[发明专利]用于治疗肥胖的大麻素受体拮抗剂/逆激动剂

摘要

本发明提供用作大麻素受体拮抗剂的新的吡唑及其药物组合物以及使用其治疗肥胖、糖尿病和/或心脏代谢病症的方法。

主权项

1.一种式I的化合物或者其立体异构体或药学上可接受的盐：其中：L是C(＝O)或SO₂；X和Y独立地选自H、卤素、C_1-6烷基、NO₂、CF₃、NR₂、-CN、O(CH₂)_nCN、OR、CO₂R、(CH₂)_nCO₂R、O(CH₂)_nCO₂R、OCH₂CH＝CHCO₂R、CH₂O(CH₂)_nCO₂R、CH₂OCH₂CH＝CHCO₂R、O(CH₂)_nPO(OR)₂、CH₂O(CH₂)_nPO(OR)₂、NR^a(CH₂)_mCO₂R、NR^a(CH₂)_nPO(OR)₂、NR^aCH₂CH＝CHCO₂R、NR^aSO₂CH₃、NR^aCO(CH₂)_nCO₂R、O(CH₂)_n-苯基、CH₂O(CH₂)_n-苯基、O(CH₂)_nC₆H₄-四唑、CH₂O(CH₂)_nC₆H₄-四唑、O(CH₂)_nC₆H₄(CH₂)_n-四唑、NR^a(CH₂)_n-苯基、CH₂NR^a(CH₂)_n-苯基、NR^a(CH₂)_nC₆H₄-四唑、CH₂NR^a(CH₂)_nC₆H₄-四唑、(CH₂)_mC(＝NH)NH₂、(CH₂)_mNHC(＝NH)NH₂、(CH₂)_mNHC(＝CHNO₂)NH₂、(CH₂)_mNHC(＝NCN)NH₂、CONR^c₂、(CH₂)_nCONH^c₂、O(CH₂)_nCONR^c₂、CH₂O(CH₂)_nCONR^c₂、NR^a(CH₂)_mCONHR^a、OCH₂CH＝CHCONR^c₂、CH₂OCH₂CH＝CHCONR^c₂、NR^aCH₂CH＝CHCONR^c₂、四唑、O(CH₂CH₂O)_pR、NR^a(CH₂CH₂O)_pR、SONH₂、SO₂NR^aCH₃、CH₂N⁺R^b₃V¹、其中每个芳基和杂芳基由选自CF₃、卤素、C_1-4烷基、-CN、CO₂R、(CH₂)_nCO₂R、CONR^c₂、(CH₂)_nCONR^c₂、NO₂、NR₂、OR、NHSO₂CH₃和SONHR的0-2个基团取代；X’和Y’独立地选自H、卤素、C_1-6烷基、NO₂、CF₃、NR₂、-CN、O(CH₂)_nCN、OR、CO₂R、(CH₂)_nCO₂R、O(CH₂)_nCO₂R、OCH₂CH＝CHCO₂R、CH₂O(CH₂)_nCO₂R、CH₂OCH₂CH＝CHCO₂R、O(CH₂)_nPO(OR)₂、CH₂O(CH₂)_nPO(OR)₂、NR^a(CH₂)_mCO₂R、NR^a(CH₂)_nPO(OR)₂、NR^aCH₂CH＝CHCO₂R、NR^aSO₂CH₃、NR^aCO(CH₂)_nCO₂R、O(CH₂)_n-苯基、CH₂O(CH₂)_n-苯基、O(CH₂)_nC₆H₄-四唑、CH₂O(CH₂)_nC₆H₄-四唑、O(CH₂)_nC₆H₄(CH₂)_n-四唑、NR^a(CH₂)_n-苯基、CH₂NR^a(CH₂)_n-苯基、NR^a(CH₂)_nC₆H₄-四唑、CH₂NR^a(CH₂)_nC₆H₄-四唑、(CH₂)_mC(＝NH)NH₂、(CH₂)_mNHC(＝NH)NH₂、(CH₂)_mNHC(＝CHNO₂)NH₂、(CH₂)_mNHC(＝NCN)NH₂、CONR^c₂、(CH₂)_nCONR^c₂、O(CH₂)_nCONR^c₂、CH₂O(CH₂)_nCONR^c₂、NR^a(CH₂)_mCONHR^a、OCH₂CH＝CHCONR^c₂、CH₂OCH₂CH＝CHCONR^c₂、NR^aCH₂CH＝CHCONR^c₂、四唑、O(CH₂CH₂O)_pR、NR^a(CH₂CH₂O)_pR、SONH₂、SO₂NR^aCH₃、CH₂N⁺R^b₃V¹、其中每个芳基和杂芳基由选自CF₃、卤素、C_1-4烷基、-CN、CO₂R、(CH₂)_nCO₂R、CONR^c₂、(CH₂)_nCONR^c₂、NO₂、NR₂、OR、NHSO₂CH₃和SONHR的0-2个基团取代；A选自H、OH、C_1-6烷基、C_1-6亚烷基-OH、(CH₂)_mNR^c₂、(CH₂)_nCONR^c₂、(CH₂)_nNHCONR^c₂、(CH₂)_mC(＝NH)NH₂、(CH₂)_mC(O)C_1-6烷基、(CH₂)_m-C_3-6-环烷基、(CH₂)_m-杂芳基和(CH₂)_m-芳基，其中每个芳基和杂芳基由选自CF₃、卤素、C_1-4烷基、-CN、CONR^c₂、NO₂、NR₂、OR、NHSO₂CH₃和SONHR的0-2个基团取代；R’选自CR(CH₂OH)₂、C(CH₂OH)₃、(CH₂)_mCH(A)(CH₂)_mCONR^dR^e、(CH₂)_mCH(A)(CH₂)_mCONH(CH₂)_mCH(A)(CH₂)_mCO₂R、(CH₂)_mCH(A)(CH₂)_mCONH(CH₂)_mCH(A)(CH₂)_mCONH(CH₂)_mCH(A)(CH₂)_mCO₂R、(CH₂)_mCH(A)(CH₂)_mCONH(CH₂)_mCH(A)(CH₂)_mCONR^dR^e、(CH₂)_mCH(A)(CH₂)_mCONH(CH₂)_mCH(A)(CH₂)_mCONH-(CH₂)_mCH(A)(CH₂)_mCONR^dR^e、(CH₂)_mCH(A)(CH₂)_mCONH(CH₂)_mCH＝CH(CH₂)_mCONR^dR^e、(CH₂)_mCH(A)(CH₂)_mCONHCH₂(CH(＝NH)NH₂)、(CH₂)_mCH(A)(CH₂)_mCONH(CH₂)_mCH(A)(CH₂)_m-四唑、(CH₂)_m-苯基-(CH₂)_mCONR^dR^e和(CH₂)_m-吡啶基-(CH₂)_mCONR^dR^e；条件是R’不是CH(A)(CH₂)_mCONH₂、(CH₂)_m-苯基-(CH₂)_mCONH₂和(CH₂)_m-吡啶基-(CH₂)_mCONH₂；可选择地，R’是R”选自H、C_1-6烷基、(CH₂)_0-6芳基和(CH₂)_0-6杂芳基，其中杂芳基经由碳原子连接；Z选自H、C_1-6烷基、芳基、NR₂、NRZ’、OR、-CN、(CH₂)_mC(＝NH)NH₂、(CH₂)_mNHC(＝NH)NH₂、(CH₂)_mNHC(＝CHNO₂)NH₂、(CH₂)_mNHC(＝NCN)NH₂、OCH₂CH＝CHCO₂R、CH₂OCH₂CH＝CHCO₂R、O(CH₂)_nPO(OR)₂、CH₂O(CH₂)_nPO(OR)₂、O(CH₂)_nC₆H₄CO₂R、CH₂O(CH₂)_nC₆H₄CO₂R、CO₂R、(CH₂)_nCO₂R、CONR^c₂、(CH₂)_nCONR^c₂、O(CH₂)_nCONR^c₂、CH₂O(CH₂)_nCONR^c₂、OCH₂CH＝CHCONR^c₂、CH₂OCH₂CH＝CHCONR^c₂和(CH₂)_mSO₃R；Z’选自CH(A)(CH₂)_mCO₂R、CH(A)(CH₂)_mCONR^c₂、CH(A)(CH₂)_mCONH-CH(A)(CH₂)_mCO₂R、CH(A)(CH₂)_mCONH-CH(A)(CH₂)_mCONH-CH(A)(CH₂)_mCO₂R、CH(A)(CH₂)_mCONH-CH(A)(CH₂)_mCONR^c₂、CH(A)(CH₂)_mCONH-CH(A)(CH₂)_mCONH-CH(A)(CH₂)_mCONR^c₂、(CH₂)_m-苯基-(CH₂)_mCO₂R、(CH₂)_m-吡啶基-(CH₂)_mCO₂R、(CH₂)_m-苯基-(CH₂)_mCONR^c₂和(CH₂)_m-吡啶基-(CH₂)_mCONR^c₂；Q选自N、-N⁺-O^-、CH和CQ’；Q”选自NH、NZ、O和S，条件是Z与和其连接的N不形成N-N或N-O键；Q’选自H、CO₂R、(CH₂)_nCO₂R、CH₂O(CH₂)_nCO₂R、CH₂OCH₂CH＝CHCO₂R、CH₂O(CH₂)_nPO(OR)₂、CONR^c₂、(CH₂)_nCONR^c₂、CH₂O(CH₂)_nCONR^c₂、CH₂OCH₂CH＝CHCONR^c₂和(CH₂)_m四唑；V选自H、C_1-6烷基、C_2-6烯基、C_2-6炔基、CF₃、芳基、CH₂OH、CH₂O(CH₂CH₂O)_pR、(CH₂)_mCN、(CH₂)_mC(＝NH)NH₂、(CH₂)_nNHC(＝NH)NH₂、(CH₂)_nNHC(＝CHNO₂)NH₂、(CH₂)_nNHC(＝NCN)NH₂、(CH₂)_mCONR^c₂、(CH₂)_mCONR^aCH(A)(CH₂)_mCO₂R、(CH₂)_mCONR^a(CH₂)_m-苯基-(CH₂)_mCO₂R、(CH₂)_mCONR^a(CH₂)_m-苯基-(CH₂)_m-四唑、CH₂O(CH₂)_nCONR^c₂、CH₂NR^a(CH₂)_nCONR^c₂、CH₂N⁺R^b₃V¹和R独立地选自H和C_1-6烷基；R^a独立地选自H、C_1-6烷基、C_2-6烯基和C_2-6炔基；R^b独立地选自O^-、C_1-6烷基、C_3-6烯基和C_3-6炔基；R^c独立地选自H、OH、C_1-6烷基和C_3-6烯基；R^d独立地选自H、OR、C_1-6烷基、C_3-6烯基、C_1-6亚烷基-OH、CR(CH₂OH)₂、C(CH₂OH)₃、(CH₂)_m-吡咯烷基、(CH₂)_m-哌啶基、(CH₂)_m-哌嗪基、(CH₂)_m-吗啉基、(CH₂)_m-芳基，其中吡咯烷基、哌啶基、哌嗪基和吗啉基由0-2个Z取代并且芳基由选自CF₃、卤素、C_1-4烷基、-CN、CONR^c₂、NO₂、NR₂、OR、NHCO₂R、NHCO₂NHR、NHSO₂CH₃和SONHR的0-2个基团取代；R^e独立地选自H和C_1-6烷基；V¹是抗衡离子，条件是当R^b是O^-时V¹不存在；m选自0、1、2、3和4；n选自1、2、3和4；并且p选自1、2、3、4、5、6、7、8、9、10、11和12；条件是：(a)当V是CH₂OH时，那么R’不是CR(CH₂OH)₂和C(CH₂OH)₃；并且(b)当V是H或C_1-6烷基并且R”是H或C_1-6烷基时，那么R’不是CH(A)(CH₂)_mCONR^c₂。