To discover dual inhibitors of 5-lipoxygenase (LO) and cyclooxygenase (CO) with improved pharmacokinetic properties, we have designed and synthesized series of 1,2,4-triazole, 1,3,4-oxadiazole, and 1,3,4-thiadiazole di-tert-butylphenol derivatives which exhibit a wide range of log P (2.3 to > 4) and pKa (5.5-12) values. From this work 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)- thione, choline salt (12a, CI-986) was found to be a potent inhibitor of 5-LO (IC50 = 2.8 microM) and CO (IC50 = 0.8 microM), orally active in rat models of inflammation and nonulcerogenic.

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Upon completion of the addition, the reaction was allowed to proceed at 6-10 °C for 4 h with stirring; during the entire reaction time the apparent pH of the mixture was monitored and kept constant at pH 7.5-8 (0.5 N KOH, Metrohom E336A pH-stat).1 Then, the CH2C12 layer was separated and the aqueous phase extracted with CH2C12 (40 mL). The combined methylene chloride extracts were dried (MgS04) and the solvent (and aceton) removed in vacuo, leaving a residue (2.2 g) containing 18-crown-6 and composed mainly of 5b and 2,6-diepoxy-3,7-dimethyl-octan-l-ol (5c)20 ( NMR analysis). The mixture was treated with AcjO/Py, affording acetylation of the alcohols; GLC analysis of the mixture of acetates allowed us to determine percent conversion, yield, and product distribution (Table I, fourth entry). Column chromatography (silica gel, petroleum ether-EtgO) separation of the mixture afforded 0.7 g of 2,6-diepoxy-3,7-dimethyl-octan-l-ol acetate (5c'): bp 90-92 °C (0.02 mm); IR (liquid film) 2980, 2940,

The synthesis and antiallergic activity of a series of novel benzothiophene-, benzofuran-, and naphthalenecarboxamidotetrazoles are described. A number of the compounds inhibit the release of histamine from anti-IgE stimulated basophils obtained from allergic donors. Optimal inhibition is exhibited in benzothiophenes with a 3-alkoxy substituent in combination with a 5-methoxy, 6-methoxy, or a 5,6-dimethoxy group. Compound 13c (CI-959) also inhibited respiratory burst of human neutrophils and the release of mediators from anti-IgE-stimulated human chopped lung.

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