ANTIHYPERGLYCEMIC ,6A-TETRAHYDRO-1H,4H-[1,3]DIOXEPINO[5,6-B]AZIRINES - SYNTHESIS, X-RAY STRUCTURE-ANALYSIS, CONFORMATIONAL BEHAVIOR, QUANTITATIVE STRUCTURE-PROPERTY RELATIONSHIPS, AND QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS

A series of 6a-tetrahydro-1H,4H-[1,3]dioxepino[5,6-b]azirines, 4, has been synthesized and evaluated for its effects on blood glucose-decrea sing activity. These derivatives were prepared from 4,7-dihydro-1,3-di oxepins 1 via vic(acylamino)halogenodioxepanes 2 and, dioxepinoazirine s 3. Quantitative structure-property relationship and quantitative str ucture-activity relationship models, based on X-ray and molecular mech anics analyses, to our knowledge the first in the field of antihypergl ycemics, were developed. They allow the prediction of properties (RP-H PLC attention times) and activities (hypoglycemic activity ratio) by t he Connolly's molecular surface areas. The lead compound in these mode ls, sulfonyldioxepinoazirine 4i, expressed superior antihyperglycemic activity in comparison to metformin in alloxanized mice, irrespective of route of application. It significantly reduced blood glucose levels in glucose-primed mice, but it did not cause a dose dependent decreas e of blood glucose level in healthy (nondiabetic, control) animals.