Ureylene anticonvulsants and related compounds

The results from a previous study led to the postulate that a number of ary l semicarbazones displaying anticonvulsant activity in the maximal electros hock (MES) screen interacted at both a hydrophobic and a hydrogen bonding a reas on a specific binding site. These two parts of the binding site may be referred to as areas A and B, respectively. In order to circumvent the pos sible problems of the carbimino group in semicarbazones, such as toxicity a nd acid lability, some related ureylenes were considered. Initial evidence suggested that a second lipophilic group in the molecule was advantageous; this group may interact at area C on the proposed binding site. Most of the compounds prepared with a view to interacting at areas A, B and C showed p rotection in mice against MES induced seizures. Of particular interest were the compounds 1d, j which contained an alpha-methylbenzyl group attached t o the N1 atom of the ureylenes which afforded good protection in the MES sc reen. The areas A and C at which lipophilic moieties were considered to int eract were capable of accommodating groups of different sizes as measured b y their solvent accessible surface areas. A number of compounds were active when given orally to rats and devoid of neurotoxicity at the doses utilize d. Several compounds including 1d, f,j, 2d are useful prototypic molecules for subsequent development of further novel anticonvulsants.