Recently it has been demonstrated that compounds with 4-aryl or 4-methylpiperazine moiety connected to 3-phenylpyrrolidine-2,5-dione fragment by the alkylene spacer exhibited high anticonvulsant activity, with ED₅₀ from 14 mg/kg to 49 mg/kg in the MES test [1, 2].
As a continuation of our research, in the present study, we designed and synthesized a new series N-[(4-arylpiperazin-1-yl)-alkyl]-3-phenylpyrrolidine-2,5-diones with different length of alkylene chain between two nitrogen atoms. On the other hand, we introduced two kind of substituents, electron-donating CH₃ and electron-attracting CF₃ at the phenyl ring connected with pyrrolidine-2,5-dione moiety.

The target compounds with ethylene and propylene chain between nitrogen atoms were synthesized by one-pot cyclization reaction of the prepared 3-phenylsuccinic acids and appropriately substituted N-aminoalkyl-4-arylpiperazine. Compounds with methylene bridge were obtained in the Mannich-type reaction from the respective 3-phenylsuccinimides, formaldehyde and the corresponding 4-arylpiperazines. The structure determination was based on ¹H-NMR spectral data and C, H, N analysis. The newly synthesized compounds (1-16) were evaluated for their anticonvulsant activity within the Antiepileptic Drug Development (ADD) Program by testing procedures described earlier [3]. The derivatives obtained revealed anticonvulsant activity in the MES-test, that depended on the character of substituents at the aromatic ring, as well as the length of linker between two nitrogen atoms.

References:
1. Obniska J., Zagórska A. Il Farmaco 58 (2003) 1227-1234.
2. Obniska J., Jurczyk S., Zejc A., Kamiński K., Tatarczyńska E., Stachowicz K. Pharmacol. Rep. 57 (2005) 170-175.
3. Kupferberg H. J. Epilepsia, 30 suppl. (1989) 51-56.

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7. N-Phenylamino derivatives of 3-substituted pyrrolidine-2,5-diones as potential anticonvulsant agents
8. Synthesis and anticonvulsant activity of new N-[(4-arylpiperazin-1-yl)-methyl]- 3-phenyl-pyrrolidine-2,5-dione derivatives
9. SYNTHESIS, PHYSICOCHEMICAL AND ANTICONVULSANT PROPERTIES OF NEW N-AMINOPHENYL AZASPIRANE AND PYRROLIDINE-2,5-DIONE DERIVATIVES
10. SYNTHESIS AND ANTICONVULSANT ACTIVITY OF NOVEL N-PYRIDINE-2-YL AND N-AMINOPHENYL DERIVATIVES OF 3,3-DIALKYL-PYRROLIDINE-2,5-DIONES
11. ANTICONVULSANT PROPERTIES AND 5-HT_1A, 5-HT_2A RECEPTOR AFFINITY OF NEW N-[(4-ARYLPIPERAZIN-1-YL)-ALKYL] - 2 - AZASPIRO[4.4]NONANE- AND [4.5]DECANE-1,3-DIONES