Synthesis and Selective Coronary Vasodilatory Activity of 3,4-Dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol Derivatives:  Novel Potassium Channel Openers

Abstract

A variety of compounds having a benzopyran such as levcromakalim generally exhibit potent antihypertensive activity. During extensive investigations aimed toward identifying K+ channel openers having selective coronary vasodilation without potent hypotensive and tachycardiac effects, we synthesized a series of 3,4-dihydro-2H-1-benzopyran-3-ol derivatives modified at positions 2, 4, and 6 in the benzopyran ring. Initially, compounds having two methoxymethyl groups at position 2 were found to show a selective effect on coronary blood flow (CoBF) relative to mean arterial pressure (MAP) in anesthetized dogs. To find more potent vasodilators, various benzopyran derivatives modified at position 4 were synthesized and structure-activity relationships were examined by evaluation of the extent and duration of the increase in CoBF in anesthetized dogs. As a result, compounds having a (1,6-dihydro-6-oxopyridazin-3-yl)amino group at position 4, in addition to the two methoxymethyl groups at position 2, were found to be more potent and to have an improved duration of action. Among these compounds, JTV-506, (-)-(3S,4R)-6-cyano-3,4-dihydro-4-[(1,6-dihydro-1-methyl-6-oxopyridaz in-3-yl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol, exhibited good selectivity for its effect. Administration of this compound (0.03 mg/kg, p.o.) elicited an increase of CoBF without a change of systemic blood pressure and heart rate (HR) in conscious dogs. Further evaluation was performed with respect to (i) the selectivity of its action on the coronary artery versus the aorta and (ii) its effects on MAP, HR, and electrocardiographic ST elevation. As a result, JTV-506 was selected as a potent and selective coronary vasodilator with various pharmacological features favoring clinical development.

New ternary immobilization of chiral sulfonato-(salen)manganese(III) complex for aqueous asymmetric oxidation reactions

“…At last, total aqueous solution was evaporated to dryness, and solid residue was washed by dichloromethane (3 × 30 mL) and a small amount of ice-water (0 • C) to afford disodium 3-tert-butyl-salicylaldehyde 5-sulfonate (aldehyde) as brown solid (yields 80-97%). 1 …”

“…Optically pure epoxides of chromene, for instance, were ever used as key intermediates in preparation of antihypertensive agents through regioselective ring opening [1], and chiral sulfoxides, more directly, exhibited great clinical values for the treatment of gastric ulcer [2] or other inflammatory diseases [3]. Therefore, the design of effective catalysts for highly asymmetric oxidation of alkenes and sulfides constitutes an important strategy for large-scale production of fine pharmaceuticals.…”

Effects of JTV‐506, a new K+ channel activator, on airway smooth muscle contraction and systemic blood pressure

“…was sythesized in the Japan Tobacco Inc. Central Pharmaceutical Research Institute ( Fig. I) [32]. Histamine dihydrochloride, glibenclamide and cromakalim were obtained from Sigma Chemical Co. (St. Louis, MO, USA).…”

Efficient Synthesis of 8-Methoxy-3,4-dihydro-2H-1-benzopyran-3-ol

“…[1][2][3] Several bioactive natural products containing benzopyranol moieties exibit antibacterial, antioxidant, and photoprotective action. [4,5] Additionally, 8-methoxy-3,4-dihydro-2H-1-benzopyran-3-ol (1) is a key intermediate in the synthesis of Nipradilol (A), a b-adrenoreceptor blocking agent with vasodilator action.…”