ABSTRACT
We have previously described a series of antagonists that showed high potency and selectivity for the NK(1) receptor. However, these compounds also had the undesirable property of existing as a mixture of interconverting rotational isomers. Here we show that alteration of the 2-naphthyl substituent can modulate the rate of isomer exchange. Comparisons of the NK(1) receptor affinity for the various conformational forms has facilitated the development of a detailed NK(1) pharmacophore model.
Subject(s)
Naphthalenes/chemical synthesis , Neurokinin-1 Receptor Antagonists , Animals , Biological Availability , Brain/metabolism , Cell Line, Tumor , Dogs , Gerbillinae , Humans , In Vitro Techniques , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Naphthalenes/chemistry , Naphthalenes/pharmacology , Pulmonary Artery/drug effects , Pulmonary Artery/metabolism , Rabbits , Radioligand Assay , Receptors, Neurokinin-1/chemistry , Receptors, Neurokinin-1/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Addition of phenyllithium to a mixture of an imine, methyl o-iodobenzoate, and BF(3).etherate at -105 degrees C gives good to excellent yields of isoindolones. The transient formation of methyl o-lithiobenzoate is proposed, which is formed by a rapid lithium/iodide exchange reaction of the phenyllithium with methyl o-iodobenzoate in the presence of the imine. The transiently generated anions can then be captured by the BF(3)-activated imines to form the isoindolones in good to high yield. The reactions conditions are sufficiently mild, and selective, to permit functional groups such carbmethoxy and aryl bromide, which could otherwise react with the added PhLi, to be tolerated.
