| 摘要 |
4-Pyridyl- or 4-pyrimidinyl-substituted fused bicyclic pyrrole derivatives (I) are new. Fused pyrrole derivatives of formula (I) and their optical isomers, salts and readily physiologically hydrolyzable esters are new: [Image] one of R 1-R 34-pyridyl, 2,4-pyrimidyl (sic) or 3-amino-2,4-pyrimidyl (sic) (optionally substituted by 1 or 2 1-4C alkyl or halo); and a second of R 1-R 3phenyl or thienyl (both optionally substituted by 1 or 2 1-4C alkyl or halo); and the third of R 1-R 3H, COOH, (1-6C) alkoxycarbonyl, CH 2OH or 1-6C alkyl; R 4, R 5H or 1-6C alkyl; X : CH 2, S or O; and n : 1 or 2. (N.B. Formulae given in the disclosure suggest that '2,4-pyrimidyl' should be 4-pyrimidyl and that '3-amino-2,4-pyrimidyl' should be 2-amino-4-pyrimidyl). - ACTIVITY : Immunomodulator; immunosuppressive; cytostatic; neuroprotective; antiarthritic; antiinflammatory; antibacterial; respiratory. - MECHANISM OF ACTION : Cytokine release inhibitor; 5-lipoxygenase inhibitor; cyclooxygenase-1 inhibitor; cyclooxygenase-2 inhibitor. In particular (I) inhibit the release of inflammatory mediators such as tumor necrosis factor-alpha (TNFalpha ), interleukin-1beta (IL-1beta ), leukotriene B4 (LTB4) and prostaglandin E2 (PGE2). (3-(4-Fluorophenyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizin-1-yl)-met hanol (Ia) had IC 50 values of 4.0 MicroM and 5.0 MicroM respectively for inhibition of Escherichia coli 026:B6 lipopolysaccharide-induced release of TNFalpha and IL-1beta in human peripheral blood mononuclear cells. |
