SYNTHESIS OF PRAZIQUANTEL ANALOGUES

Twenty-one praziquantel analogues were synthesized for evaluation of their antischistosomal activity.Compounds Ⅱ were synthesized by six steps as the route of preparation of praziquantel. Compounds Ⅲ were prepared by reduction of the intermediate 3,6-dialkyl-1, 2, 3, 6, 7, 11b-hexahydro-4H-pyrazino [2,1-a] isoquinoline-4-one(6) with LiAlH_4 and then acylation, or by alkylation of (6). Hydrolysis of 1-(benzoylamino) methyl-3-alkyl-1,2,3,4-tetrahydroisoquinoline(3) and then selective acylation gave compounds Ⅳ.The screening results of 21 compounds in mice infected with Shistosoma japonicnm indicated that when the methyl group was attached to position 3 or 6 in series Ⅱ, the given compounds exhibited antischistosomal activity, especially compounds Ⅱ_2 and Ⅱ_6. However, when both positions 3 and 6 were replaced by methyl groups, the activity was reduced. The compounds in series Ⅲ, in which the amide group or carbonyl group was substituted, showed no antischistosomal activity. The open-ring compounds (Ⅳ_1 and Ⅳ_5) still retained weaker activity. The compounds Ⅱ_2 and Ⅱ_6 with cyclohexylcarbonyl group in position 2 was more active than those with other acyl substitutes.