A nonmetabolized analog of phenytoin

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Abstract
Nine novel analogs of 5,5-diphenylhydrantoin bearing a CF3 group(s) in the meta or para position of one or both rings were synthesized. Preliminary evaluation of all the analogs (performed by the ADD [Antiepileptic Drug Development] Program, NIH [National Institute of Health]) indicated no significant anticonvulsant activity against electrical or chemical shock in mice at doses of .ltoreq. 100 mg/kg. The analog 5,5-bis[4-(trifluoromethyl)phenyl]hydantoin (1) was synthesized labeled with 14C in the 4 position of the hydantoin ring. Certain physicochemical properties (pK[negative log of Ka], partition ratio, protein binding, etc.) and the LD50 of 1 in mice (40 mg/kg, i.p.; 100 mg/kg p.o. [per os]) were determined. The disposition of [14C]1 was determined in rodents. The compound was excreted unchanged in rat feces (94% in 18 days), urinary excretion < 0.5%. The half-life of elimination of [14C]1 from plasma was 67-72 h (i.p. and i.v.) in rats and 115 h (i.p.) in mice. Studies of tissue distribution and biliary excretion of [14C]1 indicate low tissue/plasma ratios (due to high plasma binding, 97%) and low biliary excretion. The lack of metabolism of [14C]1 may possibly be explained by the strong electron-withdrawing effects of CF3 substituents, the preemption of the primary metabolic sites, the accompanying steric hindrance and the apparent inability of the CF3 group to undergo the NIH shift.