SYNTHESIS AND CLOGP CORRELATION OF IMIDOOXY ANTICONVULSANTS

Continuing structure-activity studies on the anticonvulsant activity o f analogs of N-(benzyloxy)-2-azaspiro[4.4]nonane-1,3-dione (2a), which displayed anti-electroshock seizure (MES) activity and a protective i ndex (TD50/ED50) of >4.5 are reported. An in-depth analysis of this mo iety was studied employing the Topliss structure activity and the Crai g plot analytical approaches as well as a semiempirical method. CLOG P analysis was also applied to this series after experimentally determi ning the NOR fragment. All compounds were minimized and these physicoc hemical parameters correlated to anticonvulsant activity. Several inte resting substituted benzyloxy compounds emerged from this study: the 2 ',4'-dichloro (2b), 4'-(trifluoromethyl) (2c), 2'-bromo (2d), 3'-chlor o (2o), 2'-chloro (2r), 2'-fluoro (2p), and 3'-fluoro (2w) analogs, al l of which had comparable, or better activity than the parent unsubsti tuted analog (2a). X-ray crystal analysis of the active 2a versus inac tive N-benzyl-2-azaspiro[4.4]nonane-1,3-dione (10) is discussed.