Synthesis and bronchodilator activity of endo-2-(2-cyclopentyl-2-hydroxy-2-phenyl)acetoxy-7-methyl-7- azabicyclo-[2.2.1]heptane methobromide, a potent and long-acting anticholinergic agent.

The synthesis of the alpha-cyclopentylmandelate ester of quaternized endo-7-methyl-7-azabicyclo[2.2.1]heptan-2-ol (4, RS-11635) is described. The key step of this synthesis consists of the intramolecular trans-diaxial epoxide opening of 4-(N-methylamino)-1,2-epoxycyclohexane (8) to form the endo-azabicyclic structure 9. Evaluation of anticholinergic bronchodilator activity by intravenous administration in methacholine-challenged guinea pigs indicated 4 to be approximately twice as potent as ipratropium bromide (ED50 of 1.1 versus 2 micrograms/kg) and to have a duration of action nearly five times as long (230 versus 50 min). Evaluation of anticholinergic bronchodilator activity by aerosol administration in methacholine-challenged dogs also indicated 4 to be approximately twice as potent as ipratropium bromide and to have a duration of action nearly three times as long.