The classical anticonvulsant Phenytoin (DPH, 5,5-diphenylhydantoin) is a effective drug in the treatment of grand mal epilepsy. During our studies on new anticonvulsant agents we found that some derivatives of 5-cyclopropyl-5-phenylhydantoin (CPPH) of Mannich base exhibited interesting activity. In this series of compounds the most potent was 3-[(4-benzylpiperazin-1-yl)-methyl]-5-cyclopropyl-5-phenylhydantoin (HB-48). It was protective in the maximal electroshok seizure (MES) test in rats with an oral ED₅₀ of 13,1 mg/kg, and in the subcutaneous pentylenetetrazole test (scMet) ED₅₀ of 17,5 mg/kg. Protective Index, (PI; TD₅₀/ED₅₀) 11,4 MES and 8,5 scMet respectively.

The principal objective of the present investigation was the preparation of analogs of HB-48. Starting from CPPH, formaldehyde and corresponding piperazine derivatives, a series of new compounds - Mannich base was synthesized. Lipophilicity of the all synthesized derivatives CPPH, calculated by a computer method [1] was moderate and suggested their good biological barrier penetration.
Anticonvulsant activity of the obtained compounds was tested in vivo in mice and rats in Anticonvulsant Screening Project (ASP) [2]. On the basis of the obtained results all the compounds were classified to 1st and 2nd class of ASP.
Introduction of 3-CH₃ group on the aromatic ring of benzylpiperazine led to an increase of activity in MES-test and decrease neurotoxicity. Substitution of 4-Cl decrease activity in MES test and increase neurotoxicity. Replacement of the benzylpiperazine by benzhydrylpiperazine led to decrease activity in MES-test and neurotoxicity. The study has shown that the terminal benzylpiperazine group has determined anticonvulsant activity.

1. PALLAS (version for Windows 1.2) distributed by Compu Drug Chemistry Ltd 1995
2. Kupferberg, H.J. Epilepsia, 30, (suppl.), 51-56, 1989
This work was partially supported by CMUJ Research Programme (Wł 309/P/F)

Acknowlegements: We thank Dr J. Stables from National Institute of Neurological Disorders and Stroke, Bethesda, Maryland USA for anticonvulsant testing in the frame of ASP.

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