A series of 1,2,4-oxadiazoles and 1,2,4-thiadiazoles containing a 2,6-di-tert-butylphenol substituent were prepared and evaluated as dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia (RBL-1) cells. Several of these compounds show oral efficacy in the rat carrageenan footpad edema (CFE) and mycobacterium footpad edema (MFE) antiinflammatory models, without concomitant gastric ulceration. Structure-activity relationships are discussed. The best compounds (ID40 values in MFE of 3-8 mg/kg po) contain guanidine-derived substituents on the heterocyclic ring.

The preparation of 1,2,4‐thiadiazoles with a di‐tert‐butylphenol substituent at the thiadiazole 3‐position is described. A thermally generated nitrile sulfide was reacted with tosyl cyanide in a 1,3‐dipolar cyclization reaction to provide a thiadiazole intermediate containing a labile 5‐tosyl substituent.

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The preparation of pyrimidine analogs of the 2,6‐di‐tert‐butylphenol antiinflammatory agents Prifelone (R‐830), Tebufelone (NE‐11740) and Ym‐13,162 is described. Grignard addition to the N‐methoxy‐N‐methylamide derived from 4,6‐bis(1,1‐dimethylethyl)‐5‐hydroxy‐2‐pyrimidinecarboxylic acid yielded a series of 2‐pyrimidinyl ketones. Further elaboration of an ethyl ketone and cyclization with sodium cyanate gave a pyrimidinylimidazole.

Synthesis of Pyrimidine Analogues of 2,6-Di-tert-butylphenol Antiinflammatory Agents.-Some pyrimidine analogues of the well studied di-tert-butylphenol antiinflammatory agents Prifelone (cf. (IIIb)), Tebufelone (cf. (IV)) and 162 (cf. (VIII)) are synthesized with the aim to improve the aqueous solubility and so to increase the oral bioavailability by replacement of the benzene ring with a pyrimidine ring. -(UNANGST, P. C.; CONNOR, D. T.; KOSTLAN, C. R.; SHRUM, G. P.; MILLER, S. R.; KANTER, G.; J.