A series of 1-sulfonyl-1a,2,6,6a-tetrahydro-1H,4H- [1,3]dioxepino[5,6-b]azirines, 4, has been synthesized and evaluated for its effects on blood glucose-decreasing activity. These derivatives were prepared from 4,7-dihydro-1,3-dioxepins 1 via vic(acylamino)halogenodioxepanes 2 and dioxepinoazirines 3. Quantitative structure--property relationship and quantitative structure--activity relationship models, based on X-ray and molecular mechanics analyses, to our knowledge the first in the field of antihyperglycemics, were developed. They allow the prediction of properties (RP-HPLC attention times) and activities (hypoglycemic activity ratio) by the Connolly's molecular surface areas. The lead compound in these models, 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 decrease of blood glucose level in healthy (nondiabetic, control) animals.