DERIVATIVES OF NOCARBONYL)-N-HYDROXYAMINO]METHYL]-1,4-BENZODIOXAN AS ORALLY-ACTIVE 5-LIPOXYGENASE INHIBITORS

N-Hydroxyureas based on the 1,4-benzodioxan template were prepared fro m appropriately substituted 1,4-benzodioxan-2-methanols as the key int ermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activi ty. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were s ubsequently assayed in an ex vivo dog model of LTB(4) synthesis at a d ose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest du ration of action (DA) in this dog model. The g-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p- fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25 667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-L O assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthes ized in high (>95%) enantiomeric purity from commercially available op tically active glycidyl tosylates and evaluated. In the in vitro assay , the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 - 180 n M). In the ex vivo experiment, 24, which dose dependently inhibited pl asma 5-LO activity, was shown to be significantly longer acting than 2 6, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.