Design, synthesis, and pharmacological evaluations of potential anticonvulsant amino acid derivatives, carbamate compounds, and hexahydropyrimidine-2,4-diones

Several categories of compounds were designed and explored as new anticonvulsant agents. Results from simple amino acid derivatives (1, 2, 3, 4, 5, 6, 14, 15) suggested that amide derivatives with carbamate moiety provided good protection in mice. Amide derivative 14 gave ED₅₀ of 32.4 mg/Kg in MES, and methyl amide 4 showed substantial PTZ activity (ED₅₀ = 33 mg/Kg). An intramolecular cyclization from the α-uredio acid to a hydantoin species (5, 7) was found to occur under acidic condition. Monocarbamate compounds derived from Felbamate were also selected (8, 9, 10, 11, 12, 13). The one arm analog 8, providing mediocre mice activity (SJU ED₅₀ = 71.7 mg/Kg in MES and 123.6 mg/Kg in PTZ; NIH ED₅₀ = 72.7 mg/Kg in MES and 87.6 mg/Kg in PTZ), however provided excellent activity in rats (ED₅₀ = 21 mg/Kg). Without an apparent toxicity and with PI > 15, this unique structure 8 may be a potential replacement for Felbamate. Derivatives of hexahydropyrimidine-2,4-dione (16, 17, 18, 19, 20), which are barbiturate analogs were explored as well. Compound 18 provided ED₅₀ of 26 mg/Kg in mice PTZ while 19 provided lower ED₅₀ of 11.8 mg/Kg in mice MES and substantial activity of 40 mg/Kg in rat MES. N-3 benzyl substitution (16) provided higher activity than N-3 propyl substitution (20). An extra methyl group on C-5 or C-6 with N-3 benzyl substitution further increased seizure protection. C-6 methylation (19) selectively enhanced MES protection in both mice and rats. In addition, N-hydroxyalkyl carbamates (21, 22, 23, 24, 25, 26, 27, 28) were synthesized and evaluated. In mice MES test, 28 showed significant activity (ED₅₀ = 14.9 mg/Kg) but most of them were inactive in NIH mice tests, especially in scPTZ protocol. However, a pair of enantiomers provided remarkable activity in rat tests, especially MES activity. Oral rat tests showed that R-isomer (26, ED₅₀ = 23.85 mg/Kg and PI > 21) is superior to S-isomer ( 25, ED₅₀ = 67.58 mg/Kg) against MES. Metabolic instability and a possible requirement of activation process may possibly explain no apparent SAR and inconsistency results between animal species for N-hydroxyalkyl carbamates.