Spiro oxazolidinedione aldose reductase inhibitors

Spiro oxazolidinediones (2) derived from five- and six-membered ring aralkyl ketones are potent aldose reductase inhibitors in vitro and in vivo. Their novel and general synthesis has been devised with alpha-hydroxyimidates (5) and 4-alkoxy-2-oxo-3-oxazolines (6) as key intermediates, since traditional synthetic routes through alpha-hydroxy amides (8) usually led to alpha, beta-unsaturated amides (9). Resolution with cinchonidine afforded optically active spiro oxazolidinediones. Optimum biological activity resided in (4S)-6-chlorospiro [4H-2,3-dihydrobenzopyran-4,5'-oxazolidine]-2',4'-dione (21) and its 6,8-dichloro congener (23).