SYNTHESIS AND ANTICONVULSANT ACTIVITIES OF ALPHA-HETEROCYCLIC ALPHA-ACETAMIDO-N-BENZYLACETAMIDE DERIVATIVES

Earlier studies showed that (R,S)-alpha-acetamido-N-benzylacetamides ( 2) containing a five- and six-membered aromatic or heteroaromatic grou p appended at the C(alpha) site displayed outstanding activity in the maximal electroshock-induced seizure (MES) test in mice. An expanded s et of C(alpha)-heteroaromatic analogues of 2 have been prepared and ev aluated. The observed findings extended the structure-activity relatio nships previously discerned for this novel class of anti-convulsants a nd have validated previous trends. The alpha-furan-2-yl (4), alpha-oxa zol-2-yl (18), and alpha-thiazol-2-yl (19) alpha-acetamido-N-benzylace tamides afforded excellent protection against MES-induced seizures in mice. The ED50 and PI values for these adducts rivaled those reported for phenytoin. The outstanding properties provided by 4 led to an in-d epth examination of the effect of structural modification at key sites within this compound on biological activity. The pharmacological data in this series indicated that stringent steric and electronic require ments existed for maximal activity and revealed the outstanding activi ty of ido-N-(4-fluorobenzyl)-alpha-(furan-2-yl)acetamide [(R)-30].