JP4007743B2 - Angiogenesis inhibitor - Google Patents

Description

【０００９】
（式中、Ａ環は置換基を有していてもよい、単環式または二環式芳香環を、
Ｂ環は置換基を有していてもよい、６員環式不飽和炭化水素またはヘテロ原子として窒素原子を１個含む不飽和６員ヘテロ環を、
Ｃ環は置換基を有していてもよい、窒素原子を１または２個含む５員ヘテロ環を、
Ｗは単結合または−ＣＨ＝ＣＨ−を、
Ｘは−Ｎ（Ｒ^１）−または酸素原子を、
Ｙは炭素原子または窒素原子を、
Ｚは−Ｎ（Ｒ^２）−または窒素原子を、
Ｒ^１およびＲ^２は同一または異なって水素原子または低級アルキル基を、
意味する。）で表わされるスルホンアミド誘導体およびスルホン酸エステル誘導体またはその薬理学的に許容される塩あるいはそれらの水和物を有効成分とする血管新生阻害剤に関する。
【００１０】
上記一般式（Ｉ）において、Ａ環の意味する「置換基を有していてもよい、単環式または二環式芳香環」とは、芳香族炭化水素、または窒素原子、酸素原子および硫黄原子のうち少なくとも１個を含む芳香族ヘテロ環であり、当該環上には置換基１〜３個があってもよい。Ａ環に含まれる主な芳香環を例示すると、ピロール、ピラゾール、イミダゾール、チオフェン、フラン、チアゾール、オキサゾール、ベンゼン、ピリジン、ピリミジン、ピラジン、ピリダジン、ナフタレン、キノリン、イソキノリン、フタラジン、ナフチリジン、キノキサリン、キナゾリン、シンノリン、インドール、イソインドール、インドリジン、インダゾール、ベンゾフラン、ベンゾチオフェン、ベンズオキサゾール、ベンズイミダゾール、ベンゾピラゾール、ベンゾチアゾールなどがある。上記芳香環は置換基１〜３個を有していてもよく、置換基が複数個ある場合には、同一または異なっていてもよい。置換基としては、例えば、低級アルキル基または低級シクロアルキル基で置換されていてもよいアミノ基、低級アルキル基、低級アルコキシ基、水酸基、ニトロ基、メルカプト基、シアノ基、低級アルキルチオ基、ハロゲン基、式−ａ−ｂ［式中、ａは単結合、−（ＣＨ₂）_k −、−Ｏ−（ＣＨ₂）_k −、−Ｓ−（ＣＨ₂）_k −または−Ｎ（Ｒ^３）−（ＣＨ₂）_k −を、ｋは１〜５の整数を、Ｒ^３は水素原子または低級アルキル基を、ｂは−ＣＨ₂−ｄ（式中、ｄは低級アルキル基で置換されていてもよいアミノ基、ハロゲン基、水酸基、低級アルキルチオ基、シアノ基または低級アルコキシ基を意味する）を意味する］で示される基、式−ａ−ｅ−ｆ［式中、ａは前記と同じ意味を、ｅは−ＳＯ−または−ＳＯ₂−を、ｆは低級アルキル基または低級アルコキシ基で置換されていてもよいアミノ基、低級アルキル基、トリフルオロメチル基、−（ＣＨ₂）_m −ｂまたは−Ｎ（Ｒ^４）−（ＣＨ₂）_m−ｂ（式中、ｂは前記と同じ意味を示し、Ｒ^４は水素原子または低級アルキル基を、ｍは１〜５の整数を意味する）を意味する］で示される基、式−ａ−ｇ−ｈ［式中、ａは前記と同じ意味を示し、ｇは−ＣＯ−または−ＣＳ−を、ｈは低級アルキル基で置換されていてもよいアミノ基、水酸基、低級アルキル基、低級アルコキシ基、−（ＣＨ₂）_n−ｂまたは−Ｎ（Ｒ^５）−（ＣＨ₂）_n−ｂ（式中、ｂは前記と同じ意味を示し、Ｒ^５は水素原子または低級アルキル基を、ｎは１〜５の整数を意味する）を意味する］で示される基、式−ａ−Ｎ（Ｒ^６）−ｇ−ｉ［式中、ａおよびｇは前記と同じ意味を示し、Ｒ^６は水素原子または低級アルキル基を、ｉは水素原子、低級アルコキシ基またはｆ（ｆは前記と同じ意味を示す）を意味する］で示される基、式−ａ−Ｎ（Ｒ^７）−ｅ−ｆ（式中、ａ、ｅおよびｆは前記と同じ意味を示し、Ｒ^７は水素原子または低級アルキル基を意味する）で示される基、式−（ＣＨ₂）_ｐ−ｊ−（ＣＨ₂）_q−ｂ（式中、ｊは酸素原子または硫黄原子を意味し、ｂは前記と同じ意味を示し、ｐおよびｑは同一または異なって１〜５の整数を意味する）、式−（ＣＨ₂）_u−Ａｒ（式中、Ａｒは低級アルキル基、低級アルコキシ基またはハロゲン原子で置換されていてもよい、フェニル基またはヘテロアリール基を意味し、ｕは０または１〜５の整数を意味する）、式−ＣＯＮＨ−（ＣＨ₂）_u−Ａｒ（式中、Ａｒおよびｕは前記を意味する）、または式−ＳＯ₂−（ＣＨ₂）_u−Ａｒ（式中、Ａｒおよびｕは前記を意味する）で示される基などを挙げることができる。
【００１１】
上記置換基例において、アミノ基が２個のアルキル基で置換されている場合には、これらのアルキル基が結合して５または６員環を形成していてもよい。また、Ａ環が水酸基またはメルカプト基を有する含窒素ヘテロ環である場合には、これらの基が共鳴構造をとることにより、オキソ基またはチオキソ基の形になっていてもよい。
【００１２】
Ｂ環の意味する「置換基を有していてもよい、６員環式不飽和炭化水素またはヘテロ原子として窒素原子を１個含む不飽和６員ヘテロ環」とは、一部が水素化されていてもよい、ベンゼンまたはピリジンであり、当該環上に置換基１または２個を有していてもよく、置換基が２個ある場合には同一または異なっていてもよい。
【００１３】
Ｃ環の意味する「置換基を有していてもよい、窒素原子を１または２個含む５員ヘテロ環」とは、一部が水素化されていてもよい、ピロール、ピラゾール、イミダゾールであり、当該環上に置換基１または２個を有していてもよく、置換基が２個ある場合には同一または異なっていてもよい。
Ｂ環およびＣ環が有していてもよい置換基としては、例えば、ハロゲン基、シアノ基、低級アルキル基、低級アルコキシ基、水酸基、オキソ基、式−ＣＯ−ｒ（式中、ｒは水素原子、低級アルキル基で置換されていてもよいアミノ基、低級アルキル基、低級アルコキシ基または水酸基を意味する）、低級アルキル基で置換されていてもよいアミノ基、トリフルオロメチル基などを挙げることができる。
【００１４】
上記一般式（Ｉ）において、Ｒ^１ 、Ｒ^２ およびＡ環、Ｂ環、Ｃ環が有していてもよい置換基の定義中の低級アルキル基としては、炭素数１〜６の直鎖もしくは分枝状のアルキル基、例えばメチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、sec −ブチル基、tert−ブチル基、ｎ−ペンチル基（アミル基）、イソペンチル基、ネオペンチル基、tert−ペンチル基、１−メチルブチル基、２−メチルブチル基、１，２−ジメチルプロピル基、ｎ−ヘキシル基、イソヘキシル基、１−メチルペンチル基、２−メチルペンチル基、３−メチルペンチル基、１，１−ジメチルブチル基、１，２−ジメチルブチル基、２，２−ジメチルブチル基、１，３−ジメチルブチル基、２，３−ジメチルブチル基、３，３−ジメチルブチル基、１−エチルブチル基、２−エチルブチル基、１，１，２−トリメチルプロピル基、１，２，２−トリメチルプロピル基、１−エチル−１−メチルプロピル基、１−エチル−２−メチルプロピル基などを意味する。これらのうち好ましい基としては、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基などを挙げることができ、これらのうち、最も好ましい基としてはメチル基、エチル基、ｎ−プロピル基、イソプロピル基を挙げることができる。
【００１５】
Ａ環が有していてもよい置換基の定義中の低級シクロアルキル基としては、シクロプロピル基、シクロペンチル基、シクロヘキシル基などを挙げることができる。 Ａ環、Ｂ環およびＣ環が有していてもよい置換基の定義中の低級アルコキシ基とは、メトキシ基、エトキシ基、ｎ−プロポキシ基、イソプロポキシ基、ｎ−ブトキシ基、イソブトキシ基、tert−ブトキシ基など上記の低級アルキル基から誘導される低級アルコキシ基を意味するが、これらのうち最も好ましい基としてはメトキシ基、エトキシ基を挙げることができる。またハロゲン原子としてはフッ素原子、塩素原子、臭素原子などが挙げられる。
【００１６】
上記一般式（Ｉ）で示されるスルホンアミド誘導体またはスルホン酸エステル誘導体は酸または塩基と塩を形成する場合もある。本発明は化合物（Ｉ）の塩をも包含する。酸との塩としては、たとえば塩酸塩、臭化水素酸塩、硫酸塩等の無機酸塩や酢酸、乳酸、コハク酸、フマル酸、マレイン酸、クエン酸、安息香酸、メタンスルホン酸、ｐ−トルエ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。また、塩基との塩としては、ナトリウム塩、カリウム塩、カルシウム塩などの無機塩、トリエチルアミン、アルギニン、リジン等の有機塩基との塩を挙げることができる。
【００１７】
また、これら化合物の水和物はもちろんのこと光学異性体が存在する場合はそれらすべてが含まれることはいうまでもない。また、本発明は生体内で酸化、還元、加水分解などの代謝を受けて本発明化合物を生成する化合物をも包含する。
次に本発明化合物（Ｉ）は種々の方法によって製造することができるが、それらのうち代表的な方法を示せば、以下の通りである。
１）一般式（II）
【００１８】
【化３】

【００１９】
（式中、Ａａ環は保護されたまたは保護されていない置換基を有していてもよい、単環式または二環式芳香環を意味し、Ｗは前記と同じ意味を示す）で表わされるスルホン酸またはその反応性誘導体と一般式（III ）
【００２０】
【化４】

【００２１】
（式中、Ｂａ環は保護されたまたは保護されていない置換基を有していてもよい、６員環式不飽和炭化水素またはヘテロ原子として窒素原子を１個含む不飽和６員ヘテロ環を、Ｃａ環は保護されたまたは保護されていない置換基を有していてもよい、窒素原子を１または２個含む５員ヘテロ環を意味し、Ｘ、ＹおよびＺは前記と同じ意味を示す）で表わされる化合物を反応させることにより製造することができる。
【００２２】
スルホン酸（II）の反応性誘導体としては、例えばハロゲン化スルホニル、スルホン酸無水物、Ｎ−スルホニルイミダゾリドなどのような一般的によく利用される反応性誘導体を挙げることができるが、特に好適な例はハロゲン化スルホニルである。反応に使用する溶媒は特に限定されないが、原料物質を溶解し、かつこれらと容易に反応しないものが望ましく、例えばピリジン、テトラヒドロフラン、ジオキサン、ベンゼン、エチルエーテル、ジクロロメタン、ジメチルホルムアミド、あるいはこれらから選ばれた２種以上の混合溶媒などが利用され得る。また、本反応においてハロゲン化スルホニルを用いた場合の如く、反応の進行に伴い酸が遊離してくる場合には、適当な脱酸剤の存在下に行われるのが好ましいので、ピリジンのような塩基性溶媒の使用は特に好適である。中性溶媒を使用するときは、炭酸アルカリ、有機第３級アミンなどの塩基性物質を添加してもよい。勿論、使用し得る溶媒はここに挙げたものに限定されるものではない。一般に本反応は室温で進行するが、必要に応じて冷却または加熱してもよい。反応時間は通常10分〜20時間であるが、原料化合物の種類、反応温度によって任意に選ばれる。
【００２３】
得られた生成物において、アミノ基または水酸基が保護されている場合には、所望により酸処理、アルカリ処理、接触還元など通常の脱保護法を行うことにより、遊離の水酸基またはアミノ基を有するスルホンアミド誘導体またはスルホン酸エステル誘導体（Ｉ）を得ることが可能である。
２）一般式（IV）
【００２４】
【化５】

【００２５】
（式中、Ａａ環、Ｂａ環、Ｗ、ＸおよびＺは前記と同じ意味を示す）で表わされる化合物をハロゲン化剤と反応させることにより製造することができる。ハロゲン化剤としては、Ｎ−クロロコハク酸イミド、Ｎ−ブロモコハク酸イミド、１，３−ジブロモ−５，５−ジメチルヒダントイン、Ｎ−ブロモアセトアミド、塩素、臭素などを例示することができる。反応に使用する溶媒は特に限定されないが、通常ジクロロメタン、クロロホルム、四塩化炭素等の塩化アルキル化合物やクロロベンゼン、ジクロロベンゼン等の芳香族塩化物等が使用されるが、ジメチルホルムアミド、ジオキサン、ピリジン、アセトニトリル等の水溶性溶媒も使用することができる。反応温度はハロゲン化剤および基質の種類によって異なるが、通常−50℃から 100℃の間で行われる。
【００２６】
得られた生成物において、アミノ基または水酸基が保護されている場合には、所望により酸処理、アルカリ処理、接触還元など通常の脱保護法を行うことにより、遊離の水酸基またはアミノ基を有するスルホンアミド誘導体またはスルホン酸エステル誘導体（Ｉ）を得ることが可能である。
３）一般式（Ｖ）
【００２７】
【化６】

【００２８】
（式中、Ａａ環、Ｂａ環、Ｗ、ＸおよびＺは前記と同じ意味を示し、Ｅは脱水によりシアノ基へ変換可能な置換基を意味する）で表わされる化合物を脱水剤と反応させることにより製造することができる。脱水によりシアノ基へ変換可能な置換基としては、例えば（ヒドロキシイミノ）メチル基、カルバモイル基などを挙げることができる。
【００２９】
また、原料のアルデヒドまたはカルボン酸からまずオキシムまたは酸アミドを合成し、これを単離することなく脱水剤と反応させることも可能である。脱水剤としてはニトリルの合成に一般に用いられる方法、例えば無水酢酸、塩化チオニル、オキシ塩化リン、二酸化セレン、１，３−ジシクロヘキシルカルボジイミドなどを挙げることができる。反応に使用する溶媒は特に限定されないが、原料物質を溶解し、かつこれらと容易に反応しないものが望ましく、例えばピリジン、エチルエーテル、ベンゼン、ジメチルホルムアミド、四塩化炭素、アセトニトリル、テトラヒドロフラン、あるいはこれらから選ばれた２種以上の混合溶媒などが利用され得る。反応温度は脱水剤および基質の種類によって異なるが、通常−50℃から 150℃の間で行われる。
【００３０】
得られた生成物において、アミノ基または水酸基が保護されている場合には、所望により酸処理、アルカリ処理、接触還元など通常の脱保護法を行うことにより、遊離の水酸基またはアミノ基を有するスルホンアミド誘導体またはスルホン酸エステル誘導体（Ｉ）を得ることが可能である。
４）一般式（VI）
【００３１】
【化７】

【００３２】
（式中、Ａｂ環は、還元によりアミノ基へ変換可能な置換基を有し、他に保護されたまたは保護されていない置換基を有していてもよい、単環式または二環式芳香環を意味し、Ｂａ環、Ｃａ環、Ｗ、Ｘ、ＹおよびＺは前記と同じ意味を示す）で表わされる化合物を還元剤と反応させることにより製造することができる。還元によりアミノ基へ変換可能な置換基としてはニトロ基、ニトロソ基、ヒドロキシアミノ基、アゾ基などがある。
【００３３】
還元には、一般に用いられるニトロ基の還元法を使用することができるが、好ましい例としてはパラジウム−炭素、酸化白金等を触媒とした接触還元や亜鉛、鉄またはスズと酸による還元等を挙げることができる。接触還元は通常メタノール、テトラヒドロフラン、ジメチルホルムアミドなどの有機溶媒中、常圧または加圧下で行うことができる。
【００３４】
得られた生成物において、水酸基が保護されている場合には、所望により酸処理、アルカリ処理、接触還元など通常の脱保護法を行うことにより、遊離の水酸基を有するスルホンアミド誘導体またはスルホン酸エステル誘導体（Ｉ）を得ることが可能である。
５）一般式（VII ）
【００３５】
【化８】

【００３６】
（式中、Ａｃ環は、脱離基を環上または置換基中に有し、他に保護されたまたは保護されていない置換基を有していてもよい、単環式または二環式芳香環を意味し、Ｂａ環、Ｃａ環、Ｗ、Ｘ、ＹおよびＺは前記と同じ意味を示す）で表わされる化合物を求核剤と反応させることにより製造することができる。脱離基としては、例えばハロゲン基、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基などを挙げることができる。求核剤としては、例えばアミン類、アルコール類、チオール類などを挙げることができる。アルコール類、チオール類などの場合にはアルカリ金属などとの塩の形で反応させてもよい。反応に使用する溶媒は特に限定されないが、原料物質を溶解し、かつこれらと容易に反応しないものが望ましく、例えば、テトラヒドロフラン、ジオキサン、ジメチルホルムアミド、水などが利用され得る。反応温度は基質の種類によって異なるが、通常−50℃から 150℃の間で行われる。
【００３７】
得られた生成物において、アミノ基または水酸基が保護されている場合には、所望により酸処理、アルカリ処理、接触還元など通常の脱保護法を行うことにより、遊離の水酸基またはアミノ基を有するスルホンアミド誘導体またはスルホン酸エステル誘導体 (I)を得ることが可能である。
【００３８】
次に本発明に用いられる原料化合物（II）およびその反応性誘導体ならびに（III ）を製造する方法について説明する。
原料化合物（II）およびその反応性誘導体には公知化合物および新規化合物が含まれる。新規化合物の場合、既に報告されている公知化合物の合成法を応用することにより、または、それらを組み合わせることにより製造することが可能である。例えば、新規スルホニルクロリドは Chem. Ber., 90, 841 (1957), J. Med. Chem., 6, 307 (1963), J. Chem. Soc.(c), 1968, 1265, Chem. Lett., 1992, 1483, J. Am. Chem. Soc., 59, 1837 (1937), J. Med. Chem., 23, 1376 (1980), J. Am. Chem. Soc., 70, 375 (1948), J. Am. Chem. Soc., 78, 2171 (1956) などに記載されている合成法を応用した方法により製造することができる。
【００３９】
原料化合物（III ）には公知化合物および新規化合物が含まれる。原料化合物（III ）においてＨ−Ｘ−がアミノ基Ｈ_２ Ｎ−を意味する場合には、当該ニトロ化合物を一般的に利用されるニトロ基の還元法で還元することによりＨ_２ Ｎ体（III ）を得ることができる。還元法の好ましい例としてはパラジウム−炭素を触媒とした接触還元や亜鉛末−塩酸による還元などがある。接触還元は通常メタノール、テトラヒドロフラン、ジメチルホルムアミドなどの有機溶媒中常圧または加圧下で行うことができる。
【００４０】
原料化合物（III ）において、Ｈ−Ｘ−が水酸基ＨＯ−を意味する場合には、上記アミノ体をジアゾ化した後、加水分解することによりＨＯ体（III）を得ることができる。
【００４１】
原料化合物が新規化合物の場合、既に報告されている公知化合物の合成法を応用することにより、またはそれらを組み合わせることにより製造することが可能である。新規化合物は Can. J. Chem., 42, 1235 (1964), Chem. Abst., 59, 8855f (1963), Tetrahedron Lett., 30, 2129 (1989)などに記載された方法を応用して、例えば、次に示す経路で製造することが可能である。
反応式１
【００４２】
【化９】

【００４３】
式中、Ｑは同一または異なった置換基を意味し、Ｇはハロゲン基を意味し、ｔは０〜２の整数である。
反応式２
【００４４】
【化１０】

【００４５】
式中、Ｑおよびｔは前記と同じ意味を示す。
反応式３
【００４６】
【化１１】

【００４７】
式中、Ｑ、Ｇおよびｔは前記と同じ意味を示し、ＤＰＰＡはジフェニルホスホリルアジドを意味する。
反応式４
【００４８】
【化１２】

【００４９】
式中、Ｑ、Ｇおよびｔは前記と同じ意味を示し、ＤＤＱは２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノンを意味する。
【００５０】
本発明化合物を医薬として使用する場合は、経口もしくは非経口的に投与される。投与量は、症状の程度、患者の年齢、性別、体重、感受性差、投与方法、投与時期、投与間隔、医薬製剤の性質、調剤、種類、有効成分の種類等によって異なり特に限定されないが、通常成人１日あたり10〜6000mg、好ましくは約50〜4000mg、さらに好ましくは 100〜3000mgでありこれを通常１日１〜３回に分けて投与する。
【００５１】
経口用固形製剤を調製する場合は、主薬に賦形剤さらに必要に応じて結合剤、崩壊剤、滑沢剤、着色剤、矯味矯臭剤などを加えた後、常法により錠剤、被覆錠剤、顆粒剤、細粒剤、散剤、カプセル剤等とする。
賦形剤としては、例えば乳糖、コーンスターチ、白糖、ぶどう糖、ソルビット、結晶セルロース、二酸化ケイ素などが、結合剤としては、例えばポリビニルアルコール、エチルセルロース、メチルセルロース、アラビアゴム、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース等が、滑沢剤としては、例えばステアリン酸マグネシウム、タルク、シリカ等が、着色剤としては医薬品に添加することが許可されているものが、矯味矯臭剤としては、ココア末、ハッカ脳、芳香酸、ハッカ油、龍脳、桂皮末等が用いられる。これらの錠剤、顆粒剤には糖衣、ゼラチン衣、その他必要により適宜コーティングすることは勿論差し支えない。
【００５２】
注射剤を調製する場合には、必要により主薬にpH調整剤、緩衝剤、懸濁化剤、溶解補助剤、安定化剤、等張化剤、保存剤などを添加し、常法により静脈、皮下、筋肉内注射剤とする。その際必要により、常法により凍結乾燥物とすることもある。
懸濁化剤としては、例えばメチルセルロース、ポリソルベート80、ヒドロキシエチルセルロース、アラビアゴム、トラガント末、カルボキシメチルセルロースナトリウム、ポリオキシエチレンソルビタンモノラウレートなどを挙げることができる。
【００５３】
溶解補助剤としては、例えばポリオキシエチレン硬化ヒマシ油、ポリソルベート80、ニコチン酸アミド、ポリオキシエチレンソルビタンモノラウレート、マクロゴール、ヒマシ油脂肪酸エチルエステルなどを挙げることができる。
また安定化剤としては、例えば亜硫酸ナトリウム、メタ亜硫酸ナトリウム等を、保存剤としては、例えばパラオキシ安息香酸メチル、パラオキシ安息香酸エチル、ソルビン酸、フェノール、クレゾール、クロロクレゾールなどを挙げることができる。
【００５４】
【発明の効果】
以下に薬理実験例により本化合物の効果を示す。
薬理実験例１ 血管新生阻害作用
ラット大動脈片をコラーゲン内にて培養した際に観察される新生血管に対する阻害度を血管新生阻害活性とした。すなわち、Sprague-Dawley系雌ラット（１０−１２週齢）より摘出した大動脈をハンクス液で洗浄しながら周辺の脂肪組織を丁寧に除去する。大動脈を切開し２mm角の切片を作成した後、２４ウェルプレート内へ内皮細胞面を上にして静置する。次に、500μlの中性化したタイプIコラーゲン（Cell Matrix Type I-A:新田ゼラチン）を各ウェルへ注ぎ、クリーンベンチ内で室温下約２０分間放置してゲルを固まらせる。ゲルが固まったことを確認した後に500μlのMCDB131培地（クロレラ工業）を加え、CO₂インキュベーター（５％CO₂）で３７℃下培養する。翌日、試験化合物を含む500μlのMCDB131培地と培養液を交換し、培養を続ける。３日後に再び試験化合物を含む500μlのMCDB131培地と交換し、試験化合物添加開始より７日目の時点で大動脈周囲に形成された毛細血管数を顕微鏡下に計測した。試験化合物含有溶液は10μg/mlを最高濃度として３倍希釈系列で調整した。
【００５５】
以下の式より抑制率を算出し、各試験化合物の５０％抑制濃度(IC₅₀値)を求めた。
抑制率（％）＝ (C - T) / C x 100
C:化合物無添加時の毛細血管数
T:化合物添加時の毛細血管数
【００５６】
【表１】

【００５７】
次に、本発明化合物の原料化合物の製造を示す製造例および発明化合物の代表的化合物について実施例を挙げるが、本発明がこれらのみに限定されるものではない。
製造例１
７−ブロモ−１Ｈ−インドール
２−ブロモニトロベンゼン5.05ｇ（25ミリモル）のテトラヒドロフラン溶液（ 250ml）に窒素雰囲気下−40℃でビニルマグネシウムブロミド 1.0Ｍテトラヒドロフラン溶液 100ml（ 100ミリモル）を加え、そのまま40分間撹拌した。反応混合物を飽和塩化アンモニウム水溶液 500ml中に注ぎ、エチルエーテルで抽出した。硫酸マグネシウムで乾燥、濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物2.89ｇを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.56(1H, dd, J=2.9, 1.8Hz), 6.94(1H, t, J=7.8Hz), 7.30(1H, d, J=7.8Hz), 7.40(1H, t, J=2.9Hz), 7.56(1H, d, J=7.8Hz), 11.16-11.46(1H, br m)
【００５８】
製造例２
７−アミノ−１Ｈ−インドール
製造例１の化合物2.70ｇ（13.8ミリモル）のテトラヒドロフラン溶液（50ml）に窒素雰囲気下−70℃でｎ−ブチルリチウム 2.5Ｍヘキサン溶液16.5ml（41.3ミリモル）を滴下し、−70℃で15分間、ついで−20〜−10℃で30分間撹拌した。−70℃に再び冷却後、ジフェニルホスホリルアジド 3.9ml（18ミリモル）を滴下し、−70℃で１時間、ついで−40℃で１時間撹拌した。ナトリウム ビス（２−メトキシエトキシ）アルミニウム ハイドライド 3.4Ｍトルエン溶液22.3ml（75.8ミリモル）を−40℃で加えた後、−30〜−20℃で30分間、ついで室温で30分間撹拌した。pH 7.0リン酸緩衝液を加え、不溶物を濾取し、濾液をエチルエーテルで抽出した。有機層を飽和重曹水、飽和食塩水で順次洗浄し、硫酸マグネシウムで乾燥した。濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物1.29ｇを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 5.01(2H, br s), 6.25-6.33(2H, m), 6.70(1H, dd, J=7.9, 7.3Hz), 6.78(1H, dd, J=7.9, 0.7Hz), 7.23(1H, t, J=2.7Hz), 10.48-10.72(1H, br m)
製造例１および２と同様にして、２−ブロモニトロベンゼン誘導体から以下の原料化合物を合成した。
【００５９】
７−アミノ−４−メトキシ−１Ｈ−インドール
７−アミノ−４−ブロモ−１Ｈ−インドール
【００６０】
製造例３
７−ブロモ−３−クロロ−４−メチル−１Ｈ−インドール
２−ブロモ−５−メチルニトロベンゼンから製造例１と同様にして合成した７−ブロモ−４−メチル−１Ｈ−インドール 5.8ｇ（27.6ミリモル）のアセトニトリル溶液（ 250ml）にＮ−クロロコハク酸イミド 4.0ｇ（30.0ミリモル）を加え室温で一晩撹拌した。１Ｎ水酸化ナトリウム水溶液50mlを加え、酢酸エチルで抽出した。有機層を水洗、硫酸マグネシウムで乾燥、濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物 6.7ｇを得た。
^１H-NMR(CDCl₃) δ(ppm) : 2.74(3H, s), 6.75-7.26(3H, m), 8.23(1H, br s)
【００６１】
製造例４
７−アミノ−３−クロロ−４−メチル−１Ｈ−インドール
製造例３の化合物6.37ｇ（26.1ミリモル）から製造例２と同様にして表題化合物 2.6ｇを得た。
^１H-NMR(CDCl₃) δ(ppm) : 2.70(3H, s), 6.39-7.14(3H, m), 8.15(1H, br s)
【００６２】
製造例５
４−スルファモイルベンゼンスルホニルクロリド
４−アミノベンゼンスルホンアミド 6.4ｇ（37.2ミリモル）を水12.5mlと濃塩酸 6.3mlの混液に加え撹拌した。これに亜硝酸ナトリウム2.56ｇ（37.1ミリモル）の飽和水溶液を０℃以下で滴下した。反応液を二酸化イオウ飽和酢酸液（二酸化イオウを酢酸35mlに飽和させ、塩化第二銅・２水和物 1.5ｇを加えた液）に氷冷、撹拌下加えた。10分後反応液を氷水に注ぎ、沈澱を濾取、水洗した。沈澱をテトラヒドロフランに溶解し、硫酸マグネシウムで乾燥後、濃縮乾固し、表題化合物 3.5ｇを得た。
【００６３】
製造例６
４−（スルファモイルメチル）ベンゼンスルホニルクロリド
４−ニトロフェニルメタンスルホンアミド 5.0ｇ（23.1ミリモル）を90％酢酸に懸濁し、パラジウム−炭素存在下常温常圧で水素添加した。触媒を濾去後濃縮乾固し、４−アミノフェニルメタンスルホンアミド 4.3ｇを得た。これを水40mlと濃塩酸 4.1mlの混液に加え、撹拌した。０℃以下で亜硝酸ナトリウム1.63ｇ（23.6ミリモル）の飽和水溶液を滴下した。反応液を二酸化イオウ飽和酢酸液（二酸化イオウを酢酸30mlに飽和させ、塩化第二銅・２水和物0.97ｇを加えた液）に氷冷、撹拌下加えた。室温で40分撹拌後反応液を氷水中に注ぎ、食塩を飽和させた。酢酸エチルで抽出し、硫酸マグネシウムで乾燥後、濃縮乾固し、表題化合物 1.7ｇを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 4.26(2H, s), 7.32(2H, d, J=8.4Hz), 7.59(2H, d, J=8.4Hz)
製造例５または６と同様にして以下の化合物を合成した。
【００６４】
４−（Ｎ−メチルスルファモイル）ベンゼンスルホニルクロリド
４−（Ｎ−エチルスルファモイル）ベンゼンスルホニルクロリド
４−（Ｎ−メトキシスルファモイル）ベンゼンスルホニルクロリド
４−［（メタンスルホンアミド）メチル］ベンゼンスルホニルクロリド
４−（Ｎ−メチルメタンスルホンアミド）ベンゼンスルホニルクロリド
４−（１−ピロリジニルスルホニル）ベンゼンスルホニルクロリド
４−（１−ピロリジニルカルボニル）ベンゼンスルホニルクロリド
３−シアノベンゼンスルホニルクロリド
４−（メチルスルホニル）ベンゼンスルホニルクロリド
４−［（Ｎ−メチルメタンスルホンアミド）メチル］ベンゼンスルホニルクロリド
【００６５】
製造例７
３−シアノ−７−ニトロ−１Ｈ−インドール
３−ホルミル−７−ニトロ−１Ｈ−インドール 10.15ｇ（53.4ミリモル）をジメチルホルムアミド 150mlに溶解し、ヒドロキシルアミン塩酸塩3.93ｇ（56.0ミリモル）とピリジン 4.5ml（55.6ミリモル）を加えた。70−80℃で２時間加熱撹拌後、二酸化セレン 6.3ｇ（56.8ミリモル）と硫酸マグネシウム約５ｇを加えた。70−80℃でさらに 2.5時間加熱後、不溶物を濾去し、濃縮した。水を加えて析出した結晶を濾取し、水、エチルエーテルで順次洗浄した。結晶をテトラヒドロフランとアセトンの混液に溶解し、不溶物を濾去した。濃縮後、酢酸エチルを加え結晶を濾取し、表題化合物8.61ｇを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 7.48(1H, t, J=8.1Hz), 8.17(1H, d, J=8.1Hz), 8.27(1H, d, J=8.1Hz), 8.47(1H, s), 12.70-13.00(1H, br)
【００６６】
製造例８
７−アミノ−３−シアノ−１Ｈ−インドール
製造例７の化合物2.80ｇ（15.0ミリモル）をメタノール 100mlに懸濁し、パラジウム−炭素存在下常温常圧で水素添加した。触媒を濾別後、濃縮乾固し、表題化合物2.31ｇを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 5.32, 5.34(2H, s+s), 6.47(1H, d, J=7.5Hz), 6.81(1H, d, J=7.9Hz), 6.94(1H, dd, J=7.9, 7.5Hz), 8.13(1H, s), 11.55-11.90(1H, br),
【００６７】
製造例９
７−アミノ−３，４−ジクロロ−１Ｈ−インドール
２−ブロモ−５−クロロニトロベンゼンから製造例１と同様にして得られた７−ブロモ−４−クロロ−１Ｈ−インドールを製造例３と同様にしてまず塩素化し、ついで製造例２と同様にしてブロモ基をアミノ基へ変換することにより表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 5.26(2H, s), 6.29(1H, d, J=8.1Hz), 6.74(1H, d, J=8.1Hz), 7.45-7.51(1H, m), 11.08-11.27(1H, m)
同様にして、７−アミノ−４−ｔｅｒｔ−ブチルジメチルシリルオキシ−３−クロロ−１Ｈ−インドールを合成した。
【００６８】
製造例１０
７−アミノ−３−クロロ−１Ｈ−インドール
７−ニトロ−１Ｈ−インドール 1.076g （6.64ミリモル）をアセトニトリル 30ml に溶解し、Ｎ−クロロコハク酸イミド920mg （6.89ミリモル）を加えた。室温で36時間撹拌後、飽和重曹水を加え、沈殿を濾取、水洗し、３−クロロ−７−ニトロ−１Ｈ−インドール1.2gを得た。この粉末863mg （4.39ミリモル）をエタノール10mlに懸濁し、塩化第一スズ・２水和物4.95g （21.9ミリモル）と濃塩酸100 μl を加えた。30分間加熱還流後、飽和重曹水を加え、不溶物を濾去した。酢酸エチルを加えて抽出後、硫酸マグネシウムで乾燥、濃縮、シリカゲルカラムクロマトグラフィーで精製し、表題化合物490mg を得た。
【００６９】
表題化合物は３−クロロ−７−ニトロ−１Ｈ−インド−ルを白金−炭素触媒存在下常温常圧で水素添加しても得られた。
^１H-NMR(DMSO-d₆) δ(ppm) : 5.14(2H, s), 6.36(1H, dd, J=7.5, 1.0Hz), 6.68(1H, dd, J=7.9, 0.73Hz), 6.81(1H, dd, J=7.9, 7.5Hz), 7.39(1H, d, J=2.7Hz), 10.85(1H, br s)
【００７０】
製造例１１
４−（２−スルファモイルエチル）ベンゼンスルホニルクロリド
クロロスルホン酸 2.4ｇ（36.5ミリモル）に、氷冷下２−フェニルエタンスルホンアミド 1.3ｇ（7.3 ミリモル）を20分かけて加え、室温でさらに90分撹拌した。反応混合液を氷水に注ぎ、酢酸エチルで抽出し、飽和重曹水、飽和食塩水で順次洗浄後、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、表題化合物 1.6ｇを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.97-3.02(2H, m), 3.21-3.26(2H, m), 7.21(2H, d, J=8.4Hz), 7.53(2H, d, J=8.4Hz)
同様にして以下の原料化合物を合成した。
【００７１】
４−［２−（メチルスルホニル）エチル］ベンゼンスルホニルクロリド
４−［２−（Ｎ−メチルメタンスルホンアミド）エチル］ベンゼンスルホニルクロリド
４−［２−（メタンスルホンアミド）エチル］ベンゼンスルホニルクロリド
４−（Ｎ−メチルアセトアミド）ベンゼンスルホニルクロリド
【００７２】
製造例１２
５−ブロモ−７−ニトロ−１Ｈ−インドール
１−アセチル−５−ブロモ−７−ニトロインドリン5.05ｇ（17.7ミリモル）をエタノール６mlと６Ｎ塩酸40mlの混液に加え、３時間加熱還流した。炭酸ナトリウムを加えて中和後、酢酸エチルで抽出し、水洗、硫酸マグネシウムで乾燥した。濃縮後、シリカゲルカラムクロマトグラフィーで精製し、５−ブロモ−７−ニトロインドリン4.13ｇを得た。この化合物 301mg（1.24ミリモル）をトルエン10mlに加え、次に２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノン 580mg（2.55ミリモル）を加えた。撹拌しながら 3.5時間加熱還流後、不溶物を濾去し、濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物 252mgを得た。
【００７３】
製造例１３
５−ブロモ−３−ホルミル−７−ニトロ−１Ｈ−インドール
ジメチルホルムアミド 1.0ｇ（14ミリモル）に窒素雰囲気下０℃でオキシ塩化リン 210mg（ 1.4ミリモル）を加え、30分間撹拌した。製造例１２の化合物 240mg（ 1.0ミリモル）を０℃で加え、０℃で20分間、ついで 100℃で30分間撹拌した。反応混合液を氷冷後氷水に注ぎ、１Ｎ水酸化ナトリウム水溶液を加えpH７−８に保ちながら30分間撹拌した。生じた沈澱を濾取、水洗後、シリカゲルカラムクロマトグラフィーで精製し、表題化合物 239mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 8.31(1H, d, J=1.8Hz), 8.55(1H, s), 8.65(1H, d, J=1.8Hz), 10.05(1H, s), 12.89(1H, br s)
【００７４】
製造例１４
７−アミノ−５−ブロモ−３−シアノ−１Ｈ−インドール
製造例１３の化合物から製造例７と同様にして得られた５−ブロモ−３−シアノ−７−ニトロ−１Ｈ−インドール 214mg（ 0.8ミリモル）をメタノール10mlとテトラヒドロフラン10mlの混液に溶解した。酸化白金の存在下、3.0kg ／cm^２ で水素添加後、触媒を濾去、濃縮乾固し、表題化合物 189mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 5.68-5.71(2H, m), 6.60(1H, d, J=2.0Hz), 6.91(1H, d, J=2.0Hz), 8.16(1H, s)
【００７５】
製造例１５
３−アセチル−７−アミノ−１Ｈ−インドール
窒素雰囲気下、７−ニトロ−１Ｈ−インドール 1.2ｇ（ 7.5ミリモル）のジクロロメタン溶液(50ml)に０℃でジメチルアルミニウムクロリド 1.0Ｍヘキサン溶液11ml（11ミリモル）を加えた。ついで、０℃で塩化アセチル 2.1ml（29.5ミリモル）を加え、室温で４時間撹拌した。反応系に飽和塩化アンモニウム水を加え、生じた沈澱を濾取した。この沈澱を熱エタノールで十分に洗浄し、洗液を濾液と合わせ、濃縮した。残渣に水を加え、酢酸エチルで抽出、飽和食塩水で洗浄、硫酸マグネシウムで乾燥した。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ーで精製し、３−アセチル−７−ニトロ−１Ｈ−インドールを得た。これをメタノール 100mlに溶解し、パラジウム−炭素存在下、常温常圧で水素添加した。触媒を濾去後濃縮乾固し、表題化合物 790mgを得た。
【００７６】
合成例１
Ｎ−（１Ｈ−インドール−７−イル）−４−ニトロベンゼンスルホンアミド
製造例２の化合物1.50ｇ（11.3ミリモル）をピリジン40mlに溶解し、室温撹拌下４−ニトロベンゼンスルホニルクロリド2.57ｇ（11.6ミリモル）を加えた。室温で一晩撹拌後、溶媒を減圧留去し、残渣に酢酸エチルと 0.2Ｎ塩酸を加えた。有機層を分取、水洗、硫酸マグネシウムで乾燥後、溶媒を減圧留去し、残渣をシリカゲルカラムクトマトグラフィーで精製し、表題化合物3.50ｇを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.42(1H, dd, J=2.8, 2.0Hz), 6.66(1H, d, J=7.6Hz), 6.83(1H, dd, J=8.0, 7.6Hz), 7.31(1H, dd, J=3.2, 2.8Hz), 7.36(1H, d, J=8.0Hz), 7.94-8.02(2H, m), 8.30-8.38(2H, m), 10.23(1H, s), 10.74-10.87(1H, m)
【００７７】
合成例２
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−ニトロベンゼンスルホンアミド
合成例１の化合物8.98ｇ（28.3ミリモル）をジクロロメタン 280mlとジメチルホルムアミド７mlの混合溶媒に溶解し、窒素雰囲気下撹拌しながらＮ−クロロコハク酸イミド4.16ｇ（31.2ミリモル) を加えた。室温で 1.5時間撹拌後、水50mlを加え液量が約80mlになるまで濃縮した。酢酸エチルと 0.2Ｎ塩酸を加えて有機層を分取し、飽和重曹水、飽和食塩水で順次洗浄した。硫酸マグネシウムで乾燥後、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ーで精製し、表題化合物7.98ｇを得た。
融点：199.5-200.5 ℃ (クロロホルムから再結晶)
^１H-NMR(DMSO-d₆) δ(ppm) : 6.72(1H, d, J=7.6Hz), 6.96(1H, dd, J=8.0, 7.6Hz), 7.31(1H, d, J=8.0Hz), 7.47-7.53(1H, m), 7.92-8.02(2H, m), 8.30-8.41(2H, m), 10.33(1H, s), 11.07-11.22(1H, m)
【００７８】
合成例３
４−アミノ−Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
合成例２の化合物7.98ｇ（22.7ミリモル）をメタノール 220mlに溶解し、撹拌しながら加熱還流した。これに10分間隔で濃塩酸10mlと亜鉛末7.40ｇを３回加え、さらに10分間還流した。冷却後、大過剰の重曹を加えて中和し、不溶物を濾取した。濾液を濃縮後、残渣を酢酸エチルに溶解し、飽和重曹水、２Ｎ炭酸ナトリウム水溶液、飽和食塩水で順次洗浄した。硫酸マグネシウムで乾燥後、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ーで精製し、表題化合物7.21ｇを得た。
融点：174.5-176 ℃（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 5.97(2H, br s), 6.48(2H, d, J=8.8Hz), 6.88(1H, d, J=7.6Hz), 6.95(1H, dd, J=8.0, 7.6Hz), 7.19(1H, d, J=8.0Hz), 7.36(2H, d, J=8.8Hz), 7.46(1H, d, J=2.4Hz), 9.56(1H, s), 10.86-10.98(1H, m)
【００７９】
合成例４
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（メタンスルホンアミド）ベンゼンスルホンアミド
合成例３の化合物68mg（ 0.211ミリモル）をピリジン１mlに溶解し、メタンスルホニルクロリド15μl （ 0.194ミリモル）を加えた。室温で一晩撹拌後、重曹水を加え、酢酸エチルで抽出した。有機層を希塩酸、水で順次洗浄後、硫酸マグネシウムで乾燥した。濃縮後、残渣をシリカゲル薄層クロマトグラフィーで精製し、表題化合物76mgを得た。
融点：213.5-214 ℃（分解）（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 3.08(3H, s), 6.83(1H, d, J=7.5Hz), 6.96(1H, dd, J=7.9, 7.7Hz), 7.23(2H, d, J=8.8Hz), 7.24(1H, d, J=7.5Hz), 7.47(1H, d, J=2.7Hz), 7.68(2H, d, J=8.8Hz), 9.92(1H, br s), 10.38(1H, br s), 10.99(1H, br s)
【００８０】
合成例５
４−ブロモメチル−Ｎ−（１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
４−ブロモメチルベンゼンスルホニルクロリドと製造例２の化合物を等モルのピリジン存在下テトラヒドロフラン中室温で反応させ、合成例１と同様に処理して表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 4.70(2H, s), 6.40(1H, dd, J=3.1, 1.1Hz), 6.71(1H, ddd, J=7.4, 3.2, 0.92Hz), 6.81(1H, ddd, J=8.1, 7.4, 0.92Hz), 7.29-7.32(2H, m), 7.57(2H, d, J=8.2Hz), 7.73(2H, d, J=8.4Hz), 9.96(1H, br s), 10.75(1H, br s)
【００８１】
合成例６
Ｎ−（１，３−ジヒドロ−２Ｈ−インドール−２−オン−７−イル）−４−メチルベンゼンスルホンアミド
合成例１と同様にして表題化合物を得た。
融点：246 ℃付近から徐々に分解し始め、267-269 ℃で急速に分解（ジオキサンから再結晶）
【００８２】
合成例７
３−クロロ−Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
合成例１と同様にして合成した３−クロロ−Ｎ−（１Ｈ−インドール−７−イル）ベンゼンスルホンアミド2.18ｇ（7.11ミリモル）を実施例２と同様にして塩素化し、表題化合物1.86ｇを得た。
融点：180-181 ℃（ジクロロメタン−ジイソプロピルエーテルから再結晶）
^１H-NMR(DMSO-d_６) δ(ppm) : 6.73(1H, d, J=7.6Hz), 6.97(1H, dd, J=8.0, 7.6Hz), 7.30(1H, d, J=8.0Hz), 7.45-7.51(1H, m), 7.51-7.76(4H, m), 10.09(1H, s), 11.02-11.18(1H, m)
【００８３】
合成例８
４−アミノ−Ｎ−（３，４−ジクロロ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
合成例１と同様にして合成したＮ−（３，４−ジクロロ−１Ｈ−インドール−７−イル）−４−ニトロベンゼンスルホンアミド2.43ｇ（6.29ミリモル）から実施例３と同様にして表題化合物2.03ｇを得た。
融点：205-206.5 ℃（分解）（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 6.00(2H, s), 6.50(2H, d, J=8.4Hz), 6.77(1H, d, J=8.0Hz), 6.94(1H, d, J=8.0Hz), 7.35(2H, d, J=8.4Hz), 7.51-7.58(1H, m), 9.57(1H, s), 11.20-11.38(1H, m)
【００８４】
合成例９
４−［Ｎ−（１Ｈ−インドール−７−イル）スルファモイル］安息香酸
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d_６) δ(ppm) : 6.40(1H, dd, J=2.9, 1.9Hz), 6.67(1H, d, J=7.5Hz), 6.82(1H, dd, J=7.9, 7.5Hz), 7.31(1H, dd, J=2.9, 2.7Hz), 7.33(1H, d, J=7.9Hz), 7.81-7.88(2H, m), 7.99-8.07(2H, m), 10.07(1H, s), 10.73-10.83(1H, m), 13.30-13.58(1H, br)
【００８５】
合成例１０
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−シアノベンゼンスルホンアミド
合成例１と同様にして合成した４−シアノ−Ｎ−（１Ｈ−インドール−７−イル）ベンゼンスルホンアミド 100mgから実施例２と同様にして表題化合物76mgを得た。
融点：210-211 ℃（酢酸エチル−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 6.71(1H, dd, J=7.6, 0.8Hz), 6.96(1H, dd, J=8.0, 7.6Hz), 7.30(1H, d, J=8.0Hz), 7.48(1H, dd, J=2.4, 0.8Hz), 7.82-7.90(2H, m), 7.97-8.05(2H, m), 10.25(1H, s), 11.04-11.15(1H, m)
【００８６】
合成例１１
３−クロロ−Ｎ−（３−クロロ−４−メトキシ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
合成例１と同様にして合成した３−クロロ−Ｎ−（４−メトキシ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド 100mgから実施例２と同様にして表題化合物52mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 3.79(3H, s), 6.37(1H, d, J=8.4Hz), 6.45(1H, d, J=8.4Hz), 7.24-7.31(1H, m), 7.48-7.77(4H, m), 9.76(1H, s), 11.06-11.17(1H, m)
【００８７】
合成例１２
３−クロロ−Ｎ−（３−クロロ−４−ヒドロキシ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
合成例１と同様にして合成したＮ−（４−ｔｅｒｔ−ブチルジメチルシリルオキシ−３−クロロ−１Ｈ−インドール−７−イル）−３−クロロベンゼンスルホンアミド 220mg（0.47ミリモル）を40％フッ化水素水溶液−アセトニトリル（１：10）混液（２ml）に加えた。室温で一晩撹拌後、水を加えて酢酸エチルで抽出し、硫酸マグネシウムで乾燥した。濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物 141mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.15(1H, dd, J=8.2, 1.5Hz), 6.26(1H, d, J=8.2Hz), 7.12(1H, s), 7.47-7.64(4H, m), 9.54(1H, s), 10.85(1H, s)
【００８８】
合成例１３
Ｎ−（１Ｈ−インダゾール−７−イル）−４−メトキシベンゼンスルホンアミド
合成例１と同様にして表題化合物を得た。
融点：155-156 ℃（酢酸エチル−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 3.77(3H, s), 6.91-6.99(2H, m), 6.98-7.07(2H, m), 7.45-7.53(1H, m), 7.64-7.74(2H, m), 8.01-8.07(1H, m), 9.97(1H, s), 12.61-12.72(1H, m)
【００８９】
合成例１４
６−クロロ−Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−３−ピリジンスルホンアミド
６−クロロ−３−ピリジンスルホニルクロリドと製造例２の化合物を実施例１と同様に反応させて得られた６−クロロ−Ｎ−（１Ｈ−インドール−７−イル）−３−ピリジンスルホンアミドを実施例２と同様にして塩素化し、表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.73(1H, d, J=7.7Hz), 6.97(1H, dd, J=7.9, 7.7Hz), 7.30(1H, d, J=7.9Hz), 7.46(1H, d, J=2.6Hz), 7.67(1H, d, J=8.4Hz), 8.03(1H, dd, J=8.4, 2.6Hz), 8.62(1H, d, J=2.6Hz), 10.18-10.34(1H, br), 11.06-11.17(1H, m)
【００９０】
合成例１５
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（メチルチオメチル）ベンゼンスルホンアミド
合成例５の化合物1.97ｇ（5.37ミリモル）をテトラヒドロフラン10mlに溶解し、室温で15％ナトリウムメチルチオラート水溶液10ml（39.4ミリモル）と触媒量のメチルトリオクチルアンモニウムクロリドを加え一晩撹拌した。水20mlを加え、酢酸エチルで抽出し、有機層を水洗、硫酸マグネシウムで乾燥した。濃縮後、シリカゲルカラムクロマトグラフィーで精製し、Ｎ−（１Ｈ−インドール−７−イル）−４−（メチルチオメチル）ベンゼンスルホンアミド1.51ｇを得た。これを実施例２と同様にして塩素化し、表題化合物 839mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 1.87(3H, s), 3.70(2H, s), 6.77(1H, dd, J=7.6, 2.1Hz), 6.94(1H, dd, J=7.9, 7.7Hz), 7.24(1H, d, J=7.9Hz), 7.42(2H, d, J=8.2Hz), 7.47(1H, d, J=2.6Hz), 7.67(2H, d, J=8.4Hz), 9.96(1H, br s), 11.01(1H, br s)
【００９１】
合成例１６
３−クロロ−Ｎ−（３−ホルミル−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
ジメチルホルムアミド14.5ml中に窒素雰囲気下撹拌しながらオキシ塩化リン 1.3ml(13.9 ミリモル）を10℃以下で滴下した。約５℃で30分間撹拌後、実施例１と同様にして合成した３−クロロ−Ｎ−（１Ｈ−インドール−７−イル）ベンゼンスルホンアミド2.50ｇ（8.15ミリモル）を３回に分けて加えた。約５℃でさらに30分間撹拌後、冷水 200mlを加えた。１Ｎ水酸化ナトリウム水溶液を加えて、反応混合物のpHを約14にし、ついで１Ｎ塩酸でpHを約２にした。酢酸エチルを加えて抽出し、有機層を飽和食塩水で洗浄した。硫酸マグネシウムで乾燥、濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物1.45ｇを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.70(1H, dd, J=7.6, 0.8Hz), 7.06(1H, dd, J=8.0, 7.6Hz), 7.51-7.75(4H, m), 7.93(1H, d, J=8.0Hz), 8.22-8.28(1H, m), 9.93(1H, s), 10.17(1H, s), 11.86-11.98(1H, m)
【００９２】
合成例１７
３−クロロ−Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
合成例１６の化合物1.20ｇ（3.58ミリモル）のジメチルホルムアミド溶液（18ml) に撹拌下70〜80℃でヒドロキシルアミン塩酸塩 274mg（3.94ミリモル）とピリジン0.32ml（3.96ミリモル）を加えた。そのまま 2.5時間撹拌した後、二酸化セレン 437mg（3.94ミリモル）と硫酸マグネシウム粉末約 100mgを加えた。さらに２時間同温で撹拌した後、溶媒を減圧留去し、残渣に酢酸エチルを加えて不溶物を濾取した。濾液を 0.1Ｎ塩酸、飽和食塩水で順次洗浄後、硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物 678mgを得た。
融点：204.5-205 ℃（酢酸エチル−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 6.71(1H, d, J=7.6Hz), 7.08(1H, dd, J=8.0, 7.6Hz), 7.47(1H, d, J=8.0Hz), 7.50-7.76(4H, m), 8.17-8.25(1H, m), 10.21(1H, s), 11.92-12.09(1H, m)
【００９３】
合成例１８
６−クロロ−Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）−３−ピリジンスルホンアミド
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.77(1H, d, J=7.9Hz), 7.12(1H, t, J=7.9Hz), 7.50(1H, d, J=7.9Hz), 7.72(1H, d, J=8.4Hz), 8.06(1H, dd, J=8.4, 2.6Hz), 8.23(1H, d, J=2.6Hz), 8.65(1H, d, J=2.6Hz), 10.34-10.48(1H, br), 11.98-12.12(1H, m)
【００９４】
合成例１９
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−スルファモイルベンゼンスルホンアミド
製造例５の化合物 767mg（3.0 ミリモル）と製造例２の化合物 264mg（2.0 ミリモル）を実施例１と同様に反応させ、処理し、Ｎ−（１Ｈ−インドール−７−イル）−４−スルファモイルベンゼンスルホンアミド 445mgを得た。これを実施例２と同様にして塩素化し、表題化合物 349mgを得た。
融点：220 ℃付近から部分的に黒く着色し始め、240 ℃付近より徐々に分解（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 6.75(1H, d, J=7.6Hz), 6.96(1H, dd, J=8.0, 7.6Hz), 7.29(1H, d, J=7.6Hz), 7.50(1H, d, J=2.8Hz), 7.58(2H, s), 7.90-7.98(4H, m), 10.23(1H, s), 11.07-11.17(1H, m)
【００９５】
合成例２０
３−クロロ−Ｎ−（８−イミダゾ［１，２−ａ］ピリジニル）ベンゼンスルホンアミド塩酸塩
２，３−ジアミノピリジン1.97ｇ（18ミリモル）をテトラヒドロフランと水の混液に溶解し、３−クロロベンゼンスルホニルクロリド1.90ｇ（9.0 ミリモル）のテトラヒドロフラン溶液を加えた。室温で一晩撹拌後、濃縮し、水とジクロロメタンを加えた。有機層を分取し、器壁をこすり、析出した結晶を濾取し、Ｎ−（２−アミノ−３−ピリジニル）−３−クロロベンゼンスルホンアミド1.41ｇを得た。この結晶 530mg（1.87ミリモル）をメタノールに溶解し、40％クロロアセトアルデヒド水溶液 367mg（1.87ミリモル）を加えた。４時間加熱還流後、濃縮乾固し、残渣にメタノール少量を加え、結晶を濾取し、表題化合物 373mgを得た。
融点：210 ℃付近より徐々に分解（エタノールから再結晶）
【００９６】
合成例２１
Ｎ−（３，４−ジクロロ−１Ｈ−インドール−７−イル）−４−スルファモイルベンゼンスルホンアミド
製造例５の化合物 429mg（1.68ミリモル）と製造例９の化合物 250mg（1.24ミリモル）を実施例１と同様に反応させ、処理し、表題化合物 200mgを得た。
融点： 282℃付近より着色し始め、徐々に分解（エタノール−エチルエーテルから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 6.62(1H, d, J=8.1Hz), 6.95(1H, d, J=8.1Hz), 7.53-7.62(3H, m), 7.87-7.99(4H, m), 10.17-10.33(1H, br), 11.44-11.56(1H, m)
【００９７】
合成例２２
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（メチルチオ）ベンゼンスルホンアミド
合成例１および２と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.48(3H, s), 6.82(1H, dd, J=7.9, 1.5Hz), 6.96(1H, dd, J=8.1, 7.5Hz), 7.25(1H, dd, J=7.9, 0.92Hz), 7.33(2H, d, J=8.8Hz), 7.49(1H, d, J=2.7Hz), 7.62(2H, d, J=8.6Hz), 9.96(1H, br s), 11.02(1H, br s)
【００９８】
合成例２３
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（メチルスルホニル）ベンゼンスルホンアミド
合成例２２の化合物54.2mg（0.154 ミリモル）をメタノール２mlと水 1.2mlの混液に溶解し、室温でモリブデン酸アンモニウム・４水和物30mgと30％過酸化水素水 0.6mlを加えた。一晩撹拌後、水を加え、酢酸エチルで抽出、水洗、硫酸マグネシウムで乾燥した。濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物29.4mgを得た。
融点： 250℃付近より着色し始め、 264-266℃で分解（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 3.28(3H, s), 6.75(1H, d, J=7.7Hz), 6.97(1H, dd, J=7.9, 7.7Hz), 7.30(1H, d, J=8.1Hz), 7.50(1H, d, J=2.7Hz), 7.97(2H, d, J=8.2Hz), 8.09(2H, d, J=8.4Hz), 10.29(1H, br s), 11.12(1H, br s)
【００９９】
合成例２４
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（メチルスルフィニル）ベンゼンスルホンアミド
合成例２２の化合物19.9mg（0.056 ミリモル）をジクロロメタン２mlに溶解し、氷冷下撹拌しながらｍ−クロロ過安息香酸10mg（0.058 ミリモル）を加えた。１時間後、飽和重曹水を加え、酢酸エチルで抽出、水洗、硫酸マグネシウムで乾燥した。濃縮後、シリカゲル薄層クロマトグラフィーで精製し、表題化合物14.4mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.76(3H, s), 6.78(1H, dd, J=7.5, 1.1Hz), 6.96(1H, dt, Jd=0.55Hz, Jt=7.8Hz), 7.28(1H, dd, J=7.6, 0.82Hz), 7.48(1H, d, J=2.7Hz), 7.82(2H, d, J=8.6Hz), 7.89(2H, d, J=8.8Hz), 10.15(1H, br s), 11.06(1H, br s)
【０１００】
合成例２５
３−クロロ−Ｎ−（３−クロロ−１Ｈ−ピロロ［３，２−ｃ］ピリジン−７−イル）ベンゼンスルホンアミド
合成例１および２と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 7.41-7.65(2H, m), 7.65-7.77(2H, m), 7.74-7.86(2H, m), 8.40-8.62(1H, br m), 12.38-12.58(1H, br), 13.56-13.74(1H, br)
【０１０１】
合成例２６
４−アセトアミド−Ｎ−（３−クロロ−４−メチル−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
合成例１と同様にして表題化合物を得た。
融点：225 ℃付近から徐々に分解（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 2.03(3H, s), 2.56(3H, s), 6.54-6.60(2H, m), 7.33(1H, d, J=2.6Hz), 7.60(2H, d, J=9.0Hz), 7.64(2H, d, J=9.0Hz), 9.63(1H,br s), 10.24(1H, br s), 10.92(1H, br s)
【０１０２】
合成例２７
４−アミノ−Ｎ−（３−クロロ−４−メチル−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
合成例２６の化合物3.75ｇ（9.9 ミリモル）を２Ｎ水酸化ナトリウム水溶液25mlに溶解し、100 ℃で２時間撹拌した。室温にもどした後、酢酸を加えてpH６にし、生じた沈澱を濾取、シリカゲルカラムクロマトグラフィーで精製し、表題化合物 1.1ｇを得た。
融点：230 ℃付近から徐々に分解（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 2.56(3H, s), 5.93(2H, br s), 6.46(2H, d, J=8.8Hz), 6.59(1H, d, J=7.8Hz), 6.64(1H, d, J=7.8Hz), 7.31(2H, d, J=8.8Hz), 7.36(1H, d, J=2.9Hz), 9.34(1H, br s), 10.88(1H, br s)
【０１０３】
合成例２８
４−シアノ−Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
合成例１と同様にして表題化合物を得た。
融点：250.5-252 ℃（酢酸エチル−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 6.67(1H, d, J=7.7Hz), 7.05(1H, t, J=7.9Hz), 7.44(1H, d, J=7.7Hz), 7.78-7.87(2H, m), 7.97-8.05(2H, m), 8.16-8.23(1H, m), 10.28-10.43(1H, br), 11.92-12.09(1H, m)
【０１０４】
合成例２９
４−カルバモイル−Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
合成例１０の化合物 1.0ｇ（3.01ミリモル）をエタノール4.8ml に加えた液に撹拌しながら30％過酸化水素水 2.4mlと６Ｎ水酸化ナトリウム水溶液 360μl を各々３回に分けて加えた（反応温度約50℃）。50℃でさらに30分間撹拌後、希塩酸を加えて酸性にし、酢酸エチルで抽出した。有機層を分取、水洗、硫酸マグネシウムで乾燥後、濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物 600mgを得た。
融点：248 ℃付近から着色、分解し始め、252.5-253.5 ℃で急速に分解（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 6.76(1H, d, J=7.5Hz), 6.95(1H, dd, J=8.1, 7.5Hz), 7.27(1H, d, J=8.1Hz), 7.49(1H, d, J=2.6Hz), 7.59(1H, br s), 7.76-7.83(2H, m), 7.91-7.98(2H, m), 8.12(1H, br s), 10.10(1H, s), 11.01-11.12(1H, m)
【０１０５】
合成例３０
Ｎ−（４−ブロモ−１Ｈ−インドール−７−イル）−４−ニトロベンゼンスルホンアミド
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.35-6.41(1H, m), 6.56(1H, d, J=8.4Hz), 7.06(1H, dd, J=8.4, 0.8Hz), 7.41-7.48(1H, m), 7.92-8.02(2H, m), 8.30-8.41(2H, m), 10.34(1H, s), 11.18-11.32(1H, m)
【０１０６】
合成例３１
Ｎ−（３−クロロ−４−シアノ−１Ｈ−インドール−７−イル）−４−ニトロベンゼンスルホンアミド
合成例３０の化合物 200mg（0.505 ミリモル）をＮ−メチルピロリドン0.8ml に溶解し、シアン化第一銅83mg（0.91ミリモル）を加えた。180-190 ℃で３時間撹拌後、氷水40mlを加え不溶物を濾取、水洗した。不溶物を熱エタノールと熱クロロホルムで抽出し、濃縮後、残渣をシリカゲル薄層クロマトグラフィーで精製し、Ｎ−（４−シアノ−１Ｈ−インドール−７−イル）−４−ニトロベンゼンスルホンアミド65mgを得た。これを実施例２と同様にして塩素化し、表題化合物42mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.98(1H, d, J=8.0Hz), 7.51(1H, d, J=8.0Hz), 7.79(1H, d, J=2.8Hz), 7.99-8.08(2H, m), 8.31-8.40(2H, m), 10.75-10.95(1H, br), 11.62-11.73(1H, m)
【０１０７】
合成例３２
４−アミノ−Ｎ−（３−クロロ−４−シアノ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
合成例３１の化合物から合成例３と同様にして表題化合物を得た。
融点：232 ℃付近から徐々に分解し始め、249.5-255 ℃で急速に分解（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 6.09(2H, s), 6.52(2H, d, J=8.8Hz), 7.10(1H, d, J=8.4Hz), 7.46(2H, d, J=8.8Hz), 7.50(1H, d, J=8.4Hz), 7.72-7.79(1H, m), 10.20(1H, s), 11.40-11.59(1H, m)
【０１０８】
合成例３３
６−アミノ−Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−３−ピリジンスルホンアミド
合成例１４の化合物2.48ｇ（7.25ミリモル）とヨウ化リチウム679mg （5.07ミリモル）をエタノール25mlに加えた。液体アンモニア10mlを加えて封管中120 ℃で26時間加熱後、濃縮した。残渣を酢酸エチルに溶解し、飽和重曹水、水で順次洗浄、硫酸マグネシウムで乾燥した。濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物982mg を得た。
融点：206-207 ℃（酢酸エチル−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 6.37(1H, d, J=8.8Hz), 6.83-6.94(1H, m), 6.88(2H, br s), 6.99(1H, dd, J=7.9, 7.7Hz), 7.25(1H, dd, J=7.9, 0.7Hz), 7.48(1H, d, J=2.7Hz), 7.56(1H, dd, J=8.8, 2.4Hz), 8.14(1H, d, J=2.4Hz), 9.70(1H, s), 10.92-11.03(1H, m)
【０１０９】
合成例３４
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（メチルスルフィニルメチル）ベンゼンスルホンアミド
合成例１５の化合物を実施例２４と同様に酸化して表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.41(3H, s), 3.98(1H, d, J=12.6Hz), 4.18(1H, d, J=12.8Hz), 6.77(1H, d, J=7.5Hz), 6.94(1H, dd, J=7.9, 7.7Hz), 7.25(1H, d, J=7.9Hz), 7.43(2H, d, J=8.1Hz), 7.47(1H, d, J=2.8Hz), 7.73(2H, d, J=8.1Hz), 10.01(1H, br s), 11.03(1H, br s)
【０１１０】
合成例３５
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（２−スルファモイルエチル）ベンゼンスルホンアミド
製造例１１の化合物865mg(3.05ミリモル）と製造例２の化合物376mg(2.84ミリモル) を実施例１と同様に反応させ、処理して得られたＮ−（１Ｈ−インドール−７−イル）−４−（２−スルファモイルエチル）ベンゼンスルホンアミド957mg 実施例２と同様に塩素化して表題化合物 980mgを得た。
融点：217-219 ℃（分解）（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 3.01-3.06(2H, m), 3.23-3.28(2H, m), 6.81(1H, dd, J=7.5, 0.37Hz), 6.88(2H, br s), 6.95(1H, dd, J=8.1, 7.5Hz), 7.24(1H, dd, J=7.8, 0.37Hz), 7.42(2H, d, J=8.4Hz), 7.49(1H, d, J=2.6Hz), 7.68(2H,d, J=8.2Hz), 9.99(1H, br s), 11.02(1H, br s)
【０１１１】
合成例３６
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−［２−（メチルスルホニル）エチル］ベンゼンスルホンアミド
合成例１および２と同様にして表題化合物を得た。
融点：180 ℃付近より着色し始め、201-203 ℃で分解（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 2.92(3H, s), 3.01-3.07(2H, m), 3.40-3.46(2H, m), 6.81(1H, d, J=7.9Hz), 6.94(1H, dd, J=7.9, 7.7Hz), 7.24(1H, d, J=7.7Hz), 7.45(2H, d, J=8.2Hz), 7.49(1H, d, J=2.7Hz), 7.68(2H, d, J=8.2Hz), 9.99(1H, br s), 11.03(1H, br s)
【０１１２】
合成例３７
６−アミノ−Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）−３−ピリジンスルホンアミド
合成例１８の化合物を実施例３３と同様にしてアミノ化し、表題化合物を得た。
融点：300 ℃以上（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 6.39(1H, d, J=9.0Hz), 6.88(1H, d, J=7.7Hz), 6.89(2H, s), 7.11(1H, dd, J=7.9, 7.7Hz), 7.41(1H, dd, J=7.9, 0.7Hz), 7.55(1H, dd, J=9.0, 2.6Hz), 8.12(1H, d, J=2.6Hz), 8.19(1H, s), 9.72-9.90(1H, br), 11.78-11.92(1H, m)
【０１１３】
合成例３８
４−アセトアミド−３−クロロ−Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
合成例１および２と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.14(3H, s), 6.77(1H, d, J=7.7Hz), 6.98(1H, dd, J=7.9, 7.7Hz), 7.29(1H, d, J=7.9Hz), 7.50(1H, d, J=2.7Hz), 7.64(1H, dd, J=8.6, 2.2Hz), 7.75(1H, d, J=2.2Hz), 8.04(1H, d, J=8.6Hz), 9.69(1H, br s), 10.04(1H, br s), 11.11(1H, br s)
【０１１４】
合成例３９
Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）−８−キノリンスルホンアミド
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.68(1H, d, J=7.3Hz), 6.89(1H, dd, J=7.9, 7.7Hz), 7.25(1H, d, J=8.1Hz), 7.69-7.74(2H, m), 8.21(1H, d, J=2.9Hz), 8.30(1H, dd, J=8.2, 1.3Hz), 8.35(1H, dd, J=7.4, 1.4Hz), 8.54(1H, dd, J=8.3, 1.7Hz), 9.15(1H, dd, J=4.3, 1.7Hz), 10.04(1H, br s), 12.14(1H, br s)
【０１１５】
合成例４０
５−クロロ−Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）−２−チオフェンスルホンアミド
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.88(1H, ddd, J=7.7, 2.2, 0.73Hz), 7.16(1H, dd, J=7.9, 7.7Hz), 7.20(1H, d, J=4.0Hz), 7.36(1H, d, J=4.2Hz), 7.51(1H, d, J=8.1Hz), 8.23(1H, d, J=3.1Hz), 10.42(1H, br s), 12.01(1H, br s)
【０１１６】
合成例４１
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（メトキシカルボニルアミノ）ベンゼンスルホンアミド
合成例３の化合物38mg（0.18ミリモル）のピリジン溶液（１ml）にクロロギ酸メチル 170mg（1.8 ミリモル）を加え一晩室温で撹拌した。反応混合物を濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物20mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 3.65(3H, s), 6.80(1H, d, J=7.7Hz), 6.93(1H, t, J=7.9Hz), 7.21(1H, dd, J=7.7, 0.37Hz), 7.45(1H, d, J=2.7Hz), 7.51(2H, d, J=9.0Hz), 7.63(2H, d, J=8.8Hz), 9.85(1H, br s), 10.07(1H, s), 10.97(1H, br s)
【０１１７】
合成例４２
４−アセチル−Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.60(3H, s), 6.74(1H, d, J=7.7Hz), 7.05(1H, dd, J=7.9, 7.7Hz), 7.42(1H, d, J=7.9Hz), 7.81-7.88(2H, m), 8.03-8.10(2H, m), 8.21(1H, s), 10.18-10.50(1H, br), 11.92-12.07(1H, m)
【０１１８】
合成例４３
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（Ｎ−メトキシスルファモイル）ベンゼンスルホンアミド
合成例１および２と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 3.65(3H, s), 6.73(1H, d, J=7.6Hz), 6.96(1H, dd, J=8.0, 7.6Hz), 7.30(1H, d, J=8.0Hz), 7.50(1H, d, J=2.4Hz), 7.98(4H, s), 10.29(1H, br s), 10.76(1H, br s), 11.12(1H, br s)
【０１１９】
合成例４４
Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）−β−スチレンスルホンアミド
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 7.14-7.20(2H, m), 7.32(2H, s), 7.35-7.47(4H, m), 7.60-7.68(2H, m), 8.23(1H, s), 9.70-10.03(1H, br), 11.85-12.12(1H, br)
【０１２０】
合成例４５
３−クロロ−Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）−２−メチルベンゼンスルホンアミド
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.61(3H, s), 6.69(1H, d, J=7.7Hz), 7.04(1H, t, J=7.9Hz), 7.36(1H, dd, J=8.1, 7.9Hz), 7.42(1H, d, J=7.9Hz), 7.73(1H, dd, J=8.1, 1.1Hz), 7.77(1H, dd, J=8.0, 0.82Hz), 8.25(1H, d, J=3.1Hz), 10.37(1H, s), 11.99(1H, br s)
【０１２１】
合成例４６
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−６−イソプロピルアミノ−３−ピリジンスルホンアミド
合成例１４の化合物 400mg（ 1.17 ミリモル）とイソプロピルアミン0.80ml（ 9.39 ミリモル）をジオキサン５mlに加え封管中 100℃で 7.5時間加熱した。濃縮後、酢酸エチルに溶解し、希クエン酸水、飽和重曹水、水で順次洗浄した。硫酸マグネシウムで乾燥後、濃縮し、残渣をシリカゲル薄層クロマトグラフィーで精製し、表題化合物 235mgを得た。
融点： 210℃付近から着色し始め、 213-215℃で分解（酢酸エチル−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 1.09(6H, d, J=6.6Hz), 3.90-4.08(1H, m), 6.39(1H, d, J=9.0Hz), 6.90-7.05(2H, m), 7.24(1H, d, J=7.9Hz), 7.33(1H, d, J=7.7Hz), 7.48(1H, d, J=2.4Hz), 7.54(1H, dd, J=9.0, 2.6Hz), 8.22(1H, d, J=2.6Hz), 9.65-9.84(1H, br), 10.88-11.04(1H, m)
【０１２２】
合成例４７
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−６−［［２−（ジメチルアミノ）エチル］アミノ］−３−ピリジンスルホンアミド
合成例１４の化合物とＮ，Ｎ−ジメチルエチレンジアミンから合成例４６と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.14(6H, s), 2.35(2H, t, J=6.6Hz), 3.24-3.44(2H, m), 6.48(1H, d, J=9.0Hz), 6.92(1H, d, J=7.7Hz), 6.99(1H, dd, J=7.9, 7.7Hz), 7.22(1H, d, J=7.9Hz), 7.27-7.39(1H, m), 7.47(1H, d, J=2.4Hz), 7.54(1H, dd, J=9.0, 2.6Hz), 8.21(1H, d, J=2.6Hz), 10.91-11.03(1H, m)
【０１２３】
合成例４８
Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）−２−フランスルホンアミド
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.62(1H, ddd, J=3.7, 1.8, 0.37Hz), 6.78(1H, d, J=7.5Hz), 7.04(1H, d, J=3.5Hz), 7.12(1H, t, J=7.9Hz), 7.49(1H, d, J=8.1Hz), 7.99-8.00(1H, m), 8.23(1H, d, J=3.1Hz), 10.49(1H, br s), 12.04(1H, br s)
【０１２４】
合成例４９
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−［（ジメチルアミノスルホニル）アミノ］ベンゼンスルホンアミド
合成例３の化合物とジメチルスルファモイルクロリドから合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.66(6H, s), 6.81(1H, dd, J=7.7, 0.92Hz), 6.95(1H, dd, J=7.9, 7.7Hz), 7.20(2H, d, J=8.8Hz), 7.23(1H, d, J=8.1Hz), 7.47(1H, d, J=2.7Hz), 7.64(2H, d, J=8.8Hz), 10.98(1H, br s)
【０１２５】
合成例５０
Ｎ−（３−メチル−１Ｈ−インドール−７−イル）−４−（メチルスルホニル）ベンゼンスルホンアミド
３−ホルミル−７−ニトロ−１Ｈ−インドール 300mg（1.58ミリモル）の２−プロパノール懸濁液（25ml）に水素化ホウ素ナトリウム 580mg（15.3ミリモル）と10％パラジウム−炭素 150mgを加え、６時間還流した。反応系に水を加えた後、触媒を濾取した。濾液を酢酸エチルで抽出し、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残渣をピリジン５mlに溶解した。これを４−（メチルスルホニル）ベンゼンスルホニルクロリド 170mg（0.67ミリモル）と実施例１と同様に反応させ、処理し、表題化合物 149mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.18(3H, s), 3.24(3H, s), 6.69(1H, d, J=7.7Hz), 6.81(1H, t, J=7.7Hz), 7.06(1H, br s), 7.25(1H, d, J=7.8Hz), 7.95(2H, d, J=8.8Hz), 8.04(2H, d, J=8.2Hz), 10.14(1H, br s), 10.40(1H, br s)
【０１２６】
合成例５１
３−シアノ−Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.71(1H, d, J=7.2Hz), 7.09(1H, dd, J=8.0, 7.6Hz), 7.49(1H, d, J=8.0Hz), 7.74(1H, dd, J=8.0, 7.6Hz), 7.94(1H, d, J=8.0Hz), 8.11-8.14(2H, m), 8.23(1H, d, J=2.8Hz), 10.30(1H, br s), 12.05(1H, br s)
【０１２７】
合成例５２
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（Ｎ−メチルメタンスルホンアミド）ベンゼンスルホンアミド
合成例１および２と同様にして表題化合物を得た。
融点： 199-201℃（分解）（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 2.98(3H, s), 3.24(3H, s), 6.83(1H, dd, J=7.7, 0.37Hz), 6.96(1H, dd, J=7.9, 7.7Hz), 7.26(1H, dd, J=7.9, 0.55Hz), 7.48(1H, d, J=2.7Hz), 7.50-7.54(2H, m), 7.72-7.76(2H, m), 10.04(1H, br s), 11.02(1H, br s)
【０１２８】
合成例５３
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−［（メタンスルホンアミド）メチル］ベンゼンスルホンアミド
合成例１および２と同様にして表題化合物を得た。
融点： 180℃付近より着色し始め、 189-191℃で分解（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 2.81(3H, s), 4.19(2H, d, J=6.0Hz), 6.79(1H, d, J=7.7Hz), 6.94(1H, dd, J=7.9, 7.7Hz), 7.24(1H, d, J=7.9Hz), 7.47(2H, d, J=8.8Hz), 7.47-7.49(1H, m), 7.64(1H, t, J=6.4Hz), 7.72(2H, d, J=8.4Hz), 10.00(1H, s), 11.03(1H, br s)
【０１２９】
合成例５４
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（１−ピロリジニルスルホニル）ベンゼンスルホンアミド
４−（１−ピロリジニルスルホニル）ベンゼンスルホニルクロリドと製造例１０の化合物から合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 1.55-1.59(4H, m), 3.07-3.11(4H, m), 6.71(1H, d, J=7.6Hz), 6.95(1H, ddd, J=8.2, 7.4, 1.2Hz), 7.30(1H, d, J=8.0Hz), 7.46(1H, d, J=2.4Hz), 7.89(2H, d, J=8.8Hz), 7.92(2H, d, J=8.4Hz), 10.18(1H, br s), 11.03(1H, br s)
【０１３０】
合成例５５
Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）−１−メチル−４−イミダゾールスルホンアミド
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 3.61(3H, s), 7.00(1H, dd, J=7.7, 0.92Hz), 7.07(1H, dd, J=7.9, 7.7Hz), 7.35(1H, d, J=7.9Hz), 7.75-7.76(2H, m), 8.19(1H, d, J=3.1Hz), 10.03(1H, br s), 11.92(1H, br s)
【０１３１】
合成例５６
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−６−［（２−ヒドロキシエチル）アミノ］−３−ピリジンスルホンアミド
合成例１４の化合物と２−アミノエタノールから合成例４６と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 3.24-3.40(2H, m), 3.42-3.52(2H, m), 4.66-4.77(1H, m), 6.48(1H, d, J=9.3Hz), 6.92(1H, d, J=7.7Hz), 7.00(1H, t, J=7.7Hz), 7.24(1H, d, J=7.7Hz), 7.40-7.62(2H, m), 7.48(1H, d, J=2.2Hz), 8.22(1H, d, J=2.6Hz), 9.63-9.90(1H, br), 10.90-11.07(1H, m)
【０１３２】
合成例５７
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−６−メルカプト−３−ピリジンスルホンアミド
合成例１４の化合物 340mg（0.99ミリモル）とチオウレア 151mg（1.98ミリモル）をエタノール５mlに加え、２時間加熱還流した。濃縮後、残渣に水 1.6mlと炭酸ナトリウム57mgを加え、室温で10分間撹拌した。水酸化ナトリウム85mgを加え、さらに10分間撹拌後、不溶物を濾去した。塩酸酸性にして生じた沈澱を濾取し、水洗後、テトラヒドロフランに溶解し、硫酸マグネシウムで乾燥した。濃縮後、残渣をシリカゲル薄層クロマトグラフィーで精製し、表題化合物 121mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.84(1H, d, J=7.6Hz), 7.03(1H, t, J=7.6Hz), 7.28(1H, d, J=9.2Hz), 7.31(1H, d, J=7.6Hz), 7.44(1H, dd, J=9.2, 2.4Hz), 7.48(1H, d, J=2.6Hz), 7.68(1H, d, J=2.4Hz), 9.58-9.80(1H, br), 11.08-11.19(1H, m)
【０１３３】
合成例５８
７−（４−クロロベンゼンスルホンアミド）−１Ｈ−インドール−２−カルボン酸
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.65(1H, d, J=7.6Hz), 6.87(1H, dd, J=8.0, 7.6Hz), 7.00(1H, s), 7.26(1H, d, J=8.0Hz), 7.56-7.65(2H, m), 7.68-7.77(2H, m), 9.62-10.00(1H, br), 11.40-11.74(1H, br)
【０１３４】
合成例５９
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−６−シクロプロピルアミノ−３−ピリジンスルホンアミド
合成例４６と同様にして表題化合物を得た。
融点：228 ℃付近から着色し始め、233.5-235 ℃で分解（酢酸エチル−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 0.36-0.46(2H, m), 0.63-0.75(2H, m), 2.44-2.64(1H, m), 6.45-6.64(1H, m), 6.93(1H, d, J=7.7Hz), 7.00(1H, dd, J=7.9, 7.7Hz), 7.24(1H, d, J=7.9Hz), 7.49(1H, d, J=2.7Hz), 7.57-7.73(2H, m), 8.25(1H, d, J=2.6Hz), 9.68-9.90(1H, br), 10.92-11.04(1H, m)
【０１３５】
合成例６０
Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）−５−メチル−３−ピリジンスルホンアミド
合成例１と同様にして表題化合物を得た。
融点： 288℃付近から徐々に分解（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 2.33(3H, s), 6.75(1H, d, J=7.7Hz), 7.09(1H, dd, J=7.9, 7.7Hz), 7.48(1H, d, J=7.9Hz), 7.87-7.91(1H, m), 8.22(1H, d, J=3.1Hz), 8.58-8.67(2H, m), 10.28(1H, br s), 11.95-12.08(1H, m)
【０１３６】
合成例６１
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（Ｎ−メチルスルファモイル）ベンゼンスルホンアミド
合成例１および２と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.39(3H, d, J=5.2Hz), 6.71(1H, dd, J=7.8, 2.0Hz), 6.96(1H, dd, J=8.0, 7.6Hz), 7.30(1H, d, J=8.0Hz), 7.48(1H, d, J=2.8Hz), 7.68(1H, q, J=4.9Hz), 7.87-7.93(4H, m), 10.20(1H, br s), 11.08(1H, br s)
【０１３７】
合成例６２
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−［２−（メタンスルホンアミド）エチル］ベンゼンスルホンアミド
合成例１および２と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.73-2.81(5H, m),3.13-3.19(2H, m), 6.82(1H, d,J=7.7Hz), 6.95(1H, dd, J=8.1, 7.7Hz), 7.09(1H, t, J=5.9Hz), 7.24(1H, d, J=8.1Hz), 7.39(2H, d, J=8.2Hz), 7.48(1H, d, J=2.7Hz), 7.68(2H, d, J=8.4Hz), 9.97(1H, br s), 11.02(1H, br s)
【０１３８】
合成例６３
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（スルファモイルメチル）ベンゼンスルホンアミド
製造例６の化合物 389mg（1.44ミリモル）と製造例２の化合物 159mg（ 1.2ミリモル）を実施例１と同様に反応させ、処理し、Ｎ−（１Ｈ−インドール−７−イル）−４−（スルファモイルメチル）ベンゼンスルホンアミド 233mgを得た。これを実施例２と同様にして塩素化し、表題化合物 160mgを得た。
融点： 237-238.5℃（分解）（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 4.33(2H, s), 6.84(1H, dd, J=7.7, 0.73Hz), 6.93(2H, s), 6.92-6.97(1H, m), 7.24(1H, dd, J=7.9, 0.37Hz), 7.48(1H, d, J=2.7Hz), 7.48-7.52(2H, m), 7.75-7.79(2H, m), 10.08(1H, br s), 11.04(1H, br s)
【０１３９】
合成例６４
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−チオカルバモイルベンゼンスルホンアミド
合成例１０の化合物 400mg（1.21ミリモル）をジメチルホルムアミド10mlに溶解し、トリエチルアミン 0.5mlを加えた。浴温60−70℃で硫化水素を45分間通じた。濃縮後、残渣を酢酸エチルに溶解し、希塩酸、飽和重曹水、水で順次洗浄、硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物 355mgを得た。
融点： 223-225℃（分解）（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 6.81(1H, d, J=7.7Hz), 6.96(1H, dd, J=7.9, 7.7Hz), 7.27(1H, d, J=7.9Hz), 7.50(1H, d, J=2.7Hz), 7.73-7.80(2H, m), 7.86-7.93(2H, m), 9.58-9.73(1H, br m), 10.02-10.18(1H, br m), 10.15(1H, s), 11.03-11.12(1H, m)
【０１４０】
合成例６５
５−ブロモ−Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）−２−ピリジンスルホンアミド
合成例１と同様にして表題化合物を得た。
融点： 245.5-246.5℃（分解）（酢酸エチル−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 6.82(1H, d, J=7.7Hz), 7.07(1H, dd, J=7.9, 7.7Hz), 7.44(1H, d, J=7.9Hz), 7.80(1H, d, J=8.2Hz), 8.23(1H, d, J=2.2Hz), 8.29(1H, dd, J=8.2, 2.2Hz), 8.92(1H, d, J=2.2Hz), 10.42-10.67(1H, br), 11.93-12.08(1H, m)
【０１４１】
合成例６６
Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）−２−ナフタレンスルホンアミド
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.74(1H, dd, J=7.6, 2.8Hz), 7.00(1H, dd, J=7.9, 7.7Hz), 7.39(1H, dd, J=8.0, 0.46Hz), 7.61-7.72(2H, m), 7.80(1H, dd, J=8.6, 1.8Hz), 8.01(1H, d, J=8.1Hz), 8.08(1H, s), 8.10(1H, s), 8.21(1H, d,J=2.9Hz), 8.34(1H, d, J=1.6Hz), 10.23(1H, br s), 12.01(1H, br s)
【０１４２】
合成例６７
Ｎ−（３−アセチル−１Ｈ−インドール−７−イル）−３−クロロベンゼンスルホンアミド
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.44(3H, s), 6.65(1H, d, J=7.5Hz), 7.01(1H, dd, J=7.9, 7.7Hz), 7.53-7.63(2H, m), 7.69-7.73(2H, m), 8.01(1H, dd, J=8.1, 0.73Hz), 8.26(1H, d, J=2.9Hz), 10.10(1H, s), 11.75(1H, br s)
【０１４３】
合成例６８
４−アミノ−Ｎ−（５−ブロモ−３−シアノ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
４−ニトロベンゼンスルホニルクロリドと製造例１４の化合物から実施例１と同様にして得られたＮ−（５−ブロモ−３−シアノ−１Ｈ−インドール−７−イル）−４−ニトロベンゼンスルホンアミドを酸化白金存在下常温常圧で水素添加し、表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.07(2H, br s), 6.52(2H, d, J=8.4Hz), 6.97-6.99(1H, m), 7.36(2H, dd, J=8.7, 1.6Hz), 7.51(1H, br s), 8.25(1H, s), 9.93(1H, d, J=5.5Hz), 11.97(1H, br s)
【０１４４】
合成例６９
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（Ｎ−エチルスルファモイル）ベンゼンスルホンアミド
合成例１および２と同様にして表題化合物を得た。
融点： 213-215℃（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 0.90(3H, t, J=7.2Hz), 2.76(2H, dq, Jd=5.8Hz, Jq=7.2Hz), 6.70(1H, d, J=7.4Hz), 6.95(1H, dd, J=8.0, 7.6Hz), 7.29(1H, d, J=8.0Hz), 7.47(1H, d, J=2.8Hz), 7.78(1H, t, J=5.6Hz), 7.90(4H, s), 10.18(1H, br s), 11.06(1H, br s)
【０１４５】
合成例７０
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（エタンスルホンアミド）ベンゼンスルホンアミド
合成例４と同様にして表題化合物を得た。
融点： 214-215℃（分解）（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 1.14(3H, t, J=7.3Hz), 3.16(2H, q, J=7.3Hz), 6.82(1H, d, J=7.5Hz), 6.96(1H, dd, J=7.9, 7.7Hz), 7.23(2H, d, J=8.8Hz), 7.24(1H, d, J=7.5Hz), 7.47(1H, d, J=2.6Hz), 7.66(2H, d, J=8.8Hz), 9.90(1H, br s), 10.37(1H, br s), 10.96(1H, br s)
【０１４６】
合成例７１
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル) −６−［（２−シアノエチル）アミノ］−３−ピリジンスルホンアミド
合成例４６と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.72(2H, t, J=6.4Hz)，3.46-3.55(2H, m), 6.53(1H, d, J=9.0Hz), 6.90(1H, d, J=7.7Hz), 6.99(1H, dd, J=7.9, 7.7Hz), 7.25(1H, d, J=7.9Hz), 7.48(1H, d, J=2.6Hz), 7.61(1H, dd, J=9.0, 2.4Hz), 7.78-7.87(1H, m), 8.25(1H, d, J=2.4Hz), 9.70-9.95(1H, br), 10.92-11.04(1H, m)
【０１４７】
合成例７２
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル) −４− (Ｎ−メチルカルバモイル）ベンゼンスルホンアミド
合成例９の化合物 533mg（1.68ミリモル）をジメチルホルムアミド５mlとジメチルスルホキシド 2.5mlの混液に溶解し、メチルアミン塩酸塩171mg （2.53ミリモル）、トリエチルアミン 705μl （5.06ミリモル）を加えた。ジフェニルホスホリルアジド 436μl （2.02ミリモル）を加えて室温で一晩撹拌後濃縮した。酢酸エチルで抽出し、希塩酸、飽和重曹水、水で順次洗浄後、硫酸マグネシウムで乾燥した。濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、Ｎ−（１Ｈ−インドール−７−イル）−４−（Ｎ−メチルカルバモイル）ベンゼンスルホンアミド 465mgを得た。これを合成例２と同様に塩素化し、表題化合物413mg を得た。
融点：252-253 ℃（分解）（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 2.76(3H, d, J=4.6Hz), 6.74(1H, d, J=7.7Hz), 6.94(1H, dd, J =7.9, 7.7Hz), 7.27(1H, d, J=7.9Hz), 7.49(1H, d, J=2.7Hz), 7.76-7.83(2H, m), 7.87-7.94(2H, m), 8.61(1H, q, J=4.6Hz), 10.10(1H, s), 11.03-11.13(1H, m)
【０１４８】
合成例７３
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（メチルスルホニルメチル）ベンゼンスルホンアミド
合成例３４の化合物 510mgを30％過酸化水素水により実施例２３と同様に酸化して表題化合物 307mgを得た。
融点： 225℃付近より着色し始め、 235℃付近から徐々に分解（エタノール−ｎ−ヘキサンから再結晶)
^１H-NMR(DMSO-d₆) δ(ppm) : 2.88(3H, s), 4.57(2H, s), 6.77(1H, d, J=7.6Hz), 6.94(1H, dd, J=7.9, 7.7Hz), 7.25(1H, d, J=8.0Hz), 7.47(1H, d, J=2.7Hz), 7.51-7.56(2H, m), 7.73-7.78(2H, m), 10.05(1H, br s), 11.04(1H, br s)
【０１４９】
合成例７４
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（Ｎ，Ｎ−ジメチルスルファモイル）ベンゼンスルホンアミド
合成例１および２と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.57(6H, s), 6.71(1H, dd, J=7.4, 0.6Hz), 6.97(1H, dd, J=8.0, 7.6Hz), 7.31(1H, d, J=8.0Hz), 7.47(1H, d, J=2.8Hz), 7.86(2H, d, J=8.4Hz), 7.91(2H, d, J=8.4Hz), 10.19(1H, br s), 11.04(1H, br s)
【０１５０】
合成例７５
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（１−ピロリジニルカルボニル）ベンゼンスルホンアミド
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 1.79(2H, dt, Jd=12.8Hz, Jt=6.4Hz), 1.85(2H, dt, Jd=13.6Hz, Jt=6.8Hz), 3.22(2H, t, J=6.4Hz) , 3.44(2H, t, J=6.8Hz), 6.78(1H, d, J=7.2Hz), 6.96(1H, dd, J=8.0, 7.2Hz), 7.28(1H, d, J=8.0Hz), 7.47(1H, d, J=2.4Hz), 7.60(2H, d, J=8.0Hz), 7.74(2H, d, J=8.4Hz), 10.06(1H, br s), 11.01(1H, br s)
【０１５１】
合成例７６
３−クロロ−Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−Ｎ−メチルベンゼンスルホンアミド
合成例７の化合物 120mg（0.352 ミリモル）をジメチルホルムアミド10mlに溶解し、水素化ナトリウム（60％）19.2mg（0.479 ミリモル）を加えた。室温で30分間撹拌後ヨウ化メチル30μl （0.482 ミリモル）を加えた。２時間後水を加え、酢酸エチルで抽出し、有機層を水洗、硫酸マグネシウムで乾燥した。濃縮後、残渣をシリカゲル薄層クロマトグラフィーで精製し、表題化合物87mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 3.26(3H, s), 6.51(1H, dd, J=7.6, 0.64Hz), 7.00(1H, dd, J=7.9, 7.7Hz), 7.47(1H, d, J=8.1Hz), 7.53(1H, d, J=2.7Hz), 7.54-7.59(2H, m), 7.65(1H, t, J=7.9Hz), 7.84(1H, ddd, J=8.1, 2.1, 1.1Hz), 11.62(1H, br s)
【０１５２】
合成例７７
Ｎ−（３，４−ジクロロ−１Ｈ−インドール−７−イル）−４−（スルファモイルメチル）ベンゼンスルホンアミド
合成例１と同様にして表題化合物を得た。
融点： 297℃付近から徐々に分解（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 4.34(2H, s), 6.72(1H, d, J=8.1Hz), 6.93(2H, s), 6.94(1H, d, J=8.1Hz), 7.51(2H, d, J=8.1Hz), 7.57(1H, dd, J=2.7, 0.55Hz), 7.75(2H, d, J=8.2Hz), 10.10(1H, br s), 11.44(1H, br s)
【０１５３】
合成例７８
Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）−４−［２−（メチルスルホニル）エチル］ベンゼンスルホンアミド
合成例１と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.94(3H, s), 3.03-3.08(2H, m), 3.42-3.47(2H, m), 6.77(1H, dd, J=7.7, 0.37Hz), 7.05(1H, t, J=7.9Hz), 7.41(1H, d, J=8.1Hz), 7.46(2H, d, J=8.2Hz), 7.66(2H, d, J=8.2Hz), 8.20(1H, s), 10.09(1H, br s), 11.92(1H, br s)
【０１５４】
合成例７９
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（Ｎ−メチルアセトアミド) ベンゼンスルホンアミド
合成例１および２と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 1.84(3H, br s), 3.16(3H, s), 6.81(1H, d, J=7.7Hz), 6.96(1H, dd, J=8.0, 7.6Hz), 7.27(1H, d, J=7.9Hz), 7.45-7.49(2H, m), 7.47(1H, d, J=2.7Hz), 7.70-7.75(2H, m), 10.02(1H, br s), 11.01(1H, br s)
【０１５５】
合成例８０
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−６−ヒドロキシ−３−ピリジンスルホンアミド
氷冷下氷酢酸２mlに実施例３３の化合物100mg （0.31ミリモル）を溶かした液に、亜硝酸ナトリウム32mg（0.46ミリモル）の水溶液１mlを滴下して加えた。１時間撹拌後、重曹水を加えてpH約８にし、さらに10分間撹拌した。酢酸エチルで抽出し、水洗、硫酸マグネシウムで乾燥した。濃縮後、残渣をシリカゲル薄層クロマトグラフィーで精製し、表題化合物54mgを得た。
融点： 244-245℃（分解）（酢酸エチル−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 6.39(1H, d, J=9.5Hz), 6.88(1H, d, J=7.7Hz), 7.04(1H, dd, J=7.9, 7.7Hz), 7.32(1H, d, J=7.9Hz), 7.50(1H, d, J=2.7Hz), 7.58(1H, dd, J=9.5, 3.1Hz), 7.64(1H, d, J=3.1Hz), 9.76-9.94(1H, br), 11.01-11.13(1H, m), 11.98-12.15(1H, br)
【０１５６】
合成例８１
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−［２−（Ｎ−メチルメタンスルホンアミド）エチル］ベンゼンスルホンアミド
合成例１および２と同様にして表題化合物を得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.69(3H, s), 2.76(3H, s), 2.86(2H, t, J=7.5Hz), 3.26(2H, t, J=7.5Hz), 6.78(1H, dd, J=7.4, 0.55Hz), 6.94(1H, t, J=7.7Hz), 7.24(1H, dd, J=7.7, 0.37Hz), 7.39(2H, d, J=8.2Hz), 7.48(1H, d, J=2.6Hz), 7.66(2H, d, J=8.2Hz), 9.94(1H, br s), 11.02(1H, br s)
【０１５７】
合成例８２
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（トリフルオロメタンスルホンアミド）ベンゼンスルホンアミド
合成例３の化合物62mg(0.19 ミリモル) のピリジン溶液(5ml) に0 ℃でトリフルオロメタンスルホン酸無水物 128μl(0.76ミリモル）を加え、そのまま終夜撹拌した。減圧下に反応液を濃縮し、pH7 のリン酸緩衝液を加え、酢酸エチルで抽出後、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。減圧下に溶媒を留去し、シリカゲルカラムクロマトグラフィーで精製し、表題化合物20mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.79(1H, d, J=7.7Hz), 6.94(1H, dd, J=7.9, 7.7Hz), 7.16(2H, d, J=8.6Hz), 7.23(1H, d, J=7.9Hz), 7.46(1H, d, J=2.7Hz), 7.58(2H, d, J=8.1Hz), 9.84(1H, br s), 10.98(1H, br s)
【０１５８】
合成例８３
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−［（Ｎ−メチルメタンスルホンアミド）メチル］ベンゼンスルホンアミド
合成例１および２と同様にして表題化合物を得た。
融点： 200.5-202℃（エタノールから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 2.63(3H, s), 2.94(3H, s), 4.27(2H, s), 6.80(1H, d, J=7.3Hz), 6.95(1H, dd, J=8.1, 7.5Hz), 7.25(1H, d, J=7.9Hz), 7.45(2H, d, J=8.2Hz), 7.47(1H, d, J=2.7Hz), 7.74(2H, d, J=8.2Hz), 10.00(1H, s), 11.00(1H, br s)
【０１５９】
合成例８４
３−クロロ−Ｎ−（３−クロロ−１Ｈ−ピロロ［２，３−ｃ］ピリジン−７−イル）ベンゼンスルホンアミド
２−ブロモ−３−ニトロピリジンから製造例１と同様にして合成した７−ブロモ−１Ｈ−ピロロ［２，３−ｃ］ピリジン600mg(3.05ミリモル）、銅粉194mg および塩化第一銅 603mgを濃アンモニア水84mlに加え、封管中120 ℃で１５時間加熱後、処理し、７−アミノ−１Ｈ−ピロロ［２，３−ｃ］ピリジン170mg を得た。これを実施例１および２と同様に反応、処理し、表題化合物57mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.93(1H, d, J=6.6Hz), 7.45(1H, dd, J=6.6, 5.8Hz), 7.53(1H, dd, J=8.0, 7.6Hz), 7.61(1H, d, J=7.6Hz), 7.73(1H, d, J=2.8Hz), 7.85(1H, d, J=8.0Hz), 7.96(1H, d, J=1.2Hz), 11.90-12.10(1H, m), 12.72(1H, br s)
【０１６０】
合成例８５
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−［３−（１−イミダゾリル）プロピル］ベンゼンスルホンアミド
４−（３−ブロモプロピル）−Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド 213mg（0.5 ミリモル）にイミダゾール 170mg（2.5 ミリモル）とジメチルホルムアミド６mlを加えた。窒素雰囲気下80℃で３時間加熱後、反応混合物を水に注ぎ、クロロホルムで抽出した。硫酸マグネシウムで乾燥、濃縮後、残渣をシリカゲルカムクロマトグラフィーで精製し、表題化合物 160mgを得た。
融点：86〜90℃
^１H-NMR(DMSO-d₆) δ(ppm) : 1.95-2.04(2H,m),2.55(2H,t,J=7.9Hz),3.92(2H,t,J=7.1Hz),6.81(1H,dd,J=7.7,0.9Hz),6.88(1H,t,J=1.1Hz),6.94(1H,dd,J=7.9,7.7Hz),7.16(1H,t,J=1.2Hz),7.23(1H,d,J=7.7Hz),7.32(2H,d,J=8.4Hz),7.47(1H,d,J=2.7Hz),7.60(1H,br s),7.65(2H,d,J=8.4Hz),9.91-10.01(1H,m),10.98-11.02(1H,m)
【０１６１】
合成例８６
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−［Ｎ−［２−（２−ピリジニル）エチル］カルバモイル］ベンゼンスルホンアミド
４−（クロロスルホニル）安息香酸 2.82g（12.8ミリモル）と７−アミノ−３−クロロ−１Ｈ−インドール 1.42g（8.54ミリモル）をピリジン中室温攪拌下に一晩反応させて４−［Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）スルファモイル］安息香酸 2.33gを得た。これを 303mg（0.86ミリモル）にジメチルホルムアミド 260μl ，ジフェニルホスホリルアジド 204μl （0.95ミリモル）、トリエチルアミン 132μl （0.95ミリモル）、２−（２−アミノエチル）ピリジン 113μl （0.94ミリモル）を順次加え、室温で一晩撹拌した。濃縮後酢酸エチルと飽和重曹水を加え、有機層を分取、飽和食塩水で洗浄した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物 175mgを得た。
融点：220.5 〜222 ℃
^１H-NMR(DMSO-d₆) δ(ppm) : 2.95-2.99(2H,m),3.56-3.62(2H,m),6.75(1H,d,J=7.5Hz),6.94(1H,dd,J=7.9,7.7Hz),7.19-7.28(3H,m),7.48(1H,d,J=2.8Hz),7.69(1H,dt,Jd=1.8Hz,Jt=7.7Hz),7.79(2H,d,J=8.6Hz),7.88(2H,d,J=8.6Hz),8.48-8.51(1H,m),8.75(1H,t,J=5.2Hz),10.09-10.12(1H,m),11.06-11.09(1H,m)
【０１６２】
合成例８７
４−アミジノ−Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
塩化アンモニウム 162mg（3.0 ミリモル）にトリメチルアルミニウム 1.0Ｍヘキサン溶液 3.3ml（3.3 ミリモル）とトルエン10mlを加えた。ガスの発生が止まってから液量が約３mlになるまで減圧濃縮した。撹拌しながら製造例４の化合物97mg（0.30ミリモル）を加え、80℃で４時間加熱した。冷却後、濃アンモニア水を加え、不溶物を濾去、濃縮した。酢酸エチルを加え不溶物を濾去、濃縮し、残渣をシリカゲルカムクロマトグラフィーで精製し、表題化合物35mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.93(1H,dd,J=7.7,1.5Hz),6.96(1H,dd,J=7.7,7.5Hz),7.24(1H,dd,J=7.5,1.3Hz),7.50(1H,d,J=2.7Hz),7.90(2H,d,J=8.6Hz),8.01(2H,d,J=8.6Hz),9.16-9.62(2H,br),10.40-10.75(1H,br),11.50(1H,s)
【０１６３】
合成例８８
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−［Ｎ−［２−（１−イミダゾリル）エチル］スルファモイル］ベンゼンスルホンアミド
４−［Ｎ−（２−ブロモエチル）スルファモイル］−Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド 557mg（1.13ミリモル）とイミダゾール 820mg（12.0ミリモル）をジメチルホルムアミド10mlに加え、80℃で２日間撹拌した。濃縮後残渣を酢酸エチルに溶解し、水洗、硫酸ナトリウムで乾燥、濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物 324mgを得た。
融点：200 ℃付近から徐々に着色し始め、 218〜221 ℃で分解（エタノール−ｎ−ヘキサンから再結晶）
^１H-NMR(DMSO-d₆) δ(ppm) : 3.05(2H,ddd,J=6.2,6.0,5.9Hz),3.96(2H,dd,J=6.0,5.9Hz),6.69-6.72(1H,m),6.84(1H,br s),6.92(1H,dd,J=7.9,7.7Hz),7.08(1H,br s),7.26(1H,d,J=7.5Hz),7.44(1H,d,J=2.7Hz),7.55(1H,br s),7.82-7.88(4H,m),8.06(1H,t,J=5.9Hz),10.18-10.36(1H,br),11.09(1H,d,J=2.4Hz)
【０１６４】
合成例８９
３−（５−ブロモニコチンアミド）−Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド
３−ニトロベンゼンスルホニルクロリド 785mg（3.54ミリモル）と製造例３の化合物 506mg（3.22ミリモル）を製造例４と同様に反応させ、処理してＮ−（３−シアノ−１Ｈ−インドール−７−イル）−３−ニトロベンゼンスルホンアミド 950mgを得た。これを常法に従い、メタノール30ml中亜鉛末−濃塩酸で還元を行い３−アミノ−Ｎ−（３−シアノ−１Ｈ−インドール−７−イル）ベンゼンスルホンアミド 459mgを得た。このもの 109mg（0.35ミリモル）をピリジン２mlに溶解し、５−ブロモニコチノイルクロリド塩酸塩 179mg（0.70ミリモル）を加えた。室温で一晩撹拌後濃縮し、希クエン酸水溶液を加えた。生じた沈澱を濾取し、水、希重曹水、水、エーテルで順次洗浄した。沈澱をテトラヒドロフランに溶解、硫酸マグネシウムで乾燥、濃縮後、エーテルとｎ−ヘキサンを加えて析出した結晶を濾取し、表題化合物 108mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.81(1H,dd,J=7.7,0.7Hz),7.07(1H,t,J=7.9Hz),7.42(1H,dd,J=7.9,0.7Hz),7.47-7.51(1H,m),7.55(1H,t,J=7.9Hz),7.93-7.97(1H,m),8.21-8.23(1H,m),8.31(1H,t,J=1.8Hz),8.55(1H,dd,J=2.4,2.0Hz),8.93(1H,d,J=2.4Hz),9.06(1H,d,J=2.0Hz),10.23-10.25(1H,m),10.75(1H,br s),11.94-11.96(1H,m)
【０１６５】
合成例９０
Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−［Ｎ−（２−チアゾリル）スルファモイル］ベンゼンスルホンアミド
.2g（20.4ミリモル）を水14mlと濃塩酸 3.4mlの混液に加え撹拌した。これに亜硝酸ナトリウム2.1g（30.4ミリモル）の飽和水溶液を０℃以下で滴下後、酢酸５mlを加えて５℃で約10分間撹拌した。この反応液に二酸化イオウ飽和酢酸液（二酸化イオウを酢酸18mlに飽和させ、塩化第二銅・２水和物 830mgを加えた液）を０℃で撹拌下滴下した。５分後反応液を氷水に注ぎ、沈澱を濾取、水洗、乾燥し、４−クロロスルホニル−Ｎ−（２−チアゾリル）ベンゼンスルホンアミド2.9gを得た。このもの 570mg（1.68ミリモル）と製造例１の化合物 200mg（1.2 ミリモル）を製造例４と同様に反応させ、処理し、表題化合物 456mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 6.68(1H,dd,J=7.5,0.73Hz),6.87(1H,d,J=4.6Hz),6.93(1H,dd,J=8.1,7.5Hz),7.26-7.30(1H,m),7.28(1H,d,J=4.6Hz),7.46(1H,d,J=2.7Hz),7.82-7.88(2H,m),7.88-7.94(2H,m),10.10-10.26(1H,br),11.04-11.10(1H,m),12.83-13.01(1H,br)
【０１６６】
合成例９１
５−クロロ−Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−（５−メチル−３−ピリジンスルホンアミド）−２−チオフェンスルホンアミド
５−クロロ−４−ニトロ−２−チオフェンスルホニルクロリド 645mg（2.46ミリモル）と製造例１の化合物 410mg（2.46ミリモル）を製造例４と同様に反応させ、処理して５−クロロ−Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−４−ニトロ−２−チオフェンスルホンアミド 194mgを得た。これを常法に従い、メタノール10ml中亜鉛末−濃塩酸で還元を行い４−アミノ−５−クロロ−Ｎ−（３−クロロ−１Ｈ−インドール−７−イル）−２−チオフェンスルホンアミド75mgを得た。このもの72mg（0.20ミリモル）をテトラヒドロフラン２mlに溶解し、ピリジン18μl と５−メチル−３−ピリジンスルホニルクロリド38mg（0.2 ミリモル）を加えた。室温で一晩撹拌後、酢酸エチルと１Ｎ塩酸を加え有機層を分取、水、重曹水、水で順次洗浄した。硫酸マグネシウムで乾燥、濃縮後、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物82mgを得た。
^１H-NMR(DMSO-d₆) δ(ppm) : 2.33(3H,s),6.76(1H,d,J=7.7Hz),7.03(1H,dd,J=7.9,7.7Hz),7.35(1H,s),7.38(1H,d,J=7.9Hz),7.51(1H,d,J=2.7Hz),7.80(1H,dd,J=2.0,1.5Hz),8.60(1H,dd,J=2.0,0.4Hz),8.71(1H,dd,J=1.5,0.4Hz),10.35-10.40(1H,m),10.73-10.80(1H,br),11.16-11.19(1H,m)[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an angiogenesis inhibitor containing a sulfonamide or a sulfonic acid ester derivative as an active ingredient. More specifically, the present invention relates to a cancer metastasis inhibitor, a retinal neovascularization, a diabetic retinopathy or an inflammatory disease therapeutic agent.
[0002]
[Prior art]
It has become clear that cancer growth and angiogenesis are closely related. That is, when angiogenesis does not occur at the cancer site, the cancer remains in a minute state (dormant tumor). However, it has been found that when angiogenesis occurs, the tumor is supplemented with oxygen and nutrients in the blood to promote cancer growth and metastasis and become clinically malignant. Therefore, inhibition of cancer angiogenesis is thought to suppress cancer growth and metastasis. Since new blood vessels are composed of host endothelial cells and stromal cells, the target of angiogenesis inhibitors is not cancer cells but those normal cells of the host. Not targeting cancer cells directly can be expected to be effective even for cancers that do not respond to existing anticancer drugs, and it is also unlikely that resistant cancer, which is a major problem in cancer treatment, will occur. In addition, angiogenesis is a tumor-specific phenomenon, and in mature individuals, it is limited to endometrium formation associated with the menstrual cycle. Therefore, it is thought that there are few side effects compared with the existing anticancer agent. Recently, it has been experimentally proved that an angiogenesis inhibitor can suppress or reduce the growth of cancer in a transplanted cancer model in the preclinical, and that resistant cancer does not occur. Correlation with malignant transformation of many solid cancers such as cancer, lung cancer, and colon cancer has been shown.
[0003]
In cancer tissues, proliferation and apoptosis of cancer cells are constantly occurring, and it has been found that advanced cancer and dormant tumor occur in the balance. Antiangiogenic agents do not kill cancer cells directly, but by cutting off nutrients, the balance becomes apoptotic and leads to dormant or shrinkage of cancer, leading to better effects over long periods of treatment (prolonging life and preventing recurrence) , Metastasis suppression).
[0004]
Angiogenesis inhibitors with various mechanisms of action are in the clinical stage, but their anti-tumor effects in the preclinical clinic are insufficient, and there are doubts about their usefulness in the clinic. Inhibitors are craved.
It is also known that angiogenesis is involved in retinopathy or inflammation. When blood vessels grow in the retina, visual acuity diminishes, and when it gets worse, it becomes blind. There is currently no effective therapeutic agent, and an effective prophylactic / therapeutic agent is required.
[0005]
WO9301182 discloses an antitumor agent based on the specific tyrosine kinase inhibitory activity of a compound having an indole skeleton, but these are indolylmethylene-2-indolinone compounds and are different from the present invention. Similarly, WO964016 discloses antitumor agents based on the specific tyrosine kinase inhibitory activity of compounds having an indole skeleton, but these are 2-indolinone-3-methylene derivatives and are different from the present invention. In addition, JP-A-7-165708 and JP-A-8-231505 disclose the same sulfonamide compounds and sulfonic acid ester compounds as in the present invention, but there is no description or suggestion about the angiogenesis inhibitory action.
[0006]
[Problems to be solved by the invention]
An object of this invention is to provide the sulfonamide compound and sulfonate compound which have the outstanding angiogenesis inhibitory effect.
[0007]
[Means for Solving the Problems]
In view of the above, the present inventors have conducted intensive research for an excellent angiogenesis inhibitor. As a result, sulfonamide compounds having a bicyclic heterocycle and sulfonate compounds have excellent angiogenesis inhibitory effects. And the present invention was completed.
That is, the present invention relates to the general formula (I)
[0008]
[Chemical 2]

[0009]
(In the formula, A ring represents a monocyclic or bicyclic aromatic ring optionally having a substituent,
Ring B may have a substituent, a 6-membered cyclic unsaturated hydrocarbon or an unsaturated 6-membered heterocycle containing one nitrogen atom as a heteroatom,
Ring C may have a substituent, a 5-membered heterocycle containing 1 or 2 nitrogen atoms,
W represents a single bond or —CH═CH—,
X is -N (R ¹ )-Or oxygen atom,
Y represents a carbon atom or a nitrogen atom,
Z is -N (R ² )-Or a nitrogen atom,
R ¹ And R ² Are the same or different and each represents a hydrogen atom or a lower alkyl group,
means. And an angiogenesis inhibitor comprising as an active ingredient a sulfonamide derivative and a sulfonic acid ester derivative represented by formula (1) or a pharmacologically acceptable salt thereof or a hydrate thereof.
[0010]
In the above general formula (I), the “monocyclic or bicyclic aromatic ring optionally having a substituent” in the ring A means an aromatic hydrocarbon, or a nitrogen atom, an oxygen atom and sulfur. It is an aromatic heterocycle containing at least one of the atoms, and 1 to 3 substituents may be present on the ring. Examples of the main aromatic ring contained in the A ring include pyrrole, pyrazole, imidazole, thiophene, furan, thiazole, oxazole, benzene, pyridine, pyrimidine, pyrazine, pyridazine, naphthalene, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline , Cinnoline, indole, isoindole, indolizine, indazole, benzofuran, benzothiophene, benzoxazole, benzimidazole, benzopyrazole, benzothiazole and the like. The aromatic ring may have 1 to 3 substituents, and when there are a plurality of substituents, they may be the same or different. Examples of the substituent include an amino group, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group, a mercapto group, a cyano group, a lower alkylthio group, and a halogen group, which may be substituted with a lower alkyl group or a lower cycloalkyl group. And -a-b [wherein, a is a single bond,-(CH ₂ ) _k -, -O- (CH ₂ ) _k -, -S- (CH ₂ ) _k -Or -N (R ³ )-(CH ₂ ) _k -, K is an integer of 1-5, R ³ Is a hydrogen atom or a lower alkyl group, b is -CH ₂ -D (wherein d represents an amino group, a halogen group, a hydroxyl group, a lower alkylthio group, a cyano group or a lower alkoxy group which may be substituted with a lower alkyl group), a group represented by the formula: -A-ef [wherein, a is as defined above, e is -SO- or -SO ₂ -, F is an amino group optionally substituted with a lower alkyl group or a lower alkoxy group, a lower alkyl group, a trifluoromethyl group,-(CH ₂ ) _m -B or -N (R ⁴ )-(CH ₂ ) _m -B (wherein b is as defined above, R ⁴ Represents a hydrogen atom or a lower alkyl group, m represents an integer of 1 to 5], a formula -a-g-h [wherein a represents the same meaning as described above, and g Is —CO— or —CS—, h is an amino group optionally substituted with a lower alkyl group, a hydroxyl group, a lower alkyl group, a lower alkoxy group, — (CH ₂ ) _n -B or -N (R ⁵ )-(CH ₂ ) _n -B (wherein b is as defined above, R ⁵ Represents a hydrogen atom or a lower alkyl group, n represents an integer of 1 to 5, and a group represented by the formula -a-N (R ⁶ ) -Gi [wherein a and g have the same meaning as described above; ⁶ Is a hydrogen atom or a lower alkyl group, i is a hydrogen atom, a lower alkoxy group or f (f is as defined above), a group represented by the formula -a-N (R ⁷ ) -Ef (wherein a, e and f have the same meaning as above, R ⁷ Represents a hydrogen atom or a lower alkyl group), a group represented by the formula — (CH ₂ ) _p -J- (CH ₂ ) _q -B (wherein j represents an oxygen atom or a sulfur atom, b represents the same meaning as described above, p and q are the same or different and represent an integer of 1 to 5), a formula-(CH ₂ ) _u -Ar (wherein Ar represents a phenyl group or heteroaryl group optionally substituted with a lower alkyl group, a lower alkoxy group or a halogen atom, and u represents 0 or an integer of 1 to 5), Formula -CONH- (CH ₂ ) _u -Ar (wherein Ar and u are as defined above), or -SO ₂ -(CH ₂ ) _u A group represented by -Ar (wherein Ar and u are as defined above) and the like.
[0011]
In the above substituent examples, when the amino group is substituted with two alkyl groups, these alkyl groups may be bonded to form a 5- or 6-membered ring. When the A ring is a nitrogen-containing heterocycle having a hydroxyl group or a mercapto group, these groups may take the form of an oxo group or a thioxo group by taking a resonance structure.
[0012]
The ring B means “an optionally substituted 6-membered cyclic unsaturated hydrocarbon or an unsaturated 6-membered heterocycle containing one nitrogen atom as a heteroatom” is partially hydrogenated. Benzene or pyridine, which may have one or two substituents on the ring, and when there are two substituents, they may be the same or different.
[0013]
The C ring “optionally substituted 5-membered heterocycle containing 1 or 2 nitrogen atoms” is pyrrole, pyrazole, imidazole, which may be partially hydrogenated. The ring may have 1 or 2 substituents, and when there are 2 substituents, they may be the same or different.
Examples of the substituent that the B ring and the C ring may have include, for example, a halogen group, a cyano group, a lower alkyl group, a lower alkoxy group, a hydroxyl group, an oxo group, a formula —CO—r (wherein r is a hydrogen atom) Atoms, amino groups optionally substituted with lower alkyl groups, lower alkyl groups, lower alkoxy groups or hydroxyl groups), amino groups optionally substituted with lower alkyl groups, trifluoromethyl groups, etc. Can do.
[0014]
In the above general formula (I), R ¹ , R ² And the lower alkyl group in the definition of the substituent that the A ring, the B ring, and the C ring may have include a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group and an ethyl group N-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group (amyl group), isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl Group, 2-methylbutyl group, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1 , 2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ester Rubuchiru group, 1,1,2-trimethyl propyl group, 1,2,2-trimethyl propyl group, 1-ethyl-1-methylpropyl group, means such as 1-ethyl-2-methylpropyl group. Among these, preferred groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an isobutyl group. Among these, the most preferred groups are a methyl group and an ethyl group. , N-propyl group, and isopropyl group.
[0015]
Examples of the lower cycloalkyl group in the definition of the substituent that the A ring may have include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group. The lower alkoxy group in the definition of the substituent that the A ring, B ring and C ring may have is a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, A lower alkoxy group derived from the above lower alkyl group such as a tert-butoxy group is meant, and among these, the most preferred group includes a methoxy group and an ethoxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom.
[0016]
The sulfonamide derivative or sulfonic acid ester derivative represented by the general formula (I) may form a salt with an acid or a base. The present invention also includes a salt of compound (I). Examples of the salt with an acid include inorganic acid salts such as hydrochloride, hydrobromide and sulfate, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, p- Mention may be made of salts with organic acids such as toluenesulfonic acid. Examples of the salt with a base include inorganic salts such as sodium salt, potassium salt and calcium salt, and salts with organic bases such as triethylamine, arginine and lysine.
[0017]
Needless to say, not only hydrates of these compounds but also optical isomers are present when they are present. The present invention also includes compounds that produce the compound of the present invention upon metabolism in vivo such as oxidation, reduction, and hydrolysis.
Next, although this invention compound (I) can be manufactured by various methods, if the typical method is shown among them, it will be as follows.
1) General formula (II)
[0018]
[Chemical 3]

[0019]
Wherein the Aa ring represents a monocyclic or bicyclic aromatic ring optionally having a protected or unprotected substituent, and W has the same meaning as described above. Sulfonic acid or its reactive derivatives and general formula (III)
[0020]
[Formula 4]

[0021]
(In the formula, Ba ring represents a 6-membered unsaturated hydrocarbon or an unsaturated 6-membered heterocycle containing one nitrogen atom as a heteroatom, which may have a protected or unprotected substituent. , Ca ring represents a 5-membered heterocycle containing 1 or 2 nitrogen atoms, which may have a protected or unprotected substituent, and X, Y and Z have the same meaning as described above It can manufacture by making the compound represented by this react.
[0022]
Examples of the reactive derivative of sulfonic acid (II) include commonly used reactive derivatives such as sulfonyl halides, sulfonic anhydrides, N-sulfonyl imidazolides, and the like. An example is a sulfonyl halide. The solvent used for the reaction is not particularly limited, but a solvent that dissolves the raw materials and does not easily react with them is preferable. For example, pyridine, tetrahydrofuran, dioxane, benzene, ethyl ether, dichloromethane, dimethylformamide, or the like is selected. Two or more kinds of mixed solvents may be used. In addition, when an acid is liberated as the reaction proceeds, as in the case of using a sulfonyl halide in this reaction, it is preferably carried out in the presence of a suitable deoxidizing agent. The use of a basic solvent is particularly preferred. When a neutral solvent is used, a basic substance such as an alkali carbonate or an organic tertiary amine may be added. Of course, the solvents that can be used are not limited to those listed here. In general, this reaction proceeds at room temperature, but may be cooled or heated as necessary. The reaction time is usually 10 minutes to 20 hours, but is arbitrarily selected depending on the type of raw material compound and the reaction temperature.
[0023]
In the obtained product, when the amino group or hydroxyl group is protected, a sulfone having a free hydroxyl group or amino group can be obtained by carrying out a conventional deprotection method such as acid treatment, alkali treatment, catalytic reduction, if desired. It is possible to obtain amide derivatives or sulfonic acid ester derivatives (I).
2) General formula (IV)
[0024]
[Chemical formula 5]

[0025]
(Wherein Aa ring, Ba ring, W, X and Z have the same meaning as described above) can be produced by reacting with a halogenating agent. Examples of the halogenating agent include N-chlorosuccinimide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, N-bromoacetamide, chlorine, bromine and the like. The solvent used in the reaction is not particularly limited, but usually, alkyl chloride compounds such as dichloromethane, chloroform, carbon tetrachloride, and aromatic chlorides such as chlorobenzene and dichlorobenzene are used, but dimethylformamide, dioxane, pyridine, acetonitrile Water-soluble solvents such as can also be used. The reaction temperature varies depending on the halogenating agent and the type of the substrate, but is usually between -50 ° C and 100 ° C.
[0026]
In the obtained product, when the amino group or hydroxyl group is protected, a sulfone having a free hydroxyl group or amino group can be obtained by carrying out a conventional deprotection method such as acid treatment, alkali treatment, catalytic reduction, if desired. It is possible to obtain amide derivatives or sulfonic acid ester derivatives (I).
3) General formula (V)
[0027]
[Chemical 6]

[0028]
(Wherein, Aa ring, Ba ring, W, X and Z have the same meaning as described above, and E means a substituent which can be converted to a cyano group by dehydration) and reacting with a dehydrating agent. Can be manufactured. Examples of the substituent that can be converted to a cyano group by dehydration include a (hydroxyimino) methyl group and a carbamoyl group.
[0029]
It is also possible to first synthesize an oxime or acid amide from a raw material aldehyde or carboxylic acid and react with a dehydrating agent without isolation. Examples of the dehydrating agent include methods generally used for the synthesis of nitriles such as acetic anhydride, thionyl chloride, phosphorus oxychloride, selenium dioxide, 1,3-dicyclohexylcarbodiimide and the like. The solvent used in the reaction is not particularly limited, but a solvent that dissolves the raw materials and does not easily react with them is desirable. For example, pyridine, ethyl ether, benzene, dimethylformamide, carbon tetrachloride, acetonitrile, tetrahydrofuran, or the like. Two or more selected mixed solvents can be used. While the reaction temperature varies depending on the kind of dehydrating agent and substrate, it is usually carried out between −50 ° C. and 150 ° C.
[0030]
In the obtained product, when the amino group or hydroxyl group is protected, a sulfone having a free hydroxyl group or amino group can be obtained by carrying out a conventional deprotection method such as acid treatment, alkali treatment, catalytic reduction, if desired. It is possible to obtain amide derivatives or sulfonic acid ester derivatives (I).
4) General formula (VI)
[0031]
[Chemical 7]

[0032]
(In the formula, the Ab ring has a substituent that can be converted to an amino group by reduction, and may have another protected or unprotected substituent, which may be a monocyclic or bicyclic aromatic group. Which means a ring, Ba ring, Ca ring, W, X, Y and Z have the same meaning as described above) and can be produced by reacting with a reducing agent. Examples of the substituent that can be converted to an amino group by reduction include a nitro group, a nitroso group, a hydroxyamino group, and an azo group.
[0033]
For the reduction, a commonly used nitro group reduction method can be used. Preferred examples include catalytic reduction using palladium-carbon, platinum oxide or the like as a catalyst, or reduction with zinc, iron or tin and an acid. be able to. The catalytic reduction can be usually carried out in an organic solvent such as methanol, tetrahydrofuran, dimethylformamide or the like at normal pressure or under pressure.
[0034]
In the obtained product, when a hydroxyl group is protected, a sulfonamide derivative or a sulfonate ester having a free hydroxyl group can be obtained by carrying out a conventional deprotection method such as acid treatment, alkali treatment, catalytic reduction, if desired. It is possible to obtain the derivative (I).
5) General formula (VII)
[0035]
[Chemical 8]

[0036]
(Wherein the Ac ring has a leaving group on the ring or in a substituent and may have other protected or unprotected substituents, monocyclic or bicyclic aromatics. Which means a ring, Ba ring, Ca ring, W, X, Y and Z have the same meaning as described above) and can be produced by reacting with a nucleophile. Examples of the leaving group include a halogen group, a methanesulfonyloxy group, and a p-toluenesulfonyloxy group. Examples of the nucleophilic agent include amines, alcohols, thiols and the like. In the case of alcohols, thiols, etc., they may be reacted in the form of a salt with an alkali metal or the like. The solvent used in the reaction is not particularly limited, but a solvent that dissolves the raw materials and does not easily react with them is desirable. For example, tetrahydrofuran, dioxane, dimethylformamide, water, and the like can be used. The reaction temperature varies depending on the type of substrate, but it is usually between -50 ° C and 150 ° C.
[0037]
In the obtained product, when the amino group or hydroxyl group is protected, a sulfone having a free hydroxyl group or amino group can be obtained by carrying out a conventional deprotection method such as acid treatment, alkali treatment, catalytic reduction, if desired. It is possible to obtain amide derivatives or sulfonic acid ester derivatives (I).
[0038]
Next, the raw material compound (II) and its reactive derivative used in the present invention and a method for producing (III) will be described.
The starting compound (II) and its reactive derivative include known compounds and novel compounds. In the case of a novel compound, it can be produced by applying a known method for synthesizing a known compound or by combining them. For example, novel sulfonyl chlorides are described in Chem. Ber., 90, 841 (1957), J. Med. Chem., 6, 307 (1963), J. Chem. Soc. (C), 1968, 1265, Chem. Lett. , 1992, 1483, J. Am. Chem. Soc., 59, 1837 (1937), J. Med. Chem., 23, 1376 (1980), J. Am. Chem. Soc., 70, 375 (1948) , J. Am. Chem. Soc., 78, 2171 (1956) and the like.
[0039]
The starting compound (III) includes known compounds and novel compounds. In the raw material compound (III), H—X— is an amino group H ₂ When N- is meant, the nitro compound is reduced by a commonly used nitro group reduction method to reduce H. ₂ N-form (III) can be obtained. Preferable examples of the reduction method include catalytic reduction using palladium-carbon as a catalyst and reduction with zinc dust-hydrochloric acid. Catalytic reduction can usually be carried out in an organic solvent such as methanol, tetrahydrofuran or dimethylformamide at normal pressure or under pressure.
[0040]
In the raw material compound (III), when H—X— means a hydroxyl group HO—, the amino compound can be diazotized and then hydrolyzed to obtain the HO compound (III).
[0041]
When the raw material compound is a novel compound, it can be produced by applying a known method for synthesizing a known compound or by combining them. The novel compound is obtained by applying the method described in Can. J. Chem., 42, 1235 (1964), Chem. Abst., 59, 8855f (1963), Tetrahedron Lett., 30, 2129 (1989), etc. For example, it can be manufactured by the following route.
Reaction formula 1
[0042]
[Chemical 9]

[0043]
In formula, Q means the same or different substituent, G means a halogen group, and t is an integer of 0-2.
Reaction formula 2
[0044]
Embedded image

[0045]
In the formula, Q and t have the same meaning as described above.
Reaction formula 3
[0046]
Embedded image

[0047]
In the formula, Q, G and t have the same meaning as described above, and DPPA means diphenylphosphoryl azide.
Reaction formula 4
[0048]
Embedded image

[0049]
In the formula, Q, G and t have the same meaning as described above, and DDQ means 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
[0050]
When the compound of the present invention is used as a medicine, it is administered orally or parenterally. The dose varies depending on the degree of symptoms, patient age, sex, body weight, sensitivity difference, administration method, administration timing, administration interval, properties of pharmaceutical preparation, preparation, type, type of active ingredient, etc. The daily dose for adults is 10 to 6000 mg, preferably about 50 to 4000 mg, more preferably 100 to 3000 mg, which is usually administered in 1 to 3 divided doses per day.
[0051]
When preparing an oral solid preparation, after adding a binder, a disintegrating agent, a lubricant, a coloring agent, a corrigent, etc. to the main drug as necessary, tablets, coated tablets, Granules, fine granules, powders, capsules, etc.
Examples of the excipient include lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose, silicon dioxide and the like, and examples of the binder include polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropyl methylcellulose and the like. As the lubricant, for example, magnesium stearate, talc, silica and the like are permitted to be added to the pharmaceutical as the coloring agent, and as the flavoring agent, cocoa powder, mint brain, aromatic acid, Mentha oil, Borneolum, cinnamon powder, etc. are used. Of course, these tablets and granules may be appropriately coated with sugar coating, gelatin coating, etc. if necessary.
[0052]
When preparing injections, add pH adjusters, buffers, suspending agents, solubilizing agents, solubilizers, tonicity agents, preservatives, etc. to the active ingredient as necessary. Subcutaneous and intramuscular injection. At that time, if necessary, it may be lyophilized by a conventional method.
Examples of the suspending agent include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like.
[0053]
Examples of the solubilizer include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester.
Examples of the stabilizer include sodium sulfite and sodium metasulfite, and examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.
[0054]
【The invention's effect】
The effects of this compound are shown below by pharmacological experimental examples.
Pharmacological Experiment Example 1 Angiogenesis Inhibitory Action
The degree of inhibition of neovascularization observed when rat aortic strips were cultured in collagen was defined as angiogenesis inhibitory activity. That is, the peripheral adipose tissue is carefully removed while washing the aorta extracted from a Sprague-Dawley female rat (10-12 weeks old) with Hanks' solution. The aorta is dissected and a 2 mm square section is prepared, and then placed in a 24-well plate with the endothelial cell surface facing up. Next, 500 μl of neutralized type I collagen (Cell Matrix Type IA: Nitta Gelatin) is poured into each well and left in a clean bench at room temperature for about 20 minutes to solidify the gel. After confirming that the gel has hardened, add 500 μl MCDB131 medium (Chlorella Kogyo), CO ₂ Incubator (5% CO ₂ ) At 37 ° C. On the next day, the culture medium is replaced with 500 μl of MCDB131 medium containing the test compound, and the culture is continued. Three days later, the medium was replaced again with 500 μl of MCDB131 medium containing the test compound, and the number of capillaries formed around the aorta at the seventh day from the start of the addition of the test compound was counted under a microscope. The test compound-containing solution was adjusted in a 3-fold dilution series with a maximum concentration of 10 μg / ml.
[0055]
The inhibition rate was calculated from the following formula, and the 50% inhibition concentration (IC ₅₀ Value).
Inhibition rate (%) = (C-T) / C x 100
C: number of capillaries without compound
T: number of capillaries at compound addition
[0056]
[Table 1]

[0057]
Next, although an example is given about the manufacture example which shows manufacture of the raw material compound of this invention compound, and the typical compound of this invention compound, this invention is not limited only to these.
Production Example 1
7-Bromo-1H-indole
To a tetrahydrofuran solution (250 ml) of 5.05 g (25 mmol) of 2-bromonitrobenzene, 100 ml (100 mmol) of a 1.0M vinylmagnesium bromide 1.0 M tetrahydrofuran solution was added at −40 ° C. in a nitrogen atmosphere, and the mixture was stirred as it was for 40 minutes. The reaction mixture was poured into 500 ml of saturated aqueous ammonium chloride solution and extracted with ethyl ether. After drying over magnesium sulfate and concentration, the residue was purified by silica gel column chromatography to obtain 2.89 g of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.56 (1H, dd, J = 2.9, 1.8Hz), 6.94 (1H, t, J = 7.8Hz), 7.30 (1H, d, J = 7.8Hz), 7.40 (1H, t, J = 2.9Hz), 7.56 (1H, d, J = 7.8Hz), 11.16-11.46 (1H, br m)
[0058]
Production Example 2
7-amino-1H-indole
To a solution (50 ml) of 2.70 g (13.8 mmol) of the compound of Production Example 1 was added dropwise 16.5 ml (41.3 mmol) of a 2.5M hexane solution of n-butyllithium at −70 ° C. in a nitrogen atmosphere. Subsequently, it stirred at -20--10 degreeC for 30 minutes. After cooling again to −70 ° C., 3.9 ml (18 mmol) of diphenylphosphoryl azide was added dropwise, and the mixture was stirred at −70 ° C. for 1 hour and then at −40 ° C. for 1 hour. Sodium bis (2-methoxyethoxy) aluminum hydride 3.4M toluene solution (22.3 ml, 75.8 mmol) was added at −40 ° C., followed by stirring at −30 to −20 ° C. for 30 minutes, and then at room temperature for 30 minutes. A pH 7.0 phosphate buffer was added, insolubles were filtered off, and the filtrate was extracted with ethyl ether. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography to obtain 1.29 g of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 5.01 (2H, br s), 6.25-6.33 (2H, m), 6.70 (1H, dd, J = 7.9, 7.3Hz), 6.78 (1H, dd, J = 7.9, 0.7Hz) , 7.23 (1H, t, J = 2.7Hz), 10.48-10.72 (1H, br m)
In the same manner as in Production Examples 1 and 2, the following raw material compounds were synthesized from 2-bromonitrobenzene derivatives.
[0059]
7-amino-4-methoxy-1H-indole
7-amino-4-bromo-1H-indole
[0060]
Production Example 3
7-Bromo-3-chloro-4-methyl-1H-indole
7-Bromo-4-methyl-1H-indole synthesized in the same manner as in Production Example 1 from 2-bromo-5-methylnitrobenzene in an acetonitrile solution (250 ml) of 5.8 g (27.6 mmol), 4.0 g of N-chlorosuccinimide ( 30.0 mmol) was added and stirred at room temperature overnight. 1N Aqueous sodium hydroxide solution (50 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain 6.7 g of the title compound.
¹ H-NMR (CDCl _Three ) δ (ppm): 2.74 (3H, s), 6.75-7.26 (3H, m), 8.23 (1H, br s)
[0061]
Production Example 4
7-Amino-3-chloro-4-methyl-1H-indole
In the same manner as in Production Example 2, 2.6 g of the title compound was obtained from 6.37 g (26.1 mmol) of Production Example 3.
¹ H-NMR (CDCl _Three ) δ (ppm): 2.70 (3H, s), 6.39-7.14 (3H, m), 8.15 (1H, br s)
[0062]
Production Example 5
4-sulfamoylbenzenesulfonyl chloride
6.4 g (37.2 mmol) of 4-aminobenzenesulfonamide was added to a mixture of 12.5 ml of water and 6.3 ml of concentrated hydrochloric acid and stirred. To this was added dropwise a saturated aqueous solution of 2.56 g (37.1 mmol) of sodium nitrite at 0 ° C. or lower. The reaction solution was added to a sulfur dioxide saturated acetic acid solution (a solution in which sulfur dioxide was saturated with 35 ml of acetic acid and 1.5 g of cupric chloride dihydrate was added) with ice cooling and stirring. After 10 minutes, the reaction solution was poured into ice water, and the precipitate was collected by filtration and washed with water. The precipitate was dissolved in tetrahydrofuran, dried over magnesium sulfate, and concentrated to dryness to give 3.5 g of the title compound.
[0063]
Production Example 6
4- (sulfamoylmethyl) benzenesulfonyl chloride
4-Nitrophenylmethanesulfonamide 5.0 g (23.1 mmol) was suspended in 90% acetic acid, and hydrogenated at normal temperature and pressure in the presence of palladium-carbon. The catalyst was removed by filtration and concentrated to dryness to obtain 4.3 g of 4-aminophenylmethanesulfonamide. This was added to a mixture of 40 ml of water and 4.1 ml of concentrated hydrochloric acid and stirred. A saturated aqueous solution of 1.63 g (23.6 mmol) of sodium nitrite was added dropwise at 0 ° C. or lower. The reaction solution was added to a sulfur dioxide saturated acetic acid solution (a solution in which sulfur dioxide was saturated with 30 ml of acetic acid and 0.97 g of cupric chloride dihydrate was added) with ice cooling and stirring. After stirring at room temperature for 40 minutes, the reaction solution was poured into ice water to saturate sodium chloride. The mixture was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated to dryness to give 1.7 g of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 4.26 (2H, s), 7.32 (2H, d, J = 8.4Hz), 7.59 (2H, d, J = 8.4Hz)
The following compounds were synthesized in the same manner as in Production Example 5 or 6.
[0064]
4- (N-methylsulfamoyl) benzenesulfonyl chloride
4- (N-ethylsulfamoyl) benzenesulfonyl chloride
4- (N-methoxysulfamoyl) benzenesulfonyl chloride
4-[(Methanesulfonamido) methyl] benzenesulfonyl chloride
4- (N-methylmethanesulfonamido) benzenesulfonyl chloride
4- (1-Pyrrolidinylsulfonyl) benzenesulfonyl chloride
4- (1-Pyrrolidinylcarbonyl) benzenesulfonyl chloride
3-Cyanobenzenesulfonyl chloride
4- (Methylsulfonyl) benzenesulfonyl chloride
4-[(N-methylmethanesulfonamido) methyl] benzenesulfonyl chloride
[0065]
Production Example 7
3-Cyano-7-nitro-1H-indole
10.15 g (53.4 mmol) of 3-formyl-7-nitro-1H-indole was dissolved in 150 ml of dimethylformamide, and 3.93 g (56.0 mmol) of hydroxylamine hydrochloride and 4.5 ml (55.6 mmol) of pyridine were added. After heating and stirring at 70-80 ° C. for 2 hours, 6.3 g (56.8 mmol) of selenium dioxide and about 5 g of magnesium sulfate were added. After further heating at 70-80 ° C. for 2.5 hours, the insoluble material was filtered off and concentrated. Water was added and the precipitated crystals were collected by filtration and washed successively with water and ethyl ether. The crystals were dissolved in a mixed solution of tetrahydrofuran and acetone, and insoluble materials were removed by filtration. After concentration, ethyl acetate was added and the crystals were collected by filtration to give 8.61 g of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.48 (1H, t, J = 8.1Hz), 8.17 (1H, d, J = 8.1Hz), 8.27 (1H, d, J = 8.1Hz), 8.47 (1H, s), 12.70 -13.00 (1H, br)
[0066]
Production Example 8
7-amino-3-cyano-1H-indole
2.80 g (15.0 mmol) of the compound of Production Example 7 was suspended in 100 ml of methanol and hydrogenated at normal temperature and pressure in the presence of palladium-carbon. The catalyst was filtered off and concentrated to dryness to give 2.31 g of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 5.32, 5.34 (2H, s + s), 6.47 (1H, d, J = 7.5Hz), 6.81 (1H, d, J = 7.9Hz), 6.94 (1H, dd, J = 7.9 , 7.5Hz), 8.13 (1H, s), 11.55-11.90 (1H, br),
[0067]
Production Example 9
7-amino-3,4-dichloro-1H-indole
7-Bromo-4-chloro-1H-indole obtained from 2-bromo-5-chloronitrobenzene in the same manner as in Production Example 1 is first chlorinated in the same manner as in Production Example 3, and then in the same manner as in Production Example 2. The title compound was obtained by converting the bromo group to an amino group.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 5.26 (2H, s), 6.29 (1H, d, J = 8.1Hz), 6.74 (1H, d, J = 8.1Hz), 7.45-7.51 (1H, m), 11.08-11.27 ( 1H, m)
Similarly, 7-amino-4-tert-butyldimethylsilyloxy-3-chloro-1H-indole was synthesized.
[0068]
Production Example 10
7-amino-3-chloro-1H-indole
1.076 g (6.64 mmol) of 7-nitro-1H-indole was dissolved in 30 ml of acetonitrile, and 920 mg (6.89 mmol) of N-chlorosuccinimide was added. After stirring at room temperature for 36 hours, saturated aqueous sodium hydrogen carbonate was added, and the precipitate was collected by filtration and washed with water to obtain 1.2 g of 3-chloro-7-nitro-1H-indole. 863 mg (4.39 mmol) of this powder was suspended in 10 ml of ethanol, and 4.95 g (21.9 mmol) of stannous chloride dihydrate and 100 μl of concentrated hydrochloric acid were added. After heating under reflux for 30 minutes, saturated aqueous sodium hydrogen carbonate was added, and insoluble material was removed by filtration. The mixture was extracted with ethyl acetate, dried over magnesium sulfate, concentrated, and purified by silica gel column chromatography to give the title compound (490 mg).
[0069]
The title compound was also obtained by hydrogenating 3-chloro-7-nitro-1H-indole at room temperature and pressure in the presence of a platinum-carbon catalyst.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 5.14 (2H, s), 6.36 (1H, dd, J = 7.5, 1.0Hz), 6.68 (1H, dd, J = 7.9, 0.73Hz), 6.81 (1H, dd, J = 7.9 , 7.5Hz), 7.39 (1H, d, J = 2.7Hz), 10.85 (1H, br s)
[0070]
Production Example 11
4- (2-sulfamoylethyl) benzenesulfonyl chloride
To 2.4 g (36.5 mmol) of chlorosulfonic acid, 1.3 g (7.3 mmol) of 2-phenylethanesulfonamide was added over 20 minutes under ice cooling, and the mixture was further stirred at room temperature for 90 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.6 g of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.97-3.02 (2H, m), 3.21-3.26 (2H, m), 7.21 (2H, d, J = 8.4Hz), 7.53 (2H, d, J = 8.4Hz)
Similarly, the following raw material compounds were synthesized.
[0071]
4- [2- (Methylsulfonyl) ethyl] benzenesulfonyl chloride
4- [2- (N-methylmethanesulfonamido) ethyl] benzenesulfonyl chloride
4- [2- (Methanesulfonamido) ethyl] benzenesulfonyl chloride
4- (N-methylacetamido) benzenesulfonyl chloride
[0072]
Production Example 12
5-Bromo-7-nitro-1H-indole
1-Acetyl-5-bromo-7-nitroindoline (5.05 g, 17.7 mmol) was added to a mixture of ethanol (6 ml) and 6N hydrochloric acid (40 ml), and the mixture was heated to reflux for 3 hours. The mixture was neutralized with sodium carbonate, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. After concentration, the product was purified by silica gel column chromatography to obtain 4.13 g of 5-bromo-7-nitroindoline. 301 mg (1.24 mmol) of this compound was added to 10 ml of toluene, followed by 580 mg (2.55 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The mixture was heated to reflux with stirring for 3.5 hours, and the insoluble material was removed by filtration and concentrated. The residue was purified by silica gel column chromatography to give the title compound (252 mg).
[0073]
Production Example 13
5-Bromo-3-formyl-7-nitro-1H-indole
To 1.0 g (14 mmol) of dimethylformamide was added 210 mg (1.4 mmol) of phosphorus oxychloride at 0 ° C. in a nitrogen atmosphere, and the mixture was stirred for 30 minutes. 240 mg (1.0 mmol) of the compound of Production Example 12 was added at 0 ° C., and the mixture was stirred at 0 ° C. for 20 minutes and then at 100 ° C. for 30 minutes. The reaction mixture was ice-cooled, poured into ice water, and stirred for 30 minutes while adding 1N aqueous sodium hydroxide and maintaining the pH at 7-8. The resulting precipitate was collected by filtration, washed with water, and purified by silica gel column chromatography to obtain 239 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 8.31 (1H, d, J = 1.8Hz), 8.55 (1H, s), 8.65 (1H, d, J = 1.8Hz), 10.05 (1H, s), 12.89 (1H, br s) )
[0074]
Production Example 14
7-amino-5-bromo-3-cyano-1H-indole
214 mg (0.8 mmol) of 5-bromo-3-cyano-7-nitro-1H-indole obtained from the compound of Production Example 13 in the same manner as in Production Example 7 was dissolved in a mixture of 10 ml of methanol and 10 ml of tetrahydrofuran. 3.0kg / cm in the presence of platinum oxide ² After hydrogenation, the catalyst was removed by filtration and concentrated to dryness to give 189 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 5.68-5.71 (2H, m), 6.60 (1H, d, J = 2.0Hz), 6.91 (1H, d, J = 2.0Hz), 8.16 (1H, s)
[0075]
Production Example 15
3-acetyl-7-amino-1H-indole
Under a nitrogen atmosphere, 11 ml (11 mmol) of 1.0 M hexane solution of dimethylaluminum chloride was added to a dichloromethane solution (50 ml) of 1.2 g (7.5 mmol) of 7-nitro-1H-indole at 0 ° C. Then, 2.1 ml (29.5 mmol) of acetyl chloride was added at 0 ° C., and the mixture was stirred at room temperature for 4 hours. Saturated aqueous ammonium chloride was added to the reaction system, and the resulting precipitate was collected by filtration. The precipitate was thoroughly washed with hot ethanol, and the washing was combined with the filtrate and concentrated. Water was added to the residue, extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3-acetyl-7-nitro-1H-indole. This was dissolved in 100 ml of methanol and hydrogenated in the presence of palladium-carbon at normal temperature and pressure. The catalyst was removed by filtration and then concentrated to dryness to obtain 790 mg of the title compound.
[0076]
Synthesis example 1
N- (1H-Indol-7-yl) -4-nitrobenzenesulfonamide
1.50 g (11.3 mmol) of the compound of Production Example 2 was dissolved in 40 ml of pyridine, and 2.57 g (11.6 mmol) of 4-nitrobenzenesulfonyl chloride was added with stirring at room temperature. After stirring overnight at room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate and 0.2N hydrochloric acid were added to the residue. The organic layer was separated, washed with water, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3.50 g of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.42 (1H, dd, J = 2.8, 2.0Hz), 6.66 (1H, d, J = 7.6Hz), 6.83 (1H, dd, J = 8.0, 7.6Hz), 7.31 (1H, dd, J = 3.2, 2.8Hz), 7.36 (1H, d, J = 8.0Hz), 7.94-8.02 (2H, m), 8.30-8.38 (2H, m), 10.23 (1H, s), 10.74-10.87 (1H, m)
[0077]
Synthesis example 2
N- (3-Chloro-1H-indol-7-yl) -4-nitrobenzenesulfonamide
8.98 g (28.3 mmol) of the compound of Synthesis Example 1 was dissolved in a mixed solvent of 280 ml of dichloromethane and 7 ml of dimethylformamide, and 4.16 g (31.2 mmol) of N-chlorosuccinimide was added with stirring under a nitrogen atmosphere. After stirring at room temperature for 1.5 hours, 50 ml of water was added and the mixture was concentrated until the liquid volume became about 80 ml. Ethyl acetate and 0.2N hydrochloric acid were added, and the organic layer was separated and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 7.98 g of the title compound.
Melting point: 199.5-200.5 ℃ (recrystallized from chloroform)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.72 (1H, d, J = 7.6Hz), 6.96 (1H, dd, J = 8.0, 7.6Hz), 7.31 (1H, d, J = 8.0Hz), 7.47-7.53 (1H, m), 7.92-8.02 (2H, m), 8.30-8.41 (2H, m), 10.33 (1H, s), 11.07-11.22 (1H, m)
[0078]
Synthesis example 3
4-Amino-N- (3-chloro-1H-indol-7-yl) benzenesulfonamide
7.98 g (22.7 mmol) of the compound of Synthesis Example 2 was dissolved in 220 ml of methanol and heated to reflux with stirring. To this, 10 ml of concentrated hydrochloric acid and 7.40 g of zinc powder were added three times at intervals of 10 minutes, and the mixture was further refluxed for 10 minutes. After cooling, a large excess of sodium bicarbonate was added to neutralize, and insolubles were collected by filtration. After the filtrate was concentrated, the residue was dissolved in ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate, 2N aqueous sodium carbonate, and saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 7.21 g of the title compound.
Melting point: 174.5-176 ° C (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 5.97 (2H, br s), 6.48 (2H, d, J = 8.8Hz), 6.88 (1H, d, J = 7.6Hz), 6.95 (1H, dd, J = 8.0, 7.6Hz) ), 7.19 (1H, d, J = 8.0Hz), 7.36 (2H, d, J = 8.8Hz), 7.46 (1H, d, J = 2.4Hz), 9.56 (1H, s), 10.86-10.98 (1H , m)
[0079]
Synthesis example 4
N- (3-Chloro-1H-indol-7-yl) -4- (methanesulfonamido) benzenesulfonamide
68 mg (0.211 mmol) of the compound of Synthesis Example 3 was dissolved in 1 ml of pyridine, and 15 μl (0.194 mmol) of methanesulfonyl chloride was added. After stirring at room temperature overnight, aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and water and then dried over magnesium sulfate. After concentration, the residue was purified by silica gel thin layer chromatography to give 76 mg of the title compound.
Melting point: 213.5-214 ° C (decomposition)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 3.08 (3H, s), 6.83 (1H, d, J = 7.5Hz), 6.96 (1H, dd, J = 7.9, 7.7Hz), 7.23 (2H, d, J = 8.8Hz) , 7.24 (1H, d, J = 7.5Hz), 7.47 (1H, d, J = 2.7Hz), 7.68 (2H, d, J = 8.8Hz), 9.92 (1H, br s), 10.38 (1H, br s), 10.99 (1H, br s)
[0080]
Synthesis example 5
4-Bromomethyl-N- (1H-indol-7-yl) benzenesulfonamide
4-Bromomethylbenzenesulfonyl chloride and the compound of Production Example 2 were reacted in tetrahydrofuran at room temperature in the presence of an equimolar amount of pyridine and treated in the same manner as in Synthesis Example 1 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 4.70 (2H, s), 6.40 (1H, dd, J = 3.1, 1.1Hz), 6.71 (1H, ddd, J = 7.4, 3.2, 0.92Hz), 6.81 (1H, ddd, J = 8.1, 7.4, 0.92Hz), 7.29-7.32 (2H, m), 7.57 (2H, d, J = 8.2Hz), 7.73 (2H, d, J = 8.4Hz), 9.96 (1H, br s), 10.75 (1H, br s)
[0081]
Synthesis Example 6
N- (1,3-dihydro-2H-indol-2-one-7-yl) -4-methylbenzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
Melting point: Decomposing gradually from around 246 ° C and rapidly decomposing at 267-269 ° C (recrystallization from dioxane)
[0082]
Synthesis example 7
3-Chloro-N- (3-chloro-1H-indol-7-yl) benzenesulfonamide
2.18 g (7.11 mmol) of 3-chloro-N- (1H-indol-7-yl) benzenesulfonamide synthesized in the same manner as in Synthesis Example 1 was chlorinated in the same manner as in Example 2 to obtain 1.86 g of the title compound. It was.
Melting point: 180-181 ° C (recrystallized from dichloromethane-diisopropyl ether)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.73 (1H, d, J = 7.6Hz), 6.97 (1H, dd, J = 8.0, 7.6Hz), 7.30 (1H, d, J = 8.0Hz), 7.45-7.51 (1H, m), 7.51-7.76 (4H, m), 10.09 (1H, s), 11.02-11.18 (1H, m)
[0083]
Synthesis example 8
4-Amino-N- (3,4-dichloro-1H-indol-7-yl) benzenesulfonamide
From 2.43 g (6.29 mmol) of N- (3,4-dichloro-1H-indol-7-yl) -4-nitrobenzenesulfonamide synthesized in the same manner as in Synthesis Example 1, 2.03 g of the title compound. Got.
Melting point: 205-206.5 ° C (decomposition) (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.00 (2H, s), 6.50 (2H, d, J = 8.4Hz), 6.77 (1H, d, J = 8.0Hz), 6.94 (1H, d, J = 8.0Hz), 7.35 (2H, d, J = 8.4Hz), 7.51-7.58 (1H, m), 9.57 (1H, s), 11.20-11.38 (1H, m)
[0084]
Synthesis Example 9
4- [N- (1H-Indol-7-yl) sulfamoyl] benzoic acid
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.40 (1H, dd, J = 2.9, 1.9Hz), 6.67 (1H, d, J = 7.5Hz), 6.82 (1H, dd, J = 7.9, 7.5Hz), 7.31 (1H, dd, J = 2.9, 2.7Hz), 7.33 (1H, d, J = 7.9Hz), 7.81-7.88 (2H, m), 7.99-8.07 (2H, m), 10.07 (1H, s), 10.73-10.83 (1H, m), 13.30-13.58 (1H, br)
[0085]
Synthesis Example 10
N- (3-Chloro-1H-indol-7-yl) -4-cyanobenzenesulfonamide
In the same manner as in Example 2, 76 mg of the title compound was obtained from 100 mg of 4-cyano-N- (1H-indol-7-yl) benzenesulfonamide synthesized in the same manner as in Synthesis Example 1.
Melting point: 210-211 ° C (recrystallized from ethyl acetate-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.71 (1H, dd, J = 7.6, 0.8Hz), 6.96 (1H, dd, J = 8.0, 7.6Hz), 7.30 (1H, d, J = 8.0Hz), 7.48 (1H, dd, J = 2.4, 0.8Hz), 7.82-7.90 (2H, m), 7.97-8.05 (2H, m), 10.25 (1H, s), 11.04-11.15 (1H, m)
[0086]
Synthesis Example 11
3-Chloro-N- (3-chloro-4-methoxy-1H-indol-7-yl) benzenesulfonamide
In the same manner as in Example 2, 52 mg of the title compound was obtained from 100 mg of 3-chloro-N- (4-methoxy-1H-indol-7-yl) benzenesulfonamide synthesized in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 3.79 (3H, s), 6.37 (1H, d, J = 8.4Hz), 6.45 (1H, d, J = 8.4Hz), 7.24-7.31 (1H, m), 7.48-7.77 ( 4H, m), 9.76 (1H, s), 11.06-11.17 (1H, m)
[0087]
Synthesis Example 12
3-Chloro-N- (3-chloro-4-hydroxy-1H-indol-7-yl) benzenesulfonamide
N- (4-tert-butyldimethylsilyloxy-3-chloro-1H-indol-7-yl) -3-chlorobenzenesulfonamide 220 mg (0.47 mmol) synthesized in the same manner as in Synthesis Example 1 was added to 40% hydrogen fluoride. It was added to an aqueous solution-acetonitrile (1:10) mixture (2 ml). After stirring overnight at room temperature, water was added and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography to obtain 141 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.15 (1H, dd, J = 8.2, 1.5Hz), 6.26 (1H, d, J = 8.2Hz), 7.12 (1H, s), 7.47-7.64 (4H, m), 9.54 ( 1H, s), 10.85 (1H, s)
[0088]
Synthesis Example 13
N- (1H-indazol-7-yl) -4-methoxybenzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
Melting point: 155-156 ° C (recrystallized from ethyl acetate-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 3.77 (3H, s), 6.91-6.99 (2H, m), 6.98-7.07 (2H, m), 7.45-7.53 (1H, m), 7.64-7.74 (2H, m), 8.01 -8.07 (1H, m), 9.97 (1H, s), 12.61-12.72 (1H, m)
[0089]
Synthesis Example 14
6-Chloro-N- (3-chloro-1H-indol-7-yl) -3-pyridinesulfonamide
6-chloro-3-N- (1H-indol-7-yl) -3-pyridinesulfonamide obtained by reacting 6-chloro-3-pyridinesulfonyl chloride with the compound of Production Example 2 in the same manner as in Example 1 was prepared. Chlorination was carried out in the same manner as in Example 2 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.73 (1H, d, J = 7.7Hz), 6.97 (1H, dd, J = 7.9, 7.7Hz), 7.30 (1H, d, J = 7.9Hz), 7.46 (1H, d, J = 2.6Hz), 7.67 (1H, d, J = 8.4Hz), 8.03 (1H, dd, J = 8.4, 2.6Hz), 8.62 (1H, d, J = 2.6Hz), 10.18-10.34 (1H, br), 11.06-11.17 (1H, m)
[0090]
Synthesis Example 15
N- (3-Chloro-1H-indol-7-yl) -4- (methylthiomethyl) benzenesulfonamide
1.97 g (5.37 mmol) of the compound of Synthesis Example 5 was dissolved in 10 ml of tetrahydrofuran, and 10 ml (39.4 mmol) of 15% sodium methylthiolate aqueous solution and a catalytic amount of methyltrioctylammonium chloride were added at room temperature and stirred overnight. 20 ml of water was added and extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography to obtain 1.51 g of N- (1H-indol-7-yl) -4- (methylthiomethyl) benzenesulfonamide. This was chlorinated in the same manner as in Example 2 to obtain the title compound (839 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.87 (3H, s), 3.70 (2H, s), 6.77 (1H, dd, J = 7.6, 2.1Hz), 6.94 (1H, dd, J = 7.9, 7.7Hz), 7.24 ( 1H, d, J = 7.9Hz), 7.42 (2H, d, J = 8.2Hz), 7.47 (1H, d, J = 2.6Hz), 7.67 (2H, d, J = 8.4Hz), 9.96 (1H, br s), 11.01 (1H, br s)
[0091]
Synthesis Example 16
3-Chloro-N- (3-formyl-1H-indol-7-yl) benzenesulfonamide
To 14.5 ml of dimethylformamide, 1.3 ml (13.9 mmol) of phosphorus oxychloride was added dropwise at 10 ° C. or lower while stirring under a nitrogen atmosphere. After stirring at about 5 ° C. for 30 minutes, 2.50 g (8.15 mmol) of 3-chloro-N- (1H-indol-7-yl) benzenesulfonamide synthesized in the same manner as in Example 1 was added in three portions. . After stirring at about 5 ° C. for another 30 minutes, 200 ml of cold water was added. 1N aqueous sodium hydroxide solution was added to bring the pH of the reaction mixture to about 14, and then to about 2 with 1N hydrochloric acid. Ethyl acetate was added for extraction, and the organic layer was washed with saturated brine. After drying over magnesium sulfate and concentration, the residue was purified by silica gel column chromatography to obtain 1.45 g of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.70 (1H, dd, J = 7.6, 0.8Hz), 7.06 (1H, dd, J = 8.0, 7.6Hz), 7.51-7.75 (4H, m), 7.93 (1H, d, J = 8.0Hz), 8.22-8.28 (1H, m), 9.93 (1H, s), 10.17 (1H, s), 11.86-11.98 (1H, m)
[0092]
Synthesis Example 17
3-Chloro-N- (3-cyano-1H-indol-7-yl) benzenesulfonamide
Hydroxylamine hydrochloride 274 mg (3.94 mmol) and pyridine 0.32 ml (3.96 mmol) were added to a dimethylformamide solution (18 ml) of 1.20 g (3.58 mmol) of the compound of Synthesis Example 16 at 70-80 ° C. with stirring. After stirring for 2.5 hours, 437 mg (3.94 mmol) of selenium dioxide and about 100 mg of magnesium sulfate powder were added. After further stirring at the same temperature for 2 hours, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and insolubles were collected by filtration. The filtrate was washed successively with 0.1N hydrochloric acid and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound (678 mg).
Melting point: 204.5-205 ° C (recrystallized from ethyl acetate-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.71 (1H, d, J = 7.6Hz), 7.08 (1H, dd, J = 8.0, 7.6Hz), 7.47 (1H, d, J = 8.0Hz), 7.50-7.76 (4H, m), 8.17-8.25 (1H, m), 10.21 (1H, s), 11.92-12.09 (1H, m)
[0093]
Synthesis Example 18
6-Chloro-N- (3-cyano-1H-indol-7-yl) -3-pyridinesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.77 (1H, d, J = 7.9Hz), 7.12 (1H, t, J = 7.9Hz), 7.50 (1H, d, J = 7.9Hz), 7.72 (1H, d, J = 8.4Hz), 8.06 (1H, dd, J = 8.4, 2.6Hz), 8.23 (1H, d, J = 2.6Hz), 8.65 (1H, d, J = 2.6Hz), 10.34-10.48 (1H, br) , 11.98-12.12 (1H, m)
[0094]
Synthesis Example 19
N- (3-Chloro-1H-indol-7-yl) -4-sulfamoylbenzenesulfonamide
767 mg (3.0 mmol) of the compound of Preparation Example 5 and 264 mg (2.0 mmol) of the compound of Preparation Example 2 were reacted and treated in the same manner as in Example 1 to give N- (1H-indol-7-yl) -4-sulfa. 445 mg of moylbenzenesulfonamide was obtained. This was chlorinated in the same manner as in Example 2 to obtain 349 mg of the title compound.
Melting point: Partially blackening at around 220 ° C and gradually decomposing from around 240 ° C (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.75 (1H, d, J = 7.6Hz), 6.96 (1H, dd, J = 8.0, 7.6Hz), 7.29 (1H, d, J = 7.6Hz), 7.50 (1H, d, J = 2.8Hz), 7.58 (2H, s), 7.90-7.98 (4H, m), 10.23 (1H, s), 11.07-11.17 (1H, m)
[0095]
Synthesis Example 20
3-Chloro-N- (8-imidazo [1,2-a] pyridinyl) benzenesulfonamide hydrochloride
1.97 g (18 mmol) of 2,3-diaminopyridine was dissolved in a mixed solution of tetrahydrofuran and water, and a tetrahydrofuran solution of 1.90 g (9.0 mmol) of 3-chlorobenzenesulfonyl chloride was added. After stirring overnight at room temperature, the mixture was concentrated, and water and dichloromethane were added. The organic layer was separated, the vessel wall was rubbed, and the precipitated crystals were collected by filtration to obtain 1.41 g of N- (2-amino-3-pyridinyl) -3-chlorobenzenesulfonamide. 530 mg (1.87 mmol) of this crystal was dissolved in methanol, and 367 mg (1.87 mmol) of a 40% aqueous chloroacetaldehyde solution was added. The mixture was heated to reflux for 4 hours, concentrated to dryness, a small amount of methanol was added to the residue, and the crystals were collected by filtration to give the title compound (373 mg).
Melting point: Gradual decomposition from around 210 ° C (recrystallization from ethanol)
[0096]
Synthesis Example 21
N- (3,4-dichloro-1H-indol-7-yl) -4-sulfamoylbenzenesulfonamide
429 mg (1.68 mmol) of the compound of Production Example 5 and 250 mg (1.24 mmol) of the compound of Production Example 9 were reacted in the same manner as in Example 1 and processed to obtain 200 mg of the title compound.
Melting point: Coloring starts at around 282 ° C and gradually decomposes (recrystallization from ethanol-ethyl ether)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.62 (1H, d, J = 8.1Hz), 6.95 (1H, d, J = 8.1Hz), 7.53-7.62 (3H, m), 7.87-7.99 (4H, m), 10.17- 10.33 (1H, br), 11.44-11.56 (1H, m)
[0097]
Synthesis Example 22
N- (3-Chloro-1H-indol-7-yl) -4- (methylthio) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Examples 1 and 2.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.48 (3H, s), 6.82 (1H, dd, J = 7.9, 1.5Hz), 6.96 (1H, dd, J = 8.1, 7.5Hz), 7.25 (1H, dd, J = 7.9 , 0.92Hz), 7.33 (2H, d, J = 8.8Hz), 7.49 (1H, d, J = 2.7Hz), 7.62 (2H, d, J = 8.6Hz), 9.96 (1H, br s), 11.02 (1H, br s)
[0098]
Synthesis Example 23
N- (3-Chloro-1H-indol-7-yl) -4- (methylsulfonyl) benzenesulfonamide
54.2 mg (0.154 mmol) of the compound of Synthesis Example 22 was dissolved in a mixture of 2 ml of methanol and 1.2 ml of water, and 30 mg of ammonium molybdate tetrahydrate and 0.6 ml of 30% aqueous hydrogen peroxide were added at room temperature. After stirring overnight, water was added, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography to obtain 29.4 mg of the title compound.
Melting point: Coloring starts at around 250 ° C and decomposes at 264-266 ° C (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 3.28 (3H, s), 6.75 (1H, d, J = 7.7Hz), 6.97 (1H, dd, J = 7.9, 7.7Hz), 7.30 (1H, d, J = 8.1Hz) , 7.50 (1H, d, J = 2.7Hz), 7.97 (2H, d, J = 8.2Hz), 8.09 (2H, d, J = 8.4Hz), 10.29 (1H, br s), 11.12 (1H, br s)
[0099]
Synthesis Example 24
N- (3-Chloro-1H-indol-7-yl) -4- (methylsulfinyl) benzenesulfonamide
19.9 mg (0.056 mmol) of the compound of Synthesis Example 22 was dissolved in 2 ml of dichloromethane, and 10 mg (0.058 mmol) of m-chloroperbenzoic acid was added with stirring under ice cooling. After 1 hour, saturated aqueous sodium hydrogen carbonate was added, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. After concentration, purification by silica gel thin layer chromatography gave 14.4 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.76 (3H, s), 6.78 (1H, dd, J = 7.5, 1.1Hz), 6.96 (1H, dt, Jd = 0.55Hz, Jt = 7.8Hz), 7.28 (1H, dd, J = 7.6, 0.82Hz), 7.48 (1H, d, J = 2.7Hz), 7.82 (2H, d, J = 8.6Hz), 7.89 (2H, d, J = 8.8Hz), 10.15 (1H, br s ), 11.06 (1H, br s)
[0100]
Synthesis Example 25
3-Chloro-N- (3-chloro-1H-pyrrolo [3,2-c] pyridin-7-yl) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Examples 1 and 2.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.41-7.65 (2H, m), 7.65-7.77 (2H, m), 7.74-7.86 (2H, m), 8.40-8.62 (1H, br m), 12.38-12.58 (1H, br ), 13.56-13.74 (1H, br)
[0101]
Synthesis Example 26
4-acetamido-N- (3-chloro-4-methyl-1H-indol-7-yl) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
Melting point: Slow decomposition from around 225 ° C (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.03 (3H, s), 2.56 (3H, s), 6.54-6.60 (2H, m), 7.33 (1H, d, J = 2.6Hz), 7.60 (2H, d, J = 9.0 Hz), 7.64 (2H, d, J = 9.0Hz), 9.63 (1H, br s), 10.24 (1H, br s), 10.92 (1H, br s)
[0102]
Synthesis Example 27
4-Amino-N- (3-chloro-4-methyl-1H-indol-7-yl) benzenesulfonamide
3.75 g (9.9 mmol) of the compound of Synthesis Example 26 was dissolved in 25 ml of 2N aqueous sodium hydroxide solution and stirred at 100 ° C. for 2 hours. After returning to room temperature, acetic acid was added to adjust the pH to 6, and the resulting precipitate was collected by filtration and purified by silica gel column chromatography to obtain 1.1 g of the title compound.
Melting point: Slow decomposition from around 230 ° C (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.56 (3H, s), 5.93 (2H, br s), 6.46 (2H, d, J = 8.8Hz), 6.59 (1H, d, J = 7.8Hz), 6.64 (1H, d , J = 7.8Hz), 7.31 (2H, d, J = 8.8Hz), 7.36 (1H, d, J = 2.9Hz), 9.34 (1H, br s), 10.88 (1H, br s)
[0103]
Synthesis Example 28
4-Cyano-N- (3-cyano-1H-indol-7-yl) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
Melting point: 250.5-252 ° C (recrystallized from ethyl acetate-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.67 (1H, d, J = 7.7Hz), 7.05 (1H, t, J = 7.9Hz), 7.44 (1H, d, J = 7.7Hz), 7.78-7.87 (2H, m) , 7.97-8.05 (2H, m), 8.16-8.23 (1H, m), 10.28-10.43 (1H, br), 11.92-12.09 (1H, m)
[0104]
Synthesis Example 29
4-carbamoyl-N- (3-chloro-1H-indol-7-yl) benzenesulfonamide
To a solution obtained by adding 1.0 g (3.01 mmol) of the compound of Synthesis Example 10 to 4.8 ml of ethanol, 2.4 ml of 30% hydrogen peroxide solution and 360 μl of 6N sodium hydroxide aqueous solution were added in three portions with stirring (reaction temperature). About 50 ℃). The mixture was further stirred at 50 ° C for 30 minutes, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound (600 mg).
Melting point: Colored and decomposed around 248 ° C, rapidly decomposed at 252.5-253.5 ° C (recrystallized from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.76 (1H, d, J = 7.5Hz), 6.95 (1H, dd, J = 8.1, 7.5Hz), 7.27 (1H, d, J = 8.1Hz), 7.49 (1H, d, J = 2.6Hz), 7.59 (1H, br s), 7.76-7.83 (2H, m), 7.91-7.98 (2H, m), 8.12 (1H, br s), 10.10 (1H, s), 11.01-11.12 (1H, m)
[0105]
Synthesis Example 30
N- (4-Bromo-1H-indol-7-yl) -4-nitrobenzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.35-6.41 (1H, m), 6.56 (1H, d, J = 8.4Hz), 7.06 (1H, dd, J = 8.4, 0.8Hz), 7.41-7.48 (1H, m), 7.92-8.02 (2H, m), 8.30-8.41 (2H, m), 10.34 (1H, s), 11.18-11.32 (1H, m)
[0106]
Synthesis Example 31
N- (3-Chloro-4-cyano-1H-indol-7-yl) -4-nitrobenzenesulfonamide
200 mg (0.505 mmol) of the compound of Synthesis Example 30 was dissolved in 0.8 ml of N-methylpyrrolidone, and 83 mg (0.91 mmol) of cuprous cyanide was added. After stirring at 180-190 ° C. for 3 hours, 40 ml of ice water was added and the insoluble material was collected by filtration and washed with water. The insoluble material was extracted with hot ethanol and hot chloroform and concentrated. The residue was purified by silica gel thin layer chromatography to obtain 65 mg of N- (4-cyano-1H-indol-7-yl) -4-nitrobenzenesulfonamide. It was. This was chlorinated in the same manner as in Example 2 to obtain 42 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.98 (1H, d, J = 8.0Hz), 7.51 (1H, d, J = 8.0Hz), 7.79 (1H, d, J = 2.8Hz), 7.99-8.08 (2H, m) , 8.31-8.40 (2H, m), 10.75-10.95 (1H, br), 11.62-11.73 (1H, m)
[0107]
Synthesis Example 32
4-Amino-N- (3-chloro-4-cyano-1H-indol-7-yl) benzenesulfonamide
The title compound was obtained from the compound of Synthesis Example 31 in the same manner as in Synthesis Example 3.
Melting point: Decomposing gradually from around 232 ° C and rapidly decomposing at 249.5-255 ° C (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.09 (2H, s), 6.52 (2H, d, J = 8.8Hz), 7.10 (1H, d, J = 8.4Hz), 7.46 (2H, d, J = 8.8Hz), 7.50 (1H, d, J = 8.4Hz), 7.72-7.79 (1H, m), 10.20 (1H, s), 11.40-11.59 (1H, m)
[0108]
Synthesis Example 33
6-amino-N- (3-chloro-1H-indol-7-yl) -3-pyridinesulfonamide
2.48 g (7.25 mmol) of the compound of Synthesis Example 14 and 679 mg (5.07 mmol) of lithium iodide were added to 25 ml of ethanol. 10 ml of liquid ammonia was added, heated in a sealed tube at 120 ° C. for 26 hours, and concentrated. The residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and water, and dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography to obtain 982 mg of the title compound.
Melting point: 206-207 ° C. (recrystallized from ethyl acetate-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.37 (1H, d, J = 8.8Hz), 6.83-6.94 (1H, m), 6.88 (2H, br s), 6.99 (1H, dd, J = 7.9, 7.7Hz), 7.25 (1H, dd, J = 7.9, 0.7Hz), 7.48 (1H, d, J = 2.7Hz), 7.56 (1H, dd, J = 8.8, 2.4Hz), 8.14 (1H, d, J = 2.4Hz) , 9.70 (1H, s), 10.92-11.03 (1H, m)
[0109]
Synthesis Example 34
N- (3-Chloro-1H-indol-7-yl) -4- (methylsulfinylmethyl) benzenesulfonamide
The title compound was obtained by oxidizing the compound of Synthesis Example 15 in the same manner as in Example 24.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.41 (3H, s), 3.98 (1H, d, J = 12.6Hz), 4.18 (1H, d, J = 12.8Hz), 6.77 (1H, d, J = 7.5Hz), 6.94 (1H, dd, J = 7.9, 7.7Hz), 7.25 (1H, d, J = 7.9Hz), 7.43 (2H, d, J = 8.1Hz), 7.47 (1H, d, J = 2.8Hz), 7.73 (2H, d, J = 8.1Hz), 10.01 (1H, br s), 11.03 (1H, br s)
[0110]
Synthesis Example 35
N- (3-Chloro-1H-indol-7-yl) -4- (2-sulfamoylethyl) benzenesulfonamide
N- (1H-Indol-7-yl) -4 obtained by reacting the compound of Production Example 11 with 865 mg (3.05 mmol) of Production Example 2 and 376 mg (2.84 mmol) of Production Example 2 in the same manner as in Example 1. -(2-sulfamoylethyl) benzenesulfonamide 957 mg Chlorinated in the same manner as in Example 2 to obtain 980 mg of the title compound.
Melting point: 217-219 ° C (decomposition) (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 3.01-3.06 (2H, m), 3.23-3.28 (2H, m), 6.81 (1H, dd, J = 7.5, 0.37Hz), 6.88 (2H, br s), 6.95 (1H, dd, J = 8.1, 7.5Hz), 7.24 (1H, dd, J = 7.8, 0.37Hz), 7.42 (2H, d, J = 8.4Hz), 7.49 (1H, d, J = 2.6Hz), 7.68 ( 2H, d, J = 8.2Hz), 9.99 (1H, br s), 11.02 (1H, br s)
[0111]
Synthesis Example 36
N- (3-Chloro-1H-indol-7-yl) -4- [2- (methylsulfonyl) ethyl] benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Examples 1 and 2.
Melting point: Coloring starts at around 180 ° C and decomposes at 201-203 ° C (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.92 (3H, s), 3.01-3.07 (2H, m), 3.40-3.46 (2H, m), 6.81 (1H, d, J = 7.9Hz), 6.94 (1H, dd, J = 7.9, 7.7Hz), 7.24 (1H, d, J = 7.7Hz), 7.45 (2H, d, J = 8.2Hz), 7.49 (1H, d, J = 2.7Hz), 7.68 (2H, d, J = 8.2Hz), 9.99 (1H, br s), 11.03 (1H, br s)
[0112]
Synthesis Example 37
6-amino-N- (3-cyano-1H-indol-7-yl) -3-pyridinesulfonamide
The compound of Synthesis Example 18 was aminated in the same manner as in Example 33 to obtain the title compound.
Melting point: 300 ° C or higher (recrystallized from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.39 (1H, d, J = 9.0Hz), 6.88 (1H, d, J = 7.7Hz), 6.89 (2H, s), 7.11 (1H, dd, J = 7.9, 7.7Hz) , 7.41 (1H, dd, J = 7.9, 0.7Hz), 7.55 (1H, dd, J = 9.0, 2.6Hz), 8.12 (1H, d, J = 2.6Hz), 8.19 (1H, s), 9.72- 9.90 (1H, br), 11.78-11.92 (1H, m)
[0113]
Synthesis Example 38
4-acetamido-3-chloro-N- (3-chloro-1H-indol-7-yl) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Examples 1 and 2.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.14 (3H, s), 6.77 (1H, d, J = 7.7Hz), 6.98 (1H, dd, J = 7.9, 7.7Hz), 7.29 (1H, d, J = 7.9Hz) , 7.50 (1H, d, J = 2.7Hz), 7.64 (1H, dd, J = 8.6, 2.2Hz), 7.75 (1H, d, J = 2.2Hz), 8.04 (1H, d, J = 8.6Hz) , 9.69 (1H, br s), 10.04 (1H, br s), 11.11 (1H, br s)
[0114]
Synthesis Example 39
N- (3-cyano-1H-indol-7-yl) -8-quinolinesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.68 (1H, d, J = 7.3Hz), 6.89 (1H, dd, J = 7.9, 7.7Hz), 7.25 (1H, d, J = 8.1Hz), 7.69-7.74 (2H, m), 8.21 (1H, d, J = 2.9Hz), 8.30 (1H, dd, J = 8.2, 1.3Hz), 8.35 (1H, dd, J = 7.4, 1.4Hz), 8.54 (1H, dd, J = 8.3, 1.7Hz), 9.15 (1H, dd, J = 4.3, 1.7Hz), 10.04 (1H, br s), 12.14 (1H, br s)
[0115]
Synthesis Example 40
5-Chloro-N- (3-cyano-1H-indol-7-yl) -2-thiophenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.88 (1H, ddd, J = 7.7, 2.2, 0.73Hz), 7.16 (1H, dd, J = 7.9, 7.7Hz), 7.20 (1H, d, J = 4.0Hz), 7.36 ( 1H, d, J = 4.2Hz), 7.51 (1H, d, J = 8.1Hz), 8.23 (1H, d, J = 3.1Hz), 10.42 (1H, br s), 12.01 (1H, br s)
[0116]
Synthesis Example 41
N- (3-Chloro-1H-indol-7-yl) -4- (methoxycarbonylamino) benzenesulfonamide
To a pyridine solution (1 ml) of 38 mg (0.18 mmol) of the compound of Synthesis Example 3, 170 mg (1.8 mmol) of methyl chloroformate was added and stirred overnight at room temperature. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography to obtain 20 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 3.65 (3H, s), 6.80 (1H, d, J = 7.7Hz), 6.93 (1H, t, J = 7.9Hz), 7.21 (1H, dd, J = 7.7, 0.37Hz) , 7.45 (1H, d, J = 2.7Hz), 7.51 (2H, d, J = 9.0Hz), 7.63 (2H, d, J = 8.8Hz), 9.85 (1H, br s), 10.07 (1H, s ), 10.97 (1H, br s)
[0117]
Synthesis Example 42
4-acetyl-N- (3-cyano-1H-indol-7-yl) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.60 (3H, s), 6.74 (1H, d, J = 7.7Hz), 7.05 (1H, dd, J = 7.9, 7.7Hz), 7.42 (1H, d, J = 7.9Hz) , 7.81-7.88 (2H, m), 8.03-8.10 (2H, m), 8.21 (1H, s), 10.18-10.50 (1H, br), 11.92-12.07 (1H, m)
[0118]
Synthesis Example 43
N- (3-Chloro-1H-indol-7-yl) -4- (N-methoxysulfamoyl) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Examples 1 and 2.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 3.65 (3H, s), 6.73 (1H, d, J = 7.6Hz), 6.96 (1H, dd, J = 8.0, 7.6Hz), 7.30 (1H, d, J = 8.0Hz) , 7.50 (1H, d, J = 2.4Hz), 7.98 (4H, s), 10.29 (1H, br s), 10.76 (1H, br s), 11.12 (1H, br s)
[0119]
Synthesis Example 44
N- (3-Cyano-1H-indol-7-yl) -β-styrenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.14-7.20 (2H, m), 7.32 (2H, s), 7.35-7.47 (4H, m), 7.60-7.68 (2H, m), 8.23 (1H, s), 9.70-10.03 (1H, br), 11.85-12.12 (1H, br)
[0120]
Synthesis example 45
3-Chloro-N- (3-cyano-1H-indol-7-yl) -2-methylbenzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.61 (3H, s), 6.69 (1H, d, J = 7.7Hz), 7.04 (1H, t, J = 7.9Hz), 7.36 (1H, dd, J = 8.1, 7.9Hz) , 7.42 (1H, d, J = 7.9Hz), 7.73 (1H, dd, J = 8.1, 1.1Hz), 7.77 (1H, dd, J = 8.0, 0.82Hz), 8.25 (1H, d, J = 3.1 Hz), 10.37 (1H, s), 11.99 (1H, br s)
[0121]
Synthesis Example 46
N- (3-Chloro-1H-indol-7-yl) -6-isopropylamino-3-pyridinesulfonamide
400 mg (1.17 mmol) of the compound of Synthesis Example 14 and 0.80 ml (9.39 mmol) of isopropylamine were added to 5 ml of dioxane and heated in a sealed tube at 100 ° C. for 7.5 hours. After concentration, the residue was dissolved in ethyl acetate and washed successively with dilute citric acid, saturated aqueous sodium bicarbonate, and water. After drying over magnesium sulfate and concentration, the residue was purified by silica gel thin layer chromatography to give the title compound (235 mg).
Melting point: Coloring starts at around 210 ° C and decomposes at 213-215 ° C (recrystallization from ethyl acetate-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.09 (6H, d, J = 6.6Hz), 3.90-4.08 (1H, m), 6.39 (1H, d, J = 9.0Hz), 6.90-7.05 (2H, m), 7.24 ( 1H, d, J = 7.9Hz), 7.33 (1H, d, J = 7.7Hz), 7.48 (1H, d, J = 2.4Hz), 7.54 (1H, dd, J = 9.0, 2.6Hz), 8.22 ( 1H, d, J = 2.6Hz), 9.65-9.84 (1H, br), 10.88-11.04 (1H, m)
[0122]
Synthesis Example 47
N- (3-Chloro-1H-indol-7-yl) -6-[[2- (dimethylamino) ethyl] amino] -3-pyridinesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 46 from the compound of Synthesis Example 14 and N, N-dimethylethylenediamine.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.14 (6H, s), 2.35 (2H, t, J = 6.6Hz), 3.24-3.44 (2H, m), 6.48 (1H, d, J = 9.0Hz), 6.92 (1H, d, J = 7.7Hz), 6.99 (1H, dd, J = 7.9, 7.7Hz), 7.22 (1H, d, J = 7.9Hz), 7.27-7.39 (1H, m), 7.47 (1H, d, J = 2.4Hz), 7.54 (1H, dd, J = 9.0, 2.6Hz), 8.21 (1H, d, J = 2.6Hz), 10.91-11.03 (1H, m)
[0123]
Synthesis Example 48
N- (3-Cyano-1H-indol-7-yl) -2-furansulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.62 (1H, ddd, J = 3.7, 1.8, 0.37Hz), 6.78 (1H, d, J = 7.5Hz), 7.04 (1H, d, J = 3.5Hz), 7.12 (1H, t, J = 7.9Hz), 7.49 (1H, d, J = 8.1Hz), 7.99-8.00 (1H, m), 8.23 (1H, d, J = 3.1Hz), 10.49 (1H, br s), 12.04 (1H, br s)
[0124]
Synthesis Example 49
N- (3-Chloro-1H-indol-7-yl) -4-[(dimethylaminosulfonyl) amino] benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1 from the compound of Synthesis Example 3 and dimethylsulfamoyl chloride.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.66 (6H, s), 6.81 (1H, dd, J = 7.7, 0.92Hz), 6.95 (1H, dd, J = 7.9, 7.7Hz), 7.20 (2H, d, J = 8.8 Hz), 7.23 (1H, d, J = 8.1Hz), 7.47 (1H, d, J = 2.7Hz), 7.64 (2H, d, J = 8.8Hz), 10.98 (1H, br s)
[0125]
Synthesis example 50
N- (3-Methyl-1H-indol-7-yl) -4- (methylsulfonyl) benzenesulfonamide
To a suspension of 3-formyl-7-nitro-1H-indole in 300 mg (1.58 mmol) of 2-propanol (25 ml) was added 580 mg (15.3 mmol) of sodium borohydride and 150 mg of 10% palladium-carbon, and the mixture was refluxed for 6 hours. . After adding water to the reaction system, the catalyst was collected by filtration. The filtrate was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in 5 ml of pyridine. This was reacted with 170 mg (0.67 mmol) of 4- (methylsulfonyl) benzenesulfonyl chloride in the same manner as in Example 1 and treated to give 149 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.18 (3H, s), 3.24 (3H, s), 6.69 (1H, d, J = 7.7Hz), 6.81 (1H, t, J = 7.7Hz), 7.06 (1H, br s ), 7.25 (1H, d, J = 7.8Hz), 7.95 (2H, d, J = 8.8Hz), 8.04 (2H, d, J = 8.2Hz), 10.14 (1H, br s), 10.40 (1H, br s)
[0126]
Synthesis Example 51
3-cyano-N- (3-cyano-1H-indol-7-yl) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.71 (1H, d, J = 7.2Hz), 7.09 (1H, dd, J = 8.0, 7.6Hz), 7.49 (1H, d, J = 8.0Hz), 7.74 (1H, dd, J = 8.0, 7.6Hz), 7.94 (1H, d, J = 8.0Hz), 8.11-8.14 (2H, m), 8.23 (1H, d, J = 2.8Hz), 10.30 (1H, br s), 12.05 (1H, br s)
[0127]
Synthesis Example 52
N- (3-Chloro-1H-indol-7-yl) -4- (N-methylmethanesulfonamido) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Examples 1 and 2.
Melting point: 199-201 ° C (decomposition) (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.98 (3H, s), 3.24 (3H, s), 6.83 (1H, dd, J = 7.7, 0.37Hz), 6.96 (1H, dd, J = 7.9, 7.7Hz), 7.26 ( 1H, dd, J = 7.9, 0.55Hz), 7.48 (1H, d, J = 2.7Hz), 7.50-7.54 (2H, m), 7.72-7.76 (2H, m), 10.04 (1H, br s), 11.02 (1H, br s)
[0128]
Synthesis Example 53
N- (3-Chloro-1H-indol-7-yl) -4-[(methanesulfonamido) methyl] benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Examples 1 and 2.
Melting point: Coloring starts at around 180 ° C and decomposes at 189-191 ° C (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.81 (3H, s), 4.19 (2H, d, J = 6.0Hz), 6.79 (1H, d, J = 7.7Hz), 6.94 (1H, dd, J = 7.9, 7.7Hz) , 7.24 (1H, d, J = 7.9Hz), 7.47 (2H, d, J = 8.8Hz), 7.47-7.49 (1H, m), 7.64 (1H, t, J = 6.4Hz), 7.72 (2H, d, J = 8.4Hz), 10.00 (1H, s), 11.03 (1H, br s)
[0129]
Synthesis Example 54
N- (3-Chloro-1H-indol-7-yl) -4- (1-pyrrolidinylsulfonyl) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1 from 4- (1-pyrrolidinylsulfonyl) benzenesulfonyl chloride and the compound of Production Example 10.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.55-1.59 (4H, m), 3.07-3.11 (4H, m), 6.71 (1H, d, J = 7.6Hz), 6.95 (1H, ddd, J = 8.2, 7.4, 1.2Hz ), 7.30 (1H, d, J = 8.0Hz), 7.46 (1H, d, J = 2.4Hz), 7.89 (2H, d, J = 8.8Hz), 7.92 (2H, d, J = 8.4Hz), 10.18 (1H, br s), 11.03 (1H, br s)
[0130]
Synthesis Example 55
N- (3-cyano-1H-indol-7-yl) -1-methyl-4-imidazolesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 3.61 (3H, s), 7.00 (1H, dd, J = 7.7, 0.92Hz), 7.07 (1H, dd, J = 7.9, 7.7Hz), 7.35 (1H, d, J = 7.9 Hz), 7.75-7.76 (2H, m), 8.19 (1H, d, J = 3.1Hz), 10.03 (1H, br s), 11.92 (1H, br s)
[0131]
Synthesis Example 56
N- (3-Chloro-1H-indol-7-yl) -6-[(2-hydroxyethyl) amino] -3-pyridinesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 46 from the compound of Synthesis Example 14 and 2-aminoethanol.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 3.24-3.40 (2H, m), 3.42-3.52 (2H, m), 4.66-4.77 (1H, m), 6.48 (1H, d, J = 9.3Hz), 6.92 (1H, d , J = 7.7Hz), 7.00 (1H, t, J = 7.7Hz), 7.24 (1H, d, J = 7.7Hz), 7.40-7.62 (2H, m), 7.48 (1H, d, J = 2.2Hz ), 8.22 (1H, d, J = 2.6Hz), 9.63-9.90 (1H, br), 10.90-11.07 (1H, m)
[0132]
Synthesis Example 57
N- (3-Chloro-1H-indol-7-yl) -6-mercapto-3-pyridinesulfonamide
340 mg (0.99 mmol) of the compound of Synthesis Example 14 and 151 mg (1.98 mmol) of thiourea were added to 5 ml of ethanol and heated to reflux for 2 hours. After concentration, 1.6 ml of water and 57 mg of sodium carbonate were added to the residue and stirred at room temperature for 10 minutes. Sodium hydroxide (85 mg) was added, and the mixture was further stirred for 10 min. The precipitate formed by acidification with hydrochloric acid was collected by filtration, washed with water, dissolved in tetrahydrofuran, and dried over magnesium sulfate. After concentration, the residue was purified by silica gel thin layer chromatography to give 121 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.84 (1H, d, J = 7.6Hz), 7.03 (1H, t, J = 7.6Hz), 7.28 (1H, d, J = 9.2Hz), 7.31 (1H, d, J = 7.6Hz), 7.44 (1H, dd, J = 9.2, 2.4Hz), 7.48 (1H, d, J = 2.6Hz), 7.68 (1H, d, J = 2.4Hz), 9.58-9.80 (1H, br) , 11.08-11.19 (1H, m)
[0133]
Synthesis Example 58
7- (4-Chlorobenzenesulfonamide) -1H-indole-2-carboxylic acid
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.65 (1H, d, J = 7.6Hz), 6.87 (1H, dd, J = 8.0, 7.6Hz), 7.00 (1H, s), 7.26 (1H, d, J = 8.0Hz) , 7.56-7.65 (2H, m), 7.68-7.77 (2H, m), 9.62-10.00 (1H, br), 11.40-11.74 (1H, br)
[0134]
Synthesis Example 59
N- (3-Chloro-1H-indol-7-yl) -6-cyclopropylamino-3-pyridinesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 46.
Melting point: Coloring starts at around 228 ° C and decomposes at 233.5-235 ° C (recrystallization from ethyl acetate-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.36-0.46 (2H, m), 0.63-0.75 (2H, m), 2.44-2.64 (1H, m), 6.45-6.64 (1H, m), 6.93 (1H, d, J = 7.7Hz), 7.00 (1H, dd, J = 7.9, 7.7Hz), 7.24 (1H, d, J = 7.9Hz), 7.49 (1H, d, J = 2.7Hz), 7.57-7.73 (2H, m) , 8.25 (1H, d, J = 2.6Hz), 9.68-9.90 (1H, br), 10.92-11.04 (1H, m)
[0135]
Synthesis Example 60
N- (3-Cyano-1H-indol-7-yl) -5-methyl-3-pyridinesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
Melting point: Gradual decomposition from around 288 ° C (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.33 (3H, s), 6.75 (1H, d, J = 7.7Hz), 7.09 (1H, dd, J = 7.9, 7.7Hz), 7.48 (1H, d, J = 7.9Hz) , 7.87-7.91 (1H, m), 8.22 (1H, d, J = 3.1Hz), 8.58-8.67 (2H, m), 10.28 (1H, br s), 11.95-12.08 (1H, m)
[0136]
Synthesis Example 61
N- (3-Chloro-1H-indol-7-yl) -4- (N-methylsulfamoyl) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Examples 1 and 2.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.39 (3H, d, J = 5.2Hz), 6.71 (1H, dd, J = 7.8, 2.0Hz), 6.96 (1H, dd, J = 8.0, 7.6Hz), 7.30 (1H, d, J = 8.0Hz), 7.48 (1H, d, J = 2.8Hz), 7.68 (1H, q, J = 4.9Hz), 7.87-7.93 (4H, m), 10.20 (1H, br s), 11.08 (1H, br s)
[0137]
Synthesis Example 62
N- (3-Chloro-1H-indol-7-yl) -4- [2- (methanesulfonamido) ethyl] benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Examples 1 and 2.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.73-2.81 (5H, m), 3.13-3.19 (2H, m), 6.82 (1H, d, J = 7.7Hz), 6.95 (1H, dd, J = 8.1, 7.7Hz), 7.09 (1H, t, J = 5.9Hz), 7.24 (1H, d, J = 8.1Hz), 7.39 (2H, d, J = 8.2Hz), 7.48 (1H, d, J = 2.7Hz), 7.68 ( 2H, d, J = 8.4Hz), 9.97 (1H, br s), 11.02 (1H, br s)
[0138]
Synthesis Example 63
N- (3-Chloro-1H-indol-7-yl) -4- (sulfamoylmethyl) benzenesulfonamide
389 mg (1.44 mmol) of the compound of Preparation Example 6 and 159 mg (1.2 mmol) of the compound of Preparation Example 2 were reacted and treated in the same manner as in Example 1 to give N- (1H-indol-7-yl) -4- (sulfur 233 mg of (famoylmethyl) benzenesulfonamide was obtained. This was chlorinated in the same manner as in Example 2 to obtain 160 mg of the title compound.
Melting point: 237-238.5 ° C (decomposition) (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 4.33 (2H, s), 6.84 (1H, dd, J = 7.7, 0.73Hz), 6.93 (2H, s), 6.92-6.97 (1H, m), 7.24 (1H, dd, J = 7.9, 0.37Hz), 7.48 (1H, d, J = 2.7Hz), 7.48-7.52 (2H, m), 7.75-7.79 (2H, m), 10.08 (1H, br s), 11.04 (1H, br s)
[0139]
Synthesis Example 64
N- (3-Chloro-1H-indol-7-yl) -4-thiocarbamoylbenzenesulfonamide
400 mg (1.21 mmol) of the compound of Synthesis Example 10 was dissolved in 10 ml of dimethylformamide, and 0.5 ml of triethylamine was added. Hydrogen sulfide was passed for 45 minutes at a bath temperature of 60-70 ° C. After concentration, the residue was dissolved in ethyl acetate, washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and water, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound (355 mg).
Melting point: 223-225 ° C (decomposition) (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.81 (1H, d, J = 7.7Hz), 6.96 (1H, dd, J = 7.9, 7.7Hz), 7.27 (1H, d, J = 7.9Hz), 7.50 (1H, d, J = 2.7Hz), 7.73-7.80 (2H, m), 7.86-7.93 (2H, m), 9.58-9.73 (1H, br m), 10.02-10.18 (1H, br m), 10.15 (1H, s) , 11.03-11.12 (1H, m)
[0140]
Synthesis Example 65
5-Bromo-N- (3-cyano-1H-indol-7-yl) -2-pyridinesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
Melting point: 245.5-246.5 ° C (decomposition) (recrystallization from ethyl acetate-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.82 (1H, d, J = 7.7Hz), 7.07 (1H, dd, J = 7.9, 7.7Hz), 7.44 (1H, d, J = 7.9Hz), 7.80 (1H, d, J = 8.2Hz), 8.23 (1H, d, J = 2.2Hz), 8.29 (1H, dd, J = 8.2, 2.2Hz), 8.92 (1H, d, J = 2.2Hz), 10.42-10.67 (1H, br), 11.93-12.08 (1H, m)
[0141]
Synthesis Example 66
N- (3-Cyano-1H-indol-7-yl) -2-naphthalenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.74 (1H, dd, J = 7.6, 2.8Hz), 7.00 (1H, dd, J = 7.9, 7.7Hz), 7.39 (1H, dd, J = 8.0, 0.46Hz), 7.61- 7.72 (2H, m), 7.80 (1H, dd, J = 8.6, 1.8Hz), 8.01 (1H, d, J = 8.1Hz), 8.08 (1H, s), 8.10 (1H, s), 8.21 (1H , d, J = 2.9Hz), 8.34 (1H, d, J = 1.6Hz), 10.23 (1H, br s), 12.01 (1H, br s)
[0142]
Synthesis Example 67
N- (3-acetyl-1H-indol-7-yl) -3-chlorobenzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.44 (3H, s), 6.65 (1H, d, J = 7.5Hz), 7.01 (1H, dd, J = 7.9, 7.7Hz), 7.53-7.63 (2H, m), 7.69- 7.73 (2H, m), 8.01 (1H, dd, J = 8.1, 0.73Hz), 8.26 (1H, d, J = 2.9Hz), 10.10 (1H, s), 11.75 (1H, br s)
[0143]
Synthesis Example 68
4-Amino-N- (5-bromo-3-cyano-1H-indol-7-yl) benzenesulfonamide
Platinum oxide was used to convert N- (5-bromo-3-cyano-1H-indol-7-yl) -4-nitrobenzenesulfonamide obtained from 4-nitrobenzenesulfonyl chloride and the compound of Preparation Example 14 in the same manner as in Example 1. Hydrogenated in the presence at room temperature and normal pressure to give the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.07 (2H, br s), 6.52 (2H, d, J = 8.4Hz), 6.97-6.99 (1H, m), 7.36 (2H, dd, J = 8.7, 1.6Hz), 7.51 (1H, br s), 8.25 (1H, s), 9.93 (1H, d, J = 5.5Hz), 11.97 (1H, br s)
[0144]
Synthesis Example 69
N- (3-Chloro-1H-indol-7-yl) -4- (N-ethylsulfamoyl) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Examples 1 and 2.
Melting point: 213-215 ° C (recrystallized from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.90 (3H, t, J = 7.2Hz), 2.76 (2H, dq, Jd = 5.8Hz, Jq = 7.2Hz), 6.70 (1H, d, J = 7.4Hz), 6.95 (1H , dd, J = 8.0, 7.6Hz), 7.29 (1H, d, J = 8.0Hz), 7.47 (1H, d, J = 2.8Hz), 7.78 (1H, t, J = 5.6Hz), 7.90 (4H , s), 10.18 (1H, br s), 11.06 (1H, br s)
[0145]
Synthesis Example 70
N- (3-Chloro-1H-indol-7-yl) -4- (ethanesulfonamido) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 4.
Melting point: 214-215 ° C (decomposition) (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.14 (3H, t, J = 7.3Hz), 3.16 (2H, q, J = 7.3Hz), 6.82 (1H, d, J = 7.5Hz), 6.96 (1H, dd, J = 7.9, 7.7Hz), 7.23 (2H, d, J = 8.8Hz), 7.24 (1H, d, J = 7.5Hz), 7.47 (1H, d, J = 2.6Hz), 7.66 (2H, d, J = 8.8Hz), 9.90 (1H, br s), 10.37 (1H, br s), 10.96 (1H, br s)
[0146]
Synthesis Example 71
N- (3-Chloro-1H-indol-7-yl) -6-[(2-cyanoethyl) amino] -3-pyridinesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 46.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.72 (2H, t, J = 6.4Hz), 3.46-3.55 (2H, m), 6.53 (1H, d, J = 9.0Hz), 6.90 (1H, d, J = 7.7Hz) , 6.99 (1H, dd, J = 7.9, 7.7Hz), 7.25 (1H, d, J = 7.9Hz), 7.48 (1H, d, J = 2.6Hz), 7.61 (1H, dd, J = 9.0, 2.4 Hz), 7.78-7.87 (1H, m), 8.25 (1H, d, J = 2.4Hz), 9.70-9.95 (1H, br), 10.92-11.04 (1H, m)
[0147]
Synthesis Example 72
N- (3-Chloro-1H-indol-7-yl) -4- (N-methylcarbamoyl) benzenesulfonamide
533 mg (1.68 mmol) of the compound of Synthesis Example 9 was dissolved in a mixed solution of 5 ml of dimethylformamide and 2.5 ml of dimethylsulfoxide, and 171 mg (2.53 mmol) of methylamine hydrochloride and 705 μl (5.06 mmol) of triethylamine were added. Diphenylphosphoryl azide (436 μl, 2.02 mmol) was added, and the mixture was stirred overnight at room temperature and concentrated. The mixture was extracted with ethyl acetate, washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and water, and dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography to obtain 465 mg of N- (1H-indol-7-yl) -4- (N-methylcarbamoyl) benzenesulfonamide. This was chlorinated in the same manner as in Synthesis Example 2 to obtain 413 mg of the title compound.
Melting point: 252-253 ° C. (decomposition) (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.76 (3H, d, J = 4.6Hz), 6.74 (1H, d, J = 7.7Hz), 6.94 (1H, dd, J = 7.9, 7.7Hz), 7.27 (1H, d, J = 7.9Hz), 7.49 (1H, d, J = 2.7Hz), 7.76-7.83 (2H, m), 7.87-7.94 (2H, m), 8.61 (1H, q, J = 4.6Hz), 10.10 ( 1H, s), 11.03-11.13 (1H, m)
[0148]
Synthesis Example 73
N -(3-Chloro-1H-indol-7-yl) -4- (methylsulfonylmethyl) benzenesulfonamide
510 mg of the compound of Synthesis Example 34 was oxidized with 30% hydrogen peroxide solution in the same manner as in Example 23 to obtain 307 mg of the title compound.
Melting point: Coloring starts from around 225 ° C and gradually decomposes around 235 ° C (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.88 (3H, s), 4.57 (2H, s), 6.77 (1H, d, J = 7.6Hz), 6.94 (1H, dd, J = 7.9, 7.7Hz), 7.25 (1H, d, J = 8.0Hz), 7.47 (1H, d, J = 2.7Hz), 7.51-7.56 (2H, m), 7.73-7.78 (2H, m), 10.05 (1H, br s), 11.04 (1H, br s)
[0149]
Synthesis example 74
N- (3-Chloro-1H-indol-7-yl) -4- (N, N-dimethylsulfamoyl) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Examples 1 and 2.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.57 (6H, s), 6.71 (1H, dd, J = 7.4, 0.6Hz), 6.97 (1H, dd, J = 8.0, 7.6Hz), 7.31 (1H, d, J = 8.0 Hz), 7.47 (1H, d, J = 2.8Hz), 7.86 (2H, d, J = 8.4Hz), 7.91 (2H, d, J = 8.4Hz), 10.19 (1H, br s), 11.04 (1H , br s)
[0150]
Synthesis Example 75
N- (3-Chloro-1H-indol-7-yl) -4- (1-pyrrolidinylcarbonyl) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.79 (2H, dt, Jd = 12.8Hz, Jt = 6.4Hz), 1.85 (2H, dt, Jd = 13.6Hz, Jt = 6.8Hz), 3.22 (2H, t, J = 6.4Hz) ), 3.44 (2H, t, J = 6.8Hz), 6.78 (1H, d, J = 7.2Hz), 6.96 (1H, dd, J = 8.0, 7.2Hz), 7.28 (1H, d, J = 8.0Hz) ), 7.47 (1H, d, J = 2.4Hz), 7.60 (2H, d, J = 8.0Hz), 7.74 (2H, d, J = 8.4Hz), 10.06 (1H, br s), 11.01 (1H, br s)
[0151]
Synthesis Example 76
3-Chloro-N- (3-chloro-1H-indol-7-yl) -N-methylbenzenesulfonamide
120 mg (0.352 mmol) of the compound of Synthesis Example 7 was dissolved in 10 ml of dimethylformamide, and 19.2 mg (0.479 mmol) of sodium hydride (60%) was added. After stirring at room temperature for 30 minutes, 30 μl (0.482 mmol) of methyl iodide was added. After 2 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. After concentration, the residue was purified by silica gel thin layer chromatography to give 87 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 3.26 (3H, s), 6.51 (1H, dd, J = 7.6, 0.64Hz), 7.00 (1H, dd, J = 7.9, 7.7Hz), 7.47 (1H, d, J = 8.1 Hz), 7.53 (1H, d, J = 2.7Hz), 7.54-7.59 (2H, m), 7.65 (1H, t, J = 7.9Hz), 7.84 (1H, ddd, J = 8.1, 2.1, 1.1Hz ), 11.62 (1H, br s)
[0152]
Synthesis example 77
N- (3,4-dichloro-1H-indol-7-yl) -4- (sulfamoylmethyl) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
Melting point: Gradual decomposition from around 297 ° C (recrystallization from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 4.34 (2H, s), 6.72 (1H, d, J = 8.1Hz), 6.93 (2H, s), 6.94 (1H, d, J = 8.1Hz), 7.51 (2H, d, J = 8.1Hz), 7.57 (1H, dd, J = 2.7, 0.55Hz), 7.75 (2H, d, J = 8.2Hz), 10.10 (1H, br s), 11.44 (1H, br s)
[0153]
Synthesis Example 78
N- (3-Cyano-1H-indol-7-yl) -4- [2- (methylsulfonyl) ethyl] benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Example 1.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.94 (3H, s), 3.03-3.08 (2H, m), 3.42-3.47 (2H, m), 6.77 (1H, dd, J = 7.7, 0.37Hz), 7.05 (1H, t , J = 7.9Hz), 7.41 (1H, d, J = 8.1Hz), 7.46 (2H, d, J = 8.2Hz), 7.66 (2H, d, J = 8.2Hz), 8.20 (1H, s), 10.09 (1H, br s), 11.92 (1H, br s)
[0154]
Synthesis Example 79
N- (3-Chloro-1H-indol-7-yl) -4- (N-methylacetamide) benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Examples 1 and 2.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.84 (3H, br s), 3.16 (3H, s), 6.81 (1H, d, J = 7.7Hz), 6.96 (1H, dd, J = 8.0, 7.6Hz), 7.27 (1H , d, J = 7.9Hz), 7.45-7.49 (2H, m), 7.47 (1H, d, J = 2.7Hz), 7.70-7.75 (2H, m), 10.02 (1H, br s), 11.01 (1H , br s)
[0155]
Synthesis example 80
N- (3-Chloro-1H-indol-7-yl) -6-hydroxy-3-pyridinesulfonamide
1 ml of an aqueous solution of 32 mg (0.46 mmol) of sodium nitrite was added dropwise to a solution of 100 mg (0.31 mmol) of the compound of Example 33 in 2 ml of glacial acetic acid under ice cooling. After stirring for 1 hour, sodium bicarbonate water was added to adjust the pH to about 8, and the mixture was further stirred for 10 minutes. The mixture was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. After concentration, the residue was purified by silica gel thin layer chromatography to give 54 mg of the title compound.
Melting point: 244-245 ° C (decomposition) (recrystallized from ethyl acetate-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.39 (1H, d, J = 9.5Hz), 6.88 (1H, d, J = 7.7Hz), 7.04 (1H, dd, J = 7.9, 7.7Hz), 7.32 (1H, d, J = 7.9Hz), 7.50 (1H, d, J = 2.7Hz), 7.58 (1H, dd, J = 9.5, 3.1Hz), 7.64 (1H, d, J = 3.1Hz), 9.76-9.94 (1H, br), 11.01-11.13 (1H, m), 11.98-12.15 (1H, br)
[0156]
Synthesis Example 81
N- (3-Chloro-1H-indol-7-yl) -4- [2- (N-methylmethanesulfonamido) ethyl] benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Examples 1 and 2.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.69 (3H, s), 2.76 (3H, s), 2.86 (2H, t, J = 7.5Hz), 3.26 (2H, t, J = 7.5Hz), 6.78 (1H, dd, J = 7.4, 0.55Hz), 6.94 (1H, t, J = 7.7Hz), 7.24 (1H, dd, J = 7.7, 0.37Hz), 7.39 (2H, d, J = 8.2Hz), 7.48 (1H, d, J = 2.6Hz), 7.66 (2H, d, J = 8.2Hz), 9.94 (1H, br s), 11.02 (1H, br s)
[0157]
Synthesis example 82
N- (3-Chloro-1H-indol-7-yl) -4- (trifluoromethanesulfonamide) benzenesulfonamide
To a pyridine solution (5 ml) of 62 mg (0.19 mmol) of the compound of Synthesis Example 3 was added 128 μl (0.76 mmol) of trifluoromethanesulfonic anhydride at 0 ° C., and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure, a pH 7 phosphate buffer solution was added, extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 20 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.79 (1H, d, J = 7.7Hz), 6.94 (1H, dd, J = 7.9, 7.7Hz), 7.16 (2H, d, J = 8.6Hz), 7.23 (1H, d, J = 7.9Hz), 7.46 (1H, d, J = 2.7Hz), 7.58 (2H, d, J = 8.1Hz), 9.84 (1H, br s), 10.98 (1H, br s)
[0158]
Synthesis Example 83
N- (3-Chloro-1H-indol-7-yl) -4-[(N-methylmethanesulfonamido) methyl] benzenesulfonamide
The title compound was obtained in the same manner as in Synthesis Examples 1 and 2.
Melting point: 200.5-202 ° C (recrystallized from ethanol)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.63 (3H, s), 2.94 (3H, s), 4.27 (2H, s), 6.80 (1H, d, J = 7.3Hz), 6.95 (1H, dd, J = 8.1, 7.5 Hz), 7.25 (1H, d, J = 7.9Hz), 7.45 (2H, d, J = 8.2Hz), 7.47 (1H, d, J = 2.7Hz), 7.74 (2H, d, J = 8.2Hz) , 10.00 (1H, s), 11.00 (1H, br s)
[0159]
Synthesis Example 84
3-Chloro-N- (3-chloro-1H-pyrrolo [2,3-c] pyridin-7-yl) benzenesulfonamide
Concentrate 600 mg (3.05 mmol) of 7-bromo-1H-pyrrolo [2,3-c] pyridine synthesized from 2-bromo-3-nitropyridine in the same manner as in Production Example 1, 194 mg of copper powder and 603 mg of cuprous chloride. In addition to 84 ml of aqueous ammonia, the mixture was heated in a sealed tube at 120 ° C. for 15 hours and then treated to obtain 170 mg of 7-amino-1H-pyrrolo [2,3-c] pyridine. This was reacted and treated in the same manner as in Examples 1 and 2 to obtain 57 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.93 (1H, d, J = 6.6Hz), 7.45 (1H, dd, J = 6.6, 5.8Hz), 7.53 (1H, dd, J = 8.0, 7.6Hz), 7.61 (1H, d, J = 7.6Hz), 7.73 (1H, d, J = 2.8Hz), 7.85 (1H, d, J = 8.0Hz), 7.96 (1H, d, J = 1.2Hz), 11.90-12.10 (1H, m), 12.72 (1H, br s)
[0160]
Synthesis example 85
N- (3-Chloro-1H-indol-7-yl) -4- [3- (1-imidazolyl) propyl] benzenesulfonamide
170 mg (2.5 mmol) of imidazole and 6 ml of dimethylformamide were added to 213 mg (0.5 mmol) of 4- (3-bromopropyl) -N- (3-chloro-1H-indol-7-yl) benzenesulfonamide. After heating at 80 ° C. for 3 hours under a nitrogen atmosphere, the reaction mixture was poured into water and extracted with chloroform. After drying over magnesium sulfate and concentration, the residue was purified by silica gel cam chromatography to give 160 mg of the title compound.
Melting point: 86-90 ° C
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.95-2.04 (2H, m), 2.55 (2H, t, J = 7.9Hz), 3.92 (2H, t, J = 7.1Hz), 6.81 (1H, dd, J = 7.7, 0.9) Hz), 6.88 (1H, t, J = 1.1Hz), 6.94 (1H, dd, J = 7.9, 7.7Hz), 7.16 (1H, t, J = 1.2Hz), 7.23 (1H, d, J = 7.7) Hz), 7.32 (2H, d, J = 8.4Hz), 7.47 (1H, d, J = 2.7Hz), 7.60 (1H, br s), 7.65 (2H, d, J = 8.4Hz), 9.91-10.01 (1H, m), 10.98-11.02 (1H, m)
[0161]
Synthesis example 86
N- (3-Chloro-1H-indol-7-yl) -4- [N- [2- (2-pyridinyl) ethyl] carbamoyl] benzenesulfonamide
4- (chlorosulfonyl) benzoic acid (2.82 g, 12.8 mmol) and 7-amino-3-chloro-1H-indole (1.42 g, 8.54 mmol) were reacted in pyridine overnight at room temperature with 4- [N- ( 3-Chloro-1H-indol-7-yl) sulfamoyl] benzoic acid 2.33 g was obtained. To 303 mg (0.86 mmol), 260 μl of dimethylformamide, 204 μl (0.95 mmol) of diphenylphosphoryl azide, 132 μl (0.95 mmol) of triethylamine and 113 μl (0.94 mmol) of 2- (2-aminoethyl) pyridine were added successively at room temperature overnight. Stir. After concentration, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added, and the organic layer was separated and washed with saturated brine. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography to obtain 175 mg of the title compound.
Melting point: 220.5-222 ° C
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.95-2.99 (2H, m), 3.56-3.62 (2H, m), 6.75 (1H, d, J = 7.5Hz), 6.94 (1H, dd, J = 7.9, 7.7Hz), 7.19-7.28 (3H, m), 7.48 (1H, d, J = 2.8Hz), 7.69 (1H, dt, Jd = 1.8Hz, Jt = 7.7Hz), 7.79 (2H, d, J = 8.6Hz), 7.88 (2H, d, J = 8.6Hz), 8.48-8.51 (1H, m), 8.75 (1H, t, J = 5.2Hz), 10.09-10.12 (1H, m), 11.06-11.09 (1H, m)
[0162]
Synthesis Example 87
4-Amidino-N- (3-chloro-1H-indol-7-yl) benzenesulfonamide
To 162 mg (3.0 mmol) of ammonium chloride, 3.3 ml (3.3 mmol) of trimethylaluminum 1.0M hexane solution and 10 ml of toluene were added. After gas generation ceased, the solution was concentrated under reduced pressure until the liquid volume reached about 3 ml. While stirring, 97 mg (0.30 mmol) of the compound of Production Example 4 was added and heated at 80 ° C. for 4 hours. After cooling, concentrated aqueous ammonia was added, and the insoluble material was filtered off and concentrated. Ethyl acetate was added and the insoluble material was filtered off and concentrated. The residue was purified by silica gel cam chromatography to give 35 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.93 (1H, dd, J = 7.7,1.5Hz), 6.96 (1H, dd, J = 7.7,7.5Hz), 7.24 (1H, dd, J = 7.5,1.3Hz), 7.50 ( 1H, d, J = 2.7Hz), 7.90 (2H, d, J = 8.6Hz), 8.01 (2H, d, J = 8.6Hz), 9.16-9.62 (2H, br), 10.40-10.75 (1H, br ), 11.50 (1H, s)
[0163]
Synthesis Example 88
N- (3-Chloro-1H-indol-7-yl) -4- [N- [2- (1-imidazolyl) ethyl] sulfamoyl] benzenesulfonamide
4- [N- (2-bromoethyl) sulfamoyl] -N- (3-chloro-1H-indol-7-yl) benzenesulfonamide 557 mg (1.13 mmol) and imidazole 820 mg (12.0 mmol) are added to dimethylformamide 10 ml, Stir at 80 ° C. for 2 days. After concentration, the residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (324 mg).
Melting point: Starts gradually coloring around 200 ° C and decomposes at 218-221 ° C (recrystallized from ethanol-n-hexane)
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 3.05 (2H, ddd, J = 6.2,6.0,5.9Hz), 3.96 (2H, dd, J = 6.0,5.9Hz), 6.69-6.72 (1H, m), 6.84 (1H, br s), 6.92 (1H, dd, J = 7.9, 7.7Hz), 7.08 (1H, br s), 7.26 (1H, d, J = 7.5Hz), 7.44 (1H, d, J = 2.7Hz), 7.55 (1H, br s), 7.82-7.88 (4H, m), 8.06 (1H, t, J = 5.9Hz), 10.18-10.36 (1H, br), 11.09 (1H, d, J = 2.4Hz)
[0164]
Synthesis Example 89
3- (5-Bromonicotinamide) -N- (3-cyano-1H-indol-7-yl) benzenesulfonamide
785 mg (3.54 mmol) of 3-nitrobenzenesulfonyl chloride and 506 mg (3.22 mmol) of the compound of Preparation Example 3 were reacted in the same manner as in Preparation Example 4 and treated to give N- (3-cyano-1H-indol-7-yl)- 950 mg of 3-nitrobenzenesulfonamide was obtained. This was reduced with zinc powder-concentrated hydrochloric acid in 30 ml of methanol according to a conventional method to obtain 459 mg of 3-amino-N- (3-cyano-1H-indol-7-yl) benzenesulfonamide. 109 mg (0.35 mmol) of this product was dissolved in 2 ml of pyridine, and 179 mg (0.70 mmol) of 5-bromonicotinoyl chloride hydrochloride was added. The mixture was stirred at room temperature overnight and concentrated, and a diluted aqueous citric acid solution was added. The resulting precipitate was collected by filtration and washed successively with water, dilute aqueous sodium bicarbonate, water and ether. The precipitate was dissolved in tetrahydrofuran, dried over magnesium sulfate, concentrated, ether and n-hexane were added, and the precipitated crystals were collected by filtration to give the title compound (108 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.81 (1H, dd, J = 7.7,0.7Hz), 7.07 (1H, t, J = 7.9Hz), 7.42 (1H, dd, J = 7.9,0.7Hz), 7.47-7.51 ( 1H, m), 7.55 (1H, t, J = 7.9Hz), 7.93-7.97 (1H, m), 8.21-8.23 (1H, m), 8.31 (1H, t, J = 1.8Hz), 8.55 (1H , dd, J = 2.4,2.0Hz), 8.93 (1H, d, J = 2.4Hz), 9.06 (1H, d, J = 2.0Hz), 10.23-10.25 (1H, m), 10.75 (1H, br s ), 11.94-11.96 (1H, m)
[0165]
Synthesis example 90
N- (3-Chloro-1H-indol-7-yl) -4- [N- (2-thiazolyl) sulfamoyl] benzenesulfonamide
.2 g (20.4 mmol) was added to a mixture of 14 ml of water and 3.4 ml of concentrated hydrochloric acid and stirred. To this was added dropwise a saturated aqueous solution of 2.1 g (30.4 mmol) of sodium nitrite at 0 ° C. or lower, 5 ml of acetic acid was added and the mixture was stirred at 5 ° C. for about 10 minutes. To this reaction solution was added sulfur dioxide saturated acetic acid solution (a solution obtained by saturating sulfur dioxide with 18 ml of acetic acid and adding 830 mg of cupric chloride dihydrate) at 0 ° C. with stirring. After 5 minutes, the reaction solution was poured into ice water, and the precipitate was collected by filtration, washed with water and dried to obtain 2.9 g of 4-chlorosulfonyl-N- (2-thiazolyl) benzenesulfonamide. 570 mg (1.68 mmol) of this product and 200 mg (1.2 mmol) of the compound of Production Example 1 were reacted in the same manner as in Production Example 4 and treated to give 456 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 6.68 (1H, dd, J = 7.5,0.73Hz), 6.87 (1H, d, J = 4.6Hz), 6.93 (1H, dd, J = 8.1,7.5Hz), 7.26-7.30 ( 1H, m), 7.28 (1H, d, J = 4.6Hz), 7.46 (1H, d, J = 2.7Hz), 7.82-7.88 (2H, m), 7.88-7.94 (2H, m), 10.10-10.26 (1H, br), 11.04-11.10 (1H, m), 12.83-13.01 (1H, br)
[0166]
Synthesis Example 91
5-Chloro-N- (3-chloro-1H-indol-7-yl) -4- (5-methyl-3-pyridinesulfonamide) -2-thiophenesulfonamide
645 mg (2.46 mmol) of 5-chloro-4-nitro-2-thiophenesulfonyl chloride and 410 mg (2.46 mmol) of the compound of Preparation Example 1 were reacted in the same manner as in Preparation Example 4 and treated to give 5-chloro-N- (3 194 mg of -chloro-1H-indol-7-yl) -4-nitro-2-thiophenesulfonamide were obtained. According to a conventional method, this was reduced with zinc powder-concentrated hydrochloric acid in 10 ml of methanol to obtain 75 mg of 4-amino-5-chloro-N- (3-chloro-1H-indol-7-yl) -2-thiophenesulfonamide. It was. 72 mg (0.20 mmol) of this product was dissolved in 2 ml of tetrahydrofuran, and 18 μl of pyridine and 38 mg (0.2 mmol) of 5-methyl-3-pyridinesulfonyl chloride were added. After stirring overnight at room temperature, ethyl acetate and 1N hydrochloric acid were added, the organic layer was separated, and washed successively with water, aqueous sodium bicarbonate, and water. After drying over magnesium sulfate and concentration, the residue was purified by silica gel column chromatography to give 82 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.33 (3H, s), 6.76 (1H, d, J = 7.7Hz), 7.03 (1H, dd, J = 7.9, 7.7Hz), 7.35 (1H, s), 7.38 (1H, d, J = 7.9Hz), 7.51 (1H, d, J = 2.7Hz), 7.80 (1H, dd, J = 2.0,1.5Hz), 8.60 (1H, dd, J = 2.0,0.4Hz), 8.71 ( 1H, dd, J = 1.5,0.4Hz), 10.35-10.40 (1H, m), 10.73-10.80 (1H, br), 11.16-11.19 (1H, m)

Claims (4)

A therapeutic agent for retinal neovascularization comprising a sulfonamide derivative selected from the compounds shown in the following (1) to (6), a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient.
(1) N- (1H-Indol-7-yl) -4-nitrobenzenesulfonamide
(2) 3-chloro-N- (3-chloro-4-methoxy-1H-indol-7-yl) benzenesulfonamide
(3) 3-chloro-N- (3-chloro-4-hydroxy-1H-indol-7-yl) benzenesulfonamide
(4) N- (3-Cyano-1H-indol-7-yl) -1-methyl-4-imidazolesulfonamide
(5) N- (3-acetyl-1H-indol-7-yl) -3-chlorobenzenesulfonamide
(6) 3-Chloro-N- (3-chloro-1H-pyrrolo [2,3-c] pyridin-7-yl) benzenesulfonamide A therapeutic agent for diabetic retinopathy comprising a sulfonamide derivative selected from the compounds shown in (1) to (6) according to claim 1 or a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient. The therapeutic agent for inflammatory diseases which uses the sulfonamide derivative selected from the compound shown in (1)-(6) of Claim 1 , or its pharmacologically acceptable salt, or those hydrates as an active ingredient. Deformation arthritis, psoriasis, delayed action comprising a sulfonamide derivative selected from the compounds shown in (1) to (6) according to claim 1 or a pharmacologically acceptable salt or hydrate thereof as an active ingredient A therapeutic agent for inflammatory diseases consisting of a hypersensitive reaction.