Studies on Antidiabetic Agents. IX.1) A New Aldose Reductase Inhibitor, AD-5467, and Related 1,4-Benzoxazine and 1,4-Benzothiazine Derivatives: Synthesis and Biological Activity

Abstract

N-Acetic acid derivatives (I) of 2-substituted 1,4-benzoxazines and benzothiazines were designed and synthesized for evaluation as new aldose reductase inhibitors. In general, 3-thioxo derivatives were more potent inhibitors of aldose reductase from human placenta in vitro than the corresponding 3-oxo derivatives. While many compounds (I) were not very effective in inhibiting sorbitol accumulation in the rat sciatic nerve in vivo, the 3-thioxo compounds bearing an isopropyl group at the 2-position showed highly potent activity in the in vivo assay. Compound 46 (AD-5467) was selected from this series as a candidate for further development. © 1990, The Pharmaceutical Society of Japan. All rights reserved.