NEW ANTIANGINAL NITRO ESTERS WITH REDUCED HYPOTENSIVE ACTIVITY - SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF 3-[(NITROOXY)ALKYL]-2H-1,3-BENZOXAZIN-4(3H)-ONES

New nitro ester 3-[(nitrooxy)alkyl]-2H-1,3-benzoxazin-4(3H)-ones show marked inhibitory activity against ischemia-induced electrocardiograph ic changes, with only limited systemic hemodynamic effects, and are re ported in the present study. These new nitro vasodilators are potent i nhibitors of the electrocardiographic T-wave and S-T segment elevation induced by intravenous or intracoronary administration of Arg-vasopre ssin or methacholine in the anesthetized rat. The most active compound s are up to 300- and 600-fold more potent than glyceryl trinitrate or Nicorandil, respectively. These nitro esters relax in a concentration- dependent manner the isolated rabbit aorta, at higher concentrations ( 2-40-fold) than glyceryl trinitrate, and reduce the mean arterial bloo d pressure at doses 7-300-fold higher than those required by glyceryl trinitrate to exert a similar hypotensive effect. Remarkably, these co mpounds retain their anti-ischemic and hemodynamic profile after oral (po) administration. These new nitro ester derivatives, endowed with a marked antianginal activity, which is not associated with concurrent and pronounced falls in systemic blood pressure, represent the leads o f a new class of selective nitrovasodilators having a preferential act ion on large coronary vessels, which could be clinically relevant in t he treatment of coronary artery diseases.