A series of N-hydroxyurea derivatives based on substituted benzoxepin and benzothiepin templates was prepared and the compounds were evaluated for their ability to inhibit 5-lipoxygenase in vitro and ex vivo. It is becoming increasingly evident that leukotrienes (LT's) are potent mediators of mammalian inflammatory reactions. Since the conversion of arachidonic acid to LTA4 by 5-lipoxygenase (5-LO) is the first committed step for the generation of LTs in the arachidonic acid cascade, it has long been hypothesized that inhibition of 5-LO could provide novel therapy for human inflammatory diseases, such as asthma, psoriasis, rheumatoid arthritis, inflammatory bowel disease, and allergic rhinitis. Recent clinical data on zileuton (A-64077) appear to support this hypothesis. Considerable efforts have been made to identify potent, orally active and long-acting 5-LO inhibitors. Especially since a report by Corey et al describing derivatives of arachidonic acid hydroxamic acid as potent 5-LO inhibitors in rat basophilic leukemia cells, inhibitors containing the hydroxamic acid moiety have been subjected to intensive studies. We recently reported that substituted chromene N-hydroxyureas, represented by CGS 23885, are potent and orally active inhibitors of 5-LO. In the SAR study, we noted that a small substituent at the 2-position of the chromene ring system did not have detrimental effects on 5-LO inhibitory activity. This fact prompted us to design, synthesize and evaluate 7-membered analogs, namely benzoxepin and benzothiepin derivatives (I).