A novel class of antiallergy agents, the substituted 1,8-naphthyridin-2(1H)-ones, is described. The present compounds are orally active, potent inhibitors of allergic and nonallergic bronchospasm in animal models. Structure-activity studies of the lead compound in this series, 1-phenyl-3-n-butyl-4-hydroxynaphthyridin-2(1H)-one (11), identified three compounds of interest, 1-phenyl-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H)-one (12), 1-(3'-chlorophenyl)-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H )-one (87), and 1-(3'-methoxyphenyl)-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1 H)-one (89). The mechanism of antiallergy activity may involve inhibition of the release of the sulfidopeptide leukotrienes. 1-Phenyl-3-(2-propenyl)-4-acetoxy-1,8-naphthyridin-2(1H)-one, Sch 33303 (12), was selected for preclinical development as an antiallergy agent.
A series of analogues based on the 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one ring system have been synthesized and shown to possess oral antiinflammatory activity in both the reverse passive Arthus reaction (RPAR) pleural cavity assay in rats and in the adjuvant-induced arthritic rat model (AAR). Several members of this series additionally exhibit an inhibitory effect on the in vivo production of prostaglandin- and leukotriene-derived products or arachidonic acid metabolism although these compounds exhibit no significant inhibitory activity against the cyclooxygenase and 5-lipoxygenase enzymes in vitro. Structure-activity relationships in this series are discussed.
NOTES 1229 limation gave an analytical sample, mp 49-50.5'. The infrared spectrum (neat) showed absorption a t 3300 cm-' (OH); the nmr spectrum (CDCla) showed doublets a t 7 2.70 and 3. 21 (1 H doublets, J = 5 cps, aromatic), a broad absorption a t 4.70-4. 93 (1 H, OH), and a complex multiplet a t 6.80-8.00 ( 5 H, aliphatic ring hydrogens).Anal. Calcd for C7H80S: C, 59.97; H, 5.75; S, 22.87.(4) Melting points were determined on a calibrated Fisher-Johns apparatus and are corrected. Elemental analyses were performed by Midwest Microlab, Inc., Indianapolis, Ind. 46226. Proton nmr spectra were obtained using a Varian HA-100 spectrometer in CDCls solution using tetramethylsilane as internal standard.
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