ABSTRACT
We describe the design, synthesis, and evaluation of benzimidazoles as benzamide replacements within a series of trisubstituted cyclohexane CCR2 antagonists. 7-Trifluoromethylbenzimidazoles displayed potent binding and functional antagonism of CCR2 while being selective over CCR3. These benzimidazoles were also incorporated into lactam-containing antagonists, thus completely eliminating the customary bis-amide.
Subject(s)
Benzimidazoles/pharmacology , Cyclohexanes/chemistry , Receptors, CCR2/antagonists & inhibitors , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Dose-Response Relationship, Drug , Drug Design , Humans , Microsomes/drug effects , Molecular Structure , Structure-Activity RelationshipABSTRACT
An efficient enantioselective synthesis of benzyl (1S,2R,4R)-4-(tert-butoxycarbonylamino)-2-(hydroxymethyl)cyclohexylcarbamate 2, an essential intermediate for a series of potent CCR2 antagonists, is described. The key step in the sequence is an iodolactamization to yield the highly functionalized (1R,2S,4S,5S)-tert-butyl 2-(benzyloxycarbonylamino)-4-iodo-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate 11. An examination of the reaction mechanism within the 2-step iodolactamization sequence led to the discovery of a single-pot transformation of increased efficiency.
