Synthesis, anticonvulsant properties and pharmacokinetic profile of novel 10,11-dihydro-10-oxo-5H-dibenz/b,f/azepine-5-carboxamide derivatives

A series of novel derivatives of oxcarbazepine (5), 10,11-dihydro-10-oxo-5H -dibenz/b,f/azepine-5-carboxamide was synthesised and evaluated for their a nticonvulsant activity and sodium channel blocking properties. The oxime 8 was found to be the most active compound from this series, displaying great er potency than its geometric isomer 9 and exhibiting also the highest prot ective index value. Importantly, the metabolic profile of 8 differs from th e already established dibenz/b,f/azepine-5-carboxamide drugs such as 1 and 5 which undergo rapid and complete conversion in vivo to several biological ly active metabolites. In contrast 8 is metabolised to only a very minor ex tent leading to the conclusion that the observed anti-convulsant effect is solely attributable to 8. It is concluded that 8 may be as effective as 1 a nd 5 at controlling seizures and that the low toxicity and consequently hig h protective index should provide the compound with an improved side-effect profile. (C) 2001 Editions scientifiques et medicales Elsevier SAS.