Synthesis of novel derivatives of 1H-imidazo[1,2-b]pyrazole as potential CNS-agents

Article abstract of DOI:10.1002/jhet.5570310408

As part of a preliminary study on novel 5-HT₃ ligands, the synthesis of a series of 1H-imidazo[1,2-b]-pyrazole derivatives is described. The bicyclic heteroaromatic nucleus was functionalized as positions 1, 6 and 7 to give the series of tropanyl derivatives 4a-g, 12a, 12d. Different synthetic approaches were utilized to obtain the desired molecules: endo and exo 6-amides 4a, 12a and 6-ester 4b required two independent schemes due to the opposite behavior of the intermediate imidazolide 3 towards tropine and tropanamine. The 7-congeners, ester 4c, its tropinium salt 4e, the endo and exo amides 4d and 12d were prepared from the known common precursor 8, while derivatives 4f-g, originated by functionalizing position 1, were obtained from 1H-imidazo[1,2-b]pyrazole by direct N-acylation. Since the structural features of these molecules seemed to meet the main rules of the S.A.R. studies published so far, they were evaluated 'in vitro' for 5-HT₃ receptor affinity. The biochemical data show significant activity for derivatives 4a-e, 4g. These results are encouraging and justify further investigational work on this class of molecules.