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

As part of a preliminary study on novel 5‐HT3ligands, the synthesis of a series of 1H‐imidazo[1,2‐b]‐pyrazole derivatives is described. The bicyclic heteroaromatic nucleus was functionalized at positions 1, 6 and 7 to give the series of tropanyl derivatives4a‐g, 12a, 12d(Table 1). Different synthetic approaches were utilized to obtain the desired molecules: endo and exo 6‐amides4a, 12aand 6‐ester4brequired two independent schemes due to the opposite behavior of the intermediate imidazolide3towards tropine and tropanamine. The 7‐congeners, ester4c, its tropinium salt4e, the endo and exo amides4dand12dwere prepared from the known common precursor8[1], while derivatives4f‐g, originated by functionalizing position 1, were obtained from 1H‐imidazo[1,2‐b]pyrazole by directN‐acylation. Since the structural features of these molecules seemed to meet the main rules of the S.A.R. studies published so far [2‐5], they were evaluated “in vitro” for 5‐HT3receptor affinity (Table 2). The biochemical data show significant activity for derivatives4a‐e, 4g.These results are encouraging and justify further investigational work on this class of molecules.