[发明专利]可用于治疗包括肥胖症和糖尿病的代谢疾患的大麻素受体拮抗剂/逆激动剂

摘要

本发明提供了用作大麻素受体拮抗剂的新颖吡唑及其药物组合物和使用它们治疗肥胖症、糖尿病、肝脏疾患和/或心脏代谢疾患的方法。

主权项

1.一种式I的化合物或其立体异构体或药学上可接受的盐：其中：X、Y、X′、Y′、X″和Y″独立地选自：H、C_1-6烷基、卤素、CF₃、O-C_1-6烷基、NO₂、NR₂、O(CH₂)_nCO₂R、O(CH₂)_nCN、OCH₂CH＝CHCO₂R、CH₂O(CH₂)_nCO₂R、CH₂OCH₂CH＝CHCO₂R、O(CH₂)_nPO(OR)₂、CH₂O(CH₂)_nPO(OR)₂、NR^a(CH₂)_nCO₂R、NR^a(CH₂)_nPO(OR)₂、NR^aCH₂CH＝CHCO₂R、NR^aSO₂R、NR^aCO(CH₂)_nCO₂R、NR^aCO(CH₂)_nCONR^a₂、O(CH₂)_nC₆H₄CO₂R、O(CH₂)_nC₆H₄(CH₂)_nCO₂R、CH₂O(CH₂)_nC₆H₄CO₂R、O(CH₂)_nC₆H₄CONR^a₂、O(CH₂)_nC₆H₄(CH₂)_nCONR^a₂、O(CH₂)_nC₆H₄-四唑、CH₂O(CH₂)_nC₆H₄CONR^a₂、CH₂O(CH₂)_nC₆H₄-四唑、O(CH₂)_nC₆H₄(CH₂)_n-四唑、NR^a(CH₂)_nC₆H₄CO₂R、CH₂NR^a(CH₂)_nC₆H₄CO₂R、NR^a(CH₂)_nC₆H₄(CH₂)_nCO₂R、NR^a(CH₂)_nC₆H₄CONR^a₂、CH₂NR^a(CH₂)_nC₆H₄CONR^a₂、NR^a(CH₂)_nC₆H₄(CH₂)_nCONR^a₂、NR^a(CH₂)_nC₆H₄-四唑、CH₂NR^a(CH₂)_nC₆H₄-四唑、NR^a(CH₂)_nC₆H₄(CH₂)_n-四唑、CONHOH、C(NH)NR^a₂、(CH₂)_nC(NH)NR^a₂、O(CH₂)_nCONR^a₂、O(CH₂)_nC(NH)NR^a₂、O(CH₂)_nC(NOH)NR^a₂、CH₂O(CH₂)_nCONR^a₂、NR^a(CH₂)_nCONR^a₂、OCH₂CH＝CHCONR^a₂、CH₂OCH₂CH＝CHCONR^a₂、NR^aCH₂CH＝CHCONR^a₂、(CH₂)_m-四唑、O(CH₂)_n-四唑、O(CH₂CH₂O)PR、NR^a(CH₂CH₂O)_pR和SO₂NHCH₃；Z选自：H、C_1-6烷基、OH、O-C_1-6烷基、O(CH₂CH₂O)_PR、OC(O)-C_1-6烷基、O(CH₂)_nCO₂R、OCH₂CH＝CHCO₂R、O(CH₂)_nPO(OR)₂、O(CH₂)_nCONR^a₂、O(CH₂)_nC(NH)NH₂、O(CH₂)_nC(NOH)NR^a₂、OCH₂CH＝CHCONR^a₂、O(CH₂)_n-苯基-(CH₂)_mCO₂R和O(CH₂)_n-苯基-(CH₂)_m-四唑；Z′选自H、CO₂R和CONR^a₂；Q选自：(CH₂)_nCHA(CH₂)_mC(O)NR₂、(CH₂)_mCAA″(CH₂)_mC(O)NR₂、(CH₂)_nCHA(CH₂)_mCO₂R、(CH₂)_mCAA″(CH₂)_mCO₂R、(CH₂)_mCHA(CH₂)_mSO₂NR₂、(CH₂)_mCHA(CH₂)_mSO₃R、(CH₂)_mCHA(CH₂)_mC(NH)NH₂、(CH₂)_mCHA(CH₂)_mC(NOH)NH₂、(CH₂)_mCHA(CH₂)_mCONHCHA(CH₂)_mCO₂R、(CH₂)_mCAA″(CH₂)_mCONHCHA(CH₂)_mCO₂R、(CH₂)_mCHA(CH₂)_mCONHCHA(CH₂)_mCONHCHA(CH₂)_mCO₂R、(CH₂)_mCHA(CH₂)_mCONHCHA(CH₂)_mCONR^a₂(CH₂)_mCAA″(CH₂)_mCONHCHA(CH₂)_mCONR^a₂、(CH₂)_mCHA(CH₂)_mCONHCHA(CH₂)_mCONHCHA(CH₂)_mCONR^a₂、C₃-C₆-环氨基-(CH₂)_mCO₂R、C₃-C₆-环氨基-(CH₂)_mCONR^a₂、C₃-C₆-环亚烷基-(CH₂)_mCO₂R和C₃-C₆-环亚烷基-(CH₂)_mCONR^a₂；前提是当Q是(CH₂)_mCAA″(CH₂)_mC(O)NR₂或(CH₂)_mCAA″(CH₂)_mCO₂R时，则(a)m不是0，(b)A不是H，或(c)(a)和(b)两者；A选自H、C_1-6烷基、(CH₂)_mC_3-6-环烷基、OH、CH₂OH、CH(CH₃)OH、C(CH₃)₂OH、(CH₂)_nCO₂R^b、(CH₂)_nC(O)NR^b₂和(CH₂)_m-苯基，其中所述苯基被选自H、C_1-4烷基、卤素、CF₃、O-C_1-4烷基和NO₂的0-3个基团取代；可选地，Q是CHA(CH₂)_mC(O)NR₂或CHA(CH₂)_mCO₂R，且(a)A选自OH、(CH₂)_nCO₂R^b和(CH₂)_nC(O)NR^b₂；(b)R是(CH₂)_m(CHR^b)_n(CH₂)_mOH或CH(CH₂OH)₂；或(c)(a)和(b)两者；A″是C_1-6烷基；M是C＝O或SO₂；R独立地选自H、(CH₂)_m(CHR^b)_n(CH₂)_mOH、CH(CH₂OH)₂、C_1-6烷基、C_2-6烯基和C_2-6炔基；R^a独立地选自H、(CH₂)_m(CHR)_n(CH₂)_mOH、C_1-6烷基、C_2-6烯基和C_2-6炔基，R^b独立地选自H、C_1-6烷基、C_2-6烯基和C_2-6炔基；p选自2、3、4、5、6、7、8、9、10、11和12；m选自0、1、2、3和4；且n选自1、2、3和4。