European Journal of Medicinal Chemistry 2012-05-01

Enaminones 12. An explanation of anticonvulsant activity and toxicity per Linus Pauling's clathrate hypothesis.

Patrice L Jackson, Clive D Hanson, Alanna K Farrell, Raymond J Butcher, James P Stables, Natalie D Eddington, K R Scott

Index: Eur. J. Med. Chem. 51 , 42-51, (2012)

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Abstract

The x-ray crystal structure of 3-((5-methylisoxazol-3-yl)amino)-5-methylcyclohex-2-enone (12b) and 3-((5-methylisoxazolyl-3-yl)amino)-5,5-dimethylcyclohex-2-enone (12c) were determined and correlated to their anticonvulsant activity in mice and rats. A hypothesis for the toxicity of the analogs are advanced. In addition, a series of 5-methyl-N-(3-oxocyclohex-1-enyl)-isoxazole-3-carboxamides were synthesized and evaluated for anticonvulsant activity. These compounds were compared to the activity of the corresponding amino and aminomethyl enaminones. Additional investigation involved the synthesis and evaluation of a trifluoromethyl analog of the active isoxazole tert-butyl 4-(5-methisoxazol-3-yl-amino)-6-methyl-2-oxo-cyclohex-3-ene carboxylate (4f).Published by Elsevier Masson SAS.