具有CCR10 拮抗活性的模板固定的拟肽

摘要

如说明书和权利要求中定义的通式(I)的新的模板固定的β-发夹拟肽，其中单一元件T或P是以任一方向连接的α-氨基酸残基，取决于它们在链中的位置，具有拮抗受体CCR10的性质。它们可用作药物来治疗或预防真皮和皮肤病症、炎症、过敏性病症、呼吸疾病、胃肠道疾病、眼病、血液病和癌症。这些β-发夹拟肽可通过基于混合的固相和溶液相合成策略的方法来制备。

主权项

1.通式(I)的化合物其中单一元件T或P以任一方向从羰基(C=O)附着点连接至下一个元件的氮(N)，并且其中T¹和T²独立地是：下式之一的L或Dα-氨基酸：P¹和P³独立地是：-NR¹CH(R¹⁹)CO-;P²是-NR¹C(R²⁰)(R²¹)CO-；或-NR¹C(Z)CO-;P⁴是-NR¹CH(R²⁴)CO-;A是O;NR⁹;S;SO;或SO₂R¹,R²和R³独立地是H;CF₃;低级烷基;低级烯基;芳基-低级烷基;或杂芳基-低级烷基;R⁴,R⁵,R⁶,R⁷和R⁸独立地是：H;F;CF₃;低级烷基;低级烯基;环烷基;杂环烷基;芳基;杂芳基;芳基-低级烷基;杂芳基-低级烷基;-(CHR¹³)_oOR¹⁵;-(CHR¹³)_oSR¹⁵;-(CHR¹³)_oNR¹⁵R¹⁶;-(CHR¹³)_oOCONR¹⁵R¹⁶;-(CHR¹³)_oNR¹CONR¹⁵R¹⁶;-(CHR¹³)_oNR¹COR¹⁵;-(CHR¹³)_oCOOR¹⁵;-(CHR¹³)_oCONR¹⁵R¹⁶;-(CHR¹³)_oPO(OR¹)₂;-(CHR¹³)_oSO₂R¹⁵;-(CHR¹³)_oNR¹SO₂R¹⁵;-(CHR¹³)_oSO₂NR¹⁵R¹⁶;-(CR¹R¹³)_oR³⁰;或-(CHR¹)_nO(CHR²)_mR³⁰;或R⁴和R²可以一起形成=O;-(CHR¹⁹)_p-;-(CH₂)_nO(CH₂)_m-;-(CH₂)_nS(CH₂)_m-;或-(CH₂)_nNR¹(CH₂)_m-;或R⁴和R⁵;R⁵和R⁶;R⁶和R⁷;R⁷和R⁸;或R⁶和R⁹可以一起形成-(CHR¹⁹)_p-;-(CH₂)_nO(CH₂)_m-;-(CH₂)_nS(CH₂)_m-;或-(CH₂)_nNR¹(CH₂)_m-;R⁹和R¹⁰独立地是：H;F;CF₃;低级烷基;低级烯基;环烷基;杂环烷基;芳基;杂芳基;芳基-低级烷基;杂芳基-低级烷基;-(CHR¹³)_rOR¹⁵;-(CHR¹³)_rSR¹⁵;-(CHR¹⁰)_rNR¹⁵R¹⁶;-(CHR¹³)_rOCONR¹⁵R¹⁶;-(CHR¹³)_rNR¹CONR¹⁵R¹⁶;-(CHR¹³)_rNR¹COR¹⁵;-(CHR¹³)_oCOOR¹⁵;-(CHR¹³)_oCONR¹⁵R¹⁶;-(CHR¹³)_rPO(OR¹)₂;-(CHR¹³)_rSO₂R¹⁵;-(CHR¹³)_rNR¹SO₂R¹⁵;-(CHR¹³)_rSO₂NR¹⁵R¹⁶;-(CR¹R¹³)_oR³⁰;或-(CHR¹)_rO(CHR¹)_oR³⁰;R¹¹和R¹²独立地是：H;F;Cl;Br;CF₃;OCF₃;OCHF₂;CN;NO₂;低级烷基;低级烯基;芳基;杂芳基;芳基-低级烷基;杂芳基-低级烷基;-(CHR¹³)_oOR¹⁵;-(CHR¹³)_oSR¹⁵;-(CHR¹³)_oNR¹⁵R¹⁶;-(CHR¹³)_oOCONR¹⁵R¹⁶;-(CHR¹³)_oNR¹CONR¹⁵R¹⁶;-(CHR¹³)_oNR¹COR¹⁵;-(CHR¹³)_oCOOR¹⁵;-(CHR¹³)_oCONR¹⁵R¹⁶;-(CHR¹³)_oPO(OR¹)₂;-(CHR¹³)_oSO₂R¹⁵;-(CHR¹³)_oNR¹SO₂R¹⁵;-(CHR¹³)_oSO₂NR¹⁵R¹⁶;或-(CR¹R¹³)_oR³⁰;R¹³是H;F;CF₃;低级烷基;低级烯基;环烷基;杂环烷基;环烷基-低级烷基;杂环烷基-低级烷基;芳基;杂芳基;芳基-低级烷基;杂芳基-低级烷基;-(CHR¹)_oOR¹⁵;-(CHR¹)_oSR¹⁵;-(CHR¹)_oNR¹⁵R¹⁶;-(CHR¹)_oNC(=NR¹⁷)NR¹⁵R¹⁶;-(CHR¹)_oCOOR¹⁵;-(CHR¹)_oCONR¹⁵R¹⁶;-(CHR¹)_oSO₂R¹⁵;或-(CHR¹)_oSO₂NR¹⁵R¹⁶;R¹⁴是H;CF₃;低级烷基;低级烯基;环烷基;杂环烷基;环烷基-低级烷基;杂环烷基-低级烷基;芳基;杂芳基;芳基-低级烷基;杂芳基-低级烷基;环烷基-芳基;杂环烷基-芳基;环烷基-杂芳基;杂环烷基-杂芳基;芳基-环烷基;芳基-杂环烷基;杂芳基-环烷基;杂芳基-杂环烷基;-(CHR¹)_oOR¹⁵;-(CHR¹)_oSR¹⁵;-(CHR¹)_oNR¹⁵R¹⁶;-(CHR¹)_oCOOR¹⁵;-(CHR¹)_oCONR¹⁵R¹⁶;或-(CHR¹)_oSO₂R¹⁵;R¹⁵,R¹⁶,R¹⁷和R¹⁸独立地是：H;低级烷基;低级烯基;低级烷氧基;环烷基;杂环烷基;环烷基-低级烷基;杂环烷基-低级烷基;芳基;杂芳基;芳基-低级烷基;杂芳基-低级烷基;环烷基-芳基;杂环烷基-芳基;环烷基-杂芳基;杂环烷基-杂芳基;芳基-环烷基;芳基-杂环烷基;杂芳基-环烷基;或杂芳基-杂环烷基;或结构元件-NR¹⁵R¹⁶和-NR¹⁷R¹⁸可以独立地形成：杂环烷基;芳基-杂环烷基;或杂芳基-杂环烷基;或下列式之一的基团：X和Y独立地是：-CR⁴⁵;或N;R¹⁹是烷基;烯基;环烷基-低级烷基;杂环烷基-低级烷基;-(CR¹R⁴)_nR³⁰;-(CH₂)_nO(CH₂)_mR³⁰;-(CH₂)_nS(CH₂)_mR³⁰;或-(CH₂)_nNR¹⁴(CH₂)_mR³⁰;R²⁰和R²¹独立地是：烷基;烯基;-(CHR⁴)_oOR¹⁵;-(CHR⁴)_oSR¹⁵;或-(CHR⁴)_rNR¹⁵R¹⁶;Z是-(CR²²R²³)_(n+m+1)-;-(CR²²R²³)_nNR¹⁵(CR²²R²³)_m-;-(CR²²R²³)_nO(CR²²R²³)_m-;-(CR²²R²³)_nS(CR²²R²³)_m-;-O(CR²²R²³)_rO-;或下列式之一的基团：R²²和R²³独立地是：H;F;CF₃;烷基;烯基;环烷基;杂环烷基;芳基;杂芳基;芳基-低级烷基;或杂芳基-低级烷基;-(CR¹R¹³)_oOR¹⁵;-(CR¹R¹³)_oSR¹⁵;-(CR¹R¹³)_oNR¹⁵R¹⁶;-(CR¹R¹³)_oCOOR¹⁵;-(CR¹R¹³)_oCONR¹⁵R¹⁶;或-(CR¹R¹³)_oSO₂R¹⁵;或R²²和R²³可以一起形成=O;=NR¹;=NOR¹;=NOCF₃;-(CHR¹)_p-;或-O(CR¹R²)_rO-;R²⁴是烷基;烯基;-(CR¹R¹³)_qNR¹⁵R¹⁶;-(CR¹R¹³)_qNR²⁵R²⁶;-(CR¹R¹³)_qNR¹⁴R²⁷;-(CH₂)_qC(=NR¹³)NR¹⁵R¹⁶;-(CH₂)_qC(=NOR¹⁷)NR¹⁵R¹⁶;-(CH₂)_qC(=NNR¹⁵R¹⁶)NR¹⁷R¹⁸;-(CR¹R¹³)_qNR²C(=NR¹⁷)NR¹⁵R¹⁶;-(CR¹R¹³)_qN=C(NR¹⁵R¹⁶)NR¹⁷R¹⁸;-(CR¹R¹³)_qOR¹⁴;-(CR¹R¹³)_qOR²⁵;-(CR¹R¹³)_qOR²⁷;-(CR¹R¹³)_qSR¹⁵;-(CR¹R¹³)_qSO₂R¹⁵;-(CR¹R¹³)_qNR¹⁴SO₂R¹⁵;-(CR¹R¹³)_qSO₂NR¹R¹⁴;-(CR¹R¹³)_qNR¹⁴SO₂NR¹⁵R¹⁶;-(CR¹R¹³)_qSO₂NR¹⁵R¹⁶;-(CR¹R¹³)_qPO(OR¹)₂;-(CH₂)_nO(CH₂)_mNR¹⁵R¹⁶;-(CH₂)_nO(CH₂)_mC(=NR¹⁷)NR¹⁵R¹⁶;-(CH₂)_nO(CH₂)_mC(=NOR¹⁷)NR¹⁵R¹⁶;-(CH₂)_nO(CH₂)_mC(=NNR¹⁵R¹⁶)NR¹⁷R¹⁸;-(CH₂)_nO(CH₂)_mNR¹C(=NR¹⁷)NR¹⁵R¹⁶;-(CH₂)_nO(CH₂)_mN=C(NR¹⁵R¹⁶)NR¹⁷R¹⁸;-(CH₂)_nS(CH₂)_mNR¹⁵R¹⁶;-(CH₂)_nS(CH₂)_mC(=NR¹⁷)NR¹⁵R¹⁶;-(CH₂)_nS(CH₂)_mC(=NOR¹⁷)NR¹⁵R¹⁶;-(CH₂)_nS(CH₂)_mC(=NNR¹⁵R¹⁶)NR¹⁷R¹⁸;-(CH₂)_nS(CH₂)_mNR¹C(=NR¹⁷)NR¹⁵R¹⁶;-(CH₂)_nS(CH₂)_mN=C(NR¹⁵R¹⁶)NR¹⁷R¹⁸;-(CR¹R¹³)_qCOOR¹⁵;-(CR¹R¹³)_qCOOR²⁵;-(CR¹R¹³)_qCOOR²⁸;-(CR¹R¹³)_qCONR¹⁵R¹⁶;或-(CR¹R¹³)_qCONR²⁵R²⁶;或，杂芳基;或杂芳基烷基;R²⁵和R²⁶独立地是：H;-CH₃;-[(CH₂)₂O]_rCH₃;或-[(CH₂)₂O]_rCF₃;R²⁷是-COR¹⁹;-CO(CR¹R¹³)_oR¹⁵;-CO(CR¹R¹³)_oOR¹⁴;-CO(CR¹R¹³)_oNR¹⁵R¹⁶;-CO(CR¹R¹³)_oNR²R¹⁴;-CO(CR¹R¹⁹)NR¹⁵R¹⁶;-CO(CR¹R²⁹)NR¹⁵R¹⁶;-CO(CHR¹)_oCONR¹⁵R¹⁶;-CO(CHR¹)_oCONR²SO₂R¹⁵;-CO(CR¹R¹³)_oNR²SO₂R¹⁵;-CONR¹(CHR¹⁵)_nNR²(CHR¹³)_mR¹⁴;-CO(CHR¹⁵)_nO(CHR¹³)_mR¹⁴;-CONR¹(CHR¹⁵)_nO(CHR¹³)_mR¹⁴;-SO₂R¹⁹;-SO₂(CR¹R¹³)_oR¹⁵;-SO₂(CR¹R¹³)_oNR¹⁵R¹⁶;或-SO₂(CR¹R¹³)_oNR¹R²⁵;R²⁸是-NR¹C(R²)(R¹⁹)COOR¹⁵;-NR¹C(R²)(R¹⁹)CONR¹⁵R¹⁶;-NR¹C(R²)(R²⁹)COOR¹⁵;-NR¹C(R²)(R²⁹)CONR¹⁵R¹⁶;R²⁹是-(CR¹R¹³)_qNR¹⁵R¹⁶;-(CH₂)_qC(=NR¹⁷)NR¹⁵R¹⁶;-(CH²)_qC(=NOR¹⁷)NR¹⁵R¹⁶;-(CH₂)_qC(=NNR¹⁵R¹⁶)NR¹⁷R¹⁸;-(CR¹R¹³)_qNR²C(=NR¹⁶)NR¹⁴R¹⁵;-(CR¹R¹³)_qN=C(NR¹⁵R¹⁶)NR¹⁷R¹⁸;-(CR¹R¹³)_qOR¹⁴;-(CR¹R¹³)_qSR¹⁵;-(CR¹R¹³)_qSO₂R¹⁵;-(CR¹R¹³)_qNR¹⁴SO₂R¹⁵;-(CR¹R¹³)_qSO₂NR¹R¹⁴;-(CR¹R¹³)_qSO₂NR¹⁵R¹⁶;-(CR¹R¹³)_qNR²SO₂NR¹⁵R¹⁶;-(CR¹R¹³)_qPO(OR¹)₂;-(CH₂)_nO(CH₂)_mNR¹⁵R¹⁶;-(CH₂)_nO(CH₂)_mC(=NR¹⁷)NR¹⁵R¹⁶;-(CH₂)_nO(CH₂)_mC(=NOR¹⁷)NR¹⁵R¹⁶;-(CH₂)_nO(CH₂)_mC(=NNR¹⁵R¹⁶)NR¹⁷R¹⁸;-(CH₂)_nO(CH₂)_mNR¹⁴C(=NR¹⁷)NR¹⁵R¹⁶;-(CH₂)_nO(CH₂)_mN=C(NR¹⁵R¹⁶)NR¹⁷R¹⁸;-(CH₂)_nS(CH₂)_mNR¹⁵R¹⁶;-(CH₂)_nS(CH₂)_mNR¹⁵R¹⁶;-(CH₂)_nS(CH₂)_mC(=NR¹⁷)NR¹⁵R¹⁶;-(CH₂)_nS(CH₂)_mC(=NOR¹⁷)NR¹⁵R¹⁶;-(CH₂)_nS(CH₂)_mC(=NNR¹⁵R¹⁶)NR¹⁷R¹⁸;-(CH₂)_nS(CH₂)_mNR¹⁴C(=NR¹⁷)NR¹⁵R¹⁶;-(CH₂)_nS(CH₂)_mN=C(NR¹⁵R¹⁶)NR¹⁷R¹⁸;-(CR¹R¹³)_qCOOR¹⁵;或-(CR¹R¹³)_qCONR¹⁵R¹⁶;R³⁰是下列式之一的芳基基团或下列式之一的杂芳基基团R³¹和R³²独立地是：H;F;Cl;Br;NO₂;CN;CF₃;OCHF₂;OCF₃;低级烷基;低级烯基;芳基-低级烷基;芳基;杂芳基;-(CH₂)_oR³³;-(CH₂)_oOR¹⁵;-O(CH₂)_oR³³;-(CH₂)_oSR¹⁵;-(CH₂)_oNR¹⁵R¹⁶;-(CH₂)_oOCONR¹⁵R¹⁶;-(CH₂)_oNR¹CONR¹⁵R¹⁶;-(CH₂)_oNR¹COR¹⁵;-(CH₂)_oCOOR¹⁵;-(CH₂)_oCONR¹⁵R¹⁶;-(CH₂)_oPO(OR¹)₂;-(CH₂)_oSO₂R¹⁴;或-(CH₂)_oCOR¹⁵;R³³是下列式的芳基基团R³⁴,R³⁵和R³⁶独立地是：H;F;Cl;Br;OH;NH₂;NO₂;CN;CF₃;OCHF₂;OCF₃;-NR¹R¹⁵;-(CH₂)_oCOOR¹⁵;-(CH₂)_oCONR¹R¹⁵;低级烷基;低级烷氧基;或低级烯基;R³⁷是H;低级烷基;或芳基-低级烷基;R³⁸,R³⁹,R⁴⁰和R⁴¹独立地是：H;F;CF₃;低级烷基;低级烯基;环烷基;杂环烷基;芳基;杂芳基;芳基-低级烷基;杂芳基-低级烷基;-(CHR¹)_oOR¹⁵;-(CHR¹)_oSR¹⁵;-(CHR¹)_oNR²R¹⁵;-(CHR¹)_oOCONR²R¹⁵;-(CHR¹)_oNR²CONR³R¹⁵;-(CHR¹)_oNR²COR¹⁵;-(CHR¹)_oCOOR¹⁵;-(CHR¹)_oCONR²R¹⁵;-(CHR¹)_oPO(OR²)₂;-(CHR¹)_oSO₂R¹⁵;-(CHR¹)_oNR²SO₂R¹⁵;-(CHR¹)_oSO₂NR²R¹⁵;-(CR¹R²)_oR³³;或-(CHR¹)_nO(CHR²)_mR³³;R⁴²和R⁴³独立地是：H;F;CF₃;低级烷基;低级烯基;环烷基;杂环烷基;芳基;杂芳基;芳基-低级烷基;杂芳基-低级烷基;-(CHR¹)_rOR¹⁵;-(CHR¹)_rSR¹⁵;-(CHR¹)_rNR²R¹⁵;-(CHR¹)_rOCONR²R¹⁵;-(CHR¹)_rNR²CONR³R¹⁵;-(CHR¹)_rNR²COR¹⁵;-(CHR¹)_oCOOR¹⁵;-(CHR¹)_oCONR²R¹⁵;-(CHR¹)_rPO(OR²)₂;-(CHR¹)_rSO₂R¹⁵;-(CHR¹)_rNR²SO₂R¹⁵;-(CHR¹)_rSO₂NR²R¹⁵;-(CR¹R²)_oR³³;或-(CHR¹)_rO(CHR²)_oR³³;R⁴⁴和R⁴⁵独立地是：H;F;Cl;Br;CF₃;OCF₃;OCHF₂;CN;NO₂;低级烷基;低级烯基;芳基;杂芳基;芳基-低级烷基;杂芳基-低级烷基;-(CHR¹)_oOR¹⁵;-(CHR¹)_oSR¹⁵;-(CHR¹)_oNR²R¹⁵;-(CHR¹)_oOCONR²R¹⁵;-(CHR¹)_oNR²CONR³R¹⁵;-(CHR¹)_oNR²COR¹⁵;-(CHR¹)_oCOOR¹⁵;-(CHR¹)_oCONR²R¹⁵;-(CHR¹)_oPO(OR²)₂;-(CHR¹)_oSO₂R¹⁵;-(CHR¹)_oNR²SO₂R¹⁵;-(CHR¹)_oSO₂NR²R¹⁵;或-(CR¹R²)_oR³³;n和m独立地是0-5的整数，条件是n+m≤6;o是0-4;p是2-6;q是1-6;r是1-3;或其药学上可接收的盐。