SYNTHESIS AND EVALUATION OF N-(PHENYLACETYL)TRIFLUOROMETHANESULFONAMIDES AS ANTICONVULSANT AGENTS

A series of N-(phenylacetyl)trifluoromethanesulfonamides (3a-g) was pr epared according to the Topliss scheme in order to determine if aryl s ubstitutents would influence anticonvulsant activity. In initial (phas e I) screening and quantitative (phase II) evaluation, all seven compo unds exhibited significant activity against MES- and scMet-induced sei zures. N-(Phenylacetyl)trifluoromethanesulfonamide (3a) was then advan ced through five additional testing phases (phases III-VII). Compound 3a displayed good oral bioavailability, low toxicity, and a larger pro tective index in mice than the prototype drugs, phenytoin, phenobarbit al, valproate, and ethosuximide. Additionally, 3a exhibited a longer t ime to peak effect in all tests and a greater 24-h margin of safety (H D50/ED(50)) than the prototypes. Compound 3a blocked picrotoxin-induce d seizures but was ineffective. against seizures induced by bicucullin e or strychnine. In vitro receptor binding studies revealed that 3a di d not displace [H-3]-labeled gamma-aminobutyric acid or [H-3]-labeled flunitrazepam, and tolerance did not develop during 5-day chronic admi nistration.