Tetrahydroquinoline derivatives as CRTH2 antagonists

摘要

Tetrahydroquinoline derivatives and their optical isomers, stereoisomers, N-oxides or salts are new. Tetrahydroquinoline derivatives of formula (I) and their optical isomers, stereoisomers, N-oxides or salts are new. [Image] R1>H, 1-4C alkyl, 2-4C alkenyl, 2-4C alkynyl or (CH2)m-R'1>; R'1>aromatic heterocycle, phenyl or 3-6C cycloalkyl (optionally substituted with Q1> or 1-4C alkyl (optionally substituted with Q1>)); Q1>halo, NO2, CN, SO2CH3, SO2NR9>R1>0>, OR9>, COOR9>, C(=O)NR9>R1>0>, NR9>R1>0>, NR9>SO2R1>0>, NR9>C(=O)R1>0> or C(=O)R9>; R4>, R9>, R1>0>H or (1-4C)alkyl; m : 0,1 or 2; R2>1-4C alkyl (substituted with halo, OR9>, NR9>R1>0>, COOR9>, C(=O)NR9>R1>0>, NHSO2R9> or C(=O)(1-4C)alkyl); R9>, R1>0>H or 1-4C alkyl; R3>3-6C cycloalkyl or A-R'3>; A : bond, 1-3C alkylene or (2-3C)alkenylene; R'3>6-12C aryl or heterocycle (optionally aromatic having 5-10 atoms in the cycle) (both optionally substituted by 6-12C aryl, aromatic heterocycle, Q2> or 1-4C alkyl (optionally substituted with Q2>)); Q2>halo, NO2, CN, SO2CH3, SO2NR9>R1>0>, OR9>, SR9>, OCH2CF3, COOR9>, C(=O)NR9>R1>0>, NR9>R1>0>, NR9>SO2R1>0>, NR9>C(=O)R1>0> or C(=O)R9>; R5>-R8>H, Q3> or 1-4C alkyl (optionally substituted with Q3>); and Q3>halo, NO2, CN, SO2CH3, SO2NR9>R1>0>, OR9>, SR9>, COOR9>, C(=O)NR9>R1>0>, NR9>R1>0>, NR9>SO2R1>0>, NR9>C(=O)R1>0> or C(=O)R9>. An independent claim is also included for the preparation of (I). ACTIVITY : Antiarthritic; Antirheumatic; Osteopathic; Antiarteriosclerotic; Antiinflammatory; Antiulcer; Gastrointestinal-Gen.; Dermatological; Antipsoriatic; Antipruritic; Antiseborrheic; Immunosuppressive; Respiratory-Gen.; Antiangiogenic; Cerebroprotective; Vasotropic; Antiallergic; Antiasthmatic. MECHANISM OF ACTION : Chemoattractant receptor homologous molecule expressed on T-helper-2 cells (CRTH2) antagonist. (I) were tested for its CRTH2 antagonistic activity in CRTH2-expressing L1.2 cells using scintillation proximity assay. The results showed that the median inhibitory concentration of cis-N-[2-methyl-1-(thiophene-2-carbonyl)-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-acetamide was below 5 MicroM.