Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4-benzodioxan as Orally Active 5-Lipoxygenase Inhibitors

Abstract

N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-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 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO 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 synthesized in high (> 95%) enantiomeric purity from commercially available optically 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 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.

Palladium‐Catalyzed Annulation of Aryl‐1,2‐diols and Propargylic Carbonates. Theoretical Study of the Observed Regioselectivities

“…[12] As a consequence, there has been increasing interest in their synthesis during the last years. Synthetic routes to 2-alkylidene-1,4-benzodioxanes are not straightforward and often need a tedious, multi-step sequence.…”

Synthesis and Anticancer Activity of (R,S)‐9‐(2,3‐Dihydro‐1,4‐Benzoxathiin‐3‐ylmethyl)‐9H‐Purines

“…[4] Twelve years ago, 2,3-dihydro-1,4-benzodioxins were developed as inhibitors of 5-lipoxygenase, an enzyme involved in the oxygenation of arachidonic acid to leukotrienes; they are also useful for the treatment of inflammatory diseases such as asthma and arthritis. [5] The occurrence of the 2,3-dihydro-1,4-benzodioxin structure in various natural products has been also reported. [6] Paradoxically, despite the considerable development of biologically active compounds with the 2,3-dihydro-1,4-benzodioxin moiety, the 2,3-dihydro-1,4-benzoxathiine skeleton has still remained inaccessible.…”

The anti-arthritic and anti-oxidative effect of NBD (6-nitro-1,3-benzodioxane) in adjuvant-induced arthritis (AIA) in rats

“…1), a p-nitrophenol derivative in the adjuvant-induced arthritis (AIA) model in rats. The reasons for selecting this compound were based on the fact that (1) its parent compound, i.e., p-nitrophenol, is commonly used for the synthesis of 4-aminophenol which is a potent clinically used analgesic, and (2) some of the benzodioxane derivatives are reported to have anti-inflammatory activity [51][52][53][54]. Moreover, when the dioxane ring of NBD is opened, it closely resembles salicylic acid, which is a potent anti-inflammatory drug.…”