The effects of substituting tetrazole for carboxyl in two series of anti-inflammatory phenoxyacetic acids

Abstract

Abstract Series of o-phenylcarbamoyl- and o-benzamido-phenoxymethyl tetrazoles and o-phenylcarbamoylphenoxyacetic acids have been synthesized. Anti-inflammatory activity was measured by the phenyl benzoquinone writhing test in mice and the rat foot carrageenan oedema test. Potency in the two o-benzamido substituted series could not be related with structure in a satisfactory manner. Introduction of substituents into the benzene rings of the o-phenylcarbamoyl substitued series led to complex changes. When the phenoxy ring was unsubstituted, introduction of meta- and para-substituents possessing high +ve π constants into the o-phenylcarbamoyl ring led to increased potency, and each tetrazole was appreciably more potent than the corresponding acid. When the o-phenylcarbamoyl ring was unsubstituted meta- and para-substituents with high +ve π constants introduced into the phenoxy ring caused increases in potency in the acid series but not in the tetrazole series, and each acid was more potent than the corresponding tetrazole. The two tetrazoles found to be the most active in the mouse writhing test 5-[2-(3,4-dichlorophenylcarbamoyl)phenoxymethyl]tetrazole (compound 12T, SNR.2337) and 5-[4-chloro-2-(3-trifluoromethylphenyl-carbamoyl)phenoxymethyl]tetrazole (compound 22T, SNR.2420) were selected for study in a series of other anti-inflammatory tests.