JP3734180B2 - New pyrazole derivatives - Google Patents

Description

【０００５】
で表されるアシクロビル（ＡＣＶ）がその代表化合物であり、現在も第一選択薬とされている。その他、６−アミノプリン誘導体のビダラビンやＡＣＶと同様にアサイクリックな糖を持ったグアノシン誘導体であるガンシクロビルが臨床上使用されている。
【０００６】
【発明が解決しようとする課題】
しかしながら、これらの薬剤においても、その効果や投与のし易さおよび安全性の点で十分でない。
例えば、特公昭５６−３３３９６号公報に開示されるＡＣＶは、１）溶解度が低く腎障害を起こすためゆっくり点滴静注する必要があること、２）経口吸収率が悪いこと、３）水痘帯状疱疹ウイルス（ＶＺＶ）に対して効果が低いこと、４）変異原性の基礎試験である小核試験で異常が認められていること、５）耐性株が出現していることなどの多くの欠点がある。
また、ビダラビンは効果の点で十分でなく、ガンシクロビルとともに細胞毒性が強いため長期投与ができないなどの欠点があり、今後さらに増加が予想される易感染患者のヘルペスウイルス感染症に対し、さらに優れた薬剤の出現が切望されている。
しかも、遺伝子本体であるＤＮＡは全ての生物で共通しており、核酸系化合物で人体への副作用、例えば変異原性や細胞毒性など、をなくすことは困難であると考えられる。
本発明者らは、これらの問題点を解決すべく非核酸系の抗ヘルペス剤の研究を鋭意重ねた結果、優れた活性および安全性を有する抗ヘルペス剤並びにその合成中間体および製造方法を見い出し本発明を完成した。
【０００７】
【課題を解決するための手段】
すなわち本発明は一般式
【０００８】
【化２１】

【０００９】
〔式中、環Ａは１以上のヘテロ原子を有していてもよく、１以上の置換基を有していてもよい芳香環または１以上のヘテロ原子を有していてもよく、１以上の置換基を有していてもよい縮合環を、Ｒ¹は低級アルキル基または１以上のヘテロ原子を有していてもよく、１以上の置換基を有していてもよい芳香環を、Ｒ²は水素原子、低級アルキル基またはアミノ基の保護基を、Ｒ³は水素原子、ハロゲン原子または低級アルキル基をそれぞれ示す。〕で表されるピラゾール誘導体またはその塩、このピラゾール誘導体の合成中間体である一般式
【００１０】
【化２２】

【００１１】
〔式中、環Ａは１以上のヘテロ原子を有していてもよく、１以上の置換基を有していてもよい芳香環または１以上のヘテロ原子を有していてもよく、１以上の置換基を有していてもよい縮合環を、Ｒ¹は低級アルキル基または１以上のヘテロ原子を有していてもよく、１以上の置換基を有していてもよい芳香環をそれぞれ示す。〕で表される化合物またはその塩、およびこれらの製造方法並びに抗ヘルペス剤としてのその用途に関する。
【００１２】
以下本明細書に記載された用語などについて説明する。
環Ａは１以上のヘテロ原子を有していてもよく、１以上の置換基を有していてもよい芳香環または１以上のヘテロ原子を有していてもよく、１以上の置換基を有していてもよい縮合環を示す。
ヘテロ原子とは、具体的には酸素原子、硫黄原子、窒素原子などが挙げられるが、その他にもリン、砒素、アンチモン、ケイ素、ゲルマニウム、スズ、鉛、ホウ素、水銀などがある。好ましくは酸素原子、硫黄原子、窒素原子が挙げられる。
【００１３】
置換基とは、具体的には例えば、水酸基；チオール基；ニトロ基；モルホリノ基；チオモルホリノ基；フッ素原子、塩素原子、臭素原子、ヨウ素原子などのハロゲン原子；ニトリル基；アジド基；ホルミル基；メチル基、エチル基、プロピル基、イソプロピル基、ブチル基などのアルキル基；ビニル基、アリル基、プロペニル基などのアルケニル基；エチニル基、ブチニル基、プロパルギル基などのアルキニル基、低級アルキル基に対応するメトキシ基、エトキシ基、プロポキシ基、ブトキシ基などのアルコキシ基；フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、フルオロエチル基などのハロゲノアルキル基：ヒドロキシメチル基、ヒドロキシエチル基、ヒドロキシプロピル基などのヒドロキシアルキル基；グアニジノ基；ホルムイミドイル基；アセトイミドイル基；カルバモイル基；チオカルバモイル基；カルバモイルメチル基、カルバモイルエチル基などのカルバモイルアルキル基；メチルカルバモイル基、ジメチルカルバモイル基などのアルキルカルバモイル基；カルバミド基；アセチル基などのアルカノイル基；アミノ基；メチルアミノ基、エチルアミノ基、イソプロピルアミノ基などのアルキルアミノ基；ジメチルアミノ基、メチルエチルアミノ基、ジエチルアミノ基などのジアルキルアミノ基；アミノメチル基、アミノエチル基、アミノプロピル基などのアミノアルキル基；カルボキシ基；メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基などのアルコキシカルボニル基；メトキシカルボニルメチル基、エトキシカルボニルメチル基、プロポキシカルボニルメチル基、メトキシカルボニルエチル基、エトキシカルボニルエチル基、プロポキシカルボニルエチル基などのアルコキシカルボニルアルキル基；メチルオキシメチル基、メチルオキシエチル基、エチルオキシメチル基、エチルオキシエチル基などのアルキルオキシアルキル基；メチルチオメチル基、メチルチオエチル基、エチルチオメチル基、エチルチオエチル基などのアルキルチオアルキル基；アミノメチルアミノメチル基、アミノエチルアミノメチル基などのアミノアルキルアミノアルキル基；メチルカルボニルオキシ基、エチルカルボニルオキシ基、イソプロピルカルボニルオキシ基などのアルキルカルボニルオキシ基；オキシメチル基、ベンジルオキシエチルオキシエチル基などのアリールアルコキシアルコキシアルキル基；ヒドロキシエチルオキシメチル基、ヒドロキシエチルオキシエチル基などのヒドロキシアルコキシアルキル基；ベンジルオキシメチル基、ベンジルオキシエチル基、ベンジルオキシプロピル基などのアリールアルコキシアルキル基；トリメチルアンモニオ基、メチルエチルメチルアンモニオ基、トリエチルアンモニオ基などの第四級アンモニオ基；シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基などのシクロアルキル基；シクロプロペニル基、シクロブテニル基、シクロペンテニル基、シクロヘキセニル基などのシクロアルケニル基；フェニル基、ピリジニル基、チエニル基、フリル基、ピロリル基などのアリール基；メチルチオ基、エチルチオ基、プロピルチオ基、ブチルチオ基などのアルキルチオ基；フェニルチオ基、ピリジニルチオ基、チエニルチオ基、フリルチオ基、ピロリルチオ基などのアリールチオ基；ベンジル基、トリチル基、ジメトキシトリチル基などのアリール低級アルキル基；スルホニル基、メシル基、p-トルエンスルホニル基などの置換スルホニル基；ベンゾイル基などのアリロイル基；フルオロフェニル基、ブロモフェニル基などのハロゲノアリール基；メチレンジオキシ基などのオキシアルコキシ基等を挙げることができる。１以上の置換基を有していてもよいとは、これら基を任意に組み合わせて有していてもよいことを意味し、例えば水酸基，チオール基，ニトロ基，モルホリノ基，チオモルホリノ基，ハロゲン原子，ニトリル基，アジド基，ホルミル基，アミノ基，アルキルアミノ基，ジアルキルアミノ基，カルバモイル基，スルホニル基などで置換されたアルキル基；アルケニル基；アルキニル基；アルコキシ基なども本願発明中に含まれる。
【００１４】
環Ａとしての具体例を挙げると、１以上の置換基を有していてもよい、ベンゼン、ピリジン、チオフェン、フラン、ピロール、オキサゾール、イソキサゾール、チアゾール、イソチアゾール、イミダゾール、トリアゾール、ピラゾール、フラザン、チアジアゾール、オキサジアゾール、ピリダジン、ピリミジン、ピラジン、ペンタレン、インデン、ナフタレン、アズレン、インドール、イソインドール、インダゾール、クロメン、キノリン、イソキノリン、シンノリン、キナゾリン、キノキサリン、ナフチリジン、フタラジン、プリン、プテリジン、チエノフラン、イミダゾチアゾール、ベンゾフラン、ベンゾチオフェン、ベンズオキサゾール、ベンズチアゾール、ベンズチアジアゾール、ベンズイミダゾール、イミダゾピリジン、ピロロピリジン、ピロロピリミジン、ピリドピリミジンなどを挙げることができる。好ましくはベンゼン、ピリジン、チオフェン、チアゾール、チアジアゾール、イミダゾール、ピリミジン、ベンズイミダゾール、イミダゾピリジン、プリンなどが挙げられる。
【００１５】
さらに、環Ａが５員環と６員環の縮合環である場合を、具体的に例示するとチオフェン、フラン、ピロール、オキサゾール、イソキサゾール、チアゾール、イソチアゾール、イミダゾール、トリアゾール、ピラゾール、フラザン、チアジアゾール、オキサジアゾールなどとベンゼン、ピリジン、ピリダジン、ピリミジン、ピラジンなどとの縮合環が挙げられ、例えばインデン、インドール、イソインドール、ベンゾフラン、ベンゾチオフェン、ベンズオキサゾール、ベンズチアゾール、ベンズチアジアゾール、ベンズイミダゾール、イミダゾピリジン、ピロロピリジン、ピロロピリミジン、プリンなどが挙げられる。
【００１６】
Ｒ¹は低級アルキル基または１以上のヘテロ原子を有していてもよく、１以上の置換基を有していてもよい芳香環を示す。
低級アルキル基とは、具体的には炭素数１〜６の直鎖もしくは分岐鎖状のアルキル基、例えばメチル基、エチル基、n-プロピル基、i-プロピル基、n-ブチル基、i-ブチル基、sec-ブチル基、t-ブチル基、n-ペンチル基、i-ペンチル基、sec-ペンチル基、t-ペンチル基、ネオペンチル基、1-メチルブチル基、2-メチルブチル基、1,1-ジメチルプロピル基、1,2-ジメチルプロピル基、n-ヘキシル基、i-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、3-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、ヘキシル基などを意味する。好ましくはメチル基、エチル基、n-プロピル基、i-プロピル基、n-ブチル基、i-ブチル基、sec-ブチル基、t-ブチル基などが挙げられる。
【００１７】
このＲ¹についてのヘテロ原子および置換基に関する定義は前記と同様である。従って、Ｒ¹における芳香環を具体的に挙げると、１以上の置換基を有していてもよい、ベンゼン、ピリジン、チオフェン、フラン、ピロール、オキサゾール、イソキサゾール、チアゾール、イソチアゾール、イミダゾール、トリアゾール、ピラゾール、フラザン、チアジアゾール、ピリダジン、ピリミジン、ピラジンなどを挙げることができる。
【００１８】
さらに具体的に、 Ｒ¹における１以上の置換基を有していてもよい芳香環基を例示すると、2-フルオロフェニル基、4-フルオロフェニル基、2,4-ジフルオロフェニル基、2-ブロモフェニル基、4-ブロモフェニル基、2-クロロフェニル基、4-クロロフェニル基、2-アミノフェニル基、4-アミノフェニル基、2-ニトロフェニル基、4-ニトロフェニル基、2-ジメチルアミノフェニル基、4-ジメチルアミノフェニル基、2-メトキシフェニル基、4-メトキシフェニル基、2-チエニル基、2-ピリジル基、Ｎ-メチル-2-ピロリル基などを挙げることができる。
【００１９】
Ｒ²は水素原子、低級アルキル基またはアミノ基の保護基を示す。低級アルキル基に関する定義は前記と同様である。
アミノ基の保護基とは、具体例を挙げると、通常、有機合成上アミノ基の保護基として知られている基であればいかなる基でもよく特に限定されないが、たとえばホルミル基、アセチル基、クロロアセチル基、ジクロロアセチル基、プロピオニル基、フェニルアセチル基、フェノキシアセチル基、チエニルアセチル基などの置換または非置換の低級アルカノイル基；ベンジルオキシカルボニル基、t-ブトキシカルボニル基、p-ニトロベンジルオキシカルボニル基などの置換または非置換の低級アルコキシカルボニル基；メチル基、t-ブチル基、2,2,2-トリクロロエチル基、トリチル基、p-メトキシベンジル基、p-ニトロベンジル基、ジフェニルメチル基、ピバロイルオキシメチル基などの置換低級アルキル基；トリメチルシリル基、t-ブチルジメチルシリル基などの置換シリル基；トリメチルシリルメトキシメチル基、トリメチルシリルエトキシメチル基、t-ブチルジメチルシリルメトキシメチル基、t-ブチルジメチルシリルエトキシメチル基などの置換シリルアルコキシアルキル基；ベンジリデン基、サリチリデン基、p-ニトロベンジリデン基、m-クロルベンジリデン基、3,5-ジ（t-ブチル）-4-ハイドロキシベンジリデン基、3,5-ジ（t-ブチル）ベンジリデン基などの置換または非置換のベンジリデン基などを挙げることができる。
これらの保護基の脱離は、使用した保護基の種類に応じ、加水分解、還元など常法により行うことができる。
【００２０】
Ｒ³は水素原子、ハロゲン原子または低級アルキル基を示す。ハロゲン原子とは具体的には、フッ素原子、塩素原子、臭素原子、ヨウ素原子などが挙げられる。また、低級アルキル基に関する定義は前記と同様である。
【００２１】
塩としては種類は限定されないがたとえばフッ化水素酸塩、塩酸塩、硫酸塩、硝酸塩、過塩素酸塩、リン酸塩、炭酸塩、重炭酸塩、臭化水素酸塩、ヨウ化水素酸塩などの無機酸の付加塩；酢酸塩、マレイン酸塩、フマール酸塩、蓚酸塩、乳酸塩、酒石酸塩、トリフルオロ酢酸塩などの有機カルボン酸の付加塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩、ヒドロキシメタンスルホン酸塩、ヒドロキシエタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、タウリン塩などの有機スルホン酸の付加塩；トリメチルアミン塩、トリエチルアミン塩、ピリジン塩、プロカイン塩、ピコリン塩、ジシクロヘキシルアミン塩、Ｎ,Ｎ’−ジベンジルエチレンジアミン塩、Ｎ−メチルグルカミン塩、ジエタノールアミン塩、トリエタノールアミン塩、トリス（ヒドロキシメチルアミノ）メタン塩、フェネチルベンジルアミン塩などのアミンの付加塩；ナトリウム塩、カリウム塩などのアルカリ金属の付加塩；マグネシウム塩、カルシウム塩などのアルカリ土類金属の付加塩；アルギニン塩、リジン塩、セリン塩、グリシン塩、アスパラギン酸塩、グルタミン酸塩などのアミノ酸の付加塩などを挙げることができる。
薬理学的に許容される塩とは、医薬の製造において通常用いられる慣用的なものを意味する。
【００２２】
従って、本願ピラゾール誘導体またはその塩の具体例としては、６−（３−メチル−１Ｈ−ピラゾール−４−イル）イミダゾ〔１，２−ａ〕ピリジン、３−クロロ−６−（３−メチル−１Ｈ−ピラゾール−４−イル）イミダゾ〔１，２−ａ〕ピリジン、１−メチル−６−〔３−（４−メトキシフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール、１−メチル−６−〔３−（２，４−ジフルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾールまたは２−〔３−フェニル−１Ｈ−ピラゾール−４−イル〕−９−メチルプリンまたはその塩などを挙げることができる。
【００２３】
また、本発明には化合物の構造上生ずる立体異性体、光学異性体および互変異性体のすべてが含まれる。
【００２４】
次に以下の一般式で表される本発明化合物の製造方法について説明する。一般式
【化２３】

【００２５】
〔式中、環Ａ、Ｒ¹は前記の定義と同じである。〕で表される行程(I)は、本発明化合物たるピラゾール誘導体の合成に有用な中間体であるオレフィン化合物(3)を誘導するルートである。この反応は、反応を阻害しない溶媒中で、化合物(2)をナトリウムメチラートなどの塩基の存在下に化合物(1)と反応させることにより行うことができる。反応温度は化合物の反応性により異なるが、通常氷冷下から１００℃の間で行うことができる。
【００２６】
塩基としての具体例を挙げると、通常、有機合成上塩基として知られているものであればいかなるものでもよく特に限定されないが、例えば炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、水素化ナトリウム、水素化カリウム、t-ブトキシカリウム、ピリジン、ジメチルアミノピリジン、トリメチルアミン、トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、N-メチルピロリジン、Ｎ−メチルピペリジン、Ｎ，Ｎ−ジメチルアニリン、１，８−ジアザビシクロ［５，４，０］ウンデカ−７−エン（ＤＢＵ）、ピリジン、４−ジメチルアミノピリジン、ピコリン、ルチジン、キノリン、イソキノリン、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、ブチルリチウム、ナトリウムメチラート，カリウムメチラート，ナトリウムエチラートなどのナトリウムまたはカリウムアルコラート等が挙げられる。
【００２７】
また、一般式
【化２４】

【００２８】
〔式中、環Ａ、Ｒ¹は前記の定義と同じである。Ｒ⁴は低級アルコキシ基を示す。〕で表される行程(II)によっても、本発明化合物たるピラゾール誘導体の合成に有用な中間体を合成することができる。これは、反応を阻害しない溶媒中、水素化ナトリウムなどの塩基の存在下に化合物(5)を化合物(4)と反応させることにより、化合物(4)にシアノメチレン−Ｒ¹単位を導入し、オレフィン化合物(6)を誘導するルートである。
【００２９】
ここで、Ｒ⁴の低級アルコキシ基とは、前記の低級アルキル基に対応するものであり、具体的には、炭素数１〜６の直鎖もしくは分岐鎖状のアルコキシ基をいい、例えばメトキシ基、エトキシ基、n-プロポキシ基、i-プロポキシ基、n-ブトキシ基、i-ブトキシ基、sec-ブトキシ基、t-ブトキシ基、n-ペンチルオキシ基、i-ペンチルオキシ基、sec-ペンチルオキシ基、t-ペンチルオキシ基、ネオペンチルオキシ基、1-メチルブトキシ基、2-メチルブトキシ基、1,1-ジメチルプロポキシ基、1,2-ジメチルプロポキシ基、n-ヘキシルオキシ基、i-ヘキシルオキシ基、1-メチルペンチルオキシ基、2-メチルペンチルオキシ基、3-メチルペンチルオキシ基、1,1-ジメチルブトキシ基、1,2-ジメチルブトキシ基、2,2-ジメチルブトキシ基、1,3-ジメチルブトキシ基、2,3-ジメチルブトキシ基、3,3-ジメチルブトキシ基、1-エチルブトキシ基、2-エチルブトキシ基、1,1,2-トリメチルプロポキシ基、1,2,2-トリメチルプロポキシ基、1-エチル-1-メチルプロポキシ基、1-エチル-2-メチルプロポキシ基などが挙げられる。
【００３０】
一般式
【化２５】

【００３１】
〔式中、環Ａ、Ｒ¹は前記定義と同じである。Ｒ⁵は水素原子またはトリメチルシリル基をそれぞれ示す。〕で表される行程(III)は、上記行程(I)，(II)により得られたオレフィン化合物を閉環するルートである。
この反応は、例えば反応を阻害しない溶媒中でトリメチルシリルジアゾメタン(8)を約−７８℃に冷却下、n-ブチルリチウムなどの塩基を加え、ここに化合物(7)を加えることにより行うことができる。Ｒ⁵のトリメチルシリル基の除去は、通常のシリル基が脱離する条件で行うことができ、例えば、１Ｍテトラブチルアンモニウムフルオライドで室温中攪拌することにより、又は塩酸で加熱することによりトリメチルシリル基を除去することができる。
【００３２】
一般式
【化２６】

【００３３】
〔式中、環Ａ、Ｒ¹、Ｒ²は前記定義と同じである。〕で表される行程(IV)によっても本願化合物を製造することができる。これは反応を阻害しない溶媒中で、化合物(10)をヒドラジン誘導体(11)と反応させ閉環させるルートである。
【００３４】
さらに一般式
【化２７】

【００３５】
〔式中、Ｒ¹、Ｒ²は前記定義と同じである。Ｒ⁶は水素原子または低級アルキル基を示す。〕で表される行程(V)は本願ピラゾール誘導体の合成に有用な中間体であるアミド化合物(15)を誘導するルートである。この反応は、反応を阻害しない溶媒中で、化合物(13)の酸ハライド誘導体を化合物(14)と反応させることにより行うことができる。反応温度は化合物の反応性により異なるが、通常氷冷下から100℃の間で行うことができる。
【００３６】
一般式
【化２８】

【００３７】
〔式中、Ｒ¹、Ｒ²、Ｒ⁶は前記定義と同じである。〕で表される行程(VI)は上記行程(V)により得られたアミド化合物(15)を閉環しプリン誘導体(16)を誘導するルートである。この反応は、反応を阻害しない溶媒中で、化合物(15)を炭酸水素カリウムなどの塩基の存在下反応させることにより行うことができる。反応温度は化合物の反応性により異なるが、通常氷冷下から100℃の間で行うことができる。Ｒ²がアミノ基の保護基、特に２−トリメチルシリルエトキシメチル基の場合は、ボロントリストリフルオロアセテートで氷冷下攪拌することにより、２−トリメチルシリルエトキシメチル基を除去することができる。
【００３８】
上記の行程における反応は特に記載したものを除いて一般には、−７８℃〜１５０℃、好ましくは−４０〜５０℃、より好ましくは−２０〜２５℃の温度範囲で行うことができる。
【００３９】
本発明で使用しうる溶媒としては、反応を阻害しないものであって、通常有機合成上用いられているものであればいかなる溶媒でもよく特に限定されないが、例えば、メタノール、エタノール、プロパノール、ブタノールなどの低級アルコール類、エチレングリコール、グリセリンなどのポリアルコール類、アセトン、メチルエチルケトン、ジエチルケトン、シクロヘキサノンなどのケトン類、ジエチルエーテル、イソプロピルエーテル、テトラヒドロフラン、ジオキサン、２−メトキシエタノール、１，２−ジメトキシエタンなどのエーテル類、アセトニトリル、プロピオニトリルなどのニトリル類、酢酸メチル、酢酸エチル、酢酸イソプロピル、酢酸ブチル、フタル酸ジエチルなどのエステル類、ジクロロメタン、クロロホルム、四塩化炭素、１，２−ジクロロエタン、トリクロロエチレン、テトラクロロエチレンなどのハロゲン化炭化水素類、ベンゼン、トルエン、キシレン、モノクロルベンゼン、ニトロベンゼン、インデン、ピリジン、キノリン、コリジン、フェノールなどの芳香族類、ペンタン、シクロヘキサン、ヘキサン、ヘプタン、オクタン、イソオクタン、石油ベンジン、石油エーテルなどの炭化水素類、エタノールアミン、ジエチルアミン、トリエチルアミン、ピロリジン、ピペリジン、ピペラジン、モルホリン、アニリン、ジメチルアニリン、ベンジルアミン、トルイジンなどのアミン類、ホルムアミド、Ｎ−メチルピロリドン、Ｎ，Ｎ−ジメチルイミダゾロン、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ，Ｎ−ジメチルホルムアミドなどのアミド類、ヘキサメチルリン酸トリアミド、ヘキサメチル亜リン酸トリアミドなどのリン酸アミド類、水、その他一般に使用される溶媒などの一種もしくは二種以上の混合溶媒を挙げることができ、その混合比は特に限定されない。
【００４０】
以上の反応終了後、所望により通常の処理法によって、例えばシリカゲルまたは吸着樹脂等を用いるカラムクロマトグラフィーや適当な溶媒から再結晶することにより精製することが可能である。
【００４１】
本発明に係る抗ヘルペス剤の投与量は症状の程度、年齢、性別、体重、投与形態、疾患の種類等により異なるが、通常成人１日当たり１〜１０００ｍｇであり1〜数回に分けて投与する。また、その投与形態も特に限定されず、通常用いられる方法により軟カプセル剤、硬カプセル剤、錠剤、散剤、顆粒剤、内服液剤、注射剤、輸液などにより経口または非経口的に投与することができる。
【００４２】
これら製剤化には通常用いられる賦形剤，結合剤，滑沢剤，着色剤，矯味矯臭剤等，および必要により安定化剤，乳化剤，吸収促進剤，界面活性剤等を使用することができ、常法により製剤化される。これらの成分としては例えば、動植物油（大豆油、牛脂、合成グリセライドなど）、炭化水素（流動パラフィン、スクワラン、固形パラフィンなど）、エステル油（ミリスチン酸オクチルドデシル、ミリスチン酸イソプロピルなど）、高級アルコール（セトステアリルアルコール、ベヘニルアルコールなど）、シリコン樹脂、シリコン油、界面活性剤（ポリオキシエチレン脂肪酸エステル、ソルビタン脂肪酸エステル、グリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン硬化ひまし油、ポリオキシエチレンポリオキシプロピレンブロックコポリマーなど）、水溶性高分子（ヒドロキシエチルセルロース、ポリアクリル酸、カルボキシビニルポリマー、ポリエチレングリコール、ポリビニルピロリドン、メチルセルロースなど）、アルコール（エタノール、イソプロパノールなど）、多価アルコール（グリセリン、プロピレングリコール、ジプロピレングリコール、ソルビトールなど）、糖（グルコース、ショ糖など）、無機粉体（無水ケイ酸、ケイ酸アルミニウムマグネシウム、ケイ酸アルミニウムなど）、精製水などが挙げられる。ｐＨ調製のためには無機酸（塩酸、りん酸など）、無機酸のアルカリ金属塩（りん酸ナトリウムなど）、無機塩基（水酸化ナトリウムなど）、有機酸（低級脂肪酸、クエン酸、乳酸など）、有機酸のアルカリ金属塩（クエン酸ナトリウム、乳酸ナトリウムなど）、有機塩基（アルギニン、エタノールアミンなど）などを用いることができる。また、必要に応じて、防腐剤、抗酸化剤などを添加することができる。
【００４３】
本発明化合物は、ヘルペスウイルスに対して優れた抗ウイルス作用を示し、ヘルペスウイルスが原因となって生じる感染症の治療および予防のための抗ヘルペスウイルス剤として有用な化合物である。本発明化合物の有用性を示すために本発明化合物の抗ウイルス活性を測定した。
【００４４】
抗ヘルペスウイルス活性の測定法
抗ＨＳＶ-1活性の測定はプラーク減少法により行った。２４ウェルマイクロプレートに培養したＶＥＲＯ細胞に50から100ＰＦＵのＨＳＶ-1ＫＯＳ株を吸着させる。１時間後上清を除き、0.5％のメチルセルロースを含む培地に希釈した被検物質を加え３日間培養を続ける。その後、0.25％のニュートラルレッドを加えて染色しＨＳＶ-1の感染によりできたプラークの数を計数する。なにも加えないコントロールのウェルに対しプラーク数を50％抑制する被検物質の濃度をＥＤ₅₀とした。
以下に本発明化合物の抗ヘルペスウイルス活性を示す。
【００４５】
【表１】

【００４６】
次に本発明を更に詳しく説明するためにいくつかの実施例を示すが、本発明はこれらのものに限定されるものではない。また、実施例中 ¹Ｈ Ｎ.Ｍ.Ｒ.スペクトラムはVarian社 FT NMR(400MHz)で測定した。
【００４７】
尚、以下、Ｔｒはトリチル基を、ＳＥＭはトリメチルシリルエトキシメチル基を、Ｂｎはベンジル基をそれぞれ示す。
【００４８】
【実施例】
実施例１
６−（３−メチル−１Ｈ−ピラゾール−４−イル）〔１，２−ａ〕イミダゾピリジン
【００４９】
【化２９】

【００５０】
４−ジメチルアミノ−３−（６−イミダゾ〔１，２−ａ〕ピリジニル）−３−ブテン−２−オン(M.Yamanaka et al. Chem.Pharm.Bull.,39(6),1556-67,1991)31.41gをエタノール125mlに溶解させ、ヒドラジン−水和物13.7gを加え１時間加熱還流した。冷後、析出した結晶を濾取、冷エタノール洗し乾燥すると、標題化合物が無色針状晶として得られた（収量21.25g）。
m.p.:230〜231°(dec)
MS:199(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：12.7(1H,br),8.58(1H,m),7.92(1H,br,s),7.56(1H,d,J=9.3Hz),7.54(1H,d,J=1.1Hz),7.35(1H,dd,J=1.8,9.3Hz),2.37(3H,s)
【００５１】
実施例２
３−チオモルホリノメチル−６−（３−メチル−１Ｈ−ピラゾール−４−イル）〔１，２−ａ〕イミダゾピリジン
【００５２】
【化３０】

【００５３】
チオモルホリン780mgをエタノール20mlに溶解し、２NHCl3.78ml,37％ホルマリン613mgを加え30分撹拌した。これに６−（３−メチル−１Ｈ−ピラゾール−４−イル）〔１，２−ａ〕イミダゾピリジン500mgを加え６時間加熱還流した。冷後、NaHCO３でアルカリ性とした後、ジクロロメタン70mlで抽出した。溶媒留去後、残渣をカラムクロマトグラフィー(EtOAc-Acetone=3-1)にて精製すると褐色アモルファス状固体が909mg得られた。CH₂Cl₂より再結晶すると標題化合物が無色針状晶として400mg得られた。
m.p.:222〜223°
MS:314(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：12.75(1H,br),8.41(1H,br,s),7.56(1H,d,J=9.3Hz),7.45(1H,s),7.39(1H,dd,J=9.3,1.3Hz),3.84(2H,s),2.66〜2.54(8H,m),2.41(3H,s)
【００５４】
実施例３
３−モルホリノメチル−６−（３−メチル−１Ｈ−ピラゾール−４−イル）〔１，２−ａ〕イミダゾピリジン
【００５５】
【化３１】

【００５６】
モルホリン660mgに２NHCl3.78ml、37％ホルマリン614mgを加え室温で１時間撹拌した。これに６−（３−メチル−１Ｈ−ピラゾール−４−イル）〔１，２−ａ〕イミダゾピリジンン500mgを加え、７時間80℃にて撹拌した。冷後、NaHCO₃を加えアルカリ性とした後、ジクロロメタン100mlで抽出した。溶媒留去後、残渣をカラムクロマトグラフィー(EtOAc-MeOH=10-1)にて精製すると581mg固体が得られた。これをEtOAcより再結晶すると標題化合物が無水針状晶として55mg得られた。
m.p.:244〜246°
MS:298(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：12.7(1H,br),8.45(1H,br,s),7.56(1H,dd,J=9.3,0.8Hz),7.46(1H,s),7.40(1H,dd,J=1.8,9.3Hz),3.83(2H,s),3.52(4H,m),2.41(3H,s),2.38(4H,m)
【００５７】
実施例４
３−ヨード−６−（３−メチル−１Ｈ−ピラゾール−４−イル）イミダゾ〔１，２−ａ〕ピリジン
【００５８】
【化３２】

【００５９】
６−（３−メチル−１Ｈ−ピラゾール−４−イル）〔１，２−ａ〕イミダゾピリジンン 200mgをメタノール10mlに溶解させ、ヨウ素254mgを加え室温にて１時間撹拌した。さらにヨウ素254mgを加え１時間撹拌した。ジクロロメタン50mlを加え、飽和炭酸水素ナトリウム水溶液、次いで飽和食塩水洗し、MgSO₄で乾燥した。溶媒留去後、残渣をカラムクロマトグラフィー(CH₂Cl₂-MeOH=97.5-2.5)にて精製し、ジクロロメタンより再結晶すると、標題化合物が無色結晶として150mg得られた。
m.p.:218°(decomp.)
MS:325(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：12.75(1H,br,NH),8.17(1H,m,H-5),7.70(1H,s,H-2),7.63(1H,dd,J=9.3,0.9Hz,H-8),7.47(1H,dd,J=9.3,1.8Hz,H-7),2.40(3H,s,Me)
【００６０】
実施例５
３−ブロモ−６−（３−メチル−１Ｈ−ピラゾール−４−イル）イミダゾ〔１，２−ａ〕ピリジン
【００６１】
【化３３】

【００６２】
６−（３−メチル−１Ｈ−ピラゾール−４−イル）〔１，２−ａ〕イミダゾピリジンン 795mgをジクロロメタン−メタノール（２−１）混液20mlに溶解させ、トリエチルアミン0.48ml、続いて１MBr₂/CH₂Cl₂ 3.43mlを加え、室温にて１時間撹拌した。ジクロロメタン100mlを加え、水洗し、有機層をMgSO₄で乾燥した。MeOH-EtOAcより再結晶すると標題化合物が淡黄色結晶として820mg得られた。
m.p.:264〜265°(decomp.)
¹H-NMR(CDCl₃)δ(ppm)：8.07(1H,dd,J=0.9,1.6Hz,H-5),7.72(1H,dd,J=0.9,9.3Hz,H-8),7.68(1H,br),7.62(1H,s,H-2),7.33(1H,dd,J=1.6,9.3Hz,H-7),2.43(3H,s,Me)
【００６３】
実施例６
３−クロロ−６−（３−メチル−１Ｈ−ピラゾール−４−イル）イミダゾ〔１，２−ａ〕ピリジン
【００６４】
【化３４】

【００６５】
６−（３−メチル−１Ｈ−ピラゾール−４−イル）〔１，２−ａ〕イミダゾピリジンン 240mgをメタノール30mlに溶解させ、Ｎ−クロロスクシンイミド(NCS)180mgを加え、室温にて４時間撹拌した。溶媒を留去し、ジクロロメタン100mlで抽出し、飽和食塩水で洗浄した。有機層をMgSO₄で乾燥し、溶媒留去後、残渣をカラムクロマトグラフィー(CH₂Cl₂-MeOH=98-2)にて精製すると、標題化合物が無色結晶として280mg得られた。
m.p.:207〜208℃
¹H-NMR(CDCl₃)δ(ppm)：8.19(1H,m,H-5),8.08(1H,d,J=8.8Hz,H-8),7.77(1H,s),7.72(1H,s),7.62(1H,dd,J=8.8,0.7Hz,H-7),2.50(3H,s,Me)
【００６６】
実施例７
６−〔２−シアノ−２−（２−ピリジル）〕エテニル イミダゾ〔１，２−ａ〕ピリジン
【００６７】
【化３５】

【００６８】
イミダゾ〔１，２−ａ〕ピリジン−６−カルボキシアルデヒド1.02g、２−シアノメチルピリジン900mgをエタノール50mlに溶解させナトリウムメチラート95mgを加え、80℃で１時間撹拌した。反応液を約1/3まで留去し、析出した結晶を濾取、冷エタノール洗し、乾燥すると標題化合物が淡黄色結晶として950mg得られた。
m.p.:149〜151℃
¹H-NMR(CDCl₃)δ(ppm)：8.82(1H,m),8.65(1H,ddd,J=0.9,1.6,4.6Hz),8.46(1H,s),7.94(1H,dd,J=1.8,9.5Hz),7.83(1H,ddd,J=1.8,7.8,7.8Hz),7.78(1H,s,),7.78〜7.76(1H,m),7.73(1H,m),7.69(1H,m),7.32(1H,ddd,J=1.3,4.6,7.8Hz)
【００６９】
実施例８
６−〔３−（２−ピリジル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン
【００７０】
【化３６】

【００７１】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液、東京化成株式会社製）10mlのTHF10ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）3.6mlを加え、同温度にて20分間撹拌した。これに実施例７の化合物0.95gのTHF50ml溶液を20分かけて滴下し、徐々に室温まで昇温させながら４時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン150mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。カラムクロマトグラフィー（EtoAcのみ）にて精製後、360mgをとり、これにエタノール30ml、濃塩酸1.2ml、フッ化カリウム70mgを加え0.5時間加熱還流した。冷後、炭酸カリウム溶液を加えてアルカリ性とし、エタノールを減圧下留去して、EtoAc100mlで抽出した。有機層を分取し、MgSO₄乾燥後、溶媒を留去し、残渣をメタノールより再結晶すると標題化合物が無色結晶として150mg得られた。
m.p.:287〜290°(decomp.)
¹H-NMR(CDCl₃)δ(ppm)：8.60〜8.58(1H,m),8.43〜8.42(1H,m),8.05〜8.00(1H,m),7.77(1H,d,J=1.5Hz),7.74(1H,s),7.66〜7.64(1H,m),7.66(1H,d,J=1.5Hz),7.56〜7.44(2H,m),7.30〜7.25(1H,m)
【００７２】
実施例９
６−（２−シアノ−２−フェニル）エテニル イミダゾ〔１，２−ａ〕ピリジン
【００７３】
【化３７】

【００７４】
イミダゾ〔１，２−ａ〕ピリジン−６−カルボキシアルデヒド1.02g、フェニルアセトニトリル0.86gをエタノール10mlに溶解させナトリウムメチラート87mgを加え、80℃にて１時間撹拌した。反応液より溶媒を留去し、残渣をカラムクロマトグラフィー（CH₂Cl₂-MeOH=98-2）にて精製すると、標題化合物が淡黄色の結晶として得られた。酢酸エチル−エーテル−ヘキサンにて再結晶し、淡黄色粉末を得た（収量1.01g）。
m.p.:159〜161°(decomp.)
¹H-NMR(CDCl₃)δ(ppm)：8.76(1H,dd,J=0.9,1.6Hz),7.74(1H,dd,J=1.6,9.3Hz),7.71〜7.69(2H,m),7.69〜7.66(3H,m),7.50〜7.41(4H,m)
【００７５】
実施例１０
６−（２−シアノ−２−フェニル）エテニル イミダゾ〔１，２−ａ〕ピリジン
【００７６】
【化３８】

【００７７】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）10mlのTHF30ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）3.6mlを加え、同温度にて20分間撹拌した。これに実施例９の化合物900mgのTHF10ml溶液を20分かけて滴下し、徐々に室温まで昇温させながら４時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン100mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。カラムクロマトグラフィー(EtOAc-MeOH=98.5:1.5)にて精製後、300mgをとり、これにエタノール15ml、濃塩酸26滴、フッ化カリウム53mgを加え1.5時間加熱還流した。冷後、炭酸カリウム溶液を加えてアルカリ性とし、エタノールを減圧下留去して、ジクロロメタン100mlで抽出した。有機層を分取し、MgSO₄乾燥後、溶媒を留去し、残渣をカラムクロマトグラフィー(EtOAc-MeOH=98:2)にて精製すると、標題化合物が淡褐色アモルファス状固体として140mg得られた。
¹H-NMR(CDCl₃)δ(ppm)：8.09(1H,m),7.75(1H,s),7.63(1H,d,J=1.1Hz),7.56(1H,d,J=9.3Hz),7.53(1H,d,J=1.1Hz),7.47〜7.37(5H,m),7.08(1H,dd,J=1.6,9.3Hz)
【００７８】
実施例１１
６−〔２−シアノ−２−（４−フルオロフェニル）〕エテニル イミダゾ〔１，２−ａ〕ピリジン
【００７９】
【化３９】

【００８０】
イミダゾ〔１，２−ａ〕ピリジン−６−カルボキシアルデヒド1.02g、４−フロロフェニルアセトニトリル1.01gをエタノール200mlに溶解させナトリウムメチラート90mgを加え、90℃にて１時間撹拌した。反応液より溶媒を留去し、残渣をカラムクロマトグラフィー(EtOAc-MeOH=98-2)にて精製し、EtOAc-Ether-Hexaneより再結晶すると標題化合物が無色結晶として得られた（収量1.22g）。
m.p.:157〜159℃
¹H-NMR(CDCl₃)δ(ppm)：7.74〜7.71(1H,m),7.71(1H,s),7.70(1H,s),7.68〜7.67(2H,m),7.65(2H,dd,J=5.0,8.7Hz),7.37(1H,s),7.17(2H,t,J=8.7Hz)
【００８１】
実施例１２
６−〔３−（４−フルオロフェニル−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン
【００８２】
【化４０】

【００８３】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）10mlのTHF10ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）3.6mlを加え、同温度にて20分間撹拌した。これに実施例１１の化合物1.0gのTHF50ml溶液を20分かけて滴下し、徐々に室温まで昇温させながら４時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン100mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。カラムクロマトグラフィー(EtOAc-MeOH=98:2)にて精製した。これにエタノール50ml、濃塩酸3ml、フッ化カリウム200mgを加え0.5時間加熱還流した。冷後、炭酸カリウム溶液を加えてアルカリ性とし、エタノールを減圧下留去して、ジクロロメタン100mlで抽出した。有機層を分取し、MgSO₄乾燥後、溶媒を留去し、残渣をカラムクロマトグラフィー(EtOAc-MeOH=98:2)にて精製した。MeOH-EtOAcより再結晶すると標題化合物が無色結晶として500mg得られた。
m.p.:227〜228℃
¹H-NMR(CDCl₃)δ(ppm)：8.08(1H,dd,J=0.9,1.4Hz),7.74(1H,d,J=1.1Hz),7.65(1H,d,J=1.1Hz),7.58(1H,dd,J=0.9,9.3Hz),7.54(1H,s),7.48〜7.44(2H,m),7.10〜7.04(3H,m)
【００８４】
実施例１３
３−クロロ−６−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン
【００８５】
【化４１】

【００８６】
６−〔３−（４−フルオロフェニル−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン 150mgをメタノール20mlに溶解させ、Ｎ−クロロスクシンイミド（NCS）94mgを加え、70℃にて１時間撹拌した。溶媒を留去しジクロロメタン50mlで抽出し、飽和食塩水で洗浄した。有機層をMgSO₄で乾燥し、溶媒留去後、残渣をカラムクロマトグラフィー(EtOAc-MeOH=98-2)にて精製すると標題化合物が淡黄色アモルファス状固体として64mg得られた。
¹H-NMR(CDCl₃)δ(ppm)：8.04(1H,dd,J=0.9,1.8Hz),7.78(1H,s),7.57(1H,s),7.56(1H,dd,J=0.9,9.3Hz),7.48〜7.44(2H,m),7.11〜7.05(3H,m)
【００８７】
実施例１４
６−〔２−シアノ−２−（２−メトシキフェニル）〕エテニル イミダゾ〔１，２−ａ〕ピリジン
【００８８】
【化４２】

【００８９】
イミダゾ〔１，２−ａ〕ピリジン−６−カルボキシアルデヒド1.02g、２−メトキシフェニルアセトニトリル1.13gをエタノール20mlに溶解させナトリウムメチラート76mgを加え、90℃で８時間撹拌した。反応液より溶媒を留去し、残渣をカラムクロマトグラフィー(CH₂Cl₂-MeOH=98:2)にて精製すると、標題化合物が淡黄色固体として得られた（収量1.07g）。
m.p.:174〜176℃
¹H-NMR(CDCl₃)δ(ppm)：8.84(1H,m),7.87(1H,d,J=9.3Hz),7.76(1H,dd,J=9.3,1.6Hz),7.75(1H,m),7.71(1H,s),7.46〜7.39(2H,m),7.45(1H,s),7.05(1H,td,J=1.1,7.5Hz),7.00(1H,d,J=8.4Hz),3.94(3H,s)
【００９０】
実施例１５
６−〔３−（２−メトキシフェニル）−１Ｈ−ピラゾール−４− yl 〕イミダゾ〔１，２−ａ〕ピリジン
【００９１】
【化４３】

【００９２】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）10mlのTHF10ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）3.6mlを加え、同温度にて20分間撹拌した。これに実施例１４の化合物1.06gのTHF50ml溶液を20分かけて滴下し、徐々に室温まで昇温させながら２時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン100mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。カラムクロマトグラフィー（EtoAcのみ）にて精製後、750mgをとり、これにエタノール50ml、濃塩酸２ml、フッ化カリウム120mgを加え0.5時間加熱還流した。冷後、炭酸カリウム溶液を加えてアルカリ性とし、エタノールを減圧下留去して、ジクロロメタン150mlで抽出した。有機層を分取し、MgSO₄乾燥後、溶媒を留去し、残渣をカラムクロマトグラフィー(EtOAc-MeOH=98:2)にて精製すると標題化合物が無色不定形固体として170mg得られた。
¹H-NMR(CDCl₃)δ(ppm)：8.20(1H,m),7.96(1H,d,J=8.4Hz),7.76(1H,s),7.73(1H,d,J=1.8Hz),7.60(1H,d,J=1.8Hz),7.43〜7.38(2H,m),7.24〜7.23(1H,m),7.05(1H,d,J=8.4Hz),6.95〜6.91(1H,m),3.85(3H,s)
【００９３】
実施例１６
３−クロロ−６−〔３−（２−メトキシフェニル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン
【００９４】
【化４４】

【００９５】
６−〔３−（２−メトキシフェニル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン 80mgをメタノール15mlに溶解させ、Ｎ−クロロスクシンイミド(NCS)80mgを加え、室温にて３時間撹拌した。溶媒を留去し、ジクロロメタン50mlで抽出し、飽和食塩水で洗浄した。有機層をMgSO₄で乾燥し、溶媒留去後、残渣をカラムクロマトグラフィー(EtOAc-MeOH=98:2)にて精製すると標題化合物が淡黄色アモルファス状固体として50mg得られた。
¹H-NMR(CDCl₃)δ(ppm)：8.10(1H,dd,J=0.9,1.6Hz),7.78(1H,s),7.67(1H,d,J=8.8Hz),7.59(1H,s),7.38(1H,ddd,J=8.4,7.5,1.6Hz),7.27〜7.24(2H,m),7.04(1H,d,J=8.2Hz),6.91(1H,td,J=1.1,7.5Hz),3.87(3H,s)
【００９６】
実施例１７
６−〔２−シアノ−２−（２−フルオロフェニル）〕エテニル イミダゾ〔１，２−ａ〕ピリジン
【００９７】
【化４５】

【００９８】
イミダゾ〔１，２−ａ〕ピリジン−６−カルボキシアルデヒド1.02g、２−フロロフェニルアセトニトリル1.01gをエタノール20mlに溶解させナトリウムメチラート90mgを加え、80℃で７時間撹拌した。反応液より溶媒を留去し、残渣をカラムクロマトグラフィー(EtOAc-MeOH=98:2)にて精製すると、標題化合物が淡黄色固体として得られた（収量930mg）。
m.p.:161〜162℃
¹H-NMR(CDCl₃)δ(ppm)：8.75(1H,dd,J=0.9,1.6Hz),7.76(1H,dd,J=1.6,9.3Hz),7.72(1H,d,J=0.7Hz),7.72〜7.68(1H,m),7.68(1H,d,J=0.7Hz),7.61(1H,td,J=7.8,1.8Hz),7.53(1H,s),7.44〜7.37(1H,m),7.29〜7.17(2H,m)
【００９９】
実施例１８
６−〔３−（２−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン
【０１００】
【化４６】

【０１０１】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）10mlのTHF10ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）3.6mlを加え、同温度にて20分間撹拌した。これに実施例１７の化合物0.9gのTHF50ml溶液を20分かけて滴下し、徐々に昇温させながら2.5時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン90mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。カラムクロマトグラフィー(EtOAc-MeOH=98:2)にて精製後、1.19gをとり、これにエタノール50ml、濃塩酸２ml、フッ化カリウム120mgを加え0.5時間加熱還流した。冷後、炭酸カリウム溶液を加えてアルカリ性とし、エタノールを減圧下留去して、ジクロロメタン100mlで抽出した。有機層を分取し、MgSO₄乾燥後、溶媒を留去し、残渣をカラムクロマトグラフィー(EtOAc-MeOH=97:3)にて精製した。EtOAc-n-Hexaneより再結晶すると標題化合物が無色粉末として140mg得られた。
m.p.:226〜228℃
¹H-NMR(CDCl₃)δ(ppm)：8.08(1H,m),7.78(1H,s),7.63(1H,d,J=0.9Hz),7.56(1H,d,J=9.2Hz),7.53(1H,d,J=0.9Hz),7.41〜7.36(2H,m),7.20〜7.13(2H,m),7.06(1H,dd,J=1.6,9.2Hz)
【０１０２】
実施例１９
３−クロロ−６−〔３−（２−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン
【０１０３】
【化４７】

【０１０４】
６−〔３−（２−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン 170mgをメタノール20mlに溶解させ、Ｎ−クロロスクシンイミド（NCS）100mgを加え、室温にて４時間撹拌した。溶媒を留去し、ジクロロメタン50mlで抽出し、飽和食塩水で洗浄した。有機層をMgSO₄で乾燥し、溶媒留去後、残渣をカラムクロマトグラフィー(EtOAc-MeOH=98:2)にて精製すると標題化合物が淡黄色固体として100mg得られた。
m.p.:188〜189℃
¹H-NMR(CDCl₃)δ(ppm)：8.02(1H,m),7.84(1H,s),7.56(1H,s),7.55(1H,d,J=8.4Hz),7.44〜7.38(2H,m),7.21〜7.15(2H,m),7.12(1H,dd,J=1.6,8.4Hz)
【０１０５】
実施例２０
６−〔２−シアノ−２−（４−メトキシフェニル）〕エテニル イミダゾ〔１，２−ａ〕ピリジン
【０１０６】
【化４８】

【０１０７】
イミダゾ〔１，２−ａ〕ピリジン−６−カルボキシアルデヒド1.02g、４−メトキシフェニルアセトニトリル1.13gをエタノール20mlに溶解させナトリウムメチラート120mgを加え、80℃で１時間撹拌した。冷後、析出した結晶を濾取、冷エタノール洗して乾燥すると、標題化合物が淡黄色結晶として得られた（収量1.18g）。
m.p.:125〜127℃
¹H-NMR(CDCl₃)δ(ppm)：8.73(1H,s),7.70〜7.66(3H,m),7.61(2H,d,J=8.2Hz),7.32(1H,s),7.26(1H,d,J=1.1Hz),6.98(2H,d,J=8.2Hz),3.87(3H,s)
【０１０８】
実施例２１
６−〔３−（４−メトキシフェニル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン
【０１０９】
【化４９】

【０１１０】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）10mlのTHF10ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）3.6mlを加え、同温度にて20分間撹拌した。これに実施例２０の化合物1.06gのTHF50ml溶液を20分かけて滴下し、徐々に室温まで昇温させながら５時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン150mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。カラムクロマトグラフィー(EtOAc-MeOH=98:2)にて精製後、800mgをとり、これにエタノール50ml、濃塩酸1.4ml、フッ化カリウム80mgを加え0.5時間加熱還流した。冷後、炭酸カリウム溶液を加えてアルカリ性とし、エタノールを減圧下留去して、ジクロロメタン100mlで抽出した。有機層を分取し、MgSO₄乾燥後、溶媒を留去し、残渣をカラムクロマトグラフィー(EtOAc-MeOH=98:2)にて精製すると標題化合物が淡黄色固体として340mg得られた。
m.p.:226〜227℃
¹H-NMR(CDCl₃)δ(ppm):8.09(1H,m),7.72(1H,d,J=1.1Hz),7.63(1H,d,J=1.1Hz),7.56(1H,dd,J=9.3,0.7Hz),7.53(1H,s),7.38(2H,d,J=8.2Hz),7.09(1H,dd,J=9.3,1.6Hz),6.91(2H,d,J=8.2Hz),3.84(3H,s)
【０１１１】
実施例２２
３−クロロ−６−〔３−（４−メトキシフェニル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン
【０１１２】
【化５０】

【０１１３】
６−〔３−（４−メトキシフェニル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン 300mgをメタノール50mlに溶解させ、Ｎ−クロロスクシンイミド（NCS）200mgを加え、室温にて３時間撹拌した。溶媒を留去し、ジクロロメタン100mlで抽出し、飽和食塩水で洗浄した。有機層をMgSO₄で乾燥し、溶媒留去後、残渣をカラムクロマトグラフィー(EtOAc-MeOH=98:2)にて精製すると標題化合物が淡黄色結晶として150mg得られた。
m.p.:208〜210℃
¹H-NMR(CDCl₃)δ(ppm)：8.05(1H,dd,J=0.9,1.6Hz),7.77(1H,s),7.56(1H,s),7.53(1H,dd,J=0.9,9.3Hz),7.37(2H,d,J=8.9Hz),7.12(1H,dd,J=1.6,9.3Hz),6.92(2H,d,J=8.9Hz),3.84(3H,s)
【０１１４】
製造例１
１−トリフェニルメチルベンズイミダゾール６−カルボン酸メチルエステル
【０１１５】
【化５１】

【０１１６】
ベンズイミダゾール-５−カルボン酸95.0gをメタノール800mlに加え、さらに濃硫酸86.1gを加え、16時間加熱還流した。冷後、炭酸カリウム水溶液を加えて中和し、メタノールを減圧留去した。生じた沈澱を濾取し、100℃にて乾燥すると、ベンズイミダゾール-５−カルボン酸メチルエステルが褐色粉末として得られた（収量103g）。これを精製せずに次の反応に用いた。
ベンズイミダゾール５−カルボン酸メチルエステル52.85gをDMF260mlに懸濁し、水素化ナトリウム13.2gを加え、１時間撹拌した。トリフェニルメチルクロリド100gを加え、室温にて1.5時間撹拌した。反応液を氷水４lに加え、生じた沈澱を濾取し、乾燥した。得られた粉末にメタノール1.2lを加え撹拌し、不溶性の固体を濾取した。これをCH₂Cl₂-MeOHより再結晶すると、標題化合物が無色結晶として得られた（収量65.8g）。
m.p.:171〜173℃
MS:419(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：8.08(1H,s,H-2),7.78〜7.76(2H,m),7.42〜7.37(9H,m),7.17〜7.12(7H,m),3.69(3H,s,Me)
【０１１７】
製造例２
１−トリフェニルメチル−６−ヒドロキシメチル ベンズイミダゾール
【０１１８】
【化５２】

【０１１９】
製造例１の化合物89.74gをTHF1000mlに溶解し、窒素気流下、水素化リチウムアルミニウム(LiAlH₄)20.3gのTHF100ml溶液に１時間かけて滴下し、更に室温にて３時間撹拌した。飽和塩化アンモニウム(NH₄Cl)水溶液54mlを注意して加え、濾過、溶媒を留去すると標題化合物が無色アモルファス状固体として得られた（収量75.0g）。
¹H-NMR(CDCl₃)δ(ppm)：7.93(1H,s,H-2),7.75(1H,d,J=8.2Hz,H-4),7.34〜7.16(16H,m,φ,H-7),6.45(1H,d,J=0.7Hz,H-7),4.46(2H,s,CH₂)
【０１２０】
製造例３
１−トリフェニルメチル−６−ホルミル ベンズイミダゾール
【０１２１】
【化５３】

【０１２２】
製造例２の化合物75.0gをジクロロメタン1000mlに溶解し、活性化二酸化マンガン(MnO₂)225gを加え、室温にて１日撹拌した。メタノールの100mlを加え、濾過、残渣をジクロロメタン−メタノール（５：１）１lで洗浄した。得られた溶液を合して溶媒を留去し、エタノールで再結晶すると標題化合物が無色結晶として得られた（収量48.5g）。
m.p.:199〜200℃
¹H-NMR(CDCl₃)δ(ppm)：9.66(1H,s,CHO),8.10(1H,s,H-2),7.88(1H,d,J=8.4Hz,H-4),7.74(1H,dd,J=1.5,8.4Hz,H-5),7.36〜7.16(15H,m,φ),6.95(1H,m,H-7)
【０１２３】
実施例２３
１−トリフェニルメチル−６−〔２−シアノ−２−（４−フルオロフェニル）エテニル〕ベンズイミダゾール
【０１２４】
【化５４】

【０１２５】
製造例３の化合物53.1gを４−フロロフェニルアセトニトリル(p-F-C₆H₅CH₂CN)18.5gをエタノールに懸濁し、28％ナトリウムメチラート−メタノール溶液6.6mlを加え、２時間加熱還流した。冷後、生じた沈澱を濾取し、冷エタノールで洗浄すると、標題化合物が淡黄色結晶として得られた（収量52.4g）。
m.p.:210〜212℃
¹H-NMR(CDCl₃)δ(ppm)：8.01(1H,s,H-2),7.84(1H,d,J=8.6Hz,H-4),7.81(1H,dd,J=8.6,1.6Hz,H-5),7.53〜7.50(2H,m,φ),7.36〜7.21(15H,m,Tr),7.16(1H,s,CH),7.07(2H,dd,J=8.8,8.6Hz),7.01(1H,m,H-7)
【０１２６】
実施例２４
１−トリフェニルメチル−６−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダソール
【０１２７】
【化５５】

【０１２８】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）34mlのTHF34ml溶液に−78℃にて、ｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）25mlを加え同温度にて20分間撹拌した。これに実施例２３の化合物7.22gのTHF80ml溶液を20分かけて滴下し、徐々に室温まで昇温させながら４時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン200mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をTHF50mlに溶解させ、これに１ＭテトラブチルアンモニウムフロライドのTHF溶液50mlを加え、室温にて一夜撹拌した。反応液に水100mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗し、乾燥後、ジクロロメタンで再結晶すると、標題化合物が無色の結晶として得られた（収量6.92g）。
m.p.:224〜226℃
¹H-NMR(CDCl₃)δ(ppm)：7.88(1H,s,H-2),7.70(1H,dd,J=0.7,8.4Hz,H-4),7.33〜7.24(10H,m),7.19(2H,dd,J=8.8,5.3Hz,φ-F),7.13〜7.09(7H,m),6.87(2H,t,J=8.8Hz,φ-F),6.38(1H,m,H-7)
【０１２９】
実施例２５
１−トリフェニルメチル−６−〔１−（２−トリメチルシリルエトキシメチル）−３−（４−フルオロフェニル）−ピラゾール−４−イル〕ベンズイミダゾール１−トリフェニルメチル−６−〔１−（２−トリメチルシリルエトキシメチル）−５−（４−フルオロフェニル）−ピラゾール−４−イル〕ベンズイミダゾール
【０１３０】
【化５６】

【０１３１】
実施例２４の化合物6.92gをDMF100mlに懸濁し、水素化ナトリウム(60％ in oil)637mgを加え、40分間撹拌すると、透明な溶液が得られた。これにトリメチルシリルエトキシメチルクロリド2.82mlを加え、室温にて３時間撹拌した。水300mlを加え、ジクロロメタン300mlで抽出した。有機層を飽和食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を留去した。残渣をカラムクロマトグラフィーに付し、１％メタノール−ジクロロメタンで溶出すると、標題化合物のほぼ１：１の混合物が、アメ状物として得られた（収量8.13g）。
¹H-NMR(CDCl₃)δ(ppm)：7.91(0.5H,s),7.85(0.5H,s),7.73(0.5H,d,J=8.4Hz),7.66(0.5H,d,J=8.4Hz),7.39〜7.10(19H,m),7.10〜7.05(1H,m),6.95(1H,t,J=8.6Hz),6.85(1H,t,J=8.8Hz),6.40(0.5H,d,J=1.5Hz),6.35(0.5H,d,J=1.5Hz),5.40(1H,s),5.19(1H,s),3.68〜3.63(2H,m),0.97〜0.89(2H,m),0.03〜0.00(9H,m)
【０１３２】
実施例２６
５−〔１−（２−トリメチルシリルエトキシメチル）−３−（４−フルオロフェニル）−ピラゾール−４−イル〕ベンズイミダゾール
５−〔１−（２−トリメチルシリルエトキシメチル）−５−（４−フルオロフェニル）−ピラゾール−４−イル〕ベンズイミダゾール
【０１３３】
【化５７】

【０１３４】
実施例２５の化合物8.13gをメタノールの50mlに溶解し、１Ｎ塩酸13mlを加えた。この溶液を、10％パラジウム−カーボン(Pd-C)2.8gのメタノール10ml溶液に加え、水素気流下50℃で１時間撹拌した。冷後、反応液を濾過し、濾液に飽和重層水を加えて中和し、溶媒を留去した。残渣をカラムクロマトグラフィーに付し、２％メタノール−ジクロロメタンで溶出すると、標題化合物のほぼ１：１の混合物が無色アモルファス状固体として得られた（収量4.16g）。
¹H-NMR(DMSO-d₆)δ(ppm)：12.5(1H,br),8.26(0.5H,s),8.21(0.5H,s),8.17(0.5H,s),7.95(0.5H,s),7.52〜7.47(3H,m),7.38(1H,t,J=9.0Hz),7.21(1H,t,J=9.0Hz),7.12(0.5H,dd,J=1.6,8.4Hz),7.08(0.5H,dd,J=1.6,8.4Hz),5.52(1H,s),5.35(1H,s),3.73(1H,dd,J=7.9,8.1Hz),3.61(1H,dd,J=8.1,8.1Hz),0.95(1H,dd,J=7.9,8.1Hz),0.87(1H,dd,J=7.9,8.1Hz),0.05〜0.0(9H,m)
【０１３５】
実施例２７
５−〔２−シアノ−２−（４−フルオロフェニル）エテニル〕−１Ｈ−ベンズイミダゾール
【０１３６】
【化５８】

【０１３７】
実施例２３の化合物50.0gをメタノール100mlに懸濁させ、ピリジン塩酸塩11.43gを加え、70℃で1.5時間撹拌した。冷却後、反応液を濾過し、エタノール、次いで飽和炭酸水素ナトリウム氷水で洗浄し、乾燥すると、標題化合物が淡黄色の固体として得られた。
m.p.:254〜255℃
¹H-NMR(DMSO-d₆)δ(ppm)：8.94(1H,s),8.34(1H,br,s),8.18(1H,s),7.93(1H,dd,J=1.1,8.6Hz),7.86〜7.80(3H,m),7.37(2H,t,J=8.9Hz)
【０１３８】
実施例２８
１−メチル−６−〔２−シアノ−２−（４−フルオロフェニル）〕エテニル ベンズイミダゾール
１−メチル−５−〔２−シアノ−２−（４−フルオロフェニル）〕エテニル ベンズイミダゾール
【０１３９】
【化５９】

【０１４０】
実施例２７の化合物350mgをDMF10mlに溶解し、水素化ナトリウム(60％ in oil)100mgを加え、室温で45分間間撹拌した。これにヨウ化メチル192mgを加え、室温にて４時間撹拌した。反応液に水を加え、ジクロロメタン100mlで抽出した。溶媒留去後、残渣をカラムクロマトグラフィー(CH₂Cl₂-MeOH=9:1)にて精製すると、標題化合物の混合物が褐色の不定形固体として得られた（収量200mg）。
¹H-NMR(CDCl₃)δ(ppm)：8.26(0.4H,m),8.21(0.6H,m),8.14(0.6H,dd,J=1.8,8.4Hz),8.03(0.4H,s),7.99(0.6H,s),7.90(0.4H,m),7.75〜7.70(2H,m),7.69〜7.66(0.4H,m),7.68〜7.66(1H,m),7.53(0.6H,d,J=8.4Hz),7.23〜7.17(2H,m),3.96(1.2H,s,Me),3.93(1.8H,s,Me)
【０１４１】
実施例２９
１−メチル−５ or ６−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０１４２】
【化６０】

【０１４３】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）1.85mlのTHF５ml溶液に−78℃にて、ｎ−ブチルリチウム（1.6mol/l：ヘキサン溶液）0.68mlを加え、同温度にて20分間撹拌した。これに実施例２８の化合物200mgのTHF10ml溶液を20分かけて滴下し、徐々に昇温させながら４時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン100mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をTHF10mlに溶解させ、これに１ＭテトラブチルアンモニウムフロリドのTHF溶液５mlを加え、室温にて２時間撹拌した。水50mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗し、乾燥後、カラムクロマトグラフィー(CH₂Cl₂-MeOH=98:2)にて精製した。
第１画分より６−ピラゾール体が得られ、CH₂Cl₂より再結晶すると、無色結晶として36mg得られた。第２画分より５−ピラゾール体が淡褐色アモルファス状固体として得られた（収量51mg）。
m.p.:230〜231℃
６−ピラゾール体
MS:293(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：13.05(1H,br),8.14(1H,s),7.54(1H,d,J=8.4Hz),7.46(1H,d,J=1.6Hz),7.45〜7.41(2H,m),7.20〜7.10(2H,m),7.02(1H,dd,J=8.4,1.6Hz),3.75(3H,s)
５−ピラゾール体
MS:293(MH⁺)
¹H-NMR(CDCl₃)δ(ppm)：7.87(1H,s),7.74(1H,d,J=1.6Hz),7.42(2H,dd,J=8.8,5.4Hz),7.32(1H,d,J=8.2Hz),7.21(1H,dd,J=8.2,1.6Hz),7.12(1H,s),6.98(2H,dd,J=8.8,8.8Hz),3.85(3H,s)
【０１４４】
実施例３０
１−エチル−６−〔２−シアノ−２−（４−フルオロフェニル）〕エテニル ベンズイミダゾール
１−エチル−５−〔２−シアノ−２−（４−フルオロフェニル）〕エテニル ベンズイミダゾール
【０１４５】
【化６１】

【０１４６】
実施例２７の化合物700mgをTHFに懸濁させ、水素化ナトリウム(60％ in oil)160mgを加え、室温で45分間撹拌した。これにヨウ化エチル833mgを加え、50℃で４時間撹拌後、更に416mgを加え、同温にて更に４時間撹拌した。反応液に水を加え、ジクロロメタン100mlで抽出した。溶媒留去後、残渣をカラムクロマトグラフィー(CH₂Cl₂-MeOH=99:1)にて精製すると、標題化合物の混合物が褐色のアモルファス状固体として得られた（収量580mg）。
¹H-NMR(CDCl₃)δ(ppm)：8.26(1/3H,m),8.16(2/3H,m),8.09(1/3H,m),8.07(1/3H,m),8.03(1/3H,s),8.00(2/3H,s),7.85(1/3H,dd,J=0.5,8.4Hz),7.70〜7.66(2H,m,φ),7.63(1/3H,s),7.62(2/3H,s),7.60(2/3H,dd,J=1.8,8.4Hz),7.50(2/3H,d,J=8.4Hz),7.18〜7.13(2H,m,φ)
【０１４７】
実施例３１
１−エチル−６−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
１−エチル−５−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０１４８】
【化６２】

【０１４９】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）4.83mlのTHF５ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）1.78mlを加え、同温度にて20分間撹拌した。これに実施例３０の化合物550mgのTHF10ml溶液を20分かけて滴下し、徐々に昇温させながら２時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン100mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をTHF15mlに溶解させ、これに１ＭテトラブチルアンモニウムフロリドのTHF溶液５mlを加え、室温にて2.5時間撹拌した。水50mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CH₂Cl₂-MeOH=99:1のち98:2)にて精製した。
高Rf値を示す分画より６−ピラゾール体が、また、低Rf値を示す分画より５−ピラゾール体が、ともに褐色不定形固体としてそれぞれ110mg、153mg得られた。
６−ピラゾール体
¹H-NMR(CDCl₃)δ(ppm)：7.90(1H,s),7.76(1H,s),7.75(1H,dd,J=0.7,8.4Hz),7.45(2H,dd,J=8.7,5.3Hz),7.27(1H,s),7.23(1H,dd,J=1.6,8.4Hz),7.03(2H,t,J=8.7Hz),4.13(2H,q,J=7.5Hz),1.45(3H,t,J=7.5Hz)
５−ピラゾール体
¹H-NMR(CDCl₃)δ(ppm)：7.93(1H,s),7.75(1H,m),7.73(1H,s),7.44(2H,dd,J=8.7,5.3Hz),7.34(1H,dd,J=8.4,0.5Hz),7.21(1H,dd,J=8.4,1.5Hz),7.01(2H,dd,J=8.7,8.7Hz),4.24(2H,q,J=7.3Hz),1.57(2H,t,J=7.3Hz)
【０１５０】
実施例３２
１−メチル−６−〔２−（４−トリフルオロメチルフェニル）−２−シアノ〕エテニル ベンズイミダゾール
【０１５１】
【化６３】

【０１５２】
製造例８の化合物160mg、４−トリフロロメチルフェニルアセトニトリル185mgをエタノール３mlに溶解させ、28％ナトリウムメチラートのメタノール溶液0.1mlを加え室温で２時間撹拌した。反応液より溶媒を留去し、残渣をカラムクロマトグラフィー(CH₂Cl₂-MeOH=97:3)にて精製した。CH₂Cl₂-n-Hexより再結晶すると標題化合物が無色粉末として得られた（収量257mg）。
m.p.:166〜168℃
¹H-NMR(CDCl₃)δ(ppm)：8.26(1H,m,H-7),8.00(1H,s,H-2),7.87(1H,d,J=8.4Hz,H-4),7.82(2H,d,J=8.2Hz,φ),7.76(1H,s,CH=),7.72(2H,d,J=8.2Hz,,φ),7.67(1H,dd,J=1.8,8.4Hz,H-5),3.93(3H,s,Me)
【０１５３】
実施例３３
１−メチル−６−〔３−（４−トリフルオロメチルフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０１５４】
【化６４】

【０１５５】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）1.82mlのTHF２ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ヘキサン溶液）1.34mlを加え、同温度にて20分間撹拌した。これに実施例３２の化合物250mgのTHF８ml溶液を20分かけて滴下し、徐々に室温まで昇温させながら３時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン100mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をTHF５mlに溶解させ、これに１ＭテトラブチルアンモニウムフロリドのTHF溶液1.5mlを加え、室温にて２時間撹拌した。水100mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CH₂Cl₂-MeOH=98:2)にて精製した。酢酸エチルより再結晶すると標題化合物が無色結晶として得られた（収量218mg）。
m.p.：213〜215℃
¹H-NMR(CDCl₃)δ(ppm)：7.89(1H,s,H-2),7.76(1H,s),7.76(1H,dd,J=8.4,0.7Hz,H-4),7.62(2H,d,J=8.2Hz,,φ),7.56(2H,d,J=8.2Hz,φ),7.29(1H,m,H-7),7.21(1H,dd,J=8.4,1.6Hz,H-5),3.77(3H,s,Me)
【０１５６】
実施例３４
１−メチル−６−〔２−シアノ−２−（２，４−ジフルオロフェニル）〕エテニル ベンズイミダゾール
【０１５７】
【化６５】

【０１５８】
製造例８の化合物1.00g、２，４−ジフルオロフェニルアセトニトリル966mgをエタノール11mlに溶解させ、28％ナトリウムメチラートのメタノール溶液0.2mlを加え氷冷下で７時間撹拌した。析出した結晶を濾取、冷エタノール洗し、乾燥すると、標題化合物が無色結晶として得られた（収量1.02g）。
m.p.:＞300℃
¹H-NMR(CDCl₃)δ(ppm)： 8.22(1H,m,H-7),7.98(1H,s,H-2),7.85(1H,dd,J=8.4,0.7Hz,H-4),7.66(1H,s),7.62(1H,dd,J=8.4,1.6Hz,H-5),7.62〜7.56(1H,m,φ),7.02〜6.92(2H,m,φ),3.92(3H,s,Me)
【０１５９】
実施例３５
１−メチル−６−〔３−（２，４−ジフルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０１６０】
【化６６】

【０１６１】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）12.2mlのTHF12ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）8.95mlを加え、同温度にて20分間撹拌した。これに実施例３４の化合物1.51gのTHF50ml溶液を20分かけて滴下し、徐々に室温まで昇温させながら3.5時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン100mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をTHF20mlに溶解させ、これに１ＭテトラブチルアンモニウムフロリドのTHF溶液10.7mlを加え、室温にて５時間撹拌した。水100mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CH₂Cl₂-MeOH=97:3)にて精製した。ジクロロメタンより再結晶すると標題化合物が無色の結晶として得られた（収量1.65g）。
m.p.:237〜238℃
MS:311(MH⁺)
¹H-NMR(CDCl₃)δ(ppm)：7.86(1H,s,H-2),7.80(1H,s),7.71(1H,dd,J=8.4,0.7Hz,H-4),7.36〜7.30(1H,m,φ),7.27(1H,m,H-7),7.17(1H,dd,J=8.4,1.6Hz,H-5),6.92〜6.87(1H,m,φ),6.86〜6.81(1H,m,φ),3.77(3H,s,Me)
【０１６２】
実施例３６
１−メチル−６−〔２−シアノ−２−（２−フルオロフェニル）エテニル〕ベンズイミダゾール
【０１６３】
【化６７】

【０１６４】
製造例８の化合物300mg、２−フロロフェニルアセトニトリル253mgをエタノール５mlに溶解させ、28％ナトリウムメチラートのメタノール溶液0.1mlを加え室温で３時間撹拌した。反応液より溶媒を留去し、ジクロロメタン50mlに抽出した。水洗し、MgSO₄にて乾燥後、溶媒を留去して得られた残渣をそのまま次の反応に使用した。
【０１６５】
実施例３７
１−メチル−６−〔３−（２−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０１６６】
【化６８】

【０１６７】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）6.38mlのTHF 10ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ヘキサン溶液）4.69mlを加え、同温度にて20分間撹拌した。これに実施例３６の化合物740mgのTHF８ml溶液を20分かけて滴下し、徐々に室温まで昇温させながら４時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン100mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をTHF10mlに溶解させ、これに１ＭテトラブチルアンモニウムフロリドのTHF溶液５mlを加え、室温にて３時間撹拌した。水100mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CH₂Cl₂-MeOH=98:2)にて精製した。ジクロロメタンより再結晶すると標題化合物が無色結晶として得られた（収量220mg）。
m.p.:255〜257℃
MS:293(MH⁺)
¹H-NMR(CDCl₃)δ(ppm)：7.85(1H,s,H-2),7.81(1H,s),7.72(1H,dd,J=8.2,0.5Hz,H-4),7.36〜7.31(2H,m,φ),7.30(1H,m,H-5),7.21(1H,dd,J=8.2,1.6Hz,H-5),7.15(1H,m,φ),7.06(1H,m,φ),3.76(3H,s,Me)
【０１６８】
実施例３８
１−イソプロピル−６−〔２−シアノ−２−（４−フルオロフェニル）〕エテニル ベンズイミダゾール ＆ １−イソプロピル−５−〔２−シアノ−２−（４−フルオロフェニル）〕エテニル ベンズイミダゾール
【０１６９】
【化６９】

【０１７０】
実施例２７の化合物840mgをTHFに懸濁させ、水素化ナトリウム(60％ in oil)154mgを加え、室温で45分間間撹拌した。これにイソプロピルヨージド653mgを加え、室温にて３時間撹拌した。反応液に水50mlを加え、ジクロロメタン100mlで抽出した。溶媒を留去し、残渣をカラムクロマトグラフィー(CH₂Cl₂-MeOH=99:1)にて精製すると、標題化合物の混合物が褐色のアモルファス状固体として得られた（収量790mg）。これを混合物のまま次の反応に使用した。
¹H-NMR(CDCl₃)δ(ppm)：8.31,8.16(1H,m,m),8.10,8.07(1H,s,s),8.10〜8.07(0.5H,m),7.85(0.5H,dd,J=0.5,8.4Hz),7.70〜7.67(2H,m),7.63,7.67(1H,s,s),7.58(0.5H,dd,J=1.8,9.3Hz),7.52(0.5H,d,J=8.6Hz),7.18〜7.13(2H,m),4.76〜4.65(1H,m),1.70,1.68,1.67,1.66(6H,s,s,s,s,Me)
【０１７１】
実施例３９
１−イソプロピル−６−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
１−イソプロピル−５−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０１７２】
【化７０】

【０１７３】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）6.62mlのTHF10ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l,ヘキサン溶液）25mlを加え、同温度にて20分間撹拌した。これに実施例３８の化合物0.79gのTHF10ml溶液を20分かけて滴下し、徐々に室温まで昇温させながら３時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン100mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をTHF５mlに溶解させ、これに１ＭテトラブチルアンモニウムフロリドのTHF溶液３mlを加え、室温にて１時間撹拌した。水50mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CH₂Cl₂-MeOH=99:1のち99:2)にて精製した。
高Rf値を示す分画より６−ピラゾール体が、また、低Rf値を示す分画から５−ピラゾール体が、ともに淡黄色不定形固体としてそれぞれ105mg、194mg得られた。
6-ピラゾール
MS:321(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：13.05(1H,br,NH),8.26(1H,s),7.56(1H,d,J=8.4Hz),7.46〜7.40(3H,m),7.24〜7.10(2H,m),7.08(1H,dd,J=8.4,1.6Hz),4.64〜4.57(1H,m),1.42(6H,d,J=6.8Hz)
5-ピラゾール
MS:321(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：13.00(1H,br,NH),8.29(1H,s),7.56(1H,d,J=8.4Hz),7.49(1H,m),7.45〜7.41(2H,m),7.22〜7.10(2H,m),7.11(1H,dd,J=8.4,1.3Hz),4.75〜4.68(1H,m),1.50(6H,d,J=6.8Hz)
【０１７４】
製造例４
（２−ベンジルオキシエチル ) メチルチオメチルエーテル
【０１７５】
【化７１】

【０１７６】
エチレングリコールモノベンジルエーテル9.132gをジメトキシエタン60mlに溶解させ、氷冷下、水素化ナトリウム（60％ in oil)2.4gを加え、30分撹拌した。ヨウ化ナトリウム9.0g、クロロメチルメチルスルフィド5.02mlを加え、４℃にて14時間撹拌した。反応液にチオ硫酸ナトリウム水溶液を加え、ジクロロメタン200mlで抽出した。MgSO₄で乾燥後、溶媒を留去し、残渣をカラムクロマトグラフィー(n-Hex-EtoAc=10-1)にて精製すると（２−ベンジルオキシエチル)メチルチオメチルエーテルが無色の液体として4.10g得られた。
¹H-NMR(CDCl₃)δ(ppm)：7.35〜7.25(5H,m),4.70(2H,s),4.58(2H,s),3.74〜3.65(4H,m),2.15(3H,s)
【０１７７】
製造例５
（２−ベンジルオキシエチル）クロロメチルエーテル
【０１７８】
【化７２】

【０１７９】
（２−ベンジルオキシエチル)メチルチオメチルエーテルをジクロロメタン41mlに溶解し、−78℃にてスルフェニルクロリド(SO₂Cl₂)1.55mlのジクロロメタン10ml溶液を滴下し、徐々に室温まで昇温させながら２時間撹拌した。溶媒を留去すると、標題化合物が無色の液体として3.78g得られた。これを精製せずに次の反応に使用した。
¹H-NMR(CDCl₃)：7.35〜7.27(5H,m),5.55(2H,s),4.57(2H,s),3.88〜3.85(2H,m),3.69〜3.66(2H,m)
【０１８０】
実施例４０
１−（２−ベンジルオキシエトキシメチル）−６−〔２−シアノ−２−（４−フルオロフェニル）〕エテニル ベンズイミダゾール
１−（２−ベンジルオキシエトキシメチル）−５−〔２−シアノ−２−（４−フルオロフェニル）〕エテニル ベンズイミダゾール
【０１８１】
【化７３】

【０１８２】
実施例２７の化合物1.13gをTHF20mlに溶解させ、水素化ナトリウム201mg（60％ in oil)を加え30分撹拌した。２−ベンジルオキシエトキシメチルクロライド 1.122gを加え、３時間室温にて撹拌した。溶媒を留去し残渣をカラムクロマトグラフィー(CH２Cl２-MeOH=98-2)にて精製すると、標題化合物の混合物が褐色アモルファス状固体として1.41g得られた。これを混合物のまま次の反応に使用した。
¹H-NMR(CDCl₃)δ(ppm)：8.23〜8.19(1H,m),8.09〜8.02,7.88〜7.86(2H,m),7.76〜7.58(4H,m),7.38,〜7.27(5H,m),7.18,〜7.13(2H,m,φ-F),5.70,5.67(2H,s,CH2),5.30(s),4.57〜4.50(m)(2H),3.80〜3.60(4H,m)
【０１８３】
実施例４１
１−（２−ベンジルオキシエトキシメチル）−５ or ６−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０１８４】
【化７４】

【０１８５】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）28mlのTHF30ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ヘキサン溶液）22mlを加え、同温度にて20分間撹拌した。これに実施例４０の化合物4.9gのTHF15ml溶液を20分かけて滴下し、徐々に室温まで昇温させながら３時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン300mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をTHF10mlに溶解させ、これに１ＭテトラブチルアンモニウムフロリドのTHF溶液50mlを加え、室温にて３時間撹拌した。水500mlを加え、減圧下にTHFを留去し、生じた沈澱を濾取し、水洗、乾燥後、カラムクロマトグラフィー(CH₂Cl₂-MeOH=99:1）にて精製した。
第１画分より６−ピラゾール体1.92gが、第二画分より５−ピラゾール体2.12gが、褐色アモルファス状固体としてそれぞれ得られた。
【０１８６】
【化７５】

【０１８７】
６−ピラゾール体
¹H-NMR(CDCl₃)δ(ppm)：7.97(1H,s,H-2),7.74(1H,d,J=8.4Hz,H-5),7.71(1H,s),7.45〜7.40(2H,m,φ-F),7.43(1H,m,H-8),7.35〜7.27(5H,m,φ),7.25(1H,dd,J=8.4,1.65Hz,H-6),6.99(2H,dd,J=8.7,8.7Hz,φ-F),5.55(2H,s),4.51(2H,s),3.56〜3.52(4H,m,O,O)
【０１８８】
【化７６】

【０１８９】
５−ピラゾール体
¹H-NMR(CDCl₃)δ(ppm)：7.98(1H,s,H-2),7.75(1H,m,H-5),7.73(1H,s),7.47(1H,d,J=8.4Hz,H-8),7.43(2H,dd,J=8.7,5.4Hz,φ-F),7.35〜7.29(5H,m,φ),7.22(1H,dd,J=8.4,1.5Hz,H-7),7.00(2H,dd,J=8.7,8.7Hz,φ-F),5.64(2H,s),4.53(2H,s),3.63(4H,m,O,O)
【０１９０】
実施例４２
１−（２−ヒドロキシエトキシメチル）−６−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０１９１】
【化７７】

【０１９２】
Pd-C（10％ wet)230mgをメタノール10mlに懸濁し、１−（２−ベンジルオキシエトキシメチル）−６−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール230mgのメタノール５ml溶液及び４ＮHCl／ジオキサン0.3mlを加え、常圧常温下、接触還元した。反応液を濾過し、母液に飽和炭酸水素ナトリウム溶液を加えアルカリ性とし、CH₂Cl₂-THF(4:1)混液100mlで抽出した。有機層をMgSO₄で乾燥し、溶媒を留去後、THFより再結晶すると、標題化合物が無色粉末として50mg得られた。
m.p.:238〜239℃
MS:353(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：13.08(1H,br,NH),8.31(1H,s,H-2),7.59(1H,dd,J=0.5,8.2Hz,H-5),7.52(1H,br,s,H-8),7.43(2H,dd,J=8.9,5.5Hz,φ),7.22〜7.06(2H,m,φ),7.10(1H,dd,J=8.2,1.6Hz,H-6),5.58(2H,s,N,O),4.65(1H,m,OH),3.42〜3.33(4H,m,O,O)
【０１９３】
実施例４３
１−（２−ヒドロキシエトキシメチル）−５−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０１９４】
【化７８】

【０１９５】
Pd-C（10％ wet)330mgをメタノール10mlに懸濁し、１−（２−ベンジルオキシエトキシメチル）−５−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール330mgのメタノール５ml溶液及び４ＮHCl／ジオキサン 0.5mlを加え、常温常圧下接触還元した。反応液を濾過し、母液に飽和炭酸水素ナトリウム溶液を加え、アルカリ性とし、CH₂Cl₂-THF(4:1) 混液 100mlで抽出した。有機層をMgSO₄で乾燥し、溶媒を留去後、CH₂Cl₂より再結晶すると標題化合物が無色粉末として150mg得られた。
m.p.:200〜202℃
MS:353(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：13.03(1H,br,NH),8.33(1H,s,H-2),7.58(1H,d,J=8.2Hz,H-8),7.52(1H,d,J=1.3Hz,H-5),7.43(2H,dd,J=8.8,5.5Hz,,φ),7.24〜7.08(2H,m,φ),7.16(1H,dd,J=1.3,8.2Hz,H-7),5.65(2H,s,N,O),4.68(1H,m,OH),3.46〜3.42(4H,m,O,O)
【０１９６】
実施例４４
６−〔２−シアノ−２−（３−メトキシフェニル）エテニル〕イミダゾ〔１，２−ａ〕ピリジン
【０１９７】
【化７９】

【０１９８】
イミダゾ〔１，２−ａ〕ピリジン−６−カルボキシアルデヒド500mg（３−メトキシフェニル）アセトニトリル527mgをエタノール10mlに溶解させ28％ナトリウムメチラートのメタノール溶液0.1mlを加え、室温で１時間撹拌した。反応液より溶媒を留去し、残渣をカラムクロマトグラフィー(CH₂Cl₂〜１％ MeOH in CH₂Cl₂)にて精製すると、標題化合物が淡黄色アモルファス状固体として得られた（収量785mg）。
¹H-NMR(DMSO-d₆)δ(ppm)：3.81(3H,s,OCH3),7.02(1H,d,J=9.0Hz,C-13),7.29(1H,s,C-10),7.30(1H,d,J=9.0Hz,C-11),7.43(1H,t,J=9.0Hz,C-12),7.66(1H,s,C-9),7.73(1H,d,J=9.5Hz,C-7),7.93(1H,d,J=9.5Hz,C-8),8.06(1H,s,C-3),8.11(1H,s,C-2),9.05(1H,s,C-5)
【０１９９】
実施例４５
５−〔３−（３−メトキシフェニル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン
【０２００】
【化８０】

【０２０１】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）4.34mlのTHF８ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）1.70mlを加え、同温度にて20分間撹拌した。これに実施例４４の化合物500mgのTHF８ml溶液を20分かけて滴下し、徐々に昇温させながら１時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン30mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をTHF10mlに溶解させ、これに１ＭテトラブチルアンモニウムフロリドのTHF溶液1.1mlを加え、室温にて１時間撹拌した。水10mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CH₂Cl₂〜CH₂Cl₂/(CH₃)₂C=O ＝ ９：１)にて精製すると標題化合物が淡黄色アモルファス状固体として得られた（収量100mg）。
¹H-NMR(CDCl₃)：3.75(3H,s,OCH₃),6.91(1H,dd,J=1.6Hz,9.0Hz,C-13),7.02〜7.04(2H,m,C-10,C-12),7.11(1H,dd,J=1.6Hz,9.0Hz,C-11),7.30(1H,d,J=9.0Hz,C-7),7.54(1H,s,C-9),7.57(1H,d,J=9.0Hz,C-8),7.64(1H,s,C-3),7.74(1H,s,C-2),8.11(1H,s,C-5)
【０２０２】
製造例６
５−ヒドロキシメチル−ベンズイミダゾール
【０２０３】
【化８１】

【０２０４】
水素化リチウムアルミニウム14.051gをTHF150mlに懸濁させ、室温でベンズイミダゾール−５−カルボン酸メチルエステル32.381gのTHF300ml溶液を40分間かけて滴下した。10分後にTHF200mlを加え室温で2.5時間撹拌したのち、飽和塩化アンモニウム水溶液を加え、セライト濾過した。減圧下溶媒留去し、得られた残渣にメタノールとクロロホルムを加え、再びセライト濾過し減圧下溶媒留去すると標題化合物が32.89g得られた。これは粗精製のまま次の反応に用いた。
¹H-NMR(DMSO-d₆)δ(ppm)：4.58(2H,s),5.02〜5.30(1H,br),7.12(1H,dd,J=1.2,8.4Hz),7.49〜7.50(1H,m),7.50(1H,d,J=8.4Hz),8.16(1H,s)
【０２０５】
製造例７
１−メチル−６−ヒドロキシメチルベンズイミダゾール
【０２０６】
【化８２】

【０２０７】
６−ヒドロキシメチルベンズイミダゾール27.36gをDMF135mlに溶解し、そこに水素化ナトリウム（鉱油含む。含量約60％）7.426gを加え、室温で30分間撹拌した。そこにヨウ化メチル11.5mlを室温で20分間かけて加え、さらに室温で１時間撹拌した。水を加えたのち減圧下溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(CH₂Cl₂/Acetone=1/1→1/2→1/3)にて精製し、標題化合物9.87gをアモルファス状固体として得た。
¹H-NMR(DMSO-d₆)δ(ppm)：3.80(3H,s),4.60(2H,d,J=5.6Hz),5.20(1H,dt,J=2.4,5.6Hz),7.14(1H,d,J=8.0Hz),7.48(1H,br,s),7.55(1H,d,J=8.0Hz),8.11(1H,s)
【０２０８】
製造例８
１−メチル−６−ホルミルベンズイミダゾール
【０２０９】
【化８３】

【０２１０】
１−メチル−６−ヒドロキシメチルベンズイミダゾール9.74gをアセトン200mlに懸濁させ、活性二酸化マンガン30.309gを加えて室温で13時間撹拌した。さらに活性二酸化マンガン10.080gを加え５時間加熱還流した。セライトとシリカゲルで濾過し、残渣をクロロルム：メタノール１：１で洗浄した。濾液を減圧下溶媒留去して得られた残渣をシリカゲルカラムクロマトグラフィー(CHCl₃/MeOH=100/1→50/1→10/1)にて精製し、標題化合物3.7gを得た。
¹H-NMR(CDCl₃)：3.94(3H,s),7.84(1H,dd,J=1.4,8.0Hz),7.92(1H,d,J=8.0Hz),8.00(1H,br,s),8.05(1H,s),10.12(1H,s)
【０２１１】
実施例４６
１−メチル−６−〔２−シアノ−２−（４−ニトロフェニル）エテニル〕 ベンズイミダール
【０２１２】
【化８４】

【０２１３】
製造例８の化合物336mg、(４−ニトロフェニル)アセトニトリル348mgをエタノール10mlに溶解させ、28％ナトリウムメチラートのメタノール溶液１mlを加え室温で１時間撹拌した。折出した結晶を濾取、冷エタノール洗し、乾燥すると、標題化合物が深緑色結晶として得られた（収量580mg(EtOH-IPE)）。
m.p.:249〜251℃
¹H-NMR(CDCl₃)δ(ppm)：3.96(3H,s,-CH3),7.71,(1H,dd,J=1.6Hz,8.4Hz,C-7),7.85,(1H,s,C-9),7.88(2H,d,J=8.8Hz,C10,C13),7.89(1H,d,J=8.4Hz,C-8),8.03(1H,s,C-5),8.30(1H,s,C-2),8.33(2H,d,J=8.8Hz,C11,C12)
【０２１４】
実施例４７
１−メチル−６−〔３−（４−ニトロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０２１５】
【化８５】

【０２１６】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）4.5mlのTHF９ml溶液に−78℃にてｎ−ブチルリチウム(1.6mol/l：ヘキサン溶液)5.6mlを加え、同温度にて20分間撹拌した。これに実施例４６の化合物570mgのTHF30ml溶液を20分かけて滴下し、徐々に室温まで昇温させながら４時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン30mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をTHF２mlに溶解させ、これに１ＭテトラブチルアンモニウムフロリドのTHF溶液2.5mlを加え、室温にて１時間撹拌した。水10mlを加え減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CH₂Cl₂〜１％ MeOH in CH₂Cl₂)にて精製した。CH₂Cl₂-IPEより再結晶すると標題化合物が淡黄色結晶として得られた（収量250mg）。
m.p.:244〜247℃
¹H-NMR(DMSO-d₆)δ(ppm)：3.80(3H,s,-CH₃),7.07(1H,d,J=8.2Hz,C7),7.54(1H,s,C-5),7.61(1H,d,J=8.2Hz,C8),7.71(2H,d,J=8.4Hz,C10,C12),8.05(1H,s,C2),8.17〜8.19(2H,m,C11,C13),8.20(1H,s,C9),13.41(1H,br,s,NH)
【０２１７】
実施例４８
１−メチル−６−〔３−（４−アミノフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０２１８】
【化８６】

【０２１９】
実施例４７の化合物25mgをメタノール３mlに溶解し、１NHCl 0.2ml 10％ Pd-C 46mgを加え、系内を水素置換して常温、常圧で1時間撹拌した。反応液をセライト濾過し濾液を減圧留去し、残渣を水５mlで希釈し酢酸エチル15mlで抽出した。を加え、重曹水、水、飽和食塩水で洗浄、硫酸マグネシウムで乾燥後溶媒を減圧留去すると標題化合物が淡黄色結晶として得られた（収量13mg）。
m.p.:145〜147℃
¹H-NMR(CDCl₃)δ(ppm)：3.79(3H,s,CH3),6.65(2H,d,J=8.6Hz,C10,C12),7.23(2H,d,J=8.6Hz,C11,C13),7.24〜7.25(1H,m,C7),7.35(1H,s,C5),7.71(1H,d,J=8.4Hz,C8),7.72(1H,s,C2),7.85(1H,s,C9)
【０２２０】
実施例４９
１−メチル−６−〔２−シアノ−２−（３，４−ジメトキシフェニル）エテニル〕 ベンズイミダール
【０２２１】
【化８７】

【０２２２】
製造例８の化合物500mg、（３，４−ジメトキシフェニル）アセトニトリル500mgをエタノール７mlに溶解させ、28％ナトリウムメチラートのメタノール溶液0.2mlを加え室温で３時間撹拌した。折出した結晶を濾取、冷エタノール洗し、乾燥すると、標題化合物が乳白色結晶として得られた（収量825mg）。
m.p.:175〜177℃
¹H-NMR(CDCl₃)δ(ppm)：3.93(3H,s,CH₃),3.95(3H,s,CH₃),3.99(3H,s,CH₃),6.94(1H,d,J=8.6Hz,C11),7.18(1H,d,J=2.2Hz,C12),7.29(1H,dd,J=2.2Hz,8.6Hz,C10),7.59(1H,s,C9),7.63(1H,dd,J=1.7Hz,8.4Hz,C7),7.84(1H,d,J=8.4Hz,C8),7.97(1H,s,C2),8.21(1H,d,J=1.7Hz,C5)
【０２２３】
実施例５０
１−メチル−６−〔３−（３，４−ジメトキシフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０２２４】
【化８８】

【０２２５】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）5.9mlのTHF９ml溶液に−78℃にてｎ−ブチルリチウム(1.6mol/l；ヘキサン溶液)4.7mlを加え、同温度にて20分間撹拌した。これに実施例４９の化合物800mgのTHF10ml溶液を20分かけて滴下し、徐々に昇温させながら２時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン50mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をTHF10mlに溶解させ、これに１ＭテトラブチルアンモニウムフロリドのTHF溶液５mlを加え、室温にて１時間撹拌した。水20mlを加え減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CH₂Cl₂〜１％ MeOH in CH₂Cl₂)にて精製した。CH₂Cl₂より再結晶すると標題化合物が淡黄色結晶として得られた（収量390mg）。
m.p.:215〜218℃
¹H-NMR(CDCl₃)δ(ppm)：3.66(3H,s,CH₃),3.79(3H,s,CH₃),3.89(3H,s,CH₃),6.83(1H,d,J=8.2Hz,C11),6.99(1H,d,J=2.0Hz,C10),7.03(1H,dd,J=2.0Hz,8.2Hz,C12),7.27(1H,dd,J=2.2Hz,8.4Hz,C7),7.35(1H,d,J=2.2Hz,C5),7.73(1H,d,J=8.4Hz,C8),7.76(1H,s,C2),7.86(1H,s,C9)
【０２２６】
製造例９
メチル〔２−アセチル−３−（Ｎ，Ｎ−ジメチルアミノ）〕アクリレート
【０２２７】
【化８９】

【０２２８】
メチルアセトアセテート11gをＮ，Ｎ−ジメチルホルムアミド100mlに溶解し、Ｎ，Ｎ−ジメチルホルムアミドジメチルアセタール27mlを加え100℃で２時間加温した。Ｎ，Ｎ−ジメチルホルムアミドを減圧留去し、残渣をシリカゲルクロマトグラフィーにて(CH₂Cl₂〜１％ MeOH in CH₂Cl₂)精製すると標題化合物が茶色油状物質として得られた（収量11.2g）。
¹H-NMR(CDCl₃)δ(ppm)：2.32(3H,s),2.88(3H,s),2.97(3H,s),3.76(3H,s),7.70(0.7H,s),8.01(0.3H,s)
【０２２９】
製造例１０
メチル−３−メチルピラゾール−４−カルボキシレート
【０２３０】
【化９０】

【０２３１】
メチル〔２−アセチル−３−（Ｎ，Ｎ−ジメチルアミノ）〕アクリレート11gをエタノール100mlに溶解し、ヒドラジン１水和物6.4gを加え80℃で２時間加温した。反応液を減圧留去し残渣を酢酸エチル200mlに溶解し、氷、飽和食塩水で洗浄、硫酸マグネシウムで乾燥後、溶媒を留去すると、標題化合物が淡黄色アモルファス状固体として得られた（収量5.8g）。
¹H-NMR(CDCl₃)：2.57(3H,s),3.84(3H,s),7.97(1H,s)
【０２３２】
実施例５１
２−〔１−（２−トリメチルシリルエトキシメチル）−３−メチル−ピラゾール−４−イル〕−６−ヒドロキシプリン
２−〔１−（２−トリメチルシリルエトキシメチル）−５−メチル−ピラゾール−４−イル〕−６−ヒドロキシプリン
【０２３３】
【化９１】

【０２３４】
メチル−３−メチルピラゾール−４−カルボキシレート３g をＮ，Ｎ−ジメチルホルムアミド30mlに溶解し、水素化ナトリウム（60％ in 鉱油）857mgを加え氷冷下30分撹拌した。次いで２−（トリメチルシリル)エトキシメチルクロライド3.9g加え室温で30分撹拌した。反応液に水40ml、酢酸エチル 200mlを加え、有機層を分取し、水、飽和食塩水で洗浄、硫酸マグネシウム乾燥後、溶媒を減圧留去した。得られた残渣をエタノール60ml、H₂O 20mlに溶解しNaOH 1.2gを加え、40分間加熱還流した。反応液を減圧留去し水30ml、酢酸エチル200mlを加え、水層を１Ｎ HClにて酸性にした。水層を酢酸エチル200mlで抽出、水、飽和食塩水で洗浄、硫酸マグネシウム乾燥後、溶媒を留去すると白色固体が4.81g得られた。このうち2.5gをトルエン25mlに溶解し塩化チオニル1.3gを加え60℃にて40分間加温した。溶媒を留去しピリジン20ml、４−アミノ−５−イミダゾールカルボキシアミド塩酸塩2.1g、４，４−ジメチルアミノピリジン36mgを加え60℃にて１時間撹拌した。反応液に水120mlを滴下すると白色固体が2.9g得られた。このうち１gをH₂O 40ml、エタノール10mlに懸濁させ、炭酸水素カリウム1.1gを加え23時間加熱還流した。反応液中のエタノールを留去し酢酸を１ml加え、塩化メチレン30mlにて抽出、水洗、乾燥後、溶媒を留去し残渣をカラムクロマトグラフィー(CH₂Cl₂〜２％ MeOH in CH₂Cl₂)にて精製すると白色アモルファス状固体が700mg得られた。
MS:347(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：0.01〜0.07(9H,s),0.90(2H,dd,J=1.8Hz,8.1Hz),2.74(3H,s),3.60(2H,dd,J=1.8Hz,8.1Hz),5.42(0.4H,s),5.53(0.6H,s),8.13(1H,br,s),8.28(1H,s),8.66(1H,s)
【０２３５】
実施例５２
２−〔３−メチル−１Ｈ−ピラゾール−４−イル〕−６−ヒドロキシプリン
【０２３６】
【化９２】

【０２３７】
２−〔１−（２−トリメチルシリルエトキシメチル）−３−メチル−ピラゾール−４−イル〕−６−ヒドロキシプリンと２−〔１−（２−トリメチルシリルエトキシメチル）−５−メチル−ピラゾール−４−イル〕−６−ヒドロキシプリンの混合物130mgをトリフルオロ酢酸２mlに溶解しボロントリストリフルオロアセテート400mgを加え氷冷下１時間撹拌した。反応液にメタノールを５ml加え減圧留去し、残渣をカラムクロマトグラフィー(CH₂Cl₂〜20％ in CH₂Cl₂)にて精製すると白色結晶が24mg得られた。
m.p.:240〜245℃
MS:217(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：2.48(3H,s),8.35(1H,s),8.59(1H,s)
【０２３８】
製造例１１
１−メチル−４−カルバモイル−５−アミノ−イミダゾール
【０２３９】
【化９３】

【０２４０】
２−アミノ−２−シアノアセトアミド２gをアセトニトリル20mlに溶解しトリエチルオルトホルメート30mlを加え、５分間加熱還流し次いでジメチルアミンの40％メタノール溶液940mgを加え20分後、反応液を氷冷し沈澱物を炉取し、シリカゲルクロマトグラフィーにて(CH₂Cl₂〜５％ MeOH in CH₂Cl₂)精製すると標記化合物が淡灰白色アモルファス状固体として得られた（収量770mg）。
MS:141(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：3.40(3H,s,CH₃),5.73(2H,s,),6.60(1H,br),6.74(1H,br),7.06(1H,s)
【０２４１】
製造例１２
エチル〔３−（Ｎ，Ｎ−ジメチルアミノ）−２−フェニル〕アクリレート
【０２４２】
【化９４】

【０２４３】
エチルベンゾイルアセテート10gを、Ｎ，Ｎ−ジメチルホルムアミド100mlに溶解させＮ，Ｎ−ジメチルホルムアミドジメチルアセタール13.8gを加え100℃で１時間加温した。Ｎ，Ｎ−ジメチルホルムアミドを留去し残渣をシリカゲルクロマトグラフィーにて精製（CH₂Cl₂)すると茶色油状物が得られた（収量7.3g）。
¹H-NMR(CDCl₃)δ(ppm)：0.91(3H,t,J=7.0Hz),2.74(3H,s),2.87(3H,s),3.82(2H,q,J=7.0Hz),7.37〜7.45(3H,m),7.46〜7.48(2H,m)
【０２４４】
製造例１３
エチル〔３−フェニル−１Ｈ−ピラゾール−４−イル〕カルボキシレート
【０２４５】
【化９５】

【０２４６】
エチル〔３−（Ｎ，Ｎ−ジメチルアミノ）−２−フェニル〕アクリレート7.28gをエタノール70mlに溶解し、ヒドラジン１水和物2.95gを加え80℃に1.5時間加温した。反応液を留去後、水、酢酸エチルを加え有機層を分取し、飽和食塩水で洗浄、硫酸マグネシウム乾燥後、溶媒を留去すると標題化合物が白色固体として得られた（収量3.6g）。
¹H-NMR(DMSO-d₆)δ(ppm)：1.21(3H,t,J=7.0Hz),4.17(2H,q,J=7.0Hz),7.44〜7.47(3H,m),7.69〜7.72(2H,m),8.18(1H,br,s)
【０２４７】
実施例５３
２−〔３−フェニル−１Ｈ−ピラゾール−４−イル〕−６−ヒドロキシ−９−メチルプリン
【０２４８】
【化９６】

【０２４９】
実施例５１，５２で示した方法と同様にして標題化合物を得た。
m.p.:290〜296℃
MS:293(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：3.49(3H,s,CH₃),7.32〜7.48(3H,m),7.62〜7.65(2H,m),7.93(1H,s),8.20(0.5H,br,s),8.46(0.5H,br,s),12.12(1H,br,s)
【０２５０】
実施例５４
２−〔３−フェニル−１Ｈ−ピラゾール−４−イル〕−６−クロロ−９−メチルプリン
【０２５１】
【化９７】

【０２５２】
２−〔３−フェニル−１Ｈ−ピラゾール−４−イル〕−６−ヒドロキシ−９−メチルプリン40mgをクロロホルム１mlに溶解させ塩化チオニル0.1ml、Ｎ，Ｎ−ジメチルホルムアミド12mgを加え2.5時間加熱還流した。反応液を留去し水２mlを加え結晶を濾取すると標記化合物が淡黄色固体として得られた（収量20mg）。
m.p.:133〜135℃(decomp.)
MS:311(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：3.65(3H,s,CH₃),7.36〜7.49(3H,m),7.70〜7.74(2H,m),8.49(1H,s),13.35(1H,br,s,D₂O exchangeable)
【０２５３】
実施例５５
２−〔３−フェニル−１Ｈ−ピラゾール−４−イル〕−９−メチルプリン
【０２５４】
【化９８】

【０２５５】
２−〔３−フェニル−１Ｈ−ピラゾール−４−イル〕−６−クロロ−９−メチルプリン32mgを水４mlメタノール10mlに溶解し28％アンモニア水１ml、10％Pd-C 62mgを加え、系内を水素置換し常温常圧で３時間撹拌した。反応液をセライト濾過し濾液を留去し、析出した固体を濾取すると標記化合物が淡黄色アモルファス状固体として得られた（収量10mg）。
MS:277(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：3.65(3H,s,CH₃),7.30〜7.47(3H,m),7.65〜7.70(2H,m),8.41(1H,s),9.01(1H,s),13.25(1H,br,s)
【０２５６】
実施例５６
１−（２−ベンジルオキシエチル）−５ or ６−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０２５７】
【化９９】

【０２５８】
実施例２６の化合物（４g）をDMF（40ml）に溶解させ氷冷下NaH（0.78g；60％ oil dispersion)を徐々に加えた。室温で30分間撹拌後ベンジルオキシエチル クロライド（1.8g）を加えた。70℃で４時間加温した後、反応液を室温に戻し、H₂O 50ml,AcOEt 200mlを加えた。有機層を飽和食塩水で洗浄、MgSO₄乾燥後、溶媒を留去した。得られた残渣（3.1g）をEtOH（40ml）に溶かし４NHCl-ジオキサン溶液（３ml）を加え１時間加熱還流した。反応液を室温に戻し、NaHCO₃aqで中和、H₂Oを加えAcOEt（200ml）で抽出、飽和食塩水で洗浄MgSO₄乾燥後、溶媒を留去しシリカゲルクロマトグラフィーにて精製(CH₂Cl₂〜CH₂Cl₂/MeOH=99/1)すると第１溶出物として６−ピラゾール体が720mg、第２溶出物として、５−ピラゾール体が780mg、各々アモルファス状固体として得られた。
６−ピラゾール体
¹H-NMR(CDCl₃)δ(ppm)：3.70(2H,t,J=5.0Hz),4.26(2H,t,J=5.0Hz),4.44(2H,s),6.94〜6.99(2H,m),7.13〜7.16(2H,m),7.21(1H,dd,J=1.5Hz,8.4Hz),7.23〜7.24(3H,m),7.38〜7.42(2H,m),7.68(1H,s),7.75(2H,d,J=8.42Hz),7.98(1H,s)
５−ピラゾール体
¹H-NMR(CDCl₃)δ(ppm)：3.81(2H,t,J=5.2Hz),4.35(2H,t,J=5.2Hz),4.89(2H,s),6.96〜7.00(2H,m),7.16〜7.20(3H,m),7.26〜7.30(4H,m),7.42〜7.45(2H,m),7.72(1H,s),7.76(1H,s),8.00(1H,s)
【０２５９】
実施例５７
１−ヒドロキシエチル−６−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０２６０】
【化１００】

【０２６１】
１−ベンジルオキシエチル−６−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール360mgをMeOH 10mlに溶かし10％ Pd-C 360mgを加えH₂雰囲気下室温にて２時間撹拌した。反応液をセライト濾過し、H₂Oを加えAcOEt 20mlにて抽出、飽和食塩水で洗浄、MgSO₄乾燥後溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィーにて精製する(CH₂Cl₂〜CH₂Cl₂/MeOH=98/2)と標題化合物が186mg白色結晶として得られた。
m.p.:199〜201℃
¹H-NMR(DMSO-d₆)δ(ppm)：3.64(2H,t,J=5Hz),4.18(2H,t,J=5Hz),4.93(1H,t,J=5Hz),7.04(1H,d,J=8.2Hz),7.08〜7.22(2H,m),7.43〜7.46(3H,m),7.55(1H,d,J=8.2Hz),7.94(1H,br,s),8.11(1H,s),13.06(1H,br,s)
【０２６２】
実施例５８
１−ヒドロキシエチル−５−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０２６３】
【化１０１】

【０２６４】
１−ベンジルオキシエチル−５−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール300mgを用い、実施例５７と同様にして標題化合物が108mg白色結晶として得られた。
m.p.:235〜237℃
¹H-NMR(DMSO-d₆)δ(ppm)：3.72(2H,dt,J=5.10Hz),4.26(2H,dd,J=5.10Hz),4.98(1H,t,J=5Hz),7.09〜7.15(3H,m),7.41〜7.45(2H,m),7.48(1H,s),7.52(1H,d,J=8.4Hz),7.92(1H,br,s),8.12(1H,s),13.03(1H,br,s)
【０２６５】
実施例５９
１−（２−プロピルオキシエチル）−６−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
１−（２−プロピルオキシエチル）−５−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０２６６】
【化１０２】

【０２６７】
実施例２６の化合物（100mg）をDMF（2ml）に溶解させ氷冷下NaH（21mg：60％ oil dispersion）を徐々に加えた。室温で30分間撹拌後、プロピルオキシエチル クロライド（36mg）を加えた。70℃で３時間加温した後、反応液を室温に戻しH₂O 10ml、AcOEt 50ml加えた。有機層を飽和食塩水で洗浄、MgSO₄乾燥後溶媒を留去した。得られた残渣をEtOH 10mlに溶解させ４Ｎ HCl−ジオキサン溶液（0.3ml）を加えて１時間加熱還流した。反応液を室温に戻し、NaHCO₃aqで中和、H₂Oを加えAcOEt60mlで抽出、飽和食塩水で洗浄、MgSO₄乾燥後溶媒を留去しシリカゲルクロマトグラフィーにて精製(CH₂Cl₂〜CH₂Cl₂/MeOH=99/1)すると第１溶出物として６−ピラゾール体が54mg、第２溶出物として５−ピラゾール体が54mg各々アモルファス状固体として得られた。
６−ピラゾール体
¹H-NMR(CDCl₃)δ(ppm)：0.85(3H,t,J=7.4Hz),1.52(2H,q,J=7.4Hz),3.32(2H,t,J=6.6Hz),3.65(2H,t,J=5.2Hz),4.23(2H,t,J=5.2Hz),7.17(2H,m),7.22(1H,dd,J=1.6Hz,8.4Hz),7.28(1H,m),7.43〜7.47(2H,m),7.74〜7.76(2H,m),7.96(1H,s)
５−ピラゾール体
¹H-NMR(CDCl₃)δ(ppm)：0.87(3H,t,J=7.4Hz),1.55(2H,q,J=7.4Hz),3.37(2H,t,J=6.2Hz),3.77(2H,t,J=5.1Hz),4.33(2H,t,J=5.1Hz),6.98〜7.03(2H,m),7.19(1H,dd,J=1.5Hz,8.4Hz),7.35(1H,d,J=8.4Hz),7.34〜7.46(1H,m),7.74(1H,d,J=7.5Hz),8.00(1H,s)
【０２６８】
実施例６０
１−エチルチオエチル−６−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
１−エチルチオエチル−５−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０２６９】
【化１０３】

【０２７０】
実施例２６の化合物（400mg）を用い実施例５９と同様にして６−ピラゾール体26mg、５−ピラゾール体27mg各々アモルファス状固体として得られた。
６−ピラゾール体
¹H-NMR(CDCl₃)δ(ppm)：1.23(3H,t,J=7.5Hz),2.47(2H,q,J=7.5Hz),2.97(2H,t,J=7.0Hz),4.37(2H,t,J=7.0Hz),6.99〜7.03(2H,m),7.21(1H,dd,J=1.5Hz,8.4Hz),7.33(1H,d,J=8.4Hz),7.42〜7.45(2H,m),7.74(1H,s),7.76(1H,s),7.97(1H,s)
５−ピラゾール体
¹H-NMR(CDCl₃)δ(ppm)：1.22(3H,t,J=7.4Hz),2.47(2H,q,J=7.4Hz),2.96(2H,t,J=7.0Hz),4.37(2H,t,J=7.0Hz),6.93〜6.98(2H,m),7.21(1H,dd,J=1.5Hz,8.4Hz),7.33(1H,d,J=8.4Hz),7.41〜7.45(2H,m),7.68(1H,s),7.75(1H,d,J=1.5Hz),7.98(1H,s)
【０２７１】
実施例６１
１−エトキシカルボニルメチル−６−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
１−エトキシカルボニルメチル−５−〔３−（４−フルオロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０２７２】
【化１０４】

【０２７３】
実施例２６の化合物（500mg）を用い実施例５９と同様にして６−ピラゾール体が130mg、５−ピラゾール体が120mg各々アモルファス状固体として得られた。
６−ピラゾール体
¹H-NMR(CDCl₃) δ(ppm)：1.26(3H,t,J=7.1Hz),4.21(2H,q,J=7.1Hz),4.80(2H,s),6.89〜7.03(2H,m),7.18〜7.19(1H,m),7.25(1H,dd,J=1.5Hz,8.2Hz),7.42〜7.45(2H,m),7.72(1H,s),7.76(1H,d,J=8.2Hz),7.93(1H,s),
５−ピラゾール体
¹H-NMR(CDCl₃) δ(ppm),1.29(3H,t,J=7.1Hz),4.27(2H,q,J=7.1Hz),4.90(2H,s),6.98〜7.03(2H,m),7.22(1H,dd,J=1.5Hz,8.2Hz),7.25(1H,s),7.42〜7.45(2H,m),7.73(1H,s),7.76(1H,br,s),7.94(1H,s)
【０２７４】
実施例６２
６−〔２−シアノ−２−（２−チエニル）エテニル〕 イミダゾ〔１，２−ａ〕ピリジン
【０２７５】
【化１０５】

【０２７６】
イミダゾ[１，２−ａ]ピリジン−６−カルボキシアルデヒド294mgとチオフェン−２−アセトニトリル255mgをエタノール10mlに溶解させ28％ナトリウムメチラートのメタノール溶液0.1mlを加え、室温で１時間撹拌した。反応液より溶媒を留去し、残渣をカラムクロマトグラフィー(CHCl₃/MeOH=100/1)にて精製すると、標題化合物がアモルファス状固体として得られた（収量300mg）。
¹H-NMR(CDCl₃)δ(ppm)：7.10(1H,dd,J=4.0,5.2Hz),7.28(1H,br,s),7.35(1H,dd,J=1.2,5.2Hz),7.41(1H,dd,J=1.2,4.0Hz),7.67(1H,m),7.69(1H,br,s,J=9.6Hz),7.71(1H,d,J=1.6Hz),7.74(1H,dd,J=1.6,9.6Hz),8.68(1H,m)
【０２７７】
実施例６３
６−〔３−（２−チエニル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン
【０２７８】
【化１０６】

【０２７９】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）3.08mlのTHF６ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）2.24mlを加え、同温度にて20分間撹拌した。これに実施例６２の化合物300mgのTHF６ml溶液を20分かけて滴下し、徐々に昇温させながら1.5時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン50mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣に１ＭテトラブチルアンモニウムフロリドのTHF溶液５mlを加え、室温にて１時間撹拌した。水５mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、CH₂Cl₂-IPEより再結晶すると標題化合物が淡黄色結晶として得られた（収量81mg）。
m.p.:214〜125℃
MS:267(MH⁺)
¹H-NMR(CDCl₃)δ(ppm)：7.10(1H,dd,J=3.6,5.2Hz),7.09(1H,dd,J=0.8,3.6Hz),7.19(1H,dd,J=2.0,9.2Hz),7.31(1H,dd,J=0.8,5.2Hz),7.58(1H,s),7.63(1H,d,J=9.2Hz),7.66(1H,d,J=1.2Hz),7.69(1H,s),8.16(1H,m)
【０２８０】
実施例６４
６−〔２−シアノ−２−（３−チエニル）エテニル〕 イミダゾ〔１，２−ａ〕ピリジン
【０２８１】
【化１０７】

【０２８２】
イミダゾ〔１，２−ａ〕ピリジン−６−カルボキシアルデヒド293mgとチオフェン−３−アセトニトリル270mgをエタノール10mlに溶解させ28％ナトリウムメチラートのメタノール溶液0.1mlを加え、室温で１時間撹拌した。反応液より溶媒を留去し、残渣をカラムクロマトグラフィー(CHCl₃/MeOH=100/1)にて精製すると、標題化合物がアモルファス状固体として得られた（収量400mg）。
¹H-NMR(CDCl₃)δ(ppm)：7.36(1H,s),7.37(1H,dd,J=1.2,4.8Hz),7.44(1H,dd,J=2.8,4.8Hz),7.63(1H,dd,J=1.2,2.8Hz),7.67(1H,br,s),7.69〜7.72(3H,m),8.71(1H,br,s)
【０２８３】
実施例６５
６−〔３−（３−チエニル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン
【０２８４】
【化１０８】

【０２８５】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）4.4mlのTHF８ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）3.2mlを加え、同温度にて20分間撹拌した。これに実施例６４の化合物400mgのTHF８ml溶液を20分かけて滴下し、徐々に昇温させながら1.5時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン50mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣に１ＭテトラブチルアンモニウムフロリドのTHF溶液7.8mlを加え、室温にて１時間撹拌した。水10mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CHCl₃/MeOH=100/1)にて精製した。酢酸エチルより再結晶すると標題化合物が淡黄色結晶として得られた（収量75mg）。
m.p.:220〜221°
MS:267(MH⁺)
¹H-NMR(CDCl₃)：7.15(1H,dd,J=1.6,9.2Hz),7.20(1H,br,d,J=4.4Hz),7.35〜7.40(2H,m),7.56(1H,br,s),7.61(1H,dd,J=0.6,9.2Hz),7.66(1H,br,s),7.71(1H,s),8.11〜8.13(1H,m)
【０２８６】
実施例６６
６−〔２−シアノ−２−（１−メチルピロール−２−イル）エテニル〕 イミダゾ〔１，２−ａ〕ピリジン
【０２８７】
【化１０９】

【０２８８】
イミダゾ〔１，２−ａ〕ピリジン−６−カルボキシアルデヒド366mgと１−メチル−２−ピロールアセトニトリル311mgをエタノール10mlに溶解させ28％ナトリウムメチラートのメタノール溶液0.1mlを加え、室温で19.5時間撹拌した。反応液より溶媒を留去し、残渣をカラムクロマトグラフィー(CHCl₃)にて精製すると、標題化合物がアモルファス状固体として得られた（収量310mg）。
¹H-NMR(CDCl₃)δ(ppm)：3.81(3H,s),6.18(1H,dd,J=2.8,3.6Hz),6.39(1H,dd,J=2.0,3.6Hz),6.75(1H,dd,J=2.0,2.0Hz),7.11(1H,s),7.66(1H,s),7.68(1H,s),7.69(1H,s),7.70(1H,d,J=1.2Hz),8.67〜8.68(1H,m)
【０２８９】
実施例６７
６−〔３−（１−メチルピロール−２−イル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン
【０２９０】
【化１１０】

【０２９１】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液、TCI）3.3mlのTHF６ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）2.5mlを加え、同温度にて20分間撹拌した。これに実施例６６の化合物310mgのTHF８ml溶液を20分かけて滴下し、徐々に昇温させながら２時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン100mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣に１ＭテトラブチルアンモニウムフロリドのTHF溶液５mlを加え、室温にて1.5時間撹拌した。水10mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CH₂Cl₂-MeOH=100/1)にて精製すると、標題化合物がアモルファス状固体として得られた（収量70mg）。
MS:264(MH⁺)
¹H-NMR(CDCl₃)δ(ppm):3.37(3H,s),6.25(1H,dd,J=2.4,3.6Hz),6.34(1H,dd,J=2.0,3.6Hz),6.76(1H,dd,J=2.0,2.4Hz),7.09(1H,dd,J=1.6,9.4Hz),7.50(1H,br,s),7.55(1H,d,J=9.4Hz),7.60(1H,d,J=1.6Hz),7.84(1H,s),7.97(1H,dd,J=1.0,1.6Hz)
【０２９２】
実施例６８
６−〔２−シアノ−２−（３−ピリジル）エテニル〕 イミダゾ〔１，２−ａ〕ピリジン
【０２９３】
【化１１１】

【０２９４】
イミダゾ〔１，２−ａ〕ピリジン−６−カルボキシアルデヒド440mgと３−ピリジルアセトニトリル388mgをエタノール12mlに溶解させ28％ナトリウムメチラートのメタノール溶液0.2mlを加え、室温で22.5時間撹拌した。反応液より溶媒を留去すると、標題化合物がアモルファス状固体として得られた（収量300mg）。これを未精製のまま次の反応に用いた。
¹H-NMR(DMSO-d₆)δ(ppm)：7.55(1H,dd,J=4.8,8.4Hz),7.68(1H,s),7.75(1H,d,J=9.6Hz),7.95(1H,d,J=9.6Hz),8.10〜8.16(3H,m),8.63(1H,d,J=4.8Hz),8.95(1H,d,J=2.8Hz),9.05(1H,br,s)
【０２９５】
実施例６９
６−〔３−（３−ピリジル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン
【０２９６】
【化１１２】

【０２９７】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液、TCI）3.2mlのTHF６ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）2.3mlを加え、同温度にて20分間撹拌した。これに実施例６８の化合物300mgのTHF８ml溶液を20分かけて滴下し、徐々に昇温させながら3.5時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン100mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣に１ＭテトラブチルアンモニウムフロリドのTHF溶液７mlを加え、室温にて２時間撹拌した。反応液より溶媒を留去し、水洗、乾燥後、カラムクロマトグラフィー(CH₂Cl₂/MeOH=100/2)にて精製すると、標題化合物がアモルファス状固体として得られた（収量60mg）。
MS:262(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：7.01(1H,dd,J=1.6,9.2Hz),7.34〜7.40((1H,br),7.52(1H,d,J=9.2Hz),7.56(1H,d,J=1.2Hz),7.80(1H,ddd,J=1.8,1.8,7.6Hz),7.90(1H,s),8.05〜8.10(1H,br),8.46〜8.58(2H,br),8.65(1H,d,J=1.6Hz),13.30(1H,br,s)
【０２９８】
実施例７０
１−メチル−６−〔２−シアノ−２−（２−チエニル）エテニル〕 ベンズイミダゾール
【０２９９】
【化１１３】

【０３００】
製造例８の化合物317mg、チオフェン−２−アセトニトリル266mgをエタノール12mlに溶解させ、28％ナトリウムメチラートのメタノール溶液0.1mlを加え室温で17.5時間撹拌した。反応液より溶媒を留去し、残渣をカラムクロマトグラフィー(CH₂Cl₂/MeOH=100/1)にて精製すると、標題化合物がアモルファス状固体として得られた（収量340mg）。
¹H-NMR(CDCl₃)δ(ppm)：3.91(3H,s),7.09(1H,ddd,J=0.8,4.8,3.6Hz),7.31(1H,dd,J=0.8,4.8Hz),7.40(1H,dd,J=0.8,3.6Hz),7.54(1H,s),7.63(1H,br,d,J=8.4Hz),7.83(1H,d,J=8.4Hz),7.96(1H,s),8.14(1H,br,s)
【０３０１】
実施例７１
１−メチル−６−〔３−（２−チエニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０３０２】
【化１１４】

【０３０３】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）3.4mlのTHF６ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）2.6mlを加え、同温度にて20分間撹拌した。これに実施例７０の化合物340mgのTHF６ml溶液を20分かけて滴下し、徐々に昇温させながら1.5時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン50mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣に１ＭテトラブチルアンモニウムフロリドのTHF溶液７mlを加え、室温にて３時間撹拌した。水10mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CHCl₃/MeOH=100/2）にて精製した。CH₂Cl₂より再結晶すると標題化合物が淡黄色結晶として得られた（収量116mg）。
m.p.:225〜226℃
MS:281(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：3.79(3H,s),6.86〜6.94(1H,m),7.16(1H,br,d,J=7.6Hz),7.38(1H,br,s),7.53(1H,d,J=1.6Hz),7.60(1H,d,J=7.6Hz),7.90(1H,br,s),8.16(1H,s),13.01(1H,br,s)
【０３０４】
実施例７２
１−メチル−６−〔２−シアノ−２−（４−メトキシフェニル）エテニル〕 ベンズイミダール
【０３０５】
【化１１５】

【０３０６】
製造例８の化合物1500mg、４−メトキシフェニルアセトニトリル1519mgをエタノール25mlに溶解させ、28％ナトリウムメチラートのメタノール溶液0.5mlを加え室温で2.5時間撹拌した。反応液に１Ｎ−HCl ３mlを加えたのちクロロホルムで抽出し、有機層を飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を留去して得られた残渣をそのまま次の反応に用いた（収量3.5g）。
¹H-NMR(CDCl₃)δ(ppm)：3.87(3H,s),3.92(3H,s),6.98(2H,d,J=8.8Hz),7.58(1H,s),7.61(1H,dd,J=1.4,8.4Hz),7.64(2H,d,J=8.8Hz),7.84(1H,d,J=8.4Hz),7.96(1H,s),8.21(1H,br,d,J=1.4Hz)
【０３０７】
実施例７３
１−メチル−６−〔３−（４−メトキシフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０３０８】
【化１１６】

【０３０９】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）1.6mlのTHF３ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）1.2mlを加え、同温度にて20分間撹拌した。これに実施例７２の化合物173mgのTHF３ml溶液を20分かけて滴下し、徐々に昇温させながら1.5時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン30mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣に１ＭテトラブチルアンモニウムフロリドのTHF溶液3.5mlを加え、室温にて2.5時間撹拌した。水10mlを加え減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、CH₂Cl₂より再結晶すると標題化合物が淡黄色結晶として得られた（収量54mg）。
m.p.:240〜242℃
MS:305(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：3.68(3H,s),3.70(3H,s),6.85(2H,br,s),6.98(1H,dd,J=1.6,8.4Hz),7.28(2H,d,J=8.8Hz),7.42(1H,br,s),7.47(1H,d,J=8.4Hz),8.08(1H,s),12.81〜12.89(1H,br)
【０３１０】
実施例７４
１−メチル−６−〔２−シアノ−２−（４−ブロモフェニル）エテニル〕 ベンズイミダール
【０３１１】
【化１１７】

【０３１２】
製造例８の化合物297mg、４−ブロモフェニルアセトニトリル407mgをエタノール８mlに溶解させ、28％ナトリウムメチラート0.5mlを加え室温で５時間撹拌した。析出した結晶を濾取、冷エタノール洗し、乾燥すると、標題化合物が黄白色固体として得られた（収量257mg）。
m.p.:141℃
MS:338(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：3.87(3H,s),7.72(4H,br,s),7.78(1H,d,J=8.8Hz),7.88(1H,dd,J=0.8,8.8Hz),8.17(1H,s),8.21(1H,s),8.34(1H,s)
【０３１３】
実施例７５
１−メチル−６−〔３−（４−ブロモフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０３１４】
【化１１８】

【０３１５】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液、TCI）２mlのTHF５ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）1.45mlを加え、同温度にて20分間撹拌した。これに実施例７４の化合物257mgのTHF５ml溶液を20分かけて滴下し、徐々に昇温させながら２時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン50mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣に１ＭテトラブチルアンモニウムフロリドのTHF溶液５mlを加え、室温にて２時間撹拌した。水10mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、CH₂Cl₂より再結晶すると標題化合物が白色結晶として得られた（収量130mg）。
m.p.:273℃
MS:353(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：3.76(3H,s),7.01(1H,dd,J=1.6,8.4Hz),7.35(2H,d,J=8.4Hz),7.48(1H,br,s),7.47,〜7.55(2H,m),7.55(2H,d,J=8.4Hz),8.14(1H,s)
【０３１６】
実施例７６
６−〔２−シアノ−２−（４−ピリジル）エテニル〕 イミダゾ〔１，２−ａ〕ピリジン
【０３１７】
【化１１９】

【０３１８】
イミダゾ〔１，２−ａ〕ピリジン−６−カルボキシアルデヒド297mg ４−ピリジルアセトニトリル塩酸塩630mgをエタノール10mlに溶解させ28％ナトリウムメチラートのメタノール溶液0.6mlを加え、室温で６時間撹拌した。反応液をセライト濾過した後、反応液より溶媒を留去し、残渣をカラムクロマトグラフィー(CHCl₃〜CHCl₃/MeOH=100/1→100/2)にて精製すると、標題化合物がアモルファス状固体として得られた（収量320mg）。
¹H-NMR(DMSO-d₆)δ(ppm)：7.68(1H,d,J=1.2Hz),7.72(2H,d,J=6.4Hz),7.76(1H,d,J=9.6Hz),7.98(1H,d,J=2.0,9.6Hz),8.15(1H,s),8.32(1H,s),8.70(2H,d,J=6.4Hz),9.10(1H,br,s)
【０３１９】
実施例７７
６−〔３−（４−ピリジル）−１Ｈ−ピラゾール−４−イル〕イミダゾ〔１，２−ａ〕ピリジン
【０３２０】
【化１２０】

【０３２１】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液、TCI）2.8mlのTHF６ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）2.1mlを加え、同温度にて20分間撹拌した。これに実施例７６の化合物320mgのTHF６ml溶液を20分かけて滴下し、徐々に昇温させながら２時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン50mlで抽出したところ、結晶が析出した。得られた結晶に１ＭテトラブチルアンモニウムフロリドのTHF溶液３mlを加え、室温にて1.5時間撹拌した。水10mlを加え、減圧下にTHFを留去すると沈澱が生じた。これを濾取、水洗、乾燥後、CH₂Cl₂、IPEより再結晶すると標題化合物が淡褐色結晶として得られた（収量65mg）。
m.p.:246℃
MS:262(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm):6.98(1H,dd,J=1.4,9.2Hz),7.38(2H,d,J=5.8Hz),7.49(1H,d,J=9.2Hz),7.52(1H,d,J=1.4Hz),7.87(1H,s),8.47(2H,d,J=5.8Hz),8.49(1H,br,s)
【０３２２】
製造例１４
ジエチル（１−シアノエチル）ホスホネート
【０３２３】
【化１２１】

【０３２４】
１，２−ジメトキシエタン８mlに水素化ナトリウム(Ca.60％ in mineral oil)201mgを懸濁させ、そこにジエチルシアノメチルフォスフォネート887mgを加えた。室温で１時間撹拌したのち、ヨウ化メチル730mgを加え、室温で1.5時間撹拌した。水を５ml加えクロロホルム30mlで抽出し、無水硫酸マグネシウムで乾燥した。溶媒留去したものを粗精製のまま次の反応に用いた（収量950mg）。
【０３２５】
実施例７８
１−メチル−６−（２−シアノ−１−プロペニル）ベンズイミダール
【０３２６】
【化１２２】

【０３２７】
テトラヒドロフラン５mlに水素化ナトリウム(Ca.60％ in mineral oil)206mgを懸濁させ、そこにジエチル（１−シアノエチル）ホスホネート950mgのTHF５ml溶液を加えた。０℃で１時間撹拌したのち、製造例８の化合物720mgのTHF10ml溶液を加えて、０℃でさらに２時間撹拌した。反応液に水を加え、ジクロロメタンで抽出したのち、有機層を水洗、ついで飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒留去したのち、シリカゲルカラムクロマトグラフィー(CHCl₃)で精製し、標題化合物200mgが得られた。
¹H-NMR(CDCl₃)δ(ppm)：2.22(3H,d,J=1.6Hz),3.88(3H,s),7.29(1H,dd,J=1.6,8.4Hz),7.34〜7.38(2H,m),7.81(1H,d,J=8.4Hz),7.94(1H,s)
【０３２８】
実施例７９
１−メチル−６−（３−メチル−１Ｈ−ピラゾール−４−イル）ベンズイミダゾール
【０３２９】
【化１２３】

【０３３０】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）2.45mlのTHF５ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）1.8mlを加え、同温度にて20分間撹拌した。これに実施例７８の化合物200mgのTHF５ml溶液を20分かけて滴下し、徐々に昇温させながら4.5時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン50mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣に１ＭテトラブチルアンモニウムフロリドのTHF溶液７mlを加え、室温にて2.5時間撹拌した。水10mlを加え減圧下にTHFを留去すると沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CHCl₃/MeOH=100/1→100/2→100/10)にて精製したのち、再度カラムクロマトグラフィー(CH₂Cl₂/Acetone=1/2)にて精製すると、標題化合物が淡黄色結晶として得られた（収量80mg）。
m.p.:198℃
MS:213(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：2.39(3H,s),3.83(3H,s),7.28(1H,dd,J=1.6,8.4Hz),7.55(1H,d,J=1.6Hz),7.62(1H,d,J=8.4Hz),8.12(1H,s),12.60(1H,br,s)
【０３３１】
実施例８０
１−メチル−６−〔２−シアノ−２−（２−ブロモフェニル）エテニル〕 ベンズイミダール
【０３３２】
【化１２４】

【０３３３】
製造例８の化合物243mg、２−ブロモフェニルアセトニトリル302mgをエタノール８mlに溶解させ、28％ナトリウムメチラート0.1mlを加え０℃で３時間、ついで室温で４時間、そして４℃で14時間撹拌した。反応液より溶媒を留去し、残渣をカラムクロマトグラフィー(CHCl₃only→CHCl₃/MeOH=100/1)にて精製すると、標題化合物を含む混合物が得られた（収量320mg）。
【０３３４】
実施例８１
１−メチル−６−〔３−（２−ブロモフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０３３５】
【化１２５】

【０３３６】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）1.65mlのTHF５ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）1.2mlを加え、同温度にて20分間撹拌した。これに実施例８０の化合物320mgのTHF3.5ml溶液を20分かけて滴下し、徐々に昇温させながら２時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン50mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣に１ＭテトラブチルアンモニウムフロリドのTHF溶液３mlを加え、室温にて３時間撹拌した。水10mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CH₂Cl₂/MeOH=100/1)にて精製した。CH₂Cl₂より再結晶すると標題化合物が白色結晶として得られた（収量30mg）。
m.p.:263℃
MS:353(MH⁺)
¹H-NMR(CDCl₃)δ(ppm)：3.70(3H,s),7.15(1H,dd,J=1.6,8.4Hz),7.18(1H,m),7.28〜7.37(3H,m),7.66(1H,d,J=8.4Hz),7.69(1H,dd,J=1.6,7.6Hz),7.81(1H,s),7.90(1H,s)
【０３３７】
実施例８２
１−メチル−６−〔２−シアノ−２−（４−クロロフェニル）エテニル〕 ベンズイミダール
【０３３８】
【化１２６】

【０３３９】
製造例８の化合物300mg、４−クロロフェニルアセトニトリル291mgをエタノール15mlに溶解させ、28％ナトリウムメチラートのメタノール溶液0.15mlを加え室温で２時間撹拌した。反応液より溶媒を留去し、残渣をカラムクロマトグラフィー(CHCl₃/MeOH=100/2)にて精製すると、標題化合物がアモルファス状固体として得られた（収量480mg）。
¹H-NMR(CDCl₃)δ(ppm)：3.93(3H,s),7.44(2H,d,J=8.4Hz),7.62〜7.66(3H,m),7.67(1H,s),7.85(1H,d,J=8.4Hz),7.98(1H,s),8.23〜8.24(1H,m)
【０３４０】
実施例８３
１−メチル−６−〔３−（４−クロロフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０３４１】
【化１２７】

【０３４２】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）3.95mlのTHF８ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）2.9mlを加え、同温度にて20分間撹拌した。これに実施例８２の化合物480mgのTHF８ml溶液を20分かけて滴下し、徐々に昇温させながら1.5時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン50mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣に１ＭテトラブチルアンモニウムフロリドのTHF溶液８mlを加え、室温にて2.5時間撹拌した。水20mlを加え減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CHCl₃/MeOH=100/1→100/2)にて精製した。CHCl₃より再結晶すると標題化合物が白色結晶として得られた（収量232mg）。
m.p.:268℃
MS:309(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：3.76(3H,s),7.02(1H,dd,J=1.6,8.4Hz),7.31〜7.45(4H,m),7.48(1H,br,s),8.15(1H,s),13.10(1H,br,s)
【０３４３】
製造例１５
【０３４４】
４−アミノフェニルアセトニトリル
【化１２８】

【０３４５】
４−ニトロフェニルアセトニトリル3.253gをメタノール30ml、THF５mlの混合溶媒に溶解し、そこに10％パラジウム−カーボン2.95gを懸濁させた。反応系を水素で置換し、室温で20時間激しく撹拌した。反応液をセライト濾過したのち、溶媒留去し、シリカゲルカラムクロマトグラフィー(CHCl₃〜CHCl₃/MeOH=100/1→100/2)で精製して標題化合物をろう状固体として1.780g得た。
¹H-NMR(DMSO-d₆)δ(ppm)：3.74(2H,s),5.09(2H,br,s),6.56(2H,d,J=8.4Hz),6.96(2H,d,J=8.4Hz)
【０３４６】
製造例１６
４−（Ｎ，Ｎ−ジメチルアミノ）フェニルアセトニトリル
【０３４７】
【化１２９】

【０３４８】
４−アミノフェニルアセトニトリル1.780gを37％ホルマリン水溶液15mlに溶解し、そこにギ酸10mlを加えて10時間加熱還流した。炭酸水素ナトリウムで反応液を中和し、クロロホルムで抽出した。有機層を水洗、ついで飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥したのち溶媒留去し、シリカゲルカラムクロマトグラフィー(CHCl₃)で精製して標題化合物をろう状固体として180mg得た。
¹H-NMR(DMSO-d₆)δ(ppm)：2.85(6H,s),3.82(2H,s),6.69(2H,d,J=8.8Hz),7.11(2H,d,J=8.8Hz)
【０３４９】
実施例８４
１−メチル−６−〔２−シアノ−２−（４−ジメチルアミノフェニル）エテニル〕 ベンズイミダール
【０３５０】
【化１３０】

【０３５１】
製造例８の化合物121mg、４−（Ｎ，Ｎ−ジメチルアミノ）フェニルアセトニトリル120mgをエタノール４mlに溶解させ、28％ナトリウムメチラート0.03mlを加え室温で6.5時間撹拌した。反応液に１Ｎ−HCl 0.5mlを加えたのち、溶媒を留去し、残渣をクロロホルムに溶解して飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を無水硫酸マグネシウムで乾燥したのち溶媒を留去し、残渣をカラムクロマトグラフィー(CHCl₃)にて精製すると、標題化合物がアモルファス状固体として得られた（収量140mg）。
¹H-NMR(CDCl₃)δ(ppm)：3.02(6H,s),3.88(3H,s),6.74(2H,d,J=9.2Hz),7.50(1H,s),7.57(2H,d,J=9.2Hz),7.58(1H,dd,J=1.8,8.4Hz),7.80(1H,d,J=8.4Hz),7.92(1H,s),8.15(1H,br,d,J=1.8Hz)
【０３５２】
実施例８５
１−メチル−６−〔３−（４−ジメチルアミノフェニル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０３５３】
【化１３１】

【０３５４】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）1.83mlのTHF４ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）1.35mlを加え、同温度にて20分間撹拌した。これに実施例８４の化合物140mgのTHF５ml溶液を20分かけて滴下し、徐々に昇温させながら４時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン50mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣に１ＭテトラブチルアンモニウムフロリドのTHF溶液３mlを加え、室温にて２時間撹拌した。水10mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CH₂Cl₂/Acetone=1/2)にて精製すると、標題化合物が淡黄色結晶として得られた（収量40mg）。
m.p.:199〜201℃
MS:318(MH⁺)
¹H-NMR(DMSO-d₆)δ(ppm)：2.85(6H,s),3.78(3H,s),6.66(2H,br,d,J=8.8Hz),7.05(1H,dd,J=1.6,8.4Hz),7.22(2H,br,d,J=8.8Hz),7.48(1H,br,s),7.51(1H,d,J=8.4Hz),8.12(1H,s)
【０３５５】
実施例８６
１−メチル−６−〔２−シアノ−２−（２−ピリジル）エテニル〕 ベンズイミダール
【０３５６】
【化１３２】

【０３５７】
製造例８の化合物321mg、２−ピリジルアセトニトリル254mgをエタノール12mlに溶解させ、28％ナトリウムメチラートのメタノール溶液0.1mlを加え室温で2.5時間撹拌した。反応液より溶媒を留去し、残渣をカラムクロマトグラフィー(CH₂Cl₂/MeOH=100/1)にて精製すると、標題化合物がアモルファス状固体として得られた（収量460mg）。
¹H-NMR(DMSO-d₆)δ(ppm)：3.88(3H,s),7.43(1H,ddd,J=0.8,4.8,7.6Hz),7.80(1H,d,J=8.4Hz),7.84(1H,d,J=7.6Hz),7.94(1H,dd,J=1.6,7.6Hz),7.98(1H,dd,J=1.2,8.4Hz),8.27(1H,br,s),8.37(1H,s),8.61(1H,s),8.65〜8.68(1H,m)
【０３５８】
実施例８７
１−メチル−６−〔３−（２−ピリジル）−１Ｈ−ピラゾール−４−イル〕ベンズイミダゾール
【０３５９】
【化１３３】

【０３６０】
トリメチルシリルジアゾメタン（約10％ｎ−ヘキサン溶液）4.3mlのTHF12ml溶液に−78℃にてｎ−ブチルリチウム（1.6mol/l：ｎ−ヘキサン溶液）3.1mlを加え、同温度にて20分間撹拌した。これに実施例８６の化合物460mgのTHF８ml溶液を20分かけて滴下し、徐々に昇温させながら1.5時間撹拌した。飽和塩化アンモニウム溶液を加え、ジクロロメタン50mlで抽出した。有機層を分取し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣に１ＭテトラブチルアンモニウムフロリドのTHF溶液15mlを加え、室温にて３時間撹拌した。水30mlを加え、減圧下にTHFを留去すると、沈澱が生じた。これを濾取、水洗、乾燥後、カラムクロマトグラフィー(CH₂Cl₂/Acetone=1/2)にて精製した。CH₂Cl₂-Et₂Oより再結晶すると標題化合物が淡黄色結晶として得られた（収量289mg）。
m.p.:239℃
MS:276(MH⁺)
¹H-NMR（CDCl₃）δ(ppm)：3.85(3H,s),7.19(1H,ddd,J=1.4,4.8,8.0Hz),7.30(1H,d,J=8.0Hz),7.35(1H,dd,J=1.6,8.4Hz),7.44〜7.45(1H,m),7.48(1H,ddd,J=1.4,8.0,8.0Hz),7.69(1H,s),7.83(1H,d,J=8.4Hz),7.92(1H,s),8.63(1H,br,d,J=4.8Hz)87[0001]
[Industrial application fields]
The present invention relates to a novel pyrazole derivative or a salt thereof useful as an anti-herpesvirus agent, a production method thereof, and the like.
[0002]
[Prior art]
<Background of the invention>
Viruses are special parasites whose genome is DNA or RNA. Because some of the host's genetic equipment is used to express and replicate its own genes, it can only grow in specific host cells.
Of course, most eukaryotes are infected with a wide range of viruses. Even in humans, there are many diseases caused by viruses from colds and measles to cancer and AIDS. Among them, herpes group viruses infect humans after birth and cause latent infection that lasts for life.
Herpes group viruses are spherical viruses encased in a lipid envelope derived from a host cell with a diameter of 120 to 200 nm, and have a linear double-stranded DNA in their genes.
Herpesviridae viruses that infect humans are currently Herpes simplex virus type 1 (HSV-1), type 2 (HSV-2), human cytomegalovirus (HCMV), varicella- Six types of herpes zoster virus (Varicella-zoster virus; VZV), EB virus (Epstein-Barr virus), and human B-lymphotropic virus (Human B-lymphotropic virus) are known.
[0003]
HSV-1 and 2 are the most common viruses in humans. Type 1 is mainly called the lip because it affects the lips, eyes, and skin. Type 2 causes lesions in the vulva and urethra. Called genital type.
Usually, primary infection occurs in childhood between 1 and 4 years of age, but most are subclinical. The first infection in a newborn is inapparent when the mother is an antibody carrier, but causes systemic infections such as hepatitis and adrenalitis, meningoencephalitis, thrombocytopenic purpura, and hepatosplenomegaly. In early childhood infections, acute herpes simplex stomatitis, upper and lower respiratory tract infections, herpes zoster, vulva vaginitis, Kaposi-type herpes eczema, meningoencephalitis, hepatitis, keratitis, etc. In early adulthood, Kaposi's herpes eczema, meningoencephalitis, upper and lower respiratory tract infection, keratitis, systemic infection, severe stomatitis, hepatitis, herpes zoster, neuralgia, facial paralysis, genital herpes, subacute meningitis, etc. It can be seen.
Herpesviruses are latently infected mainly in ganglia after initial infection. In the case of HSV, even a healthy person repeats cold sores, genital herpes, and corneal herpes with slight fatigue and changes in physical condition. In particular, in patients who have been immunosuppressed for organ transplantation such as bone marrow transplantation and kidney transplantation, which have been generalized in Japan in recent years, viral infections that cannot be infected in normal health or are rarely activated Symptoms develop. For example, there is a recurrence of severe cold sores, and sometimes it develops to the tail and esophageal ulcers.
<Conventional technology>
On the other hand, conventionally, nucleic acid derivatives have been used as anti-herpes agents in order to inhibit the replication of the virus by inhibiting the replication of the virus genome. For example, the following formula disclosed in Japanese Patent Publication No. 56-33396
[0004]
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[0005]
Acyclovir (ACV) represented by the formula is a representative compound, and is still regarded as a first-line drug. In addition, ganciclovir which is a guanosine derivative having an acyclic sugar like the 6-aminopurine derivatives vidarabine and ACV is clinically used.
[0006]
[Problems to be solved by the invention]
However, these drugs are not sufficient in terms of their effects, ease of administration and safety.
For example, ACV disclosed in Japanese Examined Patent Publication No. 56-33396 has the following problems: 1) Low solubility and nephropathy, necessitating slow intravenous infusion, 2) Poor oral absorption rate, 3) Varicella zoster There are many drawbacks, such as low efficacy against viruses (VZV), 4) abnormalities in micronucleus tests, which are basic tests for mutagenicity, and 5) the emergence of resistant strains. is there.
In addition, vidarabine is not sufficient in terms of effectiveness, and has the disadvantage that it cannot be administered for a long time due to its strong cytotoxicity with ganciclovir, and it is even better against herpes virus infections in susceptible patients that are expected to increase further in the future The appearance of drugs is anxious.
Moreover, the DNA that is the gene body is common to all living organisms, and it is considered difficult to eliminate side effects on the human body such as mutagenicity and cytotoxicity with nucleic acid compounds.
As a result of intensive research on non-nucleic acid anti-herpes agents to solve these problems, the present inventors have found anti-herpes agents having excellent activity and safety, synthetic intermediates thereof, and production methods thereof. The present invention has been completed.
[0007]
[Means for Solving the Problems]
That is, the present invention has the general formula
[0008]
Embedded image

[0009]
[In the formula, ring A may have one or more heteroatoms, may have one or more substituents, may have an aromatic ring, or one or more heteroatoms. A fused ring optionally having a substituent of R¹Is a lower alkyl group or an aromatic ring optionally having one or more heteroatoms and optionally having one or more substituents, R²Is a protecting group for a hydrogen atom, a lower alkyl group or an amino group, R^ThreeRepresents a hydrogen atom, a halogen atom or a lower alkyl group. Or a salt thereof, or a general formula that is a synthetic intermediate of this pyrazole derivative
[0010]
Embedded image

[0011]
[In the formula, ring A may have one or more heteroatoms, may have one or more substituents, may have an aromatic ring, or one or more heteroatoms. A fused ring optionally having a substituent of R¹Each represents a lower alkyl group or an aromatic ring which may have one or more heteroatoms and may have one or more substituents. Or a salt thereof, a process for producing them, and their use as an anti-herpes agent.
[0012]
Hereinafter, terms and the like described in this specification will be described.
Ring A may have one or more heteroatoms, may have one or more substituents, may have an aromatic ring or one or more heteroatoms, and may have one or more substituents. The condensed ring which may have is shown.
Specific examples of the hetero atom include an oxygen atom, a sulfur atom, and a nitrogen atom, but also include phosphorus, arsenic, antimony, silicon, germanium, tin, lead, boron, and mercury. Preferably an oxygen atom, a sulfur atom, and a nitrogen atom are mentioned.
[0013]
Specific examples of the substituent include, for example, hydroxyl group; thiol group; nitro group; morpholino group; thiomorpholino group; halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom; nitrile group; azide group; formyl group Alkyl group such as methyl group, ethyl group, propyl group, isopropyl group and butyl group; alkenyl group such as vinyl group, allyl group and propenyl group; alkynyl group such as ethynyl group, butynyl group and propargyl group; Corresponding alkoxy groups such as methoxy group, ethoxy group, propoxy group, butoxy group; halogenoalkyl groups such as fluoromethyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group: hydroxymethyl group, hydroxyethyl group, hydroxypropyl Hydroxyalkyl groups such as groups; guanidino groups Carbamoyl group; carbamoyl alkyl group such as carbamoylmethyl group and carbamoylethyl group; alkylcarbamoyl group such as methylcarbamoyl group and dimethylcarbamoyl group; carbamide group; acetyl group and the like Alkanoyl group; amino group; alkylamino group such as methylamino group, ethylamino group, isopropylamino group; dialkylamino group such as dimethylamino group, methylethylamino group, diethylamino group; aminomethyl group, aminoethyl group, aminopropyl An aminoalkyl group such as a group; a carboxy group; an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, or a propoxycarbonyl group; a methoxycarbonylmethyl group, an ethoxycarbonyl group; Alkoxycarbonylalkyl groups such as til group, propoxycarbonylmethyl group, methoxycarbonylethyl group, ethoxycarbonylethyl group, propoxycarbonylethyl group; methyloxymethyl group, methyloxyethyl group, ethyloxymethyl group, ethyloxyethyl group, etc. Alkyloxyalkyl group; alkylthioalkyl group such as methylthiomethyl group, methylthioethyl group, ethylthiomethyl group and ethylthioethyl group; aminoalkylaminoalkyl group such as aminomethylaminomethyl group and aminoethylaminomethyl group; methylcarbonyloxy Group, alkylcarbonyloxy group such as ethylcarbonyloxy group and isopropylcarbonyloxy group; arylalkoxy group such as oxymethyl group and benzyloxyethyloxyethyl group Sialkoxyalkyl groups; hydroxyalkoxyalkyl groups such as hydroxyethyloxymethyl group and hydroxyethyloxyethyl group; arylalkoxyalkyl groups such as benzyloxymethyl group, benzyloxyethyl group and benzyloxypropyl group; trimethylammonio group and methyl Quaternary ammonio groups such as ethylmethylammonio group and triethylammonio group; cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group Cycloalkenyl groups such as phenyl groups, aryl groups such as pyridinyl groups, thienyl groups, furyl groups, pyrrolyl groups; methylthio groups, ethylthio groups, propylthio groups, butylthio groups, etc. Alkylthio group; arylthio group such as phenylthio group, pyridinylthio group, thienylthio group, furylthio group, pyrrolylthio group; aryl lower alkyl group such as benzyl group, trityl group, dimethoxytrityl group; sulfonyl group, mesyl group, p-toluenesulfonyl group, etc. Substituted sulfonyl groups; aryloyl groups such as benzoyl groups; halogenoaryl groups such as fluorophenyl groups and bromophenyl groups; oxyalkoxy groups such as methylenedioxy groups. The phrase “may have one or more substituents” means that these groups may be arbitrarily combined, and examples thereof include a hydroxyl group, a thiol group, a nitro group, a morpholino group, a thiomorpholino group, a halogen atom. Also included in the present invention are alkyl groups substituted with atoms, nitrile groups, azide groups, formyl groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, sulfonyl groups, etc .; alkenyl groups; alkynyl groups; It is.
[0014]
Specific examples of ring A include benzene, pyridine, thiophene, furan, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, triazole, pyrazole, furazane, which may have one or more substituents. Thiadiazole, oxadiazole, pyridazine, pyrimidine, pyrazine, pentalene, indene, naphthalene, azulene, indole, isoindole, indazole, chromene, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, naphthyridine, phthalazine, purine, pteridine, thienofuran, imidazo Thiazole, benzofuran, benzothiophene, benzoxazole, benzthiazole, benzthiadiazole, benzimidazole, imidazopyridine, pyrrolopi Jin, pyrrolopyrimidine and pyridopyrimidine may be mentioned. Preferred examples include benzene, pyridine, thiophene, thiazole, thiadiazole, imidazole, pyrimidine, benzimidazole, imidazopyridine, and purine.
[0015]
Furthermore, when the ring A is a condensed ring of a 5-membered ring and a 6-membered ring, specific examples include thiophene, furan, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, triazole, pyrazole, furazane, thiadiazole, Examples include condensed rings of oxadiazole and the like with benzene, pyridine, pyridazine, pyrimidine, pyrazine, etc., for example, indene, indole, isoindole, benzofuran, benzothiophene, benzoxazole, benzthiazole, benzthiadiazole, benzimidazole, imidazopyridine , Pyrrolopyridine, pyrrolopyrimidine, purine and the like.
[0016]
R¹Represents a lower alkyl group or an aromatic ring which may have one or more heteroatoms and may have one or more substituents.
Specifically, the lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, Butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, 1,1- Dimethylpropyl group, 1,2-dimethylpropyl group, n-hexyl group, i-hexyl 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-ethylbutyl group, 3- Ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl , 1-ethyl-2-methylpropyl group, means a hexyl group. Preferable examples include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group and the like.
[0017]
This R¹The definition regarding the hetero atom and substituent about is the same as the above. Therefore, R¹Specific examples of the aromatic ring in benzene, pyridine, thiophene, furan, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, triazole, pyrazole, furazane, which may have one or more substituents, Examples include thiadiazole, pyridazine, pyrimidine, pyrazine and the like.
[0018]
More specifically, R¹Examples of the aromatic ring group which may have one or more substituents in 2-fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-bromophenyl group, 4-bromophenyl Group, 2-chlorophenyl group, 4-chlorophenyl group, 2-aminophenyl group, 4-aminophenyl group, 2-nitrophenyl group, 4-nitrophenyl group, 2-dimethylaminophenyl group, 4-dimethylaminophenyl group, Examples include 2-methoxyphenyl group, 4-methoxyphenyl group, 2-thienyl group, 2-pyridyl group, N-methyl-2-pyrrolyl group and the like.
[0019]
R²Represents a protecting group for a hydrogen atom, a lower alkyl group or an amino group. The definition relating to the lower alkyl group is the same as described above.
A specific example of the amino-protecting group is not particularly limited as long as it is a group known as an amino-protecting group for organic synthesis. Substituted or unsubstituted lower alkanoyl groups such as acetyl group, dichloroacetyl group, propionyl group, phenylacetyl group, phenoxyacetyl group, thienylacetyl group; benzyloxycarbonyl group, t-butoxycarbonyl group, p-nitrobenzyloxycarbonyl group Substituted or unsubstituted lower alkoxycarbonyl group such as methyl group, t-butyl group, 2,2,2-trichloroethyl group, trityl group, p-methoxybenzyl group, p-nitrobenzyl group, diphenylmethyl group, Substituted lower alkyl group such as valoyloxymethyl group; trimethylsilyl group, t-butyldimethyl Substituted silyl groups such as silyl groups; substituted silylalkoxyalkyl groups such as trimethylsilylmethoxymethyl group, trimethylsilylethoxymethyl group, t-butyldimethylsilylmethoxymethyl group, t-butyldimethylsilylethoxymethyl group; benzylidene group, salicylidene group, p Substituted or unsubstituted benzylidene groups such as -nitrobenzylidene group, m-chlorobenzylidene group, 3,5-di (t-butyl) -4-hydroxybenzylidene group, 3,5-di (t-butyl) benzylidene group Can be mentioned.
Removal of these protecting groups can be carried out by conventional methods such as hydrolysis and reduction, depending on the type of protecting group used.
[0020]
R^ThreeRepresents a hydrogen atom, a halogen atom or a lower alkyl group. Specific examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The definition of the lower alkyl group is the same as described above.
[0021]
Examples of the salt include, but are not limited to, for example, hydrofluoride, hydrochloride, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, hydrobromide, hydroiodide Addition salts of inorganic acids such as: acetates, maleates, fumarates, oxalates, lactates, tartrate, trifluoroacetates and other organic carboxylic acids; methanesulfonates, trifluoromethanesulfonic acid Salt, ethanesulfonate, hydroxymethanesulfonate, hydroxyethanesulfonate, benzenesulfonate, toluenesulfonate, taurine, and other organic sulfonic acid addition salts; trimethylamine, triethylamine, pyridine, procaine Salt, picoline salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, N-methylglucamine salt, dieta Addition salts of amines such as noramine salts, triethanolamine salts, tris (hydroxymethylamino) methane salts and phenethylbenzylamine salts; addition salts of alkali metals such as sodium salts and potassium salts; alkaline earths such as magnesium salts and calcium salts Addition salts of similar metals; addition salts of amino acids such as arginine salt, lysine salt, serine salt, glycine salt, aspartate, glutamate and the like.
A pharmacologically acceptable salt means a conventional salt usually used in the manufacture of a medicine.
[0022]
Accordingly, specific examples of the present pyrazole derivative or a salt thereof include 6- (3-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine, 3-chloro-6- (3-methyl- 1H-pyrazol-4-yl) imidazo [1,2-a] pyridine, 1-methyl-6- [3- (4-methoxyphenyl) -1H-pyrazol-4-yl] benzimidazole, 1-methyl-6 -[3- (2,4-difluorophenyl) -1H-pyrazol-4-yl] benzimidazole or 2- [3-phenyl-1H-pyrazol-4-yl] -9-methylpurine or a salt thereof be able to.
[0023]
In addition, the present invention includes all stereoisomers, optical isomers and tautomers generated in the structure of the compound.
[0024]
Next, the manufacturing method of this invention compound represented with the following general formula is demonstrated. General formula
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[0025]
[Wherein ring A, R¹Is the same as defined above. Step (I) is a route for deriving an olefin compound (3) which is an intermediate useful for the synthesis of the pyrazole derivative as the compound of the present invention. This reaction can be carried out by reacting compound (2) with compound (1) in the presence of a base such as sodium methylate in a solvent that does not inhibit the reaction. While the reaction temperature varies depending on the reactivity of the compound, it can usually be carried out between ice cooling and 100 ° C.
[0026]
Specific examples of bases are not particularly limited as long as they are generally known as bases for organic synthesis. For example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydride, hydrogenation Potassium, t-butoxypotassium, pyridine, dimethylaminopyridine, trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N, N-dimethylaniline, 1,8- Diazabicyclo [5,4,0] undec-7-ene (DBU), pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline, isoquinoline, sodium hydroxide, potassium hydroxide, lithium hydroxide, butyllithium, sodium methyl Lat, Kariu Examples thereof include sodium or potassium alcoholate such as mumethylate and sodium ethylate.
[0027]
The general formula
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[0028]
[Wherein ring A, R¹Is the same as defined above. R^FourRepresents a lower alkoxy group. An intermediate useful for the synthesis of the pyrazole derivative as the compound of the present invention can also be synthesized by the step (II) represented by This is accomplished by reacting compound (4) with compound (4) in the presence of a base such as sodium hydride in a solvent that does not inhibit the reaction, thereby allowing compound (4) to react with cyanomethylene-R.¹This is a route for introducing the unit and deriving the olefin compound (6).
[0029]
Where R^FourThe lower alkoxy group corresponds to the above-mentioned lower alkyl group, and specifically refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, n -Propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group, t-butoxy group, n-pentyloxy group, i-pentyloxy group, sec-pentyloxy group, t-pentyl group Oxy group, neopentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, n-hexyloxy group, i-hexyloxy group, 1- Methylpentyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,3-dimethylbutoxy group 2,3-dimethylbutoxy group, 3 , 3-dimethylbutoxy group, 1-ethylbutoxy group, 2-ethylbutoxy group, 1,1,2-trimethylpropoxy group, 1,2,2-trimethylpropoxy group, 1-ethyl-1-methylpropoxy group, 1 And -ethyl-2-methylpropoxy group.
[0030]
General formula
Embedded image

[0031]
[Wherein ring A, R¹Is the same as defined above. R^FiveRepresents a hydrogen atom or a trimethylsilyl group, respectively. The process (III) represented by the above formula is a route for ring-closing the olefin compound obtained by the processes (I) and (II).
This reaction can be carried out, for example, by adding a base such as n-butyllithium under cooling of trimethylsilyldiazomethane (8) to about −78 ° C. in a solvent that does not inhibit the reaction, and adding compound (7) thereto. . R^FiveThe removal of the trimethylsilyl group can be carried out under the condition that the usual silyl group is eliminated. For example, the trimethylsilyl group is removed by stirring with 1M tetrabutylammonium fluoride at room temperature or heating with hydrochloric acid. be able to.
[0032]
General formula
Embedded image

[0033]
[Wherein ring A, R¹, R²Is the same as defined above. The compound of the present invention can also be produced by the step (IV) represented by This is a route in which the compound (10) reacts with the hydrazine derivative (11) to cyclize in a solvent that does not inhibit the reaction.
[0034]
Further general formula
Embedded image

[0035]
[In the formula, R¹, R²Is the same as defined above. R⁶Represents a hydrogen atom or a lower alkyl group. Step (V) is a route for deriving an amide compound (15) which is an intermediate useful for the synthesis of the pyrazole derivative of the present application. This reaction can be performed by reacting the acid halide derivative of compound (13) with compound (14) in a solvent that does not inhibit the reaction. While the reaction temperature varies depending on the reactivity of the compound, it can usually be carried out between ice cooling and 100 ° C.
[0036]
General formula
Embedded image

[0037]
[In the formula, R¹, R², R⁶Is the same as defined above. Step (VI) represented by the above formula is a route for cyclizing the amide compound (15) obtained by the step (V) to induce the purine derivative (16). This reaction can be carried out by reacting compound (15) in the presence of a base such as potassium hydrogen carbonate in a solvent that does not inhibit the reaction. While the reaction temperature varies depending on the reactivity of the compound, it can usually be carried out between ice cooling and 100 ° C. R²Is a protective group for an amino group, particularly a 2-trimethylsilylethoxymethyl group, the 2-trimethylsilylethoxymethyl group can be removed by stirring with boron tristrifluoroacetate under ice-cooling.
[0038]
In general, the reaction in the above step can be carried out in a temperature range of −78 ° C. to 150 ° C., preferably −40 to 50 ° C., and more preferably −20 to 25 ° C., except as specifically described.
[0039]
The solvent that can be used in the present invention is not particularly limited as long as it does not inhibit the reaction and is usually used in organic synthesis. For example, methanol, ethanol, propanol, butanol, etc. Lower alcohols, polyalcohols such as ethylene glycol and glycerin, ketones such as acetone, methyl ethyl ketone, diethyl ketone and cyclohexanone, diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, 2-methoxyethanol, 1,2-dimethoxyethane, etc. Ethers, nitriles such as acetonitrile, propionitrile, esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, diethyl phthalate, dichloromethane, chloroform, tetrachloride Halogen, hydrocarbons such as 1,2-dichloroethane, trichloroethylene, tetrachloroethylene, aromatics such as benzene, toluene, xylene, monochlorobenzene, nitrobenzene, indene, pyridine, quinoline, collidine, phenol, pentane, cyclohexane, hexane , Hydrocarbons such as heptane, octane, isooctane, petroleum benzine, petroleum ether, ethanolamine, diethylamine, triethylamine, pyrrolidine, piperidine, piperazine, morpholine, aniline, dimethylaniline, benzylamine, toluidine and other amines, formamide, N -Amides such as methylpyrrolidone, N, N-dimethylimidazolone, N, N-dimethylacetamide, N, N-dimethylformamide, hexamethyl Phosphate triamide, phosphoric acid amides such as hexamethyl phosphorous acid triamide, water, can be exemplified one or two or more kinds of mixed solvents such as other solvents which are commonly used, the mixing ratio is not particularly limited.
[0040]
After completion of the above reaction, purification can be carried out by a usual treatment method if desired, for example, by column chromatography using silica gel or an adsorbent resin or by recrystallization from an appropriate solvent.
[0041]
The dosage of the anti-herpes agent according to the present invention varies depending on the degree of symptoms, age, sex, body weight, dosage form, disease type, etc., but is usually 1-1000 mg per day for adults, and is administered in 1 to several doses. . The administration form is not particularly limited, and it may be administered orally or parenterally by a commonly used method such as soft capsules, hard capsules, tablets, powders, granules, internal liquids, injections, infusions, and the like. it can.
[0042]
For these formulations, commonly used excipients, binders, lubricants, coloring agents, flavoring agents, etc., and if necessary, stabilizers, emulsifiers, absorption promoters, surfactants, etc. can be used. It is formulated by a conventional method. These ingredients include, for example, animal and vegetable oils (soybean oil, beef tallow, synthetic glycerides, etc.), hydrocarbons (liquid paraffin, squalane, solid paraffin, etc.), ester oils (octyldodecyl myristate, isopropyl myristate, etc.), higher alcohols ( Cetostearyl alcohol, behenyl alcohol, etc.), silicone resin, silicone oil, surfactant (polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxy) Propylene block copolymer, etc.), water-soluble polymers (hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrole) , Methylcellulose, etc.), alcohol (ethanol, isopropanol, etc.), polyhydric alcohol (glycerin, propylene glycol, dipropylene glycol, sorbitol, etc.), sugar (glucose, sucrose, etc.), inorganic powder (anhydrous silicic acid, silicic acid) Aluminum magnesium, aluminum silicate, etc.) and purified water. For pH adjustment, inorganic acids (hydrochloric acid, phosphoric acid, etc.), alkali metal salts of inorganic acids (sodium phosphate, etc.), inorganic bases (sodium hydroxide, etc.), organic acids (lower fatty acids, citric acid, lactic acid, etc.) Organic metal alkali metal salts (such as sodium citrate and sodium lactate), organic bases (such as arginine and ethanolamine) can be used. Moreover, antiseptic | preservative, antioxidant, etc. can be added as needed.
[0043]
The compound of the present invention exhibits excellent antiviral activity against herpes virus and is a useful compound as an anti-herpes virus agent for the treatment and prevention of infectious diseases caused by herpes virus. In order to show the usefulness of the compound of the present invention, the antiviral activity of the compound of the present invention was measured.
[0044]
Method for measuring anti-herpesvirus activity
Anti-HSV-1 activity was measured by the plaque reduction method. 50 to 100 PFU of HSV-1 KOS strain is adsorbed to VERO cells cultured in a 24-well microplate. After 1 hour, the supernatant is removed, the test substance diluted in a medium containing 0.5% methylcellulose is added, and the culture is continued for 3 days. Thereafter, 0.25% neutral red is added and stained, and the number of plaques formed by HSV-1 infection is counted. The concentration of the test substance that reduces the number of plaques by 50% relative to the control wells to which nothing is added is ED₅₀It was.
The anti-herpesvirus activity of the compound of the present invention is shown below.
[0045]
[Table 1]

[0046]
The following examples are given to illustrate the present invention in more detail, but the present invention is not limited to these examples. Also in the examples¹H N.M.R. spectrum was measured by Varian FT NMR (400 MHz).
[0047]
Hereinafter, Tr represents a trityl group, SEM represents a trimethylsilylethoxymethyl group, and Bn represents a benzyl group.
[0048]
【Example】
Example 1
6- (3-Methyl-1H-pyrazol-4-yl) [1,2-a] imidazopyridine
[0049]
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[0050]
4-Dimethylamino-3- (6-imidazo [1,2-a] pyridinyl) -3-buten-2-one (M. Yamanaka et al. Chem. Pharm. Bull., 39 (6), 1556-67 , 1991) 31.41 g was dissolved in 125 ml of ethanol, 13.7 g of hydrazine hydrate was added, and the mixture was heated to reflux for 1 hour. After cooling, the precipitated crystals were collected by filtration, washed with cold ethanol and dried to give the title compound as colorless needle crystals (yield 21.25 g).
m.p.:230~231°(dec)
MS: 199 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 12.7 (1H, br), 8.58 (1H, m), 7.92 (1H, br, s), 7.56 (1H, d, J = 9.3Hz), 7.54 (1H, d, J = 1.1 Hz), 7.35 (1H, dd, J = 1.8,9.3Hz), 2.37 (3H, s)
[0051]
Example 2
3-thiomorpholinomethyl-6- (3-methyl-1H-pyrazol-4-yl) [1,2-a] imidazopyridine
[0052]
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[0053]
780 mg of thiomorpholine was dissolved in 20 ml of ethanol, and 3.78 ml of 2N HCl and 613 mg of 37% formalin were added and stirred for 30 minutes. To this, 500 mg of 6- (3-methyl-1H-pyrazol-4-yl) [1,2-a] imidazopyridine was added and heated to reflux for 6 hours. After cooling, the solution was made alkaline with NaHCO 3 and extracted with 70 ml of dichloromethane. After the solvent was distilled off, the residue was purified by column chromatography (EtOAc-Acetone = 3-1) to obtain 909 mg of a brown amorphous solid. CH₂Cl₂Further recrystallization gave 400 mg of the title compound as colorless needle crystals.
m.p .: 222-223 °
MS: 314 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 12.75 (1H, br), 8.41 (1H, br, s), 7.56 (1H, d, J = 9.3Hz), 7.45 (1H, s), 7.39 (1H, dd, J = 9.3 1.3Hz), 3.84 (2H, s), 2.66 to 2.54 (8H, m), 2.41 (3H, s)
[0054]
Example 3
3-morpholinomethyl-6- (3-methyl-1H-pyrazol-4-yl) [1,2-a] imidazopyridine
[0055]
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[0056]
To 660 mg of morpholine, 3.78 ml of 2N HCl and 614 mg of 37% formalin were added and stirred at room temperature for 1 hour. To this, 500 mg of 6- (3-methyl-1H-pyrazol-4-yl) [1,2-a] imidazopyridine was added and stirred at 80 ° C. for 7 hours. After cooling, NaHCO_ThreeTo make it alkaline, followed by extraction with 100 ml of dichloromethane. After evaporating the solvent, the residue was purified by column chromatography (EtOAc-MeOH = 10-1) to give 581 mg solid. This was recrystallized from EtOAc to obtain 55 mg of the title compound as anhydrous needle crystals.
m.p.:244-246°
MS: 298 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 12.7 (1H, br), 8.45 (1H, br, s), 7.56 (1H, dd, J = 9.3, 0.8Hz), 7.46 (1H, s), 7.40 (1H, dd, J = 1.8, 9.3Hz), 3.83 (2H, s), 3.52 (4H, m), 2.41 (3H, s), 2.38 (4H, m)
[0057]
Example 4
3-Iodo-6- (3-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine
[0058]
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[0059]
200 mg of 6- (3-methyl-1H-pyrazol-4-yl) [1,2-a] imidazopyridine was dissolved in 10 ml of methanol, 254 mg of iodine was added, and the mixture was stirred at room temperature for 1 hour. Further, 254 mg of iodine was added and stirred for 1 hour. Add 50 ml of dichloromethane, wash with saturated aqueous sodium bicarbonate solution, then with saturated brine,_FourDried. After evaporation of the solvent, the residue was subjected to column chromatography (CH₂Cl₂-MeOH = 97.5-2.5) and recrystallized from dichloromethane to obtain 150 mg of the title compound as colorless crystals.
m.p.:218°(decomp.)
MS: 325 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 12.75 (1H, br, NH), 8.17 (1H, m, H-5), 7.70 (1H, s, H-2), 7.63 (1H, dd, J = 9.3, 0.9 Hz, H-8), 7.47 (1H, dd, J = 9.3,1.8Hz, H-7), 2.40 (3H, s, Me)
[0060]
Example 5
3-Bromo-6- (3-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine
[0061]
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[0062]
795 mg of 6- (3-methyl-1H-pyrazol-4-yl) [1,2-a] imidazopyridine is dissolved in 20 ml of a dichloromethane-methanol (2-1) mixture, 0.48 ml of triethylamine, followed by 1 MBr₂/ CH₂Cl₂ 3.43 ml was added and stirred at room temperature for 1 hour. Add 100 ml of dichloromethane, wash with water, and wash the organic layer with MgSO._FourDried. Recrystallization from MeOH-EtOAc gave 820 mg of the title compound as pale yellow crystals.
m.p.:264~265°(decomp.)
¹H-NMR (CDCl_Three) δ (ppm): 8.07 (1H, dd, J = 0.9, 1.6Hz, H-5), 7.72 (1H, dd, J = 0.9, 9.3Hz, H-8), 7.68 (1H, br), 7.62 (1H, s, H-2), 7.33 (1H, dd, J = 1.6,9.3Hz, H-7), 2.43 (3H, s, Me)
[0063]
Example 6
3-Chloro-6- (3-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine
[0064]
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[0065]
240 mg of 6- (3-methyl-1H-pyrazol-4-yl) [1,2-a] imidazopyridine is dissolved in 30 ml of methanol, 180 mg of N-chlorosuccinimide (NCS) is added, and the mixture is stirred at room temperature for 4 hours. did. The solvent was distilled off, extracted with 100 ml of dichloromethane and washed with saturated brine. MgSO organic layer_FourAnd the solvent is distilled off, and the residue is purified by column chromatography (CH₂Cl₂Purification by -MeOH = 98-2) gave 280 mg of the title compound as colorless crystals.
m.p.:207-208°C
¹H-NMR (CDCl_Three) δ (ppm): 8.19 (1H, m, H-5), 8.08 (1H, d, J = 8.8Hz, H-8), 7.77 (1H, s), 7.72 (1H, s), 7.62 (1H , dd, J = 8.8,0.7Hz, H-7), 2.50 (3H, s, Me)
[0066]
Example 7
6- [2-Cyano-2- (2-pyridyl)] ethenyl Imidazo [1,2-a] pyridine
[0067]
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[0068]
Imidazo [1,2-a] pyridine-6-carboxaldehyde (1.02 g) and 2-cyanomethylpyridine (900 mg) were dissolved in ethanol (50 ml), sodium methylate (95 mg) was added, and the mixture was stirred at 80 ° C. for 1 hour. The reaction solution was distilled off to about 1/3, and the precipitated crystals were collected by filtration, washed with cold ethanol and dried to obtain 950 mg of the title compound as pale yellow crystals.
m.p.:149-151°C
¹H-NMR (CDCl_Three) δ (ppm): 8.82 (1H, m), 8.65 (1H, ddd, J = 0.9, 1.6, 4.6Hz), 8.46 (1H, s), 7.94 (1H, dd, J = 1.8, 9.5Hz), 7.83 (1H, ddd, J = 1.8, 7.8, 7.8Hz), 7.78 (1H, s,), 7.78-7.76 (1H, m), 7.73 (1H, m), 7.69 (1H, m), 7.32 (1H , ddd, J = 1.3,4.6,7.8Hz)
[0069]
Example 8
6- [3- (2-Pyridyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine
[0070]
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[0071]
Trimethylsilyldiazomethane (approximately 10% n-hexane solution, manufactured by Tokyo Chemical Industry Co., Ltd.) 10 ml of THF 10 ml solution was added 3.6 ml of n-butyllithium (1.6 mol / l: n-hexane solution) at −78 ° C. And stirred for 20 minutes. A solution of 0.95 g of the compound of Example 7 in 50 ml of THF was added dropwise thereto over 20 minutes, and the mixture was stirred for 4 hours while gradually warming to room temperature. Saturated ammonium chloride solution was added and extracted with 150 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. After purification by column chromatography (EtoAc only), 360 mg was taken, and 30 ml of ethanol, 1.2 ml of concentrated hydrochloric acid and 70 mg of potassium fluoride were added thereto, and the mixture was heated to reflux for 0.5 hours. After cooling, the solution was made alkaline by adding a potassium carbonate solution. Ethanol was distilled off under reduced pressure and extracted with 100 ml of EtoAc. The organic layer was separated and MgSO_FourAfter drying, the solvent was distilled off, and the residue was recrystallized from methanol to obtain 150 mg of the title compound as colorless crystals.
m.p.:287~290°(decomp.)
¹H-NMR (CDCl_Three) δ (ppm): 8.60-8.58 (1H, m), 8.43-8.42 (1H, m), 8.05-8.00 (1H, m), 7.77 (1H, d, J = 1.5Hz), 7.74 (1H, s) ), 7.66 to 7.64 (1H, m), 7.66 (1H, d, J = 1.5Hz), 7.56 to 7.44 (2H, m), 7.30 to 7.25 (1H, m)
[0072]
Example 9
6- (2-Cyano-2-phenyl) ethenyl Imidazo [1,2-a] pyridine
[0073]
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[0074]
Imidazo [1,2-a] pyridine-6-carboxaldehyde (1.02 g) and phenylacetonitrile (0.86 g) were dissolved in ethanol (10 ml), sodium methylate (87 mg) was added, and the mixture was stirred at 80 ° C. for 1 hour. The solvent was distilled off from the reaction solution, and the residue was subjected to column chromatography (CH₂Cl₂Purification by -MeOH = 98-2) gave the title compound as pale yellow crystals. Recrystallization from ethyl acetate-ether-hexane gave a pale yellow powder (yield 1.01 g).
m.p.:159~161°(decomp.)
¹H-NMR (CDCl_Three) δ (ppm): 8.76 (1H, dd, J = 0.9,1.6Hz), 7.74 (1H, dd, J = 1.6,9.3Hz), 7.71-7.69 (2H, m), 7.69-7.66 (3H, m ), 7.50-7.41 (4H, m)
[0075]
Example 10
6- (2-Cyano-2-phenyl) ethenyl Imidazo [1,2-a] pyridine
[0076]
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[0077]
3.6 ml of n-butyllithium (1.6 mol / l: n-hexane solution) was added to a 30 ml THF solution of 10 ml of trimethylsilyldiazomethane (about 10% n-hexane solution) at −78 ° C. and stirred at the same temperature for 20 minutes. To this was added dropwise a solution of 900 mg of the compound of Example 9 in THF 10 ml over 20 minutes, and the mixture was stirred for 4 hours while gradually warming to room temperature. Saturated ammonium chloride solution was added and extracted with 100 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. After purification by column chromatography (EtOAc-MeOH = 98.5: 1.5), 300 mg was taken, and 15 ml of ethanol, 26 drops of concentrated hydrochloric acid and 53 mg of potassium fluoride were added thereto and heated under reflux for 1.5 hours. After cooling, the solution was made alkaline by adding a potassium carbonate solution, and ethanol was distilled off under reduced pressure, followed by extraction with 100 ml of dichloromethane. The organic layer was separated and MgSO_FourAfter drying, the solvent was distilled off, and the residue was purified by column chromatography (EtOAc-MeOH = 98: 2) to give 140 mg of the title compound as a light brown amorphous solid.
¹H-NMR (CDCl_Three) δ (ppm): 8.09 (1H, m), 7.75 (1H, s), 7.63 (1H, d, J = 1.1Hz), 7.56 (1H, d, J = 9.3Hz), 7.53 (1H, d, J = 1.1Hz), 7.47-7.37 (5H, m), 7.08 (1H, dd, J = 1.6,9.3Hz)
[0078]
Example 11
6- [2-Cyano-2- (4-fluorophenyl)] ethenyl Imidazo [1,2-a] pyridine
[0079]
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[0080]
Imidazo [1,2-a] pyridine-6-carboxaldehyde (1.02 g) and 4-fluorophenylacetonitrile (1.01 g) were dissolved in ethanol (200 ml), sodium methylate (90 mg) was added, and the mixture was stirred at 90 ° C. for 1 hour. The solvent was distilled off from the reaction solution, and the residue was purified by column chromatography (EtOAc-MeOH = 98-2) and recrystallized from EtOAc-Ether-Hexane to give the title compound as colorless crystals (yield 1.22 g). ).
m.p.:157-159°C
¹H-NMR (CDCl_Three) δ (ppm): 7.74-7.71 (1H, m), 7.71 (1H, s), 7.70 (1H, s), 7.68-7.67 (2H, m), 7.65 (2H, dd, J = 5.0, 8.7Hz) ), 7.37 (1H, s), 7.17 (2H, t, J = 8.7Hz)
[0081]
Example 12
6- [3- (4-Fluorophenyl-1H-pyrazol-4-yl] imidazo [1,2-a] pyridine
[0082]
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[0083]
3.6 ml of n-butyl lithium (1.6 mol / l: n-hexane solution) was added to 10 ml of THF in 10 ml of trimethylsilyldiazomethane (about 10% n-hexane solution) at −78 ° C., and the mixture was stirred at the same temperature for 20 minutes. A solution of 1.0 g of the compound of Example 11 in 50 ml of THF was added dropwise thereto over 20 minutes, and the mixture was stirred for 4 hours while gradually warming to room temperature. Saturated ammonium chloride solution was added and extracted with 100 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (EtOAc-MeOH = 98: 2). To this, 50 ml of ethanol, 3 ml of concentrated hydrochloric acid and 200 mg of potassium fluoride were added and heated to reflux for 0.5 hours. After cooling, the solution was made alkaline by adding a potassium carbonate solution, and ethanol was distilled off under reduced pressure, followed by extraction with 100 ml of dichloromethane. The organic layer was separated and MgSO_FourAfter drying, the solvent was distilled off, and the residue was purified by column chromatography (EtOAc-MeOH = 98: 2). Recrystallization from MeOH-EtOAc yielded 500 mg of the title compound as colorless crystals.
m.p .: 227-228 ° C
¹H-NMR (CDCl_Three) δ (ppm): 8.08 (1H, dd, J = 0.9,1.4Hz), 7.74 (1H, d, J = 1.1Hz), 7.65 (1H, d, J = 1.1Hz), 7.58 (1H, dd, J = 0.9, 9.3Hz), 7.54 (1H, s), 7.48 to 7.44 (2H, m), 7.10 to 7.04 (3H, m)
[0084]
Example 13
3-chloro-6- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine
[0085]
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[0086]
150 mg of 6- [3- (4-fluorophenyl-1H-pyrazol-4-yl] imidazo [1,2-a] pyridine is dissolved in 20 ml of methanol, 94 mg of N-chlorosuccinimide (NCS) is added, and the mixture is heated to 70 ° C. The solvent was distilled off, extracted with 50 ml of dichloromethane, and washed with saturated brine._FourThe residue was purified by column chromatography (EtOAc-MeOH = 98-2) to give 64 mg of the title compound as a pale yellow amorphous solid.
¹H-NMR (CDCl_Three) δ (ppm): 8.04 (1H, dd, J = 0.9, 1.8Hz), 7.78 (1H, s), 7.57 (1H, s), 7.56 (1H, dd, J = 0.9, 9.3Hz), 7.48- 7.44 (2H, m), 7.11 ~ 7.05 (3H, m)
[0087]
Example 14
6- [2-Cyano-2- (2-methoxyphenyl)] ethenyl Imidazo [1,2-a] pyridine
[0088]
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[0089]
Imidazo [1,2-a] pyridine-6-carboxaldehyde (1.02 g) and 2-methoxyphenylacetonitrile (1.13 g) were dissolved in ethanol (20 ml), sodium methylate (76 mg) was added, and the mixture was stirred at 90 ° C. for 8 hours. The solvent was distilled off from the reaction solution, and the residue was subjected to column chromatography (CH₂Cl₂Purification by -MeOH = 98: 2) gave the title compound as a pale yellow solid (yield 1.07 g).
m.p .: 174-176 ° C
¹H-NMR (CDCl_Three) δ (ppm): 8.84 (1H, m), 7.87 (1H, d, J = 9.3Hz), 7.76 (1H, dd, J = 9.3, 1.6Hz), 7.75 (1H, m), 7.71 (1H, s), 7.46-7.39 (2H, m), 7.45 (1H, s), 7.05 (1H, td, J = 1.1, 7.5Hz), 7.00 (1H, d, J = 8.4Hz), 3.94 (3H, s) )
[0090]
Example 15
6- [3- (2-Methoxyphenyl) -1H-pyrazole-4- yl ] Imidazo [1,2-a] pyridine
[0091]
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[0092]
3.6 ml of n-butyl lithium (1.6 mol / l: n-hexane solution) was added to 10 ml of THF in 10 ml of trimethylsilyldiazomethane (about 10% n-hexane solution) at −78 ° C., and the mixture was stirred at the same temperature for 20 minutes. To this was added dropwise a solution of 1.06 g of the compound of Example 14 in 50 ml of THF over 20 minutes, and the mixture was stirred for 2 hours while gradually warming to room temperature. Saturated ammonium chloride solution was added and extracted with 100 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. After purification by column chromatography (EtoAc only), 750 mg was taken, and 50 ml of ethanol, 2 ml of concentrated hydrochloric acid and 120 mg of potassium fluoride were added thereto and heated to reflux for 0.5 hours. After cooling, the solution was made alkaline by adding a potassium carbonate solution, and ethanol was distilled off under reduced pressure, followed by extraction with 150 ml of dichloromethane. The organic layer was separated and MgSO_FourAfter drying, the solvent was distilled off, and the residue was purified by column chromatography (EtOAc-MeOH = 98: 2) to give 170 mg of the title compound as a colorless amorphous solid.
¹H-NMR (CDCl_Three) δ (ppm): 8.20 (1H, m), 7.96 (1H, d, J = 8.4Hz), 7.76 (1H, s), 7.73 (1H, d, J = 1.8Hz), 7.60 (1H, d, J = 1.8Hz), 7.43-7.38 (2H, m), 7.24-7.23 (1H, m), 7.05 (1H, d, J = 8.4Hz), 6.95-6.91 (1H, m), 3.85 (3H, s )
[0093]
Example 16
3-chloro-6- [3- (2-methoxyphenyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine
[0094]
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[0095]
80 mg of 6- [3- (2-methoxyphenyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine is dissolved in 15 ml of methanol, and 80 mg of N-chlorosuccinimide (NCS) is added to room temperature. And stirred for 3 hours. The solvent was distilled off, extracted with 50 ml of dichloromethane and washed with saturated brine. MgSO organic layer_FourThe residue was purified by column chromatography (EtOAc-MeOH = 98: 2) to give 50 mg of the title compound as a pale yellow amorphous solid.
¹H-NMR (CDCl_Three) δ (ppm): 8.10 (1H, dd, J = 0.9, 1.6Hz), 7.78 (1H, s), 7.67 (1H, d, J = 8.8Hz), 7.59 (1H, s), 7.38 (1H, ddd, J = 8.4, 7.5, 1.6Hz), 7.27-7.24 (2H, m), 7.04 (1H, d, J = 8.2Hz), 6.91 (1H, td, J = 1.1, 7.5Hz), 3.87 (3H , s)
[0096]
Example 17
6- [2-Cyano-2- (2-fluorophenyl)] ethenyl Imidazo [1,2-a] pyridine
[0097]
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[0098]
Imidazo [1,2-a] pyridine-6-carboxaldehyde (1.02 g) and 2-fluorophenylacetonitrile (1.01 g) were dissolved in ethanol (20 ml), sodium methylate (90 mg) was added, and the mixture was stirred at 80 ° C. for 7 hours. The solvent was distilled off from the reaction mixture, and the residue was purified by column chromatography (EtOAc-MeOH = 98: 2) to give the title compound as a pale yellow solid (yield 930 mg).
m.p .: 161-162 ° C
¹H-NMR (CDCl_Three) δ (ppm): 8.75 (1H, dd, J = 0.9, 1.6Hz), 7.76 (1H, dd, J = 1.6, 9.3Hz), 7.72 (1H, d, J = 0.7Hz), 7.72 to 7.68 ( 1H, m), 7.68 (1H, d, J = 0.7Hz), 7.61 (1H, td, J = 7.8,1.8Hz), 7.53 (1H, s), 7.44-7.37 (1H, m), 7.29-7.17 (2H, m)
[0099]
Example 18
6- [3- (2-Fluorophenyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine
[0100]
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[0101]
3.6 ml of n-butyl lithium (1.6 mol / l: n-hexane solution) was added to 10 ml of THF in 10 ml of trimethylsilyldiazomethane (about 10% n-hexane solution) at −78 ° C., and the mixture was stirred at the same temperature for 20 minutes. A solution of 0.9 g of the compound of Example 17 in 50 ml of THF was added dropwise thereto over 20 minutes, and the mixture was stirred for 2.5 hours while gradually raising the temperature. Saturated ammonium chloride solution was added and extracted with 90 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. After purification by column chromatography (EtOAc-MeOH = 98: 2), 1.19 g was taken, 50 ml of ethanol, 2 ml of concentrated hydrochloric acid and 120 mg of potassium fluoride were added thereto, and the mixture was heated to reflux for 0.5 hours. After cooling, the solution was made alkaline by adding a potassium carbonate solution, and ethanol was distilled off under reduced pressure, followed by extraction with 100 ml of dichloromethane. The organic layer was separated and MgSO_FourAfter drying, the solvent was distilled off, and the residue was purified by column chromatography (EtOAc-MeOH = 97: 3). Recrystallization from EtOAc-n-Hexane gave 140 mg of the title compound as a colorless powder.
m.p .: 226-228 ° C
¹H-NMR (CDCl_Three) δ (ppm): 8.08 (1H, m), 7.78 (1H, s), 7.63 (1H, d, J = 0.9Hz), 7.56 (1H, d, J = 9.2Hz), 7.53 (1H, d, J = 0.9Hz), 7.41-7.36 (2H, m), 7.20-7.13 (2H, m), 7.06 (1H, dd, J = 1.6,9.2Hz)
[0102]
Example 19
3-Chloro-6- [3- (2-fluorophenyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine
[0103]
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[0104]
170 mg of 6- [3- (2-fluorophenyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine is dissolved in 20 ml of methanol, 100 mg of N-chlorosuccinimide (NCS) is added, and the mixture is brought to room temperature. And stirred for 4 hours. The solvent was distilled off, extracted with 50 ml of dichloromethane and washed with saturated brine. MgSO organic layer_FourThe residue was purified by column chromatography (EtOAc-MeOH = 98: 2) to give 100 mg of the title compound as a pale yellow solid.
m.p .: 188-189 ° C
¹H-NMR (CDCl_Three) δ (ppm): 8.02 (1H, m), 7.84 (1H, s), 7.56 (1H, s), 7.55 (1H, d, J = 8.4Hz), 7.44 to 7.38 (2H, m), 7.21 to 7.15 (2H, m), 7.12 (1H, dd, J = 1.6,8.4Hz)
[0105]
Example 20
6- [2-Cyano-2- (4-methoxyphenyl)] ethenyl Imidazo [1,2-a] pyridine
[0106]
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[0107]
Imidazo [1,2-a] pyridine-6-carboxaldehyde (1.02 g) and 4-methoxyphenylacetonitrile (1.13 g) were dissolved in ethanol (20 ml), sodium methylate (120 mg) was added, and the mixture was stirred at 80 ° C. for 1 hour. After cooling, the precipitated crystals were collected by filtration, washed with cold ethanol and dried to give the title compound as pale yellow crystals (yield 1.18 g).
m.p .: 125-127 ° C
¹H-NMR (CDCl_Three) δ (ppm): 8.73 (1H, s), 7.70 to 7.66 (3H, m), 7.61 (2H, d, J = 8.2Hz), 7.32 (1H, s), 7.26 (1H, d, J = 1.1) Hz), 6.98 (2H, d, J = 8.2Hz), 3.87 (3H, s)
[0108]
Example 21
6- [3- (4-Methoxyphenyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine
[0109]
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[0110]
3.6 ml of n-butyl lithium (1.6 mol / l: n-hexane solution) was added to 10 ml of THF in 10 ml of trimethylsilyldiazomethane (about 10% n-hexane solution) at −78 ° C., and the mixture was stirred at the same temperature for 20 minutes. A solution of 1.06 g of the compound of Example 20 in 50 ml of THF was added dropwise thereto over 20 minutes, and the mixture was stirred for 5 hours while gradually warming to room temperature. Saturated ammonium chloride solution was added and extracted with 150 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. After purification by column chromatography (EtOAc-MeOH = 98: 2), 800 mg was taken, 50 ml of ethanol, 1.4 ml of concentrated hydrochloric acid and 80 mg of potassium fluoride were added thereto, and the mixture was heated to reflux for 0.5 hours. After cooling, the solution was made alkaline by adding a potassium carbonate solution, and ethanol was distilled off under reduced pressure, followed by extraction with 100 ml of dichloromethane. The organic layer was separated and MgSO_FourAfter drying, the solvent was distilled off, and the residue was purified by column chromatography (EtOAc-MeOH = 98: 2) to give 340 mg of the title compound as a pale yellow solid.
m.p .: 226-227 ° C
¹H-NMR (CDCl_Three) δ (ppm): 8.09 (1H, m), 7.72 (1H, d, J = 1.1Hz), 7.63 (1H, d, J = 1.1Hz), 7.56 (1H, dd, J = 9.3, 0.7Hz) , 7.53 (1H, s), 7.38 (2H, d, J = 8.2Hz), 7.09 (1H, dd, J = 9.3, 1.6Hz), 6.91 (2H, d, J = 8.2Hz), 3.84 (3H, s)
[0111]
Example 22
3-chloro-6- [3- (4-methoxyphenyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine
[0112]
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[0113]
300 mg of 6- [3- (4-methoxyphenyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine is dissolved in 50 ml of methanol, 200 mg of N-chlorosuccinimide (NCS) is added, and the mixture is brought to room temperature. And stirred for 3 hours. The solvent was distilled off, extracted with 100 ml of dichloromethane and washed with saturated brine. MgSO organic layer_FourThe residue was purified by column chromatography (EtOAc-MeOH = 98: 2) to give 150 mg of the title compound as pale yellow crystals.
m.p .: 208-210 ° C
¹H-NMR (CDCl_Three) δ (ppm): 8.05 (1H, dd, J = 0.9, 1.6Hz), 7.77 (1H, s), 7.56 (1H, s), 7.53 (1H, dd, J = 0.9, 9.3Hz), 7.37 ( 2H, d, J = 8.9Hz), 7.12 (1H, dd, J = 1.6, 9.3Hz), 6.92 (2H, d, J = 8.9Hz), 3.84 (3H, s)
[0114]
Production Example 1
1-triphenylmethylbenzimidazole 6-carboxylic acid methyl ester
[0115]
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[0116]
95.0 g of benzimidazole-5-carboxylic acid was added to 800 ml of methanol, 86.1 g of concentrated sulfuric acid was further added, and the mixture was heated to reflux for 16 hours. After cooling, an aqueous potassium carbonate solution was added for neutralization, and methanol was distilled off under reduced pressure. The resulting precipitate was collected by filtration and dried at 100 ° C. to obtain benzimidazole-5-carboxylic acid methyl ester as a brown powder (yield 103 g). This was used in the next reaction without purification.
52.85 g of benzimidazole 5-carboxylic acid methyl ester was suspended in 260 ml of DMF, 13.2 g of sodium hydride was added, and the mixture was stirred for 1 hour. 100 g of triphenylmethyl chloride was added and stirred at room temperature for 1.5 hours. The reaction solution was added to 4 l of ice water, and the resulting precipitate was collected by filtration and dried. To the obtained powder, 1.2 l of methanol was added and stirred, and an insoluble solid was collected by filtration. CH₂Cl₂Recrystallization from -MeOH gave the title compound as colorless crystals (yield 65.8 g).
m.p .: 171-173 ° C
MS: 419 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 8.08 (1H, s, H-2), 7.78 to 7.76 (2H, m), 7.42 to 7.37 (9H, m), 7.17 to 7.12 (7H, m), 3.69 (3H, s, Me)
[0117]
Production Example 2
1-triphenylmethyl-6-hydroxymethyl Benzimidazole
[0118]
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[0119]
89.74 g of the compound of Production Example 1 was dissolved in 1000 ml of THF, and lithium aluminum hydride (LiAlH) was added under a nitrogen stream._Four) The solution was added dropwise to 20.3 g of a THF 100 ml solution over 1 hour and further stirred at room temperature for 3 hours. Saturated ammonium chloride (NH_FourCl) aqueous solution (54 ml) was carefully added, filtered and the solvent was distilled off to give the title compound as a colorless amorphous solid (yield 75.0 g).
¹H-NMR (CDCl_Three) δ (ppm): 7.93 (1H, s, H-2), 7.75 (1H, d, J = 8.2Hz, H-4), 7.34-7.16 (16H, m, φ, H-7), 6.45 ( 1H, d, J = 0.7Hz, H-7), 4.46 (2H, s, CH₂)
[0120]
Production Example 3
1-triphenylmethyl-6-formyl Benzimidazole
[0121]
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[0122]
75.0 g of the compound of Production Example 2 is dissolved in 1000 ml of dichloromethane, and activated manganese dioxide (MnO₂) 225 g was added and stirred at room temperature for 1 day. 100 ml of methanol was added, filtered and the residue was washed with 1 l of dichloromethane-methanol (5: 1). The obtained solutions were combined, the solvent was distilled off, and recrystallization from ethanol gave the title compound as colorless crystals (yield 48.5 g).
m.p .: 199-200 ° C
¹H-NMR (CDCl_Three) δ (ppm): 9.66 (1H, s, CHO), 8.10 (1H, s, H-2), 7.88 (1H, d, J = 8.4Hz, H-4), 7.74 (1H, dd, J = 1.5,8.4Hz, H-5), 7.36-7.16 (15H, m, φ), 6.95 (1H, m, H-7)
[0123]
Example 23
1-triphenylmethyl-6- [2-cyano-2- (4-fluorophenyl) ethenyl] benzimidazole
[0124]
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[0125]
53.1 g of the compound of Production Example 3 was added to 4-fluorophenylacetonitrile (p-F-C₆H_FiveCH₂CN) 18.5 g was suspended in ethanol, 28% sodium methylate-methanol solution 6.6 ml was added, and the mixture was heated to reflux for 2 hours. After cooling, the resulting precipitate was collected by filtration and washed with cold ethanol to give the title compound as pale yellow crystals (yield 52.4 g).
m.p .: 210-212 ° C
¹H-NMR (CDCl_Three) δ (ppm): 8.01 (1H, s, H-2), 7.84 (1H, d, J = 8.6Hz, H-4), 7.81 (1H, dd, J = 8.6,1.6Hz, H-5) , 7.53 to 7.50 (2H, m, φ), 7.36 to 7.21 (15H, m, Tr), 7.16 (1H, s, CH), 7.07 (2H, dd, J = 8.8, 8.6Hz), 7.01 (1H, m, H-7)
[0126]
Example 24
1-triphenylmethyl-6- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0127]
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[0128]
25 ml of n-butyllithium (1.6 mol / l: n-hexane solution) was added to 34 ml of THF in 34 ml of trimethylsilyldiazomethane (about 10% n-hexane solution) at −78 ° C. and stirred at the same temperature for 20 minutes. To this, 7.22 g of the compound of Example 23 in 80 ml of THF was added dropwise over 20 minutes, and the mixture was stirred for 4 hours while gradually warming to room temperature. Saturated ammonium chloride solution was added and extracted with 200 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 50 ml of THF, 50 ml of 1M tetrabutylammonium fluoride in THF was added thereto, and the mixture was stirred overnight at room temperature. When 100 ml of water was added to the reaction solution and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and recrystallized from dichloromethane to give the title compound as colorless crystals (yield 6.92 g).
m.p .: 224-226 ° C
¹H-NMR (CDCl_Three) δ (ppm): 7.88 (1H, s, H-2), 7.70 (1H, dd, J = 0.7, 8.4Hz, H-4), 7.33-7.24 (10H, m), 7.19 (2H, dd, J = 8.8, 5.3Hz, φ-F), 7.13-7.09 (7H, m), 6.87 (2H, t, J = 8.8Hz, φ-F), 6.38 (1H, m, H-7)
[0129]
Example 25
1-triphenylmethyl-6- [1- (2-trimethylsilylethoxymethyl) -3- (4-fluorophenyl) -pyrazol-4-yl] benzimidazole 1-triphenylmethyl-6- [1- (2- Trimethylsilylethoxymethyl) -5- (4-fluorophenyl) -pyrazol-4-yl] benzimidazole
[0130]
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[0131]
6.92 g of the compound of Example 24 was suspended in 100 ml of DMF, 637 mg of sodium hydride (60% in oil) was added, and the mixture was stirred for 40 minutes to obtain a clear solution. To this was added 2.82 ml of trimethylsilylethoxymethyl chloride, and the mixture was stirred at room temperature for 3 hours. 300 ml of water was added and extracted with 300 ml of dichloromethane. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography eluting with 1% methanol-dichloromethane to give an approximately 1: 1 mixture of the title compounds as an candy (yield 8.13 g).
¹H-NMR (CDCl_Three) δ (ppm): 7.91 (0.5H, s), 7.85 (0.5H, s), 7.73 (0.5H, d, J = 8.4Hz), 7.66 (0.5H, d, J = 8.4Hz), 7.39 7.10 (19H, m), 7.10 ~ 7.05 (1H, m), 6.95 (1H, t, J = 8.6Hz), 6.85 (1H, t, J = 8.8Hz), 6.40 (0.5H, d, J = 1.5 Hz), 6.35 (0.5H, d, J = 1.5Hz), 5.40 (1H, s), 5.19 (1H, s), 3.68 to 3.63 (2H, m), 0.97 to 0.89 (2H, m), 0.03 to 0.00 (9H, m)
[0132]
Example 26
5- [1- (2-Trimethylsilylethoxymethyl) -3- (4-fluorophenyl) -pyrazol-4-yl] benzimidazole
5- [1- (2-Trimethylsilylethoxymethyl) -5- (4-fluorophenyl) -pyrazol-4-yl] benzimidazole
[0133]
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[0134]
8.13 g of the compound of Example 25 was dissolved in 50 ml of methanol and 13 ml of 1N hydrochloric acid was added. This solution was added to a 10 ml solution of 2.8 g of 10% palladium-carbon (Pd-C) in methanol and stirred at 50 ° C. for 1 hour under a hydrogen stream. After cooling, the reaction solution was filtered, and saturated multistory water was added to the filtrate for neutralization, and the solvent was distilled off. The residue was subjected to column chromatography and eluted with 2% methanol-dichloromethane to give an approximately 1: 1 mixture of the title compounds as a colorless amorphous solid (yield 4.16 g).
¹H-NMR (DMSO-d₆) δ (ppm): 12.5 (1H, br), 8.26 (0.5H, s), 8.21 (0.5H, s), 8.17 (0.5H, s), 7.95 (0.5H, s), 7.52 to 7.47 (3H) , m), 7.38 (1H, t, J = 9.0Hz), 7.21 (1H, t, J = 9.0Hz), 7.12 (0.5H, dd, J = 1.6, 8.4Hz), 7.08 (0.5H, dd, J = 1.6, 8.4Hz), 5.52 (1H, s), 5.35 (1H, s), 3.73 (1H, dd, J = 7.9, 8.1Hz), 3.61 (1H, dd, J = 8.1, 8.1Hz), 0.95 (1H, dd, J = 7.9,8.1Hz), 0.87 (1H, dd, J = 7.9,8.1Hz), 0.05 to 0.0 (9H, m)
[0135]
Example 27
5- [2-Cyano-2- (4-fluorophenyl) ethenyl] -1H-benzimidazole
[0136]
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[0137]
50.0 g of the compound of Example 23 was suspended in 100 ml of methanol, 11.43 g of pyridine hydrochloride was added, and the mixture was stirred at 70 ° C. for 1.5 hours. After cooling, the reaction was filtered, washed with ethanol, then saturated aqueous sodium bicarbonate ice and dried to give the title compound as a pale yellow solid.
m.p .: 254-255 ° C
¹H-NMR (DMSO-d₆) δ (ppm): 8.94 (1H, s), 8.34 (1H, br, s), 8.18 (1H, s), 7.93 (1H, dd, J = 1.1, 8.6Hz), 7.86-7.80 (3H, m ), 7.37 (2H, t, J = 8.9Hz)
[0138]
Example 28
1-methyl-6- [2-cyano-2- (4-fluorophenyl)] ethenyl Benzimidazole
1-methyl-5- [2-cyano-2- (4-fluorophenyl)] ethenyl Benzimidazole
[0139]
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[0140]
350 mg of the compound of Example 27 was dissolved in 10 ml of DMF, 100 mg of sodium hydride (60% in oil) was added, and the mixture was stirred at room temperature for 45 minutes. To this was added 192 mg of methyl iodide, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with 100 ml of dichloromethane. After evaporation of the solvent, the residue was subjected to column chromatography (CH₂Cl₂Purification by -MeOH = 9: 1) gave a mixture of the title compounds as a brown amorphous solid (yield 200 mg).
¹H-NMR (CDCl_Three) δ (ppm): 8.26 (0.4H, m), 8.21 (0.6H, m), 8.14 (0.6H, dd, J = 1.8, 8.4Hz), 8.03 (0.4H, s), 7.99 (0.6H, s), 7.90 (0.4H, m), 7.75-7.70 (2H, m), 7.69-7.66 (0.4H, m), 7.68-7.66 (1H, m), 7.53 (0.6H, d, J = 8.4Hz ), 7.23-7.17 (2H, m), 3.96 (1.2H, s, Me), 3.93 (1.8H, s, Me)
[0141]
Example 29
1-methyl-5 or 6- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0142]
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[0143]
0.68 ml of n-butyllithium (1.6 mol / l: hexane solution) was added to a 1.85 ml THF solution containing 1.85 ml of trimethylsilyldiazomethane (about 10% n-hexane solution) at −78 ° C., and the mixture was stirred at the same temperature for 20 minutes. A solution of the compound of Example 28 (200 mg) in THF (10 ml) was added dropwise thereto over 20 minutes, and the mixture was stirred for 4 hours while gradually raising the temperature. Saturated ammonium chloride solution was added and extracted with 100 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 10 ml of THF, 5 ml of 1M tetrabutylammonium fluoride in THF was added thereto, and the mixture was stirred at room temperature for 2 hours. When 50 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CH₂Cl₂-MeOH = 98: 2)
A 6-pyrazole compound is obtained from the first fraction, and CH₂Cl₂Further recrystallization gave 36 mg as colorless crystals. From the second fraction, a 5-pyrazole compound was obtained as a light brown amorphous solid (yield 51 mg).
m.p .: 230-231 ° C
6-Pyrazole body
MS: 293 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 13.05 (1H, br), 8.14 (1H, s), 7.54 (1H, d, J = 8.4Hz), 7.46 (1H, d, J = 1.6Hz), 7.45 to 7.41 (2H, m), 7.20-7.10 (2H, m), 7.02 (1H, dd, J = 8.4, 1.6Hz), 3.75 (3H, s)
5-pyrazole body
MS: 293 (MH⁺)
¹H-NMR (CDCl_Three) δ (ppm): 7.87 (1H, s), 7.74 (1H, d, J = 1.6Hz), 7.42 (2H, dd, J = 8.8, 5.4Hz), 7.32 (1H, d, J = 8.2Hz) , 7.21 (1H, dd, J = 8.2,1.6Hz), 7.12 (1H, s), 6.98 (2H, dd, J = 8.8,8.8Hz), 3.85 (3H, s)
[0144]
Example 30
1-ethyl-6- [2-cyano-2- (4-fluorophenyl)] ethenyl Benzimidazole
1-ethyl-5- [2-cyano-2- (4-fluorophenyl)] ethenyl Benzimidazole
[0145]
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[0146]
700 mg of the compound of Example 27 was suspended in THF, 160 mg of sodium hydride (60% in oil) was added, and the mixture was stirred at room temperature for 45 minutes. To this was added 833 mg of ethyl iodide, and after stirring at 50 ° C. for 4 hours, 416 mg was further added, and the mixture was further stirred at the same temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with 100 ml of dichloromethane. After evaporation of the solvent, the residue was subjected to column chromatography (CH₂Cl₂Purification by -MeOH = 99: 1) gave a mixture of the title compounds as a brown amorphous solid (yield 580 mg).
¹H-NMR (CDCl_Three) δ (ppm): 8.26 (1 / 3H, m), 8.16 (2 / 3H, m), 8.09 (1 / 3H, m), 8.07 (1 / 3H, m), 8.03 (1 / 3H, s) , 8.00 (2 / 3H, s), 7.85 (1 / 3H, dd, J = 0.5,8.4Hz), 7.70 ~ 7.66 (2H, m, φ), 7.63 (1 / 3H, s), 7.62 (2 / 3H, s), 7.60 (2 / 3H, dd, J = 1.8, 8.4Hz), 7.50 (2 / 3H, d, J = 8.4Hz), 7.18 to 7.13 (2H, m, φ)
[0147]
Example 31
1-ethyl-6- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
1-ethyl-5- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0148]
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[0149]
1.78 ml of n-butyllithium (1.6 mol / l: n-hexane solution) was added at −78 ° C. to 4.83 ml of THF solution of 4.83 ml of trimethylsilyldiazomethane (about 10% n-hexane solution) and stirred at the same temperature for 20 minutes. . A solution of the compound of Example 30 in 550 mg in THF (10 ml) was added dropwise over 20 minutes, and the mixture was stirred for 2 hours while gradually warming. Saturated ammonium chloride solution was added and extracted with 100 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 15 ml of THF, 5 ml of 1M tetrabutylammonium fluoride in THF was added thereto, and the mixture was stirred at room temperature for 2.5 hours. When 50 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CH₂Cl₂-MeOH = 99: 1 followed by purification at 98: 2).
From the fraction showing a high Rf value, a 6-pyrazole form was obtained, and from the fraction showing a low Rf value, a 5-pyrazole form was obtained as a brown amorphous solid, respectively.
6-Pyrazole body
¹H-NMR (CDCl_Three) δ (ppm): 7.90 (1H, s), 7.76 (1H, s), 7.75 (1H, dd, J = 0.7, 8.4Hz), 7.45 (2H, dd, J = 8.7, 5.3Hz), 7.27 ( 1H, s), 7.23 (1H, dd, J = 1.6,8.4Hz), 7.03 (2H, t, J = 8.7Hz), 4.13 (2H, q, J = 7.5Hz), 1.45 (3H, t, J = 7.5Hz)
5-pyrazole body
¹H-NMR (CDCl_Three) δ (ppm): 7.93 (1H, s), 7.75 (1H, m), 7.73 (1H, s), 7.44 (2H, dd, J = 8.7, 5.3Hz), 7.34 (1H, dd, J = 8.4) 0.5Hz), 7.21 (1H, dd, J = 8.4,1.5Hz), 7.01 (2H, dd, J = 8.7,8.7Hz), 4.24 (2H, q, J = 7.3Hz), 1.57 (2H, t , J = 7.3Hz)
[0150]
Example 32
1-methyl-6- [2- (4-trifluoromethylphenyl) -2-cyano] ethenyl Benzimidazole
[0151]
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[0152]
160 mg of the compound of Production Example 8 and 185 mg of 4-trifluoromethylphenylacetonitrile were dissolved in 3 ml of ethanol, 0.1 ml of 28% sodium methylate in methanol was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off from the reaction solution, and the residue was subjected to column chromatography (CH₂Cl₂-MeOH = 97: 3) CH₂Cl₂Recrystallization from -n-Hex gave the title compound as a colorless powder (yield 257 mg).
m.p .: 166-168 ° C
¹H-NMR (CDCl_Three) δ (ppm): 8.26 (1H, m, H-7), 8.00 (1H, s, H-2), 7.87 (1H, d, J = 8.4Hz, H-4), 7.82 (2H, d, J = 8.2Hz, φ), 7.76 (1H, s, CH =), 7.72 (2H, d, J = 8.2Hz ,, φ), 7.67 (1H, dd, J = 1.8,8.4Hz, H-5) , 3.93 (3H, s, Me)
[0153]
Example 33
1-methyl-6- [3- (4-trifluoromethylphenyl) -1H-pyrazol-4-yl] benzimidazole
[0154]
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[0155]
1.34 ml of n-butyllithium (1.6 mol / l: hexane solution) was added to 1.8 ml of a trimethylsilyldiazomethane (about 10% n-hexane solution) in 2 ml of THF at -78 ° C. and stirred at the same temperature for 20 minutes. Thereto was added dropwise a solution of the compound of Example 32 in 250 mg of THF over 20 minutes, and the mixture was stirred for 3 hours while gradually warming to room temperature. Saturated ammonium chloride solution was added and extracted with 100 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 5 ml of THF, 1.5 ml of 1M tetrabutylammonium fluoride in THF was added thereto, and the mixture was stirred at room temperature for 2 hours. When 100 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CH₂Cl₂-MeOH = 98: 2) Recrystallization from ethyl acetate gave the title compound as colorless crystals (yield 218 mg).
m.p .: 213-215 ° C
¹H-NMR (CDCl_Three) δ (ppm): 7.89 (1H, s, H-2), 7.76 (1H, s), 7.76 (1H, dd, J = 8.4, 0.7Hz, H-4), 7.62 (2H, d, J = 8.2Hz ,, φ), 7.56 (2H, d, J = 8.2Hz, φ), 7.29 (1H, m, H-7), 7.21 (1H, dd, J = 8.4,1.6Hz, H-5), 3.77 (3H, s, Me)
[0156]
Example 34
1-methyl-6- [2-cyano-2- (2,4-difluorophenyl)] ethenyl Benzimidazole
[0157]
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[0158]
1.00 g of the compound of Production Example 8 and 966 mg of 2,4-difluorophenylacetonitrile were dissolved in 11 ml of ethanol, 0.2 ml of 28% sodium methylate in methanol was added, and the mixture was stirred for 7 hours under ice cooling. The precipitated crystals were collected by filtration, washed with cold ethanol and dried to give the title compound as colorless crystals (yield 1.02 g).
m.p.:>300℃
¹H-NMR (CDCl_Three) δ (ppm): 8.22 (1H, m, H-7), 7.98 (1H, s, H-2), 7.85 (1H, dd, J = 8.4,0.7Hz, H-4), 7.66 (1H, s), 7.62 (1H, dd, J = 8.4, 1.6Hz, H-5), 7.62 to 7.56 (1H, m, φ), 7.02 to 6.92 (2H, m, φ), 3.92 (3H, s, Me )
[0159]
Example 35
1-methyl-6- [3- (2,4-difluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0160]
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[0161]
8.95 ml of n-butyllithium (1.6 mol / l: n-hexane solution) was added to 12.2 ml of THF 12 ml solution of trimethylsilyldiazomethane (about 10% n-hexane solution) at −78 ° C. and stirred at the same temperature for 20 minutes. . A solution of the compound of Example 34 (1.51 g) in THF (50 ml) was added dropwise over 20 minutes, and the mixture was stirred for 3.5 hours while gradually warming to room temperature. Saturated ammonium chloride solution was added and extracted with 100 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 20 ml of THF, and 10.7 ml of 1M tetrabutylammonium fluoride in THF was added thereto, followed by stirring at room temperature for 5 hours. When 100 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CH₂Cl₂-MeOH = 97: 3) Recrystallization from dichloromethane gave the title compound as colorless crystals (yield 1.65 g).
m.p .: 237-238 ° C
MS: 311 (MH⁺)
¹H-NMR (CDCl_Three) δ (ppm): 7.86 (1H, s, H-2), 7.80 (1H, s), 7.71 (1H, dd, J = 8.4, 0.7Hz, H-4), 7.36-7.30 (1H, m, φ), 7.27 (1H, m, H-7), 7.17 (1H, dd, J = 8.4, 1.6Hz, H-5), 6.92 to 6.87 (1H, m, φ), 6.86 to 6.81 (1H, m , φ), 3.77 (3H, s, Me)
[0162]
Example 36
1-methyl-6- [2-cyano-2- (2-fluorophenyl) ethenyl] benzimidazole
[0163]
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[0164]
300 mg of the compound of Production Example 8 and 253 mg of 2-fluorophenylacetonitrile were dissolved in 5 ml of ethanol, 0.1 ml of 28% sodium methylate in methanol was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off from the reaction solution and extracted into 50 ml of dichloromethane. Wash with water, MgSO_FourThe residue obtained by distilling off the solvent was directly used in the next reaction.
[0165]
Example 37
1-methyl-6- [3- (2-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0166]
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[0167]
4.69 ml of n-butyllithium (1.6 mol / l: hexane solution) was added at −78 ° C. to 6.38 ml of THF 10 ml solution of trimethylsilyldiazomethane (about 10% n-hexane solution) and stirred at the same temperature for 20 minutes. A solution of the compound of Example 36 in 740 mg in THF (8 ml) was added dropwise over 20 minutes, and the mixture was stirred for 4 hours while gradually warming to room temperature. Saturated ammonium chloride solution was added and extracted with 100 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 10 ml of THF, 5 ml of 1M tetrabutylammonium fluoride in THF was added thereto, and the mixture was stirred at room temperature for 3 hours. When 100 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CH₂Cl₂-MeOH = 98: 2) Recrystallization from dichloromethane gave the title compound as colorless crystals (yield 220 mg).
m.p .: 255-257 ° C
MS: 293 (MH⁺)
¹H-NMR (CDCl_Three) δ (ppm): 7.85 (1H, s, H-2), 7.81 (1H, s), 7.72 (1H, dd, J = 8.2, 0.5Hz, H-4), 7.36 to 7.31 (2H, m, φ), 7.30 (1H, m, H-5), 7.21 (1H, dd, J = 8.2, 1.6Hz, H-5), 7.15 (1H, m, φ), 7.06 (1H, m, φ), 3.76 (3H, s, Me)
[0168]
Example 38
1-isopropyl-6- [2-cyano-2- (4-fluorophenyl)] ethenyl Benzimidazole & 1-isopropyl-5- [2-cyano-2- (4-fluorophenyl)] ethenyl Benzimidazole
[0169]
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[0170]
840 mg of the compound of Example 27 was suspended in THF, 154 mg of sodium hydride (60% in oil) was added, and the mixture was stirred at room temperature for 45 minutes. To this was added 653 mg of isopropyl iodide, and the mixture was stirred at room temperature for 3 hours. 50 ml of water was added to the reaction solution, and extracted with 100 ml of dichloromethane. The solvent was distilled off and the residue was subjected to column chromatography (CH₂Cl₂Purification by -MeOH = 99: 1) gave a mixture of the title compounds as a brown amorphous solid (yield 790 mg). This was used in the next reaction as a mixture.
¹H-NMR (CDCl_Three) δ (ppm): 8.31, 8.16 (1H, m, m), 8.10, 8.07 (1H, s, s), 8.10 to 8.07 (0.5H, m), 7.85 (0.5H, dd, J = 0.5, 8.4) Hz), 7.70 to 7.67 (2H, m), 7.63, 7.67 (1H, s, s), 7.58 (0.5H, dd, J = 1.8, 9.3Hz), 7.52 (0.5H, d, J = 8.6Hz) , 7.18 ~ 7.13 (2H, m), 4.76 ~ 4.65 (1H, m), 1.70,1.68,1.67,1.66 (6H, s, s, s, s, Me)
[0171]
Example 39
1-isopropyl-6- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
1-isopropyl-5- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0172]
Embedded image

[0173]
25 ml of n-butyllithium (1.6 mol / l, hexane solution) was added to 10 ml of THF solution of 6.62 ml of trimethylsilyldiazomethane (about 10% n-hexane solution) at −78 ° C., and the mixture was stirred at the same temperature for 20 minutes. A solution of 0.79 g of the compound of Example 38 in THF 10 ml was added dropwise thereto over 20 minutes, and the mixture was stirred for 3 hours while gradually warming to room temperature. Saturated ammonium chloride solution was added and extracted with 100 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 5 ml of THF, 3 ml of 1M tetrabutylammonium fluoride in THF was added thereto, and the mixture was stirred at room temperature for 1 hour. When 50 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CH₂Cl₂-MeOH = 99: 1 followed by 99: 2).
From the fraction showing a high Rf value, 105 mg and 194 mg of a 6-pyrazole form and a 5-pyrazole form from a fraction showing a low Rf value were obtained as pale yellow amorphous solids, respectively.
6-pyrazole
MS: 321 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 13.05 (1H, br, NH), 8.26 (1H, s), 7.56 (1H, d, J = 8.4Hz), 7.46-7.40 (3H, m), 7.24-7.10 (2H, m ), 7.08 (1H, dd, J = 8.4,1.6Hz), 4.64 to 4.57 (1H, m), 1.42 (6H, d, J = 6.8Hz)
5-pyrazole
MS: 321 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 13.00 (1H, br, NH), 8.29 (1H, s), 7.56 (1H, d, J = 8.4Hz), 7.49 (1H, m), 7.45-7.41 (2H, m), 7.22 to 7.10 (2H, m), 7.11 (1H, dd, J = 8.4,1.3Hz), 4.75 to 4.68 (1H, m), 1.50 (6H, d, J = 6.8Hz)
[0174]
Production Example 4
(2-Benzyloxyethyl ) Methyl thiomethyl ether
[0175]
Embedded image

[0176]
9.132 g of ethylene glycol monobenzyl ether was dissolved in 60 ml of dimethoxyethane, and 2.4 g of sodium hydride (60% in oil) was added under ice cooling, followed by stirring for 30 minutes. 9.0 g of sodium iodide and 5.02 ml of chloromethyl methyl sulfide were added, and the mixture was stirred at 4 ° C. for 14 hours. A sodium thiosulfate aqueous solution was added to the reaction solution, and the mixture was extracted with 200 ml of dichloromethane. MgSO_FourAfter drying, the solvent was distilled off, and the residue was purified by column chromatography (n-Hex-EtoAc = 10-1) to obtain 4.10 g of (2-benzyloxyethyl) methylthiomethyl ether as a colorless liquid. .
¹H-NMR (CDCl_Three) δ (ppm): 7.35-7.25 (5H, m), 4.70 (2H, s), 4.58 (2H, s), 3.74-3.65 (4H, m), 2.15 (3H, s)
[0177]
Production Example 5
(2-Benzyloxyethyl) chloromethyl ether
[0178]
Embedded image

[0179]
(2-Benzyloxyethyl) methylthiomethyl ether is dissolved in 41 ml of dichloromethane, and sulfenyl chloride (SO₂Cl₂) A 1.55 ml dichloromethane 10 ml solution was added dropwise and stirred for 2 hours while gradually warming to room temperature. When the solvent was distilled off, 3.78 g of the title compound was obtained as a colorless liquid. This was used in the next reaction without purification.
¹H-NMR (CDCl_Three): 7.35-7.27 (5H, m), 5.55 (2H, s), 4.57 (2H, s), 3.88-3.85 (2H, m), 3.69-3.66 (2H, m)
[0180]
Example 40
1- (2-Benzyloxyethoxymethyl) -6- [2-cyano-2- (4-fluorophenyl)] ethenyl Benzimidazole
1- (2-Benzyloxyethoxymethyl) -5- [2-cyano-2- (4-fluorophenyl)] ethenyl Benzimidazole
[0181]
Embedded image

[0182]
1.13 g of the compound of Example 27 was dissolved in 20 ml of THF, and 201 mg (60% in oil) of sodium hydride was added and stirred for 30 minutes. 1.122 g of 2-benzyloxyethoxymethyl chloride was added and stirred at room temperature for 3 hours. The solvent was distilled off and the residue was purified by column chromatography (CH2Cl2-MeOH = 98-2) to obtain 1.41 g of a mixture of the title compounds as a brown amorphous solid. This was used in the next reaction as a mixture.
¹H-NMR (CDCl_Three) δ (ppm): 8.23 to 8.19 (1H, m), 8.09 to 8.02, 7.88 to 7.86 (2H, m), 7.76 to 7.58 (4H, m), 7.38, to 7.27 (5H, m), 7.18, 7.13 (2H, m, φ-F), 5.70,5.67 (2H, s, CH2), 5.30 (s), 4.57 ~ 4.50 (m) (2H), 3.80 ~ 3.60 (4H, m)
[0183]
Example 41
1- (2-Benzyloxyethoxymethyl) -5 or 6- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0184]
Embedded image

[0185]
22 ml of n-butyllithium (1.6 mol / l: hexane solution) was added to a 30 ml THF solution of 28 ml of trimethylsilyldiazomethane (about 10% n-hexane solution) at −78 ° C. and stirred at the same temperature for 20 minutes. A solution of the compound of Example 40 (4.9 g) in THF (15 ml) was added dropwise thereto over 20 minutes, and the mixture was stirred for 3 hours while gradually warming to room temperature. Saturated ammonium chloride solution was added and extracted with 300 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 10 ml of THF, 50 ml of 1M tetrabutylammonium fluoride in THF was added thereto, and the mixture was stirred at room temperature for 3 hours. 500 ml of water was added, THF was distilled off under reduced pressure, and the resulting precipitate was collected by filtration, washed with water, dried and then subjected to column chromatography (CH₂Cl₂-MeOH = 99: 1)
From the first fraction, 1.92 g of 6-pyrazole was obtained as a brown amorphous solid, and 2.12 g of 5-pyrazole was obtained from the second fraction.
[0186]
Embedded image

[0187]
6-Pyrazole body
¹H-NMR (CDCl_Three) δ (ppm): 7.97 (1H, s, H-2), 7.74 (1H, d, J = 8.4Hz, H-5), 7.71 (1H, s), 7.45-7.40 (2H, m, φ- F), 7.43 (1H, m, H-8), 7.35-7.27 (5H, m, φ), 7.25 (1H, dd, J = 8.4,1.65Hz, H-6), 6.99 (2H, dd, J = 8.7, 8.7Hz, φ-F), 5.55 (2H, s), 4.51 (2H, s), 3.56 to 3.52 (4H, m, O, O)
[0188]
Embedded image

[0189]
5-pyrazole body
¹H-NMR (CDCl_Three) δ (ppm): 7.98 (1H, s, H-2), 7.75 (1H, m, H-5), 7.73 (1H, s), 7.47 (1H, d, J = 8.4Hz, H-8) , 7.43 (2H, dd, J = 8.7,5.4Hz, φ-F), 7.35-7.29 (5H, m, φ), 7.22 (1H, dd, J = 8.4,1.5Hz, H-7), 7.00 ( 2H, dd, J = 8.7,8.7Hz, φ-F), 5.64 (2H, s), 4.53 (2H, s), 3.63 (4H, m, O, O)
[0190]
Example 42
1- (2-hydroxyethoxymethyl) -6- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0191]
Embedded image

[0192]
Pd—C (10% wet) 230 mg was suspended in methanol 10 ml, and 1- (2-benzyloxyethoxymethyl) -6- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole 230 mg A 5 ml solution of methanol and 0.3 ml of 4N HCl / dioxane were added, and catalytic reduction was performed at normal pressure and normal temperature. The reaction solution was filtered, and the mother liquor was made alkaline by adding saturated sodium hydrogen carbonate solution, and CH.₂Cl₂Extracted with 100 ml of a THF (4: 1) mixture. MgSO organic layer_FourAfter drying, the solvent was distilled off, and recrystallization from THF gave 50 mg of the title compound as a colorless powder.
m.p .: 238-239 ° C
MS: 353 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 13.08 (1H, br, NH), 8.31 (1H, s, H-2), 7.59 (1H, dd, J = 0.5, 8.2Hz, H-5), 7.52 (1H, br, s, H-8), 7.43 (2H, dd, J = 8.9, 5.5Hz, φ), 7.22 to 7.06 (2H, m, φ), 7.10 (1H, dd, J = 8.2, 1.6Hz, H-6 ), 5.58 (2H, s, N, O), 4.65 (1H, m, OH), 3.42 to 3.33 (4H, m, O, O)
[0193]
Example 43
1- (2-hydroxyethoxymethyl) -5- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0194]
Embedded image

[0195]
Pd—C (10% wet) 330 mg was suspended in methanol 10 ml, and 1- (2-benzyloxyethoxymethyl) -5- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole 330 mg 5 ml of methanol and 0.5 ml of 4N HCl / dioxane were added, and catalytic reduction was performed under normal temperature and pressure. The reaction solution is filtered, saturated sodium bicarbonate solution is added to the mother liquor to make it alkaline, and CH₂Cl₂Extracted with 100 ml of -THF (4: 1) mixture. MgSO organic layer_FourAnd then the solvent is distilled off and CH₂Cl₂Further recrystallization gave 150 mg of the title compound as a colorless powder.
m.p .: 200-202 ° C
MS: 353 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 13.03 (1H, br, NH), 8.33 (1H, s, H-2), 7.58 (1H, d, J = 8.2Hz, H-8), 7.52 (1H, d, J = 1.3Hz, H-5), 7.43 (2H, dd, J = 8.8,5.5Hz ,, φ), 7.24 to 7.08 (2H, m, φ), 7.16 (1H, dd, J = 1.3,8.2Hz, H -7), 5.65 (2H, s, N, O), 4.68 (1H, m, OH), 3.46 to 3.42 (4H, m, O, O)
[0196]
Example 44
6- [2-Cyano-2- (3-methoxyphenyl) ethenyl] imidazo [1,2-a] pyridine
[0197]
Embedded image

[0198]
Imidazo [1,2-a] pyridine-6-carboxaldehyde 500 mg (3-methoxyphenyl) acetonitrile (527 mg) was dissolved in ethanol (10 ml), 28% sodium methylate in methanol (0.1 ml) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction solution, and the residue was subjected to column chromatography (CH₂Cl₂~ 1% MeOH in CH₂Cl₂) To give the title compound as a pale yellow amorphous solid (yield 785 mg).
¹H-NMR (DMSO-d₆) δ (ppm): 3.81 (3H, s, OCH3), 7.02 (1H, d, J = 9.0Hz, C-13), 7.29 (1H, s, C-10), 7.30 (1H, d, J = 9.0Hz, C-11), 7.43 (1H, t, J = 9.0Hz, C-12), 7.66 (1H, s, C-9), 7.73 (1H, d, J = 9.5Hz, C-7) , 7.93 (1H, d, J = 9.5Hz, C-8), 8.06 (1H, s, C-3), 8.11 (1H, s, C-2), 9.05 (1H, s, C-5)
[0199]
Example 45
5- [3- (3-Methoxyphenyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine
[0200]
Embedded image

[0201]
1.70 ml of n-butyllithium (1.6 mol / l: n-hexane solution) was added to a solution of 4.34 ml of trimethylsilyldiazomethane (approximately 10% n-hexane solution) at −78 ° C. at −78 ° C. and stirred at the same temperature for 20 minutes. . To this was added dropwise a solution of 500 mg of the compound of Example 44 in 8 ml of THF over 20 minutes, and the mixture was stirred for 1 hour while gradually raising the temperature. Saturated ammonium chloride solution was added and extracted with 30 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 10 ml of THF, and 1.1 ml of 1M tetrabutylammonium fluoride in THF was added thereto, followed by stirring at room temperature for 1 hour. When 10 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CH₂Cl₂~ CH₂Cl₂/ (CH_Three)₂Purification by C = O = 9: 1) gave the title compound as a pale yellow amorphous solid (yield 100 mg).
¹H-NMR (CDCl_Three) ： 3.75 (3H, s, OCH_Three), 6.91 (1H, dd, J = 1.6Hz, 9.0Hz, C-13), 7.02 to 7.04 (2H, m, C-10, C-12), 7.11 (1H, dd, J = 1.6Hz, 9.0 Hz, C-11), 7.30 (1H, d, J = 9.0Hz, C-7), 7.54 (1H, s, C-9), 7.57 (1H, d, J = 9.0Hz, C-8), 7.64 (1H, s, C-3), 7.74 (1H, s, C-2), 8.11 (1H, s, C-5)
[0202]
Production Example 6
5-hydroxymethyl-benzimidazole
[0203]
Embedded image

[0204]
Lithium aluminum hydride (14.051 g) was suspended in THF (150 ml), and a solution of benzimidazole-5-carboxylic acid methyl ester (32.381 g) in THF (300 ml) was added dropwise over 40 minutes. Ten minutes later, 200 ml of THF was added, and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was filtered through Celite. The solvent was distilled off under reduced pressure, and methanol and chloroform were added to the resulting residue. The mixture was filtered again through Celite, and the solvent was distilled off under reduced pressure to obtain 32.89 g of the title compound. This was used for the next reaction with crude purification.
¹H-NMR (DMSO-d₆) δ (ppm): 4.58 (2H, s), 5.02 to 5.30 (1H, br), 7.12 (1H, dd, J = 1.2, 8.4Hz), 7.49 to 7.50 (1H, m), 7.50 (1H, d) , J = 8.4Hz), 8.16 (1H, s)
[0205]
Production Example 7
1-methyl-6-hydroxymethylbenzimidazole
[0206]
Embedded image

[0207]
27.36 g of 6-hydroxymethylbenzimidazole was dissolved in 135 ml of DMF, and 7.426 g of sodium hydride (including mineral oil, content: about 60%) was added thereto, followed by stirring at room temperature for 30 minutes. Thereto was added 11.5 ml of methyl iodide at room temperature over 20 minutes, and the mixture was further stirred at room temperature for 1 hour. After adding water, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (CH₂Cl₂/ Acetone = 1/1 → 1/2 → 1/3) to give 9.87 g of the title compound as an amorphous solid.
¹H-NMR (DMSO-d₆) δ (ppm): 3.80 (3H, s), 4.60 (2H, d, J = 5.6Hz), 5.20 (1H, dt, J = 2.4, 5.6Hz), 7.14 (1H, d, J = 8.0Hz) , 7.48 (1H, br, s), 7.55 (1H, d, J = 8.0Hz), 8.11 (1H, s)
[0208]
Production Example 8
1-methyl-6-formylbenzimidazole
[0209]
Embedded image

[0210]
9.74 g of 1-methyl-6-hydroxymethylbenzimidazole was suspended in 200 ml of acetone, 30.309 g of active manganese dioxide was added, and the mixture was stirred at room temperature for 13 hours. Further, 10.080 g of active manganese dioxide was added and heated to reflux for 5 hours. The mixture was filtered through celite and silica gel, and the residue was washed with chloroform: methanol 1: 1. The filtrate was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (CHCl_Three/ MeOH = 100/1 → 50/1 → 10/1) to obtain 3.7 g of the title compound.
¹H-NMR (CDCl_Three) ： 3.94 (3H, s), 7.84 (1H, dd, J = 1.4,8.0Hz), 7.92 (1H, d, J = 8.0Hz), 8.00 (1H, br, s), 8.05 (1H, s) , 10.12 (1H, s)
[0211]
Example 46
1-methyl-6- [2-cyano-2- (4-nitrophenyl) ethenyl] Benzimidar
[0212]
Embedded image

[0213]
336 mg of the compound of Production Example 8 and 348 mg of (4-nitrophenyl) acetonitrile were dissolved in 10 ml of ethanol, 1 ml of 28% sodium methylate in methanol was added, and the mixture was stirred at room temperature for 1 hour. The folded crystals were collected by filtration, washed with cold ethanol and dried to give the title compound as dark green crystals (yield 580 mg (EtOH-IPE)).
m.p .: 249-251 ° C
¹H-NMR (CDCl_Three) δ (ppm): 3.96 (3H, s, -CH3), 7.71 (1H, dd, J = 1.6Hz, 8.4Hz, C-7), 7.85, (1H, s, C-9), 7.88 ( 2H, d, J = 8.8Hz, C10, C13), 7.89 (1H, d, J = 8.4Hz, C-8), 8.03 (1H, s, C-5), 8.30 (1H, s, C-2 ), 8.33 (2H, d, J = 8.8Hz, C11, C12)
[0214]
Example 47
1-methyl-6- [3- (4-nitrophenyl) -1H-pyrazol-4-yl] benzimidazole
[0215]
Embedded image

[0216]
5.6 ml of n-butyllithium (1.6 mol / l: hexane solution) was added to 9 ml of THF in 4.5 ml of trimethylsilyldiazomethane (about 10% n-hexane solution) at −78 ° C. and stirred at the same temperature for 20 minutes. A solution of the compound of Example 46 (570 mg) in THF (30 ml) was added dropwise over 20 minutes, and the mixture was stirred for 4 hours while gradually warming to room temperature. Saturated ammonium chloride solution was added and extracted with 30 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 2 ml of THF, and 2.5 ml of 1M tetrabutylammonium fluoride in THF was added thereto, followed by stirring at room temperature for 1 hour. When 10 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CH₂Cl₂~ 1% MeOH in CH₂Cl₂). CH₂Cl₂Recrystallization from -IPE gave the title compound as pale yellow crystals (yield 250 mg).
m.p .: 244-247 ° C
¹H-NMR (DMSO-d₆) δ (ppm) ： 3.80 (3H, s, -CH_Three), 7.07 (1H, d, J = 8.2Hz, C7), 7.54 (1H, s, C-5), 7.61 (1H, d, J = 8.2Hz, C8), 7.71 (2H, d, J = 8.4 Hz, C10, C12), 8.05 (1H, s, C2), 8.17-8.19 (2H, m, C11, C13), 8.20 (1H, s, C9), 13.41 (1H, br, s, NH)
[0217]
Example 48
1-methyl-6- [3- (4-aminophenyl) -1H-pyrazol-4-yl] benzimidazole
[0218]
[Chemical Formula 86]

[0219]
25 mg of the compound of Example 47 was dissolved in 3 ml of methanol, 0.2 ml of 1N HCl 10% Pd-C 46 mg was added, the inside of the system was replaced with hydrogen, and the mixture was stirred at room temperature and normal pressure for 1 hour. The reaction solution was filtered through Celite, and the filtrate was distilled off under reduced pressure. The residue was diluted with 5 ml of water and extracted with 15 ml of ethyl acetate. Was washed with aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as pale yellow crystals (yield 13 mg).
m.p.:145-147°C
¹H-NMR (CDCl_Three) δ (ppm): 3.79 (3H, s, CH3), 6.65 (2H, d, J = 8.6Hz, C10, C12), 7.23 (2H, d, J = 8.6Hz, C11, C13), 7.24 to 7.25 (1H, m, C7), 7.35 (1H, s, C5), 7.71 (1H, d, J = 8.4Hz, C8), 7.72 (1H, s, C2), 7.85 (1H, s, C9)
[0220]
Example 49
1-methyl-6- [2-cyano-2- (3,4-dimethoxyphenyl) ethenyl] Benzimidar
[0221]
Embedded image

[0222]
500 mg of the compound of Production Example 8 and 500 mg of (3,4-dimethoxyphenyl) acetonitrile were dissolved in 7 ml of ethanol, 0.2 ml of 28% sodium methylate in methanol was added, and the mixture was stirred at room temperature for 3 hours. The folded crystals were collected by filtration, washed with cold ethanol and dried to give the title compound as milky white crystals (yield 825 mg).
m.p .: 175-177 ° C
¹H-NMR (CDCl_Three) δ (ppm): 3.93 (3H, s, CH_Three), 3.95 (3H, s, CH_Three), 3.99 (3H, s, CH_Three), 6.94 (1H, d, J = 8.6Hz, C11), 7.18 (1H, d, J = 2.2Hz, C12), 7.29 (1H, dd, J = 2.2Hz, 8.6Hz, C10), 7.59 (1H , s, C9), 7.63 (1H, dd, J = 1.7Hz, 8.4Hz, C7), 7.84 (1H, d, J = 8.4Hz, C8), 7.97 (1H, s, C2), 8.21 (1H, d, J = 1.7Hz, C5)
[0223]
Example 50
1-methyl-6- [3- (3,4-dimethoxyphenyl) -1H-pyrazol-4-yl] benzimidazole
[0224]
Embedded image

[0225]
4.7 ml of n-butyllithium (1.6 mol / l; hexane solution) was added to a 9 ml THF solution of 5.9 ml of trimethylsilyldiazomethane (about 10% n-hexane solution) at −78 ° C., and the mixture was stirred at the same temperature for 20 minutes. A solution of the compound of Example 49 in 10 mg of THF in 10 ml was added dropwise thereto over 20 minutes, and the mixture was stirred for 2 hours while gradually raising the temperature. Saturated ammonium chloride solution was added and extracted with 50 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 10 ml of THF, 5 ml of 1M tetrabutylammonium fluoride in THF was added thereto, and the mixture was stirred at room temperature for 1 hour. When 20 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CH₂Cl₂~ 1% MeOH in CH₂Cl₂). CH₂Cl₂Further recrystallization gave the title compound as pale yellow crystals (yield 390 mg).
m.p.:215-218°C
¹H-NMR (CDCl_Three) δ (ppm): 3.66 (3H, s, CH_Three), 3.79 (3H, s, CH_Three), 3.89 (3H, s, CH_Three), 6.83 (1H, d, J = 8.2Hz, C11), 6.99 (1H, d, J = 2.0Hz, C10), 7.03 (1H, dd, J = 2.0Hz, 8.2Hz, C12), 7.27 (1H , dd, J = 2.2Hz, 8.4Hz, C7), 7.35 (1H, d, J = 2.2Hz, C5), 7.73 (1H, d, J = 8.4Hz, C8), 7.76 (1H, s, C2) , 7.86 (1H, s, C9)
[0226]
Production Example 9
Methyl [2-acetyl-3- (N, N-dimethylamino)] acrylate
[0227]
Embedded image

[0228]
11 g of methyl acetoacetate was dissolved in 100 ml of N, N-dimethylformamide, 27 ml of N, N-dimethylformamide dimethylacetal was added, and the mixture was heated at 100 ° C. for 2 hours. N, N-dimethylformamide was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (CH₂Cl₂~ 1% MeOH in CH₂Cl₂) Purification gave the title compound as a brown oil (yield 11.2 g).
¹H-NMR (CDCl_Three) δ (ppm): 2.32 (3H, s), 2.88 (3H, s), 2.97 (3H, s), 3.76 (3H, s), 7.70 (0.7H, s), 8.01 (0.3H, s)
[0229]
Production Example 10
Methyl-3-methylpyrazole-4-carboxylate
[0230]
Embedded image

[0231]
11 g of methyl [2-acetyl-3- (N, N-dimethylamino)] acrylate was dissolved in 100 ml of ethanol, 6.4 g of hydrazine monohydrate was added, and the mixture was heated at 80 ° C. for 2 hours. The reaction mixture was evaporated under reduced pressure, the residue was dissolved in 200 ml of ethyl acetate, washed with ice and saturated brine, dried over magnesium sulfate, and the solvent was evaporated to give the title compound as a pale yellow amorphous solid (yield). 5.8g).
¹H-NMR (CDCl_Three): 2.57 (3H, s), 3.84 (3H, s), 7.97 (1H, s)
[0232]
Example 51
2- [1- (2-Trimethylsilylethoxymethyl) -3-methyl-pyrazol-4-yl] -6-hydroxypurine
2- [1- (2-Trimethylsilylethoxymethyl) -5-methyl-pyrazol-4-yl] -6-hydroxypurine
[0233]
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[0234]
3 g of methyl-3-methylpyrazole-4-carboxylate was dissolved in 30 ml of N, N-dimethylformamide, 857 mg of sodium hydride (60% in mineral oil) was added, and the mixture was stirred for 30 minutes under ice cooling. Next, 3.9 g of 2- (trimethylsilyl) ethoxymethyl chloride was added and stirred at room temperature for 30 minutes. 40 ml of water and 200 ml of ethyl acetate were added to the reaction solution, the organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was added with ethanol 60 ml, H₂Dissolved in 20 ml of O, added 1.2 g of NaOH, and heated to reflux for 40 minutes. The reaction mixture was evaporated under reduced pressure, 30 ml of water and 200 ml of ethyl acetate were added, and the aqueous layer was acidified with 1N HCl. The aqueous layer was extracted with 200 ml of ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated to obtain 4.81 g of a white solid. 2.5 g of this was dissolved in 25 ml of toluene, 1.3 g of thionyl chloride was added, and the mixture was heated at 60 ° C. for 40 minutes. The solvent was distilled off, 20 ml of pyridine, 2.1 g of 4-amino-5-imidazolecarboxamide hydrochloride and 36 mg of 4,4-dimethylaminopyridine were added, and the mixture was stirred at 60 ° C. for 1 hour. When 120 ml of water was added dropwise to the reaction solution, 2.9 g of a white solid was obtained. 1g of this is H₂The suspension was suspended in 40 ml of O and 10 ml of ethanol, 1.1 g of potassium bicarbonate was added, and the mixture was heated to reflux for 23 hours. Ethanol in the reaction solution was distilled off, 1 ml of acetic acid was added, extracted with 30 ml of methylene chloride, washed with water and dried.₂Cl₂~ 2% MeOH in CH₂Cl₂) To obtain 700 mg of a white amorphous solid.
MS: 347 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 0.01 to 0.07 (9H, s), 0.90 (2H, dd, J = 1.8Hz, 8.1Hz), 2.74 (3H, s), 3.60 (2H, dd, J = 1.8Hz, 8.1Hz) ), 5.42 (0.4H, s), 5.53 (0.6H, s), 8.13 (1H, br, s), 8.28 (1H, s), 8.66 (1H, s)
[0235]
Example 52
2- [3-Methyl-1H-pyrazol-4-yl] -6-hydroxypurine
[0236]
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[0237]
2- [1- (2-Trimethylsilylethoxymethyl) -3-methyl-pyrazol-4-yl] -6-hydroxypurine and 2- [1- (2-trimethylsilylethoxymethyl) -5-methyl-pyrazole-4- Il] -6-hydroxypurine mixture (130 mg) was dissolved in trifluoroacetic acid (2 ml), borontostrifluoroacetate (400 mg) was added, and the mixture was stirred for 1 hour under ice cooling. Add 5 ml of methanol to the reaction solution and evaporate under reduced pressure.₂Cl₂~ 20% in CH₂Cl₂) To obtain 24 mg of white crystals.
m.p .: 240-245 ° C
MS: 217 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 2.48 (3H, s), 8.35 (1H, s), 8.59 (1H, s)
[0238]
Production Example 11
1-methyl-4-carbamoyl-5-amino-imidazole
[0239]
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[0240]
Dissolve 2 g of 2-amino-2-cyanoacetamide in 20 ml of acetonitrile, add 30 ml of triethylorthoformate, heat to reflux for 5 minutes, add 940 mg of a 40% methanol solution of dimethylamine, and after 20 minutes, cool the reaction solution with ice and precipitate. The product is removed from the furnace, and silica gel chromatography (CH₂Cl₂~ 5% MeOH in CH₂Cl₂) Purification gave the title compound as a pale gray white amorphous solid (yield 770 mg).
MS: 141 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm) ： 3.40 (3H, s, CH_Three), 5.73 (2H, s,), 6.60 (1H, br), 6.74 (1H, br), 7.06 (1H, s)
[0241]
Production Example 12
Ethyl [3- (N, N-dimethylamino) -2-phenyl] acrylate
[0242]
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[0243]
10 g of ethylbenzoyl acetate was dissolved in 100 ml of N, N-dimethylformamide, 13.8 g of N, N-dimethylformamide dimethylacetal was added, and the mixture was heated at 100 ° C. for 1 hour. N, N-dimethylformamide was distilled off and the residue was purified by silica gel chromatography (CH₂Cl₂) To give a brown oil (yield 7.3 g).
¹H-NMR (CDCl_Three) δ (ppm): 0.91 (3H, t, J = 7.0Hz), 2.74 (3H, s), 2.87 (3H, s), 3.82 (2H, q, J = 7.0Hz), 7.37 to 7.45 (3H, m), 7.46-7.48 (2H, m)
[0244]
Production Example 13
Ethyl [3-phenyl-1H-pyrazol-4-yl] carboxylate
[0245]
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[0246]
7.28 g of ethyl [3- (N, N-dimethylamino) -2-phenyl] acrylate was dissolved in 70 ml of ethanol, 2.95 g of hydrazine monohydrate was added, and the mixture was heated to 80 ° C. for 1.5 hours. After evaporating the reaction solution, water and ethyl acetate were added, and the organic layer was separated, washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated to give the title compound as a white solid (yield 3.6 g). .
¹H-NMR (DMSO-d₆) δ (ppm): 1.21 (3H, t, J = 7.0Hz), 4.17 (2H, q, J = 7.0Hz), 7.44-7.47 (3H, m), 7.69-7.72 (2H, m), 8.18 ( 1H, br, s)
[0247]
Example 53
2- [3-Phenyl-1H-pyrazol-4-yl] -6-hydroxy-9-methylpurine
[0248]
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[0249]
In the same manner as in Examples 51 and 52, the title compound was obtained.
m.p .: 290-296 ° C
MS: 293 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 3.49 (3H, s, CH_Three), 7.32-7.48 (3H, m), 7.62-7.65 (2H, m), 7.93 (1H, s), 8.20 (0.5H, br, s), 8.46 (0.5H, br, s), 12.12 (1H , br, s)
[0250]
Example 54
2- [3-Phenyl-1H-pyrazol-4-yl] -6-chloro-9-methylpurine
[0251]
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[0252]
40 mg of 2- [3-phenyl-1H-pyrazol-4-yl] -6-hydroxy-9-methylpurine was dissolved in 1 ml of chloroform, 0.1 ml of thionyl chloride and 12 mg of N, N-dimethylformamide were added, and the mixture was heated to reflux for 2.5 hours. . The reaction mixture was evaporated, 2 ml of water was added and the crystals were collected by filtration to give the title compound as a pale yellow solid (yield 20 mg).
m.p .: 133-135 ° C (decomp.)
MS: 311 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 3.65 (3H, s, CH_Three), 7.36-7.49 (3H, m), 7.70-7.74 (2H, m), 8.49 (1H, s), 13.35 (1H, br, s, D₂O exchangeable)
[0253]
Example 55
2- [3-Phenyl-1H-pyrazol-4-yl] -9-methylpurine
[0254]
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[0255]
2- [3-Phenyl-1H-pyrazol-4-yl] -6-chloro-9-methylpurine (32 mg) was dissolved in water (4 ml) and methanol (10 ml), 28% aqueous ammonia (1 ml) and 10% Pd-C (62 mg) were added. Was replaced with hydrogen and stirred at room temperature and normal pressure for 3 hours. The reaction solution was filtered through Celite, the filtrate was evaporated, and the precipitated solid was collected by filtration to give the title compound as a pale yellow amorphous solid (yield 10 mg).
MS: 277 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 3.65 (3H, s, CH_Three), 7.30 to 7.47 (3H, m), 7.65 to 7.70 (2H, m), 8.41 (1H, s), 9.01 (1H, s), 13.25 (1H, br, s)
[0256]
Example 56
1- (2-benzyloxyethyl) -5 or 6- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0257]
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[0258]
The compound of Example 26 (4 g) was dissolved in DMF (40 ml), and NaH (0.78 g; 60% oil dispersion) was gradually added under ice cooling. After stirring at room temperature for 30 minutes, benzyloxyethyl chloride (1.8 g) was added. After heating at 70 ° C. for 4 hours, the reaction solution is returned to room temperature and H₂50 ml of O and 200 ml of AcOEt were added. The organic layer is washed with saturated brine, MgSO_FourAfter drying, the solvent was distilled off. The obtained residue (3.1 g) was dissolved in EtOH (40 ml), 4N HCl-dioxane solution (3 ml) was added, and the mixture was heated to reflux for 1 hour. The reaction is brought to room temperature and NaHCO_ThreeNeutralize with aq, H₂Add O, extract with AcOEt (200 ml), wash with saturated brine MgSO_FourAfter drying, the solvent was distilled off and purified by silica gel chromatography (CH₂Cl₂~ CH₂Cl₂/ MeOH = 99/1) As a first eluate, 720 mg of 6-pyrazole was obtained, and as a second eluate, 780 mg of 5-pyrazole was obtained as an amorphous solid.
6-Pyrazole body
¹H-NMR (CDCl_Three) δ (ppm): 3.70 (2H, t, J = 5.0Hz), 4.26 (2H, t, J = 5.0Hz), 4.44 (2H, s), 6.94 to 6.99 (2H, m), 7.13 to 7.16 ( 2H, m), 7.21 (1H, dd, J = 1.5Hz, 8.4Hz), 7.23-7.24 (3H, m), 7.38-7.42 (2H, m), 7.68 (1H, s), 7.75 (2H, d , J = 8.42Hz), 7.98 (1H, s)
5-pyrazole body
¹H-NMR (CDCl_Three) δ (ppm): 3.81 (2H, t, J = 5.2Hz), 4.35 (2H, t, J = 5.2Hz), 4.89 (2H, s), 6.96 to 7.00 (2H, m), 7.16 to 7.20 ( 3H, m), 7.26-7.30 (4H, m), 7.42-7.45 (2H, m), 7.72 (1H, s), 7.76 (1H, s), 8.00 (1H, s)
[0259]
Example 57
1-hydroxyethyl-6- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0260]
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[0261]
1-Benzyloxyethyl-6- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole (360 mg) was dissolved in MeOH (10 ml) and 10% Pd—C (360 mg) was added.₂Stir for 2 hours at room temperature under atmosphere. The reaction solution was filtered through Celite and H₂Add O, extract with AcOEt 20 ml, wash with saturated brine, MgSO_FourAfter drying, the solvent was distilled off. The resulting residue is purified by silica gel chromatography (CH₂Cl₂~ CH₂Cl₂/ MeOH = 98/2) and the title compound was obtained as 186 mg white crystals.
m.p .: 199-201 ° C
¹H-NMR (DMSO-d₆) δ (ppm): 3.64 (2H, t, J = 5Hz), 4.18 (2H, t, J = 5Hz), 4.93 (1H, t, J = 5Hz), 7.04 (1H, d, J = 8.2Hz) , 7.08 ~ 7.22 (2H, m), 7.43 ~ 7.46 (3H, m), 7.55 (1H, d, J = 8.2Hz), 7.94 (1H, br, s), 8.11 (1H, s), 13.06 (1H , br, s)
[0262]
Example 58
1-hydroxyethyl-5- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0263]
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[0264]
Using 300 mg of 1-benzyloxyethyl-5- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole, the title compound was obtained as white crystals in the same manner as in Example 57.
m.p .: 235-237 ° C
¹H-NMR (DMSO-d₆) δ (ppm): 3.72 (2H, dt, J = 5.10Hz), 4.26 (2H, dd, J = 5.10Hz), 4.98 (1H, t, J = 5Hz), 7.09-7.15 (3H, m), 7.41 ~ 7.45 (2H, m), 7.48 (1H, s), 7.52 (1H, d, J = 8.4Hz), 7.92 (1H, br, s), 8.12 (1H, s), 13.03 (1H, br, s)
[0265]
Example 59
1- (2-propyloxyethyl) -6- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
1- (2-propyloxyethyl) -5- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0266]
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[0267]
The compound of Example 26 (100 mg) was dissolved in DMF (2 ml), and NaH (21 mg: 60% oil dispersion) was gradually added under ice cooling. After stirring at room temperature for 30 minutes, propyloxyethyl chloride (36 mg) was added. After heating at 70 ° C for 3 hours, the reaction solution is returned to room temperature.₂10 ml of O and 50 ml of AcOEt were added. The organic layer is washed with saturated brine, MgSO_FourAfter drying, the solvent was distilled off. The obtained residue was dissolved in 10 ml of EtOH, 4N HCl-dioxane solution (0.3 ml) was added, and the mixture was heated to reflux for 1 hour. The reaction is brought to room temperature and NaHCO_ThreeNeutralize with aq, H₂Add O, extract with AcOEt 60ml, wash with saturated brine, MgSO_FourAfter drying, the solvent was distilled off and purified by silica gel chromatography (CH₂Cl₂~ CH₂Cl₂/ MeOH = 99/1) As a first eluate, 54 mg of 6-pyrazole was obtained as an amorphous solid, and 54 mg of 5-pyrazole was obtained as a second eluate.
6-Pyrazole body
¹H-NMR (CDCl_Three) δ (ppm): 0.85 (3H, t, J = 7.4Hz), 1.52 (2H, q, J = 7.4Hz), 3.32 (2H, t, J = 6.6Hz), 3.65 (2H, t, J = 5.2Hz), 4.23 (2H, t, J = 5.2Hz), 7.17 (2H, m), 7.22 (1H, dd, J = 1.6Hz, 8.4Hz), 7.28 (1H, m), 7.43-7.47 (2H , m), 7.74-7.76 (2H, m), 7.96 (1H, s)
5-pyrazole body
¹H-NMR (CDCl_Three) δ (ppm): 0.87 (3H, t, J = 7.4Hz), 1.55 (2H, q, J = 7.4Hz), 3.37 (2H, t, J = 6.2Hz), 3.77 (2H, t, J = 5.1Hz), 4.33 (2H, t, J = 5.1Hz), 6.98 to 7.03 (2H, m), 7.19 (1H, dd, J = 1.5Hz, 8.4Hz), 7.35 (1H, d, J = 8.4Hz) ), 7.34 to 7.46 (1H, m), 7.74 (1H, d, J = 7.5Hz), 8.00 (1H, s)
[0268]
Example 60
1-ethylthioethyl-6- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
1-ethylthioethyl-5- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0269]
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[0270]
Using the compound of Example 26 (400 mg), in the same manner as in Example 59, 26 mg of 6-pyrazole compound and 27 mg of 5-pyrazole compound were obtained as amorphous solids.
6-Pyrazole body
¹H-NMR (CDCl_Three) δ (ppm): 1.23 (3H, t, J = 7.5Hz), 2.47 (2H, q, J = 7.5Hz), 2.97 (2H, t, J = 7.0Hz), 4.37 (2H, t, J = 7.0Hz), 6.99 ~ 7.03 (2H, m), 7.21 (1H, dd, J = 1.5Hz, 8.4Hz), 7.33 (1H, d, J = 8.4Hz), 7.42 ~ 7.45 (2H, m), 7.74 (1H, s), 7.76 (1H, s), 7.97 (1H, s)
5-pyrazole body
¹H-NMR (CDCl_Three) δ (ppm): 1.22 (3H, t, J = 7.4Hz), 2.47 (2H, q, J = 7.4Hz), 2.96 (2H, t, J = 7.0Hz), 4.37 (2H, t, J = 7.0Hz), 6.93-6.98 (2H, m), 7.21 (1H, dd, J = 1.5Hz, 8.4Hz), 7.33 (1H, d, J = 8.4Hz), 7.41-7.45 (2H, m), 7.68 (1H, s), 7.75 (1H, d, J = 1.5Hz), 7.98 (1H, s)
[0271]
Example 61
1-ethoxycarbonylmethyl-6- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
1-ethoxycarbonylmethyl-5- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0272]
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[0273]
Using the compound of Example 26 (500 mg), 130 mg of the 6-pyrazole compound and 120 mg of the 5-pyrazole compound were each obtained as an amorphous solid in the same manner as in Example 59.
6-Pyrazole body
¹H-NMR (CDCl_Three) δ (ppm): 1.26 (3H, t, J = 7.1Hz), 4.21 (2H, q, J = 7.1Hz), 4.80 (2H, s), 6.89 to 7.03 (2H, m), 7.18 to 7.19 ( 1H, m), 7.25 (1H, dd, J = 1.5Hz, 8.2Hz), 7.42-7.45 (2H, m), 7.72 (1H, s), 7.76 (1H, d, J = 8.2Hz), 7.93 ( 1H, s),
5-pyrazole body
¹H-NMR (CDCl_Three) δ (ppm), 1.29 (3H, t, J = 7.1Hz), 4.27 (2H, q, J = 7.1Hz), 4.90 (2H, s), 6.98 to 7.03 (2H, m), 7.22 (1H, dd, J = 1.5Hz, 8.2Hz), 7.25 (1H, s), 7.42-7.45 (2H, m), 7.73 (1H, s), 7.76 (1H, br, s), 7.94 (1H, s)
[0274]
Example 62
6- [2-Cyano-2- (2-thienyl) ethenyl] Imidazo [1,2-a] pyridine
[0275]
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[0276]
294 mg of imidazo [1,2-a] pyridine-6-carboxaldehyde and 255 mg of thiophene-2-acetonitrile were dissolved in 10 ml of ethanol, 0.1 ml of 28% sodium methylate in methanol was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction solution, and the residue was subjected to column chromatography (CHCl_Three/ MeOH = 100/1) to give the title compound as an amorphous solid (yield 300 mg).
¹H-NMR (CDCl_Three) δ (ppm): 7.10 (1H, dd, J = 4.0, 5.2Hz), 7.28 (1H, br, s), 7.35 (1H, dd, J = 1.2, 5.2Hz), 7.41 (1H, dd, J = 1.2,4.0Hz), 7.67 (1H, m), 7.69 (1H, br, s, J = 9.6Hz), 7.71 (1H, d, J = 1.6Hz), 7.74 (1H, dd, J = 1.6, 9.6Hz), 8.68 (1H, m)
[0277]
Example 63
6- [3- (2-Thienyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine
[0278]
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[0279]
2.24 ml of n-butyllithium (1.6 mol / l: n-hexane solution) was added to 3.08 ml of THF 6 ml solution of trimethylsilyldiazomethane (about 10% n-hexane solution) at −78 ° C. and stirred at the same temperature for 20 minutes. . A solution of 300 mg of the compound of Example 62 in 6 ml of THF was added dropwise thereto over 20 minutes, and the mixture was stirred for 1.5 hours while gradually warming. Saturated ammonium chloride solution was added and extracted with 50 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. To the obtained residue was added 5 ml of 1M tetrabutylammonium fluoride in THF, and the mixture was stirred at room temperature for 1 hour. When 5 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This is filtered, washed with water, dried, and CH₂Cl₂Recrystallization from -IPE gave the title compound as pale yellow crystals (yield 81 mg).
m.p .: 214-125 ° C
MS: 267 (MH⁺)
¹H-NMR (CDCl_Three) δ (ppm): 7.10 (1H, dd, J = 3.6, 5.2Hz), 7.09 (1H, dd, J = 0.8, 3.6Hz), 7.19 (1H, dd, J = 2.0, 9.2Hz), 7.31 ( 1H, dd, J = 0.8,5.2Hz), 7.58 (1H, s), 7.63 (1H, d, J = 9.2Hz), 7.66 (1H, d, J = 1.2Hz), 7.69 (1H, s), 8.16 (1H, m)
[0280]
Example 64
6- [2-Cyano-2- (3-thienyl) ethenyl] Imidazo [1,2-a] pyridine
[0281]
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[0282]
293 mg of imidazo [1,2-a] pyridine-6-carboxaldehyde and 270 mg of thiophene-3-acetonitrile were dissolved in 10 ml of ethanol, 0.1 ml of 28% sodium methylate in methanol was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction solution, and the residue was subjected to column chromatography (CHCl_Three/ MeOH = 100/1) to give the title compound as an amorphous solid (yield 400 mg).
¹H-NMR (CDCl_Three) δ (ppm): 7.36 (1H, s), 7.37 (1H, dd, J = 1.2, 4.8Hz), 7.44 (1H, dd, J = 2.8, 4.8Hz), 7.63 (1H, dd, J = 1.2) , 2.8Hz), 7.67 (1H, br, s), 7.69-7.72 (3H, m), 8.71 (1H, br, s)
[0283]
Example 65
6- [3- (3-Thienyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine
[0284]
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[0285]
Trimethylsilyldiazomethane (approximately 10% n-hexane solution) 4.4 ml of THF 8 ml solution was added 3.2 ml of n-butyllithium (1.6 mol / l: n-hexane solution) at −78 ° C. and stirred at the same temperature for 20 minutes. . To this was added dropwise a solution of 400 mg of the compound of Example 64 in 8 ml of THF over 20 minutes, and the mixture was stirred for 1.5 hours while gradually raising the temperature. Saturated ammonium chloride solution was added and extracted with 50 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. To the obtained residue was added 1M tetrabutylammonium fluoride in THF (7.8 ml), and the mixture was stirred at room temperature for 1 hour. When 10 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CHCl_Three/ MeOH = 100/1). Recrystallization from ethyl acetate gave the title compound as pale yellow crystals (yield 75 mg).
m.p .: 220-221 °
MS: 267 (MH⁺)
¹H-NMR (CDCl_Three): 7.15 (1H, dd, J = 1.6,9.2Hz), 7.20 (1H, br, d, J = 4.4Hz), 7.35-7.40 (2H, m), 7.56 (1H, br, s), 7.61 ( 1H, dd, J = 0.6,9.2Hz), 7.66 (1H, br, s), 7.71 (1H, s), 8.11 ~ 8.13 (1H, m)
[0286]
Example 66
6- [2-cyano-2- (1-methylpyrrol-2-yl) ethenyl] Imidazo [1,2-a] pyridine
[0287]
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[0288]
366 mg of imidazo [1,2-a] pyridine-6-carboxaldehyde and 311 mg of 1-methyl-2-pyrrole acetonitrile were dissolved in 10 ml of ethanol, 0.1 ml of 28% sodium methylate in methanol was added, and the mixture was stirred at room temperature for 19.5 hours. . The solvent was distilled off from the reaction solution, and the residue was subjected to column chromatography (CHCl_Three) To give the title compound as an amorphous solid (yield 310 mg).
¹H-NMR (CDCl_Three) δ (ppm): 3.81 (3H, s), 6.18 (1H, dd, J = 2.8, 3.6Hz), 6.39 (1H, dd, J = 2.0, 3.6Hz), 6.75 (1H, dd, J = 2.0) 2.0Hz), 7.11 (1H, s), 7.66 (1H, s), 7.68 (1H, s), 7.69 (1H, s), 7.70 (1H, d, J = 1.2Hz), 8.67 to 8.68 (1H , m)
[0289]
Example 67
6- [3- (1-Methylpyrrol-2-yl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine
[0290]
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[0291]
Trimethylsilyldiazomethane (approx. 10% n-hexane solution, TCI) 2.5 ml of n-butyllithium (1.6 mol / l: n-hexane solution) is added to 3.3 ml of THF 6 ml solution at −78 ° C. and the same temperature for 20 minutes. Stir. Thereto was added dropwise a solution of 310 mg of the compound of Example 66 in 8 ml of THF over 20 minutes, and the mixture was stirred for 2 hours while gradually raising the temperature. Saturated ammonium chloride solution was added and extracted with 100 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. To the obtained residue was added 5 ml of 1M tetrabutylammonium fluoride in THF, and the mixture was stirred at room temperature for 1.5 hours. When 10 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CH₂Cl₂Purification with -MeOH = 100/1) gave the title compound as an amorphous solid (yield 70 mg).
MS: 264 (MH⁺)
¹H-NMR (CDCl_Three) δ (ppm): 3.37 (3H, s), 6.25 (1H, dd, J = 2.4, 3.6Hz), 6.34 (1H, dd, J = 2.0, 3.6Hz), 6.76 (1H, dd, J = 2.0) , 2.4Hz), 7.09 (1H, dd, J = 1.6,9.4Hz), 7.50 (1H, br, s), 7.55 (1H, d, J = 9.4Hz), 7.60 (1H, d, J = 1.6Hz ), 7.84 (1H, s), 7.97 (1H, dd, J = 1.0,1.6Hz)
[0292]
Example 68
6- [2-Cyano-2- (3-pyridyl) ethenyl] Imidazo [1,2-a] pyridine
[0293]
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[0294]
440 mg of imidazo [1,2-a] pyridine-6-carboxaldehyde and 388 mg of 3-pyridylacetonitrile were dissolved in 12 ml of ethanol, 0.2 ml of 28% sodium methylate in methanol was added, and the mixture was stirred at room temperature for 22.5 hours. When the solvent was distilled off from the reaction solution, the title compound was obtained as an amorphous solid (yield 300 mg). This was used in the next reaction without purification.
¹H-NMR (DMSO-d₆) δ (ppm): 7.55 (1H, dd, J = 4.8, 8.4Hz), 7.68 (1H, s), 7.75 (1H, d, J = 9.6Hz), 7.95 (1H, d, J = 9.6Hz) , 8.10-8.16 (3H, m), 8.63 (1H, d, J = 4.8Hz), 8.95 (1H, d, J = 2.8Hz), 9.05 (1H, br, s)
[0295]
Example 69
6- [3- (3-Pyridyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine
[0296]
Embedded image

[0297]
Add 2.3 ml of n-butyllithium (1.6 mol / l: n-hexane solution) at -78 ° C to 3.2 ml of THF in 3.2 ml of trimethylsilyldiazomethane (approximately 10% n-hexane solution, TCI) and continue at the same temperature for 20 minutes. Stir. To this was added dropwise a solution of 300 mg of the compound of Example 68 in 8 ml of THF over 20 minutes, and the mixture was stirred for 3.5 hours while gradually raising the temperature. Saturated ammonium chloride solution was added and extracted with 100 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. To the obtained residue, 7 ml of 1M tetrabutylammonium fluoride in THF was added and stirred at room temperature for 2 hours. After removing the solvent from the reaction solution, washing with water and drying, column chromatography (CH₂Cl₂/ MeOH = 100/2) to give the title compound as an amorphous solid (yield 60 mg).
MS: 262 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 7.01 (1H, dd, J = 1.6,9.2Hz), 7.34-7.40 ((1H, br), 7.52 (1H, d, J = 9.2Hz), 7.56 (1H, d, J = 1.2Hz), 7.80 (1H, ddd, J = 1.8, 1.8, 7.6Hz), 7.90 (1H, s), 8.05 to 8.10 (1H, br), 8.46 to 8.58 (2H, br), 8.65 (1H, d , J = 1.6Hz), 13.30 (1H, br, s)
[0298]
Example 70
1-methyl-6- [2-cyano-2- (2-thienyl) ethenyl] Benzimidazole
[0299]
Embedded image

[0300]
317 mg of the compound of Production Example 8 and 266 mg of thiophene-2-acetonitrile were dissolved in 12 ml of ethanol, 0.1 ml of 28% sodium methylate in methanol was added, and the mixture was stirred at room temperature for 17.5 hours. The solvent was distilled off from the reaction solution, and the residue was subjected to column chromatography (CH₂Cl₂/ MeOH = 100/1) to give the title compound as an amorphous solid (yield 340 mg).
¹H-NMR (CDCl_Three) δ (ppm): 3.91 (3H, s), 7.09 (1H, ddd, J = 0.8, 4.8, 3.6Hz), 7.31 (1H, dd, J = 0.8, 4.8Hz), 7.40 (1H, dd, J = 0.8, 3.6Hz), 7.54 (1H, s), 7.63 (1H, br, d, J = 8.4Hz), 7.83 (1H, d, J = 8.4Hz), 7.96 (1H, s), 8.14 (1H , br, s)
[0301]
Example 71
1-methyl-6- [3- (2-thienyl) -1H-pyrazol-4-yl] benzimidazole
[0302]
Embedded image

[0303]
Trimethylsilyldiazomethane (approx. 10% n-hexane solution) 3.4 ml of THF 6 ml solution was added 2.6 ml of n-butyllithium (1.6 mol / l: n-hexane solution) at −78 ° C. and stirred at the same temperature for 20 minutes. . To this was added dropwise a solution of the compound of Example 70 in 340 mg in THF over 6 minutes, and the mixture was stirred for 1.5 hours while gradually raising the temperature. Saturated ammonium chloride solution was added and extracted with 50 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. To the obtained residue, 7 ml of 1M tetrabutylammonium fluoride in THF was added and stirred at room temperature for 3 hours. When 10 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CHCl_Three/ MeOH = 100/2). CH₂Cl₂Further recrystallization gave the title compound as pale yellow crystals (yield 116 mg).
m.p .: 225-226 ° C
MS: 281 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 3.79 (3H, s), 6.86-6.94 (1H, m), 7.16 (1H, br, d, J = 7.6Hz), 7.38 (1H, br, s), 7.53 (1H, d , J = 1.6Hz), 7.60 (1H, d, J = 7.6Hz), 7.90 (1H, br, s), 8.16 (1H, s), 13.01 (1H, br, s)
[0304]
Example 72
1-methyl-6- [2-cyano-2- (4-methoxyphenyl) ethenyl] benzimidazole
[0305]
Embedded image

[0306]
1500 mg of the compound of Production Example 8 and 1519 mg of 4-methoxyphenylacetonitrile were dissolved in 25 ml of ethanol, 0.5 ml of 28% sodium methylate in methanol was added, and the mixture was stirred at room temperature for 2.5 hours. To the reaction solution was added 3 ml of 1N HCl, followed by extraction with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was directly used in the next reaction (yield 3.5 g).
¹H-NMR (CDCl_Three) δ (ppm): 3.87 (3H, s), 3.92 (3H, s), 6.98 (2H, d, J = 8.8Hz), 7.58 (1H, s), 7.61 (1H, dd, J = 1.4, 8.4) Hz), 7.64 (2H, d, J = 8.8Hz), 7.84 (1H, d, J = 8.4Hz), 7.96 (1H, s), 8.21 (1H, br, d, J = 1.4Hz)
[0307]
Example 73
1-methyl-6- [3- (4-methoxyphenyl) -1H-pyrazol-4-yl] benzimidazole
[0308]
Embedded image

[0309]
Trimethylsilyldiazomethane (approximately 10% n-hexane solution) 1.6 ml of THF 3 ml solution was added 1.2 ml of n-butyllithium (1.6 mol / l: n-hexane solution) at −78 ° C. and stirred at the same temperature for 20 minutes. . To this was added dropwise a solution of 173 mg of the compound of Example 72 in 3 ml of THF over 20 minutes, and the mixture was stirred for 1.5 hours while gradually raising the temperature. Saturated ammonium chloride solution was added and extracted with 30 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. To the obtained residue was added 3.5 ml of 1M tetrabutylammonium fluoride in THF, and the mixture was stirred at room temperature for 2.5 hours. When 10 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This is filtered, washed with water, dried, and CH₂Cl₂Further recrystallization gave the title compound as pale yellow crystals (yield 54 mg).
m.p .: 240-242 ° C
MS: 305 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 3.68 (3H, s), 3.70 (3H, s), 6.85 (2H, br, s), 6.98 (1H, dd, J = 1.6, 8.4Hz), 7.28 (2H, d, J = 8.8Hz), 7.42 (1H, br, s), 7.47 (1H, d, J = 8.4Hz), 8.08 (1H, s), 12.81-12.89 (1H, br)
[0310]
Example 74
1-methyl-6- [2-cyano-2- (4-bromophenyl) ethenyl] Benzimidar
[0311]
Embedded image

[0312]
297 mg of the compound of Production Example 8 and 407 mg of 4-bromophenylacetonitrile were dissolved in 8 ml of ethanol, 0.5 ml of 28% sodium methylate was added, and the mixture was stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration, washed with cold ethanol and dried to give the title compound as a pale yellow solid (yield 257 mg).
m.p.:141℃
MS: 338 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 3.87 (3H, s), 7.72 (4H, br, s), 7.78 (1H, d, J = 8.8Hz), 7.88 (1H, dd, J = 0.8, 8.8Hz), 8.17 ( 1H, s), 8.21 (1H, s), 8.34 (1H, s)
[0313]
Example 75
1-methyl-6- [3- (4-bromophenyl) -1H-pyrazol-4-yl] benzimidazole
[0314]
Embedded image

[0315]
1.45 ml of n-butyllithium (1.6 mol / l: n-hexane solution) is added to 5 ml of THF in 2 ml of trimethylsilyldiazomethane (approximately 10% n-hexane solution, TCI) and stirred at the same temperature for 20 minutes. did. A solution of the compound of Example 74 in 257 mg in THF (5 ml) was added dropwise thereto over 20 minutes, and the mixture was stirred for 2 hours while gradually raising the temperature. Saturated ammonium chloride solution was added and extracted with 50 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. To the obtained residue was added 5 ml of 1M tetrabutylammonium fluoride in THF, and the mixture was stirred at room temperature for 2 hours. When 10 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This is filtered, washed with water, dried, and CH₂Cl₂Further recrystallization gave the title compound as white crystals (yield 130 mg).
m.p.:273°C
MS: 353 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 3.76 (3H, s), 7.01 (1H, dd, J = 1.6, 8.4Hz), 7.35 (2H, d, J = 8.4Hz), 7.48 (1H, br, s), 7.47, 7.55 (2H, m), 7.55 (2H, d, J = 8.4Hz), 8.14 (1H, s)
[0316]
Example 76
6- [2-Cyano-2- (4-pyridyl) ethenyl] Imidazo [1,2-a] pyridine
[0317]
Embedded image

[0318]
Imidazo [1,2-a] pyridine-6-carboxaldehyde 297 mg 4-pyridylacetonitrile hydrochloride 630 mg was dissolved in ethanol 10 ml, 28% sodium methylate in methanol 0.6 ml was added, and the mixture was stirred at room temperature for 6 hours. After the reaction solution was filtered through Celite, the solvent was distilled off from the reaction solution, and the residue was subjected to column chromatography (CHCl_Three~ CHCl_Three/ MeOH = 100/1 → 100/2) to give the title compound as an amorphous solid (yield 320 mg).
¹H-NMR (DMSO-d₆) δ (ppm): 7.68 (1H, d, J = 1.2Hz), 7.72 (2H, d, J = 6.4Hz), 7.76 (1H, d, J = 9.6Hz), 7.98 (1H, d, J = 2.0, 9.6Hz), 8.15 (1H, s), 8.32 (1H, s), 8.70 (2H, d, J = 6.4Hz), 9.10 (1H, br, s)
[0319]
Example 77
6- [3- (4-Pyridyl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridine
[0320]
Embedded image

[0321]
Trimethylsilyldiazomethane (approx. 10% n-hexane solution, TCI) 2.8 ml of THF 6 ml solution was added 2.1 ml of n-butyllithium (1.6 mol / l: n-hexane solution) at −78 ° C., and the same temperature was maintained for 20 minutes. Stir. A solution of 320 mg of the compound of Example 76 in 6 ml of THF was added dropwise thereto over 20 minutes, and the mixture was stirred for 2 hours while gradually raising the temperature. A saturated ammonium chloride solution was added, and extraction was performed with 50 ml of dichloromethane, whereby crystals were precipitated. To the obtained crystals, 3 ml of 1M tetrabutylammonium fluoride in THF was added and stirred at room temperature for 1.5 hours. When 10 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This is filtered, washed with water, dried, and CH₂Cl₂When recrystallized from IPE, the title compound was obtained as pale brown crystals (yield 65 mg).
m.p.:246°C
MS: 262 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 6.98 (1H, dd, J = 1.4,9.2Hz), 7.38 (2H, d, J = 5.8Hz), 7.49 (1H, d, J = 9.2Hz), 7.52 (1H, d, J = 1.4Hz), 7.87 (1H, s), 8.47 (2H, d, J = 5.8Hz), 8.49 (1H, br, s)
[0322]
Production Example 14
Diethyl (1-cyanoethyl) phosphonate
[0323]
Embedded image

[0324]
In 8 ml of 1,2-dimethoxyethane, 201 mg of sodium hydride (Ca. 60% in mineral oil) was suspended, and 887 mg of diethyl cyanomethyl phosphonate was added thereto. After stirring at room temperature for 1 hour, 730 mg of methyl iodide was added and stirred at room temperature for 1.5 hours. 5 ml of water was added, extracted with 30 ml of chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off and used for the next reaction with crude purification (yield 950 mg).
[0325]
Example 78
1-methyl-6- (2-cyano-1-propenyl) benzimidazole
[0326]
Embedded image

[0327]
In 5 ml of tetrahydrofuran, 206 mg of sodium hydride (Ca. 60% in mineral oil) was suspended, and a solution of 950 mg of diethyl (1-cyanoethyl) phosphonate in 5 ml of THF was added thereto. After stirring at 0 ° C. for 1 hour, a solution of 720 mg of the compound of Production Example 8 in 10 ml of THF was added, and the mixture was further stirred at 0 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water, then with saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent, silica gel column chromatography (CHCl_Three) To give 200 mg of the title compound.
¹H-NMR (CDCl_Three) δ (ppm): 2.22 (3H, d, J = 1.6Hz), 3.88 (3H, s), 7.29 (1H, dd, J = 1.6, 8.4Hz), 7.34 to 7.38 (2H, m), 7.81 ( 1H, d, J = 8.4Hz), 7.94 (1H, s)
[0328]
Example 79
1-methyl-6- (3-methyl-1H-pyrazol-4-yl) benzimidazole
[0329]
Embedded image

[0330]
Trimethylsilyldiazomethane (approximately 10% n-hexane solution) 1.8 ml of n-butyllithium (1.6 mol / l: n-hexane solution) was added at −78 ° C. to 2.45 ml of THF 5 ml solution and stirred at the same temperature for 20 minutes. . A solution of the compound of Example 78 (200 mg) in THF (5 ml) was added dropwise thereto over 20 minutes, and the mixture was stirred for 4.5 hours while gradually raising the temperature. Saturated ammonium chloride solution was added and extracted with 50 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. To the obtained residue, 7 ml of 1M tetrabutylammonium fluoride in THF was added and stirred at room temperature for 2.5 hours. When 10 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CHCl_Three/ MeOH = 100/1 → 100/2 → 100/10) and then purified again by column chromatography (CH₂Cl₂/ Acetone = 1/2), the title compound was obtained as pale yellow crystals (yield 80 mg).
m.p.:198°C
MS: 213 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 2.39 (3H, s), 3.83 (3H, s), 7.28 (1H, dd, J = 1.6, 8.4Hz), 7.55 (1H, d, J = 1.6Hz), 7.62 (1H, d, J = 8.4Hz), 8.12 (1H, s), 12.60 (1H, br, s)
[0331]
Example 80
1-methyl-6- [2-cyano-2- (2-bromophenyl) ethenyl] Benzimidar
[0332]
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[0333]
243 mg of the compound of Production Example 8 and 302 mg of 2-bromophenylacetonitrile were dissolved in 8 ml of ethanol, and 0.1 ml of 28% sodium methylate was added, followed by stirring at 0 ° C. for 3 hours, then at room temperature for 4 hours, and at 4 ° C. for 14 hours. The solvent was distilled off from the reaction solution, and the residue was subjected to column chromatography (CHCl_Threeonly → CHCl_Three/ MeOH = 100/1) to give a mixture containing the title compound (yield 320 mg).
[0334]
Example 81
1-methyl-6- [3- (2-bromophenyl) -1H-pyrazol-4-yl] benzimidazole
[0335]
Embedded image

[0336]
Trimethylsilyldiazomethane (approximately 10% n-hexane solution) 1.2 ml of n-butyllithium (1.6 mol / l: n-hexane solution) was added to 1.65 ml of THF 5 ml solution at −78 ° C. and stirred at the same temperature for 20 minutes. . A solution of 320 mg of the compound of Example 80 in 3.5 ml of THF was added dropwise thereto over 20 minutes, and the mixture was stirred for 2 hours while gradually raising the temperature. Saturated ammonium chloride solution was added and extracted with 50 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. To the obtained residue, 3 ml of 1M tetrabutylammonium fluoride in THF was added and stirred at room temperature for 3 hours. When 10 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CH₂Cl₂/ MeOH = 100/1). CH₂Cl₂Further recrystallization gave the title compound as white crystals (yield 30 mg).
m.p .: 263 ° C
MS: 353 (MH⁺)
¹H-NMR (CDCl_Three) δ (ppm): 3.70 (3H, s), 7.15 (1H, dd, J = 1.6, 8.4Hz), 7.18 (1H, m), 7.28-7.37 (3H, m), 7.66 (1H, d, J = 8.4Hz), 7.69 (1H, dd, J = 1.6,7.6Hz), 7.81 (1H, s), 7.90 (1H, s)
[0337]
Example 82
1-methyl-6- [2-cyano-2- (4-chlorophenyl) ethenyl] Benzimidar
[0338]
Embedded image

[0339]
300 mg of the compound of Production Example 8 and 291 mg of 4-chlorophenylacetonitrile were dissolved in 15 ml of ethanol, 0.15 ml of 28% sodium methylate in methanol was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off from the reaction solution, and the residue was subjected to column chromatography (CHCl_Three/ MeOH = 100/2) to give the title compound as an amorphous solid (yield 480 mg).
¹H-NMR (CDCl_Three) δ (ppm): 3.93 (3H, s), 7.44 (2H, d, J = 8.4Hz), 7.62 to 7.66 (3H, m), 7.67 (1H, s), 7.85 (1H, d, J = 8.4) Hz), 7.98 (1H, s), 8.23 to 8.24 (1H, m)
[0340]
Example 83
1-methyl-6- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] benzimidazole
[0341]
Embedded image

[0342]
Trimethylsilyldiazomethane (approximately 10% n-hexane solution) 3.95 ml of THF 8 ml solution was added 2.9 ml of n-butyllithium (1.6 mol / l: n-hexane solution) at −78 ° C. and stirred at the same temperature for 20 minutes. . A solution of the compound of Example 82 in 480 mg in THF (8 ml) was added dropwise over 20 minutes, and the mixture was stirred for 1.5 hours while gradually warming. Saturated ammonium chloride solution was added and extracted with 50 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. To the obtained residue, 8 ml of 1M tetrabutylammonium fluoride in THF was added and stirred at room temperature for 2.5 hours. When 20 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CHCl_Three/ MeOH = 100/1 → 100/2). CHCl_ThreeFurther recrystallization gave the title compound as white crystals (yield 232 mg).
m.p.:268°C
MS: 309 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 3.76 (3H, s), 7.02 (1H, dd, J = 1.6, 8.4Hz), 7.31 to 7.45 (4H, m), 7.48 (1H, br, s), 8.15 (1H, s) ), 13.10 (1H, br, s)
[0343]
Production Example 15
[0344]
4-aminophenylacetonitrile
Embedded image

[0345]
3.253 g of 4-nitrophenylacetonitrile was dissolved in a mixed solvent of 30 ml of methanol and 5 ml of THF, and 2.95 g of 10% palladium-carbon was suspended therein. The reaction system was replaced with hydrogen and stirred vigorously at room temperature for 20 hours. The reaction solution was filtered through Celite, the solvent was distilled off, and silica gel column chromatography (CHCl_Three~ CHCl_Three/ MeOH = 100/1 → 100/2) to give 1.780 g of the title compound as a waxy solid.
¹H-NMR (DMSO-d₆) δ (ppm): 3.74 (2H, s), 5.09 (2H, br, s), 6.56 (2H, d, J = 8.4Hz), 6.96 (2H, d, J = 8.4Hz)
[0346]
Production Example 16
4- (N, N-dimethylamino) phenylacetonitrile
[0347]
Embedded image

[0348]
1.780 g of 4-aminophenylacetonitrile was dissolved in 15 ml of 37% formalin aqueous solution, 10 ml of formic acid was added thereto, and the mixture was heated to reflux for 10 hours. The reaction solution was neutralized with sodium bicarbonate and extracted with chloroform. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, evaporated, and silica gel column chromatography (CHCl_Three) To give 180 mg of the title compound as a waxy solid.
¹H-NMR (DMSO-d₆) δ (ppm): 2.85 (6H, s), 3.82 (2H, s), 6.69 (2H, d, J = 8.8Hz), 7.11 (2H, d, J = 8.8Hz)
[0349]
Example 84
1-methyl-6- [2-cyano-2- (4-dimethylaminophenyl) ethenyl] Benzimidar
[0350]
Embedded image

[0351]
121 mg of the compound of Production Example 8 and 120 mg of 4- (N, N-dimethylamino) phenylacetonitrile were dissolved in 4 ml of ethanol, 0.03 ml of 28% sodium methylate was added, and the mixture was stirred at room temperature for 6.5 hours. After adding 0.5 ml of 1N HCl to the reaction solution, the solvent was distilled off, and the residue was dissolved in chloroform and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to column chromatography (CHCl_Three) To give the title compound as an amorphous solid (yield 140 mg).
¹H-NMR (CDCl_Three) δ (ppm): 3.02 (6H, s), 3.88 (3H, s), 6.74 (2H, d, J = 9.2Hz), 7.50 (1H, s), 7.57 (2H, d, J = 9.2Hz) , 7.58 (1H, dd, J = 1.8,8.4Hz), 7.80 (1H, d, J = 8.4Hz), 7.92 (1H, s), 8.15 (1H, br, d, J = 1.8Hz)
[0352]
Example 85
1-methyl-6- [3- (4-dimethylaminophenyl) -1H-pyrazol-4-yl] benzimidazole
[0353]
Embedded image

[0354]
1.35 ml of n-butyllithium (1.6 mol / l: n-hexane solution) was added at −78 ° C. to 1.83 ml of THF solution of 1.83 ml of trimethylsilyldiazomethane (about 10% n-hexane solution) and stirred at the same temperature for 20 minutes. . A solution of the compound of Example 84 140 mg in THF 5 ml was added dropwise thereto over 20 minutes, and the mixture was stirred for 4 hours while gradually warming. Saturated ammonium chloride solution was added and extracted with 50 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. To the obtained residue was added 3 ml of 1M tetrabutylammonium fluoride in THF, and the mixture was stirred at room temperature for 2 hours. When 10 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CH₂Cl₂/ Acetone = 1/2), the title compound was obtained as pale yellow crystals (yield 40 mg).
m.p .: 199-201 ° C
MS: 318 (MH⁺)
¹H-NMR (DMSO-d₆) δ (ppm): 2.85 (6H, s), 3.78 (3H, s), 6.66 (2H, br, d, J = 8.8Hz), 7.05 (1H, dd, J = 1.6, 8.4Hz), 7.22 ( 2H, br, d, J = 8.8Hz), 7.48 (1H, br, s), 7.51 (1H, d, J = 8.4Hz), 8.12 (1H, s)
[0355]
Example 86
1-methyl-6- [2-cyano-2- (2-pyridyl) ethenyl] Benzimidar
[0356]
Embedded image

[0357]
321 mg of the compound of Production Example 8 and 254 mg of 2-pyridylacetonitrile were dissolved in 12 ml of ethanol, 0.1 ml of 28% sodium methylate in methanol was added, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off from the reaction solution, and the residue was subjected to column chromatography (CH₂Cl₂/ MeOH = 100/1) to give the title compound as an amorphous solid (yield 460 mg).
¹H-NMR (DMSO-d₆) δ (ppm): 3.88 (3H, s), 7.43 (1H, ddd, J = 0.8, 4.8, 7.6Hz), 7.80 (1H, d, J = 8.4Hz), 7.84 (1H, d, J = 7.6) Hz), 7.94 (1H, dd, J = 1.6,7.6Hz), 7.98 (1H, dd, J = 1.2,8.4Hz), 8.27 (1H, br, s), 8.37 (1H, s), 8.61 (1H , s), 8.65 to 8.68 (1H, m)
[0358]
Example 87
1-methyl-6- [3- (2-pyridyl) -1H-pyrazol-4-yl] benzimidazole
[0359]
Embedded image

[0360]
Trimethylsilyldiazomethane (about 10% n-hexane solution) 4.3 ml of THF 12 ml solution was added with 3.1 ml of n-butyllithium (1.6 mol / l: n-hexane solution) at −78 ° C. and stirred at the same temperature for 20 minutes. . A solution of the compound of Example 86 (460 mg) in THF (8 ml) was added dropwise thereto over 20 minutes, and the mixture was stirred for 1.5 hours while gradually warming. Saturated ammonium chloride solution was added and extracted with 50 ml of dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off. 15 ml of 1M tetrabutylammonium fluoride in THF was added to the resulting residue, and the mixture was stirred at room temperature for 3 hours. When 30 ml of water was added and THF was distilled off under reduced pressure, precipitation occurred. This was collected by filtration, washed with water, dried, and column chromatography (CH₂Cl₂/ Acetone = 1/2). CH₂Cl₂-Et₂Recrystallization from O gave the title compound as pale yellow crystals (yield 289 mg).
m.p .: 239 ° C
MS: 276 (MH⁺)
¹H-NMR (CDCl_Three) Δ (ppm): 3.85 (3H, s), 7.19 (1H, ddd, J = 1.4, 4.8, 8.0Hz), 7.30 (1H, d, J = 8.0Hz), 7.35 (1H, dd, J = 1.6) , 8.4Hz), 7.44-7.45 (1H, m), 7.48 (1H, ddd, J = 1.4, 8.0, 8.0Hz), 7.69 (1H, s), 7.83 (1H, d, J = 8.4Hz), 7.92 (1H, s), 8.63 (1H, br, d, J = 4.8Hz) 87

Claims (7)

General formula

[Wherein ring A may have one or more substituents, a benzimidazole ring, one or more substituents, an imidazopyridine ring, or one or more substituents. A good purine ring, R ¹ may have a lower alkyl group or one or more heteroatoms or an aromatic ring optionally having one or more substituents, R ² may be a hydrogen atom, a lower alkyl group Or an amino-protecting group, and R ³ represents a hydrogen atom. ] The pyrazole derivative represented by these, or its salt. The pyrazole derivative or a salt thereof according to claim 1, wherein R ² is a hydrogen atom. The pyrazole derivative or a salt thereof according to claim ^{1, wherein} the substituent of ring A or R ¹ is a halogen atom.   6- (3-Methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine, 3-chloro-6- (3-methyl-1H-pyrazol-4-yl) imidazo [1,2- a] pyridine, 1-methyl-6- [3- (4-methoxyphenyl) -1H-pyrazol-4-yl] benzimidazole, 1-methyl-6- [3- (2,4-difluorophenyl) -1H The pyrazole derivative or a salt thereof according to claim 1, which is -pyrazol-4-yl] benzimidazole or 2- [3-phenyl-1H-pyrazol-4-yl] -9-methylpurine. General formula

[Wherein ring A may have one or more substituents, a benzimidazole ring, one or more substituents, an imidazopyridine ring, or one or more substituents. As a good purine ring, R ¹ represents a lower alkyl group or an aromatic ring which may have one or more heteroatoms and may have one or more substituents. A compound represented by formula (II) and trimethylsilyldiazomethane

[Wherein, ring A and R ¹ represent the same group as defined above, and R ⁵ represents a hydrogen atom or a trimethylsilyl group, respectively. ] The manufacturing method of the pyrazole derivative represented by these, or its salt. General formula

[Wherein R ¹ represents a lower alkyl group or an aromatic ring optionally having one or more heteroatoms and optionally having one or more substituents, R ² represents a hydrogen atom, a lower alkyl group or An amino protecting group, R ⁶ represents a hydrogen atom or a lower alkyl group. A compound represented by the formula:

[Wherein, R ¹ , R ² and R ⁶ each represent the same group as defined above. ] The manufacturing method of the pyrazole derivative represented by these, or its salt. General formula

[Wherein ring A may have one or more substituents, a benzimidazole ring, one or more substituents, an imidazopyridine ring, or one or more substituents. R ¹ is a lower alkyl group or an aromatic ring optionally having one or more substituents, R ² is a hydrogen atom, a lower alkyl group or An amino protecting group, R ³ represents a hydrogen atom. ] The anti-herpes agent which uses the pyrazole derivative represented by this, or its pharmacologically acceptable salt as an active ingredient.