Previously the anticonvulsant properties many of 2-azaspiro[4.4]nonane- and [4.5]decane-1,3-diones differently substituted at the imide nitrogen atom were described. Among those derivatives the most active was N-aminophenyl-2-azaspiro[4.4]nonane-1,3-dione, with ED₅₀=76,27 mg/kg in the maximal electroshock test (MES) [1-3]. Based on these findings, in effort to obtain compounds with enhanced anticonvulsant activity new series of 2-azaspiro[4.4]nonane- and [4.5]decane-1,3-diones with aminophenyl moiety at the nitrogen atom have been synthesized. On the other hand, to investigate the influence of the cycloalkyl system, attached to the imide through the C3 spiro carbon atom, on the anticonvulsant activity, two analogues with cyclohexyl moiety as a flexible fragment at position-3 of pyrrolidine-2,5-dione ring were obtained.


The compounds were evaluated for their anticonvulsant activity within the Antiepileptic Drug Development (ADD) Program (Epilepsy Branch, Neurological Disorders Program, National Institute of the Neurological and Communicative Disorders and Stroke (NINCDS), Bethesda) [4]. The lipophilic character of the molecules, which is one of the crucial physicochemical parameters of bioactive compounds, was estimated by use of RP-TLC, RP-HPLC methods and Pallas 3.1 computer program. The data obtained enable to evaluate the correlation between different measurements of lipophilc properties. The structural characterization of the selected compounds has been done by crystal X-ray structure analysis to determine the parameters important for anticonvulsant activity.

References:
1. Obniska J.; Acta Polon. Pharm. - Drug Res. 61 (6) (2004) 467-472.
2. Obniska J., Dzierżawska-Majewska A., Zagórska A., Zajdel P.,
Karolak-Wojciechowska J.; Il Farmaco 60 (2005) 529-539.
3. Kamiński K., Obniska J., Zagórska A., Maciąg D.; Arch. Pharm.
in press (2006).
4. Kupferberg H.J.; Epilepsia 30 (suppl.) (1989) 51-56.

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