Spiro hydantoin aldose reductase inhibitors derived from 8-aza-4-chromanones.
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.
Sarges
R
R
Pfizer Central Research, Groton, Connecticut 06340.
Goldstein
S W
SW
Welch
W M
WM
Swindell
A C
AC
Siegel
T W
TW
Beyer
T A
TA
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D000818:Animals; D001372:Aza Compounds; D001578:Benzopyrans; D002839:Chromans; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D007908:Lens, Crystalline / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D051381:Rats; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D001372:Aza Compounds; D001578:Benzopyrans; D002839:Chromans; D006827:Hydantoins; D007202:Indicators and Reagents; D013141:Spiro Compounds; D013012:Sorbitol; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase