I. 0. Edafiogho, M. S. Alexander, J. A. Moore, V. A. Farrar and K. R. Scott* Pages 159 - 175 ( 17 )
Enaminones, enamines of B-dicarbonyl compounds have been known for many years. Their main therapeutic utility was as prodrugs for various amines, stabilizing these active compounds principally in basic media. Our laboratory discovered a series of enamines of cyclic 1,3-diketo esters which were stable and possessed significant anticonvulsant activity. The most notable compound was methyl 4- [(p chlorophenyl)amino)-6-methyl-2-oxocyclohex-3-en-1-oate, 15, desig nated ADD 196022 by the Anti-convulsant Drug Development (ADD) Program of the National Institutes of Health. Compound 15 displayed an intraperitoneal (ip) EDso of 26.2 mg/kg and a TDso of 254.8 mg/kg in the mouse and an oral (po) EDso of 5.8 mg/kg and a TDso of >380 mg/kg in the rat. The protective indices (TDso/EDso) were 9.7 in the mouse and >65.6 in the rat, respectively. This data compared favorably to phenytoin and carbamazepine. In addition, 15 demonstrated oral effectiveness in the rat corneal kindling model, providing an EDso of 34.2 mg/kg. Quantitative structure-activity studies in this series successfully utilized the Craig Plot method (Craig, P. N.J. Med Chern. 1971, 14, 680; Craig, P. N.J. Med Chern. 1972, 15, 144). High field NMR , molecular modeling studies and CLOGP were also employed to assess the potential interactions of these compounds and phenytoin in its relationship to potential anticonvulsant activity. Each of these factors is discussed.