In aim to search of new anticonvulsants our attention was focused on a group of pyrrolidine-2,5-diones differently substituted at position-1 and -3 of imide ring. Among these compounds, the most active were N-Mannich bases with the spiro-β-tetralone moiety at position-3 of pyrrolidine-2,5-dione ring and 4-phenyl-piperazines with electron-withdrawing atoms as basic fragment. The obtained ED₅₀ values were comparable to the that of known antiepileptic drugs [1].

Taking into consideration the above, in aim to obtain more potent compounds, in the present studies we designed and synthesized new series of derivatives in which we replaced the spiro-β-tetralone nucleus in position-3 into the phenyl ring without or with chloro atom at position-2, -3 or -4. At the imide nitrogen atom differently substituted piperazines, morpholine or 4-benzylpiperidine have been introduced. The results of pharmacological investigations showed, that introduction of mentioned aromatic rings in place of spiro fragment as well as exchange of phenyl moiety at position-4 of piperazines into other substituents increased anticonvulsant activity especially in MES and 6-Hz tests. The structures of the most active molecules (data in mice, i.p.) are presented in Fig. 1.

All the compounds were tested 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), Rockville, USA), by using of the procedures described elsewhere [2].

References:

[1] Obniska J., Byrtus H.; Kamiński K., Pawłowski M.; Szczesio M., Karolak-Wojciechowska J. Bioorg. Med. Chem. 2010, 18, 6134-6142.

[2] Kupferberg, H.J. Epilepsy 1989, 30 suppl., 51-56.

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