2,2-Dialkylnaphthalen-1-ones as new potassium channel activators

Abstract

A new series of 2,2-dialkylnaphthalen-1-one potassium channel activators has been prepared, and their in vitro relaxant activities in isolated rat portal vein and guinea pig tracheal spirals as well as their oral antihypertensive effect in spontaneously hypertensive rats have been evaluated. The group of 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethylnaphthalen -1- ones with an electron-withdrawing substituent at the 6-position contain the most active compounds and 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-1-oxonaphtha lene-6- carbonitrile, 17f (UR-8225), has been selected for further pharmacological development.

Structure-Activity Relationships of KATP Channel Openers

“…The impact of 1-position on potency gives the following ranking: O ≈ S > NH ≈ CH 2 > CO >> SO, SO 2 . Dialkylnaphthalenones [36] such as UR-8225 18 are noteworthy because some of its derivatives are reportedly trachea selective. Advantageous replacements of the pyran ring comprise 1,4-benzoxazines such as YM934 19; it is a potent vasodilator with particularly pronounced effects on coronary arteries [37,38].…”

Synthesis of Phosphonoindoprofen

“…The reaction of aniline 2 with methyl orthobrommethylbenzoate 4 [14][15][16][17][18][19] led first to N-alkylated product 5, which was then cyclizated into isoindolone 1b (Scheme 1). The conversion of 5 into phosphonoisoindolone 1b essentially depended on the nature of the base and the solvent, and in all cases resulted in mixture of 1b and 5.…”

Second-Generation KATP Channel Openers

“…Studying relaxant activities in isolated rat portal vein versus guinea-pig tracheal spirals, airways selectivity by a factor of roughly 12 was shown for compound 8 [50].…”