Spiro hydantoin aldose reductase inhibitors derived from 8-aza-4-chromanones

• Published in: Journal of medicinal chemistry 1990-07, Vol.33 (7), p.1859-1865
• Main Authors: Sarges, Reinhard, Goldstein, Steven W, Welch, Willard M, Swindell, Archie C, Siegel, Todd W, Beyer, Thomas A
• Format: Article
• Language: English
• Subjects: 8-aza-4-chromanone; Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - isolation & purification; Animals; Aza Compounds; Benzopyrans; Chemistry; Chromans; Diabetes Mellitus, Experimental - enzymology; Diabetes Mellitus, Experimental - metabolism; Exact sciences and technology; Female; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Humans; Hydantoins - chemical synthesis; Hydantoins - pharmacology; Indicators and Reagents; Lens, Crystalline - drug effects; Lens, Crystalline - metabolism; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; Organic chemistry; Placenta - enzymology; Pregnancy; Preparations and properties; Rats; Sciatic Nerve - drug effects; Sciatic Nerve - metabolism; Sorbitol - metabolism; Spiro Compounds - chemical synthesis; Spiro Compounds - pharmacology; Stereoisomerism; Structure-Activity Relationship; Sugar Alcohol Dehydrogenases - antagonists & inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00169a005

A series of spiro hydantoins derived from 8-azachromanones (2,3-dihydro-4H-pyrano[2,3-b]pyridin-4-ones) has been prepared and tested for aldose reductase inhibitory activity. The standard Bucherer-Bergs conditions had to be drastically modified to increase yields from less than 1% to an acceptable 50% range. One of the most potent compounds was cis-6'-chloro-2',3'-dihydro-2'-methylspiro[imidazolidine-4,4'-4'H- pyrano[2,3-b]pyridine]-2,5-dione; resolution of this compound showed that the 2'R,4'S enantiomer 16 was the most active spiro hydantoin in this series with an IC50 of 7.5 x 10(-9) against human placenta aldose reductase.