Synthesis of conformationally restricted substance P antagonists

Abstract Reaction of CP-99,994 ( 1 ) with benzyl chloromethyl ether under basic conditions produced the novel 1,6-diazabicyclo[3.2.1]octane system in good yield; analogs containing this nucleus display high binding affinity for substance P receptors. The ethylene homologue of 1a , diamine 7 , shows enhanced inhibitory activity and may more closely approximate the binding conformation of 1a at the NK 1 receptor.