JP2005023038A - Therapeutic agent for chronic renal disease - Google Patents
Therapeutic agent for chronic renal disease Download PDFInfo
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- JP2005023038A JP2005023038A JP2003191787A JP2003191787A JP2005023038A JP 2005023038 A JP2005023038 A JP 2005023038A JP 2003191787 A JP2003191787 A JP 2003191787A JP 2003191787 A JP2003191787 A JP 2003191787A JP 2005023038 A JP2005023038 A JP 2005023038A
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Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、新規な慢性腎疾患治療薬に関する。
【０００２】
【従来の技術】
ジペプチジルペプチダーゼＩＶ（ＤＰＰＩＶ）はＮ末端から２番目にプロリン又はアラニンを有するペプチド鎖からジペプチドを加水分解するセリンプロテアーゼの一種である。ＤＰＰＩＶは腎臓、肝臓など広く組織、血漿中に分布しており、さまざまな生理活性ペプチドの代謝に関与している。
【０００３】
ＤＰＰＩＶを阻害することは、２型糖尿病治療、免疫疾患、皮膚病及び良性の前立腺肥大の治療に有用であると期待されている。
【０００４】
これまで、ＤＰＰＩＶ阻害化合物としては、ピロリジンの２位がリンで置換された化合物（非特許文献１）、ホウ素で置換された化合物（非特許文献２）、ピロリジンの２位がシアノ基で置換された化合物（非特許文献３〜５）、２−シアノピロリジン誘導体で３位、４位に置換基を有する化合物（特許文献１）の報告がある。
【特許文献】ＷＯ０２／３８５４１
【非特許文献】Ｊ．Ｍｅｄ．Ｃｈｅｍ．３７，３９６９−３９７６，１９９４
【非特許文献】Ｂｉｏｃｈｅｍｉｓｔｒｙ ３２，８７２３−８７３１，１９９３
【非特許文献】Ａｒｃｈ．Ｂｉｏｃｈｅｍ．ｂｉｏｐｈｙｓ．３２３，１４８−１５２，１９９５
【非特許文献】Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．６，１１６３−１１６６，１９９６
【非特許文献】Ｂｉｏｃｈｅｍｉｓｔｒｙ ３８，１１５９７−１１６０３，１９９９
【発明が解決しようとする課題】
本発明は、新規な作用に基づく慢性腎疾患治療薬を提供することを目的とする。
【０００５】
【課題を解決するための手段】
本発明者らは、上記目的を達成するべく鋭意検討を重ねた結果、ＤＰＰＩＶ阻害活性を有する化合物が優れた腎保護作用を有することを見出し、本発明を完成するに至った。
【０００６】
すなわち、本発明の１の態様によると、本発明は、ＤＰＰＩＶ阻害活性を有する化合物を有効成分とする慢性腎疾患治療薬（以下「本発明の慢性腎疾患治療薬」または「本発明治療薬」という）を提供する。
【０００７】
また、本発明の他の態様によると、本発明は、式（１）
【０００８】
【化３】
［式中、Ｒ１及びＲ２は同一又は異なって水素原子、ハロゲン原子、水酸基、炭素数１〜５のアルコキシ基又は炭素数１〜５のアルキル基を示すか、又はＲ１及びＲ２が一緒になってオキソ、ヒドロキシイミノ基、炭素数１〜５のアルコキシイミノ基又は炭素数１〜５のアルキリデン基を形成し、
Ｒ３及びＲ４は同一又は異なって水素原子、ハロゲン原子、水酸基、炭素数１〜５のアルコキシ基又は炭素数１〜５のアルキル基を示すか、又はＲ３及びＲ４が一緒になってオキソ、ヒドロキシイミノ基、炭素数１〜５のアルコキシイミノ基又は炭素数１〜５のアルキリデン基を形成し、
Ｘは酸素原子又は硫黄原子を示し、
Ｙは式−ＣＲ５Ｒ６−［式中、Ｒ５及びＲ６は同一又は異なって水素原子；ハロゲン原子；ハロゲン原子、水酸基、炭素数１〜５のヒドロキシアルキル基、カルボキシル基、メルカプト基、炭素数１〜５のアルキルチオ基、グアニジル基、置換されてもよいフェニル基、イミダゾリル基、インドリル基、−ＮＨＲ１１（式中Ｒ１１は水素原子、置換されてもよいフェニル基、置換されてもよいピリジル基、ｔｅｒｔ−ブトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）、−ＣＯＮＨＲ１２｛式中Ｒ１２は水素原子又は−（ＣＨ２）ｍ−Ｒ１３（式中ｍは整数１〜５を示し、Ｒ１３は水素原子、メトキシカルボニル基、エトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）を示す｝並びに−ＯＲ１４（式中Ｒ１４は炭素数１〜５の鎖状アルキル基若しくはベンジル基を示す）からなる群より選ばれる一つ以上の基で置換されてもよい炭素数１〜１０のアルキル基；若しくはハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数２〜１０のアルケニル基である］を示すか、
又は式−ＣＲ７Ｒ８−ＣＲ９Ｒ１０−（式中、Ｒ７、Ｒ８、Ｒ９及びＲ１０は同一又は異なって水素原子；ハロゲン原子；ハロゲン原子、水酸基、炭素数１〜５のヒドロキシアルキル基、カルボキシル基、メルカプト基、炭素数１〜５のアルキルチオ基、グアニジル基、置換されてもよいフェニル基、イミダゾリル基、インドリル基、−ＮＨＲ１１（式中Ｒ１１は水素原子、置換されてもよいフェニル基、置換されてもよいピリジル基、ｔｅｒｔ−ブトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）、−ＣＯＮＨＲ１２｛式中Ｒ１２は水素原子又は−（ＣＨ２）ｍ−Ｒ１３（式中ｍは整数１〜５を示し、Ｒ１３は水素原子、メトキシカルボニル基、エトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）を示す｝並びに−ＯＲ１４（式中Ｒ１４は炭素数１〜５の鎖状アルキル基若しくはベンジル基を示す）からなる群より選ばれる一つ以上の基で置換されてもよい炭素数１〜１０のアルキル基を示すか、又はＲ７とＲ９が隣接する炭素原子と一緒になって、ハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、炭素数１〜５の鎖状アルキル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数３〜８のシクロアルキル基；ハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、炭素数１〜５の鎖状アルキル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数４〜８のシクロアルケニル基；ハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、炭素数１〜５の鎖状アルキル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数５〜１０のビシクロアルキル基；又はハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、炭素数１〜５の鎖状アルキル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数５〜１０のビシクロアルケニル基を形成する）を示し、
Ｚは水素原子；又はハロゲン原子、水酸基、炭素数１〜５のヒドロキシアルキル基、カルボキシル基、メルカプト基、炭素数１〜５のアルキルチオ基、グアニジル基、置換されてもよいフェニル基、イミダゾリル基、インドリル基、−ＮＨＲ１１（式中Ｒ１１は水素原子、置換されてもよいフェニル基、置換されてもよいピリジル基、ｔｅｒｔ−ブトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）、−ＣＯＮＨＲ１２｛式中Ｒ１２は水素原子又は−（ＣＨ２）ｍ−Ｒ１３（式中ｍは整数１〜５を示し、Ｒ１３は水素原子、メトキシカルボニル基、エトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）を示す｝並びに−ＯＲ１４（式中Ｒ１４は炭素数１〜５の鎖状アルキル基若しくはベンジル基を示す）からなる群より選ばれる一つ以上の基で置換されてもよい炭素数１〜１０のアルキル基を示すか、
又はＹ及びＺが隣接する窒素原子とともに一緒になって、ハロゲン原子、水酸基、アミノ基、炭素数１〜５の鎖状アルキル基及び−ＯＲ１５（式中Ｒ１５は炭素数１〜５の鎖状アルキル基、アミノカルボニルメチル基若しくはベンジル基を示す）からなる群より選ばれる一つ以上の基で置換されてもよい炭素数２〜１０の環状アミノ基を形成する］で表されるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬を提供する。
【００１０】
本発明の他の態様によると、本発明は、式（１）においてＲ１はハロゲン原子、水酸基、炭素数１〜５のアルコキシ基又は炭素数１〜５のアルキル基を示し、Ｒ２、Ｒ３及びＲ４がそれぞれ水素原子、ハロゲン原子、水酸基、炭素数１〜５のアルコキシ基又は炭素数１〜５のアルキル基であるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬を提供する。
【００１１】
本発明の他の態様によると、本発明は、式（１）においてＲ１がフッ素原子又は塩素原子であるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬を提供する。
【００１２】
本発明の他の態様によると、本発明は、式（１）において Ｒ１がフッ素原子であり、Ｒ２が水素原子であるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬を提供する。
【００１３】
本発明の他の態様によると、本発明は、式（１）においてＲ１がフッ素原子であり、Ｒ２、Ｒ３及びＲ４が水素原子であるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬を提供する。
【００１４】
本発明の他の態様によると、本発明は、式（２）
【００１５】
【化４】
（式中、Ｘ、Ｙ及びＺは、上記と同じである。）
で表されるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬を提供する。
【００１７】
本発明の他の態様によると、本発明は、式（１）又は式（２）においてＸが酸素原子であるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬を提供する。
【００１８】
本発明の他の態様によると、本発明は、式（１）又は式（２）においてＹが−ＣＨ２−であるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬を提供する。
【００１９】
本発明の他の態様によると、本発明は、式（１）又は式（２）においてＹが−ＣＨ２−であり、Ｚが水酸基及び炭素数１〜５のヒドロキシアルキル基からなる群より選ばれる一つ以上で置換されてよい、炭素数４〜１０の分岐鎖状又は環状アルキル基であるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬を提供する。
【００２０】
本発明の他の態様によると、本発明は、式（１）又は式（２）においてＹが−ＣＨ２−であり、Ｚがｔｅｒｔ−ブチル基、（１−ヒドロキシメチル）シクロペンチル基又は（２−ヒドロキシ−１，１−ジメチル）エチル基であるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬を提供する。
【００２１】
本発明の他の態様によると、本発明は、式（１）又は式（２）においてＹが−ＣＲ５Ｒ６−（式中、Ｒ５が水素である）であり、Ｚが水素原子であるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬を提供する。
【００２２】
本発明の他の態様によると、本発明は、式（１）又は式（２）においてＹが−ＣＲ５Ｒ６−（式中、Ｒ５が水素であり、Ｒ６が炭素数３〜６の分岐鎖状又は環状アルキル基である）であり、Ｚが水素原子であるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬を提供する。
【００２３】
本発明の他の態様によると、本発明は、式（１）又は式（２）においてＹが−ＣＨ［ＣＨ（ＣＨ３）２］−、−ＣＨ［Ｃ（ＣＨ３）３］−又は−ＣＨ［ＣＨ（ＣＨ３）ＣＨ２ＣＨ３］−であり、Ｚが水素原子であるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬を提供する。
【００２４】
【発明の実施の形態】
本発明においてジペプチジルペプチダーゼＩＶ（ＤＰＰＩＶ）阻害活性を有する化合物とは、ペプチド鎖からジペプチドを加水分解するプロテアーゼ活性を阻害する化合物であれば特に制限はなく、例えば、Ｄｉａｂｅｔｅｓ、４７、７６４−７６９、１９９８に掲載された方法により測定し、ジペプチジルペプチダーゼＩＶ阻害活性が認められた化合物を挙げることができる。さらに、具体的には、以下の公報に記載された化合物を挙げることができる。
【００２５】
ＷＯ９５／１５３０９、ＷＯ９８／１９９９８、ＷＯ００／３４２４１、ＷＯ０１／５５１０５、ＷＯ０１／６８６０３、ＷＯ０１／９６２９５、ＷＯ０２／１４２７１、ＷＯ０２／３０８９１、ＷＯ０２／３０８９１、ＷＯ０２／５１８３６、ＷＯ０２／０７６４５０、ＷＯ０２／０８３１２８、ＷＯ０３／０００２５０、ＷＯ０３／０００１８０、ＷＯ０３／０００１８１、ＷＯ０３／００４４９８、ＷＯ０３／００２５３０、ＷＯ０３／００２５３１、ＷＯ０３／００２５５３、ＷＯ０３／００２５９５、ＷＯ０３／０３５０５７、ＷＯ０３／０３５０６７、ＷＯ０３／０３７３２７、ＷＯ０２／０２５６０、ＷＯ０２／６２７６４、ＷＯ０２／６８４２０、ＷＯ０３／００４４９６、ＷＯ０３／００４４９８。
【００２６】
特に、式（１）で表されるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とすることが好ましく、さらに好ましくは式（２）で表されるシアノピロリジン誘導体又はその薬学的に許容される塩である。
【００２７】
式（１）および（２）において、鎖状とは、直鎖状又は分岐鎖状を意味する。
ハロゲン原子とは、フッ素原子、塩素原子、臭素原子又はヨウ素原子を示す。
炭素数１〜５のアルコキシ基とは、直鎖状、分岐鎖状又は環状のアルコキシ基を意味し、例えばメトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、ｔｅｒｔ−ブトキシ基、シクロプロピルメトキシ基、ペンチルオキシ基、イソペンチルオキシ基などを挙げることができる。
【００２８】
炭素数１〜５のアルキル基とは、直鎖状、分岐鎖状又は環状のアルキル基（シクロアルキルアルキル基も含む）を意味し、例えばメチル基、エチル基、プロピル基、イソプロピル基、シクロプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、シクロブチル基、シクロプロピルメチル基、ペンチル基、イソペンチル基、シクロペンチル基、シクロブチルメチル基、１−エチルプロピル基などを挙げることができる。
【００２９】
炭素数１〜５のアルコキシイミノ基とは直鎖状、分岐鎖状又は環状のアルコキシ基で置換されたイミノ基を意味し、メトキシイミノ基、エトキシイミノ基、プロポキシイミノ基、イソプロポシイミノ基、ブトキシイミノ基、イソブトキシイミノ基、ｔｅｒｔ−ブトキシイミノ基、シクロプロピルメトキシイミノ基、ペンチルオキシイミノ基、イソペンチルオキシイミノ基などを挙げることができる。
【００３０】
炭素数１〜５のアルキリデン基とは、直鎖状、分岐鎖状又は環状のアルキリデン基を意味し、例えばメチレン基、エチリデン基、プロピリデン基、イソプロピリデン基、ブチリデン基、イソブチリデン基、シクロプロピルメチレン基、ペンチリデン基などを挙げることができる。
【００３１】
置換されてもよい炭素数１〜１０のアルキル基とは、置換又は無置換の直鎖状、分岐鎖状又は環状の炭素数１〜１０のアルキル基（シクロアルキルアルキル基も含む）を意味し、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、ペンチル基、イソペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、炭素数３〜１０のシクロアルキル基（例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロブチルメチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基など）、炭素数４〜８のシクロアルケニル基（例えば、シクロブテニル基、シクロペンテニル基、シクロヘキセニル基、シクロヘプテニル基、シクロオクテニル基など）、置換されてもよい炭素数５〜１０のビシクロアルキル基（例えば、ビシクロペンチル基、ビシクロヘキシル基、ビシクロヘプチル基、ビシクロオクチル基、ビシクロノニル基、ビシクロデシル基など）、置換されてもよい炭素数５〜１０のビシクロアルケニル基（例えば、ビシクロペンテニル基、ビシクロヘキセニル基、ビシクロヘプテニル基、ビシクロオクテニル基、ビシクロノネル基、ビシクロデセル基など）、架橋環式炭化水素（例えば、アダマンチル基、ボルニル基、ノルボルニル基、ピナニル基、ツヨイル基、カルイル基、カルファニル基など）などのアルキル基の他、これらのアルキル基の水素原子をハロゲン原子、水酸基、炭素数１〜５のヒドロキシアルキル基、カルボキシル基、メルカプト基、炭素数１〜５のアルキルチオ基、グアニジル基、置換されてもよいフェニル基、イミダゾリル基、インドリル基、−ＮＨＲ１１（式中Ｒ１１は水素原子、置換されてもよいフェニル基、置換されてもよいピリジル基、ｔｅｒｔ−ブトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）、−ＣＯＮＨＲ１２｛式中Ｒ１２は水素原子又は−（ＣＨ２）ｍ−Ｒ１３（式中ｍは整数１〜５を示し、Ｒ１３は水素原子、メトキシカルボニル基、エトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）を示す｝並びに−ＯＲ１４（式中Ｒ１４は炭素数１〜５の直鎖状又は分岐鎖状アルキル基若しくはベンジル基を示す）からなる群より選ばれる一つ以上の基で置換したアルキル基を挙げることができる。
【００３２】
置換されてもよいフェニル基の置換されたフェニル基とは、例えば、水酸基及び直鎖状又は分岐鎖状の炭素数１〜５のアルコキシ基からなる群より選ばれる一つ以上の基で置換されたフェニル基（例えば、４−ヒドロキシフェニル基、３，４−ジメトキシフェニル基など）を挙げることができる。
【００３３】
置換されてもよいピリジル基（例えば、ピリジン−２−イル基など）の置換されたピリジル基とは、例えば、シアノ基、ニトロ基、ハロゲン原子及びアミノカルボニル基からなる群より選ばれる一つ以上の基で置換されたピリジル基（例えば、５−シアノピリジン−２−イル基、５−ニトロピリジン−２−イル基、５−クロロピリジン−２−イル基、５−アミノカルボニルピリジン−２−イル基など）を挙げることができる。
【００３４】
炭素数１〜５のヒドロキシアルキル基とは、ヒドロキシメチル基、１−ヒドロキシエチル基、２−ヒドロキシエチル基、１−ヒドロキシプロピル基、２−ヒドロキシプロピル基、３−ヒドロキシプロピル基、１−（ヒドロキシメチル）エチル基、１−ヒドロキシ−１−メチルエチル基、４−ヒドロキシブチル基、５−ヒドロキシペンチル基などがあげられる。
【００３５】
炭素数１〜５のアルキルチオ基とは、メチルチオ基、エチルチオ基、プロピルチオ基、イソプロピルチオ基、ブチルチオ基、ｔｅｒｔ−ブチルチオ基、ペンチルチオ基などがあげられる。
【００３６】
置換されてもよい炭素数２〜１０のアルケニル基とは、置換又は無置換の直鎖状、分岐鎖状又は環状の炭素数２〜１０のアルケニル基を意味し、例えばビニル基、アリル基、プロペニル基、イソプロペニル基、ブテニル基、イソブテニル基、ペンテニル基、ヘキセニル基、ヘプテニル基、オクテニル基、シクロペンテニル基、シクロヘキセニル基などのアルケニル基の他、これらアルケニル基の水素原子をハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基及び直鎖状又は分岐鎖状の炭素数１〜５のアルコキシ基からなる群より選ばれる一つ以上の基で置換したアルケニル基を挙げることができる。
【００３７】
置換されてもよい炭素数３〜８のシクロアルキル基とは、置換又は無置換のシクロアルキル基を意味し、例えば、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、シクロオクチル基などのシクロアルキル基の他、これらシクロアルキル基の水素原子をハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、直鎖状又は分岐鎖状の炭素数１〜５のアルキル基及び直鎖状又は分岐鎖状の炭素数１〜５のアルコキシ基からなる群より選ばれる一つ以上の基で置換したシクロアルキル基を挙げることができる。
【００３８】
置換されてもよい炭素数４〜８のシクロアルケニル基とは、置換又は無置換のシクロアルケニル基を意味し、例えば、シクロブテニル基、シクロペンテニル基、シクロヘキセニル基、シクロヘプテニル基、シクロオクテニル基などのシクロアルケニル基の他、これらシクロアルケニル基の水素原子をハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、直鎖状又は分岐鎖状の炭素数１〜５のアルキル基及び直鎖状又は分岐鎖状の炭素数１〜５のアルコキシ基からなる群より選ばれる一つ以上の基で置換したシクロアルケニル基を挙げることができる。
【００３９】
置換されてもよい炭素数５〜１０のビシクロアルキル基とは、置換又は無置換のビシクロアルキル基を意味し、例えば、ビシクロペンチル基、ビシクロヘキシル基、ビシクロヘプチル基、ビシクロオクチル基、ビシクロノニル基、ビシクロデシル基などのビシクロアルキル基の他、これらビシクロアルキル基の水素原子をハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、直鎖状又は分岐鎖状の炭素数１〜５のアルキル基及び直鎖状又は分岐鎖状の炭素数１〜５のアルコキシ基からなる群より選ばれる一つ以上の基で置換したビシクロアルキル基を挙げることができる。
【００４０】
置換されてもよい炭素数５〜１０のビシクロアルケニル基とは、置換又は無置換のビシクロアルケニル基を意味し、例えば、ビシクロペンテニル基、ビシクロヘキセニル基、ビシクロヘプテニル基、ビシクロオクテニル基、ビシクロノネル基、ビシクロデセル基などのビシクロアルケニル基の他、これらビシクロアルケニル基の水素原子をハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、直鎖状又は分岐鎖状の炭素数１〜５のアルキル基及び直鎖状又は分岐鎖状の炭素数１〜５のアルコキシ基からなる群より選ばれる一つ以上の基で置換したビシクロアルケニル基を挙げることができる。
【００４１】
置換されてもよい炭素数２〜１０の環状アミノ基とは、環内に一つ以上の窒素原子を有し、また一つ以上の酸素原子、硫黄原子が存在してもよい置換又は無置換の環状アミノ基を意味し、例えばアジリジル基、アゼチジル基、ピロリジル基、イミダゾリジル基、オキサゾリジル基、チアゾリジル基、ピペリジル基、モルホリル基、アザビシクロヘプチル基、アザビシクロオクチル基などの環状アミノ基の他、これら環状アミノ基にベンゼン環又はピリジン環が縮合した環状アミノ基や環状アミノ基（環状アミノ基に縮合したベンゼン環又はピリジン環も含む）の水素原子をハロゲン原子、水酸基、アミノ基、直鎖状又は分岐鎖状の炭素数１〜５のアルキル基及び−ＯＲ１５（式中Ｒ１５は直鎖状又は分岐鎖状の炭素数１〜５のアルキル基、アミノカルボニルメチル基若しくはベンジル基を示す）からなる群より選ばれる一つ以上の基で置換した環状アミノ基を挙げることができる。
【００４２】
また、薬学的に許容される塩とは、例えば硫酸、塩酸、臭化水素酸、燐酸などの鉱酸との塩、酢酸、シュウ酸、乳酸、酒石酸、フマール酸、マレイン酸、トリフルオロ酢酸、メタンスルホン酸などの有機酸との塩を挙げることができる。
【００４３】
式（１）において、Ｒ１はハロゲン原子であることが好ましく、さらに好ましくはフッ素原子である。Ｒ２は水素原子又はハロゲン原子であることが好ましいが、水素原子であることがさらに好ましい。
【００４４】
式（１）又は式（２）において、Ｙが−ＣＨ２−であるとき、Ｚは、水酸基、炭素数１〜５のアルコキシル基、炭素数１〜５のヒドロキシアルキル基、置換されてもよいフェニル基及び−ＮＨＲ１１（式中Ｒ１１は置換されてもよいピリジル基である）からなる群の一つ以上で置換されてよい、炭素数１〜１０のアルキル基が好ましい。この場合、Ｚは、好ましくは、水酸基、炭素数１〜５のヒドロキシアルキル基及び炭素数１〜５のアルコキシル基からなる群の一つ以上で置換されてよい、炭素数４〜１０の分岐鎖状若しくは環状アルキル基であり、より好ましくは、水酸基及び炭素数１〜５のヒドロキシアルキル基からなる群の一つ以上で置換されてよい、炭素数４〜１０の分岐鎖状アルキル基、炭素数４〜１０のシクロアルキル基若しくはアダマンチル基であり、さらに好ましくは、ｔｅｒｔ−ブチル基、（１−ヒドロキシメチル）シクロペンチル基又は（２−ヒドロキシ−１，１−ジメチル）エチル基である。
【００４５】
式（１）又は式（２）において、Ｙが、式−ＣＲ５Ｒ６−（式中、Ｒ５が水素であり、Ｒ６が置換されてもよい炭素数１〜１０のアルキル基または式−ＣＲ７Ｒ８−ＣＲ９Ｒ１０−（式中、Ｒ８とＲ１０は水素であり、Ｒ７とＲ９が隣接する炭素原子と一緒になって炭素数３〜８のシクロアルキル基を形成する）であるとき、ＺはＨ又はＣＨ３が好ましい。
【００４６】
この場合、好ましくは、Ｙが、式−ＣＲ５Ｒ６−｛式中、Ｒ５が水素であり、Ｒ６が水酸基及び−ＯＲ１４（式中Ｒ１４は炭素数１〜５の直鎖状又は分岐鎖状のアルキル基若しくはベンジル基を示す）からなる群から選択される一つ以上で置換されてもよい炭素数３〜６の分岐鎖状又は環状アルキル基である）であるとき、Ｚが水素原子であり、より好ましくは、Ｙが、−ＣＲ５Ｒ６−（式中、Ｒ５が水素であり、Ｒ６が炭素数３〜６の分岐鎖状又は環状アルキル基である）であるとき、Ｚが水素原子であり、さらにより好ましくは、Ｙが−ＣＨ［ＣＨ（ＣＨ３）２］−、−ＣＨ［Ｃ（ＣＨ３）３］−又は−ＣＨ［ＣＨ（ＣＨ３）ＣＨ２ＣＨ３］−であるとき、Ｚが水素原子である。
【００４７】
式（１）又は式（２）において、Ｙ及びＺが隣接する窒素原子とともに一緒になって形成する置換されてもよい炭素数２〜１０の環状アミノ基を形成する場合の好ましい例としては、ピロリジル基、ピペリジル基又はこれらの基にベンゼン環が縮合した環状アミノ基であり、好ましい置換基としては水酸基及び−ＯＲ１５（式中Ｒ１５は上記で定義した通りである）があげられる。
【００４８】
本発明において慢性腎疾患治療薬とは、慢性腎不全、腎糸球体硬化症、糖尿病性腎症、腎硬化症、慢性腎炎、慢性糸球体腎炎、多発性嚢胞腎等を含む慢性腎疾患の腎生理機能を低下させる疾患の治療薬を意味し、尿中蛋白やアルブミンを減少させるなど優れた腎保護作用を有する。
【００４９】
本発明の医薬は、全身的又は局所的に経口又は直腸内、皮下、筋肉内、静脈内、経皮等の非経口投与することができる。
【００５０】
本発明の化合物を医薬として用いるためには、固体組成物、液体組成物、及びその他の組成物のいずれの形態でもよく、必要に応じて最適のものが選択される。本発明の医薬は、本発明の化合物に薬学的に許容されるキャリヤーを配合して製造することができる。具体的には、常用の賦形剤、増量剤、結合剤、崩壊剤、被覆剤、糖衣剤、ｐＨ調整剤、溶解剤、又は水性若しくは非水性溶媒などを添加し、常用の製剤技術によって、錠剤、丸剤、カプセル剤、顆粒剤、粉剤、散剤、液剤、乳剤、懸濁剤、注射剤、などに調製する事ができる。賦形剤、増量剤としては、たとえば、乳糖、ステアリン酸マグネシウム、デンプン、タルク、ゼラチン、寒天、ペクチン、アラビアゴム、オリーブ油、ゴマ油、カカオバター、エチレングリコールなどやその他常用されるものをあげる事ができる。
【００５１】
また、本発明の慢性腎疾患治療薬は、α、β若しくはγ−シクロデキストリン又はメチル化シクロデキストリン等と包接化合物を形成させて製剤化することができる。
【００５２】
本発明の慢性腎疾患治療薬の投与量は、疾患、症状、体重、年齢、性別、投与経路等により異なるが、成人に対し、経口投与の場合、好ましくは約１〜約１０００ ｍｇ ／ ｋｇ体重／日であり、より好ましくは約１０〜約２００ ｍｇ ／ ｋｇ体重／日であり、これを１日１回又は数回に分けて投与することができる。
【００５３】
さらに、試験例により本発明を説明するが、本発明はこれらの実施例に限定されるものではない。
試験例 １［ジペプチジルペプチダーゼＩＶ活性阻害実験］
ジペプチジルペプチダーゼＩＶ（ＤＰＰＩＶ）活性阻害実験はＤｉａｂｅｔｅｓ、４７、７６４−７６９、１９９８に掲載された方法に従って行った。ジペプチジルペプチダーゼＩＶを含む血漿は、健常人ボランティアから血液を採取し、遠心分離により調製した。酵素反応は９６穴平底プレートを用い、２５ｍＭ ＨＥＰＥＳ、１４０ｍＭ ＮａＣｌ、１％ＢＳＡ、ｐＨ７．８から成る緩衝液中で行った。 １００μＭ Ｇｌｙ−Ｐｒｏ−４−メチルクマリル−７−アミド（ペプチド研究所製）溶液 ２５μｌ、１３３ｍＭ 塩化マグネシウム溶液７．５μｌ、検体化合物５μｌを混合し、次いで上記緩衝液で１／１００倍に希釈した血漿１２．５μｌを加えた。室温で２時間反応させた後、２５％酢酸水溶液５０μｌを添加し反応を止めた。遊離した７−アミノ−４−メチルクマリン量を蛍光プレートリーダー（１４２０ ＡＲＶＯＴＭ Ｍｕｌｔｉｌａｂｅｌ Ｃｏｕｎｔｅｒ；Ｗａｌｌａｃ社製）を用いて３９０ｎｍで励起させたときの４６０ｎｍの蛍光強度を測定した。溶媒添加して反応時間を０分としたときの蛍光強度をブランク値とし、各測定値からブランク値を差し引いたものを特異的蛍光強度とした。得られた特異的蛍光強度から、下式によりジペプチジルペプチダーゼＩＶ活性阻害率（％）を求めた。被検化合物は１０００倍高濃度のジメチルスルフォキシド溶液を調製し、上記緩衝液で希釈して使用した。各濃度の阻害率から５０％阻害を示す化合物濃度（ＩＣ５０値）を算出した。
【００５４】
阻害率（％）＝Ａ÷Ｂ×１００
（Ａ＝溶媒添加における蛍光強度−検体化合物添加における蛍光強度）
（Ｂ＝溶媒添加における蛍光強度）
（２Ｓ，４Ｓ）―２―シアノ−フルオロ―１―［（２−ヒドロキシ―１，１―ジメチレル）エチルアミノ］アセチルピロリジン・ベンゼンスルホン酸塩（以下化合物Ａとする）、（２Ｓ，４Ｓ）―１―［（２Ｓ，３Ｓ）−２−アミノ−３−メチルペンタノイル］―２−シアノ−４−フルオロピロリジン塩酸塩、（２Ｓ，４Ｓ）―１―［（２Ｓ）−２−アミノ−３−メチルブタノイル］―２−シアノ−４−フルオロピロリジン塩酸塩、（２Ｓ，４Ｓ）―１―［（２Ｓ）−２−アミノ−３，３−ジメチルブタノイル］―２−シアノ−４−フルオロピロリジン塩酸塩、（２Ｓ，４Ｓ）―１―（ｔｅｒｔ−ブチルアミノ）アセチル−２−シアノ−４−フルオロピロリジン塩酸塩、（２Ｓ，４Ｓ）―２―シアノ−１−［２−［（５−シアノピリジン−２−イル）アミノ］エチルアミノ］アセチル−４−フルオロピロリジンマレイン酸塩のＩＣ５０値は、それぞれ５．４ｎＭ、０．６ｎＭ、０．７ｎＭ、０．６ｎＭ、２．９ｎＭ、１．１ｎＭであった。
【００５５】
試験例２
Ｄａｈｌ−ｓａｌｔ ｓｅｎｓｉｔｉｖｅ ｒａｔ における ＤＰＰＩＶ阻害による腎保護作用
本試験は、Ｊ． Ｃａｒｄｉｏｖａｓｃｕｌａｒ Ｐｈａｒｍａｃｏｌｏｇｙ 第 ２３ 巻 ９７０ 頁（１９９４）に記載の方法に準拠して行なった。具体的には、以下のように行なった。
＜方法＞
実験には Ｄａｈｌ−ｓａｌｔ ｓｅｎｓｉｔｉｖｅ （Ｄａｈｌ−Ｓ） ｒａｔ および対照動物であるＤａｈｌ−ｓａｌｔ ｒｅｓｉｓｔａｎｃｅ （Ｄａｈｌ−Ｒ） ｒａｔ （オス、７ 週齢）を用い、下記のように ３ 群に分けて（１ 群各 ６ 例）試験を行なった。
Ｉ群： Ｄａｈｌ−Ｒ ＋ ４％ ＮａＣｌ食 ＋ 溶媒経口投与（１ 日 ２ 回）
ＩＩ群： Ｄａｈｌ−Ｓ ＋ ４％ ＮａＣｌ食 ＋ 溶媒経口投与（１ 日 ２ 回）
ＩＩＩ群： Ｄａｈｌ−Ｓ ＋ ４％ ＮａＣｌ食 ＋ 化合物Ａ １０ ｍｇ／ｋｇ 経口投与（１ 日 ２ 回）
【００５６】
各群の動物には ４％ ＮａＣｌ 高食塩含有飼料（正常飼料は ０．６ ％）を与え、飲料水は自由に摂取させた。溶媒および 化合物Ａ は １ 日 ２ 回経口投与し（１ 回目は ８：３０〜９：３０， ２ 回目は１６：３０〜１７：３０） ６ 週間連続経口投与する。投与開始より ６ 週間後、代謝ケージにラットを一匹ずつ入れて尿を採取し、尿中蛋白およびアルブミン量を測定して腎機能に及ぼす影響を観察した。尿中蛋白およびアルブミンの測定は、それぞれ Ｂｕｎｓｅｋｉ Ｋａｇａｋｕ 第 ３２ 巻 Ｅ３７９−Ｅ３８６ 頁（１９８３）および Ｈｙｐｅｒｔｅｎｓｉｏｎ 第 ４０ 巻 ６ 号 ８３４−８３９ 頁（２００２）に記載の方法に準拠して、日立自動分析装置 ７０６０を用いて行なった。
【００５７】
試験開始 ６ 週間後の尿中蛋白排泄量は、化合物Ａ 投与群（ＩＩＩ群）では 溶媒投与群（ＩＩ群）と比較して低値であった。
また、尿中アルブミン排泄量は、化合物Ａ 投与群（ＩＩＩ群）では 溶媒投与群（ＩＩ群）と比較して低値であった。
【００５８】
試験例３
自然発症糖尿病ラット（ＺＳＦ−１）におけるＤＰＰＩＶ阻害による腎保護作用
＜方法＞
ＺＳＦ−１ は自然発症の糖尿病ラットであり、腎機能障害を来たすことが知られている（Ｒｅｎａｌ Ｆａｉｌｕｒｅ 第 ２２ 巻 ４ 号， ３８７−４０６ 頁、２０００）。本試験では、Ｔｈｅ Ｊａｃｋｓｏｎ Ｌａｂｏｒａｔｏｒｙ から入手した ８ 週齢の ＺＳＦ−１ および対照動物である ＺＳＦ−１／ｌｅａｎ を用い、下記のように ５ 群に分けて（１ 群各 ８ 例）試験を行なった。
Ｉ群： ＺＳＦ−１／ｌｅａｎ ＋ 溶媒経口投与（１ 日 ２ 回）
ＩＩ群： ＺＳＦ−１ ＋ 溶媒経口投与（１ 日 ２ 回）
ＩＩＩ群： ＺＳＦ−１ ＋ 化合物Ａ １ ｍｇ／ｋｇ 経口投与（１ 日 ２ 回）
ＩＶ群： ＺＳＦ−１ ＋ 化合物Ａ ３ ｍｇ／ｋｇ 経口投与（１ 日 ２ 回）
Ｖ群： ＺＳＦ−１ ＋ 化合物Ａ １０ ｍｇ／ｋｇ 経口投与（１ 日 ２ 回）
【００５９】
溶媒および 化合物Ａ は １ 日 ２ 回（１ 回目は ８：３０〜１０：３０， ２ 回目は１６：３０〜１８：３０）で ８週間連続経口投与する。投与開始から ８週間後、代謝ケージにラットを一匹ずつ入れて尿を採取し、尿中蛋白およびアルブミン量を測定して腎機能に及ぼす影響を観察した。尿中蛋白およびアルブミン量の測定は、上記の文献の記載に準拠して、日立自動分析装置 ７０６０ で行なった。
【００６０】
試験開始 ８ 週間後の尿中蛋白排泄量は、化合物Ａ １０ ｍｇ／ｋｇ 投与群（Ｖ群）は溶媒投与群（ＩＩ群）と比較して低値であった。
また、尿中アルブミン排泄量は、 化合物Ａ １０ ｍｇ／ｋｇ 投与群（Ｖ群）は溶媒投与群（ＩＩ群）と比較して低値であった。
【００６１】
【発明の効果】
本発明により、新規な作用機序に基づく慢性腎疾患治療薬の提供が可能となり、副作用の少ない慢性腎疾患の治療、予防に有用である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel therapeutic agent for chronic kidney disease.
[0002]
[Prior art]
Dipeptidyl peptidase IV (DPPIV) is a kind of serine protease that hydrolyzes a dipeptide from a peptide chain having proline or alanine second from the N-terminus. DPPIV is widely distributed in tissues such as kidney and liver and in plasma, and is involved in the metabolism of various physiologically active peptides.
[0003]
Inhibiting DPPIV is expected to be useful in the treatment of type 2 diabetes, immune diseases, skin diseases and benign prostatic hypertrophy.
[0004]
So far, as DPPIV-inhibiting compounds, a compound in which the 2-position of pyrrolidine is substituted with phosphorus (Non-patent Document 1), a compound in which boron is substituted (Non-patent Document 2), and the 2-position of pyrrolidine is substituted with a cyano group There are reports of compounds (Non-Patent Documents 3 to 5) and 2-cyanopyrrolidine derivatives having a substituent at the 3-position and 4-position (Patent Document 1).
[Patent Document] WO02 / 38541
[Non-patent Document] Med. Chem. 37, 3969-3976, 1994
[Non-patent literature] Biochemistry 32, 8723-8931, 1993
[Non-Patent Document] Arch. Biochem. biophys. 323, 148-152, 1995
[Non-Patent Document] Bioorg. Med. Chem. Lett. 6,1163-1166,1996
[Non Patent Literature] Biochemistry 38, 11597-11603, 1999
[Problems to be solved by the invention]
An object of the present invention is to provide a therapeutic agent for chronic kidney disease based on a novel action.
[0005]
[Means for Solving the Problems]
As a result of intensive studies to achieve the above object, the present inventors have found that a compound having DPPIV inhibitory activity has an excellent renal protective action, and have completed the present invention.
[0006]
That is, according to one aspect of the present invention, the present invention relates to a therapeutic agent for chronic kidney disease comprising a compound having DPPIV inhibitory activity as an active ingredient (hereinafter referred to as “the therapeutic agent for chronic kidney disease of the present invention” or “therapeutic agent of the present invention”). Provided).
[0007]
According to another aspect of the present invention, the present invention provides a compound of formula (1)
[0008]
[Chemical 3]
[Wherein R 1 And R 2 Are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, or R 1 And R 2 Together form an oxo, hydroxyimino group, C1-C5 alkoxyimino group or C1-C5 alkylidene group,
R 3 And R 4 Are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, or R 3 And R 4 Together form an oxo, hydroxyimino group, C1-C5 alkoxyimino group or C1-C5 alkylidene group,
X represents an oxygen atom or a sulfur atom,
Y is the formula -CR 5 R 6 -[Wherein R 5 And R 6 Are the same or different and are a hydrogen atom; a halogen atom; a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1 to 5 carbon atoms, a guanidyl group, and an optionally substituted phenyl. Group, imidazolyl group, indolyl group, -NHR 11 (Where R 11 Represents a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), -CONHR 12 {Where R is 12 Is a hydrogen atom or-(CH 2 ) m -R 13 (In the formula, m represents an integer of 1 to 5, R 13 Represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) and -OR 14 (Where R 14 Represents a chain alkyl group having 1 to 5 carbon atoms or a benzyl group), an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of: a halogen atom, a hydroxyl group, a carboxyl group Or an alkenyl group having 2 to 10 carbon atoms that may be substituted with one or more groups selected from the group consisting of a group, an amino group, an aminocarbonyl group, and a chain alkoxy group having 1 to 5 carbon atoms. ,
Or the formula -CR 7 R 8 -CR 9 R 10 -(Wherein R 7 , R 8 , R 9 And R 10 Are the same or different and are a hydrogen atom; a halogen atom; a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1 to 5 carbon atoms, a guanidyl group, and an optionally substituted phenyl. Group, imidazolyl group, indolyl group, -NHR 11 (Where R 11 Represents a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), -CONHR 12 {Where R is 12 Is a hydrogen atom or-(CH 2 ) m -R 13 (In the formula, m represents an integer of 1 to 5, R 13 Represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) and -OR 14 (Where R 14 Represents a C 1-5 alkyl group or a benzyl group), or a C 1-10 alkyl group which may be substituted with one or more groups selected from the group consisting of R or R 7 And R 9 A group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group having 1 to 5 carbon atoms, and a chain alkoxy group having 1 to 5 carbon atoms, together with adjacent carbon atoms A cycloalkyl group having 3 to 8 carbon atoms which may be substituted with one or more groups selected from a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group having 1 to 5 carbon atoms, and A cycloalkenyl group having 4 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of chain alkoxy groups having 1 to 5 carbon atoms; halogen atom, hydroxyl group, carboxyl group, amino group, aminocarbonyl 5-10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a group, a chain alkyl group having 1 to 5 carbon atoms and a chain alkoxy group having 1 to 5 carbon atoms Or one or more selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group having 1 to 5 carbon atoms, and a chain alkoxy group having 1 to 5 carbon atoms. A C5-C10 bicycloalkenyl group which may be substituted with a group)
Z is a hydrogen atom; or a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1 to 5 carbon atoms, a guanidyl group, an optionally substituted phenyl group, an imidazolyl group, Indolyl group, -NHR 11 (Where R 11 Represents a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), -CONHR 12 {Where R is 12 Is a hydrogen atom or-(CH 2 ) m -R 13 (In the formula, m represents an integer of 1 to 5, R 13 Represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) and -OR 14 (Where R 14 Represents a chain alkyl group having 1 to 5 carbon atoms or a benzyl group), or an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of
Or Y and Z together with the adjacent nitrogen atom, a halogen atom, a hydroxyl group, an amino group, a chain alkyl group having 1 to 5 carbon atoms, and -OR 15 (Where R 15 Form a cyclic amino group having 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of a chain alkyl group having 1 to 5 carbon atoms, an aminocarbonylmethyl group or a benzyl group. A therapeutic agent for chronic kidney disease comprising a cyanopyrrolidine derivative represented by the above or a pharmaceutically acceptable salt thereof as an active ingredient.
[0010]
According to another aspect of the present invention, the present invention relates to R in formula (1) 1 Represents a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms; 2 , R 3 And R 4 Treatment of chronic kidney disease comprising as an active ingredient a cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof, wherein each is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms Provide medicine.
[0011]
According to another aspect of the present invention, the present invention relates to R in formula (1) 1 The present invention provides a therapeutic agent for chronic kidney disease, which comprises, as an active ingredient, a cyanopyrrolidine derivative wherein is a fluorine atom or a chlorine atom, or a pharmaceutically acceptable salt thereof.
[0012]
According to another aspect of the present invention, the present invention provides a compound of formula (1) R 1 Is a fluorine atom and R 2 The present invention provides a therapeutic agent for chronic kidney disease comprising as an active ingredient a cyanopyrrolidine derivative in which is hydrogen atom or a pharmaceutically acceptable salt thereof.
[0013]
According to another aspect of the present invention, the present invention relates to R in formula (1) 1 Is a fluorine atom and R 2 , R 3 And R 4 The present invention provides a therapeutic agent for chronic kidney disease comprising as an active ingredient a cyanopyrrolidine derivative in which is hydrogen atom or a pharmaceutically acceptable salt thereof.
[0014]
According to another aspect of the present invention, the present invention provides compounds of formula (2)
[0015]
[Formula 4]
(In the formula, X, Y and Z are the same as above.)
A therapeutic agent for chronic kidney disease comprising a cyanopyrrolidine derivative represented by the formula: or a pharmaceutically acceptable salt thereof as an active ingredient.
[0017]
According to another aspect of the present invention, the present invention provides a treatment for chronic kidney disease comprising as an active ingredient a cyanopyrrolidine derivative in which X is an oxygen atom in formula (1) or formula (2) or a pharmaceutically acceptable salt thereof. Provide medicine.
[0018]
According to another aspect of the present invention, the present invention provides that in the formula (1) or the formula (2), Y is —CH 2 A therapeutic agent for chronic kidney disease comprising a cyanopyrrolidine derivative which is-or a pharmaceutically acceptable salt thereof as an active ingredient.
[0019]
According to another aspect of the present invention, the present invention provides that in the formula (1) or the formula (2), Y is —CH 2 A cyanopyrrolidine derivative, which is a branched or cyclic alkyl group having 4 to 10 carbon atoms, which may be substituted with one or more selected from the group consisting of a hydroxyl group and a hydroxyalkyl group having 1 to 5 carbon atoms Alternatively, a therapeutic agent for chronic kidney disease comprising a pharmaceutically acceptable salt thereof as an active ingredient is provided.
[0020]
According to another aspect of the present invention, the present invention provides that in the formula (1) or the formula (2), Y is —CH 2 A cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof, wherein Z is tert-butyl group, (1-hydroxymethyl) cyclopentyl group or (2-hydroxy-1,1-dimethyl) ethyl group To provide a therapeutic agent for chronic kidney disease.
[0021]
According to another aspect of the present invention, the present invention provides a compound of formula (1) or formula (2) wherein Y is -CR. 5 R 6 -(Wherein R 5 Is a cyanopyrrolidine derivative in which Z is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and a therapeutic agent for chronic kidney disease.
[0022]
According to another aspect of the present invention, the present invention provides a compound of formula (1) or formula (2) wherein Y is -CR. 5 R 6 -(Wherein R 5 Is hydrogen and R 6 Is a branched or cyclic alkyl group having 3 to 6 carbon atoms), and a therapeutic agent for chronic kidney disease comprising a cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof in which Z is a hydrogen atom as an active ingredient To do.
[0023]
According to another aspect of the present invention, the present invention provides a compound of formula (1) or formula (2) wherein Y is -CH [CH (CH 3 ) 2 ]-, -CH [C (CH 3 ) 3 ]-Or -CH [CH (CH 3 ) CH 2 CH 3 -And a therapeutic agent for chronic kidney disease comprising a cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof, wherein Z is a hydrogen atom, as an active ingredient.
[0024]
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, the compound having dipeptidyl peptidase IV (DPPIV) inhibitory activity is not particularly limited as long as it is a compound that inhibits protease activity that hydrolyzes a dipeptide from a peptide chain. For example, Diabetes, 47, 764-769, The compound which measured by the method published in 1998, and the dipeptidyl peptidase IV inhibitory activity was recognized can be mentioned. More specifically, the compounds described in the following publications can be mentioned.
[0025]
WO95 / 15309, WO98 / 19998, WO00 / 34241, WO01 / 55105, WO01 / 68603, WO01 / 96295, WO02 / 14271, WO02 / 30891, WO02 / 30891, WO02 / 51836, WO02 / 076450, WO02 / 083128, WO03 / 000250, WO03 / 000180, WO03 / 000181, WO03 / 004498, WO03 / 002530, WO03 / 002531, WO03 / 002553, WO03 / 002595, WO03 / 035057, WO03 / 035067, WO03 / 037327, WO02 / 02560, WO02 / 62764, WO02 / 68420, WO03 / 004496, WO03 / 004498.
[0026]
In particular, the cyanopyrrolidine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof is preferably used as an active ingredient, and more preferably the cyanopyrrolidine derivative represented by the formula (2) or a pharmaceutically acceptable salt thereof. It is an acceptable salt.
[0027]
In the formulas (1) and (2), the chain means a straight chain or a branched chain.
A halogen atom shows a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
The alkoxy group having 1 to 5 carbon atoms means a linear, branched or cyclic alkoxy group, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, or a tert-butoxy group. Group, cyclopropylmethoxy group, pentyloxy group, isopentyloxy group and the like.
[0028]
The alkyl group having 1 to 5 carbon atoms means a linear, branched or cyclic alkyl group (including a cycloalkylalkyl group), for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group. Group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl group, cyclopropylmethyl group, pentyl group, isopentyl group, cyclopentyl group, cyclobutylmethyl group, 1-ethylpropyl group, etc. it can.
[0029]
The C1-C5 alkoxyimino group means an imino group substituted with a linear, branched or cyclic alkoxy group, and includes a methoxyimino group, an ethoxyimino group, a propoxyimino group, and an isopropocinomino group. , Butoxyimino group, isobutoxyimino group, tert-butoxyimino group, cyclopropylmethoxyimino group, pentyloxyimino group, isopentyloxyimino group, and the like.
[0030]
The alkylidene group having 1 to 5 carbon atoms means a linear, branched or cyclic alkylidene group, such as a methylene group, an ethylidene group, a propylidene group, an isopropylidene group, a butylidene group, an isobutylidene group, or a cyclopropylmethylene group. Group, pentylidene group and the like.
[0031]
The optionally substituted alkyl group having 1 to 10 carbon atoms means a substituted or unsubstituted linear, branched or cyclic alkyl group having 1 to 10 carbon atoms (including a cycloalkylalkyl group). For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl Group, cycloalkyl group having 3 to 10 carbon atoms (for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclobutylmethyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, etc.), cycloalkenyl having 4 to 8 carbon atoms Groups (for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, A substituted or unsubstituted bicycloalkyl group having 5 to 10 carbon atoms (for example, a bicyclopentyl group, a bicyclohexyl group, a bicycloheptyl group, a bicyclooctyl group, a bicyclononyl group, or a bicyclodecyl group), which may be substituted. C5-C10 bicycloalkenyl group (for example, bicyclopentenyl group, bicyclohexenyl group, bicycloheptenyl group, bicyclooctenyl group, bicyclononel group, bicyclodecel group, etc.), bridged cyclic hydrocarbon (for example, adamantyl) Group, bornyl group, norbornyl group, pinanyl group, tyoyl group, carbyl group, carphanyl group, etc.), as well as hydrogen atoms of these alkyl groups as halogen atoms, hydroxyl groups, and hydroxyalkyl groups having 1 to 5 carbon atoms. , Carboxyl group, mercapto group, carbon number 1 5 alkylthio group, a guanidyl group, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, -NHR 11 (Where R 11 Represents a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), -CONHR 12 {Where R is 12 Is a hydrogen atom or-(CH 2 ) m -R 13 (In the formula, m represents an integer of 1 to 5, R 13 Represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) and -OR 14 (Where R 14 May be an alkyl group substituted with one or more groups selected from the group consisting of a linear or branched alkyl group having 1 to 5 carbon atoms or a benzyl group.
[0032]
The substituted phenyl group of the optionally substituted phenyl group is, for example, substituted with one or more groups selected from the group consisting of a hydroxyl group and a linear or branched alkoxy group having 1 to 5 carbon atoms. And phenyl groups (for example, 4-hydroxyphenyl group, 3,4-dimethoxyphenyl group, etc.).
[0033]
The substituted pyridyl group of an optionally substituted pyridyl group (eg, pyridin-2-yl group) is, for example, one or more selected from the group consisting of a cyano group, a nitro group, a halogen atom and an aminocarbonyl group A pyridyl group substituted with a group of (for example, 5-cyanopyridin-2-yl group, 5-nitropyridin-2-yl group, 5-chloropyridin-2-yl group, 5-aminocarbonylpyridin-2-yl group) Group).
[0034]
The hydroxyalkyl group having 1 to 5 carbon atoms is hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1- (hydroxy Methyl) ethyl group, 1-hydroxy-1-methylethyl group, 4-hydroxybutyl group, 5-hydroxypentyl group and the like.
[0035]
Examples of the alkylthio group having 1 to 5 carbon atoms include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, a tert-butylthio group, and a pentylthio group.
[0036]
The alkenyl group having 2 to 10 carbon atoms which may be substituted means a substituted or unsubstituted linear, branched or cyclic alkenyl group having 2 to 10 carbon atoms, such as vinyl group, allyl group, In addition to alkenyl groups such as propenyl group, isopropenyl group, butenyl group, isobutenyl group, pentenyl group, hexenyl group, heptenyl group, octenyl group, cyclopentenyl group, cyclohexenyl group, etc. And an alkenyl group substituted with one or more groups selected from the group consisting of a carboxyl group, an amino group, an aminocarbonyl group, and a linear or branched alkoxy group having 1 to 5 carbon atoms.
[0037]
The C3-C8 cycloalkyl group which may be substituted means a substituted or unsubstituted cycloalkyl group, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl. In addition to a cycloalkyl group such as a group, the hydrogen atom of these cycloalkyl groups can be a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a linear or branched alkyl group having 1 to 5 carbon atoms, Examples thereof include a cycloalkyl group substituted with one or more groups selected from the group consisting of linear or branched alkoxy groups having 1 to 5 carbon atoms.
[0038]
The C4-C8 cycloalkenyl group which may be substituted means a substituted or unsubstituted cycloalkenyl group, for example, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group or the like. In addition to alkenyl groups, the hydrogen atoms of these cycloalkenyl groups can be halogen atoms, hydroxyl groups, carboxyl groups, amino groups, aminocarbonyl groups, linear or branched alkyl groups having 1 to 5 carbon atoms, and linear or branched. A cycloalkenyl group substituted with one or more groups selected from the group consisting of chain-like alkoxy groups having 1 to 5 carbon atoms can be mentioned.
[0039]
The C5-C10 bicycloalkyl group which may be substituted means a substituted or unsubstituted bicycloalkyl group, for example, a bicyclopentyl group, a bicyclohexyl group, a bicycloheptyl group, a bicyclooctyl group, a bicyclononyl group. In addition to bicycloalkyl groups such as bicyclodecyl groups, the hydrogen atoms of these bicycloalkyl groups are halogen atoms, hydroxyl groups, carboxyl groups, amino groups, aminocarbonyl groups, linear or branched alkyls having 1 to 5 carbon atoms. And a bicycloalkyl group substituted with one or more groups selected from the group consisting of a group and a linear or branched alkoxy group having 1 to 5 carbon atoms.
[0040]
The C5-C10 bicycloalkenyl group which may be substituted means a substituted or unsubstituted bicycloalkenyl group, for example, a bicyclopentenyl group, a bicyclohexenyl group, a bicycloheptenyl group, a bicyclooctenyl group, a bicyclononel. Group, bicycloalkenyl group such as bicyclodecel group, etc., hydrogen atom of these bicycloalkenyl groups is halogen atom, hydroxyl group, carboxyl group, amino group, aminocarbonyl group, linear or branched alkyl having 1 to 5 carbon atoms And a bicycloalkenyl group substituted with one or more groups selected from the group consisting of a group and a linear or branched alkoxy group having 1 to 5 carbon atoms.
[0041]
The C2-C10 cyclic amino group that may be substituted is a substituted or unsubstituted group having one or more nitrogen atoms in the ring and one or more oxygen atoms or sulfur atoms may be present. A cyclic amino group of A hydrogen atom of a cyclic amino group in which a benzene ring or a pyridine ring is condensed with these cyclic amino groups or a cyclic amino group (including a benzene ring or a pyridine ring condensed with a cyclic amino group) is a halogen atom, hydroxyl group, amino group, linear Or a branched alkyl group having 1 to 5 carbon atoms and -OR 15 (Where R 15 And a cyclic amino group substituted with one or more groups selected from the group consisting of a linear or branched alkyl group having 1 to 5 carbon atoms, an aminocarbonylmethyl group or a benzyl group. .
[0042]
Examples of the pharmaceutically acceptable salt include salts with mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, trifluoroacetic acid, Mention may be made of salts with organic acids such as methanesulfonic acid.
[0043]
In formula (1), R 1 Is preferably a halogen atom, more preferably a fluorine atom. R 2 Is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom.
[0044]
In Formula (1) or Formula (2), Y is —CH 2 When-, Z is a hydroxyl group, an alkoxyl group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, an optionally substituted phenyl group, and -NHR. 11 (Where R 11 Is an optionally substituted pyridyl group) and is preferably an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more of the group consisting of: In this case, Z is preferably a branched chain having 4 to 10 carbon atoms which may be substituted with one or more of the group consisting of a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms and an alkoxyl group having 1 to 5 carbon atoms. Or a branched alkyl group having 4 to 10 carbon atoms, which may be substituted with one or more of the group consisting of a hydroxyl group and a hydroxyalkyl group having 1 to 5 carbon atoms, It is a 4-10 cycloalkyl group or an adamantyl group, More preferably, they are a tert- butyl group, (1-hydroxymethyl) cyclopentyl group, or (2-hydroxy-1, 1-dimethyl) ethyl group.
[0045]
In Formula (1) or Formula (2), Y is a formula —CR 5 R 6 -(Wherein R 5 Is hydrogen and R 6 Is an optionally substituted alkyl group having 1 to 10 carbon atoms or the formula -CR 7 R 8 -CR 9 R 10 -(Wherein R 8 And R 10 Is hydrogen and R 7 And R 9 Z together with adjacent carbon atoms form a cycloalkyl group having 3 to 8 carbon atoms, Z is H or CH 3 Is preferred.
[0046]
In this case, preferably Y is of the formula -CR 5 R 6 -{Wherein R 5 Is hydrogen and R 6 Is a hydroxyl group and -OR 14 (Where R 14 Represents a straight-chain or branched alkyl group or benzyl group having 1 to 5 carbon atoms), which may be substituted with one or more selected from the group consisting of a branched or cyclic group having 3 to 6 carbon atoms Z is a hydrogen atom, more preferably Y is —CR. 5 R 6 -(Wherein R 5 Is hydrogen and R 6 Is a branched or cyclic alkyl group having 3 to 6 carbon atoms), Z is a hydrogen atom, and even more preferably, Y is —CH [CH (CH 3 ) 2 ]-, -CH [C (CH 3 ) 3 ]-Or -CH [CH (CH 3 ) CH 2 CH 3 ] Is-, Z is a hydrogen atom.
[0047]
In Formula (1) or Formula (2), as a preferable example when Y and Z form an optionally substituted cyclic amino group having 2 to 10 carbon atoms formed together with an adjacent nitrogen atom, A pyrrolidyl group, a piperidyl group, or a cyclic amino group obtained by condensing a benzene ring to these groups, and preferred substituents include a hydroxyl group and —OR 15 (Where R 15 Is as defined above).
[0048]
In the present invention, the therapeutic agent for chronic kidney disease refers to kidneys of chronic kidney diseases including chronic renal failure, glomerulosclerosis, diabetic nephropathy, nephrosclerosis, chronic nephritis, chronic glomerulonephritis, polycystic kidney disease and the like. It means a therapeutic agent for diseases that reduce physiological functions, and has excellent renal protective effects such as reducing urinary protein and albumin.
[0049]
The medicament of the present invention can be systemically or locally administered orally or parenterally such as rectal, subcutaneous, intramuscular, intravenous and transdermal.
[0050]
In order to use the compound of the present invention as a pharmaceutical, any form of a solid composition, a liquid composition, and other compositions may be used, and the optimum one is selected as necessary. The medicament of the present invention can be produced by blending the compound of the present invention with a pharmaceutically acceptable carrier. Specifically, conventional excipients, extenders, binders, disintegrants, coating agents, sugar coatings, pH adjusters, solubilizers, aqueous or non-aqueous solvents, etc. are added, and by conventional formulation techniques, It can be prepared into tablets, pills, capsules, granules, powders, powders, solutions, emulsions, suspensions, injections, and the like. Examples of excipients and extenders include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and other commonly used ones. it can.
[0051]
The therapeutic agent for chronic kidney disease of the present invention can be formulated by forming an inclusion compound with α, β, γ-cyclodextrin, methylated cyclodextrin, or the like.
[0052]
The dose of the therapeutic agent for chronic kidney disease of the present invention varies depending on the disease, symptoms, body weight, age, sex, route of administration, etc., but preferably about 1 to about 1000 mg / kg body weight for oral administration to adults. / Day, more preferably about 10 to about 200 mg / kg body weight / day, which can be administered once or divided into several times a day.
[0053]
Furthermore, although this invention is demonstrated by a test example, this invention is not limited to these Examples.
Test Example 1 [Dipeptidyl peptidase IV activity inhibition experiment]
The dipeptidyl peptidase IV (DPPIV) activity inhibition experiment was performed according to the method described in Diabetes, 47, 764-769, 1998. Plasma containing dipeptidyl peptidase IV was prepared by collecting blood from healthy volunteers and centrifuging. The enzyme reaction was performed using a 96-well flat bottom plate in a buffer solution consisting of 25 mM HEPES, 140 mM NaCl, 1% BSA, pH 7.8. 100 μM Gly-Pro-4-methylcoumaryl-7-amide (manufactured by Peptide Institute) 25 μl, 133 mM magnesium chloride solution 7.5 μl, sample compound 5 μl were mixed, and then plasma 12 diluted 1 / 100-fold with the above buffer .5 μl was added. After reacting for 2 hours at room temperature, 50 μl of 25% acetic acid aqueous solution was added to stop the reaction. The amount of 7-amino-4-methylcoumarin released was measured using a fluorescence plate reader (1420 ARVO ™ Multilabel Counter; manufactured by Wallac), and the fluorescence intensity at 460 nm was measured. The fluorescence intensity when the reaction time was 0 minutes after adding the solvent was taken as the blank value, and the value obtained by subtracting the blank value from each measured value was taken as the specific fluorescence intensity. From the obtained specific fluorescence intensity, the dipeptidyl peptidase IV activity inhibition rate (%) was determined by the following equation. The test compound was used after preparing a dimethyl sulfoxide solution having a concentration 1000 times higher and diluting with the above buffer solution. Compound concentration showing 50% inhibition from the inhibition rate of each concentration (IC 50 Value).
[0054]
Inhibition rate (%) = A ÷ B × 100
(A = fluorescence intensity when solvent is added-fluorescence intensity when sample compound is added)
(B = fluorescence intensity upon addition of solvent)
(2S, 4S) -2-cyano-fluoro-1-[(2-hydroxy-1,1-dimethylol) ethylamino] acetylpyrrolidine benzenesulfonate (hereinafter referred to as Compound A), (2S, 4S)- 1-[(2S, 3S) -2-amino-3-methylpentanoyl] -2-cyano-4-fluoropyrrolidine hydrochloride, (2S, 4S) -1-[(2S) -2-amino-3- Methylbutanoyl] -2-cyano-4-fluoropyrrolidine hydrochloride, (2S, 4S) -1-[(2S) -2-amino-3,3-dimethylbutanoyl] -2-cyano-4-fluoropyrrolidine Hydrochloride, (2S, 4S) -1- (tert-butylamino) acetyl-2-cyano-4-fluoropyrrolidine hydrochloride, (2S, 4S) -2-cyano-1- [2-[(5-cyano Pyridine-2 Yl) amino] ethylamino] acetyl-4-fluoropyrrolidine-maleate IC 50 The values were 5.4 nM, 0.6 nM, 0.7 nM, 0.6 nM, 2.9 nM and 1.1 nM, respectively.
[0055]
Test example 2
Renal protection effect by DPPIV inhibition in Dahl-salt sensitive rat
This test is described in J. Org. Cardiovascular Pharmacology, Volume 23, page 970 (1994). Specifically, it was performed as follows.
<Method>
For the experiment, Dahl-salt sensitive (Dahl-S) rat and control animal Dahl-salt resistance (Dahl-R) rat (male, 7 weeks old) were used and divided into 3 groups as follows (1 group) Each of 6 cases) was tested.
Group I: Dahl-R + 4% NaCl diet + solvent oral administration (twice a day)
Group II: Dahl-S + 4% NaCl diet + solvent oral administration (twice a day)
Group III: Dahl-S + 4% NaCl diet + Compound A 10 mg / kg Oral administration (twice a day)
[0056]
Each group of animals was fed a diet containing 4% NaCl high salt (normal diet was 0.6%) and had free access to drinking water. The solvent and Compound A are orally administered twice a day (8: 30-9: 30 for the first time, 16: 30-17: 30 for the second time) and administered orally for 6 weeks. Six weeks after the start of administration, rats were placed in metabolic cages one by one, and urine was collected. The amount of protein and albumin in urine was measured to observe the effect on renal function. The urinary protein and albumin were measured in accordance with the methods described in Bunski Kagaku Vol. 32, E379-E386 (1983) and Hypertension Vol. 40, No. 6, pp. 834-839 (2002), respectively. It was performed using.
[0057]
The urinary protein excretion 6 weeks after the start of the test was lower in the Compound A administration group (Group III) than in the solvent administration group (Group II).
Urinary albumin excretion was lower in the Compound A administration group (Group III) than in the solvent administration group (Group II).
[0058]
Test example 3
Renal protective effect by DPPIV inhibition in spontaneously diabetic rats (ZSF-1)
<Method>
ZSF-1 is a spontaneously diabetic rat, and is known to cause renal dysfunction (Renal Failure, Vol. 22, No. 4, pages 387-406, 2000). In this study, 8-week-old ZSF-1 obtained from The Jackson Laboratory and the control animal ZSF-1 / lean were used and divided into 5 groups as follows (8 cases per group). .
Group I: ZSF-1 / lean + oral solvent administration (twice a day)
Group II: ZSF-1 + vehicle oral administration (twice a day)
Group III: ZSF-1 + Compound A 1 mg / kg orally (twice a day)
Group IV: ZSF-1 + Compound A 3 mg / kg orally (twice a day)
Group V: ZSF-1 + Compound A 10 mg / kg orally (twice a day)
[0059]
The solvent and Compound A are orally administered twice a day (8: 30-10: 30 for the first time and 16: 30-18: 30 for the second time) for 8 weeks. Eight weeks after the start of administration, rats were placed in metabolic cages one by one, and urine was collected. The amount of urine protein and albumin was measured to observe the effect on renal function. The urinary protein and albumin levels were measured with a Hitachi automatic analyzer 7060 in accordance with the description in the above literature.
[0060]
Eight weeks after the start of the test, the amount of protein excreted in urine was lower in the compound A 10 mg / kg administration group (Group V) than in the solvent administration group (Group II).
The urinary albumin excretion was lower in the Compound A 10 mg / kg administration group (Group V) than in the solvent administration group (Group II).
[0061]
【The invention's effect】
The present invention makes it possible to provide a therapeutic agent for chronic kidney disease based on a novel mechanism of action, and is useful for the treatment and prevention of chronic kidney disease with few side effects.
Claims (14)
Ｒ３及びＲ４は同一又は異なって水素原子、ハロゲン原子、水酸基、炭素数１〜５のアルコキシ基又は炭素数１〜５のアルキル基を示すか、又はＲ３及びＲ４が一緒になってオキソ、ヒドロキシイミノ基、炭素数１〜５のアルコキシイミノ基又は炭素数１〜５のアルキリデン基を形成し、
Ｘは酸素原子又は硫黄原子を示し、
Ｙは式−ＣＲ５Ｒ６−［式中、Ｒ５及びＲ６は同一又は異なって水素原子；ハロゲン原子；ハロゲン原子、水酸基、炭素数１〜５のヒドロキシアルキル基、カルボキシル基、メルカプト基、炭素数１〜５のアルキルチオ基、グアニジル基、置換されてもよいフェニル基、イミダゾリル基、インドリル基、−ＮＨＲ１１（式中Ｒ１１は水素原子、置換されてもよいフェニル基、置換されてもよいピリジル基、ｔｅｒｔ−ブトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）、−ＣＯＮＨＲ１２｛式中Ｒ１２は水素原子又は−（ＣＨ２）ｍ−Ｒ１３（式中ｍは整数１〜５を示し、Ｒ１３は水素原子、メトキシカルボニル基、エトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）を示す｝並びに−ＯＲ１４（式中Ｒ１４は炭素数１〜５の鎖状アルキル基若しくはベンジル基を示す）からなる群より選ばれる一つ以上の基で置換されてもよい炭素数１〜１０のアルキル基；若しくはハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数２〜１０のアルケニル基である］を示すか、
又は式−ＣＲ７Ｒ８−ＣＲ９Ｒ１０−（式中、Ｒ７、Ｒ８、Ｒ９及びＲ１０は同一又は異なって水素原子；ハロゲン原子；ハロゲン原子、水酸基、炭素数１〜５のヒドロキシアルキル基、カルボキシル基、メルカプト基、炭素数１〜５のアルキルチオ基、グアニジル基、置換されてもよいフェニル基、イミダゾリル基、インドリル基、−ＮＨＲ１１（式中Ｒ１１は水素原子、置換されてもよいフェニル基、置換されてもよいピリジル基、ｔｅｒｔ−ブトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）、−ＣＯＮＨＲ１２｛式中Ｒ１２は水素原子又は−（ＣＨ２）ｍ−Ｒ１３（式中ｍは整数１〜５を示し、Ｒ１３は水素原子、メトキシカルボニル基、エトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）を示す｝並びに−ＯＲ１４（式中Ｒ１４は炭素数１〜５の鎖状アルキル基若しくはベンジル基を示す）からなる群より選ばれる一つ以上の基で置換されてもよい炭素数１〜１０のアルキル基を示すか、又はＲ７とＲ９が隣接する炭素原子と一緒になって、ハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、炭素数１〜５の鎖状アルキル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数３〜８のシクロアルキル基；ハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、炭素数１〜５の鎖状アルキル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数４〜８のシクロアルケニル基；ハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、炭素数１〜５の鎖状アルキル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数５〜１０のビシクロアルキル基；又はハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、炭素数１〜５の鎖状アルキル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数５〜１０のビシクロアルケニル基を形成する）を示し、
Ｚは水素原子；又はハロゲン原子、水酸基、炭素数１〜５のヒドロキシアルキル基、カルボキシル基、メルカプト基、炭素数１〜５のアルキルチオ基、グアニジル基、置換されてもよいフェニル基、イミダゾリル基、インドリル基、−ＮＨＲ１１（式中Ｒ１１は水素原子、置換されてもよいフェニル基、置換されてもよいピリジル基、ｔｅｒｔ−ブトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）、−ＣＯＮＨＲ１２｛式中Ｒ１２は水素原子又は−（ＣＨ２）ｍ−Ｒ１３（式中ｍは整数１〜５を示し、Ｒ１３は水素原子、メトキシカルボニル基、エトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）を示す｝並びに−ＯＲ１４（式中Ｒ１４は炭素数１〜５の鎖状アルキル基若しくはベンジル基を示す）からなる群より選ばれる一つ以上の基で置換されてもよい炭素数１〜１０のアルキル基を示すか、
又はＹ及びＺが隣接する窒素原子とともに一緒になって、ハロゲン原子、水酸基、アミノ基、炭素数１〜５の鎖状アルキル基及び−ＯＲ１５（式中Ｒ１５は炭素数１〜５の鎖状アルキル基、アミノカルボニルメチル基若しくはベンジル基を示す）からなる群より選ばれる一つ以上の基で置換されてもよい炭素数２〜１０の環状アミノ基を形成する］で表されるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬。Formula (1)
R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, or R 3 and R 4 are combined together Forming an oxo, hydroxyimino group, an alkoxyimino group having 1 to 5 carbon atoms or an alkylidene group having 1 to 5 carbon atoms;
X represents an oxygen atom or a sulfur atom,
Y is a formula —CR 5 R 6 — [wherein R 5 and R 6 are the same or different and represent a hydrogen atom; a halogen atom; a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms, a carboxyl group, a mercapto group, An alkylthio group having 1 to 5 carbon atoms, a guanidyl group, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, —NHR 11 (wherein R 11 is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted group) A good pyridyl group, tert-butoxycarbonyl group or benzyloxycarbonyl group), —CONHR 12 (wherein R 12 is a hydrogen atom or — (CH 2 ) m —R 13 , wherein m represents an integer of 1 to 5); , R 13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)} and -OR 4 (wherein R 14 represents a linear alkyl group or benzyl group having 1 to 5 carbon atoms) alkyl group having 1 to 10 carbon atoms which may be substituted by one or more groups selected from the group consisting of; or C2-C10 alkenyl group optionally substituted with one or more groups selected from the group consisting of halogen atoms, hydroxyl groups, carboxyl groups, amino groups, aminocarbonyl groups and C1-C5 chain alkoxy groups Or
Or the formula —CR 7 R 8 —CR 9 R 10 — (wherein R 7 , R 8 , R 9 and R 10 are the same or different, a hydrogen atom; a halogen atom; a halogen atom, a hydroxyl group, and a carbon number of 1 to 5) A hydroxyalkyl group, a carboxyl group, a mercapto group, an alkylthio group having 1 to 5 carbon atoms, a guanidyl group, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, —NHR 11 (wherein R 11 is a hydrogen atom, substituted) An optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), -CONHR 12 (wherein R 12 is a hydrogen atom or-(CH 2 ) m -R 13 ( wherein m represents an integer 1 to 5, R 13 is a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl carbonylation Shows a shows a group)} and -OR 14 (wherein R 14 may be substituted by one or more groups selected from the group consisting of indicating a chain alkyl group or benzyl group having 1 to 5 carbon atoms) An alkyl group having 1 to 10 carbon atoms, or R 7 and R 9 together with adjacent carbon atoms, a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, A cycloalkyl group having 3 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of a chain alkyl group and a chain alkoxy group having 1 to 5 carbon atoms; a halogen atom, a hydroxyl group, a carboxyl group, 4-8 carbon atoms that may be substituted with one or more groups selected from the group consisting of an amino group, an aminocarbonyl group, a chain alkyl group having 1 to 5 carbon atoms, and a chain alkoxy group having 1 to 5 carbon atoms. Cycloarkeni One or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group having 1 to 5 carbon atoms and a chain alkoxy group having 1 to 5 carbon atoms A bicycloalkyl group having 5 to 10 carbon atoms which may be substituted with a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group having 1 to 5 carbon atoms and a chain having 1 to 5 carbon atoms A bicycloalkenyl group having 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of alkenyl-like alkoxy groups),
Z is a hydrogen atom; or a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1 to 5 carbon atoms, a guanidyl group, an optionally substituted phenyl group, an imidazolyl group, Indolyl group, -NHR 11 (wherein R 11 represents a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), -CONHR 12 {formula R 12 represents a hydrogen atom or — (CH 2 ) m —R 13 (wherein m represents an integer of 1 to 5, and R 13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group). And —OR 14 (wherein R 14 represents a chain alkyl group having 1 to 5 carbon atoms or a benzyl group). Or an alkyl group having 1 to 10 carbon atoms that may be substituted with one or more groups selected from the group consisting of:
Or Y and Z together with the adjacent nitrogen atom, a halogen atom, a hydroxyl group, an amino group, a chain alkyl group having 1 to 5 carbon atoms and —OR 15 (wherein R 15 is a chain having 1 to 5 carbon atoms) A cyclic amino group having 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of: a group of alkyl groups, aminocarbonylmethyl groups or benzyl groups] A therapeutic agent for chronic kidney disease comprising a derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
Ｙは式−ＣＲ５Ｒ６−［式中、Ｒ５及びＲ６は同一又は異なって水素原子；ハロゲン原子；ハロゲン原子、水酸基、炭素数１〜５のヒドロキシアルキル基、カルボキシル基、メルカプト基、炭素数１〜５のアルキルチオ基、グアニジル基、置換されてもよいフェニル基、イミダゾリル基、インドリル基、−ＮＨＲ１１（式中Ｒ１１は水素原子、置換されてもよいフェニル基、置換されてもよいピリジル基、ｔｅｒｔ−ブトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）、−ＣＯＮＨＲ１２｛式中Ｒ１２は水素原子又は−（ＣＨ２）ｍ−Ｒ１３（式中ｍは整数１〜５を示し、Ｒ１３は水素原子、メトキシカルボニル基、エトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）を示す｝並びに−ＯＲ１４（式中Ｒ１４は炭素数１〜５の鎖状アルキル基若しくはベンジル基を示す）からなる群より選ばれる一つ以上の基で置換されてもよい炭素数１〜１０のアルキル基；若しくはハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数２〜１０のアルケニル基である］を示すか、
又は式−ＣＲ７Ｒ８−ＣＲ９Ｒ１０−（式中、Ｒ７、Ｒ８、Ｒ９及びＲ１０は同一又は異なって水素原子；ハロゲン原子；ハロゲン原子、水酸基、炭素数１〜５のヒドロキシアルキル基、カルボキシル基、メルカプト基、炭素数１〜５のアルキルチオ基、グアニジル基、置換されてもよいフェニル基、イミダゾリル基、インドリル基、−ＮＨＲ１１（式中Ｒ１１は水素原子、置換されてもよいフェニル基、置換されてもよいピリジル基、ｔｅｒｔ−ブトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）、−ＣＯＮＨＲ１２｛式中Ｒ１２は水素原子又は−（ＣＨ２）ｍ−Ｒ１３（式中ｍは整数１〜５を示し、Ｒ１３は水素原子、メトキシカルボニル基、エトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）を示す｝並びに−ＯＲ１４（式中Ｒ１４は炭素数１〜５の鎖状アルキル基若しくはベンジル基を示す）からなる群より選ばれる一つ以上の基で置換されてもよい炭素数１〜１０のアルキル基を示すか、又はＲ７とＲ９が隣接する炭素原子と一緒になって、ハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、炭素数１〜５の鎖状アルキル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数３〜８のシクロアルキル基；ハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、炭素数１〜５の鎖状アルキル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数４〜８のシクロアルケニル基；ハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、炭素数１〜５の鎖状アルキル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数５〜１０のビシクロアルキル基；又はハロゲン原子、水酸基、カルボキシル基、アミノ基、アミノカルボニル基、炭素数１〜５の鎖状アルキル基及び炭素数１〜５の鎖状アルコキシ基からなる群より選ばれる一つ以上の基で置換されてもよい炭素数５〜１０のビシクロアルケニル基を形成する）を示し、
Ｚは水素原子；又はハロゲン原子、水酸基、炭素数１〜５のヒドロキシアルキル基、カルボキシル基、メルカプト基、炭素数１〜５のアルキルチオ基、グアニジル基、置換されてもよいフェニル基、イミダゾリル基、インドリル基、−ＮＨＲ１１（式中Ｒ１１は水素原子、置換されてもよいフェニル基、置換されてもよいピリジル基、ｔｅｒｔ−ブトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）、−ＣＯＮＨＲ１２｛式中Ｒ１２は水素原子又は−（ＣＨ２）ｍ−Ｒ１３（式中ｍは整数１〜５を示し、Ｒ１３は水素原子、メトキシカルボニル基、エトキシカルボニル基若しくはベンジルオキシカルボニル基を示す）を示す｝並びに−ＯＲ１４（式中Ｒ１４は炭素数１〜５の鎖状アルキル基若しくはベンジル基を示す）からなる群より選ばれる一つ以上の基で置換されてもよい炭素数１〜１０のアルキル基を示すか、
又はＹ及びＺが隣接する窒素原子とともに一緒になって、ハロゲン原子、水酸基、アミノ基、炭素数１〜５の鎖状アルキル基及び−ＯＲ１５（式中Ｒ１５は炭素数１〜５の鎖状アルキル基、アミノカルボニルメチル基若しくはベンジル基を示す）からなる群より選ばれる一つ以上の基で置換されてもよい炭素数２〜１０の環状アミノ基を形成する］で表されるシアノピロリジン誘導体又はその薬学的に許容される塩を有効成分とする慢性腎疾患治療薬。Formula (2)
Y is a formula —CR 5 R 6 — [wherein R 5 and R 6 are the same or different and represent a hydrogen atom; a halogen atom; a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms, a carboxyl group, a mercapto group, An alkylthio group having 1 to 5 carbon atoms, a guanidyl group, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, —NHR 11 (wherein R 11 is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted group) A good pyridyl group, tert-butoxycarbonyl group or benzyloxycarbonyl group), —CONHR 12 (wherein R 12 is a hydrogen atom or — (CH 2 ) m —R 13 , wherein m represents an integer of 1 to 5); , R 13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)} and -OR 4 (wherein R 14 represents a linear alkyl group or benzyl group having 1 to 5 carbon atoms) alkyl group having 1 to 10 carbon atoms which may be substituted by one or more groups selected from the group consisting of; or C2-C10 alkenyl group optionally substituted with one or more groups selected from the group consisting of halogen atoms, hydroxyl groups, carboxyl groups, amino groups, aminocarbonyl groups and C1-C5 chain alkoxy groups Or
Or the formula —CR 7 R 8 —CR 9 R 10 — (wherein R 7 , R 8 , R 9 and R 10 are the same or different, a hydrogen atom; a halogen atom; a halogen atom, a hydroxyl group, and a carbon number of 1 to 5) A hydroxyalkyl group, a carboxyl group, a mercapto group, an alkylthio group having 1 to 5 carbon atoms, a guanidyl group, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, —NHR 11 (wherein R 11 is a hydrogen atom, substituted) An optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), -CONHR 12 (wherein R 12 is a hydrogen atom or-(CH 2 ) m -R 13 ( wherein m represents an integer 1 to 5, R 13 is a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl carbonylation Shows a shows a group)} and -OR 14 (wherein R 14 may be substituted by one or more groups selected from the group consisting of indicating a chain alkyl group or benzyl group having 1 to 5 carbon atoms) An alkyl group having 1 to 10 carbon atoms, or R 7 and R 9 together with adjacent carbon atoms, a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, A cycloalkyl group having 3 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of a chain alkyl group and a chain alkoxy group having 1 to 5 carbon atoms; a halogen atom, a hydroxyl group, a carboxyl group, 4-8 carbon atoms that may be substituted with one or more groups selected from the group consisting of an amino group, an aminocarbonyl group, a chain alkyl group having 1 to 5 carbon atoms, and a chain alkoxy group having 1 to 5 carbon atoms. Cycloarkeni One or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group having 1 to 5 carbon atoms and a chain alkoxy group having 1 to 5 carbon atoms A bicycloalkyl group having 5 to 10 carbon atoms which may be substituted with a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group having 1 to 5 carbon atoms and a chain having 1 to 5 carbon atoms A bicycloalkenyl group having 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of alkenyl-like alkoxy groups),
Z is a hydrogen atom; or a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1 to 5 carbon atoms, a guanidyl group, an optionally substituted phenyl group, an imidazolyl group, Indolyl group, -NHR 11 (wherein R 11 represents a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), -CONHR 12 {formula R 12 represents a hydrogen atom or — (CH 2 ) m —R 13 (wherein m represents an integer of 1 to 5, and R 13 represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group). And —OR 14 (wherein R 14 represents a chain alkyl group having 1 to 5 carbon atoms or a benzyl group). Or an alkyl group having 1 to 10 carbon atoms that may be substituted with one or more groups selected from the group consisting of:
Or Y and Z together with the adjacent nitrogen atom, a halogen atom, a hydroxyl group, an amino group, a chain alkyl group having 1 to 5 carbon atoms and —OR 15 (wherein R 15 is a chain having 1 to 5 carbon atoms) A cyclic amino group having 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of: a group of alkyl groups, aminocarbonylmethyl groups or benzyl groups] A therapeutic agent for chronic kidney disease comprising a derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
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