1,4 3,6-DIANHYDROHEXITOL NITRATE DERIVATIVES .2. SYNTHESIS AND ANTIANGINAL ACTIVITY OF ARYLCARBONYLPIPERAZINE OR ARYLCARBONYLPIPERAZINE DERIVATIVES/

A series of 5-(4-aryl- or piperazin-1-yl)-5-deoxy-1,4:3,6-dianhydro-L- iditol 2-nitrates was prepared in order to obtain orally active, nitra te-type vasodilators with reduced side effects. Our drug design was ba sed on a small reduction in the lipophilicity compared to that of opro pyl)piperazin-1-yl]-1,4:3,6-dianhydro-L-iditol 2-nitrate (1, KF14124). Compounds 4h (aryl=benzimidazol-2-yl), 4i (arylcarbonyl=nicotinoyl), and 4w (arylcarbonyl=3-furoyl) showed potent anti-ischemic activity in a lysine-vasopressin-induced angina pectoris model (rats), and their structure-activity relationships are discussed. Compound 4i exhibited potent vasodilation of the coronary artery in anesthetized dogs and al so exhibited potent preload reduction in a heart failure model (dogs) as compared with isosorbide dinitrate (2), nicorandil (3), and KF14124 (1). Furthermore, 4i showed much weaker acute lethal toxicity and les s central nervous system depression than 1 in mice. Thus, 4i (KW-3196) is under development as a vasodilator and a drug for treating angina pectoris.