A series of the little compounds was prepared by cyclization of the appropriate 5-(aryloxy)-v-triazole-4-carboxylic acids and evaluated for antiallergic activity by the rat passive cutaneous anaphylaxis (PCA) screen. The most potent compounds were 6-(mesyloxy)-9-oxo-1H,9H-benzopyrano[2,3-d]-v-triazole and its 5-methyl homologue, which were some tenfold more potent than disodium cromoglycate. Dialkyl derivatives, especially those substituted at C-5 and C-6 or C-6 and C-7, and 6-methoxy compounds were also among the more potent compounds. One compound, 6,7-dimethyl-9-oxo-1H,9H-benzopyrano[2,3-d]-v-triazole, was further evaluated and shown to be a potent inhibitor of rat PCA when given orally.
The syntheses and structure--activity relationships of a number of 4-hydroxy-3-nitrocoumarins, which are both antagonists of a slow reacting substance of anaphylaxis and potent inhibitors of antigen-induced histamine release in the rat, are described. Most active among these are 7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy(-2-hydroxypropoxy] derivatives having hydrogen or lower alkyl substituents at the C-8 position of the coumarin ring, 168, 171, 173, and 174.
In a small range finding study a number of N-benzylpiperazino derivates of 3-nitro-4-hydroxycoumarin have been shown to combine potent H1-antihistamine activity with that of mast cell stabilization as demonstrated by their activity as antagonists of histamine on guinea pig ileum and by their inhibition of the release of histamine in rat passive peritoneal anaphylaxis (PPA). The most potent compound, 1-[2-hydroxy-3-[(4-hydroxy-3-nitrocoumarin-7-yl)oxy]propyl]-4- (4-chlorobenzyl)piperazine, 30, had a pA2 of 9.0 against histamine on guinea pig ileum and inhibited histamine release in the rat PPA test with a potency similar to that of disodium cromoglycate.
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