Synthesis and Evaluation of 2-[(5-Methylbenz-1-ox-4-azin-6-yl)imino]imidazoline, a Potent, Peripherally Acting α2 Adrenoceptor Agonist†

We have synthesized 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline, 3, a potent, peripherally acting α2 adrenoceptor agonist. The agent is conveniently prepared in five steps from 2-amino-m-cresol. The agent has demonstrated good selectivity for α2 adrenoceptors in binding and functional studies. When applied topically to eyes, the agent is efficacious for the reduction of intraocular pressure. The agent does not penetrate the blood−brain barrier and, as a consequence, does not lower blood pressure or induce sedation when administered topically or intravenously. We have determined the pKa and log P in water versus both octanol and dodecane of 3 and a set of related agents. The best physical parameter to explain its lack of central nervous system penetration appears to be log P measured in octanol versus water.