Design, synthesis, and development of novel caprolactam anticonvulsants

Abstract

Epilepsy afflicts 1–2% of the world's population and often goes untreated; nearly 70% of those with a form of epilepsy fail to receive proper treatment. Therefore, there is great demand for the design of novel, effective anticonvulsants to combat epilepsy in its numerous forms. Previously, α-hydroxy-α-phenylcaprolactam was found to have rather potent antiepileptic activity [anti-maximal electroshock (MES) ED 50=63 mg/kg and anti-subcutaneous Metrazol (scMet) ED 50=74 mg/kg] when administered intraperitoneally in mice. We focused our attention on the development of this compound through traditional medicinal chemistry techniques—including the Topliss approach, isosteric replacement, methylene insertion, and rigid analogue approach—in the hopes of determining the effect of caprolactam α-substitution and other structural modifications on anticonvulsant activity. A number of the desired targets were successfully synthesized and submitted to the Anticonvulsant Screening Program of the National Institute of Neurological Disorders and Stroke (NINDS). Phase I results were quite promising for at least three of the compounds: α-ethynyl-α-hydroxycaprolactam ( 10), α-benzyl-α-hydroxycaprolactam ( 11), and α-hydroxy-α-(phenylethynyl)caprolactam ( 13). Phase II results for 11 strongly suggested it as a new structural class for further development, as it exhibited an anti-MES T.I. in excess of 4.0. Further, the potent activity of 13 in all models also pointed to the substituted alkynylcaprolactams as a new anticonvulsant structural class.