Triazolyl-benzimidazolones and triazolyl-benzotriazoles: new potential potassium channel activators. II

This paper reports the synthesis and pharmacological evaluation of a series of 5-substituted-triazolyl-benzotriazoles (2a-f) and the corresponding ser ies of 5-substituted-triazolyl-benzimidazolones (6a-f), as potential activa tors of the big-conductance calcium-activated potassium channels (BKCa). Th e synthesis and structure demonstration of the stock compounds of the two s eries have been described in our previous works, as well as the common star ting compounds 4-carboxamido-5-(4-substituted-2-amino-anilino)-1,2,3-triazo les (1a-f). The triazolyl-benzotriazoles were obtained by diazotization, wh ile the triazolyl-benzimida-zolones were obtained by thermal intramolecular cyclization of ethoxycarbonylamino derivatives or directly with phosgene. Benzimidazolone compounds generally showed little effect whilst the compoun ds with a benzotriazole ring showed full efficacy, with vasorelaxing proper ties and potency parameters a little lower than that of the reference compo und NS 1619. These effects were significantly reduced by an increased membr ane depolarization. This depolarization-sensitive response is in agreement with the pharmacodynamic hypothesis of activation of potassium channels. (C ) 2000 Editions scientifiques et medicales Elsevier SAS.