Chem. Pharm. Bull. 52(6) 675—687 (2004)

cule-1 (ICAM-1), E-selectin and vascular cell adhesion molecule-1 (VCAM-1), play a pivotal role in the inflammatory and immunological responses. They are initially upregulated on the endothelium by tumor necrosis factor-a (TNF-a) or interleukin-1 (IL-1) and go on to mediate the steps of leukocyte migration from the vasculature into the inflamed tissue, these leukocytes then promote the inflammatory response. Also, the interaction of ICAM-1 and VCAM-1 expressed on antigen presenting cells with their ligands, such as lymphocyte function associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4), has been involved in activation of T cells. Recently, the antigen recognition step has been visualized and ICAM-1 identified as one important component of the immunological synapse. Hence, it is hoped that interfering with these interactions will not only have an effect on leukocyte infiltration, but also modulate T cell response. Furthermore, it has been reported that anti-adhesion molecule antibodies can ameliorate the inflammatory reaction and immunological parameters in various animal models. For these reasons the development of cell adhesion molecule inhibitors as novel therapeutics for inflammatory and autoimmune diseases has been widely anticipated, and a considerable literature on such compounds has appeared. We have reported that the piperidine sulfonamide and sulfamide derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine 1a and 1b have potent ICAM-1 upregulation inhibitory activity and suppresses neutrophil infiltration in an IL-1-induced paw inflammation model. We report here the effect of replacing the piperidine sulfonamide moiety of 1a in order to investigate further the structure–activity relationships of this family. Of particular interest to us was the introduction of a carboxylic acid group, a bioisostere of the sulfonamide function. Chemistry We first prepared the right moieties of the compounds 2. The piperidine carboxylates 4a—c are either commercially available or known in the literature. The other piperidine carboxylates 4d—i and 4l—v were prepared as shown in Charts 1—11. The syntheses of 4d and 4e are shown in Chart 1. Coupling the aldehyde 6 with the appropriate Horner–Emmons reagent gave the unsaturated ester 7. Hydrogenation of the resulting ester 7 using 10% palladium on carbon (Pd/C) followed by deprotection of the piperidine amine group with 4 N HCl/AcOEt provided saturated ester 4d. The unsaturated ester 4e was also obtained by removal of the Boc group of compound 7 using the same procedure. The acetylenic ester 4f was prepared as shown in Chart 2. Reaction of 4-piperidine aldehyde 9 with the Corey–Fuchs June 2004 Chem. Pharm. Bull. 52(6) 675—687 (2004) 675