641144-58-3Relevant articles and documents
Design, synthesis, and development of novel caprolactam anticonvulsants
Grimm, Jonathan B.,Stables, James P.,Brown, Milton L.
, p. 4133 - 4141 (2007/10/03)
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) ED50=63 mg/ kg and anti-subcutaneous Metrazol (scMet) ED50=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.
