JP2017528467A5 - - Google Patents

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JP2017528467A5
JP2017528467A5 JP2017513438A JP2017513438A JP2017528467A5 JP 2017528467 A5 JP2017528467 A5 JP 2017528467A5 JP 2017513438 A JP2017513438 A JP 2017513438A JP 2017513438 A JP2017513438 A JP 2017513438A JP 2017528467 A5 JP2017528467 A5 JP 2017528467A5
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文献
ＥＰ０５２２８６８
ＥＰ０８７５５６９
ＥＰ１２９５９４４
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ＷＯ ２００４／０４５５２０
ＷＯ ２００４／０４５５５３
ＷＯ ２００４／０４６３４２
ＷＯ ２００４／０４７７４９
ＷＯ ２００４／０４８９３８
ＷＯ ２００４／０５３０７９
ＷＯ ２００４／０６３３５５
ＷＯ ２００４／０６３３６２
ＷＯ ２００４／０６３７０９
ＷＯ ２００４／０６５５７７
ＷＯ ２００４／０７４３２０
ＷＯ ２００４０００２２１
ＷＯ ２００４０２０５８３
ＷＯ ２００４０４２３４６
ＷＯ ２００４０６５５７６
ＷＯ ２００５／０２３８１４
ＷＯ ２００５／０８２０２３
ＷＯ ２００５／０８５２５１
ＷＯ ２００６／１１１７５９
ＷＯ ２００７／０４４５１５
ＷＯ ２００７／０８５９３０
ＷＯ ２００９／０５２２４９
ＷＯ ２０１０／０９１１５０
ＷＯ ９１／０２５３６
ＷＯ ９２／０７５７４
ＷＯ ９２／１７４９７
ＷＯ ９４／１０３１２
ＷＯ ９４／２８９３１
ＷＯ ９６３０５１４
ＷＯ ９７／０７１９８
ＷＯ ９７／４４４５２
ＷＯ ９８／１３０５９
ＷＯ ９８／３７１９３
ＷＯ ９８／４０４０３
ＷＯ ９８／５１８０５
ＷＯ ９８／５１８２４
ＷＯ ９９／２８４６８
ＷＯ ９９／４６２８４
ＷＯ ９９／５８６５８

Claims (19)

  1. 式（Ａ）のコンジュゲートであって、
    Figure 2017528467
     式中、
    Ｄが、基Ｄ１またはＤ２
    Figure 2017528467
     のいずれかを示し：
    点線が、Ｃ２及びＣ３間の二重結合の任意の存在を示し；
    Ｃ２及びＣ３との間に二重結合が存在する場合、Ｒ2が、以下からなる群から選択され：
    （ｉａ）ハロ、ニトロ、シアノ、エーテル、カルボキシ、エステル、Ｃ1-7アルキル、Ｃ3-7ヘテロシクリル及びビス−オキシ−Ｃ1-3アルキレンを含む群から選択される１つ以上の置換基によって任意に置換されたＣ5-10アリール基；
    （ｉｂ）Ｃ1-5飽和脂肪族アルキル；
    （ｉｃ）Ｃ3-6飽和シクロアルキル；
    （ｉｄ）
    Figure 2017528467
     Ｒ31、Ｒ32及びＲ33の各々が、独立して、Ｈ、Ｃ1-3飽和アルキル、Ｃ2-3アルケニル、Ｃ2-3アルキニル及びシクロプロピルから選択され、Ｒ2基の炭素原子の総数は、５以下である；
    （ｉｅ）
    Figure 2017528467
     Ｒ35a及びＲ35bの一方が、Ｈであり、他方が、フェニル（フェニルは、任意でハロ、メチル、メトキシから選択される基によって置換される）；ピリジル；及びチオフェニルから選択される；及び
    （ｉｆ）
    Figure 2017528467
     Ｒ34が、Ｈ；Ｃ1-3飽和アルキル；Ｃ2-3アルケニル；Ｃ2-3アルキニル；シクロプロピル；フェニル、（フェニルは、任意でハロ、メチル、メトキシから選択される基によって置換される）；ピリジル；及びチオフェニルから選択される；
    （ｉｇ）ハロ；
    Ｃ２とＣ３との間に単結合が存在する場合、
    Ｒ2が、
    Figure 2017528467
     であり、Ｒ36a及びＲ36bが、独立して、Ｈ、Ｆ、Ｃ1-4飽和アルキル、Ｃ2-3アルケニルから選択され、アルキル及びアルケニル基は、任意でＣ1-4アルキルアミド及びＣ1-4アルキルエステルから選択される基によって置換され；または、Ｒ16a及びＲ16bの一方が、Ｈである場合、他方が、ニトリル及びＣ1-4アルキルエステルから選択され；
    Ｚが、ＮまたはＣＨであり；
    Ｄ’が、基Ｄ’１またはＤ’２
    Figure 2017528467
     のいずれかを示し：
    点線が、Ｃ２’及びＣ３’間の二重結合の任意の存在を示し；
    Ｒ6及びＲ9が、独立して、Ｈ、Ｒ、ＯＨ、ＯＲ、ＳＨ、ＳＲ、ＮＨ2、ＮＨＲ、ＮＲＲ’、ＮＯ2、Ｍｅ3Ｓｎ及びハロから選択され；
    Ｒ7が、独立して、Ｈ、Ｒ、ＯＨ、ＯＲ、ＳＨ、ＳＲ、ＮＨ2、ＮＨＲ、ＮＲＲ’、ＮＯ2、Ｍｅ3Ｓｎ及びハロから選択され；
    Ｙが、式Ａ１のものであり：
    Figure 2017528467
     ＲN1が、Ｈ及びＣ１−４アルキルから選択され；
    Ｌが、細胞結合剤に結合されたリンカーであり；
    ＣＢＡが、前記細胞結合剤であり；
    ｎが、０〜４８の範囲で選択される整数であり；
    Ｑが、
    Figure 2017528467
     であり、ＱXは、Ｑが、アミノ酸残基、ジペプチド残基またはトリペプチド残基であるものであり；
    以下のいずれかであり
    （ａ）Ｒ10が、Ｈであり、Ｒ11が、ＯＨ、ＯＲAであり、ＲAが、Ｃ1-4アルキルである；または
    （ｂ）Ｒ10及びＲ11が、それらが結合されている窒素及び炭素原子間に窒素−炭素二重結合を形成する；または
    （ｃ）Ｒ10が、Ｈであり、Ｒ11が、ＯＳＯzＭであり、ｚが、２または３であり、Ｍが、一価の製剤的に許容可能なカチオンである；
    Ｒ及びＲ’が、それぞれ独立して、任意に置換されたＣ1-12アルキル、Ｃ3-20ヘテロシクリル及びＣ5-20アリール基から選択され、任意で基ＮＲＲ’に関して、Ｒ及びＲ’が、これらが結合する窒素原子とともに任意に置換された４、５、６または７員の複素環式環を形成し；
    式中、Ｒ16、Ｒ17、Ｒ19、Ｒ20、Ｒ21及びＲ22が、Ｒ6、Ｒ7、Ｒ9、Ｒ10、Ｒ11及びＲ2それぞれに対して定義したとおりであり；
    式中、Ｔ及びＴ”が、独立して、単結合またはＣ1-9アルキレンから選択され、その鎖が１つ以上のヘテロ原子、例えば、Ｏ、Ｓ、Ｎ（Ｈ）、ＮＭｅによって中断されてよいが、Ｘ及びＸ’間の原子の最短の鎖中の原子の数が、３〜１２個の原子であることを条件とし；及び
    Ｘ及びＸ’が、独立して、Ｏ、Ｓ及びＮ（Ｈ）から選択される、前記コンジュゲート。
  2. Ｒ9 がＨであり、Ｒ 6 がＨであり、Ｒ 7 がＯＲ 7A であり、ここで、Ｒ 7A が任意に置換されたＣ 1-4 アルキルであり、ＸがＯであり、且つＴが単結合、Ｃ 1 、及びＣ 2 アルキレン基から選択される、請求項１に記載のコンジュゲート。
  3. Ｔが、Ｃ1アルキレン基である、請求項２に記載のコンジュゲート。
  4. Ｄが、Ｄ１であり、Ｃ２及びＣ３との間に二重結合があり、
    Ｒ2が、
    （ａ）メトキシ、エトキシ、フルオロ、クロロ、シアノ、ビス−オキシ−メチレン、メチル−ピペラジニル、モルホリノ及びメチル−チオフェニルから選択される１〜３個の置換基を保持するＣ 5-7 アリール基、又は
    （ｂ）Ｃ 1-5 飽和脂肪族アルキル基、又は
    （ｃ）Ｃ 3-6 飽和シクロアルキル基、又は
    （ｄ）次式：
    Figure 2017528467
     （ここで、Ｒ 2 基の炭素原子の総数は４以下である）
    の基、又は
    （ｅ）次式：
    Figure 2017528467
     の基、又は
    （ｆ）次式：
    Figure 2017528467
     （ここで、Ｒ 34 は、Ｈ、メチル、エチル、エテニル及びエチニルから選択される）
    の基
    である、請求項１から３のいずれか一項に記載のコンジュゲート。
  5. ＤがＤ１であり、Ｃ２及びＣ３との間に単結合があり、
    Ｒ2が、
    Figure 2017528467
     （ここで、Ｒ 36a 及びＲ 36b は、
    （ａ）共にＨであるか、又は
    （ｂ）共にメチルであるか、又は
    （ｃ）一方がＨであり、他方がＣ 1-4 飽和アルキル及びＣ 2-3 アルケニルから選択され、ここで、前記アルキル及びアルケニル基は随意に置換されていてよい）
    である、請求項１から３のいずれか一項に記載のコンジュゲート。
  6. Ｒ10 がＨであり、Ｒ11 がＯＨである、請求項１から５のいずれか一項に記載のコンジュゲート。
  7. Ｒ10及びＲ11が、それらが結合されている窒素及び炭素原子間に窒素−炭素二重結合を形成する、請求項１から５のいずれか一項に記載のコンジュゲート。
  8. Ｒ16、Ｒ17、Ｒ19、Ｒ20、Ｒ21、Ｄ’、Ｘ’及びＴ’が、それぞれＲ6、Ｒ7、Ｒ9、Ｒ10、Ｒ11、Ｄ、Ｘ及びＴと同じである、請求項１から７のいずれか一項に記載のコンジュゲート。
  9. Ｑが、
    NH −Ｐｈｅ−Ｌｙｓ− C=O 、
    NH −Ｖａｌ−Ａｌａ− C=O 、
    NH −Ｖａｌ−Ｌｙｓ− C=O 、
    NH −Ａｌａ−Ｌｙｓ− C=O 、
    NH −Ｖａｌ−Ｃｉｔ− C=O 、
    NH −Ｐｈｅ−Ｃｉｔ− C=O 、
    NH −Ｌｅｕ−Ｃｉｔ− C=O 、
    NH −Ｉｌｅ−Ｃｉｔ− C=O 、
    NH −Ｐｈｅ−Ａｒｇ− C=O 、及び
    NH −Ｔｒｐ−Ｃｉｔ− C=O
    から選択されるジペプチド残基である、請求項１から８のいずれか一項に記載のコンジュゲート。
  10. Ｌが、以下の式：
    −ＬA−（ＣＨ2）m− （Ｌ１）
    （式中、ｍは０〜６である）；又は
    −Ｌ A −（ＣＨ 2 ） m −Ｏ− （Ｌ２）
    （式中、ｍは０〜６である）；又は
    −Ｌ A −（ＣＨ 2 ） q −Ｏ−Ｃ（＝Ｏ）−ＮＨ−（ＣＨ 2 ） p − （Ｌ３）
    （式中、ｑは１〜３であり、ｐは１〜３である）：
    のものであり、
    ここで、ＬAが、以下のもの：
    Figure 2017528467
     （式中、Ａｒが、Ｃ5-6アリーレン基を示す）
    から選択される、請求項１から９のいずれか一項に記載のコンジュゲート。
  11. 前記細胞結合剤が、抗体またはその活性フラグメントである、請求項１から１０のいずれか一項に記載のコンジュゲート。
  12. 前記抗体または抗体フラグメントが、腫瘍関連抗原のための抗体または抗体フラグメントである、請求項１１に記載のコンジュゲート。
  13. 療法に使用するための請求項１から１２のいずれか一項に記載のコンジュゲート。
  14. 請求項１から１２のいずれか一項に記載のコンジュゲート、製剤的に許容可能な希釈剤、キャリアまたは賦形剤を含む医薬組成物。
  15. 対象の増殖性疾患の治療に使用するための請求項１から１２のいずれか一項に記載のコンジュゲートまたは請求項１４に記載の医薬組成物。
  16. 式（Ｂ）の化合物であって、
    Figure 2017528467
     式中、
    Ｄ、Ｄ’、Ｒ6、Ｒ7、Ｒ9、Ｒ10、Ｒ11、Ｒ16、Ｒ17、Ｒ19、Ｒ20、Ｒ21、Ｚ、Ｔ、Ｔ’、Ｘ及びＸ’が、請求項１から８のいずれか一項に定義されるとおりであり；
    ＹLが、式Ｂ１のものであり：
    Figure 2017528467
     Ｇが、細胞結合剤に結合するための反応基であり、
    Ｑ、ＲN1及びｎが、請求項１から９のいずれか一項に定義されるとおりである、前記化合物。
  17. Ｇが、以下の式：
    ＧA−（ＣＨ2）m− （Ｇ１）
    （式中、ｍは０〜６である）；又は
    Ｇ A −（ＣＨ 2 ） m −Ｏ− （Ｇ２）
    （式中、ｍは０〜６である）；又は
    Ｇ A −（ＣＨ 2 ） q −Ｏ−Ｃ（＝Ｏ）−ＮＨ−（ＣＨ 2 ） p − （Ｇ３）
    （式中、ｑは１〜３であり、ｐは１〜３である）：
    のものであり、
    ここで、ＧAが、以下のもの：
    Figure 2017528467
     （式中、ＡｒはＣ5-6アリーレン基を示す）
    から選択される、請求項１６に記載の化合物。
  18. 式（Ｃ）の化合物であって、
    Figure 2017528467
     式中、
    Ｄ、Ｄ’、Ｒ6、Ｒ7、Ｒ9、Ｒ16、Ｒ17、Ｒ19、Ｚ、Ｔ、Ｔ’、Ｘ及びＸ’が、請求項１から８のいずれか一項に定義されるとおりであり；
    ＹCが、式Ｃ１のものであり：
    Figure 2017528467
     Ｑ、ＲN1及びｎが、請求項１から９のいずれか一項に定義されるとおりであり；
    以下のいずれかであり
    （ａ）Ｒ30が、Ｈであり、Ｒ31が、ＯＨ、ＯＲAであり、ＲAが、Ｃ1-4アルキルである；または
    （ｂ）Ｒ30及びＲ31が、それらが結合されている窒素及び炭素原子間に窒素−炭素二重結合を形成する；または
    （ｃ）Ｒ30が、Ｈであり、Ｒ31が、ＯＳＯzＭであり、ｚが、２または３であり、Ｍが、一価の製剤的に許容可能なカチオンである；または
    （ｄ）Ｒ30が、窒素保護基であり、Ｒ31が、ＯＰｒｏｔOであり、ＰｒｏｔOが、ヒドロキシ保護基である；及び
    Ｒ40及びＲ41が、Ｒ30及びＲ31それぞれに対して定義したとおりである、前記化合物。
  19. 細胞結合薬剤と請求項１６又は１７に記載の薬剤−リンカーをコンジュゲートするステップを含む、請求項１から１２のいずれか一項に記載のコンジュゲートの合成方法。
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