The conditions grouped under the term epilepsy constitute an area of continuing medical need. Coatsworth estimated that available medication controlled seizures in only 50% of patients and decreased the incidence in only 75% of patients (NINDS Monograph No. 12, HEW Publication No.(NIH) 73-51, 1971 U.S. Government Printing Office, Washington D.C.). Since the time of his estimate, a handful of new drugs have entered clinical practice worldwide. The impact of these newly emerging drugs has yet to be fully evaluated.
The currently used anti-epileptic drugs such as phenytoin and carbamazepine contain a urea function as well as aryl rings. They prevent ##STR1## seizure spread and are useful in treating generalized tonic-clonic and complex partial seizures. Sodium valproate is a simple branched chain aliphatic carboxylate salt. It elevates seizure threshold as well as prevents seizure spread. The benzodiazepines (diazepam, clonazepam, nitrazepam, clobazam) elevate seizure threshold and are used to treat generalized absence seizures.
Among the newly emerging drugs, several structural classes are apparent. Oxcarbamazepine is closely related to carbamazepine. Vigabatrin, gabapentin ##STR2## and progabide, though they may not be mechanistically homogeneous, all share the GABA backbone. Topiramate and zonisamide both have a sulfamyl group. Felbamate is a biscarbamate. Of all the structural classes of anticonvulsants, the only drug to show the pattern of two aromatic rings and a dialkylaminoalkyl chain, which is so prevalent among CNS drugs, is flunarizine. ##STR3## The structures of newer anticonvulsants have been summarized (Drugs of the Future 1991, 16: 317-320).
No theories have been put forward which would explain why many epileptic patients are currently not adequately treated with current therapy. The strategy of seeking drugs which are structurally, mechanistically and pharmacologically unique seems to be the most appropriate approach to improving current therapy. We describe herein a series of anticonvulsant aroyl aminoacyl pyrroles which, we believe, fulfill these criteria.