JP2005526062A - 低分子侵入阻害剤 - Google Patents
低分子侵入阻害剤 Download PDFInfo
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Abstract
Description
本発明の化合物はHIVウイルスが宿主細胞に侵入する過程を阻害する阻害剤であることを見いだした。前記化合物は式(I)
Aは、アリール、ヘテロアリールまたはヘテロシクロアルキルであり、
R1は、水素、ハロゲン、ヒドロキシ、アミノ、ニトロ、アルキル、アルキルオキシまたは式(II)
R2は、アルキル、アルケニル、アルキニル、ヒドロキシ、ハロゲン、ニトロ、シアノ、アミノ、ハロアルキル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクロアルキル、R8−O−、R8−S−、R8−S(=O)2−、R8−C(=O)−、R8−C(=S)−、R8−C(=NH)−、R8−C(=NCN)−、R8−NH−、(R8)2−N−、HO−C(=O)−、NH2−C(=O)−、NH2−S(=O)2−、NH2−C(=S)−、NH2−C(=NH)−、NH2−C(=NCN)−、R8−NR4−C(=O)−、R8−NR4−S(=O)2−、R8−O−C(=O)−、R8−C(=O)−NR4−、R8−S(=O)2−NR4−、R8−C(=O)−O−、R8−S−CH2−またはR8−O−CH2−C(=O)−を表し、
R3は、ヒドロキシ、アミノ、アルキルオキシ、シクロアルキルオキシまたは一置換もしくは二置換アミノ[ここで、置換基はアルキルおよびシクロアルキルから選択可能である]を表し、
R4は、水素、アルキルまたはシクロアルキルを表し、
R6は、水素、アミノ、R7−C(=O)−、R8−S(=O)2−NH−、R8−C(=O)−NH−、R8−C(=S)−NH−、R8−C(=NH)−NH−、R8−C(=NCN)−NH−、R8−O−C(=O)−NH−、R8−O−アルカンジイル−C(=O)−NH−、R8−アルカンジイル−S(=O)2−NH−、アリール−アルカンジイル−C(=O)−NH−、アリール−アルケンジイル−C(=O)−NH−、ヘテロアリール−アルカンジイル−C(=O)−NH−、シクロアルキル−アルカンジイル−C(=O)−NH−、ヘテロシクロアルキル−アルカンジイル−C(=O)−NH−または置換アルキル[ここで、置換基はアミノ、R7−C(=O)−、R8−S(=O)2−NH−、R8−C(=O)−NH−、R8−C(=S)−NH−、R8−C(=NH)−NH−、R8−C(=NCN)−NH−、R8−O−C(=O)−NH−、R8−O−アルカンジイル−C(=O)−NH−、R8−アルカンジイル−S(=O)2−NH−、アリール−アルカンジイル−C(=O)−NH−、ヘテロアリール−アルカンジイル−C(=O)−NH−、シクロアルキル−アルカンジイル−C(=O)−NH−およびヘテロシクロアルキル−アルカンジイル−C(=O)−NH−から選択可能である]であり、
R7は、ヒドロキシ、アミノ、アルキルオキシ、シクロアルキルオキシまたは一置換もしくは二置換アミノ[ここで、置換基はアルキルおよびシクロアルキルから選択可能である]を表し、
R8は、アルキル、ハロアルキル、シクロアルキル、アリール、ヘテロアリールまたはヘテロシクロアルキルを表し、
Yは、アルカンジイル、−C(=O)−、−C(=S)−、−C(=NH)−、−C(=NCN)−、−S(=O)−、−S(=O)2−、−C(=O)−CH2−O−、−C(=O)−O−、−C(=O)−(CH2)p−、−C(=O)−NH−またはアルケンジイル−C(=O)−を表し、
Xは、直接結合、−O−、−S−、−S(=O)2−、−O−S(=O)2−、−S(=O)2−O−、−NH−S(=O)2−、−S(=O)2−NH−、−C(=O)−、−C(=S)−、−C(=NH)−、−C(=NCN)−、−O−C(=O)−、−C(=O)−O−、−NH−C(=O)−、−C(=O)−NH−またはアルカンジイルであり、
mおよびnは、各々独立して、ゼロ、1または2であり、
pは、1から4の整数である}
で表される化合物、これらのN−オキサイド形態、立体化学異性体、ラセミ混合物、塩、プロドラッグ、エステルおよび代謝産物である。
R1は、水素、ハロゲンまたは式(II)
R2は、アルキル、アルケニル、アルキニル、ヒドロキシ、ハロゲン、ニトロ、シアノ、アミノ、ハロアルキル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクロアルキル、R8−O−、R8−S−、R8−S(=O)2−、R8−C(=O)−、R8−C(=S)−、R8−C(=NH)−、R8−C(=NCN)−、R8−NH−、(R8)2−N−、HO−C(=O)−、NH2−C(=O)−、NH2−S(=O)2−、NH2−C(=S)−、NH2−C(=NH)−、NH2−C(=NCN)−、R8−NR4−C(=O)−、R8−NR4−S(=O)2−、R8−O−C(=O)−、R8−C(=O)−NR4−、R8−S(=O)2−NR4−またはR8−C(=O)−O−を表し、
R3は、ヒドロキシ、アミノ、アルキルオキシ、シクロアルキルオキシまたは一置換もしくは二置換アミノ[ここで、置換基はアルキルおよびシクロアルキルから選択可能である]を表し、
R4は、水素、アルキルまたはシクロアルキルを表し、
R6は、水素、アミノ、R7−C(=O)−、R8−S(=O)2−NH−、R8−C(=O)−NH−、R8−C(=S)−NH−、R8−C(=NH)−NH−、R8−C(=NCN)−NH−、R8−O−C(=O)−NH−、R8−O−アルカンジイル−C(=O)−NH−、R8−アルカンジイル−S(=O)2−NH−、アリール−アルカンジイル−C(=O)−NH−、ヘテロアリール−アルカンジイル−C(=O)−NH−、シクロアルキル−アルカンジイル−C(=O)−NH−、ヘテロシクロアルキル−アルカンジイル−C(=O)−NH−または置換アルキル[ここで、置換基はアミノ、R7−C(=O)−、R8−S(=O)2−NH−、R8−C(=O)−NH−、R8−C(=S)−NH−、R8−C(=NH)−NH−、R8−C(=NCN)−NH−、R8−O−C(=O)−NH−、R8−O−アルカンジイル−C(=O)−NH−、R8−アルカンジイル−S(=O)2−NH−、アリール−アルカンジイル−C(=O)−NH−、ヘテロアリール−アルカンジイル−C(=O)−NH−、シクロアルキル−アルカンジイル−C(=O)−NH−およびヘテロシクロアルキル−アルカンジイル−C(=O)−NH−から選択可能である]であり、
R7は、ヒドロキシ、アミノ、アルキルオキシ、シクロアルキルオキシまたは一置換もしくは二置換アミノ[ここで、置換基はアルキルおよびシクロアルキルから選択可能である]を表し、
R8は、アルキル、シクロアルキル、アリール、ヘテロアリールまたはヘテロシクロアルキルを表し、
Yは、アルカンジイル、−C(=O)−、−C(=S)−、−C(=NH)−、−C(=NCN)−、−S(=O)−、−S(=O)2−、−C(=O)−CH2−O−、−C(=O)−O−、−C(=O)−(CH2)p−を表し、
Xは、直接結合、−O−、−S−、−S(=O)2−、−O−S(=O)2−、−S(=O)2−O−、−NH−S(=O)2−、−S(=O)2−NH−、−C(=O)−、−C(=S)−、−C(=NH)−、−C(=NCN)−、−O−C(=O)−、−C(=O)−O−、−NH−C(=O)−、−C(=O)−NH−またはアルカンジイルであり、
mおよびnは、各々独立して、ゼロ、1または2であり、
pは、1から4の整数である}
で表される化合物、これらのN−オキサイド形態、立体化学異性体、ラセミ混合物、塩、プロドラッグ、エステルおよび代謝産物も包含する。
・ Yが−C(=O)−または−S(=O)2−であり、
・ R1が式(II)であり、
・ R2がハロゲン、ブロモ、クロロ、アルキル、ハロアルキル、アルキルオキシ、アルケニルまたはアルキニルであり、前記R2基が式(III)で表される化合物の中に部分Yからそれぞれメタ、パラ、およびメタとパラ位に位置しており、
・ nが1であり、
・ Xが−CH2−、−NH−S(=O)2−、−S(=O)2−NH−、−NH−C(=O)−または−C(=O)−NH−であり、
・ R6がR7−C(=O)−、R8−S(=O)2−NH−またはR8−C(=O)−NH−であり、前記R6基が式(II)で表される化合物の中に互いに隣接して位置、即ち部分Xからそれぞれメタとパラ位またはオルソとメタ位に位置し、
・ mが2であり、
・ R7がヒドロキシまたはアルキルオキシであり、
・ R8がハロゲン、ブロモ、クロロ、アルキル、アルキルオキシ、ハロアルキル、アルケニル、アルキニルで置換されているアリールであり、前記アリール基上の前記置換基が前記アリール基の結合点からそれぞれメタもしくはパラ位に位置する。
スキーム1
種類1−Aの化合物、例えばアントラニル酸などをTHFの如き溶媒および水に溶解させておいた塩基、例えばK2CO3またはNa2CO3などと混合した後、前記混合物に化合物1−Bを添加する。撹拌を室温で数時間行うと化合物1−Cが生じる。高純度の化合物1−Cをその溶液から得る目的で、前記混合物を酸性にした後、溶媒、例えば酢酸エチルなどを用いた抽出を適用する。次に、化合物1−Cに還元を例えばPd/Cと水素を用いて溶媒、例えばアルコールであるエタノールまたはメタノールなど中で受けさせる。その後、混合を室温で行いそして濾過を行った後に溶媒を除去することで、化合物1−Dを得る。化合物1−Eを添加し、そして1番目の段階と同様にしてTHF、K2CO3またはNa2CO3および水を用いることで、化合物1−Fを最終的に得る。
0.5gの化合物5−Aを25mlのTHFに入れることで生じさせた室温の混合物に水を5mlおよび炭酸ナトリウムを745mg加えた。この混合物を30分間撹拌した後、2.2当量の化合物5−BをTHF(5ml)に入れて滴下した。この反応混合物を3時間撹拌した後、濾過することで、化合物5−Cを得た。化合物5−Cを水に溶解させ、この溶液を濃塩酸溶液でpH=3になるまで酸性にした後、酢酸エチルで抽出した。その有機層を分離し、MgSO4で乾燥させた後、蒸発させることで、化合物5−Dを514mg(54%)得た。
1gの化合物6−Aを30mlのTHFに入れることで生じさせた室温の混合物に水を10mlおよび炭酸カリウムを1.57g加えた。この混合物を30分間撹拌した後、1.1当量の化合物6−Bを滴下した。この反応混合物を3時間撹拌した後、濃塩酸溶液でpH=3になるまで酸性にした。その結果として生じた溶液を酢酸エチルで抽出した。その有機層を分離し、MgSO4で乾燥させた後、蒸発させることで、化合物6−Cを503mg(32%)得た。
1.5gの化合物7−A(R1=−CN)を25mlのDMFに入れることで生じさせた室温の混合物に炭酸カリウムを5.2g(3当量)加えた。この混合物を80℃で30分間撹拌した後、化合物7−Bを2.33g加えた。この反応混合物を140℃で12時間撹拌した。反応をTLCで監視し、出発材料が消費された時点で、その混合物を室温になるまで温めた後、水を加えた。塩酸溶液をpH=3になるまで添加することでその溶液を酸性にした。生成物を酢酸エチルで抽出した。その有機層を分離し、MgSO4で乾燥させた後、蒸発させることで、化合物7−Cを3g(83%)得た。
Claims (11)
- 式(I)
Aは、アリール、ヘテロアリールまたはヘテロシクロアルキルであり、
R1は、水素、ハロゲン、ヒドロキシ、アミノ、ニトロ、アルキル、アルキルオキシまたは式(II)
R2は、アルキル、アルケニル、アルキニル、ヒドロキシ、ハロゲン、ニトロ、シアノ、アミノ、ハロアルキル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクロアルキル、R8−O−、R8−S−、R8−S(=O)2−、R8−C(=O)−、R8−C(=S)−、R8−C(=NH)−、R8−C(=NCN)−、R8−NH−、(R8)2−N−、HO−C(=O)−、NH2−C(=O)−、NH2−S(=O)2−、NH2−C(=S)−、NH2−C(=NH)−、NH2−C(=NCN)−、R8−NR4−C(=O)−、R8−NR4−S(=O)2−、R8−O−C(=O)−、R8−C(=O)−NR4−、R8−S(=O)2−NR4−、R8−C(=O)−O−、R8−S−CH2−またはR8−O−CH2−C(=O)−を表し、
R3は、ヒドロキシ、アミノ、アルキルオキシ、シクロアルキルオキシまたは一置換もしくは二置換アミノ[ここで、置換基はアルキルおよびシクロアルキルから選択可能である]を表し、
R4は、水素、アルキルまたはシクロアルキルを表し、
R6は、水素、アミノ、R7−C(=O)−、R8−S(=O)2−NH−、R8−C(=O)−NH−、R8−C(=S)−NH−、R8−C(=NH)−NH−、R8−C(=NCN)−NH−、R8−O−C(=O)−NH−、R8−O−アルカンジイル−C(=O)−NH−、R8−アルカンジイル−S(=O)2−NH−、アリール−アルカンジイル−C(=O)−NH−、アリール−アルケンジイル−C(=O)−NH−、ヘテロアリール−アルカンジイル−C(=O)−NH−、シクロアルキル−アルカンジイル−C(=O)−NH−、ヘテロシクロアルキル−アルカンジイル−C(=O)−NH−または置換アルキル[ここで、置換基はアミノ、R7−C(=O)−、R8−S(=O)2−NH−、R8−C(=O)−NH−、R8−C(=S)−NH−、R8−C(=NH)−NH−、R8−C(=NCN)−NH−、R8−O−C(=O)−NH−、R8−O−アルカンジイル−C(=O)−NH−、R8−アルカンジイル−S(=O)2−NH−、アリール−アルカンジイル−C(=O)−NH−、ヘテロアリール−アルカンジイル−C(=O)−NH−、シクロアルキル−アルカンジイル−C(=O)−NH−およびヘテロシクロアルキル−アルカンジイル−C(=O)−NH−から選択可能である]であり、
R7は、ヒドロキシ、アミノ、アルキルオキシ、シクロアルキルオキシまたは一置換もしくは二置換アミノ[ここで、置換基はアルキルおよびシクロアルキルから選択可能である]を表し、
R8は、アルキル、ハロアルキル、シクロアルキル、アリール、ヘテロアリールまたはヘテロシクロアルキルを表し、
Yは、アルカンジイル、−C(=O)−、−C(=S)−、−C(=NH)−、−C(=NCN)−、−S(=O)−、−S(=O)2−、−C(=O)−CH2−O−、−C(=O)−O−、−C(=O)−(CH2)p−、−C(=O)−NH−またはアルケンジイル−C(=O)−を表し、
Xは、直接結合、−O−、−S−、−S(=O)2−、−O−S(=O)2−、−S(=O)2−O−、−NH−S(=O)2−、−S(=O)2−NH−、−C(=O)−、−C(=S)−、−C(=NH)−、−C(=NCN)−、−O−C(=O)−、−C(=O)−O−、−NH−C(=O)−、−C(=O)−NH−またはアルカンジイルであり、
mおよびnは、各々独立して、ゼロ、1または2であり、
pは、1から4の整数である}
で表される化合物、これのN−オキサイド形態、立体化学異性体、ラセミ混合物、塩、プロドラッグ、エステルまたは代謝産物。 - 式(III)
R1は、ハロゲン、水素または式(II)
R2は、アルキル、アルケニル、アルキニル、ヒドロキシ、ハロゲン、ニトロ、シアノ、アミノ、ハロアルキル、シクロアルキル、アリール、ヘテロアリール、ヘテロシクロアルキル、R8−O−、R8−S−、R8−S(=O)2−、R8−C(=O)−、R8−C(=S)−、R8−C(=NH)−、R8−C(=NCN)−、R8−NH−、(R8)2−N−、HO−C(=O)−、NH2−C(=O)−、NH2−S(=O)2−、NH2−C(=S)−、NH2−C(=NH)−、NH2−C(=NCN)−、R8−NR4−C(=O)−、R8−NR4−S(=O)2−、R8−O−C(=O)−、R8−C(=O)−NR4−、R8−S(=O)2−NR4−またはR8−C(=O)−O−を表し、
R3は、ヒドロキシ、アミノ、アルキルオキシ、シクロアルキルオキシまたは一置換もしくは二置換アミノ[ここで、置換基はアルキルおよびシクロアルキルから選択可能である]を表し、
R4は、水素、アルキルまたはシクロアルキルを表し、
R6は、水素、アミノ、R7−C(=O)−、R8−S(=O)2−NH−、R8−C(=O)−NH−、R8−C(=S)−NH−、R8−C(=NH)−NH−、R8−C(=NCN)−NH−、R8−O−C(=O)−NH−、R8−O−アルカンジイル−C(=O)−NH−、R8−アルカンジイル−S(=O)2−NH−、アリール−アルカンジイル−C(=O)−NH−、ヘテロアリール−アルカンジイル−C(=O)−NH−、シクロアルキル−アルカンジイル−C(=O)−NH−、ヘテロシクロアルキル−アルカンジイル−C(=O)−NH−または置換アルキル[ここで、置換基はアミノ、R7−C(=O)−、R8−S(=O)2−NH−、R8−C(=O)−NH−、R8−C(=S)−NH−、R8−C(=NH)−NH−、R8−C(=NCN)−NH−、R8−O−C(=O)−NH−、R8−O−アルカンジイル−C(=O)−NH−、R8−アルカンジイル−S(=O)2−NH−、アリール−アルカンジイル−C(=O)−NH−、ヘテロアリール−アルカンジイル−C(=O)−NH−、シクロアルキル−アルカンジイル−C(=O)−NH−およびヘテロシクロアルキル−アルカンジイル−C(=O)−NH−から選択可能である]であり、
R7は、ヒドロキシ、アミノ、アルキルオキシ、シクロアルキルオキシまたは一置換もしくは二置換アミノ[ここで、置換基はアルキルおよびシクロアルキルから選択可能である]を表し、
R8は、アルキル、シクロアルキル、アリール、ヘテロアリールまたはヘテロシクロアルキルを表し、
Yは、アルカンジイル、−C(=O)−、−C(=S)−、−C(=NH)−、−C(=NCN)−、−S(=O)−、−S(=O)2−、−C(=O)−CH2−O−、−C(=O)−O−、−C(=O)−(CH2)p−を表し、
Xは、直接結合、−O−、−S−、−S(=O)2−、−O−S(=O)2−、−S(=O)2−O−、−NH−S(=O)2−、−S(=O)2−NH−、−C(=O)−、−C(=S)−、−C(=NH)−、−C(=NCN)−、−O−C(=O)−、−C(=O)−O−、−NH−C(=O)−、−C(=O)−NH−またはアルカンジイルであり、
mおよびnは、各々独立して、ゼロ、1または2であり、
pは、1から4の整数である}
で表される化合物、これのN−オキサイド形態、立体化学異性体、ラセミ混合物、塩、プロドラッグ、エステルまたは代謝産物。 - Yが−C(=O)−、−S(=O)2−である請求項1または2記載の化合物。
- Xが−NH−S(=O)2、−S(=O)2−NH−、−NH−C(=O)、−C(=O)−NH−である請求項1または2記載の化合物。
- R2がハロゲン、ブロモ、クロロ、アルキル、アルキルオキシ、ハロアルキル、アルケニル、アルキニルであり、前記置換基がメタまたはパラ位に位置しそしてnが1である請求項1または2記載の化合物。
- 単量体である請求項1から6のいずれか1項記載の化合物。
- 二量体である請求項1から6のいずれか1項記載の化合物。
- 薬剤として用いるための請求項1から8のいずれか1項記載の化合物。
- HIVウイルスが哺乳動物宿主細胞の中に侵入する過程を阻害し得る薬剤を製造するための請求項1から8のいずれか1項記載化合物の使用。
- 請求項1から8のいずれか1項記載の活性材料を治療有効量で含有しかつ1種以上の薬学的に受け入れられる賦形剤を含有する薬剤組成物。
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SG145742A1 (en) * | 2003-09-11 | 2008-09-29 | Tibotec Pharm Ltd | Entry inhibitors of the hiv virus |
BRPI0510059B8 (pt) * | 2004-04-23 | 2021-05-25 | Hoffmann La Roche | inibidores da transcriptase reversa não-nucleosídica e seus usos |
US20060025480A1 (en) | 2004-08-02 | 2006-02-02 | Boehringer Ingelheim International Gmbh | Benzoic acid derivatives as non nucleoside reverse transcriptase inhibitors |
US7569725B2 (en) | 2004-10-21 | 2009-08-04 | Britsol-Myers Squibb Company | Anthranilic acid derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase 3 |
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US20110294853A1 (en) * | 2008-09-12 | 2011-12-01 | Benjamin Pelcman | Bis Aromatic Compounds for Use in the Treatment of Inflammation |
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Also Published As
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NZ535614A (en) | 2006-10-27 |
MX263097B (es) | 2008-12-15 |
CA2477851C (en) | 2009-12-29 |
ZA200406986B (en) | 2005-09-22 |
AU2003219158B2 (en) | 2008-09-11 |
US20060025594A1 (en) | 2006-02-02 |
US7429677B2 (en) | 2008-09-30 |
IL163959A0 (en) | 2005-12-18 |
AU2003219158C1 (en) | 2009-04-02 |
CA2477851A1 (en) | 2003-09-18 |
JP4627987B2 (ja) | 2011-02-09 |
CN101519368A (zh) | 2009-09-02 |
NO20044269L (no) | 2004-10-08 |
RU2004130295A (ru) | 2005-10-27 |
RU2395491C2 (ru) | 2010-07-27 |
IL163959A (en) | 2010-12-30 |
AU2003219158A1 (en) | 2003-09-22 |
PH12004501358B1 (en) | 2010-02-08 |
MXPA04008926A (es) | 2004-12-13 |
EP1485079B1 (en) | 2014-04-02 |
WO2003075907A3 (en) | 2004-03-04 |
CN1652759A (zh) | 2005-08-10 |
HRP20040937A2 (en) | 2005-10-31 |
PL373030A1 (en) | 2005-08-08 |
BR0308588A (pt) | 2005-02-15 |
EP1485079A2 (en) | 2004-12-15 |
WO2003075907A2 (en) | 2003-09-18 |
KR20040091722A (ko) | 2004-10-28 |
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