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.
Nishijima
K
K
Fuji Central Research Laboratory, Mochida Pharmaceutical Co. Ltd., 722 Jinba-aza-Uenohara, Gotemba, Shizuoka, Japan. kazumi@mochida.co.jp
Nishida
H
H
Yamashita
Y
Y
Ito
M
M
Onuki
Y
Y
Mizota
M
M
Miyano
S
S
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004231:Diuresis / Q000187:drug effects; D004232:Diuretics / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D015195:Drug Design; D005665:Furosemide / Q000494:pharmacology; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000494:pharmacology; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010091:Oximes / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004232:Diuretics; D006574:Heterocyclic Compounds, 2-Ring; D010091:Oximes; D005665:Furosemide