JP2005298343A - Benzodiazepine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound having excellent inhibitory activity against activated blood coagulation factor X. <P>SOLUTION: The benzodiazepine derivative which is represented by the formula, its analog or its pharmaceutically acceptable salt is obtained. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

（１）
[一般式（１）中、
環Aは、炭素数６〜１０のアリール基、炭素数３〜１０のヘテロアリール基又は炭素数４〜１０の環状アルキル基のいずれかを表し、
【０００６】
R1は、水素原子、ハロゲノ基、置換基を有してもよいヒドロキシル基、炭素数１〜１０のアルコキシル基、ニトロ基、ホルミル基、トリフルオロメチル基、トリフルオロメトキシ基、トリフルオロメタンスルホニルオキシ基、メチレンジオキシ基、カルバモイル基、チオカルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、シアノ基、炭素数１〜６のモノもしくはジアルキルアミノ基、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数３〜７のヒドロキシカルボニルアルケニル基、炭素数４〜８のアルコキシカルボニルアルケニル基、ホスホノ基、炭素数２〜９のジアルコキシホスホリル基、炭素数１〜４のモノアルコキシヒドロキシホスホリル基、炭素数１〜６のアルキルチオ基、炭素数１〜６のアルキルスルホニル基、アミノスルホニル基、炭素数２〜８のモノもしくはジアルキルアミノスルホニル基、置換基を有してもよい炭素数１〜６のアルキル基、置換基を有してもよい炭素数６〜１０のアリール基、置換基を有してもよい炭素数１〜１０のヘテロアリール基、置換基を有してもよい炭素数６〜１０のアリールスルホニル基、置換基を有してもよい炭素数４〜１０のヘテロアリールスルホニル基、置換基を有してもよい炭素数６〜１０のアリールチオ基、置換基を有してもよい炭素数４〜１０のヘテロアリールチオ基、置換基を有してもよい炭素数１〜８のアシル基、置換基を有してもよい炭素数６〜１０のアリール基で置換された炭素数１〜６のアルキル基、置換基を有してもよい炭素数５〜１０のヘテロアリール基で置換された炭素数１〜６のアルキル基、置換基を有してもよい炭素数１〜６のアルキル基で置換された炭素数６〜１０のアリール基、置換基を有してもよい炭素数１〜６のアルキル基で置換された炭素数５〜１０のヘテロアリール基、炭素数１〜６のモノもしくはジアルキルアミノ基、置換基を有してもよいアミノ基、置換基を有してもよい炭素数１〜７のアミノアルキル基、置換基を有してもよいピロリジン基、置換基を有してもよいピロリジルオキシ基、置換基を有してもよいピペリジン基、置換基を有してもよいピペリジルオキシ基、置換基を有してもよいピペラジン基、置換基を有してもよいピペラジンカルボニル基、置換基を有してもよいアミジノ基又は置換基を有してもよいグアニジノ基のいずれかを表し、
【０００７】
ここで、R1が置換基を有する場合の置換基は、炭素数１〜６のアルキル基、ハロゲノ基、ヒドロキシル基、炭素数１〜１０のアルコキシル基、トリフルオロメチル基、トリフルオロメトキシ基、カルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、アミノ基、炭素数１〜７のアミノアルキル基、炭素数１〜６のモノもしくはジアルキルアミノ基、アミジノ基、炭素数２〜７のモノもしくはジアルキルアミジノ基、炭素数４〜７のトリアルキルアミジノ基、炭素数５〜８のテトラアルキルアミジノ基、グアニジノ基、炭素数３〜８のジアルキルグアニジノ基、炭素数４〜９のトリアルキルグアニジノ基、炭素数６〜１０のアリ−ル基、炭素数１〜１０のヘテロアリ−ル基、炭素数６〜１０のアリール基で置換された炭素数１〜６のアルキル基、炭素数５〜１０のヘテロアリール基で置換された炭素数１〜６のアルキル基、炭素数１〜６のアルキル基で置換された炭素数６〜１０のアリール基、炭素数１〜６のアルキル基で置換された炭素数５〜１０のヘテロアリール基、炭素数６〜１０のアリ−ルスルホニル基、炭素数４〜１０のヘテロアリ−ルスルホニル基、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、窒素、酸素及び硫黄のいずれかから選ばれる１つ以上の複素原子を含む、炭素数１〜６のアルキル基で置換されていてもよい炭素数１〜６の炭素環、窒素、酸素及び硫黄のいずれかから選ばれる１つ以上の複素原子を含む、炭素数１〜６のアルキル基で置換されていてもよい炭素数１〜６の炭素環で置換されたカルボニル基、炭素数７〜１０のイミノアルキルピペラジンカルボニル基、ピペリジルオキシ基、炭素数６〜１０のアルキルピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、ピロリジルオキシ基、炭素数６〜１０のアルキルピロリジルオキシ基、炭素数７〜１０のイミノアルキルピロリジルオキシ基、メチレンジオキシ基、シアノ基、炭素数２〜７のイミノアルキル基、炭素数１〜８のアシル基、ホスホノ基、炭素数２〜９のジアルコキシホスホリル基、炭素数１〜４のモノアルコキシヒドロキシホスホリル基、炭素数１〜６のアルキルスルホニル基、アミノスルホニル基又は炭素数２〜８のジアルキルアミノスルホニル基のいずれかを表し、
【０００８】
環Bは、炭素数６〜１０のアリール基、炭素数３〜１０のヘテロアリール基のいずれかを表し、
環Cは、少なくとも１つ以上の窒素原子を含む炭素数２〜８の非芳香族炭素環を表し、酸素及び／又は硫黄から選ばれるヘテロ原子を一つ以上含んでいても良く、ただし、ピロリジル基、ピペリジル基又はピペラジニル基を除く、
【０００９】
R2は、水素原子、炭素数１〜６のアルキル基、ハロゲノ基、ヒドロキシル基、炭素数１〜１０のヒドロキシアルキル基、炭素数１〜１０のアルコキシル基、炭素数１〜１０のアルコキシアルキル基、ニトロ基、ホルミル基、トリフルオロメトキシ基、トリフルオロメチル基、カルバモイル基、チオカルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、アミノ基、炭素数１〜６のモノもしくはジアルキルアミノ基、炭素数１〜９のアミノアルキル基、炭素数２〜９のモノもしくはジアルキルアミノアルキル基、アミジノ基、炭素数２〜７のモノもしくはジアルキルアミジノ基、炭素数４〜７のトリアルキルアミジノ基、炭素数５〜８のテトラアルキルアミジノ基、グアニジノ基、炭素数３〜８のジアルキルグアニジノ基、炭素数４〜９のトリアルキルグアニジノ基、メチレンジオキシ基、シアノ基、炭素数２〜７のイミノアルキル基、炭素数１〜８のアシル基、ピペリジルオキシ基、炭素数６〜１０のアルキルピペリジルオキシ基、炭素数６〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、ピロリジルオキシ基、炭素数５〜９のアルキルピロリジルオキシ基、炭素数５〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、ピロリジン基、炭素数５〜９のアルキルピロリジン基、炭素数５〜９のイミノアルキルピロリジン基、ピぺリジン基、炭素数６〜１０のアルキルピぺリジン基、炭素数６〜１０のイミノアルキルピぺリジン基、ピペラジン基、炭素数５〜１３のアルキルピペラジン基、炭素数６〜９のイミノアルキルピペラジン基、炭素数６〜１０のアリ−ル基、炭素数１〜１０のヘテロアリ−ル基、炭素数６〜１０のアリ−ルスルホニル基、炭素数４〜１０のヘテロアリ−ルスルホニル基、炭素数７〜１０のイミノアルキルピペラジンカルボニル基、炭素数６〜１０のアルキルピペラジンカルボニル基、ピペラジンスルホニル基、炭素数５〜９のアルキルピペラジンスルホニル基、炭素数６〜９のイミノアルキルピペラジンスルホニル基、炭素数１〜８アルキルスルホニル基、アミノスルホニル基、炭素数２〜８モノもしくはジアルキルアミノスルホニル基、炭素数６〜９のピペリジルアルキル基又は炭素数８〜１２のイミノアルミルピペリジルアルキル基のいずれかを表し、
【００１０】
R3は、水素原子、ハロゲノ基、ヒドロキシル基、炭素数１〜１０のアルコキシル基、ニトロ基、ホルミル基、トリフルオロメチル基、トリフルオロメトキシ基、カルバモイル基、チオカルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、メチレンジオキシ基、シアノ基、炭素数２〜７のイミノアルキル基、炭素数１〜８のアシル基、炭素数２〜７のアルコキシカルボニル基、ピペリジルオキシ基、炭素数６〜１０のイミノアルキルピペリジルオキシ基、炭素数５〜１０のアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、ピロリジルオキシ基、炭素数５〜９のイミノアルキルピロリジルオキシ基、炭素数５〜１０のアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、炭素数６〜１０のアリ−ルスルホニル基、炭素数４〜１０のヘテロアリ−ルスルホニル基、炭素数７〜１０のイミノアルキルピペラジンカルボニル基、ピペラジンスルホニル基、炭素数６〜９のイミノアルキルピペラジンスルホニル基、置換基を有してもよい炭素数１〜６のアルキル基、炭素数１〜６のモノもしくはジアルキルアミノ基、置換基を有してもよいアミノ基、置換基を有してもよい炭素数１〜９のアミノアルキル基、置換基を有してもよいピロリジン基、置換基を有してもよいピペリジル基、置換基を有してもよいピペラジン基、置換基を有してもよい炭素数６〜１０のアリール基、置換基を有してもよい炭素数１〜１０のヘテロアリール基、置換基を有してもよい炭素数１〜６のアルキル基で置換された炭素数６〜１０のアリール基、置換基を有してもよい炭素数１〜６のアルキル基で置換された炭素数５〜１０のヘテロアリール基、置換基を有してもよい炭素数６〜１０のアリール基で置換された炭素数１〜６のアルキル基、置換基を有してもよい炭素数５〜１０のヘテロアリール基で置換された炭素数１〜６のアルキル基、置換基を有してもよいアミジノ基、置換基を有してもよいグアニジノ基、炭素数６〜９のピペリジルアルキル基又は炭素数８〜１２のイミノアルミルピペリジルアルキル基のいずれかを表し、
【００１１】
R3が置換基を有する場合の置換基は、炭素数１〜６のアルキル基、ハロゲノ基、ヒドロキシル基、炭素数１〜１０のヒドロキシアルキル基、炭素数１〜１０のアルコキシル基、炭素数１〜１０のアルコキシアルキル基、ニトロ基、ホルミル基、トリフルオロメトキシ基、トリフルオロメチル基、カルバモイル基、チオカルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、アミノ基、炭素数１〜６のモノもしくはジアルキルアミノ基、炭素数１〜９のアミノアルキル基、炭素数２〜９のモノもしくはジアルキルアミノアルキル基、アミジノ基、炭素数２〜７のモノもしくはジアルキルアミジノ基、炭素数４〜７のトリアルキルアミジノ基、炭素数５〜８のテトラアルキルアミジノ基、グアニジノ基、炭素数３〜８のジアルキルグアニジノ基、炭素数４〜９のトリアルキルグアニジノ基、メチレンジオキシ基、シアノ基、炭素数２〜７のイミノアルキル基、炭素数１〜８のアシル基、ピペリジルオキシ基、炭素数６〜１０のアルキルピペリジルオキシ基、炭素数６〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、ピロリジルオキシ基、炭素数５〜９のアルキルピロリジルオキシ基、炭素数５〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、ピロリジン基、炭素数５〜９のアルキルピロリジン基、炭素数５〜９のイミノアルキルピロリジン基、ピぺリジン基、炭素数６〜１０のアルキルピぺリジン基、炭素数６〜１０のイミノアルキルピぺリジン基、ピペラジン基、炭素数５〜１３のアルキルピペラジン基、炭素数６〜９のイミノアルキルピペラジン基、炭素数６〜１０のアリ−ル基、炭素数１〜１０のヘテロアリ−ル基、炭素数６〜１０のアリ−ルスルホニル基、炭素数４〜１０のヘテロアリ−ルスルホニル基、炭素数７〜１０のイミノアルキルピペラジンカルボニル基、炭素数６〜１０のアルキルピペラジンカルボニル基、ピペラジンスルホニル基、炭素数５〜９のアルキルピペラジンスルホニル基、炭素数６〜９のイミノアルキルピペラジンスルホニル基、炭素数１〜８アルキルスルホニル基、アミノスルホニル基又は炭素数２〜８モノもしくはジアルキルアミノスルホニル基のいずれかを表し、
【００１２】
R4,R5,R6,R7,R8及びR9は、各々同じでも異なってもよく、水素原子、炭素数１〜６のアルキル基、ハロゲノ基、オキソ基、ヒドロキシル基、炭素数１〜１０のヒドロキシアルキル基、炭素数１〜１０のアルコキシル基、炭素数１〜１０のアルコキシアルキル基、ニトロ基、トリフルオロメトキシ基、トリフルオロメチル基、アミノ基、炭素数１〜６のモノもしくはジアルキルアミノ基、炭素数１〜９のアミノアルキル基、炭素数２〜９のモノもしくはジアルキルアミノアルキル基、メチレンジオキシ基、シアノ基、ホルミル基、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数３〜９のアルコキシカルボニルアルキル基、炭素数３〜９のヒドロキシカルボニルアルキル基、炭素数３〜７のヒドロキシカルボニルアルケニル基、炭素数４〜８のアルコキシカルボニルアルケニル基、ホスホノ基、炭素数２〜９のジアルコキシホスホリル基、炭素数１〜４のモノアルコキシヒドロキシホスホリル基、炭素数１〜６のアルキルチオ基、炭素数１〜６のアルキルスルホニル基、置換基を有してもよい炭素数６〜１０のアリールチオ基、置換基を有してもよい炭素数４〜１０のヘテロアリールチオ基、炭素数１〜９ホスホリルアルキル基、炭素数３〜９のジアルコキシホスホリルアルキル基、炭素数２〜９のモノアルコキシヒドロキシホスホリル基、２−カルボキシ−２−オキソエチル基又は炭素数１〜１０のヘテロアリール基のいずれかを表し、
【００１３】
Xは、炭素数１〜６のアルキレン基（鎖中に、-NH-、-C(=O)-、-NHC(=O)-、-C(=O)NH-、-NHC(=O) NH - を含んでいてもよい）を示し、及び
Z1及びZ2は、各々同じでも異なってもよく、水素原子、ハロゲノ基、炭素数１〜６のアルキル基、ヒドロキシ基、炭素数１〜６のヒドロキシアルキル基、炭素数２〜６のアルコキシアルキル基、炭素数１〜６のチオアルキル基、炭素数２〜８のアルキルチオアルキル基、炭素数１〜６のカルバモイルアルキル基、炭素数６〜１０のアリール基、炭素数１〜１０のヘテロアリール基、炭素数１〜６のアルキル基で置換された炭素数６〜１０のアリール基、炭素数１〜６のアルキル基で置換された炭素数４〜１０のヘテロアリール基、炭素数１〜６のアミノアルキル基、カルボキシル基、炭素数２〜６のアルコキシカルボニル基、炭素数２〜８ヒドロキシカルボニルアルキル基、炭素数３〜８アルコキシカルボニルアルキル基、炭素数１〜６のアミノアルキル基又は炭素数２〜１０のモノもしくはジアルキルアミノアルキル基のいずれかを表し、また、Z1及びZ2は、結合して環を形成してもよく、この場合、−Z1−Z2−はエチレン基、トリメチレン基もしくはテトラメチレン基を示す。]
【００１４】
本発明はまた、上記ベンゾジアゼピン誘導体またはその医薬的に許容しうる塩を有効成分として含有する活性化血液凝固第Ｘ因子阻害剤を提供する。
本発明はまた、上記ベンゾジアゼピン誘導体またはその医薬的に許容しうる塩を有効成分として含有する医薬組成物を提供する。
本発明はまた、上記ベンゾジアゼピン誘導体またはその医薬的に許容しうる塩を有効成分として含有する抗血液凝固剤または血栓もしくは塞栓の予防剤又は治療剤を提供する。
【００１５】
【発明の実施の形態】
本明細書において、アリール基とは、炭素数６〜１０の芳香族炭化水素環基を示す。具体的には、フェニル基、１−ナフチル基及び２−ナフチル基等があげられる。このうち、フェニル基が好ましい。
なお、他に特に記載がない限り、本明細書に記載したアリールスルホニル基等における「アリール」も上述のアリールと同義である。
ヘテロアリール基とは、Ｏ、Ｎ及びＳから選ばれる１〜３個の複素原子を有する炭素数１〜１０の芳香族炭化水素環基を示す。具体的には、ピリジル基、ピリミジル基、ピリダジニル基、ピラジニル基、イミダゾーリル基、ピローリル基、チエニル基、ピラジル基、ピラゾリル基、ピロリル基、トリアジル基、フリル基、イソキサゾリル基、イソチアゾリル基、インドリル基、キノリル基、イソキノリル基、テトラゾール基等が挙げられる。このうち、複素原子として１又は２個のＮ及び／又はＳを有する炭素数４〜１０のヘテロアリール基がより好ましく、特にピリジル基及びチエニル基が好ましい。
なお、他に特に記載がない限り、本明細書に記載したヘテロアリールスルホニル基等における「ヘテロアリール」も上述のヘテロアリールと同義である。
【００１６】
アルキル基とは、炭素数１〜６のアルキル基をいい、直鎖でも分岐でも環状でもよい。このうち、炭素数１〜３のアルキル基が好ましい。具体的には、メチル基、エチル基、ｎ−プロピル基、ｉ−プロピル基、ｎ−ブチル基、ｓｅｃ−及びｔｅｒｔ−ブチル基、ｎ−ペンチル基、ｉ−ペンチル基、ｔｅｒｔ−ペンチル基、ネオペンチル基、２−ペンチル基、３−ペンチル基、ｎ−ヘキシル基及び２−ヘキシル基等があげられる。このうち、メチル基、エチル基、ｎ−プロピル基及びｉ−プロピル基が好ましい。
【００１７】
環状アルキル基とは、炭素数３〜１０のアルキル基をいう。炭素数５又は６の環状アルキル基が好ましい。具体的には、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基及びシクロオクチル基等があげられる。このうち、シクロプロピル基、シクロブチル基、シクロペンチル基又はシクロヘキシル基が好ましく、シクロヘキシル基が特に好ましい。
なお、他に特に記載がない限り、本明細書に記載したヒドロキシアルキル基及びイミノアルキル基等における「アルキル」も上述のアルキルと同義である。
アルケニル基とは、炭素数２〜６の直鎖又は分岐鎖を有するアルケニル基をいう。具体的には、ビニル基、プロペニル基、2-メチル-1-プロペニル基等があげられる。
なお、他に特に記載がない限り、本明細書に記載したヒドロキシカルボニルアルケニル基及びアルコキシカルボニルアルケニル基等における「アルケニル」も上述のアルケニルと同義である。
【００１８】
ハロゲノ基としては、フルオロ基、クロロ基、ブロモ基、ヨード基が挙げられる。このうち、フルオロ基、クロロ基及びブロモ基が好ましい。フルオロ基、クロロ基が特に好ましい。
アルコキシル基とは、炭素数１〜１０の直鎖又は分岐鎖を有するアルコキシル基、炭素数４〜１０の環状アルキル基を有するアルコキシル基、又は縮環していてもよい環状炭素鎖を有するアルコキシル基を示す。具体的には、メトキシ基、エトキシ基、ｎ−プロポキシ基、イソプロポキシ基、ｎ−ブトキシ基、ｉ−ブトキシ基、ｓｅｃ−ブトキシ基、ｔｅｒｔ−ブトキシ基、ベンジルオキシ基、２−フェニルエトキシ基、３−フェニルプロピルオキシ基、４−フェニルブトキシ基、５−フェニルペンチルオキシ基、６−フェニルヘキシルオキシ基、シクロプロピルオキシ基、シクロブトキシ基、シクロペンチルオキシ基、シクロヘキシルオキシ基、１−インダニルオキシ基及び２−インダニルオキシ基等があげられる。このうち、メトキシ基、エトキシ基及びｎ−プロポキシ基が好ましい。
なお、他に特に記載がない限り、本明細書に記載したアルコキシアルキル基及びアルコキシカルボニルピペリジルオキシ基等における「アルコキシ」も上述のアルコキシと同義である。
【００１９】
モノもしくはジアルキルカルバモイル基としては、メチルカルバモイル基、エチルカルバモイル基、ｎ−プロピルカルバモイル基及びｉ−プロピルカルバモイル基等のモノアルキルカルバモイル基、及びジメチルカルバモイル基、ジエチルカルバモイル基、ジ（ｎ−プロピル）カルバモイル基及びジ（ｉ−プロピル）カルバモイル基等のジアルキルカルバモイル基があげられる。ここで、ジアルキルカルバモイル基の二つのアルキル基の鎖長は同じでも異なっていても良い。また、ジアルキルカルバモイル基の二つのアルキル基は結合して環を形成してもよく、不飽和炭化水素基を含んで環を形成してもよい。またこのとき-CH₂-基の一つがＯ、ＮＨ又はＳで置換されていてもよい。具体的には、１−ピロリジンカルボニル基、２，５−ジヒドロ−１Ｈ−ピロール−１−イルカルボニル基、１−ピペリジンカルボニル基、１−ピペラジンカルボニル基、（モルホリン−４−イル）カルボニル基及び（チオモルホリン−４−イル）カルボニル基等があげられる。このうち、ジメチルカルバモイル基、１−ピロリジンカルボニル基、（モルホリン−４−イル）カルボニル基、２，５−ジヒドロ−１Ｈ−ピロール−１−イルカルボニル基及び（チオモルホリン−４−イル）カルボニル基が好ましい。
【００２０】
炭素数１〜６のモノもしくはジアルキルアミノ基としては、メチルアミノ基、エチルアミノ基、ｎ−プロピルアミノ基及びｉ−プロピルアミノ基等のモノアルキルアミノ基、及びジメチルアミノ基、ジエチルアミノ基、ジ（ｎ−プロピル）アミノ基及びジ（ｉ−プロピル）アミノ基等のジアルキルアミノ基があげられる。ここで、ジアルキルアミノ基の二つのアルキル基の鎖長は同じでも異なっていても良い。また、ジアルキルアミノ基の二つのアルキル基は結合して環を形成してもよい。またこのとき-CH₂-基の一つがＯ、ＮＨ又はＳで置換されていてもよい。具体的には、ピロリジニル基、ピペリジニル基、モルホリニル基及びチオモルホリニル基等があげられる。このうち、モルホリニル基及びチオモルホリニル基が好ましい。
【００２１】
炭素数２〜７のアルコキシカルボニル基としては、メトキシカルボニル基、エトキシカルボニル基、ｎ−プロポキシカルボニル基、イソプロポキシカルボニル基、ｎ−ブトキシカルボニル基、ｉ−ブトキシカルボニル基、ｓｅｃ−ブトキシカルボニル基及びｔｅｒｔ−ブトキシカルボニル基等があげられる。このうち、メトキシカルボニル基及びエトキシカルボニル基が好ましい。
炭素数２〜９のジアルコキシホスホリル基としては、ジエトキシホスホリル基、ジ（ｎ−プロポキシ）ホスホリル基、ジ（イソプロポキシ）ホスホリル基、ジ（ｎ−ブトキシ）ホスホリル基、ジ（ｉ−ブトキシ）ホスホリル基及びジ（ｓｅｃ−ブトキシ）ホスホリル基及びジ（ｔｅｒｔ−ブトキシ）ホスホリル基等があげられる。このうち、ジエトキシホスホリル基が好ましい。
【００２２】
モノアルコキシヒドロキシホスホリル基としては、モノメトキシヒドロキシホスホリル基、モノエトキシヒドロキシホスホリル基、モノｎ−プロポキシヒドロキシホスホリル基、モノイソプロポキシヒドロキシホスホリル基、モノｎ−ブトキシヒドロキシホスホリル基、モノｉ−ブトキシヒドロキシホスホリル基、モノｓｅｃ−ブトキシヒドロキシホスホリル基、モノｔｅｒｔ−ブトキシヒドロキシホスホリル基等があげられる。このうち、モノエトキシヒドロキシホスホリル基が好ましい。
【００２３】
アルキルチオ基としては、メチルチオ基、エチルチオ基、ｎ−プロピルチオ基、ｉ−プロピルチオ基等が上げられる。このうち、メチルチオ基が好ましい。
アルキルスルホニル基としては、メチルスルホニル基、エチルスルホニル基、スルホニル基、ｎ−プロピルスルホニル基及びｉ−プロピルスルホニル基等があげられる。このうち、メチルスルホニル基が好ましい。
【００２４】
モノもしくはジアルキルアミノスルホニル基としては、メチルアミノスルホニル基、エチルアミノスルホニル基、ｎ−プロピルアミノスルホニル基、ｉ−プロピルアミノスルホニル基等のモノアルキルアミノスルホニル基、及びジメチルアミノスルホニル基、ジエチルアミノスルホニル基、ジ（ｎ−プロピル）アミノスルホニル基、ジ（ｉ−プロピル）アミノスルホニル基等のジアルキルアミノスルホニル基があげられる。ここで、ジアルキルアミノスルホニル基の二つのアルキル基の鎖長は異なっていても良い。また、ジアルキルアミノスルホニル基の二つのアルキル基が結合して環を形成してもよい。またこのとき-CH₂-基の一つがＯ、ＮＨ又はＳで置換されていてもよい。具体的には、（ピロリジン−１−イル）スルホニル基、（ピペリジン−１−イル）スルホニル基、（モルホリン−４−イル）スルホニル基及び（チオモルホリン−４−イル）スルホニル基等があげられる。このうち、（ピロリジン−１−イル）スルホニル基が好ましい。
【００２５】
アシル基としては、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基、イソバレリル基及びピバロイル基等があげられる。
アミノアルキル基としては、アミノメチル基、２−アミノエチル基、２−アミノプロピル及び３−アミノプロピル等があげられる。このうち、炭素数１〜７のアミノアルキル基、特に３−アミノプロピル基が好ましい。
【００２６】
モノもしくはジアルキルアミジノ基としては、メチルアミジノ基、エチルアミジノ基等のモノアルキルアミジノ基、及びジメチルアミジノ基及びジエチルアミジノ基等のジアルキルアミジノ基があげられる。ここで、ジアルキルアミジノ基の二つのアルキル基の鎖長は異なっていても良い。また、ジアルキルアミジノ基の二つのアルキル基は結合して環を形成してもよく、不飽和炭化水素基を含んで環を形成してもよい。またこのとき-CH₂-基の一つがＯ、ＮＨ又はＳで置換されていてもよい。具体的には、（ピロリジン−１−イル）（イミノ）メチル基、（ピペリジン−１−イル）（イミノ）メチル基、１，４，５，６，−テトラヒドロ−２−ピリミジニル基、（モルホリン−４−イル）（イミノ）メチル基、２，５−ジヒドロ−１Ｈ−ピロール−１−イル（イミノ）メチル基及び（チオモルホリン−４−イル）（イミノ）メチル基等があげられる。このうち、２，５−ジヒドロ−１Ｈ−ピロール−１−イル（イミノ）メチル基、ジメチルアミジノ基、（ピロリジン−１−イル）（イミノ）メチル基、（チオモルホリン−４−イル）（イミノ）メチル基が好ましい。
【００２７】
トリアルキルアミジノ基としては、トリメチルアミジノ基、トリエチルアミジノ基、トリ（ｎ−プロピル）アミジノ基及びトリ（ｉ−プロピル）アミジノ基等があげられる。ここで、トリアルキルアミジノ基の三つのアルキル基の鎖長は異なっていても良い。また、トリアルキルアミジノ基の三つのアルキル基のうちの二つのアルキル基が結合して環を形成してもよい。またこのとき-CH₂-基の一つがＯ、ＮＨ又はＳで置換されていてもよい。具体的には、１−メチル−１Ｈ−イミダゾール−２−イル基及び１−エチル−１Ｈ−イミダゾール−２−イル基等があげられる。このうち、１−メチル−１Ｈ−イミダゾール−２−イル基が好ましい。
【００２８】
炭素数５〜８のテトラアルキルアミジノ基としては、（ジメチルアミノ）（ジメチルイミニオ）メチル基等があげられる。ここで、テトラアルキルアミジノ基の四つのアルキル基の鎖長は同一でも異なっていても良い。また、テトラアルキルアミジノ基の四つのアルキル基のうちの二つのアルキル基が結合して環を形成してもよい。またこのとき-CH₂-基の一つがＯ、ＮＨ又はＳで置換されていてもよい。具体的には、１，３−ジメチル−４，５−ジヒドロ−１Ｈ−イミダゾール−３−イウム−２−イル基及び１−エチル−３−メチル−４，５−ジヒドロ−１Ｈ−イミダゾール−３−イウム−２−イル基等があげられる。このうち、１，３−ジメチル−４，５−ジヒドロ−１Ｈ−イミダゾール−３−イウム−２−イル基が好ましい。
【００２９】
ジアルキルグアニジノ基としては、ジメチルグアニジノ基、ジエチルグアニジノ基、ジ（ｎ−プロピル）グアニジノ基及びジ（ｉ−プロピル）グアニジノ基等があげられる。ここで、ジアルキルグアニジノ基の二つのアルキル基の鎖長は異なっていても良い。また、ジアルキルグアニジノ基の二つのアルキル基が結合して環を形成してもよい。またこのとき-CH₂-基の一つがＯ、ＮＨ又はＳで置換されていてもよい。具体的には、イミダゾリン−２−アミノ基等があげられる。
【００３０】
トリアルキルグアニジノ基としては、トリメチルグアジニノ基、トリエチルグアニジノ基、トリ（ｎ−プロピル）グアニジノ基及びトリ（ｉ−プロピル）グアニジノ基等があげられる。ここで、トリアルキルグアニジノ基の三つのアルキル基の鎖長は同一でも異なっていても良い。また、トリアルキルグアニジノ基の三つのアルキル基のうちの二つのアルキル基が結合して環を形成してもよい。またこのとき-CH₂-基の一つがＯ、ＮＨ又はＳで置換されていてもよい。具体的には、１−メチル−２−イミダゾリン−２−イル−アミノ基、１−エチル−２−イミダゾリン−２−イル−アミノ基、１−（ｎ−プロピル）−２−イミダゾリン−２−イル−アミノ基及び１−（ｉ−プロピル）−２−イミダゾリン−２−イル−アミノ基等があげられる。このうち、１−メチル−２−イミダゾリン−２−イル−アミノ基が好ましい。
【００３１】
炭素数６〜１０のアルキルピペラジンカルボニル基としては、メチルピペラジンカルボニル基、エチルピペラジンカルボニル基、ｎ−プロピルピペラジンカルボニル基、ｉ−プロピルピペラジンカルボニル基、ｎ−ブチルピペラジンカルボニル基、ｉ−ブチルピペラジンカルボニル基、ｓｅｃ−ブチルピペラジンカルボニル基及びｔｅｒｔ−ブチルピペラジンカルボニル基等があげられる。このうち、ｉ−プロピルピペラジンカルボニル基が好ましい。
【００３２】
モノもしくはジアルキルアミノアルキル基としては、メチルアミノメチル基、メチルアミノエチル基、メチルアミノプロピル基、エチルアミノメチル基、エチルアミノエチル基、エチルアミノプロピル基、ｎ−プロピルアミノメチル基、ｎ−プロピルアミノエチル基、ｎ−プロピルアミノプロピル基、ｉ−プロピルアミノメチル基、ｉ−プロピルアミノエチル基及びｉ−プロピルアミノプロピル基等のモノアルキルアミノアルキル基、及びジメチルアミノメチル基、ジメチルアミノエチル基、ジメチルアミノプロピル基、ジエチルアミノメチル基、ジエチルアミノエチル基、ジエチルアミノプロピル基、ジ（ｎ−プロピル）アミノメチル基、ジ（ｎ−プロピル）アミノエチル基、ジ（ｎ−プロピル）アミノプロピル基、ジ（ｉ−プロピル）アミノメチル基、ジ（ｉ−プロピル）アミノエチル基及びジ（ｉ−プロピル）アミノプロピル基等のジアルキルアミノアルキル基があげられる。ここで、ジアルキルアミノアルキル基の三つのアルキル基の鎖長は同一でも異なっていても良い。また、ジアルキルアミノアルキル基の二つのアルキル基が結合して環を形成してもよい。またこのとき-CH₂-基の一つがＯ、ＮＨ又はＳで置換されていてもよい。具体的には、（ピロリジン−１−イル）メチル基、（ピロリジン−１−イル）エチル基、（ピロリジン−１−イル）プロピル基、（ピペリジン−１−イル基）メチル基、（ピペリジン−１−イル基）エチル基、（ピペリジン−１−イル基）プロピル基、（モルホリン−４−イル）メチル基、（モルホリン−４−イル）エチル基、（モルホリン−４−イル）プロピル基、（チオモルホリン−１−イル）メチル基、（チオモルホリン−１−イル）エチル基及び（チオモルホリン−１−イル）プロピル基等があげられる。
【００３３】
アリールチオ基としては、フェニルチオ基、ナフチルチオ基等があげられる。このうち、フェニルチオ基が好ましい。
ヘテロアリールチオ基としては、チエニルチオ基、ピリジルチオ基、インドリルチオ基等があげられる。このうち、チエニルチオ基が好ましい。
【００３４】
窒素、酸素及び硫黄のいずれかから選ばれる１つ以上の複素原子を含む、炭素数１〜６のアルキル基で置換されていてもよい炭素数１〜６の炭素環としては、下式（３）で示される構造が挙げられる。他の基との結合位置は特に限定されない。

【００３５】
好ましくは、下式（４）で示される構造が挙げられる。
ここで、窒素原子において、炭素数１〜６のアルキル基で置換されている場合が好ましい。

【００３６】
特に、下記一般式（２）で表される基が好ましい。

【００３７】
酸素及び／又は硫黄から選ばれるヘテロ原子を一つ以上含んでいても良く、ピロリジル基、ピペリジル基又はピペラジニル基を除く、少なくとも１つの窒素原子を含む炭素数２〜８（好ましくは４〜６）の非芳香族炭素環としては、下記式（５）で示される構造が挙げられる。ここで、該非芳香族炭素環は二重結合を有していてもよい。また、X、R3、R8、又は、R9との結合位置は特に限定されないが、窒素原子において、X、又は、R3と結合しているのが好ましい。
【００３８】

より好ましくは上記一般式（２）で表される基が挙げられる。
【００３９】
上記一般式（１）において、環Aとしては、炭素数６〜１０のアリール基、炭素数３〜１０のヘテロアリール基（特に炭素数４〜１０のヘテロアリール基、さらに特に炭素数３〜５のヘテロアリール基）又は炭素数５又は６の環状アルキル基が好ましい。このうち、フェニル基、ピリジル基及びピラゾリル基及びシクロヘキシル基が好ましい。さらに特にフェニル基が好ましい。
【００４０】
R1としては、水素原子、ハロゲノ基、置換基を有してもよいヒドロキシル基、炭素数１〜１０のアルコキシル基、トリフルオロメチル基、トリフルオロメタンスルホニルオキシ基、カルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、シアノ基、ニトロ基、炭素数１から６のモノもしくはジアルキルアミノ基、置換基を有してもよいアミノ基、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数１〜６のアルキルチオ基、炭素数１〜６のアルキルスルホニル基、置換基を有してもよい炭素数１〜６のアルキル基、置換基を有してもよい炭素数２〜７のアミノアルキル基、置換基を有してもよいピペラジンカルボニル基及び置換基を有してもよいアミジノ基等が好ましい。
R1としては、水素原子、フルオロ基、クロロ基、ブロモ基、ヨード基、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数１〜６のモノもしくはジアルキルアミノ基、置換基を有してもよいヒドロキシル基、置換基を有してもよい炭素数１〜６のアルキル基、置換基を有してもよい炭素数１〜６のアルキルチオ基又は置換基を有してもよい炭素数１〜６のアルキルスルホニル基もまた好ましい。
R1としては、水素原子、ハロゲノ基、カルボキシル基、シアノ基、ニトロ基、炭素数２〜７のアルコキシカルボニル基、炭素数１から６のモノもしくはジアルキルアミノ基、置換基を有してもよいアミノ基、置換基を有してもよいヒドロキシル基、炭素数１〜６のアルキルチオ基及び置換基を有してもよい炭素数１〜６のアルキル基もまた好ましい。
【００４１】
R1が置換を有する場合の置換基としては、炭素数１〜６のアルキル基、ヒドロキシル基、炭素数１〜６のモノもしくはジアルキルアミノ基、炭素数１〜１０のヘテロアリール基、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、窒素、酸素及び硫黄のいずれかから選ばれる１つ以上の複素原子を含む、炭素数１〜６のアルキル基で置換されていても良い炭素数１〜６の炭素環、窒素、酸素及び硫黄のいずれかから選ばれる１つ以上の複素原子を含む、炭素数１〜６のアルキル基で置換されていても良い炭素数１〜６の炭素環で置換されたカルボニル基、ホスホノ基、炭素数２〜９のジアルコキシホスホリル基、炭素数１〜４のモノアルコキシヒドロキシホスホリル基、炭素数１〜６のアルキルスルホニル基及びジアルキルアミジノ基が好ましい。
【００４２】
ヒドロキシル基、ホスホノ基、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、炭素数１〜６のモノもしくはジアルキルアミノ基、ピペラジンカルボニル基、炭素数６〜１０のアルキルピペラジンカルボニル基及び炭素数１〜６のアルキルスルホニル基がより好ましい。
さらに、R1が、水素原子、フルオロ基、クロロ基、ブロモ基、ヨード基、アミノ基、カルボキシル基、エトキシカルボニル基、カルボキシエチル基、エトキシカルボニルエチル基、モルホリンアルキル基、ヒドロキシル基、メチル基、メチルチオ基、メチルホスホリル基、ホスホノエチル基、トリフルオロメチル基、メトキシ基、トリフルオロメトキシ基、シアノ基、ニトロ基、モルホリンカルボニルエチル基、ピペラジンカルボニルエチル基、イソプロピルピペラジンカルボニルエチル基、メタンスルホニルアミノプロピル基及びヒドロキシプロピル基であるのがさらに好ましい。
【００４３】
R1が、水素原子、カルボキシル基、エトキシカルボニル基、カルボキシエチル基、エトキシカルボニルエチル基、モルホリンアルキル基、モルホリンカルボニルエチル基、ピペラジンカルボニルエチル基、イソプロピルピペラジンカルボニルエチル基を示すのもまた好ましい。
【００４４】
R4及びR5としては、それぞれ、水素原子、ハロゲノ基、トリフルオロメチル基、メトキシ基及びヒドロキシル基であるのが好ましい。特に、Ｒ４が水素原子、フルオロ基、クロロ基、メトキシ基、メチル基であるのが好ましい。さらに特に、R4及びR5の少なくともどちらか一方が水素原子であるのが好ましい。
R1、R4及びR5は、互いに同一でも異なっていてもよく、特に、環Aがフェニル基を表すとき、R1が、６−及び／又は８−位において該フェニル基に結合しているのが好ましい。
【００４５】
Xとしては、炭素数１〜６のアルキレン基が好ましく、炭素数１〜３の直鎖アルキレン基がより好ましく、メチレン基、エチレン基又はプロピレン基がさらに好ましい。エチレン基が最も好ましい。アルキレン基Xの鎖中に含まれる基としては、−Ｃ（＝Ｏ）−、−Ｃ（＝Ｏ）ＮＨ−、−ＮＨＣ（＝Ｏ）−が好ましい。環Bとしては炭素数６〜１０のアリール基、炭素数３〜１０のヘテロアリール基（特に炭素数４〜１０のヘテロアリール基）が好ましい。アリール基としてはフェニル基及び２−ナフチル基が好ましい。ヘテロアリール基としては、チエニル基及びピリジル基が好ましい。さらに特に、フェニル基及びチエニル基がより好ましい。
【００４６】
R2としては、水素原子、ハロゲノ基、特にクロロ基、ブロモ基；炭素数１〜１０のアルコキシル基、特に炭素数１〜３のアルコキシル基、さらに特にメトキシ基；炭素数１〜６のアルキル基、特にメチル基、エチル基；及びトリフルオロメチル基が好ましい。ハロゲノ基、特にクロロ基及びブロモ基並びにメチル基が最も好ましい。
R6及びR7としては、各々同じでも異なってもよく、水素原子、ハロゲノ基、トリフルオロメチル基、メトキシ基、ヒドロキシル基のいずれかであるのが好ましい。R6及びR7が共に水素原子であるのがより好ましい。
【００４７】
R2、R6及びR7は、互いに同一でも異なっていてもよく、特に、R2が、環Bがフェニル基のとき3-及び／又は4-位において該フェニル基に、環Bがチエニル基のとき５位において該チエニル基に、環Bがピリジル基のとき５位において該チエニル基に、及び環Bがピペリジル基のとき１位において該ピペリジル基に結合しているのが好ましい。
さらに特に、環Bがフェニル基であり、R2が４位において該フェニル環に結合しており、R6及びR7がともに水素原子であるのが好ましい。
【００４８】
また特に、環Ｂがチエニル基であり、Ｒ２が５位において該チエニル基に結合しており、R6及びR7がともに水素原子であるのが好ましい。
環Cとしては、酸素及び／又は硫黄から選ばれるヘテロ原子を一つ以上含んでいても良く、ピロリジル基、ピペリジル基又はピペラジニル基を除く、少なくとも１つ以上の窒素原子を含む炭素数２〜８の非芳香族炭素環であることが好ましい。特に、上記式（５）で表される炭素環が好ましい。
特に、上記一般式（２）で表される炭素環であるのがより好ましい。
又、環ＣとＸとの結合位置は特に限定されるものではない。
【００４９】
R3としては、ハロゲノ基、ニトロ基、炭素数２〜７のイミノアルキル基、ピペリジルオキシ基、炭素数２〜７のモノ又はジアルキルカルバモイル基、ピペリジルオキシ基、炭素数６〜１０のイミノアルキルピペリジルオキシ基、炭素数５〜１０のアルキルピペリジルオキシ基、置換基を有していてもよいアミノ基、置換基を有していてもよい炭素数２〜９のアミノアルキル基、置換基を有していてもよい炭素数１〜６のアルキル基、炭素数１〜８のアシル基、炭素数２〜７のアルコキシカルボニル基、置換基を有していてもよいピロリジン基、置換基を有していてもよいピペラジン基、置換基を有していてもよい炭素数１〜１０のヘテロアリール基又は置換基を有していてもよいアミジノ基のいずれかであるのが好ましい。炭素数２〜７のモノもしくはジアルキルカルバモイル基、置換基を有してもよい炭素数１〜６のアルキル基及び置換基を有してもよいアミジノ基がより好ましい。置換基を有していてもよい炭素数１〜１０のヘテロアリール基もまた好ましく、特にピリジル基、さらに特に４−ピリジル基が好ましい。さらに特に、置換基を有してもよい炭素数１〜６のアルキル基、ハロゲノ基、ピリジル基（特に４−ピリジル基）、ニトロ基、アミノ基、ジアルキルアミノ基、置換基を有してもよいアミジノ基又は置換基を有してもよいピペリジルオキシ基もまた好ましい。水素原子、メチル基、イソプロピル基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、ピリジル基のいずれかを示すのもまた好ましい。メチル基、イソプロピル基のいずれかを示すのもまた好ましい。
【００５０】
R3が置換基を有する場合の置換基としては、炭素数１〜６のアルキル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、炭素数２〜９のモノもしくはジアルキルアミノアルキル基、炭素数２〜７のモノもしくはジアルキルアミジノ基、炭素数４〜７のトリアルキルアミジノ基、ピロリジン基、ピペリジン基、炭素数１〜８のアルキルスルホニル基又はピリジル基のいずれかであるのが好ましい。このうち、炭素数１〜６のアルキル基及びピリジル基がより好ましい。
さらに、R3が、メチル基、イソプロピル基、シクロヘキシル基、ピリジル基のいずれかであるのがより好ましい。
【００５１】
R8及びR9は、各々同じでも異なってもよく、それぞれ、水素原子、ハロゲノ基炭素数１〜６のアルキル基、オキソ基、トリフルオロメチル基、ニトロ基、メトキシ基又はヒドロキシル基のいずれかであるのが好ましい。特に水素原子、メチル基、フルオロ基、クロロ基、ブロモ基又はオキソ基のいずれかであるのがより好ましい。R8及びR9が共に水素原子であるのが好ましい。
R3、R8及びR9の置換位置は特に限定されない。
【００５２】
Z1及びZ2としては、各々同じでも異なってもよく、水素原子、炭素数１〜６のアルキル基、炭素数６〜１０のアリール基、炭素数４〜１０のヘテロアリール基が好ましい。特に、Z1及びZ2がともに水素原子であるのが好ましい。
【００５３】
又、一般式（１）中、環Aが、炭素数６〜１０のアリール基、炭素数３〜１０のヘテロアリール基又は炭素数５又は６の環状アルキル基であり、
R1が、水素原子、ハロゲノ基、置換基を有していてもよいヒドロキシル基、炭素数１〜１０のアルコキシル基、トリフルオロメチル基、トリフルオロメタンスルホニルオキシ基、カルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、シアノ基、ニトロ基、炭素数１から６のモノもしくはジアルキルアミノ基、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、置換基を有してもよい炭素数１〜６のアルキル基、炭素数１〜６のアルキルチオ基、炭素数１〜６のアルキルスルホニル基、置換基を有してもよい炭素数２〜７のアミノアルキル基、置換基を有してもよいピペラジンカルボニル基又は置換基を有してもよいアミジノ基のいずれかを示し、
【００５４】
R1が置換を有する場合の置換基が、炭素数１〜６のアルキル基、ヒドロキシル基、炭素数１〜６のモノもしくはジアルキルアミノ基、炭素数１〜１０のヘテロアリール基、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、窒素、酸素及び硫黄のいずれかから選ばれる１つ以上の複素原子を含む、炭素数１〜６のアルキル基で置換されていても良い炭素数１〜６の炭素環、窒素、酸素及び硫黄のいずれかから選ばれる１つ以上の複素原子を含む、炭素数１〜６のアルキル基で置換されていても良い炭素数１〜６の炭素環で置換されたカルボニル基、ホスホノ基、炭素数２〜９のジアルコキシホスホリル基、炭素数１〜４のモノアルコキシヒドロキシホスホリル基、炭素数１〜６のアルキルスルホニル基又は炭素数１〜６のジアルキルアミジノ基のいずれかであるのが好ましい。
【００５５】
又、一般式（１）中、環Aがフェニル基を示し、
R1が水素原子、フルオロ基、クロロ基、ブロモ基、ヨード基、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数１〜６のモノもしくはジアルキルアミノ基、置換基を有してもよいヒドロキシル基、置換基を有してもよい炭素数１〜６のアルキル基、置換基を有してもよい炭素数１〜６のアルキルチオ基又は置換基を有してもよい炭素数１〜６のアルキルスルホニル基を示し、
【００５６】
R1が置換基を有する場合の置換基が、ヒドロキシル基、ホスホノ基、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、炭素数１〜６のモノもしくはジアルキルアミノ基、窒素、酸素及び硫黄のいずれかから選ばれる１つ以上の複素原子を含む、炭素数１〜６のアルキル基で置換されていても良い炭素数１〜６の炭素環、窒素、酸素及び硫黄のいずれかから選ばれる１つ以上の複素原子を含む、炭素数１〜６のアルキル基で置換されていても良い炭素数１〜６の炭素環で置換されたカルボニル基又は炭素数１〜６のアルキルスルホニル基であり、及び
【００５７】
R4及びＲ５は同じでも異なっていてもよく、水素原子、ハロゲノ基、炭素数１〜６のアルキル基、トリフルオロメチル基、炭素数１〜６のアルコキシル基、トリフルオロメトキシ基、ヒドロキシル基、炭素数１〜６のアルキルチオ基、炭素数１〜６のアルキルスルホニル基のいずれかであるのが好ましい。
【００５８】
又、一般式（１）中、環Aがフェニル基を示し、
R1が、水素原子、フルオロ基、クロロ基、ブロモ基、ヨード基、アミノ基、シアノ基、ニトロ基、カルボキシル基、エトキシカルボニル基、カルボキシエチル基、エトキシカルボニルエチル基、モルホリンアルキル基、ヒドロキシル基、メチル基、メトキシ基、メチルチオ基、メチルスルホニル基、ホスホノエチル基、モルホリンカルボニルエチル基、ピペラジンカルボニルエチル基、イソプロピルピペラジンカルボニルエチル基、メタンスルホニルアミノプロピル基又はヒドロキシプロピル基であるのがより好ましい。ここで、Ｒ４及びＲ５の少なくともどちらか一方が水素原子であるのが更に好ましい。
【００５９】
又、一般式（１）中、環Bが炭素数６〜１０のアリール基又は炭素数４〜１０のヘテロアリール基を示し、
R2が、水素原子、ハロゲノ基、炭素数１〜６のアルキル基、トリフルオロメチル基、炭素数１〜１０のアルコキシル基のいずれかであるのが好ましい。
【００６０】
又、一般式（１）中、環Bが炭素数６〜１０のアリール基又は炭素数４〜１０のヘテロアリール基であり、
R2がクロロ基、ブロモ基又はメチル基であり、及び
R6及びR7が、各々同じでも異なってもよく、水素原子、ハロゲノ基、トリフルオロメチル基、メトキシ基又はヒドロキシル基のいずれかであるのがより好ましい。
【００６１】
又、一般式（１）中、環Bが炭素数６〜１０のアリール基又は炭素数４〜１０のヘテロアリール基であり、
R2がクロロ基、ブロモ基又はメチル基のいずれかであり、
R６及びR７がともに水素原子であるのがより好ましい。
【００６２】
又、一般式（１）中、環Bがフェニル基又はチエニル基であり、
R2がクロロ基、ブロモ基又はメチル基のいずれかであり、
R６及びR７がともに水素原子であるのが特に好ましい。
【００６３】
又、一般式（１）中、環Cが、少なくとも１つ以上の窒素原子を含む、酸素及び／又は硫黄から選ばれるヘテロ原子を一つ以上含んでいても良い炭素数２〜８の非芳香族炭素環であり、ただしピロリジル基、ピペリジル基又はピペラジニル基を除く、
R3が、ハロゲノ基、ニトロ基、炭素数２〜７のイミノアルキル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、炭素数１〜８のアシル基、炭素数２〜７のアルコキシカルボニル基、ピペリジルオキシ基、炭素数６〜１０のイミノアルキルピペリジルオキシ基、炭素数５〜１０のアルキルピペリジルオキシ基、置換基を有していてもよいアミノ基、置換基を有していてもよい炭素数２〜９のアミノアルキル基、置換基を有していても良い炭素数１〜６のアルキル基、置換基を有していてもよいピロリジン基、置換基を有していてもよいピペラジン基、置換基を有していてもよい炭素数１〜１０のヘテロアリール基又は置換基を有していてもよいアミジノ基のいずれかであり、
R3が置換基を有する場合の置換基が、炭素数１〜６のアルキル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、炭素数２〜９のモノもしくはジアルキルアミノアルキル基、炭素数２〜７のモノもしくはジアルキルアミジノ基、炭素数４〜７のトリアルキルアミジノ基、ピロリジン基、ピペリジン基又は炭素数１〜８のアルキルスルホニル基又はピリジル基のいずれかであるのが好ましい。ここで、一般式（１）中、R3が置換基を有しても良い炭素数１〜６のアルキル基であるのがより好ましい。又、一般式（１）中、環Cが上記一般式（２）で表される基のいずれかであり、R3が置換基を有しても良い炭素数１〜６のアルキル基であるのが特に好ましい。さらに特に、Ｒ８及びＲ９が共に水素原子であるのが好ましい。
又、一般式（１）中、Xが炭素数１〜６のアルキレン基であるのが好ましい。
【００６４】
又、一般式（１）中、環Aがフェニル基を示し、
R1が、水素原子、フルオロ基、クロロ基、ブロモ基、ヨード基、アミノ基、シアノ基、ニトロ基、カルボキシル基、エトキシカルボニル基、カルボキシエチル基、エトキシカルボニルエチル基、モルホリンアルキル基、ヒドロキシル基、メチル基、メトキシ基、メチルチオ基、メチルスルホニル基、ホスホノエチル基、モルホリンカルボニルエチル基、ピペラジンカルボニルエチル基、イソプロピルピペラジンカルボニルエチル基、メタンスルホニルアミノプロピル基又はヒドロキシプロピル基を示し、
【００６５】
環Bがフェニル基又はチオフェン基のいずれかを表し、
R2が水素原子、クロロ基、ブロモ基又はメチル基を示し、
環Cが上記一般式（２）で表される基のいずれかを示し、
R3が、水素原子、メチル基、イソプロピル基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、ピリジル基のいずれかを示し、
Xがメチレン基又はエチレン基、プロピレン基であり（鎖中に−Ｃ（＝Ｏ）−を含んでも良い）、及び
Z1及びZ2がともに水素原子であるのが好ましい。ここで、一般式（１）中、Ｒ５、Ｒ６、Ｒ７及びＲ９が水素原子であるのがより好ましい。
【００６６】
特に、一般式（１）中、環Aがフェニル基を示し、
R1が、水素原子、カルボキシル基、エトキシカルボニル基、カルボキシエチル基、エトキシカルボニルエチル基、モルホリンアルキル基、モルホリンカルボニルエチル基、ピペラジンカルボニルエチル基、イソプロピルピペラジンカルボニルエチル基を示し、
環Bがフェニル基又はチエニル基のいずれかを表し、
R2がクロロ基、ブロモ基又はメチル基を示し、
環Cが上記一般式（２）で表される基のいずれかを示し、
R3が、メチル基、イソプロピル基のいずれかを示し、
Xがメチレン基又はエチレン基、プロピレン基であり、
Ｒ４が水素原子、フルオロ基、クロロ基、メトキシ基、メチル基であり、
Ｒ５、Ｒ６、Ｒ７及びＲ９がともに水素原子であり、及び
Z1及びZ2がともに水素原子であるのがより好ましい。
【００６７】
本発明の化合物（１）の代表的な製造法を説明する。例えば、環Aが置換基を有してもよいフェニル基、Xが炭素数１〜６のアルキル基である場合は、次に示した方法を用いることにより製造できる。
【００６８】
すなわち、アミノ酸エステル（２）に、溶媒として例えばエタノール等を用い、例えば炭酸水素ナトリウム等の塩基存在下、例えば２−ニトロベンジルハライド（３）を作用させることにより、（４）を得ることができる。そして得られた（４）を、溶媒として、例えばジクロロメタン等を用い、例えばトリエチルアミン等の塩基存在下、例えば、酸ハライド（５）等を作用させることにより、（６）へ導くことができる。得られた（６）を溶媒として、例えばテトラヒドロフラン等を用い、例えば水酸化ナトリウム等の塩基存在下、加水分解を行い、その後、溶媒として、例えばエタノール等を用い、例えばパラジウム−炭素等の触媒を用い、例えば水素雰囲気下で反応を行うことにより、（７）へ導くことができる。得られた（７）を溶媒として、例えばジメチルホルムアミド等を用い、例えばトリエチルアミン等の塩基存在下、縮合剤を作用させることにより、分子内縮合を行い、（８）へ導くことができる。得られた（８）を溶媒として、例えばジメチルホルムアミド等を用い、例えば水素化ナトリウム等の塩基存在下、（９）を作用させることにより、ベンゾジアゼピン誘導体（１０）へ導くことができる。
【００６９】
なお、出発原料（３）を変えることにより、一般式（１）における環Aがフェニル基以外のアリール基、ヘテロアリール基、環状アルキル基のいずれかである化合物を合成することもできる。
【００７０】

【００７１】
また、（６）を、例えば酢酸エチル等を用い、例えばパラジウム−炭素等の触媒を用い、例えば水素雰囲気下で反応を行うことにより、（１１）へ導くことができる。続いて、溶媒として例えばジクロロメタン等を用い、例えば（１２）、例えば酢酸等の酸存在下、例えば、ナトリウムトリアセトキシボロハイドライド等の還元剤を作用させることにより、（１３）を得ることができる。そして得られた（１３）を、溶媒として、例えばテトラヒドロフラン等を用い、例えば水酸化ナトリウム等の塩基存在下、加水分解を行い、その後、溶媒として、例えばジクロロメタン等を用い、例えばトリエチルアミン等の塩基存在下、縮合剤を作用させることにより、分子内縮合を行い、ベンゾジアゼピン誘導体（１４）へ導くことができる。
【００７２】

【００７３】
このようにして製造される一般式（１）で表される化合物およびその塩は、公知の分離精製手段、例えば抽出、濃縮、減圧濃縮、溶媒抽出、晶析、再結晶、転溶、各種クロマトグラフィーなどにより単離精製することができる。
一般式（１）で示されるベンゾジアゼピン誘導体の塩は医薬的に許容しうるものであれば良く、式中の塩基性基に対しては、例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸等の鉱酸、ギ酸、酢酸、乳酸、サリチル酸、マンデル酸、クエン酸、シュウ酸、マレイン酸、フマル酸、酒石酸、タンニン酸、リンゴ酸、トシル酸、メタンスルホン酸、ベンゼンスルホン酸などの有機酸との酸付加塩を挙げることができる。また、式中にカルボキシル基等の酸性基が存在する場合の酸性基に対しては、例えば、アンモニウム塩、ナトリウム、カリウム等のアルカリ金属との塩、カルシウム、マグネシウム等のアルカリ土類金属との塩、アルミニウム塩、亜鉛塩、トリエチルアミン、エタノールアミン、モルホリン、ピペリジン、ジシクロへキシルアミン等の有機アミンとの塩、アルギニン、リジン等の塩基性アミノ酸との塩基付加塩を挙げることができる。
【００７４】
又、本発明の一般式（１）で示される化合物にはその溶媒和物、例えば水和物、アルコール付加物等も含んでいる。
一般式（１）で示される化合物またはその塩は、そのままあるいは各種の医薬組成物として投与される。このような医薬組成物の剤形としては、例えば錠剤、散財、丸剤、顆粒剤、カプセル剤、坐剤、溶液剤、糖衣剤、またはデボー剤にしてよく、普通の製剤助剤を用いて常法に従って製造する事ができる。例えば錠剤は、本発明の有効成分であるベンゾジアゼピン誘導体を既知の補助物質、例えば乳糖、炭酸カルシウムまたは燐酸カルシウム等の不活性希釈剤、アラビアゴム、コーンスターチまたはゼラチン等の結合剤、アルギン酸、コーンスターチまたは前ゼラチン化デンプン等の膨化剤、ショ糖、乳糖またはサッカリン等の甘味剤、ペパーミント、またはチェリー等の香味剤、ステアリン酸マグネシウム、タルクまたはカルボキシメチルセルロース等の滑湿剤と混合することによって得られる。
【００７５】
一般式（１）で示されるベンゾジアゼピン誘導体またはその塩を有効成分とする抗血液凝固剤は、脳梗塞、脳血栓、脳塞栓、一過性脳虚血発作（ＴＩＡ）、くも膜下出血（血管れん縮）等の脳血管障害における疾病、急性及び慢性心筋梗塞、不安定狭心症、冠動脈血栓溶解等の虚血性心疾患における疾病、肺梗塞、肺塞栓等の肺血管障害における疾病、末梢動脈閉塞症、深部静脈血栓症、汎発性血管内凝固症候群、さらに人工血管術及び人工弁置換後の血栓形成、冠動脈バイパス術後における再閉塞及び再狭窄、経皮的経管式冠動脈形成術（ＰＴＣＡ）または経皮的経管式冠動脈再開通療法（ＰＴＣＲ）等の血行再建後の再閉塞及び再狭窄、体外循環時の血栓形成などの予防・治療剤として利用できる。
【００７６】
一般式（１）で示されるベンゾジアゼピン誘導体を抗血液凝固剤として使用する場合の投与経路は、経口、非経口のいずれであってもよく、投与量は患者の年齢、体重、状態、および投与法によって異なるが、成人への一日当りの投与量としては、通常、経口投与の場合で０．０１〜１０００ｍｇ、好ましくは０．１〜５０ｍｇであり、非経口投与の場合で１μｇ〜１００ｍｇ、好ましくは０．０１〜１０ｍｇである。
【００７７】
実施例
以下の実施例により本発明を詳細に説明する。これらは本発明の好ましい実施態様でありこれら実施例に限定されるものではない。
実施例１ ４−（（５−クロロ（２−チエニル））カルボニル）−６−フルオロ−１−［２−（４−イソプロピル−１，４−ジアゼパン−１−イル）エチル］−１，３，４，５テトラヒドロベンゾ［e］［1,4］ジアゼピン−２−オン 二トリフルオロ酢酸塩の合成
【００７８】
工程１ ｔ−ブチル ４−［２−（ベンジルオキシ）エチル］−１，４−ジアゼパン−１−カルボキシレートの合成
ｔ−ブチル １，４−ジアゼパン−１−カルボキシレート１．００６ｇ（５．０２ｍｍｏｌ）、２−（ベンジルオキシ）エチルブロマイド０．７９４ｍｌ（５．０２ｍｍｏｌ）、炭酸カリウム３．１３５ｇ（２２．７ｍｍｏｌ）、ヨウ化ナトリウム１６７ｍｇ（１．１１ｍｍｏｌ）をトルエン２５ｍｌ中１００℃で９．５時間加熱攪拌した。室温で濾過、濾液を減圧下留去、残渣をシリカゲルクロマトグラフィーで精製し表題化合物を得た。
収量 ７５２ｍｇ（２．２５ｍｍｏｌ） 収率 ４５％
MS (ESI, m/z) 335(MH+)
H-NMR (CDCl3)δ1.46 (9H, s), 1.75-1.88 (2H, m), 2.63-2.78 (4H, m), 2.75 (2H, t), 3.38-3.53 (4H, m), 3.56 (2H, t), 4.53 (2H, s), 7.27-7.38 (5H, m)
【００７９】
工程２ ｔ−ブチル ４−（２−ヒドロキシエチル）−１，４−ジアゼパン−１−カルボキシレートの合成
ｔ−ブチル ４−［２−（ベンジルオキシ）エチル］−１，４−ジアゼパン−１−カルボキシレート７４８ｍｇ（２．２４ｍｍｏｌ）をエタノール２０ｍｌ中、１０％パラジウム−炭素の存在下５０℃４気圧で水素添加を行った。常法に従って後処理を行い表題化合物を得た。
収量 ４８５ｍｇ（１．９９ｍｍｏｌ） 収率 ８９％
MS (ESI, m/z) 245(MH+)
H-NMR (CDCl3)δ1.47 (9H, s), 1.83-1.96 (2H, m), 2.68-2.85 (6H, m), 3.42-3.58 (4H, m), 3.61 (2H, t)
【００８０】
工程３ ｔ−ブチル ４−（２−クロロエチル）−１，４−ジアゼパン−１−カルボキシレートの合成
ｔ−ブチル ４−（２−ヒドロキシエチル）−１，４−ジアゼパン−１−カルボキシレート１９１ｍｇ（０．７８ｍｍｏｌ）をジクロロメタン５ｍｌに溶解しメタンスルホニルクロライド０．０７ｍｌ（０．９０ｍｍｏｌ）、トリエチルアミン０．１４ｍｌ（１．０ｍｍｏｌ）を加え室温で１晩攪拌した。溶媒を減圧下留去、残渣をシリカゲルクロマトグラフィーで精製し表題化合物を得た。
収量 １５６ｍｇ（０．５９ｍｍｏｌ） 収率 ７６％
H-NMR (CDCl3)δ1.46 (9H, s), 1.75-1.87 (2H, m), 2.67-2.80 (4H, m), 2.87 (2H, t), 3.38-3.58 (4H, m), 3.54 (2H, t)
【００８１】
工程４ （２−フルオロ−６−ニトロベンジル）アミノ酢酸エチルの合成
２−フルオロ−６−ニトロトルエン５．０ｇ（３２．２ｍｍｏｌ）、Ｎ−ブロモサクシイミド６．３ｇ（３５．４ｍｍｏｌ）、過安息香酸５０ｍｇをベンゼン５０ｍｌに溶解し、８５℃で２日間撹拌した。溶媒を減圧留去した後、ヘキサンを加えて析出した結晶を濾別した。濾液を濃縮、乾燥し、エタノール１００ｍｌ、グリシンエチルエステル塩酸塩１０．３ｇ（７３．８ｍｍｏｌ）、炭酸水素ナトリウム６．２ｇ（７３．８ｍｍｏｌ）を加えて８０℃で６時間撹拌した。溶媒を減圧留去した後、水と酢酸エチルに分配した。１規定塩酸にて抽出し、得られた水層を水酸化ナトリウム溶液により塩基性にして酢酸エチルで抽出した。得られた有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を留去して表題化合物を得た。
収量 ５．６ｇ（２２．０ｍｍｏｌ） 収率 ６８％
H-NMR (CDCl3)δ 1.26 (3H, t, J=6.6Hz), 3.45 (2H, s), 4.08 (2H, s), 4.16 (2H, q, J=6.6Hz), 7.31-7.47 (2H, m), 7.74 (1H, d, J=7.8Hz)
【００８２】
工程５ ４−（（５−クロロ（２−チエニル））カルボニル）−６−フルオロ−１，３，４，５テトラヒドロベンゾ［e］［1,4］ジアゼピン−２−オンの合成
（２−フルオロ−６−ニトロベンジル）アミノ酢酸エチル５．６ｇ（２２．０ｍｍｏｌ）をジクロロメタン１５０ｍｌに溶解し、トリエチルアミン３．０ｍｌ（２２．０ｍｍｏｌ）とジ−ｔ−ブチルジカルボネート４．８ｇ（２２．４ｍｍｏｌ）を加え、室温で一晩撹拌した。ジクロロメタンを抽出溶媒として処理した後、得られた粗製物をエタノールに溶解して１０％パラジウム−炭素を加え、水素存在下室温で一晩撹拌した。反応液をセライト濾過した後、濾液の溶媒を留去して得られた粗製物にＴＨＦ２０ｍｌと１Ｍ水酸化リチウム溶液２７ｍｌを加えて４時間撹拌した。溶媒を留去した後、ＤＭＦ／ジクロロメタン（１／１）溶液１００ｍｌに溶解し、２−クロロ−１、３−ジメチルイミダゾリニウムクロライド４．５ｇ（２６．５ｍｍｏｌ）とトリエチルアミン４．６ｍｌ（３３．２ｍｍｏｌ）を加えて一晩撹拌した。ジクロロメタンを抽出溶媒として処理し、粗生成物６．４ｇを得た。粗生成物のうち１ｇを４規定塩酸ジオキサン５ｍｌに溶解し、室温で１時間撹拌した。溶媒を留去して粗生成物０．７５ｇを得た。粗生成物うちの０．３２ｇをＤＭＦ５ｍｌに溶解し、２−クロロ−１、３−ジメチルイミダゾリニウムクロライド０．３３ｇ（２．０ｍｍｏｌ）とトリエチルアミン０．８４ｍｌ（６．１ｍｍｏｌ）を加えて室温で２時間撹拌した。ジクロロメタンを抽出溶媒として抽出し、析出した結晶を濾取、減圧乾燥した。
収量 ０．１６ｇ（０．４９ｍｍｏｌ） 収率 １９％
MS (ESI, m/z) 325(MH+)
H-NMR (CDCl3)δ 4.53 (2H, brs), 5.00 (2H, brs), 6.80-7.13 (3H, m), 7.20-7.42 (2H, m), 8.22 (1H, brs)
【００８３】
工程６ ４−（（５−クロロ（２−チエニル））カルボニル）−６−フルオロ−１−［２−（４−イソプロピルジアゼパン−１−イル）エチル］−１，３，４，５テトラヒドロベンゾ［e］［1,4］ジアゼピン−２−オン 二トリフルオロ酢酸塩の合成
ヘキサン洗浄した水素化ナトリウム４ｍｇ（０．１０ｍｍｏｌ）をＤＭＦ５ｍｌに懸濁し、４−（（５−クロロ（２−チエニル））カルボニル）−６−フルオロ−１，３，４，５テトラヒドロベンゾ［e］［1,4］ジアゼピン−２−オン２４ｍｇ（０．０７５ｍｍｏｌ）を加えて室温で３０分撹拌した。次いで、工程３で得られるｔ−ブチル ４−（２−クロロエチル）−１，４−ジアゼパン−１−カルボキシレート２０ｍｇ（０．０７６ｍｍｏｌ）を加え、６５℃で３時間撹拌した。溶媒を減圧留去した後、残査に４規定塩酸ジオキサン５ｍｌを加えて１時間攪拌した。溶媒を減圧留去した後、残査の３分の２をジクロロメタン８ｍｌに溶解し、アセトン２ｍｌ、酢酸２０ｍｇ（０．３３ｍｍｏｌ）、ナトリウムトリアセトキシボロハイドライド８０ｍｇ（０．３８ｍｍｏｌ）を加えて室温で一晩撹拌した。溶媒を留去して得られた粗製物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶液で溶出し目的のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １９．４ｍｇ（０．０２７ｍｍｏｌ） 収率 ５４％
MS (ESI, m/z) 493 (MH+)
H-NMR (DMSO-d6)δ 1.18 (6H, d, J=6.6Hz), 1.88-2.18 (2H, m), 2.80-3.60 (11H, m), 4.05-4.20 (4H, m), 4.60-4.85 (2H, m), 7.20-7.32 (2H, m), 7.42-7.60 (3H, m)
【００８４】
実施例２ ４−（（５−クロロ（２−チエニル））カルボニル）−６−フルオロ−１−［２−（４−メチル−１，４−ジアゼパン−１−イル）エチル］−１，３，４，５テトラヒドロベンゾ［e］［1,4］ジアゼピン−２−オン 二トリフルオロ酢酸塩の合成
実施例１の工程６と同様の操作で、アセトンの代わりにパラホルムアルデヒドを用いて表題化合物を得た。
収量 １１．５ｍｇ（０．０１７ｍｍｏｌ） 収率 ６６％
MS (ESI, m/z) 465 (MH+)
H-NMR (DMSO-d6)δ 1.88-2.18 (2H, m), 2.78 (3H, s), 2.80-3.58(11H, m), 4.05-4.20 (4H, m), 4.60-4.4.85 (2H, m), 7.20-7.32 (2H, m), 7.42-7.60 (3H, m)
【００８５】
実施例３ ４−（（５−クロロ（２−チエニル））カルボニル）−１−［２−（４−イソプロピル−１，４−ジアゼパン−１−イル）エチル］−６−メトキシ−１，３，４，５テトラヒドロベンゾ［e］［1,4］ジアゼピン−２−オン 二トリフルオロ酢酸塩の合成
４−（（５−クロロ（２−チエニル））カルボニル）−６−メトキシ−１，３，４，５テトラヒドロベンゾ［e］［1,4］ジアゼピン−２−オンより実施例１の工程６と同様の操作で表題化合物を得た。
収量 １８．８ｍｇ（０．０２６ｍｍｏｌ） 収率 ２７％
MS (ESI, m/z) 505 (MH+)
H-NMR (DMSO-d6)δ 1.18 (6H, d, J=6.6Hz), 1.85-2.20 (2H, m), 2.80-3.92 (14H, m), 3.94-4.93 (6H, m), 7.01-7.80 (5H, m)
【００８６】
実施例４ 活性化血液凝固第Ｘ因子阻害活性の測定
評価化合物の水溶液１０μｌにｐＨ８．４に調製した１００ｍＭトリス−塩酸緩衝液１３０μｌを加え、次いでヒト活性化血液凝固第Ｘ因子（Enzyme Research社製）をｐＨ８．４トリス−塩酸緩衝液で０．５ユニット／ｍｌに調製した溶液１０μｌを加え、室温で１０分間インキュベートした。次いで、Ｎ−ベンゾイル−Ｌ−イソロイシル−Ｌ−グルタミル−グリシル−Ｌ−アルギニル−Ｐ−ニトロアニリド塩酸塩（（（株）ペプチド研究所 製）をｐＨ８．４トリス−塩酸緩衝液で０．８ｍＭに調製した溶液５０μｌを加え、吸光度を測定し、反応初速度を求めた。評価化合物の溶液の代わりにｐＨ８．４に調製したトリス−塩酸緩衝液１０μｌを加えたものをコントロールとした。吸光度の測定はMICROPLATE READER Model 3550-UV（BIO RAD）を用い、４０５ｎｍの波長で１５秒間隔で１６分間測定した。評価化合物無添加の時の活性化血液凝固第Ｘ因子の活性（初速度）を５０％阻害するときの評価化合物の濃度の負の対数値を求め（ｐＩＣ５０と略す）、活性化血液凝固第Ｘ因子阻害活性の指標とした。代表的な化合物の活性化血液凝固第Ｘ因子阻害活性を表１に示す。
【００８７】
実施例５ トロンビン阻害活性の測定
評価化合物の水溶液１０μｌにｐＨ８．４に調製した１００ｍＭトリス−塩酸緩衝液１３０μｌを加え、次いでヒトのトロンビン（SIGMA社製）をｐＨ８．４トリス−塩酸緩衝液で２ユニット／ｍｌに調製した溶液１０μｌを加え、室温で１０分間インキュベートした。次いで、Ｄ−フェニルアラニル−Ｌ−ピペコリル−Ｌ−アルギニル−Ｐ−ニトロアニリド二塩酸塩（第一化学薬品、Ｓ−２２３８）をｐＨ８．４トリス−塩酸緩衝液で０．４ｍＭに調製した溶液５０μｌを加え、吸光度を測定し、反応初速度を求めた。評価化合物の溶液の代わりにｐＨ８．４に調製したトリス−塩酸緩衝液１０μｌを加えたものをコントロールとした。吸光度の測定はMICROPLATE READER Model 3550-UV（BIO RAD）を用い、４０５ｎｍの波長で１５秒間隔で１６分間測定した。評価化合物無添加の時のトロンビンの活性（初速度）を５０％阻害するときの評価化合物の濃度の負の対数値を求め（ｐＩＣ５０と略す）、トロンビン阻害活性の指標とした。代表的な化合物のトロンビン阻害活性を表１に示す。
【００８８】
実施例６ 抗血液凝固活性の測定
抗血液凝固活性はプロトロンビン時間（ＰＴ）測定法を用いて決定した。ＰＴ測定は以下に示す通りに行った。すなわち、健常人より採血を行い、３．８％クエン酸三ナトリウム水溶液を１０分の１容量加え、遠心操作により血漿を分離した。血漿４５μｌに評価化合物を含むＤＭＳＯ溶液５μｌを加え、室温で２分間インキュベートした。その血漿溶液を含む試験管をSysmex CA-3000全自動血液凝固測定装置（東亜医用電子社）に設置後、３７℃で３分間インキュベートし、Sysmex PT II（東亜医用電子社、ウサギ脳組織トロンボプラスチン、１３．２ｍＭ塩化カルシウム）１００μｌを加えた。ＰＴは同装置により自動測定した。評価化合物の溶液の代わりにＤＭＳＯ５μｌを加えたものをコントロールとし、コントロールのＰＴを２倍に延長する評価化合物濃度の負の対数値を求め（ｐＰＴ２と略す）、抗血液凝固活性の指標とした。
表１

この結果より本発明のベンゾジアゼピン誘導体は、活性化血液凝固第Ｘ因子に特異的な高い阻害活性を示し、これに基づく高い抗凝固活性を示すことがわかる。
以下、実施例で述べた本発明化合物の構造式を示す。

本発明化合物又はその塩を有効成分とする抗血液凝固剤は優れた活性化血液凝固第Ｘ因子阻害作用に基づく抗血液凝固作用を示す。本発明の化合物又はその塩を有効成分とする抗血液凝固剤はまた、経口吸収性にも優れる。従って、本発明化合物は脳梗塞、脳血栓、脳塞栓、一過性脳虚血発作（ＴＩＡ）、くも膜下出血（血管れん縮）等の脳血管障害における疾病、急性及び慢性心筋梗塞、不安定狭心症、冠動脈血栓溶解等の虚血性心疾患における疾病、肺梗塞、肺塞栓等の肺血管障害における疾病、末梢動脈閉塞症、深部静脈血栓症、汎発性血管内凝固症候群、さらに人工血管術及び人工弁置換後の血栓形成、冠動脈バイパス術後における再閉塞及び再狭窄、経皮的経管式冠動脈形成術（ＰＴＣＡ）または経皮的経管式冠動脈再開通療法（ＰＴＣＲ）等の血行再建後の再閉塞及び再狭窄、体外循環時の血栓形成などの予防・治療剤として利用できる。[0001]
BACKGROUND OF THE INVENTION
The present invention is caused by novel orally administrable benzodiazepine derivatives capable of reversibly inhibiting activated blood coagulation factor X and exhibiting a strong anticoagulant action, and blood coagulation inhibitors or thrombi or emboli containing them as active ingredients The present invention relates to a preventive / therapeutic agent for diseases. Examples of the diseases to be applied include diseases in cerebrovascular disorders such as cerebral infarction, cerebral thrombus, cerebral embolism, transient cerebral ischemic attack (TIA), subarachnoid hemorrhage (vasospasm), acute and chronic myocardial infarction, unstable narrowness Diseases in ischemic heart diseases such as heart disease, coronary artery thrombolysis, diseases in pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism, peripheral arterial occlusion, deep vein thrombosis, generalized intravascular coagulation syndrome, and artificial vascular surgery Revascularization such as thrombus formation after prosthetic valve replacement, reocclusion and restenosis after coronary artery bypass grafting, percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary artery recurrent therapy (PTCR) Later reocclusion and restenosis, thrombus formation during extracorporeal circulation, and the like.
[0002]
[Prior art]
Thromboembolic diseases such as myocardial infarction, cerebral thrombosis, and peripheral arterial thrombosis tend to increase year by year as the lifestyles become westernized and the population ages, and the social importance of treatment is increasing It is growing. Anticoagulant therapy is part of a medical therapy in the treatment and prevention of thrombosis along with fibrinolysis and antiplatelet therapy. Conventionally, antithrombin agents have been developed as thrombus formation inhibitors, but thrombin not only controls the activation of fibrinogen, which is the final stage of the coagulation reaction, but also deeply activates and aggregates platelets. Because of its involvement, its inhibition was known to be at risk of bleeding tendency. In addition, the bioavailability of oral administration is low, and no thrombin inhibitor that can be administered orally has been marketed.
Activated blood coagulation factor X is located at the confluence of extrinsic and intrinsic coagulation cascade reactions and is located upstream of thrombin, so that inhibition of this factor is more efficient and specific than thrombin inhibition The system may be inhibited [Tidwell, R .; Webster, WP; Shaver, SR; Geratz, JD THROMBOSIS RESEARCH 19: 339-349, 1980].
[0003]
[Problems to be solved by the invention]
An object of the present invention is to provide a compound having an excellent activated blood coagulation factor X inhibitory action.
It is an object of the present invention to provide a compound having an inhibitory action specific to activated blood coagulation factor X that can be administered orally.
An object of the present invention is to provide a pharmaceutical composition containing the above compound.
An object of the present invention is to provide an anticoagulant or a prophylactic or therapeutic agent for thrombus or embolus containing the above compound.
[0004]
[Means for Solving the Problems]
As a result of conducting various studies in view of the above circumstances, the present inventors have found that a specific novel benzodiazepine derivative has an activated blood coagulation factor X inhibitory effect, and further, as a result of various studies on the substituents thereof, It has been found that a compound in which the ring C in the following general formula (1) is a specific carbocyclic ring containing a nitrogen atom has an excellent activated blood coagulation factor X inhibitory action. Furthermore, the present inventors have found that these series of compounds are useful as preventive and therapeutic agents for various diseases based on thrombus / emboli, and have completed the present invention.
[0005]
That is, the present invention provides a benzodiazepine derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof.

(1)
[In general formula (1),
Ring A represents any of an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms, or a cyclic alkyl group having 4 to 10 carbon atoms,
[0006]
R1 represents a hydrogen atom, a halogeno group, an optionally substituted hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a nitro group, a formyl group, a trifluoromethyl group, a trifluoromethoxy group, or a trifluoromethanesulfonyloxy group. , Methylenedioxy group, carbamoyl group, thiocarbamoyl group, mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, cyano group, mono- or dialkylamino group having 1 to 6 carbon atoms, carboxyl group, alkoxy having 2 to 7 carbon atoms Carbonyl group, C3-C7 hydroxycarbonylalkenyl group, C4-C8 alkoxycarbonylalkenyl group, phosphono group, C2-C9 dialkoxyphosphoryl group, C1-C4 monoalkoxyhydroxyphosphoryl group , An alkylthio group having 1 to 6 carbon atoms, A killsulfonyl group, an aminosulfonyl group, a mono- or dialkylaminosulfonyl group having 2 to 8 carbon atoms, an optionally substituted alkyl group having 1 to 6 carbon atoms, and an optionally substituted carbon group having 6 to 6 carbon atoms. 10 aryl groups, optionally substituted heteroaryl groups having 1 to 10 carbon atoms, optionally substituted arylsulfonyl groups having 6 to 10 carbon atoms, and optionally substituted carbons A heteroarylsulfonyl group having 4 to 10 carbon atoms, an arylthio group having 6 to 10 carbon atoms that may have a substituent, a heteroarylthio group having 4 to 10 carbon atoms that may have a substituent, and a substituent; An optionally substituted acyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms which may have a substituent, and a substituent. Substituted with a heteroaryl group having 5 to 10 carbon atoms An alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms substituted with an alkyl group having 1 to 6 carbon atoms which may have a substituent, and 1 to carbon atoms which may have a substituent A heteroaryl group having 5 to 10 carbon atoms substituted with 6 alkyl groups, a mono- or dialkylamino group having 1 to 6 carbon atoms, an amino group which may have a substituent, and an optionally substituted carbon A number 1-7 aminoalkyl group, a pyrrolidine group that may have a substituent, a pyrrolidyloxy group that may have a substituent, a piperidine group that may have a substituent, and a substituent A piperidyloxy group which may have a substituent, a piperazine group which may have a substituent, a piperazinecarbonyl group which may have a substituent, an amidino group which may have a substituent or a guanidino group which may have a substituent Represents one of the following:
[0007]
Here, when R1 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group, or a carbamoyl group. Group, mono or dialkylcarbamoyl group having 2 to 7 carbon atoms, amino group, aminoalkyl group having 1 to 7 carbon atoms, mono or dialkylamino group having 1 to 6 carbon atoms, amidino group, mono or 2 to 7 carbon atoms A dialkylamidino group, a C4-7 trialkylamidino group, a C5-8 tetraalkylamidino group, a guanidino group, a C3-8 dialkylguanidino group, a C4-9 trialkylguanidino group, The number of carbon atoms substituted by an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, and an aryl group having 6 to 10 carbon atoms An alkyl group having 6 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with a heteroaryl group having 5 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms substituted with an alkyl group having 1 to 6 carbon atoms, carbon C5-C10 heteroaryl group substituted with C1-C6 alkyl group, C6-C10 arylsulfonyl group, C4-C10 heteroarylsulfonyl group, carboxyl group, carbon number 1 to 6 carbon atoms optionally substituted with an alkyl group having 1 to 6 carbon atoms, including one or more heteroatoms selected from 2 to 7 alkoxycarbonyl groups, nitrogen, oxygen and sulfur Carbonyl substituted with a C1-C6 carbocyclic ring optionally substituted with a C1-C6 alkyl group containing one or more heteroatoms selected from any of ring, nitrogen, oxygen and sulfur Group, 7-10 carbon atoms Iminoalkylpiperazinecarbonyl group, piperidyloxy group, alkylpiperidyloxy group having 6 to 10 carbon atoms, iminoalkylpiperidyloxy group having 7 to 10 carbon atoms, pyrrolidyloxy group, alkylpyrrolidyloxy group having 6 to 10 carbon atoms, C7-10 iminoalkylpyrrolidyloxy group, methylenedioxy group, cyano group, C2-7 iminoalkyl group, C1-8 acyl group, phosphono group, C2-9 di Represents an alkoxyphosphoryl group, a monoalkoxyhydroxyphosphoryl group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an aminosulfonyl group, or a dialkylaminosulfonyl group having 2 to 8 carbon atoms,
[0008]
Ring B represents any of an aryl group having 6 to 10 carbon atoms and a heteroaryl group having 3 to 10 carbon atoms,
Ring C represents a non-aromatic carbocycle having 2 to 8 carbon atoms containing at least one nitrogen atom, and may contain one or more heteroatoms selected from oxygen and / or sulfur, provided that pyrrolidyl Group, piperidyl group or piperazinyl group,
[0009]
R2 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, a hydroxyalkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, an alkoxyalkyl group having 1 to 10 carbon atoms, Nitro group, formyl group, trifluoromethoxy group, trifluoromethyl group, carbamoyl group, thiocarbamoyl group, mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, amino group, mono- or dialkylamino group having 1 to 6 carbon atoms, C1-C9 aminoalkyl group, C2-C9 mono- or dialkylaminoalkyl group, amidino group, C2-C7 mono- or dialkylamidino group, C4-C7 trialkylamidino group, carbon A tetraalkylamidino group having 5 to 8 carbon atoms, a guanidino group, a dialkylguanidino group having 3 to 8 carbon atoms, 4 to 9 prime trialkylguanidino group, methylenedioxy group, cyano group, iminoalkyl group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, piperidyloxy group, alkylpiperidyloxy group having 6 to 10 carbon atoms Group, iminoalkylpiperidyloxy group having 6 to 10 carbon atoms, alkoxycarbonylpiperidyloxy group having 8 to 14 carbon atoms, pyrrolidyloxy group, alkylpyrrolidyloxy group having 5 to 9 carbon atoms, imino having 5 to 9 carbon atoms Alkylpyrrolidyloxy group, C7-13 alkoxycarbonylpyrrolidyloxy group, pyrrolidine group, C5-9 alkylpyrrolidine group, C5-9 iminoalkylpyrrolidine group, piperidine group, carbon number 6-10 alkyl piperidine groups, 6-10 carbon iminoalkyl piperidine groups, piperazine groups, carbon An alkylpiperazine group having 5 to 13 carbon atoms, an iminoalkylpiperazine group having 6 to 9 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, and an aryl group having 6 to 10 carbon atoms Rusulfonyl group, heteroarylsulfonyl group having 4 to 10 carbon atoms, iminoalkylpiperazinecarbonyl group having 7 to 10 carbon atoms, alkylpiperazinecarbonyl group having 6 to 10 carbon atoms, piperazinesulfonyl group, alkyl having 5 to 9 carbon atoms Piperazinesulfonyl group, iminoalkylpiperazinesulfonyl group having 6 to 9 carbon atoms, 1 to 8 alkylsulfonyl group, aminosulfonyl group, mono or dialkylaminosulfonyl group having 2 to 8 carbon atoms, piperidylalkyl group having 6 to 9 carbon atoms Or an iminoaluminum piperidylalkyl group having 8 to 12 carbon atoms,
[0010]
R3 is a hydrogen atom, halogeno group, hydroxyl group, alkoxyl group having 1 to 10 carbon atoms, nitro group, formyl group, trifluoromethyl group, trifluoromethoxy group, carbamoyl group, thiocarbamoyl group, 2 to 7 carbon atoms Mono or dialkylcarbamoyl group, methylenedioxy group, cyano group, iminoalkyl group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, alkoxycarbonyl group having 2 to 7 carbon atoms, piperidyloxy group, 6 carbon atoms -10 iminoalkylpiperidyloxy group, C5-10 alkylpiperidyloxy group, C8-14 alkoxycarbonylpiperidyloxy group, pyrrolidyloxy group, C5-9 iminoalkylpyrrolidyloxy group, C5-C10 alkylpyrrolidyloxy group, C7-C13 alkoxy group Bonylpyrrolidyloxy group, arylsulfonyl group having 6 to 10 carbon atoms, heteroarylsulfonyl group having 4 to 10 carbon atoms, iminoalkylpiperazinecarbonyl group having 7 to 10 carbon atoms, piperazinesulfonyl group, and 6 to 6 carbon atoms 9 iminoalkylpiperazinesulfonyl groups, optionally substituted alkyl groups having 1 to 6 carbon atoms, mono- or dialkylamino groups having 1 to 6 carbon atoms, optionally substituted amino groups, substituents A C1-C9 aminoalkyl group which may have a substituent, a pyrrolidine group which may have a substituent, a piperidyl group which may have a substituent, a piperazine group which may have a substituent, a substituent An aryl group having 6 to 10 carbon atoms which may have a group, a heteroaryl group having 1 to 10 carbon atoms which may have a substituent, and an alkyl group having 1 to 6 carbon atoms which may have a substituent Replace with Carbon atoms having 6 to 10 carbon atoms, optionally substituted heteroaryl groups having 5 to 10 carbon atoms substituted with alkyl groups having 1 to 6 carbon atoms, and optionally substituted carbons. An alkyl group having 1 to 6 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with an optionally substituted heteroaryl group having 5 to 10 carbon atoms, Represents an amidino group which may have a substituent, a guanidino group which may have a substituent, a piperidylalkyl group having 6 to 9 carbon atoms or an iminoaluminum piperidylalkyl group having 8 to 12 carbon atoms,
[0011]
When R3 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, a hydroxyalkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, or 1 to 1 carbon atoms. 10 alkoxyalkyl groups, nitro group, formyl group, trifluoromethoxy group, trifluoromethyl group, carbamoyl group, thiocarbamoyl group, mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, amino group, 1 to 6 carbon atoms Mono- or dialkylamino group, C1-C9 aminoalkyl group, C2-C9 mono- or dialkylaminoalkyl group, amidino group, C2-C7 mono- or dialkylamidino group, C4-C7 Trialkylamidino group, C5-C8 tetraalkylamidino group, guanidino group, C3-C8 dial Luguanidino group, trialkylguanidino group having 4 to 9 carbon atoms, methylenedioxy group, cyano group, iminoalkyl group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, piperidyloxy group, 6 to 10 carbon atoms Alkylpiperidyloxy group, iminoalkylpiperidyloxy group having 6 to 10 carbon atoms, alkoxycarbonylpiperidyloxy group having 8 to 14 carbon atoms, pyrrolidyloxy group, alkylpyrrolidyloxy group having 5 to 9 carbon atoms, carbon number 5 -9 iminoalkylpyrrolidyloxy group, C7-13 alkoxycarbonylpyrrolidyloxy group, pyrrolidine group, C5-9 alkylpyrrolidine group, C5-9 iminoalkylpyrrolidine group, piperidine Group, an alkyl piperidine group having 6 to 10 carbon atoms, an iminoalkyl piperidine group having 6 to 10 carbon atoms, Piperazine group, alkylpiperazine group having 5 to 13 carbon atoms, iminoalkylpiperazine group having 6 to 9 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, and 6 to 6 carbon atoms 10 arylsulfonyl groups, heteroarylsulfonyl groups having 4 to 10 carbon atoms, iminoalkylpiperazinecarbonyl groups having 7 to 10 carbon atoms, alkylpiperazinecarbonyl groups having 6 to 10 carbon atoms, piperazinesulfonyl groups, 5 carbon atoms Represents an alkylpiperazinesulfonyl group of -9, an iminoalkylpiperazinesulfonyl group of 6-9 carbon atoms, an alkylsulfonyl group of 1-8 carbon atoms, an aminosulfonyl group, or a mono- or dialkylaminosulfonyl group of 2-8 carbon atoms,
[0012]
R4, R5, R6, R7, R8 and R9 may be the same or different and each is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, an oxo group, a hydroxyl group, or a hydroxyalkyl having 1 to 10 carbon atoms. Group, alkoxy group having 1 to 10 carbon atoms, alkoxyalkyl group having 1 to 10 carbon atoms, nitro group, trifluoromethoxy group, trifluoromethyl group, amino group, mono- or dialkylamino group having 1 to 6 carbon atoms, carbon An aminoalkyl group having 1 to 9 carbon atoms, a mono- or dialkylaminoalkyl group having 2 to 9 carbon atoms, a methylenedioxy group, a cyano group, a formyl group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, and 3 to 3 carbon atoms 9 alkoxycarbonylalkyl groups, 3 to 9 hydroxycarbonylalkyl groups, 3 to 7 hydroxycarbonylalkenyl groups, carbon An alkoxycarbonylalkenyl group having 4 to 8 carbon atoms, a phosphono group, a dialkoxyphosphoryl group having 2 to 9 carbon atoms, a monoalkoxyhydroxyphosphoryl group having 1 to 4 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and 1 to 6 carbon atoms An alkylsulfonyl group, an arylthio group having 6 to 10 carbon atoms which may have a substituent, a heteroarylthio group having 4 to 10 carbon atoms which may have a substituent, a phosphorylalkyl group having 1 to 9 carbon atoms, Represents a dialkoxyphosphorylalkyl group having 3 to 9 carbon atoms, a monoalkoxyhydroxyphosphoryl group having 2 to 9 carbon atoms, a 2-carboxy-2-oxoethyl group, or a heteroaryl group having 1 to 10 carbon atoms,
[0013]
X represents an alkylene group having 1 to 6 carbon atoms (in the chain, -NH-, -C (= O)-, -NHC (= O)-, -C (= O) NH-, -NHC (= O ) May contain NH −), and
Z1 and Z2 may be the same or different from each other, and are a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a hydroxy group, a hydroxyalkyl group having 1 to 6 carbon atoms, or an alkoxyalkyl group having 2 to 6 carbon atoms. , A thioalkyl group having 1 to 6 carbon atoms, an alkylthioalkyl group having 2 to 8 carbon atoms, a carbamoylalkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, carbon C6-C10 aryl group substituted with C1-C6 alkyl group, C4-C10 heteroaryl group substituted with C1-C6 alkyl group, C1-C6 aminoalkyl Group, carboxyl group, C2-C6 alkoxycarbonyl group, C2-C8 hydroxycarbonylalkyl group, C3-C8 alkoxycarbonylalkyl group, C1-C6 amino acid It represents either a noalkyl group or a mono- or dialkylaminoalkyl group having 2 to 10 carbon atoms, and Z1 and Z2 may be bonded to form a ring, in which case -Z1-Z2- is an ethylene group Represents a trimethylene group or a tetramethylene group. ]
[0014]
The present invention also provides an activated blood coagulation factor X inhibitor containing the benzodiazepine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention also provides a pharmaceutical composition comprising the benzodiazepine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention also provides an anticoagulant or a prophylactic or therapeutic agent for thrombosis or embolism containing the benzodiazepine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
[0015]
DETAILED DESCRIPTION OF THE INVENTION
In the present specification, the aryl group refers to an aromatic hydrocarbon ring group having 6 to 10 carbon atoms. Specific examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group. Of these, a phenyl group is preferred.
Unless otherwise specified, “aryl” in the arylsulfonyl group and the like described in the present specification is also synonymous with the above-described aryl.
The heteroaryl group refers to an aromatic hydrocarbon ring group having 1 to 10 carbon atoms and having 1 to 3 heteroatoms selected from O, N and S. Specifically, pyridyl group, pyrimidyl group, pyridazinyl group, pyrazinyl group, imidazolyl group, pyrrolyl group, thienyl group, pyrazyl group, pyrazolyl group, pyrrolyl group, triazyl group, furyl group, isoxazolyl group, isothiazolyl group, indolyl group, A quinolyl group, an isoquinolyl group, a tetrazole group, etc. are mentioned. Among these, a C4-C10 heteroaryl group which has 1 or 2 N and / or S as a hetero atom is more preferable, and especially a pyridyl group and a thienyl group are preferable.
Unless otherwise specified, “heteroaryl” in the heteroarylsulfonyl group and the like described in the present specification is also synonymous with the above-described heteroaryl.
[0016]
The alkyl group means an alkyl group having 1 to 6 carbon atoms and may be linear, branched or cyclic. Among these, a C1-C3 alkyl group is preferable. Specifically, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, sec- and tert-butyl group, n-pentyl group, i-pentyl group, tert-pentyl group, neopentyl Group, 2-pentyl group, 3-pentyl group, n-hexyl group, 2-hexyl group and the like. Among these, a methyl group, an ethyl group, an n-propyl group, and an i-propyl group are preferable.
[0017]
A cyclic alkyl group refers to an alkyl group having 3 to 10 carbon atoms. A cyclic alkyl group having 5 or 6 carbon atoms is preferred. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Among these, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group is preferable, and a cyclohexyl group is particularly preferable.
Unless otherwise specified, “alkyl” in the hydroxyalkyl group and iminoalkyl group described in the present specification is also synonymous with the above-described alkyl.
An alkenyl group refers to an alkenyl group having a straight or branched chain having 2 to 6 carbon atoms. Specific examples include a vinyl group, a propenyl group, and a 2-methyl-1-propenyl group.
Unless otherwise specified, “alkenyl” in the hydroxycarbonylalkenyl group, alkoxycarbonylalkenyl group and the like described in the present specification is also synonymous with the above-mentioned alkenyl.
[0018]
Examples of the halogeno group include a fluoro group, a chloro group, a bromo group, and an iodo group. Of these, a fluoro group, a chloro group and a bromo group are preferred. A fluoro group and a chloro group are particularly preferred.
The alkoxyl group is an alkoxyl group having a linear or branched chain having 1 to 10 carbon atoms, an alkoxyl group having a cyclic alkyl group having 4 to 10 carbon atoms, or an alkoxyl group having an optionally condensed cyclic carbon chain. Indicates. Specifically, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, i-butoxy group, sec-butoxy group, tert-butoxy group, benzyloxy group, 2-phenylethoxy group, 3-phenylpropyloxy group, 4-phenylbutoxy group, 5-phenylpentyloxy group, 6-phenylhexyloxy group, cyclopropyloxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, 1-indanyloxy group And 2-indanyloxy group. Of these, a methoxy group, an ethoxy group, and an n-propoxy group are preferable.
Unless otherwise specified, “alkoxy” in the alkoxyalkyl group and alkoxycarbonylpiperidyloxy group described in the present specification is also synonymous with the above-described alkoxy.
[0019]
Examples of the mono- or dialkylcarbamoyl group include a methylcarbamoyl group, an ethylcarbamoyl group, a monoalkylcarbamoyl group such as an n-propylcarbamoyl group and an i-propylcarbamoyl group, a dimethylcarbamoyl group, a diethylcarbamoyl group, and di (n-propyl) carbamoyl. And dialkylcarbamoyl groups such as a di (i-propyl) carbamoyl group. Here, the chain lengths of the two alkyl groups of the dialkylcarbamoyl group may be the same or different. In addition, two alkyl groups of the dialkylcarbamoyl group may be bonded to form a ring, or an unsaturated hydrocarbon group may be included to form a ring. Also at this time -CH ₂ -One of the groups may be substituted with O, NH or S; Specifically, 1-pyrrolidinecarbonyl group, 2,5-dihydro-1H-pyrrol-1-ylcarbonyl group, 1-piperidinecarbonyl group, 1-piperazinecarbonyl group, (morpholin-4-yl) carbonyl group and ( And thiomorpholin-4-yl) carbonyl group. Among these, a dimethylcarbamoyl group, 1-pyrrolidinecarbonyl group, (morpholin-4-yl) carbonyl group, 2,5-dihydro-1H-pyrrol-1-ylcarbonyl group and (thiomorpholin-4-yl) carbonyl group preferable.
[0020]
Examples of the mono- or dialkylamino group having 1 to 6 carbon atoms include monoalkylamino groups such as methylamino group, ethylamino group, n-propylamino group and i-propylamino group, dimethylamino group, diethylamino group, di ( and dialkylamino groups such as n-propyl) amino group and di (i-propyl) amino group. Here, the chain lengths of the two alkyl groups of the dialkylamino group may be the same or different. Two alkyl groups of the dialkylamino group may be bonded to form a ring. Also at this time -CH ₂ -One of the groups may be substituted with O, NH or S; Specific examples include a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, and the like. Among these, a morpholinyl group and a thiomorpholinyl group are preferable.
[0021]
Examples of the alkoxycarbonyl group having 2 to 7 carbon atoms include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonyl group, sec-butoxycarbonyl group, and tert. -Butoxycarbonyl group etc. are mention | raise | lifted. Of these, a methoxycarbonyl group and an ethoxycarbonyl group are preferable.
Examples of the dialkoxyphosphoryl group having 2 to 9 carbon atoms include diethoxyphosphoryl group, di (n-propoxy) phosphoryl group, di (isopropoxy) phosphoryl group, di (n-butoxy) phosphoryl group, and di (i-butoxy). Examples thereof include a phosphoryl group, a di (sec-butoxy) phosphoryl group, and a di (tert-butoxy) phosphoryl group. Of these, a diethoxyphosphoryl group is preferred.
[0022]
As monoalkoxyhydroxyphosphoryl group, monomethoxyhydroxyphosphoryl group, monoethoxyhydroxyphosphoryl group, mono n-propoxyhydroxyphosphoryl group, monoisopropoxyhydroxyphosphoryl group, mono n-butoxyhydroxyphosphoryl group, mono i-butoxyhydroxyphosphoryl group Mono-sec-butoxyhydroxyphosphoryl group, mono-tert-butoxyhydroxyphosphoryl group, and the like. Of these, a monoethoxyhydroxyphosphoryl group is preferred.
[0023]
Examples of the alkylthio group include a methylthio group, an ethylthio group, an n-propylthio group, and an i-propylthio group. Of these, a methylthio group is preferred.
Examples of the alkylsulfonyl group include a methylsulfonyl group, an ethylsulfonyl group, a sulfonyl group, an n-propylsulfonyl group, and an i-propylsulfonyl group. Of these, a methylsulfonyl group is preferred.
[0024]
Examples of the mono- or dialkylaminosulfonyl group include a methylaminosulfonyl group, an ethylaminosulfonyl group, a n-propylaminosulfonyl group, a monoalkylaminosulfonyl group such as an i-propylaminosulfonyl group, a dimethylaminosulfonyl group, a diethylaminosulfonyl group, Examples thereof include dialkylaminosulfonyl groups such as di (n-propyl) aminosulfonyl group and di (i-propyl) aminosulfonyl group. Here, the chain lengths of the two alkyl groups of the dialkylaminosulfonyl group may be different. Further, two alkyl groups of the dialkylaminosulfonyl group may be bonded to form a ring. Also at this time -CH ₂ -One of the groups may be substituted with O, NH or S; Specific examples include (pyrrolidin-1-yl) sulfonyl group, (piperidin-1-yl) sulfonyl group, (morpholin-4-yl) sulfonyl group, and (thiomorpholin-4-yl) sulfonyl group. Of these, a (pyrrolidin-1-yl) sulfonyl group is preferred.
[0025]
Examples of the acyl group include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, and pivaloyl group.
Examples of the aminoalkyl group include an aminomethyl group, a 2-aminoethyl group, 2-aminopropyl, and 3-aminopropyl. Among these, a C1-C7 aminoalkyl group, especially a 3-aminopropyl group are preferable.
[0026]
Examples of the mono- or dialkylamidino group include monoalkylamidino groups such as methylamidino group and ethylamidino group, and dialkylamidino groups such as dimethylamidino group and diethylamidino group. Here, the chain lengths of the two alkyl groups of the dialkylamidino group may be different. Further, two alkyl groups of the dialkylamidino group may be bonded to form a ring, or may contain an unsaturated hydrocarbon group to form a ring. Also at this time -CH ₂ -One of the groups may be substituted with O, NH or S; Specifically, (pyrrolidin-1-yl) (imino) methyl group, (piperidin-1-yl) (imino) methyl group, 1,4,5,6, -tetrahydro-2-pyrimidinyl group, (morpholine- 4-yl) (imino) methyl group, 2,5-dihydro-1H-pyrrol-1-yl (imino) methyl group, (thiomorpholin-4-yl) (imino) methyl group and the like. Among these, 2,5-dihydro-1H-pyrrol-1-yl (imino) methyl group, dimethylamidino group, (pyrrolidin-1-yl) (imino) methyl group, (thiomorpholin-4-yl) (imino) A methyl group is preferred.
[0027]
Examples of the trialkylamidino group include a trimethylamidino group, a triethylamidino group, a tri (n-propyl) amidino group, and a tri (i-propyl) amidino group. Here, the chain lengths of the three alkyl groups of the trialkylamidino group may be different. Further, two of the three alkyl groups of the trialkylamidino group may be bonded to form a ring. Also at this time -CH ₂ -One of the groups may be substituted with O, NH or S; Specific examples include a 1-methyl-1H-imidazol-2-yl group and a 1-ethyl-1H-imidazol-2-yl group. Of these, a 1-methyl-1H-imidazol-2-yl group is preferred.
[0028]
Examples of the tetraalkylamidino group having 5 to 8 carbon atoms include (dimethylamino) (dimethyliminio) methyl group. Here, the chain lengths of the four alkyl groups of the tetraalkylamidino group may be the same or different. Further, two alkyl groups out of four alkyl groups of the tetraalkylamidino group may be bonded to form a ring. Also at this time -CH ₂ -One of the groups may be substituted with O, NH or S; Specifically, 1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium-2-yl group and 1-ethyl-3-methyl-4,5-dihydro-1H-imidazole-3- Examples thereof include an ium-2-yl group. Of these, a 1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium-2-yl group is preferable.
[0029]
Examples of the dialkylguanidino group include a dimethylguanidino group, a diethylguanidino group, a di (n-propyl) guanidino group, and a di (i-propyl) guanidino group. Here, the chain lengths of the two alkyl groups of the dialkylguanidino group may be different. Two alkyl groups of a dialkylguanidino group may be bonded to form a ring. Also at this time -CH ₂ -One of the groups may be substituted with O, NH or S; Specific examples include an imidazoline-2-amino group.
[0030]
Examples of the trialkyl guanidino group include a trimethyl guanidino group, a triethyl guanidino group, a tri (n-propyl) guanidino group, and a tri (i-propyl) guanidino group. Here, the chain lengths of the three alkyl groups of the trialkylguanidino group may be the same or different. Also, two of the three alkyl groups of the trialkylguanidino group may be bonded to form a ring. Also at this time -CH ₂ -One of the groups may be substituted with O, NH or S; Specifically, 1-methyl-2-imidazolin-2-yl-amino group, 1-ethyl-2-imidazolin-2-yl-amino group, 1- (n-propyl) -2-imidazolin-2-yl -Amino group and 1- (i-propyl) -2-imidazolin-2-yl-amino group and the like. Of these, a 1-methyl-2-imidazolin-2-yl-amino group is preferable.
[0031]
Examples of the alkyl piperazine carbonyl group having 6 to 10 carbon atoms include methyl piperazine carbonyl group, ethyl piperazine carbonyl group, n-propyl piperazine carbonyl group, i-propyl piperazine carbonyl group, n-butyl piperazine carbonyl group and i-butyl piperazine carbonyl group. , Sec-butyl piperazine carbonyl group, tert-butyl piperazine carbonyl group and the like. Among these, i-propyl piperazine carbonyl group is preferable.
[0032]
Mono- or dialkylaminoalkyl groups include methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminomethyl, ethylaminoethyl, ethylaminopropyl, n-propylaminomethyl, n-propylamino. Monoalkylaminoalkyl groups such as ethyl group, n-propylaminopropyl group, i-propylaminomethyl group, i-propylaminoethyl group and i-propylaminopropyl group, and dimethylaminomethyl group, dimethylaminoethyl group, dimethyl group Aminopropyl group, diethylaminomethyl group, diethylaminoethyl group, diethylaminopropyl group, di (n-propyl) aminomethyl group, di (n-propyl) aminoethyl group, di (n-propyl) aminopropyl group, di (i- Propyl) Nomechiru group, di (i-propyl) aminoethyl group and di (i-propyl) dialkylaminoalkyl groups such as aminopropyl group. Here, the chain lengths of the three alkyl groups of the dialkylaminoalkyl group may be the same or different. Further, two alkyl groups of a dialkylaminoalkyl group may be bonded to form a ring. Also at this time -CH ₂ -One of the groups may be substituted with O, NH or S; Specifically, (pyrrolidin-1-yl) methyl group, (pyrrolidin-1-yl) ethyl group, (pyrrolidin-1-yl) propyl group, (piperidin-1-yl group) methyl group, (piperidine-1) -Yl group) ethyl group, (piperidin-1-yl group) propyl group, (morpholin-4-yl) methyl group, (morpholin-4-yl) ethyl group, (morpholin-4-yl) propyl group, (thiol) Examples thereof include morpholin-1-yl) methyl group, (thiomorpholin-1-yl) ethyl group, and (thiomorpholin-1-yl) propyl group.
[0033]
Examples of the arylthio group include a phenylthio group and a naphthylthio group. Of these, a phenylthio group is preferred.
Examples of the heteroarylthio group include a thienylthio group, a pyridylthio group, an indolylthio group, and the like. Of these, a thienylthio group is preferable.
[0034]
The carbocyclic ring having 1 to 6 carbon atoms which is substituted with an alkyl group having 1 to 6 carbon atoms and includes one or more heteroatoms selected from nitrogen, oxygen and sulfur may have the following formula (3 ). The bonding position with other groups is not particularly limited.

[0035]
A structure represented by the following formula (4) is preferable.
Here, it is preferable that the nitrogen atom is substituted with an alkyl group having 1 to 6 carbon atoms.

[0036]
In particular, a group represented by the following general formula (2) is preferable.

[0037]
It may contain one or more heteroatoms selected from oxygen and / or sulfur, and contains at least one nitrogen atom excluding pyrrolidyl group, piperidyl group or piperazinyl group, and has 2 to 8 carbon atoms (preferably 4 to 6). Examples of the non-aromatic carbocycle include a structure represented by the following formula (5). Here, the non-aromatic carbocycle may have a double bond. The bonding position with X, R3, R8, or R9 is not particularly limited, but is preferably bonded with X or R3 at a nitrogen atom.
[0038]

More preferably, group represented by the said General formula (2) is mentioned.
[0039]
In the general formula (1), the ring A includes an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms (particularly a heteroaryl group having 4 to 10 carbon atoms, and more particularly 3 to 5 carbon atoms). A heteroaryl group) or a cyclic alkyl group having 5 or 6 carbon atoms. Among these, a phenyl group, a pyridyl group, a pyrazolyl group, and a cyclohexyl group are preferable. Further, a phenyl group is particularly preferable.
[0040]
As R1, a hydrogen atom, a halogeno group, a hydroxyl group which may have a substituent, an alkoxyl group having 1 to 10 carbon atoms, a trifluoromethyl group, a trifluoromethanesulfonyloxy group, a carbamoyl group, or a group having 2 to 7 carbon atoms Mono or dialkylcarbamoyl group, cyano group, nitro group, mono or dialkylamino group having 1 to 6 carbon atoms, amino group which may have a substituent, carboxyl group, alkoxycarbonyl group having 2 to 7 carbon atoms, carbon number An alkylthio group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms which may have a substituent, and an aminoalkyl having 2 to 7 carbon atoms which may have a substituent A group, a piperazinecarbonyl group which may have a substituent, an amidino group which may have a substituent, and the like are preferable.
R1 has a hydrogen atom, a fluoro group, a chloro group, a bromo group, an iodo group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, and a substituent. A hydroxyl group that may have a substituent, an alkyl group having 1 to 6 carbon atoms that may have a substituent, an alkylthio group having 1 to 6 carbon atoms that may have a substituent, or a carbon number that may have 1 substituent Also preferred are alkylsulfonyl groups of ˜6.
R1 includes a hydrogen atom, a halogeno group, a carboxyl group, a cyano group, a nitro group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, and an amino group that may have a substituent. A group, a hydroxyl group which may have a substituent, an alkylthio group having 1 to 6 carbon atoms and an alkyl group having 1 to 6 carbon atoms which may have a substituent are also preferable.
[0041]
In the case where R1 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, a mono- or dialkylamino group having 1 to 6 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, a carboxyl group, carbon 1 to 6 carbon atoms which may be substituted with an alkyl group having 1 to 6 carbon atoms, including one or more heteroatoms selected from any one of alkoxycarbonyl groups having 2 to 7 carbon atoms, nitrogen, oxygen and sulfur Substituted with a carbocycle having 1 to 6 carbon atoms which may be substituted with an alkyl group having 1 to 6 carbon atoms, including one or more heteroatoms selected from carbocycle, nitrogen, oxygen and sulfur Carbonyl group, phosphono group, C2-C9 dialkoxyphosphoryl group, C1-C4 monoalkoxyhydroxyphosphoryl group, C1-C6 alkylsulfonyl group and dialkylamidino It is preferred.
[0042]
Hydroxyl group, phosphono group, carboxyl group, alkoxycarbonyl group having 2 to 7 carbon atoms, mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, mono- or dialkylamino group having 1 to 6 carbon atoms, piperazine carbonyl group, 6 carbon atoms -10 alkyl piperazine carbonyl groups and C1-C6 alkyl sulfonyl groups are more preferable.
Further, R1 is a hydrogen atom, fluoro group, chloro group, bromo group, iodo group, amino group, carboxyl group, ethoxycarbonyl group, carboxyethyl group, ethoxycarbonylethyl group, morpholine alkyl group, hydroxyl group, methyl group, methylthio group. Group, methylphosphoryl group, phosphonoethyl group, trifluoromethyl group, methoxy group, trifluoromethoxy group, cyano group, nitro group, morpholinecarbonylethyl group, piperazinecarbonylethyl group, isopropylpiperazinecarbonylethyl group, methanesulfonylaminopropyl group and More preferred is a hydroxypropyl group.
[0043]
It is also preferable that R1 represents a hydrogen atom, a carboxyl group, an ethoxycarbonyl group, a carboxyethyl group, an ethoxycarbonylethyl group, a morpholinealkyl group, a morpholinecarbonylethyl group, a piperazinecarbonylethyl group, or an isopropylpiperazinecarbonylethyl group.
[0044]
R4 and R5 are preferably a hydrogen atom, a halogeno group, a trifluoromethyl group, a methoxy group and a hydroxyl group, respectively. In particular, R4 is preferably a hydrogen atom, a fluoro group, a chloro group, a methoxy group, or a methyl group. More particularly, at least one of R4 and R5 is preferably a hydrogen atom.
R1, R4 and R5 may be the same or different from each other, and in particular, when ring A represents a phenyl group, R1 is preferably bonded to the phenyl group at the 6- and / or 8-position. .
[0045]
X is preferably an alkylene group having 1 to 6 carbon atoms, more preferably a linear alkylene group having 1 to 3 carbon atoms, and further preferably a methylene group, an ethylene group or a propylene group. Most preferred is an ethylene group. As the group contained in the chain of the alkylene group X, —C (═O) —, —C (═O) NH—, and —NHC (═O) — are preferable. Ring B is preferably an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 3 to 10 carbon atoms (particularly a heteroaryl group having 4 to 10 carbon atoms). As the aryl group, a phenyl group and a 2-naphthyl group are preferable. As the heteroaryl group, a thienyl group and a pyridyl group are preferable. More particularly, a phenyl group and a thienyl group are more preferable.
[0046]
R2 includes a hydrogen atom, a halogeno group, particularly a chloro group, a bromo group; an alkoxyl group having 1 to 10 carbon atoms, particularly an alkoxyl group having 1 to 3 carbon atoms, more particularly a methoxy group; an alkyl group having 1 to 6 carbon atoms; Particularly preferred are a methyl group, an ethyl group; and a trifluoromethyl group. Most preferred are halogeno groups, especially chloro and bromo groups and methyl groups.
R6 and R7 may be the same or different, and are preferably any of a hydrogen atom, a halogeno group, a trifluoromethyl group, a methoxy group, and a hydroxyl group. More preferably, R6 and R7 are both hydrogen atoms.
[0047]
R2, R6 and R7 may be the same or different from each other, and in particular, R2 is the phenyl group at the 3- and / or 4-position when ring B is a phenyl group, and 5 when ring B is a thienyl group. It is preferably bonded to the thienyl group at the position, to the thienyl group at the 5-position when the ring B is a pyridyl group, and to the piperidyl group at the 1-position when the ring B is a piperidyl group.
More particularly, it is preferable that ring B is a phenyl group, R2 is bonded to the phenyl ring at the 4-position, and R6 and R7 are both hydrogen atoms.
[0048]
In particular, it is preferable that ring B is a thienyl group, R2 is bonded to the thienyl group at the 5-position, and R6 and R7 are both hydrogen atoms.
Ring C may contain one or more heteroatoms selected from oxygen and / or sulfur, and contains at least one or more nitrogen atoms excluding pyrrolidyl group, piperidyl group or piperazinyl group. The non-aromatic carbocyclic ring is preferable. In particular, the carbocycle represented by the above formula (5) is preferable.
In particular, the carbocycle represented by the general formula (2) is more preferable.
Further, the bonding position between rings C and X is not particularly limited.
[0049]
R3 includes a halogeno group, a nitro group, an iminoalkyl group having 2 to 7 carbon atoms, a piperidyloxy group, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, a piperidyloxy group, and an iminoalkylpiperidyloxy group having 6 to 10 carbon atoms. Group, an alkyl piperidyloxy group having 5 to 10 carbon atoms, an amino group which may have a substituent, an aminoalkyl group having 2 to 9 carbon atoms which may have a substituent, and a substituent. An alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, an pyrrolidine group which may have a substituent, and a substituent. It is preferably any one of a piperazine group, a C1-C10 heteroaryl group which may have a substituent, or an amidino group which may have a substituent. A mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, an alkyl group having 1 to 6 carbon atoms which may have a substituent, and an amidino group which may have a substituent are more preferable. A heteroaryl group having 1 to 10 carbon atoms which may have a substituent is also preferred, particularly a pyridyl group, more preferably a 4-pyridyl group. More particularly, the alkyl group having 1 to 6 carbon atoms which may have a substituent, a halogeno group, a pyridyl group (particularly a 4-pyridyl group), a nitro group, an amino group, a dialkylamino group, and a substituent. Also preferred are good amidino groups or optionally piperidyloxy groups. It is also preferable to show any of a hydrogen atom, a methyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a pyridyl group. It is also preferable to show either a methyl group or an isopropyl group.
[0050]
When R3 has a substituent, examples of the substituent include an alkyl group having 1 to 6 carbon atoms, a mono or dialkyl carbamoyl group having 2 to 7 carbon atoms, a mono or dialkylaminoalkyl group having 2 to 9 carbon atoms, and 2 carbon atoms. It is preferably any one of ˜7 mono- or dialkylamidino group, C 4-7 trialkylamidino group, pyrrolidine group, piperidine group, C 1-8 alkylsulfonyl group or pyridyl group. Among these, a C1-C6 alkyl group and a pyridyl group are more preferable.
Further, R3 is more preferably any of a methyl group, an isopropyl group, a cyclohexyl group, and a pyridyl group.
[0051]
R8 and R9 may be the same or different and are each a hydrogen atom, a halogeno group having 1 to 6 carbon atoms, an oxo group, a trifluoromethyl group, a nitro group, a methoxy group, or a hydroxyl group. Is preferred. In particular, a hydrogen atom, a methyl group, a fluoro group, a chloro group, a bromo group, or an oxo group is more preferable. R8 and R9 are preferably both hydrogen atoms.
The substitution position of R3, R8 and R9 is not particularly limited.
[0052]
Z1 and Z2 may be the same or different, and are preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, or a heteroaryl group having 4 to 10 carbon atoms. In particular, both Z1 and Z2 are preferably hydrogen atoms.
[0053]
In general formula (1), ring A is an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms, or a cyclic alkyl group having 5 or 6 carbon atoms,
R1 is a hydrogen atom, a halogeno group, an optionally substituted hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a trifluoromethyl group, a trifluoromethanesulfonyloxy group, a carbamoyl group, or a group having 2 to 7 carbon atoms. Mono- or dialkylcarbamoyl group, cyano group, nitro group, mono- or dialkylamino group having 1 to 6 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 7 carbon atoms, and optionally having 1 to 6 carbon atoms An alkylthio group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an aminoalkyl group having 2 to 7 carbon atoms which may have a substituent, and piperazine which may have a substituent Either a carbonyl group or an amidino group optionally having substituents,
[0054]
When R1 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, a mono- or dialkylamino group having 1 to 6 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, a carboxyl group, or a carbon number 1 to 6 carbon atoms which may be substituted with an alkyl group having 1 to 6 carbon atoms, including one or more heteroatoms selected from 2 to 7 alkoxycarbonyl groups, nitrogen, oxygen and sulfur Carbonyl substituted with a carbocyclic ring having 1 to 6 carbon atoms, which may be substituted with an alkyl group having 1 to 6 carbon atoms, containing one or more heteroatoms selected from any of rings, nitrogen, oxygen and sulfur Group, phosphono group, C2-C9 dialkoxyphosphoryl group, C1-C4 monoalkoxyhydroxyphosphoryl group, C1-C6 alkylsulfonyl group or C1-C6 dialkyl Preferably is any of Mijino group.
[0055]
In general formula (1), ring A represents a phenyl group,
R1 may have a hydrogen atom, a fluoro group, a chloro group, a bromo group, an iodo group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, or a substituent. A hydroxyl group, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted carbon group having 1 to 6 carbon atoms An alkylsulfonyl group of
[0056]
When R1 has a substituent, the substituent is a hydroxyl group, a phosphono group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono or dialkylcarbamoyl group having 2 to 7 carbon atoms, or a mono group having 1 to 6 carbon atoms. Or a C1-C6 carbocycle optionally substituted with a C1-C6 alkyl group containing one or more heteroatoms selected from dialkylamino groups, nitrogen, oxygen and sulfur, nitrogen , A carbonyl group or carbon substituted with a carbon ring having 1 to 6 carbon atoms, which may be substituted with an alkyl group having 1 to 6 carbon atoms, containing one or more heteroatoms selected from oxygen and sulfur An alkylsulfonyl group of the number 1-6, and
[0057]
R4 and R5 may be the same or different and are a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkoxyl group having 1 to 6 carbon atoms, a trifluoromethoxy group, a hydroxyl group, carbon It is preferably any one of an alkylthio group having 1 to 6 carbon atoms and an alkylsulfonyl group having 1 to 6 carbon atoms.
[0058]
In general formula (1), ring A represents a phenyl group,
R1 is a hydrogen atom, fluoro group, chloro group, bromo group, iodo group, amino group, cyano group, nitro group, carboxyl group, ethoxycarbonyl group, carboxyethyl group, ethoxycarbonylethyl group, morpholine alkyl group, hydroxyl group, A methyl group, a methoxy group, a methylthio group, a methylsulfonyl group, a phosphonoethyl group, a morpholinecarbonylethyl group, a piperazinecarbonylethyl group, an isopropylpiperazinecarbonylethyl group, a methanesulfonylaminopropyl group or a hydroxypropyl group is more preferable. Here, it is more preferable that at least one of R4 and R5 is a hydrogen atom.
[0059]
In general formula (1), ring B represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms,
R2 is preferably a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, or an alkoxyl group having 1 to 10 carbon atoms.
[0060]
In general formula (1), ring B is an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms,
R2 is a chloro group, a bromo group or a methyl group, and
R6 and R7 may be the same as or different from each other, and are more preferably any of a hydrogen atom, a halogeno group, a trifluoromethyl group, a methoxy group, or a hydroxyl group.
[0061]
In general formula (1), ring B is an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms,
R2 is either a chloro group, a bromo group or a methyl group,
More preferably, R6 and R7 are both hydrogen atoms.
[0062]
In general formula (1), ring B is a phenyl group or a thienyl group,
R2 is either a chloro group, a bromo group or a methyl group,
It is particularly preferred that R6 and R7 are both hydrogen atoms.
[0063]
In general formula (1), ring C contains at least one nitrogen atom, and may contain one or more heteroatoms selected from oxygen and / or sulfur. Group carbocycle, except pyrrolidyl group, piperidyl group or piperazinyl group,
R3 is a halogeno group, a nitro group, an iminoalkyl group having 2 to 7 carbon atoms, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, an acyl group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, A piperidyloxy group, an iminoalkylpiperidyloxy group having 6 to 10 carbon atoms, an alkylpiperidyloxy group having 5 to 10 carbon atoms, an amino group which may have a substituent, and a carbon number which may have a substituent. A 2-9 aminoalkyl group, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted pyrrolidine group, an optionally substituted piperazine group, It is either a C1-C10 heteroaryl group which may have a substituent or an amidino group which may have a substituent,
When R3 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a mono or dialkylcarbamoyl group having 2 to 7 carbon atoms, a mono or dialkylaminoalkyl group having 2 to 9 carbon atoms, or 2 to 2 carbon atoms. It is preferably any one of 7 mono- or dialkylamidino groups, trialkylamidino groups having 4 to 7 carbon atoms, pyrrolidine groups, piperidine groups, alkylsulfonyl groups having 1 to 8 carbon atoms, or pyridyl groups. Here, in General formula (1), it is more preferable that R3 is a C1-C6 alkyl group which may have a substituent. In general formula (1), ring C is any of the groups represented by general formula (2), and R3 is an optionally substituted alkyl group having 1 to 6 carbon atoms. Is particularly preferred. More particularly, both R8 and R9 are preferably hydrogen atoms.
Moreover, in General formula (1), it is preferable that X is a C1-C6 alkylene group.
[0064]
In general formula (1), ring A represents a phenyl group,
R1 is a hydrogen atom, fluoro group, chloro group, bromo group, iodo group, amino group, cyano group, nitro group, carboxyl group, ethoxycarbonyl group, carboxyethyl group, ethoxycarbonylethyl group, morpholine alkyl group, hydroxyl group, A methyl group, a methoxy group, a methylthio group, a methylsulfonyl group, a phosphonoethyl group, a morpholinecarbonylethyl group, a piperazinecarbonylethyl group, an isopropylpiperazinecarbonylethyl group, a methanesulfonylaminopropyl group or a hydroxypropyl group;
[0065]
Ring B represents either a phenyl group or a thiophene group,
R2 represents a hydrogen atom, a chloro group, a bromo group or a methyl group,
Ring C represents any of the groups represented by the general formula (2),
R3 represents a hydrogen atom, a methyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a pyridyl group;
X is a methylene group or ethylene group, a propylene group (-C (= O)-may be included in the chain), and
Z1 and Z2 are preferably both hydrogen atoms. Here, in general formula (1), it is more preferable that R5, R6, R7 and R9 are hydrogen atoms.
[0066]
In particular, in general formula (1), ring A represents a phenyl group,
R1 represents a hydrogen atom, a carboxyl group, an ethoxycarbonyl group, a carboxyethyl group, an ethoxycarbonylethyl group, a morpholinealkyl group, a morpholinecarbonylethyl group, a piperazinecarbonylethyl group, an isopropylpiperazinecarbonylethyl group,
Ring B represents either a phenyl group or a thienyl group,
R2 represents a chloro group, a bromo group or a methyl group,
Ring C represents any of the groups represented by the general formula (2),
R3 represents either a methyl group or an isopropyl group;
X is a methylene group or ethylene group, propylene group,
R4 is a hydrogen atom, a fluoro group, a chloro group, a methoxy group, or a methyl group,
R5, R6, R7 and R9 are all hydrogen atoms, and
More preferably, both Z1 and Z2 are hydrogen atoms.
[0067]
A typical production method of the compound (1) of the present invention will be described. For example, when ring A is a phenyl group which may have a substituent and X is an alkyl group having 1 to 6 carbon atoms, it can be produced by using the following method.
[0068]
That is, (4) can be obtained by reacting amino acid ester (2) with, for example, ethanol or the like as a solvent and, for example, 2-nitrobenzyl halide (3) in the presence of a base such as sodium bicarbonate. . The obtained (4) can be led to (6) by using, for example, dichloromethane or the like as a solvent in the presence of a base such as triethylamine, for example, by acting an acid halide (5) or the like. The obtained (6) is used as a solvent, for example, using tetrahydrofuran or the like, for example, in the presence of a base such as sodium hydroxide, and then hydrolyzed, and then, for example, using ethanol or the like as a solvent, for example, a catalyst such as palladium-carbon. For example, by carrying out the reaction in a hydrogen atmosphere, it is possible to lead to (7). Using the obtained (7) as a solvent, for example, dimethylformamide or the like is used, and a condensing agent is allowed to act in the presence of a base such as triethylamine, for example, whereby intramolecular condensation can be carried out, leading to (8). The obtained (8) can be led to the benzodiazepine derivative (10) by using (9) in the presence of a base such as sodium hydride, for example, using dimethylformamide or the like as a solvent.
[0069]
By changing the starting material (3), a compound in which the ring A in the general formula (1) is any of an aryl group other than a phenyl group, a heteroaryl group, and a cyclic alkyl group can also be synthesized.
[0070]

[0071]
Further, (6) can be led to (11) by carrying out the reaction in, for example, a hydrogen atmosphere using, for example, ethyl acetate or the like and a catalyst such as palladium-carbon. Subsequently, using, for example, dichloromethane or the like as a solvent, (13) can be obtained by allowing a reducing agent such as sodium triacetoxyborohydride to act, for example, in the presence of an acid such as acetic acid. Then, the obtained (13) is hydrolyzed in the presence of a base such as sodium hydroxide as a solvent, for example, using a solvent such as tetrahydrofuran, and then used as a solvent in the presence of a base such as triethylamine. Then, by allowing a condensing agent to act, intramolecular condensation can be performed and led to the benzodiazepine derivative (14).
[0072]

[0073]
The compound represented by the general formula (1) and the salt thereof thus produced are known separation and purification means such as extraction, concentration, vacuum concentration, solvent extraction, crystallization, recrystallization, transfer dissolution, various chromatographies. It can be isolated and purified by chromatography or the like.
The salt of the benzodiazepine derivative represented by the general formula (1) may be any pharmaceutically acceptable salt. For the basic group in the formula, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphorus Organic acids such as mineral acids such as acids, formic acid, acetic acid, lactic acid, salicylic acid, mandelic acid, citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, tannic acid, malic acid, tosylic acid, methanesulfonic acid, benzenesulfonic acid Mention may be made of acid addition salts with acids. In addition, in the case where an acidic group such as a carboxyl group is present in the formula, for example, an ammonium salt, a salt with an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, etc. Examples thereof include salts with organic amines such as salts, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, piperidine and dicyclohexylamine, and base addition salts with basic amino acids such as arginine and lysine.
[0074]
The compound represented by the general formula (1) of the present invention includes solvates thereof, such as hydrates, alcohol adducts, and the like.
The compound represented by the general formula (1) or a salt thereof is administered as it is or as various pharmaceutical compositions. The dosage form of such a pharmaceutical composition may be, for example, a tablet, powder, pill, granule, capsule, suppository, solution, dragee, or devoted drug, using ordinary formulation aids. Can be manufactured according to conventional methods. For example, tablets may contain benzodiazepine derivatives, which are the active ingredients of the present invention, known auxiliary substances such as lactose, inert diluents such as calcium carbonate or calcium phosphate, binders such as gum arabic, corn starch or gelatin, alginic acid, corn starch or the like It is obtained by mixing with a swelling agent such as gelatinized starch, a sweetening agent such as sucrose, lactose or saccharin, a flavoring agent such as peppermint or cherry, and a moisturizing agent such as magnesium stearate, talc or carboxymethylcellulose.
[0075]
Anticoagulants containing a benzodiazepine derivative represented by the general formula (1) or a salt thereof as an active ingredient are cerebral infarction, cerebral thrombus, cerebral embolism, transient cerebral ischemic attack (TIA), subarachnoid hemorrhage (vascular spasm) ) Diseases in cerebrovascular disorders such as, acute and chronic myocardial infarction, unstable angina, diseases in ischemic heart diseases such as coronary thrombolysis, diseases in pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism, peripheral artery occlusion , Deep vein thrombosis, generalized intravascular coagulation syndrome, thrombus formation after artificial blood vessel surgery and valve replacement, reocclusion and restenosis after coronary artery bypass surgery, percutaneous transluminal coronary angioplasty (PTCA) Alternatively, it can be used as a prophylactic / therapeutic agent for reocclusion and restenosis after revascularization, such as percutaneous transluminal coronary artery recurrent therapy (PTCR), and thrombus formation during extracorporeal circulation.
[0076]
When the benzodiazepine derivative represented by the general formula (1) is used as an anticoagulant, the administration route may be either oral or parenteral, and the dosage is the patient's age, weight, condition, and administration method. The dose per day for an adult is usually 0.01 to 1000 mg, preferably 0.1 to 50 mg for oral administration, and 1 μg to 100 mg for parenteral administration, preferably 0.01 to 10 mg.
[0077]
Example
The following examples illustrate the invention in detail. These are preferred embodiments of the present invention and are not limited to these examples.
Example 1 4-((5-Chloro (2-thienyl)) carbonyl) -6-fluoro-1- [2- (4-isopropyl-1,4-diazepan-1-yl) ethyl] -1,3 Synthesis of 4,5-tetrahydrobenzo [e] [1,4] diazepin-2-one ditrifluoroacetate
[0078]
Step 1 Synthesis of t-butyl 4- [2- (benzyloxy) ethyl] -1,4-diazepane-1-carboxylate
t-butyl 1,4-diazepan-1-carboxylate 1.006 g (5.02 mmol), 2- (benzyloxy) ethyl bromide 0.794 ml (5.02 mmol), potassium carbonate 3.135 g (22.7 mmol), 167 mg (1.11 mmol) of sodium iodide was heated and stirred in 25 ml of toluene at 100 ° C. for 9.5 hours. Filtration at room temperature, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound.
Yield 752 mg (2.25 mmol) Yield 45%
MS (ESI, m / z) 335 (MH +)
H-NMR (CDCl3) δ1.46 (9H, s), 1.75-1.88 (2H, m), 2.63-2.78 (4H, m), 2.75 (2H, t), 3.38-3.53 (4H, m), 3.56 (2H, t), 4.53 (2H, s), 7.27-7.38 (5H, m)
[0079]
Step 2 Synthesis of t-butyl 4- (2-hydroxyethyl) -1,4-diazepane-1-carboxylate
748 mg (2.24 mmol) of t-butyl 4- [2- (benzyloxy) ethyl] -1,4-diazepane-1-carboxylate in 20 ml of ethanol at 50 ° C. and 4 atm in the presence of 10% palladium-carbon The addition was made. Work-up was performed according to a conventional method to obtain the title compound.
Yield 485 mg (1.99 mmol) Yield 89%
MS (ESI, m / z) 245 (MH +)
H-NMR (CDCl3) δ1.47 (9H, s), 1.83-1.96 (2H, m), 2.68-2.85 (6H, m), 3.42-3.58 (4H, m), 3.61 (2H, t)
[0080]
Step 3 Synthesis of t-butyl 4- (2-chloroethyl) -1,4-diazepane-1-carboxylate
191 mg (0.78 mmol) of t-butyl 4- (2-hydroxyethyl) -1,4-diazepane-1-carboxylate was dissolved in 5 ml of dichloromethane, 0.07 ml (0.90 mmol) of methanesulfonyl chloride, 0.14 ml of triethylamine. (1.0 mmol) was added and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound.
Yield 156 mg (0.59 mmol) Yield 76%
H-NMR (CDCl3) δ1.46 (9H, s), 1.75-1.87 (2H, m), 2.67-2.80 (4H, m), 2.87 (2H, t), 3.38-3.58 (4H, m), 3.54 (2H, t)
[0081]
Step 4 Synthesis of ethyl (2-fluoro-6-nitrobenzyl) aminoacetate
2-fluoro-6-nitrotoluene 5.0 g (32.2 mmol), N-bromosuccinimide 6.3 g (35.4 mmol) and perbenzoic acid 50 mg were dissolved in benzene 50 ml, and the mixture was stirred at 85 ° C. for 2 days. After the solvent was distilled off under reduced pressure, hexane was added and the precipitated crystals were separated by filtration. The filtrate was concentrated and dried, 100 ml of ethanol, 10.3 g (73.8 mmol) of glycine ethyl ester hydrochloride and 6.2 g (73.8 mmol) of sodium hydrogen carbonate were added, and the mixture was stirred at 80 ° C. for 6 hours. The solvent was distilled off under reduced pressure and then partitioned between water and ethyl acetate. The mixture was extracted with 1N hydrochloric acid, and the obtained aqueous layer was made basic with sodium hydroxide solution and extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain the title compound.
Yield 5.6 g (22.0 mmol) Yield 68%
H-NMR (CDCl3) δ 1.26 (3H, t, J = 6.6Hz), 3.45 (2H, s), 4.08 (2H, s), 4.16 (2H, q, J = 6.6Hz), 7.31-7.47 (2H , m), 7.74 (1H, d, J = 7.8Hz)
[0082]
Step 5 Synthesis of 4-((5-chloro (2-thienyl)) carbonyl) -6-fluoro-1,3,4,5 tetrahydrobenzo [e] [1,4] diazepin-2-one
5.6 g (22.0 mmol) of ethyl (2-fluoro-6-nitrobenzyl) aminoacetate was dissolved in 150 ml of dichloromethane, 3.0 ml (22.0 mmol) of triethylamine and 4.8 g of di-t-butyl dicarbonate (22 4 mmol) and stirred at room temperature overnight. After treating with dichloromethane as an extraction solvent, the obtained crude product was dissolved in ethanol, 10% palladium-carbon was added, and the mixture was stirred overnight at room temperature in the presence of hydrogen. After the reaction solution was filtered through Celite, 20 ml of THF and 27 ml of 1M lithium hydroxide solution were added to the crude product obtained by evaporating the solvent of the filtrate and stirred for 4 hours. After the solvent was distilled off, the residue was dissolved in 100 ml of a DMF / dichloromethane (1/1) solution, 4.5 g (26.5 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride and 4.6 ml (33. 3) of triethylamine. 2 mmol) was added and stirred overnight. Dichloromethane was treated as an extraction solvent to obtain 6.4 g of a crude product. 1 g of the crude product was dissolved in 5 ml of 4N dioxane hydrochloride and stirred at room temperature for 1 hour. The solvent was distilled off to obtain 0.75 g of a crude product. Dissolve 0.32 g of the crude product in 5 ml of DMF, add 0.33 g (2.0 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride and 0.84 ml (6.1 mmol) of triethylamine at room temperature. Stir for 2 hours. Dichloromethane was extracted as an extraction solvent, and the precipitated crystals were collected by filtration and dried under reduced pressure.
Yield 0.16 g (0.49 mmol) Yield 19%
MS (ESI, m / z) 325 (MH +)
H-NMR (CDCl3) δ 4.53 (2H, brs), 5.00 (2H, brs), 6.80-7.13 (3H, m), 7.20-7.42 (2H, m), 8.22 (1H, brs)
[0083]
Step 6 4-((5-Chloro (2-thienyl)) carbonyl) -6-fluoro-1- [2- (4-isopropyldiazepan-1-yl) ethyl] -1,3,4,5 tetrahydro Synthesis of benzo [e] [1,4] diazepin-2-one ditrifluoroacetate
4 mg (0.10 mmol) of sodium hydride washed with hexane was suspended in 5 ml of DMF, and 4-((5-chloro (2-thienyl)) carbonyl) -6-fluoro-1,3,4,5 tetrahydrobenzo [e]. 24 mg (0.075 mmol) of [1,4] diazepin-2-one was added and stirred at room temperature for 30 minutes. Subsequently, 20 mg (0.076 mmol) of t-butyl 4- (2-chloroethyl) -1,4-diazepan-1-carboxylate obtained in Step 3 was added, and the mixture was stirred at 65 ° C. for 3 hours. After distilling off the solvent under reduced pressure, 5 ml of 4N dioxane hydrochloride was added to the residue and stirred for 1 hour. After distilling off the solvent under reduced pressure, 2/3 of the residue was dissolved in 8 ml of dichloromethane, and 2 ml of acetone, 20 mg (0.33 mmol) of acetic acid and 80 mg (0.38 mmol) of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature. Stir overnight. The crude product obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, containing 0.1% of trifluoroacetic acid (v / v), The title compound was obtained by elution with a mixed solution of water and acetonitrile and lyophilizing the desired fraction.
Yield 19.4 mg (0.027 mmol) Yield 54%
MS (ESI, m / z) 493 (MH +)
H-NMR (DMSO-d6) δ 1.18 (6H, d, J = 6.6Hz), 1.88-2.18 (2H, m), 2.80-3.60 (11H, m), 4.05-4.20 (4H, m), 4.60- 4.85 (2H, m), 7.20-7.32 (2H, m), 7.42-7.60 (3H, m)
[0084]
Example 2 4-((5-Chloro (2-thienyl)) carbonyl) -6-fluoro-1- [2- (4-methyl-1,4-diazepan-1-yl) ethyl] -1,3 Synthesis of 4,5-tetrahydrobenzo [e] [1,4] diazepin-2-one ditrifluoroacetate
The title compound was obtained in the same manner as in Step 6 of Example 1 using paraformaldehyde instead of acetone.
Yield 11.5 mg (0.017 mmol) Yield 66%
MS (ESI, m / z) 465 (MH +)
H-NMR (DMSO-d6) δ 1.88-2.18 (2H, m), 2.78 (3H, s), 2.80-3.58 (11H, m), 4.05-4.20 (4H, m), 4.60-4.4.85 (2H , m), 7.20-7.32 (2H, m), 7.42-7.60 (3H, m)
[0085]
Example 3 4-((5-Chloro (2-thienyl)) carbonyl) -1- [2- (4-isopropyl-1,4-diazepan-1-yl) ethyl] -6-methoxy-1,3 Synthesis of 4,5-tetrahydrobenzo [e] [1,4] diazepin-2-one ditrifluoroacetate
4-((5-chloro (2-thienyl)) carbonyl) -6-methoxy-1,3,4,5 tetrahydrobenzo [e] [1,4] diazepin-2-one and step 6 of Example 1 The title compound was obtained by the same operation.
Yield 18.8 mg (0.026 mmol) Yield 27%
MS (ESI, m / z) 505 (MH +)
H-NMR (DMSO-d6) δ 1.18 (6H, d, J = 6.6Hz), 1.85-2.20 (2H, m), 2.80-3.92 (14H, m), 3.94-4.93 (6H, m), 7.01- 7.80 (5H, m)
[0086]
Example 4 Measurement of activated blood coagulation factor X inhibitory activity
130 μl of 100 mM Tris-HCl buffer adjusted to pH 8.4 was added to 10 μl of the aqueous solution of the evaluation compound, and then human activated blood coagulation factor X (manufactured by Enzyme Research) was added to 0.5 with pH 8.4 Tris-HCl buffer. 10 μl of the prepared solution in units / ml was added and incubated for 10 minutes at room temperature. Next, N-benzoyl-L-isoleucil-L-glutamyl-glycyl-L-arginyl-P-nitroanilide hydrochloride (manufactured by Peptide Institute, Inc.) was adjusted to 0.8 mM with pH 8.4 Tris-HCl buffer. 50 μl of the prepared solution was added, the absorbance was measured, and the initial reaction rate was determined.The control was a solution obtained by adding 10 μl of Tris-HCl buffer prepared to pH 8.4 instead of the solution of the evaluation compound. Was measured using a MICROPLATE READER Model 3550-UV (BIO RAD) for 16 minutes at an interval of 15 seconds at a wavelength of 405 nm, and the activity (initial rate) of activated blood coagulation factor X when no evaluation compound was added was 50%. The negative logarithmic value of the concentration of the evaluation compound at the time of inhibition was determined (abbreviated as pIC50) and used as an index of the activated blood coagulation factor X inhibitory activity. The inhibitory activity is shown in Table 1.
[0087]
Example 5 Measurement of thrombin inhibitory activity
130 μl of 100 mM Tris-HCl buffer adjusted to pH 8.4 was added to 10 μl of an aqueous solution of the evaluation compound, and then human thrombin (manufactured by SIGMA) was adjusted to 2 units / ml with pH 8.4 Tris-HCl buffer 10 μl. And incubated for 10 minutes at room temperature. Next, a solution prepared by adjusting D-phenylalanyl-L-pipecholyl-L-arginyl-P-nitroanilide dihydrochloride (Daiichi Kagaku, S-2238) to 0.4 mM with pH 8.4 Tris-HCl buffer 50 μl was added, the absorbance was measured, and the initial reaction rate was determined. A control prepared by adding 10 μl of Tris-HCl buffer prepared to pH 8.4 instead of the solution of the evaluation compound was used as a control. Absorbance was measured using MICROPLATE READER Model 3550-UV (BIO RAD) at a wavelength of 405 nm for 16 minutes at 15 second intervals. A negative logarithmic value of the concentration of the evaluation compound when 50% of the thrombin activity (initial rate) when the evaluation compound was not added was inhibited (abbreviated as pIC50) was used as an index of thrombin inhibition activity. Table 1 shows the thrombin inhibitory activity of representative compounds.
[0088]
Example 6 Measurement of anticoagulant activity
Anticoagulant activity was determined using a prothrombin time (PT) assay. PT measurement was performed as shown below. That is, blood was collected from a healthy person, and 1/10 volume of 3.8% trisodium citrate aqueous solution was added, and plasma was separated by centrifugation. To 45 μl of plasma, 5 μl of DMSO solution containing the evaluation compound was added and incubated at room temperature for 2 minutes. The test tube containing the plasma solution was placed in a Sysmex CA-3000 fully automatic blood coagulation analyzer (Toa Medical Electronics), incubated at 37 ° C for 3 minutes, and Sysmex PT II (Toa Medical Electronics, rabbit brain tissue thromboplastin, 13.2 mM calcium chloride) 100 μl was added. PT was automatically measured by the same apparatus. A control added with 5 μl of DMSO instead of the solution of the evaluation compound was used as a control, and a negative logarithmic value of the evaluation compound concentration that doubles the PT of the control was obtained (abbreviated as pPT2), and used as an index of anticoagulant activity.
Table 1

This result shows that the benzodiazepine derivative of the present invention exhibits high inhibitory activity specific to activated blood coagulation factor X, and exhibits high anticoagulant activity based on this.
The structural formulas of the compounds of the present invention described in the examples are shown below.

The anticoagulant containing the compound of the present invention or a salt thereof as an active ingredient exhibits an excellent anticoagulant action based on an activated blood coagulation factor X inhibitory action. The anticoagulant containing the compound of the present invention or a salt thereof as an active ingredient is also excellent in oral absorbability. Therefore, the compound of the present invention is used for diseases in cerebrovascular disorders such as cerebral infarction, cerebral thrombus, cerebral embolism, transient cerebral ischemic attack (TIA), subarachnoid hemorrhage (vasospasm), acute and chronic myocardial infarction, unstable narrowing Diseases in ischemic heart diseases such as heart disease, coronary artery thrombolysis, diseases in pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism, peripheral arterial occlusion, deep vein thrombosis, generalized intravascular coagulation syndrome, and artificial vascular surgery Revascularization such as thrombus formation after prosthetic valve replacement, reocclusion and restenosis after coronary artery bypass grafting, percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary artery recurrent therapy (PTCR) It can be used as a prophylactic / therapeutic agent for subsequent re-occlusion and restenosis and thrombus formation during extracorporeal circulation.

Claims (20)

A benzodiazepine derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof.

(1)
[In general formula (1),
Ring A represents any of an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms, or a cyclic alkyl group having 4 to 10 carbon atoms,
R1 represents a hydrogen atom, a halogeno group, an optionally substituted hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a nitro group, a formyl group, a trifluoromethyl group, a trifluoromethoxy group, or a trifluoromethanesulfonyloxy group. , Methylenedioxy group, carbamoyl group, thiocarbamoyl group, mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, cyano group, mono- or dialkylamino group having 1 to 6 carbon atoms, carboxyl group, alkoxy having 2 to 7 carbon atoms Carbonyl group, C3-C7 hydroxycarbonylalkenyl group, C4-C8 alkoxycarbonylalkenyl group, phosphono group, C2-C9 dialkoxyphosphoryl group, C1-C4 monoalkoxyhydroxyphosphoryl group , An alkylthio group having 1 to 6 carbon atoms, A killsulfonyl group, an aminosulfonyl group, a mono- or dialkylaminosulfonyl group having 2 to 8 carbon atoms, an optionally substituted alkyl group having 1 to 6 carbon atoms, and an optionally substituted carbon group having 6 to 6 carbon atoms. 10 aryl groups, optionally substituted heteroaryl groups having 1 to 10 carbon atoms, optionally substituted arylsulfonyl groups having 6 to 10 carbon atoms, and optionally substituted carbons A heteroarylsulfonyl group having 4 to 10 carbon atoms, an arylthio group having 6 to 10 carbon atoms that may have a substituent, a heteroarylthio group having 4 to 10 carbon atoms that may have a substituent, and a substituent; An optionally substituted acyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms which may have a substituent, and a substituent. Substituted with a heteroaryl group having 5 to 10 carbon atoms An alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms substituted with an alkyl group having 1 to 6 carbon atoms which may have a substituent, and 1 to carbon atoms which may have a substituent A heteroaryl group having 5 to 10 carbon atoms substituted with 6 alkyl groups, a mono- or dialkylamino group having 1 to 6 carbon atoms, an amino group which may have a substituent, and an optionally substituted carbon A number 1-7 aminoalkyl group, a pyrrolidine group that may have a substituent, a pyrrolidyloxy group that may have a substituent, a piperidine group that may have a substituent, and a substituent A piperidyloxy group which may have a substituent, a piperazine group which may have a substituent, a piperazinecarbonyl group which may have a substituent, an amidino group which may have a substituent or a guanidino group which may have a substituent Represents one of the following:
Here, when R1 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, an alkoxyl group having 1 to 10 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group, or a carbamoyl group. Group, mono or dialkylcarbamoyl group having 2 to 7 carbon atoms, amino group, aminoalkyl group having 1 to 7 carbon atoms, mono or dialkylamino group having 1 to 6 carbon atoms, amidino group, mono or 2 to 7 carbon atoms A dialkylamidino group, a C4-7 trialkylamidino group, a C5-8 tetraalkylamidino group, a guanidino group, a C3-8 dialkylguanidino group, a C4-9 trialkylguanidino group, The number of carbon atoms substituted by an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, and an aryl group having 6 to 10 carbon atoms An alkyl group having 6 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with a heteroaryl group having 5 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms substituted with an alkyl group having 1 to 6 carbon atoms, carbon C5-C10 heteroaryl group substituted with C1-C6 alkyl group, C6-C10 arylsulfonyl group, C4-C10 heteroarylsulfonyl group, carboxyl group, carbon number 1 to 6 carbon atoms optionally substituted with an alkyl group having 1 to 6 carbon atoms, including one or more heteroatoms selected from 2 to 7 alkoxycarbonyl groups, nitrogen, oxygen and sulfur Carbonyl substituted with a C1-C6 carbocyclic ring optionally substituted with a C1-C6 alkyl group containing one or more heteroatoms selected from any of ring, nitrogen, oxygen and sulfur Group, 7-10 carbon atoms Iminoalkylpiperazinecarbonyl group, piperidyloxy group, alkylpiperidyloxy group having 6 to 10 carbon atoms, iminoalkylpiperidyloxy group having 7 to 10 carbon atoms, pyrrolidyloxy group, alkylpyrrolidyloxy group having 6 to 10 carbon atoms, C7-10 iminoalkylpyrrolidyloxy group, methylenedioxy group, cyano group, C2-7 iminoalkyl group, C1-8 acyl group, phosphono group, C2-9 di Represents an alkoxyphosphoryl group, a monoalkoxyhydroxyphosphoryl group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an aminosulfonyl group, or a dialkylaminosulfonyl group having 2 to 8 carbon atoms,
Ring B represents any of an aryl group having 6 to 10 carbon atoms and a heteroaryl group having 3 to 10 carbon atoms,
Ring C represents a non-aromatic carbocycle having 2 to 8 carbon atoms containing at least one nitrogen atom, and may contain one or more heteroatoms selected from oxygen and / or sulfur, provided that a pyrrolidyl group, Excluding piperidyl group or piperazinyl group,
R2 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, a hydroxyalkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, an alkoxyalkyl group having 1 to 10 carbon atoms, Nitro group, formyl group, trifluoromethoxy group, trifluoromethyl group, carbamoyl group, thiocarbamoyl group, mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, amino group, mono- or dialkylamino group having 1 to 6 carbon atoms, C1-C9 aminoalkyl group, C2-C9 mono- or dialkylaminoalkyl group, amidino group, C2-C7 mono- or dialkylamidino group, C4-C7 trialkylamidino group, carbon A tetraalkylamidino group having 5 to 8 carbon atoms, a guanidino group, a dialkylguanidino group having 3 to 8 carbon atoms, 4 to 9 prime trialkylguanidino group, methylenedioxy group, cyano group, iminoalkyl group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, piperidyloxy group, alkylpiperidyloxy group having 6 to 10 carbon atoms Group, iminoalkylpiperidyloxy group having 6 to 10 carbon atoms, alkoxycarbonylpiperidyloxy group having 8 to 14 carbon atoms, pyrrolidyloxy group, alkylpyrrolidyloxy group having 5 to 9 carbon atoms, imino having 5 to 9 carbon atoms Alkylpyrrolidyloxy group, C7-13 alkoxycarbonylpyrrolidyloxy group, pyrrolidine group, C5-9 alkylpyrrolidine group, C5-9 iminoalkylpyrrolidine group, piperidine group, carbon number 6-10 alkyl piperidine groups, 6-10 carbon iminoalkyl piperidine groups, piperazine groups, carbon An alkylpiperazine group having 5 to 13 carbon atoms, an iminoalkylpiperazine group having 6 to 9 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, and an aryl group having 6 to 10 carbon atoms Rusulfonyl group, heteroarylsulfonyl group having 4 to 10 carbon atoms, iminoalkylpiperazinecarbonyl group having 7 to 10 carbon atoms, alkylpiperazinecarbonyl group having 6 to 10 carbon atoms, piperazinesulfonyl group, alkyl having 5 to 9 carbon atoms Piperazinesulfonyl group, iminoalkylpiperazinesulfonyl group having 6 to 9 carbon atoms, 1 to 8 alkylsulfonyl group, aminosulfonyl group, mono or dialkylaminosulfonyl group having 2 to 8 carbon atoms, piperidylalkyl group having 6 to 9 carbon atoms Or an iminoaluminum piperidylalkyl group having 8 to 12 carbon atoms,
R3 is a hydrogen atom, halogeno group, hydroxyl group, alkoxyl group having 1 to 10 carbon atoms, nitro group, formyl group, trifluoromethyl group, trifluoromethoxy group, carbamoyl group, thiocarbamoyl group, 2 to 7 carbon atoms Mono or dialkylcarbamoyl group, methylenedioxy group, cyano group, iminoalkyl group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, alkoxycarbonyl group having 2 to 7 carbon atoms, piperidyloxy group, 6 carbon atoms -10 iminoalkylpiperidyloxy group, C5-10 alkylpiperidyloxy group, C8-14 alkoxycarbonylpiperidyloxy group, pyrrolidyloxy group, C5-9 iminoalkylpyrrolidyloxy group, C5-C10 alkylpyrrolidyloxy group, C7-C13 alkoxy group Bonylpyrrolidyloxy group, arylsulfonyl group having 6 to 10 carbon atoms, heteroarylsulfonyl group having 4 to 10 carbon atoms, iminoalkylpiperazinecarbonyl group having 7 to 10 carbon atoms, piperazinesulfonyl group, and 6 to 6 carbon atoms 9 iminoalkylpiperazinesulfonyl groups, optionally substituted alkyl groups having 1 to 6 carbon atoms, mono- or dialkylamino groups having 1 to 6 carbon atoms, optionally substituted amino groups, substituents A C1-C9 aminoalkyl group which may have a substituent, a pyrrolidine group which may have a substituent, a piperidyl group which may have a substituent, a piperazine group which may have a substituent, a substituent An aryl group having 6 to 10 carbon atoms which may have a group, a heteroaryl group having 1 to 10 carbon atoms which may have a substituent, and an alkyl group having 1 to 6 carbon atoms which may have a substituent Replace with Carbon atoms having 6 to 10 carbon atoms, optionally substituted heteroaryl groups having 5 to 10 carbon atoms substituted with alkyl groups having 1 to 6 carbon atoms, and optionally substituted carbons. An alkyl group having 1 to 6 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with an optionally substituted heteroaryl group having 5 to 10 carbon atoms, Represents an amidino group which may have a substituent, a guanidino group which may have a substituent, a piperidylalkyl group having 6 to 9 carbon atoms or an iminoaluminum piperidylalkyl group having 8 to 12 carbon atoms,
When R3 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a halogeno group, a hydroxyl group, a hydroxyalkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, or 1 to 1 carbon atoms. 10 alkoxyalkyl groups, nitro group, formyl group, trifluoromethoxy group, trifluoromethyl group, carbamoyl group, thiocarbamoyl group, mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, amino group, 1 to 6 carbon atoms Mono- or dialkylamino group, C1-C9 aminoalkyl group, C2-C9 mono- or dialkylaminoalkyl group, amidino group, C2-C7 mono- or dialkylamidino group, C4-C7 Trialkylamidino group, C5-C8 tetraalkylamidino group, guanidino group, C3-C8 dial Luguanidino group, trialkylguanidino group having 4 to 9 carbon atoms, methylenedioxy group, cyano group, iminoalkyl group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, piperidyloxy group, 6 to 10 carbon atoms Alkylpiperidyloxy group, iminoalkylpiperidyloxy group having 6 to 10 carbon atoms, alkoxycarbonylpiperidyloxy group having 8 to 14 carbon atoms, pyrrolidyloxy group, alkylpyrrolidyloxy group having 5 to 9 carbon atoms, carbon number 5 -9 iminoalkylpyrrolidyloxy group, C7-13 alkoxycarbonylpyrrolidyloxy group, pyrrolidine group, C5-9 alkylpyrrolidine group, C5-9 iminoalkylpyrrolidine group, piperidine Group, an alkyl piperidine group having 6 to 10 carbon atoms, an iminoalkyl piperidine group having 6 to 10 carbon atoms, Piperazine group, alkylpiperazine group having 5 to 13 carbon atoms, iminoalkylpiperazine group having 6 to 9 carbon atoms, aryl group having 6 to 10 carbon atoms, heteroaryl group having 1 to 10 carbon atoms, and 6 to 6 carbon atoms 10 arylsulfonyl groups, heteroarylsulfonyl groups having 4 to 10 carbon atoms, iminoalkylpiperazinecarbonyl groups having 7 to 10 carbon atoms, alkylpiperazinecarbonyl groups having 6 to 10 carbon atoms, piperazinesulfonyl groups, 5 carbon atoms Represents an alkylpiperazinesulfonyl group of -9, an iminoalkylpiperazinesulfonyl group of 6-9 carbon atoms, an alkylsulfonyl group of 1-8 carbon atoms, an aminosulfonyl group, or a mono- or dialkylaminosulfonyl group of 2-8 carbon atoms,
R4, R5, R6, R7, R8 and R9 may be the same or different and each is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, an oxo group, a hydroxyl group, or a hydroxyalkyl having 1 to 10 carbon atoms. Group, alkoxy group having 1 to 10 carbon atoms, alkoxyalkyl group having 1 to 10 carbon atoms, nitro group, trifluoromethoxy group, trifluoromethyl group, amino group, mono- or dialkylamino group having 1 to 6 carbon atoms, carbon An aminoalkyl group having 1 to 9 carbon atoms, a mono- or dialkylaminoalkyl group having 2 to 9 carbon atoms, a methylenedioxy group, a cyano group, a formyl group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, and 3 to 3 carbon atoms 9 alkoxycarbonylalkyl groups, 3 to 9 hydroxycarbonylalkyl groups, 3 to 7 hydroxycarbonylalkenyl groups, carbon An alkoxycarbonylalkenyl group having 4 to 8 carbon atoms, a phosphono group, a dialkoxyphosphoryl group having 2 to 9 carbon atoms, a monoalkoxyhydroxyphosphoryl group having 1 to 4 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and 1 to 6 carbon atoms An alkylsulfonyl group, an arylthio group having 6 to 10 carbon atoms which may have a substituent, a heteroarylthio group having 4 to 10 carbon atoms which may have a substituent, a phosphorylalkyl group having 1 to 9 carbon atoms, Represents a dialkoxyphosphorylalkyl group having 3 to 9 carbon atoms, a monoalkoxyhydroxyphosphoryl group having 2 to 9 carbon atoms, a 2-carboxy-2-oxoethyl group, or a heteroaryl group having 1 to 10 carbon atoms,
X represents an alkylene group having 1 to 6 carbon atoms (in the chain, -NH-, -C (= O)-, -NHC (= O)-, -C (= O) NH-, -NHC (= O ) May contain NH −), and
Z1 and Z2 may be the same or different from each other, and are a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a hydroxy group, a hydroxyalkyl group having 1 to 6 carbon atoms, or an alkoxyalkyl group having 2 to 6 carbon atoms. , A thioalkyl group having 1 to 6 carbon atoms, an alkylthioalkyl group having 2 to 8 carbon atoms, a carbamoylalkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, carbon C6-C10 aryl group substituted with C1-C6 alkyl group, C4-C10 heteroaryl group substituted with C1-C6 alkyl group, C1-C6 aminoalkyl Group, carboxyl group, C2-C6 alkoxycarbonyl group, C2-C8 hydroxycarbonylalkyl group, C3-C8 alkoxycarbonylalkyl group, C1-C6 amino acid It represents either a noalkyl group or a mono- or dialkylaminoalkyl group having 2 to 10 carbon atoms, and Z1 and Z2 may be bonded to form a ring, in which case -Z1-Z2- is an ethylene group Represents a trimethylene group or a tetramethylene group. ] In general formula (1), ring A is an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 3 to 10 carbon atoms, or a cyclic alkyl group having 5 or 6 carbon atoms, and R1 is a hydrogen atom or a halogeno group. , A hydroxyl group which may have a substituent, an alkoxyl group having 1 to 10 carbon atoms, a trifluoromethyl group, a trifluoromethanesulfonyloxy group, a carbamoyl group, a mono or dialkylcarbamoyl group having 2 to 7 carbon atoms, a cyano group, A nitro group, a mono- or dialkylamino group having 1 to 6 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, an optionally substituted alkyl group having 1 to 6 carbon atoms, and 1 to 6 carbon atoms An alkylthio group, an alkylsulfonyl group having 1 to 6 carbon atoms, an aminoalkyl group having 2 to 7 carbon atoms which may have a substituent, and a piperazine catalyst which may have a substituent Any one of a sulfonyl group or an amidino group which may have a substituent,
When R1 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, a mono- or dialkylamino group having 1 to 6 carbon atoms, a heteroaryl group having 1 to 10 carbon atoms, a carboxyl group, or a carbon number 1 to 6 carbon atoms which may be substituted with an alkyl group having 1 to 6 carbon atoms, including one or more heteroatoms selected from 2 to 7 alkoxycarbonyl groups, nitrogen, oxygen and sulfur Carbonyl substituted with a carbocyclic ring having 1 to 6 carbon atoms, which may be substituted with an alkyl group having 1 to 6 carbon atoms, containing one or more heteroatoms selected from any of rings, nitrogen, oxygen and sulfur Group, phosphono group, C2-C9 dialkoxyphosphoryl group, C1-C4 monoalkoxyhydroxyphosphoryl group, C1-C6 alkylsulfonyl group or C1-C6 dialkyl Show one of the Mijino group,
The benzodiazepine derivative according to claim 1 or a pharmaceutically acceptable salt thereof. In general formula (1), ring A represents a phenyl group,
R1 may have a hydrogen atom, a fluoro group, a chloro group, a bromo group, an iodo group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono- or dialkylamino group having 1 to 6 carbon atoms, or a substituent. A hydroxyl group, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted carbon group having 1 to 6 carbon atoms An alkylsulfonyl group of
When R1 has a substituent, the substituent is a hydroxyl group, a phosphono group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a mono or dialkylcarbamoyl group having 2 to 7 carbon atoms, or a mono group having 1 to 6 carbon atoms. Or a C1-C6 carbocycle optionally substituted with a C1-C6 alkyl group containing one or more heteroatoms selected from dialkylamino groups, nitrogen, oxygen and sulfur, nitrogen , A carbonyl group or carbon substituted with a carbon ring having 1 to 6 carbon atoms, which may be substituted with an alkyl group having 1 to 6 carbon atoms, containing one or more heteroatoms selected from oxygen and sulfur An alkylsulfonyl group of the number 1-6, and
R4 and R5 may be the same or different, and are a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkoxyl group having 1 to 6 carbon atoms, a trifluoromethoxy group, a hydroxyl group, carbon The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is any one of an alkylthio group having 1 to 6 carbon atoms and an alkylsulfonyl group having 1 to 6 carbon atoms. In general formula (1), ring A represents a phenyl group,
R1 is a hydrogen atom, fluoro group, chloro group, bromo group, iodo group, amino group, cyano group, nitro group, carboxyl group, ethoxycarbonyl group, carboxyethyl group, ethoxycarbonylethyl group, morpholine alkyl group, hydroxyl group, The benzodiazepine derivative according to claim 1, which is a methyl group, a methoxy group, a methylthio group, a methylsulfonyl group, a phosphonoethyl group, a morpholinecarbonylethyl group, a piperazinecarbonylethyl group, an isopropylpiperazinecarbonylethyl group, a methanesulfonylaminopropyl group or a hydroxypropyl group. Or a pharmaceutically acceptable salt thereof.   The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 4, wherein in general formula (1), at least one of R4 and R5 is a hydrogen atom. In general formula (1), ring B represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms,
The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R2 is any one of a hydrogen atom, a halogeno group, an alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, and an alkoxyl group having 1 to 10 carbon atoms. Uru salt. In general formula (1), ring B is an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms,
R2 is a hydrogen atom, a chloro group, a bromo group or a methyl group, and
The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R6 and R7 may be the same or different and are each a hydrogen atom, a halogeno group, a trifluoromethyl group, a methoxy group or a hydroxyl group. . In general formula (1), ring B is an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 4 to 10 carbon atoms,
R2 is either a chloro group, a bromo group or a methyl group,
The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R6 and R7 are both hydrogen atoms.   The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 8, wherein in formula (1), ring B is either a phenyl group or a thiophene group. In general formula (1), ring C may contain one or more heteroatoms selected from oxygen and / or sulfur, including at least one nitrogen atom, excluding pyrrolidyl group, piperidyl group or piperazinyl group. A non-aromatic carbocyclic ring of 2 to 8,
R3 is a halogeno group, a nitro group, an iminoalkyl group having 2 to 7 carbon atoms, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, an acyl group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, A piperidyloxy group, an iminoalkylpiperidyloxy group having 6 to 10 carbon atoms, an alkylpiperidyloxy group having 5 to 10 carbon atoms, an amino group which may have a substituent, and a carbon number which may have a substituent. A 2-9 aminoalkyl group, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted pyrrolidine group, an optionally substituted piperazine group, It is either a C1-C10 heteroaryl group which may have a substituent or an amidino group which may have a substituent,
When R3 has a substituent, the substituent is an alkyl group having 1 to 6 carbon atoms, a mono or dialkylcarbamoyl group having 2 to 7 carbon atoms, a mono or dialkylaminoalkyl group having 2 to 9 carbon atoms, or 2 to 2 carbon atoms. The benzodiazepine derivative according to claim 1, which is any one of 7 mono- or dialkylamidino groups, trialkylamidino groups having 4 to 7 carbon atoms, pyrrolidine groups, piperidine groups, alkylsulfonyl groups having 1 to 8 carbon atoms, or pyridyl groups. Its pharmaceutically acceptable salt.   The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 10, wherein R3 in formula (1) is an optionally substituted alkyl group having 1 to 6 carbon atoms. The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 11, wherein, in general formula (1), ring C is any of the groups represented by the following general formula (2).

  The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 12, wherein R8 and R9 are both hydrogen atoms in the general formula (1).   The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is an alkylene group having 1 to 6 carbon atoms. In general formula (1), ring A represents a phenyl group,
R1 is a hydrogen atom, fluoro group, chloro group, bromo group, iodo group, amino group, cyano group, nitro group, carboxyl group, ethoxycarbonyl group, carboxyethyl group, ethoxycarbonylethyl group, morpholine alkyl group, hydroxyl group, A methyl group, a methoxy group, a methylthio group, a methylsulfonyl group, a phosphonoethyl group, a morpholinecarbonylethyl group, a piperazinecarbonylethyl group, an isopropylpiperazinecarbonylethyl group, a methanesulfonylaminopropyl group or a hydroxypropyl group;
Ring B represents either a phenyl group or a thiophene group,
R2 represents a hydrogen atom, a chloro group, a bromo group or a methyl group,
Ring C represents any of the groups represented by the general formula (2) according to claim 12,
R3 represents a hydrogen atom, a methyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a pyridyl group;
X is a methylene group or ethylene group, a propylene group (-C (= O)-may be included in the chain), and
The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein Z1 and Z2 are both hydrogen atoms.   The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 15, wherein, in the general formula (1), R5, R6, R7 and R9 are hydrogen atoms. In general formula (1), ring A represents a phenyl group,
R1 represents a hydrogen atom, a carboxyl group, an ethoxycarbonyl group, a carboxyethyl group, an ethoxycarbonylethyl group, a morpholinealkyl group, a morpholinecarbonylethyl group, a piperazinecarbonylethyl group, an isopropylpiperazinecarbonylethyl group,
Ring B represents either a phenyl group or a thienyl group,
R2 represents a chloro group, a bromo group or a methyl group,
Ring C represents any of the groups represented by the general formula (2) according to claim 12,
R3 represents either a methyl group or an isopropyl group;
X is a methylene group or ethylene group, propylene group,
R4 is a hydrogen atom, a fluoro group, a chloro group, a methoxy group, or a methyl group,
R5, R6, R7 and R9 are all hydrogen atoms, and
The benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein Z1 and Z2 are both hydrogen atoms.   An activated blood coagulation factor X inhibitor comprising the benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 as an active ingredient.   A pharmaceutical composition comprising the benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 as an active ingredient.   An anti-coagulant or a prophylactic or therapeutic agent for thrombosis or embolism comprising the benzodiazepine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 as an active ingredient.