Inhibitors of adhesion molecules expression; The synthesis and pharmacological properties of 10H-pyrazino[2,3-b][1,4]benzothiazine derivatives

Abstract

During a search for novel, orally-active inhibitors of upregulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), we found a new series of 10H-pyrazino[2,3-b][1,4]benzothiazine derivatives to be potent ICAM-1 inhibitors. Of these compounds, N-[1-(10H-Pyrazino[2,3-b][1,4] benzothiazin-8-ylmethyl)-piperidin-4-yl]-N′,N′-dimethylsulfamide 7p showed the potent oral inhibitory activities against neutrophil migration in a murine interleukin-1 (IL-1) induced paw inflammation model. The synthesis and structure-activity relationships of these amide derivatives are described. © 2002 Pharmaceutical Society of Japan.