Synthesis of pentacyclic indolealkaloid hybrids

Hybrid compounds were synthesized combining the structural features of two isomer natural indolealkaloids rutaecarpine (1) and nauklefine (3). These a za-bioisosteric analogues are the first representatives of a new heterocycl ic ring system. Two alternative reaction routes were developed for the synt hesis of pentacyclic compounds (4,5) in which the key step is the Fischer i ndolization of the 6-phenylhydrazono-dipyrido[1,2-a;4,3-d] pyrimidine-11-on es. In the case of E-ring substituted derivatives we performed the synthesi s via preparation and chemical transformation of pyrido[1,2-a]pyrimidine-4- ones (14,15) to 2-substituted-3-aza-rutaecarpines (17-20). Finally, the nuc leophilic displacement of the chlorine atom of 2-chlolo-3-aza-rutaecarpine (18) by dialkylaminoethylamine provided the 2-amino-substituted derivative (20) having improved physico-chemical properties and increased antitumour a ctivity. The new compounds are characterized by UV, IR,H-1,C-13 nmr spectro scopy.