Synthesis, stability and anticonvulsant activity of two 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) prodrugs, were synthesized and studied to determine their stability in aqueous buffer and their susceptibility to undergo enzymatic hydrolysis in vitro (mouse plasma). Both compounds were fairly stable in aqueous media, (t(1/2) = 68.2 h and 25.7 h, respectively). The 3,4-dihydro-2,4-dioxo-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 opened by mouse plasma esterases within the observation time (3 h). Both compounds were tested for their anticonvulsant activity in pentetrazole (PTZ) treated mice, and showed significant activity. Compound 7, administered as sodium salt 8, was active at relatively low doses and can be considered a very interesting GABA prodrug.