1-[(Imidazolidin-2-yl)imino]indazole.: Highly α2/I1 selective agonist:: Synthesis, X-ray structure, and biological activity

Novel benzazole derivatives bearing a (imidazolidin-2-yl)imino moiety at position I or 2 were synthesized by reacting 1-amino- or 2-aminobenzazoles with N,N'-bis(tert-butoxycarbonyl)imidazolidine-2-thione in the presence of HgCl2. Structures of 1-[(imidazolidin-2-yl)imino]indazole (marsanidine, 13a) and free base of the 4-Cl derivative 12e were confirmed by X-ray single crystal structure analysis. Compound 13a was found to be the selective alpha(2)-adrenoceptor ligand with alpha(2)-adrenoceptor/imidazoline I-1 receptor selectivity ratio of 3879, while 1-[(imidazolidin-2-yl)imino]-7-methylindazole (13k) proved to be a mixed alpha(2)-adrenoceptor/imidazoline I-1 receptor agonist with alpha 2/I-1 selectivity ratio of 7.2. Compound 13k when administered intravenously to male Wistar rats induced a dose-dependent decrease in mean arterial blood pressure (ED50 = 0.6 mu g/kg) and heart rate, which was attenuated following pretreatment with alpha(2A)-adrenoceptor antagonist RX821002. Compound 13a may find a variety of medical uses ascribed to alpha(2)-adrenoceptor agonists, and its 7-methyl derivative 13k is a good candidate for development as a centrally acting antihypertensive drug.