A series of spiro[imidazolidine-4,4'(1'H)-quinazoline]- 2,2'5(3'H)-triones were prepared and tested for aldose reductase inhibitory activity. The 6'-halogenated derivatives were found to be highly potent in vitro inhibitors of male rabbit lens aldose reductase and in vivo inhibitors of polyol accumulation in the sciatic nerves of galactosemic rats. Of these, (4R)-6'-chloro-3'-methylspiro[imidazolidine-4,4'(1'H)-quinazoline] -2,2',5(3'H)-trione (67) showed the most potent in vitro and in vivo activities. An oral dose of 3 g/kg of compound 67 caused neither death nor behavioral abnormality in the preliminary acute toxicity study using mice and rats. Compound 67 was selected as a candidate for further evaluation. The quantitative structure-activity relationships in this series are also discussed.

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Optically pure 3'-methylspiro[imidazolidine-4,4'(l'/i)-qumazoline]-2,2',5(3/H)-trione was prepared by optical resolution using brucine as a resolving agent. The resulting optically pure spirohydantoin was racemized by refluxing in 1,2-dichlorobenzene for 17 h, or more effectively upon heating in 10% HC1 at 90 °C for 2 h. In the acid-catalyzed racemization, the introduction of difluoromethyl group at the 3-nitrogen of hydantoin ring increased the racemization rate, while the introduction of methyl group at the 3-nitrogen reduced it. These results suggest that the acid-catalyzed racemization proceeds via the N-acyliminium ion generated by the cleavage of the N3-C4 bond of the spirohydantoin ring.Several spirohydantoin derivatives which exhibit potent aldose reductase (AR) inhibitory activity are of potential value in the therapy of diabetic complications.1 We have previously reported the synthesis of a variety of spiro[imidazolidine-4,4/(TH)-quinazoline]-2,2',5(3,H)-triones by the reactions of isatin derivatives with either urea or isothiourea, followed by acid treatment.2,3 Of these, 3'methylspiro[imidazolidine-4,4'(l'fi)-quinazoline]-2,2/,5-

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