JP4105451B2 - Differentiation inducer - Google Patents

Differentiation inducer Download PDF

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JP4105451B2
JP4105451B2 JP2002050102A JP2002050102A JP4105451B2 JP 4105451 B2 JP4105451 B2 JP 4105451B2 JP 2002050102 A JP2002050102 A JP 2002050102A JP 2002050102 A JP2002050102 A JP 2002050102A JP 4105451 B2 JP4105451 B2 JP 4105451B2
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carbon atoms
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benzamide
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JP2002332267A (en
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鈴木　　常司
知行 安藤
土屋　　克敏
理 中西
明子 齊藤
俊 山下
厳悟 白石
英司 田中
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Bayer Pharma AG
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Bayer Schering Pharma AG
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Description

【０００１】
【産業上の利用分野】
本発明は分化誘導剤に関する。さらに詳しくは、新規ベンズアミド誘導体または新規アリニド誘導体の分化誘導作用に基づく制癌剤およびその他の医薬品への利用に関するものである。
【０００２】
【従来の技術】
現在、癌は死亡原因の中で心疾患、脳血管疾患を抜いて最大の原因となっており、これまで多くの研究が多額の費用と時間をかけて行われてきた。しかし、外科的手術、放射線療法、温熱療法など多岐にわたる治療法の研究にも拘らず癌は克服されていない。その中で化学療法は癌治療の大きな柱の一つであるが、今日に至っても十分満足のゆく薬剤は見いだされておらず、毒性が低く治療効果の高い制癌剤が待ち望まれている。これまでの多くの制癌剤は細胞、主にＤＮＡに作用し細胞毒性を発現することで癌細胞に傷害を与え、制癌効果を発揮している。しかし、癌細胞と正常細胞との選択性が十分でないため、正常細胞において発現する副作用が治療の限界となっている。
【０００３】
ところが制癌剤の中でも分化誘導剤は直接の殺細胞ではなく、癌細胞に分化を促し癌細胞の無限増殖を抑えることを目的としている。そのため癌の退縮においては直接細胞を殺す種類の制癌剤には及ばないが、低い毒性と異なる選択性が期待できる。実際、分化誘導剤であるレチノイン酸が治療に用いられ急性前骨髄性白血病で高い効果を示すことはよく知られている［Ｈｕａｎｇら；Blood、72、567-572(1988)、Ｃａｓｔａｉｇｎら；Blood、76、1704-1709、(1990)、Ｗａｒｒｅｌｌら；New Engl.J.Med.324、1385-1393(1991)など］。また、ビタミンＤ誘導体が分化誘導作用を示すことから制癌剤への応用も多く研究されている［Ｏｌｓｓｏｎら；Cancer Res.43、5862-5867(1983)他］。
【０００４】
これらの研究を受けて、分化誘導剤であるビタミンＤ誘導体（特開平６−１７９６２２号公報）、イソプレン誘導体（特開平６−１９２０７３号公報）、トコフェロール（特開平６−２５６１８１号公報）、キノン誘導体（特開平６−３０５９５５号公報）、非環状ポリイソプレノイド（特開平６−３１６５２０号公報）、安息香酸誘導体（特開平７−２０６７６５号公報）、糖脂質（特開平７−２５８１００号公報）等の制癌剤への応用が報告されている。しかしながら、これらの研究によっても癌治療上十分なレベルに達した薬剤はなく、各種の癌に対し有効で安全性の高い薬剤が強く望まれている。
【０００５】
【発明が解決しようとする課題】
本発明の課題は、分化誘導作用を有し、悪性腫瘍、自己免疫疾患、皮膚病、寄生虫感染症の治療・改善薬などの医薬品として有用な化合物を提供することにある。
【０００６】
【課題を解決するための手段】
本発明者は上記課題を解決すべく鋭意検討した結果、分化誘導作用を有する新規ベンズアミド誘導体および新規アリニド誘導体が抗腫瘍効果を示すことを見いだし、本発明を完成させた。すなわち本発明は、
［１］ 式（１）［化１４］
【０００７】
【化２】

Figure 0004105451
［式中、Ａは置換されていてもよいフェニル基または複素環（置換基として、ハロゲン原子、水酸基、アミノ基、ニトロ基、シアノ基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のアミノアルキル基、炭素数１〜４のアルキルアミノ基、炭素数１〜４のアシル基、炭素数１〜４のアシルアミノ基、炭素数１〜４のアルキルチオ基、炭素数１〜４のパーフルオロアルキル基、炭素数１〜４のパーフルオロアルキルオキシ基、カルボキシル基、炭素数１〜４のアルコキシカルボニル基、フェニル基、複素環からなる群より選ばれた基を１〜４個有する）を表す。
Ｘは直接結合または式（２）［化１５］
【０００８】
【化３】
Figure 0004105451
｛式中、ｅは１〜４の整数を表す。ｇおよびｍはそれぞれ独立して０〜４の整数を表す。Ｒ４は水素原子、置換されていてもよい炭素数１〜４のアルキル基または式（３）［化１６］
【０００９】
【化４】
Figure 0004105451
（式中、Ｒ６は置換されていてもよい炭素数１〜４のアルキル基、炭素数１〜４のパーフルオロアルキル基、フェニル基または複素環を表す）で表されるアシル基を表す。Ｒ５は水素原子または置換されていてもよい炭素数１〜４のアルキル基を表す｝で示される構造のいずれかを表す。
ｎは０〜４の整数を表す。但しＸが直接結合の場合は、ｎは０とはならない。
Ｑは式（４）［化１７］
【００１０】
【化５】
Figure 0004105451
（式中、Ｒ７およびＲ８はそれぞれ独立して、水素原子または置換されていてもよい炭素数１〜４のアルキル基を表す）で示される構造のいずれかを表す。
【００１１】
Ｒ１およびＲ２はそれぞれ独立して、水素原子、ハロゲン原子、水酸基、アミノ基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のアミノアルキル基、炭素数１〜４のアルキルアミノ基、炭素数１〜４のアシル基、炭素数１〜４のアシルアミノ基、炭素数１〜４のアルキルチオ基、炭素数１〜４のパーフルオロアルキル基、炭素数１〜４のパーフルオロアルキルオキシ基、カルボキシル基または炭素数１〜４のアルコキシカルボニル基を表す。
Ｒ３は水酸基またはアミノ基を表す。］で表されるベンズアミド誘導体および薬学的に許容される塩であり、また、
【００１２】
［２］ ｎが１〜４の整数である［１］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００１３】
［３］ Ｑが式（５）［化１８］
【００１４】
【化６】
Figure 0004105451
（式中、Ｒ７およびＲ８は前記と同義。）で示される構造のいずれかである［２］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００１５】
［４］ Ａが置換されていてもよいヘテロ環である［３］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００１６】
［５］ Ａが置換されていてもよいピリジル基である［４］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００１７】
［６］ Ｘが直接結合である［４］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００１８】
［７］ Ｒ１およびＲ２が水素原子である［６］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００１９】
［８］ Ｒ３がアミノ基である［７］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００２０】
［９］ Ｘが式（６）［化１９］
【００２１】
【化７】
Figure 0004105451
（式中、ｅは前記と同義。）で示される構造である［５］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００２２】
［１０］ ｎが１で、Ｒ１およびＲ２が水素原子である［９］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００２３】
［１１］ Ｒ３がアミノ基である［１０］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００２４】
［１２］ Ｘが式（７）［化２０］
【００２５】
【化８】
Figure 0004105451
（式中、ｅ、ｇおよびＲ４は前記と同義。）示される構造のいずれかである［５］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００２６】
［１３］ ｎが１で、Ｒ１およびＲ２が水素原子である［１２］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００２７】
［１４］ Ｒ３がアミノ基である［１３］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００２８】
［１５］ Ｘが式（８）［化２１］
【００２９】
【化９】
Figure 0004105451
（式中、ｇ、ｍおよびＲ５は前記と同義。）示される構造のいずれかである［５］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００３０】
［１６］ ｎが１で、Ｒ１およびＲ２が水素原子である［１５］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００３１】
［１７］ Ｒ３がアミノ基である［１６］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００３２】
［１８］ ｎが０である［１］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００３３】
［１９］ Ｑが式（５）で示される構造のいずれかである［１８］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００３４】
［２０］ Ａが置換されていてもよいヘテロ環である［１９］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００３５】
［２１］ Ａが置換されていてもよいピリジル基である［２０］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００３６】
［２２］ Ｒ１およびＲ２が水素原子である［２１］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００３７】
［２３］ Ｒ３がアミノ基である［２２］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００３８】
［２４］ 式（９）［化２２］
【００３９】
【化１０】
Figure 0004105451
で示される［１］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００４０】
［２５］ 式（１０）［化２３］
【００４１】
【化１１】
Figure 0004105451
で示される［１］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００４２】
［２６］ 式（１１）［化２４］
【００４３】
【化１２】
Figure 0004105451
で示される［１］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００４４】
［２７］ 式（１２）［化２５］
【００４５】
【化１３】
Figure 0004105451
で示される［１］記載のベンズアミド誘導体および薬学的に許容される塩であり、また、
【００４６】
［２８］ 式（１３）［化２６］
【００４７】
【化１４】
Figure 0004105451
［式中、ＡおよびＢは置換されていてもよいフェニル基または複素環（置換基として、ハロゲン原子、水酸基、アミノ基、ニトロ基、シアノ基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のアミノアルキル基、炭素数１〜４のアルキルアミノ基、炭素数１〜４のアシル基、炭素数１〜４のアシルアミノ基、炭素数１〜４のアルキルチオ基、炭素数１〜４のパーフルオロアルキル基、炭素数１〜４のパーフルオロアルキルオキシ基、カルボキシル基、炭素数１〜４のアルコキシカルボニル基、フェニル基、複素環からなる群より選ばれた基を１〜４個有する）を表す。
【００４８】
Ｙは−ＣＯ−、−ＣＳ−、−ＳＯ−および−ＳＯ2−のいずれかを構造中に有し、ＡとＢを連結する鎖状、環状またはそれらの組み合わされた構造を表す。
Ｒ３は水酸基またはアミノ基を表す。］において、Ｂ環の重心（Ｗ１）、Ａ環の重心（Ｗ２）、Ｙ中の水素結合受容体となる酸素原子または硫黄原子（Ｗ３）のなす距離が、それぞれＷ１〜Ｗ２＝６．０〜１１．０Å、Ｗ１〜Ｗ３＝３．０〜８．０Å、Ｗ２〜Ｗ３＝３．０〜８．０Åとなる立体配置をとることが可能なアニリド誘導体および薬学的に許容される塩であり、また、
【００４９】
［２９］ Ａが置換されていてもよい複素環、Ｒ３がアミノ基、Ｙが−ＣＯ−を構造中に有するＡとＢを連結する鎖状、環状またはそれらの組み合わされた構造である［２８］記載のアニリド誘導体および薬学的に許容される塩であり、また、
【００５０】
［３０］ Ｂが置換されてもよいフェニル基、Ｗ１〜Ｗ２＝７．０〜９．５Å、Ｗ１〜Ｗ３＝３．０〜５．０Å、Ｗ２〜Ｗ３＝５．０〜８．０Åである［２９］記載のアニリド誘導体および薬学的に許容される塩であり、また、
【００５１】
［３１］ ［１］〜［３０］いずれかに記載の化合物のうち、少なくとも１つを有効成分として含有する制癌剤であり、また、
【００５２】
［３２］ ［１］〜［３０］いずれかに記載の化合物のうち、少なくとも１つを有効成分として含有する医薬品である。
【００５３】
【発明の実施の形態】
以下、本発明を詳細に説明する。
本発明でいう炭素数１〜４とは、単位置換基あたりの炭素数を表す。すなわち、例えばジアルキル置換の場合は、炭素数２〜８を意味する。
【００５４】
式（１）および式（１３）で示される化合物における複素環とは、窒素原子または酸素原子または硫黄原子を１〜４個を含む５員環または６員環からなる単環式複素環または２環式縮合複素環で、例えば単環式複素環としてはピリジン、ピラジン、ピリミジン、ピリダジン、チオフェン、フラン、ピロール、ピラゾール、イソオキサゾール、イソチアゾール、イミダゾール、オキサゾール、チアゾール、ピペリジン、ピペラジン、ピロリジン、キヌクリジン、テトラヒドロフラン、モルホリン、チオモルホリンなどを、２環式縮合複素環としてはキノリン、イソキノリン、ナフチリジン、フロピリジン、チエノピリジン、ピロロピリジン、オキサゾロピリジン、イミダゾロピリジン、チアゾロピリジンなどの縮合ピリジン環、ベンゾフラン、ベンゾチオフェン、ベンズイミダゾールなどを挙げることができる。
【００５５】
ハロゲン原子とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子を挙げることができる。
炭素数１〜４のアルキル基とは、例えばメチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基などを挙げることができる。
【００５６】
炭素数１〜４のアルコキシ基とは、例えばメトキシ基、エトキシ基、ｎ−プロポキシ基、イソプロポキシ基、アリルオキシ基、ｎ−ブトキシ基、イソブトキシ基、ｓｅｃ−ブトキシ基、ｔｅｒｔ−ブトキシ基などを挙げることができる。 炭素数１〜４のアミノアルキル基とは、例えばアミノメチル基、１−アミノエチル基、２−アミノプロピル基などを挙げることができる。
【００５７】
炭素数１〜４のアルキルアミノ基とは、例えばＮ−メチルアミノ基、Ｎ，Ｎ−ジメチルアミノ基、Ｎ，Ｎ−ジエチルアミノ基、Ｎ−メチル−Ｎ−エチルアミノ基、Ｎ，Ｎ−ジイソプロピルアミノ基などを挙げることができる。
炭素数１〜４のアシル基とは、例えばアセチル基、プロパノイル基、ブタノイル基を挙げることができる。
【００５８】
炭素数１〜４のアシルアミノ基とは、例えばアセチルアミノ基、プロパノイルアミノ基、ブタノイルアミノ基などを挙げることができる。
炭素数１〜４のアルキルチオ基とは、メチルチオ基、エチルチオ基、プロピルチオ基などを挙げることができる。
【００５９】
炭素数１〜４のパーフルオロアルキル基とは、例えばトリフルオロメチル基、ペンタフルオロエチル基などを挙げることができる。
炭素数１〜４のパーフルオロアルキルオキシ基とは、例えばトリフルオロメトキシ基、ペンタフルオロエトキシ基などを挙げることができる。
【００６０】
炭素数１〜４のアルコキシカルボニル基とは、例えばメトキシカルボニル基、エトキシカルボニル基などを挙げることができる。
置換されていてもよい炭素数１〜４のアルキル基とは、例えばメチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基などやこれに置換基として、ハロゲン原子、水酸基、アミノ基、ニトロ基、シアノ基、フェニル基、複素環からなる群より選ばれた基を１〜４個有するものを挙げることができる。
【００６１】
式（１３）で表される化合物において、高い分化誘導活性を示すために重要な要素は，後述するように（ａ）環Ａ、環Ｂと水素結合受容体としての酸素原子あるいは硫黄原子の存在，（ｂ）それらの立体的構造配置によって規定される距離である。よって、Ｙはその構造中に水素結合受容体を持ち、環Ａと環Ｂの立体的配置を必要な位置に規定する構造であれば特に限定されない。すなわち、Ｙの−ＣＯ−，−ＣＳ−，−ＳＯ−または−ＳＯ2−のいずれかを構造中に有し、ＡおよびＢを連結する鎖状または環状あるいはそれらの組み合わされた構造とは、（ａ） 炭素原子やヘテロ原子などで構成された、直鎖状あるいは分枝した鎖状の構造中に−ＣＯ−，−ＣＳ−，−ＳＯ−，−ＳＯ2−を含むＡとＢを連結する構造、（ｂ）環状構造中に−ＣＯ−，−ＣＳ−，−ＳＯ−，−ＳＯ2−を持つＡとＢを連結する構造、（ｃ）環状構造と鎖状の構造が組合わさり１つの構造となり、その構造中に−ＣＯ−，−ＣＳ−，−ＳＯ−，−ＳＯ2−を含むＡとＢを連結する構造のいずれかを意味する。
【００６２】
環状構造の基本構造として、４から７員環の炭素原子あるいはヘテロ原子を含む環構造、あるいはそれらの縮合環が挙げられる。シクロブタン環、シクロペンタン環、シクロヘキサン環、シクロヘプタン環、オキセタン環、オキソラン環、オキサン環、オキセパン環、ピロリジン環、イミダゾリジン環、ピラゾリジン環、ピペリジン環、ピペラジン環、インドリン環、イソインドリン環、チオラン環、チアゾリジン環、オキサゾリジン環などが挙げられ、その構造中に不飽和結合、水素結合受容体や置換基を持つことができる。
【００６３】
式（１３）で表される化合物のコンフォメーションの自由度を考慮した解析を行うことにより、高い分化誘導活性を示す化合物において、疎水性相互作用や水素結合などの生体−薬物相互作用に関与すると考えられる原子団が特定の空間配置をとることを見いだした。
【００６４】
具体的には、高活性化合物の３次元構造を、分子モデリングソフトウェア（SYBYL6.3）を用いて発生し、すべての回転可能な結合について配座解析を行うことにより最安定構造を求めた。ここでエネルギーの評価は、Gasteiger-Huckel法により各原子上に電荷を発生させた後、Tripos力場を用いて行った。ついで最安定構造を出発構造として、コンフォメーションを考慮した重ね合わせをDISCO/SYBYLにより行った結果、ある特定の空間配置が高い分化誘導活性の発現に必要であることを見いだした。
【００６５】
上記の解析操作において、他の市販の計算パッケージ［CATALYST(MSI社）、 Cerius2/QSAR+（MSI 社）、SYBYL/DISCO（Tripos社）など］を用いることによっても解析を行うことが可能であり、本発明で得られた距離情報は特定の計算プログラムにより限定されるものではない。
【００６６】
空間配置の定義に用いた環の重心は、環を構成する原子のＸ、ＹおよびＺ軸の平均として定義することができる。また対象とする環構造が縮合多環系の場合、縮合環全体の重心あるいはその一部の環の重心のいずれかを、空間を定義するための重心として用いることができる。
【００６７】
立体配置をとることが可能なとは、空間配置を満たすコンフォーマーがエネルギー的に最安定構造から１５kcal/mol以内に存在することを意味するが、より好ましくは８kcal/mol以内に存在することが望ましい。
計算手法の詳細は、Sybylマニュアル：M.ClarkまたはJ.Comput.Chem. 10. 982(1989)に記載の方法に従い行うことができる。
【００６８】
薬学的に許容される化合物の塩とは、この分野で常用される塩酸、臭化水素酸、硫酸、燐酸などの無機酸や、酢酸、乳酸、酒石酸、リンゴ酸、コハク酸、フマル酸、マレイン酸、クエン酸、安息香酸、トリフルオロ酢酸、ｐ−トルエンスルホン酸、メタンスルホン酸などの有機酸との塩を挙げることができる。例えば、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド塩酸塩、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド臭化水素酸塩、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド硫酸塩、
【００６９】
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド燐酸塩、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド酢酸塩、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド乳酸塩、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド酒石酸、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミドリンゴ酸塩、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミドコハク酸塩、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミドフマル酸塩、
【００７０】
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミドマレイン酸塩、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミドクエン酸塩、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミドトリフルオロ酢酸、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミドｐ−トルエンスルホン酸塩、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミドメタンスルホン酸塩などを挙げることができる。
【００７１】
医薬品とは制癌剤の他、自己免疫疾患、皮膚病、寄生虫感染症などの治療および／または改善薬を表す。
【００７２】
式（１）および式（１３）で表される化合物において不斉炭素を有する場合は、異なった立体異性形態またはラセミ形態を含む立体異性形態の混合物の形態で存在することができる。すなわち、本発明はこのように規定した種々の形態をも包含するが、これらも同様に有効成分化合物として用いることができる。
【００７３】
以下、本発明の式（１）および式（１３）で示される代表的化合物を表−１［表１−表２４］、表−２［表２５−表２６］、表−３［表２７−表２８］および表−４［表２９−表３０］に具体的に例示する。
なお、本発明はこれらの例に限定されるものではない。
【００７４】
【表１】
Figure 0004105451
表−１
【００７５】
【表２】
Figure 0004105451
表−１続きの１
【００７６】
【表３】
Figure 0004105451
表−１続きの２
【００７７】
【表４】
Figure 0004105451
表−１続きの３
【００７８】
【表５】
Figure 0004105451
表−１続きの４
【００７９】
【表６】
Figure 0004105451
表−１続きの５
【００８０】
【表７】
Figure 0004105451
表−１続きの６
【００８１】
【表８】
Figure 0004105451
表−１続きの７
【００８２】
【表９】
Figure 0004105451
表−１続きの８
【００８３】
【表１０】
Figure 0004105451
表−１続きの９
【００８４】
【表１１】
Figure 0004105451
表−１続きの１０
【００８５】
【表１２】
Figure 0004105451
表−１続きの１１
【００８６】
【表１３】
Figure 0004105451
表−１続きの１２
【００８７】
【表１４】
Figure 0004105451
表−１続きの１３
【００８８】
【表１５】
Figure 0004105451
表−１続きの１４
【００８９】
【表１６】
Figure 0004105451
表−１続きの１５
【００９０】
【表１７】
Figure 0004105451
表−１続きの１６
【００９１】
【表１８】
Figure 0004105451
表−１続きの１７
【００９２】
【表１９】
Figure 0004105451
表−１続きの１８
【００９３】
【表２０】
Figure 0004105451
表−１続きの１９
【００９４】
【表２１】
Figure 0004105451
表−１続きの２０
【００９５】
【表２２】
Figure 0004105451
表−１続きの２１
【００９６】
【表２３】
Figure 0004105451
表−１続きの２２
【００９７】
【表２４】
Figure 0004105451
表−１続きの２３
【００９８】
【表２５】
Figure 0004105451
表−２
【００９９】
【表２６】
Figure 0004105451
表−２続きの１
【０１００】
【表２７】
Figure 0004105451
表−２続きの２
【０１０１】
【表２８】
Figure 0004105451
表−３
【０１０２】
【表２９】
Figure 0004105451
表−３続きの１
【０１０３】
【表３０】
Figure 0004105451
表−４
【０１０４】
【表３１】
Figure 0004105451
表−４続きの１
【０１０５】
本発明の化合物は、例えば下記のような方法により製造することができる。
（ａ） 式（１４）［化２７］
【０１０６】
【化１５】
Figure 0004105451
［式中、ＡおよびＸは前記と同義。Ｒ９は−Ｃ（＝Ｇ）ＯＨ（Ｇは、酸素原子または硫黄原子を表す）または−ＮＨ2を表す。］で示される化合物と式（１５）［化２８］
【０１０７】
【化１６】
Figure 0004105451
［式中、Ｒ１、Ｒ２およびｎは前記と同義。Ｒ１０はＲ９が−Ｃ（＝Ｇ）ＯＨ（Ｇは前記と同義）のときは−ＮＨ2を表し、Ｒ９が−ＮＨ2のときは−Ｃ（＝Ｇ）ＯＨ（Ｇは前記と同義）を表す。Ｒ１１はｔｅｒｔ−ブトキシカルボニル基などの通常のペプチド形成反応に用いられる保護基で保護されたアミノ基またはベンジル基などの通常のペプチド形成反応に用いられる保護基で保護された水酸基を表す。］で示される化合物を縮合反応に付すか、
（ｂ） 式（１６）［化２９］
【０１０８】
【化１７】
Figure 0004105451
（式中、ＡおよびＸは前記と同義。Ｒ１２は−ＯＨまたは−ＮＨ2を表す。）で示される化合物と式（１７）［化３０］
【０１０９】
【化１８】
Figure 0004105451
（式中、Ｒ１、Ｒ２、Ｒ１１およびｎは前記と同義。Ｒ１３は−ＯＨまたは−ＮＨ2を表す。）で示される化合物を、Ｎ，Ｎ’−カルボニルジイミダゾール、Ｎ，Ｎ’−チオカルボニルジイミダゾール、ホスゲンまたはチオホスゲンなどを用いて縮合反応に付して得られる式（１８）［化３１］
【０１１０】
【化１９】
Figure 0004105451
（式中、Ａ、Ｘ、Ｑ、ｎ、Ｒ１、Ｒ２およびＲ１１は前記と同義。）で示される化合物の保護基を除去することにより本発明の化合物を得ることができる。
（ｃ） 式（１４）で示される化合物と式（１９）［化３２］
【０１１１】
【化２０】
Figure 0004105451
（式中、Ｒ１、Ｒ１０およびｎは前記と同義。Ｒ１４は、メチル基、エチル基またはｔｅｒｔ−ブチル基を表す。）で示される化合物を縮合反応に付すか、
（ｄ） 式（１６）で示される化合物と式（２０）［化３３］
【０１１２】
【化２１】
Figure 0004105451
（式中、Ｒ１、Ｒ１３、Ｒ１４およびｎは前記と同義。）で示される化合物を、Ｎ，Ｎ’−カルボニルジイミダゾール、Ｎ，Ｎ’−チオカルボニルジイミダゾール、ホスゲンまたはチオホスゲンなどを用いて縮合反応に付して得られる式（２１）［化３４］
【０１１３】
【化２２】
Figure 0004105451
（式中、Ａ、Ｘ、Ｑ、ｎ、Ｒ１およびＲ１４は前記と同義。）で示される化合物を加水分解して得られる式（２２）［化３５］
【０１１４】
【化２３】
Figure 0004105451
（式中、Ａ、Ｘ、Ｑ、ｎおよびＲ１は前記と同義。）で示される化合物を式（２３）［化３６］
【０１１５】
【化２４】
Figure 0004105451
（式中、Ｒ２およびＲ１１は前記と同義。）で示される化合物と縮合反応に付して得られる式（１８）で示される化合物の保護基を除去することによっても本発明の化合物を得ることができる。
（ｅ） 式（２２）で示される化合物と式（２４）［化３７］
【０１１６】
【化２５】
Figure 0004105451
（式中、Ｒ２およびＲ３は前記と同義。）で示される化合物を縮合反応に付すことによっても本発明の化合物を得ることができる。
【０１１７】
代表的な中間体の合成について述べる。
式（１５）で示される化合物は、式（２５）［化３８］
【０１１８】
【化２６】
Figure 0004105451
（式中、Ｒ１、Ｒ１０およびｎは前記と同義。）で示される安息香酸誘導体に適当な保護基を導入した後、式（２３）で示される化合物と縮合反応に付し、さらに脱保護を行うことにより得ることができる。
式（１７）で示される化合物は、式（２６）［化３９］
【０１１９】
【化２７】
Figure 0004105451
（式中、Ｒ１、Ｒ１３およびｎは前記と同義。）で示される安息香酸誘導体に適当な保護基を導入した後、式（２３）で示される化合物と縮合反応に付し、さらに脱保護を行うことにより得ることができる。
式（２３）で示される化合物は、式（２４）で示される化合物に保護基を導入することにより得ることができる。
【０１２０】
次に反応について述べる。
（ａ）の縮合反応は、通常のペプチドにおけるアミド結合形成反応、例えば活性エステルまたは混合酸無水物または酸塩化物の方法によって実施することができる。例えば、カルボン酸成分［式（１４）においてＲ９が−Ｃ（＝Ｇ）ＯＨ（Ｇは前記と同義。）で示される化合物または式（１５）においてＲ１０が−Ｃ（＝Ｇ）ＯＨ（Ｇは前記と同義）で示される化合物］と２、４、５−トリクロロフェノール、ペンタクロロフェノールもしくは４−ニトロフェノールなどのフェノール類、またはＮ−ヒドロキシスクシイミド、Ｎ−ヒドキシベンズトリアゾールなどのＮ−ヒドロキシ化合物を、ジシクロヘキシルカルボジイミドの存在下に縮合させ、活性エステル体に変換した後、アミン成分［式（１４）においてＲ９が−ＮＨ2で示される化合物または式（１５）においてＲ１０が−ＮＨ2で示される化合物］と縮合させることによって行うことができる。
【０１２１】
また、カルボン酸成分［式（１４）においてＲ９が−Ｃ（＝Ｇ）ＯＨ（Ｇは前記と同義）で示される化合物または式（１５）においてＲ１０が−Ｃ（＝Ｇ）ＯＨ（Ｇは前記と同義）で示される化合物］を塩化オキザリル、塩化チオニル、オキシ塩化リンなどと反応させ、酸塩化物に変換した後、アミン成分［式（１４）においてＲ９が−ＮＨ2で示される化合物または式（１５）においてＲ１０が−ＮＨ2で示される化合物］と縮合させることによって行うことができる。
【０１２２】
また、カルボン酸成分［式（１４）においてＲ９が−Ｃ（＝Ｇ）ＯＨ（Ｇは前記と同義）で示される化合物または式（１５）においてＲ１０が−Ｃ（＝Ｇ）ＯＨ（Ｇは前記と同義）で示される化合物］をクロロ炭酸イソブチルまたはメタンスルホニルクロライドなどと反応させることによって混合酸無水物を得た後、アミン成分［式（１４）においてＲ９が−ＮＨ2で示される化合物または式（１５）においてＲ１０が−ＮＨ2で示される化合物］と縮合させることによって行うことができる。
【０１２３】
さらにまた、当該縮合反応は、ジシクロヘキシルカルボジイミド、Ｎ，Ｎ’−カルボニルジイミダゾール、ジフェニルリン酸アジド、ジエチルリン酸シアニド、２−クロロ−１，３−ジメチルイミダゾロニウムクロライドなどのペプチド縮合試薬を単独で用いて行うこともできる。
【０１２４】
反応は、通常−２０〜＋５０℃で０．５〜４８時間行う。用いられる溶媒としては例えば、ベンゼン、トルエンなどの芳香族炭化水素類、テトラヒドロフラン、ジオキサン、ジエチルエーテルなどのエーテル類、塩化メチレン、クロロホルムなどのハロゲン化炭化水素類、Ｎ，Ｎ−ジメチルホルムアミドの他、メタノール、エタノールなどのアルコール類またはこれらの混合物が挙げられる。必要により有機塩基例えば、トリエチルアミンまたはピリジンなどを加えて反応する。
【０１２５】
（ｂ）の縮合反応は、式（１６）または式（１７）で示される化合物のどちらか一方をホスゲン、チオホスゲン、Ｎ，Ｎ’−カルボニルジイミダゾールやＮ，Ｎ’−チオカルボニルジイミダゾールなどを用いて活性化した後、もう一方の化合物と反応させることによって行うことができる。反応は、通常−２０〜＋５０℃で０．５〜４８時間反応行う。用いられる溶媒としては例えば、ベンゼン、トルエンなどの芳香族炭化水素類、テトラヒドロフラン、ジオキサン、ジエチルエーテルなどのエーテル類、塩化メチレン、クロロホルムなどのハロゲン化炭化水素類、Ｎ，Ｎ−ジメチルホルムアミド、またはこれらの混合物が挙げられる。必要により有機塩基例えば、トリエチルアミンまたはピリジンなどを加えて反応を行う。
【０１２６】
（ｃ）の縮合反応は（ａ）の縮合反応と同様の方法により行うことができる。
（ｄ）の縮合反応は（ｂ）の縮合反応と同様の方法により行うことができる。
【０１２７】
式（１７）で示される化合物の保護基の除去は、通常のペプチド形成反応に用いられる条件で行われる。例えば、式（１８）においてＲ１１が、ｔｅｒｔ−ブトキシカルボニル基で保護されたアミノ基の場合は、塩酸またはトリフルオロ酢酸などの酸で処理することにより脱保護反応を行うことができる。
【０１２８】
式（１）および式（１３）で示される化合物の塩は、式（１）および式（１３）で示される化合物を製造する反応で得ることもできるが、薬学的に許容される酸と容易に塩を形成し得る。その酸としては、例えば塩酸、臭化水素酸、硫酸、燐酸などの無機酸や、酢酸、酒石酸、フマル酸、マレイン酸、クエン酸、安息香酸、トリフルオロ酢酸、ｐ−トルエンスルホン酸などの有機酸を挙げることができる。これらの塩もまたフリー体の式（１）および式（１３）の化合物と同様に本発明の有効成分化合物として用いることができる。
【０１２９】
式（１）および式（１３）で示される化合物は、反応混合物から通常の分離手段、例えば抽出法、再結晶法、カラムクロマトグラフィーなどの方法により単離精製することができる。
【０１３０】
本発明の新規ベンズアミド誘導体および新規アリニド誘導体は分化誘導作用を有しており、悪性腫瘍、自己免疫疾患、皮膚病、寄生虫感染症などの治療および／または改善剤として有用である。
【０１３１】
ここで悪性腫瘍とは急性白血病、慢性白血病、悪性リンパ腫、多発性骨髄腫、マクログロブリン血症などの造血器腫瘍の他、大腸癌、脳腫瘍、頭頚部癌、乳癌、肺癌、食道癌、胃癌、肝癌、胆嚢癌、胆管癌、膵癌、膵島細胞癌、腎細胞癌、副腎皮質癌、膀胱癌、前立腺癌、睾丸腫瘍、卵巣癌、子宮癌、絨毛癌、甲状腺癌、悪性カルチノイド腫瘍、皮膚癌、悪性黒色腫、骨肉腫、軟部組織肉腫、神経芽細胞腫、ウィルムス腫瘍、網膜芽細胞腫などの固形腫瘍が挙げられる。
【０１３２】
自己免疫疾患とはリウマチ、腎炎、糖尿病、全身性エリテマトーデス、ヒト自己免疫生リンパ球増殖性リンパ節症、免疫芽細胞性リンパ節症、クローン病、潰瘍性大腸炎などを示す。
皮膚病とは、乾せん、アクネ、湿疹、アトピー性皮膚炎などを示す。
寄生虫感染症とは、マラリア感染症等の寄生虫の感染によってひきおこされる疾患を示す。
なお、本発明の対象疾患はこれらに限定されることはない。
【０１３３】
本発明の有効成分化合物は、医薬品として有用であり、これらは一般的な医療製剤の形態で用いられる。製剤は通常使用される充填剤、増量剤、結合剤、保湿剤、崩壊剤、界面活性剤、滑沢剤等の希釈剤あるいは賦形剤を用いて調製される。この医薬製剤としては各種の形態が治療目的に応じて選択でき、その代表的なものとして錠剤、丸剤、散剤、液剤、懸濁剤、乳剤、顆粒剤、カプセル剤、注射剤（液剤、懸濁剤等）および坐剤等が挙げられる。
【０１３４】
錠剤の形態に成形するに際しては、担体としてこの分野で従来よりよく知られている各種のものを広く使用することができる。その例としては、例えば乳糖、ブドウ糖、デンプン、炭酸カルシウム、カオリン、結晶セルロース、ケイ酸等の賦形剤、水、エタノール、プロピルアルコール、単シロップ、ブドウ糖液、デンプン液、ゼラチン溶液、カルボキシメチルセルロース、セラック、メチルセルロース、ポリビニルピロリドン等の結合剤、乾燥デンプン、アルギン酸ナトリウム、カンテン末、カルメロースカルシウム、デンプン、乳糖等の崩壊剤、白糖、
【０１３５】
カカオバター、水素添加油等の崩壊抑制剤、第４級アンモニウム塩基、ラウリル硫酸ナトリウム等の吸収促進剤、グリセリン、デンプン等の保湿剤、デンプン、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等の吸着剤、タルク、ステアリン酸塩、ポリエチレングリコール等の滑沢剤等を使用することができる。さらに錠剤については、必要に応じ通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被包錠、腸溶性被包錠、フィルムコーティング錠あるいは二層錠、多層錠とすることができる。
【０１３６】
丸剤の形態に成形するに際しては、担体として従来この分野で公知のものを広く使用できる。その例としては、例えば結晶セルロース、乳糖、デンプン、硬化植物油、カオリン、タルク等の賦形剤、アラビアゴム末、トラガント末、ゼラチン等の結合剤、カルメロースカルシウム、カンテン等の崩壊剤等が挙げられる。
【０１３７】
カプセル剤は、常法に従い通常有効成分化合物を上記で例示した各種の担体と混合して、硬質ゼラチンカプセル、軟質カプセル等に充填して調製される。
【０１３８】
注射剤として調製する場合、液剤、乳剤および懸濁剤は殺菌され、かつ血液と等張であることが好ましく、これらの形態に成形するに際しては、希釈剤としてこの分野において慣用されているもの、例えば水、エタノール、マクロゴール、プロピレングリコール、エトキシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル類等を使用することができる。この場合等張性の溶液を調製するのに必要な量の食塩、ブドウ糖あるいはグリセリンを医薬製剤中に含有させてもよく、また通常の溶解補助剤、緩衝剤、無痛化剤等を添加してもよい。
【０１３９】
坐剤の形態に成形するに際しては、担体として従来公知のものを広く使用することができる。その例としては、例えば半合成グリセライド、カカオ脂、高級アルコール、高級アルコールのエステル類、ポリエチレングリコール等を挙げることができる。
【０１４０】
さらに必要に応じて着色剤、保存剤、香料、風味剤、甘味剤等や他の医薬品を医薬製剤中に含有させることもできる。
本発明のこれらの医薬製剤中に含有されるべき有効成分化合物の量は、特に限定されずに広範囲から適宜選択されるが、通常製剤組成物中に約１〜７０重量％、好ましくは約５〜５０重量％とするのがよい。
【０１４１】
本発明のこれら医薬製剤の投与方法は特に制限はなく、各種製剤形態、患者の年齢、性別、疾患の程度およびその他の条件に応じた方法で投与される。例えば錠剤、丸剤、液剤、懸濁剤、乳剤、顆粒剤およびカプセル剤の場合には、経口投与され、注射剤の場合は、単独でまたはブドウ糖、アミノ酸等の通常の補液と混合して静脈内投与され、さらに必要に応じて単独で筋肉内、皮下もしくは腹腔内投与される。坐剤の場合は直腸内投与される。
【０１４２】
本発明のこれら医薬製剤の投与量は、用法、患者の年齢、性別、疾患の程度およびその他の条件により適宜選択されるが、通常有効成分化合物の量としては、体重１ｋｇ当り、一日約0.0001〜100ｍｇ程度とするのがよい。また投与単位形態の製剤中には有効成分化合物が約0.001〜1,000ｍｇの範囲で含有されることが望ましい。
本発明の式（１）および式（１３）で表される化合物およびその塩は、薬理学的に効果を示す投与量において問題となるような毒性を示さない。
【０１４３】
【実施例】
以下に本発明を実施例で詳細に説明するが、本発明はこれらに限定されるものではない。なお、表題の括弧内の番号は詳細な説明に例示した化合物の番号である。
【０１４４】
実施例１
Ｎ−（２−アミノフェニル）−４−（Ｎ−ベンゾイルアミノメチル）ベンズアミド 塩酸塩（表−１：化合物番号１の塩酸塩）の合成
（１−１） ４−アミノメチル安息香酸２１．１６ｇ（１４０ｍｍｏｌ）のジクロロメタン（４５０ｍｌ）懸濁液に、トリエチルアミン４２ｍｌ（３００ｍｍｏｌ）を加えた。氷冷下、内温を３〜８℃に保ちながら無水トリフルオロ酢酸６０．４ｇ（２８７ｍｍｏｌ）のジクロロメタン（５０ｍｌ）溶液を滴下した後、３時間攪拌した。飽和重曹水中に反応液をあけた後、さらに１０％塩酸水溶液で酸性にした。析出したゲル状沈澱物を、濾取、乾燥することにより、４−（Ｎ−トリフルオロアセチルアミノメチル）安息香酸３０．４ｇ（収率８７．８％）を乳白色固体として得た。
1H NMR(270MHz, DMSO-d6)δppm: 4.47(2H,d,J=5.8Hz), 7.39(2H,d,J=8.1Hz), 7.93(2H,d,J=8.1Hz), 10.08(1H,t,J=5.8Hz), 12.95(1H,br.s).
【０１４５】
（１−２） ｏ−フェニレンジアミン１０８ｇ（１．０ｍｏｌ）のジオキサン（１０００ｍｌ）溶液に１規定水酸化ナトリウム水溶液（５００ｍｌ）を加え、氷冷下ジｔｅｒｔ−ブチルジカーボネート２１８ｇ（１．１ｍｏｌ）のジオキサン（５００ｍｌ）溶液を加えた。室温で６時間攪拌後、一晩放置した。溶媒を１／２容にまで濃縮した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得た残渣をシリカゲルカラムクロマトグラフィー（クロロホルム）で精製し、得られた固体をエチルエーテルで洗浄することによりＮ−ｔｅｒｔ−ブトキシカルボニル−ｏ−フェニレンジアミン６８．４ｇ（収率３２．８％）を白色固体として得た。
1H NMR(270MHz, CDCl3)δppm: 1.51(9H,s), 3.75(2H,s), 6.26(1H,s), 6.77(1H,d,J=8.1Hz), 6.79(1H,dd,J=7.3,8.1Hz), 7.00(1H,dd,J=7.3,8.1Hz), 7.27(1H,d,J=8.1Hz).
【０１４６】
（１−３） 工程（１−１）で得られた化合物３０．０ｇ（１２１ｍｍｏｌ）のジクロロメタン（２００ｍｌ）懸濁液に、氷冷しながら（内温１０〜１５℃）オキザリルクロライド２１ｇ（１６５ｍｍｏｌ）を徐々に滴下した。その際にときどき（およそ２ｍｌ滴下する毎に０．１ｍｌ）ＤＭＦを加えた。全量滴下後、発泡が止まるまで攪拌し、その後４０℃で１時間攪拌した。溶媒を留去した後、トルエンで過剰のオキザリルクロライドを共沸し、再度ジクロロメタン（１００ｍｌ）に溶解した。工程（１−２）で得られた化合物２２．８８ｇ（１１０ｍｍｏｌ）のジクロロメタン（１００ｍｌ）−ピリジン（２００ｍｌ）溶液に、先に調製した酸クロライド溶液を氷冷下（内温７〜９℃）滴下した。
【０１４７】
滴下終了後、室温まで昇温させた後、一晩放置した。反応混合物に飽和重曹水を加えた後、クロロホルムで抽出し、飽和食塩水で洗浄後、乾燥、溶媒を留去した。得られた残渣にメタノール−ジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］−４−（Ｎ−トリフルオロアセチルアミノメチル）ベンズアミド２８．１ｇ（収率５８％）を淡黄色固体として得た。
1H NMR(270MHz, DMSO-d6)δppm: 1.44(9H,s), 4.48(2H,d,J=5.9Hz), 7.12-7.23(2H,m), 7.44(2H,d,J=8.1Hz), 7.54(2H,d,J=8.1Hz), 7.94(2H,d,J=8.1Hz), 8.68(1H,br.s), 9.83(1H,s), 10.10(1H,br.t,J=5.9Hz).
【０１４８】
（１−４） 工程（１−３）の化合物１３．１２ｇ（３０ｍｍｏｌ）のメタノール（１２０ｍｌ）−水（１８０ｍｌ）懸濁液に炭酸カリウム４．７０ｇ（３４．０ｍｍｏｌ）を加え、７０℃で４時間加熱攪拌した。クロロホルムで抽出し、有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去し、乾燥することにより、４−アミノメチル−Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］ベンズアミド１０．３ｇ（定量的）を淡黄色アモルファス状固体として得た。1H NMR(270MHz, DMSO-d6)δppm: 3.80(2H,s), 7.13-7.23(2H,m), 7.48-7.58(4H,m), 7.90(2H,d,J=8.1Hz), 8.69(1H,br.s), 9.77(1H,br.s).
【０１４９】
（１−５） 工程（１−４）の化合物０．１１ｇ（０．４４ｍｍｏｌ）のピリジン（５ｍｌ）溶液に氷冷下、ベンゾイルクロライド０．０８ｇ（０．５３ｍｍｏｌ）を加えた後、室温まで徐々に温度を上げながら８時間攪拌した。飽和重曹水を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、乾燥、溶媒を留去して得られた残渣をジイソプロピルエーテルで洗浄し、得られた固体を乾燥することにより、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］−４−（Ｎ−ベンゾイルアミノメチル）ベンズアミド０．１４ｇ（収率７１．４％）を白色固体として得た。
1H NMR(270MHz, DMSO-d6)δppm: 1.44(9H,s), 4.56(2H,d,J=5.9Hz), 7.11-7.22(2H,m), 7.46-7.56(7H,m), 7.90-7.94(4H,m), 8.67(1H,s), 9.15(1H,t,J= 5.9Hz), 9.81(1H,s).
【０１５０】
（１−６） 工程（１−５）の化合物０．１０ｇ（０．２２４ｍｍｏｌ）のジオキサン（５ｍｌ）−メタノール（１ｍｌ）溶液に４規定塩酸−ジオキサン（５ｍｌ）を加え、室温で７時間攪拌した。溶媒を留去した残渣にジイソプロピルエーテルを加え、得られた固体を濾取、乾燥することにより、Ｎ−（２−アミノフェニル）−４−（Ｎ−ベンゾイルアミノメチル）ベンズアミド 塩酸塩０．０８ｇ（収率９３％）を淡褐色固体として得た。
mp. 206-209℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.57(2H,d,J=5.8Hz), 7.27-7.38(4H,m), 7.47-7.59(5H,m), 7.92(1H,d,J=8.1Hz), 8.05(1H,d,J=8.1Hz), 9.19(1H,t,J=5.8Hz), 10.38(1H,br.s).
IR(KBr)cm-1: 3286,3003(br.),1630,1551,1492,1306,1250,749,695.
実施例１と同様の方法により、実施例２から実施例４４の化合物を合成した。以下に、化合物の融点（mp.）、1H NMR、IRの測定値を示す。
【０１５１】
実施例２
Ｎ−（２−アミノフェニル）−４−［Ｎ−（２−クロロベンゾイル）アミノメチル］ベンズアミド（表−１：化合物番号１４）
mp. 201-204℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.52(2H,t,J=5.9Hz), 4.89(2H,br.s), 6.60(1H,ddd,J=1.5,7.3,8.1Hz), 6.78(1H,dd,J=1.5,8.1Hz), 6.97(1H,ddd,J=1.5,7.3,8.1Hz), 7.17(1H,d,J=8.1Hz), 7.38-7.54(6H,m), 7.97(2H,d,J=8.1Hz), 9.06(1H,br.t,J=5.9Hz), 9.63(1H,br.s).
IR(KBr)cm-1: 3268,1649,1458,1304,748.
【０１５２】
実施例３
Ｎ−（２−アミノフェニル）−４−［Ｎ−（２−ニトロベンゾイル）アミノメチル］ベンズアミド 塩酸塩（表−１：化合物番号１８の塩酸塩）
mp. 210-212℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.55(2H,t,J=5.9Hz), 7.20-7.40(3H,m), 7.50-7.60(1H,m), 7.53(2H,d,J=8.1Hz), 7.60-7.70(2H,m), 7.83(1H,ddd,J=1.5,8.1,8.1Hz), 8.00-8.10(3H,m), 9.34(1H,t,J=5.9Hz), 10.43(1H,br.s).
IR(KBr)cm-1: 3283,2500-3000(br.),1648,1534,1461,1362,1314,754,701.
【０１５３】
実施例４
Ｎ−（２−アミノフェニル）−４−［Ｎ−（４−メチルベンゾイル）アミノメチル］ベンズアミド 塩酸塩（表−１：化合物番号２８の塩酸塩）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 2.37(3H,s), 4.56(2H,d,J=5.0Hz), 7.20-7.30(6H,m), 7.47(4H,d,J=8.8Hz), 7.82(2H,d,J=8.8Hz), 8.03(2H,d,J=8.8Hz), 9.09(1H,t,J=5Hz), 10.36(1H,br.s).
IR(KBr)cm-1: 3269(br.),2861(br.),1743,1636,1534,1505,1456,1308,1120,753.
【０１５４】
実施例５
Ｎ−（２−アミノフェニル）−４−［Ｎ−（３−メトキシベンゾイル）アミノメチル］ベンズアミド（表−１：化合物番号３０）
mp. 182-185℃.
1H NMR(270MHz, DMSO-d6)δppm: 3.81(3H,s), 4.54(2H,d,J=5.9Hz), 4.88(2H,br.s), 6.60(1H,dd,J=6.6,7.3Hz), 6,78(1H,d,J=7.3Hz), 6.97(1H,dd,J=6.6,7.3Hz), 7.11(1H,dd,J=1.5,8.1Hz), 7.16(1H,d,J=7.3Hz), 7.35-7.51(5H,m), 7.94(2H,d,J=8.1Hz), 9.12(1H,br.t,J=5.9Hz), 9.63(1H,br.s).
IR(KBr)cm-1: 3301,1637,1524,1489,1457,1314,1248,752.
【０１５５】
実施例６
Ｎ−（２−アミノフェニル）−４−［Ｎ−（４−メトキシベンゾイル）アミノメチル］ベンズアミド（表−１：化合物番号３１）
mp. 149-151℃.
1H NMR(270MHz, DMSO-d6)δppm: 3.82(3H,s), 4.53(2H,d,J=5.9Hz), 4.88(2H,s), 6.59(1H,dd,J=7.3,7.3Hz), 6.77(1H,d,J=8.1Hz), 6.94-7.00(1H,m), 7.02(2H,d,J=8.8Hz), 7.16(1H,d,J=8.1Hz), 7.43(2H,d,J=8.1Hz), 7.89(2H,d,J=8.8Hz), 7.94(2H,d,J=8.1Hz), 8.98(1H,br.t,J= 5.9Hz), 9.61(1H,br.s).
IR(KBr)cm-1: 3297,1630,1527,1505,1457,1256,1177,1024,843,749.
【０１５６】
実施例７
Ｎ−（２−アミノフェニル）−４−［Ｎ−（３，４，５−トリメトキシベンゾイル）アミノメチル］ベンズアミド（表−１：化合物番号３３）
mp. 208-210℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 3.71(3H,s), 3.83(6H,s), 4.55(2H,d,J=5.9Hz), 4.88(2H,br.s), 6.60(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=6.6,8.1Hz), 7,16(1H,d,J=8.1Hz), 7.26(2H,s), 7.44(2H,d,J=8.1Hz), 7.95(2H,d,J=8.8Hz), 9.07(1H,t,J=5.9Hz), 9.62(1H,br.s).
IR(KBr)cm-1: 3267,1635,1582,1457,1237,1132,755.
【０１５７】
実施例８
Ｎ−（２−アミノフェニル）−４−［Ｎ−［４−（Ｎ，Ｎ−ジメチル）アミノベンゾイル］アミノメチル］ベンズアミド（表−１：化合物番号３６）
mp. 216-219℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 2.98(6H,s), 4.51(2H,d,J=5.9Hz), 4.88(2H,br.s), 6.60(1H,dd,J=8.1,8.1Hz), 6.71(2H,d,J=8.8Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.16(1H,d,J=7.3Hz), 7.41(2H,d,J=8.1Hz), 7.78(2H,d,J=8.8Hz), 7.93(2H,d,J=8.1Hz), 8.77(1H,t,J=5.9Hz), 9.63(1H,br.s).
IR(KBr)cm-1: 3301,1632,1519,1457,1298,754.
【０１５８】
実施例９
Ｎ−（２−アミノフェニル）−４−［Ｎ−（４−トリフルオロメチルベンゾイル）アミノメチル］ベンズアミド（表−１：化合物番号４２）
mp. 243-246℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.58(2H,d,J=5.9Hz), 4.88(2H,br.s), 6.59(1H,dd,J=6.6,7.3Hz), 6.77(1H,d,J=8.1Hz), 6.94(1H,dd,J=5.9,6.6Hz), 7.16(1H,d,J=8.1Hz), 7.45(2H,d,J=8.1Hz), 7.88(2H,d,J=8.8Hz), 7.95(2H,d,J=8.1Hz), 8.11(2H,d,J=8.1Hz), 9.38(1H,t,J=5.9Hz), 9.64(1H,br.s).
IR(KBr)cm-1: 3301,1640,1549,1523,1458,1334,1162,1120,1070,856,750.
【０１５９】
実施例１０
Ｎ−（２−アミノフェニル）−４−［Ｎ−（４−カルボキシベンゾイル）アミノメチル］ベンズアミド 塩酸塩（表−１：化合物番号４５の塩酸塩）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 4.58(2H,d,J=5.9Hz), 7.29-7.37(3H,m), 7.49(3H,d,J=8.1Hz), 8.02-8.06(6H,m), 9.36(1H,t,J=5.9Hz), 10.4(1H,br.s).
IR(KBr)cm-1: 3432(br.),1718,1637,1542,1499,1303(br.),1116,1018,757.
【０１６０】
実施例１１
Ｎ−（２−アミノフェニル）−４−［Ｎ−（４−メトキシカルボニルベンゾイル）アミノメチル］ベンズアミド（表−１：化合物番号４６）
mp. 204-209℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 3.89(3H,s), 4.57(2H,d,J=5.9Hz), 4.88(2H,br.s), 6.60(1H,dd,J=6.6,7.3Hz), 6.78(2H,d,J=7.3Hz), 6.97(1H,ddd,J=1.5,6.6,7.3Hz), 7.16(1H,d,J=7.3Hz), 7.45(2H,d,J=8.1Hz), 7.95(2H,d,J=8.1Hz), 8.03(2H,d,J=8.8Hz), 8.07(2H,d,J=8.8Hz), 9.35(1H,t,J=5.9Hz), 9.64(1H,br.s).
IR(KBr)cm-1: 3287(br.),1721,1634,1281,1113,750,703.
【０１６１】
実施例１２
Ｎ−（２−アミノフェニル）−４−（Ｎ−ピコリノイルアミノメチル）ベンズアミド（表−１：化合物番号１７３）
mp. 173-178℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.57(2H,d,J=6.6Hz), 4.88(2H,br.s), 6.59(1H,dd,J=7.3,8.1Hz), 6.77(1H,d,J=8.1Hz), 6.96(1H,dd,J=7.3,8.1Hz), 7.16(1H,d,J=7.3Hz), 7.44(2H,d,J=8.1Hz), 7.60-7.65(1H,m), 7.93(2H,d,J=8.1Hz), 7.98-8.08(2H,m), 8.67(1H,d,J=4.4Hz), 9.45(1H,t,J=6.6Hz), 9.61(1H,br.s).
IR(KBr)cm-1: 3330,1656,1634,1523,1456,1294,752.
【０１６２】
実施例１３
Ｎ−（２−アミノフェニル）−４−［Ｎ−（６−メチルピコリノイル）アミノメチル］ベンズアミド（表−１：化合物番号１７８）
mp. 172-173℃.
1H NMR(270MHz, DMSO-d6)δppm: 2.51(3H,s), 4.57(2H,d,J=6.6Hz), 5.0(2H,br.s), 6.61(1H,dd,J=7.3,8.1Hz), 6.79(1H,d,J=7.3Hz), 6.98(1H,dd,J=7.3,8.1Hz), 7.17(1H,d,J=7.3Hz), 7.44(2H,d,J=8.1Hz), 7.43-7.49(1H,m), 7.84-7.90(2H,m), 7.94(2H,d,J=8.1Hz), 9.27(1H,t,J=5.9Hz), 9.64(1H,br.s).
IR(KBr)cm-1: 3331,1675,1634,1594,1523,1454,1307,1292,750.
【０１６３】
実施例１４
Ｎ−（２−アミノフェニル）−４−（Ｎ−ニコチノイルアミノメチル）ベンズアミド（表−１：化合物番号７１）
mp. 193-196℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.58(2H,d), 4.88(2H,br.s), 6.60(1H,t), 6.78(1H,d), 6.97(1H,t), 7.16(1H,d), 7.46(2H,d), 7.53(1H,dd), 7.95(2H,d), 8.24(1H,ddd), 8.73(1H,dd), 9.07(1H,d), 9.32(1H,br.t), 9.63(1H,br.s)IR(KBr)cm-1: 3301,1639,1522,1457,1314,749,705.
【０１６４】
実施例１５
Ｎ−（２−アミノフェニル）−４−［Ｎ−（２−メチルニコチノイル）アミノメチル］ベンズアミド（表−１：化合物番号１４１）
mp. 191-194℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 2.53(3H,s), 4.53(2H,d,J=5.9Hz), 4.88(2H,br.s), 6.60(1H,dd,J=6.6,8.1Hz), 6.78(1H,d,J=7.3Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.17(1H,d,J=7.3Hz), 7.29(1H,dd,J=5.1,8.1Hz), 7.47(2H,d,J=8.1Hz), 7.77(1H,dd,J=1.5,8.1Hz), 7.97(2H,d,J=8.1Hz), 8.51(1H,dd,J=1.5,5.1Hz), 9.06(1H,t,J=5.9Hz), 9.64(1H,s).
IR(KBr)cm-1: 3261,1642,1523,1310,753.
【０１６５】
実施例１６
Ｎ−（２−アミノフェニル）−４−［Ｎ−（６−メチルニコチノイル）アミノメチル］ベンズアミド（表−１：化合物番号１４３）
mp. 186-190℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 2.36(3H,s), 4.56(2H,d,J=5.9Hz), 4.88(2H,s), 6.60(1H,dd,J=7.4,7.8Hz), 6.78(1H,d,J=7.8Hz), 6.97(1H,dd,J=6.9,6.9Hz), 7.16(1H,d,J=7.4Hz), 7.37(1H,d,J=8.3Hz), 7.45(2H,d,J=8.3Hz), 7.95(2H,d,J=8.3Hz), 8.13(1H,dd,J=2.0,8.3Hz), 8.96(1H,s), 9.24(1H,t,J=5.9Hz), 9.63(1H,br.s).
IR(KBr)cm-1: 3302,1636,1602,1523,1489,1457,1313,751.
【０１６６】
実施例１７
Ｎ−（２−アミノフェニル）−４−［Ｎ−（２−クロロニコチノイル）アミノメチル］ベンズアミド（表−１：化合物番号１５４）
mp. 176-178℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.54(2H,t,J=5.9Hz), 4.90(2H,br.s), 6.60(1H,ddd,J=1.5,7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,ddd,J=1.5,7.3,7.3Hz), 7.18(1H,d,J=8.1Hz), 7.48-7.54(3H,m), 7.94-7.99(3H,m), 8.49(1H,dd,J=2.1,5.1Hz), 9.23(1H,br.t,J=5.9Hz), 9.65(1H,br.s).
IR(KBr)cm-1: 3264,1649,1524,1400,1309,751.
【０１６７】
実施例１８
Ｎ−（２−アミノフェニル）−４−［Ｎ−（６−クロロニコチノイル）アミノメチル］ベンズアミド（表−１：化合物番号１５６）
mp. 205-208℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 5.57(2H,d,J=5.9Hz), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.96(1H,dd,J=7.3,8.1Hz), 7.16(1H,d,J=8.1Hz), 7.45(2H,d,J=8.1Hz), 7.66(1H,d,J=8.8Hz), 7.95(2H,d,J=8.1Hz), 8.27-8.32(1H,m), 8.90(1H,d,J=2.1Hz), 9.38(1H,t,J=5.9Hz), 9.63(1H,s).
IR(KBr)cm-1: 3318(br.),2929,1646,1590,1525,1503,1454,1108,745.
【０１６８】
実施例１９
Ｎ−（２−アミノフェニル）−４−（Ｎ−イソニコチノイルアミノメチル）ベンズアミド（表−１：化合物番号１８３）
mp. 234-237℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.57(2H,t,J=5.9Hz), 4.88(2H,br.s), 6.59(1H,dd,J=6.6,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.96(1H,dd,J=7.3,7.3Hz), 7.16(1H,d,J=7.3Hz), 7.45(2H,d,J=8.1Hz), 7.81(2H,d,J=1.5,4.4Hz), 7.95(2H,d,J=8.1Hz), 8.75(2H,d,J=6.6Hz), 9.41(1H,t,J=5.9Hz), 9.62(1H,br.s).
IR(KBr)cm-1: 3298,1646,1550,1525,1457,1304,843,760,695.
【０１６９】
実施例２０
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピラジン−２−イル）カルボニルアミノメチル］ベンズアミド（表−１：化合物番号１９１）
mp. 207℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.58(2H,d,J=5.9Hz), 4.88(2H,br.s), 6.59(1H,dd,J=7.3,7.3Hz), 6.77(1H,d,J=8.1Hz), 6.94(1H,ddd,J=1.5,7.3,8.1Hz), 7.15(1H,d,J=7.3Hz), 7.45(2H,d,J=8.1Hz), 7.93(2H,d,J=8.1Hz), 8.77(1H,d,J=1.5Hz), 8.90(1H,d,J=2.1Hz), 9.21(1H,s), 9.55-9.61(2H,m).
IR(KBr)cm-1: 3368(br.),1657,1524,1455,1295,1023,751.
【０１７０】
実施例２１
Ｎ−（２−アミノフェニル）−４−［Ｎ−（チオフェン−２−イル）カルボニルアミノメチル］ベンズアミド（表−１：化合物番号２０１）
mp. 202-205℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.52(2H,t,J=5.9Hz), 4.88(2H,br.s), 6.60(1H,dd,J=6.6,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.15-7.18(2H,m), 7.43(2H,d,J=8.1Hz), 7.78(1H,d,J=4.4), 7.82(1H,d,J=3.7Hz), 7.95(2H,d,J=8.1Hz), 9.12(1H,br.t,J=5.9Hz), 9.62(1H,br.s).
IR(KBr)cm-1: 3306,1633,1523,1456,1297,750,716.
【０１７１】
実施例２２
Ｎ−（２−アミノフェニル）−４−［Ｎ−（フラン−２−イル）カルボニルアミノメチル］ベンズアミド（表−１：化合物番号２０５）
mp. 197℃(dec.).
【０１７２】
1H NMR(270MHz, DMSO-d6)δppm: 4.59(2H,d,J=6.6Hz), 4.86(2H,br.s), 6.59(1H,dd,J=6.6,6.6Hz), 6.63(1H,dd,J=1.5,3.6Hz), 6.78(1H,d,J=8.1Hz), 6.96(1H,dd,J=7.3,6.6Hz), 7.10-7.20(2H,m), 7.41(2H,d,J=8.1Hz), 7.84(1H,s), 7.94(2H,d,J=8.1Hz), 9.00(1H,br.t,J= 5.9Hz), 9.62(1H,s).
IR(KBr)cm-1: 3245,1651,1573,1545,1323,1241,745.
【０１７３】
実施例２３
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピロール−２−イル）カルボニルアミノメチル］ベンズアミド（表−１：化合物番号２０９）
mp. 216-220℃(dec.)
1H NMR(270MHz, DMSO-d6)δppm: 4.50(2H,d,J=5.9Hz), 4.88(2H,br.s), 6.10(1H,dd,J=2.1,5.9Hz), 6.59(1H,dd,J=7.3,7.3Hz), 6.77(1H,dd,J=1.5,8.1Hz), 6.84-6.88(2H,m), 6.97(1H,ddd,J=1.5,7.3,8.1Hz), 7.16(1H,d,J=7.3Hz), 7.41(2H,d,J=8.1Hz), 7.94(2H,d,J=8.1Hz), 8.62(1H,br.t,J=5.9Hz), 9.62(1H,br.s).
IR(KBr)cm-1: 3275,1655,1584,1534,1458,1316,747.
【０１７４】
実施例２４
Ｎ−（２−アミノフェニル）−４−［Ｎ−（１−メチル−１Ｈ−ピロール−２−イル）カルボニルアミノメチル］ベンズアミド（表−１：化合物番号２１０）
mp. 177ー179℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 3.84(3H,s), 4.46(2H,d,J=5.9Hz), 4.88(2H,br.s), 6.03(1H,dd,J=2.1,4.4Hz), 6.59(1H,dd,J=8.1,8.1Hz), 6.77(1H,d,J=8.1Hz), 6.84-6.97(2H,m), 7.16(1H,d,J=7.3Hz), 7.41(2H,d,J=8.1Hz), 7.93(2H,d,J=8.1Hz), 8.61(1H,t,J=5.9Hz), 9.62(1H,br.s).
IR(KBr)cm-1: 3325(br.),1630,1551,1520,1507,1324,1265,1154,740.
【０１７５】
実施例２５
Ｎ−（２−アミノフェニル）−４−［Ｎ−（イソオキサゾール−５−イル）カルボニルアミノメチル］ベンズアミド（表−１：化合物番号２１２）
mp. 183-185℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.53(2H,d,J=6.6Hz), 4.89(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=7.3Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.12(1H,d,J=2.1Hz), 7.16(1H,d,J=8.1Hz), 7.44(2H,d,J=8.1Hz), 7.95(2H,d,J=8.1Hz), 8.76(1H,d,J=1.5Hz), 9.61(1H,t,J=5.9Hz), 9.64(1H,br.s).
IR(KBr)cm-1: 3278(br.),1636,1576,1522,1458,1220,749.
【０１７６】
実施例２６
Ｎ−（２−アミノフェニル）−４−［Ｎ−（３−メチルイソチアゾール−５−イル）カルボニルアミノメチル］ベンズアミド（表−１：化合物番号２１３）
mp. 168-169℃.
1H NMR(270MHz, DMSO-d6)δppm: 2.47(3H,s), 4.54(2H,d,J=5.9Hz), 4.89(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=7.3Hz), 6.97(1H,ddd,J=1.0,7.3,8.1Hz), 7.17(1H,d,J=7.3Hz), 7.44(2H,d,J=8.1Hz), 7.73(1H,s), 7.96(2H,d,J=8.1Hz), 9.44(1H,t,J=5.9Hz), 9.64(1H,br.s).
IR(KBr)cm-1: 3310,1637,1503,1294,751.
【０１７７】
実施例２７
Ｎ−（２−アミノフェニル）−４−［Ｎ−（イミダゾール−４−イル）カルボニルアミノメチル］ベンズアミド（表−１：化合物番号２１４）
mp.(amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 4.49(2H,d,J=6.4Hz), 4.87(2H,br.s), 6.59(1H,dd,J=6.9,6.9Hz), 6.77(1H,d,J=6.9Hz), 6.96(1H,dd,J=7.4,7.4Hz), 7.16(1H,d,J=6.9Hz), 7.41(2H,d,J=6.9Hz), 7.64(1H,br.s), 7.73(1H,br.s), 7.92(2H,d,J=6.9Hz), 8.56(1H,br.t,J=6.4Hz), 9.61(1H,s), 12.5(1H,br.s).
IR(KBr)cm-1: 3278(br.),1636,1576,1522,1458,1220,749.
【０１７８】
実施例２８
Ｎ−（２−アミノフェニル）−４−［Ｎ−（３−アミノフェニル）アセチルアミノメチル］ベンズアミド（表−１：化合物番号２３の化合物）
mp. 171-176℃
1H NMR(270MHz, DMSO-d6)δppm: 4.34(2H,d,J=5.9Hz), 5.24(4H,br.s), 6.48-6.63(4H,m), 6.78-6.81(1H,m), 6.94-7.00(2H,m), 7.18(1H,d,J=8.1Hz), 7.34(2H,d,J=8.1Hz), 7.92(2H,d,J=8.1Hz), 8.50(1H,t,J=5.9Hz), 9.61(1H,s).
【０１７９】
実施例２９
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）アセチルアミノメチル］ベンズアミド（表−１：化合物番号７４）
mp. 127℃.
1H NMR(270MHz, DMSO-d6)δppm: 3.84(2H,s), 4.40(2H,d,J=5.8Hz), 7.15-7.29(3H,m), 7.37(1H,d,J=6.6Hz), 7.43(2H,d,J=8.8Hz), 7.96(1H,m), 7.98(2H,d,J=8.8Hz), 8.40(1H,d,J=8.8Hz), 8.79-8.87(3H,m), 10.20(1H,s).
【０１８０】
実施例３０
Ｎ−（２−アミノフェニル）−４−［Ｎ−［３−（ピリジン−３−イル）プロピオニル］アミノメチル］ベンズアミド（表−１：化合物番号７５の化合物）
mp. 183-186℃.
1H NMR(270MHz, DMSO-d6)δppm: 2.51(2H,t,J=7.3Hz), 2.88(2H,d,J=7.3Hz), 4.31(2H,d,J=5.9Hz), 4.89(2H,br.s), 6.60(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,ddd,J=1.5,7.3,8.1Hz), 7.16(1H,d,J=8.1Hz), 7.23(2H,d,J=8.8Hz), 7.28-7.33(1H,m), 7.63(1H,d,J=8.1Hz), 7.89(2H,d,J=8.1Hz), 8.41-8.45(3H,m), 9.62(1H,br.s).
IR(KBr)cm-1: 3407,3313,1640,1552,1522,1456,1309,746,717.
【０１８１】
実施例３１
Ｎ−（２−アミノフェニル）−４−［Ｎ−［４−（ピリジン−３−イル）−１，４−ジオキソブチル］アミノメチル］ベンズアミド（表−１：化合物番号１００）
mp. 145-147℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 2.37-2.50(2H,m), 2.62-2.68(2H,m), 4.13(2H,s), 4.86(2H,s), 6.56-6.61(1H,m), 6.76-6.79(1H,m), 6.94-6.99(1H,m), 7.10-7.39(4H,m), 7.43-7.46(1H,m), 7.78(2H,d,J=8.1Hz), 8.60-8.64(1H,m), 9.58(1H,s).
IR(KBr)cm-1:3348,1691,1655,1534,1508,1458,1395,1315,1083,746.
【０１８２】
実施例３２
Ｎ−（２−アミノフェニル）−４−［Ｎ−（５−クロロピリジン−３−イル）オキシアセチルアミノメチル］ベンツアミド（表−１：化合物番号１５８）
mp. 199-201℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.43(2H,d,J=6.6Hz), 4.75(2H,s), 4.87(2H,br.s), 6.60(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.16(1H,d,J=8.1Hz), 7.37(2H,d,J=8.1Hz), 7.59(1H,d,J=2.2Hz), 7.93(2H,d,J=8.1Hz), 8.25(1H,d,J=1.5Hz), 8.81(1H,t,J=6.6Hz), 9.64(1H,s).
IR(KBr)cm-1:3288,3058,1675,1633,1523,1457,1314,912,755.
【０１８３】
実施例３３
Ｎ−（２−アミノ−５−メトキシフェニル）−４−［Ｎ−（ピリジン−３−イル）オキシアセチルアミノメチル］ベンズアミド（表−１：化合物番号１７５）
mp. 141-144℃.
1H NMR(270MHz, DMSO-d6)δppm: 3.66(3H,s), 4.43(2H,d,J=5.9Hz), 4.49(2H,br.s), 4.68(2H,s), 6.62(1H,dd,J=2.9,8.8Hz), 6.75(1H,d,J=8.8Hz), 6.91(1H,d,J=2.2Hz), 7.37(4H,m), 7.92(2H,d,J=8.8Hz), 8.21(1H,dd,J=1.5,4.4Hz), 8.35(1H,d,J=2.7Hz), 8.81(1H,s), 9.65(1H,s).
【０１８４】
実施例３４
Ｎ−（２−アミノフェニル）−４−［Ｎ−［３−（ピリジン−３−イル）−１、３−ジオキソプロピル］アミノメチル］ベンズアミド（表−１：化合物番号９８）
mp. 204-206℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.08(4/3H,s), 4.39(4/3H,d,J=5.9Hz), 4.49(2/3H,d,J=5.9Hz), 4.90(2H,br.s), 5.93(1/3H,s), 6.60(1H,t,J=7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,t,J=7.3Hz), 7.16(1H,d,J=7.3Hz), 7.3-7.7(3H,m), 7.8-8.4(3H,m), 8.6-9.2(3H,m), 9.64(1H,s), 14.74(1/3H,s).（２：１の平衡混合物）
IR(KBr)cm-1:3282,1690,1645,1527,1421,1314,1217,1028,994,911,753,701.
【０１８５】
実施例３５
Ｎ−（２−アミノフェニル）−４−［Ｎ−［Ｎ−（ピリジン−３−イル）アミノアセチル］アミノメチル］ベンズアミド（表−１：化合物番号９６）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 3.77(2H,d,=6.6Hz), 4.37(2H,d,J=5.9Hz), 4.87(2H,br.s), 6.27(1H,t,J=5.9Hz), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,7.3Hz), 6.87(1H,d,J=8.1Hz), 6.96(1H,dd,J=7.3,8.1Hz), 7.09(1H,d,J=4.4Hz), 7.12(1H,d,J=4.4Hz), 7.16(1H,d,J=8.1Hz), 7.33(2H,d,J=8.8Hz), 7.81(1H,d,J=4.4Hz), 7.91(2H,d,J=7.3Hz), 7.99(1H,d,J=2.9Hz), 8.59(1H,br.t,J=5.1Hz), 9.63(1H,br.s).
IR(KBr)cm-1:3350,1658,1525,1502,1314,750.
【０１８６】
実施例３６
Ｎ−（２−アミノフェニル）−４−［Ｎ−（２−アミノチアゾール−４−イル）アセチルアミノメチル］ベンズアミド（表−１：化合物番号２２０）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 3.34(2H,s), 4.35(2H,d,J=5.9Hz), 4.87(2H,s), 6.25(1H,s), 6.59(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=7.3Hz), 6.87(2H,s), 6.96(1H,dd,J=7.3,7.3Hz), 7.16(1H,d,J=7.3Hz), 7.37(2H,d,J=8.1Hz), 7.93(2H,d,J=8.1Hz), 8.44(1H,t,J=5.9Hz), 9.62(1H,s).
【０１８７】
実施例３７
Ｎ−（２−アミノフェニル）−４−［Ｎ−（キノリン−６−イル）カルボニルアミノメチル］ベンズアミド（表−１：化合物番号２３１）
mp. 209-210℃.
1H NMR(270MHz, DMSO-d6)δppm:4.62(2H,d,J=5.9Hz), 4.88(2H,s), 6.60(1H,t,J=7.7Hz), 6.78(1H,d,J=7.3Hz), 6.95(1H,d,J=7.3Hz), 7.17(1H,d,J=7.3Hz), 7.49(2H,d,J=8.8Hz), 7.62(1H,dd,J=4.4,8.1Hz), 7.96(2H,d,J=8.8Hz), 8.10(1H,d,J=8.8Hz), 8.23(1H,dd,J=2.2,8.8Hz), 8.38(1H,m), 8.49(1H,d,J=8.1Hz), 8.58(1H,s), 8.99(1H,s), 9.64(1H,s).
IR(KBr)cm-1:3301,1640,1614,1545,1496,1312,910,853,745.
【０１８８】
実施例３８
Ｎ−（２−アミノフェニル）−４−［Ｎ−（フロ［３，２−ｂ］ピリジン−２−イル）カルボニルアミノメチル］ベンズアミド（表−１：化合物番号２３３）
mp. 191℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.58(2H,d,J=5.9Hz), 4.88(2H,s), 6.57-6.62(1H,m), 6.76-6.79(1H,m), 6.93-6.99(1H,m), 7.15-7.25(1H,m), 7.45-7.52(3H,m), 7.74(1H,s), 7.95(2H,d,J=8.1Hz), 8.13(1H,d,J=8.8Hz), 8.63(1H,d,J=3.7Hz), 9.54(1H,t,J=5.9Hz), 9.64(1H,s).
IR(KBr)cm-1:3406,1662,1529,1507.1420,1313,1209,1139,1170,1139,924,741.
【０１８９】
実施例３９
Ｎ−（２−アミノフェニル）−４−［Ｎ−（フロ［２，３−ｃ］ピリジン−２−イル）カルボニルアミノメチル］ベンズアミド（表−１：化合物番号２３４）
mp. 210℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.58(2H,J=6.6Hz), 4.87(2H,s), 6.57-6.62(1H,m), 6.76-6.79(1H,m), 6.93-6.99(1H,m), 7.14-7.17(1H,m), 7.47(2H,d,J=8.1Hz), 7.66(1H,s), 7.82(1H,d,J=4.4Hz), 7.96(2H,d,J=8.1Hz), 8.48(1H,d,J=5.1Hz), 9.06(1H,s), 9.60-9.64(2H,m).
IR(KBr)cm-1:3320,1653,1632,1598,1457,1424,1308,1187,1033,853,749.
【０１９０】
実施例４０
Ｎ−（２−ヒドロキシフェニル）−４−［Ｎ−［３−（ピリジン−３−イル）プロピオニル］アミノメチル］ベンズアミド（表−１：化合物番号１２５）
mp. (amorphous).
1H NMR(270MHz, CD3OD)δppm: 2.61(2H,t,J=7.3Hz), 3.00(2H,t,J=7.3Hz), 4.39(2H,s), 7.04(1H,ddd,J=1.5,8.1,8.1Hz), 7.25(2H,d,J=8.1Hz), 7.33(1H,dd,J=5.1,8.1Hz), 7.69(1H,d,J=8.1Hz), 7.85(2H,d,J=8.1Hz), 7.86(1H,d,J=8.1Hz), 8.41(2H,br.s).
IR(neat)cm-1:3276,1645,1614,1536,1509,1435,1415,1385,1333,1280,1247,1091,737.
【０１９１】
実施例４１
Ｎ−（２−ヒドロキシフェニル）−４−［Ｎ−（ピリジン−３−イル）オキシアセチルアミノメチル］ベンズアミド（表−１：化合物番号９３）
mp. (amorphous).
1H-NMR(270MHz,DMSO-d6)：4.43(2H,d,J=6.6Hz), 4.69(2H,s), 6.83(1H,t,J=6.6Hz), 6.91(1H,d,J=8.1Hz), 7.68(1H,d,J=6.6Hz), 7.82(2H,d,J=8.1Hz), 8.21(1H,d,J=4.4Hz), 8.35 (1H,d,J=2.2Hz), 8.81(1H,t,J=6.6Hz), 9.48(1H,s), 9.75(1H,s).
IR(KBr)cm-1:3399,1664,1535,1236,1064.
【０１９２】
実施例４２
Ｎ−（２−ヒドロキシフェニル）−４−［Ｎ−（ピリジン−３−イル）アセチルアミノメチル］ベンズアミド（表−１：化合物番号１１７）
mp. 201-202℃.
1H NMR(270MHz, DMSO-d6)δppm: 3.56(2H,s), 4.37(2H,d,J=5.9Hz), 6.83(1H,ddd,J=1.5,8.1,8.1Hz), 6.92(1H,br.d,J=8.1Hz), 7.03(1H,ddd,J=1.5,8.1,8.1Hz),7.34(1H,dd,J=3.7,8.1Hz), 7.37(2H,d,J=8.1Hz), 7.70(2H,d,J=8.1Hz), 7.91(2H,d,J=8.1Hz), 8.45(1H,br.d,J=3.7Hz), 8.49(1H,s), 8.73(1H,t,J=5.9Hz), 9.47(1H,s), 9.73(1H,br.s).
IR(KBr)cm-1:3272,3067,1661,1647,1598,1536,1455,1334,1288,1194,1024,742.
【０１９３】
実施例４３
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）オキシアセチル−Ｎ−［３−（ピリジン−３−イル）プロピル］アミノメチル］ベンズアミド（表−１：化合物番号９１）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 1.77-1.93(2H,m), 2.50-2.63(2H,m), 3.16-3.30(2H,m), 4.63(1.2H,s), 4.71(0.8H,s), 4.88(1.2H,s), 4.95(0.8H,s), 5.05(2H,s), 6.57-6.63(1H,m), 6.77-6.79(1H,m), 6.94-7.00(1H,m), 7.11-7.42(5H,m), 7.58-7.64(1H,m), 7.92-8.02(2H,m), 8.15-8.43(5H,m), 9.65(0.6H,s), 9.69(0.4H,s).（回転異性体の混合物）
【０１９４】
実施例４４
Ｎ−（２−アミノフェニル）−４−［Ｎ−メチル−Ｎ−（ピリジン−３−イル）オキシアセチル］アミノメチルベンズアミド（表−１：化合物番号９２）
mp. 117-120℃.
1H NMR(270MHz, DMSO-d6)δppm: 2.84 and 2.99(total 3H,s), 4.60 and 4.69(total 2H,s), 4.90(2H,br.s), 4.99 and 5.08(total 2H,s), 6.60(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,7.3Hz), 7.16(1H,d,J=7.3Hz), 7.30-7.43(4H,m), 7.95 and 8.01(total 2H,d,J=8.1Hz), 8.17(1H,d,J=4.4Hz), 8.31(1H,d,J=2.9Hz), 9.65 and 9.68(total 1H,br.s).（回転異性体の混合物）
IR(KBr)cm-1:3298,1665,1501,1425,1310,1276,1254,1078,799,746,703.
【０１９５】
実施例４５
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）オキサモイルアミノメチル］ベンズアミド（表−１：化合物番号９５）の合成
（４５−１） Ｎ−（ピリジン−３−イル）オキサミン酸エチルエステル３８８ｍｇ（２ｍｍｏｌ）と実施例１の工程（１−４）で得られた化合物６３８ｍｇ（２ｍｍｏｌ）をエタノールに溶解し、４０〜５０℃に２．５時間加熱撹拌した。析出した結晶をろ取し、エタノール２mlとエチルエーテル３ｍｌで洗浄した。得られた結晶を乾燥し、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］−４−［Ｎ−（ピリジン−３−イル）オキサモイルアミノメチル］ベンズアミド７２４ｍｇ（収率７４％）を得た。
1H NMR(270MHz, DMSO-d6)δppm: 1.44(9H,s), 4.49(2H,d,J=5.9Hz), 7.10-7.30(2H,m), 7.35-7.57(5H,m), 7.93(2H,d,J=8.1Hz), 8.21(1H,br.d,J=5.1Hz), 8.35(1H,dd,J=1.5,5.1Hz), 8.68(1H,br.s), 9.00(1H,d,J=2.9Hz), 9.70(1H,t,J=5.9Hz), 9.82(1H,s), 10.98(1H,br.s).
【０１９６】
（４５−２） 工程（４５−１）の化合物７２０ｍｇをメタノール８ｍｌに懸濁し、４規定塩酸−ジオキサン溶液８ｍｌを加えた。３時間撹拌し、希水酸化ナトリウム水溶液へあけアルカリ性とした後、析出した結晶をろ取した。得られた結晶をＴＨＦ／メタノール=１／１で再結晶し、目的物２８０ｍｇを得た。
mp. 254-258℃(dec.)
1H NMR(270MHz, DMSO-d6)δppm: 4.67(2H,d,J=5.9Hz), 4.89(2H,br.s), 6.59(1H,dd,J=7.3Hz), 6.77(1H,d,J=8.1Hz), 6.97(1H,dd,J=6.6,7.3Hz), 7.16(1H,d,J=8.1Hz), 7.38-7.44(1H,m), 7.43(2H,d,J=8.1Hz), 7.95(2H,d,J=8.1Hz), 8.18-8.24(1H,m), 8.34(1H,dd,J=1.5,4.4Hz), 9.00(1H,d,J=2.1Hz), 9.63(1H,s), 9.69(1H,br.t,J=6.6Hz), 10.97(1H,br.s).
IR(KBr,cm-1):3312,3270,1663,1636,1521,1312,1296,1019
【０１９７】
実施例４６
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）オキシアセチルアミノメチル］ベンズアミド（表−１：化合物番号６１）の合成
（４６−１） 水素化ナトリウム（６０％油状懸濁）０．２２ｇ（５．５ｍｍｏｌ）のＤＭＦ（２ｍｌ）懸濁液に、３−ヒドロキシピリジン０．４８ｇ（５．０ｍｍｏｌ）のＤＭＦ（２ｍｌ）溶液を室温で滴下した後、１時間攪拌した。得られた褐色溶液を氷冷した後、ブロモ酢酸 ｔｅｒｔ−ブチルエステル０．８１ｍｌ（５．５ｍｍｏｌ）を加え、氷冷下で１時間、室温で２時間攪拌した。水を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒を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（クロロホルム：酢酸エチル＝５：１）で精製することにより、３−ピリジルオキシ酢酸 ｔｅｒｔ−ブチルエステル０．３４ｇ（収率３２．５％）を無色油状物として得た。
1H NMR(270MHz, CDCl3)δppm: 1.49(9H,s), 4.56(2H,s), 7.18-7.24(2H,m), 8.26(1H,dd,J=1.5,3.6Hz), 8.32(1H,d,J=2.9Hz).
【０１９８】
（４６−２） 工程（４６−１）の化合物０．１４ｇ（０．６７ｍｍｏｌ）のジクロロメタン（２ｍｌ）溶液にトリフルオロ酢酸２ｍｌを加えて室温で３時間攪拌した。溶媒を留去した後、ジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより、３−ピリジルオキシ酢酸トリフルオロ酢酸塩０．１５ｇ（収率８３．８％）を淡黄色固体として得た。
1H NMR(270MHz, DMSO-d6)δppm: 4.86(2H,s), 7.57(1H,dd,J=4.4,8.1Hz), 7.67(1H,ddd,J=1.5,1.5,8.8Hz), 8.31(1H,d,J=5.1Hz), 8.46(1H,d,J=2.1Hz), 13.00(1H,br.s).
【０１９９】
（４６−３） 工程（４６−２）の化合物１００ｍｇ（０．３７ｍｍｏｌ）および実施例１の工程（１−４）で得られた化合物２５５ｍｇ（０．７５ｍｍｏｌ）のジクロロメタン（５ｍｌ）懸濁液にトリエチルアミン０．１４ｍｌ（１．０ｍｍｏｌ）を加え、氷冷した。氷冷下２−クロロ−１，３−ジメチルイミダゾリニウムクロライド１４０ｍｇ（０．８３ｍｍｏｌ）のジクロロメタン（６ｍｌ）溶液を加え、室温まで昇温させながら７時間攪拌した後、室温で一晩放置した。水および飽和食塩水を加えた後、クロロホルムで抽出した。
【０２００】
有機層を飽和食塩水で洗浄後、乾燥、溶媒を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（酢酸エチル：メタノール＝１０：１）で精製することにより、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］−４−［Ｎ−（ピリジン−３−イル）オキシアセチルアミノメチル］ベンズアミド０．３７ｇ（定量的）を無色油状物として得た。
mp. 154-155℃
1H NMR(270MHz, CDCl3)δppm: 1.52(9H,s), 4.62(2H,s), 4.63(2H,d,J=7.3Hz), 6.76(1H,br.s), 6.90-7.00(1H,br.s), 7.15-7.35(5H,m), 7.40(2H,d,J=8.1Hz), 7.82(1H,d,J=8.1Hz), 7.95(2H,d,J=8.1Hz), 8.32(1H,dd,J=2.1,4.4Hz), 8.37(1H,d,J=2.8Hz), 9.20(1H,br.s).
【０２０１】
（４６−４） 工程（４６−３）の化合物１７５ｍｇ（０．３７ｍｍｏｌ）のジオキサン（２ｍｌ）−メタノール（２ｍｌ）溶液に、４規定塩酸−ジオキサン（２ｍｌ）を加えて室温で２時間攪拌した。飽和重曹水を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得られた残渣にメタノールおよびジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）オキシアセチルアミノメチル］ベンズアミド９０ｍｇ（収率６４．６％）を乳白色固体として得た。
1H NMR(270MHz, DMSO-d6)δppm: 4.42(2H,d,J=5.9Hz), 4.69(2H,s), 4.89(2H,br.s), 6.59(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=6.6,7.3Hz), 7.16(1H,d,J=7.3Hz), 7.33-7.39(4H,m), 7.92(2H,d,J=8.1Hz), 8.21(1H,dd,J=1.5,4.4Hz), 8.35(1H,d,J=2.9Hz), 8.80(1H,br.t,J=5.9Hz), 9.63(1H,br.s).
IR(KBr)cm-1: 3307,1672,1631,1523,1456,1429,1269,1231,803,756.
【０２０２】
実施例４７
Ｎ−（２−アミノフェニル）−４−［Ｎ−［２−（ピリジン−３−イル）オキシ］プロピオニルアミノメチル］ベンズアミド（表−４：化合物番号３）の合成
【０２０３】
（４７−１） 水素化ナトリウム（６０％油状懸濁）１．２０ｇ（３０．０ｍｍｏｌ）の乾燥ＤＭＦ（１０ｍｌ）懸濁液に、室温で３−ヒドロキシピリジン２．８５ｇ（３０ｍｍｏｌ）の乾燥ＤＭＦ（１０ｍｌ）溶液を４０℃以下になるようにしながら滴下した後、室温で９０分間攪拌した。氷冷下内温を５〜１０℃に保ちながら２−ブロモプロピオン酸 ｔｅｒｔ−ブチルエステル６．２８ｇ（３０ｍｍｏｌ）の乾燥ＤＭＦ（１０ｍｌ）溶液を徐々に滴下した後、室温まで昇温させながら４時間攪拌した。飽和重曹水を加えて中和した後、酢酸エチルで抽出した。有機層を、水、飽和食塩水で洗浄後、乾燥、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（ｎ−ヘキサン：酢酸エチル＝２：１）で精製することにより２−（ピリジン−３−イル）オキシプロピオン酸 ｔｅｒｔ−ブチルエステル ４．１５ｇ（収率６２％）を茶色油状物として得た。
1H-NMR(270MHz, CDCl3)δppm: 1.44(9H,s), 1.61(3H,d,J=7.3Hz), 4.66(1H,q,J=7.3Hz), 7.13-7.23(2H,m) 8.24(1H,dd,J=1.5,4.4Hz), 8.29(1H,d,J=2.1Hz).
【０２０４】
（４７−２） 工程（４７−１）で得た化合物１．６５ｇ（７．４ｍｍｏｌ）のジクロロメタン（９ｍｌ）溶液に３０℃以下を保ちながらでトリフルオロ酢酸（９ｍｌ）を加えた後、室温で８時間攪拌した。溶媒を留去した後、ジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより２−（ピリジン−３−イル）オキシプロピオン酸 トリフルオロ酢酸塩１．８６ｇ（収率４３．５％）を淡褐色固体として得た。
1H-NMR(270MHz, DMSO-d6)δppm: 1.53(3H,d,J=6.6Hz), 5.12(1H,q,J=6.6Hz), 7.60-7.75(2H,m), 8.35(1H,d,J=5.1Hz), 8.47(1H,s), 12.9(1H,br.s).
【０２０５】
（４７−３） 工程（４７−２）で得た化合物０．９８ｇ（３．５ｍｍｏｌ）、実施例１の工程（１−４）で得た化合物１．０２ｇ（３．０ｍｍｏｌ）をジクロロメタン（２０ｍｌ）に懸濁させた後、トリエチルアミン１．３ｍｌ（９．０ｍｍｏｌ）を加え氷冷した。氷冷下、２−クロロ−１，３−ジメチルイミダゾリニウムクロライド０．５９ｇ（３．５ｍｍｏｌ）のジクロロメタン（５ｍｌ）溶液を滴下した後、さらに２時間攪拌した。飽和重曹水を加え中和した後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することによりＮ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニルアミノ）フェニル］−４−［Ｎ−［２−（ピリジン−３−イル）オキシプロピオニル］アミノメチル］ベンズアミド１．６４ｇを１，３−ジメチル−２−イミダゾリノンとの混合物として得た。
1H-NMR(270MHz, CDCl3)δppm: 1.51(9H,s), 1.64(3H,d,J=7.3Hz), 4.54(2H,m), 4.78(1H,q,J=6.6Hz), 6.87(2H,br.s), 7.13-7.30(6H,m), 7.81(1H,d,J=7.3Hz), 7.90(2H,d,J=8.1Hz), 8.29(1H,dd,J=1.5,4.4Hz), 8.33(1H,d,J=2.1Hz), 9.22(1H,br.s).
【０２０６】
（４７−４） 工程（４７−３）で得た化合物１．６４ｇをジオキサン（１０ｍｌ）−メタノール（４ｍｌ）に溶解した。室温下４規定塩酸−ジオキサン溶液（１０ｍｌ）を加え、２時間攪拌した。飽和重曹水を加え中和した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た残渣にメタノールおよびジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより、Ｎ−（２−アミノフェニル）−４−［Ｎ−［２−（ピリジン−３−イル）オキシ］プロピオニルアミノメチル］ベンズアミド０．７１ｇ（２ｓｔｅｐｓで収率６０．５％）を白色固体として得た。
【０２０７】
mp. 171-173℃(dec.).
1H-NMR(270MHz,DMSO-d6)δppm:1.51(3H,d,J=6.6Hz), 4.36(2H,d,J=5.9Hz), 4.89(2H,br.s), 4.90(1H,t,J=6.6Hz), 6.60(1H,dd,J=6.6,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=6.6,7.3Hz), 7.15(1H,d,J=7.3Hz), 7.27(2H,d,J=8.1Hz), 7.33-7.37(2H,m), 7.89(2H,d,J=8.1Hz), 8.21(1H,dd,J=2.9,2.9Hz), 8.32(1H,d,J=1.5Hz), 8.82(1H,t,J=5.9Hz), 9.63(1H,br.s).
【０２０８】
実施例４８
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号８２）の合成
（４８−１） ３−ピリジンメタノール３８４ｍｇ（３．５２ｍｍｏｌ）を５ｍｌの乾燥ＴＨＦに溶解し、Ｎ，Ｎ’−カルボニルジイミダゾール５２３ｍｇ（３．２２ｍｍｏｌ）を室温で加えた。１時間撹拌した後、実施例１の工程（１−４）の化合物１．０ｇ（２．９３ｍｍｏｌ）の乾燥ＴＨＦ溶液６ｍｌを加えた。
【０２０９】
室温で一夜放置後、クロロホルム１００ｍｌを加え、水２０ｍｌで３回洗浄した。ついで飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、シリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝３０：１）で精製し、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド１．２７ｇをアモルファス状固体として得た（定量的）。
1H NMR(270MHz, CDCl3)δppm: 1.51(9H,s), 4.45(2H,d,J=5.9Hz), 5.16(1H,s), 7.10-7.50(7H,m), 7.70(1H,d,J=8.1Hz), 7.80(1H,d,J=7.3Hz), 7.93(1H,d,J=8.1Hz), 8.57(1H,d,J=4.4Hz), 8.63(1H,s), 9.17(1H,s).
【０２１０】
（４８−２） 工程（４８−１）の化合物１．２ｇ（２．８ｍｍｏｌ）をメタノール１０ｍｌに溶解した。４規定塩酸−ジオキサン溶液２０ｍｌを加え、室温で１．５時間撹拌した。希水酸化ナトリウム水溶液にあけた後、クロロホルム６０ｍｌで３回抽出した。飽和食塩水で２回洗浄後、無水硫酸マグネシウムで乾燥し、濃縮して０．８８ｇの結晶を得た。ついでエタノール１６ｍｌで再結晶を行い、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド６６８ｍｇ（収率７３％）を得た。
【０２１１】
mp. 159-160℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=5.9Hz), 4.86(2H,s), 5.10(2H,s), 6.60(1H,t,J=7.3Hz), 6.78(1H,d,J=7Hz), 6.97(1H,t,J=7Hz), 7.17(1H,d,J=8Hz), 7.30-7.50(3H,m), 7.78(1H,d,J=8Hz), 7.93(2H,d,J=8Hz), 8.53(1H,d,J=3.7Hz), 8.59(1H,s), 9.61(1H,s).
IR(KBr)cm-1: 3295,1648,1541,1508,1457,1309,1183,742.実施例４８と同様の方法により、実施例４９から実施例８７の化合物を合成した。以下に、化合物の融点（mp.）、1H NMR、IRの測定値を示す。
【０２１２】
実施例４９
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ベンジルオキシカルボニル）アミノメチル］ベンズアミド（表−１：化合物番号１１）
mp. 174-178℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=5.9Hz), 4.89(2H,br.s), 5.06(2H,s), 6.59(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.16(1H,d,J=7.3Hz), 7.30-7.40(6H,m), 7.93(3H,m), 9.63(1H,s).
IR(KBr)cm-1: 3332,1687,1652,1536,1456,1279,747.
【０２１３】
実施例５０
Ｎ−（２−アミノフェニル）−４−［Ｎ−（４−（イミダゾール−１−イル）ベンジル）オキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号４７）
mp. 195-198℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.29(2H,d,J=6.6Hz), 4.88(2H,s), 5.10(2H,s), 6.60-6.63(1H,m), 6.78(1H,d,J=8.1Hz), 6.97(1H,t,J=7.3Hz), 7.11(1H,s), 7.16(1H,d,J=7.3Hz), 7.37(2H,d,J=8.1Hz), 7.49(2H,d,J=8.8Hz), 7.66(2H,d,J=8.1Hz), 7.74(1H,s), 7.92-7.96(3H,m), 8.25(1H,s), 9.62(1H,s).
【０２１４】
実施例５１
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−２−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１７１）
mp. 166-167℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.30(2H,d,J=5.9Hz), 4.88(2H,br.s), 5.12(2H,s), 6.60(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,ddd,J=1.5,7.3,8.1Hz), 7.16(1H,d,J=7.3Hz), 7.33(1H,dd,J=3.7,7.3Hz), 7.40(3H,d,J=8.1Hz), 7.83(1H,ddd,J=1.5,7.3,8.1Hz), 7.94(2H,d,J=8.1Hz), 8.03(1H,t,J=5.9Hz), 8.55(1H,d,J=5.1Hz), 9.62(1H,br.s).
IR(KBr)cm-1: 3334,1694,1632,1580,1276,755.
【０２１５】
実施例５２
Ｎ−（２−アミノフェニル）−４−［Ｎ−［２−（ピリジン−２−イル）エトキシカルボニル］アミノメチル］ベンズアミド（表−１：化合物番号１７２）
mp. 146-148℃.
1H NMR(270MHz, DMSO-d6)δppm: 3.04(2H,t,J=6.6Hz), 4.23(2H,d,J=5.9Hz), 4.36(2H,t,J=6.6Hz), 4.88(2H,br.s), 6.60(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.15-7.30(3H,m), 7.34(2H,d,J=8.1Hz), 7.69-7.77(2H,m), 7.92(2H,d,J=7.3Hz), 8.50(1H,d,J=4.4Hz), 9.62(1H,br.s).
IR(KBr)cm-1: 3330,1690,1633,1594,1524,1277,760.
【０２１６】
実施例５３
Ｎ−（２−アミノフェニル）−４−［Ｎ−（６−メチルピリジン−２−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１７９）
mp. 138℃.
1H NMR(270MHz, DMSO-d6)δppm： 2.47(3H,s), 4.30(2H,d,J=5.9Hz), 5.07(4H,s), 6.63(1H,t,J=8.1Hz), 6.80(1H,d,J=7.34), 6.98(1H,t,J=8.1Hz), 7.18(3H,d,J=7.3Hz), 7.40(2H,d,J=8.1Hz), 7.71(1H,t,J=8.1Hz), 7.94(2H,d,J=8.1Hz), 8.03(1H,t,J=5.9Hz), 9.66(1H,s).
IR(KBr)cm-1: 3335,1693,1634,1259.
【０２１７】
実施例５４
Ｎ−（２−アミノフェニル）−４−［Ｎ−［２−（ピリジン−３−イル）エトキシカルボニル］アミノメチル］ベンズアミド（表−１：化合物番号８３）
mp. 120-125℃.
1H NMR(270MHz, DMSO-d6)δppm：2.91(2H,t,J=6.6Hz), 4.22(4H,t,J=6.6Hz), 4.89(2H,s), 6.55-6.63(1H,m), 6.78(1H,dd,J=8.1,1.5Hz), 6.97(1H,t,J=6.6Hz), 7.17(1H,d,J=6.6Hz), 7.33(3H,d,J=8.1Hz), 7.69(1H,d,J=8.1Hz), 7.79(1H,t,J=6.6Hz), 7.93(2H,d,J=8.0Hz), 8.43-8.49(2H,m), 9.62(1H,s).
IR(KBr)cm-1: 3234,1705,1655,1260.
【０２１８】
実施例５５
Ｎ−（２−アミノフェニル）−４−［Ｎ−［３−（ピリジン−３−イル）プロピルオキシカルボニル］アミノメチル］ベンズアミド（表−１：化合物番号８４）mp. 121-124℃.
1H NMR(270MHz, DMSO-d6)δppm: 1.83-1.94(2H,m), 2.67(2H,t,J=7.3Hz), 3.98(2H,t,J=6.6Hz), 4.26(2H,d,J=5.9Hz), 4.89(2H,br.s), 6.60(1H,dd,J=8.1,8.1Hz), 6.78(1H,d,J=7.3Hz), 6.97(1H,ddd,J=1.5,7.3,8.1Hz), 7.16(1H,d,J=8.1Hz), 7.29-7.33(1H,m), 7.37(1H,d,J=8.1Hz), 7.64(1H,d,J=8.1Hz), 7.81(1H,dd,J=5.9,6.6Hz), 7.94(2H,d,J=8.1Hz), 8.40-8.44(2H,m), 9.63(1H,br.s).
IR(KBr)cm-1: 3348,1696,1635,1523,1458,1302,1272,1141,1019,754,713.
【０２１９】
実施例５６
Ｎ−（２−アミノフェニル）−４−［Ｎ−（２−メチルピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１４２）
mp. 164-165℃.
1H NMR(270MHz, DMSO-d6)δppm： 2.49(3H,s), 4.28(2H,d,J=6.6Hz), 4.89(2H,s), 5.10(2H,s), 6.60(1H,t,J=6.6Hz), 6.78(1H,d,J=8.1Hz), 6.90(1H,t,J=7.3Hz), 7.17(1H,d,J=7.3Hz), 7.21-7.26(1H,m), 7.37(2H,d,J=8.1Hz), 7.68(1H,d,J=6.6Hz), 7.92-8.00(3H,m), 8.39(1H,d,J=4.4Hz), 9.62(1H,s).
IR(KBr)cm-1: 3332,1719,1630,1260.
【０２２０】
実施例５７
Ｎ−（２−アミノフェニル）−４−［Ｎ−（６−メチルピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１４４）
mp. 164-165℃.
1H NMR(270MHz, DMSO-d6)δppm： 2.46(3H,s), 4.27(2H,d,J=6.6Hz), 4.88(2H,s), 5.05(2H,s), 6.59(1H,dt,J=1.5,8.1Hz), 6.78(1H,dd,J=8.1,1.5Hz), 6.97(1H,dt,J=1.5,7.3Hz), 7.17(1H,d,J=7.3Hz), 7.26(1H d,J=8.1Hz), 7.36(2H,d,J=8.1Hz), 7.67(1H,dd,J=8.1,2.2Hz), 7.93(3H,d,J=8.1Hz), 8.45(1H,d,J=1.5Hz), 9.62(1H,s).
IR(KBr)cm-1: 3293,1701,1632,1260.
【０２２１】
実施例５８
Ｎ−（２−アミノフェニル）−４−［Ｎ−（２−クロロピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１５５）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm： 4.30(2H,d,J=5.9Hz), 5.00(2H,s), 5.13(2H,s), 6.61(1H,t,J=7.3Hz), 6.79(1H,dd,J=8.1,1.5Hz), 6.98(1H,dt,J=1.5,7.3Hz), 7.17(1H,d,J=6.6Hz), 7.39(2H,d,J=8.8Hz), 7.47-7.52(1H,m), 7.91-7.96(3H,m), 8.08(1H,t,J=5.9Hz), 8.40(1H,dd,J=4.4,1.5Hz), 9.64(1H,s).
IR(KBr)cm-1: 3340,1702,1632,1273.
【０２２２】
実施例５９
Ｎ−（２−アミノフェニル）−４−［Ｎ−（６−クロロピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１５７）
mp. 180-185℃.
1H NMR(270MHz, DMSO-d6)δppm： 4.24(2H,d,J=5.9Hz), 4.89(2H,br.s), 5.10(2H,s), 6.60(1H,t,J=7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dt,J=1.5,8.1Hz), 7.16(1H,d,J=6.6Hz), 7.37(2H,d,J=8.1Hz), 7.56(1H,d,J=8.1Hz), 7.85-8.02(4H,m), 8.44(1H,d,J=2.2Hz), 9.62(1H,s).
IR(KBr)cm-1: 3346,3282,1696,1533,1271.
【０２２３】
実施例６０
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−４−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１８１）
mp. 180-183℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.30(2H,d,J=6.6Hz), 4.89(2H,s), 5.12(2H,s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,dd,J=1.5,7.3Hz), 6.97(1H,ddd,J=1.5,7.3,8.1Hz), 7.16(1H,d,J=7.3Hz), 7.34(2H,d,J=5.9Hz), 7.39(2H,d,J=8.1Hz), 7.94(2H,d,J=8.1Hz), 8.09(1H,t,J=5.9Hz), 8.57(1H,d), 9.64(1H,br.s).
IR(KBr)cm-1: 3394,3290,1711,1645,1624,1535,1504,1321,1251,1138,1049,763.
【０２２４】
実施例６１
Ｎ−（２−アミノフェニル）−４−［Ｎ−［２−（チオフェン−３−イル）エトキシカルボニル］アミノメチル］ベンズアミド（表−１：化合物番号２０３）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm： 2.90(2H,t,J=7.3Hz), 4.17-4.26(4H,m), 4.89(2H,s), 6.60(1H,t,J=8.1Hz), 6.78(1H,d,J=6.6Hz), 6.97(1H,t,J=7.3Hz), 7.06(1H,d,J=5.1Hz), 7.17(1H,d,J=7.3Hz), 7.26(1H,s), 7.36(2H,d,J=8.1Hz), 7.47(1H,t,J=2.2Hz), 7.81(1H,t,J=5.9Hz), 7.93(2H,d,J=8.1Hz), 9.63(1H,s).
IR(KBr)cm-1: 3314,1716,1638,1252.
【０２２５】
実施例６２
Ｎ−（２−アミノフェニル）−４−［Ｎ−（３−フェニルオキサゾール−５−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号２１１）
mp. 192-195℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.30(2H,d,J=5.9Hz), 4.89(2H,s), 5.25(2H,s), 6.60(1H,t,J=6.6Hz), 6.68(1H,d,J=8.1Hz), 6.94(1H,t,J=7.3Hz), 7.09(1H,s), 7.16(1H,d,J=7.3Hz), 7.39(2H,d,J=8.1Hz), 7.51(4H,d,J=2.2Hz), 7.87-7.96(5H,m), 8.12(1H,t,J=5.9Hz), 9.63(1H,s).
IR(KBr)cm-1: 3292,1718,1630,1262.
【０２２６】
実施例６３
Ｎ−（２−アミノフェニル）−４−［Ｎ−（チアゾール−５−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号２１６）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=5.9Hz), 4.91(2H,br.s), 5.30(2H,s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.16(1H,d,J=7.3Hz), 7.36(2H,d,J=8.1Hz), 7.91-8.00(4H,m), 9.09(1H,s), 9.63(1H,s).
IR(KBr)cm-1: 3346(br.),1697,1636,1525,1456,1271,873,753.
【０２２７】
実施例６４
Ｎ−（２−アミノフェニル）−４−［Ｎ−［２−（４−メチルチアゾール−５−イル）エトキシカルボニル］アミノメチル］ベンズアミド（表−１：化合物番号２１７）
mp. 130-133℃.
1H NMR(270MHz, DMSO-d6)δppm： 2.32(3H,s), 3.07(2H,t,J=5.9Hz), 4.15(2H,t,J=5.9Hz), 4.25(2H,d,J=6.6Hz), 4.89(2H,s), 6.60(1H,t,J=5.9Hz), 6.78(1H,dd,J=7.3,1.5Hz), 6.97(1H,dt,J=1.5,7.3Hz), 7.16(1H,d,J=8.1Hz), 7.35(2H,d,J=8.1Hz), 7.83(1H,t,J=5.9Hz), 7.94(2H,d,J=8.1Hz), 8.85(1H,s), 9.62(1H,s).
IR(KBr)cm-1: 3350,1691,1635,1270.
【０２２８】
実施例６５
Ｎ−（２−アミノフェニル）−４−［Ｎ−（１−メチルピペリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号２２５）
mp. 130-135℃.
1H NMR(270MHz, DMSO-d6)δppm： 1.49-1.78(3H,m), 1.83-2.01(3H,m), 2.30(3H,s), 2.85(2H,s), 3.74-3.94(2H,m), 4.25(2H,d,J=5.8Hz), 6.55-6.62(3H,m), 6.78(1H,d,J=8.1Hz), 6.97(1H,t,J=7.3Hz), 7.16(1H,d,J=8.1Hz), 7.37(2H,d,J=8.1Hz), 7.79(1H,t,J=6.6Hz), 7.93(2H,d,J=8.0Hz), 9.66(1H,s).
IR(KBr)cm-1: 3323,2722,1702,1648,1263.
【０２２９】
実施例６６
Ｎ−（２−アミノフェニル）−４−［Ｎ−（４−メチルピペラジン−１−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号２２７）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm： 1.73(2H,t,J=6.6Hz), 2.36-2.63(13H,m), 4.00(2H,t,J=6.6Hz), 4.30(2H,d,J=5.8Hz), 6.55-6.63(4H,m), 6.78(1H,d,J=6.6Hz), 6.97(1H,t,J=7.3Hz), 7.16(1H,d,J=7.3Hz), 7.37(2H,d,J=8.7Hz), 7.73(1H,t,J=5.9Hz), 7.94(2H,d,J=8.0Hz), 9.66(1H,s).
IR(KBr)cm-1: 3341,2706,1701,1262.
【０２３０】
実施例６７
Ｎ−（２−アミノフェニル）−４−［Ｎ−（テトラヒドロフラン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号２２１）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 1.50-1.60(1H,m), 1.88-2.00(1H,m), 2.44-2.54(1H,m), 3.41-3.47(1H,m), 3.56-3.77(3H,m), 3.85-4.04(2H,m), 4.25(2H,d,J=5.9Hz), 4.89(2H,s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.17(1H,d,J=8.1Hz), 7.37(2H,d,J=8.1Hz), 7.81(1H,t,J=5.9Hz), 7.94(2H,d,J=8.1Hz), 9.62(1H,br.s).
IR(KBr)cm-1: 3349,1695,1635,1523,1457,1259,754.
【０２３１】
実施例６８
Ｎ−（２−アミノフェニル）−４−［Ｎ−（フェノキシカルボニル）アミノメチル］ベンズアミド（表−１：化合物番号１２）
mp.174-175℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.36(2H,d,J=5.9Hz), 4.90(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.77(1H,dd,J=7.3,7.3Hz), 6.98(1H,ddd,J=1.5,7.3,7.3Hz), 7.05-7.24(4H,m), 7.39-7.46(4H,m), 7.97(2H,d,J=8.1Hz), 8.41(1H,t,J=5.9Hz), 9.65(1H,br.s).
IR(KBr)cm-1: 3443,3362,3313,1732,1706,1636,1527,1493,1458,1305,1217,748.
【０２３２】
実施例６９
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）オキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号８１）
mp. 209℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.38(2H,d,J=6.6Hz), 4.90(2H,br.s), 6.55-6.63(1H,m), 6.78(1H,d,J=8.1Hz), 7.00(1H,dd,J=7.3,7.3Hz), 7.17(1H,d,J=8.8Hz), 7.37-7.47(3H,m), 7.64(1H,d,J=8.8Hz), 7.97(2H,d,J=8.1Hz), 8.43(2H,d,J=3.1Hz), 8.59(1H,t,J=5.9Hz), 9.66(1H,br.s).
【０２３３】
実施例７０
Ｎ−（２−アミノ−５−フルオロフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１１０）
mp. 160-162℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=6.6Hz), 4.81(2H,s), 5.10(2H,s), 6.70-6.90(2H,m), 7.10-8.00(8H,m), 8.53(1H,d,J=3.6Hz), 8.59(1H,s), 9.61(1H,s).
IR(KBr)cm-1:3269,1716,1638,1488,1436,1247,1141,1043,744.
【０２３４】
実施例７１
Ｎ−（２−アミノフェニル）−４−［Ｎ−（２−アミノフェニル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号５１）
mp. 149-151℃(dec.)
1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=5.9Hz), 4.88(2H,s), 4.96(2H,s), 5.06(2H,s), 6.53(1H,dd,J=7.3,7.3Hz), 6.56-6.67(2H,m), 6.78(1H,dd,J=1.5,8.1Hz), 6.93-7.12(3H,m), 7.16(1H,d,J=6.6Hz), 7.38(2H,d,J=8.1Hz), 7.86(1H,t-like,J=5.9Hz), 7.93(2H,d,J=8.1Hz), 9.61(1H,s).
IR(KBr)cm-1:3336,1685,1632,1527,1276,748.
【０２３５】
実施例７２
Ｎ−（２−アミノフェニル）−４−［Ｎ−（キヌクリジン−３−イル）オキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号２２８）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 1.30-1.90(4H,m), 1.90(1H,br.s), 2.45-2.80(6H,m), 3.04-3.13(1H,m), 4.15(2H,d,J=5.9Hz), 4.55-4.60(1H,m), 4.88(2H,br.s), 6.60(1H,ddd,J=1.5,7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,ddd,J=1.5,7.3,7.3Hz), 7.17(1H,d,J=6.6Hz), 7.37(2H,d,J=8.1Hz), 7.78(1H,t,J=5.9Hz), 7.94(1H,d,J=7.3Hz), 9.62(1H,s).
IR(KBr)cm-1:3328,2942,1700,1648,1504,1259,749.
【０２３６】
実施例７３
Ｎ−（２−アミノフェニル）−４−［Ｎ−（３−アミノフェニル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号５２）
mp. 149-153℃(dec.)
1H NMR(270MHz, DMSO-d6)δppm: 4.27(2H,d,J=5.9Hz), 4.88 and 4.89(total 4H, each br.s), 5.08(2H,s), 6.47-6.63(3H,m), 6.78(1H,d,J=8.1Hz), 6.94-7.02(2H,m), 7.15(1H,dd,J=7.3,8.8Hz), 7.37(2H,d,J=8.1Hz), 7.84(1H,t,J=5.9Hz), 7.93(2H,d,J=8.8Hz), 9.61(1H,br.s).
IR(KBr)cm-1:3367,1682,1632,1523,1457,1261,754.
【０２３７】
実施例７４
Ｎ−（２−アミノフェニル）−４−［Ｎ−（１−メチルイミダゾール−５−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号２１８）
mp. 162-165℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 3.62(3H,s), 4.27(2H,d,J=5.9Hz), 4.91(2H,br.s), 5.05(2H,s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.95-7.00(2H,m), 7.16(1H,d,J=7.3Hz), 7.36(2H,d,J=8.1Hz), 7.63(1H,s), 7.87-7.95(3H,m), 9.64(1H,br.s).
IR(KBr)cm-1:3293,1688,1651,1534,1506,1259,1121,1043,748.
【０２３８】
実施例７５
Ｎ−（２−アミノ−４−クロロフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１１３）
mp. 167-170℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=5.9Hz), 5.10(2H,s), 5.21(2H,s), 6.72(1H,dd,J=2.2,8.1Hz), 6.81(1H,d,J=2.2Hz), 7.16(1H,d,J=8.1Hz), 7.37(2H,d,J=8.1Hz), 7.78(1H,d,J=8.1Hz), 7.92(2H,d,J=8.1Hz), 8.53(1H,d,J=4.4Hz), 8.59(1H,s), 9.60(1H,s).
IR(KBr)cm-1:3347,3062,2931,1653,1576,1505,1456,1428,1301,1232,1114,1070,1019.
【０２３９】
実施例７６
Ｎ−（２−アミノフェニル）−４−［Ｎ−（５−メトキシピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１６１）
mp. 169-170℃.
1H NMR(270MHz, DMSO-d6)δppm: 3.83(3H,s), 4.29(2H,d,J=6.6Hz), 4.87(2H,s), 5.09(2H,s), 6.57-6.62(1H,m), 6.76-6.79(1H,m), 6.94-6.99(1H,m), 7.14-7.18(1H,m), 7.36-7.39(3H,m), 7.91-7.99(3H,m), 8.19-8.30(2H,m), 9.63(1H,s).
IR(KBr)cm-1:3330,1694,1633,1524,1457,1298,1269,1045,760.
【０２４０】
実施例７７
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピラジン−２−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１９２）
mp. 182℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.30(2H,d,J=6.6Hz), 4.88(2H,br.s), 5.20(2H,s), 6.60(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=6.6,8.1Hz), 7.16(1H,d,J=7.3Hz), 7.39(2H,d,J=8.8Hz), 7.94(2H,d,J=8.8Hz), 8.08(1H,t-like,J=6.6Hz), 8.61(1H,s), 8.65(1H,s), 8.68(1H,s), 9.63(1H,s).
IR(KBr)cm-1:3266,1709,1632,1535,1508,1284,1055,1022,744.
【０２４１】
実施例７８
Ｎ−（２−アミノ−５−メトキシフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１２１）
mp.141-143℃.
1H NMR(270MHz, DMSO-d6)δppm: 3.66(3H,s), 4.29(2H,d,J=5.9Hz), 4.51(2H,br.s), 5.10(2H,s), 6.63(1H,dd,J=2.9,8.8Hz), 6.74(1H,d,J=8.8Hz), 6.91(1H,d,J=2.2Hz), 7.38(2H,d,J=8.8Hz), 7.41(1H,s), 7.79(1H,d,J=8.1Hz), 7.92(2H,d,J=8.1Hz), 7.98(1H,t,J=5.9Hz), 8.54(1H,d,J=3.7Hz), 8.60(1H,s), 9.65(1H,s).
【０２４２】
実施例７９
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン３−イル）メチル−Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１０９）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 4.50(2H,s), 4.56(2H,s), 4.87(2H,s), 5.21(2H,s), 6.60(1H,t,J=7.7Hz), 6.78(1H,d,J=7.3Hz), 6.97(1H,d,J=7.3Hz), 7.17(1H,d,J=7.3Hz), 7.20-7.50(4H,m), 7.60-8.00(4H,m), 8.40-8.60(4H,m), 9.65(1H,s).
IR(KBr)cm-1: 3268,1700,1504,1246,1120,940,714.
【０２４３】
実施例８０
Ｎ−（２−アミノフェニル）−４−［Ｎ−［３−（ピリジン−３−イル）プロピル］−Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１２０）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 1.75-1.90(2H,m), 2.48-2.62(2H,m), 3.20-3.36(2H,m), 4.55(2H,s), 4.89(2H,s), 5.16(2H,s), 6.57-6.63(1H,m), 6.76-6.80(1H,m), 6.94-6.99(1H,m), 7.14-7.17(1H,m), 7.32-7.74(6H,m), 7.94(2H,d,J=8.1Hz), 8.30-8.65(4H,m), 9.64(1H,s).
【０２４４】
実施例８１
Ｎ−（２−ヒドロキシフェニル）−４−［Ｎ−（ピリジン−３−イル）メチル−Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１１５）
mp. (amorphous).
1H NMR(270MHz,DMSO-d6)： 4.52(2H,s), 4.57(2H,s), 5.20(2H,s), 6.84(1H,t,J=6.6Hz), 6.93(1H,d,J=6.6Hz), 7.03(1H,d,J=7.3Hz), 7.37(4H,m), 7.68(2H,dd,J=1.5,8.1Hz), 7.92(2H,br.s), 8.53(4H,m), 9.49(1H,s), 9.77(1H,br.s).
IR(KBr)cm-1: 3035,1698,1243,1118,754,640.
【０２４５】
実施例８２
Ｎ−（２−ヒドロキシフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１１１）
mp.162-164℃.
1H NMR(270MHz, DMSO-d6)： 4.29(1H,d,J=5.9Hz), 5.10(2H,s), 6.83(1H,t,J=8.1Hz), 6.92(1H,d,J=6.6Hz), 7.07(1H,t,J=6.6Hz), 7.39(2H,d,J=8.8Hz), 7.43(1H,d,J=5.1Hz), 7.68(2H,d,J=8.1Hz), 7.80(1H,d,J=8.1Hz), 7.92(2H,d,J=8.1Hz), 7.99(1H,t,J=5.9Hz), 8.54(1H,d,J=4.4Hz), 8.60(1H,s), 9.49(1H,s), 9.76(1H,br.s).
IR(KBr)cm-1: 3333,3259,1694,1645,1529,1267,720.
【０２４６】
実施例８３
Ｎ−（２，４−ジヒドロキシフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１１６）
mp. (amorphous)
1H NMR(270MHz,DMSO-d6)： 4.27(2H,d,J=6.6Hz), 5.10(2H,s), 6.20(2H,dd,J=2.2,8.1Hz), 6.39(2H,d,J=2.9Hz), 6.88(2H,d,J=8.8Hz), 7.33(1H,d,J=8.1Hz), 7.41(1H,dd,J=5.1,7.1Hz), 7.89(1H,d,J=8.8Hz), 7.98(1H,t,J=6.6Hz), 8.05(2H,s), 8.52(1H,m), 8.59(1H,s), 9.30(2H,br.s).
IR(KBr)cm-1: 3387,1702,1612,1311,1169,845.
【０２４７】
実施例８４
Ｎ−（２−ヒドロキシ−５−メチルフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１１８）
mp. 155-155.5℃.
1H NMR(270MHz,DMSO-d6)： 2.22(3H,s), 4.29(2H,d,J=5.8Hz), 5.11(2H,s), 6.82(2H,m), 7.39(2H,d,J=8.8Hz), 7.42(2H,m), 7.51(1H,s), 7.79(1H,d,J=8.1Hz), 7.92(1H,d,J=8.1Hz), 7.98(1H,t,J=5.9Hz), 8.54(1H,d,J=4.4Hz), 8.60(1H,s), 9.48(2H,d,J=8.1Hz).
IR(KBr)cm-1: 3306,1723,1655,1525,801,639.
【０２４８】
実施例８５
Ｎ−（２−ヒドロキシ−５−メトキシフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド（表−１：化合物番号１１９）
mp. 175-176℃.
1H NMR(270MHz,DMSO-d6)： 3.69(3H,s), 4.29(2H,d,J=5.9Hz), 5.10(2H,s), 6.63(1H,dd,J=2.9,8.7Hz), 6.84(1H,d,J=8.8Hz), 7.41(4H,m), 7.79(1H,d,J=8.1Hz), 7.91(1H,d,J=8.1Hz), 7.99(1H,t,J=5.9Hz), 8.54(1H,d,J=5.1Hz), 8.60(1H,s), 9.31(1H,s), 9.45(1H,s).
IR(KBr)cm-1:3305,1687,1573,1262,1039,868.
【０２４９】
実施例８６
Ｎ−（２−アミノフェニル）−４−［Ｎ−［２−（ピリジン−３−イル）エトキシカルボニル］アミノ］ベンズアミド（表−１：化合物番号１２４）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 3.00(2H,t,J=6.6H), 4.37(2H,t,J=6.6Hz), 4.87(2H,br.s), 6.60(1H,t,J=7.3Hz), 6.97(1H,t,J=7.3Hz), 7.15(1H,d,J=7.3Hz), 7.36(1H,dd,J=4.4,8.1Hz), 7.56(2H,d,J=8.8Hz), 7.92(2H,d,J=8.8Hz), 8.46(1H,d,J=4.4Hz), 8.54(1H,d,J=2.2Hz), 9.95(1H,s).
IR(KBr)cm-1:3285,1695,1519,1315,1233,1079.
【０２５０】
実施例８７
Ｎ−（２−アミノフェニル）−５−［（ピリジン−３−イル）メトキシカルボニル］アミノベンゾフラン−２−カルボキシアミド（表−３：化合物番号２）
mp.173-174℃.
1H NMR(270MHz, DMSO-d6)δppm: 5.22(2H,s), 6.60(1H,dd,J=8.1,8.1Hz), 6.79(1H,dd,J=1.5,8.1Hz),7.00(1H,dd,J=8.1,8.1Hz),7.20(1H,dd,J=1.5,8.1Hz),7.44(1H,m),7.48(1H,dd,J=1.5,8.8Hz), 7.61(1H,d,J=8.8Hz), 7.67(1H,s), 7.88(1H,dd,J=1.5,8.1Hz), 7.96(1H,d,J=1.5Hz), 8.56(1H,dd,J=1.5,4.8Hz), 8.68(1H,d,J=1.5Hz),9.83(1H,s), 9.91(1H,s).
IR(KBr)cm-1:3308,1707,1667,1584,1536,1452,1316,1248,1157,1128,1070,955,879,795,748,710.
【０２５１】
実施例８８
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシチオカルボニルアミノメチル］ベンズアミド（表−１：化合物番号８６）の合成
（８８−１） ３−ピリジンメタノール２０ｍｇ（０．１８ｍｍｏｌ）を５ｍｌの乾燥ＴＨＦに溶解し、Ｎ，Ｎ’−チオカルボニルジイミダゾール３０ｍｇ（０．１６ｍｍｏｌ）を室温で加えた。終夜撹拌した後、実施例１の工程（１−４）の化合物５０ｍｇ（０．１４ｍｍｏｌ）を加えた。
【０２５２】
室温で一夜放置後、クロロホルム１００ｍｌを加え、水２０ｍｌで３回洗浄した。ついで飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後シリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝３０：１）で精製し、Ｎ−［２−（Ｎ−ｔｅｒｔーブトキシカルボニル）アミノフェニル］−４−［Ｎ−（ピリジン−３−イル）メトキシチオカルボニルアミノメチル］ベンズアミド７０ｍｇ（収率８８％）をアモルファスとして得た。
1H NMR(270MHz, DMSO-d6)δppm: 1.45(9H,s), 4.73(2H,d,J=5.9Hz), 5.52(2H,s), 6.73-7.33(3H,m), 7.35-7.43(2H,m), 7.58-7.95(5H,m), 8.14-8.65(3H,m), 9.80(1H,s), 9.91(1H,br.t).
【０２５３】
（８８−２） 工程（８８−１）の化合物５０ｍｇ（０．１０ｍｍｏｌ）をメタノール３ｍｌに溶解した。４規定塩酸−ジオキサン溶液３ｍｌを加え、室温で１．５時間撹拌した。希水酸化ナトリウム水溶液にあけ塩酸を中和した後、クロロホルム１０ｍｌで３回抽出した。飽和食塩水で２回洗浄後、無水硫酸マグネシウムで乾燥し、濃縮して３４ｍｇ（収率８７％）のＮ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシチオカルボニルアミノメチル］ベンズアミドを得た。
mp. 154-156℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.73(2H,d,J=5.9Hz), 4.88(2H,s), 5.52(2H,s), 6.60(1H,t,J=7.3Hz), 6.77(1H,d,J=8.1Hz), 6.96(1H,t,J=8.1Hz), 7.16(1H,d,J=7.3Hz), 7.29-7.41(3H,m), 7.83-7.95(3H,m), 8.50-8.56(1H,m), 8.65(1H,s), 9.62(1H,s), 9.93(1H,s).
IR(KBr)cm-1:3204,3035,1631,1523,1456,1289,1191,920,753.
【０２５４】
実施例８９
Ｎ−（２−アミノフェニル）−４−［Ｎ’−（ピリジン−３−イルメチル）ウレイドメチル］ベンズアミド（表−１：化合物番号８８）の合成
（８９−１） ３−ピコリルアミン０．２８ｇ（２．６ｍｍｏｌ）のＴＨＦ（１０ｍｌ）溶液に室温でＮ，Ｎ’−カルボニルジイミダゾール０．４２ｇ（２．４ｍｍｏｌ）を加え、１時間攪拌した。この溶液に室温で実施例１の工程（１−４）で得られた化合物０．５８ｇ（１．８ｍｍｏｌ）を加え、３時間攪拌した後、一晩放置した。
【０２５５】
水を加え希釈した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得た残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル−メタノール＝１０：１）で精製して、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノ］フェニル−４−［Ｎ’−（ピリジン−３−イルメチル）ウレイドメチル］ベンズアミド０．７７ｇ（収率９０％）を白色アモルファス状固体として得た。
1H NMR(270MHz, CDCl3)δppm: 1.46(9H,s), 4.20(2H,d,J=5.1Hz), 4.28(2H,d,J=4.3Hz), 6.10-6.30(2H,m), 7.00-7.25(4H,m), 7.33(1H,d,J=7.3Hz), 7.49-7.54(2H,m), 7.58-7.64(3H,m), 7.75(1H,s), 8.28(1H,br.s), 8.39(1H,d,J=5.1Hz), 9.65(1H,br.s).
【０２５６】
（８９−２） 工程（８９−１）で得た化合物０．６３ｇ（１．３２ｍｍｏｌ）のジオキサン（４ｍｌ）−メタノール（２ｍｌ）溶液に４規定塩酸−ジオキサン（４ｍｌ）を加え、室温２時間で攪拌した。飽和重曹水を加えた後、酢酸エチル−メチルエチルケトンで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得た残渣をジイソプロピルエーテルで洗浄することにより、Ｎ−（２−アミノフェニル）−４−［Ｎ’−（ピリジン−３−イルメチル）ウレイドメチル］ベンズアミド０．３７ｇ（収率７４．７％）を褐色固体として得た。
【０２５７】
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm： 4.27(2H,d,J=5.9Hz), 4.31(2H,d,J=5.9Hz), 4.89(2H,br.s), 6.57-6.63(3H,m), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.17(1H,d,J=7.3Hz), 7.32-7.38(3H,m), 7.66(1H,d,J=8.1Hz), 7.93(2H,d,J=8.1Hz), 8.44(1H,d,J=5.1Hz), 8.49(1H,d,J=2.1Hz), 9.63(1H,br.s).
IR(KBr)cm-1: 3344,3241,1645,1560,1527,1505,1283,751,708.
【０２５８】
実施例８９と同様の方法により、実施例９０から実施例９５の化合物を合成した。以下に、化合物の融点（mp.）、1H NMR、IRの測定値を示す。
【０２５９】
実施例９０
Ｎ−（２−アミノフェニル）−４−［Ｎ’−（３−アミノフェニル）ウレイドメチル］ベンズアミド（表−１：化合物番号２４）
mp. 206-208℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.35(2H,d,J=5.9Hz), 4.93(4H,br.s), 6.13(1H,d,J=7.3Hz), 6.51-6.62(3H,m), 6.74-6.98(3H,m), 7.12-7.18(1H,m), 7.41(2H,d,J=8.1Hz), 7.94(2H,d,J=8.1Hz), 8.28(1H,s), 9.61(1H,s).
IR(KBr)cm-1:3356,3269,1640,1555,1495,1458,1308,1236,753.
【０２６０】
実施例９１
Ｎ−（２−アミノフェニル）−４−［Ｎ’−（ピリジン−３−イル）ウレイドメチル］ベンズアミド（表−１：化合物番号８７）
mp. 187-190℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.39(2H,d,J=5.9Hz), 4.89(2H,br.s), 6.59(1H,d,J=7.3,7.3Hz), 6.77(1H,d,J=6.6Hz), 6.88(1H,t,J=5.9Hz), 6.97(1H,ddd,J=1.5,6.6,7.3Hz), 7.16(1H,d,J=8.1Hz), 7.26(1H,dd,J=4.4,8.1Hz), 7.42(2H,d,J=8.8Hz), 7.95(2H,d,J=8.1Hz), 7.89-7.96(1H,m), 8.12(1H,dd,J=1.5,4.4Hz), 8.56(1H,d,J=3.0Hz), 8.85(1H,s), 9.62(1H,s).
IR(KBr)cm-1: 3248,1663,1541,1423,1280,1054.
【０２６１】
実施例９２
Ｎ−（２−アミノフェニル）−４−［Ｎ’−（３−アミノフェニル）チオウレイドメチル］ベンズアミド（表−１：化合物番号２５）
mp. 123℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.80(2H,d,J=5.1Hz), 4.87(2H,s), 5.12(2H,s), 6.36(1H,dd,J=1.5,8.1Hz), 6.48-6.63(3H,m), 6.78(1H,d,J=6.6Hz), 6.94-7.00(2H,m), 7.17(1H,d,J=8.1Hz), 7.42(2H,d,J=8.1Hz), 7.92-8.01(3H,m), 9.46(1H,s), 9.61(1H,s).
IR(KBr)cm-1: 3335,1616,1528,1503,1456,1311,864,751.
【０２６２】
実施例９３
Ｎ−（２−アミノフェニル）−４−［Ｎ’−（３−ニトロフェニル）チオウレイドメチル］ベンズアミド（表−１：化合物番号２０）
mp. 160℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.87(2H,d,J=5.1Hz), 7.27-7.33(3H,m), 7.46-7.63(5H,m), 7.89-7.95(2H,m), 8.05(2H,d,J=8.1Hz), 8.70(1H,s), 8.84(1H,t,J=8.9Hz), 10.37(1H,s).
【０２６３】
実施例９４
Ｎ−（２−アミノ−５−フロロフェニル）−４−［Ｎ’−（ピリジン−３−イル）メチルウレイドメチル］ベンズアミド（表−１：化合物番号１１２）
mp. (amorphous).
1H-NMR(270MHz, DMSO-d6)：4.77(4H,d,J=5.1Hz), 4.85(2H,s), 6.81(2H,m), 7.16(1H,dd,J=2.9,10.3Hz), 7.39(1H,dd,J=5.1,8.1Hz), 7.53(2H,d,J=8.1Hz), 7.81(1H,d,J=8.1Hz), 7.93(2H,d,J=8.1Hz), 8.51(1H,dd,J=1.5,5.1Hz), 8.62(1H,d,J=1.5Hz), 9.66(1H,s).
IR(KBr)cm-1: 3399,1730,1638,1508,1444,1411.
【０２６４】
実施例９５
Ｎ−（２−ヒドロキシフェニル）−４−［Ｎ’−（ピリジン−３−イル）メチルウレイドメチル］ベンズアミド（表−１：化合物番号１１４）
mp. (amorphous).
1H-NMR(270MHz, DMSO-d6)：4.43(2H,d,J=6.6Hz), 4.69(2H,s), 6.83(1H,t,J=6.6Hz), 6.91(1H,d,J=8.1Hz), 7.68(1H,d,J=6.6Hz), 7.82(2H,d,J=8.1Hz), 8.21(1H,d,J=4.4Hz), 8.35(1H,d,J=2.2Hz), 8.81(1H,t,J=6.6Hz), 9.48(1H,s), 9.75(1H,s).
IR(KBr)cm-1: 3399,1664,1535,1236,1064.
【０２６５】
実施例９６
Ｎ−（２−アミノフェニル）−４−［２−［Ｎ−（ピリジン−３−イル）アセチルアミノ］エチル］ベンズアミド（表−１：化合物番号７７）の合成
（９６−１） テレフタルアルデヒド酸３．４０ｇ（２２．６ｍｍｏｌ）のトルエン（２５ｍｌ）懸濁液にチオニルクロライド（４ｍｌ）を加え、８０℃で２時間加熱攪拌した。放冷後、溶媒を留去し得られた残渣をＴＨＦ（５０ｍｌ）に溶解し、酸クロライドを調製した。実施例１の工程（１−２）の化合物４．１６ｇ（２０．０ｍｍｏｌ）のＴＨＦ（１０ｍｌ）溶液にトリエチルアミン（６ｍｌ，４２．８ｍｍｏｌ）を加え、さらに先に調製した酸クロライドを氷冷下３０分かけて滴下した。
【０２６６】
５時間攪拌後、飽和重曹水を加え、酢酸エチルで抽出した。有機層を飽和食塩水洗浄後、乾燥、溶媒を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（クロロホルム→クロロホルム：酢酸エチル＝１０：１）で精製し、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］−４−ホルミルベンズアミド３．４２ｇ（収率５０．２％）を淡褐色固体として得た。
1H NMR(270MHz, CDCl3)δppm: 1.52(9H,s), 6.77(1H,br.s), 7.16-7.18(2H,m), 7.23-7.26(1H,m), 7.88(1H,d,J=8.8Hz), 7.98(2H,d,J=8.8Hz), 8.13(2H,d,J=8.8Hz), 9.57(1H,br.s), 10.11(1H,br.s).
IR(KBr)cm-1: 3326,3251,1707,1696,1659,1603,1165.
【０２６７】
（９６−２） 工程（９６−１）で得られた化合物３．０ｇ（８．８２ｍｍｏｌ）およびエトキシカルボニルメチルトリフェニルホスフィン４．５ｇ（１２．９ｍｍｏｌ）のトルエン（１０ｍｌ）懸濁液を窒素気流下８０℃で、５．５時間攪拌した。放冷後、酢酸エチルで希釈した後、飽和重曹水、水、飽和食塩水で洗浄し、乾燥した。溶媒を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（クロロホルム：酢酸エチル＝２０：１）で精製し、エチル ４−［Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］アミノカルボニル］シンナメート３．３ｇ（収率９１．１％）を黄色アモルファス状固体として得た。
1H NMR(270MHz, CDCl3)δppm: 1.35(3H,t,J=7.3Hz), 1.52(9H,s), 4.28(2H,q,J=7.3Hz), 6.52(1H,d,J=15.1Hz), 6.80(1H,br.s), 7.16-7.25(3H,m), 7.61(2H,d,J=8.1Hz), 7.71(1H,d,J=15.1Hz), 7.82(1H,d,7.3Hz), 7.98(2H,d,J=8.1Hz), 9.34(1H,br.s).
【０２６８】
（９６−３） 工程（９６−２）で得られた化合物２．５０ｇ（６．０９ｍｍｏｌ）のＴＨＦ（３０ｍｌ）−メタノール（４０ｍｌ）溶液に窒素気流下１０％Ｐｄ／Ｃ（含水，０．５ｇ）を加えた後、水素気流下３０分間攪拌した。窒素置換した後、触媒を濾過した。濾液の溶媒を留去して得た残渣にジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することによりＮ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］−４−（２−エトキシカルボニルエチル）ベンズアミド２．２３ｇ（収率８８．８％）を白色固体として得た。
1H NMR(270MHz, CDCl3)δppm: 1.25(3H,t,J=7.3Hz), 1.52(9H,s), 2.65(2H,t,J=7.3Hz), 3.02(2H,t,J=7.3Hz), 4.13(2H,q,J=7.3Hz), 6.77(1H,br.s), 7.16-7.33(5H,m), 7.78(1H,d,J=8.1Hz), 7.89(2H,d,J=8.8Hz), 9.06(1H,br.s).
【０２６９】
（９６−４） 工程（９６−３）で得られた化合物２．２１ｇ（５．３６ｍｍｏｌ）のメタノール（１０ｍｌ）−水（１５ｍｌ）懸濁液に水酸化リチウム１水和物０．３７ｇ（８．８２ｍｍｏｌ）を加え、４０℃で３時間攪拌した。放冷後１０％塩酸水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得られた残渣にジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］−４−（２−カルボキシエチル）ベンズアミド１．８７ｇ（収率９０．８％）を白色固体として得た。
1H NMR(270MHz, DMSO-d6)δppm: 1.45(9H,s), 2.59(2H,t,J=7.3Hz), 2.91(2H,t,J=7.3Hz), 7.13-7.20(2H,m), 7.40(2H,d,J=8.1Hz), 7.54(2H,dd,J=7.3,2.1Hz), 7.88(2H,d,J=8.1Hz), 8.66(1H,br.s), 9.79(1H,br.s).
【０２７０】
（９６−５） 工程（９６−４）で得られた化合物０．１２ｇ（０．３ｍｍｏｌ）のベンゼン（５ｍｌ）懸濁液にトリエチルアミン０．１ｍｌ（０．７ｍｍｏｌ）およびモレキュラーシーブ４Ａ０．３ｇを加え、窒素気流下０．５時間攪拌した。この溶液にジフェニルホスホリルアジド０．１５ｍｌ（０．７ｍｍｏｌ）を加え、２時間加熱還流した。放冷後、ベンジルアルコール０．４ｍｌ（３．８ｍｍｏｌ）を加え、さらに２．５時間加熱還流した。酢酸エチルで希釈した後、水、飽和食塩水で洗浄した。
【０２７１】
有機層を乾燥後、溶媒を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（クロロホルム：酢酸エチル＝４：１）で精製することにより、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］−４−［２−（Ｎ−ベンジルオキシカルボニルアミノ）エチル］ベンズアミド１２９ｍｇ（８８％）を無色油状物として得た。
1H NMR(270MHz, CDCl3)δppm: 1.51(9H,s), 2.89(2H,t,J=7.3Hz), 3.45-3.54(2H,m), 4.80(1H,m), 5.10(2H,s), 6.76(1H,br.s), 7.20-7.38(10H,m), 7.79(1H,d,J=8.8Hz), 7.89(2H,d,J=8.1Hz), 9.10(1H,br.s).
【０２７２】
（９６−６） 工程（９６−５）で得られた化合物１２９ｍｇ（０．２６ｍｍｏｌ）のメタノール（１０ｍｌ）溶液に窒素気流下１０％Ｐｄ／Ｃ（含水，０．０５ｇ）を加え、水素気流下２時間攪拌した。触媒を留去した後、乾燥することにより得られた残渣をジクロロメタン（５ｍｌ）に溶解した。この溶液に３−ピリジン酢酸塩酸塩０．１８ｇ（１．０４ｍｍｏｌ）を加え、さらにトリエチルアミン０．２８ｇ（２．０ｍｍｏｌ）を加えて氷冷した。氷冷下、２−クロロ−１，３−ジメチルイミダゾリニウムクロライド０．１７ｇ（１．０ｍｍｏｌ）を加え、２時間攪拌した。飽和重曹水を加えた後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得た残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することにより、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］−４−［２−［Ｎ−（ピリジン−３−イル）アセチルアミノ］エチル］ベンズアミド５０ｍｇ（収率４０％）を無色油状物として得た。
【０２７３】
1H NMR(270MHz, CDCl3)δppm: 1.48(9H,s), 2.80(2H,t,J=6.6Hz), 3.42(2H,m), 3.52(2H,s), 6.33(1H,t-like,J=5.9Hz), 7.09(2H,d,J=8.1Hz), 7.14-7.20(2H,m), 7.24(1H,dd,J=4.4,7.3Hz), 7.41(1H,dd,J=3.7,5.9Hz), 7.50(1H,s), 7.58(1H,dd,J=1.5,5.9Hz), 7.69(1H,dd,J=3.7,5.9Hz), 7.75(2H,d,J=8.1Hz), 8.22(1H,d,J=2.1Hz), 8.44(1H,dd,J=1.5,4.4Hz), 9.49(1H,br.s).
【０２７４】
（９６−７） 工程（９６−６）の化合物５０ｍｇ（０．１０ｍｍｏｌ）のジオキサン（２ｍｌ）−メタノール（１ｍｌ）溶液に４規定塩酸−ジオキサン（２ｍｌ）を加え、室温で２．５時間攪拌した。飽和重曹水を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得られた残渣を乾燥することにより、Ｎ−（２−アミノフェニル）−４−［２−［Ｎ−（ピリジン−３−イル）アセチルアミノ］エチル］ベンズアミド２２ｍｇ（収率５９％）をアモルファス状固体として得た。
【０２７５】
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 2.70-2.90(4H,m), 3.42(2H,s), 4.89(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=7.3Hz), 6.97(1H,dd,J=7.3,7.3Hz), 7.16(1H,d,J=7.3Hz), 7.29-7.32(3H,m), 7.59(1H,d,J=8.1Hz), 7.89(1H,d,J=8.1Hz), 8.22(1H,t-like), 8.41-8.43(2H,m), 9.62(1H,br.s).
【０２７６】
実施例９７
Ｎ−（２−アミノフェニル）−４−［２−［Ｎ−（３−ピコリル）アミノカルボニル］エチル］ベンズアミド（表−１：化合物番号８０）の合成
（９７−１） 実施例９６の工程（９６−４）で得られた化合物０．５８ｇ（１．５ｍｍｏｌ）のジクロロメタン（５ｍｌ）懸濁液に、３−ピコリルアミン０．２２ｇ（２．０ｍｍｏｌ）およびトリエチルアミン０．５６ｍｌ（４．０ｍｍｏｌ）を加えた。氷冷下、２−クロロ−１，３−ジメチルイミダゾリニウムクロライド０．３９ｇ（２．０ｍｍｏｌ）のジクロロメタン（５ｍｌ）溶液を加え、１．５時間攪拌した。飽和重曹水を加えた後、クロロホルムで抽出した。
【０２７７】
有機層を水、飽和食塩水で洗浄後、乾燥、溶媒を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（クロロホルム：メタノール：アンモニア水＝１００：１０：１）で精製することにより、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］−４−［２−［Ｎ−（３−ピコリル）アミノカルボニル］エチル］ベンズアミド０．７１ｇ（収率９４％）を淡褐色油状物として得た。
1H NMR(270MHz, CDCl3)δppm: 1.45(9H,s), 2.42(2H,t,J=7.3Hz), 2.98(2H,t,J=7.3Hz), 4.32(2H,d,J=6.6Hz), 6.44(1H,t,J=6.6Hz), 7.14-7.27(5H,m), 7.48-7.57(3H,m), 7.63-7.68(3H,m), 7.90(1H,d,J=2.1Hz), 8.43(1H,dd,J=1.4,4.4Hz), 9.86(1H,br.s).
【０２７８】
（９７−２） 工程（９７−１）の化合物０．７０ｇ（１．４７ｍｍｏｌ）のジオキサン（５ｍｌ）溶液に４規定塩酸−ジオキサン（５ｍｌ）を加え、さらにメタノール（２ｍｌ）を加えて室温で２時間攪拌した。飽和重曹水を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得られた残渣にジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより、Ｎ−（２−アミノフェニル）−４−［２−［Ｎ−（３−ピコリル）アミノカルボニル］エチル］ベンズアミド０．４２ｇ（収率７６．３％）を乳白色固体として得た。
【０２７９】
mp. 168-170℃.
1H NMR(270MHz, DMSO-d6)δppm: 2.47-2.53(2H,m), 2.93(2H,t,J=7.3Hz), 4.27(2H,d,J=5.9Hz), 4.90(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=6.6,7.3Hz), 7.16(1H,d,J=6.6Hz), 7.28-7.35(1H,m), 7.33(2H,d,J=8.1Hz), 7.49(1H,dd,J=2.1,5.9Hz), 7.89(2H,d,J=8.1Hz), 8.39-8.44(3H,m), 9.62(1H,br.s).
IR(KBr)cm-1: 3313,1641,1523,1457,1300,748,713.
【０２８０】
実施例９８
Ｎ−（２−アミノフェニル）−４−［（ピリジン−３−イル）メチルアミノカルボニルオキシメチル］ベンズアミド（表−１：化合物番号８５）の合成
（９８−１） メチル ４−ヒドロキシメチルベンゾエート１．９９ｇ（１２．０ｍｍｏｌ）のＴＨＦ（２０ｍｌ）溶液に室温でＮ，Ｎ’−カルボニルジイミダゾール１．７８ｇ（１１．０ｍｍｏｌ）を加え、１時間攪拌した。この溶液に室温で３−ピコリルアミン１．０８ｇ（１０．０ｍｍｏｌ）を加え、３．５時間攪拌した後、一晩放置した。これに水を加え希釈した後、酢酸エチルで抽出した。
【０２８１】
有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得た残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製して、Ｎ−（４−メトキシカルボニル）ベンジルオキシカルボニル−３−ピコリルアミン２．７６ｇ（収率９１．９％）を白色ワックス状固体として得た。
1H NMR(270MHz, CDCl3)δppm: 3.91(3H,s), 4.40(2H,d,J=5.9Hz), 5.18(2H,s), 5.50(1H,br.s), 7.24-7.28(1H,m), 7.40(2H,d,J=8.1Hz), 7.65(1H,d,J=7.3Hz), 8.02(2H,d,J=8.8Hz), 8.50-8.53(2H,m).
【０２８２】
（９８−２） 工程（９８−１）の化合物２．４０ｇ（８．０ｍｍｏｌ）のメタノール（１０ｍｌ）−水（２０ｍｌ）懸濁液に、水酸化リチウム１水和物０．４２ｇ（１０．０ｍｍｏｌ）を加え、室温で５時間攪拌した。１０％塩酸水溶液を加え、酸性（ｐＨ２〜４）にした後、析出した固体を濾取、乾燥することにより、Ｎ−（４−カルボキシ）ベンジルオキシカルボニル−３−ピコリルアミン１．８３ｇ（収率７９．９％）を白色固体として得た。
1H NMR(270MHz, DMSO-d6)δppm: 4.24(2H,d,J=5.9Hz), 5.13(2H,s), 7.33-7.38(1H,m), 7.46(2H,d,J=8.1Hz), 7.94(2H,d,J=8.1Hz), 7.95-8.01(1H,m), 8.46(1H,d,J=5.1Hz), 8.49(1H,d,J=1.5Hz), 13.0(1H,br.s).
【０２８３】
（９８−３） 工程（９８−２）の化合物１．２６ｇ（４．４ｍｍｏｌ）のジクロロメタン（２０ｍｌ）懸濁液にオキザリルクロライド１．０ｍｌ（１１．４ｍｌ）を徐々に加え、さらにＤＭＦを数滴加えた後室温で１０分間、さらに４０℃で３０分間攪拌した。放冷後、溶媒を留去し、更にトルエンで過剰のオキザリルクロライドを留去した。この残渣にジクロロメタン（１０ｍｌ）を加えた後、氷冷し、さらに実施例１の工程（１−２）で得られた化合物０．８３ｇ（４．０ｍｍｏｌ）のジクロロメタン（８ｍｌ）−ピリジン（８ｍｌ）溶液を滴下した後、室温まで昇温させながら７時間攪拌し、一晩放置した。
【０２８４】
飽和重曹水を加えた後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得られた残渣にトルエンを加え。さらに過剰のピリジンを共沸した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することによりＮ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］−４−［（ピリジン−３−イル）メチルアミノカルボニルオキシメチル］ベンズアミド１．４０ｇ（収率７３．４％）を淡褐色固体として得た。
1H NMR(270MHz, CDCl3)δppm: 1.51(9H,s), 4.40(2H,d,J=5.9Hz), 5.19(2H,s), 5.56(1H,m), 7.07(1H,br.s), 7.14-7.31(4H,m), 7.43(2H,d,J=8.1Hz), 7.65(1H,d,J=8.1Hz), 7.76(1H,d,J=7.3Hz), 7.95(2H,d,J=8.1Hz), 8.52(2H,d,J=4.1Hz), 9.32(1H,br.s).
【０２８５】
（９８−４） 工程（９８−３）の化合物１．００ｇ（２．１０ｍｍｏｌ）のジオキサン（１０ｍｌ）−メタノール（２ｍｌ）溶液に室温で４規定塩酸−ジオキサン（９ｍｌ）を加えて２時間攪拌した。飽和重曹水を加えた後、酢酸エチル−メチルエチルケトン（１：１）で抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去し、得られた残渣にメタノール−ジイソプロピルエーテルを加え、生成した固体を濾取、乾燥することにより、Ｎ−（２−アミノフェニル）−４−［（ピリジン−３−イル）メチルアミノカルボニルオキシメチル］ベンズアミド０．７９ｇ（定量的）を白色固体として得た。
【０２８６】
mp. 139-141℃
1H NMR(270MHz, DMSO-d6)δppm: 4.25(2H,d,J=5.9Hz), 4.90(2H,s), 5.13(2H,s), 6.60(1H,dd,J=6.6,7.3Hz), 6.78(1H,d,J=7.3Hz), 6.97(1H,dd,J=6.6,7.3Hz), 7.17(1H,d,J=7.3Hz), 7.36(1H,dd,J=4.4,8.1Hz), 7.47(2H,d,J=8.1Hz), 7.67(1H,d,J=8.1Hz), 7.97(2H,d,J=7.3Hz), 7.90-8.00(1H,m), 8.46(1H,dd,J=1.5,5.1Hz), 8.49(1H,d,J=2.1Hz), 9.65(1H,br.s).
IR(KBr)cm-1: 3326(br),1694,1637,1526,1458,1147,750,712.
【０２８７】
実施例９９
Ｎ−（２−アミノフェニル）−４−［３−（イミダゾール−１−イル）プロピルアミノカルボニルオキシメチル］ベンズアミド（表−１：化合物番号２１５）
実施例９８と同様の方法により合成した。
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 1.80-1.89(2H,m), 2.94-3.02(2H,m), 3.98(2H,t,J=7.3Hz), 4.88(2H,s), 5.11(2H,s), 6.55-6.63(1H,m), 6.76-6.97(3H,m), 7.10-7.18(2H,m), 7.43-7.48(3H,m), 7.61(1H,s), 7.98(2H,d,J=8.1Hz), 9.66(1H,s).
【０２８８】
実施例１００
Ｎ−（２−アミノフェニル）−４−（フェニルアセチルアミノ）ベンズアミド（表−１：化合物番号２）の合成
（１００−１） 実施例１の工程（１−２）で得た化合物１６．６ｇ（８０ｍｍｏｌ）のジクロロメタン（１２０ｍｌ）溶液にトリエチルアミン１６．８ｍｌ（１２０ｍｍｏｌ）を加え、さらに氷冷下、４−ニトロベンゾイルクロライド１６．０ｇ（８６．４ｍｍｏｌ）のジクロロメタン（４０ｍｌ）溶液を徐々に加えた後、７時間攪拌した。飽和重曹水を加えた後、クロロホルムで抽出した。
【０２８９】
有機層を１規定塩酸水溶液、飽和重曹水、飽和食塩水で洗浄した後、乾燥、溶媒を留去した。得られた残渣をジイソプロピルエーテルで洗浄することにより、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニルアミノ）フェニル］−４−ニトロベンズアミド２８．０ｇ（収率９８％）を淡黄色固体として得た。
1H NMR(270MHz, CDCl3)δppm: 1.53(9H,s), 7.17-7.29(4H,m), 7.85(1H,br.d,J=7.3Hz), 8.17(2H,d,J=8.8Hz), 8.32(2H,d,J=8.8Hz), 9.88(1H,br.s).
【０２９０】
（１００−２） 工程（１００−１）で得た化合物２４．０ｇ（６７．２ｍｍｏｌ）のＴＨＦ（８０ｍｌ）−メタノール（８０ｍｌ）混合溶液に窒素気流下１０％Ｐｄ／Ｃ（含水，２．４ｇ）を加え、水素気流下１．５時間攪拌した。水素の吸収が停止した後、触媒を濾別、溶媒を留去して得られた残渣にジイソプロピルエーテルおよび酢酸エチルを加え、得られた固体を濾取、乾燥することにより、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニルアミノ）フェニル］−４−アミノベンズアミド１８．９６ｇ（収率８６％）を白色固体として得た。
1H NMR(270MHz, DMSO-d6)δppm: 1.46(9H.s), 5.84(2H,s), 6.61(2H,d,J=8.8Hz), 7.10-7.18(2H,m), 7.46-7.55(2H,m), 7.68(2H,d,J=8.8Hz), 8.67(1H,s), 9.49(1H,s).
【０２９１】
（１００−３） 工程（１００−２）で得た化合物１．６ｇ（４．８８ｍｍｏｌ）の塩化メチレン溶液（１５ｍｌ）に、ピリジン０．８ｍｌ（９．９ｍｍｏｌ）、フェニルアセチルクロライド０．９６ｍｌ（７．２６ｍｍｏｌ）を加え１日間撹拌した。反応終了後、水を加え、析出した結晶を濾取し、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニルアミノ）フェニル］−４−（フェニルアセチルアミノ)ベンズアミド１．６６ｇ（収率７６％）を得た。
【０２９２】
（１００−４） 工程（１００−３）で得た化合物１ｇ（２．２４ｍｍｏｌ）のアセトニトリル溶液（２５ｍｌ）に室温でヨードトリメチルシラン０．８８ｍｌ（６．１８ｍｍｏｌ）を加え３時間撹拌した。反応終了後、溶媒を濃縮し得られた残留物をメタノールから再結晶して、Ｎ−（２−アミノフェニル）−４−（フェニルアセチルアミノ）ベンズアミド０．２９ｇ（収率３８％）を白色結晶として得た。
【０２９３】
mp. 232-237℃.
1H NMR(270MHz, DMSO-d6)δppm: 3.69(2H,s), 4.90(2H,s), 6.60(1H,t,J=7.3Hz), 6.77(1H,d,J=7.3Hz), 6.96(1H,t,J=7.3Hz), 7.15(1H,d,J=7.4Hz), 7.22-7.35(5H,m), 7.72(2H,d,J=8.8Hz), 7.95(2H,d,J=8.8Hz), 9.57(1H,s), 10.43(1H,s)
IR(KBr)cm-1: 2937,2764,1660,1598,1506,1459.
【０２９４】
実施例１００と同様の方法により、実施例１０１から実施例１２８の化合物を合成した。以下に、化合物の融点（mp.）、1H NMR、IRの測定値を示す。
【０２９５】
実施例１０１
Ｎ−（２−アミノフェニル）−４−［（４−フェニルブタノイル）アミノ］ベンズアミド（表−１：化合物番号４）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 1.91(2H,hep,J=7.3Hz), 2.37(2H,t,J=7.3Hz), 2.64(2H,t,J=7.3Hz), 5.0(2H,br.s), 6.61(1H,t,7.0Hz), 6.79(1H,dd,J=1.5,8.1Hz), 6.97(1H,t,J=7.0Hz), 7.10-7.40(6H,m), 7.71(2H,d,J=8.8Hz), 7.94(2H,d,J=8.8Hz), 9.57(1H,s), 10.15(1H,s).
IR(KBr)cm-1; 3344,1687,1603,1542,1460,1315,1033,842,737.
【０２９６】
実施例１０２
Ｎ−（２−アミノフェニル）−４−［（４−クロロフェニルアセチル）アミノ］ベンズアミド（表−１：化合物番号１５）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 3.72(2H,s),7.29-7.43(8H,m),7.77(2H,d,J=8.8Hz),8.00(2H,d,J=8.8Hz),10.29(1H,s),10.52(1H,s).
IR(KBr)cm-1: 3300,2868,1664,1638,1520.
【０２９７】
実施例１０３
Ｎ−（２−アミノフェニル）−４−［（２−ニトロフェニルアセチル）アミノ］ベンズアミド 塩酸塩（表−１：化合物番号１９の塩酸塩）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 4.20(2H,s), 7.20-7.30(3H,m), 7.40-7.45(1H,m), 7.60(2H,d), 7.71-7.77(3H,m), 8.02-8.10(4H,m), 10.27(1H,br.s), 10.64(1H,br.s).
IR(KBr)cm-1: 3263,1676,1647,1518,1184,759.
【０２９８】
実施例１０４
Ｎ−（２−アミノフェニル）−４−［（４−ニトロフェニルアセチル）アミノ］ベンズアミド（表−１：化合物番号２１）
mp. 222-226℃.
1H NMR(270MHz, DMSO-d6)δppm: 3.90(2H,s), 4.96(2H,br.s), 6.60(1H,dt,J=1.5,6.6Hz), 6.78(1H,dd,J=1.5,6.6Hz), 6.97(1H,dt,J=1.5,6.6Hz), 7.15(1H,dd,J=1.5,6.6Hz), 7.63(2H,d,J=8.8Hz), 7.71(2H,d,J=8.8Hz), 7.95(2H,d,J=8.8Hz), 8.22(2H,d,J=8.8Hz), 9.59(1H,s), 10.54(1H,s).
IR(KBr)cm-1: 3395,3334,1671,1630,1519,1346.
【０２９９】
実施例１０５
Ｎ−（２−アミノフェニル）−４−［（２−アミノフェニルアセチル）アミノ］ベンズアミド（表−１：化合物番号２２）
mp. 177-182℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 3.54(2H,s), 4.88(2H,br.s), 5.09(2H,br.s), 6.55(1H,dd,J=6.6,7.3Hz), 6.59(1H,dd,J=7.3,7.3Hz), 6.68(1H,d,J=7.3Hz), 6.78(1H,d,J=7.3Hz), 6.96(2H,dd,J=7.3,7.3Hz), 7.06(1H,d,J=6.6Hz), 7.15(1H,d,J=7.3Hz), 7.71(2H,d,J=8.8Hz), 7.95(2H,d,J=8.8Hz), 9.57(1H,br.s), 10.39(1H,br.s).
IR(KBr)cm-1: 3374,3256(br.),1683,1597,1503,1317,1262,1180,1153,747.
【０３００】
実施例１０６
Ｎ−（２−アミノフェニル）−４−［（４−アミノフェニルアセチル）アミノ］ベンズアミド（表−１：化合物番号２６）
mp. 219-226℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 3.46(2H,s), 4.93(4H,br.s), 6.52(2H,d,J=8.1Hz), 6.59(1H,dt,J=1.5,7.3Hz), 6.77(1H,dd,J=1.4,7.3Hz), 6.97(1H,dt,J=1.4,7.3Hz), 6.99(2H,d,J=8.1Hz), 7.15(1H,dd,J=1.5,7.3Hz), 7.70(2H,d,J=8.8Hz), 7.93(2H,d,J=8.8Hz).
IR(KBr)cm-1: 3278,3032,1675,1628,1516.
【０３０１】
実施例１０７
Ｎ−（２−アミノフェニル）−４−［（４−メトキシフェニルアセチル）アミノ］ベンズアミド（表−１：化合物番号３２）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm： 3.62(2H,s), 3.74(3H,s), 6.90(2H,d,J=8.8Hz), 7.26(2H.d.J=8.8Hz), 7.30(3H,m), 7.39(1H,m), 7.77(2H,d,J=8.8Hz), 7.99(2H,d,J=8.8Hz), 10.26(1H,s), 10.44(1H,s).
IR(KBr)cm-1: 3300,2759,1670,1638,1514,1250.
【０３０２】
実施例１０８
Ｎ−（２−アミノフェニル）−４−［［４−（Ｎ，Ｎ−ジメチルアミノ）フェニルアセチル］アミノ］ベンズアミド（表−１：化合物番号５３）
mp. 140℃.
1H NMR(270MHz, DMSO-d6)δppm: 3.04(6H,s), 3.67(2H,s), 7.16(2H,d,J=8.1Hz), 7.29-7.40(6H,m), 7.76(2H,d,J=8.8Hz), 7.99(2H,d,J=8.8Hz), 10.29(1H,s), 10.47(1H,s).
IR(KBr)cm-1: 3244,2951,2639,1647,1599,1507.
【０３０３】
実施例１０９
Ｎ−（２−アミノフェニル）−４−［（４−トリフルオロメチルフェニルアセチル）アミノ］ベンズアミド（表−１：化合物番号４３）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 3.84(2H,s), 6.89(1H,t,J=7.4Hz), 7.00(1H,d,J=7.4Hz), 7.11(1H,t,J=7.4Hz), 7.25(1H,d,J=7.4Hz), 7.57(2H,d,J=8.8Hz), 7.71(2H,d,J=8.8Hz), 7.73(2H,d,J=8.8Hz), 7.97(2H,d,J=8.8Hz), 9.87(1H,s), 10.54(1H,s).
IR(KBr)cm-1: 3260,1664,1605,1521,1327,1119.
【０３０４】
実施例１１０
Ｎ−（２−アミノフェニル）−４−［（ピリジン−２−イル）アセチルアミノ］ベンズアミド ２塩酸塩（表−１：化合物番号１７４の塩酸塩）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 4.60(2H,s), 7.30-7.46(3H,m), 7.56(1H,d,J=7.4Hz), 7.79(2H,d,J=8.8Hz), 7.95(1H,t,J=6.6Hz), 8.01(1H,d,J=7.4Hz), 8.11(2H,d,J=8.8Hz), 8.49(1H,t,J=7.4Hz), 8.87(1H,d,J=5.1Hz), 10.46(1H,s).
【０３０５】
実施例１１１
Ｎ−（２−アミノフェニル）−４−［（ピリジン−３−イル）アセチルアミノ］ベンズアミド ２塩酸塩（表−１：化合物番号６８の塩酸塩）
mp. 182-189℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.12(2H,s), 7.29-7.59(4H,m), 7.80(2H,d,J=8.8Hz), 8.05(1H,m), 8.11(2H,d,J=8.8Hz), 8.57(1H,d,J=8.1Hz), 8.85(1H,d,J=5.2Hz), 8.95(1H,s), 10.25(1H,s), 10.48(1H,s).
【０３０６】
実施例１１２
Ｎ−（２−アミノフェニル）−４−［［３−（ピリジン−３−イル）プロパノイル］アミノ］ベンズアミド（表−１：化合物番号６９）
mp. 184-186℃.
1H NMR(270MHz, DMSO-d6)δppm: 2.80(2H,t,J=7.3Hz), 3.08(2H,t,J=7.3Hz), 6.87(1H,t,J=8.0Hz), 6.99(1H,dd,J=1.4,8.0Hz), 7.11(1H,dt,J=1.4,8.0Hz), 7.25(1H,d,J=8.0Hz), 7.70(2H,d,J=8.8Hz), 7.77(1H,dd,J=5.8,8.0Hz), 7.96(2H,d,J=8.8Hz), 8.22(1H,d,J=8.0Hz), 8.75(1H,d,J=1.4Hz), 9.83(1H,s), 10.25(1H,s).
【０３０７】
実施例１１３
Ｎ−（２−アミノフェニル）−２−クロロ−４−［３−（ピリジン−３−イル）プロパノイルアミノ］ベンズアミド（表−１：化合物番号１２３）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm： 2.70(2H,t,J=8.1Hz), 2.96(2H,t,J=7.3Hz), 4 .74(2H,br.s), 6.60(1H,t,J=6.6Hz), 6.78(1H,d,J=6.6Hz), 6.95(1H,t,J=6.6Hz), 7.19(1H,dd,J=1.5,7.3Hz), 7.29(1H,dd,J=5.1,7.3Hz), 7.66(2H,d,J=8.8Hz), 7.92(2H,d,J=8.8Hz), 8.48(1H,d,J=2.2Hz), 9.37(1H,s), 10.00(1H,s).
IR(KBr)cm-1: 3273,1675,1519,1315,1181,852,747.
【０３０８】
実施例１１４
Ｎ−（２−アミノフェニル）−４−［［Ｎ−（ピリジン−３−イル）メチル−Ｎ−トリフルオロアセチルアミノ］アセチルアミノ］ベンズアミド（表−１：化合物番号１０７）
mp. 145℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.18 and 4.42(total 2H,s), 4.73 and 4.83(total 2H,s), 4.87(2H,br.s), 6.60(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=8.1Hz), 6.96(1H,dd,J=7.3,7.3Hz), 7.16(1H,d,J=8.1Hz), 7.35-7.45(1H,m), 7.66(2H,d,J=5.9Hz), 7.70-7.80(1H,m), 7.90-8.00(2H,m), 8.51-8.55(1H,m), 8.58(1H,s), 9.60(1H,br.s), 10.36 and 10.43(total 1H,br.s).
【０３０９】
実施例１１５
Ｎ−（２−アミノフェニル）−４−［［Ｎ−（ピリジン−３−イル）メチルアミノ］アセチルアミノ］ベンズアミド（表−１：化合物番号１０５）
mp. 160℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 3.30(2H,s), 3.79(2H,s), 4.88(2H,s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.16(1H,d,J=8.1Hz), 7.74(2H,d,J=8.8Hz), 7.80(1H,d,J=7.3Hz), 7.95(2H,d,J=8.1Hz), 8.46(1H,d,J=3.7Hz), 8.57(1H,s), 9.57(1H,s), 10.08(1H,br.s).
IR(KBr)cm-1: 3298,1693,1637,1602,1544,1454,1262,848,762.
【０３１０】
実施例１１６
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メチルオキサモイルアミノ］ベンズアミド（表−１：化合物番号１０４）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 4.43(2H,d,J=6.6Hz), 4.90(2H,br.s), 6.60(1H,dd,J=6.6,7.3Hz), 6.78(1H,d,J=7.3Hz), 6.97(1H,ddd,J=1.5,6.6,7.3Hz), 7.16(1H,d,J=7.3Hz), 7.37(1H,dd,J=4.4,8.1Hz), 7.73(1H,d,J=8.1Hz), 7.96 and 7.96(4H,AA'BB',J=9.4Hz), 8.47(1H,dd,J=1.5,5.1Hz), 8.56(1H,d,J=1.5Hz), 9.59(1H,s), 9.67(1H,t,J=6.6Hz), 10.92(1H,br.s).
IR(KBr)cm-1: 3299,1644,1518,1320,1119,748.
【０３１１】
実施例１１７
Ｎ−（２−アミノフェニル）−４−［［Ｎ−（ピリジン−３−イル）メチル−Ｎ−ニコチノイルアミノ］アセチルアミノ］ベンズアミド（表−１：化合物番号１０６）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 4.11(major 2H,s), 4.26(minor 2H,s), 4.75(major 2H,s), 4.65(minor 2H,s), 4.88(total 2H,br.s), 6.60(total 1H,dd,J=7.3,8.1Hz), 6.78(total 1H,d,J=7.3Hz), 6.97(total 1H,dd,J=7.3,8.1Hz), 7.15(total 1H,d,J=8.1Hz), 7.41-7.95(total 8H,m), 8.46-8.52(total 1H,m), 8.63-8.70(total 2H,m), 9.59(total 1H,s), 10.22(major 1H,br.s), 10.37(minor 1H,br.s).
IR(KBr)cm-1:3269,1701,1637,1603,1534,1506,1312,1254,752.
【０３１２】
実施例１１８
Ｎ−（２−アミノフェニル）−４−［［４−（ピリジン−３−イル）ブタノイル］アミノ］ベンズアミド（表−１：化合物番号７０）
mp. 165-167℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 1.88-1.99(2H,m), 2.68(2H,t,J=7.3Hz), 2.39(2H,t,J=7.3Hz), 6.78-6.81(1H,m), 6.94-6.99(1H,m), 7.15-7.18(1H,m), 7.34-7.39(1H,m), 7.69-7.72(3H,m), 7.94(2h,d,J=8.8Hz), 8.43-8.48(2H,m).
IR(KBr)cm-1: 3291,1660,1626,1308,1261,1182,1027,825,747.
【０３１３】
実施例１１９
Ｎ−（２−アミノフェニル）−４−［［Ｎ−（ピリジン−３−イル）メチル−Ｎ−メチルアミノ］アセチルアミノ］ベンズアミド（表−１：化合物番号１０８）mp. 154-155℃.
1H NMR(270MHz, DMSO-d6)δppm: 2.28(3H,s), 3.27(2H,s), 3.71(2H,s), 4.88(2H,br.s), 6.60(1H,dd,J=6.6,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.16(1H,d,J=8.1Hz), 7.38(1H,dd,J=2.9,8.1Hz), 7.77(2H,d,J=8.8Hz), 7.75-7.85(1H,m), 7.95(2H,d,J=8.8Hz), 8.47(1H,d,J=1.5Hz), 8.49(1H,s), 9.56(1H,s), 10.02(1H,br.s).
【０３１４】
実施例１２０
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）オキシアセチルアミノ］ベンズアミド（表−１：化合物番号６５）
mp. 175-179℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.86(2H,s), 4.90(2H,br.s), 6.60(1H,d,J=7.3,7.3Hz), 6.78(1H,d,J=7.3Hz), 6.97(1H,dd,J=6.6,7.3Hz), 7.16(1H,d,J=8.1Hz), 7.34-7.47(2H,m), 7.76(2H,d,J=8.8Hz), 7.98(2H,d,J=8.8Hz), 8.22(1H,d,J=3.6Hz), 8.39(1H,d,J=2.9Hz), 9.60(1H,br.s), 10.40(1H,br.s).
IR(KBr)cm-1: 3321,1655,1530,1276,1231,1068,757.
【０３１５】
実施例１２１
Ｎ−（２−アミノフェニル）−４−［４−（ピリジン−３−イル）−１、４−ジオキソブチルアミノ］ベンズアミド（表−１：化合物番号９９）
mp. 190-194℃.
1H NMR(270MHz, DMSO-d6)δppm: 2.08(2H,t,J=6.4Hz), 3.41(2H,t,J=6.4Hz), 4.86(2H,s), 6.59(1H,t,J=5.6Hz), 6.78(1H,d,J=7.9Hz), 6.96(1H,t,J=7.4Hz), 7.15(1H,d,J=7Hz), 7.58(1H,dd,J=4.9,7.9Hz), 7.70(2H,d,J=8.9Hz), 7.94(2H,d,J=8.9Hz), 8.35(1H,d,J=7.9Hz), 8.81(1H,d,J=4Hz), 9.18(1H,s), 9.56(1H,s), 10.32(1H,s).
IR(KBr)cm-1: 3317,1691,1652,1601,1522,1312,982,847,764,701.
【０３１６】
実施例１２２
Ｎ−（２−アミノフェニル）−４−［３−［Ｎ−（ピリジン−３−イル）アミノ］−１，３−ジオキソプロピルアミノ］ベンズアミド（表−１：化合物番号９４）
mp. 196℃(dec.)
1H NMR(270MHz, DMSO-d6)δppm: 3.57(2H,s), 4.87(2H,s), 6.57-6.62(1H,m), 6.76-6.79(1H,m), 6.94-6.99(1H,m), 7.14-7.17(1H,m), 7.33-7.38(1H,m), 7.73(2H,d,J=8.8Hz), 7.97(2H,d,J=8.8Hz), 8.05-8.08(1H,m), 8.27-8.30(1H,m), 8.75-8.76(1H,m), 9.59(1H,s), 10.44(1H,s), 10.47(1H,s).
IR(KBr)cm-1: 3410,3315,1685,1655,1625,1536,1428,1362,1263,1201,744.
【０３１７】
実施例１２３
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシアセチルアミノ］−３−メチルベンズアミド（表−１：化合物番号１０２）
mp. 178-181℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 2.28(3H,s), 4.22(2H,s), 4.71(2H,s), 4.89(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.16(1H,d,J=7.3Hz), 7.43(1H,dd,J=4.4,8.1Hz), 7.71(1H,d,J=8.1Hz), 7.79-7.89(3H,m), 8.54(1H,dd,J=1.5,4.4Hz), 8.66(1H,d,J=1.5Hz), 9.36(1H,br.s), 9.60(1H,br.s).
IR(KBr)cm-1:3394,3269,1683,1630,1593,1521,1460,1131,750,716.
【０３１８】
実施例１２４
Ｎ−（２−アミノフェニル）−４−［Ｎ−（チオフェン−３−イル）メトキシアセチルアミノ］ベンズアミド（表−１：化合物番号２０４）
mp. 186-189℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.11(2H,s), 4.63(2H,s), 4.89(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,7.3Hz), 7.12-7.19(2H,m), 7.53-7.57(2H,m), 7.78(2H,d,J=8.8Hz), 7.95(2H,d,J=8.8Hz), 9.58(1H,br.s), 10.04(1H,br.s).
IR(KBr)cm-1: 3341,3248,1694,1631,1611,1506,1314,1126.
【０３１９】
実施例１２５
Ｎ−（２−アミノフェニル）−４−［Ｎ−メチル−Ｎ−（ピリジン−３−イル）メトキシアセチルアミノ］ベンズアミド（表−１：化合物番号１０３）
mp. 180-183℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 3.24(3H,s), 4.08(2H,br.s), 4.50(2H,s), 4.94(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.79(1H,d,J=8.1Hz), 6.98(1H,dd,J=7.3,8.1Hz), 8.03(1H,d,J=8.1Hz), 8.48-8.50(2H,m), 9.72(1H,br.s).
IR(KBr)cm-1: 3395,3283,1683,1639,1604,1506,1459,1307,1124.
【０３２０】
実施例１２６
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−２−イル）メトキシアセチルアミノ］ベンズアミド（表−１：化合物番号１７６）
mp.171-173℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.26(2H,s), 4.74(2H,s), 4.89(2H,br.s), 6.60(1H,dd,J=6.6,8.1Hz), 6.78(1H,d,J=7.3Hz), 6.97(1H,ddd,J=1.5,7.3,8.1Hz), 7.16(1H,d,J=7.3Hz), 7.35(1H,dd,J=5.1,6.6Hz), 7.80(2H,d,J=8.1Hz), 7.80-7.89(1H,m), 7.97(2H,d,J=8.1Hz), 8.59(1H,d,J=4.4Hz), 9.59(1H,br.s), 10.30(1H,br.s).
IR(KBr)cm-1: 3391,3258,1678,1629,1593,1517,1128,767,742.
【０３２１】
実施例１２７
Ｎ−（２−アミノフェニル）−４−［Ｎ−（Ｎ−ニコチノイルアミノ）アセチルアミノ］ベンズアミド（表−１：化合物番号９７
）mp. 218-220℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.13(2H,d,J=5.9Hz), 4.89(2H,s), 6.59(1H,dd,J=7.3,7.3Hz), 6.77(1H,d,J=8.1Hz), 6.96(1H,dd,J=7.3,8.1Hz), 7.15(1H,d,J=7.3Hz), 7.55(1H,dd,J=5.1,8.1Hz), 7.73(2H,d,J=8.8Hz), 7.96(2H,d,J=8.8Hz), 8.25(1H,d,J=8.1Hz), 8.74(1H,d,J=5.1Hz), 9.07(1H,d,J=1.5Hz), 9.13(1H,t-like,J=5.9Hz), 9.58(1H,s), 10.36(1H,s).
【０３２２】
実施例１２８
Ｎ−（２−アミノフェニル）−５−［３−（ピリジン−３−イル）プロピオンアミド］ベンゾフラン−２−カルボキシアミド（表−３：化合物番号１）
mp. 267-272℃.
1H NMR(270MHz, DMSO-d6)δppm: 2.51(2H,t,J=7.3Hz), 2.97(2H,t,J=7.3Hz), 6.61(1H,dd,J=8.1,8.8Hz), 6.80(1H,dd,J=1.5,8.1Hz), 6.99(1H,dd,J=8.1,8.8Hz), 7.20(1H,dd,J=1.5,8.1Hz), 7.32(1H,dd,J=5.2,8.1Hz), 7.49(1H,dd,J=1.5,8.8Hz),7.61(1H,d,J=8.8Hz), 7.67(1H,s), 7.70(1H,m), 8.15(1H,d,J=1.5Hz), 8.40(1H,dd,J=1.5,5.2Hz), 8.51(1H,d,J=1.5Hz), 9.84(1H,s), 10.1(1H,s).
IR(KBr)cm-1: 3333,3272,1666,1583,1561,1458,1314,1247,1143,807,746,713.
【０３２３】
実施例１２９
Ｎ−（２−アミノフェニル）−４−［Ｎ−［２−（ピリジン−３−イル）オキシプロピオニル］アミノ］ベンズアミド（表−４：化合物番号２）の合成
（１２９−１） 実施例４７の工程（４７−２）で得た化合物０．３４ｇ（１．２ｍｍｏｌ）、実施例１００の工程（１００−２）で得た化合物０．３４ｇ（１．０ｍｍｏｌ）をジクロロメタン（１０ｍｌ）に溶解し、さらにトリエチルアミン０．５ｍｌ（３．６ｍｍｏｌ）を加えた。この溶液を氷冷下、２−クロロ−１，３−ジメチルイミダゾリニウムクロライド０．２１ｇ（１．２４ｍｍｏｌ）のジクロロメタン（５ｍｌ）溶液を加え、氷冷下さらに２時間攪拌した。飽和重曹水を加え中和した後、水で希釈してクロロホルムで抽出した。
【０３２４】
有機層を飽和食塩水で洗浄後、乾燥、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（酢酸エチル：メタノール＝１０：１）で精製することにより、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニルアミノ）フェニル］−４−［Ｎ−［２−（ピリジン−３−イル）オキシプロピオニル］アミノ］ベンズアミド０．６８ｇを１，３−ジメチル−２−イミダゾリノンの混合物として得た。
1H-NMR(270MHz, CDCl3)δppm: 1.52(9H,s), 1.70(3H,d,J=6.6Hz), 4.84(1H,q,J=6.6Hz), 6.89(1H,br.s), 7.12-7.31(6H,m), 7.68(2H,d,J=8.8Hz), 7.79(1H,d,J=8.1Hz), 7.96(2H,d,J=8.8Hz), 8.34(1H,d,J=2.9,2.9Hz), 8.43(1H,d,J=1.5Hz), 9.25(1H,br.s).
【０３２５】
（１２９−２） 工程（１２９−１）で得た化合物０．６８ｇのジクロロメタン（５ｍｌ）溶液に室温で１５％（ｖｏｌ／ｖｏｌ）トリフルオロ酢酸・ジクロロメタン溶液（１０ｍｌ）を加え室温で４．５時間攪拌した。飽和重曹水を加え中和した後ジクロロメタンを留去した。この溶液を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た残渣にメタノールおよびジイソプロピルエーテルを加え析出した沈澱を濾取、乾燥することにより、Ｎ−（２−アミノフェニル）−４−［Ｎ−［２−（ピリジン−３−イル）オキシプロピオニル］アミノ］ベンズアミド０．２２ｇ（２ｓｔｅｐｓ，収率５８％）を乳白色固体として得た。
mp. 193-196℃.
1H-NMR(270MHz, DMSO-d6)δppm: 1.60(3H,d,J=6.6Hz), 4.88(2H,br.s), 5.04(1H,q,J=6.6Hz), 6.60(1H,dd,J=6.6,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.15(1H,d,J=7.3Hz),7.32-7.39(2H,m), 7.75(2H,d,J=8.8Hz), 7.96(2H,d,J=8.1Hz), 8.20(1H,dd,J=1.5,3.7Hz), 8.35(1H,d,J=2.1Hz), 9.59(1H,br.s), 10.44(1H,br.s).
【０３２６】
実施例１３０
Ｎ−（２−アミノフェニル）−４−［（ピリジン−３−イル）メトキシアセチルアミノ］ベンズアミド（表−１：化合物番号１０１）の合成
（１３０−１） 水素化ナトリウム（６０％油懸濁状）４．４ｇ（１１０ｍｍｏｌ）のＴＨＦ（３００ｍｌ）懸濁液に、室温で３−ピリジンメタノール１０．９１ｇ（１００ｍｍｏｌ）のＴＨＦ（２０ｍｌ）溶液を滴下した後、室温で２時間攪拌した。得られた白色懸濁液を氷冷し、内温１０〜１２℃を保ちながらブロモ酢酸ｔｅｒｔ−ブチル１９．５１ｇ（１００ｍｍｏｌ）のＴＨＦ（２０ｍｌ）溶液を滴下した。この懸濁液を室温まで昇温させながら３時間攪拌した後、一晩放置した。水および飽和重曹水を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥し、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（ｎ−ヘキサン：酢酸エチル＝１：１→酢酸エチル）で精製し、（ピリジン−３−イル）メトキシ酢酸ｔｅｒｔ−ブチルエステル７．５６ｇ（３３．８％）を茶色油状物として得た。
【０３２７】
1H NMR(270MHz, CDCl3)δppm: 1.49(9H,s), 4.03(2H,s), 4.64(2H,s), 7.30(1H,dd,J=4.9,7.3Hz), 7.76(1H,d,J=7.3Hz), 8.56(1H,d,J=4.9Hz), 8.60(1H,s).
（１３０−２） 工程（１３０−１）で得た化合物３．５ｇ（１５．７ｍｍｏｌ）に氷冷下トリフルオロ酢酸（１２ｍｌ）を加えた後、室温で６時間攪拌した。その後トリフルオロ酢酸を一部留去し（ピリジン−３−イル）メトキシ酢酸とトリフルオロ酢酸の混合物６．５ｇを得た。これにジクロロメタン（７０ｍｌ）を加え溶解させた後、ピリジン（２５ｍｌ）を加えた。さらに実施例１００の工程（１００−２）で得られた化合物４．２６ｇ（１３ｍｍｏｌ）を加えた。氷冷下、２−クロロ−１，３−ジメチルイミダゾリニウムクロライド２．３７ｇ（１４．０ｍｍｏｌ）のジクロロメタン（２０ｍｌ）溶液を３０分かけて徐々に滴下した。
【０３２８】
氷冷下さらに５時間攪拌した後、飽和重曹水を加え、室温で発泡が止まるまで攪拌した。クロロホルムで抽出し、得られた有機層を飽和食塩水で洗浄後、乾燥、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（酢酸エチル→酢酸エチル：メタノール＝１０：１）で精製して、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］−４−［Ｎ−（ピリジン−３−イル）メトキシアセチルアミノ］ベンズアミド４．７８ｇ（収率６２％）をＤＭＩ（１，３−ジメチル−２−イミダゾリノン）との１：１（ｍｏｌ）混合物として得た。
1H NMR(270MHz, CDCl3)δppm: 1.51(9H,s), 4.15(2H,s), 4.70(2H,s), 6.92(1H,br.s), 7.15-7.29(3H,m), 7.37(1H,dd,J=7.3,5.1Hz), 7.67(2H,d,J=8.8Hz), 7.71-7.79(2H,m), 7.96(2H,d,J=8.8Hz), 8.41(1H,s), 8.62-8.66(2H,m), 9.23(1H,br.s).
【０３２９】
（１３０−３） 工程（１３０−２）で得られた化合物２．３９ｇ（４．０ｍｍｏｌ）のジクロロメタン（２８ｍｌ）溶液に１５％（ｖｏｌ／ｖｏｌ）トリフルオロ酢酸・ジクロロメタン溶液（５５ｍｌ）を加え室温で７時間攪拌した。飽和重曹水を加え、中和した後に水を加え室温で攪拌した。反応混合物を酢酸エチル−メチルエチルケトン（２：１）、酢酸エチル−ＴＨＦ（２：１）、酢酸エチルで順に抽出し、全有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤を濾別した後、濾液を濃縮し、得られた残渣にメタノールおよびジイソプロピルエーテルを加え析出した固体を濾取、乾燥することにより、Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシアセチルアミノ］ベンズアミド１．２９ｇ（収率８５．６％）を茶褐色固体として得た。
【０３３０】
1H NMR(270MHz, DMSO-d6)δppm: 4.19(2H,s), 4.68(2H,s), 4.90(2H,br.s), 6.60(1H,ddd,J=1.5,7.3,8.1Hz), 6.78(1H,dd,J=1.5,8.1Hz), 6.97(1H,dd,J=7.3,7.3Hz), 7.15(1H,d,J=7.3Hz), 7.42(1H,dd,J=4.4,8.1Hz), 7.77(2H,d,J=8.8Hz), 7.85(1H,d,J=7.3Hz), 7.96(2H,d,J=8.8Hz), 8.54(1H,dd,J=1.5,5.1Hz), 8.63(1H,s), 9.58(1H,s), 10.09(1H,s).
IR(KBr)cm-1: 3403,3341,3250,1694,1630,1610,1506,1314,1259,1118,764.
【０３３１】
実施例１３１
Ｎ−（２−アミノフェニル）−４−［Ｎ−［２−（ピリジン−３−イル）メトキシプロピオニル］アミノ］ベンズアミド（表−４：化合物番号１番）
（１３１−１） 水素化ナトリウム（６０％油状懸濁）１．２４ｇ（３１ｍｍｏｌ）を乾燥ＴＨＦ（９０ｍｌ）に懸濁させた後、室温で３−ピリジンメタノール３．２７ｇ（３０ｍｍｏｌ）の乾燥ＴＨＦ（１０ｍｌ）溶液を５分間かけて滴下した。得られた白色懸濁液を１時間室温で攪拌したのち、室温で２−ブロモプロピオン酸 ｔｅｒｔ−ブチルエステル６．２７ｇ（３０ｍｍｏｌ）の乾燥ＴＨＦ（１０ｍｌ）溶液を５分間かけて滴下した。室温で１１．５時間攪拌した。水を加えた後酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た残渣をシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン：酢酸エチル＝１：１）で精製することにより（ピリジン−３−イル）メトキシ酢酸 ｔｅｒｔ−ブチルエステル４．０１ｇ（収率５６．３％）を茶褐色油状物として得た。
1H-NMR(270MHz, CDCl3)δppm: 1.42(3H,d,J=7.3Hz), 1.50(9H,s), 3.96(1H,q,J=6.6Hz), 4.47, 4.69(2H,ABq,J=11.0Hz), 7.29(1H,dd,J=5.1,8.1Hz), 7.75(1H,d,J=8.1Hz), 8.50(1H,d,J=4.4Hz), 8.60(1H,s).
【０３３２】
（１３１−２） 工程（１３１−１）で得た化合物１．０９ｇ（４．５９ｍｍｏｌ）のジクロロメタン（５ｍｌ）溶液にトリフルオロ酢酸（８ｍｌ）を加え室温で９．５時間攪拌した。溶媒を留去して得た残渣にジクロロメタン（２５ｍｌ）を加え、さらにピリジン（３ｍｌ）を加えた。氷冷下、２−クロロ−１，３−ジメチルイミダゾリジニウムクロライド０．７０ｇ（４．１ｍｍｏｌ）のジクロロメタン（８ｍｌ）溶液を滴下した後、３０分間攪拌した。この溶液に実施例１００の工程（１００−２）で得た化合物０．９８ｇ（３．０ｍｍｏｌ）のジクロロメタン（２０ｍｌ）−ピリジン（１０ｍｌ）溶液を氷冷下１５分かけて徐々に滴下した後、室温まで昇温させながら８時間攪拌した。飽和重曹水を加えた後、水で希釈してクロロホルムで抽出した。
【０３３３】
有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル−メタノール＝８：１）で精製する事により、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニルアミノ）フェニル］−４−［Ｎ−［２−（ピリジン−３−イル）メトキシプロピオニル］アミノ］ベンズアミド１．１９ｇを１，３−ジメチル−２−イミダゾリノンとの２：３（モル比）混合物として得た。
1H-NMR(270MHz, CDCl3)δppm: 1.51(9H,s), 1.54(3H,d,J=6.6Hz), 4.13(1H,q,J=6.6Hz), 4.65, 4.71(2H,ABq,J=11.7Hz), 7.12-7.18(2H,m), 7.28-7.37(3H,m), 7.65(2H,d,J=8.1Hz), 7.73(2H,br.d,J=5.9Hz), 7.96(2H,d,J=8.8Hz), 8.59-8.64(3H,m), 9.39(1H,br.s).
【０３３４】
（１３１−３） 工程（１３１−２）で得た化合物１．１９ｇ（１．８ｍｍｏｌ）のジクロロメタン（１０ｍｌ）溶液に１５％（ｖｏｌ／ｖｏｌ）トリフルオロ酢酸・ジクロロメタン溶液（２０ｍｌ）を加え、室温で４．５時間攪拌した。飽和重曹水中にあけた後、ジクロロメタンを濃縮して得られた水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得られた残渣にメタノールおよびジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することによりＮ−（２−アミノフェニル）−４−［Ｎ−［２−（ピリジン−３−イル）メトキシプロピオニル］アミノ］ベンズアミド５８５ｍｇを淡褐色固体として得た。
【０３３５】
mp. 144-148℃.
1H NMR(270MHz, DMSO-d6)δppm: 1.40(3H,d,J=6.6Hz), 4.14(1H,q,J=6.6Hz), 4.56 and 4.65(2H,ABq,J=11.8Hz), 4.89(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=6.6,7.3Hz), 7.16(1H,d,J=7.3Hz), 7.40(1H,dd,J=4.4Hz,7.3Hz), 7.78-7.85(3H,m), 7.97(2H,d,J=8.8Hz), 8.52(1H,dd,J=1.5,5.1Hz), 8.61(1H,d,J=2.1Hz), 9.60(1H,s), 10.15(1H,s).
【０３３６】
実施例１３２
Ｎ−（２−アミノフェニル）−４−（Ｎ−ベンジルアミノ）カルボニルベンズアミド（表−１：化合物番号８番）の合成
（１３２−１） テレフタル酸モノメチル１３．０ｇ（７２．２ｍｍｏｌ）のトルエン（１００ｍｌ）懸濁液にチオニルクロライド（１０ｍｌ）を室温で滴下した。８０℃で３時間攪拌した後、溶媒および過剰のチオニルクロライドを留去した。得られた残渣をジオキサン（１００ｍｌ）に懸濁させた後、２−ニトロアニリン９．９８ｇ（７２．２ｍｍｏｌ）を加え、４時間加熱還流した。
【０３３７】
冷却後、溶媒を留去し、得られた残渣をメタノールで洗浄することにより、Ｎ−（２−ニトロフェニル）−４−メトキシカルボニルベンズアミド２０．３ｇ（収率９３．７％）を黄色固体として得た。
1H NMR(270MHz, DMSO-d6)δppm: 3.91(3H,s), 7.43-7.49(1H,m), 7.76-7.78(2H,m), 8.03(1H,d,J=8.1Hz), 8.08(2H,d,J=8.8Hz), 8.14(2H,d,J=8.8Hz), 10.94(1H,s).
【０３３８】
（１３２−２） 工程（１３２−１）で得られた化合物４．２４ｇ（１４．１２ｍｍｏｌ）のＴＨＦ（５０ｍｌ）−メタノール（５０ｍｌ）混合溶液に、窒素気流下１０％Ｐｄ／Ｃ０．４ｇを加えた後、水素気流下で１．５時間攪拌した。触媒をろ過後、溶媒を留去し、得られた残渣をメタノールで洗浄することによりＮ−（２−アミノフェニル）−４ーメトキシカルボニルベンズアミド３．４ｇ（収率８７．５％）を淡黄色固体として得た。
1H NMR(270MHz, DMSO-d6)δppm: 3.90(3H,s), 4.95(2H,s), 6.60(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=7.3Hz), 6.99(1H,dd,J=7.3,7.3Hz), 7.17(1H,d,J=7.3Hz), 8.08(2H,d,J=8.1Hz), 8.11(2H,d,J=8.1Hz), 9.85(1H,s)
【０３３９】
（１３２−３） 工程（１３２−２）で得られた化合物２．７１ｇ（１０．０ｍｍｏｌ）のジオキサン（１００ｍｌ）−水（５０ｍｌ）溶液に５％水酸化ナトリウム水溶液を氷冷下で加えた後、さらにジ−ｔｅｒｔ−ブチルジカ−ボネート２．６２ｇ（１２．０ｍｍｏｌ）のジオキサン（４０ｍｌ）溶液を滴下した。室温で４時間攪拌後、一晩放置した。飽和食塩水及び酢酸エチルを加え二層に分離した後、水層を酢酸エチルで抽出した。有機層を飽和食塩水洗浄した後、乾燥、溶媒を留去して得られた残渣をメタノールで洗浄することにより、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノフェニル］−４−メトキシカルボニルベンズアミド３．５４ｇ（収率９５．７％）を淡褐色固体として得た。
1H NMR(270MHz, DMSO-d6)δppm: 1.44(9H,s), 3.90(3H,s), 7.12-7.24(2H,m), 7.55-7.58(2H,m), 8.09(2H,d,J=8.8Hz), 8.10(2H,d,J=8.8Hz), 8.72(1H,s), 10.00(1H,s).
【０３４０】
（１３２−４） 工程（１３２−３）で得た化合物３．００ｇ（８．１０ｍｍｏｌ）のメタノール（５０ｍｌ）−０．５規定水酸化リチウム水溶液（２５ｍｌ）懸濁液を４０℃で５時間加温攪拌した。メタノールを留去した後、得られた残渣に１規定塩酸水溶液を加え、さらに酢酸エチルで抽出した。有機層を少量の水及び飽和食塩水で洗浄した後、乾燥した。溶媒を留去して得られた残渣をメタノールで洗浄することにより、テレフタル酸 モノ−２−（Ｎ−ｔｅｒｔ−ブトキシカルボニル）アミノアニリド２．２４ｇ（収率７７．６％）を淡褐色固体として得た。
1H NMR(270MHz, DMSO-d6)δppm: 1.45(9H,s), 7.12-7.21(2H,m), 7.53-7.58(2H,m), 8.06(2H,d,J=8.8Hz), 8.10(2H,d,J=8.8Hz), 8.71(1H,s), 9.97(1H,s).
【０３４１】
（１３２−５） 工程（１３２−４）で得た化合物０．２０ｇ（０．５６ｍｍｏｌ）のジクロロメタン（４ｍｌ）懸濁液にベンジルアミン０．１４ｇ（１．３ｍｍｏｌ）を加え、さらにトリエチルアミン０．２１ｍｌ（１．５ｍｍｏｌ）を加えた。この溶液に氷冷下２−クロロ−１，３−ジメチルイミダゾリウムクロライド０．２５ｇ（１．４８ｍｍｏｌ）を加え、さらに氷冷下１時間、室温で１時間攪拌した。クロロホルムで希釈した後、水を加え、水層をクロロホルムで抽出した。
【０３４２】
有機層を飽和食塩水洗浄後、乾燥、溶媒を留去して得た残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製し、得られた固体をエチルエーテルで洗浄することにより、Ｎ−（２−ｔｅｒｔ−ブトキシカルボニルアミノフェニル）−４−（Ｎ−ベンジルアミノ）カルボニルベンズアミド２７９ｍｇ（収率６２．６％）を白色固体として得た。
1H NMR(270MHz, DMSO-d6)δppm: 1.45(9H,s), 4.52(2H,d,J=5.8Hz), 7.13-7.28(4H,m), 7.34-7.35(3H,m), 7.56(2H,d,J=8.1Hz), 8.05(4H,s), 8.71(1H,br.s), 9.23(1H,t), 9.94(1H,s).
【０３４３】
（１３２−６） 工程（１３２−５）で得た化合物１５１ｍｇ（０．３３９ｍｍｏｌ）に４規定塩酸−ジオキサン溶液（５ｍｌ）を室温で加え、４時間攪拌した。溶媒を留去した後、酢酸エチル／飽和重曹水で分離し、析出した沈澱を除いた後に水層をさらに酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得た残渣にエチルエーテルを加え、析出した沈澱を濾取、乾燥することによりＮ−（２−アミノフェニル）−４−（Ｎ−ベンジルアミノ）カルボニルベンズアミド７８ｍｇ（収率６７％）を白色固体として得た。
mp. 239-241℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.51(2H,s), 4.93(2H,br.d), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.95(1H,dd,J=7.3,8.3Hz), 7.18(1H,d), 7.23-7.35(5H,m), 8.01(2H,d,J=8.8Hz), 8.07(2H,d,J=8.8Hz), 9.22(1H,br.t), 9.81(1H,br.s).
【０３４４】
実施例１３２と同様の方法により、実施例１３３の化合物を合成した。以下に、化合物の融点（mp.）、1H NMR、IRの測定値を示す。
【０３４５】
実施例１３３
Ｎ−（２−アミノフェニル）−４−［Ｎ−（２−フェニルエチル）アミノ］カルボニルベンズアミド（表−１：化合物番号９）
mp. 237-240℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 2.87(2H,t,J=7.3Hz), 3.51(2H,dt,J=5.9,7.3Hz), 4.94(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=7.3Hz), 6.98(1H,dd,J=7.3,7.3Hz), 7.15-7.34(6H,m), 7.93(2H,d,J=8.1Hz), 8.04(2H,d,J=8.1Hz), 8.73(1H,t,J=5.1Hz), 9.76(1H,br.s).
IR(KBr)cm-1: 3396,3320,1625,1602,1539,1458,1313,699.
【０３４６】
実施例１３４
Ｎ−（２−アミノフェニル）−４−［Ｎ−（４−ニトロフェノキシアセチル）アミノ］ベンズアミド（表−１：化合物番号５４）の合成
（１３４−１） 実施例１００の工程（１００−２）で得られた化合物３ｇ（９．２ｍｍｏｌ）、４−ニトロフェノキシ酢酸２．１６ｇ（１１．０ｍｍｏｌ）のＤＭＦ溶液（７ｍｌ）にジシクロヘキシルカルボジイミド２．８２ｇ（１３．８ｍｍｏｌ）のＤＭＦ溶液（５ｍｌ）、触媒量のＮ，Ｎ−ジメチルアミノピリジンを加え１日間撹拌した。反応終了後、酢酸エチルを加え、不溶物をセライト濾過し、溶媒を留去した。
【０３４７】
得られた残留物をクロロホルムから再結晶し、Ｎ−［２−（ｔｅｒｔ−ブトキシカルボニルアミノ）フェニル］−４−［（４−ニトロフェノキシアセチル）アミノ］ベンズアミド２．３４ｇ（収率５０％）を得た。
1H NMR(270MHz, DMSO-d6)δppm: 1.45(9H,s), 4.97(2H,s), 7.12-7.26(3H,m), 7.23(2H,d,J=8.8Hz), 7.53(1H,dt,J=2.2,7.3Hz), 7.79(2H,d,J=8.8Hz), 7.95(2H,d,J=8.8Hz), 8.25(2H,d,J=8.8Hz), 8.71(1H,s), 9.79(1H,s), 10.52(1H,s).
【０３４８】
（１３４−２） 工程（１３４−１）で得られた化合物０．７ｇ（１．３８ｍｍｏｌ）のアセトニトリル溶液（１０ｍｌ）に室温でヨードトリメチルシラン１．２６ｍｌ（８．８５ｍｍｏｌ）を加え、２時間撹拌した。反応終了後、溶媒を濃縮し、酢酸エチルを加え２０分間撹拌し、析出した結晶を濾取した。得られた結晶をメチルエチルケトンに溶解し、飽和チオ硫酸ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残留物を酢酸エチルで洗浄し、Ｎ−（２−アミノフェニル）−４−［Ｎ−（４−ニトロフェノキシアセチル）アミノ］ベンズアミド０．２２ｇ（収率３９％）を白色結晶として得た。
【０３４９】
mp. 212-215℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.97(2H,s), 6.88(1H,t,J=7.3Hz), 6.99(1H,d,J=7.3Hz), 7.11(1H,t,J=7.3Hz), 7.23(2H,d,J=8.8Hz), 7.24(1H,m), 7.77(2H,d,J=8.8Hz), 8.00(2H,d,J=8.8Hz), 8.25(2H,d,J=8.8Hz), 9.89(1H,s), 10.52(1H,s).
IR(KBr)cm-1: 3382,3109,1650,1591,1508,1341.
【０３５０】
実施例１３５
Ｎ−（２−アミノフェニル）−４−［（４−アミノフェノキシアセチル）アミノ］ベンズアミド（表−１：化合物番号５５）の合成
実施例１３４の工程（１３４−１）で得られた化合物１．４１ｇ（２．７８ｍｍｏｌ）のメタノール（１５ｍｌ）−ＴＨＦ（２５ｍｌ）溶液に１０％Ｐｄ−Ｃを加え水素雰囲気下室温で１時間撹拌した。反応終了後、触媒を濾過し溶媒を濃縮後、ジイソプロピルエーテルでスラッジングして、Ｎ−［２−（ｔｅｒｔ−ブトキシカルボニルアミノ）フェニル］−４−［（４−アミノフェノキシアセチル）アミノ］ベンズアミド１．１ｇを得た。
【０３５１】
これをアセトニトリル１５ｍｌに溶解し、ヨードトリメチルシラン０．７４ｍｌ（５．２０ｍｍｏｌ）を加え、室温で３時間撹拌した。反応終了後、溶媒を濃縮しメチルエチルケトンで洗浄して、Ｎ−（２−アミノフェニル）−４−［（４−アミノフェノキシアセチル）アミノ］ベンズアミド０．８６ｇ（収率８３％）を得た。
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 4.82(2H,s), 7.13(2H,d,J=8.8Hz), 7.30-7.48(6H,m), 7.82(2H,d,J=8.8Hz), 8.03(2H,d,J=8.8Hz), 10.34(1H,s), 10.46(1H,s).IR(KBr)cm-1: 2873,2590,1680,1602,1505,1243.
【０３５２】
実施例１３６
Ｎ−（２−アミノフェニル）−４−（５−フェノキシメチル−１，３−オキサゾリン−２−オン−３−イル）ベンズアミド（表−２：化合物番号１）の合成
（１３６−１) ４−（Ｎ−ベンジルオキシカルボニルアミノ）安息香酸ｔ−ブチルエステル０．７ｇ（２．１４ｍｍｏｌ）のＴＨＦ溶液（１０ｍｌ）に、−７８℃でｎ−ブチルリチウム１．３３ｍｌ（２．２５ｍｍｏｌ）を５分間かけて滴下した。同温でさらに１．５時間撹拌した後、フェニルグリシドール０．３１ｍｌ（２．２９ｍｍｏｌ）を加え同温で更に１時間撹拌した。室温で１日間放置した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで２回抽出し、有機層を硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残査をエーテルから再結晶し、Ｎ−［４−（ｔｅｒｔ−ブトキシカルボニル）フェニル］−５−フェノキシメチル−１，３−オキサゾリジン−２−オン０．３１ｇ（収率３９％）を得た。
1H NMR(270MHz, DMSO-d6)δppm: 1.53(9H,s), 3.97(1H,dd,J=6.0,8.8Hz), 4.23-4.34(3H,m), 5.11(1H,m), 6.94-7.00(3H,m), 7.31(2H,m), 7.71(2H,d,J=8.8Hz), 7.93(2H,d,J=8.8Hz).
【０３５３】
（１３６−２） 工程（１３６−１）の化合物０．２６ｇ（０．７０４ｍｍｏｌ）のアセトニトリル溶液（４ｍｌ）にトリメチルシリルアイオダイド０．１５ｍｌ（１．０５ｍｍｏｌ）を加え、室温で２時間撹拌した。反応終了後、溶媒を濃縮し得られた濃縮物を酢酸エチル−メチルエチルケトンでスラッジングし、Ｎ−（４−カルボキシフェニル）−５−フェノキシメチル−１，３−オキサゾリジン−２−オン０．２ｇ（収率９１％）を得た。
1H NMR(270MHz, DMSO-d6)δppm: 3.98(1H,dd,J=6.6,9.6Hz), 4.23-4.34(3H,m), 5.10(1H,m), 6.94-6.99(3H,m), 7.30(2H,t,J=8.1Hz), 7.72(2H,d,J=8.8Hz), 7.98(2H,d,J=8.8Hz), 12.85(1H,s).
【０３５４】
（１３６−３） 工程（１３６−２）の化合物０．１５ｇ（０．４７９ｍｍｏｌ）の塩化メチレン溶液（７ｍｌ）に触媒量のＤＭＦを加えた後、オキザリルクロライド０．１２ｍｌ（１．４０ｍｍｏｌ）を加え室温で２時間撹拌した。次に溶媒を濃縮し、トルエンで２回共沸した後塩化メチレン（４ｍｌ）に溶解し、氷冷下実施例１の工程（１−２）の化合物０．１０５ｇ（０．５０４ｍｍｏｌ）、ピリジン０．１２ｇ（１．５２ｍｍｏｌ）の塩化メチレン溶液（１ｍｌ）を加えた後、室温に昇温し１時間撹拌した。反応終了後、水を加えクロロホルムで２回抽出し、有機層を飽和食塩水で洗浄した。硫酸マグネシウムで乾燥後、溶媒を留去した。得られた残査をイソプロピルエーテルでスラッジングし、Ｎ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニルアミノ）フェニル］−４−（５−フェノキシメチル−１，３−オキサゾリン−２−オン−３−イル）ベンズアミド０．２５ｇ（定量的）を得た。
1H NMR(270MHz, DMSO-d6)δppm: 1.52(9H,s), 4.11(1H,dd,J=5.9,6.6Hz), 4.21-4.27(3H,m), 5.01(1H,m), 6.84(1H,br.s), 6.91(2H,d,J=8.8Hz), 7.01(1H,t,J=7.4Hz), 7.12-7.34(5H,m), 7.68(2H,d,J=8.8Hz).
【０３５５】
（１３６−４） 工程（１３６−３）の化合物０．２２ｇ（０．４３７ｍｍｏｌ）のアセトニトリル溶液（４ｍｌ）に室温でトリメチルシリルアイオダイド０．１ｍｌ（０．７０３ｍｍｏｌ）を加え２時間撹拌した。飽和チオ硫酸ナトリウム水溶液を加えた後、酢酸エチルで２回抽出し、有機層を硫酸マグネシウムで乾燥後、溶媒を留去した。得られた残留物をメタノールから再結晶し、Ｎ−（２−アミノフェニル）−４−（５−フェノキシメチル−１，３−オキサゾリン−２−オン−３−イル）ベンズアミド０．１３ｇ（収率７４％）を白色結晶として得た。
mp. 165-170℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.01(1H,dd,J=6.6,9.6Hz), 4.28-4.34(3H,m), 5.12(1H,m), 5.23(2H,br.s), 6.64(1H,t,J=7.4Hz), 6.81(1H,d,J=8.1Hz), 6.95-7.00(3H,m), 7.18(1H,d,J=6.6Hz), 7.31(2H,t,J=8.1Hz), 7.72(2H,d,J=8.8Hz), 8.05(2H,d,J=8.8Hz), 9.69(1H,s).
IR(KBr)cm-1: 3393,1740,1610,1508,1253.
【０３５６】
実施例１３６と同様の方法により、実施例１３７から１４３の化合物を合成した。以下に、化合物の化合物の融点（mp.）、1H NMR、IRの測定値を示す。
【０３５７】
実施例１３７
Ｎ−（２−アミノフェニル）−４−［５−（４−ニトロフェノキシ）メチル−１，３−オキサゾリン−２−オン−３−イル］ベンズアミド（表−２：化合物番号２）
mp. 162-164℃.
1H NMR(270MHz, DMSO-d6)δppm: 3.97(1H,dd,J=6.6,9.5Hz), 4.10(1H,dd,J=5.1,11.0Hz), 4.17(1H,dd,J=3.7,11.0Hz), 4.27(1H,t,J=8.8Hz), 6.53-6.80(6H,m), 6.97(1H,t,J=8.1Hz), 7.16(1H,d,J=6.6Hz), 7.72(2H,d,J=8.8Hz), 8.04(2H,d,J=8.8Hz), 9.65(1H,s).
IR(KBr)cm-1: 3356,2365,1741,1609,1510,1247.
【０３５８】
実施例１３８
Ｎ−（２−アミノフェニル）−４−（５−ベンジルオキシメチル−１，３−オキサゾリン−２−オン−３−イル）ベンズアミド 塩酸塩（表−２：化合物番号３の塩酸塩）
mp. 181-183℃.
1H NMR(270MHz, DMSO-d6)δppm: 3.69(1H,dd,J=5.2,11.0Hz), 3.76(1H,dd,J=3.7,11.0Hz), 3.91(1H,dd,J=5.9,8.8Hz), 4.59(2H,s), 4.93(1H,m), 7.26-7.41(8H,m), 7.51(1H,m), 7.74(2H,d,J=8.8Hz), 8.15(2H,d,J=8.8Hz), 10.42(1H,s).
【０３５９】
実施例１３９
Ｎ−（２−アミノフェニル）−４−［５−（ピリジン−３−イル）オキシメチル−１，３−オキサゾリン−２−オン−３−イル］ベンズアミド（表−２：化合物番号４）
mp. 199-201℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.01(1H,dd,J=6.6,8.8Hz), 4.28-4.46(3H,m), 4.96(2H,br.s), 5.14(1H,m), 6.61(1H,t,J=7.4Hz), 6.79(1H,d,J=7.4Hz), 6.98(1H,t,J=7.4Hz), 7.16(1H,d,J=7.4Hz), 7.36(1H,dd,J=4.4,8.1Hz), 7.44(1H,dd,J=1.5,8.1Hz).
IR(KBr)cm-1: 2815,2631,2365,1752,1610,1520,1225.
【０３６０】
実施例１４０
Ｎ−（２−アミノフェニル）−４−［５−（ピリジン−３−イル）メチルオキシメチル−１，３−オキサゾリン−２−オン−３−イル］ベンズアミド（表−２：化合物番号５）
mp. 160-164℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 3.73(1H,dd,J=5.2,11.7Hz), 3.79(1H,dd,J=2.9,11.7Hz), 3.91(1H,dd,J=5.9,8.8Hz), 4.21(1H,t,J=8.8Hz), 4.62(2H,s), 4.91(3H,br.s), 6.60(1H,t,J=7.4Hz), 6.78(1H,d,J=7.4Hz), 6.98(1H,t,J=7.4Hz), 7.16(1H,d,J=7.4Hz), 7.38(1H,dd,J=4.4,7.4Hz), 7.69(2H,d,J=8.8Hz), 7.71(1H,m), 8.03(2H,d,J=8.8Hz), 8.51(1H,dd,J=1.5,4.4Hz), 8.54(1H,d,J=1.5Hz), 9.65(1H,s).
IR(KBr)cm-1: 3368,1742,1648,1608,1492,1226.
【０３６１】
実施例１４１
Ｎ−（２−アミノフェニル）−４−［５−（３−ニトロフェノキシ）メチル−１，３−オキサゾリン−２−オン−３−イル］ベンズアミド（表−２：化合物番号６）
mp. 230℃(dec.).
1H NMR(270MHz, DMSO-d6)δppm: 4.04(1H,t,J=8.8Hz), 4.32(1H,t,J=8.8Hz), 4.41-4.53(2H,m), 4.91(2H,s), 5.15(1H,m), 6.61(1H,t,J=7.4Hz), 6.79(1H,d,J=7.4Hz), 6.98(1H,t,J=7.4Hz), 7.16(1H,d,J=7.4Hz), 7.46(1H,dd,J=1.5,8.1Hz), 7.61(1H,t,J=8.1Hz), 7.71-7.79(3H,m), 7.87(1H,d,J=8.1Hz), 8.06(2H,d,J=8.8Hz), 9.66(1H,s).
IR(KBr)cm-1: 3363,3095,2365,1741,1608,1529.
【０３６２】
実施例１４２
Ｎ−（２−アミノフェニル）−４−［５−（ピリジン−２−イル）メチルオキシメチル−１，３−オキサゾリン−２−オン−３−イル］ベンズアミド（表−２：化合物番号７）
mp. 172-174℃.
1H NMR(270MHz, DMSO-d6)δppm: 3.79(1H,dd,J=5.2,11.0Hz), 3.85(1H,dd,J=2.9,11.0Hz), 3.95(1H,dd,J=6.6,9.6Hz), 4.23(1H,t,J=9.6Hz), 4.67(2H,s), 4.90(2H,s), 4.95(1H,m), 6.60(1H,t,J=7.4Hz), 6.78(1H,d,J=7.4Hz), 6.97(1H,t,J=7.4Hz), 7.16(1H,d,J=7.4Hz), 7.29(1H,dd,J=5.2,6.6Hz), 7.40(1H,d,J=6.6Hz), 7.70(2H,d,J=8.8Hz), 7.78(1H,dt,J=2.2,7.4Hz), 8.03(2H,d,J=8.8Hz), 8.51(1H.d,J=4.4Hz), 9.64(1H,s).
IR(KBr)cm-1: 3369,1743,1651,1608,1492,1283.
【０３６３】
実施例１４３
Ｎ−（２−アミノフェニル）−４−［５−（ピリジン−２−イル）オキシメチル−１，３−オキサゾリン−２−オン−３−イル］ベンズアミド（表−２：化合物番号８）
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 3.96(1H,dd,J=5.9,9.6Hz), 4.21-4.40(3H,m), 4.90(2H,s), 5.03(1H,m), 6.28(1H,t,J=6.6Hz), 6.43(1H,d,J=9.6Hz), 6.60(1H,t,J=6.6Hz), 6.78(1H,d,J=6.6Hz), 6.97(1H,t,J=7.4Hz), 7.15(1H,d,J=6.6Hz), 7.46(1H,dt,J=7.4,1.5Hz), 7.67(2H,d,J=8.8Hz), 7.69(1H,m), 8.03(2H,d,=8.8Hz), 9.64(1H,s).
【０３６４】
実施例１４４
Ｎ−（２−アミノフェニル）−４−［Ｎ−［３−［（ピリジン−３−イル）メチルアミノ］シクロブテン−１，２−ジオン−４−イル］アミノメチル］ベンズアミド（表−２：化合物番号９）
（１４４−１） ３，４−ジ−ｎ−ブトキシ−３−シクロブテン−１，２−ジオン０．０７３ｇ（０．３２３ｍｍｏｌ）のＴＨＦ溶液（２ｍｌ）に実施例１の工程（１−４）の化合物０．１ｇ（０．２９３ｍｍｏｌ）を加え４時間撹拌した後、さらに３−アミノメチルピリジン０．０３３ｍｌ（０．３２７ｍｍｏｌ）を加え１日間反応した。反応終了後、水を加えメチルエチルケトンで２回抽出した。有機層を無水硫酸マグネシウムで乾燥後、溶媒を留去した。
【０３６５】
得られた残留物をメタノールでスラッジングしてＮ−［２−（Ｎ−ｔｅｒｔ−ブトキシカルボニルアミノ）フェニル］−４−［Ｎ−［３−［（ピリジン−３−イル）メチルアミノ］シクロブテン−１，２−ジオン−４−イル］アミノメチル］ベンズアミド０．１２ｇ（収率７８％）を得た。
1H NMR(270MHz, DMSO-d6)δppm: 1.44(9H,s), 4.75-4.81(4H,m), 7.15(1H,dt,J=2.2,7.4Hz), 7.20(1H,dt,J=2.2,7.4Hz), 7.40(1H,dd,J=2.2,7.4Hz), 7.47(2H,d.J=8.1Hz), 7.54(2H,dd,J=2.2,7.4Hz), 7.73(1H,m), 7.94(2H,d,J=8.1Hz), 8.50(1H,m), 8.55(1H,d,J=1.5Hz), 8.67(1H,s), 9.82(1H,s).
【０３６６】
（１４４−２） 工程（１４４−１）の化合物０．１ｇ（０．１９ｍｍｏｌ）のジオキサン（４ｍｌ）−メタノール（１ｍｌ）溶液に４規定塩酸−ジオキサン（４ｍｌ）を加え２時間反応した。反応終了後、溶媒を濃縮し飽和重曹水で中和後、メチルエチルケトンを加え、得られた結晶を濾取してＮ−（２−アミノフェニル）−４−［Ｎ−［３−［（ピリジン−３−イル）メチルアミノ］シクロブテン−１，２−ジオン−４−イル］アミノメチル］ベンズアミド０．０４ｇ（収率４９％）を得た。
mp. 230℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.76(2H,s), 4.79(2H,s), 4.90(2H,s), 6.60(1H,t,J=7.4Hz), 6.78(1H,d,J=7.4Hz), 6.97(1H,t,J=7.4Hz), 7.16(1H,d,J=7.4Hz), 7.39(1H,m), 7.43(2H,d,J=8.1Hz), 7.73(1H,d,J=8.1Hz), 7.97(2H,d,J=8.1Hz), 7.99(1H,br.s), 8.51(1H,d,J=8.1Hz), 8.55(1H,s), 9.64(1H,s).
【０３６７】
実施例１４５
Ｎ−（２−アミノフェニル）−４−［３−（ピリジン−３−イル）メチルイミダゾリン−２−オン−１−イル］メチルベンズアミド（表−２：化合部番号１０番）
（１４５−１） エチレン尿素４．９２ｇ（５７ｍｍｏｌ），メチル ４−ブロモメチルベンゾエート５．７３ｇ（２５ｍｍｏｌ）、ヨウ化 テトラノルマルブチルアンモニウム１．８５ｇ（５．０ｍｍｏｌ）のＤＭＦ（３０ｍｌ）溶液に炭酸カリウム７．８８ｇ（５７ｍｍｏｌ）を加え、８０℃で５時間加熱攪拌した。
【０３６８】
放冷後、固体分を濾取した後酢酸エチルで固体分を洗浄した。濾液を濃縮した後、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製して得られた淡黄色油状物にジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより、Ｎ−（４−メトキシカルボニルフェニルメチル）イミダゾリン−２−オン３．３６ｇ（収率５７．４％）を淡褐色固体として得た。
1H-NMR(270MHz,CDCl3)δppm: 3.28-3.35(2H,m), 3.41-3.47(2H,m), 3.92(3H,s), 4.42(2H,s), 4.61(1H,br.s), 7.35(2H,d,J=8.1Hz), 8.01(2H,d,J=8.1Hz).
【０３６９】
（１４５−２） ３−クロロメチルピリジン塩酸塩２．０５ｇ（１２．５ｍｍｏｌ）に飽和重曹水を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た残渣にトルエンを加え共沸し、さらに得られた残渣にＤＭＦ（５ｍｌ）を加えた後、ヨウ化 テトラノルマルブチルアンモニウム０．３７ｇ（１．０ｍｍｏｌ）を加え、ベンジルハライドのＤＭＦ溶液を調製した。水素化ナトリウム（６０％油状懸濁）０．３０ｇ（７．５ｍｍｏｌ）のＤＭＦ（５ｍｌ）懸濁液に室温で、工程（１４５−１）で得た化合物１．１７ｇ（５．０ｍｍｏｌ）のＤＭＦ（１０ｍｌ）溶液を徐々に滴下した後、室温で３０分攪拌した。この溶液に先に調製したベンジルハライド溶液を加えた後、８０℃で７時間加熱攪拌した。
【０３７０】
一晩室温で放置した。ＤＭＦを濃縮した後、酢酸エチル及び水を加え分離した。さらに水層を酢酸エチル−メチルエチルケトン（２：１）で抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製し、Ｎ−（４−メトキシカルボニルフェニルメチル）−Ｎ’−（ピリジン−３−イル）メチルイミダゾリン−２−オン１．１７ｇ（収率７２．３％）を茶色油状物として得た。
1H NMR(270MHz, CDCl3)δppm: 3.20(4H,s), 3.92(3H,s), 4.44(2H,s), 4.46(2H,s), 7.27-7.36(3H,m), 7.64-7.69(1H,m), 8.01(2H,d,J=8.1Hz), 8.53-8.56(2H,m).
【０３７１】
（１４５−３） 工程（１４５−２）で得た化合物０．５５ｇ（１．７ｍｍｏｌ）のメタノール（８ｍｌ）−水（８ｍｌ）溶液に室温で水酸化リチウム１水和物１１０ｍｇ（２．６２ｍｍｏｌ）を加え５０℃で１．５時間加熱攪拌した後、さらに水酸化リチウム１水和物０．０５ｇ（１．２ｍｍｏｌ）を加え、５０℃で１．５時間攪拌した。１０％塩酸水溶液を用いて酸性（ｐＨ３〜４）にしたのち、飽和食塩水を加え、酢酸エチルで２回、酢酸エチル−メチルエチルケトン（１：１）で１回抽出した。有機層を無水硫酸ナトリウムで乾燥後、溶媒留去して得た残渣を乾燥することにより４−［３−（ピリジン−３−イル）メチルイミダゾリン−２−オン−１−イル］メチル安息香酸０．３２ｇ（収率６１％）を茶色油状物として得た。
1H NMR(270MHz, DMSO-d6)δppm: 3.17(2H,s), 3.20(2H,s), 4.36(2H,s), 4.38(2H,s), 7.35-7.42(3H,m), 7.68(1H,dd,J=6.6Hz),7.92(2H,d,J=8.1Hz), 8.51(2H,m).
【０３７２】
（１４５−４） 工程（１４５−３）で得た化合物０．３１ｇ（１．０ｍｍｏｌ）のジクロロメタン（１２ｍｌ）溶液に室温でオキザリルクロライド０．３ｍｌ（３．５ｍｍｏｌ）を滴下した後室温で３０分、４０℃で１．５時間攪拌した。溶媒を留去した後トルエンで共沸し、ジクロロメタン１０ｍｌに懸濁した。この反応懸濁液を氷冷した後、実施例１の工程（１−２）の化合物０．２１ｇ（１．０ｍｍｏｌ）のジクロロメタン（２ｍｌ）−ピリジン（２ｍｌ）溶液を滴下した。室温まで昇温させながら攪拌した後、室温で一晩放置した。飽和重曹水を加えた後クロロホルムで抽出した。
【０３７３】
有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル−メタノール＝２０：１）で精製することによりＮ−（２−ｔｅｒｔ−ブトキシカルボニルアミノフェニル）−４−［３−（ピリジン−３−イルメチル）イミダゾリン−２−オン−１−イル］メチルベンズアミド０．１０ｇ（収率２０％）を茶色油状物として得た。
1H NMR(270MHz, CDCl3)δppm: 1.52(9H,s), 3.20(4H,s), 4.45(2H,s),4.48(2H,s), 6.75(1H,br.s), 7.15-7.40(5H,m),7.65-7.70(2H,m), 7.83(1H,d,J=7.3Hz), 7.94(2H,d,J=8.1Hz), 8.50-8.60(3H,br.m).
【０３７４】
（１４５−５） 工程（１４５−４）で得た化合物１００ｍｇ（０．２０ｍｍｏｌ）をジオキサン（２ｍｌ）に溶解した後、４規定塩酸−ジオキサン（２ｍｌ）を加えた後、メタノール（０．５ｍｌ）を加え溶解させた。２時間攪拌後、飽和重曹水を加え中和した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た残渣を室温で減圧下乾燥することによりＮ−（２−アミノフェニル）−４−［３−（ピリジン−３−イル）メチルイミダゾリン−２−オン−１−イル］メチルベンズアミド４７ｍｇ（収率５８％）を褐色油状物として得た。
mp. (amorphous).
1H NMR(270MHz, DMSO-d6)δppm: 3.20(4H,s), 4.37(2H,s), 4.39(2H,s), 4.87(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=6.6,7.3Hz), 7.16(1H,d,J=7.3Hz), 7.35-7.41(3H,m), 7.68(1H,d,J=8.1Hz), 7.90-8.00(2H,m), 8.50(2H,br.s), 9.63(1H,br.s).
【０３７５】
実施例１４６
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド ０．５フマル酸塩（表−１：化合物番号８２のフマル酸塩）の合成
実施例４８で得られた化合物３１０ｍｇをメタノール１０ｍｌに加え、加熱して溶解させた。フマル酸９６ｍｇをメタノールに溶解した溶液を加えた後、冷却した。析出した結晶をろ取し、メタノール５ｍｌで再結晶し、目的物を２００ｍｇ得た（収率５６％）。
【０３７６】
mp. 166-167℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=6.6Hz), 5.10(2H,s), 6.60(1H,t,J=8.0Hz), 6.63(1H,s), 6.78(1H,d,J=8.0Hz), 6.90-7.50(5H,m), 7.70-8.00(4H,m), 8.53(1H,d,J=3.6Hz), 8.60(1H,s), 9.63(1H,s).
IR(KBr)cm-1: 3332,1715,1665,1505,1283,1136,1044,983,760,712.
Figure 0004105451
【０３７７】
実施例１４６と同様の方法により、実施例１４７から１４９の化合物を合成した。以下に、化合物の融点（mp.）、1H NMR、IRの測定値を示す。
【０３７８】
実施例１４７
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド マレイン酸塩（表−１：化合物番号８２のマレイン酸塩）
mp. 123-124℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=6.6Hz), 5.11(2H,s), 6.24(2H,s), 6.66(1H,t,J=8.0Hz), 6.83(1H,d,J=8.0Hz), 6.90-8.00(9H,m), 8.56(1H,d,J=3.6Hz), 8.62(1H,s), 9.69(1H,s).
IR(KBr)cm-1: 3298,1719,1546,1365,1313,1250,1194,1149,1044,993,862,751.
Figure 0004105451
【０３７９】
実施例１４８
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド 塩酸塩（表−１：化合物番号８２の塩酸塩）
mp. 140(dec.)℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.31(2H,d,J=5.8Hz), 5.24(2H,s), 7.10-7.60(6H,m), 7.90-8.50(5H,m), 8.70-8.90(2H,m), 10.46(1H,s).
IR(KBr)cm-1: 2553,1715,1628,1556,1486,1254,1049,778,687.
【０３８０】
実施例１４９
Ｎ−（２−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）オキシアセチルアミノメチル］ベンズアミド ０．７フマル酸（表−１：化合物番号６１のフマル酸塩）
実施例１４６と同様の方法により、実施例４６の化合物より合成した。
mp. 154-155℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.42(2H,d,J=5.9Hz), 4.69(2H,s), 6.60(1H,t,J=8.0Hz), 6.63(0.7H,s), 6.78(1H,d,J=8.0Hz), 6.90-7.50(6H,m), 7.93(2H,d,J=8.0Hz), 8.20-8.40(2H,m), 8.82(1H,br.s), 9.63(1H,s).
IR(KBr)cm-1: 3324,1709,1631,1521,1457,1428,1260,1064,806,698.
Figure 0004105451
【０３８１】
参考例１
Ｎ−（３−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド
実施例４８と同様の方法により合成した。
mp. 156℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.27(2H,d,J=6.6Hz), 5.06(2H,s), 5.10(2H,s), 6.20-6.40(1H,m), 6.80-7.10(3H,m), 7.30-7.50(3H,m), 7.70-8.00(4H,m), 8.53(1H,d,J=3.6Hz), 8.59(1H,s), 9.88(1H,s).
IR(KBr)cm-1: 3327,3218,1708,1639,1536,1279,1147,1050,859,788.
【０３８２】
参考例２
Ｎ−（４−アミノフェニル）−４−［Ｎ−（ピリジン−３−イル）メトキシカルボニルアミノメチル］ベンズアミド
実施例４８と同様の方法により合成した。
mp. 204-205℃.
1H NMR(270MHz, DMSO-d6)δppm: 4.27(2H,d,J=6.6Hz), 4.91(2H,s), 5.10(2H,s), 6.52(2H,d,J=8.8Hz), 7.30-7.50(5H,m), 7.70-8.00(4H,m), 8.50-8.60(2H,m), 9.80(1H,s).
IR(KBr)cm-1: 3336,3224,1706,1638,1530,1279,1145,1050,1005,827.
【０３８３】
薬理試験例１
Ａ２７８０細胞に対する分化誘導作用試験
アルカリフォスファターゼ（ＡＬＰ）活性の上昇は、ヒト大腸癌細胞の分化の指標として知られており、例えば酪酸ナトリウムがＡＬＰ活性を上昇させることが知られている［Ｙｏｕｎｇら；Ｃａｎｃｅｒ Ｒｅｓ．、４５、２９７６（１９８５）、Ｍｏｒｉｔａら；Ｃａｎｃｅｒ Ｒｅｓ．、４２、４５４０（１９８２）］。そこでＡＬＰ活性を指標に分化誘導作用の評価を行った。
【０３８４】
（実験方法） ９６穴プレートに15,000ヶ／ｗｅｌｌとなるように、Ａ２７８０細胞を０．１ｍｌずつまき、翌日培地にて段階希釈した被験薬の溶液を０．１ｍｌずつ添加した。３日間培養後、プレート上の細胞をＴＢＳ緩衝液（２０ｍＭ Ｔｒｉｓ，１３７ｍＭ ＮａＣｌ、ｐＨ７．６）で２回洗浄した。ついで、０．６ｍｇ／ｍｌの濃度のｐ−ニトロフェニルフォスフェイト（９．６％ ジエタノールアミン、０．５ｍＭ ＭｇＣｌ2（ｐＨ９．６））溶液を０．０５ｍｌずつ添加し、室温で３０分インキュベートした。３規定水酸化ナトリウム水溶液０．０５ｍｌで反応を停止した後、４０５ｎｍの吸光度を測定し、ＡＬＰ活性の上昇を惹起する薬物の最小濃度（ALPmin）を求めた。
（実験結果） 実験結果を、表−５［表３１］に示した。
【０３８５】
〔表３１〕
表−５：Ａ２７８０細胞に対する分化誘導作用
供試化合物 ALPmin（μM)
実施例１の化合物 1
実施例２の化合物 3
実施例３の化合物 3
実施例４の化合物 1
実施例５の化合物 1
実施例６の化合物 1
実施例７の化合物 1
実施例８の化合物 1
実施例９の化合物 1
【０３８６】
実施例１０の化合物 3
実施例１１の化合物 1
実施例１３の化合物 1
実施例１５の化合物 3
実施例１６の化合物 3
実施例１７の化合物 3
実施例１８の化合物 3
実施例２３の化合物 1
実施例２４の化合物 1
実施例２５の化合物 3
【０３８７】
実施例２６の化合物 1
実施例２７の化合物 10
実施例２８の化合物 10
実施例２９の化合物 10
実施例３０の化合物 0.1
実施例３１の化合物 10
実施例３２の化合物 3
実施例３３の化合物 0.3
実施例３４の化合物 0.1
実施例３５の化合物 0.3
【０３８８】
実施例３６の化合物 10
実施例３７の化合物 1
実施例３８の化合物 3
実施例３９の化合物 0.1
実施例４０の化合物 10
実施例４１の化合物 0.3
実施例４２の化合物 10
実施例４３の化合物 3
実施例４４の化合物 0.01
実施例４５の化合物 0.003
【０３８９】
実施例４６の化合物 0.1
実施例４８の化合物 0.1
実施例４９の化合物 1
実施例５０の化合物 1
実施例５１の化合物 1
実施例５２の化合物 1
実施例５３の化合物 3
実施例５４の化合物 1
実施例５５の化合物 1
実施例５６の化合物 3
【０３９０】
実施例５７の化合物 3
実施例５８の化合物 3
実施例５９の化合物 3
実施例６０の化合物 3
実施例６３の化合物 3
実施例６４の化合物 3
実施例６５の化合物 3
実施例６６の化合物 3
実施例６７の化合物 3
実施例６８の化合物 3
【０３９１】
実施例７０の化合物 0.1
実施例７１の化合物 10
実施例７２の化合物 10
実施例７３の化合物 3
実施例７４の化合物 10
実施例７６の化合物 1
実施例７７の化合物 3
実施例７９の化合物 0.1
実施例８０の化合物 0.1
実施例８１の化合物 10
【０３９２】
実施例８２の化合物 1
実施例８５の化合物 3
実施例８６の化合物 0.3
実施例８７の化合物 0.1
実施例８８の化合物 0.1
実施例８９の化合物 0.3
実施例９０の化合物 3
実施例９１の化合物 0.1
実施例９２の化合物 3
実施例９３の化合物 3
【０３９３】
実施例９４の化合物 3
実施例９５の化合物 3
実施例９６の化合物 10
実施例９７の化合物 0.1
実施例９８の化合物 0.1
実施例９９の化合物 3
実施例１００の化合物 1
実施例１０１の化合物 3
実施例１０２の化合物 3
実施例１０３の化合物 1
【０３９４】
実施例１０４の化合物 1
実施例１０５の化合物 1
実施例１０６の化合物 1
実施例１０７の化合物 1
実施例１０８の化合物 3
実施例１０９の化合物 1
実施例１１０の化合物 3
実施例１１１の化合物 3
実施例１１２の化合物 0.1
実施例１１３の化合物 0.3
【０３９５】
実施例１１４の化合物 3
実施例１１５の化合物 0.01
実施例１１６の化合物 0.01
実施例１１９の化合物 3
実施例１２０の化合物 0.3
実施例１２１の化合物 3
実施例１２２の化合物 0.03
実施例１２３の化合物 3
実施例１２４の化合物 3
実施例１２５の化合物 0.1
【０３９６】
実施例１２６の化合物 3
実施例１２７の化合物 0.3
実施例１２８の化合物 0.1
実施例１２９の化合物 1
実施例１３０の化合物 0.03
実施例１３１の化合物 0.3
実施例１３２の化合物 10
実施例１３３の化合物 3
実施例１３４の化合物 3
実施例１３５の化合物 3
【０３９７】
実施例１３６の化合物 1
実施例１３７の化合物 1
実施例１３８の化合物 1
実施例１３９の化合物 0.3
実施例１４０の化合物 0.3
実施例１４１の化合物 1
実施例１４２の化合物 0.1
実施例１４３の化合物 3
実施例１４５の化合物 3
比較例１の化合物 >100
比較例２の化合物 >100
【０３９８】
薬理試験例２
抗腫瘍試験
（実験方法） マウス骨髄性白血病細胞ＷＥＨＩ−３（１〜３ｘ１０6ｃｅｌｌｓ）をＢａｌｂ／ｃマウス腹腔内に移植し、翌日から薬物の投与を開始した。これを１日目とし以後１〜４日および７〜１１日に薬剤を１日１回経口投与した。移植後の生存日数を観察し、Ｃｏｎｔｒｏｌ群の生存日数に対する薬物投与群の生存日数の比（Ｔ／Ｃ、％）を算出し、これを延命効果として評価した。
（実験結果） 実験結果を、表−６［表３２］に示した。
【０３９９】
〔表３２〕
表−６：ＷＥＨＩ−３細胞に対する抗腫瘍作用
供試化合物 投与量（ μｍｏｌ／ｋｇ） Ｔ／Ｃ（％）
実施例４５の化合物 １６ １３８
実施例４６の化合物 ３２ １４１
実施例４８の化合物 １３０ １９０
実施例１３０の化合物 １３０ １８９
【０４００】
薬理試験例３
抗腫瘍作用試験
（実験方法） ヌードマウス皮下で継代された腫瘍細胞（ＨＴ−２９，ＫＢ−３−１）をヌードマウスに移植し、体積が２０〜１００ｍｍ3程度になり、生着が確認されたところで薬剤の投与を開始した。これを１日目とし以後１〜５日、８〜１２日、１５〜１９日および２２〜２６日に薬剤を経口投与した。
腫瘍体積は、（腫瘍体積）＝１／２ｘ（長径）ｘ（短径）2 により求めた。
【０４０１】
（実験結果） ＨＴ−２９に対する実施例４８の化合物（投与量６６μｍｏｌ／ｋｇ）の実験結果を、［図１］に示した。
【０４０２】
ＫＢ−３−１に対する実施例４８の化合物（投与量６６μｍｏｌ／ｋｇ）の実験結果を、［図２］に示した。
【０４０３】
計算実施例
（高活性化合物による重ね合わせモデルの構築）
高い分化誘導活性を示す化合物である実施例４５、実施例４６および実施例４８の化合物を用い、活性発現に必要な原子団の空間配置に関する情報を抽出するため３次元構造の重ね合わせを行った。
【０４０４】
この目的のためには、市販されている計算パッケージ［CATALYST(MSI社）、Cerius2/QSAR+（MSI社）、SYBYL/DISCO（Tripos社）など］のいずれを用いても同様な解析を行うことが可能であるが、今回の重ね合わせ構造の作成および解析には、SYBYL/DISCO（Tripos社）を用いた。
【０４０５】
実施例４８の化合物について、SYBYLのスケッチ機能を用いて３次元構造を発生し、Gasteiger-Huckel法により各原子上に点電荷を付与した後、Tripos力場を用いて構造最適化を行った。次に、薬物−生体間相互作用に重要と考えられる疎水性相互作用部位（芳香環、脂肪族側鎖）および水素結合部位（カルボニル酸素、ヒドロキシル基、アミノ基など）などの相互作用が想定される部位を特定するためにダミー原子を相互作用が可能な部位に置いた。
【０４０６】
この時、疎水性相互作用、水素結合および静電相互作用部位などの相互作用の種類を区別するために、相互作用の分類を行い各々異なるダミー原子タイプを設定した。さらに、回転可能結合について回転させたコンフォーマーを発生させ、想定される相互作用部位に配置したダミー原子間の距離が変化するものを、新規なコンフォメーションとして、コンフォメーションファイルに保存した。実施例４５および実施例４６の化合物についても同様に３次元構造の作成およびコンフォメーションの発生を行った。
【０４０７】
実施例４８の化合物を鋳型分子として、そのそれぞれのコンフォメーションに対して実施例４５および実施例４６の化合物のすべてのコンフォメーションについて同じ種類の相互作用を示すダミー原子が重なるように重ね合わせ構造を作成した。
【０４０８】
得られた重ね合わせ構造について、重ね合わせに用いられたダミー原子の個数（共通な相互作用の数）、立体的な重なり具合（重なり体積）および活性値を用いた３次元ＱＳＡＲの解析結果などをもとに、最適な重ね合わせ構造を選択した。
【０４０９】
今回得られた重ね合わせ構造では、式（１３）の化合物のＢ環の重心（Ｗ１）、Ａ環の重心（Ｗ２）および水素結合受容体（カルボニル酸素など）（Ｗ３）において、Ｗ１〜Ｗ２＝８．３４Å、Ｗ１〜Ｗ３＝３．８０Å、Ｗ２〜Ｗ３＝５．５５Åの配置をとることが示された。
【０４１０】
（計算例１：実施例１３０の化合物） 実施例１３０の化合物の相互作用想定部位およびベンズアミド構造の構成原子から適当な７個の原子を選択し、上記の重ね合わせに用いた実施例４５、実施例４６および実施例４８の化合物を標的構造として、実施例１３０の化合物に拘束ポテンシャルを与えて構造最適化を行った。次に、拘束ポテンシャルを解除して構造最適化を行い、実施例１３０の化合物の活性コンフォメーションを得た。この活性コンフォメーションに対し、ベンズアミドのベンゼン環の重心（Ｗ１）およびピリジン環の重心（Ｗ２）およびカルボニル酸素（Ｗ３）を定義し、空間配置のパラメータの抽出を行った。
【０４１１】
また、回転可能な結合についてすべてのコンフォメーションを発生し各コンフォメーションでのエネルギーを計算し、最安定構造を求めた。最安定構造でのエネルギーを計算し、活性コンフォメーションとのエネルギー差を求めた。その結果、今回得られた構造では、Ｗ１〜Ｗ２＝８．４３Å、Ｗ１〜Ｗ３＝３．８２Å、Ｗ２〜Ｗ３＝５．８８Å（最安定構造とのエネルギー差：２．８６kcal/mol）の配置をとることが示された。
【０４１２】
また、前記の重ね合わせ構造モデルの構築で得られたダミー原子を標的構造として、解析操作を行うことによっても同一の結果が得られた。（計算結果） 計算結果を表−７［表３３］に示した。表−７：空間配置のパラメータの計算結果
【０４１３】
Figure 0004105451
【０４１４】
Figure 0004105451
【０４１５】
Figure 0004105451
【０４１６】
【発明の効果】
本発明の新規ベンズアミド誘導体および新規アリニド誘導体は分化誘導作用を有し、悪性腫瘍、自己免疫疾患、皮膚病、寄生虫感染症の治療・改善薬などの医薬品として有用である。特に制癌剤として効果が高く、造血器腫瘍、固形癌に有効である。
【図面の簡単な説明】
【図１】腫瘍細胞（ＨＴ−２９）に対して実施例４８の化合物投与時の腫瘍体積の変化を示す図である。
【図２】腫瘍細胞（ＫＢ−３−１）に対して実施例４８の化合物投与時の腫瘍体積の変化を示す図である。[0001]
[Industrial application fields]
The present invention relates to a differentiation inducer. More specifically, the present invention relates to use of a novel benzamide derivative or a novel alinide derivative for anticancer agents and other pharmaceuticals based on the differentiation-inducing action.
[0002]
[Prior art]
Currently, cancer is the leading cause of death, surpassing heart disease and cerebrovascular disease, and many studies have so far been conducted with great expense and time. However, cancer has not been overcome in spite of research on various treatment methods such as surgery, radiation therapy, and hyperthermia. Among them, chemotherapy is one of the major pillars of cancer treatment, but no satisfactory drug has been found to date, and anticancer agents with low toxicity and high therapeutic effect are awaited. Many conventional anticancer agents act on cells, mainly DNA, to express cytotoxicity, thereby damaging cancer cells and exhibiting anticancer effects. However, since the selectivity between cancer cells and normal cells is not sufficient, the side effects expressed in normal cells are the limits of treatment.
[0003]
However, among the anticancer agents, differentiation-inducing agents are not direct cell killing, but are aimed at promoting differentiation of cancer cells and suppressing infinite proliferation of cancer cells. Therefore, in cancer regression, it does not reach the kind of anticancer agent that directly kills cells, but low toxicity and selectivity can be expected. In fact, it is well known that retinoic acid, a differentiation inducer, is used in therapy and is highly effective in acute promyelocytic leukemia [Huang et al .; Blood, 72 567-572 (1988), Castaign et al .; Blood, 76 1704-1709, (1990), Warrel et al .; New Engl. J. Med. 324 1385-1393 (1991) etc.]. In addition, since vitamin D derivatives exhibit differentiation-inducing action, many applications to anticancer agents have been studied [Olsson et al .; Cancer Res. 43 5862-5867 (1983) et al.].
[0004]
In response to these studies, differentiation-inducing agents such as vitamin D derivatives (JP-A-6-179622), isoprene derivatives (JP-A-6-192073), tocopherols (JP-A-6-256181), quinone derivatives (JP-A-6-305955), acyclic polyisoprenoids (JP-A-6-316520), benzoic acid derivatives (JP-A-7-206765), glycolipids (JP-A-7-258100), etc. Application to cancer drugs has been reported. However, there is no drug that has reached a sufficient level for cancer treatment in these studies, and a drug that is effective and highly safe for various cancers is strongly desired.
[0005]
[Problems to be solved by the invention]
An object of the present invention is to provide a compound having a differentiation-inducing action and useful as a pharmaceutical agent such as a therapeutic / ameliorating agent for malignant tumors, autoimmune diseases, skin diseases, and parasitic infections.
[0006]
[Means for Solving the Problems]
As a result of intensive studies to solve the above-mentioned problems, the present inventor has found that a novel benzamide derivative and a novel alinide derivative having a differentiation-inducing action exhibit an antitumor effect, and completed the present invention. That is, the present invention
[1] Formula (1) [Formula 14]
[0007]
[Chemical formula 2]
Figure 0004105451
[In the formula, A represents an optionally substituted phenyl group or heterocyclic ring (as a substituent, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkyl group having 1 to 4 carbon atoms, or 1 to 4 carbon atoms). An alkoxy group having 1 to 4 carbon atoms, an alkylamino group having 1 to 4 carbon atoms, an acyl group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, and an alkylthio group having 1 to 4 carbon atoms , A group selected from the group consisting of a C 1-4 perfluoroalkyl group, a C 1-4 perfluoroalkyloxy group, a carboxyl group, a C 1-4 alkoxycarbonyl group, a phenyl group, and a heterocyclic ring 1 to 4).
X is a direct bond or Formula (2)
[0008]
[Chemical 3]
Figure 0004105451
{Wherein e represents an integer of 1 to 4. g and m each independently represent an integer of 0 to 4. R4 represents a hydrogen atom, an optionally substituted alkyl group having 1 to 4 carbon atoms, or a compound represented by the formula (3)
[0009]
[Formula 4]
Figure 0004105451
(Wherein R6 represents an optionally substituted alkyl group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 4 carbon atoms, a phenyl group, or a heterocyclic ring). R5 represents either a hydrogen atom or a structure represented by an optionally substituted alkyl group having 1 to 4 carbon atoms.
n represents an integer of 0 to 4. However, when X is a direct bond, n is not 0.
Q is the formula (4)
[0010]
[Chemical formula 5]
Figure 0004105451
(Wherein R7 and R8 each independently represents a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbon atoms).
[0011]
R1 and R2 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an aminoalkyl group having 1 to 4 carbon atoms, or a carbon number 1 to 4 alkylamino groups, 1 to 4 carbon acyl groups, 1 to 4 carbon acylamino groups, 1 to 4 carbon alkylthio groups, 1 to 4 carbon perfluoroalkyl groups, 1 to 4 carbon atoms 4 represents a perfluoroalkyloxy group, a carboxyl group, or an alkoxycarbonyl group having 1 to 4 carbon atoms.
R3 represents a hydroxyl group or an amino group. And a pharmaceutically acceptable salt thereof, and
[0012]
[2] A benzamide derivative and a pharmaceutically acceptable salt according to [1], wherein n is an integer of 1 to 4,
[0013]
[3] Q is the formula (5)
[0014]
[Chemical 6]
Figure 0004105451
(Wherein R7 and R8 are as defined above), the benzamide derivative according to [2] and a pharmaceutically acceptable salt thereof,
[0015]
[4] A benzamide derivative and a pharmaceutically acceptable salt according to [3], wherein A is an optionally substituted heterocycle, and
[0016]
[5] A benzamide derivative and a pharmaceutically acceptable salt according to [4], wherein A is an optionally substituted pyridyl group,
[0017]
[6] The benzamide derivative and the pharmaceutically acceptable salt according to [4], wherein X is a direct bond,
[0018]
[7] The benzamide derivative and the pharmaceutically acceptable salt according to [6], wherein R1 and R2 are hydrogen atoms,
[0019]
[8] The benzamide derivative and the pharmaceutically acceptable salt according to [7], wherein R3 is an amino group,
[0020]
[9] X is the formula (6) [Formula 19]
[0021]
[Chemical 7]
Figure 0004105451
(Wherein e is as defined above), a benzamide derivative according to [5] and a pharmaceutically acceptable salt thereof,
[0022]
[10] The benzamide derivative and the pharmaceutically acceptable salt according to [9], wherein n is 1, and R1 and R2 are hydrogen atoms,
[0023]
[11] The benzamide derivative and the pharmaceutically acceptable salt according to [10], wherein R3 is an amino group,
[0024]
[12] X is the formula (7)
[0025]
[Chemical 8]
Figure 0004105451
(Wherein e, g and R4 have the same meanings as described above.) Are the benzamide derivatives and pharmaceutically acceptable salts according to [5], which are any of the structures shown.
[0026]
[13] The benzamide derivative and the pharmaceutically acceptable salt according to [12], wherein n is 1, and R1 and R2 are hydrogen atoms,
[0027]
[14] The benzamide derivative and the pharmaceutically acceptable salt according to [13], wherein R3 is an amino group,
[0028]
[15] X is the formula (8) [Chemical Formula 21]
[0029]
[Chemical 9]
Figure 0004105451
(Wherein g, m and R5 have the same meanings as described above.) Are the benzamide derivatives and pharmaceutically acceptable salts according to [5], which are any of the structures shown.
[0030]
[16] The benzamide derivative and pharmaceutically acceptable salt according to [15], wherein n is 1, and R1 and R2 are hydrogen atoms,
[0031]
[17] The benzamide derivative and the pharmaceutically acceptable salt according to [16], wherein R3 is an amino group,
[0032]
[18] The benzamide derivative and the pharmaceutically acceptable salt according to [1], wherein n is 0,
[0033]
[19] A benzamide derivative and a pharmaceutically acceptable salt according to [18], wherein Q is any one of the structures represented by formula (5), and
[0034]
[20] A benzamide derivative and a pharmaceutically acceptable salt according to [19], wherein A is an optionally substituted heterocycle, and
[0035]
[21] A benzamide derivative and a pharmaceutically acceptable salt according to [20], wherein A is an optionally substituted pyridyl group,
[0036]
[22] The benzamide derivative and the pharmaceutically acceptable salt according to [21], wherein R1 and R2 are hydrogen atoms,
[0037]
[23] The benzamide derivative and the pharmaceutically acceptable salt according to [22], wherein R3 is an amino group,
[0038]
[24] Formula (9) [Formula 22]
[0039]
[Chemical Formula 10]
Figure 0004105451
A benzamide derivative and a pharmaceutically acceptable salt according to [1], which is represented by:
[0040]
[25] Formula (10) [Chemical Formula 23]
[0041]
Embedded image
Figure 0004105451
A benzamide derivative and a pharmaceutically acceptable salt according to [1], which is represented by:
[0042]
[26] Formula (11) [Formula 24]
[0043]
Embedded image
Figure 0004105451
A benzamide derivative and a pharmaceutically acceptable salt according to [1], which is represented by:
[0044]
[27] Formula (12) [Formula 25]
[0045]
Embedded image
Figure 0004105451
A benzamide derivative and a pharmaceutically acceptable salt according to [1], which is represented by:
[0046]
[28] Formula (13) [Chemical Formula 26]
[0047]
Embedded image
Figure 0004105451
[Wherein, A and B are an optionally substituted phenyl group or heterocyclic ring (as a substituent, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkyl group having 1 to 4 carbon atoms, a carbon number of 1 -4 alkoxy group, C1-C4 aminoalkyl group, C1-C4 alkylamino group, C1-C4 acyl group, C1-C4 acylamino group, C1-C4 Selected from the group consisting of an alkylthio group, a C 1-4 perfluoroalkyl group, a C 1-4 perfluoroalkyloxy group, a carboxyl group, a C 1-4 alkoxycarbonyl group, a phenyl group, and a heterocyclic ring. 1 to 4 groups).
[0048]
Y represents -CO-, -CS-, -SO- and -SO. 2 -It has either of-in the structure, and represents a chain structure, a cyclic structure, or a combination thereof connecting A and B.
R3 represents a hydroxyl group or an amino group. ], The distance formed by the centroid (W1) of the B ring, the centroid (W2) of the A ring, and the oxygen atom or sulfur atom (W3) serving as a hydrogen bond acceptor in Y is W1 to W2 = 6.0. 11.0 リ, W1-W3 = 3.0-8.0Å, W2-W3 = 3.0-8.0Å, an anilide derivative capable of adopting a configuration and a pharmaceutically acceptable salt, Also,
[0049]
[29] A is a heterocyclic ring which may be substituted, R3 is an amino group, Y is a chain, A or B or a combination thereof connecting A and B having —CO— in the structure [28] Anilide derivatives and pharmaceutically acceptable salts thereof, and
[0050]
[30] B is a phenyl group which may be substituted, W1-W2 = 7.0-9.5９, W1-W3 = 3.0-5.0Å, W2-W3 = 5.0-8.0Å. [29] The anilide derivative and pharmaceutically acceptable salt according to [29],
[0051]
[31] A cancer drug containing at least one of the compounds according to any one of [1] to [30] as an active ingredient,
[0052]
[32] A pharmaceutical product containing at least one of the compounds according to any one of [1] to [30] as an active ingredient.
[0053]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
In the present invention, 1 to 4 carbon atoms represents the number of carbon atoms per unit substituent. That is, for example, in the case of dialkyl substitution, it means 2 to 8 carbon atoms.
[0054]
The heterocyclic ring in the compounds represented by the formulas (1) and (13) is a monocyclic heterocyclic ring consisting of a 5-membered or 6-membered ring containing 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms, or 2 Cyclic condensed heterocycles, for example, monocyclic heterocycles include pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, pyrrole, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, piperidine, piperazine, pyrrolidine, quinuclidine , Tetrahydrofuran, morpholine, thiomorpholine, etc., as the bicyclic condensed heterocycle, quinoline, isoquinoline, naphthyridine, furopyridine, thienopyridine, pyrrolopyridine, oxazolopyridine, imidazolopyridine, thiazolopyridine and the like, benzofuran, Nzochiofen and benzimidazole can be exemplified.
[0055]
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Examples of the alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and tert-butyl group.
[0056]
Examples of the alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an allyloxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group. be able to. Examples of the aminoalkyl group having 1 to 4 carbon atoms include an aminomethyl group, a 1-aminoethyl group, and a 2-aminopropyl group.
[0057]
Examples of the alkylamino group having 1 to 4 carbon atoms include N-methylamino group, N, N-dimethylamino group, N, N-diethylamino group, N-methyl-N-ethylamino group, N, N-diisopropylamino. Examples include groups.
Examples of the acyl group having 1 to 4 carbon atoms include acetyl group, propanoyl group, and butanoyl group.
[0058]
Examples of the acylamino group having 1 to 4 carbon atoms include an acetylamino group, a propanoylamino group, and a butanoylamino group.
Examples of the alkylthio group having 1 to 4 carbon atoms include a methylthio group, an ethylthio group, and a propylthio group.
[0059]
Examples of the perfluoroalkyl group having 1 to 4 carbon atoms include a trifluoromethyl group and a pentafluoroethyl group.
Examples of the perfluoroalkyloxy group having 1 to 4 carbon atoms include a trifluoromethoxy group and a pentafluoroethoxy group.
[0060]
Examples of the alkoxycarbonyl group having 1 to 4 carbon atoms include a methoxycarbonyl group and an ethoxycarbonyl group.
Examples of the optionally substituted alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like. In addition, examples of the substituent include those having 1 to 4 groups selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a phenyl group, and a heterocyclic ring.
[0061]
In the compound represented by the formula (13), important elements for exhibiting high differentiation-inducing activity are (a) the presence of oxygen atoms or sulfur atoms as ring A and ring B and hydrogen bond acceptors as described later. , (B) A distance defined by their three-dimensional structural arrangement. Therefore, Y is not particularly limited as long as it has a hydrogen bond acceptor in its structure and defines the steric arrangement of ring A and ring B at a required position. That is, -CO-, -CS-, -SO- or -SO of Y 2 A chain-like or cyclic structure having any of-in the structure and linking A and B, or a combined structure thereof is (a) a linear or molecular structure composed of carbon atoms, heteroatoms, etc. -CO-, -CS-, -SO-, -SO in a branched chain structure 2 A structure connecting A and B containing-, (b) -CO-, -CS-, -SO-, -SO in the cyclic structure 2 A structure connecting A and B having —, (c) a ring structure and a chain structure are combined to form one structure, and —CO—, —CS—, —SO—, —SO 2 It means any one of the structures connecting A and B including-.
[0062]
Examples of the basic structure of the cyclic structure include a ring structure containing a 4- to 7-membered carbon atom or hetero atom, or a condensed ring thereof. Cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, oxetane ring, oxolane ring, oxane ring, oxepane ring, pyrrolidine ring, imidazolidine ring, pyrazolidine ring, piperidine ring, piperazine ring, indoline ring, isoindoline ring, thiolane A ring, a thiazolidine ring, an oxazolidine ring, and the like, and the structure can have an unsaturated bond, a hydrogen bond acceptor, and a substituent.
[0063]
By conducting an analysis taking into account the degree of freedom of conformation of the compound represented by formula (13), a compound exhibiting high differentiation-inducing activity is involved in biological-drug interactions such as hydrophobic interaction and hydrogen bonding. We have found that the possible atomic groups have a specific spatial arrangement.
[0064]
Specifically, the three-dimensional structure of a highly active compound was generated using molecular modeling software (SYBYL6.3), and the most stable structure was determined by conducting conformational analysis for all rotatable bonds. Here, the energy was evaluated by generating a charge on each atom by the Gasteiger-Huckel method and then using the Tripos force field. Then, using the most stable structure as the starting structure, the superposition considering the conformation was performed by DISCO / SYBYL. As a result, it was found that a specific spatial arrangement was necessary for the expression of high differentiation-inducing activity.
[0065]
In the above analysis operation, it is also possible to perform analysis using other commercially available calculation packages [CATALYST (MSI), Cerius2 / QSAR + (MSI), SYBYL / DISCO (Tripos), etc.] The distance information obtained by the present invention is not limited by a specific calculation program.
[0066]
The center of gravity of the ring used to define the spatial arrangement can be defined as the average of the X, Y and Z axes of the atoms making up the ring. When the target ring structure is a condensed polycyclic system, either the center of gravity of the whole condensed ring or the center of gravity of a part of the rings can be used as the center of gravity for defining the space.
[0067]
To be able to take a configuration means that a conformer satisfying the spatial configuration exists within 15 kcal / mol from the most stable structure in terms of energy, but more preferably within 8 kcal / mol. desirable.
The details of the calculation method can be performed according to the method described in the Sybyl manual: M. Clark or J. Comput. Chem. 10. 982 (1989).
[0068]
Pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid commonly used in this field, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, fumaric acid and maleic acid. Examples include salts with organic acids such as acid, citric acid, benzoic acid, trifluoroacetic acid, p-toluenesulfonic acid, and methanesulfonic acid. For example, N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide hydrochloride, N- (2-aminophenyl) -4- [N- (pyridine-3 -Yl) methoxycarbonylaminomethyl] benzamide hydrobromide, N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide sulfate,
[0069]
N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide phosphate, N- (2-aminophenyl) -4- [N- (pyridin-3-yl) ) Methoxycarbonylaminomethyl] benzamide acetate, N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide lactate, N- (2-aminophenyl) -4 -[N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide tartaric acid, N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide malate, N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzami Succinate, N-(2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylamino-methyl] benzamide fumarate,
[0070]
N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide maleate, N- (2-aminophenyl) -4- [N- (pyridine-3- Yl) methoxycarbonylaminomethyl] benzamide citrate, N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide trifluoroacetic acid, N- (2-aminophenyl) ) -4- [N- (Pyridin-3-yl) methoxycarbonylaminomethyl] benzamide p-toluenesulfonate, N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonyl Aminomethyl] benzamide methanesulfonate and the like.
[0071]
In addition to anticancer drugs, pharmaceuticals represent therapeutic and / or ameliorating drugs for autoimmune diseases, skin diseases, parasitic infections and the like.
[0072]
When the compounds represented by formula (1) and formula (13) have an asymmetric carbon, they can exist in the form of a mixture of different stereoisomeric forms or stereoisomeric forms including racemic forms. That is, the present invention includes various forms defined as described above, and these can also be used as active ingredient compounds.
[0073]
Hereinafter, representative compounds represented by the formulas (1) and (13) of the present invention are shown in Table-1 [Table 1-Table 24], Table-2 [Table 25-Table 26], Table-3 [Table 27- Specific examples are shown in Table 28] and Table-4 [Table 29-Table 30].
The present invention is not limited to these examples.
[0074]
[Table 1]
Figure 0004105451
Table-1
[0075]
[Table 2]
Figure 0004105451
Table 1 Continuation 1
[0076]
[Table 3]
Figure 0004105451
Table 1 Continuation 2
[0077]
[Table 4]
Figure 0004105451
Table 1 Continuation 3
[0078]
[Table 5]
Figure 0004105451
Table 1 Continuation 4
[0079]
[Table 6]
Figure 0004105451
Table 1 continued 5
[0080]
[Table 7]
Figure 0004105451
Table 1 continued 6
[0081]
[Table 8]
Figure 0004105451
Table 1 continued 7
[0082]
[Table 9]
Figure 0004105451
Table 1 continued 8
[0083]
[Table 10]
Figure 0004105451
Table 1 continued 9
[0084]
[Table 11]
Figure 0004105451
Table 1 continued 10
[0085]
[Table 12]
Figure 0004105451
Table 1 continued 11
[0086]
[Table 13]
Figure 0004105451
Table 1 Continuation 12
[0087]
[Table 14]
Figure 0004105451
Table 1 continued 13
[0088]
[Table 15]
Figure 0004105451
Table 1 continued 14
[0089]
[Table 16]
Figure 0004105451
Table 1 Continuation 15
[0090]
[Table 17]
Figure 0004105451
Table 1 continued 16
[0091]
[Table 18]
Figure 0004105451
Table 1 continued 17
[0092]
[Table 19]
Figure 0004105451
Table 1 continued 18
[0093]
[Table 20]
Figure 0004105451
Table 19 continued 19
[0094]
[Table 21]
Figure 0004105451
Table 1 continued 20
[0095]
[Table 22]
Figure 0004105451
Table 21 continued 21
[0096]
[Table 23]
Figure 0004105451
Table 1 continued 22
[0097]
[Table 24]
Figure 0004105451
Table 1 continued 23
[0098]
[Table 25]
Figure 0004105451
Table-2
[0099]
[Table 26]
Figure 0004105451
Table 2 continued 1
[0100]
[Table 27]
Figure 0004105451
Table 2 Continuation 2
[0101]
[Table 28]
Figure 0004105451
Table-3
[0102]
[Table 29]
Figure 0004105451
Table 3 continued 1
[0103]
[Table 30]
Figure 0004105451
Table-4
[0104]
[Table 31]
Figure 0004105451
Table 4 continued 1
[0105]
The compound of the present invention can be produced, for example, by the following method.
(A) Formula (14) [Chemical 27]
[0106]
Embedded image
Figure 0004105451
[Wherein, A and X are as defined above. R9 is -C (= G) OH (G represents an oxygen atom or a sulfur atom) or -NH 2 Represents. And a compound of the formula (15)
[0107]
Embedded image
Figure 0004105451
[Wherein R 1, R 2 and n are as defined above. R10 is —NH when R9 is —C (═G) OH (G is as defined above). 2 R9 is —NH 2 Represents -C (= G) OH (G is as defined above). R11 represents a hydroxyl group protected with a protecting group used for a normal peptide forming reaction such as an amino group or a benzyl group protected with a protecting group used for a normal peptide forming reaction such as a tert-butoxycarbonyl group. Or a compound represented by the
(B) Formula (16) [Chemical 29]
[0108]
Embedded image
Figure 0004105451
(In the formula, A and X are as defined above. R12 represents —OH or —NH. 2 Represents. And a compound represented by formula (17)
[0109]
Embedded image
Figure 0004105451
(In the formula, R1, R2, R11 and n are as defined above. R13 is —OH or —NH. 2 Represents. The compound represented by the formula (18) obtained by subjecting the compound represented by formula (8) to a condensation reaction using N, N′-carbonyldiimidazole, N, N′-thiocarbonyldiimidazole, phosgene, thiophosgene or the like.
[0110]
Embedded image
Figure 0004105451
(Wherein A, X, Q, n, R 1, R 2 and R 11 are as defined above), the compound of the present invention can be obtained by removing the protecting group.
(C) the compound represented by the formula (14) and the formula (19)
[0111]
Embedded image
Figure 0004105451
(Wherein R1, R10 and n are as defined above; R14 represents a methyl group, an ethyl group or a tert-butyl group)
(D) Compound represented by formula (16) and formula (20) [Chemical Formula 33]
[0112]
Embedded image
Figure 0004105451
(In the formula, R1, R13, R14 and n are as defined above.) A compound represented by N, N′-carbonyldiimidazole, N, N′-thiocarbonyldiimidazole, phosgene or thiophosgene is condensed. Formula (21) obtained by the reaction [Chemical Formula 34]
[0113]
Embedded image
Figure 0004105451
(Wherein A, X, Q, n, R1 and R14 have the same meanings as described above.) Formula (22) [Chemical Formula 35] obtained by hydrolysis of a compound represented by
[0114]
Embedded image
Figure 0004105451
(Wherein A, X, Q, n and R1 have the same meanings as described above), the compound represented by formula (23) [Chemical Formula 36]
[0115]
Embedded image
Figure 0004105451
(In the formula, R2 and R11 are as defined above.) The compound of the present invention can also be obtained by removing the protecting group of the compound represented by the formula (18) obtained by subjecting the compound to a condensation reaction. Can do.
(E) Compound represented by formula (22) and formula (24) [Chemical Formula 37]
[0116]
Embedded image
Figure 0004105451
The compound of the present invention can also be obtained by subjecting the compound represented by the formula (wherein R2 and R3 are as defined above) to a condensation reaction.
[0117]
The synthesis of representative intermediates will be described.
The compound represented by the formula (15) has the formula (25)
[0118]
Embedded image
Figure 0004105451
(In the formula, R1, R10 and n are as defined above.) After introducing an appropriate protecting group into the benzoic acid derivative represented by the formula, it is subjected to a condensation reaction with the compound represented by the formula (23) to further deprotect. It can be obtained by doing.
The compound represented by the formula (17) has the formula (26)
[0119]
Embedded image
Figure 0004105451
(In the formula, R1, R13 and n are as defined above.) After introducing a suitable protecting group into the benzoic acid derivative represented by the formula (1), it is subjected to a condensation reaction with the compound represented by the formula (23), followed by further deprotection. It can be obtained by doing.
The compound represented by the formula (23) can be obtained by introducing a protecting group into the compound represented by the formula (24).
[0120]
Next, the reaction will be described.
The condensation reaction (a) can be carried out by an amide bond forming reaction in a normal peptide, for example, an active ester or mixed acid anhydride or acid chloride method. For example, in the carboxylic acid component [R14 in the formula (14) is represented by -C (= G) OH (G is as defined above) or in the formula (15), R10 is -C (= G) OH (G is A compound represented by the same definition as above] and a phenol such as 2,4,5-trichlorophenol, pentachlorophenol or 4-nitrophenol, or N- such as N-hydroxysuccinimide and N-hydroxybenztriazole. The hydroxy compound is condensed in the presence of dicyclohexylcarbodiimide and converted into an active ester, and then the amine component [in formula (14), R9 is —NH 2 Or a compound represented by formula (15) wherein R10 is -NH 2 It can be carried out by condensation with a compound represented by
[0121]
In addition, in the carboxylic acid component [R9 in the formula (14) is represented by -C (= G) OH (G is as defined above) or in the formula (15), R10 is -C (= G) OH (G is the above And a compound represented by the same definition as above) are reacted with oxalyl chloride, thionyl chloride, phosphorus oxychloride and the like, converted to an acid chloride, and then the amine component [wherein R9 is —NH 2 Or a compound represented by formula (15) wherein R10 is -NH 2 It can be carried out by condensation with a compound represented by
[0122]
In addition, in the carboxylic acid component [R9 in the formula (14) is represented by -C (= G) OH (G is as defined above) or in the formula (15), R10 is -C (= G) OH (G is the above Compound] is reacted with isobutyl chlorocarbonate or methanesulfonyl chloride to obtain a mixed acid anhydride, and then the amine component [wherein R9 in formula (14) is —NH 2 Or a compound represented by formula (15) wherein R10 is -NH 2 It can be carried out by condensation with a compound represented by
[0123]
Furthermore, the condensation reaction is performed by using a peptide condensing reagent such as dicyclohexylcarbodiimide, N, N′-carbonyldiimidazole, diphenylphosphoric azide, diethyl phosphate cyanide, 2-chloro-1,3-dimethylimidazolonium chloride alone. Can also be used.
[0124]
The reaction is usually carried out at -20 to + 50 ° C for 0.5 to 48 hours. Examples of the solvent used include aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, dioxane and diethyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, N, N-dimethylformamide, Examples thereof include alcohols such as methanol and ethanol, or a mixture thereof. If necessary, an organic base such as triethylamine or pyridine is added to react.
[0125]
In the condensation reaction of (b), either one of the compounds represented by formula (16) or formula (17) is converted to phosgene, thiophosgene, N, N′-carbonyldiimidazole, N, N′-thiocarbonyldiimidazole, or the like. After activation using, it can be carried out by reacting with the other compound. The reaction is usually carried out at -20 to + 50 ° C for 0.5 to 48 hours. Examples of the solvent used include aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, dioxane and diethyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, N, N-dimethylformamide, and these. Of the mixture. If necessary, the reaction is carried out by adding an organic base such as triethylamine or pyridine.
[0126]
The condensation reaction (c) can be carried out by the same method as the condensation reaction (a).
The condensation reaction (d) can be carried out by the same method as the condensation reaction (b).
[0127]
Removal of the protecting group of the compound represented by the formula (17) is performed under the conditions used for ordinary peptide formation reactions. For example, in the formula (18), when R11 is an amino group protected with a tert-butoxycarbonyl group, the deprotection reaction can be carried out by treatment with an acid such as hydrochloric acid or trifluoroacetic acid.
[0128]
The salt of the compound represented by the formula (1) and the formula (13) can be obtained by a reaction for producing the compound represented by the formula (1) and the formula (13). Can form salts. Examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzoic acid, trifluoroacetic acid, and p-toluenesulfonic acid. Mention may be made of acids. These salts can also be used as the active ingredient compound of the present invention in the same manner as the free compounds of the formulas (1) and (13).
[0129]
The compounds represented by formula (1) and formula (13) can be isolated and purified from the reaction mixture by a conventional separation means such as extraction, recrystallization, column chromatography and the like.
[0130]
The novel benzamide derivatives and novel alinide derivatives of the present invention have a differentiation-inducing action and are useful as therapeutic and / or ameliorating agents for malignant tumors, autoimmune diseases, skin diseases, parasitic infections and the like.
[0131]
Here, malignant tumors include hematopoietic tumors such as acute leukemia, chronic leukemia, malignant lymphoma, multiple myeloma, macroglobulinemia, colon cancer, brain tumor, head and neck cancer, breast cancer, lung cancer, esophageal cancer, stomach cancer, Liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, islet cell cancer, renal cell cancer, adrenocortical cancer, bladder cancer, prostate cancer, testicular tumor, ovarian cancer, uterine cancer, choriocarcinoma, thyroid cancer, malignant carcinoid tumor, skin cancer, Examples include solid tumors such as malignant melanoma, osteosarcoma, soft tissue sarcoma, neuroblastoma, Wilms tumor, retinoblastoma.
[0132]
Autoimmune diseases include rheumatism, nephritis, diabetes, systemic lupus erythematosus, human autoimmune live lymphoproliferative lymphadenopathy, immunoblastic lymphadenopathy, Crohn's disease, ulcerative colitis and the like.
Skin diseases include psoriasis, acne, eczema, and atopic dermatitis.
Parasitic infection refers to a disease caused by parasitic infection such as malaria infection.
The target disease of the present invention is not limited to these.
[0133]
The active ingredient compounds of the present invention are useful as pharmaceuticals, and these are used in the form of general medical preparations. The preparation is prepared by using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants, lubricants and the like that are usually used. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, injections (solutions, suspensions). And suppositories.
[0134]
In molding into a tablet form, various carriers well known in the art can be widely used as carriers. Examples thereof include excipients such as lactose, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propyl alcohol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, Binding agents such as shellac, methylcellulose, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, carmellose calcium, starch, lactose and other disintegrants, white sugar,
[0135]
Adsorption of cocoa butter, decay inhibitors such as hydrogenated oils, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorption of starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Agents, lubricants such as talc, stearate, and polyethylene glycol can be used. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-encapsulated tablets, film-coated tablets, bilayer tablets, and multilayer tablets.
[0136]
In molding into a pill form, a wide variety of carriers conventionally known in this field can be used. Examples thereof include excipients such as crystalline cellulose, lactose, starch, hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder and gelatin, and disintegrants such as carmellose calcium and agar. It is done.
[0137]
Capsules are usually prepared by mixing the active ingredient compound with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules and the like according to conventional methods.
[0138]
When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and when used in these forms, those commonly used in this field as diluents, For example, water, ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, the amount of sodium chloride, glucose or glycerin necessary to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a normal solubilizing agent, buffering agent, soothing agent, etc. may be added. Also good.
[0139]
In molding into a suppository form, conventionally known carriers can be widely used. Examples thereof include semi-synthetic glycerides, cocoa butter, higher alcohols, higher alcohol esters, polyethylene glycol and the like.
[0140]
Furthermore, a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, etc. and other pharmaceuticals can also be contained in a pharmaceutical formulation as needed.
The amount of the active ingredient compound to be contained in these pharmaceutical preparations of the present invention is not particularly limited and is appropriately selected from a wide range, but is usually about 1 to 70% by weight, preferably about 5%, in the preparation composition. It should be ˜50% by weight.
[0141]
The administration method of these pharmaceutical preparations of the present invention is not particularly limited, and is administered by a method according to various preparation forms, patient age, sex, disease severity and other conditions. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules, it is administered orally, and in the case of injections, it is intravenously mixed alone or with a normal fluid such as glucose or amino acids. Intramuscularly, intramuscularly, subcutaneously or intraperitoneally alone as needed. In the case of a suppository, it is administered intrarectally.
[0142]
The dosage of these pharmaceutical preparations of the present invention is appropriately selected depending on the usage, patient age, sex, disease severity and other conditions. The amount of the active ingredient compound is usually about 0.0001 per kg body weight per day. It should be about ~ 100 mg. In addition, it is desirable that the active ingredient compound is contained in the dosage unit form in a range of about 0.001 to 1,000 mg.
The compounds represented by the formulas (1) and (13) and salts thereof according to the present invention do not exhibit toxicity that causes problems at pharmacologically effective doses.
[0143]
【Example】
EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. The numbers in parentheses in the title are the numbers of the compounds exemplified in the detailed description.
[0144]
Example 1
Synthesis of N- (2-aminophenyl) -4- (N-benzoylaminomethyl) benzamide hydrochloride (Table-1: Hydrochloride of Compound No. 1)
(1-1) 42 ml (300 mmol) of triethylamine was added to a suspension of 21.16 g (140 mmol) of 4-aminomethylbenzoic acid in dichloromethane (450 ml). A solution of 60.4 g (287 mmol) of trifluoroacetic anhydride in dichloromethane (50 ml) was added dropwise while keeping the internal temperature at 3 to 8 ° C. under ice cooling, followed by stirring for 3 hours. The reaction solution was poured into saturated sodium bicarbonate water, and further acidified with a 10% aqueous hydrochloric acid solution. The precipitated gel-like precipitate was collected by filtration and dried to obtain 30.4 g (yield 87.8%) of 4- (N-trifluoroacetylaminomethyl) benzoic acid as a milky white solid.
1H NMR (270MHz, DMSO-d6) δppm: 4.47 (2H, d, J = 5.8Hz), 7.39 (2H, d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 10.08 (1H , t, J = 5.8Hz), 12.95 (1H, br.s).
[0145]
(1-2) 1N aqueous sodium hydroxide solution (500 ml) was added to a solution of 108 g (1.0 mol) of o-phenylenediamine in dioxane (1000 ml), and 218 g (1.1 mol) of ditert-butyl dicarbonate was added under ice cooling. Dioxane (500 ml) solution was added. The mixture was stirred at room temperature for 6 hours and then left overnight. The solvent was concentrated to 1/2 volume and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried, the solvent is distilled off, the residue obtained is purified by silica gel column chromatography (chloroform), and the resulting solid is washed with ethyl ether to give N-tert-butoxy. 68.4 g (yield 32.8%) of carbonyl-o-phenylenediamine was obtained as a white solid.
1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 3.75 (2H, s), 6.26 (1H, s), 6.77 (1H, d, J = 8.1Hz), 6.79 (1H, dd, J = 7.3, 8.1 Hz), 7.00 (1 H, dd, J = 7.3, 8.1 Hz), 7.27 (1 H, d, J = 8.1 Hz).
[0146]
(1-3) 21 g (165 mmol) of oxalyl chloride was added to a suspension of 30.0 g (121 mmol) of the compound obtained in step (1-1) in dichloromethane (200 ml) while cooling with ice (internal temperature: 10 to 15 ° C.). ) Was gradually added dropwise. At that time, DMF was added occasionally (approximately 0.1 ml for each 2 ml drop). After dropping the whole amount, the mixture was stirred until foaming stopped, and then stirred at 40 ° C. for 1 hour. After the solvent was distilled off, excess oxalyl chloride was azeotroped with toluene and dissolved again in dichloromethane (100 ml). To the solution of 22.88 g (110 mmol) of the compound obtained in step (1-2) in dichloromethane (100 ml) -pyridine (200 ml), the previously prepared acid chloride solution was added dropwise under ice cooling (internal temperature 7-9 ° C.). did.
[0147]
After completion of the dropwise addition, the temperature was raised to room temperature and left overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform, washed with saturated brine, dried, and the solvent was evaporated. Methanol-diisopropyl ether was added to the resulting residue, and the precipitated solid was collected by filtration and dried to give N- [2- (N-tert-butoxycarbonyl) aminophenyl] -4- (N-trifluoroacetylamino). 28.1 g (yield 58%) of methyl) benzamide were obtained as a pale yellow solid.
1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 4.48 (2H, d, J = 5.9Hz), 7.12-7.23 (2H, m), 7.44 (2H, d, J = 8.1Hz) , 7.54 (2H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.68 (1H, br.s), 9.83 (1H, s), 10.10 (1H, br.t, J = 5.9Hz).
[0148]
(1-4) To a suspension of 13.12 g (30 mmol) of the compound of step (1-3) in methanol (120 ml) -water (180 ml), 4.70 g (34.0 mmol) of potassium carbonate was added, and 4 at 70 ° C. Stir with heating for hours. Extraction with chloroform was performed, and the organic layer was washed with saturated brine, dried, the solvent was evaporated, and the residue was dried to give 4-aminomethyl-N- [2- (N-tert-butoxycarbonyl) aminophenyl] benzamide. 10.3 g (quantitative) was obtained as a pale yellow amorphous solid. 1H NMR (270 MHz, DMSO-d6) δ ppm: 3.80 (2H, s), 7.13-7.23 (2H, m), 7.48-7.58 (4H, m), 7.90 (2H, d, J = 8.1 Hz), 8.69 ( 1H, br.s), 9.77 (1H, br.s).
[0149]
(1-5) To a solution of 0.11 g (0.44 mmol) of the compound of step (1-4) in pyridine (5 ml) under ice cooling, 0.08 g (0.53 mmol) of benzoyl chloride was added, and then gradually to room temperature. The mixture was stirred for 8 hours while raising the temperature. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, the solvent was distilled off, the resulting residue was washed with diisopropyl ether, and the obtained solid was dried to give N- [2- (N-tert-butoxy). Carbonyl) aminophenyl] -4- (N-benzoylaminomethyl) benzamide (0.14 g, yield 71.4%) was obtained as a white solid.
1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 4.56 (2H, d, J = 5.9Hz), 7.11-7.22 (2H, m), 7.46-7.56 (7H, m), 7.90- 7.94 (4H, m), 8.67 (1H, s), 9.15 (1H, t, J = 5.9Hz), 9.81 (1H, s).
[0150]
(1-6) 4N Hydrochloric acid-dioxane (5 ml) was added to a solution of 0.10 g (0.224 mmol) of the compound of step (1-5) in dioxane (5 ml) -methanol (1 ml), and the mixture was stirred at room temperature for 7 hours. . Diisopropyl ether was added to the residue obtained by distilling off the solvent, and the resulting solid was collected by filtration and dried to give 0.08 g of N- (2-aminophenyl) -4- (N-benzoylaminomethyl) benzamide hydrochloride ( Yield 93%) was obtained as a light brown solid.
mp. 206-209 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.57 (2H, d, J = 5.8Hz), 7.27-7.38 (4H, m), 7.47-7.59 (5H, m), 7.92 (1H, d, J = 8.1 Hz), 8.05 (1H, d, J = 8.1Hz), 9.19 (1H, t, J = 5.8Hz), 10.38 (1H, br.s).
IR (KBr) cm-1: 3286,3003 (br.), 1630,1551,1492,1306,1250,749,695.
The compounds of Examples 2 to 44 were synthesized in the same manner as in Example 1. The measured values of the melting point (mp.), 1H NMR and IR of the compound are shown below.
[0151]
Example 2
N- (2-aminophenyl) -4- [N- (2-chlorobenzoyl) aminomethyl] benzamide (Table-1: Compound No. 14)
mp. 201-204 ℃ (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.52 (2H, t, J = 5.9Hz), 4.89 (2H, br.s), 6.60 (1H, ddd, J = 1.5,7.3,8.1Hz), 6.78 ( 1H, dd, J = 1.5,8.1Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.17 (1H, d, J = 8.1Hz), 7.38-7.54 (6H, m), 7.97 (2H, d, J = 8.1Hz), 9.06 (1H, br.t, J = 5.9Hz), 9.63 (1H, br.s).
IR (KBr) cm-1: 3268,1649,1458,1304,748.
[0152]
Example 3
N- (2-aminophenyl) -4- [N- (2-nitrobenzoyl) aminomethyl] benzamide hydrochloride (Table-1: Hydrochloride of Compound No. 18)
mp. 210-212 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.55 (2H, t, J = 5.9Hz), 7.20-7.40 (3H, m), 7.50-7.60 (1H, m), 7.53 (2H, d, J = 8.1 Hz), 7.60-7.70 (2H, m), 7.83 (1H, ddd, J = 1.5,8.1,8.1Hz), 8.00-8.10 (3H, m), 9.34 (1H, t, J = 5.9Hz), 10.43 (1H, br.s).
IR (KBr) cm-1: 3283, 2500-3000 (br.), 1648, 1534, 1461, 1362, 1314, 754, 701.
[0153]
Example 4
N- (2-aminophenyl) -4- [N- (4-methylbenzoyl) aminomethyl] benzamide hydrochloride (Table-1: Hydrochloride of compound number 28)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 2.37 (3H, s), 4.56 (2H, d, J = 5.0Hz), 7.20-7.30 (6H, m), 7.47 (4H, d, J = 8.8Hz) , 7.82 (2H, d, J = 8.8Hz), 8.03 (2H, d, J = 8.8Hz), 9.09 (1H, t, J = 5Hz), 10.36 (1H, br.s).
IR (KBr) cm-1: 3269 (br.), 2861 (br.), 1743, 1636, 1534, 1505, 1456, 1308, 1120, 753.
[0154]
Example 5
N- (2-aminophenyl) -4- [N- (3-methoxybenzoyl) aminomethyl] benzamide (Table-1: Compound No. 30)
mp. 182-185 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 3.81 (3H, s), 4.54 (2H, d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6,7.3 Hz), 6,78 (1H, d, J = 7.3Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.11 (1H, dd, J = 1.5,8.1Hz), 7.16 (1H, d , J = 7.3Hz), 7.35-7.51 (5H, m), 7.94 (2H, d, J = 8.1Hz), 9.12 (1H, br.t, J = 5.9Hz), 9.63 (1H, br.s) .
IR (KBr) cm-1: 3301,1637,1524,1489,1457,1314,1248,752.
[0155]
Example 6
N- (2-aminophenyl) -4- [N- (4-methoxybenzoyl) aminomethyl] benzamide (Table-1: Compound No. 31)
mp. 149-151 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 3.82 (3H, s), 4.53 (2H, d, J = 5.9Hz), 4.88 (2H, s), 6.59 (1H, dd, J = 7.3,7.3Hz) , 6.77 (1H, d, J = 8.1Hz), 6.94-7.00 (1H, m), 7.02 (2H, d, J = 8.8Hz), 7.16 (1H, d, J = 8.1Hz), 7.43 (2H, d, J = 8.1Hz), 7.89 (2H, d, J = 8.8Hz), 7.94 (2H, d, J = 8.1Hz), 8.98 (1H, br.t, J = 5.9Hz), 9.61 (1H, br.s).
IR (KBr) cm-1: 3297,1630,1527,1505,1457,1256,1177,1024,843,749.
[0156]
Example 7
N- (2-aminophenyl) -4- [N- (3,4,5-trimethoxybenzoyl) aminomethyl] benzamide (Table-1: Compound No. 33)
mp. 208-210 ℃ (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 3.71 (3H, s), 3.83 (6H, s), 4.55 (2H, d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J = 7.3,8.1Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,8.1Hz), 7,16 (1H, d, J = 8.1Hz), 7.26 (2H, s), 7.44 (2H, d, J = 8.1Hz), 7.95 (2H, d, J = 8.8Hz), 9.07 (1H, t, J = 5.9Hz), 9.62 (1H, br.s ).
IR (KBr) cm-1: 3267,1635,1582,1457,1237,1132,755.
[0157]
Example 8
N- (2-aminophenyl) -4- [N- [4- (N, N-dimethyl) aminobenzoyl] aminomethyl] benzamide (Table-1: Compound No. 36)
mp. 216-219 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 2.98 (6H, s), 4.51 (2H, d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J = 8.1,8.1 Hz), 6.71 (2H, d, J = 8.8Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J = 7.3Hz), 7.41 (2H, d, J = 8.1 Hz), 7.78 (2H, d, J = 8.8Hz), 7.93 (2H, d, J = 8.1Hz), 8.77 (1H, t, J = 5.9Hz), 9.63 (1H, br.s).
IR (KBr) cm-1: 3301,1632,1519,1457,1298,754.
[0158]
Example 9
N- (2-aminophenyl) -4- [N- (4-trifluoromethylbenzoyl) aminomethyl] benzamide (Table-1: Compound No. 42)
mp. 243-246 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.58 (2H, d, J = 5.9Hz), 4.88 (2H, br.s), 6.59 (1H, dd, J = 6.6,7.3Hz), 6.77 (1H, d, J = 8.1Hz), 6.94 (1H, dd, J = 5.9,6.6Hz), 7.16 (1H, d, J = 8.1Hz), 7.45 (2H, d, J = 8.1Hz), 7.88 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.1Hz), 8.11 (2H, d, J = 8.1Hz), 9.38 (1H, t, J = 5.9Hz), 9.64 (1H, br. s).
IR (KBr) cm-1: 3301,1640,1549,1523,1458,1334,1162,1120,1070,856,750.
[0159]
Example 10
N- (2-aminophenyl) -4- [N- (4-carboxybenzoyl) aminomethyl] benzamide hydrochloride (Table-1: Hydrochloride of compound number 45)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 4.58 (2H, d, J = 5.9Hz), 7.29-7.37 (3H, m), 7.49 (3H, d, J = 8.1Hz), 8.02-8.06 (6H, m), 9.36 (1H, t, J = 5.9Hz), 10.4 (1H, br.s).
IR (KBr) cm-1: 3432 (br.), 1718, 1637, 1542, 1499, 1303 (br.), 1116, 1018, 757.
[0160]
Example 11
N- (2-aminophenyl) -4- [N- (4-methoxycarbonylbenzoyl) aminomethyl] benzamide (Table-1: Compound No. 46)
mp. 204-209 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 3.89 (3H, s), 4.57 (2H, d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6,7.3 Hz), 6.78 (2H, d, J = 7.3Hz), 6.97 (1H, ddd, J = 1.5,6.6,7.3Hz), 7.16 (1H, d, J = 7.3Hz), 7.45 (2H, d, J = 8.1Hz), 7.95 (2H, d, J = 8.1Hz), 8.03 (2H, d, J = 8.8Hz), 8.07 (2H, d, J = 8.8Hz), 9.35 (1H, t, J = 5.9 Hz), 9.64 (1H, br.s).
IR (KBr) cm-1: 3287 (br.), 1721, 1634, 1281, 1113, 750, 703.
[0161]
Example 12
N- (2-aminophenyl) -4- (N-picolinoylaminomethyl) benzamide (Table-1: Compound No. 173)
mp. 173-178 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.57 (2H, d, J = 6.6Hz), 4.88 (2H, br.s), 6.59 (1H, dd, J = 7.3,8.1Hz), 6.77 (1H, d, J = 8.1Hz), 6.96 (1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J = 7.3Hz), 7.44 (2H, d, J = 8.1Hz), 7.60-7.65 ( 1H, m), 7.93 (2H, d, J = 8.1Hz), 7.98-8.08 (2H, m), 8.67 (1H, d, J = 4.4Hz), 9.45 (1H, t, J = 6.6Hz), 9.61 (1H, br.s).
IR (KBr) cm-1: 3330,1656,1634,1523,1456,1294,752.
[0162]
Example 13
N- (2-aminophenyl) -4- [N- (6-methylpicolinoyl) aminomethyl] benzamide (Table-1: Compound No. 178)
mp. 172-173 ° C.
1H NMR (270 MHz, DMSO-d6) δ ppm: 2.51 (3H, s), 4.57 (2H, d, J = 6.6 Hz), 5.0 (2H, br.s), 6.61 (1H, dd, J = 7.3, 8.1) Hz), 6.79 (1H, d, J = 7.3Hz), 6.98 (1H, dd, J = 7.3,8.1Hz), 7.17 (1H, d, J = 7.3Hz), 7.44 (2H, d, J = 8.1 Hz), 7.43-7.49 (1H, m), 7.84-7.90 (2H, m), 7.94 (2H, d, J = 8.1Hz), 9.27 (1H, t, J = 5.9Hz), 9.64 (1H, br .s).
IR (KBr) cm-1: 3331,1675,1634,1594,1523,1454,1307,1292,750.
[0163]
Example 14
N- (2-aminophenyl) -4- (N-nicotinoylaminomethyl) benzamide (Table-1: Compound No. 71)
mp. 193-196 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.58 (2H, d), 4.88 (2H, br.s), 6.60 (1H, t), 6.78 (1H, d), 6.97 (1H, t), 7.16 ( 1H, d), 7.46 (2H, d), 7.53 (1H, dd), 7.95 (2H, d), 8.24 (1H, ddd), 8.73 (1H, dd), 9.07 (1H, d), 9.32 (1H , br.t), 9.63 (1H, br.s) IR (KBr) cm-1: 3301,1639,1522,1457,1314,749,705.
[0164]
Example 15
N- (2-aminophenyl) -4- [N- (2-methylnicotinoyl) aminomethyl] benzamide (Table-1: Compound No. 141)
mp. 191-194 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 2.53 (3H, s), 4.53 (2H, d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6,8.1 Hz), 6.78 (1H, d, J = 7.3Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.17 (1H, d, J = 7.3Hz), 7.29 (1H, dd, J = 5.1 8.1Hz), 7.47 (2H, d, J = 8.1Hz), 7.77 (1H, dd, J = 1.5,8.1Hz), 7.97 (2H, d, J = 8.1Hz), 8.51 (1H, dd, J = 1.5,5.1Hz), 9.06 (1H, t, J = 5.9Hz), 9.64 (1H, s).
IR (KBr) cm-1: 3261,1642,1523,1310,753.
[0165]
Example 16
N- (2-aminophenyl) -4- [N- (6-methylnicotinoyl) aminomethyl] benzamide (Table-1: Compound No. 143)
mp. 186-190 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 2.36 (3H, s), 4.56 (2H, d, J = 5.9Hz), 4.88 (2H, s), 6.60 (1H, dd, J = 7.4,7.8Hz) , 6.78 (1H, d, J = 7.8Hz), 6.97 (1H, dd, J = 6.9,6.9Hz), 7.16 (1H, d, J = 7.4Hz), 7.37 (1H, d, J = 8.3Hz) , 7.45 (2H, d, J = 8.3Hz), 7.95 (2H, d, J = 8.3Hz), 8.13 (1H, dd, J = 2.0,8.3Hz), 8.96 (1H, s), 9.24 (1H, t, J = 5.9Hz), 9.63 (1H, br.s).
IR (KBr) cm-1: 3302,1636,1602,1523,1489,1457,1313,751.
[0166]
Example 17
N- (2-aminophenyl) -4- [N- (2-chloronicotinoyl) aminomethyl] benzamide (Table-1: Compound No. 154)
mp. 176-178 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.54 (2H, t, J = 5.9Hz), 4.90 (2H, br.s), 6.60 (1H, ddd, J = 1.5, 7.3, 7.3Hz), 6.78 ( 1H, d, J = 8.1Hz), 6.97 (1H, ddd, J = 1.5,7.3,7.3Hz), 7.18 (1H, d, J = 8.1Hz), 7.48-7.54 (3H, m), 7.94-7.99 (3H, m), 8.49 (1H, dd, J = 2.1,5.1Hz), 9.23 (1H, br.t, J = 5.9Hz), 9.65 (1H, br.s).
IR (KBr) cm-1: 3264,1649,1524,1400,1309,751.
[0167]
Example 18
N- (2-aminophenyl) -4- [N- (6-chloronicotinoyl) aminomethyl] benzamide (Table-1: Compound No. 156)
mp. 205-208 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 5.57 (2H, d, J = 5.9Hz), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.96 (1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J = 8.1Hz), 7.45 (2H, d, J = 8.1Hz), 7.66 (1H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.1Hz), 8.27-8.32 (1H, m), 8.90 (1H, d, J = 2.1Hz), 9.38 (1H, t, J = 5.9Hz), 9.63 (1H, s) .
IR (KBr) cm-1: 3318 (br.), 2929, 1646, 1590, 1525, 1503, 1454, 1108, 745.
[0168]
Example 19
N- (2-aminophenyl) -4- (N-isonicotinoylaminomethyl) benzamide (Table-1: Compound No. 183)
mp. 234-237 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.57 (2H, t, J = 5.9Hz), 4.88 (2H, br.s), 6.59 (1H, dd, J = 6.6,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.96 (1H, dd, J = 7.3,7.3Hz), 7.16 (1H, d, J = 7.3Hz), 7.45 (2H, d, J = 8.1Hz), 7.81 (2H, d, J = 1.5,4.4Hz), 7.95 (2H, d, J = 8.1Hz), 8.75 (2H, d, J = 6.6Hz), 9.41 (1H, t, J = 5.9Hz), 9.62 (1H, br.s).
IR (KBr) cm-1: 3298,1646,1550,1525,1457,1304,843,760,695.
[0169]
Example 20
N- (2-aminophenyl) -4- [N- (pyrazin-2-yl) carbonylaminomethyl] benzamide (Table-1: Compound No. 191)
mp.207 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.58 (2H, d, J = 5.9Hz), 4.88 (2H, br.s), 6.59 (1H, dd, J = 7.3,7.3Hz), 6.77 (1H, d, J = 8.1Hz), 6.94 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.15 (1H, d, J = 7.3Hz), 7.45 (2H, d, J = 8.1Hz), 7.93 ( 2H, d, J = 8.1Hz), 8.77 (1H, d, J = 1.5Hz), 8.90 (1H, d, J = 2.1Hz), 9.21 (1H, s), 9.55-9.61 (2H, m).
IR (KBr) cm-1: 3368 (br.), 1657,1524,1455,1295,1023,751.
[0170]
Example 21
N- (2-aminophenyl) -4- [N- (thiophen-2-yl) carbonylaminomethyl] benzamide (Table-1: Compound No. 201)
mp. 202-205 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.52 (2H, t, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.15-7.18 (2H, m), 7.43 (2H, d, J = 8.1Hz), 7.78 (1H, d, J = 4.4), 7.82 (1H, d, J = 3.7Hz), 7.95 (2H, d, J = 8.1Hz), 9.12 (1H, br.t, J = 5.9Hz), 9.62 (1H, br.s) .
IR (KBr) cm-1: 3306,1633,1523,1456,1297,750,716.
[0171]
Example 22
N- (2-aminophenyl) -4- [N- (furan-2-yl) carbonylaminomethyl] benzamide (Table 1: Compound No. 205)
mp.197 ° C (dec.).
[0172]
1H NMR (270MHz, DMSO-d6) δppm: 4.59 (2H, d, J = 6.6Hz), 4.86 (2H, br.s), 6.59 (1H, dd, J = 6.6,6.6Hz), 6.63 (1H, dd, J = 1.5,3.6Hz), 6.78 (1H, d, J = 8.1Hz), 6.96 (1H, dd, J = 7.3,6.6Hz), 7.10-7.20 (2H, m), 7.41 (2H, d , J = 8.1Hz), 7.84 (1H, s), 7.94 (2H, d, J = 8.1Hz), 9.00 (1H, br.t, J = 5.9Hz), 9.62 (1H, s).
IR (KBr) cm-1: 3245,1651,1573,1545,1323,1241,745.
[0173]
Example 23
N- (2-aminophenyl) -4- [N- (pyrrol-2-yl) carbonylaminomethyl] benzamide (Table-1: Compound No. 209)
mp. 216-220 ° C (dec.)
1H NMR (270MHz, DMSO-d6) δppm: 4.50 (2H, d, J = 5.9Hz), 4.88 (2H, br.s), 6.10 (1H, dd, J = 2.1,5.9Hz), 6.59 (1H, dd, J = 7.3,7.3Hz), 6.77 (1H, dd, J = 1.5,8.1Hz), 6.84-6.88 (2H, m), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.16 (1H, d, J = 7.3Hz), 7.41 (2H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.62 (1H, br.t, J = 5.9Hz), 9.62 (1H, br.s).
IR (KBr) cm-1: 3275,1655,1584,1534,1458,1316,747.
[0174]
Example 24
N- (2-aminophenyl) -4- [N- (1-methyl-1H-pyrrol-2-yl) carbonylaminomethyl] benzamide (Table 1: Compound No. 210)
mp. 177-179 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 3.84 (3H, s), 4.46 (2H, d, J = 5.9Hz), 4.88 (2H, br.s), 6.03 (1H, dd, J = 2.1,4.4 Hz), 6.59 (1H, dd, J = 8.1,8.1Hz), 6.77 (1H, d, J = 8.1Hz), 6.84-6.97 (2H, m), 7.16 (1H, d, J = 7.3Hz), 7.41 (2H, d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 8.61 (1H, t, J = 5.9Hz), 9.62 (1H, br.s).
IR (KBr) cm-1: 3325 (br.), 1630, 1551, 1520, 1507, 1324, 1265, 1154, 740.
[0175]
Example 25
N- (2-aminophenyl) -4- [N- (isoxazol-5-yl) carbonylaminomethyl] benzamide (Table-1: Compound No. 212)
mp. 183-185 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.53 (2H, d, J = 6.6Hz), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 7.3Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.12 (1H, d, J = 2.1Hz), 7.16 (1H, d, J = 8.1Hz), 7.44 (2H, d, J = 8.1Hz), 7.95 (2H, d, J = 8.1Hz), 8.76 (1H, d, J = 1.5Hz), 9.61 (1H, t, J = 5.9Hz), 9.64 (1H, br. s).
IR (KBr) cm-1: 3278 (br.), 1636, 1576, 1522, 1458, 1220, 749.
[0176]
Example 26
N- (2-aminophenyl) -4- [N- (3-methylisothiazol-5-yl) carbonylaminomethyl] benzamide (Table-1: Compound No. 213)
mp. 168-169 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 2.47 (3H, s), 4.54 (2H, d, J = 5.9Hz), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3 Hz), 6.78 (1H, d, J = 7.3Hz), 6.97 (1H, ddd, J = 1.0,7.3,8.1Hz), 7.17 (1H, d, J = 7.3Hz), 7.44 (2H, d, J = 8.1Hz), 7.73 (1H, s), 7.96 (2H, d, J = 8.1Hz), 9.44 (1H, t, J = 5.9Hz), 9.64 (1H, br.s).
IR (KBr) cm-1: 3310, 1637, 1503, 1294,751.
[0177]
Example 27
N- (2-aminophenyl) -4- [N- (imidazol-4-yl) carbonylaminomethyl] benzamide (Table-1: Compound No. 214)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 4.49 (2H, d, J = 6.4Hz), 4.87 (2H, br.s), 6.59 (1H, dd, J = 6.9,6.9Hz), 6.77 (1H, d, J = 6.9Hz), 6.96 (1H, dd, J = 7.4,7.4Hz), 7.16 (1H, d, J = 6.9Hz), 7.41 (2H, d, J = 6.9Hz), 7.64 (1H, br.s), 7.73 (1H, br.s), 7.92 (2H, d, J = 6.9Hz), 8.56 (1H, br.t, J = 6.4Hz), 9.61 (1H, s), 12.5 (1H , br.s).
IR (KBr) cm-1: 3278 (br.), 1636, 1576, 1522, 1458, 1220, 749.
[0178]
Example 28
N- (2-aminophenyl) -4- [N- (3-aminophenyl) acetylaminomethyl] benzamide (Table 1: Compound No. 23)
mp. 171-176 ℃
1H NMR (270MHz, DMSO-d6) δppm: 4.34 (2H, d, J = 5.9Hz), 5.24 (4H, br.s), 6.48-6.63 (4H, m), 6.78-6.81 (1H, m), 6.94-7.00 (2H, m), 7.18 (1H, d, J = 8.1Hz), 7.34 (2H, d, J = 8.1Hz), 7.92 (2H, d, J = 8.1Hz), 8.50 (1H, t , J = 5.9Hz), 9.61 (1H, s).
[0179]
Example 29
N- (2-aminophenyl) -4- [N- (pyridin-3-yl) acetylaminomethyl] benzamide (Table-1: Compound No. 74)
mp.127 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 3.84 (2H, s), 4.40 (2H, d, J = 5.8Hz), 7.15-7.29 (3H, m), 7.37 (1H, d, J = 6.6Hz) , 7.43 (2H, d, J = 8.8Hz), 7.96 (1H, m), 7.98 (2H, d, J = 8.8Hz), 8.40 (1H, d, J = 8.8Hz), 8.79-8.87 (3H, m), 10.20 (1H, s).
[0180]
Example 30
N- (2-aminophenyl) -4- [N- [3- (pyridin-3-yl) propionyl] aminomethyl] benzamide (Table 1: Compound No. 75)
mp. 183-186 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 2.51 (2H, t, J = 7.3Hz), 2.88 (2H, d, J = 7.3Hz), 4.31 (2H, d, J = 5.9Hz), 4.89 (2H , br.s), 6.60 (1H, dd, J = 7.3,8.1Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.16 ( 1H, d, J = 8.1Hz), 7.23 (2H, d, J = 8.8Hz), 7.28-7.33 (1H, m), 7.63 (1H, d, J = 8.1Hz), 7.89 (2H, d, J = 8.1Hz), 8.41-8.45 (3H, m), 9.62 (1H, br.s).
IR (KBr) cm-1: 3407,3313,1640,1552,1522,1456,1309,746,717.
[0181]
Example 31
N- (2-aminophenyl) -4- [N- [4- (pyridin-3-yl) -1,4-dioxobutyl] aminomethyl] benzamide (Table-1: Compound No. 100)
mp. 145-147 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 2.37-2.50 (2H, m), 2.62-2.68 (2H, m), 4.13 (2H, s), 4.86 (2H, s), 6.56-6.61 (1H, m ), 6.76-6.79 (1H, m), 6.94-6.99 (1H, m), 7.10-7.39 (4H, m), 7.43-7.46 (1H, m), 7.78 (2H, d, J = 8.1Hz), 8.60-8.64 (1H, m), 9.58 (1H, s).
IR (KBr) cm-1: 3348, 1691, 1655, 1534, 1508, 1458, 1395, 1315, 1083, 746.
[0182]
Example 32
N- (2-aminophenyl) -4- [N- (5-chloropyridin-3-yl) oxyacetylaminomethyl] benzamide (Table-1: Compound No. 158)
mp. 199-201 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.43 (2H, d, J = 6.6Hz), 4.75 (2H, s), 4.87 (2H, br.s), 6.60 (1H, dd, J = 7.3,8.1 Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J = 8.1Hz), 7.37 (2H, d, J = 8.1 Hz), 7.59 (1H, d, J = 2.2Hz), 7.93 (2H, d, J = 8.1Hz), 8.25 (1H, d, J = 1.5Hz), 8.81 (1H, t, J = 6.6Hz) , 9.64 (1H, s).
IR (KBr) cm-1: 3288,3058,1675,1633,1523,1457,1314,912,755.
[0183]
Example 33
N- (2-amino-5-methoxyphenyl) -4- [N- (pyridin-3-yl) oxyacetylaminomethyl] benzamide (Table-1: Compound No. 175)
mp. 141-144 ℃.
1H NMR (270MHz, DMSO-d6) δppm: 3.66 (3H, s), 4.43 (2H, d, J = 5.9Hz), 4.49 (2H, br.s), 4.68 (2H, s), 6.62 (1H, dd, J = 2.9,8.8Hz), 6.75 (1H, d, J = 8.8Hz), 6.91 (1H, d, J = 2.2Hz), 7.37 (4H, m), 7.92 (2H, d, J = 8.8 Hz), 8.21 (1H, dd, J = 1.5,4.4Hz), 8.35 (1H, d, J = 2.7Hz), 8.81 (1H, s), 9.65 (1H, s).
[0184]
Example 34
N- (2-aminophenyl) -4- [N- [3- (pyridin-3-yl) -1,3-dioxopropyl] aminomethyl] benzamide (Table-1: Compound No. 98)
mp. 204-206 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.08 (4 / 3H, s), 4.39 (4 / 3H, d, J = 5.9Hz), 4.49 (2 / 3H, d, J = 5.9Hz), 4.90 ( 2H, br.s), 5.93 (1 / 3H, s), 6.60 (1H, t, J = 7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, t, J = 7.3Hz ), 7.16 (1H, d, J = 7.3Hz), 7.3-7.7 (3H, m), 7.8-8.4 (3H, m), 8.6-9.2 (3H, m), 9.64 (1H, s), 14.74 ( 1 / 3H, s). (2: 1 equilibrium mixture)
IR (KBr) cm-1: 3282, 1690, 1645, 1527, 1421, 1314, 1217, 1028, 994, 911, 753, 701.
[0185]
Example 35
N- (2-aminophenyl) -4- [N- [N- (pyridin-3-yl) aminoacetyl] aminomethyl] benzamide (Table 1: Compound No. 96)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 3.77 (2H, d, = 6.6Hz), 4.37 (2H, d, J = 5.9Hz), 4.87 (2H, br.s), 6.27 (1H, t, J = 5.9Hz), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.87 (1H, d, J = 8.1Hz), 6.96 (1H, dd, J = 7.3 8.1Hz), 7.09 (1H, d, J = 4.4Hz), 7.12 (1H, d, J = 4.4Hz), 7.16 (1H, d, J = 8.1Hz), 7.33 (2H, d, J = 8.8 Hz), 7.81 (1H, d, J = 4.4Hz), 7.91 (2H, d, J = 7.3Hz), 7.99 (1H, d, J = 2.9Hz), 8.59 (1H, br.t, J = 5.1 Hz), 9.63 (1H, br.s).
IR (KBr) cm-1: 3350, 1658, 1525, 1502, 1314, 750.
[0186]
Example 36
N- (2-aminophenyl) -4- [N- (2-aminothiazol-4-yl) acetylaminomethyl] benzamide (Table-1: Compound No. 220)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 3.34 (2H, s), 4.35 (2H, d, J = 5.9Hz), 4.87 (2H, s), 6.25 (1H, s), 6.59 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 7.3Hz), 6.87 (2H, s), 6.96 (1H, dd, J = 7.3,7.3Hz), 7.16 (1H, d, J = 7.3 Hz), 7.37 (2H, d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 8.44 (1H, t, J = 5.9Hz), 9.62 (1H, s).
[0187]
Example 37
N- (2-aminophenyl) -4- [N- (quinolin-6-yl) carbonylaminomethyl] benzamide (Table-1: Compound No. 231)
mp. 209-210 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.62 (2H, d, J = 5.9Hz), 4.88 (2H, s), 6.60 (1H, t, J = 7.7Hz), 6.78 (1H, d, J = 7.3Hz), 6.95 (1H, d, J = 7.3Hz), 7.17 (1H, d, J = 7.3Hz), 7.49 (2H, d, J = 8.8Hz), 7.62 (1H, dd, J = 4.4, 8.1Hz), 7.96 (2H, d, J = 8.8Hz), 8.10 (1H, d, J = 8.8Hz), 8.23 (1H, dd, J = 2.2,8.8Hz), 8.38 (1H, m), 8.49 (1H, d, J = 8.1Hz), 8.58 (1H, s), 8.99 (1H, s), 9.64 (1H, s).
IR (KBr) cm-1: 3301,1640,1614,1545,1496,1312,910,853,745.
[0188]
Example 38
N- (2-aminophenyl) -4- [N- (furo [3,2-b] pyridin-2-yl) carbonylaminomethyl] benzamide (Table 1: Compound No. 233)
mp.191 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.58 (2H, d, J = 5.9Hz), 4.88 (2H, s), 6.57-6.62 (1H, m), 6.76-6.79 (1H, m), 6.93- 6.99 (1H, m), 7.15-7.25 (1H, m), 7.45-7.52 (3H, m), 7.74 (1H, s), 7.95 (2H, d, J = 8.1Hz), 8.13 (1H, d, J = 8.8Hz), 8.63 (1H, d, J = 3.7Hz), 9.54 (1H, t, J = 5.9Hz), 9.64 (1H, s).
IR (KBr) cm-1: 3406,1662,1529,1507.1420,1313,1209,1139,1170,1139,924,741.
[0189]
Example 39
N- (2-aminophenyl) -4- [N- (furo [2,3-c] pyridin-2-yl) carbonylaminomethyl] benzamide (Table 1: Compound No. 234)
mp.210 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.58 (2H, J = 6.6Hz), 4.87 (2H, s), 6.57-6.62 (1H, m), 6.76-6.79 (1H, m), 6.93-6.99 ( 1H, m), 7.14-7.17 (1H, m), 7.47 (2H, d, J = 8.1Hz), 7.66 (1H, s), 7.82 (1H, d, J = 4.4Hz), 7.96 (2H, d , J = 8.1Hz), 8.48 (1H, d, J = 5.1Hz), 9.06 (1H, s), 9.60-9.64 (2H, m).
IR (KBr) cm-1: 3320,1653,1632,1598,1457,1424,1308,1187,1033,853,749.
[0190]
Example 40
N- (2-hydroxyphenyl) -4- [N- [3- (pyridin-3-yl) propionyl] aminomethyl] benzamide (Table-1: Compound No. 125)
mp. (amorphous).
1H NMR (270MHz, CD3OD) δppm: 2.61 (2H, t, J = 7.3Hz), 3.00 (2H, t, J = 7.3Hz), 4.39 (2H, s), 7.04 (1H, ddd, J = 1.5, 8.1, 8.1Hz), 7.25 (2H, d, J = 8.1Hz), 7.33 (1H, dd, J = 5.1,8.1Hz), 7.69 (1H, d, J = 8.1Hz), 7.85 (2H, d, J = 8.1Hz), 7.86 (1H, d, J = 8.1Hz), 8.41 (2H, br.s).
IR (neat) cm-1: 3276,1645,1614,1536,1509,1435,1415,1385,1333,1280,1247,1091,737.
[0191]
Example 41
N- (2-hydroxyphenyl) -4- [N- (pyridin-3-yl) oxyacetylaminomethyl] benzamide (Table-1: Compound No. 93)
mp. (amorphous).
1H-NMR (270 MHz, DMSO-d6): 4.43 (2H, d, J = 6.6 Hz), 4.69 (2H, s), 6.83 (1H, t, J = 6.6 Hz), 6.91 (1H, d, J = 8.1Hz), 7.68 (1H, d, J = 6.6Hz), 7.82 (2H, d, J = 8.1Hz), 8.21 (1H, d, J = 4.4Hz), 8.35 (1H, d, J = 2.2Hz) ), 8.81 (1H, t, J = 6.6Hz), 9.48 (1H, s), 9.75 (1H, s).
IR (KBr) cm-1: 3399, 1664, 1535, 1236, 1064.
[0192]
Example 42
N- (2-hydroxyphenyl) -4- [N- (pyridin-3-yl) acetylaminomethyl] benzamide (Table-1: Compound No. 117)
mp. 201-202 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 3.56 (2H, s), 4.37 (2H, d, J = 5.9Hz), 6.83 (1H, ddd, J = 1.5,8.1,8.1Hz), 6.92 (1H, br.d, J = 8.1Hz), 7.03 (1H, ddd, J = 1.5,8.1,8.1Hz), 7.34 (1H, dd, J = 3.7,8.1Hz), 7.37 (2H, d, J = 8.1Hz) ), 7.70 (2H, d, J = 8.1Hz), 7.91 (2H, d, J = 8.1Hz), 8.45 (1H, br.d, J = 3.7Hz), 8.49 (1H, s), 8.73 (1H , t, J = 5.9Hz), 9.47 (1H, s), 9.73 (1H, br.s).
IR (KBr) cm-1: 3272, 3067, 1661, 1647, 1598, 1536, 1455, 1334, 1288, 1194, 1024, 742.
[0193]
Example 43
N- (2-aminophenyl) -4- [N- (pyridin-3-yl) oxyacetyl-N- [3- (pyridin-3-yl) propyl] aminomethyl] benzamide (Table-1: Compound No. 91 )
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 1.77-1.93 (2H, m), 2.50-2.63 (2H, m), 3.16-3.30 (2H, m), 4.63 (1.2H, s), 4.71 (0.8H , s), 4.88 (1.2H, s), 4.95 (0.8H, s), 5.05 (2H, s), 6.57-6.63 (1H, m), 6.77-6.79 (1H, m), 6.94-7.00 (1H , m), 7.11-7.42 (5H, m), 7.58-7.64 (1H, m), 7.92-8.02 (2H, m), 8.15-8.43 (5H, m), 9.65 (0.6H, s), 9.69 ( 0.4H, s). (Mixture of rotamers)
[0194]
Example 44
N- (2-aminophenyl) -4- [N-methyl-N- (pyridin-3-yl) oxyacetyl] aminomethylbenzamide (Table-1: Compound No. 92)
mp. 117-120 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 2.84 and 2.99 (total 3H, s), 4.60 and 4.69 (total 2H, s), 4.90 (2H, br.s), 4.99 and 5.08 (total 2H, s), 6.60 (1H, dd, J = 7.3,8.1Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,7.3Hz), 7.16 (1H, d, J = 7.3Hz) ), 7.30-7.43 (4H, m), 7.95 and 8.01 (total 2H, d, J = 8.1Hz), 8.17 (1H, d, J = 4.4Hz), 8.31 (1H, d, J = 2.9Hz), 9.65 and 9.68 (total 1H, br.s). (Mixture of rotamers)
IR (KBr) cm-1: 3298,1665,1501,1425,1310,1276,1254,1078,799,746,703.
[0195]
Example 45
Synthesis of N- (2-aminophenyl) -4- [N- (pyridin-3-yl) oxamoylaminomethyl] benzamide (Table-1: Compound No. 95)
(45-1) 388 mg (2 mmol) of N- (pyridin-3-yl) oxamic acid ethyl ester and 638 mg (2 mmol) of the compound obtained in Step (1-4) of Example 1 were dissolved in ethanol. The mixture was heated and stirred at 50 ° C. for 2.5 hours. The precipitated crystals were collected by filtration and washed with 2 ml of ethanol and 3 ml of ethyl ether. The obtained crystals were dried and N- [2- (N-tert-butoxycarbonyl) aminophenyl] -4- [N- (pyridin-3-yl) oxamoylaminomethyl] benzamide 724 mg (yield 74%) Got.
1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 4.49 (2H, d, J = 5.9Hz), 7.10-7.30 (2H, m), 7.35-7.57 (5H, m), 7.93 ( 2H, d, J = 8.1Hz), 8.21 (1H, br.d, J = 5.1Hz), 8.35 (1H, dd, J = 1.5,5.1Hz), 8.68 (1H, br.s), 9.00 (1H , d, J = 2.9Hz), 9.70 (1H, t, J = 5.9Hz), 9.82 (1H, s), 10.98 (1H, br.s).
[0196]
(45-2) 720 mg of the compound of the step (45-1) was suspended in 8 ml of methanol, and 8 ml of 4N hydrochloric acid-dioxane solution was added. The mixture was stirred for 3 hours and poured into a dilute aqueous sodium hydroxide solution to make it alkaline, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from THF / methanol = 1/1 to obtain 280 mg of the desired product.
mp. 254-258 ℃ (dec.)
1H NMR (270MHz, DMSO-d6) δppm: 4.67 (2H, d, J = 5.9Hz), 4.89 (2H, br.s), 6.59 (1H, dd, J = 7.3Hz), 6.77 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.16 (1H, d, J = 8.1Hz), 7.38-7.44 (1H, m), 7.43 (2H, d, J = 8.1 Hz), 7.95 (2H, d, J = 8.1Hz), 8.18-8.24 (1H, m), 8.34 (1H, dd, J = 1.5,4.4Hz), 9.00 (1H, d, J = 2.1Hz), 9.63 (1H, s), 9.69 (1H, br.t, J = 6.6Hz), 10.97 (1H, br.s).
IR (KBr, cm-1): 3312,3270,1663,1636,1521,1312,1296,1019
[0197]
Example 46
Synthesis of N- (2-aminophenyl) -4- [N- (pyridin-3-yl) oxyacetylaminomethyl] benzamide (Table-1: Compound No. 61)
(46-1) Sodium hydride (60% oil suspension) 0.22 g (5.5 mmol) in DMF (2 ml) suspension with 3-hydroxypyridine 0.48 g (5.0 mmol) in DMF (2 ml) The solution was added dropwise at room temperature and stirred for 1 hour. The obtained brown solution was ice-cooled, 0.81 ml (5.5 mmol) of bromoacetic acid tert-butyl ester was added, and the mixture was stirred for 1 hour under ice-cooling and at room temperature for 2 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 5: 1) to give 3-pyridyloxyacetic acid tert- 0.34 g (yield 32.5%) of butyl ester was obtained as a colorless oil.
1H NMR (270MHz, CDCl3) δppm: 1.49 (9H, s), 4.56 (2H, s), 7.18-7.24 (2H, m), 8.26 (1H, dd, J = 1.5,3.6Hz), 8.32 (1H, d, J = 2.9Hz).
[0198]
(46-2) 2 ml of trifluoroacetic acid was added to a solution of 0.14 g (0.67 mmol) of the compound of step (46-1) in dichloromethane (2 ml), and the mixture was stirred at room temperature for 3 hours. After distilling off the solvent, diisopropyl ether was added, and the precipitated solid was collected by filtration and dried to obtain 0.15 g (yield 83.8%) of 3-pyridyloxyacetic acid trifluoroacetate as a pale yellow solid. It was.
1H NMR (270MHz, DMSO-d6) δppm: 4.86 (2H, s), 7.57 (1H, dd, J = 4.4,8.1Hz), 7.67 (1H, ddd, J = 1.5,1.5,8.8Hz), 8.31 ( 1H, d, J = 5.1Hz), 8.46 (1H, d, J = 2.1Hz), 13.00 (1H, br.s).
[0199]
(46-3) To a suspension of 100 mg (0.37 mmol) of the compound of step (46-2) and 255 mg (0.75 mmol) of the compound obtained in step (1-4) of Example 1 in dichloromethane (5 ml) Triethylamine 0.14 ml (1.0 mmol) was added, and the mixture was ice-cooled. Under ice cooling, a solution of 140 mg (0.83 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride in dichloromethane (6 ml) was added, stirred for 7 hours while warming to room temperature, and then allowed to stand overnight at room temperature. Water and saturated brine were added, and the mixture was extracted with chloroform.
[0200]
The organic layer was washed with saturated brine, dried, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give N- [2- (N There was obtained 0.37 g (quantitative) of -tert-butoxycarbonyl) aminophenyl] -4- [N- (pyridin-3-yl) oxyacetylaminomethyl] benzamide as a colorless oil.
mp. 154-155 ℃
1H NMR (270MHz, CDCl3) δppm: 1.52 (9H, s), 4.62 (2H, s), 4.63 (2H, d, J = 7.3Hz), 6.76 (1H, br.s), 6.90-7.00 (1H, br.s), 7.15-7.35 (5H, m), 7.40 (2H, d, J = 8.1Hz), 7.82 (1H, d, J = 8.1Hz), 7.95 (2H, d, J = 8.1Hz), 8.32 (1H, dd, J = 2.1,4.4Hz), 8.37 (1H, d, J = 2.8Hz), 9.20 (1H, br.s).
[0201]
(46-4) 4N Hydrochloric acid-dioxane (2 ml) was added to a solution of 175 mg (0.37 mmol) of the compound of step (46-3) in dioxane (2 ml) -methanol (2 ml), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, the solvent was distilled off, methanol and diisopropyl ether were added to the resulting residue, and the precipitated solid was collected by filtration and dried to give N- (2-aminophenyl). 90 mg (yield 64.6%) of -4- [N- (pyridin-3-yl) oxyacetylaminomethyl] benzamide was obtained as a milky white solid.
1H NMR (270MHz, DMSO-d6) δppm: 4.42 (2H, d, J = 5.9Hz), 4.69 (2H, s), 4.89 (2H, br.s), 6.59 (1H, dd, J = 7.3,8.1 Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.16 (1H, d, J = 7.3Hz), 7.33-7.39 (4H, m), 7.92 (2H, d, J = 8.1Hz), 8.21 (1H, dd, J = 1.5,4.4Hz), 8.35 (1H, d, J = 2.9Hz), 8.80 (1H, br.t, J = 5.9Hz ), 9.63 (1H, br.s).
IR (KBr) cm-1: 3307,1672,1631,1523,1456,1429,1269,1231,803,756.
[0202]
Example 47
Synthesis of N- (2-aminophenyl) -4- [N- [2- (pyridin-3-yl) oxy] propionylaminomethyl] benzamide (Table-4: Compound No. 3)
[0203]
(47-1) A suspension of 1.20 g (30.0 mmol) of sodium hydride (60% oil suspension) in dry DMF (10 ml) was added to 2.85 g (30 mmol) of dry DMF (3-mmol) at room temperature. 10 ml) The solution was added dropwise while keeping the temperature to 40 ° C. or lower, and then stirred at room temperature for 90 minutes. A solution of 6.28 g (30 mmol) of 2-bromopropionic acid tert-butyl ester in dry DMF (10 ml) was gradually added dropwise while maintaining the internal temperature at 5 to 10 ° C. under ice cooling, and then the temperature was raised to room temperature for 4 hours. Stir. Saturated aqueous sodium hydrogen carbonate was added for neutralization, followed by extraction with ethyl acetate. The organic layer is washed with water and saturated brine, dried and evaporated to give a residue, which is purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give 2- (pyridine -3-yl) oxypropionic acid tert-butyl ester 4.15 g (62% yield) was obtained as a brown oil.
1H-NMR (270MHz, CDCl3) δppm: 1.44 (9H, s), 1.61 (3H, d, J = 7.3Hz), 4.66 (1H, q, J = 7.3Hz), 7.13-7.23 (2H, m) 8.24 (1H, dd, J = 1.5,4.4Hz), 8.29 (1H, d, J = 2.1Hz).
[0204]
(47-2) Trifluoroacetic acid (9 ml) was added to a solution of 1.65 g (7.4 mmol) of the compound obtained in step (47-1) in dichloromethane (9 ml) while maintaining the temperature at 30 ° C. or lower, and then at room temperature. Stir for 8 hours. After distilling off the solvent, diisopropyl ether was added, and the precipitated solid was collected by filtration and dried to give 1.86 g of 2- (pyridin-3-yl) oxypropionic acid trifluoroacetate (yield 43.5%). Was obtained as a light brown solid.
1H-NMR (270MHz, DMSO-d6) δppm: 1.53 (3H, d, J = 6.6Hz), 5.12 (1H, q, J = 6.6Hz), 7.60-7.75 (2H, m), 8.35 (1H, d , J = 5.1Hz), 8.47 (1H, s), 12.9 (1H, br.s).
[0205]
(47-3) 0.98 g (3.5 mmol) of the compound obtained in the step (47-2) and 1.02 g (3.0 mmol) of the compound obtained in the step (1-4) of Example 1 were mixed with dichloromethane (20 ml). Then, 1.3 ml (9.0 mmol) of triethylamine was added and the mixture was ice-cooled. Under ice cooling, a solution of 0.59 g (3.5 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride in dichloromethane (5 ml) was added dropwise, and the mixture was further stirred for 2 hours. Saturated aqueous sodium bicarbonate was added for neutralization, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and evaporated to give a residue, which was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give N- [2- (N-tert- 1.64 g of butoxycarbonylamino) phenyl] -4- [N- [2- (pyridin-3-yl) oxypropionyl] aminomethyl] benzamide were obtained as a mixture with 1,3-dimethyl-2-imidazolinone.
1H-NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 1.64 (3H, d, J = 7.3Hz), 4.54 (2H, m), 4.78 (1H, q, J = 6.6Hz), 6.87 ( 2H, br.s), 7.13-7.30 (6H, m), 7.81 (1H, d, J = 7.3Hz), 7.90 (2H, d, J = 8.1Hz), 8.29 (1H, dd, J = 1.5, 4.4Hz), 8.33 (1H, d, J = 2.1Hz), 9.22 (1H, br.s).
[0206]
(47-4) 1.64 g of the compound obtained in the step (47-3) was dissolved in dioxane (10 ml) -methanol (4 ml). A 4N hydrochloric acid-dioxane solution (10 ml) was added at room temperature, and the mixture was stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate was added for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, evaporated to the residue, methanol and diisopropyl ether were added, and the precipitated solid was collected by filtration and dried to give N- (2-aminophenyl) -4. There was obtained 0.71 g (60.5% yield at 2 steps) of-[N- [2- (pyridin-3-yl) oxy] propionylaminomethyl] benzamide as a white solid.
[0207]
mp. 171-173 ° C (dec.).
1H-NMR (270MHz, DMSO-d6) δppm: 1.51 (3H, d, J = 6.6Hz), 4.36 (2H, d, J = 5.9Hz), 4.89 (2H, br.s), 4.90 (1H, t , J = 6.6Hz), 6.60 (1H, dd, J = 6.6,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.15 (1H , d, J = 7.3Hz), 7.27 (2H, d, J = 8.1Hz), 7.33-7.37 (2H, m), 7.89 (2H, d, J = 8.1Hz), 8.21 (1H, dd, J = 2.9, 2.9Hz), 8.32 (1H, d, J = 1.5Hz), 8.82 (1H, t, J = 5.9Hz), 9.63 (1H, br.s).
[0208]
Example 48
Synthesis of N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 82)
(48-1) 384 mg (3.52 mmol) of 3-pyridinemethanol was dissolved in 5 ml of dry THF, and 523 mg (3.22 mmol) of N, N′-carbonyldiimidazole was added at room temperature. After stirring for 1 hour, 6 ml of a dry THF solution of 1.0 g (2.93 mmol) of the compound of Step (1-4) of Example 1 was added.
[0209]
After standing overnight at room temperature, 100 ml of chloroform was added, and the mixture was washed 3 times with 20 ml of water. Then, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1), and N- [2- (N-tert-butoxycarbonyl) aminophenyl] -4- [N- (pyridine-3) -Yl) methoxycarbonylaminomethyl] benzamide 1.27 g was obtained as an amorphous solid (quantitative).
1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 4.45 (2H, d, J = 5.9Hz), 5.16 (1H, s), 7.10-7.50 (7H, m), 7.70 (1H, d, J = 8.1Hz), 7.80 (1H, d, J = 7.3Hz), 7.93 (1H, d, J = 8.1Hz), 8.57 (1H, d, J = 4.4Hz), 8.63 (1H, s), 9.17 (1H, s).
[0210]
(48-2) 1.2 g (2.8 mmol) of the compound of the step (48-1) was dissolved in 10 ml of methanol. 20 ml of 4N hydrochloric acid-dioxane solution was added and stirred at room temperature for 1.5 hours. After pouring into dilute aqueous sodium hydroxide solution, extraction was performed 3 times with 60 ml of chloroform. The extract was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain 0.88 g of crystals. Subsequently, recrystallization was performed with 16 ml of ethanol to obtain 668 mg (yield 73%) of N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide.
[0211]
mp. 159-160 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 5.9Hz), 4.86 (2H, s), 5.10 (2H, s), 6.60 (1H, t, J = 7.3Hz), 6.78 (1H, d, J = 7Hz), 6.97 (1H, t, J = 7Hz), 7.17 (1H, d, J = 8Hz), 7.30-7.50 (3H, m), 7.78 (1H, d, J = 8Hz ), 7.93 (2H, d, J = 8Hz), 8.53 (1H, d, J = 3.7Hz), 8.59 (1H, s), 9.61 (1H, s).
IR (KBr) cm-1: 3295, 1648, 1541, 1508, 1457, 1309, 1183, 742. The compounds of Example 49 to Example 87 were synthesized in the same manner as in Example 48. The measured values of the melting point (mp.), 1H NMR and IR of the compound are shown below.
[0212]
Example 49
N- (2-aminophenyl) -4- [N- (benzyloxycarbonyl) aminomethyl] benzamide (Table-1: Compound No. 11)
mp. 174-178 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 5.9Hz), 4.89 (2H, br.s), 5.06 (2H, s), 6.59 (1H, dd, J = 7.3,8.1 Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J = 7.3Hz), 7.30-7.40 (6H, m), 7.93 (3H, m), 9.63 (1H, s).
IR (KBr) cm-1: 3332,1687,1652,1536,1456,1279,747.
[0213]
Example 50
N- (2-aminophenyl) -4- [N- (4- (imidazol-1-yl) benzyl) oxycarbonylaminomethyl] benzamide (Table 1: Compound No. 47)
mp. 195-198 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.29 (2H, d, J = 6.6Hz), 4.88 (2H, s), 5.10 (2H, s), 6.60-6.63 (1H, m), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, t, J = 7.3Hz), 7.11 (1H, s), 7.16 (1H, d, J = 7.3Hz), 7.37 (2H, d, J = 8.1Hz) , 7.49 (2H, d, J = 8.8Hz), 7.66 (2H, d, J = 8.1Hz), 7.74 (1H, s), 7.92-7.96 (3H, m), 8.25 (1H, s), 9.62 ( 1H, s).
[0214]
Example 51
N- (2-aminophenyl) -4- [N- (pyridin-2-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 171)
mp. 166-167 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.30 (2H, d, J = 5.9Hz), 4.88 (2H, br.s), 5.12 (2H, s), 6.60 (1H, dd, J = 7.3,8.1 Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.16 (1H, d, J = 7.3Hz), 7.33 (1H, dd, J = 3.7,7.3Hz), 7.40 (3H, d, J = 8.1Hz), 7.83 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.03 (1H , t, J = 5.9Hz), 8.55 (1H, d, J = 5.1Hz), 9.62 (1H, br.s).
IR (KBr) cm-1: 3334,1694,1632,1580,1276,755.
[0215]
Example 52
N- (2-aminophenyl) -4- [N- [2- (pyridin-2-yl) ethoxycarbonyl] aminomethyl] benzamide (Table-1: Compound No. 172)
mp. 146-148 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 3.04 (2H, t, J = 6.6Hz), 4.23 (2H, d, J = 5.9Hz), 4.36 (2H, t, J = 6.6Hz), 4.88 (2H , br.s), 6.60 (1H, dd, J = 7.3,8.1Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.15-7.30 ( 3H, m), 7.34 (2H, d, J = 8.1Hz), 7.69-7.77 (2H, m), 7.92 (2H, d, J = 7.3Hz), 8.50 (1H, d, J = 4.4Hz), 9.62 (1H, br.s).
IR (KBr) cm-1: 3330,1690,1633,1594,1524,1277,760.
[0216]
Example 53
N- (2-aminophenyl) -4- [N- (6-methylpyridin-2-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 179)
mp.138 ° C.
1H NMR (270 MHz, DMSO-d6) δ ppm: 2.47 (3H, s), 4.30 (2H, d, J = 5.9 Hz), 5.07 (4H, s), 6.63 (1H, t, J = 8.1 Hz), 6.80 (1H, d, J = 7.34), 6.98 (1H, t, J = 8.1Hz), 7.18 (3H, d, J = 7.3Hz), 7.40 (2H, d, J = 8.1Hz), 7.71 (1H, t, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.03 (1H, t, J = 5.9Hz), 9.66 (1H, s).
IR (KBr) cm-1: 3335,1693,1634,1259.
[0217]
Example 54
N- (2-aminophenyl) -4- [N- [2- (pyridin-3-yl) ethoxycarbonyl] aminomethyl] benzamide (Table-1: Compound No. 83)
mp. 120-125 ℃.
1H NMR (270 MHz, DMSO-d6) δ ppm: 2.91 (2H, t, J = 6.6 Hz), 4.22 (4H, t, J = 6.6 Hz), 4.89 (2H, s), 6.55-6.63 (1H, m) , 6.78 (1H, dd, J = 8.1,1.5Hz), 6.97 (1H, t, J = 6.6Hz), 7.17 (1H, d, J = 6.6Hz), 7.33 (3H, d, J = 8.1Hz) , 7.69 (1H, d, J = 8.1Hz), 7.79 (1H, t, J = 6.6Hz), 7.93 (2H, d, J = 8.0Hz), 8.43-8.49 (2H, m), 9.62 (1H, s).
IR (KBr) cm-1: 3234,1705,1655,1260.
[0218]
Example 55
N- (2-aminophenyl) -4- [N- [3- (pyridin-3-yl) propyloxycarbonyl] aminomethyl] benzamide (Table 1: Compound No. 84) mp. 121-124 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 1.83-1.94 (2H, m), 2.67 (2H, t, J = 7.3Hz), 3.98 (2H, t, J = 6.6Hz), 4.26 (2H, d, J = 5.9Hz), 4.89 (2H, br.s), 6.60 (1H, dd, J = 8.1,8.1Hz), 6.78 (1H, d, J = 7.3Hz), 6.97 (1H, ddd, J = 1.5 , 7.3,8.1Hz), 7.16 (1H, d, J = 8.1Hz), 7.29-7.33 (1H, m), 7.37 (1H, d, J = 8.1Hz), 7.64 (1H, d, J = 8.1Hz) ), 7.81 (1H, dd, J = 5.9,6.6Hz), 7.94 (2H, d, J = 8.1Hz), 8.40-8.44 (2H, m), 9.63 (1H, br.s).
IR (KBr) cm-1: 3348,1696,1635,1523,1458,1302,1272,1141,1019,754,713.
[0219]
Example 56
N- (2-aminophenyl) -4- [N- (2-methylpyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 142)
mp. 164-165 ° C.
1H NMR (270 MHz, DMSO-d6) δ ppm: 2.49 (3H, s), 4.28 (2H, d, J = 6.6 Hz), 4.89 (2H, s), 5.10 (2H, s), 6.60 (1H, t, J = 6.6Hz), 6.78 (1H, d, J = 8.1Hz), 6.90 (1H, t, J = 7.3Hz), 7.17 (1H, d, J = 7.3Hz), 7.21-7.26 (1H, m) , 7.37 (2H, d, J = 8.1Hz), 7.68 (1H, d, J = 6.6Hz), 7.92-8.00 (3H, m), 8.39 (1H, d, J = 4.4Hz), 9.62 (1H, s).
IR (KBr) cm-1: 3332, 1719, 1630, 1260.
[0220]
Example 57
N- (2-aminophenyl) -4- [N- (6-methylpyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 144)
mp. 164-165 ° C.
1H NMR (270 MHz, DMSO-d6) δ ppm: 2.46 (3H, s), 4.27 (2H, d, J = 6.6 Hz), 4.88 (2H, s), 5.05 (2H, s), 6.59 (1H, dt, J = 1.5,8.1Hz), 6.78 (1H, dd, J = 8.1,1.5Hz), 6.97 (1H, dt, J = 1.5,7.3Hz), 7.17 (1H, d, J = 7.3Hz), 7.26 ( 1H d, J = 8.1Hz), 7.36 (2H, d, J = 8.1Hz), 7.67 (1H, dd, J = 8.1,2.2Hz), 7.93 (3H, d, J = 8.1Hz), 8.45 (1H , d, J = 1.5Hz), 9.62 (1H, s).
IR (KBr) cm-1: 3293,1701,1632,1260.
[0221]
Example 58
N- (2-aminophenyl) -4- [N- (2-chloropyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 155)
mp. (amorphous).
1H NMR (270 MHz, DMSO-d6) δ ppm: 4.30 (2H, d, J = 5.9 Hz), 5.00 (2H, s), 5.13 (2H, s), 6.61 (1H, t, J = 7.3 Hz), 6.79 (1H, dd, J = 8.1,1.5Hz), 6.98 (1H, dt, J = 1.5,7.3Hz), 7.17 (1H, d, J = 6.6Hz), 7.39 (2H, d, J = 8.8Hz) , 7.47-7.52 (1H, m), 7.91-7.96 (3H, m), 8.08 (1H, t, J = 5.9Hz), 8.40 (1H, dd, J = 4.4,1.5Hz), 9.64 (1H, s ).
IR (KBr) cm-1: 3340,1702,1632,1273.
[0222]
Example 59
N- (2-aminophenyl) -4- [N- (6-chloropyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 157)
mp. 180-185 ℃.
1H NMR (270MHz, DMSO-d6) δppm: 4.24 (2H, d, J = 5.9Hz), 4.89 (2H, br.s), 5.10 (2H, s), 6.60 (1H, t, J = 7.3Hz) , 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dt, J = 1.5,8.1Hz), 7.16 (1H, d, J = 6.6Hz), 7.37 (2H, d, J = 8.1Hz) , 7.56 (1H, d, J = 8.1Hz), 7.85-8.02 (4H, m), 8.44 (1H, d, J = 2.2Hz), 9.62 (1H, s).
IR (KBr) cm-1: 3346,3282,1696,1533,1271.
[0223]
Example 60
N- (2-aminophenyl) -4- [N- (pyridin-4-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 181)
mp. 180-183 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.30 (2H, d, J = 6.6Hz), 4.89 (2H, s), 5.12 (2H, s), 6.60 (1H, dd, J = 7.3,7.3Hz) , 6.78 (1H, dd, J = 1.5,7.3Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.16 (1H, d, J = 7.3Hz), 7.34 (2H, d, J = 5.9Hz), 7.39 (2H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.09 (1H, t, J = 5.9Hz), 8.57 (1H, d), 9.64 ( 1H, br.s).
IR (KBr) cm-1: 3394,3290,1711,1645,1624,1535,1504,1321,1251,1138,1049,763.
[0224]
Example 61
N- (2-aminophenyl) -4- [N- [2- (thiophen-3-yl) ethoxycarbonyl] aminomethyl] benzamide (Table 1: Compound No. 203)
mp. (amorphous).
1H NMR (270 MHz, DMSO-d6) δ ppm: 2.90 (2H, t, J = 7.3 Hz), 4.17-4.26 (4H, m), 4.89 (2H, s), 6.60 (1H, t, J = 8.1 Hz) , 6.78 (1H, d, J = 6.6Hz), 6.97 (1H, t, J = 7.3Hz), 7.06 (1H, d, J = 5.1Hz), 7.17 (1H, d, J = 7.3Hz), 7.26 (1H, s), 7.36 (2H, d, J = 8.1Hz), 7.47 (1H, t, J = 2.2Hz), 7.81 (1H, t, J = 5.9Hz), 7.93 (2H, d, J = 8.1Hz), 9.63 (1H, s).
IR (KBr) cm-1: 3314,1716,1638,1252.
[0225]
Example 62
N- (2-aminophenyl) -4- [N- (3-phenyloxazol-5-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 211)
mp. 192-195 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.30 (2H, d, J = 5.9Hz), 4.89 (2H, s), 5.25 (2H, s), 6.60 (1H, t, J = 6.6Hz), 6.68 (1H, d, J = 8.1Hz), 6.94 (1H, t, J = 7.3Hz), 7.09 (1H, s), 7.16 (1H, d, J = 7.3Hz), 7.39 (2H, d, J = 8.1Hz), 7.51 (4H, d, J = 2.2Hz), 7.87-7.96 (5H, m), 8.12 (1H, t, J = 5.9Hz), 9.63 (1H, s).
IR (KBr) cm-1: 3292,1718,1630,1262.
[0226]
Example 63
N- (2-aminophenyl) -4- [N- (thiazol-5-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 216)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 5.9Hz), 4.91 (2H, br.s), 5.30 (2H, s), 6.60 (1H, dd, J = 7.3,7.3 Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J = 7.3Hz), 7.36 (2H, d, J = 8.1 Hz), 7.91-8.00 (4H, m), 9.09 (1H, s), 9.63 (1H, s).
IR (KBr) cm-1: 3346 (br.), 1697, 1636, 1525, 1456, 1271, 873, 753.
[0227]
Example 64
N- (2-aminophenyl) -4- [N- [2- (4-methylthiazol-5-yl) ethoxycarbonyl] aminomethyl] benzamide (Table-1: Compound No. 217)
mp. 130-133 ° C.
1H NMR (270 MHz, DMSO-d6) δ ppm: 2.32 (3H, s), 3.07 (2H, t, J = 5.9 Hz), 4.15 (2H, t, J = 5.9 Hz), 4.25 (2H, d, J = 6.6Hz), 4.89 (2H, s), 6.60 (1H, t, J = 5.9Hz), 6.78 (1H, dd, J = 7.3,1.5Hz), 6.97 (1H, dt, J = 1.5,7.3Hz) , 7.16 (1H, d, J = 8.1Hz), 7.35 (2H, d, J = 8.1Hz), 7.83 (1H, t, J = 5.9Hz), 7.94 (2H, d, J = 8.1Hz), 8.85 (1H, s), 9.62 (1H, s).
IR (KBr) cm-1: 3350, 1691, 1635, 1270.
[0228]
Example 65
N- (2-aminophenyl) -4- [N- (1-methylpiperidin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 225)
mp. 130-135 ℃.
1H NMR (270MHz, DMSO-d6) δppm: 1.49-1.78 (3H, m), 1.83-2.01 (3H, m), 2.30 (3H, s), 2.85 (2H, s), 3.74-3.94 (2H, m ), 4.25 (2H, d, J = 5.8Hz), 6.55-6.62 (3H, m), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, t, J = 7.3Hz), 7.16 (1H , d, J = 8.1Hz), 7.37 (2H, d, J = 8.1Hz), 7.79 (1H, t, J = 6.6Hz), 7.93 (2H, d, J = 8.0Hz), 9.66 (1H, s ).
IR (KBr) cm-1: 3323,2722,1702,1648,1263.
[0229]
Example 66
N- (2-aminophenyl) -4- [N- (4-methylpiperazin-1-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 227)
mp. (amorphous).
1H NMR (270 MHz, DMSO-d6) δ ppm: 1.73 (2H, t, J = 6.6 Hz), 2.36-2.63 (13H, m), 4.00 (2H, t, J = 6.6 Hz), 4.30 (2H, d, J = 5.8Hz), 6.55-6.63 (4H, m), 6.78 (1H, d, J = 6.6Hz), 6.97 (1H, t, J = 7.3Hz), 7.16 (1H, d, J = 7.3Hz) , 7.37 (2H, d, J = 8.7Hz), 7.73 (1H, t, J = 5.9Hz), 7.94 (2H, d, J = 8.0Hz), 9.66 (1H, s).
IR (KBr) cm-1: 3341,2706,1701,1262.
[0230]
Example 67
N- (2-aminophenyl) -4- [N- (tetrahydrofuran-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 221)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 1.50-1.60 (1H, m), 1.88-2.00 (1H, m), 2.44-2.54 (1H, m), 3.41-3.47 (1H, m), 3.56-3.77 (3H, m), 3.85-4.04 (2H, m), 4.25 (2H, d, J = 5.9Hz), 4.89 (2H, s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 ( 1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.17 (1H, d, J = 8.1Hz), 7.37 (2H, d, J = 8.1Hz), 7.81 ( 1H, t, J = 5.9Hz), 7.94 (2H, d, J = 8.1Hz), 9.62 (1H, br.s).
IR (KBr) cm-1: 3349,1695,1635,1523,1457,1259,754.
[0231]
Example 68
N- (2-aminophenyl) -4- [N- (phenoxycarbonyl) aminomethyl] benzamide (Table-1: Compound No. 12)
mp.174-175 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.36 (2H, d, J = 5.9Hz), 4.90 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.77 (1H, dd, J = 7.3,7.3Hz), 6.98 (1H, ddd, J = 1.5,7.3,7.3Hz), 7.05-7.24 (4H, m), 7.39-7.46 (4H, m), 7.97 (2H, d, J = 8.1Hz), 8.41 (1H, t, J = 5.9Hz), 9.65 (1H, br.s).
IR (KBr) cm-1: 3443,3362,3313,1732,1706,1636,1527,1493,1458,1305,1217,748.
[0232]
Example 69
N- (2-aminophenyl) -4- [N- (pyridin-3-yl) oxycarbonylaminomethyl] benzamide (Table-1: Compound No. 81)
mp.209 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.38 (2H, d, J = 6.6Hz), 4.90 (2H, br.s), 6.55-6.63 (1H, m), 6.78 (1H, d, J = 8.1 Hz), 7.00 (1H, dd, J = 7.3,7.3Hz), 7.17 (1H, d, J = 8.8Hz), 7.37-7.47 (3H, m), 7.64 (1H, d, J = 8.8Hz), 7.97 (2H, d, J = 8.1Hz), 8.43 (2H, d, J = 3.1Hz), 8.59 (1H, t, J = 5.9Hz), 9.66 (1H, br.s).
[0233]
Example 70
N- (2-amino-5-fluorophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 110)
mp. 160-162 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 6.6Hz), 4.81 (2H, s), 5.10 (2H, s), 6.70-6.90 (2H, m), 7.10-8.00 ( 8H, m), 8.53 (1H, d, J = 3.6Hz), 8.59 (1H, s), 9.61 (1H, s).
IR (KBr) cm-1: 3269, 1716, 1638, 1488, 1436, 1247, 1141, 1043, 744.
[0234]
Example 71
N- (2-aminophenyl) -4- [N- (2-aminophenyl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 51)
mp. 149-151 ℃ (dec.)
1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 5.9Hz), 4.88 (2H, s), 4.96 (2H, s), 5.06 (2H, s), 6.53 (1H, dd, J = 7.3,7.3Hz), 6.56-6.67 (2H, m), 6.78 (1H, dd, J = 1.5,8.1Hz), 6.93-7.12 (3H, m), 7.16 (1H, d, J = 6.6Hz ), 7.38 (2H, d, J = 8.1Hz), 7.86 (1H, t-like, J = 5.9Hz), 7.93 (2H, d, J = 8.1Hz), 9.61 (1H, s).
IR (KBr) cm-1: 3336,1685,1632,1527,1276,748.
[0235]
Example 72
N- (2-aminophenyl) -4- [N- (quinuclidin-3-yl) oxycarbonylaminomethyl] benzamide (Table-1: Compound No. 228)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 1.30-1.90 (4H, m), 1.90 (1H, br.s), 2.45-2.80 (6H, m), 3.04-3.13 (1H, m), 4.15 (2H , d, J = 5.9Hz), 4.55-4.60 (1H, m), 4.88 (2H, br.s), 6.60 (1H, ddd, J = 1.5,7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, ddd, J = 1.5,7.3,7.3Hz), 7.17 (1H, d, J = 6.6Hz), 7.37 (2H, d, J = 8.1Hz), 7.78 (1H, t , J = 5.9Hz), 7.94 (1H, d, J = 7.3Hz), 9.62 (1H, s).
IR (KBr) cm-1: 3328,2942,1700,1648,1504,1259,749.
[0236]
Example 73
N- (2-aminophenyl) -4- [N- (3-aminophenyl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 52)
mp. 149-153 ℃ (dec.)
1H NMR (270MHz, DMSO-d6) δppm: 4.27 (2H, d, J = 5.9Hz), 4.88 and 4.89 (total 4H, each br.s), 5.08 (2H, s), 6.47-6.63 (3H, m ), 6.78 (1H, d, J = 8.1Hz), 6.94-7.02 (2H, m), 7.15 (1H, dd, J = 7.3,8.8Hz), 7.37 (2H, d, J = 8.1Hz), 7.84 (1H, t, J = 5.9Hz), 7.93 (2H, d, J = 8.8Hz), 9.61 (1H, br.s).
IR (KBr) cm-1: 3367, 1682, 1632, 1523, 1457, 1261, 754.
[0237]
Example 74
N- (2-aminophenyl) -4- [N- (1-methylimidazol-5-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 218)
mp. 162-165 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 3.62 (3H, s), 4.27 (2H, d, J = 5.9Hz), 4.91 (2H, br.s), 5.05 (2H, s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.95-7.00 (2H, m), 7.16 (1H, d, J = 7.3Hz), 7.36 (2H, d, J = 8.1Hz), 7.63 (1H, s), 7.87-7.95 (3H, m), 9.64 (1H, br.s).
IR (KBr) cm-1: 3293,1688,1651,1534,1506,1259,1121,1043,748.
[0238]
Example 75
N- (2-amino-4-chlorophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 113)
mp. 167-170 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 5.9Hz), 5.10 (2H, s), 5.21 (2H, s), 6.72 (1H, dd, J = 2.2,8.1Hz) , 6.81 (1H, d, J = 2.2Hz), 7.16 (1H, d, J = 8.1Hz), 7.37 (2H, d, J = 8.1Hz), 7.78 (1H, d, J = 8.1Hz), 7.92 (2H, d, J = 8.1Hz), 8.53 (1H, d, J = 4.4Hz), 8.59 (1H, s), 9.60 (1H, s).
IR (KBr) cm-1: 3347,3062,2931,1653,1576,1505,1456,1428,1301,1232,1114,1070,1019.
[0239]
Example 76
N- (2-aminophenyl) -4- [N- (5-methoxypyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 161)
mp. 169-170 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 3.83 (3H, s), 4.29 (2H, d, J = 6.6Hz), 4.87 (2H, s), 5.09 (2H, s), 6.57-6.62 (1H, m), 6.76-6.79 (1H, m), 6.94-6.99 (1H, m), 7.14-7.18 (1H, m), 7.36-7.39 (3H, m), 7.91-7.99 (3H, m), 8.19- 8.30 (2H, m), 9.63 (1H, s).
IR (KBr) cm-1: 3330, 1694, 1633, 1524, 1457, 1298, 1269, 1045, 760.
[0240]
Example 77
N- (2-aminophenyl) -4- [N- (pyrazin-2-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 192)
mp. 182 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.30 (2H, d, J = 6.6Hz), 4.88 (2H, br.s), 5.20 (2H, s), 6.60 (1H, dd, J = 7.3,8.1 Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,8.1Hz), 7.16 (1H, d, J = 7.3Hz), 7.39 (2H, d, J = 8.8 Hz), 7.94 (2H, d, J = 8.8Hz), 8.08 (1H, t-like, J = 6.6Hz), 8.61 (1H, s), 8.65 (1H, s), 8.68 (1H, s), 9.63 (1H, s).
IR (KBr) cm-1: 3266, 1709, 1632, 1535, 1508, 1284, 1055, 1022, 744.
[0241]
Example 78
N- (2-amino-5-methoxyphenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 121)
mp.141-143 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 3.66 (3H, s), 4.29 (2H, d, J = 5.9Hz), 4.51 (2H, br.s), 5.10 (2H, s), 6.63 (1H, dd, J = 2.9,8.8Hz), 6.74 (1H, d, J = 8.8Hz), 6.91 (1H, d, J = 2.2Hz), 7.38 (2H, d, J = 8.8Hz), 7.41 (1H, s), 7.79 (1H, d, J = 8.1Hz), 7.92 (2H, d, J = 8.1Hz), 7.98 (1H, t, J = 5.9Hz), 8.54 (1H, d, J = 3.7Hz) , 8.60 (1H, s), 9.65 (1H, s).
[0242]
Example 79
N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methyl-N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 109)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 4.50 (2H, s), 4.56 (2H, s), 4.87 (2H, s), 5.21 (2H, s), 6.60 (1H, t, J = 7.7Hz) , 6.78 (1H, d, J = 7.3Hz), 6.97 (1H, d, J = 7.3Hz), 7.17 (1H, d, J = 7.3Hz), 7.20-7.50 (4H, m), 7.60-8.00 ( 4H, m), 8.40-8.60 (4H, m), 9.65 (1H, s).
IR (KBr) cm-1: 3268,1700,1504,1246,1120,940,714.
[0243]
Example 80
N- (2-aminophenyl) -4- [N- [3- (pyridin-3-yl) propyl] -N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 120 )
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 1.75-1.90 (2H, m), 2.48-2.62 (2H, m), 3.20-3.36 (2H, m), 4.55 (2H, s), 4.89 (2H, s ), 5.16 (2H, s), 6.57-6.63 (1H, m), 6.76-6.80 (1H, m), 6.94-6.99 (1H, m), 7.14-7.17 (1H, m), 7.32-7.74 (6H , m), 7.94 (2H, d, J = 8.1Hz), 8.30-8.65 (4H, m), 9.64 (1H, s).
[0244]
Example 81
N- (2-hydroxyphenyl) -4- [N- (pyridin-3-yl) methyl-N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table 1: Compound No. 115)
mp. (amorphous).
1H NMR (270 MHz, DMSO-d6): 4.52 (2H, s), 4.57 (2H, s), 5.20 (2H, s), 6.84 (1H, t, J = 6.6Hz), 6.93 (1H, d, J = 6.6Hz), 7.03 (1H, d, J = 7.3Hz), 7.37 (4H, m), 7.68 (2H, dd, J = 1.5,8.1Hz), 7.92 (2H, br.s), 8.53 (4H , m), 9.49 (1H, s), 9.77 (1H, br.s).
IR (KBr) cm-1: 3035,1698,1243,1118,754,640.
[0245]
Example 82
N- (2-hydroxyphenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 111)
mp.162-164 ° C.
1H NMR (270 MHz, DMSO-d6): 4.29 (1H, d, J = 5.9 Hz), 5.10 (2H, s), 6.83 (1H, t, J = 8.1 Hz), 6.92 (1H, d, J = 6.6 Hz), 7.07 (1H, t, J = 6.6Hz), 7.39 (2H, d, J = 8.8Hz), 7.43 (1H, d, J = 5.1Hz), 7.68 (2H, d, J = 8.1Hz) , 7.80 (1H, d, J = 8.1Hz), 7.92 (2H, d, J = 8.1Hz), 7.99 (1H, t, J = 5.9Hz), 8.54 (1H, d, J = 4.4Hz), 8.60 (1H, s), 9.49 (1H, s), 9.76 (1H, br.s).
IR (KBr) cm-1: 3333,3259,1694,1645,1529,1267,720.
[0246]
Example 83
N- (2,4-dihydroxyphenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 116)
mp. (amorphous)
1H NMR (270 MHz, DMSO-d6): 4.27 (2H, d, J = 6.6 Hz), 5.10 (2H, s), 6.20 (2H, dd, J = 2.2,8.1 Hz), 6.39 (2H, d, J = 2.9Hz), 6.88 (2H, d, J = 8.8Hz), 7.33 (1H, d, J = 8.1Hz), 7.41 (1H, dd, J = 5.1,7.1Hz), 7.89 (1H, d, J = 8.8Hz), 7.98 (1H, t, J = 6.6Hz), 8.05 (2H, s), 8.52 (1H, m), 8.59 (1H, s), 9.30 (2H, br.s).
IR (KBr) cm-1: 3387,1702,1612,1311,1169,845.
[0247]
Example 84
N- (2-hydroxy-5-methylphenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 118)
mp. 155-155.5 ° C.
1H NMR (270MHz, DMSO-d6): 2.22 (3H, s), 4.29 (2H, d, J = 5.8Hz), 5.11 (2H, s), 6.82 (2H, m), 7.39 (2H, d, J = 8.8Hz), 7.42 (2H, m), 7.51 (1H, s), 7.79 (1H, d, J = 8.1Hz), 7.92 (1H, d, J = 8.1Hz), 7.98 (1H, t, J = 5.9Hz), 8.54 (1H, d, J = 4.4Hz), 8.60 (1H, s), 9.48 (2H, d, J = 8.1Hz).
IR (KBr) cm-1: 3306,1723,1655,1525,801,639.
[0248]
Example 85
N- (2-hydroxy-5-methoxyphenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide (Table-1: Compound No. 119)
mp. 175-176 ° C.
1H NMR (270 MHz, DMSO-d6): 3.69 (3H, s), 4.29 (2H, d, J = 5.9 Hz), 5.10 (2H, s), 6.63 (1H, dd, J = 2.9, 8.7 Hz), 6.84 (1H, d, J = 8.8Hz), 7.41 (4H, m), 7.79 (1H, d, J = 8.1Hz), 7.91 (1H, d, J = 8.1Hz), 7.99 (1H, t, J = 5.9Hz), 8.54 (1H, d, J = 5.1Hz), 8.60 (1H, s), 9.31 (1H, s), 9.45 (1H, s).
IR (KBr) cm-1: 3305, 1687, 1573, 1262, 1039, 868.
[0249]
Example 86
N- (2-aminophenyl) -4- [N- [2- (pyridin-3-yl) ethoxycarbonyl] amino] benzamide (Table-1: Compound No. 124)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 3.00 (2H, t, J = 6.6H), 4.37 (2H, t, J = 6.6Hz), 4.87 (2H, br.s), 6.60 (1H, t, J = 7.3Hz), 6.97 (1H, t, J = 7.3Hz), 7.15 (1H, d, J = 7.3Hz), 7.36 (1H, dd, J = 4.4,8.1Hz), 7.56 (2H, d, J = 8.8Hz), 7.92 (2H, d, J = 8.8Hz), 8.46 (1H, d, J = 4.4Hz), 8.54 (1H, d, J = 2.2Hz), 9.95 (1H, s).
IR (KBr) cm-1: 3285, 1695, 1519, 1315, 1233, 1079.
[0250]
Example 87
N- (2-aminophenyl) -5-[(pyridin-3-yl) methoxycarbonyl] aminobenzofuran-2-carboxamide (Table-3: Compound No. 2)
mp.173-174 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 5.22 (2H, s), 6.60 (1H, dd, J = 8.1,8.1Hz), 6.79 (1H, dd, J = 1.5,8.1Hz), 7.00 (1H, dd, J = 8.1,8.1Hz), 7.20 (1H, dd, J = 1.5,8.1Hz), 7.44 (1H, m), 7.48 (1H, dd, J = 1.5,8.8Hz), 7.61 (1H, d , J = 8.8Hz), 7.67 (1H, s), 7.88 (1H, dd, J = 1.5,8.1Hz), 7.96 (1H, d, J = 1.5Hz), 8.56 (1H, dd, J = 1.5, 4.8Hz), 8.68 (1H, d, J = 1.5Hz), 9.83 (1H, s), 9.91 (1H, s).
IR (KBr) cm-1: 3308,1707,1667,1584,1536,1452,1316,1248,1157,1128,1070,955,879,795,748,710.
[0251]
Example 88
Synthesis of N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxythiocarbonylaminomethyl] benzamide (Table-1: Compound No. 86)
(88-1) 20 mg (0.18 mmol) of 3-pyridinemethanol was dissolved in 5 ml of dry THF, and 30 mg (0.16 mmol) of N, N′-thiocarbonyldiimidazole was added at room temperature. After stirring overnight, 50 mg (0.14 mmol) of the compound of step (1-4) of Example 1 was added.
[0252]
After standing overnight at room temperature, 100 ml of chloroform was added, and the mixture was washed 3 times with 20 ml of water. Then, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1), and N- [2- (N-tert-butoxycarbonyl) aminophenyl] -4- [N- (pyridine-3- Yl) methoxythiocarbonylaminomethyl] benzamide 70 mg (yield 88%) was obtained as amorphous.
1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 4.73 (2H, d, J = 5.9Hz), 5.52 (2H, s), 6.73-7.33 (3H, m), 7.35-7.43 ( 2H, m), 7.58-7.95 (5H, m), 8.14-8.65 (3H, m), 9.80 (1H, s), 9.91 (1H, br.t).
[0253]
(88-2) 50 mg (0.10 mmol) of the compound of the step (88-1) was dissolved in 3 ml of methanol. 4N hydrochloric acid-dioxane solution (3 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. After pouring into dilute aqueous sodium hydroxide solution and neutralizing hydrochloric acid, the mixture was extracted 3 times with 10 ml of chloroform. The extract was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 34 mg (yield 87%) of N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxythio. Carbonylaminomethyl] benzamide was obtained.
mp. 154-156 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.73 (2H, d, J = 5.9Hz), 4.88 (2H, s), 5.52 (2H, s), 6.60 (1H, t, J = 7.3Hz), 6.77 (1H, d, J = 8.1Hz), 6.96 (1H, t, J = 8.1Hz), 7.16 (1H, d, J = 7.3Hz), 7.29-7.41 (3H, m), 7.83-7.95 (3H, m), 8.50-8.56 (1H, m), 8.65 (1H, s), 9.62 (1H, s), 9.93 (1H, s).
IR (KBr) cm-1: 3204, 3035, 1631, 1523, 1456, 1289, 1191, 920, 753.
[0254]
Example 89
Synthesis of N- (2-aminophenyl) -4- [N ′-(pyridin-3-ylmethyl) ureidomethyl] benzamide (Table-1: Compound No. 88)
(89-1) To a solution of 0.28 g (2.6 mmol) of 3-picolylamine in THF (10 ml) was added 0.42 g (2.4 mmol) of N, N′-carbonyldiimidazole at room temperature, and the mixture was stirred for 1 hour. To this solution was added 0.58 g (1.8 mmol) of the compound obtained in Step (1-4) of Example 1 at room temperature, and the mixture was stirred for 3 hours and then allowed to stand overnight.
[0255]
The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate-methanol = 10: 1), and N- [2- (N-tert -Butoxycarbonyl) amino] phenyl-4- [N '-(pyridin-3-ylmethyl) ureidomethyl] benzamide 0.77 g (90% yield) was obtained as a white amorphous solid.
1H NMR (270MHz, CDCl3) δppm: 1.46 (9H, s), 4.20 (2H, d, J = 5.1Hz), 4.28 (2H, d, J = 4.3Hz), 6.10-6.30 (2H, m), 7.00 -7.25 (4H, m), 7.33 (1H, d, J = 7.3Hz), 7.49-7.54 (2H, m), 7.58-7.64 (3H, m), 7.75 (1H, s), 8.28 (1H, br .s), 8.39 (1H, d, J = 5.1Hz), 9.65 (1H, br.s).
[0256]
(89-2) 4N Hydrochloric acid-dioxane (4 ml) was added to a solution of 0.63 g (1.32 mmol) of the compound obtained in step (89-1) in dioxane (4 ml) -methanol (2 ml), and the mixture was stirred at room temperature for 2 hours. Stir. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate-methyl ethyl ketone. The organic layer was washed with saturated brine, dried, and the residue obtained by distilling off the solvent was washed with diisopropyl ether to give N- (2-aminophenyl) -4- [N ′-(pyridine-3- Irmethyl) ureidomethyl] benzamide (0.37 g, yield 74.7%) was obtained as a brown solid.
[0257]
mp. (amorphous).
1H NMR (270 MHz, DMSO-d6) δ ppm: 4.27 (2H, d, J = 5.9 Hz), 4.31 (2H, d, J = 5.9 Hz), 4.89 (2H, br.s), 6.57-6.63 (3H, m), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.17 (1H, d, J = 7.3Hz), 7.32-7.38 (3H, m), 7.66 (1H, d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 8.44 (1H, d, J = 5.1Hz), 8.49 (1H, d, J = 2.1Hz), 9.63 ( 1H, br.s).
IR (KBr) cm-1: 3344,3241,1645,1560,1527,1505,1283,751,708.
[0258]
The compounds of Example 90 to Example 95 were synthesized by the same method as in Example 89. The measured values of the melting point (mp.), 1H NMR and IR of the compound are shown below.
[0259]
Example 90
N- (2-aminophenyl) -4- [N ′-(3-aminophenyl) ureidomethyl] benzamide (Table-1: Compound No. 24)
mp. 206-208 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.35 (2H, d, J = 5.9Hz), 4.93 (4H, br.s), 6.13 (1H, d, J = 7.3Hz), 6.51-6.62 (3H, m), 6.74-6.98 (3H, m), 7.12-7.18 (1H, m), 7.41 (2H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.28 (1H, s ), 9.61 (1H, s).
IR (KBr) cm-1: 3356, 3269, 1640, 1555, 1495, 1458, 1308, 1236, 753.
[0260]
Example 91
N- (2-aminophenyl) -4- [N ′-(pyridin-3-yl) ureidomethyl] benzamide (Table-1: Compound No. 87)
mp. 187-190 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.39 (2H, d, J = 5.9Hz), 4.89 (2H, br.s), 6.59 (1H, d, J = 7.3,7.3Hz), 6.77 (1H, d, J = 6.6Hz), 6.88 (1H, t, J = 5.9Hz), 6.97 (1H, ddd, J = 1.5,6.6,7.3Hz), 7.16 (1H, d, J = 8.1Hz), 7.26 ( 1H, dd, J = 4.4,8.1Hz), 7.42 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.1Hz), 7.89-7.96 (1H, m), 8.12 (1H, dd , J = 1.5,4.4Hz), 8.56 (1H, d, J = 3.0Hz), 8.85 (1H, s), 9.62 (1H, s).
IR (KBr) cm-1: 3248,1663,1541,1423,1280,1054.
[0261]
Example 92
N- (2-aminophenyl) -4- [N ′-(3-aminophenyl) thioureidomethyl] benzamide (Table-1: Compound No. 25)
mp.123 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.80 (2H, d, J = 5.1Hz), 4.87 (2H, s), 5.12 (2H, s), 6.36 (1H, dd, J = 1.5,8.1Hz) , 6.48-6.63 (3H, m), 6.78 (1H, d, J = 6.6Hz), 6.94-7.00 (2H, m), 7.17 (1H, d, J = 8.1Hz), 7.42 (2H, d, J = 8.1Hz), 7.92-8.01 (3H, m), 9.46 (1H, s), 9.61 (1H, s).
IR (KBr) cm-1: 3335,1616,1528,1503,1456,1311,864,751.
[0262]
Example 93
N- (2-aminophenyl) -4- [N ′-(3-nitrophenyl) thioureidomethyl] benzamide (Table-1: Compound No. 20)
mp.160 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.87 (2H, d, J = 5.1Hz), 7.27-7.33 (3H, m), 7.46-7.63 (5H, m), 7.89-7.95 (2H, m), 8.05 (2H, d, J = 8.1Hz), 8.70 (1H, s), 8.84 (1H, t, J = 8.9Hz), 10.37 (1H, s).
[0263]
Example 94
N- (2-amino-5-fluorophenyl) -4- [N ′-(pyridin-3-yl) methylureidomethyl] benzamide (Table-1: Compound No. 112)
mp. (amorphous).
1H-NMR (270 MHz, DMSO-d6): 4.77 (4H, d, J = 5.1 Hz), 4.85 (2H, s), 6.81 (2H, m), 7.16 (1H, dd, J = 2.9,10.3 Hz) , 7.39 (1H, dd, J = 5.1,8.1Hz), 7.53 (2H, d, J = 8.1Hz), 7.81 (1H, d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz) , 8.51 (1H, dd, J = 1.5,5.1Hz), 8.62 (1H, d, J = 1.5Hz), 9.66 (1H, s).
IR (KBr) cm-1: 3399,1730,1638,1508,1444,1411.
[0264]
Example 95
N- (2-hydroxyphenyl) -4- [N ′-(pyridin-3-yl) methylureidomethyl] benzamide (Table-1: Compound No. 114)
mp. (amorphous).
1H-NMR (270 MHz, DMSO-d6): 4.43 (2H, d, J = 6.6 Hz), 4.69 (2H, s), 6.83 (1H, t, J = 6.6 Hz), 6.91 (1H, d, J = 8.1Hz), 7.68 (1H, d, J = 6.6Hz), 7.82 (2H, d, J = 8.1Hz), 8.21 (1H, d, J = 4.4Hz), 8.35 (1H, d, J = 2.2Hz) ), 8.81 (1H, t, J = 6.6Hz), 9.48 (1H, s), 9.75 (1H, s).
IR (KBr) cm-1: 3399, 1664, 1535, 1236, 1064.
[0265]
Example 96
Synthesis of N- (2-aminophenyl) -4- [2- [N- (pyridin-3-yl) acetylamino] ethyl] benzamide (Table-1: Compound No. 77)
(96-1) Thionyl chloride (4 ml) was added to a suspension of 3.40 g (22.6 mmol) of terephthalaldehyde acid in toluene (25 ml), and the mixture was heated and stirred at 80 ° C. for 2 hours. After allowing to cool, the solvent was distilled off and the resulting residue was dissolved in THF (50 ml) to prepare acid chloride. Triethylamine (6 ml, 42.8 mmol) was added to a solution of 4.16 g (20.0 mmol) of the compound of Step (1-2) in Example 1 in THF (10 ml), and the acid chloride prepared earlier was further cooled under ice-cooling. It was added dropwise over a period of minutes.
[0266]
After stirring for 5 hours, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (chloroform → chloroform: ethyl acetate = 10: 1) to give N- [2- (N- There were obtained 3.42 g (yield 50.2%) of tert-butoxycarbonyl) aminophenyl] -4-formylbenzamide as a light brown solid.
1H NMR (270MHz, CDCl3) δppm: 1.52 (9H, s), 6.77 (1H, br.s), 7.16-7.18 (2H, m), 7.23-7.26 (1H, m), 7.88 (1H, d, J = 8.8Hz), 7.98 (2H, d, J = 8.8Hz), 8.13 (2H, d, J = 8.8Hz), 9.57 (1H, br.s), 10.11 (1H, br.s).
IR (KBr) cm-1: 3326,3251,1707,1696,1659,1603,1165.
[0267]
(96-2) A suspension of 3.0 g (8.82 mmol) of the compound obtained in step (96-1) and 4.5 g (12.9 mmol) of ethoxycarbonylmethyltriphenylphosphine in toluene (10 ml) was streamed with nitrogen. The mixture was stirred at 80 ° C. for 5.5 hours. The mixture was allowed to cool, diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform: ethyl acetate = 20: 1), and ethyl 4- [N- [2- (N-tert-butoxycarbonyl) aminophenyl] amino was purified. Carbonyl] cinnamate (3.3 g, yield 91.1%) was obtained as a yellow amorphous solid.
1H NMR (270MHz, CDCl3) δppm: 1.35 (3H, t, J = 7.3Hz), 1.52 (9H, s), 4.28 (2H, q, J = 7.3Hz), 6.52 (1H, d, J = 15.1Hz ), 6.80 (1H, br.s), 7.16-7.25 (3H, m), 7.61 (2H, d, J = 8.1Hz), 7.71 (1H, d, J = 15.1Hz), 7.82 (1H, d, 7.3Hz), 7.98 (2H, d, J = 8.1Hz), 9.34 (1H, br.s).
[0268]
(96-3) To a solution of 2.50 g (6.09 mmol) of the compound obtained in step (96-2) in THF (30 ml) -methanol (40 ml) under a nitrogen stream, 10% Pd / C (containing water, 0.5 g) ) And then stirred for 30 minutes under a hydrogen stream. After purging with nitrogen, the catalyst was filtered. Diisopropyl ether was added to the residue obtained by evaporating the solvent of the filtrate, and the precipitated solid was collected by filtration and dried to give N- [2- (N-tert-butoxycarbonyl) aminophenyl] -4- (2- There were obtained 2.23 g (88.8% yield) of ethoxycarbonylethyl) benzamide as a white solid.
1H NMR (270MHz, CDCl3) δppm: 1.25 (3H, t, J = 7.3Hz), 1.52 (9H, s), 2.65 (2H, t, J = 7.3Hz), 3.02 (2H, t, J = 7.3Hz ), 4.13 (2H, q, J = 7.3Hz), 6.77 (1H, br.s), 7.16-7.33 (5H, m), 7.78 (1H, d, J = 8.1Hz), 7.89 (2H, d, J = 8.8Hz), 9.06 (1H, br.s).
[0269]
(96-4) Lithium hydroxide monohydrate (0.37 g, 8) was added to a suspension of 2.21 g (5.36 mmol) of the compound obtained in step (96-3) in methanol (10 ml) -water (15 ml). .82 mmol) was added, and the mixture was stirred at 40 ° C. for 3 hours. After allowing to cool, a 10% aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried, and the solvent is distilled off. Diisopropyl ether is added to the resulting residue, and the precipitated solid is collected by filtration and dried to give N- [2- (N-tert- 1.87 g (90.8% yield) of butoxycarbonyl) aminophenyl] -4- (2-carboxyethyl) benzamide was obtained as a white solid.
1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 2.59 (2H, t, J = 7.3Hz), 2.91 (2H, t, J = 7.3Hz), 7.13-7.20 (2H, m) , 7.40 (2H, d, J = 8.1Hz), 7.54 (2H, dd, J = 7.3,2.1Hz), 7.88 (2H, d, J = 8.1Hz), 8.66 (1H, br.s), 9.79 ( 1H, br.s).
[0270]
(96-5) To a suspension of 0.12 g (0.3 mmol) of the compound obtained in step (96-4) in benzene (5 ml) was added 0.1 ml (0.7 mmol) of triethylamine and 0.3 g of molecular sieve 4A. The mixture was stirred for 0.5 hours under a nitrogen stream. To this solution, 0.15 ml (0.7 mmol) of diphenylphosphoryl azide was added and heated to reflux for 2 hours. After allowing to cool, 0.4 ml (3.8 mmol) of benzyl alcohol was added, and the mixture was further heated to reflux for 2.5 hours. After dilution with ethyl acetate, the mixture was washed with water and saturated brine.
[0271]
After drying the organic layer, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 4: 1) to give N- [2- (N-tert-butoxycarbonyl). Aminophenyl] -4- [2- (N-benzyloxycarbonylamino) ethyl] benzamide (129 mg, 88%) was obtained as a colorless oil.
1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 2.89 (2H, t, J = 7.3Hz), 3.45-3.54 (2H, m), 4.80 (1H, m), 5.10 (2H, s) , 6.76 (1H, br.s), 7.20-7.38 (10H, m), 7.79 (1H, d, J = 8.8Hz), 7.89 (2H, d, J = 8.1Hz), 9.10 (1H, br.s ).
[0272]
(96-6) To a solution of the compound 129 mg (0.26 mmol) obtained in step (96-5) in methanol (10 ml) was added 10% Pd / C (containing water, 0.05 g) under a nitrogen stream, and under a hydrogen stream. Stir for 2 hours. After the catalyst was distilled off, the residue obtained by drying was dissolved in dichloromethane (5 ml). To this solution, 0.18 g (1.04 mmol) of 3-pyridineacetic acid hydrochloride was added, and 0.28 g (2.0 mmol) of triethylamine was further added, followed by ice cooling. Under ice cooling, 0.17 g (1.0 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride was added and stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried, and the solvent was evaporated. The residue obtained was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give N- [2- (N- 50 mg (40% yield) of tert-butoxycarbonyl) aminophenyl] -4- [2- [N- (pyridin-3-yl) acetylamino] ethyl] benzamide were obtained as a colorless oil.
[0273]
1H NMR (270MHz, CDCl3) δppm: 1.48 (9H, s), 2.80 (2H, t, J = 6.6Hz), 3.42 (2H, m), 3.52 (2H, s), 6.33 (1H, t-like, J = 5.9Hz), 7.09 (2H, d, J = 8.1Hz), 7.14-7.20 (2H, m), 7.24 (1H, dd, J = 4.4,7.3Hz), 7.41 (1H, dd, J = 3.7 , 5.9Hz), 7.50 (1H, s), 7.58 (1H, dd, J = 1.5,5.9Hz), 7.69 (1H, dd, J = 3.7,5.9Hz), 7.75 (2H, d, J = 8.1Hz ), 8.22 (1H, d, J = 2.1Hz), 8.44 (1H, dd, J = 1.5,4.4Hz), 9.49 (1H, br.s).
[0274]
(96-7) To a solution of 50 mg (0.10 mmol) of the compound of step (96-6) in dioxane (2 ml) -methanol (1 ml) was added 4N hydrochloric acid-dioxane (2 ml), and the mixture was stirred at room temperature for 2.5 hours. . Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried, and the residue obtained by evaporating the solvent is dried, thereby drying N- (2-aminophenyl) -4- [2- [N- (pyridine-3- Yl) acetylamino] ethyl] benzamide 22 mg (59% yield) was obtained as an amorphous solid.
[0275]
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 2.70-2.90 (4H, m), 3.42 (2H, s), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 7.3Hz), 6.97 (1H, dd, J = 7.3,7.3Hz), 7.16 (1H, d, J = 7.3Hz), 7.29-7.32 (3H, m), 7.59 (1H , d, J = 8.1Hz), 7.89 (1H, d, J = 8.1Hz), 8.22 (1H, t-like), 8.41-8.43 (2H, m), 9.62 (1H, br.s).
[0276]
Example 97
Synthesis of N- (2-aminophenyl) -4- [2- [N- (3-picolyl) aminocarbonyl] ethyl] benzamide (Table-1: Compound No. 80)
(97-1) To a suspension of 0.58 g (1.5 mmol) of the compound obtained in Step (96-4) of Example 96 in dichloromethane (5 ml), 0.22 g (2.0 mmol) of 3-picolylamine was obtained. And 0.56 ml (4.0 mmol) of triethylamine were added. Under ice cooling, a solution of 0.39 g (2.0 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride in dichloromethane (5 ml) was added and stirred for 1.5 hours. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
[0277]
The organic layer was washed with water and saturated brine, dried, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 100: 10: 1) to give N 0.71 g (94% yield) of [2- (N-tert-butoxycarbonyl) aminophenyl] -4- [2- [N- (3-picolyl) aminocarbonyl] ethyl] benzamide as a light brown oil Obtained.
1H NMR (270MHz, CDCl3) δppm: 1.45 (9H, s), 2.42 (2H, t, J = 7.3Hz), 2.98 (2H, t, J = 7.3Hz), 4.32 (2H, d, J = 6.6Hz ), 6.44 (1H, t, J = 6.6Hz), 7.14-7.27 (5H, m), 7.48-7.57 (3H, m), 7.63-7.68 (3H, m), 7.90 (1H, d, J = 2.1 Hz), 8.43 (1H, dd, J = 1.4,4.4Hz), 9.86 (1H, br.s).
[0278]
(97-2) To a solution of 0.70 g (1.47 mmol) of the compound of Step (97-1) in dioxane (5 ml) was added 4N hydrochloric acid-dioxane (5 ml), and methanol (2 ml) was further added at room temperature. Stir for hours. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried, the solvent is distilled off, diisopropyl ether is added to the resulting residue, and the precipitated solid is collected by filtration and dried to give N- (2-aminophenyl) -4. 0.42 g (yield 76.3%) of [2- [N- (3-picolyl) aminocarbonyl] ethyl] benzamide was obtained as a milky white solid.
[0279]
mp. 168-170 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 2.47-2.53 (2H, m), 2.93 (2H, t, J = 7.3Hz), 4.27 (2H, d, J = 5.9Hz), 4.90 (2H, br. s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.16 (1H, d, J = 6.6Hz), 7.28-7.35 (1H, m), 7.33 (2H, d, J = 8.1Hz), 7.49 (1H, dd, J = 2.1,5.9Hz), 7.89 (2H, d, J = 8.1Hz) ), 8.39-8.44 (3H, m), 9.62 (1H, br.s).
IR (KBr) cm-1: 3313,1641,1523,1457,1300,748,713.
[0280]
Example 98
Synthesis of N- (2-aminophenyl) -4-[(pyridin-3-yl) methylaminocarbonyloxymethyl] benzamide (Table-1: Compound No. 85)
(98-1) 1.78 g (11.0 mmol) of N, N′-carbonyldiimidazole was added to a solution of 1.99 g (12.0 mmol) of methyl 4-hydroxymethylbenzoate in THF (20 ml) at room temperature and stirred for 1 hour. did. To this solution, 1.08 g (10.0 mmol) of 3-picolylamine was added at room temperature, stirred for 3.5 hours, and then left overnight. The mixture was diluted with water and extracted with ethyl acetate.
[0281]
The organic layer was washed with saturated brine, dried, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate), and N- (4-methoxycarbonyl) benzyloxycarbonyl-3-picoline. 2.76 g (91.9% yield) of ruamine was obtained as a white waxy solid.
1H NMR (270MHz, CDCl3) δppm: 3.91 (3H, s), 4.40 (2H, d, J = 5.9Hz), 5.18 (2H, s), 5.50 (1H, br.s), 7.24-7.28 (1H, m), 7.40 (2H, d, J = 8.1Hz), 7.65 (1H, d, J = 7.3Hz), 8.02 (2H, d, J = 8.8Hz), 8.50-8.53 (2H, m).
[0282]
(98-2) Lithium hydroxide monohydrate 0.42 g (10.0 mmol) was added to a suspension of 2.40 g (8.0 mmol) of the compound of step (98-1) in methanol (10 ml) -water (20 ml). ) And stirred at room temperature for 5 hours. After adding 10% hydrochloric acid aqueous solution to make it acidic (pH 2-4), the precipitated solid was collected by filtration and dried to obtain 1.83 g (yield) of N- (4-carboxy) benzyloxycarbonyl-3-picolylamine. 79.9%) was obtained as a white solid.
1H NMR (270MHz, DMSO-d6) δppm: 4.24 (2H, d, J = 5.9Hz), 5.13 (2H, s), 7.33-7.38 (1H, m), 7.46 (2H, d, J = 8.1Hz) , 7.94 (2H, d, J = 8.1Hz), 7.95-8.01 (1H, m), 8.46 (1H, d, J = 5.1Hz), 8.49 (1H, d, J = 1.5Hz), 13.0 (1H, br.s).
[0283]
(98-3) To a suspension of 1.26 g (4.4 mmol) of the compound of step (98-2) in dichloromethane (20 ml) was gradually added 1.0 ml (11.4 ml) of oxalyl chloride, and DMF was added to several After the dropwise addition, the mixture was stirred at room temperature for 10 minutes and further at 40 ° C. for 30 minutes. After allowing to cool, the solvent was distilled off, and excess oxalyl chloride was further distilled off with toluene. Dichloromethane (10 ml) was added to the residue, and then ice-cooled. Further, 0.83 g (4.0 mmol) of dichloromethane (8 ml) -pyridine (8 ml) of the compound obtained in Step (1-2) of Example 1 was added. After the solution was added dropwise, the solution was stirred for 7 hours while warming to room temperature and left overnight.
[0284]
Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried, and toluene was added to the residue obtained by evaporating the solvent. Further excess pyridine was azeotroped. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give N- [2- (N-tert-butoxycarbonyl) aminophenyl] -4-[(pyridin-3-yl) methylaminocarbonyloxymethyl. There was obtained 1.40 g (yield 73.4%) of benzamide as a light brown solid.
1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 4.40 (2H, d, J = 5.9Hz), 5.19 (2H, s), 5.56 (1H, m), 7.07 (1H, br.s) , 7.14-7.31 (4H, m), 7.43 (2H, d, J = 8.1Hz), 7.65 (1H, d, J = 8.1Hz), 7.76 (1H, d, J = 7.3Hz), 7.95 (2H, d, J = 8.1Hz), 8.52 (2H, d, J = 4.1Hz), 9.32 (1H, br.s).
[0285]
(98-4) 4N Hydrochloric acid-dioxane (9 ml) was added to a dioxane (10 ml) -methanol (2 ml) solution of 1.00 g (2.10 mmol) of the compound of step (98-3) at room temperature, and the mixture was stirred for 2 hours. . Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate-methyl ethyl ketone (1: 1). The organic layer was washed with saturated brine, dried, the solvent was distilled off, methanol-diisopropyl ether was added to the resulting residue, and the resulting solid was collected by filtration and dried to give N- (2-aminophenyl). There was obtained 0.79 g (quantitative) of -4-[(pyridin-3-yl) methylaminocarbonyloxymethyl] benzamide as a white solid.
[0286]
mp. 139-141 ℃
1H NMR (270MHz, DMSO-d6) δppm: 4.25 (2H, d, J = 5.9Hz), 4.90 (2H, s), 5.13 (2H, s), 6.60 (1H, dd, J = 6.6,7.3Hz) , 6.78 (1H, d, J = 7.3Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.17 (1H, d, J = 7.3Hz), 7.36 (1H, dd, J = 4.4,8.1 Hz), 7.47 (2H, d, J = 8.1Hz), 7.67 (1H, d, J = 8.1Hz), 7.97 (2H, d, J = 7.3Hz), 7.90-8.00 (1H, m), 8.46 ( 1H, dd, J = 1.5,5.1Hz), 8.49 (1H, d, J = 2.1Hz), 9.65 (1H, br.s).
IR (KBr) cm-1: 3326 (br), 1694, 1637, 1526, 1458, 1147, 750, 712.
[0287]
Example 99
N- (2-aminophenyl) -4- [3- (imidazol-1-yl) propylaminocarbonyloxymethyl] benzamide (Table-1: Compound No. 215)
The compound was synthesized by the same method as in Example 98.
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 1.80-1.89 (2H, m), 2.94-3.02 (2H, m), 3.98 (2H, t, J = 7.3Hz), 4.88 (2H, s), 5.11 ( 2H, s), 6.55-6.63 (1H, m), 6.76-6.97 (3H, m), 7.10-7.18 (2H, m), 7.43-7.48 (3H, m), 7.61 (1H, s), 7.98 ( 2H, d, J = 8.1Hz), 9.66 (1H, s).
[0288]
Example 100
Synthesis of N- (2-aminophenyl) -4- (phenylacetylamino) benzamide (Table-1: Compound No. 2)
(100-1) To a solution of 16.6 g (80 mmol) of the compound obtained in Step (1-2) of Example 1 in dichloromethane (120 ml) was added 16.8 ml (120 mmol) of triethylamine, and further, 4-nitro was added under ice cooling. A solution of 16.0 g (86.4 mmol) of benzoyl chloride in dichloromethane (40 ml) was gradually added, followed by stirring for 7 hours. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform.
[0289]
The organic layer was washed with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, dried and evaporated. The obtained residue was washed with diisopropyl ether to obtain 28.0 g (yield 98%) of N- [2- (N-tert-butoxycarbonylamino) phenyl] -4-nitrobenzamide as a pale yellow solid. .
1H NMR (270MHz, CDCl3) δppm: 1.53 (9H, s), 7.17-7.29 (4H, m), 7.85 (1H, br.d, J = 7.3Hz), 8.17 (2H, d, J = 8.8Hz) , 8.32 (2H, d, J = 8.8Hz), 9.88 (1H, br.s).
[0290]
(100-2) To a mixed solution of 24.0 g (67.2 mmol) of the compound obtained in the step (100-1) in THF (80 ml) -methanol (80 ml) under a nitrogen stream, 10% Pd / C (containing water, 2.4 g) And stirred for 1.5 hours under a hydrogen stream. After absorption of hydrogen ceased, the catalyst was filtered off, the solvent was distilled off, diisopropyl ether and ethyl acetate were added to the resulting residue, and the resulting solid was collected by filtration and dried to give N- [2- 18.96 g (86% yield) of (N-tert-butoxycarbonylamino) phenyl] -4-aminobenzamide was obtained as a white solid.
1H NMR (270MHz, DMSO-d6) δppm: 1.46 (9H.s), 5.84 (2H, s), 6.61 (2H, d, J = 8.8Hz), 7.10-7.18 (2H, m), 7.46-7.55 ( 2H, m), 7.68 (2H, d, J = 8.8Hz), 8.67 (1H, s), 9.49 (1H, s).
[0291]
(100-3) To a methylene chloride solution (15 ml) of 1.6 g (4.88 mmol) of the compound obtained in the step (100-2), 0.8 ml (9.9 mmol) of pyridine and 0.96 ml of phenylacetyl chloride (7 .26 mmol) was added and stirred for 1 day. After completion of the reaction, water was added and the precipitated crystals were collected by filtration and 1.66 g of N- [2- (N-tert-butoxycarbonylamino) phenyl] -4- (phenylacetylamino) benzamide (yield 76%). Got.
[0292]
(100-4) To an acetonitrile solution (25 ml) of 1 g (2.24 mmol) of the compound obtained in the step (100-3), 0.88 ml (6.18 mmol) of iodotrimethylsilane was added at room temperature and stirred for 3 hours. After completion of the reaction, the solvent was concentrated and the resulting residue was recrystallized from methanol to give 0.29 g (yield 38%) of N- (2-aminophenyl) -4- (phenylacetylamino) benzamide as white crystals. Got as.
[0293]
mp. 232-237 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 3.69 (2H, s), 4.90 (2H, s), 6.60 (1H, t, J = 7.3Hz), 6.77 (1H, d, J = 7.3Hz), 6.96 (1H, t, J = 7.3Hz), 7.15 (1H, d, J = 7.4Hz), 7.22-7.35 (5H, m), 7.72 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.8Hz), 9.57 (1H, s), 10.43 (1H, s)
IR (KBr) cm-1: 2937, 2764, 1660, 1598, 1506, 1459.
[0294]
In the same manner as in Example 100, the compounds of Examples 101 to 128 were synthesized. The measured values of the melting point (mp.), 1H NMR and IR of the compound are shown below.
[0295]
Example 101
N- (2-aminophenyl) -4-[(4-phenylbutanoyl) amino] benzamide (Table-1: Compound No. 4)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 1.91 (2H, hep, J = 7.3Hz), 2.37 (2H, t, J = 7.3Hz), 2.64 (2H, t, J = 7.3Hz), 5.0 (2H , br.s), 6.61 (1H, t, 7.0Hz), 6.79 (1H, dd, J = 1.5,8.1Hz), 6.97 (1H, t, J = 7.0Hz), 7.10-7.40 (6H, m) , 7.71 (2H, d, J = 8.8Hz), 7.94 (2H, d, J = 8.8Hz), 9.57 (1H, s), 10.15 (1H, s).
IR (KBr) cm-1; 3344,1687,1603,1542,1460,1315,1033,842,737.
[0296]
Example 102
N- (2-aminophenyl) -4-[(4-chlorophenylacetyl) amino] benzamide (Table-1: Compound No. 15)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 3.72 (2H, s), 7.29-7.43 (8H, m), 7.77 (2H, d, J = 8.8Hz), 8.00 (2H, d, J = 8.8Hz) , 10.29 (1H, s), 10.52 (1H, s).
IR (KBr) cm-1: 3300, 2868, 1664, 1638, 1520.
[0297]
Example 103
N- (2-aminophenyl) -4-[(2-nitrophenylacetyl) amino] benzamide hydrochloride (Table-1: Hydrochloride of Compound No. 19)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 4.20 (2H, s), 7.20-7.30 (3H, m), 7.40-7.45 (1H, m), 7.60 (2H, d), 7.71-7.77 (3H, m ), 8.02-8.10 (4H, m), 10.27 (1H, br.s), 10.64 (1H, br.s).
IR (KBr) cm-1: 3263, 1676, 1647, 1518, 1184, 759.
[0298]
Example 104
N- (2-aminophenyl) -4-[(4-nitrophenylacetyl) amino] benzamide (Table-1: Compound No. 21)
mp. 222-226 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 3.90 (2H, s), 4.96 (2H, br.s), 6.60 (1H, dt, J = 1.5,6.6Hz), 6.78 (1H, dd, J = 1.5 , 6.6Hz), 6.97 (1H, dt, J = 1.5,6.6Hz), 7.15 (1H, dd, J = 1.5,6.6Hz), 7.63 (2H, d, J = 8.8Hz), 7.71 (2H, d , J = 8.8Hz), 7.95 (2H, d, J = 8.8Hz), 8.22 (2H, d, J = 8.8Hz), 9.59 (1H, s), 10.54 (1H, s).
IR (KBr) cm-1: 3395, 3334, 1671, 1630, 1519, 1346.
[0299]
Example 105
N- (2-aminophenyl) -4-[(2-aminophenylacetyl) amino] benzamide (Table-1: Compound No. 22)
mp. 177-182 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 3.54 (2H, s), 4.88 (2H, br.s), 5.09 (2H, br.s), 6.55 (1H, dd, J = 6.6, 7.3Hz), 6.59 (1H, dd, J = 7.3,7.3Hz), 6.68 (1H, d, J = 7.3Hz), 6.78 (1H, d, J = 7.3Hz), 6.96 (2H, dd, J = 7.3,7.3Hz) ), 7.06 (1H, d, J = 6.6Hz), 7.15 (1H, d, J = 7.3Hz), 7.71 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.8Hz), 9.57 (1H, br.s), 10.39 (1H, br.s).
IR (KBr) cm-1: 3374, 3256 (br.), 1683, 1597, 1503, 1317, 1262, 1180, 1153, 747.
[0300]
Example 106
N- (2-aminophenyl) -4-[(4-aminophenylacetyl) amino] benzamide (Table-1: Compound No. 26)
mp. 219-226 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 3.46 (2H, s), 4.93 (4H, br.s), 6.52 (2H, d, J = 8.1Hz), 6.59 (1H, dt, J = 1.5,7.3 Hz), 6.77 (1H, dd, J = 1.4,7.3Hz), 6.97 (1H, dt, J = 1.4,7.3Hz), 6.99 (2H, d, J = 8.1Hz), 7.15 (1H, dd, J = 1.5,7.3Hz), 7.70 (2H, d, J = 8.8Hz), 7.93 (2H, d, J = 8.8Hz).
IR (KBr) cm-1: 3278,3032,1675,1628,1516.
[0301]
Example 107
N- (2-aminophenyl) -4-[(4-methoxyphenylacetyl) amino] benzamide (Table-1: Compound No. 32)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 3.62 (2H, s), 3.74 (3H, s), 6.90 (2H, d, J = 8.8Hz), 7.26 (2H.dJ = 8.8Hz), 7.30 (3H , m), 7.39 (1H, m), 7.77 (2H, d, J = 8.8Hz), 7.99 (2H, d, J = 8.8Hz), 10.26 (1H, s), 10.44 (1H, s).
IR (KBr) cm-1: 3300, 2759, 1670, 1638, 1514, 1250.
[0302]
Example 108
N- (2-aminophenyl) -4-[[4- (N, N-dimethylamino) phenylacetyl] amino] benzamide (Table-1: Compound No. 53)
mp.140 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 3.04 (6H, s), 3.67 (2H, s), 7.16 (2H, d, J = 8.1Hz), 7.29-7.40 (6H, m), 7.76 (2H, d, J = 8.8Hz), 7.99 (2H, d, J = 8.8Hz), 10.29 (1H, s), 10.47 (1H, s).
IR (KBr) cm-1: 3244,2951,2639,1647,1599,1507.
[0303]
Example 109
N- (2-aminophenyl) -4-[(4-trifluoromethylphenylacetyl) amino] benzamide (Table 1: Compound No. 43)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 3.84 (2H, s), 6.89 (1H, t, J = 7.4Hz), 7.00 (1H, d, J = 7.4Hz), 7.11 (1H, t, J = 7.4Hz), 7.25 (1H, d, J = 7.4Hz), 7.57 (2H, d, J = 8.8Hz), 7.71 (2H, d, J = 8.8Hz), 7.73 (2H, d, J = 8.8Hz) ), 7.97 (2H, d, J = 8.8Hz), 9.87 (1H, s), 10.54 (1H, s).
IR (KBr) cm-1: 3260,1664,1605,1521,1327,1119.
[0304]
Example 110
N- (2-aminophenyl) -4-[(pyridin-2-yl) acetylamino] benzamide dihydrochloride (Table-1: Hydrochloride of Compound No. 174)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 4.60 (2H, s), 7.30-7.46 (3H, m), 7.56 (1H, d, J = 7.4Hz), 7.79 (2H, d, J = 8.8Hz) , 7.95 (1H, t, J = 6.6Hz), 8.01 (1H, d, J = 7.4Hz), 8.11 (2H, d, J = 8.8Hz), 8.49 (1H, t, J = 7.4Hz), 8.87 (1H, d, J = 5.1Hz), 10.46 (1H, s).
[0305]
Example 111
N- (2-aminophenyl) -4-[(pyridin-3-yl) acetylamino] benzamide dihydrochloride (Table-1: Hydrochloride of Compound No. 68)
mp. 182-189 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.12 (2H, s), 7.29-7.59 (4H, m), 7.80 (2H, d, J = 8.8Hz), 8.05 (1H, m), 8.11 (2H, d, J = 8.8Hz), 8.57 (1H, d, J = 8.1Hz), 8.85 (1H, d, J = 5.2Hz), 8.95 (1H, s), 10.25 (1H, s), 10.48 (1H, s).
[0306]
Example 112
N- (2-aminophenyl) -4-[[3- (pyridin-3-yl) propanoyl] amino] benzamide (Table-1: Compound No. 69)
mp. 184-186 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 2.80 (2H, t, J = 7.3Hz), 3.08 (2H, t, J = 7.3Hz), 6.87 (1H, t, J = 8.0Hz), 6.99 (1H , dd, J = 1.4,8.0Hz), 7.11 (1H, dt, J = 1.4,8.0Hz), 7.25 (1H, d, J = 8.0Hz), 7.70 (2H, d, J = 8.8Hz), 7.77 (1H, dd, J = 5.8,8.0Hz), 7.96 (2H, d, J = 8.8Hz), 8.22 (1H, d, J = 8.0Hz), 8.75 (1H, d, J = 1.4Hz), 9.83 (1H, s), 10.25 (1H, s).
[0307]
Example 113
N- (2-aminophenyl) -2-chloro-4- [3- (pyridin-3-yl) propanoylamino] benzamide (Table-1: Compound No. 123)
mp. (amorphous).
1H NMR (270 MHz, DMSO-d6) δ ppm: 2.70 (2H, t, J = 8.1 Hz), 2.96 (2H, t, J = 7.3 Hz), 4.74 (2H, br.s), 6.60 (1H, t, J = 6.6Hz), 6.78 (1H, d, J = 6.6Hz), 6.95 (1H, t, J = 6.6Hz), 7.19 (1H, dd, J = 1.5,7.3Hz), 7.29 (1H, dd, J = 5.1,7.3Hz), 7.66 (2H, d, J = 8.8Hz), 7.92 (2H, d, J = 8.8Hz), 8.48 (1H, d, J = 2.2Hz), 9.37 (1H, s), 10.00 (1H, s).
IR (KBr) cm-1: 3273,1675,1519,1315,1181,852,747.
[0308]
Example 114
N- (2-aminophenyl) -4-[[N- (pyridin-3-yl) methyl-N-trifluoroacetylamino] acetylamino] benzamide (Table-1: Compound No. 107)
mp.145 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.18 and 4.42 (total 2H, s), 4.73 and 4.83 (total 2H, s), 4.87 (2H, br.s), 6.60 (1H, dd, J = 7.3, 8.1Hz), 6.78 (1H, d, J = 8.1Hz), 6.96 (1H, dd, J = 7.3,7.3Hz), 7.16 (1H, d, J = 8.1Hz), 7.35-7.45 (1H, m) , 7.66 (2H, d, J = 5.9Hz), 7.70-7.80 (1H, m), 7.90-8.00 (2H, m), 8.51-8.55 (1H, m), 8.58 (1H, s), 9.60 (1H , br.s), 10.36 and 10.43 (total 1H, br.s).
[0309]
Example 115
N- (2-aminophenyl) -4-[[N- (pyridin-3-yl) methylamino] acetylamino] benzamide (Table-1: Compound No. 105)
mp.160 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 3.30 (2H, s), 3.79 (2H, s), 4.88 (2H, s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J = 8.1Hz), 7.74 (2H, d, J = 8.8Hz), 7.80 (1H, d, J = 7.3Hz), 7.95 (2H, d, J = 8.1Hz), 8.46 (1H, d, J = 3.7Hz), 8.57 (1H, s), 9.57 (1H, s), 10.08 (1H, br.s).
IR (KBr) cm-1: 3298,1693,1637,1602,1544,1454,1262,848,762.
[0310]
Example 116
N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methyloxamoylamino] benzamide (Table-1: Compound No. 104)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 4.43 (2H, d, J = 6.6Hz), 4.90 (2H, br.s), 6.60 (1H, dd, J = 6.6,7.3Hz), 6.78 (1H, d, J = 7.3Hz), 6.97 (1H, ddd, J = 1.5,6.6,7.3Hz), 7.16 (1H, d, J = 7.3Hz), 7.37 (1H, dd, J = 4.4,8.1Hz), 7.73 (1H, d, J = 8.1Hz), 7.96 and 7.96 (4H, AA'BB ', J = 9.4Hz), 8.47 (1H, dd, J = 1.5,5.1Hz), 8.56 (1H, d, J = 1.5Hz), 9.59 (1H, s), 9.67 (1H, t, J = 6.6Hz), 10.92 (1H, br.s).
IR (KBr) cm-1: 3299,1644,1518,1320,1119,748.
[0311]
Example 117
N- (2-aminophenyl) -4-[[N- (pyridin-3-yl) methyl-N-nicotinoylamino] acetylamino] benzamide (Table-1: Compound No. 106)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 4.11 (major 2H, s), 4.26 (minor 2H, s), 4.75 (major 2H, s), 4.65 (minor 2H, s), 4.88 (total 2H, br. s), 6.60 (total 1H, dd, J = 7.3,8.1Hz), 6.78 (total 1H, d, J = 7.3Hz), 6.97 (total 1H, dd, J = 7.3,8.1Hz), 7.15 (total 1H , d, J = 8.1Hz), 7.41-7.95 (total 8H, m), 8.46-8.52 (total 1H, m), 8.63-8.70 (total 2H, m), 9.59 (total 1H, s), 10.22 (major 1H, br.s), 10.37 (minor 1H, br.s).
IR (KBr) cm-1: 3269, 1701, 1637, 1603, 1534, 1506, 1312, 1254, 752.
[0312]
Example 118
N- (2-aminophenyl) -4-[[4- (pyridin-3-yl) butanoyl] amino] benzamide (Table-1: Compound No. 70)
mp. 165-167 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 1.88-1.99 (2H, m), 2.68 (2H, t, J = 7.3Hz), 2.39 (2H, t, J = 7.3Hz), 6.78-6.81 (1H, m), 6.94-6.99 (1H, m), 7.15-7.18 (1H, m), 7.34-7.39 (1H, m), 7.69-7.72 (3H, m), 7.94 (2h, d, J = 8.8Hz) , 8.43-8.48 (2H, m).
IR (KBr) cm-1: 3291,1660,1626,1308,1261,1182,1027,825,747.
[0313]
Example 119
N- (2-aminophenyl) -4-[[N- (pyridin-3-yl) methyl-N-methylamino] acetylamino] benzamide (Table 1: Compound No. 108) mp. 154-155 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 2.28 (3H, s), 3.27 (2H, s), 3.71 (2H, s), 4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6 , 7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J = 8.1Hz), 7.38 (1H, dd, J = 2.9,8.1Hz), 7.77 (2H, d, J = 8.8Hz), 7.75-7.85 (1H, m), 7.95 (2H, d, J = 8.8Hz), 8.47 (1H, d, J = 1.5Hz ), 8.49 (1H, s), 9.56 (1H, s), 10.02 (1H, br.s).
[0314]
Example 120
N- (2-aminophenyl) -4- [N- (pyridin-3-yl) oxyacetylamino] benzamide (Table-1: Compound No. 65)
mp. 175-179 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.86 (2H, s), 4.90 (2H, br.s), 6.60 (1H, d, J = 7.3,7.3Hz), 6.78 (1H, d, J = 7.3 Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.16 (1H, d, J = 8.1Hz), 7.34-7.47 (2H, m), 7.76 (2H, d, J = 8.8Hz), 7.98 (2H, d, J = 8.8Hz), 8.22 (1H, d, J = 3.6Hz), 8.39 (1H, d, J = 2.9Hz), 9.60 (1H, br.s), 10.40 (1H, br .s).
IR (KBr) cm-1: 3321,1655,1530,1276,1231,1068,757.
[0315]
Example 121
N- (2-aminophenyl) -4- [4- (pyridin-3-yl) -1,4-dioxobutylamino] benzamide (Table-1: Compound No. 99)
mp. 190-194 ℃.
1H NMR (270MHz, DMSO-d6) δppm: 2.08 (2H, t, J = 6.4Hz), 3.41 (2H, t, J = 6.4Hz), 4.86 (2H, s), 6.59 (1H, t, J = 5.6Hz), 6.78 (1H, d, J = 7.9Hz), 6.96 (1H, t, J = 7.4Hz), 7.15 (1H, d, J = 7Hz), 7.58 (1H, dd, J = 4.9,7.9 Hz), 7.70 (2H, d, J = 8.9Hz), 7.94 (2H, d, J = 8.9Hz), 8.35 (1H, d, J = 7.9Hz), 8.81 (1H, d, J = 4Hz), 9.18 (1H, s), 9.56 (1H, s), 10.32 (1H, s).
IR (KBr) cm-1: 3317,1691,1652,1601,1522,1312,982,847,764,701.
[0316]
Example 122
N- (2-aminophenyl) -4- [3- [N- (pyridin-3-yl) amino] -1,3-dioxopropylamino] benzamide (Table-1: Compound No. 94)
mp.196 ° C (dec.)
1H NMR (270MHz, DMSO-d6) δppm: 3.57 (2H, s), 4.87 (2H, s), 6.57-6.62 (1H, m), 6.76-6.79 (1H, m), 6.94-6.99 (1H, m ), 7.14-7.17 (1H, m), 7.33-7.38 (1H, m), 7.73 (2H, d, J = 8.8Hz), 7.97 (2H, d, J = 8.8Hz), 8.05-8.08 (1H, m), 8.27-8.30 (1H, m), 8.75-8.76 (1H, m), 9.59 (1H, s), 10.44 (1H, s), 10.47 (1H, s).
IR (KBr) cm-1: 3410,3315,1685,1655,1625,1536,1428,1362,1263,1201,744.
[0317]
Example 123
N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxyacetylamino] -3-methylbenzamide (Table-1: Compound No. 102)
mp. 178-181 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 2.28 (3H, s), 4.22 (2H, s), 4.71 (2H, s), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3 , 7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J = 7.3Hz), 7.43 (1H, dd, J = 4.4,8.1Hz), 7.71 (1H, d, J = 8.1Hz), 7.79-7.89 (3H, m), 8.54 (1H, dd, J = 1.5,4.4Hz), 8.66 (1H, d, J = 1.5Hz), 9.36 (1H, br.s), 9.60 (1H, br.s).
IR (KBr) cm-1: 3394,3269,1683,1630,1593,1521,1460,1131,750,716.
[0318]
Example 124
N- (2-aminophenyl) -4- [N- (thiophen-3-yl) methoxyacetylamino] benzamide (Table-1: Compound No. 204)
mp. 186-189 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.11 (2H, s), 4.63 (2H, s), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 ( 1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,7.3Hz), 7.12-7.19 (2H, m), 7.53-7.57 (2H, m), 7.78 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.8Hz), 9.58 (1H, br.s), 10.04 (1H, br.s).
IR (KBr) cm-1: 3341, 3248, 1694, 1631, 1611, 1506, 1314, 1126.
[0319]
Example 125
N- (2-aminophenyl) -4- [N-methyl-N- (pyridin-3-yl) methoxyacetylamino] benzamide (Table-1: Compound No. 103)
mp. 180-183 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 3.24 (3H, s), 4.08 (2H, br.s), 4.50 (2H, s), 4.94 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.79 (1H, d, J = 8.1Hz), 6.98 (1H, dd, J = 7.3,8.1Hz), 8.03 (1H, d, J = 8.1Hz), 8.48-8.50 (2H , m), 9.72 (1H, br.s).
IR (KBr) cm-1: 3395, 3283, 1683, 1639, 1604, 1506, 1459, 1307, 1124.
[0320]
Example 126
N- (2-aminophenyl) -4- [N- (pyridin-2-yl) methoxyacetylamino] benzamide (Table 1: Compound No. 176)
mp.171-173 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.26 (2H, s), 4.74 (2H, s), 4.89 (2H, br.s), 6.60 (1H, dd, J = 6.6,8.1Hz), 6.78 ( 1H, d, J = 7.3Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.16 (1H, d, J = 7.3Hz), 7.35 (1H, dd, J = 5.1,6.6Hz ), 7.80 (2H, d, J = 8.1Hz), 7.80-7.89 (1H, m), 7.97 (2H, d, J = 8.1Hz), 8.59 (1H, d, J = 4.4Hz), 9.59 (1H , br.s), 10.30 (1H, br.s).
IR (KBr) cm-1: 3391,3258,1678,1629,1593,1517,1128,767,742.
[0321]
Example 127
N- (2-aminophenyl) -4- [N- (N-nicotinoylamino) acetylamino] benzamide (Table 1: Compound No. 97)
) Mp. 218-220 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.13 (2H, d, J = 5.9Hz), 4.89 (2H, s), 6.59 (1H, dd, J = 7.3,7.3Hz), 6.77 (1H, d, J = 8.1Hz), 6.96 (1H, dd, J = 7.3,8.1Hz), 7.15 (1H, d, J = 7.3Hz), 7.55 (1H, dd, J = 5.1,8.1Hz), 7.73 (2H, d, J = 8.8Hz), 7.96 (2H, d, J = 8.8Hz), 8.25 (1H, d, J = 8.1Hz), 8.74 (1H, d, J = 5.1Hz), 9.07 (1H, d, J = 1.5Hz), 9.13 (1H, t-like, J = 5.9Hz), 9.58 (1H, s), 10.36 (1H, s).
[0322]
Example 128
N- (2-aminophenyl) -5- [3- (pyridin-3-yl) propionamide] benzofuran-2-carboxamide (Table-3: Compound No. 1)
mp. 267-272 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 2.51 (2H, t, J = 7.3Hz), 2.97 (2H, t, J = 7.3Hz), 6.61 (1H, dd, J = 8.1,8.8Hz), 6.80 (1H, dd, J = 1.5,8.1Hz), 6.99 (1H, dd, J = 8.1,8.8Hz), 7.20 (1H, dd, J = 1.5,8.1Hz), 7.32 (1H, dd, J = 5.2 8.1Hz), 7.49 (1H, dd, J = 1.5,8.8Hz), 7.61 (1H, d, J = 8.8Hz), 7.67 (1H, s), 7.70 (1H, m), 8.15 (1H, d , J = 1.5Hz), 8.40 (1H, dd, J = 1.5,5.2Hz), 8.51 (1H, d, J = 1.5Hz), 9.84 (1H, s), 10.1 (1H, s).
IR (KBr) cm-1: 3333,3272,1666,1583,1561,1458,1314,1247,1143,807,746,713.
[0323]
Example 129
Synthesis of N- (2-aminophenyl) -4- [N- [2- (pyridin-3-yl) oxypropionyl] amino] benzamide (Table-4: Compound No. 2)
(129-1) 0.34 g (1.2 mmol) of the compound obtained in Step (47-2) of Example 47, 0.34 g (1.0 mmol) of the compound obtained in Step (100-2) of Example 100 Was dissolved in dichloromethane (10 ml), and 0.5 ml (3.6 mmol) of triethylamine was further added. To this solution was added a solution of 0.21 g (1.24 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride in dichloromethane (5 ml) under ice cooling, and the mixture was further stirred for 2 hours under ice cooling. Saturated aqueous sodium bicarbonate was added for neutralization, and the mixture was diluted with water and extracted with chloroform.
[0324]
The organic layer was washed with saturated brine, dried and evaporated to give a residue, which was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give N- [2- (N- 0.68 g of tert-butoxycarbonylamino) phenyl] -4- [N- [2- (pyridin-3-yl) oxypropionyl] amino] benzamide was obtained as a mixture of 1,3-dimethyl-2-imidazolinone.
1H-NMR (270MHz, CDCl3) δppm: 1.52 (9H, s), 1.70 (3H, d, J = 6.6Hz), 4.84 (1H, q, J = 6.6Hz), 6.89 (1H, br.s), 7.12-7.31 (6H, m), 7.68 (2H, d, J = 8.8Hz), 7.79 (1H, d, J = 8.1Hz), 7.96 (2H, d, J = 8.8Hz), 8.34 (1H, d , J = 2.9, 2.9Hz), 8.43 (1H, d, J = 1.5Hz), 9.25 (1H, br.s).
[0325]
(129-2) To a solution of 0.68 g of the compound obtained in step (129-1) in dichloromethane (5 ml) was added 15% (vol / vol) trifluoroacetic acid / dichloromethane solution (10 ml) at room temperature, and 4.5 at room temperature. Stir for hours. Saturated aqueous sodium bicarbonate was added for neutralization, and then dichloromethane was distilled off. This solution was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried and evaporated to give methanol and diisopropyl ether. The precipitated precipitate is collected by filtration and dried to give N- (2-aminophenyl) -4- 0.22 g (2 steps, 58% yield) of [N- [2- (pyridin-3-yl) oxypropionyl] amino] benzamide was obtained as an opalescent solid.
mp. 193-196 ° C.
1H-NMR (270MHz, DMSO-d6) δppm: 1.60 (3H, d, J = 6.6Hz), 4.88 (2H, br.s), 5.04 (1H, q, J = 6.6Hz), 6.60 (1H, dd , J = 6.6,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.15 (1H, d, J = 7.3Hz), 7.32-7.39 (2H, m), 7.75 (2H, d, J = 8.8Hz), 7.96 (2H, d, J = 8.1Hz), 8.20 (1H, dd, J = 1.5,3.7Hz), 8.35 (1H, d, J = 2.1Hz), 9.59 (1H, br.s), 10.44 (1H, br.s).
[0326]
Example 130
Synthesis of N- (2-aminophenyl) -4-[(pyridin-3-yl) methoxyacetylamino] benzamide (Table-1: Compound No. 101)
(130-1) A solution of 4.4 g (110 mmol) of sodium hydride (60% oil suspension) in THF (300 ml) and a solution of 10.91 g (100 mmol) of 3-pyridinemethanol in THF (20 ml) at room temperature Was added dropwise and stirred at room temperature for 2 hours. The obtained white suspension was ice-cooled, and a solution of 19.51 g (100 mmol) of tert-butyl bromoacetate in THF (20 ml) was added dropwise while maintaining an internal temperature of 10 to 12 ° C. The suspension was stirred for 3 hours while warming to room temperature, and then left overnight. Water and saturated aqueous sodium hydrogen carbonate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was evaporated. The residue obtained was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1 → ethyl acetate), and (pyridine-3 -Yl) 7.56 g (33.8%) of methoxyacetic acid tert-butyl ester were obtained as a brown oil.
[0327]
1H NMR (270MHz, CDCl3) δppm: 1.49 (9H, s), 4.03 (2H, s), 4.64 (2H, s), 7.30 (1H, dd, J = 4.9,7.3Hz), 7.76 (1H, d, J = 7.3Hz), 8.56 (1H, d, J = 4.9Hz), 8.60 (1H, s).
(130-2) Trifluoroacetic acid (12 ml) was added to 3.5 g (15.7 mmol) of the compound obtained in the step (130-1) under ice cooling, and the mixture was stirred at room temperature for 6 hours. Thereafter, trifluoroacetic acid was partially distilled off to obtain 6.5 g of a mixture of (pyridin-3-yl) methoxyacetic acid and trifluoroacetic acid. Dichloromethane (70 ml) was added and dissolved therein, and then pyridine (25 ml) was added. Further, 4.26 g (13 mmol) of the compound obtained in the step (100-2) of Example 100 was added. Under ice cooling, a solution of 2.37 g (14.0 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride in dichloromethane (20 ml) was gradually added dropwise over 30 minutes.
[0328]
After further stirring for 5 hours under ice-cooling, saturated aqueous sodium hydrogen carbonate was added, and the mixture was stirred at room temperature until foaming stopped. The mixture was extracted with chloroform, and the resulting organic layer was washed with saturated brine, dried and evaporated to give a residue, which was purified by silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 10: 1). N- [2- (N-tert-butoxycarbonyl) aminophenyl] -4- [N- (pyridin-3-yl) methoxyacetylamino] benzamide (4.78 g, 62% yield) was converted into DMI (1, Obtained as a 1: 1 (mol) mixture with 3-dimethyl-2-imidazolinone).
1H NMR (270 MHz, CDCl3) δ ppm: 1.51 (9H, s), 4.15 (2H, s), 4.70 (2H, s), 6.92 (1H, br.s), 7.15-7.29 (3H, m), 7.37 ( 1H, dd, J = 7.3,5.1Hz), 7.67 (2H, d, J = 8.8Hz), 7.71-7.79 (2H, m), 7.96 (2H, d, J = 8.8Hz), 8.41 (1H, s ), 8.62-8.66 (2H, m), 9.23 (1H, br.s).
[0329]
(130-3) 15% (vol / vol) trifluoroacetic acid / dichloromethane solution (55 ml) was added to a solution of 2.39 g (4.0 mmol) of the compound obtained in step (130-2) in dichloromethane (28 ml) at room temperature. For 7 hours. Saturated sodium hydrogen carbonate solution was added and neutralized, then water was added and stirred at room temperature. The reaction mixture was extracted with ethyl acetate-methyl ethyl ketone (2: 1), ethyl acetate-THF (2: 1) and ethyl acetate in this order, and the entire organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated, methanol and diisopropyl ether were added to the resulting residue, and the precipitated solid was collected by filtration and dried to give N- (2-aminophenyl) -4- [N- 1.29 g (yield 85.6%) of (pyridin-3-yl) methoxyacetylamino] benzamide was obtained as a brown solid.
[0330]
1H NMR (270MHz, DMSO-d6) δppm: 4.19 (2H, s), 4.68 (2H, s), 4.90 (2H, br.s), 6.60 (1H, ddd, J = 1.5, 7.3, 8.1Hz), 6.78 (1H, dd, J = 1.5,8.1Hz), 6.97 (1H, dd, J = 7.3,7.3Hz), 7.15 (1H, d, J = 7.3Hz), 7.42 (1H, dd, J = 4.4, 8.1Hz), 7.77 (2H, d, J = 8.8Hz), 7.85 (1H, d, J = 7.3Hz), 7.96 (2H, d, J = 8.8Hz), 8.54 (1H, dd, J = 1.5, 5.1Hz), 8.63 (1H, s), 9.58 (1H, s), 10.09 (1H, s).
IR (KBr) cm-1: 3403,3341,3250,1694,1630,1610,1506,1314,1259,1118,764.
[0331]
Example 131
N- (2-aminophenyl) -4- [N- [2- (pyridin-3-yl) methoxypropionyl] amino] benzamide (Table-4: Compound No. 1)
(131-1) 1.24 g (31 mmol) of sodium hydride (60% oil suspension) was suspended in dry THF (90 ml), and then 3.27 g (30 mmol) of 3-pyridinemethanol in dry THF (at room temperature). 10 ml) solution was added dropwise over 5 minutes. The resulting white suspension was stirred for 1 hour at room temperature, and then a solution of 6.27 g (30 mmol) of 2-bromopropionic acid tert-butyl ester in dry THF (10 ml) was added dropwise at room temperature over 5 minutes. Stir at room temperature for 11.5 hours. Water was added and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried and the solvent is distilled off. The residue obtained is purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give (pyridin-3-yl) methoxy. Acetic acid tert-butyl ester (4.01 g, yield 56.3%) was obtained as a brown oil.
1H-NMR (270MHz, CDCl3) δppm: 1.42 (3H, d, J = 7.3Hz), 1.50 (9H, s), 3.96 (1H, q, J = 6.6Hz), 4.47, 4.69 (2H, ABq, J = 11.0Hz), 7.29 (1H, dd, J = 5.1,8.1Hz), 7.75 (1H, d, J = 8.1Hz), 8.50 (1H, d, J = 4.4Hz), 8.60 (1H, s).
[0332]
(131-2) Trifluoroacetic acid (8 ml) was added to a dichloromethane (5 ml) solution of the compound 1.09 g (4.59 mmol) obtained in the step (131-1), and the mixture was stirred at room temperature for 9.5 hours. Dichloromethane (25 ml) was added to the residue obtained by distilling off the solvent, and pyridine (3 ml) was further added. Under ice cooling, a solution of 0.70 g (4.1 mmol) of 2-chloro-1,3-dimethylimidazolidinium chloride in dichloromethane (8 ml) was added dropwise, followed by stirring for 30 minutes. To this solution, a solution of 0.98 g (3.0 mmol) of the compound obtained in Step (100-2) of Example 100 in dichloromethane (20 ml) -pyridine (10 ml) was gradually added dropwise over 15 minutes under ice cooling, The mixture was stirred for 8 hours while raising the temperature to room temperature. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was diluted with water and extracted with chloroform.
[0333]
The organic layer was washed with saturated brine, dried and evaporated to give a residue, which was purified by silica gel column chromatography (ethyl acetate-methanol = 8: 1) to give N- [2- (N-tert -Butoxycarbonylamino) phenyl] -4- [N- [2- (pyridin-3-yl) methoxypropionyl] amino] benzamide 1.19 g with 1,3-dimethyl-2-imidazolinone 2: 3 (moles) Ratio) obtained as a mixture.
1H-NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 1.54 (3H, d, J = 6.6Hz), 4.13 (1H, q, J = 6.6Hz), 4.65, 4.71 (2H, ABq, J = 11.7Hz), 7.12-7.18 (2H, m), 7.28-7.37 (3H, m), 7.65 (2H, d, J = 8.1Hz), 7.73 (2H, br.d, J = 5.9Hz), 7.96 (2H, d, J = 8.8Hz), 8.59-8.64 (3H, m), 9.39 (1H, br.s).
[0334]
(131-3) To a solution of 1.19 g (1.8 mmol) of the compound obtained in step (131-2) in dichloromethane (10 ml) was added 15% (vol / vol) trifluoroacetic acid / dichloromethane solution (20 ml), and For 4.5 hours. After pouring into saturated sodium bicarbonate water, the aqueous layer obtained by concentrating dichloromethane was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried and evaporated to the residue, methanol and diisopropyl ether are added, and the precipitated solid is collected by filtration and dried to give N- (2-aminophenyl) -4. -585 mg of-[N- [2- (pyridin-3-yl) methoxypropionyl] amino] benzamide was obtained as a light brown solid.
[0335]
mp. 144-148 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 1.40 (3H, d, J = 6.6Hz), 4.14 (1H, q, J = 6.6Hz), 4.56 and 4.65 (2H, ABq, J = 11.8Hz), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.16 ( 1H, d, J = 7.3Hz), 7.40 (1H, dd, J = 4.4Hz, 7.3Hz), 7.78-7.85 (3H, m), 7.97 (2H, d, J = 8.8Hz), 8.52 (1H, dd, J = 1.5,5.1Hz), 8.61 (1H, d, J = 2.1Hz), 9.60 (1H, s), 10.15 (1H, s).
[0336]
Example 132
Synthesis of N- (2-aminophenyl) -4- (N-benzylamino) carbonylbenzamide (Table-1: Compound No. 8)
(132-1) Thionyl chloride (10 ml) was added dropwise at room temperature to a suspension of 13.0 g (72.2 mmol) of monomethyl terephthalate in toluene (100 ml). After stirring at 80 ° C. for 3 hours, the solvent and excess thionyl chloride were distilled off. After the obtained residue was suspended in dioxane (100 ml), 9.98 g (72.2 mmol) of 2-nitroaniline was added, and the mixture was heated to reflux for 4 hours.
[0337]
After cooling, the solvent was distilled off, and the resulting residue was washed with methanol to obtain 20.3 g (yield 93.7%) of N- (2-nitrophenyl) -4-methoxycarbonylbenzamide as a yellow solid. Obtained.
1H NMR (270MHz, DMSO-d6) δppm: 3.91 (3H, s), 7.43-7.49 (1H, m), 7.76-7.78 (2H, m), 8.03 (1H, d, J = 8.1Hz), 8.08 ( 2H, d, J = 8.8Hz), 8.14 (2H, d, J = 8.8Hz), 10.94 (1H, s).
[0338]
(132-2) To a mixed solution of 4.24 g (14.12 mmol) of the compound obtained in the step (132-1) in THF (50 ml) -methanol (50 ml), 0.4 g of 10% Pd / C was added under a nitrogen stream. Then, the mixture was stirred for 1.5 hours under a hydrogen stream. After filtering the catalyst, the solvent was distilled off, and the resulting residue was washed with methanol, whereby 3.4 g (yield 87.5%) of N- (2-aminophenyl) -4-methoxycarbonylbenzamide was pale yellow. Obtained as a solid.
1H NMR (270MHz, DMSO-d6) δppm: 3.90 (3H, s), 4.95 (2H, s), 6.60 (1H, dd, J = 7.3,8.1Hz), 6.78 (1H, d, J = 7.3Hz) , 6.99 (1H, dd, J = 7.3,7.3Hz), 7.17 (1H, d, J = 7.3Hz), 8.08 (2H, d, J = 8.1Hz), 8.11 (2H, d, J = 8.1Hz) , 9.85 (1H, s)
[0339]
(132-3) After adding 5% aqueous sodium hydroxide solution to an aqueous solution of dioxane (100 ml) -water (50 ml) of the compound obtained in the step (132-2) (2.71 g, 10.0 mmol) under ice-cooling. Further, a dioxane (40 ml) solution of 2.62 g (12.0 mmol) of di-tert-butyl dicarbonate was added dropwise. The mixture was stirred at room temperature for 4 hours and then left overnight. Saturated brine and ethyl acetate were added to separate into two layers, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, the solvent was evaporated, and the resulting residue was washed with methanol to give N- [2- (N-tert-butoxycarbonyl) aminophenyl] -4-methoxy. Carbonylbenzamide (3.54 g, yield 95.7%) was obtained as a light brown solid.
1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 3.90 (3H, s), 7.12-7.24 (2H, m), 7.55-7.58 (2H, m), 8.09 (2H, d, J = 8.8Hz), 8.10 (2H, d, J = 8.8Hz), 8.72 (1H, s), 10.00 (1H, s).
[0340]
(132-4) A suspension of 3.00 g (8.10 mmol) of the compound obtained in step (132-3) in methanol (50 ml) -0.5N aqueous lithium hydroxide solution (25 ml) was added at 40 ° C. for 5 hours. Stir warm. Methanol was distilled off, 1N aqueous hydrochloric acid was added to the resulting residue, and the mixture was further extracted with ethyl acetate. The organic layer was washed with a small amount of water and saturated brine, and then dried. The residue obtained by distilling off the solvent was washed with methanol to obtain 2.24 g (yield 77.6%) of terephthalic acid mono-2- (N-tert-butoxycarbonyl) aminoanilide as a light brown solid. Obtained.
1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 7.12-7.21 (2H, m), 7.53-7.58 (2H, m), 8.06 (2H, d, J = 8.8Hz), 8.10 ( 2H, d, J = 8.8Hz), 8.71 (1H, s), 9.97 (1H, s).
[0341]
(132-5) To a suspension of 0.20 g (0.56 mmol) of the compound obtained in step (132-4) in dichloromethane (4 ml) was added 0.14 g (1.3 mmol) of benzylamine, and 0.21 ml of triethylamine. (1.5 mmol) was added. To this solution, 0.25 g (1.48 mmol) of 2-chloro-1,3-dimethylimidazolium chloride was added under ice cooling, and the mixture was further stirred at room temperature for 1 hour under ice cooling. After dilution with chloroform, water was added and the aqueous layer was extracted with chloroform.
[0342]
The organic layer was washed with saturated brine, dried, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1). The resulting solid was washed with ethyl ether. , 279 mg (yield 62.6%) of N- (2-tert-butoxycarbonylaminophenyl) -4- (N-benzylamino) carbonylbenzamide was obtained as a white solid.
1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 4.52 (2H, d, J = 5.8Hz), 7.13-7.28 (4H, m), 7.34-7.35 (3H, m), 7.56 ( 2H, d, J = 8.1Hz), 8.05 (4H, s), 8.71 (1H, br.s), 9.23 (1H, t), 9.94 (1H, s).
[0343]
(132-6) 4N Hydrochloric acid-dioxane solution (5 ml) was added to 151 mg (0.339 mmol) of the compound obtained in Step (132-5) at room temperature, and the mixture was stirred for 4 hours. After the solvent was distilled off, the residue was separated with ethyl acetate / saturated aqueous sodium hydrogen carbonate, the precipitated precipitate was removed, and the aqueous layer was further extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was evaporated. Ethyl ether was added to the resulting residue, and the deposited precipitate was collected by filtration and dried to give N- (2-aminophenyl) -4- ( 78 mg (yield 67%) of N-benzylamino) carbonylbenzamide were obtained as a white solid.
mp. 239-241 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.51 (2H, s), 4.93 (2H, br.d), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1 Hz), 6.95 (1H, dd, J = 7.3,8.3Hz), 7.18 (1H, d), 7.23-7.35 (5H, m), 8.01 (2H, d, J = 8.8Hz), 8.07 (2H, d , J = 8.8Hz), 9.22 (1H, br.t), 9.81 (1H, br.s).
[0344]
The compound of Example 133 was synthesized in the same manner as in Example 132. The measured values of the melting point (mp.), 1H NMR and IR of the compound are shown below.
[0345]
Example 133
N- (2-aminophenyl) -4- [N- (2-phenylethyl) amino] carbonylbenzamide (Table 1: Compound No. 9)
mp. 237-240 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 2.87 (2H, t, J = 7.3Hz), 3.51 (2H, dt, J = 5.9,7.3Hz), 4.94 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 7.3Hz), 6.98 (1H, dd, J = 7.3,7.3Hz), 7.15-7.34 (6H, m), 7.93 (2H, d , J = 8.1Hz), 8.04 (2H, d, J = 8.1Hz), 8.73 (1H, t, J = 5.1Hz), 9.76 (1H, br.s).
IR (KBr) cm-1: 3396, 3320, 1625, 1602, 1539, 1458, 1313, 699.
[0346]
Example 134
Synthesis of N- (2-aminophenyl) -4- [N- (4-nitrophenoxyacetyl) amino] benzamide (Table-1: Compound No. 54)
(134-1) Dicyclohexylcarbodiimide 2 was added to a DMF solution (7 ml) of 3 g (9.2 mmol) of the compound obtained in the step (100-2) of Example 100 and 2.16 g (11.0 mmol) of 4-nitrophenoxyacetic acid. .82 g (13.8 mmol) of DMF solution (5 ml) and a catalytic amount of N, N-dimethylaminopyridine were added and stirred for 1 day. After completion of the reaction, ethyl acetate was added, insoluble matter was filtered through Celite, and the solvent was distilled off.
[0347]
The obtained residue was recrystallized from chloroform to obtain 2.34 g (yield 50%) of N- [2- (tert-butoxycarbonylamino) phenyl] -4-[(4-nitrophenoxyacetyl) amino] benzamide. Obtained.
1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 4.97 (2H, s), 7.12-7.26 (3H, m), 7.23 (2H, d, J = 8.8Hz), 7.53 (1H, dt, J = 2.2,7.3Hz), 7.79 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.8Hz), 8.25 (2H, d, J = 8.8Hz), 8.71 (1H, s), 9.79 (1H, s), 10.52 (1H, s).
[0348]
(134-2) 1.26 ml (8.85 mmol) of iodotrimethylsilane was added to an acetonitrile solution (10 ml) of 0.7 g (1.38 mmol) of the compound obtained in the step (134-1) at room temperature and stirred for 2 hours. did. After completion of the reaction, the solvent was concentrated, ethyl acetate was added and stirred for 20 minutes, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in methyl ethyl ketone, washed successively with saturated aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was washed with ethyl acetate to obtain 0.22 g (yield 39%) of N- (2-aminophenyl) -4- [N- (4-nitrophenoxyacetyl) amino] benzamide as white crystals. It was.
[0349]
mp. 212-215 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.97 (2H, s), 6.88 (1H, t, J = 7.3Hz), 6.99 (1H, d, J = 7.3Hz), 7.11 (1H, t, J = 7.3Hz), 7.23 (2H, d, J = 8.8Hz), 7.24 (1H, m), 7.77 (2H, d, J = 8.8Hz), 8.00 (2H, d, J = 8.8Hz), 8.25 (2H , d, J = 8.8Hz), 9.89 (1H, s), 10.52 (1H, s).
IR (KBr) cm-1: 3382,3109,1650,1591,1508,1341.
[0350]
Example 135
Synthesis of N- (2-aminophenyl) -4-[(4-aminophenoxyacetyl) amino] benzamide (Table-1: Compound No. 55)
10% Pd-C was added to a methanol (15 ml) -THF (25 ml) solution of the compound obtained in the step (134-1) of Example 134 in 1.41 g (2.78 mmol) and stirred at room temperature for 1 hour in a hydrogen atmosphere. did. After completion of the reaction, the catalyst was filtered and the solvent was concentrated and sludged with diisopropyl ether to give N- [2- (tert-butoxycarbonylamino) phenyl] -4-[(4-aminophenoxyacetyl) amino] benzamide 1 0.1 g was obtained.
[0351]
This was dissolved in 15 ml of acetonitrile, 0.74 ml (5.20 mmol) of iodotrimethylsilane was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was concentrated and washed with methyl ethyl ketone to obtain 0.86 g (yield 83%) of N- (2-aminophenyl) -4-[(4-aminophenoxyacetyl) amino] benzamide.
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 4.82 (2H, s), 7.13 (2H, d, J = 8.8Hz), 7.30-7.48 (6H, m), 7.82 (2H, d, J = 8.8Hz) , 8.03 (2H, d, J = 8.8Hz), 10.34 (1H, s), 10.46 (1H, s) .IR (KBr) cm-1: 2873,2590,1680,1602,1505,1243.
[0352]
Example 136
Synthesis of N- (2-aminophenyl) -4- (5-phenoxymethyl-1,3-oxazolin-2-one-3-yl) benzamide (Table-2: Compound No. 1)
(136-1) 4- (N-benzyloxycarbonylamino) benzoic acid t-butyl ester 0.7 g (2.14 mmol) in THF solution (10 ml) at −78 ° C. with n-butyllithium 1.33 ml (2 .25 mmol) was added dropwise over 5 minutes. After further stirring at the same temperature for 1.5 hours, 0.31 ml (2.29 mmol) of phenylglycidol was added and the mixture was further stirred at the same temperature for 1 hour. After standing at room temperature for 1 day, a saturated aqueous ammonium chloride solution was added, the mixture was extracted twice with ethyl acetate, the organic layer was dried over magnesium sulfate, and the solvent was distilled off. The obtained residue was recrystallized from ether, and 0.31 g (yield 39%) of N- [4- (tert-butoxycarbonyl) phenyl] -5-phenoxymethyl-1,3-oxazolidine-2-one was obtained. Obtained.
1H NMR (270MHz, DMSO-d6) δppm: 1.53 (9H, s), 3.97 (1H, dd, J = 6.0,8.8Hz), 4.23-4.34 (3H, m), 5.11 (1H, m), 6.94- 7.00 (3H, m), 7.31 (2H, m), 7.71 (2H, d, J = 8.8Hz), 7.93 (2H, d, J = 8.8Hz).
[0353]
(136-2) To an acetonitrile solution (4 ml) of 0.26 g (0.704 mmol) of the compound of step (136-1) was added 0.15 ml (1.05 mmol) of trimethylsilyl iodide, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was concentrated and the resulting concentrate was sludged with ethyl acetate-methyl ethyl ketone to give 0.2 g of N- (4-carboxyphenyl) -5-phenoxymethyl-1,3-oxazolidine-2-one ( Yield 91%) was obtained.
1H NMR (270MHz, DMSO-d6) δppm: 3.98 (1H, dd, J = 6.6,9.6Hz), 4.23-4.34 (3H, m), 5.10 (1H, m), 6.94-6.99 (3H, m), 7.30 (2H, t, J = 8.1Hz), 7.72 (2H, d, J = 8.8Hz), 7.98 (2H, d, J = 8.8Hz), 12.85 (1H, s).
[0354]
(136-3) After adding a catalytic amount of DMF to a methylene chloride solution (7 ml) of 0.15 g (0.479 mmol) of the compound of step (136-2), 0.12 ml (1.40 mmol) of oxalyl chloride was added. The mixture was further stirred at room temperature for 2 hours. Next, the solvent was concentrated, azeotroped twice with toluene, and then dissolved in methylene chloride (4 ml). Under ice cooling, 0.105 g (0.504 mmol) of the compound of Example 1 step (1-2), pyridine 0 After adding .12 g (1.52 mmol) of methylene chloride solution (1 ml), the mixture was warmed to room temperature and stirred for 1 hour. After completion of the reaction, water was added and the mixture was extracted twice with chloroform, and the organic layer was washed with saturated brine. After drying with magnesium sulfate, the solvent was distilled off. The obtained residue was sludged with isopropyl ether, and N- [2- (N-tert-butoxycarbonylamino) phenyl] -4- (5-phenoxymethyl-1,3-oxazolin-2-one-3- Yl) benzamide 0.25 g (quantitative) was obtained.
1H NMR (270MHz, DMSO-d6) δppm: 1.52 (9H, s), 4.11 (1H, dd, J = 5.9,6.6Hz), 4.21-4.27 (3H, m), 5.01 (1H, m), 6.84 ( 1H, br.s), 6.91 (2H, d, J = 8.8Hz), 7.01 (1H, t, J = 7.4Hz), 7.12-7.34 (5H, m), 7.68 (2H, d, J = 8.8Hz) ).
[0355]
(136-4) To an acetonitrile solution (4 ml) of 0.22 g (0.437 mmol) of the compound of step (136-3) was added 0.1 ml (0.703 mmol) of trimethylsilyl iodide at room temperature, and the mixture was stirred for 2 hours. A saturated aqueous sodium thiosulfate solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The obtained residue was recrystallized from methanol to give 0.13 g (yield) of N- (2-aminophenyl) -4- (5-phenoxymethyl-1,3-oxazolin-2-one-3-yl) benzamide. 74%) was obtained as white crystals.
mp. 165-170 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.01 (1H, dd, J = 6.6,9.6Hz), 4.28-4.34 (3H, m), 5.12 (1H, m), 5.23 (2H, br.s), 6.64 (1H, t, J = 7.4Hz), 6.81 (1H, d, J = 8.1Hz), 6.95-7.00 (3H, m), 7.18 (1H, d, J = 6.6Hz), 7.31 (2H, t , J = 8.1Hz), 7.72 (2H, d, J = 8.8Hz), 8.05 (2H, d, J = 8.8Hz), 9.69 (1H, s).
IR (KBr) cm-1: 3393,1740,1610,1508,1253.
[0356]
In the same manner as in Example 136, the compounds of Examples 137 to 143 were synthesized. The measured values of the melting point (mp.), 1H NMR and IR of the compound are shown below.
[0357]
Example 137
N- (2-aminophenyl) -4- [5- (4-nitrophenoxy) methyl-1,3-oxazolin-2-one-3-yl] benzamide (Table-2: Compound No. 2)
mp. 162-164 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 3.97 (1H, dd, J = 6.6,9.5Hz), 4.10 (1H, dd, J = 5.1,11.0Hz), 4.17 (1H, dd, J = 3.7,11.0 Hz), 4.27 (1H, t, J = 8.8Hz), 6.53-6.80 (6H, m), 6.97 (1H, t, J = 8.1Hz), 7.16 (1H, d, J = 6.6Hz), 7.72 ( 2H, d, J = 8.8Hz), 8.04 (2H, d, J = 8.8Hz), 9.65 (1H, s).
IR (KBr) cm-1: 3356,2365,1741,1609,1510,1247.
[0358]
Example 138
N- (2-aminophenyl) -4- (5-benzyloxymethyl-1,3-oxazolin-2-one-3-yl) benzamide hydrochloride (Table-2: Hydrochloride of compound number 3)
mp. 181-183 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 3.69 (1H, dd, J = 5.2,11.0Hz), 3.76 (1H, dd, J = 3.7,11.0Hz), 3.91 (1H, dd, J = 5.9,8.8 Hz), 4.59 (2H, s), 4.93 (1H, m), 7.26-7.41 (8H, m), 7.51 (1H, m), 7.74 (2H, d, J = 8.8Hz), 8.15 (2H, d , J = 8.8Hz), 10.42 (1H, s).
[0359]
Example 139
N- (2-aminophenyl) -4- [5- (pyridin-3-yl) oxymethyl-1,3-oxazolin-2-one-3-yl] benzamide (Table-2: Compound No. 4)
mp. 199-201 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.01 (1H, dd, J = 6.6,8.8Hz), 4.28-4.46 (3H, m), 4.96 (2H, br.s), 5.14 (1H, m), 6.61 (1H, t, J = 7.4Hz), 6.79 (1H, d, J = 7.4Hz), 6.98 (1H, t, J = 7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.36 ( 1H, dd, J = 4.4,8.1Hz), 7.44 (1H, dd, J = 1.5,8.1Hz).
IR (KBr) cm-1: 2815,2631,2365,1752,1610,1520,1225.
[0360]
Example 140
N- (2-aminophenyl) -4- [5- (pyridin-3-yl) methyloxymethyl-1,3-oxazolin-2-one-3-yl] benzamide (Table-2: Compound No. 5)
mp. 160-164 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 3.73 (1H, dd, J = 5.2,11.7Hz), 3.79 (1H, dd, J = 2.9,11.7Hz), 3.91 (1H, dd, J = 5.9,8.8 Hz), 4.21 (1H, t, J = 8.8Hz), 4.62 (2H, s), 4.91 (3H, br.s), 6.60 (1H, t, J = 7.4Hz), 6.78 (1H, d, J = 7.4Hz), 6.98 (1H, t, J = 7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.38 (1H, dd, J = 4.4,7.4Hz), 7.69 (2H, d, J = 8.8Hz), 7.71 (1H, m), 8.03 (2H, d, J = 8.8Hz), 8.51 (1H, dd, J = 1.5,4.4Hz), 8.54 (1H, d, J = 1.5Hz), 9.65 (1H, s).
IR (KBr) cm-1: 3368,1742,1648,1608,1492,1226.
[0361]
Example 141
N- (2-aminophenyl) -4- [5- (3-nitrophenoxy) methyl-1,3-oxazolin-2-one-3-yl] benzamide (Table-2: Compound No. 6)
mp.230 ° C (dec.).
1H NMR (270MHz, DMSO-d6) δppm: 4.04 (1H, t, J = 8.8Hz), 4.32 (1H, t, J = 8.8Hz), 4.41-4.53 (2H, m), 4.91 (2H, s) , 5.15 (1H, m), 6.61 (1H, t, J = 7.4Hz), 6.79 (1H, d, J = 7.4Hz), 6.98 (1H, t, J = 7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.46 (1H, dd, J = 1.5,8.1Hz), 7.61 (1H, t, J = 8.1Hz), 7.71-7.79 (3H, m), 7.87 (1H, d, J = 8.1 Hz), 8.06 (2H, d, J = 8.8Hz), 9.66 (1H, s).
IR (KBr) cm-1: 3363,3095,2365,1741,1608,1529.
[0362]
Example 142
N- (2-aminophenyl) -4- [5- (pyridin-2-yl) methyloxymethyl-1,3-oxazolin-2-one-3-yl] benzamide (Table-2: Compound No. 7)
mp. 172-174 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 3.79 (1H, dd, J = 5.2,11.0Hz), 3.85 (1H, dd, J = 2.9,11.0Hz), 3.95 (1H, dd, J = 6.6,9.6 Hz), 4.23 (1H, t, J = 9.6Hz), 4.67 (2H, s), 4.90 (2H, s), 4.95 (1H, m), 6.60 (1H, t, J = 7.4Hz), 6.78 ( 1H, d, J = 7.4Hz), 6.97 (1H, t, J = 7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.29 (1H, dd, J = 5.2,6.6Hz), 7.40 ( 1H, d, J = 6.6Hz), 7.70 (2H, d, J = 8.8Hz), 7.78 (1H, dt, J = 2.2,7.4Hz), 8.03 (2H, d, J = 8.8Hz), 8.51 ( 1H.d, J = 4.4Hz), 9.64 (1H, s).
IR (KBr) cm-1: 3369,1743,1651,1608,1492,1283.
[0363]
Example 143
N- (2-aminophenyl) -4- [5- (pyridin-2-yl) oxymethyl-1,3-oxazolin-2-one-3-yl] benzamide (Table-2: Compound No. 8)
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 3.96 (1H, dd, J = 5.9,9.6Hz), 4.21-4.40 (3H, m), 4.90 (2H, s), 5.03 (1H, m), 6.28 ( 1H, t, J = 6.6Hz), 6.43 (1H, d, J = 9.6Hz), 6.60 (1H, t, J = 6.6Hz), 6.78 (1H, d, J = 6.6Hz), 6.97 (1H, t, J = 7.4Hz), 7.15 (1H, d, J = 6.6Hz), 7.46 (1H, dt, J = 7.4,1.5Hz), 7.67 (2H, d, J = 8.8Hz), 7.69 (1H, m), 8.03 (2H, d, = 8.8Hz), 9.64 (1H, s).
[0364]
Example 144
N- (2-aminophenyl) -4- [N- [3-[(pyridin-3-yl) methylamino] cyclobuten-1,2-dione-4-yl] aminomethyl] benzamide (Table-2: Compounds Number 9)
(144-1) To a THF solution (2 ml) of 0.04 g (0.323 mmol) of 3,4-di-n-butoxy-3-cyclobutene-1,2-dione, the step (1-4) of Example 1 was carried out. After adding 0.1 g (0.293 mmol) of the compound and stirring for 4 hours, 0.033 ml (0.327 mmol) of 3-aminomethylpyridine was further added and reacted for 1 day. After completion of the reaction, water was added and extracted twice with methyl ethyl ketone. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off.
[0365]
The obtained residue was sludged with methanol to give N- [2- (N-tert-butoxycarbonylamino) phenyl] -4- [N- [3-[(pyridin-3-yl) methylamino] cyclobutene- There was obtained 0.12 g (yield 78%) of 1,2-dione-4-yl] aminomethyl] benzamide.
1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 4.75-4.81 (4H, m), 7.15 (1H, dt, J = 2.2,7.4Hz), 7.20 (1H, dt, J = 2.2 , 7.4Hz), 7.40 (1H, dd, J = 2.2,7.4Hz), 7.47 (2H, dJ = 8.1Hz), 7.54 (2H, dd, J = 2.2,7.4Hz), 7.73 (1H, m), 7.94 (2H, d, J = 8.1Hz), 8.50 (1H, m), 8.55 (1H, d, J = 1.5Hz), 8.67 (1H, s), 9.82 (1H, s).
[0366]
(144-2) 4N Hydrochloric acid-dioxane (4 ml) was added to a dioxane (4 ml) -methanol (1 ml) solution of 0.1 g (0.19 mmol) of the compound of step (144-1) and reacted for 2 hours. After completion of the reaction, the solvent was concentrated and neutralized with saturated aqueous sodium hydrogen carbonate, methyl ethyl ketone was added, and the resulting crystals were collected by filtration to give N- (2-aminophenyl) -4- [N- [3-[(pyridine- There was obtained 0.04 g (yield 49%) of 3-yl) methylamino] cyclobuten-1,2-dione-4-yl] aminomethyl] benzamide.
mp.230 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.76 (2H, s), 4.79 (2H, s), 4.90 (2H, s), 6.60 (1H, t, J = 7.4Hz), 6.78 (1H, d, J = 7.4Hz), 6.97 (1H, t, J = 7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.39 (1H, m), 7.43 (2H, d, J = 8.1Hz), 7.73 (1H, d, J = 8.1Hz), 7.97 (2H, d, J = 8.1Hz), 7.99 (1H, br.s), 8.51 (1H, d, J = 8.1Hz), 8.55 (1H, s) , 9.64 (1H, s).
[0367]
Example 145
N- (2-aminophenyl) -4- [3- (pyridin-3-yl) methylimidazolin-2-one-1-yl] methylbenzamide (Table-2: Compound No. 10)
(145-1) Potassium carbonate in a solution of 4.92 g (57 mmol) of ethylene urea, 5.73 g (25 mmol) of methyl 4-bromomethylbenzoate, 1.85 g (5.0 mmol) of tetranormalbutylammonium iodide in DMF (30 ml) 7.88 g (57 mmol) was added, and the mixture was heated and stirred at 80 ° C. for 5 hours.
[0368]
After allowing to cool, the solid content was collected by filtration and then washed with ethyl acetate. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1). Diisopropyl ether was added to the pale yellow oil obtained, and the precipitated solid was collected by filtration and dried. As a result, 3.36 g (yield 57.4%) of N- (4-methoxycarbonylphenylmethyl) imidazolin-2-one was obtained as a light brown solid.
1H-NMR (270MHz, CDCl3) δppm: 3.28-3.35 (2H, m), 3.41-3.47 (2H, m), 3.92 (3H, s), 4.42 (2H, s), 4.61 (1H, br.s) , 7.35 (2H, d, J = 8.1Hz), 8.01 (2H, d, J = 8.1Hz).
[0369]
(145-2) Saturated aqueous sodium bicarbonate was added to 2.05 g (12.5 mmol) of 3-chloromethylpyridine hydrochloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated to the residue. Toluene was added to the residue, and azeotropic distillation was performed. Further, DMF (5 ml) was added to the obtained residue, and tetranormalbutylammonium iodide was added. .37 g (1.0 mmol) was added to prepare a DMF solution of benzyl halide. Sodium hydride (60% oil suspension) 0.30 g (7.5 mmol) of DMF (5 ml) in DMF (5 ml) suspension at room temperature, 1.17 g (5.0 mmol) of DMF obtained in step (145-1) (10 ml) The solution was gradually added dropwise and then stirred at room temperature for 30 minutes. The benzyl halide solution prepared previously was added to this solution, and then heated and stirred at 80 ° C. for 7 hours.
[0370]
Left at room temperature overnight. After concentrating DMF, ethyl acetate and water were added and separated. Further, the aqueous layer was extracted with ethyl acetate-methyl ethyl ketone (2: 1). The organic layer was washed with saturated brine, dried and evaporated to give a residue, which was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1), N- (4-methoxycarbonylphenylmethyl)- 1.17 g (yield 72.3%) of N ′-(pyridin-3-yl) methylimidazolin-2-one was obtained as a brown oil.
1H NMR (270 MHz, CDCl3) δ ppm: 3.20 (4H, s), 3.92 (3H, s), 4.44 (2H, s), 4.46 (2H, s), 7.27-7.36 (3H, m), 7.64-7.69 ( 1H, m), 8.01 (2H, d, J = 8.1Hz), 8.53-8.56 (2H, m).
[0371]
(145-3) Lithium hydroxide monohydrate 110 mg (2.62 mmol) in a methanol (8 ml) -water (8 ml) solution of 0.55 g (1.7 mmol) of the compound obtained in step (145-2) at room temperature After stirring for 1.5 hours at 50 ° C., 0.05 g (1.2 mmol) of lithium hydroxide monohydrate was further added, and the mixture was stirred at 50 ° C. for 1.5 hours. After acidification (pH 3-4) with 10% aqueous hydrochloric acid, saturated brine was added, and the mixture was extracted twice with ethyl acetate and once with ethyl acetate-methyl ethyl ketone (1: 1). The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by evaporating the solvent was dried to dry 4- [3- (pyridin-3-yl) methylimidazolin-2-one-1-yl] methylbenzoic acid 0 .32 g (61% yield) was obtained as a brown oil.
1H NMR (270MHz, DMSO-d6) δppm: 3.17 (2H, s), 3.20 (2H, s), 4.36 (2H, s), 4.38 (2H, s), 7.35-7.42 (3H, m), 7.68 ( 1H, dd, J = 6.6Hz), 7.92 (2H, d, J = 8.1Hz), 8.51 (2H, m).
[0372]
(145-4) To a solution of 0.31 g (1.0 mmol) of the compound obtained in step (145-3) in dichloromethane (12 ml) was added dropwise 0.3 ml (3.5 mmol) of oxalyl chloride at room temperature, and then 30 at room temperature. And stirred at 40 ° C. for 1.5 hours. After the solvent was distilled off, it was azeotroped with toluene and suspended in 10 ml of dichloromethane. The reaction suspension was ice-cooled, and a solution of 0.21 g (1.0 mmol) of the compound of Step (1-2) in Example 1 in dichloromethane (2 ml) -pyridine (2 ml) was added dropwise. After stirring while raising the temperature to room temperature, the mixture was allowed to stand overnight at room temperature. Saturated aqueous sodium hydrogen carbonate was added, followed by extraction with chloroform.
[0373]
The organic layer was washed with saturated brine, dried and evaporated to give a residue, which was purified by silica gel column chromatography (ethyl acetate-methanol = 20: 1) to give N- (2-tert-butoxycarbonylamino). Phenyl) -4- [3- (pyridin-3-ylmethyl) imidazolin-2-one-1-yl] methylbenzamide (0.10 g, yield 20%) was obtained as a brown oil.
1H NMR (270 MHz, CDCl3) δppm: 1.52 (9H, s), 3.20 (4H, s), 4.45 (2H, s), 4.48 (2H, s), 6.75 (1H, br.s), 7.15-7.40 ( 5H, m), 7.65-7.70 (2H, m), 7.83 (1H, d, J = 7.3Hz), 7.94 (2H, d, J = 8.1Hz), 8.50-8.60 (3H, br.m).
[0374]
(145-5) After dissolving 100 mg (0.20 mmol) of the compound obtained in the step (145-4) in dioxane (2 ml), 4N hydrochloric acid-dioxane (2 ml) was added, and then methanol (0.5 ml) Was added and dissolved. After stirring for 2 hours, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and the solvent was evaporated. The residue obtained was dried at room temperature under reduced pressure to give N- (2-aminophenyl) -4- [3- (pyridin-3-yl). 47 mg (58% yield) of methylimidazolin-2-one-1-yl] methylbenzamide were obtained as a brown oil.
mp. (amorphous).
1H NMR (270MHz, DMSO-d6) δppm: 3.20 (4H, s), 4.37 (2H, s), 4.39 (2H, s), 4.87 (2H, br.s), 6.60 (1H, dd, J = 7.3 , 7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.16 (1H, d, J = 7.3Hz), 7.35-7.41 (3H, m ), 7.68 (1H, d, J = 8.1Hz), 7.90-8.00 (2H, m), 8.50 (2H, br.s), 9.63 (1H, br.s).
[0375]
Example 146
Synthesis of N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide 0.5 fumarate (Table-1: Fumarate of Compound No. 82)
310 mg of the compound obtained in Example 48 was added to 10 ml of methanol and dissolved by heating. A solution in which 96 mg of fumaric acid was dissolved in methanol was added, followed by cooling. The precipitated crystals were collected by filtration and recrystallized from 5 ml of methanol to obtain 200 mg of the desired product (yield 56%).
[0376]
mp. 166-167 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 6.6Hz), 5.10 (2H, s), 6.60 (1H, t, J = 8.0Hz), 6.63 (1H, s), 6.78 (1H, d, J = 8.0Hz), 6.90-7.50 (5H, m), 7.70-8.00 (4H, m), 8.53 (1H, d, J = 3.6Hz), 8.60 (1H, s), 9.63 ( 1H, s).
IR (KBr) cm-1: 3332,1715,1665,1505,1283,1136,1044,983,760,712.
Figure 0004105451
[0377]
In the same manner as in Example 146, the compounds of Examples 147 to 149 were synthesized. The measured values of the melting point (mp.), 1H NMR and IR of the compound are shown below.
[0378]
Example 147
N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide maleate (Table-1: maleate of compound no. 82)
mp. 123-124 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 6.6Hz), 5.11 (2H, s), 6.24 (2H, s), 6.66 (1H, t, J = 8.0Hz), 6.83 (1H, d, J = 8.0Hz), 6.90-8.00 (9H, m), 8.56 (1H, d, J = 3.6Hz), 8.62 (1H, s), 9.69 (1H, s).
IR (KBr) cm-1: 3298,1719,1546,1365,1313,1250,1194,1149,1044,993,862,751.
Figure 0004105451
[0379]
Example 148
N- (2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide hydrochloride (Table-1: Hydrochloride of Compound No. 82)
mp.140 (dec.) ℃.
1H NMR (270MHz, DMSO-d6) δppm: 4.31 (2H, d, J = 5.8Hz), 5.24 (2H, s), 7.10-7.60 (6H, m), 7.90-8.50 (5H, m), 8.70- 8.90 (2H, m), 10.46 (1H, s).
IR (KBr) cm-1: 2553,1715,1628,1556,1486,1254,1049,778,687.
[0380]
Example 149
N- (2-aminophenyl) -4- [N- (pyridin-3-yl) oxyacetylaminomethyl] benzamide 0.7 fumaric acid (Table-1: Fumarate salt of Compound No. 61)
The compound was synthesized from the compound of Example 46 by a method similar to that of Example 146.
mp. 154-155 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.42 (2H, d, J = 5.9Hz), 4.69 (2H, s), 6.60 (1H, t, J = 8.0Hz), 6.63 (0.7H, s), 6.78 (1H, d, J = 8.0Hz), 6.90-7.50 (6H, m), 7.93 (2H, d, J = 8.0Hz), 8.20-8.40 (2H, m), 8.82 (1H, br.s) , 9.63 (1H, s).
IR (KBr) cm-1: 3324,1709,1631,1521,1457,1428,1260,1064,806,698.
Figure 0004105451
[0381]
Reference example 1
N- (3-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide
The compound was synthesized by the same method as in Example 48.
mp.156 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.27 (2H, d, J = 6.6Hz), 5.06 (2H, s), 5.10 (2H, s), 6.20-6.40 (1H, m), 6.80-7.10 ( 3H, m), 7.30-7.50 (3H, m), 7.70-8.00 (4H, m), 8.53 (1H, d, J = 3.6Hz), 8.59 (1H, s), 9.88 (1H, s).
IR (KBr) cm-1: 3327,3218,1708,1639,1536,1279,1147,1050,859,788.
[0382]
Reference example 2
N- (4-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylaminomethyl] benzamide
The compound was synthesized by the same method as in Example 48.
mp. 204-205 ° C.
1H NMR (270MHz, DMSO-d6) δppm: 4.27 (2H, d, J = 6.6Hz), 4.91 (2H, s), 5.10 (2H, s), 6.52 (2H, d, J = 8.8Hz), 7.30 -7.50 (5H, m), 7.70-8.00 (4H, m), 8.50-8.60 (2H, m), 9.80 (1H, s).
IR (KBr) cm-1: 3336,3224,1706,1638,1530,1279,1145,1050,1005,827.
[0383]
Pharmacological test example 1
Differentiation-inducing action test on A2780 cells
An increase in alkaline phosphatase (ALP) activity is known as an indicator of differentiation of human colon cancer cells. For example, sodium butyrate is known to increase ALP activity [Young et al .; Cancer Res. , 45 2976 (1985), Morita et al .; Cancer Res. , 42 4540 (1982)]. Therefore, the differentiation induction action was evaluated using ALP activity as an index.
[0384]
(Experimental Method) 0.1 ml of A2780 cells were seeded in a 96-well plate at 15,000 cells / well, and 0.1 ml of a test drug solution serially diluted in the medium was added the next day. After culturing for 3 days, the cells on the plate were washed twice with TBS buffer (20 mM Tris, 137 mM NaCl, pH 7.6). Subsequently, p-nitrophenyl phosphate (9.6% diethanolamine, 0.5 mM MgCl 2) at a concentration of 0.6 mg / ml. 2 (PH 9.6)) 0.05 ml of the solution was added and incubated at room temperature for 30 minutes. After stopping the reaction with 0.05 ml of 3N aqueous sodium hydroxide solution, the absorbance at 405 nm was measured to determine the minimum drug concentration (ALPmin) that caused an increase in ALP activity.
(Experimental result) The experimental result was shown in Table-5 [Table 31].
[0385]
[Table 31]
Table-5: Differentiation inducing action on A2780 cells
Test compound ALPmin (μM)
Compound 1 of Example 1
Compound 2 of Example 2
Compound 3 of Example 3
Compound 1 of Example 4
Compound 1 of Example 5
Compound 1 of Example 6
Compound of Example 7 1
Compound 1 of Example 8
Compound 1 of Example 9
[0386]
Compound 3 of Example 10
Compound 1 of Example 11
Compound 1 of Example 13
Compound 3 of Example 15
Compound 3 of Example 16
Compound 3 of Example 17
Compound 3 of Example 18
Compound 1 of Example 23
Compound of Example 24 1
Compound 3 of Example 25
[0387]
Compound of Example 26 1
Compound of Example 27 10
Compound of Example 28 10
Compound of Example 29 10
Compound of Example 30 0.1
Compound of Example 31 10
Compound of Example 32 3
Compound of Example 33 0.3
Compound of Example 34 0.1
Compound of Example 35 0.3
[0388]
Compound of Example 36 10
Compound of Example 37 1
Compound 3 of Example 38
Compound of Example 390.1
Compound of Example 40 10
Compound of Example 41 0.3
Compound of Example 42 10
Compound 3 of Example 43
Compound of Example 44 0.01
Compound of Example 45 0.003
[0389]
Compound of Example 460.1
Compound of Example 480.1
Compound of Example 49 1
Compound of Example 50 1
Compound of Example 51 1
Compound of Example 52 1
Compound 3 of Example 53
Compound of Example 54
Compound 1 of Example 55
Compound 3 of Example 56
[0390]
Compound 3 of Example 57
Compound 3 of Example 58
Compound 3 of Example 59
Compound 3 of Example 60
Compound 3 of Example 63
Compound 3 of Example 64
Compound 3 of Example 65
Compound 3 of Example 66
Compound 3 of Example 67
Compound of Example 68 3
[0390]
Compound of Example 700.1
Compound of Example 71 10
Compound of Example 72 10
Compound 3 of Example 73
Compound of Example 74 10
Compound of Example 76 1
Compound 3 of Example 77
Compound of Example 790.1
Compound of Example 800.1
Compound of Example 81 10
[0392]
Compound of Example 82 1
Compound 3 of Example 85
Compound of Example 86 0.3
Compound of Example 870.1
Compound of Example 880.1
Compound of Example 89 0.3
Compound 90 of Example 90
Compound of Example 910.1
Compound of Example 92
Compound 3 of Example 93
[0393]
Compound 3 of Example 94
Compound 3 of Example 95
Compound of Example 96 10
Compound of Example 970.1
Compound of Example 98 0.1
Compound 3 of Example 99
Compound of Example 100 1
Compound 3 of Example 101
Compound 3 of Example 102
Compound of Example 103 1
[0394]
Compound of Example 104 1
Compound 1 of Example 105
Compound 1 of Example 106
Compound of Example 107 1
Compound 3 of Example 108
Compound of Example 109 1
Compound 3 of Example 110
Compound 3 of Example 111
Compound of Example 1120.1
Compound of Example 113 0.3
[0395]
Compound 3 of Example 114
Compound of Example 115 0.01
Compound of Example 116 0.01
Compound 3 of Example 119
Compound of Example 120 0.3
Compound 3 of Example 121
Compound of Example 122 0.03
Compound 3 of Example 123
Compound 3 of Example 124
Compound of Example 1250.1
[0396]
Compound 3 of Example 126
Compound of Example 127 0.3
Compound of Example 128 0.1
Compound of Example 129 1
Compound of Example 130 0.03
Compound of Example 131 0.3
Compound of Example 132 10
Compound 3 of Example 133
Compound 3 of Example 134
Compound 3 of Example 135
[0397]
Compound of Example 136 1
Compound of Example 137 1
Compound of Example 138 1
Compound of Example 139 0.3
Compound of Example 140 0.3
Compound of Example 141 1
Compound of Example 1420.1
Compound 3 of Example 143
Compound of Example 145 3
Compound of Comparative Example 1> 100
Compound of Comparative Example 2> 100
[0398]
Pharmacological test example 2
Anti-tumor test
(Experimental method) Mouse myeloid leukemia cell WEHI-3 (1-3 × 10 6 cells) were transplanted into the abdominal cavity of Balb / c mice, and drug administration was started the next day. On this day 1, the drug was orally administered once a day on days 1-4 and 7-11. The survival days after transplantation were observed, and the ratio (T / C,%) of the survival days of the drug administration group to the survival days of the Control group was calculated and evaluated as a life prolonging effect.
(Experimental results) The experimental results are shown in Table-6 [Table 32].
[0399]
[Table 32]
Table-6: Antitumor effect on WEHI-3 cells
Test compound Dose (μmol / kg) T / C (%)
Compound of Example 45 16 138
Compound of Example 46 32 141
Compound of Example 48 130 190
Compound of Example 130 130 189
[0400]
Pharmacological test example 3
Anti-tumor effect test
(Experimental method) Tumor cells (HT-29, KB-3-1) subcultured subcutaneously in nude mice were transplanted into nude mice, the volume became about 20 to 100 mm 3, and engraftment was confirmed. Administration was started. On this day 1, the drug was orally administered on days 1-5, 8-12, 15-19 and 22-26.
The tumor volume was determined by (tumor volume) = 1/2 × (major axis) × (minor axis) 2.
[0401]
(Experimental result) The experimental result of the compound of Example 48 (dosage 66micromol / kg) with respect to HT-29 was shown in [FIG. 1].
[0402]
The experimental results of the compound of Example 48 (dosage 66 μmol / kg) against KB-3-1 are shown in FIG.
[0403]
Example of calculation
(Building a superposition model with highly active compounds)
Using the compounds of Example 45, Example 46, and Example 48, which are compounds showing high differentiation-inducing activity, three-dimensional structures were superimposed in order to extract information on the spatial arrangement of atomic groups necessary for activity expression. .
[0404]
For this purpose, the same analysis can be performed using any of the commercially available calculation packages [CATALYST (MSI), Cerius2 / QSAR + (MSI), SYBYL / DISCO (Tripos), etc.]]. Although it is possible, SYBYL / DISCO (Tripos) was used for the creation and analysis of the overlay structure this time.
[0405]
For the compound of Example 48, a three-dimensional structure was generated using the sketch function of SYBYL, a point charge was imparted on each atom by the Gasteiger-Huckel method, and the structure was optimized using the Tripos force field. Next, interactions such as hydrophobic interaction sites (aromatic rings, aliphatic side chains) and hydrogen bonding sites (carbonyl oxygen, hydroxyl groups, amino groups, etc.) that are considered to be important for drug-body interactions are assumed. In order to identify the site to be detected, a dummy atom was placed at a site where interaction was possible.
[0406]
At this time, in order to distinguish the types of interaction such as hydrophobic interaction, hydrogen bond and electrostatic interaction site, the interaction was classified and different dummy atom types were set. Furthermore, a conformer rotated with respect to a rotatable bond was generated, and the one in which the distance between dummy atoms arranged at an assumed interaction site was changed was saved in a conformation file as a new conformation. For the compounds of Example 45 and Example 46, creation of a three-dimensional structure and generation of conformation were performed in the same manner.
[0407]
Using the compound of Example 48 as a template molecule, a superposition structure was formed so that dummy atoms showing the same kind of interaction in all the conformations of the compounds of Example 45 and Example 46 overlap for each conformation. Created.
[0408]
For the obtained superposition structure, the number of dummy atoms used for superposition (number of common interactions), three-dimensional overlap (overlap volume), and three-dimensional QSAR analysis results using activity values, etc. Based on this, the optimum overlay structure was selected.
[0409]
In the superposition structure obtained this time, in the centroid (W1) of the B ring, the centroid (W2) of the A ring and the hydrogen bond acceptor (such as carbonyl oxygen) (W3) of the compound of formula (13), W1 to W2 = It was shown that the arrangement was 8.34 cm, W1 to W3 = 3.80 cm, and W2 to W3 = 5.55 cm.
[0410]
(Calculation Example 1: Compound of Example 130) Example 45 used in the above-described superposition was performed by selecting appropriate seven atoms from the assumed interaction site of the compound of Example 130 and the constituent atoms of the benzamide structure. The compounds of Example 46 and Example 48 were used as target structures, and structural optimization was performed by giving a constraint potential to the compound of Example 130. Next, the constraint potential was released and the structure was optimized to obtain the active conformation of the compound of Example 130. For this active conformation, the center of gravity of the benzene ring of benzamide (W1), the center of gravity of the pyridine ring (W2) and the carbonyl oxygen (W3) were defined, and spatial configuration parameters were extracted.
[0411]
In addition, all conformations were generated for rotatable bonds, and the energy in each conformation was calculated to obtain the most stable structure. The energy in the most stable structure was calculated, and the energy difference from the active conformation was obtained. As a result, in the structure obtained this time, W1 to W2 = 8.43 Å, W1 to W3 = 3.82 Å, W2 to W3 = 5.88 Å (energy difference from the most stable structure: 2.86 kcal / mol) It was shown to take.
[0412]
In addition, the same result was obtained by performing an analysis operation using the dummy atom obtained by the construction of the superposition structure model as a target structure. (Calculation results) The calculation results are shown in Table-7 [Table 33]. Table-7: Results of calculation of parameters for spatial layout
[0413]
Figure 0004105451
[0414]
Figure 0004105451
[0415]
Figure 0004105451
[0416]
【The invention's effect】
The novel benzamide derivatives and novel alinide derivatives of the present invention have a differentiation-inducing action, and are useful as pharmaceuticals such as malignant tumors, autoimmune diseases, skin diseases, and parasitic infections. It is particularly effective as an anticancer drug and is effective for hematopoietic tumors and solid cancers.
[Brief description of the drawings]
FIG. 1 shows changes in tumor volume upon administration of the compound of Example 48 to tumor cells (HT-29).
FIG. 2 shows changes in tumor volume when the compound of Example 48 is administered to tumor cells (KB-3-1).

Claims (11)

下記式（１）：
Figure 0004105451
 [式中、Aは、ピリジル基、又は１〜４個の置換基を有するピリジル基であり、ここで前記ピリジル基についての置換基が、ハロゲン原子、ヒドロキシル基、アミノ基、ニトロ基、シアノ基、１〜４個の炭素原子を有するアルキル基、１〜４個の炭素原子を有するアルコキシ基、１〜４個の炭素原子を有するアミノアルキル基、１〜４個の炭素原子を有するアルキルアミノ基、１〜４個の炭素原子を有するアシル基、１〜４個の炭素原子を有するアシルアミノ基、１〜４個の炭素原子を有するアルキルチオ基、１〜４個の炭素原子を有するペルフルオロアルキル基、１〜４個の炭素原子を有するペルフルオロアルキルオキシ基、カルボキシル基、１〜４個の炭素原子を有するアルコキシカルボニル基及びフェニル基から成る群から選択され；
Xは、下記式（２）：
−(CH2)e− ， −(CH2)g−O−(CH2)e− (2)
で表されるものから選択された構造であり、ここでeは１〜４の整数であり；g及びmは独立して、０〜４の整数であり；
nは、１であり；
Qは、下記式（４）：
Figure 0004105451
 により表されるものから選択された構造であり、ここでR7及びR8は独立して、水素原子、１〜４個の炭素原子有するアルキル基、又は置換基として、ハロゲン原子、ヒドロキシル基、アミノ基、ニトロ基、シアノ基、フェニル基及びピリジル基から成る群から選択された１〜４個の置換基を有する、１〜４個の炭素原子有するアルキル基であり；
R1は、水素原子であり；
R2は、水素原子、ヒドロキシル基、１〜４個の炭素原子有するアルキル基、１〜４個の炭素原子有するアルコキシ基である]
で表される化合物、又は医薬的に許容できるその塩。Following formula (1):
Figure 0004105451
 [Wherein, A is a pyridyl group or a pyridyl group having 1 to 4 substituents, wherein the substituent for the pyridyl group is a halogen atom, a hydroxyl group, an amino group, a nitro group, or a cyano group. , An alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an aminoalkyl group having 1 to 4 carbon atoms, an alkylamino group having 1 to 4 carbon atoms An acyl group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 4 carbon atoms, Selected from the group consisting of a perfluoroalkyloxy group having 1 to 4 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 1 to 4 carbon atoms, and a phenyl group;
X is the following formula (2):
− (CH 2 ) e −, − (CH 2 ) g −O− (CH 2 ) e − (2)
Wherein e is an integer from 1 to 4; g and m are each independently an integer from 0 to 4;
n is 1;
Q is the following formula (4):
Figure 0004105451
 Wherein R7 and R8 are independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a substituent such as a halogen atom, a hydroxyl group, or an amino group. An alkyl group having 1 to 4 carbon atoms having 1 to 4 substituents selected from the group consisting of nitro group, cyano group, phenyl group and pyridyl group;
R1 is a hydrogen atom;
R2 is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms]
Or a pharmaceutically acceptable salt thereof. R1及びR2が水素原子である請求項１記載の化合物又は医薬的に許容できるその塩。  The compound according to claim 1, wherein R1 and R2 are hydrogen atoms, or a pharmaceutically acceptable salt thereof. 下記式（13）：
Figure 0004105451
 [式中、Aは、フェニル基、１〜４個の置換基を有するフェニル基、複素環基、又は１〜４個の置換基を有する複素環基であり；ここで前記複素環基の複素環部分は、ピリジン、ピラジン、ピリミジン、ピリダジン、チオフェン、フラン、ピロール、ピラゾール、イソキサゾール、イソチアゾール、イミダゾール、オキサゾール、チアゾール、ピペリジン、ピペラジン、ピロリジン、キヌクリジン、テトラヒドロフラン、モルホリン、チオモルホリン、キノリン、イソキノリン、ナフチリジン、フロピリジン、チエノピリジン、ピロロピリジン、オキサゾロピリジン、イミダゾロピリジン、チアゾロピリジン、ベンゾフラン、ベンゾチオフェン及びベンズイミダゾールから成る群から選択され、そして前記フェニル基又は複素環基についての置換基は、ハロゲン原子、ヒドロキシル基、アミノ基、ニトロ基、シアノ基、１〜４個の炭素原子有するアルキル基、１〜４個の炭素原子有するアルコキシ基、１〜４個の炭素原子有するアミノアルキル基、１〜４個の炭素原子有するアルキルアミノ基、１〜４個の炭素原子有するアシル基、１〜４個の炭素原子有するアシルアミノ基、１〜４個の炭素原子有するアルキルチオ基、１〜４個の炭素原子有するペルフルオロアルキル基、１〜４個の炭素原子有するペルフルオロアルキルオキシ基、カルボキシル基、１〜４個の炭素原子有するアルコキシカルボニル基及びフェニル基から成る群から選択された、1〜４個の置換基であり；
-Y-B-は、下記のような（１）又は（２）であり；
（１）Bは、フェニル基、１〜４個の置換基を有するフェニル基であり、ここで前記フェニル基についての置換基は、ハロゲン原子、ヒドロキシル基、アミノ基、ニトロ基、シアノ基、１〜４個の炭素原子有するアルキル基、１〜４個の炭素原子有するアルコキシ基、１〜４個の炭素原子有するアミノアルキル基、１〜４個の炭素原子有するアルキルアミノ基、１〜４個の炭素原子有するアシル基、１〜４個の炭素原子有するアシルアミノ基、１〜４個の炭素原子有するアルキルチオ基、１〜４個の炭素原子有するペルフルオロアルキル基、１〜４個の炭素原子有するペルフルオロアルキルオキシ基、カルボキシル基、１〜４個の炭素原子有するアルコキシカルボニル基及びフェニル基から成る群から選択された、1〜４個の置換基であり；そしてYは、下記式（29）又は（31）：
Figure 0004105451
Figure 0004105451
 で表される基の1つであり；又は
（２）Bは、複素環基、又は１〜４個の置換基を有する複素環基であり；ここで前記複素環基の複素環部分は、ベンゾチオフェン、ベンゾフラン及びチオフェンから成る群から選択され、ここで前記複素環基についての置換基が、ハロゲン原子、ヒドロキシル基、アミノ基、ニトロ基、シアノ基、１〜４個の炭素原子有するアルキル基、１〜４個の炭素原子有するアルコキシ基、１〜４個の炭素原子有するアミノアルキル基、１〜４個の炭素原子有するアルキルアミノ基、１〜４個の炭素原子有するアシル基、１〜４個の炭素原子有するアシルアミノ基、１〜４個の炭素原子有するアルキルチオ基、１〜４個の炭素原子有するペルフルオロアルキル基、１〜４個の炭素原子有するペルフルオロアルキルオキシ基、カルボキシル基、１〜４個の炭素原子有するアルコキシカルボニル基及びフェニル基から成る群から選択された、1〜４個の置換基であり；そしてYは、下記式（30）：
Figure 0004105451
 で表される基の１つであり；
R3は、アミノ基である]
で表される構造を有するアニリド化合物、又は医薬的に許容できるその塩。Following formula (13):
Figure 0004105451
 [Wherein, A is a phenyl group, a phenyl group having 1 to 4 substituents, a heterocyclic group, or a heterocyclic group having 1 to 4 substituents; The ring moiety is pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, pyrrole, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, piperidine, piperazine, pyrrolidine, quinuclidine, tetrahydrofuran, morpholine, thiomorpholine, quinoline, isoquinoline, Selected from the group consisting of naphthyridine, furopyridine, thienopyridine, pyrrolopyridine, oxazolopyridine, imidazolopyridine, thiazolopyridine, benzofuran, benzothiophene, and benzimidazole, and for the phenyl or heterocyclic group Groups are halogen atom, hydroxyl group, amino group, nitro group, cyano group, alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, aminoalkyl having 1 to 4 carbon atoms Groups, alkylamino groups having 1 to 4 carbon atoms, acyl groups having 1 to 4 carbon atoms, acylamino groups having 1 to 4 carbon atoms, alkylthio groups having 1 to 4 carbon atoms, 1 to 4 1 to 4 selected from the group consisting of perfluoroalkyl groups having 1 carbon atom, perfluoroalkyloxy groups having 1 to 4 carbon atoms, carboxyl groups, alkoxycarbonyl groups having 1 to 4 carbon atoms, and phenyl groups Substituents;
-YB- is (1) or (2) as follows;
(1) B is a phenyl group and a phenyl group having 1 to 4 substituents, wherein the substituents for the phenyl group are a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, 1 Alkyl group having ˜4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, aminoalkyl group having 1 to 4 carbon atoms, alkylamino group having 1 to 4 carbon atoms, 1 to 4 carbon atoms Acyl group having carbon atoms, acylamino group having 1 to 4 carbon atoms, alkylthio group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, perfluoroalkyl having 1 to 4 carbon atoms 1 to 4 substituents selected from the group consisting of an oxy group, a carboxyl group, an alkoxycarbonyl group having 1 to 4 carbon atoms and a phenyl group; Te Y is represented by the following formula (29) or (31):
Figure 0004105451
Figure 0004105451
 Or (2) B is a heterocyclic group or a heterocyclic group having 1 to 4 substituents; wherein the heterocyclic portion of the heterocyclic group is Selected from the group consisting of benzothiophene, benzofuran and thiophene, wherein the substituent for the heterocyclic group is a halogen atom, hydroxyl group, amino group, nitro group, cyano group, alkyl group having 1 to 4 carbon atoms , An alkoxy group having 1 to 4 carbon atoms, an aminoalkyl group having 1 to 4 carbon atoms, an alkylamino group having 1 to 4 carbon atoms, an acyl group having 1 to 4 carbon atoms, 1 to 4 Acylamino group having 1 carbon atom, alkylthio group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, perfluoroalkyloxy group having 1 to 4 carbon atoms Carboxyl groups, selected from the group consisting of 1-4 alkoxycarbonyl group and a phenyl group having a carbon atom, with 1-4 substituents; and Y is represented by the following formula (30):
Figure 0004105451
 One of the groups represented by
R3 is an amino group]
An anilide compound having a structure represented by the formula: or a pharmaceutically acceptable salt thereof. Yが、下記式（31）：
Figure 0004105451
 で表される基の１つである請求項３記載のアニリド化合物、又は医薬的に許容できるその塩。Y is the following formula (31):
Figure 0004105451
 The anilide compound according to claim 3, or a pharmaceutically acceptable salt thereof. Yが、下記式（29）：
Figure 0004105451
 で表される基の１つである請求項３記載のアニリド化合物、又は医薬的に許容できるその塩。Y is the following formula (29):
Figure 0004105451
 The anilide compound according to claim 3, or a pharmaceutically acceptable salt thereof. Aが複素環基、又は置換基として、ハロゲン原子、ヒドロキシル基、アミノ基、ニトロ基、シアノ基、１〜４個の炭素原子有するアルキル基、１〜４個の炭素原子有するアルコキシ基、１〜４個の炭素原子有するアミノアルキル基、１〜４個の炭素原子有するアルキルアミノ基、１〜４個の炭素原子有するアシル基、１〜４個の炭素原子有するアシルアミノ基、１〜４個の炭素原子有するアルキルチオ基、１〜４個の炭素原子有するペルフルオロアルキル基、１〜４個の炭素原子有するペルフルオロアルキルオキシ基、カルボキシル基、１〜４個の炭素原子有するアルコキシカルボニル基及びフェニル基から成る群から選択された、１〜４個の置換基を有する複素環基である請求項３記載のアニリド化合物、又は医薬的に許容できるその塩。  A is a heterocyclic group, or a substituent such as a halogen atom, hydroxyl group, amino group, nitro group, cyano group, alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, 1 to Aminoalkyl group having 4 carbon atoms, alkylamino group having 1 to 4 carbon atoms, acyl group having 1 to 4 carbon atoms, acylamino group having 1 to 4 carbon atoms, 1 to 4 carbons A group consisting of an alkylthio group having an atom, a perfluoroalkyl group having 1 to 4 carbon atoms, a perfluoroalkyloxy group having 1 to 4 carbon atoms, a carboxyl group, an alkoxycarbonyl group having 1 to 4 carbon atoms, and a phenyl group The anilide compound according to claim 3, which is a heterocyclic group having 1 to 4 substituents selected from: or a pharmaceutically acceptable salt thereof. 下記式：
Figure 0004105451
 で表される化合物、又は医薬的に許容できるその塩。Following formula:
Figure 0004105451
 Or a pharmaceutically acceptable salt thereof. 下記式：
Figure 0004105451
 で表される化合物、又は医薬的に許容できるその塩。Following formula:
Figure 0004105451
 Or a pharmaceutically acceptable salt thereof. 請求項１〜８のいずれか１項記載の１又は複数の化合物又は医薬的に許容できるその塩を、活性成分として含んで成る医薬組成物。  A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof as an active ingredient. 請求項１〜８のいずれか１項記載の１又は複数の化合物又は医薬的に許容できるその塩を、活性成分として含んで成る抗癌薬。  An anticancer drug comprising one or more compounds according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof as an active ingredient. 癌、自己免疫疾患、皮膚病又は寄生虫感染症の治療への使用のための組成物の製造への請求項１〜８のいずれか１項記載の化合物又は医薬的に許容できるその塩の使用。  Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the manufacture of a composition for use in the treatment of cancer, autoimmune diseases, skin diseases or parasitic infections. .
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US8030344B2 (en) 2007-03-13 2011-10-04 Methylgene Inc. Inhibitors of histone deacetylase
US20100056522A1 (en) 2007-03-28 2010-03-04 Santen Pharmaceutical Co., Ltd. Intraocular pressure-lowering agent comprising compound having histone deacetylase inhibitor effect as active ingredient
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