Design, Synthesis and Antihistamine Evaluations of Several N-hydroxyalkyl Desloratadine Analogues

Several N-hydroxyalkyl desloratadines and N-methoxyl ethyl desloratadine were prepared and evaluated for H1 antihistamine activity. The effects on isolated ileum smooth muscle tension in guinea pigs in vitro and asthma-relieving effects on the histamine-induced asthmatic reaction in guinea-pigs in vivo were examined. Most of them exhibited satisfactory H1 antihistamine activity and were obviously more potent than loratadine. Among these, Compound 3, N-(3- hydroxy)propyl desloratadine was the most active one. And it was chosen as a candidate for evaluation of acute toxicity (LD50= 0.876(0.784-0.980) g/kg), significantly superior to that of desloratadine (LD50=0.353 g/kg). Meanwhile, the experimental results demonstrated that the oxygen atom in the side carbon chain is crucial for enhancing the antihistamine activities.