Side-chain modified analogues of histaprodifen: Asymmetric synthesis and histamine H1-receptor activity

New analogues of histaprodifen with polar side chains have been stereoselectively synthesized and evaluated as histamine H1-receptor agonists. As a key transformation the asymmetric aminohydroxylation has been used, which was successfully realized for the first time on an imidazolyl derivative. While all chiral analogues proved to be weak H1-receptor antagonists, an achiral keto derivative of histaprodifen turned out to be the first 2-acylated histamine congener displaying partial H1-receptor agonism (relative potency 12%).