SYNTHESIS, STABILITY AND ANTICONVULSANT ACTIVITY OF 2 NEW GABA PRODRUGS

4-(3,4-Dihydro-2,4-dioxo-2 H-1,3-benzoxazin-3-yl)-butylic acid (7) and its ethyl ester 6, two potential gamma-aminabutyric acid (GABA) prodr ugs, were synthesized and studied to determine their stability in aque ous buffer and their susceptibility to undergo enzymatic hydrolysis in vitro (mouse plasma). Both compounds were fairly stable in aqueous me dia, (t(1/2) = 68.2 h and 25.7 h, respectively). The 3,4-dihydro-2,4-d ioxo-2 H-1,3-benzoxazine ring underwent enzymatic hydrolysis (t(1/2) = 5.8 h) in compound 7, whereas in compound 6 it seemed not to be opene d by mouse plasma esterases within the observation time (3 h). Both co mpounds were tested for their anticonvulsant activity in pentetrazole (PTZ) treated mice, and showed significant activity. Compound 7, admin istered as sodium salt 8, was active at relatively low doses and can b e considered a very interesting GABA prodrug.