3-benzhydryl-4-piperidones as novel neurokinin-1 receptor antagonists and their efficient synthesis

A series of novel 3-benzhydryl-4-piperidone derivatives were identified as potent tachykinin neurokinin-1 (NK(1)) receptor antagonists. An efficient and versatile synthesis of this series was achieved with a coupling reaction of 1-benzylpiperidones with benzhydryl bromides or benzhydrols in the presence of trifluoromethanesulfonate and a condensation reaction of piperidones with benzyl alcohols using ethyl o-phenylenephosphate. The 3-benzhydryl-4-piperidone skeleton, which has a 1,1-diphenylmethane moiety that is a known privileged substructure targeting G-protein coupled receptors, can be used for chemical library synthesis because of chemical accessibility and diversity.