2-(beta-Arylethylamino)- and 4-(beta-arylethylamino)quinazolines as phosphodiesterase inhibitors

The existence of several forms of cAMP phosphodiesterase having differing kinetic characteristics suggests the feasibility of developing tissue-selective inhibitors of this enzyme. This observation is of particular importance in the development of therapeutic agents for the management of reversible obstructive airways disorders. The present report describes the design, synthesis and pharmacological characterization of a series of 6,7-dimethoxyquinazoline derivatives having beta-arylethylamine substituents at the 2- or 4-positions. The quinazoline nucleus is intended to confer a high degree of inhibitory activity for phosphodiesterase while the beta-aryethylamine moieties are designed to provide selectivity for adrenergically innervated tissue. The target compounds of this study, 6 and 7, were prepared via beta-arylethylamine displacement of chloride from an appropriate chloroquinazoline intermediate. The resulting products were evaluated for their ability to relax guinea pig tracheal smooth muscle and as inhibitors of phosphodiesterase.