Substituted carbazole or hydrogenated carbazole derivatives; useful for inhibiting sPLA2 (human non-pancreatic secretory phospholipase A2) mediated release of fatty acids for conditions such as septic shock

摘要

The compound has the formula (I), wherein: R1 is -NHNH2 or -NH2; R2 is -O(CH2)mR5 where R5 is H, -CO2H, -CO2(C1-C4alkyl), CN, tetrazolyl, -P(=O)R6R7, phenyl or phenyl substituted with -CO2H or -CO2(C1-C4alkyl) where R6 and R7 are each independently -OH or -O(C1-C4 alkyl) and m is 1-3; R3 is H, -O(C1-C4alkyl), or -(CH2)nR8 where R8 is H, phenyl or -phenyl(C1-C4 alkyl) and n is 1-8; R4 is phenyl Z is cyclohexenyl or phenyl; or a pharmaceutically acceptable salt, racemate, optical isomer, solvate, tautomer or prodrug derivative thereof; provided that when R3 is H and R2 is substituted at the 6 position, R5 cannot be H; and when R3 is -O(C1-C4 alkyl) or -(CH2)nR8, where n is 1-6 and R8 is H, and is substituted at the 7 position and R2 is substituted at the 6 position, R5 cannot be H. A pharmaceutical composition comprising the compound of formula (I) and a carrier or diluent is also described. Also described is the use of a compound of formula (II) to selectively inhibit sPLA2 in a mammal, wherein: R1, R2, R3 and Z are as defined for the compound of formula (I) (above), R5 is H, -CO2H, -CO2(C1-C4alkyl), CN, tetrazolyl, -NHSO2(C1-C6 alkyl), -CONHSO2(C1-C6)alkyl, -P(=O)R6R7, phenyl or phenyl substituted with -CO2H or -CO2(C1-C4alkyl) where R6 and R7 are each independently -OH or -O(C1-C4 alkyl) and m is 1-3; R8 is H, -CN, phenyl or -phenyl(C1-C4 alkyl) and n is 1-8; and R4 is H, -(C5-C14)alkyl, -(C3-C14)cycloalkyl, phenyl, or phenyl substituted with 1 or 2 substituents selected from the group consisting of -(C1-C4)alkyl, -(C1-C4)alkoxy, -phenyl(C1-C4)alkyl, -(C1-C4)alkylthio, halo and phenyl. Also described is a compound of formula (III), wherein: R1, R2, R3, R5 and R8 are as defined for the compound of formula (I) (above); R4 is H, -(C5-C14)alkyl, -(C3-C14)cycloalkyl, phenyl, or phenyl substituted with 1 or 2 substituents selected from the group consisting of -(C1-C4)alkyl, -(C1-C4)alkoxy, -phenyl(C1-C4)alkyl, -(C1-C4)alkylthio, halo and phenyl; and Z is phenyl, when prepared by dehydrogenating the compound corresponding to the compound of formula (III) where Z is cyclohexenyl. The compounds of formulae (I) and (II) can be used for treating shock, adult respiratory distress syndrome, pancreatitis, asthma, allergic rhinitis, arthritis, cystic fibrosis, stroke, bronchitis, gout, spondylarthropathris, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, spondylitis, Reactive arthropathy, Lyme disease, polyarteritis nodosa, hypersensitivity vasculitis, Luegenec's granulomatosis, rheumatism, joint cell arteritis, calcium crystal deposition arthropathris, muscular injuries, neuropathic joint disease (charco and joint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, surcoilosis, hemochromatosis, sickle cell disease, hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat's Disease, systemic lupus erythematosis, or relapsing polychondritis.