| Due to the discovery of the highly potent anticonvulsant enaminone, methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate, 1 (R = CO2CH3), at Howard University (Scott, et. al. J. Med. Chem. 1993, 36, p. 1947), an extensive synthetic program was generated. The homologous unsubstituted benzylamine, 2 (R=CO2CH3, R1=R2=R 3=H), also possessed significant anticonvulsant activity, while the chiral methyl benzyl analogs, (+) 2a (R=CO2CH 3, R1=R3=H, R2=CH3) and (-) 2b (R=CO2CH3, R1=R 3=H, R2=CH3) were both inactive. The current research involves the synthesis of homologous benzamides, 3 (R=H, CO 2CH3, CO2CH5 and CO2C(CH 3)3; R1 = CH3, R2 = H), (R=R1=R2=H) and (R=H; R1=R2=CH 3). The R3 substituent was varied based upon electronic (sigma), lipophilic (pi) and steric (Es) properties. The R3 substituent included either a hydrogen, a chloro group, a cyano group, a methoxy group or a methyl group. The most active analog tested was 5,5-dimethyl-3-[(p-methoxy)benzamido] cyclohex-2-en-1-one, 4, which provided protection against electroshock seizures at 30 mg/kg intraperitoneally (ip) in mice and at the same dosage orally in rats. In addition, the compound was non-toxic at ip dosages of 300 mg/kg in mice. The properties of the series of benzamides were contrasted and compared to those of the analogous benzylamines.*;*Please refer to dissertation for diagrams. |
