SYNTHESIS AND ANTICONVULSANT ACTIVITY OF ENAMINONES .3. INVESTIGATIONS ON 4'-SUBSTITUTED, 3'-SUBSTITUTED, AND 2'-SUBSTITUTED AND POLYSUBSTITUTED ANILINO COMPOUNDS, SODIUM-CHANNEL BINDING-STUDIES, AND TOXICITY EVALUATIONS

In a continuing evaluation of the aniline-substituted enaminones, the synthesis of additional para-substituted analogs has been made in an a ttempt to further quantify the electronic (sigma) and lipophilic (pi) requirements for anticonvulsant activity in this series. In addition, meta- and ortho-substituted and polysubstituted compounds have been sy nthesized and evaluated for anticonvulsant activity. In the para-subst ituted series, 4-cyano analogs (32 and 33) (+sigma, -pi), which were h ighly active via intraperitoneal (ip) injection in mice, were inactive on oral (po) administration in rats. The para-substituted trifluorome thoxy (+sigma, +pi) analog (8) had significant potency by both routes. Meta substitution limited the activity due to steric factors. Bromo a nd iodo substituents produced active para-substituted analogs (5 and 1 7) but were inactive when substituted in the meta position (37 and 41, respectively). Ortho substitution provided no clear relationship due to nonparametric deviations. Neither 1, the prototype enaminone, nor 2 , the putative metabolite, produced significant nephrotoxicity or hepa totoxicity. Sodium channel binding of 1 and 8 indicated that 8 display ed relatively potent sodium channel binding but 1 showed weaker effect s with IC50 values of 489 and 170 mu M respectively against [H-3]batra chotoxinin A 20 alpha-benzoate ([H-3]BTX-B).