Acta Pharm. 49 (1999) 21–27

Synthesis and antiseizure activity of three new derivatives of valproic acid amide>

ELLY BEHAR,¹   HENRI ASTROUG,² and  TATIANA NETZEVA^*3

¹Department of Pharmaceutical Chemistry,  Faculty of Pharmacy,  2 Dunav St.,  1000 Sofia,  Bulgaria,
²Department of Pharmacology and Toxicology,  Faculty of Pharmacy,  2 Dunav St.,  1000 Sofia,  Bulgaria,
³Department of Chemistry,  Faculty of Pharmacy,  2 Dunav St.,  1000 Sofia,  Bulgaria

Valpramide (VPD), a primary valproic acid amide (VPA), is a widely used antiepileptic agent. However, major adverse reactions are associated with this drug. The substitution in the –CONH group might lead to compounds with pharmacological profile identical to that of VPD but lacking its adverse effects. Newly synthesized compounds such as N1-phenethyl -2-propylpentanamide, N1-phenyl-2-propylpentanamide and N1-cyclohexyl-2-propylpentanamide were obtained from VPA applying the method reported earlier. The first two new VPD derivatives administered intraperitoneally in doses 1/10 of LD50 exibit an effective antiseizure activity. An attempt has been made to explain the differences in the antiseizure activity degree of the new compounds compared to that of VPD with the changes in their n-octanol/water partition coefficient, molecular and submolecular properties, attributed to the substituents. It is supposed that the degree of antiseizure activity mainly depends on the distribution of electrostatic potential around the substituents.

Keywords: valpramide derivatives, antiseizure activity, lipophilicity, quantum mechanics, electrostatic potential