1-[(Imidazolidin-2-yl)imino]indazole. Highly α2/I1 Selective Agonist: Synthesis, X-ray Structure, and Biological Activity

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• 作者：Franciszek Sa̧ ; czewski ; Anita Kornicka ; Apolonia Rybczyń ; ska ; Alan L. Hudson ; Shu Sean Miao ; Maria Gdaniec ; Konrad Boblewski ; Artur Lehmann
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：June 26, 2008
• 年：2008
• 卷：51
• 期：12
• 页码：3599 - 3608
• 全文大小：431K
• 年卷期：v.51,no.12(June 26, 2008)
• ISSN：1520-4804

文摘

Novel benzazole derivatives bearing a (imidazolidin-2-yl)imino moiety at position 1 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 α₂-adrenoceptor ligand with α₂-adrenoceptor/imidazoline I₁ receptor selectivity ratio of 3879, while 1-[(imidazolidin-2-yl)imino]-7-methylindazole (13k) proved to be a mixed α₂-adrenoceptor/imidazoline I₁ receptor agonist with α₂/I₁ 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 μg/kg) and heart rate, which was attenuated following pretreatment with α_2A-adrenoceptor antagonist RX821002. Compound 13a may find a variety of medical uses ascribed to α₂-adrenoceptor agonists, and its 7-methyl derivative 13k is a good candidate for development as a centrally acting antihypertensive drug.