JP4385113B2 - Novel biphenylimidazopyridine derivatives and pharmaceuticals containing them as active ingredients - Google Patents

Description

【０００９】
（式中、Ｒ¹及びＲ²はそれぞれ独立に炭素数１〜６の直鎖、分岐鎖又は環状のアルキル基を示し；Ｒ³は、置換基として炭素数１〜６の直鎖、分岐鎖又は環状のアルキル基及び／又はハロゲン原子を有してもよいフェニル基、又は炭素数１〜８の直鎖、分岐鎖又は環状のアルキル基を示し；Ｘはアミノスルホニル結合（−ＮＨＳＯ₂−）、スルホニルアミノスルホニル結合（−ＳＯ₂ＮＨＳＯ₂−）、スルホニルアミノカルボニル結合（−ＳＯ₂ＮＨＣＯ−）又はスルホニルウレア結合（−ＳＯ₂ＮＨＣＯＮＨ−）を示す）で表されるビフェニルイミダゾピリジン誘導体又はその塩、及びその製造法を提供するものである。
また、本発明は当該一般式（１）で表されるビフェニルイミダゾピリジン誘導体又はその塩を有効成分とする医薬を提供するものである。
さらに、本発明は当該一般式（１）で表される化合物の製造中間体として有用な下記一般式（２）
【００１０】
【化３９】

【００１１】
（式中、Ｒ¹及びＲ²は一般式（１）で定義した通りの基を示し；Ｒ⁴はジ（Ｃ_1-6アルキル）アミノメチレンアミノスルホニル基（−ＳＯ₂Ｎ＝ＣＨＮ（Ｃ_1-6アルキル）₂）、アミノ基（−ＮＨ₂）、アミノスルホニル基（−ＳＯ₂ＮＨ₂）、Ｃ_1-6アルキルオキシカルボニルアミノスルホニル基（−ＳＯ₂ＮＨ（ＣＯ）ＯＣ_1-6アルキル）又はニトロ基（−ＮＯ₂）を示す）で表される化合物又はその塩を提供するものである。
【００１２】
【発明の実施の形態】
以下、本発明について、更に詳細に説明を加える。
本発明のビフェニルイミダゾピリジン誘導体は上記一般式（１）で表される化合物又はその塩であることを特徴とする。一般式（１）において、Ｒ¹及びＲ²はそれぞれ独立に炭素数１〜６の直鎖、分岐鎖又は環状のアルキル基を示し、Ｒ³は、置換基として炭素数１〜６の直鎖、分岐鎖又は環状のアルキル基及び／又はハロゲン原子を有してもよいフェニル基、又は炭素数１〜８の直鎖、分岐鎖又は環状のアルキル基を示し、Ｘはアミノスルホニル結合（−ＮＨＳＯ₂−）、スルホニルアミノスルホニル結合（−ＳＯ₂ＮＨＳＯ₂−）、スルホニルアミノカルボニル結合（−ＳＯ₂ＮＨＣＯ−）又はスルホニルウレア結合（−ＳＯ₂ＮＨＣＯＮＨ−）を示す。
【００１３】
Ｒ¹及びＲ²の炭素数１〜６のアルキル基としては、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、ｓｅｃ−ブチル基、イソブチル基、ｔｅｒｔ−ブチル基、シクロプロピルメチル基、シクロブチル基、ペンチル基、ヘキシル基、シクロペンチル基、シクロヘキシル基などが例示できる。この内、Ｒ¹としては炭素数１〜４のアルキル基が好ましく、メチル基、エチル基、プロピル基、ブチル基などの直鎖のＣ_1-4アルキル基がより好ましく、中でもメチル基が特に好ましい。Ｒ²としては環状構造を有するアルキル基が好ましく、シクロプロピル基、シクロプロピルメチル基、シクロブチル基、シクロペンチル基、シクロヘキシル基が好ましく例示でき、シクロプロピル基が特に好ましい。
【００１４】
Ｒ³で示される置換基を有してもよいフェニル基の置換基としては、炭素数１〜６の直鎖、分岐鎖又は環状のアルキル基及び／又はハロゲン原子が好ましく例示でき、前記炭素数１〜６のアルキル基としては、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、ｓｅｃ−ブチル基、イソブチル基、ｔｅｒｔ−ブチル基、シクロプロピルメチル基、シクロブチル基、ペンチル基、ヘキシル基、シクロペンチル基、シクロヘキシル基などが例示できる。この内、炭素数１〜４のアルキル基がより好ましく、メチル基、エチル基、プロピル基、及びイソプロピル基が特に好ましい。又、ハロゲン原子としては、塩素原子、フッ素原子、臭素原子、ヨウ素原子が好ましく例示でき、フッ素原子が特に好ましい。前記置換基を有さないこともできるが、１〜３個の置換基を有することが好ましい。２又は３個の置換基を有する場合、これらは異なっていても同じでも良く、同一の置換基を２又は３個有することが好ましい。炭素数１〜８の直鎖、分岐鎖又は環状のアルキル基としては、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、sec-ブチル基、イソブチル基、tert-ブチル基、シクロプロピルメチル基、シクロブチル基、ペンチル基、tert-アミル基、シクロペンチル基、へキシル基、ヘプチル基、シクロヘプチル基、オクチル基、シクロオクチル基等が例示でき、シクロヘキシル基及びシクロヘプチル基が特に好ましい。
【００１５】
Ｘはアミノスルホニル結合（−ＮＨＳＯ₂−）、スルホニルアミノスルホニル結合（−ＳＯ₂ＮＨＳＯ₂−）、スルホニルアミノカルボニル結合（−ＳＯ₂ＮＨＣＯ−）又はスルホニルウレア結合（−ＳＯ₂ＮＨＣＯＮＨ−）を示し、これらの結合の何れもが選択可能である。かかる一般式（１）で表される化合物又はその塩は何れも文献未記載の新規化合物である。
【００１６】
この様な一般式（１）で表される化合物の内、特に好ましいものとしては、２−シクロプロピル−７−メチル−３−［［２’−［［［［（２−メチルフェニル）アミノ］カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１）、２−シクロプロピル−３−［［２’−［［［［（２−フルオロフェニル）アミノ］カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物２）、２−シクロプロピル−３−［［２’−［［［［（２，４−ジフルオロフェニル）アミノ］カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物３）、２−シクロプロピル−３−［［２’−［［［［（２，６−ジイソプロピルフェニル）アミノ］カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物４）、２−シクロプロピル−３−［［２’−［［［（２−フルオロフェニル）カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物５）、２−シクロプロピル−７−メチル−３−［［２’−［［［［（２，４，６−トリメチルフェニル）アミノ］カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物６）、２−シクロプロピル−３−［［２’−［［（２，４−ジフルオロフェニル）スルホニル］アミノ］−１，１’−ビフェニル−４−イル］メチル］−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物７）、２−シクロプロピル−７ーメチル−３−［［２’−［［［（２−メチルフェニル）スルホニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−３Ｈ−イミダゾ［４，５−ｂ］ピリジン・ＤＢＵ塩（化合物８）、３−［［２’−［［［（シクロヘキシルアミノ）カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−２−シクロプロピル−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物９）及び３−［［２’−［［［（シクロヘプチルアミノ）カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−２−シクロプロピル−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１０）が挙げられる。
【００１７】
【化４０】

【００１８】
【化４１】

【００１９】
【化４２】

【００２０】
【化４３】

【００２１】
【化４４】

【００２２】
【化４５】

【００２３】
【化４６】

【００２４】
【化４７】

【００２５】
【化４８】

【００２６】
【化４９】

【００２７】
一般式（２）において、Ｃ_1-6アルキル基としては、直鎖又は分岐鎖のアルキル基が挙げられ、このうちＣ_1-4アルキル基が好ましく、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、ｓｅｃ−ブチル基、イソブチル基、ｔｅｒｔ−ブチル基、ペンチル基、ヘキシル基が挙げられるが、メチル基が特に好ましい。Ｃ_1-6アルキルオキシ基としては、直鎖又は分岐鎖のアルキルオキシ基が挙げられ、このうちＣ_1-4アルキルオキシ基が好ましく、例えば、メチルオキシ基、エチルオキシ基、プロピルオキシ基が挙げられるが、エチルオキシ基が特に好ましい。好ましいＲ⁴は、ジメチルアミノメチレンアミノスルホニル基（−ＳＯ₂Ｎ＝ＣＨＮ（ＣＨ₃）₂）、アミノ基（−ＮＨ₂）、アミノスルホニル基（−ＳＯ₂ＮＨ₂）、Ｃ_1-4アルキルオキシカルボニルアミノスルホニル基（−ＳＯ₂ＮＨ（ＣＯ）ＯＣ_1-4アルキル）又はニトロ基（−ＮＯ₂）である。
【００２８】
一般式（２）で表される化合物のうち、好ましいものとしては、２−シクロプロピル−３−［［２’−［［［（ジメチルアミノ）メチレン］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１１）、３−［［２’−（アミノスルホニル）−１，１’−ビフェニル−４−イル］メチル］−２−シクロプロピル−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１２）、２−シクロプロピル−３−［［２’−［［（エトキシカルボニル）アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１３）、２−シクロプロピル−７−メチル−３−［［２’−ニトロ−１，１’−ビフェニル−４−イル］メチル］−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１４）及び３−［［２’−アミノ−１，１’−ビフェニル−４−イル］メチル］−２−シクロプロピル−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１５）が挙げられる。
【００２９】
【化５０】

【００３０】
【化５１】

【００３１】
【化５２】

【００３２】
【化５３】

【００３３】
【化５４】

【００３４】
本発明の化合物（１）又はその塩は、例えば次の製造法（ａ）〜（ｄ）に従って製造することができる。
【００３５】
製造法（ａ）
【００３６】
【化５５】

【００３７】
（式中、Ｈａｌはハロゲン原子を示し、Ｒ¹、Ｒ²及びＲ³は前記と同じである。）
【００３８】
すなわち、式（３）で表される化合物又はその塩を加水分解して式（４）の化合物を得、次いで当該化合物と式（５）で表される化合物とをアルカリ性条件下で反応させることにより、一般式（１ａ）で表される化合物又はその塩が得られる。
【００３９】
ここで式（３）の化合物は、例えば４’−（ブロモメチル）−Ｎ−［（ジメチルアミノ）メチレン］−１，１’−ビフェニル−２−スルホンアミドと２，７−置換−３Ｈ−イミダゾ［４，５−ｂ］ピリジンとを水素化ナトリウムのようなアルカリ存在下で縮合させることにより得られる。
【００４０】
式（３）の化合物の加水分解は、例えば塩酸、硫酸、硝酸等の酸の存在下で行うのが好ましい。また、式（４）の化合物と式（５）の化合物の反応は、１，８−ジアザビシクロ［５．４．０］−ウンデカ−７−エン（ＤＢＵ）等のアルカリ触媒の存在下で行うのが好ましい。
【００４１】
製造法（ｂ）
【００４２】
【化５６】

【００４３】
（式中、Ｒ¹、Ｒ²及びＲ³は前記と同じである。）
【００４４】
すなわち、前記製造法（ａ）と同様にして得られた式（４）の化合物とＣ_1-6アルキルオキシカルボニルハライドとをアルカリ性条件下で反応させて式（６）で表される化合物を得、次いで当該化合物と式（７）の化合物とを反応させることにより、一般式（１ｂ）で表される化合物又はその塩が得られる。また、式（４）で表される化合物と式（８）で表される化合物とをアルカリ性条件下で付加反応させることによっても式（１ｂ）で表される化合物が得られる。
【００４５】
Ｃ_1-6アルキルオキシカルボニルハライドとしては、例えばクロロギ酸エチルエステル等が挙げられる。式（４）の化合物とＣ_1-6アルキルオキシカルボニルハライドとの反応は、例えば炭酸カリウム、炭酸ナトリウム等のアルカリの存在下で行うのが好ましい。また、式（６）の化合物と式（７）のアミン類との反応は、通常のアミド化反応、例えばベンゼン、トルエン等の溶媒中で加熱することにより容易に行われる。式（８）のイソシアナートは、対応するカルボン酸から常法により得られる。式（４）の化合物と式（８）の化合物との反応は、例えば炭酸カリウム、炭酸ナトリウム等のアルカリの存在下で行うのが好ましい。
【００４６】
製造法（ｃ）
【００４７】
【化５７】

【００４８】
（式中、Ｒ¹、Ｒ²、Ｒ³及びＨａｌは前記と同じである。）
【００４９】
すなわち、前記製造法（ａ）と同様にして得られた式（４）の化合物と式（９）の化合物とをアルカリ条件下で反応させることにより一般式（１ｃ）で表される化合物又はその塩が得られる。この反応は、ピリジン類、トリエチルアミン等の第三級アミン類の有機塩基の存在下に行うのが好ましい。
【００５０】
製造法（ｄ）
【００５１】
【化５８】

【００５２】
（式中、Ｒ¹、Ｒ²、Ｒ³及びＨａｌは前記と同じである。）
【００５３】
すなわち、式（１０）の化合物を還元して式（１１）の化合物を得、次いで当該化合物と式（５）の化合物とをアルカリ性条件下で反応させることにより、一般式（１ｄ）で表される化合物又はその塩が得られる。
【００５４】
ここで、式（１０）の化合物は、例えば２，３−ジアミノ−４−メチルピリジンとシクロプロパンカルボン酸クロリドをオキシ塩化リンの存在下縮合させて得られる２，７−置換−３Ｈ−イミダゾ［４，５−ｂ］ピリジンと、［［２’−ニトロ−１，１−ビフェニル−４−イル］メチル］ブロミドとを水素化ナトリウムの存在下で縮合させることにより得られる。
【００５５】
式（１０）の化合物の還元は、例えば無水塩化スズ等の還元剤を用いて行うのが好ましい。また、式（１１）の化合物と式（５）の化合物との反応は、ピリジン類、第三級アミン類等の有機塩基の存在下に行うのが好ましい。
【００５６】
かくして得られた、一般式（１）で表される化合物は、常法に従って塩に誘導することができる。かかる塩としては、生理的又は薬学的に許容されるものであれば、特段の限定はなく、例えば、酸との塩としては、塩酸塩、硝酸塩、硫酸塩、炭酸塩、リン酸塩などの鉱酸塩、クエン酸塩、フマル酸塩、マレイン酸塩、蓚酸塩、メタンスルホン酸塩、ｐ−トルエンスルホン酸塩等の有機酸塩などが例示でき、アルカリとの塩であれば、ナトリウム塩、カリウム塩等のアルカリ金属塩、カルシウム塩、マグネシウム塩等のアルカリ土類金属塩、アンモニウム塩、トリエタノールアミン塩、トリエチルアミン塩、ＤＢＵ塩、ピペラジン塩、モルフォリン塩等の有機アミン塩類、リジン塩、アルギニン塩等の塩基性アミノ酸塩等が好ましく例示できる。
一般式（１）の化合物には、水和物等の溶媒和物が含まれる。また一般式（１）の化合物には、立体異性体及びその混合物が含まれる。
【００５７】
かかる一般式（１）の化合物又は生理的（又は薬学的）に許容されるその塩は、優れたアンジオテンシンＩＩ受容体拮抗作用及びＡＣＡＴ阻害作用を有し、ヒトを含む哺乳類用の高血圧症と高脂血症の合併症の予防及び治療剤として、更には、動脈硬化性疾患及びシンドロームＸの予防及び／又は治療剤として有用である。
【００５８】
本発明の一般式（１）の化合物又はその塩を高血圧高脂血合併症の治療薬乃至は予防薬（現在の症状が更に悪化をするのを防ぐ意味での予防も含む）として用いる場合、一般式（１）に表される化合物又はその塩の用量は、一日成人１人あたり、１〜１０００ｍｇ、好ましくは５〜５００ｍｇを１回乃至は数回に分けて投与することが好ましい。投与経路としては、医薬で知られているものであれば特段の限定はなく、例えば、経口投与、静脈内投与、動脈内投与、皮下投与、筋肉内投与、経皮投与、直腸内投与などが例示できる。かかる投与にあたっては、本発明の化合物である一般式（１）に表される化合物又はその塩を製剤化のための任意成分とともに常法に従い加工することができる。かかる製剤上の任意成分としては、例えば、賦形剤、崩壊剤、滑沢剤、結合剤、着色剤、被覆剤、可溶化分散剤、乳化剤、安定化剤、矯味矯臭剤などが例示できる。
【００５９】
【実施例】
以下に実施例を挙げ、本発明について更に詳細に説明を加えるが、本発明がかかる実施例に限定されないことは言うまでもない。
【００６０】
＜参考例１＞
２−ブロモベンゼンスルホンアミド
２−ブロモスルホニルクロリド１２．５３ｇをアンモニア水１２５ｍＬ（２５％−２８％ｗ／ｗ）に加え、３０分間加熱還流した。その後、反応液を室温まで放冷し、析出物を吸引濾過し、水にて数回洗浄後、風乾することにより２−ブロモベンゼンスルホンアミドを１０．７４ｇ得た（収率９２．７％）。
【００６１】
＜参考例２＞
２−ブロモ−Ｎ−［（ジメチルアミノ）メチレン］ベンゼンスルホンアミド
２−ブロモベンゼンスルホンアミド１０．７４ｇを乾燥ジメチルホルムアミド（７０ｍＬ）に溶解し、これにジメチルホルムアミドジメチルアセタ−ル５．６０ｇを加え、室温にて２時間撹拌した。その後、反応液を氷水（３６０ｍＬ）に注ぎ、析出物を吸引濾過し、水にて数回洗浄後、風乾し、２−ブロモ−Ｎ−［（ジメチルアミノ）メチレン］ベンゼンスルホンアミドを１２．２７ｇ得た（収率８７．８％）。
【００６２】
＜参考例３＞
Ｎ−［（ジメチルアミノ）メチレン］−４’−メチル−１，１’−ビフェニル−２−スルホンアミド
２−ブロモ−Ｎ−［（ジメチルアミノ）メチレン］ベンゼンスルホンアミド８．０ｇ、トリフェニルホスフィン０．７３ｇ、炭酸ナトリウム６．９８ｇ、酢酸パラジウム０．３１ｇをトルエン：水（１１０ｍＬ：３０ｍＬ）に加え、窒素雰囲気下、室温にて撹拌しながら、４−メチルフェニルボロン酸４．９４ｇ／ＥｔＯＨ（７０ｍＬ）溶液を滴下した後、６時間加熱還流した。その後、反応液を室温まで放冷し、吸引濾過後、濃縮した。残渣を酢酸エチル（１００ｍＬ）に溶解し、水（１００ｍＬ）を加え振とう後、析出物を吸引濾過、風乾した。固形物をシリカゲルカラムクロマトグラフィ−（クロロホルム）に付し、Ｎ−［（ジメチルアミノ）メチレン］−４’−メチル−１，１’−ビフェニル−２−スルホンアミドを７．５６ｇ得た。
収率；９１．２％
¹H-NMR(CDCl₃)δ:2.41(3H,s),2.73(3H,s),2.76(3H,s),7.00(1H,s),7.1-7.2(3H,m),7.2-7.3(2H,m),7.4-7.5(2H,m),8.30(1H,dd,J=7.6Hz,J=1.9Hz)
【００６３】
＜参考例４＞
４’−（ブロモメチル）−Ｎ−［（ジメチルアミノ）メチレン］−１，１’−ビフェニル−２−スルホンアミド
Ｎ−［（ジメチルアミノ）メチレン］−４’−メチル−１，１’−ビフェニル−２−スルホンアミド１．０ｇ、Ｎ−ブロモ琥珀酸イミド０．５８ｇ、過酸化ベンゾイル０．０４ｇにクロロベンゼン（１３ｍＬ）を加え、４時間加熱還流した。その後、反応液を室温まで放冷し、吸引濾過後、濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィ−（クロロホルム）に付し、４’−（ブロモメチル）−Ｎ−［（ジメチルアミノ）メチレン］−１，１’−ビフェニル−２−スルホンアミドを１．０３ｇ得た。
収率：８３．１％
¹H-NMR(CDCl₃)δ:2.77(3H,s),2.82(3H,s),4.55(2H,s),7.1-7.3(2H,m),7.4-7.6(6H,m),8.32(1H,dd,J=6.2Hz,J=2.4Hz)
【００６４】
＜参考例５＞
２−シクロプロピル−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン
２，３−ジアミノ−４−メチルピリジン１．０ｇ、シクロプロパンカルボン酸クロリド１．１１ｇをオキシ塩化リン（１４．６ｍＬ）に加え、９０分間加熱還流した。その後、反応液を氷冷し、氷水（１５０ｍＬ）に注ぎ、濃アンモニア水を加えアルカリ性とした。これに、クロロホルムを加え、振とう後、有機層を分離し、水層はクロロホルムにて５回抽出した。全有機層を合わせて飽和食塩水にて洗浄後、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去後、残渣を酢酸エチルにて再結晶することにより２−シクロプロピル−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジンを１．０ｇ得た。
収率：７０．９％
¹H-NMR(CDCl₃)δ:1.3-1.4(4H,m),2.2-2.3(1H,m),2.67(3H,s),7.01(1H,d,J=4.6Hz),8.17(1H,d,J=4.6Hz)
【００６５】
＜実施例１＞
２−シクロプロピル−３−［［２’−［［［（ジメチルアミノ）メチレン］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１１）
２−シクロプロピル−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン０．４９ｇをジメチルホルムアミド（４ｍＬ）に溶解し、水素化ナトリウム（６０％油性）０．２３ｇを加え、窒素雰囲気下、室温にて３０分間撹拌した。その後、４’−（ブロモメチル）−Ｎ−［（ジメチルアミノ）メチレン］−１，１’−ビフェニル−２−スルホンアミド１．０３ｇを加え、同条件下、３０分間撹拌した。反応液を酢酸エチル（５０ｍＬ）、飽和塩化アンモニウム水溶液（１３０ｍＬ）の系に注ぎ、振とう後、有機層を分離し、水層は酢酸エチルにて３回抽出した。全有機層を合わせて、飽和食塩水にて洗浄後、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィ−（クロロホルム：メタノ−ル＝１９：１）に付し、一般式（２）の化合物である、化合物１１を０．４３ｇ得た。
収率：３３．８％
¹H-NMR(CDCl₃)δ:1.3-1.4(4H,m),1.9-2.0(1H,m),2.59(3H,s),2.71(3H,s),2.74(3H,s),5.64(2H,s),6.9-7.0(2H,m),7.1-7.3(5H,m),7.4-7.5(2H,m),8.13(1H,d,J=4.9Hz),8.27(1H,dd,J=5.9Hz,J=1.6Hz)
【００６６】
＜実施例２＞
３−［［２’−（アミノスルホニル）−１，１’−ビフェニル−４−イル］メチル］−２−シクロプロピル−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１２）
化合物１１の０．２９ｇをエタノ−ル（１１ｍＬ）に溶解し、濃塩酸１．２ｇを加え、６時間加熱還流した。その後、反応液を室温まで放冷し、溶媒を減圧留去した。残渣を酢酸エチル（３００ｍＬ）、飽和炭酸水素ナトリウム水溶液（２００ｍＬ）に溶解し、振とう後、有機層を分離し、水層は酢酸エチルにて３回抽出した。全有機層を合わせて、飽和食塩水にて洗浄後、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去することにより、一般式（２）で表される化合物である化合物１２を０．２４ｇ得た。
収率：９６．０％
¹H-NMR(CDCl₃)δ:1.1-1.2(2H,m),1.2-1.3(2H,m),1.9-2.0(1H,m),2.64(3H,s),5.66(2H,s),7.01(1H,d,J=5.9Hz),7.30(3H,d,J=7.8Hz),7.4-7.6(4H,m),8.1-8.2(2H,m)
【００６７】
＜実施例３＞
２−シクロプロピル−３−［［２’−［［（エトキシカルボニル）アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１３）
化合物１２の０．０９ｇ、炭酸カリウム０．６４ｇ、クロロギ酸エチル（０．０４ｍＬ）に乾燥ジメトキシメタン（１．６ｍＬ）を加え、室温にて６時間撹拌した。その後、リン酸二水素カリウム水溶液にてｐＨ＝４とし、酢酸エチル（５０ｍＬ）を加え、振とう後有機層を分離し、飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去することにより、一般式（２）で表される化合物である化合物１３を０．１０ｇ得た。
収率：９５．２％
¹H-NMR(CDCl₃)δ:1.07(3H,t,J=6.8Hz),1.1-1.2(2H,m),1.3-1.4(2H,m),1.9-2.0(1H,m),2.65(3H,s),4.01(2H,q,J=6.8Hz),5.66(2H,s),7.01(1H,d,J=4.9Hz),7.2-7.4(4H,m),7.4-7.7(3H,m),8.16(1H,d,J=5.1Hz),8.25(1H,dd,J=7.8Hz,J=1.9Hz)
【００６８】
＜実施例４＞
２−シクロプロピル−７−メチル−３−［［２’−［［［［（２−メチルフェニル）アミノ］カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１）
化合物１３の０．１０ｇ、ｏ−トルイジン０．０２１ｇにトルエン（５ｍＬ）を加え、２時間加熱還流した。その後、溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィ−（ｎ−ヘキサン：酢酸エチル＝１：１）に付し、一般式（１）で表される化合物である化合物１を０．０７１ｇ得た。
収率：６３．４％
ｍｐ．：９２．５−１０１．５℃
¹H-NMR(CDCl₃)δ:1.3-1.4(4H,m),1.9-2.0(1H,m),2.05(3H,s),2.65(3H,s),5.58(2H,s),6.9-7.0(2H,m),7.0-7.1(2H,m),7.2-7.4(5H,m),7.5-7.7(3H,m),7.87(1H,brs),8.12(1H,d,J=5.4Hz),8.19(1H,dd,J=7.8,J=1.1Hz)
【００６９】
＜実施例５＞
２−シクロプロピル−３−［［２’−［［［［（２−フルオロフェニル）アミノ］カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物２）
化合物１３とｏ−フルオロアニリンを用い、実施例４と同様の方法にて、一般式（１）の化合物である化合物２を得た。
収率：３８．０％
ｍｐ．：８４．５−９４．０℃
¹H-NMR(CDCl₃)δ:1.0-1.3(4H,m),1.9-2.0(1H,m),2.65(3H,s), 5.58(2H,s),6.9-7.1(4H,m),7.1-7.4(5H,m),7.5-7.7(2H,m),7.9-8.0(1H,m),8.08(1H,d,J=5.1Hz),8.25(1H,dd,J=7.6Hz,J=1.4Hz),8.23(1H,s)
IR(KBr錠剤):1622,1546,1488,1344,1152,756(cm^-1)
【００７０】
＜実施例６＞
２−シクロプロピル−３−［［２’−［［［［（２，４−ジフルオロフェニル）アミノ］カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物３）化合物１３と２，４−ジフルオロアニリンを用い、実施例４と同様の方法にて、一般式（１）の化合物である化合物３を得た。
収率：５６．３％
ｍｐ．：１００．５−１０９℃
¹H-NMR(CDCl₃)δ:1.1-1.2(2H,m),1.2-1.3(2H,m),2.0-2.1(1H,m),2.66(3H,s),5.63(2H,s),6.78(2H,t,J=8.1Hz),7.01(1H,d,J=4.9Hz),7.20(2H,d,J=7.8Hz),7.3-7.4(4H,m),7.4-7.6(2H,m),7.8-7.9(1H,m),8.07(1H,d,J=4.9Hz),8.22(2H,d,J=8.1Hz)IR(KBr錠剤):1600,1517,1155(cm^-1)
【００７１】
＜実施例７＞
２−シクロプロピル−３−［［２’−［［［［（２，６−ジイソプロピルフェニル）アミノ］カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物４）
化合物１２の０．０５ｇをアセトン（５ｍＬ）に溶解し、これに炭酸カリウム０．０８５ｇ、２，６−ジイソプロピルフェニルイソシアネ−ト５０μｌを加え、１時間加熱還流した。その後、反応液を室温に戻し、リン酸二水素カリウム水溶液にてｐＨ＝４とし、酢酸エチル（５０ｍＬ）を加え、振とう後有機層を分離し、水層は酢酸エチルにて抽出した。全有機層を合わせて、飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィ−（ベンゼン：アセトン＝８：２）に付し、一般式（１）の化合物である化合物４を０．０７ｇ得た。
収率：９３．９％
ｍｐ．：１７１．５−１７６．５℃
¹H-NMR(CDCl₃)δ:0.98(12H,d,J=6.8Hz),1.0-1.1(2H,m),1.2-1.3(2H,m), 1.9-2.0(1H,m),1.5-1.6(2H,m),2.64(3H,s),5.50(2H,s),6.99(1H,d,J=5.1Hz),7.07(2H,d,J=8.1Hz),7.2-7.4(6H,m),7.5-7.8(3H,m),8.16(1H,d,J=5.1Hz),8.23(1H,d,J=7.8Hz)
IR(KBr錠剤):1514,1468,1156(cm^-1)
【００７２】
＜実施例８＞
２−シクロプロピル−３−［［２’−［［［（２−フルオロフェニル）カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物５）
化合物１２の０．２２ｇをピリジン（１０ｍＬ）に溶解し、ｏ−フルオロベンゾイルクロリド（０．６ｍＬ）を加え、窒素雰囲気下、室温にて２４時間撹拌した。その後、反応液を酢酸エチル（３００ｍＬ）に注ぎ、飽和塩化第二銅水溶液にて洗浄した。析出物をセライト濾過により除去し、有機層を分離し、水層は酢酸エチルにて抽出した。全有機層を合わせて、飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィ−（クロロホルム：メタノ−ル＝１９：１）に付し、一般式（１）の化合物である化合物５を０．１５ｇ得た。
収率：５３．４％
ｍｐ．：１５４．５−１６２．５℃
¹H-NMR(CDCl₃)δ:1.0-1.1(2H,m),1.2-1.3(2H,m),1.9-2.0(1H,m),2.66(3H,s),5.58(2H,s),6.7-6.8(1H,m),7.00(1H,d,J=5.1Hz),7.12(3H,d,J=8.1Hz),7.2-7.3(3H,m),7.3-7.4(1H,m),7.4-7.5(2H,m),7.8-7.9(1H,m),8.16(1H,d,J=4.9Hz),8.35(1H,d,J=7.6Hz)
IR(KBr錠剤):1701,1613,1467,1424,1347,1171(cm^-1)
【００７３】
＜実施例９＞
２−シクロプロピル−７−メチル−３−［［２’−［［［［（２，４，６−トリメチルフェニル）アミノ］カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物６）
２，４，６−トリメチル安息香酸１６４ｍｇ、ジフェニルホスホリルアジド３３０ｍｇ、ベンゼン４ｍＬ及びトリエチルアミン０．１５ｍＬを加え、加熱還流した。５０分後、反応溶媒を濃縮した。残渣に乾燥アセトン（４ｍＬ）に溶解した化合物１２の１８０ｍｇ及び炭酸カリウム２４０ｍｇを加え、加熱還流した。２時間後反応溶媒を減圧下濃縮し、リン酸二水素カリウムを加えｐＨ＝５とし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグフィ−に付した後、さらに分取用シリカゲル薄層クロマトグラフィ−に付し、一般式（１）の化合物である化合物６を７８ｍｇ得た。
収率：１３．５％
ｍｐ．：１２１．５−１２９．６℃
¹H-NMR(CDCl₃)δ:1.0-1.1(2H,m),1.2-1.3(2H,m),1.84(6H,s), 1.9-2.0(1H,m),2.16(3H,s),2.64(3H,s),5.64(2H,s),6.77(2H,s),6.98(1H,d,J=4.86Hz),7.3-7.7(8H,m),8.13(1H,dJ=5.4Hz),8.19(1H,d,5.1Hz)
IR(KBr錠剤):1611,1517,1450,1243,1162(cm^-1)
【００７４】
＜実施例１０＞
２−シクロプロピル−７−メチル−３−［［２’−ニトロ−１，１’−ビフェニル−４−イル］メチル］−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１４）
６０％水素化ナトリウム０．５７５ｇをジメチルホルムアミド２０ｍＬに懸濁し、２−シクロプロピル−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン１．１４ｇを窒素雰囲気下にて加え室温で撹拌した。３０分後［［２’−ニトロ−１，１’−ビフェニル−４−イル］メチル］ブロミド１．８６ｇを加え３０分間撹拌した。反応液を飽和塩化アンモニウム（１５０ｍＬ）に注いだ。振とう後水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。有機層を飽和食塩水（５０ｍＬ）で５回洗浄し、有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィ−（クロロホルム）に付し黄色固体として、一般式（２）で表される化合物である化合物１４を０．９１ｇ得た。
収率：３７．２％
¹H-NMR(CDCl₃)δ:1.0-1.1(2H,m),1.2-1.3(2H,m),1.9-2.0(1H,m),1.84(6H,s),2.64(3H,s),5.64(2H,s),7.00(1H,d,J=4.9Hz),7.2-7.3(4H,m),7.3-7.7(3H,m),7.84(1H,dd,J=8.4Hz,J=1.4Hz),8.18(1H,d,J=5.1Hz)
【００７５】
＜実施例１１＞
３−［［２’−アミノ−１，１’−ビフェニル−４−イル］メチル］−２−シクロプロピル−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１５）
化合物１４の０．９６ｇ及び無水塩化スズ（ＩＩ）２．３６ｇをエタノール４０ｍＬに加え加熱還流した。３０分後飽和重曹水を加えｐＨ＝８〜９となるように調整し、酢酸エチル（２０ｍＬ）を加えしばらく撹拌した。生じた不溶物をセライトで濾去し、酢酸エチルで数回洗い、濾液及び洗液を合わせ、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィ−（ｎ−ヘキサン：酢酸エチル＝７：３）に付し、得られた分画を濃縮し、さらにクロロホルムに溶解し、飽和重曹水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、減圧下濃縮し、一般式（２）で表される化合物である化合物１５を０．６７ｇ得た。
収率：７５．７％
¹H-NMR(CDCl₃)δ:1.0-1.1(2H,m),1.2-1.3(2H,m),1.9-2.1(1H,m),2.64(3H,s),3.70(2H,brs),5.63(2H,s),6.6-6.9(2H,m),7.0-7.2(3H,m),7.3-7.5(4H,m),8.19(1H,d,J=4.9Hz)
【００７６】
＜実施例１２＞
２−シクロプロピル−３−［［２’−［［（２，４−ジフルオロフェニル）スルホニル］アミノ］−１，１’−ビフェニル−４−イル］メチル］−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物７）
化合物１５の０．６６ｇ及び２，６−ジ−ｔ−ブチル−４−メチルピリジン４００ｍｇをジクロロメタン１２ｍＬに溶解し、窒素雰囲気下−１５〜−５℃に冷却し、１２ｍＬのジクロロメタンに溶解した２，４−ジフルオロベンゼンスルホニルクロリド４００ｍｇを同温で滴下した。同温にて３時間撹拌後、室温にて１５時間撹拌した。反応液を飽和重曹水及び飽和食塩水で洗浄し、有機層を無水硫酸ナトリウムで乾燥した。減圧下濃縮後、残渣をシリカゲルカラムクロマトグラフィ−（ｎ−ヘキサン：酢酸エチル＝７：３）に付し、得られた分画を濃縮し、さらにクロロホルムに溶解し、飽和重曹水、水及び飽和食塩水で順次洗浄した。有機層を無水硫酸ナトリウムで乾燥後、減圧下濃縮し、一般式（１）に表される化合物である化合物７を０．４０ｇ得た。
収率：４０．４％
¹H-NMR(CDCl₃)δ:1.0-1.2(2H,m),1.2-1.3(2H,m),1.9-2.1(1H,m),2.66(3H,s),5.67(2H,s),6.6-6.7(1H,m),6.8-7.0(2H,m),7.0-7.2(5H,m),7.2-7.3(3H,m),7.52(1H,d,J=8.1Hz),7.7-7.9(1H,m),8.21(1H,d,J=5.1Hz)
IR(KBr錠剤):1603,1486,1430,1169,1074(cm^-1)
【００７７】
＜実施例１３＞
２−シクロプロピル−７−メチル−３−［［２’−［［［（２−メチルフェニル）スルホニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−３Ｈ−イミダゾ［４，５−ｂ］ピリジン・ＤＢＵ塩（化合物８）
化合物１２と２−メチルベンゼンスルホニルクロリドを用いアルカリ触媒としてＤＢＵ（１，８−ｄｉａｚａｂｉｃｙｃｌｏ［５．４．０］−ｕｎｄｅｃ−７−ｅｎｅ；１，８−ジアザビシクロ［５．４．０］−ウンデカ−７−エン）を用いることにより、実施例１２と同様の方法にて化合物８を得た。
¹H-NMR(CDCl₃)δ:1.1-1.6(14H,m),1.9-2.1(2H,m),2.64(3H,s),2.7-2.8(4H,s),5.64(2H,m),6.74(1H,t,J=5.9Hz),7.00(1H,d,J=4.9Hz),7.2-7.3(2H,m),7.4-7.6(8H,m),7.8-7.9(2H,m),8.07(1H,d,J=5.1Hz),8.25(2H,dd,J=7.8Hz,J=1.4Hz)
IR(KBr錠剤):1551,1161(cm^-1)
【００７８】
＜実施例１４＞
３−［［２’−［［［（シクロヘキシルアミノ）カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−２−シクロプロピル−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物９）
実施例７と同様に、化合物１２の０．０８ｇとシクロヘキシルイソシアネート０．０７ｇとを用いて、３−［［２’−［［［（シクロヘキシルアミノ）カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−２−シクロプロピル−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物９）を０．１０ｇ得た。
収率９０．０％
m.p.:156.0-158.0℃
¹H-NMR(CDCl₃)δ:0.87-1.34(8H,m),1.45-1.94(6H,m),1.94-2.06(1H,m),2.65(3H,s),3.35-3.51(1H,m),5.65(2H,s),5.99(1H,d,J=7.83Hz),7.00(1H,d,J=5.13Hz),7.2-7.42(5H,m),7.46-7.68(2H,m),8.07-8.18(2H,m)
IR(KBr錠剤):3343,1707,1676,1546,1449,1329,1164（cm^-1）
【００７９】
＜実施例１５＞
３−［［２’−［［［（シクロヘプチルアミノ）カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−２−シクロプロピル−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１０）
実施例４と同様に、化合物１３の０．０７ｇとシクロヘプチルアミン０．０２ｇを処理して、３−［［２’−［［［（シクロヘプチルアミノ）カルボニル］アミノ］スルホニル］−１，１’−ビフェニル−４−イル］メチル］−２−シクロプロピル−７−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン（化合物１０）を０．０６ｇ得た。
収率７５．０％
m.p.:157.5-160.0℃
¹H-NMR(CDCl₃)δ:1.00-1.73(16H,m),1.94-2.06(1H,m),2.65(3H,s),3.52-3.68(1H,m),5.65(2H,s),5.96(1H,d,J=8.1Hz),7.00(1H,d,J=4.6Hz),7.15-7.40(5H,m),7.46-7.66(2H,m),8.05-8.18(2H,m)
IR(KBr錠剤):3344,1675,1540,1437,1165（cm^-1）
【００８０】
＜試験例１＞
（アンジオテンシンＩＩ受容体拮抗作用の評価）
日本白色家兎を放血致死後、直ちに胸部大動脈若しくは大腿動脈を摘出し、脂肪組織及び結合組織を除去し、幅２〜３ｍｍのリング標本を作製した。標本は、９５％酸素と５％二酸化炭素混合ガスを通気したクレブス−ヘンゼライト溶液１０ｍＬを満たした温浴中に懸垂し、３７℃に保温した。初期張力（胸部大動脈：２ｇ、大腿動脈：１ｇ）を負荷し、反応は等尺性に記録した。標本が安定した後に、６０ｍＭ ＫＣｌによる収縮を確認し、再び標本が安定した後に、３×１０^-7Ｍ ノルエピネフリン（ＮＥ）を処理し、収縮が一定になった後に、１０^-7Ｍアセチルコリンを処理することによる弛緩反応から内皮の有無を確認し、内皮除去標本のみを用いて以下の評価を行った。
１０^-6Ｍ ＮＥを処理し、収縮が最大になったところで洗浄した。この操作を３回繰り返した後、種々の濃度の評価化合物、又はそれに相当する溶媒を処理し、処理１５分後、アンジオテンシンＩＩを累積投与（１０^-10〜１０^-7Ｍ又は１０^-6Ｍ）して収縮反応を検討し、競合的な拮抗作用の指標となるｐＡ₂値をファン・ロッサム（Van Rossum）の方法又はシルド（Schihild）の方法を用いて算出した。非競合的な拮抗作用が確認された場合は、その指標となるｐＤ’₂を算出した。結果を表１に示す。表中、ｐＤ’₂値は＊を付した。
表１の結果より、本発明の化合物である、一般式（１）に表される化合物及び／又はその塩が優れたアンジオテンシンＩＩ拮抗作用を有することが判る。
【００８１】
【表１】

【００８２】
＜試験例２＞
（アシルコエンザイムＡコレステロールアシルトランスフェラーゼ（ＡＣＡＴ）阻害作用の評価）
（１）ＡＣＡＴの調製
（１−１）ラットを高コレステロール飼料（基本飼料ＭＦに１％コレステロール、０．３％コール酸ナトリウム、０．１％プロピルチオウラシル及び３％ラードを添加した固形の飼料）で約３週間飼育した。
（１−２）（１−１）のラットの肝臓を採取し、細切後、その重量の約３倍量の０．２５Ｍスクロース及び１ｍＭ ＥＤＴＡを含む１０ｍＭヘペス緩衝液（ｐＨ７．４）を加えて懸濁し、ガラステフロン（登録商標）ホモジナイザーでホモジナイズした。
（１−３）ホモジナイズした肝臓を２２，０００×ｇで１５分間遠心分離し、上清を採取した。
（１−４）この上清を更に１００，０００×ｇで６０分間遠心分離し、得られた沈殿に（１−２）で使用した約１／２容量の０．２５Ｍスクロース及び１ｍＭＥＤＴＡを含む１０ｍＭヘペス緩衝液（ｐＨ７．４）を加えて再度懸濁した。（１−５）この懸濁液を１００，０００×ｇで６０分間再度遠心分離して得られた沈殿を採取し、０．２５Ｍスクロース及び２ｍＭ ＤＴＴを含む１０ｍＭヘペス緩衝液（ｐＨ７．４）を加えて懸濁し、−８０℃で保存した。
【００８３】
（２）薬液の調製：
（２−１）反応用緩衝液：０．７５Ｍリン酸緩衝液（ｐＨ７．４）、８００μＭ ＢＳＡ、１００ｍＭ ＤＴＴをそれぞれ１．０、０．５、０．１ｍＬずつ混和し、超純水を３．４ｍＬ加えた。
（２−２）ＡＣＡＴ：冷凍保存してあるＡＣＡＴを前記した「反応用緩衝液」で希釈し、２．５ｍｇプロテイン／ｍＬとした。
（２−３）試験サンプル：評価化合物の１０^-3Ｍ溶液をメタノールで調製した。３×１０^-4Ｍは１０^-3Ｍ溶液３００μＬに５０％メタノール７００μＬを加えて調製した。１０^-4Ｍは３×１０^-4Ｍ溶液３００μＬに５０％メタノール６００μＬを加えて調製した。以下、１０^-7Ｍの溶液（３倍希釈列）まで、同様の手順で調製した。
（３）ＡＣＡＴ活性の測定方法：
（３−１）１．５ｍＬのテストチューブ内に、ＡＣＡＴ２０μＬ、反応用緩衝液２０μＬ、試験サンプル５μＬを入れ、３０℃で１０分間温めた（この溶液を以下「Ｉ」と呼ぶ）。
（３−２）「Ｉ」の中に反応用［¹⁴Ｃ］−オレオイルＣｏＡ５μＬを添加し、攪拌後、３０℃で４分間反応させた。
（３−３）４分後にメタノール２５０μｌを加えて反応を停止し、次いでテストチューブ内に脂質混合物４０μＬ、回収率補正用［³Ｈ］コレステリル・オレート１０μＬ、ヘキサン７００μＬを加えた（この溶液を以下「II」と呼ぶ）。
（３−４）「II」をミキサーで攪拌後、ヘキサン層を５００μＬ採り、別のテストチューブ内に移した（この溶液を以下「III」と呼ぶ）。
（３−５）「III」を蒸発乾固させ、クロロホルム１０μＬに溶かしてＴＬＣ上にスポットした。この時、コレステリル・オレートもスポットした。
（３−６）乾燥後、ヘキサン：ジエチルエーテル：酢酸＝８５：１５：０．５の展開溶媒で展開し、次いでヨウ素で発色させ、コレステリル・オレートのスポットを切り取りバイアル瓶に入れた。これと同時に反応用［¹⁴Ｃ］−オレオイルＣｏＡ５μＬと回収率補正用［³Ｈ］コレステリル・オレート１０μＬをＴＬＣ上にスポットし、同様に切り取ってバイアル瓶に入れた。
（３−７）この後、バイアル瓶に約１０ｍＬのアクアゾルIIを加えて攪拌し、しばらく放置した後、［¹⁴Ｃ］と［³Ｈ］の放射活性を測定した。
【００８４】
得られた放射活性については、［³Ｈ］の放射活性から酵素反応生成した［¹⁴Ｃ］コレステリル・オレートの回収率を計算し、［¹⁴Ｃ］の放射活性からコレステリル・オレートの生成量を算出した。この結果から、濃度反応曲線を作成するとともに非線形最少２乗法を用いてｐＩＣ₅₀値を算出し、活性阻害効果の指標とした。結果を表２に示す。
表２の結果より、本発明の化合物である一般式（１）で表される化合物及び／又はその塩が優れたＡＣＡＴ阻害作用を有することが判る。
【００８５】
【表２】

【００８６】
【発明の効果】
本発明の化合物は、アンジオテンシンＩＩ受容体拮抗作用とＡＣＡＴ阻害作用を併せ持ち、高血圧症と高脂血症の合併症及び合併症に起因する疾患の予防及び／又は治療に有用である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel biphenylimidazopyridine derivative useful for pharmaceuticals and the like, and more particularly to a novel compound useful for the treatment of hypertensive hyperlipidemic complications.
[0002]
[Prior art]
The number of patients with hypertension is about 20 million in Japan. In addition, the number of patients with hyperlipidemia is about 2,000 to 30 million, both of which are frequent diseases. Furthermore, both diseases are frequent not only in Japan but also overseas. These frequencies are independent of each other, and the ratio of hyperlipidemia (eg, hypercholesterolemia, hypertriglyceridemia, low HDL-cholesterolemia, etc.) in hypertensive patients is normal blood pressure Is about 20-30% increase in the rate of developing hyperlipidemia, and hypertension and hyperlipidemia are at high risk of complications. Since hypertension and hyperlipidemia are risk factors for arteriosclerosis, when combined, the incidence of arteriosclerotic diseases such as ischemic heart diseases such as myocardial infarction and angina, and cerebrovascular disorders such as cerebral infarction is It is said to increase synergistically. Furthermore, it is said that the risk of developing Syndrome X increases when hypertension and hyperlipidemia are combined.
[0003]
Conventionally, as therapeutic agents for hypertension, angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, calcium antagonists, β- or α-blockers, antihypertensive diuretics, etc. have been used, and therapeutic agents for hyperlipidemia As 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, nicotinic acid drugs, anion exchange resin drugs, fibrates, probucol, dextran sulfate sodium, eicosapentaic acid and the like are used (for example, Non-patent document 1). However, all of these have only an effect on hypertension or only an effect on hyperlipidemia, and drugs that are applied alone to hypertension and hyperlipidemia complications are currently known. Absent.
[0004]
[Non-Patent Document 1]
Takahisa Sano, Nobuo Sakamoto, “Medicine and Drugs”, Vol. 31, No. 6, published by Natural Sciences, p. 1301-1307 (1994)
[0005]
[Problems to be solved by the invention]
An object of the present invention is to provide a compound useful for the prevention and / or treatment of diseases caused by complications and complications of hypertension and hyperlipidemia.
[0006]
[Means for solving problems]
In view of such circumstances, the present inventors have sought a compound having both angiotensin II receptor antagonistic action and ACAT inhibitory action, and useful for the prevention and / or treatment of hypertension and hyperlipidemia complications. As a result of intensive research efforts, the inventors have found such an action in the biphenylimidazopyridine derivative represented by the following general formula (1) or a salt thereof, and have completed the invention.
[0007]
The present invention relates to the following general formula (1)
[0008]
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[0009]
(Wherein R ¹ And R ² Each independently represents a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms; R ^Three Is a phenyl group which may have a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms and / or a halogen atom as a substituent, or a linear, branched or cyclic group having 1 to 8 carbon atoms. Represents an alkyl group; X represents an aminosulfonyl bond (—NHSO ₂ -), Sulfonylaminosulfonyl bond (-SO ₂ NHSO ₂ -), Sulfonylaminocarbonyl bond (-SO ₂ NHCO-) or sulfonylurea bond (-SO ₂ The present invention provides a biphenylimidazopyridine derivative represented by the following formula: NHCONH-) or a salt thereof, and a production method thereof.
Moreover, this invention provides the pharmaceutical which uses the biphenylimidazopyridine derivative or its salt represented by the said General formula (1) as an active ingredient.
Furthermore, the present invention provides the following general formula (2) useful as a production intermediate for the compound represented by the general formula (1).
[0010]
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[0011]
(Wherein R ¹ And R ² Represents a group as defined in general formula (1); ^Four Is di (C _1-6 Alkyl) aminomethyleneaminosulfonyl group (-SO ₂ N = CHN (C _1-6 Alkyl) ₂ ), Amino group (-NH ₂ ), Aminosulfonyl group (-SO ₂ NH ₂ ), C _1-6 Alkyloxycarbonylaminosulfonyl group (-SO ₂ NH (CO) OC _1-6 Alkyl) or nitro group (—NO ₂ And a salt thereof are provided.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in more detail.
The biphenylimidazopyridine derivative of the present invention is a compound represented by the above general formula (1) or a salt thereof. In the general formula (1), R ¹ And R ² Each independently represents a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, R ^Three Is a phenyl group which may have a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms and / or a halogen atom as a substituent, or a linear, branched or cyclic group having 1 to 8 carbon atoms. Represents an alkyl group, and X represents an aminosulfonyl bond (—NHSO ₂ -), Sulfonylaminosulfonyl bond (-SO ₂ NHSO ₂ -), Sulfonylaminocarbonyl bond (-SO ₂ NHCO-) or sulfonylurea bond (-SO ₂ NHCONH-).
[0013]
R ¹ And R ² Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, and a cyclopropylmethyl group. And cyclobutyl group, pentyl group, hexyl group, cyclopentyl group, cyclohexyl group and the like. Of these, R ¹ Is preferably an alkyl group having 1 to 4 carbon atoms, and linear C such as methyl group, ethyl group, propyl group, and butyl group. _1-4 An alkyl group is more preferable, and a methyl group is particularly preferable among them. R ² As an alkyl group having a cyclic structure, a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group can be preferably exemplified, and a cyclopropyl group is particularly preferable.
[0014]
R ^Three As the substituent of the phenyl group which may have a substituent represented by the above, a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms and / or a halogen atom can be preferably exemplified. Examples of the alkyl group 6 include, for example, methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, sec-butyl group, isobutyl group, tert-butyl group, cyclopropylmethyl group, cyclobutyl group, and pentyl. Group, hexyl group, cyclopentyl group, cyclohexyl group and the like. Among these, an alkyl group having 1 to 4 carbon atoms is more preferable, and a methyl group, an ethyl group, a propyl group, and an isopropyl group are particularly preferable. Moreover, as a halogen atom, a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom can be illustrated preferably, and a fluorine atom is especially preferable. Although it may not have the substituent, it preferably has 1 to 3 substituents. When it has 2 or 3 substituents, these may be different or the same, and preferably have 2 or 3 identical substituents. Examples of the linear, branched or cyclic alkyl group having 1 to 8 carbon atoms include methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, sec-butyl group, isobutyl group, and tert-butyl group. , Cyclopropylmethyl group, cyclobutyl group, pentyl group, tert-amyl group, cyclopentyl group, hexyl group, heptyl group, cycloheptyl group, octyl group, cyclooctyl group and the like, and cyclohexyl group and cycloheptyl group are particularly preferred preferable.
[0015]
X is an aminosulfonyl bond (—NHSO ₂ -), Sulfonylaminosulfonyl bond (-SO ₂ NHSO ₂ -), Sulfonylaminocarbonyl bond (-SO ₂ NHCO-) or sulfonylurea bond (-SO ₂ NHCONH-), any of these bonds being selectable. The compound represented by the general formula (1) or a salt thereof is a novel compound not described in any literature.
[0016]
Among the compounds represented by the general formula (1), 2-cyclopropyl-7-methyl-3-[[2 ′-[[[[(2-methylphenyl) amino]] is particularly preferable. Carbonyl] amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -3H-imidazo [4,5-b] pyridine (Compound 1), 2-cyclopropyl-3-[[2 ′-[ [[[(2-Fluorophenyl) amino] carbonyl] amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4,5-b] pyridine (Compound 2 ), 2-cyclopropyl-3-[[2 ′-[[[[(2,4-difluorophenyl) amino] carbonyl] amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -7 -Methyl-3H-imidazo [ , 5-b] pyridine (compound 3), 2-cyclopropyl-3-[[2 ′-[[[[(2,6-diisopropylphenyl) amino] carbonyl] amino] sulfonyl] -1,1′-biphenyl -4-yl] methyl] -7-methyl-3H-imidazo [4,5-b] pyridine (compound 4), 2-cyclopropyl-3-[[2 ′-[[[(2-fluorophenyl) carbonyl] Amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4,5-b] pyridine (Compound 5), 2-cyclopropyl-7-methyl-3 -[[2 '-[[[[(2,4,6-trimethylphenyl) amino] carbonyl] amino] sulfonyl] -1,1'-biphenyl-4-yl] methyl] -3H-imidazo [4,5 -B] pyridine (compound ), 2-cyclopropyl-3-[[2 ′-[[(2,4-difluorophenyl) sulfonyl] amino] -1,1′-biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4,5-b] pyridine (Compound 7), 2-cyclopropyl-7-methyl-3-[[2 ′-[[[(2-methylphenyl) sulfonyl] amino] sulfonyl] -1,1′-biphenyl -4-yl] methyl] -3H-imidazo [4,5-b] pyridine · DBU salt (compound 8), 3-[[2 ′-[[[(cyclohexylamino) carbonyl] amino] sulfonyl] -1, 1′-biphenyl-4-yl] methyl] -2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine (compound 9) and 3-[[2 ′-[[[(cycloheptyl Amino) carbonyl] amino Sulfonyl] -1,1'-biphenyl-4-yl] methyl] -2-cyclopropyl-7-methyl -3H- imidazo [4,5-b] pyridine (Compound 10) can be mentioned.
[0017]
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[0018]
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[0019]
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[0020]
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[0021]
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[0022]
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[0023]
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[0024]
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[0025]
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[0026]
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[0027]
In the general formula (2), C _1-6 Examples of the alkyl group include linear or branched alkyl groups, of which C _1-4 An alkyl group is preferable, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, and a hexyl group, and a methyl group is particularly preferable. . C _1-6 Examples of the alkyloxy group include straight-chain or branched-chain alkyloxy groups, of which C _1-4 An alkyloxy group is preferable, and examples thereof include a methyloxy group, an ethyloxy group, and a propyloxy group, and an ethyloxy group is particularly preferable. Preferred R ^Four Is a dimethylaminomethyleneaminosulfonyl group (—SO ₂ N = CHN (CH _Three ) ₂ ), Amino group (-NH ₂ ), Aminosulfonyl group (-SO ₂ NH ₂ ), C _1-4 Alkyloxycarbonylaminosulfonyl group (-SO ₂ NH (CO) OC _1-4 Alkyl) or nitro group (—NO ₂ ).
[0028]
Of the compounds represented by the general formula (2), 2-cyclopropyl-3-[[2 ′-[[[(dimethylamino) methylene] amino] sulfonyl] -1,1′-biphenyl is preferable. -4-yl] methyl] -7-methyl-3H-imidazo [4,5-b] pyridine (compound 11), 3-[[2 ′-(aminosulfonyl) -1,1′-biphenyl-4-yl ] Methyl] -2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine (compound 12), 2-cyclopropyl-3-[[2 '-[[(ethoxycarbonyl) amino] sulfonyl ] -1,1′-biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4,5-b] pyridine (compound 13), 2-cyclopropyl-7-methyl-3-[[2 '-Nitro-1,1'-bifeni -4-yl] methyl] -3H-imidazo [4,5-b] pyridine (compound 14) and 3-[[2′-amino-1,1′-biphenyl-4-yl] methyl] -2-cyclo And propyl-7-methyl-3H-imidazo [4,5-b] pyridine (compound 15).
[0029]
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[0030]
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[0031]
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[0032]
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[0033]
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[0034]
Compound (1) or a salt thereof of the present invention can be produced, for example, according to the following production methods (a) to (d).
[0035]
Manufacturing method (a)
[0036]
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[0037]
(In the formula, Hal represents a halogen atom, R ¹ , R ² And R ^Three Is the same as above. )
[0038]
That is, the compound represented by formula (3) or a salt thereof is hydrolyzed to obtain the compound represented by formula (4), and then the compound and the compound represented by formula (5) are reacted under alkaline conditions. Thus, a compound represented by the general formula (1a) or a salt thereof is obtained.
[0039]
Here, the compound of the formula (3) is, for example, 4 ′-(bromomethyl) -N-[(dimethylamino) methylene] -1,1′-biphenyl-2-sulfonamide and 2,7-substituted-3H-imidazo [ 4,5-b] pyridine is condensed in the presence of an alkali such as sodium hydride.
[0040]
The hydrolysis of the compound of formula (3) is preferably carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, nitric acid. The reaction of the compound of formula (4) and the compound of formula (5) is carried out in the presence of an alkaline catalyst such as 1,8-diazabicyclo [5.4.0] -undec-7-ene (DBU). Is preferred.
[0041]
Manufacturing method (b)
[0042]
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[0043]
(Wherein R ¹ , R ² And R ^Three Is the same as above. )
[0044]
That is, the compound of formula (4) obtained in the same manner as in the production method (a) and C _1-6 A compound represented by the formula (6) is obtained by reacting an alkyloxycarbonyl halide with an alkaline condition, and then the compound is represented by the general formula (1b) by reacting the compound with the compound of the formula (7). Or a salt thereof. The compound represented by the formula (1b) can also be obtained by subjecting the compound represented by the formula (4) and the compound represented by the formula (8) to an addition reaction under alkaline conditions.
[0045]
C _1-6 Examples of the alkyloxycarbonyl halide include chloroformic acid ethyl ester. Compound of formula (4) and C _1-6 The reaction with the alkyloxycarbonyl halide is preferably performed in the presence of an alkali such as potassium carbonate or sodium carbonate. The reaction of the compound of formula (6) with the amine of formula (7) is easily carried out by heating in a usual amidation reaction, for example, a solvent such as benzene or toluene. The isocyanate of the formula (8) can be obtained from the corresponding carboxylic acid by a conventional method. The reaction between the compound of formula (4) and the compound of formula (8) is preferably carried out in the presence of an alkali such as potassium carbonate or sodium carbonate.
[0046]
Production method (c)
[0047]
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[0048]
(Wherein R ¹ , R ² , R ^Three And Hal are the same as described above. )
[0049]
That is, the compound represented by the general formula (1c) or the compound represented by the general formula (1c) by reacting the compound of the formula (4) obtained in the same manner as in the production method (a) with the compound of the formula (9) under alkaline conditions. A salt is obtained. This reaction is preferably carried out in the presence of an organic base of a tertiary amine such as pyridines or triethylamine.
[0050]
Manufacturing method (d)
[0051]
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[0052]
(Wherein R ¹ , R ² , R ^Three And Hal are the same as described above. )
[0053]
That is, the compound of formula (10) is reduced to obtain a compound of formula (11), and then the compound of formula (5) is reacted with the compound of formula (5) under alkaline conditions to express the compound of formula (1d). Or a salt thereof.
[0054]
Here, the compound of the formula (10) is, for example, 2,7-substituted-3H-imidazo obtained by condensing 2,3-diamino-4-methylpyridine and cyclopropanecarboxylic acid chloride in the presence of phosphorus oxychloride. It can be obtained by condensing 4,5-b] pyridine and [[2′-nitro-1,1-biphenyl-4-yl] methyl] bromide in the presence of sodium hydride.
[0055]
The reduction of the compound of formula (10) is preferably performed using a reducing agent such as anhydrous tin chloride. The reaction of the compound of formula (11) with the compound of formula (5) is preferably carried out in the presence of an organic base such as pyridines and tertiary amines.
[0056]
The compound represented by the general formula (1) thus obtained can be derived into a salt according to a conventional method. Such a salt is not particularly limited as long as it is physiologically or pharmaceutically acceptable. Examples of the salt with an acid include hydrochloride, nitrate, sulfate, carbonate, phosphate and the like. Examples include mineral acid salts, citrate salts, fumarate salts, maleate salts, oxalate salts, organic acid salts such as methanesulfonate, p-toluenesulfonate, etc. Alkali metal salts such as potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, triethanolamine salts, triethylamine salts, DBU salts, piperazine salts, organic amine salts such as morpholine salts, lysine salts Preferred examples include basic amino acid salts such as arginine salt.
The compound of the general formula (1) includes solvates such as hydrates. The compound of the general formula (1) includes stereoisomers and mixtures thereof.
[0057]
Such a compound of the general formula (1) or a physiologically (or pharmaceutically) acceptable salt thereof has an excellent angiotensin II receptor antagonistic action and ACAT inhibitory action, and has high hypertension for mammals including humans. It is useful as a prophylactic and therapeutic agent for complications of lipemia, and further as a prophylactic and / or therapeutic agent for arteriosclerotic diseases and syndrome X.
[0058]
When the compound of the general formula (1) of the present invention or a salt thereof is used as a therapeutic or prophylactic agent for hypertensive hyperlipidemic complications (including prevention in the sense of preventing further deterioration of current symptoms) As for the dose of the compound represented by the general formula (1) or a salt thereof, it is preferable to administer 1 to 1000 mg, preferably 5 to 500 mg per adult per day, once or several times. The administration route is not particularly limited as long as it is known in medicine, and examples thereof include oral administration, intravenous administration, intraarterial administration, subcutaneous administration, intramuscular administration, transdermal administration, and rectal administration. It can be illustrated. In such administration, the compound represented by the general formula (1), which is the compound of the present invention, or a salt thereof can be processed according to a conventional method together with an optional component for formulation. Examples of the optional components on the preparation include excipients, disintegrants, lubricants, binders, colorants, coating agents, solubilizing dispersants, emulsifiers, stabilizers, and flavoring agents.
[0059]
【Example】
The present invention will be described in more detail with reference to the following examples, but it goes without saying that the present invention is not limited to these examples.
[0060]
<Reference Example 1>
2-Bromobenzenesulfonamide
12.53 g of 2-bromosulfonyl chloride was added to 125 mL of ammonia water (25% -28% w / w) and heated to reflux for 30 minutes. Thereafter, the reaction solution was allowed to cool to room temperature, the precipitate was filtered by suction, washed several times with water, and then air-dried to obtain 10.74 g of 2-bromobenzenesulfonamide (yield 92.7%). .
[0061]
<Reference Example 2>
2-Bromo-N-[(dimethylamino) methylene] benzenesulfonamide
2-Bromobenzenesulfonamide (10.74 g) was dissolved in dry dimethylformamide (70 mL), and dimethylformamide dimethylacetate (5.60 g) was added thereto, followed by stirring at room temperature for 2 hours. Thereafter, the reaction solution was poured into ice water (360 mL), the precipitate was suction filtered, washed several times with water and air-dried, and 12.27 g of 2-bromo-N-[(dimethylamino) methylene] benzenesulfonamide. Obtained (yield 87.8%).
[0062]
<Reference Example 3>
N-[(Dimethylamino) methylene] -4′-methyl-1,1′-biphenyl-2-sulfonamide
Add 2-bromo-N-[(dimethylamino) methylene] benzenesulfonamide 8.0 g, triphenylphosphine 0.73 g, sodium carbonate 6.98 g, palladium acetate 0.31 g to toluene: water (110 mL: 30 mL), While stirring at room temperature under a nitrogen atmosphere, a 4-methylphenylboronic acid 4.94 g / EtOH (70 mL) solution was added dropwise, and the mixture was heated to reflux for 6 hours. Thereafter, the reaction solution was allowed to cool to room temperature, filtered after suction and concentrated. The residue was dissolved in ethyl acetate (100 mL), water (100 mL) was added and shaken, and the precipitate was filtered off with suction and air-dried. The solid was subjected to silica gel column chromatography (chloroform) to obtain 7.56 g of N-[(dimethylamino) methylene] -4′-methyl-1,1′-biphenyl-2-sulfonamide.
Yield: 91.2%
¹ H-NMR (CDCl _Three ) δ: 2.41 (3H, s), 2.73 (3H, s), 2.76 (3H, s), 7.00 (1H, s), 7.1-7.2 (3H, m), 7.2-7.3 (2H, m), 7.4 -7.5 (2H, m), 8.30 (1H, dd, J = 7.6Hz, J = 1.9Hz)
[0063]
<Reference Example 4>
4 ′-(Bromomethyl) -N-[(dimethylamino) methylene] -1,1′-biphenyl-2-sulfonamide
N-[(dimethylamino) methylene] -4′-methyl-1,1′-biphenyl-2-sulfonamide 1.0 g, N-bromosuccinimide 0.58 g, benzoyl peroxide 0.04 g and chlorobenzene (13 mL) ) And heated to reflux for 4 hours. Thereafter, the reaction solution was allowed to cool to room temperature, filtered with suction, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform) to obtain 1.03 g of 4 ′-(bromomethyl) -N-[(dimethylamino) methylene] -1,1′-biphenyl-2-sulfonamide.
Yield: 83.1%
¹ H-NMR (CDCl _Three ) δ: 2.77 (3H, s), 2.82 (3H, s), 4.55 (2H, s), 7.1-7.3 (2H, m), 7.4-7.6 (6H, m), 8.32 (1H, dd, J = (6.2Hz, J = 2.4Hz)
[0064]
<Reference Example 5>
2-Cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine
2,3-Diamino-4-methylpyridine (1.0 g) and cyclopropanecarboxylic acid chloride (1.11 g) were added to phosphorus oxychloride (14.6 mL), and the mixture was heated to reflux for 90 minutes. Then, the reaction solution was ice-cooled, poured into ice water (150 mL), and concentrated aqueous ammonia was added to make it alkaline. Chloroform was added thereto, and after shaking, the organic layer was separated, and the aqueous layer was extracted five times with chloroform. All organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized with ethyl acetate to obtain 1.0 g of 2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine.
Yield: 70.9%
¹ H-NMR (CDCl _Three ) δ: 1.3-1.4 (4H, m), 2.2-2.3 (1H, m), 2.67 (3H, s), 7.01 (1H, d, J = 4.6Hz), 8.17 (1H, d, J = 4.6Hz) )
[0065]
<Example 1>
2-cyclopropyl-3-[[2 ′-[[[(dimethylamino) methylene] amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4 5-b] pyridine (Compound 11)
0.49 g of 2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine is dissolved in dimethylformamide (4 mL), 0.23 g of sodium hydride (60% oily) is added, and nitrogen atmosphere is added. And stirred at room temperature for 30 minutes. Thereafter, 1.03 g of 4 ′-(bromomethyl) -N-[(dimethylamino) methylene] -1,1′-biphenyl-2-sulfonamide was added, and the mixture was stirred for 30 minutes under the same conditions. The reaction solution was poured into a system of ethyl acetate (50 mL) and saturated aqueous ammonium chloride solution (130 mL), shaken, the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. All organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 19: 1) to obtain 0.43 g of compound 11, which is a compound of general formula (2).
Yield: 33.8%
¹ H-NMR (CDCl _Three ) δ: 1.3-1.4 (4H, m), 1.9-2.0 (1H, m), 2.59 (3H, s), 2.71 (3H, s), 2.74 (3H, s), 5.64 (2H, s), 6.9 -7.0 (2H, m), 7.1-7.3 (5H, m), 7.4-7.5 (2H, m), 8.13 (1H, d, J = 4.9Hz), 8.27 (1H, dd, J = 5.9Hz, J = 1.6Hz)
[0066]
<Example 2>
3-[[2 ′-(Aminosulfonyl) -1,1′-biphenyl-4-yl] methyl] -2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine (Compound 12)
0.29 g of Compound 11 was dissolved in ethanol (11 mL), 1.2 g of concentrated hydrochloric acid was added, and the mixture was heated to reflux for 6 hours. Thereafter, the reaction solution was allowed to cool to room temperature, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (300 mL) and saturated aqueous sodium hydrogen carbonate solution (200 mL). After shaking, the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. All organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.24 g of compound 12 represented by the general formula (2). Obtained.
Yield: 96.0%
¹ H-NMR (CDCl _Three ) δ: 1.1-1.2 (2H, m), 1.2-1.3 (2H, m), 1.9-2.0 (1H, m), 2.64 (3H, s), 5.66 (2H, s), 7.01 (1H, d, J = 5.9Hz), 7.30 (3H, d, J = 7.8Hz), 7.4-7.6 (4H, m), 8.1-8.2 (2H, m)
[0067]
<Example 3>
2-cyclopropyl-3-[[2 ′-[[(ethoxycarbonyl) amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4,5-b Pyridine (Compound 13)
Dry dimethoxymethane (1.6 mL) was added to 0.09 g of compound 12, 0.64 g of potassium carbonate, and ethyl chloroformate (0.04 mL), and the mixture was stirred at room temperature for 6 hours. Thereafter, the pH was adjusted to 4 with an aqueous potassium dihydrogen phosphate solution, ethyl acetate (50 mL) was added, and after shaking, the organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. By depressurizingly distilling a solvent, 0.10g of compounds 13 which are compounds represented by General formula (2) were obtained.
Yield: 95.2%
¹ H-NMR (CDCl _Three ) δ: 1.07 (3H, t, J = 6.8Hz), 1.1-1.2 (2H, m), 1.3-1.4 (2H, m), 1.9-2.0 (1H, m), 2.65 (3H, s), 4.01 (2H, q, J = 6.8Hz), 5.66 (2H, s), 7.01 (1H, d, J = 4.9Hz), 7.2-7.4 (4H, m), 7.4-7.7 (3H, m), 8.16 ( 1H, d, J = 5.1Hz), 8.25 (1H, dd, J = 7.8Hz, J = 1.9Hz)
[0068]
<Example 4>
2-cyclopropyl-7-methyl-3-[[2 '-[[[[(2-methylphenyl) amino] carbonyl] amino] sulfonyl] -1,1'-biphenyl-4-yl] methyl] -3H -Imidazo [4,5-b] pyridine (Compound 1)
Toluene (5 mL) was added to 0.10 g of compound 13 and 0.021 g of o-toluidine, and the mixture was heated to reflux for 2 hours. Thereafter, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 0.071 g of compound 1 which is a compound represented by the general formula (1). It was.
Yield: 63.4%
mp. : 92.5-101.5 ° C
¹ H-NMR (CDCl _Three ) δ: 1.3-1.4 (4H, m), 1.9-2.0 (1H, m), 2.05 (3H, s), 2.65 (3H, s), 5.58 (2H, s), 6.9-7.0 (2H, m) , 7.0-7.1 (2H, m), 7.2-7.4 (5H, m), 7.5-7.7 (3H, m), 7.87 (1H, brs), 8.12 (1H, d, J = 5.4Hz), 8.19 (1H , dd, J = 7.8, J = 1.1Hz)
[0069]
<Example 5>
2-cyclopropyl-3-[[2 ′-[[[[(2-fluorophenyl) amino] carbonyl] amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -7-methyl-3H -Imidazo [4,5-b] pyridine (Compound 2)
Compound 2 which is a compound of the general formula (1) was obtained in the same manner as in Example 4 using Compound 13 and o-fluoroaniline.
Yield: 38.0%
mp. : 84.5-94.0 ° C
¹ H-NMR (CDCl _Three ) δ: 1.0-1.3 (4H, m), 1.9-2.0 (1H, m), 2.65 (3H, s), 5.58 (2H, s), 6.9-7.1 (4H, m), 7.1-7.4 (5H, m), 7.5-7.7 (2H, m), 7.9-8.0 (1H, m), 8.08 (1H, d, J = 5.1Hz), 8.25 (1H, dd, J = 7.6Hz, J = 1.4Hz), 8.23 (1H, s)
IR (KBr tablet): 1622,1546,1488,1344,1152,756 (cm ^-1 )
[0070]
<Example 6>
2-cyclopropyl-3-[[2 ′-[[[[(2,4-difluorophenyl) amino] carbonyl] amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -7-methyl -3H-imidazo [4,5-b] pyridine (Compound 3) Using Compound 13 and 2,4-difluoroaniline, Compound 3 which is a compound of the general formula (1) was prepared in the same manner as in Example 4. Obtained.
Yield: 56.3%
mp. : 100.5-109 ° C
¹ H-NMR (CDCl _Three ) δ: 1.1-1.2 (2H, m), 1.2-1.3 (2H, m), 2.0-2.1 (1H, m), 2.66 (3H, s), 5.63 (2H, s), 6.78 (2H, t, J = 8.1Hz), 7.01 (1H, d, J = 4.9Hz), 7.20 (2H, d, J = 7.8Hz), 7.3-7.4 (4H, m), 7.4-7.6 (2H, m), 7.8- 7.9 (1H, m), 8.07 (1H, d, J = 4.9Hz), 8.22 (2H, d, J = 8.1Hz) IR (KBr tablet): 1600, 1517, 1155 (cm ^-1 )
[0071]
<Example 7>
2-cyclopropyl-3-[[2 ′-[[[[(2,6-diisopropylphenyl) amino] carbonyl] amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -7-methyl -3H-imidazo [4,5-b] pyridine (compound 4)
0.05 g of Compound 12 was dissolved in acetone (5 mL), 0.085 g of potassium carbonate and 50 μl of 2,6-diisopropylphenyl isocyanate were added thereto, and the mixture was heated to reflux for 1 hour. Thereafter, the reaction solution was returned to room temperature, adjusted to pH = 4 with an aqueous potassium dihydrogen phosphate solution, ethyl acetate (50 mL) was added, the organic layer was separated after shaking, and the aqueous layer was extracted with ethyl acetate. All organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (benzene: acetone = 8: 2) to obtain 0.07 g of compound 4 which is a compound of the general formula (1).
Yield: 93.9%
mp. : 171.5-176.5 ° C
¹ H-NMR (CDCl _Three ) δ: 0.98 (12H, d, J = 6.8Hz), 1.0-1.1 (2H, m), 1.2-1.3 (2H, m), 1.9-2.0 (1H, m), 1.5-1.6 (2H, m) , 2.64 (3H, s), 5.50 (2H, s), 6.99 (1H, d, J = 5.1Hz), 7.07 (2H, d, J = 8.1Hz), 7.2-7.4 (6H, m), 7.5- 7.8 (3H, m), 8.16 (1H, d, J = 5.1Hz), 8.23 (1H, d, J = 7.8Hz)
IR (KBr tablet): 1514, 1468, 1156 (cm ^-1 )
[0072]
<Example 8>
2-cyclopropyl-3-[[2 ′-[[[(2-fluorophenyl) carbonyl] amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [ 4,5-b] pyridine (Compound 5)
0.22 g of Compound 12 was dissolved in pyridine (10 mL), o-fluorobenzoyl chloride (0.6 mL) was added, and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. Thereafter, the reaction solution was poured into ethyl acetate (300 mL) and washed with a saturated aqueous cupric chloride solution. The precipitate was removed by celite filtration, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. All organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 19: 1) to obtain 0.15 g of compound 5, which is a compound of general formula (1).
Yield: 53.4%
mp. : 154.5-162.5 ° C
¹ H-NMR (CDCl _Three ) δ: 1.0-1.1 (2H, m), 1.2-1.3 (2H, m), 1.9-2.0 (1H, m), 2.66 (3H, s), 5.58 (2H, s), 6.7-6.8 (1H, m), 7.00 (1H, d, J = 5.1Hz), 7.12 (3H, d, J = 8.1Hz), 7.2-7.3 (3H, m), 7.3-7.4 (1H, m), 7.4-7.5 (2H , m), 7.8-7.9 (1H, m), 8.16 (1H, d, J = 4.9Hz), 8.35 (1H, d, J = 7.6Hz)
IR (KBr tablet): 1701, 1613, 1467, 1424, 1347, 1171 (cm ^-1 )
[0073]
<Example 9>
2-cyclopropyl-7-methyl-3-[[2 ′-[[[[(2,4,6-trimethylphenyl) amino] carbonyl] amino] sulfonyl] -1,1′-biphenyl-4-yl] Methyl] -3H-imidazo [4,5-b] pyridine (Compound 6)
164 mg of 2,4,6-trimethylbenzoic acid, 330 mg of diphenylphosphoryl azide, 4 mL of benzene and 0.15 mL of triethylamine were added and heated to reflux. After 50 minutes, the reaction solvent was concentrated. 180 mg of compound 12 and 240 mg of potassium carbonate dissolved in dry acetone (4 mL) were added to the residue, and the mixture was heated to reflux. After 2 hours, the reaction solvent was concentrated under reduced pressure, potassium dihydrogen phosphate was added to adjust to pH = 5, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and further subjected to preparative silica gel thin layer chromatography to obtain 78 mg of compound 6, which is a compound of general formula (1).
Yield: 13.5%
mp. : 121.5-129.6 ° C
¹ H-NMR (CDCl _Three ) δ: 1.0-1.1 (2H, m), 1.2-1.3 (2H, m), 1.84 (6H, s), 1.9-2.0 (1H, m), 2.16 (3H, s), 2.64 (3H, s) , 5.64 (2H, s), 6.77 (2H, s), 6.98 (1H, d, J = 4.86Hz), 7.3-7.7 (8H, m), 8.13 (1H, dJ = 5.4Hz), 8.19 (1H, d, 5.1Hz)
IR (KBr tablet): 1611, 1517, 1450, 1243, 1162 (cm ^-1 )
[0074]
<Example 10>
2-Cyclopropyl-7-methyl-3-[[2′-nitro-1,1′-biphenyl-4-yl] methyl] -3H-imidazo [4,5-b] pyridine (Compound 14)
0.575 g of 60% sodium hydride was suspended in 20 mL of dimethylformamide, and 1.14 g of 2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine was added under a nitrogen atmosphere and stirred at room temperature. . After 30 minutes, 1.86 g of [[2′-nitro-1,1′-biphenyl-4-yl] methyl] bromide was added and stirred for 30 minutes. The reaction was poured into saturated ammonium chloride (150 mL). After shaking, water (100 mL) was added and extracted with ethyl acetate (100 mL). The organic layer was washed 5 times with saturated brine (50 mL), and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform) to obtain 0.91 g of a compound 14 represented by the general formula (2) as a yellow solid.
Yield: 37.2%
¹ H-NMR (CDCl _Three ) δ: 1.0-1.1 (2H, m), 1.2-1.3 (2H, m), 1.9-2.0 (1H, m), 1.84 (6H, s), 2.64 (3H, s), 5.64 (2H, s) , 7.00 (1H, d, J = 4.9Hz), 7.2-7.3 (4H, m), 7.3-7.7 (3H, m), 7.84 (1H, dd, J = 8.4Hz, J = 1.4Hz), 8.18 ( (1H, d, J = 5.1Hz)
[0075]
<Example 11>
3-[[2′-Amino-1,1′-biphenyl-4-yl] methyl] -2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine (Compound 15)
0.96 g of compound 14 and 2.36 g of anhydrous tin (II) chloride were added to 40 mL of ethanol and heated to reflux. After 30 minutes, saturated aqueous sodium hydrogen carbonate was added to adjust the pH to 8 to 9, and ethyl acetate (20 mL) was added and stirred for a while. The resulting insoluble material was filtered off through celite, washed several times with ethyl acetate, the filtrate and the washings were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 7: 3), and the obtained fraction was concentrated, further dissolved in chloroform, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 0.67 g of compound 15, which is a compound represented by the general formula (2).
Yield: 75.7%
¹ H-NMR (CDCl _Three ) δ: 1.0-1.1 (2H, m), 1.2-1.3 (2H, m), 1.9-2.1 (1H, m), 2.64 (3H, s), 3.70 (2H, brs), 5.63 (2H, s) , 6.6-6.9 (2H, m), 7.0-7.2 (3H, m), 7.3-7.5 (4H, m), 8.19 (1H, d, J = 4.9Hz)
[0076]
<Example 12>
2-cyclopropyl-3-[[2 '-[[(2,4-difluorophenyl) sulfonyl] amino] -1,1'-biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4 , 5-b] pyridine (Compound 7)
0.66 g of Compound 15 and 400 mg of 2,6-di-t-butyl-4-methylpyridine were dissolved in 12 mL of dichloromethane, cooled to -15 to -5 ° C under a nitrogen atmosphere, and dissolved in 12 mL of dichloromethane. 400 mg of 4-difluorobenzenesulfonyl chloride was added dropwise at the same temperature. After stirring at the same temperature for 3 hours, the mixture was stirred at room temperature for 15 hours. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 7: 3), and the obtained fraction was concentrated, further dissolved in chloroform, saturated aqueous sodium hydrogen carbonate, water and saturated sodium chloride. Washed sequentially with water. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 0.40 g of compound 7, which is a compound represented by the general formula (1).
Yield: 40.4%
¹ H-NMR (CDCl _Three ) δ: 1.0-1.2 (2H, m), 1.2-1.3 (2H, m), 1.9-2.1 (1H, m), 2.66 (3H, s), 5.67 (2H, s), 6.6-6.7 (1H, m), 6.8-7.0 (2H, m), 7.0-7.2 (5H, m), 7.2-7.3 (3H, m), 7.52 (1H, d, J = 8.1Hz), 7.7-7.9 (1H, m) , 8.21 (1H, d, J = 5.1Hz)
IR (KBr tablet): 1603,1486,1430,1169,1074 (cm ^-1 )
[0077]
<Example 13>
2-cyclopropyl-7-methyl-3-[[2 ′-[[[(2-methylphenyl) sulfonyl] amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -3H-imidazo [ 4,5-b] pyridine / DBU salt (compound 8)
DBU (1,8-diazabiccyclo [5.4.0] -undec-7-ene; 1,8-diazabicyclo [5.4.0] -undeca-) as an alkali catalyst using compound 12 and 2-methylbenzenesulfonyl chloride 7-ene) was used to obtain Compound 8 in the same manner as in Example 12.
¹ H-NMR (CDCl _Three ) δ: 1.1-1.6 (14H, m), 1.9-2.1 (2H, m), 2.64 (3H, s), 2.7-2.8 (4H, s), 5.64 (2H, m), 6.74 (1H, t, J = 5.9Hz), 7.00 (1H, d, J = 4.9Hz), 7.2-7.3 (2H, m), 7.4-7.6 (8H, m), 7.8-7.9 (2H, m), 8.07 (1H, d , J = 5.1Hz), 8.25 (2H, dd, J = 7.8Hz, J = 1.4Hz)
IR (KBr tablet): 1551,1161 (cm ^-1 )
[0078]
<Example 14>
3-[[2 ′-[[[(Cyclohexylamino) carbonyl] amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -2-cyclopropyl-7-methyl-3H-imidazo [4 5-b] pyridine (Compound 9)
Similarly to Example 7, using 0.08 g of Compound 12 and 0.07 g of cyclohexyl isocyanate, 3-[[2 ′-[[[(cyclohexylamino) carbonyl] amino] sulfonyl] -1,1′- 0.10 g of biphenyl-4-yl] methyl] -2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine (Compound 9) was obtained.
Yield 90.0%
mp: 156.0-158.0 ℃
¹ H-NMR (CDCl _Three ) δ: 0.87-1.34 (8H, m), 1.45-1.94 (6H, m), 1.94-2.06 (1H, m), 2.65 (3H, s), 3.35-3.51 (1H, m), 5.65 (2H, s), 5.99 (1H, d, J = 7.83Hz), 7.00 (1H, d, J = 5.13Hz), 7.2-7.42 (5H, m), 7.46-7.68 (2H, m), 8.07-8.18 (2H , m)
IR (KBr tablet): 3343,1707,1676,1546,1449,1329,1164 (cm ^-1 )
[0079]
<Example 15>
3-[[2 ′-[[[(Cycloheptylamino) carbonyl] amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -2-cyclopropyl-7-methyl-3H-imidazo [4 , 5-b] pyridine (Compound 10)
As in Example 4, 0.07 g of compound 13 and 0.02 g of cycloheptylamine were treated to give 3-[[2 ′-[[[(cycloheptylamino) carbonyl] amino] sulfonyl] -1,1. 0.06 g of '-biphenyl-4-yl] methyl] -2-cyclopropyl-7-methyl-3H-imidazo [4,5-b] pyridine (Compound 10) was obtained.
Yield 75.0%
mp: 157.5-160.0 ℃
¹ H-NMR (CDCl _Three ) δ: 1.00-1.73 (16H, m), 1.94-2.06 (1H, m), 2.65 (3H, s), 3.52-3.68 (1H, m), 5.65 (2H, s), 5.96 (1H, d, J = 8.1Hz), 7.00 (1H, d, J = 4.6Hz), 7.15-7.40 (5H, m), 7.46-7.66 (2H, m), 8.05-8.18 (2H, m)
IR (KBr tablets): 3344,1675,1540,1437,1165 (cm ^-1 )
[0080]
<Test Example 1>
(Evaluation of angiotensin II receptor antagonism)
Immediately after exsanguination of Japanese white rabbits, the thoracic aorta or femoral artery was immediately removed and adipose tissue and connective tissue were removed to prepare a ring specimen having a width of 2 to 3 mm. The specimen was suspended in a warm bath filled with 10 mL of Krebs-Henseleit solution aerated with 95% oxygen and 5% carbon dioxide mixed gas, and kept at 37 ° C. Initial tension (thoracic aorta: 2 g, femoral artery: 1 g) was applied and responses were recorded isometrically. After the specimen was stabilized, the contraction by 60 mM KCl was confirmed, and after the specimen was stabilized again, 3 × 10 ^-7 After treatment with M norepinephrine (NE) and the contraction is constant, 10 ^-7 The presence or absence of endothelium was confirmed from the relaxation reaction by treating with M acetylcholine, and the following evaluation was performed using only the endothelium-removed specimen.
10 ^-6 M NE was treated and washed when shrinkage was maximized. After this operation was repeated three times, various concentrations of the evaluation compound or the solvent corresponding thereto were treated, and 15 minutes after the treatment, angiotensin II was cumulatively administered (10 ^-Ten -10 ^-7 M or 10 ^-6 M) to examine the contractile response and pA as an index of competitive antagonism ₂ Values were calculated using Van Rossum's method or Schihild's method. When non-competitive antagonism is confirmed, pD ′ serving as an index thereof ₂ Was calculated. The results are shown in Table 1. In the table, pD ' ₂ Values are marked with *.
From the results of Table 1, it can be seen that the compound represented by the general formula (1) and / or a salt thereof, which is a compound of the present invention, has an excellent angiotensin II antagonistic action.
[0081]
[Table 1]

[0082]
<Test Example 2>
(Evaluation of acyl coenzyme A cholesterol acyltransferase (ACAT) inhibitory effect)
(1) Preparation of ACAT
(1-1) Rats are bred for about 3 weeks on a high cholesterol diet (a solid diet in which 1% cholesterol, 0.3% sodium cholate, 0.1% propylthiouracil and 3% lard are added to the basic diet MF) did.
(1-2) Collect the rat liver of (1-1), cut into small pieces, and add 10 mM hepes buffer (pH 7.4) containing 0.25 M sucrose and 1 mM EDTA in an amount approximately 3 times its weight. The mixture was suspended and homogenized with a glass Teflon (registered trademark) homogenizer.
(1-3) The homogenized liver was centrifuged at 22,000 × g for 15 minutes, and the supernatant was collected.
(1-4) The supernatant was further centrifuged at 100,000 × g for 60 minutes, and the resulting precipitate was 10 mM containing about 1/2 volume of 0.25 M sucrose and 1 mM EDTA used in (1-2). Hepes buffer (pH 7.4) was added and resuspended. (1-5) The precipitate obtained by re-centrifuging this suspension at 100,000 × g for 60 minutes was collected, and 10 mM hepes buffer (pH 7.4) containing 0.25 M sucrose and 2 mM DTT was collected. In addition, it was suspended and stored at -80 ° C.
[0083]
(2) Preparation of chemical solution:
(2-1) Reaction buffer: 0.75 M phosphate buffer (pH 7.4), 800 μM BSA, and 100 mM DTT are mixed at 1.0, 0.5, and 0.1 mL, respectively, and ultrapure water is added in 3 parts. 4 mL was added.
(2-2) ACAT: ACAT that had been stored in a frozen state was diluted with the above-mentioned “reaction buffer” to give 2.5 mg protein / mL.
(2-3) Test sample: 10 of the evaluation compound ^-3 M solution was prepared with methanol. 3 × 10 ^-Four M is 10 ^-3 It was prepared by adding 700 μL of 50% methanol to 300 μL of M solution. 10 ^-Four M is 3 × 10 ^-Four It was prepared by adding 600 μL of 50% methanol to 300 μL of M solution. 10 ^-7 It prepared in the same procedure until the solution of M (3 times dilution series).
(3) Method for measuring ACAT activity:
(3-1) In a 1.5 mL test tube, 20 μL of ACAT, 20 μL of reaction buffer, and 5 μL of a test sample were placed and warmed at 30 ° C. for 10 minutes (this solution is hereinafter referred to as “I”).
(3-2) For reaction in “I” [ ¹⁴ C] -oleoyl CoA (5 μL) was added, and the mixture was stirred and reacted at 30 ° C. for 4 minutes.
(3-3) After 4 minutes, 250 μl of methanol was added to stop the reaction, and then 40 μL of the lipid mixture in the test tube was used for recovery rate correction [ ^Three H] 10 μL of cholesteryl oleate and 700 μL of hexane were added (this solution is hereinafter referred to as “II”).
(3-4) After stirring “II” with a mixer, 500 μL of a hexane layer was taken and transferred into another test tube (this solution is hereinafter referred to as “III”).
(3-5) “III” was evaporated to dryness, dissolved in 10 μL of chloroform and spotted on TLC. At this time, cholesteryl oleate was also spotted.
(3-6) After drying, development was performed with a developing solvent of hexane: diethyl ether: acetic acid = 85: 15: 0.5, followed by color development with iodine, and a cholesteryl oleate spot was cut out and placed in a vial. At the same time for reaction [ ¹⁴ C] -Oleoyl CoA 5 μL and recovery rate correction [ ^Three H] 10 μL of cholesteryl oleate was spotted on TLC and cut in the same manner into a vial.
(3-7) After that, about 10 mL of Aquasol II was added to the vial and stirred. ¹⁴ C] and [ ^Three H] was measured for radioactivity.
[0084]
For the radioactivity obtained, [ ^Three H] produced from an enzymatic reaction from the radioactivity [ ¹⁴ C] Calculate the recovery rate of cholesteryl oleate, ¹⁴ The amount of cholesteryl oleate produced was calculated from the radioactivity of [C]. From this result, a concentration response curve was created and pIC was calculated using the nonlinear least squares method. ₅₀ The value was calculated and used as an index of the activity inhibition effect. The results are shown in Table 2.
From the results in Table 2, it can be seen that the compound represented by the general formula (1) and / or a salt thereof, which is a compound of the present invention, has an excellent ACAT inhibitory action.
[0085]
[Table 2]

[0086]
【The invention's effect】
The compound of the present invention has both an angiotensin II receptor antagonistic action and an ACAT inhibitory action, and is useful for the prevention and / or treatment of diseases caused by hypertension and hyperlipidemia complications and complications.

Claims (2)

2-cyclopropyl-7-methyl-3-[[2 '-[[[[(2-methylphenyl) amino] carbonyl] amino] sulfonyl] -1,1'-biphenyl-4-yl] methyl] -3H -Imidazo [4,5-b] pyridine (compound 1), 2-cyclopropyl-3-[[2 '-[[[[(2-fluorophenyl) amino] carbonyl] amino] sulfonyl] -1,1' -Biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4,5-b] pyridine (compound 2), 2-cyclopropyl-3-[[2 '-[[[[(2,4 -Difluorophenyl) amino] carbonyl] amino] sulfonyl] -1,1'-biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4,5-b] pyridine (compound 3), 2-cyclo Propyl-3-[[2 '-[ [[[(2,6-diisopropylphenyl) amino] carbonyl] amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4,5-b] pyridine ( Compound 4), 2-cyclopropyl-3-[[2 '-[[[(2-fluorophenyl) carbonyl] amino] sulfonyl] -1,1'-biphenyl-4-yl] methyl] -7-methyl- 3H-imidazo [4,5-b] pyridine (compound 5), 2-cyclopropyl-7-methyl-3-[[2 '-[[[[(2,4,6-trimethylphenyl) amino] carbonyl] Amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -3H-imidazo [4,5-b] pyridine (Compound 6), 2-cyclopropyl-3-[[2 ′-[[( 2,4-difluoropheny ) Sulfonyl] amino] -1,1′-biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4,5-b] pyridine (compound 7) or 2-cyclopropyl-7-methyl-3 -[[2 '-[[[(2-Methylphenyl) sulfonyl] amino] sulfonyl] -1,1'-biphenyl-4-yl] methyl] -3H-imidazo [4,5-b] pyridine / DBU salt An angiotensin II receptor antagonistic action and an acyl coenzyme A cholesterol acyltransferase (ACAT) inhibitory action comprising any biphenylimidazopyridine derivative of (Compound 8) or a salt thereof as an active ingredient Prophylactic and / or therapeutic agent. 2-cyclopropyl-7-methyl-3-[[2 '-[[[[(2-methylphenyl) amino] carbonyl] amino] sulfonyl] -1,1'-biphenyl-4-yl] methyl] -3H -Imidazo [4,5-b] pyridine (compound 1), 2-cyclopropyl-3-[[2 '-[[[[(2-fluorophenyl) amino] carbonyl] amino] sulfonyl] -1,1' -Biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4,5-b] pyridine (compound 2), 2-cyclopropyl-3-[[2 '-[[[[(2,4 -Difluorophenyl) amino] carbonyl] amino] sulfonyl] -1,1'-biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4,5-b] pyridine (compound 3), 2-cyclo Propyl-3-[[2 '-[ [[[(2,6-diisopropylphenyl) amino] carbonyl] amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4,5-b] pyridine ( Compound 4), 2-cyclopropyl-3-[[2 '-[[[(2-fluorophenyl) carbonyl] amino] sulfonyl] -1,1'-biphenyl-4-yl] methyl] -7-methyl- 3H-imidazo [4,5-b] pyridine (compound 5), 2-cyclopropyl-7-methyl-3-[[2 '-[[[[(2,4,6-trimethylphenyl) amino] carbonyl] Amino] sulfonyl] -1,1′-biphenyl-4-yl] methyl] -3H-imidazo [4,5-b] pyridine (Compound 6), 2-cyclopropyl-3-[[2 ′-[[( 2,4-difluoropheny ) Sulfonyl] amino] -1,1′-biphenyl-4-yl] methyl] -7-methyl-3H-imidazo [4,5-b] pyridine (compound 7) or 2-cyclopropyl-7-methyl-3 -[[2 '-[[[(2-Methylphenyl) sulfonyl] amino] sulfonyl] -1,1'-biphenyl-4-yl] methyl] -3H-imidazo [4,5-b] pyridine / DBU salt An acyl coenzyme A cholesterol acyltransferase (ACAT) inhibitor comprising as an active ingredient any of the biphenylimidazopyridine derivatives of (Compound 8) or a salt thereof.