Synthesis and anticonvulsant activity of enaminones - Part 7. Synthesis and anticonvulsant evaluation of ethyl 4-[(substituted phenyl)amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylates and their corresponding 5-methylcyclohex-2-enone derivatives

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European Journal of Medicinal Chemistry


Further investigation of the potential anticonvulsant activity of the enaminones was attempted to discern the possible role of metabolites as the active/co-active entities of the esters of the enaminones. A series of 5-methyl-2-cyclohexene enaminones, the hypothesised metabolites corresponding to a sequence of active and inactive esters were synthesised and evaluated for anticonvulsant activity. With two exceptions, ethyl 4-[(4-cyanophenyl)amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylate (1k), and 3-[N-(4-cyanophenyl)amino]-5-methyl-2-cyclohexenone (3g), and ethyl 4-(phenylamino)-6-methyl-2-cyclohexenone (1n), and 3-N-(phenylamino)-5-methyl-2-cyclohexenone (3j), anticonvulsant screening data were parallel, with the ester and their putative decarboxylated analogue displaying similar activity. The most active analogue evaluated in this series, ethyl 4-[(4-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylate (1e), which displayed an ED50 of 16.7 mg kg-1 and a TD50 of 110.7 mg kg-1 (protective index, PI = TD50/ED50 = 6.6) in the maximal electroshock seizure (MES) test in mice and an ED50 of 3.0 mg kg-1 and a TD50 > 250 mg kg-1 (PI > 83.3) in rats in the same evaluation, making this compound the most potent enaminone emanating from our laboratories. Pharmacokinetic evaluation of compound 1e in rats using LC/MS analysis unequivocally provides evidence that this compound is converted into the decarboxylated analogue 3a in the brain and the urine. © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.

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