvent such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvent such as DMF or DMSO or nitrile such as acetonitrile or propionitrile. Examples thereof include a system solvent, water and a mixed solvent thereof, but a mixed solvent of an

The scope of the claims
[Claim 1]
　A cyclic amine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
[Chemical formula 1]

wherein, R 1 represents an alkyl group having 1 to 3 carbon atoms, A is represented by the following general formula (II-1), (II -2) or (II-3)
[Formula 2 ]

(wherein, R 2 represents a hydrogen atom or a halogen atom, R 3 represents an aryl group or a cycloalkyl group having a carbon number of 4-6 (where, R 3 the aryl group and the cycloalkyl group in the Independently, 1 or 2 arbitrary hydrogen atoms may be substituted with an alkyl group having 1 to 3 carbon atoms or an alkyloxy group having 1 to 3 carbon atoms, the aryl group and the cycloalkyl group In the alkyl group having 1 to 3 carbon atoms and the alkyloxy group having 1 to 3 carbon atoms which can be substituted with, each independently 1 to 3 arbitrary hydrogen atoms may be substituted with a halogen atom.), n represents 1 or 2, and the wavy line represents a group represented by the bonding point with the general formula (I). ]
[Claim 2]
　R 2 is a hydrogen atom, a fluorine atom or a chlorine atom, and
　R 3 is an aryl group or a cycloalkyl group having 4 to 6 carbon atoms (provided that the aryl group and the cycloalkyl group in R 3 are, respectively, Independently, one or two arbitrary hydrogen atoms may be substituted with a methyl group or a methoxy group, and the aryl group and the cycloalkyl group-substitutable methyl group and methoxy group are each independently 1 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom.), The cyclic amine derivative according to claim 1, or a pharmaceutically acceptable salt thereof.
[Claim 3]
　R 2 is a fluorine atom or a chlorine atom,
　R 3 is a phenyl group or a cyclohexyl group (provided that the phenyl group and the cyclohexyl group in R 3 are each independently one or two arbitrary hydrogen atoms). Atoms may be substituted with a methyl group or a methoxy group, and the methyl group and the methoxy group which can be substituted with the phenyl group and the cyclohexyl group each independently have 1 to 3 arbitrary hydrogen atoms as a fluorine atom. Or
　n may be substituted with a chlorine atom), and n is 1. The cyclic amine derivative or the pharmaceutically acceptable salt thereof according to claim 1.
[Claim 4]
　R 1 is a methyl group,
　A is the following general formula (II-1) or (II-2)
[Chemical

Formula 3] [in the formula, R 2 is a chlorine atom, and R 3 is a phenyl group] Or a cyclohexyl group (however, in the phenyl group and the cyclohexyl group in R 3 , each independently one arbitrary hydrogen atom may be substituted with a trifluoromethyl group or a trifluoromethoxy group). , N is 1, and the wavy line represents the point of connection with the general formula (I). ]
The cyclic amine derivative of Claim 1 which is a group shown by these, or its pharmacologically acceptable salt.
[Claim 5]
　A pharmaceutical comprising the cyclic amine derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.
[Claim 6]
　A retinoid-related orphan receptor γ antagonist containing the cyclic amine derivative according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.
[Claim 7]
　A therapeutic or prophylactic agent for an autoimmune disease, which comprises the cyclic amine derivative according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.
[Claim 8]
　A therapeutic or prophylactic agent for psoriasis or alopecia areata containing the cyclic amine derivative according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.
[Claim 9]
　A therapeutic or prophylactic agent for allergic diseases, which comprises the cyclic amine derivative according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.
[Claim 10]
　A therapeutic or preventive agent for allergic dermatitis, which comprises the cyclic amine derivative according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.
[Claim 11]
　A therapeutic or preventive agent for contact dermatitis or atopic dermatitis, which comprises the cyclic amine derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.