New tetracyclic guanidine derivatives with H1-antihistaminic properties. Chemistry of epinastine.

A series of new tetracyclic guanidines were synthesized by various methods. Specific binding of the described compounds to histamine-1 and histamine-2 receptors was determined. The compound 3-amino-9,13b-dihydro-1H-dibenz[c,flimidazo[1,5-a]azepine (epinastine, WAL 801, compound IIIa) combines high selectivity with high affinity for the H1 receptor and was selected from the compounds studied for further pharmacological and clinical investigations. Experimentally determined physicochemical parameters (pka-value, partition coefficient) and the hydrogen-bonding ability of epinastine are indications that this compound will not easily cross the blood-brain barrier. This explains the absence of CNS side-effects of epinastine in pharmacological and clinical studies.