SYNTHESIS AND SELECTIVE COROLLARY VASODILATORY ACTIVITY OF IHYDRO-2,2-BIS(METHOXYMETHYL)-2H-1-BENZOPYRAN-3-OL DERIVATIVES - NOVEL POTASSIUMCHANNEL OPENERS

A variety of compounds having a benzopyran such as levcromakalim gener ally exhibit potent antihypertensive activity. During extensive invest igations aimed toward identifying K+ channel openers having selective coronary vasodilation without potent hypotensive and tachycardiac effe cts, we synthesized a series of 3,4-dihydro-2H-1-benzopyran-3-ol deriv atives modified at positions 2, 4, and 6 in the benzopyran ring. Initi ally, compounds having two methoxymethyl groups at position 2 were fou nd to show a selective effect on coronary blood flow (CoBF) relative t o mean arterial pressure (MAP) in anesthetized dogs. To find more pote nt vasodilators, various benzopyran derivatives modified at position 4 were synthesized and structure-activity relationships were examined b y evaluation of the extent and duration of the increase in CoBF in ane sthetized dogs. As a result, compounds having a (1,6-dihydro-6-oxopyri dazin-3-yl)amino group at position 4, in addition to the two methoxyme thyl groups at position 2, were found to be more potent and to have an improved duration of action. Among these compounds, JTV-506, mino]-2, 2-bis(methoxymethyl)-2H-1-benzopyran-3-ol, exhibited good selectivity for its effect. Administration of this compound (0.03 mg/kg, po) elici ted an increase of CoBF without a change of systemic blood pressure an d heart rate (HR) in conscious dogs. Further evaluation was performed with respect to (i) the selectivity of its action on the coronary arte ry versus the aorta and (ii) its effects on MAP, HR, and electrocardio graphic ST elevation. As a result, JTV-506 was selected as a potent an d selective coronary vasodilator with various pharmacological features favoring clinical development.