Hidemitsu Nishida

Synthesis and diuretic activity of 4,5-dihydro-6H-imidazo[4,5,1-ij]quinoline-6-one6-oxime-O-sulfonic acid derivatives

Abstract Using our previously reported 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid potassium salt 1a (M17055) as a lead, a series of tricyclic (2a-o, 3, 4, 5) and tetracyclic (6) quinolinone oxime O-sulfonic acid derivatives were synthesized by ring annulation of the 1-(2-methylbenzoyl) moiety to the quinolinone skeleton. They were compared with furosemide and compound 1a for diuretic activity in dogs; some tricyclic 4,5-dihydro-6H-imidazo[4,5,1-ij]quinoline-6-one 6-oxime-O-sulfonic acid derivatives showed diuretic activity comparable (2c,e) or superior (2m) to the lead compound 1a. These results are discussed on the basis of a comparison of the conformational and electronic characteristics of the relevant compounds with the aid of computer graphics.

Synthesis and diuretic activity of 2,3-dihydro-4(1H)-quinolinone 4-oxime-O-sulfonic acid derivatives

Abstract The diuretic activity of 6-chloro-2,3-dihydro-1-propionyl-4(1H)-quinolinone 4-oxime 1 (M12285) was previously shown to derive from a 6-chloro-2,3-dihydro-1-propionyl-4(1H)-quinolinone 4-oxime-O-sulfonic acid salt as a rat metabolite. Thus, in the present study, the potassium salt 2 (M17000) was synthesized to unambiguously establish the structure as well as the stereochemistry of the oxime. The structural features of compounds 1 and 2 were compared with those of conventional diuretics by electrostatic potential maps. Using compound 2 as a lead compound, various quinolinone oxime sulfonic acid derivatives were synthesized and the diuretic activity for elucidation of the structure-activity relationships examined. Among the compounds synthesized, 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid potassium salt 3 (M17055) showed a particularly high activity.

Synthesis and diuretic activity of bicyclic fused heterocycles containing oxime-O-sulfonic acid moiety

In order to investigate the origin of the loop-type diuretic activity of M17055 (1), several variants (3-9) were designed and synthesized by modifying the quinolinone skeleton, and their diuretic activities were compared with the lead 1 and furosemide in dogs. It was found that the negative charge distribution pattern afforded by the dispositional arrangement of the 4-oxime-O-sulfonic acid and 1-N-acyl carbonyl moiety attached to the tetrahydropyridine ring system is inevitable for the development of the activity, which strongly supports the previously proposed model for the active site of the Na(+)-K(+)-2Cl(-) cotransporter. Also reported is the first synthesis of the dihydrothieno[3,2-b]pyridine-7(4H)-one ring system required in the synthesis of compound 9.