[發明所欲解決之問題] 本發明之課題在於提供一種以D1
受體拮抗作用、D2
受體拮抗作用及5-HT2A
受體拮抗作用為特徵之用於中樞神經系統疾病之預防或治療的化合物或其製藥學上所容許之鹽、其製造方法、包含該化合物之組合物等。 [解決問題之技術手段] 本發明者等人認為對D1
受體、D2
受體及5-HT2A
受體具有拮抗作用之化合物對包含難治性之精神***症或其他精神疾病表現出較強之藥效並進行努力研究，結果發現下述式(1)所表示之化合物及其製藥學上所容許之鹽(以下，有時視需要簡稱為「本發明化合物」)對D1
受體、D2
受體及5-HT2A
受體具有較強之拮抗作用，從而完成本發明。 即，本發明如下所述。 [項1]一種化合物或其製藥學上所容許之鹽，其係由式(1)表示： [化1][式中，環Q1
表示可經取代之苯環、或可經取代之吡啶環； 環Q2
表示可經取代之苯環、或可經取代之吡啶環； Ra
表示氫原子、或者可經同種或異種之1～3個鹵素原子取代之C1-6
烷基； n表示0、1或2； m表示1、2、3或4； Rb
於存在複數個之情形時，分別獨立地表示氫原子、鹵素原子、或者可經同種或異種之1～3個鹵素原子取代之C1-6
烷基]。 [項2]如項1記載之化合物或其製藥學上所容許之鹽，其中環Q1
為苯環或吡啶環(該苯環或吡啶環可經選自由鹵素原子、氰基、可經同種或異種之1～3個鹵素原子取代之C1-6
烷基、可經同種或異種之1～3個鹵素原子取代之C1-6
烷氧基、及可經同種或異種之1～2個C1-6
烷基取代之胺基所組成之群中之同種或異種之1～4個基取代)； 環Q2
為苯環或吡啶環(該苯環或吡啶環可經選自由鹵素原子、氰基、可經同種或異種之1～3個鹵素原子取代之C1-6
烷基、可經同種或異種之1～3個鹵素原子取代之C1-6
烷氧基、及可經同種或異種之1～2個C1-6
烷基取代之胺基所組成之群中之同種或異種之1～4個基取代)。 [項3]如項1或2記載之化合物或其製藥學上所容許之鹽，其中環Q1
為苯環(該環可經選自由鹵素原子、氰基、可經同種或異種之1～3個鹵素原子取代之C1-6
烷基、及可經同種或異種之1～3個鹵素原子取代之C1-6
烷氧基所組成之群中之同種或異種之1～4個基取代)； 環Q2
為苯環(該環可經選自由鹵素原子、氰基、可經同種或異種之1～3個鹵素原子取代之C1-6
烷基、及可經同種或異種之1～3個鹵素原子取代之C1-6
烷氧基所組成之群中之同種或異種之1～4個基取代)。 [項4]如項1至3中任一項記載之化合物或其製藥學上所容許之鹽，其中n為1。 [項5]如項1至4中任一項記載之化合物或其製藥學上所容許之鹽，其中Rb
於存在複數個之情形時，分別獨立地為鹵素原子、或者可經同種或異種之1～3個鹵素原子取代之C1-6
烷基。 [項6]如項1記載之化合物或其製藥學上所容許之鹽，其係由式(1a)表示： [化2][式中，Ra
表示氫原子、或者可經同種或異種之1～3個鹵素原子取代之C1-6
烷基； R1
、R2
、R3
、R4
、R5
、R6
、R7
及R8
分別獨立地表示氫原子、鹵素原子、氰基、可經同種或異種之1～3個鹵素原子取代之C1-6
烷基、可經同種或異種之1～3個鹵素原子取代之C1-6
烷氧基、或者可經同種或異種之1～2個C1-6
烷基取代之胺基； R11
、R12
、R13
及R14
分別獨立地表示氫原子、鹵素原子、或者可經同種或異種之1～3個鹵素原子取代之C1-6
烷基]。 [項7]如項6記載之化合物或其製藥學上所容許之鹽，其中R11
、R12
、R13
及R14
中之任一者以上為鹵素原子、或者可經同種或異種之1～3個鹵素原子取代之C1-6
烷基。 [項8]如項6記載之化合物或其製藥學上所容許之鹽，其係由式(1b)表示： [化3][式中，Ra
、R2
、R7
、R13
及R14
係與項6中同義]。 [項9]如項6至8中任一項記載之化合物或其製藥學上所容許之鹽，其中R13
為C1-6
烷基。 [項10]如項6至8中任一項記載之化合物或其製藥學上所容許之鹽，其中R13
為甲基。 [項11]如項6至10中任一項記載之化合物或其製藥學上所容許之鹽，其中R14
為氫原子。 [項12]如項6記載之化合物或其製藥學上所容許之鹽，其係由式(1b-1)表示： [化4][式中，Ra
、R2
及R7
係與項6中同義]。 [項13]如項1至12中任一項記載之化合物或其製藥學上所容許之鹽，其中Ra
係可經同種或異種之1～3個鹵素原子取代之C1-6
烷基。 [項14]如項1至12中任一項記載之化合物或其製藥學上所容許之鹽，其中Ra
為甲基。 [項15]如項6至14中任一項記載之化合物或其製藥學上所容許之鹽，其中R2
及R7
分別獨立地為氫原子、鹵素原子、氰基、可經同種或異種之1～3個鹵素原子取代之C1-6
烷基、或者可經同種或異種之1～3個鹵素原子取代之C1-6
烷氧基。 [項16]如項6至14中任一項記載之化合物或其製藥學上所容許之鹽，其中R2
及R7
中之任一者以上為鹵素原子、氰基、可經同種或異種之1～3個鹵素原子取代之C1-6
烷基、或者可經同種或異種之1～3個鹵素原子取代之C1-6
烷氧基。 [項17]如項6至14中任一項記載之化合物或其製藥學上所容許之鹽，其中R2
為氫原子、氟原子、氯原子、C1-3
烷基或C1-3
烷氧基， R7
為氫原子、氟原子、氯原子、氰基、可經1～3個氟原子取代之C1-3
烷基、或可經1～3個氟原子取代之C1-6
烷氧基。 [項18]如項1記載之化合物或其製藥學上所容許之鹽，其係選自以下之化合物群中： 11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-8-甲基-2-(三氟甲基)-5H-二苯并[b,e][1,4]二氮呯(實施例32)、 8-甲基-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-2-(三氟甲基)-5H-二苯并[b,e][1,4]二氮呯(實施例33)、 8-氯-11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-2-(三氟甲氧基)-5H-二苯并[b,e][1,4]二氮呯(實施例38)、 8-氯-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-2-(三氟甲氧基)-5H-二苯并[b,e][1,4]二氮呯(實施例39)、 8-氯-11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-2-乙基-5H-二苯并[b,e][1,4]二氮呯(實施例45)、 8-氯-2-乙基-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-5H-二苯并[b,e][1,4]二氮呯(實施例46)、 11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-2-乙基-8-氟-5H-二苯并[b,e][1,4]二氮呯(實施例49)、 2-乙基-8-氟-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-5H-二苯并[b,e][1,4]二氮呯(實施例50)、 2-氯-11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-8-氟-5H-二苯并[b,e][1,4]二氮呯(實施例57)、 2-氯-8-氟-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-5H-二苯并[b,e][1,4]二氮呯(實施例58)、 8-氯-11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-2-甲基-5H-二苯并[b,e][1,4]二氮呯(實施例65)、 8-氯-2-甲基-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-5H-二苯并[b,e][1,4]二氮呯(實施例66)、 8-氯-11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-2-甲氧基-5H-二苯并[b,e][1,4]二氮呯(實施例72)、 8-氯-2-甲氧基-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-5H-二苯并[b,e][1,4]二氮呯(實施例73)、 8-氯-11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-2-乙氧基-5H-二苯并[b,e][1,4]二氮呯(實施例88)及 8-氯-2-乙氧基-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-5H-二苯并[b,e][1,4]二氮呯(實施例89)。 [項19]如項1記載之化合物或其製藥學上所容許之鹽，其係選自以下之化合物群中： 11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-8-甲基-2-(三氟甲基)-5H-二苯并[b,e][1,4]二氮呯(實施例32)、 8-甲基-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-2-(三氟甲基)-5H-二苯并[b,e][1,4]二氮呯(實施例33)、 8-氯-11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-2-(三氟甲氧基)-5H-二苯并[b,e][1,4]二氮呯(實施例38)、 8-氯-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-2-(三氟甲氧基)-5H-二苯并[b,e][1,4]二氮呯(實施例39)、 8-氯-11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-2-乙基-5H-二苯并[b,e][1,4]二氮呯(實施例45)、 8-氯-2-乙基-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-5H-二苯并[b,e][1,4]二氮呯(實施例46)、 11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-2-乙基-8-氟-5H-二苯并[b,e][1,4]二氮呯(實施例49)、 2-乙基-8-氟-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-5H-二苯并[b,e][1,4]二氮呯(實施例50)、 8-氯-11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-2-甲氧基-5H-二苯并[b,e][1,4]二氮呯(實施例72)、 8-氯-2-甲氧基-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-5H-二苯并[b,e][1,4]二氮呯(實施例73)、 8-氯-11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-2-乙氧基-5H-二苯并[b,e][1,4]二氮呯(實施例88)及 8-氯-2-乙氧基-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-5H-二苯并[b,e][1,4]二氮呯(實施例89)。 [項20]如項1記載之化合物或其製藥學上所容許之鹽，其係選自以下之化合物群中： 11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-8-甲基-2-(三氟甲基)-5H-二苯并[b,e][1,4]二氮呯(實施例32)、 8-甲基-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-2-(三氟甲基)-5H-二苯并[b,e][1,4]二氮呯(實施例33)、 8-氯-11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-2-(三氟甲氧基)-5H-二苯并[b,e][1,4]二氮呯(實施例38)、 8-氯-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-2-(三氟甲氧基)-5H-二苯并[b,e][1,4]二氮呯(實施例39)、 8-氯-11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-2-乙基-5H-二苯并[b,e][1,4]二氮呯(實施例45)、 8-氯-2-乙基-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-5H-二苯并[b,e][1,4]二氮呯(實施例46)、 8-氯-11-[(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基]-2-乙氧基-5H-二苯并[b,e][1,4]二氮呯(實施例88)及 8-氯-2-乙氧基-11-[(6S)-6-甲基-1-(2
H3
)甲基-1,2,3,6-四氫吡啶-4-基]-5H-二苯并[b,e][1,4]二氮呯(實施例89)。 [項21]一種醫藥，其含有如項1至20中任一項記載之化合物或其製藥學上所容許之鹽作為有效成分。 [項22]一種中樞神經系統疾病之治療劑，其含有如項1至20中任一項記載之化合物或其製藥學上所容許之鹽作為有效成分。 [項23]如項22記載之治療劑，其中中樞神經系統疾病為精神***症、躁鬱症、自閉症、ADHD、抑鬱症、焦慮症、睡眠障礙、癡呆症之行為・心理症狀(BPSD(Behavioral and Psychological Symptoms of Dementia))或神經退化性疾病之精神症狀。 [項24]一種用以治療中樞神經系統疾病之方法，其包括對需進行治療之患者投予治療上之有效量之如項1至20中任一項記載之化合物或其製藥學上所容許之鹽。 [項25]一種如項1至20中任一項記載之化合物或其製藥學上所容許之鹽之用途，其係用以製造中樞神經系統疾病之治療劑。 [項26]如項1至20中任一項記載之化合物或其製藥學上所容許之鹽，其係用於治療中樞神經系統疾病。 [項27]一種中樞神經系統疾病之治療劑，其係將如項1至20中任一項記載之化合物或其製藥學上所容許之鹽與選自由阿立哌唑、奧氮平、喹硫平、利培酮、布南色林、哌羅匹隆、帕潘立酮、齊拉西酮、阿塞那平、伊潘立酮、舍吲哚、魯拉西酮及該等之製藥學上所容許之鹽所組成之群中之至少一種藥劑加以組合而成。 [項28]一種含有如項1至20中任一項記載之化合物或其製藥學上所容許之鹽作為有效成分之治療劑，其係與選自由阿立哌唑、奧氮平、喹硫平、利培酮、布南色林、哌羅匹隆、帕潘立酮、齊拉西酮、阿塞那平、伊潘立酮、舍吲哚、魯拉西酮及該等之製藥學上所容許之鹽所組成之群中之至少一種藥劑併用而用以治療中樞神經系統疾病。 [發明之效果] 本發明化合物係對D1
受體、D2
受體及5-HT2A
受體表現出拮抗作用。除此以外，於較佳之態樣中，腦移行性優異，進而，視為顆粒性球缺乏症之一因之反應性代謝物之生成量亦較低。於進而較佳之態樣中，對視為與消化系統損傷、鎮靜、體重增加等副作用相關之組織胺受體、毒蕈鹼受體、血清素5-HT2c
受體(以下稱為5-HT2c
受體)等之拮抗作用較弱。因此，本發明化合物可用作安全性較高之優異之中樞神經系統疾病(例如精神***症)之治療劑及/或預防劑。[Problems to be Solved by the Invention] An object of the present invention is to provide a prevention for central nervous system diseases characterized by D 1 receptor antagonism, D 2 receptor antagonism, and 5-HT 2A receptor antagonism. A therapeutic compound or a pharmaceutically acceptable salt thereof, a process for producing the same, a composition comprising the same, and the like. [Technical means for solving the problem] The present inventors believe that compounds having antagonistic effects on the D 1 receptor, the D 2 receptor, and the 5-HT 2A receptor exhibit a refractory schizophrenia or other mental illness. As a result of the intensive study of the drug, it has been found that the compound represented by the following formula (1) and the pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as "the compound of the present invention" as needed) are for the D 1 receptor. The D 2 receptor and the 5-HT 2A receptor have strong antagonistic effects, thereby completing the present invention. That is, the present invention is as follows. [Item 1] A compound or a pharmaceutically acceptable salt thereof, which is represented by the formula (1): [wherein, ring Q 1 represents a benzene ring which may be substituted or a pyridine ring which may be substituted; ring Q 2 represents a benzene ring which may be substituted, or a pyridine ring which may be substituted; R a represents a hydrogen atom, or may be a C 1-6 alkyl group substituted with 1 to 3 halogen atoms of the same or different species; n represents 0, 1 or 2; m represents 1, 2, 3 or 4; R b is independently in the presence of a plurality of cases The ground represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms of the same or different species. [Claim 2] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein the ring Q 1 is a benzene ring or a pyridine ring (the benzene ring or the pyridine ring may be selected from a halogen atom, a cyano group, and the same species) Or a C 1-6 alkyl group substituted with 1 to 3 halogen atoms of a heterogeneous group, a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms of the same or different kinds, and 1 to 2 which may be homologous or heterologous a group of 1 to 4 groups of the same or different species in the group consisting of a C 1-6 alkyl-substituted amine group; the ring Q 2 is a benzene ring or a pyridine ring (the benzene ring or the pyridine ring may be selected from a halogen group) An atom, a cyano group, a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms of the same or different species, a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms of the same or different kinds, and 1 to 4 groups of the same or different species in the group consisting of 1 or 2 C 1-6 alkyl-substituted amine groups of the same or different species). [Item 3] as permitted by the compound or a pharmaceutically described in item 1 or 2, wherein the ring Q 1 is a benzene ring (which ring may be selected from the group consisting of a halogen atom, a cyano group, may be the same or different species of ~ 1 the 3 halogen atoms substituted C 1-6 alkyl group, and the group may be substituted with the same species or different species of 1 to 3 halogen atoms, C 1-6 alkoxy group consisting of heterogeneous or in the 1 to 4 groups of Substituted); ring Q 2 is a benzene ring (the ring may be selected from a C 1-6 alkyl group substituted by a halogen atom, a cyano group, a 1-3 ring halogen atom of the same or different species, and may be homologous or heterologous) One to four bases of the same or different species in the group consisting of 1 to 3 halogen atoms substituted by C 1-6 alkoxy groups). The compound according to any one of items 1 to 3, wherein the n is 1 or a pharmaceutically acceptable salt thereof. The compound according to any one of items 1 to 4, wherein the R b is independently a halogen atom or may be homologous or heterogeneous, in the case where a plurality of compounds are present, respectively. One to three halogen atoms are substituted for the C 1-6 alkyl group. [Claim 6] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, which is represented by the formula (1a): Wherein R a represents a hydrogen atom or a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms of the same or different species; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 each independently represent a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms of the same or different kinds, and may have 1 to 3 halogens of the same or different species. An atom-substituted C 1-6 alkoxy group, or an amine group which may be substituted with 1 to 2 C 1-6 alkyl groups of the same or different species; R 11 , R 12 , R 13 and R 14 each independently represent a hydrogen atom a halogen atom or a C 1-6 alkyl group which may be substituted by 1 to 3 halogen atoms of the same or different species. The compound according to Item 6, wherein the compound of any one of R 11 , R 12 , R 13 and R 14 is a halogen atom or may be the same or a heterogeneous one. ～3 halogen atoms substituted by C 1-6 alkyl. [Claim 8] The compound according to Item 6, or a pharmaceutically acceptable salt thereof, which is represented by the formula (1b): [wherein, R a , R 2 , R 7 , R 13 and R 14 are synonymous with the term 6]. The compound according to any one of items 6 to 8, wherein R 13 is a C 1-6 alkyl group, or a pharmaceutically acceptable salt thereof. The compound according to any one of items 6 to 8, wherein R 13 is a methyl group, or a pharmaceutically acceptable salt thereof. The compound according to any one of items 6 to 10, wherein R 14 is a hydrogen atom, or a pharmaceutically acceptable salt thereof. [Claim 12] The compound according to Item 6, or a pharmaceutically acceptable salt thereof, which is represented by the formula (1b-1): [wherein, R a , R 2 and R 7 are synonymous with item 6]. The compound according to any one of items 1 to 12, wherein the R a is a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms of the same or different species, or a pharmaceutically acceptable salt thereof. . The compound according to any one of items 1 to 12, wherein R a is a methyl group, or a pharmaceutically acceptable salt thereof. [Claim 15] The compound according to any one of items 6 to 14, wherein R 2 and R 7 are each independently a hydrogen atom, a halogen atom, a cyano group, or the same or a heterogeneous group, or a pharmaceutically acceptable salt thereof. the substituent of from 1 to 3 halogen atoms, C 1-6 alkyl group, a substituted or may be of the same type or different 1 to 3 halogen atoms, C 1-6 alkoxy group. The compound according to any one of items 6 to 14, or a pharmaceutically acceptable salt thereof, wherein any one of R 2 and R 7 is a halogen atom, a cyano group, or the same or different species the substituent of from 1 to 3 halogen atoms, C 1-6 alkyl group, a substituted or may be of the same type or different 1 to 3 halogen atoms, C 1-6 alkoxy group. The compound according to any one of items 6 to 14, wherein R 2 is a hydrogen atom, a fluorine atom, a chlorine atom, a C 1-3 alkyl group or a C 1-3 , or a pharmaceutically acceptable salt thereof. alkoxy, R 7 is a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, the substituents may be 1 to 3 fluorine atoms, C 1-3 alkyl, or may be substituted with 1 to 3 fluorine atoms C 1- 6 alkoxy. [Claim 18] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 11-[(6S)-1,6-dimethyl-1,2,3 ,6-tetrahydropyridin-4-yl]-8-methyl-2-(trifluoromethyl)-5H-dibenzo[b,e][1,4]diazepine (Example 32), 8-Methyl-11-[(6S)-6-methyl-1-( 2 H 3 )methyl-1,2,3,6-tetrahydropyridin-4-yl]-2-(trifluoromethyl) -5H-dibenzo[b,e][1,4]diazepine (Example 33), 8-chloro-11-[(6S)-1,6-dimethyl-1,2, 3,6-tetrahydropyridin-4-yl]-2-(trifluoromethoxy)-5H-dibenzo[b,e][1,4]diazepine (Example 38), 8-chloro -11-[(6S)-6-methyl-1-( 2 H 3 )methyl-1,2,3,6-tetrahydropyridin-4-yl]-2-(trifluoromethoxy)- 5H-dibenzo[b,e][1,4]diazepine (Example 39), 8-chloro-11-[(6S)-1,6-dimethyl-1,2,3,6 -tetrahydropyridin-4-yl]-2-ethyl-5H-dibenzo[b,e][1,4]diazepine (Example 45), 8-chloro-2-ethyl-11- [(6S)-6-methyl-1-( 2 H 3 )methyl-1,2,3,6-tetrahydropyridin-4-yl]-5H-dibenzo[b,e][1, 4] diazepine (Example 46), 11-[(6S)-1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl]-2-ethyl-8- Fluoro-5H-dibenzo[b,e][1,4]diazepine (Example 49), 2-ethyl-8- Fluor-11-[(6S)-6-methyl-1-( 2 H 3 )methyl-1,2,3,6-tetrahydropyridin-4-yl]-5H-dibenzo[b,e ][1,4]diazepine (Example 50), 2-chloro-11-[(6S)-1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] -8-fluoro-5H-dibenzo[b,e][1,4]diazepine (Example 57), 2-chloro-8-fluoro-11-[(6S)-6-methyl-1 -( 2 H 3 )methyl-1,2,3,6-tetrahydropyridin-4-yl]-5H-dibenzo[b,e][1,4]diazepine (Example 58), 8-Chloro-11-[(6S)-1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl]-2-methyl-5H-dibenzo[b,e ][1,4]diazepine (Example 65), 8-chloro-2-methyl-11-[(6S)-6-methyl-1-( 2 H 3 )methyl-1,2, 3,6-tetrahydropyridin-4-yl]-5H-dibenzo[b,e][1,4]diazepine (Example 66), 8-chloro-11-[(6S)-1, 6-Dimethyl-1,2,3,6-tetrahydropyridin-4-yl]-2-methoxy-5H-dibenzo[b,e][1,4]diazepine (Example 72), 8-Chloro-2-methoxy-11-[(6S)-6-methyl-1-( 2 H 3 )methyl-1,2,3,6-tetrahydropyridin-4-yl ]-5H-dibenzo[b,e][1,4]diazepine (Example 73), 8-chloro-11-[(6S)-1,6-dimethyl-1,2,3 ,6-tetrahydropyridin-4-yl]-2-ethoxy-5H-dibenzo[b,e][1,4]diazepine (Example 88) and 8-chloro-2-ethoxyl Base-11-[(6S)-6-methyl-1-( 2 H 3 Methyl-1,2,3,6-tetrahydropyridin-4-yl]-5H-dibenzo[b,e][1,4]diazepine (Example 89). [Claim 19] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 11-[(6S)-1,6-dimethyl-1,2,3 ,6-tetrahydropyridin-4-yl]-8-methyl-2-(trifluoromethyl)-5H-dibenzo[b,e][1,4]diazepine (Example 32), 8-Methyl-11-[(6S)-6-methyl-1-( 2 H 3 )methyl-1,2,3,6-tetrahydropyridin-4-yl]-2-(trifluoromethyl) -5H-dibenzo[b,e][1,4]diazepine (Example 33), 8-chloro-11-[(6S)-1,6-dimethyl-1,2, 3,6-tetrahydropyridin-4-yl]-2-(trifluoromethoxy)-5H-dibenzo[b,e][1,4]diazepine (Example 38), 8-chloro -11-[(6S)-6-methyl-1-( 2 H 3 )methyl-1,2,3,6-tetrahydropyridin-4-yl]-2-(trifluoromethoxy)- 5H-dibenzo[b,e][1,4]diazepine (Example 39), 8-chloro-11-[(6S)-1,6-dimethyl-1,2,3,6 -tetrahydropyridin-4-yl]-2-ethyl-5H-dibenzo[b,e][1,4]diazepine (Example 45), 8-chloro-2-ethyl-11- [(6S)-6-methyl-1-( 2 H 3 )methyl-1,2,3,6-tetrahydropyridin-4-yl]-5H-dibenzo[b,e][1, 4] diazepine (Example 46), 11-[(6S)-1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl]-2-ethyl-8- Fluoro-5H-dibenzo[b,e][1,4]diazepine (Example 49), 2-ethyl-8- Fluor-11-[(6S)-6-methyl-1-( 2 H 3 )methyl-1,2,3,6-tetrahydropyridin-4-yl]-5H-dibenzo[b,e ][1,4]diazepine (Example 50), 8-chloro-11-[(6S)-1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl] 2-methoxy-5H-dibenzo[b,e][1,4]diazepine (Example 72), 8-chloro-2-methoxy-11-[(6S)-6- Methyl-1-( 2 H 3 )methyl-1,2,3,6-tetrahydropyridin-4-yl]-5H-dibenzo[b,e][1,4]diazepine Example 73), 8-chloro-11-[(6S)-1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl]-2-ethoxy-5H-diphenyl And [b,e][1,4]diazepine (Example 88) and 8-chloro-2-ethoxy-11-[(6S)-6-methyl-1-( 2 H 3 ) A Base-1,2,3,6-tetrahydropyridin-4-yl]-5H-dibenzo[b,e][1,4]diazepine (Example 89). [20] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 11-[(6S)-1,6-dimethyl-1,2,3 ,6-tetrahydropyridin-4-yl]-8-methyl-2-(trifluoromethyl)-5H-dibenzo[b,e][1,4]diazepine (Example 32), 8-Methyl-11-[(6S)-6-methyl-1-( 2 H 3 )methyl-1,2,3,6-tetrahydropyridin-4-yl]-2-(trifluoromethyl) -5H-dibenzo[b,e][1,4]diazepine (Example 33), 8-chloro-11-[(6S)-1,6-dimethyl-1,2, 3,6-tetrahydropyridin-4-yl]-2-(trifluoromethoxy)-5H-dibenzo[b,e][1,4]diazepine (Example 38), 8-chloro -11-[(6S)-6-methyl-1-( 2 H 3 )methyl-1,2,3,6-tetrahydropyridin-4-yl]-2-(trifluoromethoxy)- 5H-dibenzo[b,e][1,4]diazepine (Example 39), 8-chloro-11-[(6S)-1,6-dimethyl-1,2,3,6 -tetrahydropyridin-4-yl]-2-ethyl-5H-dibenzo[b,e][1,4]diazepine (Example 45), 8-chloro-2-ethyl-11- [(6S)-6-methyl-1-( 2 H 3 )methyl-1,2,3,6-tetrahydropyridin-4-yl]-5H-dibenzo[b,e][1, 4] diazepine (Example 46), 8-chloro-11-[(6S)-1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl]-2-ethyl Oxy-5H-dibenzo[b,e][1,4]diazepine (Example 88) and 8-chloro-2- Oxy -11 - [(6S) -6- methyl -1- (2 H 3) methyl-1,2,3,6-tetrahydropyridin-4-yl] -5H- dibenzo [b, e] [1,4]diazepine (Example 89). [Claim 21] A pharmaceutical composition containing the compound according to any one of Items 1 to 20 or a pharmaceutically acceptable salt thereof as an active ingredient. [Claim 22] A therapeutic agent for a central nervous system disease, which comprises the compound according to any one of Items 1 to 20 or a pharmaceutically acceptable salt thereof as an active ingredient. [Claim 23] The therapeutic agent according to Item 22, wherein the central nervous system disease is schizophrenia, bipolar disorder, autism, ADHD, depression, anxiety, sleep disorder, behavior and psychological symptoms of dementia (BPSD ( Behavioral and Psychological Symptoms of Dementia)) or psychotic symptoms of neurodegenerative diseases. [Claim 24] A method for treating a central nervous system disease, which comprises administering a therapeutically effective amount of a compound according to any one of items 1 to 20 or a pharmaceutically acceptable compound thereof to a patient in need of treatment. Salt. [Claim 25] The use of a compound according to any one of items 1 to 20, or a pharmaceutically acceptable salt thereof, for the manufacture of a therapeutic agent for diseases of the central nervous system. [Claim 26] The compound according to any one of items 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases of the central nervous system. [Claim 27] A therapeutic agent for a central nervous system disease, which comprises the compound according to any one of items 1 to 20, or a pharmaceutically acceptable salt thereof, selected from the group consisting of aripiprazole, olanzapine, and quinine. Thiopenic, risperidone, bunnerin, piperpirone, paliperidone, ziprasidone, asenapine, ipidine, sputum, lurasidone and the like At least one agent selected from the group consisting of pharmaceutically acceptable salts is combined. [Claim 28] A therapeutic agent containing the compound according to any one of Items 1 to 20 or a pharmaceutically acceptable salt thereof as an active ingredient, which is selected from the group consisting of aripiprazole, olanzapine, quetiapine Ping, risperidone, bunnerin, piperpirone, paliperidone, ziprasidone, asenapine, ipidine, sputum, lurasidone and the pharmacy of these At least one agent selected from the group consisting of the above-mentioned salts is used in combination to treat diseases of the central nervous system. [Effect of the Invention] The compound of the present invention exhibits an antagonistic action against the D 1 receptor, the D 2 receptor, and the 5-HT 2A receptor. In addition, in a preferred aspect, brain transition property is excellent, and further, it is considered to be one of particulate ball deficiencies because the amount of reactive metabolites produced is also low. In a further preferred aspect, the histamine receptor, the muscarinic receptor, and the serotonin 5-HT 2c receptor (hereinafter referred to as 5-HT) are considered to be associated with side effects such as digestive system damage, sedation, and weight gain. The antagonistic effect of 2c receptors and the like is weak. Therefore, the compound of the present invention can be used as a therapeutic and/or preventive agent for a highly safe and excellent central nervous system disease such as schizophrenia.
以下，詳細地說明本發明。於本說明書中，亦有將「取代基」之定義中之碳之數量例如記載為「C1-6
」等之情形。具體而言，「C1-6
烷基」之記載係與碳數1至6之烷基同義。 作為「鹵素原子」之具體例，可列舉：氟原子、氯原子、溴原子或碘原子。較佳為氟原子、氯原子。 「C1-6
烷基」意指具有碳數1～6個之直鏈狀或支鏈狀之飽和烴基。較佳為「C1-4
烷基」。作為「C1-6
烷基」之具體例，例如可列舉：甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、新戊基、1-乙基丙基、己基、異己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、2-乙基丁基等。 「C1-6
烷氧基」之「C1-6
烷基」部分係與上述「C1-6
烷基」同義。較佳為「C1-4
烷氧基」。作為「C1-6
烷氧基」之具體例，例如可列舉：甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、異丁氧基、第二丁氧基、第三丁氧基等。 於式(1)所表示之化合物中，Rb
基若可取代，則可於含氮單環上之任一碳原子進行取代，若可取代，則可於同一碳原子上相同或不同之2個Rb
基進行取代。 於式(1)所表示之化合物中，於環Q1
及/或環Q2
為吡啶環時，與該等進行稠合之環共有之箭頭所表示之4個原子為碳。 [化5]作為「可經取代之苯環」、「可經取代之吡啶環」中之取代基，例如可列舉： (a)鹵素原子、 (b)氰基、 (c)C1-6
烷基(該基可經選自由鹵素原子、羥基及C1-6
烷氧基所組成之群中之同種或異種之1～3個基取代)、 (d)C1-6
烷氧基(該基可經選自由鹵素原子、羥基及C1-6
烷氧基所組成之群中之同種或異種之1～3個基取代)、 (e)苯基(該基可經選自由鹵素原子、C1-6
烷基及C1-6
烷氧基所組成之群中之同種或異種之1～4個基取代)、 (f)5員或6員之雜芳基(該基可經選自由鹵素原子、C1-6
烷基及C1-6
烷氧基所組成之群中之同種或異種之1～4個基取代)、 (g)苯氧基(該基可經選自由鹵素原子、C1-6
烷基及C1-6
烷氧基所組成之群中之同種或異種之1～4個基取代)、 (h)羥基、 (i)胺基(該基可經同種或異種之1～2個C1-6
烷基取代)及 (j)胺基羰基(該胺基可經同種或異種之1～2個C1-6
烷基取代)等。 較佳為可列舉：鹵素原子、氰基、可經同種或異種之1～3個鹵素原子取代之C1-6
烷基、可經同種或異種之1～3個鹵素原子取代之C1-6
烷氧基、及可經同種或異種之1～2個C1-6
烷基取代之胺基。 更佳為可列舉：鹵素原子、可經同種或異種之1～3個鹵素原子取代之C1-6
烷基、及可經同種或異種之1～3個鹵素原子取代之C1-6
烷氧基。 於式(1a)所表示之本發明化合物中，Ra
、R1
、R2
、R3
、R4
、R5
、R6
、R7
、R8
、R11
、R12
、R13
及R14
中較佳者如下所述，但本發明之技術範圍並不限定於下述列舉之化合物之範圍。 作為Ra
，較佳為可列舉經同種或異種之1～3個鹵素原子取代之C1-6
烷基。更佳為C1-3
烷基；進而較佳為甲基。又，作為Ra
之另一態樣，可列舉氘甲基(CD3
)。 作為R1
、R3
、R4
、R5
、R6
及R8
，較佳為可列舉氫原子及鹵素原子。更佳為氫原子。 作為R2
及R7
，較佳為可列舉：氫原子、鹵素原子、氰基、可經同種或異種之1～3個鹵素原子取代之C1-6
烷基、及可經同種或異種之1～3個鹵素原子取代之C1-6
烷氧基。更佳為可列舉：鹵素原子、可經同種或異種之1～3個鹵素原子取代之C1-6
烷基、及可經同種或異種之1～3個鹵素原子取代之C1-6
烷氧基。 R11
、R12
、R13
及R14
分別獨立地為氫原子、鹵素原子、或者可經同種或異種之1～3個鹵素原子取代之C1-6
烷基，較佳為R11
、R12
、R13
及R14
中之任一者以上為鹵素原子、或者可經同種或異種之1～3個鹵素原子取代之C1-6
烷基。更佳為R11
、R12
、R13
及R14
中之任一者以上為C1-6
烷基。 作為R11
、R12
及R14
，較佳為可列舉氫原子及C1-6
烷基。更佳為氫原子。 作為R13
，較佳為可列舉氫原子及C1-6
烷基。更佳為C1-4
烷基；進而較佳為甲基。 作為R11
、R12
、R13
及R14
之另一態樣，R11
及R12
為氫原子；R13
為C1-6
烷基；R14
為氫原子或C1-6
烷基。 作為R11
、R12
、R13
及R14
之另一態樣，R11
、R12
及R14
為氫原子；R13
為C1-4
烷基。 式(1)所表示之化合物亦可有以互變異構物之形式存在之情形。因此，本發明化合物亦包含式(1)所表示之化合物之互變異構物。 式(1)所表示之化合物亦可有具有至少一個不對稱碳原子之情形。因此，本發明化合物不僅包含式(1)所表示之化合物之外消旋體，亦包含該等化合物之光學活性體。 又，將式(1)所表示之化合物中之任1者或2者以上之1
H轉換為2
H(D)而成之氘轉換體亦包含於式(1)所表示之化合物中。 式(1)所表示之化合物及其製藥學上所容許之鹽亦有以水合物及/或溶劑合物之形式存在的情況，故而該等之水合物或乙醇溶劑合物等溶劑合物亦包含於本發明化合物中。進而，本發明化合物亦包含所有態樣之晶形者。 作為製藥學上所容許之鹽，於式(1)所表示之化合物具有酸性基之情形時，例如可列舉：鈉鹽、鉀鹽等鹼金屬鹽；鈣鹽、鎂鹽等鹼土金屬鹽；鋅鹽等無機金屬鹽；三乙胺、三乙醇胺、三羥基甲基胺基甲烷、胺基酸等有機鹼鹽等。 於式(1)所表示之化合物具有鹼性基之情形時，例如可列舉：鹽酸鹽、氫溴酸鹽、硫酸鹽、磷酸鹽、硝酸鹽等無機酸鹽；及乙酸鹽、丙酸鹽、丁二酸鹽、乳酸鹽、蘋果酸鹽、酒石酸鹽、檸檬酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、甲磺酸鹽、對甲苯磺酸鹽、苯磺酸鹽、抗壞血酸鹽等有機酸鹽等。 以下，舉例對本發明中之式(1)所表示之化合物之製造方法進行說明，但本發明當然並不限定於此。 製造方法 本發明化合物係藉由將下述所示之製造方法及公知之合成方法加以組合之方法進行合成。 反應式中之化合物亦包含分別形成鹽之情形，作為該鹽，例如可列舉與式(1)所表示之化合物之鹽相同者。再者，該等之反應僅為例示，亦可基於熟習有機合成者之知識，適當藉由其他方法製造本發明化合物。 於下述說明之各製造方法中，即便於未具體明示保護基之使用之情形時，於存在必需保護之官能基之情形時，亦有視需要保護該官能基，於反應結束後或者進行一連串之反應後進行去保護，藉此獲得目標物之情況。 保護基之導入及脫離可藉由有機合成化學中常用之方法(例如T. W. Greene and P. G. M. Wuts, 「Protective Groups in Organic Synthesis」, 3rd Ed., John Wiley and Sons, inc., New York(1999)中所記載之方法等)或依據其之方法進行。 作為胺基之保護基，例如可列舉：第三丁氧基羰基、苄氧基羰基、對甲苯磺醯基、鄰硝基苯磺醯基等。 製造方法1 於式(1)所表示之化合物中，式(1c)及(1d)所表示之化合物例如藉由下述所示之方法製造。 [化6][式中，環Q1
、環Q2
、Rb
、m及n係與上述[項1]中同義；Ra1
表示可經同種或異種之1～3個鹵素原子取代之C1-6
烷基；X表示鹵素；Pro表示胺基之保護基；A表示硼酸或硼酸酯] 步驟1-1：化合物(1-2)之製造步驟 化合物(1-2)係藉由於適當之惰性溶劑中，於鹼之存在下或者不於鹼之存在下，使鹵化試劑作用於化合物(1-1)而製造。 化合物(1-1)可使用市售之化合物、或藉由公知之方法(例如國際公開第2007/047776號公報)所製造者。 作為鹵化試劑，例如可列舉：1-氯-N,N,2-三甲基丙烯基胺、***、三氯化磷、亞硫醯氯、五氯化磷等。 作為鹼，例如可列舉N,N-二甲基苯胺等。 作為惰性溶劑，例如可列舉：甲苯、二氯甲烷等。 反應時間通常為5分鐘～72小時，較佳為30分鐘～2小時。 反應溫度通常為-78℃～200℃，較佳為20℃～100℃。 步驟1-2：化合物(1d)之製造步驟 化合物(1d)係藉由於適當之惰性溶劑中，於鈀觸媒之存在下，使化合物(1-2)與化合物(1-3)進行偶合而製造。本步驟可視需要於鹼及/或磷配位基之存在下進行。 化合物(1-3)可使用市售之化合物、或藉由公知之方法(例如國際公開第2002/066470)所製造者。又，可使用藉由下述製造方法4所製造者。 作為鈀觸媒，可使用常規方法中所使用之各種鈀觸媒，較佳為可列舉四(三苯基膦)鈀(0)。 作為鹼，例如可列舉：碳酸鉀、碳酸銫等。 作為磷配位基，例如可列舉三苯基膦或雙(二苯基膦)甲烷等。 作為惰性溶劑，例如可列舉：1,4-二㗁烷、四氫呋喃、水及該等之混合溶劑等。 反應溫度通常為0℃～200℃，較佳為20℃～150℃，亦可視需要於微波照射下進行。 反應時間係根據反應溫度、所使用之鈀觸媒、原料及溶劑等條件而不同，通常為5分鐘～72小時，較佳為30分鐘～24小時。 步驟1-3：化合物(1-5)之製造步驟 化合物(1-5)係自化合物(1-2)及化合物(1-4)，依據步驟1-2中記載之方法製造。 化合物(1-4)可使用藉由下述製造方法2所製造者。 步驟1-4：化合物(1c)之製造步驟 化合物(1c)係藉由利用公知之方法(例如Protective Group in Organic Synthesis第3版(Theodora W. Green, Peter G. M. Wuts著，John Wiley＆Sons Inc發行，1999年)使化合物(1-5)之胺基之保護基Pro去保護而製造。 步驟1-5：化合物(1d)之製造步驟 化合物(1d)亦藉由於適當之惰性溶劑中，於還原劑之存在下，使化合物(1c)與各種烷基醛進行反應而製造。 作為還原劑，例如可列舉：硼氫化鈉、三乙醯氧基硼氫化鈉、氰基硼氫化鈉等。 作為惰性溶劑，例如可列舉：甲苯、THF(tetrahydrofuran，四氫呋喃)、二氯乙烷、甲醇等。 反應時間通常為5分鐘～48小時，較佳為1小時～24小時。 反應溫度通常為-78℃～100℃，較佳為0℃～80℃。 又，化合物(1d)亦藉由於適當之惰性溶劑中，於鹼之存在下，使化合物(1c)與各種烷基鹵化物進行反應而製造。 作為鹼，例如可列舉：碳酸鉀、碳酸銫、氫化鈉、二異丙基醯胺鋰等。 作為惰性溶劑，例如可列舉：DMF(dimethylformamide，二甲基甲醯胺)、二甲基亞碸、THF、1,4-二㗁烷等。 反應時間通常為5分鐘～48小時，較佳為1小時～24小時。 反應溫度通常為-78℃～100℃，較佳為0℃～80℃。 製造方法2 式(1-4)所表示之化合物例如藉由下述所示之方法製造。 [化7][式中，Rb
、m及n係與上述[項1]中同義；X1
表示鹵素或三氟甲磺酸鹽(三氟甲磺醯氧基)；Pro表示胺基之保護基；A表示硼酸或硼酸酯] 步驟2-1：化合物(2-2)之製造步驟 化合物(2-2)係藉由於適當之惰性溶劑中，於鹼之存在下，使三氟甲磺酸鹽化劑作用於化合物(2-1)而製造。 化合物(2-1)可使用市售之化合物、或藉由公知之方法(例如國際公開第2012/142668)所製造者。 作為鹼，例如可列舉二異丙基醯胺鋰或雙(三甲基矽烷基)醯胺鈉。 作為三氟甲磺酸鹽化劑，可使用常規方法中所使用之各種三氟甲磺酸鹽化劑，較佳為可列舉N-苯基雙(三氟甲磺醯亞胺)。 作為惰性溶劑，例如可列舉THF等。 反應時間通常為5分鐘～72小時，較佳為30分鐘～8小時。 反應溫度通常為-78℃～200℃，較佳為-78℃～20℃。 步驟2-2：化合物(1-4)之製造步驟 化合物(1-4)係藉由於適當之惰性溶劑中，於鈀觸媒之存在下，使化合物(2-2)與硼化試劑進行偶合而製造。本步驟可視需要於鹼及/或磷配位基之存在下進行。 作為鹼，例如可列舉乙酸鉀。 作為磷配位基，例如可列舉三苯基膦或雙(二苯基膦)甲烷等。 作為硼化試劑，可使用常規方法中所使用之各種硼化試劑，較佳為可列舉雙(頻那醇酯)二硼烷。 作為鈀觸媒，可使用常規方法中所使用之各種鈀觸媒，較佳為可列舉1,1'-雙(二苯基膦)二茂鐵-二氯化鈀(II)。 作為惰性溶劑，例如可列舉：1,4-二㗁烷、THF等。 反應溫度通常為0℃～200℃，較佳為50℃～120℃，亦可視需要於微波照射下進行。 反應時間係根據反應溫度、所使用之鈀觸媒、原料及溶劑等條件而不同，通常為5分鐘～72小時，較佳為2小時～8小時。 製造方法3 於式(1)所表示之化合物中，式(1e)所表示之化合物例如藉由下述所示之方法製造。 [化8][式中，環Q1
、環Q2
、Rb
及m係與上述[項1]中同義；Ra1
表示可經同種或異種之1～3個鹵素原子取代之C1-6
烷基；X表示鹵素；A表示硼酸或硼酸酯] 步驟3-1：化合物(3-2)之製造步驟 化合物(3-2)係自化合物(1-2)及化合物(3-1)，依據步驟1-2中記載之方法製造。 化合物(3-1)可使用市售之化合物、或藉由公知之方法(例如國際公開第2011/119518)所製造者。 步驟3-2：化合物(1e)之製造步驟 化合物(1e)係藉由於適當之惰性溶劑中，使化合物(3-2)與化合物(3-3)進行反應而產生四級銨陽離子後，使還原劑發揮作用而製造。 作為惰性溶劑，例如可列舉：乙腈、THF、1,4-二㗁烷等。 烷基化之步驟之反應時間通常為5分鐘～48小時，較佳為1小時～24小時。烷基化之步驟之反應溫度為0℃～100℃。 作為後續之還原反應之步驟中所使用之還原劑，可列舉：硼氫化鈉、三乙醯氧基硼氫化鈉、氰基硼氫化鈉等。 作為所使用之溶劑，例如可列舉：甲苯、THF、二氯乙烷、甲醇等。 反應時間通常為5分鐘～48小時，較佳為1小時～24小時。 反應溫度通常為-78℃～100℃，較佳為-78℃～20℃。 製造方法4 式(1-3)所表示之化合物例如亦藉由下述所示之方法製造。 [化9][式中，Rb
、m及n係與上述[項1]中同義；Ra1
表示可經同種或異種之1～3個鹵素原子取代之C1-6
烷基；X1
表示鹵素或三氟甲磺酸鹽；Pro表示胺基之保護基；A表示硼酸或硼酸酯] 步驟4-1：化合物(4-1)之製造步驟 化合物(4-1)係藉由利用公知之方法(例如Protective Group in Organic Synthesis第3版(Theodora W. Green, Peter G. M. Wuts著，John Wiley＆Sons Inc發行，1999年)使化合物(2-2)之胺基之保護基Pro去保護而製造。 步驟4-2：化合物(4-2)之製造步驟 化合物(4-2)亦藉由於適當之惰性溶劑中，於還原劑之存在下，使化合物(4-1)與各種烷基醛進行反應而製造。 作為還原劑，例如可列舉：硼氫化鈉、三乙醯氧基硼氫化鈉、氰基硼氫化鈉等。 作為惰性溶劑，例如可列舉：甲苯、THF、二氯乙烷、甲醇等。 反應時間通常為5分鐘～48小時，較佳為1小時～24小時。 反應溫度通常為-78℃～100℃，較佳為0℃～80℃。 又，化合物(4-2)亦藉由於適當之惰性溶劑中，於鹼之存在下，使化合物(4-1)與各種烷基鹵化物進行反應而製造。 作為鹼，例如可列舉：碳酸鉀、碳酸銫、氫化鈉、二異丙基醯胺鋰等。 作為惰性溶劑，例如可列舉：DMF、二甲基亞碸、THF、1,4-二㗁烷等。 反應時間通常為5分鐘～48小時，較佳為1小時～24小時。 反應溫度通常為-78℃～100℃，較佳為0℃～80℃。 步驟4-3：化合物(1-3)之製造步驟 化合物(1-3)係藉由於適當之惰性溶劑中，於鈀觸媒之存在下，使化合物(4-2)與硼化試劑進行偶合而製造。本步驟可視需要於鹼及/或磷配位基之存在下進行。 作為鹼，例如可列舉乙酸鉀。 作為磷配位基，例如可列舉三苯基膦或雙(二苯基膦)甲烷等。 作為硼化試劑，可使用常規方法中所使用之各種硼化試劑，較佳為可列舉雙(頻那醇酯)二硼烷。 作為鈀觸媒，可使用常規方法中所使用之各種鈀觸媒，較佳為可列舉1,1'-雙(二苯基膦)二茂鐵-二氯化鈀(II)。 作為惰性溶劑，例如可列舉：1,4-二㗁烷、THF等。 反應溫度通常為0℃～200℃，較佳為50℃～120℃，亦可視需要於微波照射下進行。 反應時間係根據反應溫度、所使用之鈀觸媒、原料及溶劑等條件而不同，通常為5分鐘～72小時，較佳為2小時～8小時。 藉由適當組合上述製造方法而實施，可獲得於所需之位置具有所需之取代基之本發明化合物。上述製造方法中之中間物及產物之單離、精製可適當組合通常之有機合成中所使用之方法、例如過濾、萃取、清洗、乾燥、濃縮、結晶化、各種層析法等而進行。又，於中間物中，亦可不特別進行精製而供於下一反應。 上述製造方法中之原料化合物或中間物亦有根據反應條件等，例如可以鹽酸鹽等鹽之形態存在者，但可直接或者以游離之形式使用。於欲以鹽之形態獲得原料化合物或中間物，以游離之形式使用或取得原料化合物或中間物之情形時，可使該等溶解或懸浮於適當之溶劑中，例如藉由碳酸氫鈉水溶液等鹼等進行中和，藉此轉換為游離之形式。 於式(1)所表示之化合物或其製藥學上所容許之鹽中，亦有可存在酮-烯醇體之類之互變異構物、位置異構物、幾何異構物或光學異構物之類之異構物者，可包含該等之所有異構物及該異構物之任一比率下之混合物均包含於本發明中。 又，光學異構物可藉由利用上述製造方法之適當之步驟，實施使用光學活性管柱之方法、分級結晶化法等公知之分離步驟而分離。又，亦可使用光學活性體作為起始原料。 於欲取得式(1)所表示之化合物之鹽之情形時，於獲得式(1)所表示之化合物之鹽之情形時，只要直接進行精製即可，又，於獲得游離形態之式(1)所表示之化合物之情形時，只要使式(1)所表示之化合物溶解或懸浮於適當之溶劑中，加入酸或鹼而形成鹽即可。又，化合物(1)或其製藥學上所容許之鹽亦有以與水或各種溶劑之溶劑合物之形式存在之情況，該等溶劑合物亦包含於本發明中。 於本說明書中，「難治性精神***症」係指即便於足夠長之期間投予充足量之2種以上之抗精神病藥物，亦未見充分改善之精神***症。於日本精神***症藥物準則中定義為如下情況：以氯丙𠯤換算計600 mg/天以上之量投予2種以上之抗精神病藥物，經過4週以上之投予而未達到相當於全面功能評估(Global Assessment of Functioning：GAF)41分以上之狀態。 已知對難治性精神***症有效之氯氮平除D2
受體拮抗作用、5-HT2A
受體拮抗作用以外，亦對D1
受體具有拮抗作用(非專利文獻4、5、6)。可期待與氯氮平同樣地對D1
受體、D2
受體及5-HT2A
受體具有拮抗作用之本發明化合物對於難治性精神***症有效。 又，由於本發明化合物對D2
受體及5-HT2A
受體表現出拮抗作用，故而期待亦對精神***症、躁鬱症、自閉症、ADHD(Attention Deficit Hyperactivity Disorder，注意力不足過動症)、抑鬱症、焦慮症、睡眠障礙、癡呆症之行為・心理症狀(BPSD(Behavioral and Psychological Symptoms of Dementia))及神經退化性疾病之精神症狀有效。 雖然目前不存在模擬難治性精神***症之普通動物模型，但認為藉由實施作為精神***症之陽性症狀之模型的大鼠***誘導運動量亢進試驗(試驗例5)，可發現精神***症治療藥物，藉由確認對上述D1
受體及D2
受體具有拮抗作用，可探索對難治性精神***症亦有效之藥劑。 醫藥品化合物於引入至活體內後，存在因受到代謝而化學結構發生變化，生成反應性較高之中間物、即反應性代謝物，從而表現出毒性(顆粒性球缺乏症、肝毒性、過敏、組織壞死、誘突變性或致癌性等)之情況。作為簡易地評價由該反應性代謝物所引起之毒性風險之試驗之一，存在使用經丹磺醯化之麩胱甘肽(dGSH)之麩胱甘肽捕捉試驗。dGSH共價鍵量之值越高之化合物，於暴露於全身之情形時，上述毒性風險越會提高。 關於氯氮平中可見之顆粒性球缺乏症，有報告表明原因之一在於反應性代謝物之生成(參照The Journal of Pharmacology and Experimental Therapeutics, 1997, 283 (3) 1375-1382等)。 對本發明化合物進行丹磺醯化麩胱甘肽(dGSH)捕捉試驗，結果意外地知曉，本發明化合物之dGSH共價鍵量之值極低，反應性代謝物之生成明顯降低(試驗例2)。由此期待，本發明化合物引起顆粒性球缺乏症等之風險較低，可安全地進行長期投予。 關於氯氮平中可見之消化系統損傷、鎮靜、體重增加等副作用，有報告表明原因之一在於對組織胺受體、毒蕈鹼受體、5-HT2c
受體等之拮抗作用(參照Molecular Psychiatry (2008) 13, 27-35; Prim Care Companion J Clin Psychiatry. 2004, 6 (suppl 2): 3-7; CNS Drugs. 2013 Jun; 27 (6): 423-34; J Clin Psychiatry 2004, 6 (Suppl 2): 20-23; Clin Psychopharmacol Neurosci. 2012 Aug; 10 (2): 71-77等)。 對本發明化合物進行針對該等受體之拮抗劑活性評價試驗，結果意外地知曉，本發明化合物於為更佳態樣時對該等受體之拮抗劑作用較低(試驗例8)。由此期待，本發明化合物於為更佳態樣時引起消化系統損傷、鎮靜、體重增加等之風險較低，可安全地投予。 再者，於本發明中，「預防」係對未發病之正常人投予本發明之有效成分之行為，例如以防止疾病之發病為目的。「治療」係對經醫生診斷已發病之人(患者)投予本發明之有效成分之行為。 本發明化合物可藉由經口投予或非經口投予，直接或者使用適當劑型製成製劑而投予。劑型例如可列舉：錠劑、膠囊劑、散劑、顆粒劑、液劑、懸浮劑、注射劑、貼附劑、敷劑等，但並不限於此。製劑係使用製藥學上所容許之添加劑，藉由公知之方法製造。 添加劑可根據目的，使用賦形劑、崩解劑、結合劑、塑化劑、潤滑劑、包衣劑、溶解劑、溶解助劑、增黏劑、分散劑、穩定劑、甜味劑、香料等。具體而言，例如可列舉：乳糖、甘露醇、結晶纖維素、低取代度羥丙基纖維素、玉米澱粉、部分α化澱粉、羧甲基纖維素鈣、交聯羧甲基纖維素鈉、羥丙基纖維素、羥丙甲纖維素、聚乙烯醇、硬脂酸鎂、反丁烯二酸硬脂酯鈉、聚乙二醇、丙二醇、氧化鈦、滑石等。 作為投予路徑，較理想為使用於治療時最有效者，可列舉：經口、或靜脈內、塗抹、吸入及滴眼等非經口，較佳為經口投予。作為投予形態，例如可列舉錠劑、注射劑等，較佳為錠劑。該等醫藥組合物之投予量或投予次數係根據投予形態、患者之疾病或其症狀、患者之年齡或體重等而不同，無法一概規定，但通常，可對成人1天1次或數次、較佳為分為1天1～3次而投予每天有效成分之量為約0.0001～約5000 mg之範圍、較佳為約0.001～約1000 mg之範圍、進而較佳為約0.1～約500 mg之範圍、尤佳為約1～約300 mg之範圍。 本發明化合物可以其效果之增強及/或副作用之減輕為目的，與其他藥物併用而使用。例如可與阿立哌唑、奧氮平、喹硫平、利培酮、布南色林、哌羅匹隆、帕潘立酮、齊拉西酮、阿塞那平、伊潘立酮、舍吲哚、魯拉西酮或其製藥學上所容許之鹽等抗精神病藥物併用。以下，將可與本發明化合物併用之藥物簡稱為併用藥劑。 本發明化合物及併用藥劑之投予時間並無限定，可對投予對象同時投予該等，亦可間隔時間差而投予。又，亦可採用本發明化合物與併用藥劑之合劑。併用藥劑之投予量可以臨床上使用之用量作為基準而適當選擇。又，本發明化合物與併用藥劑之調配比可根據投予對象、投予路徑、對象疾病、症狀、組合等而適當選擇。例如於投予對象為人類之情形時，相對於本發明化合物1重量份，使用併用藥劑0.01～100重量份即可。又，以抑制其副作用為目的，可與止吐劑、睡眠導入劑、抗痙攣藥等藥劑(併用藥劑)加以組合而使用。 [實施例] 以下，藉由參考例、實施例及試驗例，更具體地說明本發明，但本發明並不限定於此。再者，以下之參考例及實施例中所示之化合物名稱不一定依據IUPAC(International Union of Pure and Applied Chemistry，國際純化學及應用化學聯合會)命名法。 為了簡化說明書之記載，於參考例、實施例及試驗例中，亦有使用如下所示之縮寫之情況。 Me：甲基 Et：乙基 DMF：N,N-二甲基甲醯胺 DMSO：二甲基亞碸 THF：四氫呋喃 TFA：三氟乙酸 作為NMR(nuclear magnetic resonance，核磁共振)中所使用之記號，s意指單峰，d意指二重峰，dd意指二重峰之二重峰，t意指三重峰，td意指三重峰之二重峰，q意指四重峰，m意指多重峰，br意指寬幅，brs意指寬幅之單峰，brm意指寬幅之多重峰，且J意指耦合常數。 高速液相層析質譜儀；LCMS之測定條件如下所述，以[M＋H]+
或[M－H]-
表示觀察到之質量分析之值[MS(m/z)]，以Rt(分鐘)表示保持時間。 測定條件(1) 檢測機器：ACQUITY(註冊商標) SQ deteceter(Waters公司) HPLC：ACQUITY UPLC(註冊商標) system 管柱：Waters ACQUITY UPLC(註冊商標) BEH C18(1.7 μm，2.1 mm×30 mm) 流速：0.75 mL/min 測定波長：254 nm 移動床：A液 0.05%甲酸水溶液 B液 乙腈 時間程式： 步驟 時間(分鐘) 1 0.0-1.3 A液：B液＝90：10～1：99 2 1.3-1.5 A液：B液＝1：99 3 1.5-2.0 A液：B液＝90：10 測定條件(2) 檢測機器：ACQUITY(註冊商標) SQ deteceter(Waters公司) HPLC：ACQUITY UPLC(註冊商標) system 管柱：Waters ACQUITY UPLC(註冊商標) BEH C18(1.7 μm，2.1 mm×30 mm) 流速：0.80 mL/min 測定波長：254 nm 移動床：A液 0.05%甲酸水溶液 B液 乙腈 時間程式： 步驟 時間(分鐘) 1 0.0-1.3 A液：B液＝90：10～5：95 2 1.3-1.5 A液：B液＝90：10 測定條件(3) MS檢測器：LCMS-IT-TOF HPLC：Shimadzu Nexera X2 LC 30AD 管柱：Kinetex 1.7 μ C18 100A New column 50×2.1 mm 流速：1.2 mL/min 測定波長：254 nm 移動床：A液；0.1%甲酸水溶液 B液；乙腈 時間程式： 步驟 時間(分鐘) 1 0.01-1.40 A液：B液＝90：10～5：95 2 1.40-1.60 A液：B液＝5：95 3 1.61-2.00 A液：B液＝99：1 測定條件(4) 檢測機器：LCMS-2020(島津公司) 管柱：Phenomenex Kinetex(1.7 μm，C18，50 mm×2.10 mm) 流速：0.50 mL/min 測定波長：220、254 nm 移動床：A液 0.05%TFA水溶液 B液 乙腈 管柱溫度：40℃ 時間程式： 步驟 時間(分鐘) 1 0.0 A液：B液＝90：10 2 0.0-1.9 A液：B液＝90：10～1：99 3 1.9-3.0 A液：B液＝90：10 參考例1 8-氯-2-氟-5,10-二氫-11H-二苯并[b,e][1,4]二氮呯-11-酮 [化10]a)2-[(4-氯-2-硝基苯基)胺基]-5-氟苯甲酸(化合物W1)之製造 於4-氯-1-氟-2-硝基苯(5.0 g)之DMF(29 mL)溶液中加入2-胺基-5-氟苯甲酸(4.4 g)及碳酸銫(28 g)，於120℃下攪拌一晚。於反應液中於0℃下加入水，藉由1 mol/L之鹽酸調整為pH值5後，藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除，藉此獲得化合物W1(8.8 g)。 LC-MS([M+H]+
/Rt(min))：311/1.18 測定條件(1) b)2-[(2-胺基-4-氯苯基)胺基]-5-氟苯甲酸(化合物W2)之製造 於化合物W1(8.8 g)之THF/MeOH/H2
O(3：2：1)(300 mL)溶液中加入氯化銨(15 g)及鐵(16 g)，於80℃下攪拌2小時。將反應液冷卻後，進行矽藻土過濾，藉由甲醇進行清洗，然後將溶劑減壓蒸餾去除。將所獲得之殘渣藉由乙酸乙酯-水進行分液萃取後，藉由飽和食鹽水清洗所獲得之有機層。將有機層藉由硫酸鈉進行乾燥，將溶劑減壓蒸餾去除，藉此獲得化合物W2(8.0 g)。 LC-MS([M+H]+
/Rt(min))：281/1.06 測定條件(1) c)8-氯-2-氟-5,10-二氫-11H-二苯并[b,e][1,4]二氮呯-11-酮(參考例1)之製造 於化合物W2(8.0 g)之DMF(143 mL)溶液中加入1-(3-二甲基胺基丙基)-3-乙基碳二醯亞胺鹽酸鹽(6.0 g)及1-羥基苯并***(4.2 g)，於室溫下攪拌2小時。於反應液中加入水，藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥，將溶劑減壓蒸餾去除。藉由氯仿(20 mL)清洗所獲得之殘渣，藉此獲得標題化合物(3 g)。 LC-MS([M+H]+
/Rt(min))：263/0.93 測定條件(1) 參考例2～8 依據參考例1中記載之方法，使用對應之原料化合物，獲得下表所示之化合物。 [表1]
上表中之LC-MS係使用測定條件(1)進行測定。參考例 9
6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯及2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯 [化11]a)6-甲基-4-{[(三氟甲基)磺醯基]氧基}-3,6-二氫吡啶-1(2H)-羧酸第三丁酯及2-甲基-4-{[(三氟甲基)磺醯基]氧基}-3,6-二氫吡啶-1(2H)-羧酸第三丁酯(物質A)之製造 於1-(第三丁氧基羰基)-2-甲基哌啶-4-酮(1.1 g)之THF溶液(10 mL)中於-78℃下滴下1.5 mol/L之二異丙基醯胺鋰-THF溶液(4.0 mL)。於-78℃下攪拌10分鐘後，滴下N-苯基雙(三氟甲磺醯亞胺)(2.1 g)之THF溶液(5 mL)。於室溫下攪拌4小時後，於0℃下加入飽和氯化銨水溶液，藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除後，藉由矽膠管柱層析法(溶出溶劑；氯仿/甲醇)及NH2
矽膠管柱層析法(溶出溶劑；己烷/乙酸乙酯)進行精製，藉此獲得物質A(1.7 g，異構物之混合物)。1
H-NMR(400 MHz, CDCl3
)δ: 5.73, 5.69(s, 1H, isomer ratio＝1：1), 4.65-4.23(m, 2H), 3.64-2.52(m, 2H), 2.21-2.02(m, 1H), 1.45(s, 9H), 1.23, 1.16(ds, 3H, J＝6.8 Hz, isomer ratio＝1：1). b)6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯及2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯(參考例9)之製造 於物質A(1.7 g)之THF溶液(50 mL)中加入雙(頻那醇酯)二硼烷(1.4 g)、1,1'-雙(二苯基膦)二茂鐵-二氯化鈀(II)(0.73 g)及乙酸鉀(1.5 g)。於80℃下攪拌2小時後，冷卻至室溫，藉由矽藻土過濾而去除沈澱物。於濾液中加入水，藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除後，藉由矽膠管柱層析法(溶出溶劑；己烷/乙酸乙酯)進行精製，藉此獲得參考例9之化合物(1.2 g，異構物之混合物)。 LC-MS([M+H]+
/Rt(min))：324/1.37 測定條件(1)1
H-NMR(400 MHz, CDCl3
)δ: 5.73, 5.69(s, 1H, isomer ratio＝1：1), 4.43-4.16(m, 2H), 3.61-2.37(m, 2H), 2.13-2.01(m, 1H), 1.44(s, 9H), 1.24(s, 12H), 1.16, 1.03(d, 3H, J＝6.8 Hz, isomer ratio＝1：1). 參考例10～12 依據參考例9中記載之方法，使用對應之原料化合物，獲得下表所示之化合物(異構物之混合物)。 [表2]
上表中之LC-MS係使用測定條件(1)進行測定。 參考例13～29 依據參考例1中記載之方法，使用對應之原料化合物，獲得下表所示之化合物。 [表3]
上表中之LC-MS係使用測定條件(2)進行測定。 參考例30 8-甲基-2-(三氟甲基)-5,10-二氫-11H-二苯并[b,e][1,4]二氮呯-11-酮 [化12]a)三氟甲磺酸4-甲基-2-硝基苯酯(化合物W3)之製造 將4-甲基-2-硝基苯酚(2.0 g)之氯仿(26 mL)溶液冷卻至0℃，加入三乙胺(5.4 mL)及三氟甲磺酸酐(2.4 mL)，於0℃下攪拌1小時。於反應液中於0℃下加入碳酸氫鈉水，藉由氯仿進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鎂進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除後，藉由矽膠層析法(溶出溶劑；己烷/乙酸乙酯)進行精製，藉此獲得標題化合物(3.4 g)。 LC-MS([M-H]-
/Rt(min))：283/0.99 測定條件(2) b)2-[(4-甲基-2-硝基苯基)胺基]-5-(三氟甲基)苯甲酸甲酯(化合物W4)之製造 於化合物W3(2.0 g)之甲苯(68 mL)溶液中加入2-胺基-5-(三氟甲基)苯甲酸甲酯(1.5 g)、碳酸鉀(0.95 g)、三苯基膦(0.36 g)及四(三苯基膦)鈀(0)(0.79 g)，於加熱回流下攪拌2小時。使反應液恢復至室溫，加入水並藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鎂進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除後，藉由矽膠層析法(溶出溶劑；己烷/乙酸乙酯)進行精製，藉此獲得標題化合物(2.0 g)。 LC-MS([M+H]+
/Rt(min))：355/1.21 測定條件(2) c)2-[(2-胺基-4-甲基苯基)胺基]-5-(三氟甲基)苯甲酸甲酯(化合物W5)之製造 於化合物W4(2.0 g)之THF/MeOH/H2
O(3：2：1)(30 mL)溶液中加入氯化銨(3.6 g)及鐵(1.9 g)，於加熱回流下攪拌1小時。將反應液冷卻後，進行矽藻土過濾，藉由乙酸乙酯進行清洗。將所獲得之濾液藉由乙酸乙酯-水進行分液萃取後，藉由飽和食鹽水清洗有機層。將有機層藉由硫酸鎂進行乾燥，將溶劑減壓蒸餾去除，藉此以粗產物之形式獲得標題化合物(1.8 g)。 LC-MS([M+H]+
/Rt(min))：325/1.17 測定條件(2) d)2-[(2-胺基-4-甲基苯基)胺基]-5-(三氟甲基)苯甲酸(化合物W6)之製造 於化合物W5(1.8 g)之THF/H2
O(1：1)(30 mL)溶液中加入氫氧化鋰(1.6 g)，於加熱回流下攪拌2小時。將反應液冷卻後，於0℃下加入水，藉由1 mol/L之鹽酸調整為pH值5後，藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層，藉由硫酸鎂進行乾燥，將溶劑減壓蒸餾去除，藉此以粗產物之形式獲得標題化合物(1.6 g)。 LC-MS([M+H]+
/Rt(min))：311/0.98 測定條件(2) e)8-甲基-2-(三氟甲基)-5,10-二氫-11H-二苯并[b,e][1,4]二氮呯-11-酮之製造 於化合物W6(1.6 g)之DMF(23 mL)溶液中加入1-(3-二甲基胺基丙基)-3-乙基碳二醯亞胺鹽酸鹽(1.4 g)及1-羥基苯并***(1.0 g)，於室溫下攪拌1小時。於反應液中加入水，藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鎂進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除後，藉由矽膠層析法(溶出溶劑；己烷/乙酸乙酯)進行精製，藉此獲得標題化合物(0.41 g)。 LC-MS([M+H]+
/Rt(min))：293/0.89 測定條件(2)參考例 31 及 32
依據參考例30中記載之方法，使用對應之原料化合物，獲得下表所示之化合物。 [表4]
上表中之LC-MS係使用測定條件(2)進行測定。 參考例33 8-氯-11-側氧基-10,11-二氫-5H-二苯并[b,e][1,4]二氮呯-2-甲腈 [化13]a)2-[(4-氯-2-硝基苯基)胺基]-5-氰基苯甲酸(化合物W7)之製造 於4-氯-1-氟-2-硝基苯(0.50 g)之DMF(2.8 mL)溶液中加入2-胺基-5-氰基苯甲酸甲酯(0.50 g)及碳酸銫(2.8 g)，於120℃下攪拌4小時。將反應液冷卻後，於0℃下加入水，藉由1 mol/L之鹽酸調整為pH值5後，藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除，藉此以粗產物之形式獲得標題化合物(0.90 g)。 LC-MS([M-H]-
/Rt(min))：316/0.87 測定條件(2) b)2-[(2-胺基-4-氯苯基)胺基]-5-氰基苯甲酸(化合物W8)之製造 於化合物W7(0.90 g)之THF/MeOH/H2
O(3：2：1)(30 mL)溶液中加入氯化銨(1.5 g)及鐵(0.73 g)，於加熱回流下攪拌1小時。將反應液冷卻後，進行矽藻土過濾，藉由乙酸乙酯進行清洗。將所獲得之濾液藉由乙酸乙酯-水進行分液萃取後，藉由飽和食鹽水清洗有機層。將有機層藉由硫酸鎂進行乾燥，將溶劑減壓蒸餾去除，藉此以粗產物之形式獲得標題化合物(0.82 g)。 LC-MS([M+H]+
/Rt(min))：288/0.84 測定條件(2) c)8-氯-11-側氧基-10,11-二氫-5H-二苯并[b,e][1,4]二氮呯-2-甲腈之製造 於化合物W8(0.82 g)之DMF(14 mL)溶液中加入1-(3-二甲基胺基丙基)-3-乙基碳二醯亞胺鹽酸鹽(0.60 g)及1-羥基苯并***(0.42 g)，於室溫下攪拌1小時。於反應液中加入水，藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鎂進行乾燥，將溶劑減壓蒸餾去除。藉由氯仿(5 mL)清洗所獲得之殘渣，藉此獲得標題化合物(0.25 g)。 LC-MS([M+H]+
/Rt(min))：270/0.71 測定條件(2) 參考例34 (6S)-1,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,2,3,6-四氫吡啶鹽酸鹽 [化14]a)(6S)-6-甲基-4-[(三氟甲磺醯基)氧基]-3,6-二氫吡啶-1(2H)-羧酸第三丁酯及(2S)-2-甲基-4-[(三氟甲磺醯基)氧基]-3,6-二氫吡啶-1(2H)-羧酸第三丁酯(物質C)之製造 於(2S)-2-甲基-4-氧代哌啶-1-羧酸第三丁酯(10 g)之THF溶液(117 mL)中，於0℃下滴下1.1 mol/L之二異丙基醯胺鋰-THF溶液(56 mL)。於0℃下攪拌10分鐘後，於-78℃下加入N-苯基雙(三氟甲磺醯亞胺)(22 g)。於-78℃下攪拌10分鐘後，進而於室溫下攪拌3小時。於室溫下加入飽和氯化銨水溶液，藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除後，藉由矽膠管柱層析法(溶出溶劑；己烷/乙酸乙酯)進行精製，藉此獲得物質C(18 g，異構物之混合物)。1
H-NMR(400 MHz, CDCl3
)δ: 5.73, 5.69(s, 1H, isomer ratio＝1：1), 4.65-4.24(m, 2H), 3.64-2.52(m, 2H), 2.21-2.02(m, 1H), 1.45(s, 9H), 1.21, 1.16(d, 3H, J＝6.8 Hz, isomer ratio＝1：1). b)(6S)-6-甲基-1,2,3,6-四氫吡啶-4-基三氟甲磺酸酯及(2S)-2-甲基-1,2,3,6-四氫吡啶-4-基三氟甲磺酸酯(物質D)之製造 於物質C(17 g)之乙酸乙酯溶液(98 mL)中加入4 mol/L之氯化氫-乙酸乙酯溶液(61 mL)。於室溫下攪拌3小時後，將溶劑減壓蒸餾去除。於所獲得之粗產物中加入飽和碳酸氫鈉水，藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除，藉此獲得物質D(14 g，異構物之混合物)。 LC-MS([M+H]+
/Rt(min))：246/0.76 測定條件(4) c)(6S)-1,6-二甲基-1,2,3,6-四氫吡啶-4-基三氟甲磺酸酯(化合物W11)之製造 於物質D(12 g)之甲醇溶液(163 mL)中，於0℃下加入37%之甲醛水溶液(11 mL)及三乙醯氧基硼氫化鈉(21 g)。於室溫下攪拌1小時後，將溶劑減壓蒸餾去除。於所獲得之粗產物中加入飽和碳酸氫鈉水，藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除後，藉由矽膠管柱層析法(溶出溶劑；氯仿/乙酸乙酯)及NH2
矽膠管柱層析法(溶出溶劑；氯仿/乙酸乙酯)進行精製，藉此獲得化合物W11(3.9 g)。1
H-NMR(400 MHz, CDCl3
)δ: 5.60(s, 1H), 2.94-2.92(m, 2H), 2.61-2.53(m, 2H), 2.32-2.25(m, 1H), 2.36(s, 3H), 1.18(d, 3H, J＝6.7 Hz). d)(6S)-1,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,2,3,6-四氫吡啶鹽酸鹽(參考例34)之製造 於化合物W11(3.9 g)之THF溶液(51 mL)中，於室溫下加入雙(頻那醇酯)二硼烷(4.3 g)、1,1'-雙(二苯基膦)二茂鐵-二氯化鈀(II)(0.62 g)及乙酸鉀(4.5 g)。於80℃下攪拌1小時後，冷卻至室溫。藉由矽藻土過濾而去除沈澱物後，將溶劑減壓蒸餾去除。於粗產物中加入二***，再次藉由矽藻土過濾而去除沈澱物後，將溶劑減壓蒸餾去除。將所獲得之粗產物(6.5 g)溶解於二***(40 mL)中，加入4 mol/L之氯化氫-乙酸乙酯溶液(4.0 mL)。將析出之固體進行過濾，藉由己烷進行清洗，藉此獲得參考例34(3.5 g)。 LC-MS([M+H]+
/Rt(min))：238/1.25 測定條件(4) 實施例1 8-氯-2-氟-11-(1-甲基-1,2,3,6-四氫吡啶-4-基)-5H-二苯并[b,e][1,4]二氮呯 [化15]a)8,11-二氯-2-氟-5H-二苯并[b,e][1,4]二氮呯(化合物W9)之製造 於參考例1之化合物(1.0 g)之甲苯(20 mL)溶液中加入N,N-二甲基苯胺(2.3 g)及***(1.8 g)。於95℃下攪拌2小時後，進行冷卻。於反應液中加入THF、飽和碳酸氫鈉水溶液，藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除後，藉由矽膠管柱層析法(溶出溶劑；己烷/乙酸乙酯)去除N,N-二甲基苯胺，獲得化合物W9(0.9 g)。 b)8-氯-2-氟-11-(1-甲基-1,2,3,6-四氫吡啶-4-基)-5H-二苯并[b,e][1,4]二氮呯(實施例1)之製造 於化合物W9(0.9 g)之THF/水(4/1)(50 mL)溶液中加入1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,2,3,6-四氫吡啶(1.0 g)、碳酸鉀(1.6 g)及四(三苯基膦)鈀(0)(0.88 g)。於75℃下攪拌1小時後，進行冷卻。於反應液中加入水並藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除後，藉由矽膠管柱層析法(溶出溶劑；氯仿/甲醇)及NH2
矽膠管柱層析法(溶出溶劑；己烷/乙酸乙酯)進行精製，藉此獲得標題化合物(0.70 g)。 LC-MS([M+H]+
/Rt(min))：342/0.67 測定條件(1)1
H-NMR(400 MHz, CDCl3
)δ: 7.20(d, 1H, J＝2.4 Hz), 7.00-6.92(m, 3H), 6.72-6.68(m, 1H), 6.61(d, 1H, J＝8.0 Hz), 6.09-6.05(m, 1H), 4.78(s, 1H), 3.15-3.11(m, 2H), 2.74-2.70(m, 2H), 2.64(t, 2H, J＝5.2 Hz), 2.40(s, 3H). 實施例2～6 依據實施例1中記載之方法，使用對應之參考例之化合物及原料化合物，獲得實施例2～6之化合物。 [表5]上表中之LC-MS係使用測定條件(1)進行測定。 實施例7及實施例8 8-氯-2-氟-11-(6-甲基-1,2,3,6-四氫吡啶-4-基)-5H-二苯并[b,e][1,4]二氮呯(實施例7) 8-氯-2-氟-11-(2-甲基-1,2,3,6-四氫吡啶-4-基)-5H-二苯并[b,e][1,4]二氮呯(實施例8) [化16]a)4-(8-氯-2-氟-5H-二苯并[b,e][1,4]二氮呯-11-基)-6-甲基-3,6-二氫吡啶-1(2H)-羧酸第三丁酯及4-(8-氯-2-氟-5H-二苯并[b,e][1,4]二氮呯-11-基)-2-甲基-3,6-二氫吡啶-1(2H)-羧酸第三丁酯(物質B)之製造 於化合物W9(1.1 g)之THF/水(4/1)(50 mL)溶液中加入參考例9之化合物(異構物之混合物)(1.3 g)、碳酸鉀(1.7 g)及四(三苯基膦)鈀(0)(0.92 g)。於75℃下攪拌1小時後進行冷卻，於反應液中加入水並藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除後，藉由矽膠管柱層析法(溶出溶劑；己烷/乙酸乙酯)進行精製，藉此獲得物質B(1.0 g，異構物之混合物)。 LC-MS([M+H]+
/Rt(min))：442/1.45 測定條件(1) b)8-氯-2-氟-11-(6-甲基-1,2,3,6-四氫吡啶-4-基)-5H-二苯并[b,e][1,4]二氮呯(實施例7)及8-氯-2-氟-11-(2-甲基-1,2,3,6-四氫吡啶-4-基)-5H-二苯并[b,e][1,4]二氮呯(實施例8)之製造 於物質B(0.17 g)之二氯甲烷(4 mL)溶液中加入三氟乙酸(1 mL)，於室溫下攪拌1小時。於經冰浴冷卻之反應液中加入飽和碳酸氫鈉水，藉由氯仿進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除後，將所獲得之殘渣藉由ODS (octadecylsilyl，十八烷基矽烷基)管柱(0.05%三氟乙酸水溶液：乙腈)進行逆相精製，藉由利用氯仿-飽和碳酸氫鈉水之分液操作而使TFA鹽游離化，藉此獲得實施例7之化合物(10 mg)及實施例8之化合物(10 mg)。 8-氯-2-氟-11-(6-甲基-1,2,3,6-四氫吡啶-4-基)-5H-二苯并[b,e][1,4]二氮呯(實施例7)： LC-MS([M+H]+
/Rt(min))：342/0.73 測定條件(1)1
H-NMR(400 MHz, CDCl3
)δ：7.19(d, 1H, J＝2.3 Hz), 7.00-6.89(m,3H), 6.73-6.70(m, 1H), 6.62(d, 1H, 8.3 Hz), 5.98(s, 1H), 4.80(s, 1H), 3.64-3.62(m, 1H), 3.28-3.23(m, 1H), 2.98-2.91(m, 1H), 2.61-2.46(m, 2H), 1.19(d, 3H, J＝6.9 Hz). 8-氯-2-氟-11-(2-甲基-1,2,3,6-四氫吡啶-4-基)-5H-二苯并[b,e][1,4]二氮呯(實施例8)： LC-MS([M+H]+
/Rt(min))：342/0.75 測定條件(1)1
H-NMR(400 MHz, CDCl3
)δ: 7.20(d, 1H, J＝2.3 Hz), 7.01-6.89(m, 3H), 6.73-6.69(m, 1H), 6.61(d, 1H, J＝8.7 Hz), 6.12(s, 1H), 4.79(s, 1H), 3.65-3.62(m, 2H), 2.98-2.89(m, 1H), 2.84-2.79(m, 1H), 2.16-2.06(m, 1H), 1.25(d, 3H, J＝6.4 Hz). 實施例9～16 依據實施例7及實施例8中記載之方法，使用對應之參考例之化合物及原料化合物，獲得實施例9～16之化合物。 [表6]上表中之LC-MS係使用測定條件(1)進行測定。 實施例17及實施例18 8-氯-11-(1,6-二甲基-1,2,3,6-四氫吡啶-4-基)-2-氟-5H-二苯并[b,e][1,4]二氮呯(實施例17) 8-氯-11-(1,2-二甲基-1,2,3,6-四氫吡啶-4-基)-2-氟-5H-二苯并[b,e][1,4]二氮呯(實施例18) [化17]於實施例7及實施例8(1：1)之混合物之(1.0 g)甲醇(20 mL)溶液中加入37%甲醛溶液(0.73 g)及硫酸鎂(5.0 g)，於50℃下攪拌1小時。將反應液進行冰浴冷卻，緩慢加入硼氫化鈉(0.68 g)。於室溫下攪拌1小時，藉由矽藻土過濾而去除固形物。於濾液中加入水，藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除後，藉由NH2
矽膠管柱層析法(溶出溶劑；己烷/乙酸乙酯)進行精製，藉此獲得實施例17之化合物(0.20 g)及實施例18之化合物(0.20 g)。 8-氯-11-(1,6-二甲基-1,2,3,6-四氫吡啶-4-基)-2-氟-5H-二苯并[b,e][1,4]二氮呯(實施例17)：1
H-NMR(400 MHz, CDCl3
)δ: 7.20(d, 1H, J＝2.3 Hz), 7.01-6.89(m, 3H), 6.72-6.69(m, 1H), 6.61(d, 1H, J＝8.7 Hz), 5.87(s, 1H), 4.78(s, 1H), 3.01-2.88(m, 2H), 2.73-2.43(m, 3H), 2.41(s, 3H), 1.19(d, 3H, J＝6.8 Hz). LC-MS([M+H]+
/Rt(min))：356/0.71 測定條件(1) 8-氯-11-(1,2-二甲基-1,2,3,6-四氫吡啶-4-基)-2-氟-5H-二苯并[b,e][1,4]二氮呯(實施例18)：1
H-NMR(400 MHz, CDCl3
)δ: 7.20(d, 1H, J＝2.8 Hz), 7.00-6.92(m, 3H), 6.72-6.68(m, 1H), 6.61(d, 1H, J＝8.7 Hz), 6.05(s, 1H), 4.77(s, 1H), 3.49-3.39(m, 2H), 3.06-2.22(m, 3H), 2.36(s, 3H), 1.18(d, 3H, J＝4.8 Hz). LC-MS([M+H]+
/Rt(min))：356/0.73 測定條件(1) 實施例19～21 依據實施例17及實施例18中記載之方法，使用對應之參考例之化合物及原料化合物，獲得實施例19～21之化合物。 [表7]上表中之LC-MS係使用測定條件(1)進行測定。 實施例22 8-氯-2-氟-11-(1-甲基-1,2,3,6-四氫吡啶-4-基)-5H-二苯并[b,e][1,4]二氮呯 [化18]a)8-氯-2-氟-11-(吡啶-4-基)-5H-二苯并[b,e][1,4]二氮呯(W10)之製造 於化合物W9(107 mg)之THF/水(4/1)(5 mL)溶液中加入吡啶-4-硼酸(94 mg)、碳酸鉀(0.16 g)及四(三苯基膦)鈀(0)(88 mg)。於75℃下攪拌1小時後，於經冰浴冷卻之反應液中加入水，藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除後，藉由矽膠管柱層析法(溶出溶劑；氯仿/甲醇)及NH2
矽膠管柱層析法(溶出溶劑；己烷/乙酸乙酯)進行精製，藉此獲得化合物W10(45 mg)。 LC-MS([M+H]+
/Rt(min))：324/1.03 測定條件(1) b)8-氯-2-氟-11-(1-甲基-1,2,3,6-四氫吡啶-4-基)-5H-二苯并[b,e][1,4]二氮呯(實施例22)之製造 於化合物W10(15 mg)之乙腈(0.42 mL)溶液中加入碘甲烷(59 mg)。於60℃下攪拌1小時後，將反應液濃縮。將所獲得之殘渣溶解於甲醇(0.20 mL)中，於0℃下加入硼氫化鈉(16 mg)。於室溫下攪拌1小時後，於反應液中加入水並藉由乙酸乙酯進行萃取。藉由飽和食鹽水清洗所獲得之有機層後，藉由硫酸鈉進行乾燥。將乾燥後之有機層之溶劑減壓蒸餾去除後，藉由矽膠管柱層析法(溶出溶劑；氯仿/甲醇)及NH2
矽膠管柱層析法(溶出溶劑；己烷/乙酸乙酯)進行精製，藉此獲得標題化合物(10 mg)。 LC-MS([M+H]+
/Rt(min))：342/0.67 測定條件(1)1
H-NMR(400 MHz, CDCl3
)δ: 7.20(d, 1H, J＝2.4 Hz), 7.00-6.92(m, 3H), 6.72-6.68(m, 1H), 6.61(d, 1H, J＝8.0 Hz), 6.09-6.05(m, 1H), 4.78(s, 1H), 3.15-3.11(m, 2H), 2.74-2.70(m, 2H), 2.64(t, 2H, J＝5.2 Hz), 2.40(s, 3H). 實施例23～31 依據實施例22中記載之方法，使用對應之參考例之化合物及原料化合物，獲得實施例23～31之化合物。 [表8][表9]上表中之LC-MS係使用測定條件(1)進行測定。 實施例32～89 依據實施例1、實施例7及實施例8、實施例17及實施例18中記載之方法，使用對應之參考例之化合物及原料化合物，獲得實施例32～89之化合物。 [表10][表11][表12][表13][表14][表15][表16][表17][表18][表19]試驗例 以下，示出本發明化合物之藥理試驗結果，說明關於該化合物之藥理作用，但本發明並不限定於該等試驗例。 試驗例1：對人型D1
受體、人型D2
受體、人型5-HT2A
受體之拮抗劑活性評價試驗 針對對人型D1
受體、人型D2
受體、人型5-HT2A
受體之拮抗劑活性，以細胞內鈣濃度作為指標進行測定。暫時於CHO-K1細胞(Chinese hamster ovary，中國倉鼠卵巢)中表現水母素、Gα16蛋白、各受體後，播種於384孔板，於CO2
培養箱內於37℃下培養整夜。於添加腔腸素後，使用FDSS(Hamamatsu Photonics公司製造)，添加本發明化合物之DMSO懸浮液，然後添加多巴胺(最終濃度100 nmol/L)或血清素(最終濃度30 nmol/L)，測定發光量之變化。 拮抗劑活性係算出將僅添加有DMSO之孔之發光量設為100%抑制，將僅添加有多巴胺或血清素之孔之發光量設為0%抑制之情形時的本發明化合物1 μmol/L下之抑制率。又，下表中記載濃度者表示記載之濃度下之抑制率(例如，記載為[email protected] μmol/L者表示0.1 μmol/L下之抑制率為58%)。再者，使用氯氮平作為比較對象物質而作為比較例。將結果示於下表。 [表20]
[表21]
[表22]
試驗例2：丹磺醯化麩胱甘肽(dGSH)捕捉分析 使本發明化合物於肝臟微粒體進行代謝，自生成之代謝物檢測與丹磺醯化麩胱甘肽(dGSH)進行反應之反應性代謝物並進行定量。代謝反應係使用篩選機器人(Tecan公司製造)，代謝物-dGSH結合物濃度係使用螢光檢測UPLC(ultra performance liquid chromatography，超高效液相層析法)系統(Waters公司製造)進行測定。 (溶液製備) 將本發明化合物溶解於DMSO中，製備10 mmol/L之受驗物質溶液。再者，使用氯氮平作為比較對象物質而作為比較例。 將磷酸鉀緩衝液(500 mmol/L，pH值7.4)7.6 mL、人類肝臟微粒體(Xenotech公司製造，20 mg protein/mL)1.9 mL及純水1.27 mL進行混合，製備微粒體溶液。 於微粒體溶液3.78 mL中加入純水0.67 mL而製備微粒體(dGSH(-))溶液。 於微粒體溶液6.48 mL中加入dGSH溶液(20 mmol/L)1.14 mL而製備微粒體(dGSH(+))溶液。 將NADPH(nicotinamide adenine dinucleotide phosphate，煙醯胺腺嘌呤二核苷酸磷酸)80.9 mg溶解於純水30 mL中而製備輔因子(cofactor)溶液。 將三(2-羧基乙基)膦(TECP，Tris(2-carboxyethyl)phosphin)33 mg溶解於甲醇115 mL中而製備反應終止液。 (反應) 將受驗物質溶液12 μL與純水388 μL進行混合，於96孔板每50 μL分注至6孔。將上述6孔每2孔分為3群，分別設為「反應群」、「未反應群」及「dGSH未添加群」。 於「反應群」及「未反應群」中每50 μL添加微粒體(dGSH(+))溶液，於「dGSH未添加群」中每50 μL添加微粒體(dGSH(-))溶液。 於「反應群」及「dGSH未添加群」中每50 μL添加輔因子(cofactor)溶液，於「未反應群」中每50 μL添加純水。 於37℃下培養60分鐘後，每450 μL添加反應終止液而終止反應。於「反應群」及「dGSH未添加群」中每50 μL添加純水，於「未反應群」中每50 μL添加輔因子(cofactor)溶液，將培養盤於-20℃下冷卻1小時後，進行離心分離(4000 rpm，10分鐘)。將上清液回收於另一培養盤，供於分析。 (分析) 使用螢光檢測UPLC系統(Waters公司製造)，於以下之條件下分析「反應群」、「未反應群」及「dGSH未添加群」。 管柱：Waters ACQUITY UPLC(註冊商標) BEH C18(1.7 μm，2.1 mm×10 mm) 溶出溶劑：A液 0.2%甲酸/40%甲醇 B液 0.2%甲酸/甲醇 梯度：B液，0%(0 min)→83.3%(9.33 min)→83.3%(10.63 min)→0%(10.64 min)→0%(13 min) 螢光強度係根據有機溶劑組成而發生變化，故而以溶出時之有機溶劑組成進行修正。 「反應群」之代謝物-dGSH結合物濃度係藉由自「反應群」中檢測到之螢光波峰減去「未反應群」及「dGSH未添加群」中檢測到之螢光波峰而算出。藉由測定「反應群」之代謝物-dGSH結合物濃度，可評價受驗物質之反應性代謝物之風險。 將氯氮平及本發明化合物之「反應群」之代謝物-dGSH結合物濃度之結果示於下表。 [表23]
[表24]
又，基於試驗例2之分析結果，自「未反應群」中檢測到之螢光波峰減去「dGSH未添加群」中檢測到之螢光波峰，藉此算出「未反應群」之dGSH結合物濃度。藉由測定「未反應群」之dGSH結合物濃度，可評價視為與細胞毒性或免疫毒性相關之受驗物質之共價鍵結性。 將本發明化合物之「未反應群」之dGSH結合物濃度之結果示於下表。 [表25]
試驗例3：人類肝臟微粒體代謝穩定性試驗 於本試驗中，可評價受驗物質對人類肝臟微粒體代謝之穩定性。藉由以下之方法評價本發明化合物之人類肝臟微粒體代謝穩定性(Metabolic Stability；MS)。人類肝臟微粒體係使用Xenontech公司製造者。將人類肝臟微粒體、NADPH、受驗物質於125 mmol/L磷酸緩衝液(pH值7.4)中以成為以下之濃度之方式進行混合，於37℃下培養30分鐘。 ・人類肝臟微粒體：0.1 mg/mL ・NAPDH：3.2 mmol/L ・受驗物質：0.1 μmol/L 藉由LC-MS測定30分鐘後之樣本中之受驗物質之殘存率，根據以下之式算出受驗物質對人類肝臟微粒體代謝之穩定性。 對人類肝臟微粒體代謝之穩定性(mL/min/mg protein)＝－LN(殘存率)/30/0.1 將結果示於下表。 [表26]
試驗例4：大鼠腦內移行性試驗 於本試驗中，可評價本發明化合物之腦內移行性。針對SD系7週之大鼠，藉由0.01 mol/L鹽酸水溶液而皮下投予本發明化合物，於投予後1小時後採集血漿及腦，藉由LC-MS測定血漿中及腦內藥物濃度。 使用平衡透析法測定本發明化合物之血清及腦內蛋白結合率。 藉由將利用上述試驗所獲得之血漿中及腦內化合物濃度以及血清中及腦內蛋白結合率適用於下述式，可算出Kp, uu, brain(腦/血漿間非結合型藥物濃度比)。 Kp, uu, brain＝(腦內化合物濃度×(100－腦內蛋白結合率(%))/100)/(血漿中化合物濃度×(100－血清中蛋白結合率(%))/100) 將結果示於下表。 [表27]
試驗例5：藉由大鼠***誘導運動量亢進試驗之對陽性症狀之評價 由對大鼠之***投予所引起之運動量亢進作用係用作精神***症之陽性症狀之評價系統，可評價投予本發明化合物時之抑制作用。對6-10週之大鼠投予本發明化合物後，測定自剛投予***後起90分鐘之運動量。於測定中使用SuperMex(室町機械股份有限公司)。算出將溶劑投予群之運動量設為100%時之抑制率。 試驗例6：對精神***症患者之有效性之評價 於臨床中，作為精神***症之精神症狀之評價標準，使用PANSS(Positive and Negative Syndrome Scale，陽性與陰性症狀量表)、CGI-S(Clinical Global Impression Severity scale，臨床總體印象量表)等。投予本發明化合物6～24週後，使用上述評價標準評價有效性。 試驗例7：氰基捕捉分析 於本試驗中，可檢測丹磺醯化麩胱甘肽未捕捉之反應性代謝物。使本發明化合物於人類肝臟微粒體進行代謝，與放射性氰化鉀(K14
CN)進行反應，藉此檢測反應性代謝物並進行定量。人類肝臟微粒體係使用Xenontech公司製造者，於以下之濃度條件下於37℃下實施60分鐘反應。 濃度條件 ・磷酸緩衝液(pH值7.4)：100 mM ・人類肝臟微粒體：1 mg/mL ・K14
CN：0.1 mM ・受驗物質：50 μM ・NADPH：0 mM或1 mM 將與K14
CN進行反應之反應性代謝物藉由固相萃取而分取，使用液體閃爍計數器測定放射性濃度。藉由自於加入有NADPH之條件下所獲得之測定值減去於未加入NADPH之條件下所獲得之測定值，算出反應性代謝物之生成間隙。 試驗例8：對人型5-HT2C
受體、人型組織胺H1
受體(以下稱為H1
受體)、人型毒蕈鹼M1
受體(以下稱為M1
受體)、人型毒蕈鹼M2
受體(以下稱為M2
受體)、人型毒蕈鹼M3
受體(以下稱為M3
受體)及人型毒蕈鹼M4
受體(以下稱為M4
受體)之拮抗劑活性評價試驗 針對對人型5-HT2C
受體、人型H1
受體、人型M1
受體、人型M2
受體、人型M3
受體及人型M4
受體之拮抗劑活性，以細胞內鈣濃度作為指標進行測定。暫時於CHO-K1細胞(Chinese hamster ovary)中表現水母素、Gα16蛋白及各受體後，播種於384孔板，於CO2
培養箱內於37℃下培養整夜。於添加腔腸素後，使用FDSS(Hamamatsu Photonics公司製造)，添加本發明化合物之DMSO懸浮液，然後添加下表所示之對應之配體，測定發光量之變化。於下表中示出各受體之拮抗劑活性評價中所使用之配體及其使用濃度。 [表28]
拮抗劑活性係將僅添加有DMSO之孔之發光量設為100%抑制，將僅添加有對應之配體之孔之發光量設為0%抑制，算出本發明化合物之濃度為1 μmol/L或0.1 μmol/L之情形時之抑制率。 [表29]
試驗例9：對人型5-HT2A
受體、人型D1
受體、人型D2
受體、人型5-HT2C
受體、人型H1
受體、人型M1
受體、人型M2
受體、人型M3
受體及人型M4
受體之結合活性評價 於本試驗中，可測定本發明化合物對人型5-HT2A
受體、人型D1
受體、人型D2
受體、人型5-HT2C
受體、人型H1
受體、人型M1
受體、人型M2
受體、人型M3
受體及人型M4
受體之結合親和性。使用表現該等受體之CHO細胞膜組分或CHO-K1細胞膜組分等，於結合評價試驗中，將溶解於DMSO中之受驗化合物、經緩衝液稀釋之各種受體膜標本、及針對該等受體之經RI(Radio Isotope，放射性同位素)標記之配體進行混合，分別於室溫下培養30分鐘或60分鐘。作為針對受體之經RI標記之配體，可根據試驗條件等適當選擇，可對5-HT2A
受體使用[3H]酮色林(Ketanserin)，對D2
受體使用[3H]螺哌隆(Spiperone)，對D1
受體使用[3H]SCH23390。對受體之非特異性結合係根據針對5-HT2A
受體存在米安色林(Mianserin)，針對D2
受體存在多巴胺(Dopamine)，針對D1
受體存在SCH23390等之競爭結合試驗求出。使用液體閃爍計數器測定與受體結合之放射活性後，算出50%抑制濃度，自根據飽和結合試驗算出之解離常數及基質濃度評價Ki值，用作結合親和性。除此以外，關於對人型5-HT2C
受體、人型H1
受體、人型M1
受體、人型M2
受體、人型M3
受體及人型M4
受體之結合親和性，亦可依據上述方法進行測定。作為針對該等受體之經RI標記之配體，可根據試驗條件等適當選擇，例如，可對人型5-HT2C
受體使用[3H]美舒麥角(Mesulergine)，對人型H1
受體使用[3H]吡拉明(Pyrilamine)，對人型M1
受體、人型M2
受體、人型M3
受體及人型M4
受體使用[3H]N-甲基東莨菪鹼(N-Methylscopolamine)等。進而，對該等受體之非特異性結合係根據針對人型5-HT2C
受體存在米安色林(Mianserin)，針對人型H1
受體存在吡拉明(Pyrilamine)，針對人型M1
受體、人型M2
受體、人型M3
受體及人型M4
受體存在阿托品(Atropine)等之競爭結合試驗求出。 [產業上之可利用性] 本發明化合物由於對多巴胺D1
受體、多巴胺D2
受體及血清素5-HT2A
受體表現出拮抗作用，故而可用作中樞神經系統疾病之治療劑及/或預防劑。Hereinafter, the present invention will be described in detail. In the present specification, the amount of carbon in the definition of "substituent" is also referred to as "C".1-6
"etc. Specifically, "C1-6
The description of "alkyl" is synonymous with an alkyl group having 1 to 6 carbon atoms. Specific examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. It is preferably a fluorine atom or a chlorine atom. "C1-6
"Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferably "C1-4
alkyl". As "C1-6
Specific examples of the alkyl group include, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a second butyl group, a tert-butyl group, a pentyl group, an isopentyl group, and a neopentyl group. Base, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl Wait. "C1-6
"Alkoxy"1-6
"Alkyl" part is related to the above "C1-6
Alkyl is synonymous. Preferably "C1-4
Alkoxy group". As "C1-6
Specific examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a second butoxy group, a third butoxy group, and the like. . In the compound represented by the formula (1), Rb
If the group is substitutable, it can be substituted with any carbon atom on the nitrogen-containing monocyclic ring. If it is substitutable, it can be the same or different two R groups on the same carbon atom.b
The base is substituted. In the compound represented by the formula (1), in the ring Q1
And / or ring Q2
In the case of a pyridine ring, the four atoms represented by the arrows shared by the rings which are fused are carbon. [Chemical 5]Examples of the substituent in the "substitutable benzene ring" and the "substituted pyridine ring" include (a) a halogen atom, (b) a cyano group, and (c) C.1-6
An alkyl group (the group may be selected from a halogen atom, a hydroxyl group, and C1-6
(1) to 1 or 3 of the same or different species in the group consisting of alkoxy groups), (d) C1-6
Alkoxy group (the group may be selected from a halogen atom, a hydroxyl group, and C1-6
a group of 1 to 3 groups of the same or different species in the group consisting of alkoxy groups), (e) a phenyl group (the group may be selected from a halogen atom, C1-6
Alkyl and C1-6
a group of 1 to 4 substituents of the same or different species in the group consisting of alkoxy groups, (f) a heteroaryl group of 5 or 6 members (the group may be selected from a halogen atom, C)1-6
Alkyl and C1-6
a group of 1 to 4 groups of the same or different species in the group consisting of alkoxy groups), (g) a phenoxy group (the group may be selected from a halogen atom, C)1-6
Alkyl and C1-6
1 to 4 substituents of the same or different species in the group consisting of alkoxy groups), (h) hydroxyl groups, (i) amine groups (the group may be 1 to 2 C of the same or different species)1-6
Alkyl substituted) and (j) aminocarbonyl (the amine group may be 1 to 2 C of the same or different species)1-6
Alkyl substitution) and the like. Preferably, it is a halogen atom, a cyano group, and a C which may be substituted by 1 to 3 halogen atoms of the same or different species.1-6
Alkyl, which may be substituted by one or three halogen atoms of the same or different species1-6
Alkoxy group, and 1 to 2 C which can be homologous or heterologous1-6
Alkyl substituted amino group. More preferably, it is a halogen atom, which may be substituted by one or three halogen atoms of the same or different species.1-6
Alkyl, and C which may be substituted by 1 to 3 halogen atoms of the same or different species1-6
Alkoxy. In the compound of the present invention represented by the formula (1a), Ra
, R1
, R2
, R3
, R4
, R5
, R6
, R7
, R8
, R11
, R12
, R13
And R14
The preferred ones are as follows, but the technical scope of the present invention is not limited to the scope of the compounds listed below. As Ra
Preferably, C is substituted by one or three halogen atoms of the same or different species.1-6
alkyl. Better for C1-3
An alkyl group; further preferably a methyl group. Also, as Ra
Another aspect is 氘methyl (CD)3
). As R1
, R3
, R4
, R5
, R6
And R8
Preferably, a hydrogen atom and a halogen atom are mentioned. More preferably, it is a hydrogen atom. As R2
And R7
Preferably, it is a hydrogen atom, a halogen atom, a cyano group, and a C which may be substituted by one or three halogen atoms of the same or different species.1-6
Alkyl, and C which may be substituted by 1 to 3 halogen atoms of the same or different species1-6
Alkoxy. More preferably, it is a halogen atom, which may be substituted by one or three halogen atoms of the same or different species.1-6
Alkyl, and C which may be substituted by 1 to 3 halogen atoms of the same or different species1-6
Alkoxy. R11
, R12
, R13
And R14
Individually substituted by a hydrogen atom, a halogen atom, or a C atom which may be substituted by one or three halogen atoms of the same or different species1-6
Alkyl group, preferably R11
, R12
, R13
And R14
Any one of the above is a halogen atom, or may be substituted by one or three halogen atoms of the same or different species.1-6
alkyl. More preferably R11
, R12
, R13
And R14
Any one of them is C1-6
alkyl. As R11
, R12
And R14
Preferably, a hydrogen atom and C are exemplified1-6
alkyl. More preferably, it is a hydrogen atom. As R13
Preferably, a hydrogen atom and C are exemplified1-6
alkyl. Better for C1-4
An alkyl group; further preferably a methyl group. As R11
, R12
, R13
And R14
Another aspect, R11
And R12
Is a hydrogen atom; R13
For C1-6
Alkyl; R14
Is a hydrogen atom or C1-6
alkyl. As R11
, R12
, R13
And R14
Another aspect, R11
, R12
And R14
Is a hydrogen atom; R13
For C1-4
alkyl. The compound represented by the formula (1) may also exist in the form of a tautomer. Therefore, the compound of the present invention also contains a tautomer of the compound represented by the formula (1). The compound represented by the formula (1) may also have a case of having at least one asymmetric carbon atom. Therefore, the compound of the present invention contains not only the racemates of the compounds represented by the formula (1) but also optically active compounds of the compounds. Further, any one or more of the compounds represented by the formula (1)1
H is converted to2
The hydrazone transformant formed by H(D) is also included in the compound represented by the formula (1). The compound represented by the formula (1) and the pharmaceutically acceptable salt thereof are also present in the form of a hydrate and/or a solvate, and the solvate such as the hydrate or the ethanol solvate is also Included in the compounds of the invention. Further, the compounds of the present invention also encompass all forms of crystal form. In the case where the compound represented by the formula (1) has an acidic group, examples of the pharmaceutically acceptable salt include an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; and zinc. An inorganic metal salt such as a salt; an organic alkali salt such as triethylamine, triethanolamine, trishydroxymethylaminomethane or amino acid. When the compound represented by the formula (1) has a basic group, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; and acetate, propionate; , succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, besylate, An organic acid salt such as ascorbate. Hereinafter, a method for producing the compound represented by the formula (1) in the present invention will be described by way of example, but the present invention is of course not limited thereto. Production Method The compound of the present invention is synthesized by a combination of the production method shown below and a known synthesis method. The compound in the reaction formula also contains a salt, and the salt is the same as the salt of the compound represented by the formula (1). Furthermore, the reactions are merely illustrative, and the compounds of the invention may be suitably prepared by other methods based on the knowledge of an organic synthesizer. In each of the production methods described below, even in the case where the use of the protective group is not specifically indicated, in the case where the functional group to be protected is present, the functional group is optionally protected, after the reaction is completed or a series of After the reaction, deprotection is carried out, whereby the target is obtained. The introduction and detachment of the protecting group can be carried out by a method commonly used in organic synthetic chemistry (for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999). The method described, etc.) or according to the method thereof. Examples of the protective group of the amino group include a third butoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, an o-nitrophenylsulfonyl group, and the like. Production Method 1 Among the compounds represented by the formula (1), the compounds represented by the formulae (1c) and (1d) are produced, for example, by the method shown below. [Chemical 6][in the formula, ring Q1
Ring Q2
, Rb
, m and n are synonymous with [Item 1] above; RA1
Represents C which can be substituted by 1 to 3 halogen atoms of the same or different species1-6
Alkyl; X represents halogen; Pro represents a protecting group of an amine group; A represents a boronic acid or a boronic ester] Step 1-1: Production step of the compound (1-2) The compound (1-2) is obtained by a suitable inert solvent The halogenating agent is produced by allowing the halogenating agent to act on the compound (1-1) in the presence of a base or in the absence of a base. The compound (1-1) can be produced by a commercially available compound or by a known method (for example, International Publication No. 2007/047776). Examples of the halogenating agent include 1-chloro-N,N,2-trimethylpropenylamine, phosphorus oxychloride, phosphorus trichloride, sulfinium chloride, and phosphorus pentachloride. Examples of the base include N,N-dimethylaniline and the like. Examples of the inert solvent include toluene, dichloromethane, and the like. The reaction time is usually from 5 minutes to 72 hours, preferably from 30 minutes to 2 hours. The reaction temperature is usually -78 ° C to 200 ° C, preferably 20 ° C to 100 ° C. Step 1-2: Production step of compound (1d) Compound (1d) is obtained by coupling compound (1-2) with compound (1-3) in the presence of a palladium catalyst in a suitable inert solvent. Manufacturing. This step can be carried out as needed in the presence of a base and/or a phosphorus ligand. The compound (1-3) can be produced by using a commercially available compound or by a known method (for example, International Publication No. 2002/066470). Further, those manufactured by the following production method 4 can be used. As the palladium catalyst, various palladium catalysts used in a conventional method can be used, and tetrakis(triphenylphosphine)palladium (0) is preferable. Examples of the base include potassium carbonate and cesium carbonate. Examples of the phosphorus ligand include triphenylphosphine or bis(diphenylphosphino)methane. Examples of the inert solvent include 1,4-dioxane, tetrahydrofuran, water, and a mixed solvent thereof. The reaction temperature is usually from 0 ° C to 200 ° C, preferably from 20 ° C to 150 ° C, and may be carried out under microwave irradiation as needed. The reaction time varies depending on the reaction temperature, the palladium catalyst to be used, the raw material, and the solvent, and is usually from 5 minutes to 72 hours, preferably from 30 minutes to 24 hours. Step 1-3: Production step of the compound (1-5) The compound (1-5) is produced from the compound (1-2) and the compound (1-4) according to the method described in the step 1-2. The compound (1-4) can be produced by the following Production Method 2. Step 1-4: Production Step of Compound (1c) Compound (1c) is obtained by using a known method (for example, Protective Group in Organic Synthesis, 3rd edition (Theodora W. Green, Peter GM Wuts, issued by John Wiley & Sons Inc, 1999) Manufactured according to the deprotection of the protecting group Pro of the amine group of the compound (1-5). Step 1-5: The production step of the compound (1d) The compound (1d) is also used in a suitable inert solvent in the reducing agent. In the presence of the compound (1c), it is produced by reacting the compound (1c) with various alkyl aldehydes. Examples of the reducing agent include sodium borohydride, sodium triethoxy borohydride, sodium cyanoborohydride, and the like. For example, toluene, THF (tetrahydrofuran, tetrahydrofuran), dichloroethane, methanol, etc. The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually -78 ° C to 100 ° C. Further, the compound (1d) is also produced by reacting the compound (1c) with various alkyl halides in the presence of a base in a suitable inert solvent. For example, potassium carbonate, Carbonic acid hydride, sodium hydride, lithium diisopropyl guanamine, etc. Examples of the inert solvent include DMF (dimethylformamide, dimethylformamide), dimethyl hydrazine, THF, and 1,4-dioxane. The reaction time is usually from 5 minutes to 48 hours, preferably from 1 hour to 24 hours. The reaction temperature is usually -78 ° C to 100 ° C, preferably 0 ° C to 80 ° C. Manufacturing Method 2 Formula (1-4) The compound represented is produced, for example, by the method shown below.[where, Rb
, m and n are synonymous with [Item 1] above; X1
Represents a halogen or a triflate (trifluoromethanesulfonyloxy); Pro represents a protecting group for an amine group; A represents a boronic acid or a boronic ester] Step 2-1: a compound of the compound (2-2) (2-2) is produced by allowing a trifluoromethanesulfonating agent to act on the compound (2-1) in the presence of a base in a suitable inert solvent. The compound (2-1) can be produced by a commercially available compound or by a known method (for example, International Publication No. 2012/142668). Examples of the base include lithium diisopropylguanamine or sodium bis(trimethyldecyl)decylamine. As the trifluoromethanesulfonating agent, various trifluoromethanesulfonating agents used in the conventional methods can be used, and preferably N-phenylbis(trifluoromethanesulfonimide) is exemplified. Examples of the inert solvent include THF and the like. The reaction time is usually from 5 minutes to 72 hours, preferably from 30 minutes to 8 hours. The reaction temperature is usually -78 ° C to 200 ° C, preferably -78 ° C to 20 ° C. Step 2-2: Production Step of Compound (1-4) Compound (1-4) is obtained by coupling compound (2-2) with a boronating reagent in the presence of a palladium catalyst in a suitable inert solvent. And manufacturing. This step can be carried out as needed in the presence of a base and/or a phosphorus ligand. As a base, potassium acetate is mentioned, for example. Examples of the phosphorus ligand include triphenylphosphine or bis(diphenylphosphino)methane. As the borating agent, various boronating agents used in the conventional method can be used, and preferably, bis(pinacol ester) diborane is exemplified. As the palladium catalyst, various palladium catalysts used in a conventional method can be used, and preferably, 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloride is exemplified. Examples of the inert solvent include 1,4-dioxane, THF, and the like. The reaction temperature is usually from 0 ° C to 200 ° C, preferably from 50 ° C to 120 ° C, and may be carried out under microwave irradiation as needed. The reaction time varies depending on the reaction temperature, the palladium catalyst to be used, the raw material, and the solvent, and is usually from 5 minutes to 72 hours, preferably from 2 hours to 8 hours. Production Method 3 Among the compounds represented by the formula (1), the compound represented by the formula (1e) is produced, for example, by the method shown below. [化8][in the formula, ring Q1
Ring Q2
, Rb
And the m system are synonymous with the above [Item 1]; RA1
Represents C which can be substituted by 1 to 3 halogen atoms of the same or different species1-6
Alkyl; X represents halogen; A represents boric acid or borate] Step 3-1: Production step of compound (3-2) Compound (3-2) is derived from compound (1-2) and compound (3-1) , manufactured according to the method described in step 1-2. The compound (3-1) can be produced by using a commercially available compound or by a known method (for example, International Publication No. 2011/119518). Step 3-2: Production step of compound (1e) Compound (1e) is obtained by reacting compound (3-2) with compound (3-3) to produce a quaternary ammonium cation by a suitable inert solvent. The reducing agent acts to produce it. Examples of the inert solvent include acetonitrile, THF, and 1,4-dioxane. The reaction time of the alkylation step is usually from 5 minutes to 48 hours, preferably from 1 hour to 24 hours. The reaction temperature of the alkylation step is from 0 ° C to 100 ° C. Examples of the reducing agent used in the subsequent reduction reaction include sodium borohydride, sodium triethoxy borohydride, sodium cyanoborohydride and the like. Examples of the solvent to be used include toluene, THF, dichloroethane, and methanol. The reaction time is usually from 5 minutes to 48 hours, preferably from 1 hour to 24 hours. The reaction temperature is usually -78 ° C to 100 ° C, preferably -78 ° C to 20 ° C. Production Method 4 The compound represented by the formula (1-3) is also produced, for example, by the method shown below. [Chemistry 9][where, Rb
, m and n are synonymous with [Item 1] above; RA1
Represents C which can be substituted by 1 to 3 halogen atoms of the same or different species1-6
Alkyl; X1
Represents a halogen or a triflate; Pro represents a protecting group of an amine group; A represents a boric acid or a boric acid ester] Step 4-1: Production Step of Compound (4-1) Compound (4-1) is utilized A known method (for example, Protective Group in Organic Synthesis, 3rd edition (Theodora W. Green, by Peter GM Wuts, issued by John Wiley & Sons Inc, 1999), which is produced by deprotecting the protecting group Pro of the amine group of the compound (2-2) Step 4-2: Production Step of Compound (4-2) Compound (4-2) is also subjected to compound (4-1) and various alkyl aldehydes in the presence of a reducing agent in a suitable inert solvent. The reducing agent may, for example, be sodium borohydride, sodium triethoxy borohydride or sodium cyanoborohydride. Examples of the inert solvent include toluene, THF, dichloroethane and methanol. The reaction time is usually from 5 minutes to 48 hours, preferably from 1 hour to 24 hours. The reaction temperature is usually -78 ° C to 100 ° C, preferably 0 ° C to 80 ° C. Further, the compound (4-2) is also Halogenation of compound (4-1) with various alkyl groups in the presence of a base in a suitable inert solvent The base is, for example, potassium carbonate, cesium carbonate, sodium hydride, lithium diisopropyl guanamine or the like. Examples of the inert solvent include DMF, dimethyl hydrazine, THF, and 1, 4-dioxane, etc. The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually -78 ° C to 100 ° C, preferably 0 ° C to 80 ° C. Step 4-3 Production Step of Compound (1-3) The compound (1-3) is produced by coupling a compound (4-2) with a boronating reagent in the presence of a palladium catalyst in a suitable inert solvent. The step may be carried out in the presence of a base and/or a phosphorus ligand. The base may, for example, be potassium acetate. Examples of the phosphorus ligand include triphenylphosphine or bis(diphenylphosphino)methane. As the borating agent, various boriding agents used in the conventional method can be used, and preferably, bis(pinacol ester) diborane is used. As the palladium catalyst, various palladium contacts used in the conventional method can be used. The medium is preferably 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloride as an inert solvent. For example, 1,4-dioxane, THF, etc. The reaction temperature is usually 0 ° C to 200 ° C, preferably 50 ° C to 120 ° C, and may be carried out under microwave irradiation as needed. The reaction time is based on the reaction temperature, The conditions of the palladium catalyst, the raw material and the solvent to be used are usually from 5 minutes to 72 hours, preferably from 2 hours to 8 hours. By appropriately combining the above-described production methods, it is possible to obtain at a desired position. The compound of the present invention which is a desired substituent, and the separation and purification of the intermediate and the product in the above production method can be appropriately combined with a method used in usual organic synthesis, for example, filtration, extraction, washing, drying, concentration, and crystallization. And various kinds of chromatography methods and the like. Further, the intermediate may be supplied to the next reaction without special purification. The raw material compound or the intermediate in the above production method may be present in the form of a salt such as a hydrochloride salt depending on the reaction conditions and the like, but may be used as it is or in a free form. When the raw material compound or the intermediate is to be obtained in the form of a salt, and the raw material compound or the intermediate is used in a free form, the solvent may be dissolved or suspended in a suitable solvent, for example, by an aqueous solution of sodium hydrogencarbonate or the like. The base or the like is neutralized, thereby being converted into a free form. In the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, there may be a tautomer, a positional isomer, a geometric isomer or an optical isomerism such as a keto-enol group. Any of the isomers and the mixture of any of the isomers may be included in the present invention. Further, the optical isomer can be separated by a known separation step such as a method using an optically active column or a fractional crystallization method by an appropriate step of the above production method. Further, an optically active substance can also be used as a starting material. In the case of obtaining a salt of the compound represented by the formula (1), in the case of obtaining a salt of the compound represented by the formula (1), it is only necessary to directly carry out the purification, and further, a formula for obtaining a free form (1) In the case of the compound represented by the formula (1), the compound represented by the formula (1) may be dissolved or suspended in a suitable solvent, and an acid or a base may be added to form a salt. Further, the compound (1) or a pharmaceutically acceptable salt thereof may be present in the form of a solvate with water or various solvents, and such solvates are also included in the present invention. In the present specification, "refractory schizophrenia" refers to schizophrenia in which a sufficient amount of two or more antipsychotic drugs are administered even after a sufficiently long period of time. It is defined in the Japanese schizophrenia drug guidelines as follows: Two or more antipsychotic drugs are administered in an amount of 600 mg/day or more in terms of chlorpromium, and after four weeks or more, the equivalent function is not achieved. The Global Assessment of Functioning (GAF) is 41 or more. It is known that clozapine is effective for refractory schizophrenia except D2
Receptor antagonism, 5-HT2A
In addition to receptor antagonism, also on D1
The receptor has an antagonistic action (Non-Patent Documents 4, 5, and 6). It can be expected to be the same as clozapine1
Receptor, D2
Receptor and 5-HT2A
The compounds of the invention in which the receptor has an antagonistic effect are effective against refractory schizophrenia. Also, due to the compound of the invention versus D2
Receptor and 5-HT2A
Receptors show antagonism, so expect to be also schizophrenia, bipolar disorder, autism, ADHD (Attention Deficit Hyperactivity Disorder), depression, anxiety, sleep disorders, dementia behavior・Psychiatric symptoms of BPSD (Behavioral and Psychological Symptoms of Dementia) and neurodegenerative diseases are effective. Although there is currently no common animal model for refractory schizophrenia, it is considered that by performing a hyperalkamine-induced hyperactivity test (test case 5) in a rat model of positive symptoms of schizophrenia, it can be found Schizophrenia treatment drug, by confirming the above D1
Receptor and D2
The receptor has an antagonistic effect and can be used to explore agents that are also effective against refractory schizophrenia. When a pharmaceutical compound is introduced into a living body, the chemical structure changes due to metabolism, and a highly reactive intermediate, that is, a reactive metabolite is formed, thereby exhibiting toxicity (granular ball deficiency, hepatotoxicity, allergy). , tissue necrosis, mutagenicity or carcinogenicity, etc.). As one of the tests for easily evaluating the risk of toxicity caused by the reactive metabolite, there is a glutathione capture test using dansylsulfonated glutathione (dGSH). The higher the value of the dGSH covalent bond amount, the more the above-mentioned toxicity risk is increased when exposed to the whole body. Regarding the particulate spherical deficiency seen in clozapine, it has been reported that one of the causes is the formation of a reactive metabolite (refer to The Journal of Pharmacology and Experimental Therapeutics, 1997, 283 (3) 1375-1382, etc.). The compound of the present invention was subjected to a dansyl glutathione (dGSH) capture test, and as a result, it was unexpectedly known that the value of the dGSH covalent bond of the compound of the present invention was extremely low, and the formation of a reactive metabolite was remarkably lowered (Test Example 2). . From this, it is expected that the compound of the present invention has a low risk of causing particulate globus deficiency and the like, and can be safely administered for a long period of time. Regarding side effects such as digestive system damage, sedation, and weight gain seen in clozapine, it has been reported that one of the causes is the histamine receptor, muscarinic receptor, 5-HT.2c
Antagonism of receptors and the like (cf. Molecular Psychiatry (2008) 13, 27-35; Prim Care Companion J Clin Psychiatry. 2004, 6 (suppl 2): 3-7; CNS Drugs. 2013 Jun; 27 (6): 423 -34; J Clin Psychiatry 2004, 6 (Suppl 2): 20-23; Clin Psychopharmacol Neurosci. 2012 Aug; 10 (2): 71-77, etc.). The compounds of the present invention were subjected to an antagonist activity evaluation test for these receptors, and as a result, it was unexpectedly known that the compounds of the present invention have a lower antagonistic effect on the receptors when they are in a better aspect (Test Example 8). It is thus expected that the compounds of the present invention have a lower risk of causing digestive system damage, sedation, weight gain, etc., in a more favorable manner, and can be administered safely. Further, in the present invention, "prevention" is an action of administering the active ingredient of the present invention to a normal person who is not afflicted, for example, for the purpose of preventing the onset of the disease. "Treatment" is the act of administering the active ingredient of the present invention to a person (patient) who has been diagnosed by a doctor. The compounds of the present invention can be administered by oral administration or parenteral administration, either directly or by using a suitable dosage form. The dosage form may, for example, be a tablet, a capsule, a powder, a granule, a liquid, a suspension, an injection, a patch, a dressing or the like, but is not limited thereto. The preparation is produced by a known method using a pharmaceutically acceptable additive. The additive may be used according to the purpose, using an excipient, a disintegrating agent, a binder, a plasticizer, a lubricant, a coating agent, a dissolving agent, a dissolution aid, a tackifier, a dispersing agent, a stabilizer, a sweetener, and a fragrance. Wait. Specific examples thereof include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially gelatinized starch, calcium carboxymethylcellulose, and croscarmellose sodium. Hydroxypropyl cellulose, hypromellose, polyvinyl alcohol, magnesium stearate, sodium stearyl succinate, polyethylene glycol, propylene glycol, titanium oxide, talc, and the like. The administration route is preferably the most effective for use in the treatment, and examples thereof include oral, intravenous, smear, inhalation, and eye drops, and oral administration is preferred. Examples of the administration form include a tablet, an injection, and the like, and a tablet is preferred. The dosage or the number of administrations of the pharmaceutical compositions differs depending on the form of administration, the disease or symptom of the patient, the age or weight of the patient, and the like, and cannot be generally prescribed, but usually, the adult can be administered once a day or The amount of the active ingredient per day is preferably from about 0.0001 to about 5000 mg, preferably from about 0.001 to about 1000 mg, more preferably about 0.1, preferably divided into one to three times a day. It is in the range of about 500 mg, particularly preferably in the range of about 1 to about 300 mg. The compound of the present invention can be used in combination with other drugs for the purpose of enhancing the effect and/or reducing the side effects. For example, it can be combined with aripiprazole, olanzapine, quetiapine, risperidone, bunnerin, piperoprolone, paliperidone, ziprasidone, asenapine, iloperidone, Antipsychotic drugs such as sputum, lurasidone or a pharmaceutically acceptable salt thereof are used in combination. Hereinafter, the drug which can be used in combination with the compound of the present invention is simply referred to as a concomitant drug. The administration time of the compound of the present invention and the concomitant drug is not limited, and it may be administered to the subject at the same time, or may be administered at intervals. Further, a combination of the compound of the present invention and a concomitant agent can also be used. The dosage of the pharmaceutical agent can be appropriately selected based on the amount of the clinical use. Further, the ratio of the compound of the present invention to the concomitant agent can be appropriately selected depending on the administration target, the administration route, the target disease, the symptom, the combination, and the like. For example, when the administration target is a human, it may be used in an amount of 0.01 to 100 parts by weight based on 1 part by weight of the compound of the present invention. Moreover, for the purpose of suppressing the side effects, it can be used in combination with an agent such as an antiemetic agent, a sleep introducing agent, or an anticonvulsant (a combination). [Examples] Hereinafter, the present invention will be specifically described by reference examples, examples, and test examples, but the present invention is not limited thereto. Further, the names of the compounds shown in the following Reference Examples and Examples are not necessarily based on the IUPAC (International Union of Pure and Applied Chemistry) nomenclature. In order to simplify the description of the specification, in the reference examples, examples, and test examples, the following abbreviations are also used. Me: methyl Et: ethyl DMF: N, N-dimethylformamide DMSO: dimethyl hydrazine THF: tetrahydrofuran TFA: trifluoroacetic acid as a mark used in NMR (nuclear magnetic resonance) , s means single peak, d means doublet, dd means doublet of doublet, t means triplet, td means doublet of triplet, q means quadruple, m means multiple Peak, br means wide, brs means wide singlet, brm means wide multiple peak, and J means coupling constant. High-speed liquid chromatography mass spectrometer; LCMS measurement conditions are as follows, with [M+H]+
Or [M-H]-
Indicates the value of the observed mass analysis [MS(m/z)], and the retention time is expressed in Rt (minutes). Measurement conditions (1) Testing equipment: ACQUITY (registered trademark) SQ deteceter (Waters) HPLC: ACQUITY UPLC (registered trademark) system Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 30 mm) Flow rate: 0.75 mL/min Measurement wavelength: 254 nm Moving bed: A solution 0.05% formic acid aqueous solution B solution acetonitrile Time program: Step time (minutes) 1 0.0-1.3 A solution: B solution = 90:10 to 1:99 2 1.3 -1.5 A liquid: B liquid = 1:99 3 1.5-2.0 A liquid: B liquid = 90:10 Measurement conditions (2) Testing equipment: ACQUITY (registered trademark) SQ deteceter (Waters) HPLC: ACQUITY UPLC (registered trademark) System Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 30 mm) Flow rate: 0.80 mL/min Measurement wavelength: 254 nm Moving bed: A solution 0.05% formic acid aqueous solution B liquid acetonitrile Time program: Step time (minutes) 1 0.0-1.3 A solution: B solution = 90:10 to 5:95 2 1.3-1.5 A solution: B solution = 90:10 Determination conditions (3) MS detector: LCMS-IT-TOF HPLC :Shimadzu Nexera X2 LC 30AD Column: Kinetex 1.7 μ C18 100A New column 50×2.1 mm Flow rate: 1.2 mL/min Measurement wavelength: 2 54 nm moving bed: liquid A; 0.1% formic acid aqueous solution B; acetonitrile time program: step time (minutes) 1 0.01-1.40 A liquid: B liquid = 90:10~5:95 2 1.40-1.60 A liquid: B liquid =5:95 3 1.61-2.00 A liquid: B liquid = 99:1 Measurement conditions (4) Testing machine: LCMS-2020 (Shimadzu Corporation) Column: Phenomenex Kinetex (1.7 μm, C18, 50 mm × 2.10 mm) Flow rate :0.50 mL/min Measurement wavelength: 220, 254 nm Moving bed: A solution 0.05% TFA aqueous solution B solution Acetonitrile column Temperature: 40 ° C Time program: Step time (minutes) 1 0.0 A solution: B solution = 90:10 2 0.0-1.9 A liquid: B liquid = 90:10～1:99 3 1.9-3.0 A liquid: B liquid=90:10 Reference example 1 8-chloro-2-fluoro-5,10-dihydro-11H-two Benzo[b,e][1,4]diazepine-11-one [10]a) Preparation of 2-[(4-chloro-2-nitrophenyl)amino]-5-fluorobenzoic acid (Compound W1) in 4-chloro-1-fluoro-2-nitrobenzene (5.0 g) 2-Amino-5-fluorobenzoic acid (4.4 g) and cesium carbonate (28 g) were added to a solution of DMF (29 mL), and stirred at 120 ° C overnight. Water was added to the reaction mixture at 0 ° C, and the mixture was adjusted to pH 5 with 1 mol/L hydrochloric acid, and then extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the dried organic layer was distilled off under reduced pressure, whereby Compound W1 (8.8 g) was obtained. LC-MS ([M+H]+
/Rt(min)): 311/1.18 Measurement conditions (1) b) 2-[(2-Amino-4-chlorophenyl)amino]-5-fluorobenzoic acid (Compound W2) was produced in Compound W1 (8.8 g) of THF/MeOH/H2
Ammonium chloride (15 g) and iron (16 g) were added to the O(3:2:1) (300 mL) solution, and stirred at 80 ° C for 2 hours. After cooling the reaction liquid, it was filtered through celite, washed with methanol, and then the solvent was distilled off under reduced pressure. After the obtained residue was subjected to liquid separation extraction with ethyl acetate-water, the obtained organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure, whereby Compound W2 (8.0 g) was obtained. LC-MS ([M+H]+
/Rt(min)): 281/1.06 Determination conditions (1) c) 8-Chloro-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine Preparation of -11-ketone (Reference Example 1) Addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to a solution of compound W2 (8.0 g) in DMF (143 mL) Hydrochloride (6.0 g) and 1-hydroxybenzotriazole (4.2 g) were stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was washed with chloroform (20 mL) to give the title compound (3 g). LC-MS ([M+H]+
/Rt(min)): 263/0.93 Measurement conditions (1) Reference examples 2 to 8 According to the method described in Reference Example 1, the compounds shown in the following table were obtained using the corresponding starting compounds. [Table 1]
The LC-MS in the above table was measured using the measurement conditions (1).Reference example 9
6-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 ( 2H)-carboxylic acid tert-butyl ester and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester [Chemical 11]a) 6-methyl-4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and 2-methyl- 4-{[(Trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (Substance A) manufactured in 1-(Third A solution of 1.5 mol/L of lithium diisopropylamide in THF (4.0 mL) was dissolved in THF (10 mL) of oxycarbonyl)-2-methylpiperidin-4-one (1.1 g) at -78 °C. mL). After stirring at -78 ° C for 10 minutes, a solution of N-phenylbis(trifluoromethanesulfonimide) (2.1 g) in THF (5 mL) was evaporated. After stirring at room temperature for 4 hours, a saturated aqueous solution of ammonium chloride was added at 0 ° C and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the dried organic layer was distilled off under reduced pressure, and then subjected to silica gel column chromatography (solvent solvent; chloroform/methanol) and NH.2
The material was purified by a silica gel column chromatography (solvent solvent; hexane/ethyl acetate), whereby substance A (1.7 g, a mixture of isomers) was obtained.1
H-NMR (400 MHz, CDCl3
) δ: 5.73, 5.69(s, 1H, isomer ratio=1:1), 4.65-4.23(m, 2H), 3.64-2.52(m, 2H), 2.21-2.02(m, 1H), 1.45(s, 9H), 1.23, 1.16 (ds, 3H, J=6.8 Hz, isomer ratio=1:1). b) 6-Methyl-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and 2-methyl-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (Reference Example 9) Adding bis(pinacol ester) diborane (1.4 g), 1,1'-bis(diphenylphosphino)ferrocene-di, to a solution of material A (1.7 g) in THF (50 mL) Palladium (II) chloride (0.73 g) and potassium acetate (1.5 g). After stirring at 80 ° C for 2 hours, it was cooled to room temperature, and the precipitate was removed by filtration through celite. Water was added to the filtrate, and extraction was performed with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the organic layer after drying was distilled off under reduced pressure, and then purified by silica gel column chromatography (solvent solvent; hexane/ethyl acetate) to obtain the compound of Reference Example 9 (1.2 g, isomer a mixture of substances). LC-MS ([M+H]+
/Rt(min)): 324/1.37 Measurement conditions (1)1
H-NMR (400 MHz, CDCl3
δ: 5.73, 5.69(s, 1H, isomer ratio=1:1), 4.43-4.16(m, 2H), 3.61-2.37(m, 2H), 2.13-2.01(m, 1H), 1.44(s, 9H), 1.24(s, 12H), 1.16, 1.03 (d, 3H, J=6.8 Hz, isomer ratio=1:1). Reference Examples 10 to 12 According to the method described in Reference Example 9, the corresponding raw material compound was used. The compound (mixture of isomers) shown in the table below was obtained. [Table 2]
The LC-MS in the above table was measured using the measurement conditions (1). Reference Examples 13 to 29 According to the method described in Reference Example 1, the compounds shown in the following Table were obtained by using the corresponding starting compounds. [table 3]
The LC-MS in the above table was measured using the measurement conditions (2). Reference Example 30 8-Methyl-2-(trifluoromethyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-one [Chemical 12]a) Preparation of 4-methyl-2-nitrophenyl trifluoromethanesulfonate (compound W3) A solution of 4-methyl-2-nitrophenol (2.0 g) in chloroform (26 mL) was cooled to 0 ° C. Triethylamine (5.4 mL) and trifluoromethanesulfonic anhydride (2.4 mL) were added and stirred at 0 ° C for 1 hour. Sodium hydrogencarbonate water was added to the reaction mixture at 0 ° C, and extracted with chloroform. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent of the organic layer after drying was evaporated under reduced pressure, and purified by silica gel chromatography (solvent solvent: hexane/ethyl acetate) to give the title compound (3.4 g). LC-MS ([M-H]-
/Rt(min)): 283/0.99 Determination conditions (2) b) Methyl 2-[(4-methyl-2-nitrophenyl)amino]-5-(trifluoromethyl)benzoate ( Preparation of Compound W4) In a solution of compound W3 (2.0 g) in toluene (68 mL), methyl 2-amino-5-(trifluoromethyl)benzoate (1.5 g), potassium carbonate (0.95 g), Triphenylphosphine (0.36 g) and tetrakis(triphenylphosphine)palladium(0) (0.79 g) were stirred under reflux for 2 hours. The reaction solution was returned to room temperature, water was added and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent of the organic layer after drying was evaporated under reduced pressure, and purified by silica gel chromatography (solvent solvent: hexane/ethyl acetate) to give the title compound (2.0 g). LC-MS ([M+H]+
/Rt(min)): 355/1.21 Determination conditions (2) c) Methyl 2-[(2-amino-4-methylphenyl)amino]-5-(trifluoromethyl)benzoate ( Compound W5) was prepared from compound W4 (2.0 g) in THF / MeOH / H2
Ammonium chloride (3.6 g) and iron (1.9 g) were added to a solution of O (3:2:1) (30 mL), and the mixture was stirred for 1 hour under reflux. After cooling the reaction mixture, it was filtered through Celite and washed with ethyl acetate. After the obtained filtrate was subjected to liquid separation extraction with ethyl acetate-water, the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. LC-MS ([M+H]+
/Rt(min)): 325/1.17 Determination conditions (2) d) 2-[(2-Amino-4-methylphenyl)amino]-5-(trifluoromethyl)benzoic acid (Compound W6 THF/H manufactured on compound W5 (1.8 g)2
Lithium hydroxide (1.6 g) was added to a solution of O (1:1) (30 mL), and stirred under heating and reflux for 2 hr. After cooling the reaction mixture, water was added thereto at 0 ° C, and adjusted to pH 5 with 1 mol/L hydrochloric acid, and then extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.6 g). LC-MS ([M+H]+
/Rt(min)): 311/0.98 Determination conditions (2) e) 8-Methyl-2-(trifluoromethyl)-5,10-dihydro-11H-dibenzo[b,e][1 , 4] Preparation of diazepine-11-one To a solution of compound W6 (1.6 g) in DMF (23 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbazide Amine hydrochloride (1.4 g) and 1-hydroxybenzotriazole (1.0 g) were stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent of the organic layer after drying was evaporated under reduced pressure, and purified by silica gel chromatography (solvent solvent: hexane/ethyl acetate) to give the title compound (0.41 g). LC-MS ([M+H]+
/Rt(min)): 293/0.89 Measurement conditions (2)Reference example 31 and 32
According to the method described in Reference Example 30, the corresponding compound was used to obtain the compound shown in the following table. [Table 4]
The LC-MS in the above table was measured using the measurement conditions (2). Reference Example 33 8-Chloro-11- pendantoxy-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine-2-carbonitrile [Chemical 13]a) 2-[(4-Chloro-2-nitrophenyl)amino]-5-cyanobenzoic acid (Compound W7) was prepared from 4-chloro-1-fluoro-2-nitrobenzene (0.50 g Methyl 2-amino-5-cyanobenzoate (0.50 g) and cesium carbonate (2.8 g) were added to a solution of DMF (2.8 mL) and stirred at 120 ° C for 4 hours. After cooling the reaction mixture, water was added thereto at 0 ° C, and adjusted to pH 5 with 1 mol/L hydrochloric acid, and then extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the dried organic layer was evaporated under reduced pressure to give the title compound (0.90 g). LC-MS ([M-H]-
/Rt(min)): 316/0.87 Determination conditions (2) b) 2-[(2-Amino-4-chlorophenyl)amino]-5-cyanobenzoic acid (Compound W8) manufactured in the compound W7 (0.90 g) in THF/MeOH/H2
Ammonium chloride (1.5 g) and iron (0.73 g) were added to a solution of O (3:2:1) (30 mL), and the mixture was stirred under reflux for 1 hour. After cooling the reaction mixture, it was filtered through Celite and washed with ethyl acetate. After the obtained filtrate was subjected to liquid separation extraction with ethyl acetate-water, the organic layer was washed with saturated brine. The title compound (0.82 g) was obtained as a crude material. LC-MS ([M+H]+
/Rt(min)): 288/0.84 Determination conditions (2) c) 8-Chloro-11-sideoxy-10,11-dihydro-5H-dibenzo[b,e][1,4] Preparation of azine-2-carbonitrile In a solution of compound W8 (0.82 g) in DMF (14 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Salt (0.60 g) and 1-hydroxybenzotriazole (0.42 g) were stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was washed with chloroform (5 mL) to give the title compound (0.25 g). LC-MS ([M+H]+
/Rt(min)): 270/0.71 Determination conditions (2) Reference Example 34 (6S)-1,6-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride [Chem. 14]a) (6S)-6-Methyl-4-[(trifluoromethanesulfonyl)oxy]-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and (2S)- Manufacture of 2-methyl-4-[(trifluoromethanesulfonyl)oxy]-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (Substance C) in (2S)- 2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (10 g) in THF (117 mL), 0.1 mol/L of lithium diisopropylamide at 0 ° C -THF solution (56 mL). After stirring at 0 ° C for 10 minutes, N-phenylbis(trifluoromethanesulfonimide) (22 g) was added at -78 °C. After stirring at -78 ° C for 10 minutes, it was further stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added at room temperature, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the dried organic layer was distilled off under reduced pressure, and then purified by silica gel column chromatography (solvent solvent; hexane/ethyl acetate) to obtain substance C (18 g, mixture of isomers) ).1
H-NMR (400 MHz, CDCl3
δ: 5.73, 5.69(s, 1H, isomer ratio=1:1), 4.65-4.24(m, 2H), 3.64-2.52(m, 2H), 2.21-2.02(m, 1H), 1.45(s, 9H), 1.21, 1.16(d, 3H, J=6.8 Hz, isomer ratio=1:1). b)(6S)-6-Methyl-1,2,3,6-tetrahydropyridin-4-yl Preparation of triflate and (2S)-2-methyl-1,2,3,6-tetrahydropyridin-4-yltrifluoromethanesulfonate (Substance D) in substance C (17 g) A 4 mol/L hydrogen chloride-ethyl acetate solution (61 mL) was added to the ethyl acetate solution (98 mL). After stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure. Saturated sodium hydrogencarbonate water was added to the obtained crude product, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the dried organic layer was distilled off under reduced pressure, whereby substance D (14 g, mixture of isomers) was obtained. LC-MS ([M+H]+
/Rt(min)): 246/0.76 Determination conditions (4) c) (6S)-1,6-Dimethyl-1,2,3,6-tetrahydropyridin-4-yltrifluoromethanesulfonate (Compound W11) Manufactured in a solution of material D (12 g) in MeOH (163 mL), EtOAc (EtOAc) After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Saturated sodium hydrogencarbonate water was added to the obtained crude product, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the dried organic layer was distilled off under reduced pressure, and then subjected to silica gel column chromatography (solvent solvent; chloroform/ethyl acetate) and NH.2
The compound was purified by a silica gel column chromatography (solvent solvent; chloroform/ethyl acetate), whereby Compound W11 (3.9 g) was obtained.1
H-NMR (400 MHz, CDCl3
) δ: 5.60 (s, 1H), 2.94-2.92 (m, 2H), 2.61-2.53 (m, 2H), 2.32-2.25 (m, 1H), 2.36 (s, 3H), 1.18 (d, 3H, J=6.7 Hz). d)(6S)-1,6-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Preparation of 2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (Reference Example 34) in a solution of compound W11 (3.9 g) in THF (51 mL). That is an alcohol ester) diborane (4.3 g), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride (0.62 g) and potassium acetate (4.5 g). After stirring at 80 ° C for 1 hour, it was cooled to room temperature. After the precipitate was removed by filtration through diatomaceous earth, the solvent was distilled off under reduced pressure. Diethyl ether was added to the crude product, and the precipitate was removed by filtration through celite, and the solvent was evaporated under reduced pressure. The obtained crude product (6.5 g) was dissolved in diethyl ether (40 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (4.0 mL) was added. The precipitated solid was filtered and washed with hexane to obtain Reference Example 34 (3.5 g). LC-MS ([M+H]+
/Rt(min)): 238/1.25 Determination conditions (4) Example 1 8-Chloro-2-fluoro-11-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -5H-dibenzo[b,e][1,4]diazepine [Chemical 15]a) 8,11-Dichloro-2-fluoro-5H-dibenzo[b,e][1,4]diazepine (Compound W9), which was produced from the compound of Reference Example 1 (1.0 g) of toluene ( 20 mL) solution was added with N,N-dimethylaniline (2.3 g) and phosphorus oxychloride (1.8 g). After stirring at 95 ° C for 2 hours, it was cooled. To the reaction mixture were added THF and aq. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. After the solvent of the dried organic layer was distilled off under reduced pressure, N,N-dimethylaniline was removed by a silica gel column chromatography (solvent solvent; hexane/ethyl acetate) to obtain compound W9 (0.9 g). . b) 8-Chloro-2-fluoro-11-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-dibenzo[b,e][1,4] Preparation of diazepine (Example 1) In a solution of compound W9 (0.9 g) in THF/water (4/1) (50 mL), 1-methyl-4-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.0 g), potassium carbonate (1.6 g) and tetrakis (triphenyl) Phenylphosphine) palladium (0) (0.88 g). After stirring at 75 ° C for 1 hour, it was cooled. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the dried organic layer was distilled off under reduced pressure, and then subjected to silica gel column chromatography (solvent solvent; chloroform/methanol) and NH.2
The title compound (0.70 g) was obtained. LC-MS ([M+H]+
/Rt(min)): 342/0.67 Measurement conditions (1)1
H-NMR (400 MHz, CDCl3
) δ: 7.20 (d, 1H, J = 2.4 Hz), 7.00-6.92 (m, 3H), 6.72-6.68 (m, 1H), 6.61 (d, 1H, J = 8.0 Hz), 6.09-6.05 (m , 1H), 4.78(s, 1H), 3.15-3.11(m, 2H), 2.74-2.70(m, 2H), 2.64(t, 2H, J=5.2 Hz), 2.40(s, 3H). 2 to 6 According to the method described in Example 1, the compounds of Examples 2 to 6 were obtained by using the compound of the corresponding Reference Example and the starting compound. [table 5]The LC-MS in the above table was measured using the measurement conditions (1). Example 7 and Example 8 8-chloro-2-fluoro-11-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-dibenzo[b,e] [1,4]diazepine (Example 7) 8-chloro-2-fluoro-11-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-diphenyl And [b,e][1,4]diazepine (Example 8) [Chemical 16]a) 4-(8-chloro-2-fluoro-5H-dibenzo[b,e][1,4]diazepine-11-yl)-6-methyl-3,6-dihydropyridine- 1(2H)-carboxylic acid tert-butyl ester and 4-(8-chloro-2-fluoro-5H-dibenzo[b,e][1,4]diazepine-11-yl)-2-yl Preparation of benzyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (substance B) was added to a solution of compound W9 (1.1 g) in THF/water (4/1) (50 mL) Reference compound 9 (mixture of isomers) (1.3 g), potassium carbonate (1.7 g) and tetrakis(triphenylphosphine)palladium(0) (0.92 g). After stirring at 75 ° C for 1 hour, it was cooled, and water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the dried organic layer was distilled off under reduced pressure, and then purified by silica gel column chromatography (solvent solvent; hexane/ethyl acetate) to obtain substance B (1.0 g, mixture of isomers) ). LC-MS ([M+H]+
/Rt(min)): 442/1.45 Determination conditions (1) b) 8-Chloro-2-fluoro-11-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)- 5H-dibenzo[b,e][1,4]diazepine (Example 7) and 8-chloro-2-fluoro-11-(2-methyl-1,2,3,6-tetrahydrol Pyridin-4-yl)-5H-dibenzo[b,e][1,4]diazepine (Example 8) was added to a solution of material B (0.17 g) in dichloromethane (4 mL) Trifluoroacetic acid (1 mL) was stirred at room temperature for 1 hour. Saturated sodium hydrogencarbonate water was added to the reaction mixture cooled in ice-bath, and extracted with chloroform. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. After the solvent of the dried organic layer was distilled off under reduced pressure, the obtained residue was subjected to reverse phase refining by ODS (octadecylsilyl, octadecyl decyl) column (0.05% aqueous solution of trifluoroacetic acid: acetonitrile). The TFA salt was freed by a liquid separation operation using chloroform-saturated sodium hydrogencarbonate, whereby the compound of Example 7 (10 mg) and the compound of Example 8 (10 mg) were obtained. 8-chloro-2-fluoro-11-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-dibenzo[b,e][1,4]diazepine呯 (Example 7): LC-MS ([M+H]+
/Rt(min)): 342/0.73 Measurement conditions (1)1
H-NMR (400 MHz, CDCl3
) δ: 7.19 (d, 1H, J = 2.3 Hz), 7.00-6.89 (m, 3H), 6.73-6.70 (m, 1H), 6.62 (d, 1H, 8.3 Hz), 5.98 (s, 1H), 4.80(s, 1H), 3.64-3.62(m, 1H), 3.28-3.23(m, 1H), 2.98-2.91(m, 1H), 2.61-2.46(m, 2H), 1.19(d, 3H, J =6.9 Hz). 8-Chloro-2-fluoro-11-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-dibenzo[b,e][1 , 4] diazepine (Example 8): LC-MS ([M+H]+
/Rt(min)): 342/0.75 Measurement conditions (1)1
H-NMR (400 MHz, CDCl3
) δ: 7.20 (d, 1H, J = 2.3 Hz), 7.01-6.89 (m, 3H), 6.73-6.69 (m, 1H), 6.61 (d, 1H, J = 8.7 Hz), 6.12 (s, 1H) ), 4.79(s, 1H), 3.65-3.62(m, 2H), 2.98-2.89(m, 1H), 2.84-2.79(m, 1H), 2.16-2.06(m, 1H), 1.25(d, 3H) , J = 6.4 Hz). Examples 9 to 16 According to the methods described in Example 7 and Example 8, the compounds of Examples 9 to 16 were obtained by using the compound of the corresponding Reference Example and the starting compound. [Table 6]The LC-MS in the above table was measured using the measurement conditions (1). Example 17 and Example 18 8-chloro-11-(1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro-5H-dibenzo[b] , e][1,4]diazepine (Example 17) 8-chloro-11-(1,2-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2- Fluoro-5H-dibenzo[b,e][1,4]diazepine (Example 18) [Chem. 17]To a solution of the mixture of Example 7 and Example 8 (1:1) (1.0 g) in methanol (20 mL) was added 37% formaldehyde solution (0.73 g) and magnesium sulfate (5.0 g), and stirred at 50 ° C hour. The reaction solution was cooled in an ice bath, and sodium borohydride (0.68 g) was slowly added. After stirring at room temperature for 1 hour, the solid matter was removed by filtration through celite. Water was added to the filtrate, and extraction was performed with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. After the solvent of the dried organic layer is distilled off under reduced pressure, by NH2
The compound of Example 17 (0.20 g) and the compound of Example 18 (0.20 g) were obtained by the purification of the column chromatography (solvent solvent; hexane/ethyl acetate). 8-Chloro-11-(1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro-5H-dibenzo[b,e][1,4 Diazoxide (Example 17):1
H-NMR (400 MHz, CDCl3
) δ: 7.20 (d, 1H, J = 2.3 Hz), 7.01-6.89 (m, 3H), 6.72-6.69 (m, 1H), 6.61 (d, 1H, J = 8.7 Hz), 5.87 (s, 1H) ), 4.78(s, 1H), 3.01-2.88(m, 2H), 2.73-2.43(m, 3H), 2.41(s, 3H), 1.19(d, 3H, J=6.8 Hz). LC-MS( [M+H]+
/Rt(min)): 356/0.71 Determination conditions (1) 8-Chloro-11-(1,2-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro -5H-dibenzo[b,e][1,4]diazepine (Example 18):1
H-NMR (400 MHz, CDCl3
) δ: 7.20 (d, 1H, J = 2.8 Hz), 7.00-6.92 (m, 3H), 6.72-6.68 (m, 1H), 6.61 (d, 1H, J = 8.7 Hz), 6.05 (s, 1H) ), 4.77(s, 1H), 3.49-3.39(m, 2H), 3.06-2.22(m, 3H), 2.36(s, 3H), 1.18(d, 3H, J=4.8 Hz). LC-MS( [M+H]+
/Rt(min)): 356/0.73 Measurement conditions (1) Examples 19 to 21 According to the methods described in Example 17 and Example 18, the compounds of the corresponding reference examples and the starting compounds were used to obtain Examples 19-21. Compound. [Table 7]The LC-MS in the above table was measured using the measurement conditions (1). Example 22 8-Chloro-2-fluoro-11-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-dibenzo[b,e][1,4 Diazoxide [Chemical 18]a) 8-Chloro-2-fluoro-11-(pyridin-4-yl)-5H-dibenzo[b,e][1,4]diazepine (W10) manufactured from compound W9 (107 mg) Pyridine-4-boronic acid (94 mg), potassium carbonate (0.16 g) and tetrakis(triphenylphosphine)palladium(0) (88 mg) were added to a solution of THF/water (4/1) (5 mL). After stirring at 75 ° C for 1 hour, water was added to the reaction mixture cooled in an ice bath, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the dried organic layer was distilled off under reduced pressure, and then subjected to silica gel column chromatography (solvent solvent; chloroform/methanol) and NH.2
This was purified by a silica gel column chromatography (solvent solvent; hexane/ethyl acetate), whereby Compound W10 (45 mg) was obtained. LC-MS ([M+H]+
/Rt(min)): 324/1.03 Determination conditions (1) b) 8-Chloro-2-fluoro-11-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)- 5H-Dibenzo[b,e][1,4]diazepine (Example 22) was added to a solution of compound W10 (15 mg) in acetonitrile (0.42 mL). After stirring at 60 ° C for 1 hour, the reaction solution was concentrated. The residue obtained was dissolved in methanol (0.20 mL), and sodium borohydride (16 mg) was added at 0 °C. After stirring at room temperature for 1 hour, water was added to the reaction mixture and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over sodium sulfate. The solvent of the dried organic layer was distilled off under reduced pressure, and then subjected to silica gel column chromatography (solvent solvent; chloroform/methanol) and NH.2
The title compound (10 mg) was obtained by chromatography eluting elution elution LC-MS ([M+H]+
/Rt(min)): 342/0.67 Measurement conditions (1)1
H-NMR (400 MHz, CDCl3
) δ: 7.20 (d, 1H, J = 2.4 Hz), 7.00-6.92 (m, 3H), 6.72-6.68 (m, 1H), 6.61 (d, 1H, J = 8.0 Hz), 6.09-6.05 (m , 1H), 4.78(s, 1H), 3.15-3.11(m, 2H), 2.74-2.70(m, 2H), 2.64(t, 2H, J=5.2 Hz), 2.40(s, 3H). 23 to 31 According to the method described in Example 22, the compounds of Examples 23 to 31 were obtained by using the compound of the corresponding Reference Example and the starting compound. [Table 8][Table 9]The LC-MS in the above table was measured using the measurement conditions (1). Examples 32 to 89 According to the methods described in Example 1, Example 7, and Example 8, Example 17 and Example 18, the compounds of Examples 32 to 89 were obtained by using the compound of the corresponding Reference Example and the starting compound. [Table 10][Table 11][Table 12][Table 13][Table 14][Table 15][Table 16][Table 17][Table 18][Table 19]Test Example Hereinafter, the pharmacological test results of the compound of the present invention will be described, and the pharmacological action of the compound will be described. However, the present invention is not limited to the test examples. Test Example 1: For human type D1
Receptor, human D2
Receptor, human 5-HT2A
Receptor antagonist activity evaluation test for human type D1
Receptor, human D2
Receptor, human 5-HT2A
The antagonist activity of the receptor was measured using intracellular calcium concentration as an index. Temporarily presenting aequorin, Gα16 protein, and each receptor in CHO-K1 cells (Chinese hamster ovary), seeded in 384-well plates, in CO2
Incubate overnight at 37 ° C in an incubator. After the addition of coelenterazine, FDSS (manufactured by Hamamatsu Photonics) was added, and a DMSO suspension of the compound of the present invention was added, followed by addition of dopamine (final concentration of 100 nmol/L) or serotonin (final concentration of 30 nmol/L) to measure luminescence. The change in quantity. The antagonist activity was calculated by setting the amount of luminescence of the well to which only DMSO was added to 100% inhibition, and the compound of the present invention 1 μmol/L when the amount of luminescence of the well to which only dopamine or serotonin was added was 0% inhibition. The inhibition rate below. Further, the concentration in the following table indicates the inhibition rate at the concentration described (for example, the expression of [email protected] μmol/L indicates that the inhibition rate at 0.1 μmol/L is 58%). Further, clozapine was used as a comparative substance as a comparative example. The results are shown in the table below. [Table 20]
[Table 21]
[Table 22]
Test Example 2: Capture analysis of dansyl glutathione (dGSH) The compound of the present invention was metabolized in liver microsomes, and the reaction of the produced metabolite was detected by reaction with dansole glutathione (dGSH). Metabolites are quantified. The metabolic reaction system was performed using a screening robot (manufactured by Tecan Co., Ltd.), and the metabolite-dGSH conjugate concentration was measured using a UPLC (ultra performance liquid chromatography) system (manufactured by Waters Co., Ltd.). (Presolution Preparation) The compound of the present invention was dissolved in DMSO to prepare a 10 mmol/L test substance solution. Further, clozapine was used as a comparative substance as a comparative example. A microsomal solution was prepared by mixing 7.6 mL of potassium phosphate buffer (500 mmol/L, pH 7.4), human liver microsomes (manufactured by Xenotech, 20 mg protein/mL), 1.9 mL, and 1.27 mL of pure water. A microsome (dGSH(-)) solution was prepared by adding 0.67 mL of pure water to 3.78 mL of the microsome solution. A microsome (dGSH(+)) solution was prepared by adding 1.14 mL of dGSH solution (20 mmol/L) to 6.48 mL of the microsome solution. A cofactor solution was prepared by dissolving 80.9 mg of NADPH (nicotinamide adenine dinucleotide phosphate) in 30 mL of pure water. A reaction stop solution was prepared by dissolving 33 mg of tris(2-carboxyethyl)phosphine (TECP, Tris(2-carboxyethyl)phosphin) in 115 mL of methanol. (Reaction) 12 μL of the test substance solution was mixed with 388 μL of pure water, and dispensed to 6 holes per 50 μL in a 96-well plate. The above 6 wells were divided into three groups of two wells, and were designated as "reaction group", "unreacted group", and "dGSH unadded group". A microsome (dGSH(+)) solution was added to 50 μL of the "reaction group" and "unreacted group", and a microsome (dGSH(-)) solution was added to 50 μL of the "dGSH unadded group". Cofactor solution was added to 50 μL of "reaction group" and "dGSH unadded group", and pure water was added to 50 μL of "unreacted group". After incubation at 37 ° C for 60 minutes, the reaction was terminated by adding a reaction stop solution per 450 μL. Add pure water to 50 μL of the "reaction group" and "dGSH unadded group", add a cofactor solution every 50 μL in the "unreacted group", and cool the plate at -20 ° C for 1 hour. , centrifuge (4000 rpm, 10 minutes). The supernatant was recovered in another dish for analysis. (Analysis) Using a fluorescent detection UPLC system (manufactured by Waters Co., Ltd.), "reaction group", "unreacted group", and "dGSH unadded group" were analyzed under the following conditions. Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 10 mm) Dissolution solvent: A solution 0.2% formic acid / 40% methanol B solution 0.2% formic acid / methanol gradient: B solution, 0% (0 Min)→83.3%(9.33 min)→83.3%(10.63 min)→0%(10.64 min)→0%(13 min) The fluorescence intensity varies depending on the composition of the organic solvent, so it is composed of the organic solvent at the time of dissolution. Make corrections. The metabolite-dGSH conjugate concentration of the "reaction group" was calculated by subtracting the fluorescence peaks detected in the "unreacted group" and "dGSH unadded group" from the fluorescence peak detected in the "reaction group". . By measuring the concentration of the metabolite-dGSH conjugate of the "reaction group", the risk of the reactive metabolite of the test substance can be evaluated. The results of the concentration of the metabolite-dGSH conjugate of the "reaction group" of clozapine and the compound of the present invention are shown in the following table. [Table 23]
[Table 24]
Further, based on the analysis result of Test Example 2, the fluorescence peak detected in the "unreacted group" was subtracted from the fluorescence peak detected in the "dGSH unadded group", thereby calculating the dGSH binding of the "unreacted group". Concentration of matter. By measuring the concentration of the dGSH conjugate of the "unreacted group", the covalent bonding property of the test substance considered to be related to cytotoxicity or immunotoxicity can be evaluated. The results of the dGSH conjugate concentration of the "unreacted group" of the compound of the present invention are shown in the following table. [Table 25]
Test Example 3: Human liver microsome metabolic stability test In this test, the stability of the test substance to human liver microsome metabolism can be evaluated. The human liver microsomal stability (MS) of the compounds of the present invention was evaluated by the following method. The human liver particle system uses the manufacturer of Xenontech. Human liver microsomes, NADPH, and test substances were mixed in a 125 mmol/L phosphate buffer (pH 7.4) to have the following concentrations, and cultured at 37 ° C for 30 minutes.・Human liver microsomes: 0.1 mg/mL ・NAPDH: 3.2 mmol/L ・Substance: 0.1 μmol/L The residual rate of the test substance in the sample after 30 minutes by LC-MS, according to the following formula Calculate the stability of the test substance to human liver microsome metabolism. Stability to human liver microsome metabolism (mL/min/mg protein) = -LN (residual ratio) / 30/0.1 The results are shown in the table below. [Table 26]
Test Example 4: Rat brain transition test In this test, the intracerebral mobility of the compound of the present invention can be evaluated. For the SD rats of 7 weeks, the compound of the present invention was administered subcutaneously by a 0.01 mol/L hydrochloric acid aqueous solution, and plasma and brain were collected 1 hour after the administration, and the plasma and brain drug concentrations were measured by LC-MS. Serum and brain protein binding rates of the compounds of the invention were determined using equilibrium dialysis. Kp, uu, brain (brain/plasma unconjugated drug concentration ratio) can be calculated by applying the plasma and intracerebral compound concentration obtained by the above test and the serum and intracerebral protein binding rate to the following formula. . Kp, uu, brain=(concentration of compound in brain × (100-intraceramic protein binding rate (%)) / 100) / (concentration of compound in plasma × (100 - serum protein binding rate (%)) / 100) The results are shown in the table below. [Table 27]
Test Example 5: Evaluation of Positive Symptoms by Induction of Hyperactivity of Rat Methamphetamine The exercise hyperactivity caused by administration of methamphetamine to rats was used as schizophrenia. The evaluation system for positive symptoms can evaluate the inhibitory effect when the compound of the present invention is administered. After administration of the compound of the present invention to rats of 6 to 10 weeks, the amount of exercise from 90 minutes after the administration of methamphetamine was measured. SuperMex (Muromachi Machinery Co., Ltd.) was used for the measurement. The inhibition rate when the amount of exercise in which the solvent was administered to the group was set to 100% was calculated. Test Example 6: Evaluation of the effectiveness of patients with schizophrenia In the clinical, as a criterion for evaluating the psychotic symptoms of schizophrenia, PANSS (Positive and Negative Syndrome Scale) and CGI-S (CGI-S) were used. Clinical Global Impression Severity scale, etc. After administration of the compound of the present invention for 6 to 24 weeks, the effectiveness was evaluated using the above evaluation criteria. Test Example 7: Cyano capture assay In this test, a reactive metabolite not captured by sulforaphane glutathione was detected. Metabolizing a compound of the invention in human liver microsomes with radioactive potassium cyanide (K14
CN) The reaction is carried out, whereby the reactive metabolite is detected and quantified. The human liver microparticle system was subjected to a reaction at 37 ° C for 60 minutes under the following conditions using a manufacturer of Xenontech. Concentration conditions ・Phosphate buffer (pH 7.4): 100 mM ・Human liver microsomes: 1 mg/mL ・K14
CN: 0.1 mM ・Test substance: 50 μM ・NADPH: 0 mM or 1 mM will be combined with K14
The reactive metabolite in which the CN is reacted is fractionated by solid phase extraction, and the radioactive concentration is measured using a liquid scintillation counter. The generation gap of the reactive metabolite was calculated by subtracting the measurement value obtained under the condition that NADPH was not added from the measurement value obtained under the condition of adding NADPH. Test Example 8: For human 5-HT2C
Receptor, human histamine H1
Receptor (hereinafter referred to as H1
Receptor), human muscarinic M1
Receptor (hereinafter referred to as M1
Receptor), human muscarinic M2
Receptor (hereinafter referred to as M2
Receptor), human muscarinic M3
Receptor (hereinafter referred to as M3
Receptor) and human muscarinic M4
Receptor (hereinafter referred to as M4
Receptor) antagonist activity evaluation test for human 5-HT2C
Receptor, human H1
Receptor, human M1
Receptor, human M2
Receptor, human M3
Receptor and human M4
The antagonist activity of the receptor was measured using intracellular calcium concentration as an index. Temporarily presenting aequorin, Gα16 protein and each receptor in CHO-K1 cells (Chinese hamster ovary), seeded in 384-well plates, in CO2
Incubate overnight at 37 ° C in an incubator. After the addition of coelenterazine, a DMSO suspension of the compound of the present invention was added using FDSS (manufactured by Hamamatsu Photonics Co., Ltd.), and then the corresponding ligand shown in the following table was added, and the change in the amount of luminescence was measured. The ligands used in the evaluation of the antagonist activity of each receptor and the concentrations thereof used are shown in the table below. [Table 28]
The antagonist activity was such that the amount of luminescence of the well to which only DMSO was added was 100% inhibition, and the amount of luminescence of the well to which only the corresponding ligand was added was set to 0% inhibition, and the concentration of the compound of the present invention was calculated to be 1 μmol/L. Or inhibition rate in the case of 0.1 μmol/L. [Table 29]
Test Example 9: For human 5-HT2A
Receptor, human D1
Receptor, human D2
Receptor, human 5-HT2C
Receptor, human H1
Receptor, human M1
Receptor, human M2
Receptor, human M3
Receptor and human M4
Evaluation of binding activity of the receptor In this test, the compound of the present invention can be assayed for human 5-HT2A
Receptor, human D1
Receptor, human D2
Receptor, human 5-HT2C
Receptor, human H1
Receptor, human M1
Receptor, human M2
Receptor, human M3
Receptor and human M4
The binding affinity of the receptor. Using a CHO cell membrane component or a CHO-K1 cell membrane component or the like which exhibits such receptors, in a binding evaluation test, a test compound dissolved in DMSO, a sample of various receptor membranes diluted with a buffer, and The receptors are mixed with RI (Radio Isotope) labeled ligands and incubated at room temperature for 30 minutes or 60 minutes, respectively. As an RI-labeled ligand for a receptor, it can be appropriately selected according to test conditions, etc., and can be used for 5-HT.2A
The receptor uses [3H] ketanserin (Ketanserin), for D2
The receptor uses [3H] Spiperone, for D1
The receptor used [3H]SCH23390. Non-specific binding to receptors based on 5-HT2A
The receptor exists in Mianserin, for D2
Receptor in the presence of dopamine, for D1
The receptor is determined by a competitive binding assay such as SCH23390. After measuring the radioactivity bound to the receptor using a liquid scintillation counter, the 50% inhibitory concentration was calculated, and the Ki value was evaluated from the dissociation constant and the substrate concentration calculated from the saturation binding test, and used as the binding affinity. In addition to this, about the human 5-HT2C
Receptor, human H1
Receptor, human M1
Receptor, human M2
Receptor, human M3
Receptor and human M4
The binding affinity of the receptor can also be determined according to the above method. As the RI-labeled ligand for the receptors, it can be appropriately selected according to the test conditions and the like, for example, for human 5-HT2C
The receptor uses [3H] Mesulergine for human H1
The receptor uses [3H] Pyrilamine for human M1
Receptor, human M2
Receptor, human M3
Receptor and human M4
As the receptor, [3H]N-methylethylpolamine or the like is used. Furthermore, the non-specific binding of these receptors is based on human 5-HT2C
The receptor exists in Mianserin, targeting human H1
Receptor Pyrilamine for human M1
Receptor, human M2
Receptor, human M3
Receptor and human M4
The receptor is determined by a competitive binding assay such as Atropine. [Industrial Applicability] The compound of the present invention is due to dopamine D1
Receptor, dopamine D2
Receptor and serotonin 5-HT2A
The receptor exhibits antagonism and is therefore useful as a therapeutic and/or prophylactic agent for central nervous system diseases.