A series of 3,3-dialkyl- and 3-alkyl-3-benzyl-substituted 2-pyrrolidinones (lactams) have been prepared and evaluated for their anticonvulsant activities. In the pentylenetetrazole mouse seizure model, 3,3-diethyl lactam 7c and 3-benzyl-3-ethyl lactam 7j are the most effective anticonvulsants (ED50 = 46 and 42 mg/kg, respectively) and have protective index (PI = TD50/ED50) values of 5.65 and 3.00, respectively. These protective index values compare favorably to those of the clinically used antiepileptic drugs ethosuximide (ED50 = 161 mg/kg), phenobarbital (ED50 = 22 mg/kg), and valproic acid (ED50 = 133 mg/kg), which have PI values of 2.35, 4.00, and 2.12, respectively. The benzyl compounds [3-substituents are Bn, H (7h); Bn, Me (7i); and Bn, Et (7j)] are also very effective anticonvulsants against seizures induced by maximal electroshock (ED50 = 41, 55, and 74 mg/kg, respectively) and have PI values of 3.51, 3.04, and 1.70, respectively. The corresponding PI values for phenobarbital and valproic acid are 1.37 and 5.18, respectively. As a class of anticonvulsants, the 3,3-disubstituted 2-pyrrolidinones have a broad spectrum of action and may be useful for the treatment of human epilepsies.

A series of 3-substituted 2-piperidinone (delta-valerolactam) and hexahydro-2H-azepin-2-one (epsilon-caprolactam) derivatives were prepared and evaluated as anticonvulsants in mice. In the 2-piperidinone series, 3,3-diethyl compound 7b is the most effective anticonvulsant against pentylenetetrazole-induced seizures (ED50, 37 mg/kg; PI (TD50/ED50), 4.46), and 3-benzyl compound 4c (ED50, 41 mg/kg; PI, 7.05) is the most effective anticonvulsant against seizures induced by maximal electroshock. By contrast, none of the epsilon-caprolactams tested had anticonvulsant effects below doses causing rotorod toxicity. log P values were correlated with neurotoxicity and [35S]TBPS displacement, but not with anticonvulsant activity. Electrophysiological evaluations of selected compounds from each series indicated that both the delta-valero-lactams and epsilon-caprolactams potentiated GABA-mediated chloride currents in rat hippocampal neurons.

Synthesis and Anticonvulsant Activities of 3,3-Dialkyl-and 3-Alkyl-3benzyl-2-piperidinones (δ-Valerolactams) and Hexahydro-2H-azepin-2-ones (.epsilon.-Caprolactams).-A series of δ-valerolactam, such as (VI) or (X), and .epsilon.-caprolactam derivatives (XI) are prepared and evaluated as anticonvulsants in mice. The most effective compound is (X). In contrast, none of the compounds (XI) has anticonvulsant effect. -(REDDY, P. A.; WOODWARD, K. E.; MCILHERAN, S. M.; HSIANG, B. C. H.; LATIFI, T. N.; HILL, M. W.; ROTHMAN, S. M.; FERRENDELLI, J. A.; COVEY, D.

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Partial Structures of the Fungal Toxin Aflatrem, Methyl-Substituted 6, 8-Dioxabicyclo(3.2.1)octan-2-ones Having Anticonvulsant Activity. -The synthesis of a number of methyl-substituted 6,8-dioxabicyclooctanes (cf. (V), (VII)), substructures of the fungal toxin aflatrem (I), in racemic and enantiopure form is given. All of these compounds display anticonvulsant activity, whereat highest levels are observed for the (-)-enantiomer of (VIIa). -(TINAO-WOOLDRIDGE, L. V.; HSIANG, B. C. H.; LATIFI, T. N.; FERRENDELLI, J. A.; COVEY, D. F.; Bioorg. Med.