Synthesis of constrained l-phenylalanine derivatives incorporating a benzazepinone or an azepinone ring as VCAM/VLA-4 antagonists

Novel constrained l-phenylalanine derivatives incorporating a benzazepinone or an azepinone ring were synthesized in 13 and 8 steps, respectively, employing a key base-catalyzed intramolecular cyclization reaction. The product, 2, was comparable in potency in a VCAM/VLA-4 ELISA assay to the corresponding unconstrained analog 1 suggesting that cyclization favored the bioactive conformation. However, compound 4 was 100-fold less potent than the unconstrained analog 3.