4-Trifluoromethylimidazoles and 5-(4-pyridyl)-1,2,4-triazoles, new classes of xanthine oxidase inhibitors

Abstract

The syntheses of a number of 2-substituted 4-trifluoromethylimidazoles and 3-substituted 5-(4-pyridyl)-1,2,4-triazoles are described. The trifluoromethylimidazoles were prepared from 3,3-dibromo-1,1,1-trifluoroacetone after hydrolysis with aqueous sodium acetate solution and condensation with an aldehyde in the presence of ammonia. Basic hydrolysis of the trifluoromethyl group was found to provide a facile method for the synthesis of imidazole-4-carboxylic acids. In the imidazole series a 2-aryl substituent and a free imino group were required for xanthine oxidase inhibitory activity. The triazoles were obtained through the reaction of an aroylhydrazine and an imino ether followed by thermal ring closure of the intermediate acylamidrazone. As in the imidazole series, a free imino group is an absolute requirement for in vitro activity. Additional structure-activity relationships of these compounds are presented.

Selective angiotensin II AT2 receptor agonists with reduced CYP 450 inhibition

“…The residue was purified on silica gel with hexane/acetone (10:1) as eluent to obtain 10 (1.17 g, 3.83 mmol) as colorless solids, yield: 91%. 1 H NMR d 4-(Trifluoromethyl)imidazole (272 mg, 2.01 mmol), 32 4-bromobenzylbromide (525 mg, 2.12 mmol) and of KO-tBu (247 mg, 2.21 mmol) were mixed in DMSO (20 mL, dried over 4 Å molecular sieve). The mixture was stirred for 2 h at room temperature before water (50 mL) was added.…”

Fluorinated Five‐Membered Nitrogen‐Containing Heterocycles

“…3.58). 113 Hydrolysis of the CF 3 group provides a route to the corresponding imidazole carboxylic acids.…”

Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma

“…Gratifyingly, imidazole substitution also provided incremental reduction in CYP3A4 inhibition 14 (4,10,11); however, the CYP3A4 profile could be further modulated by the anilide substitution pattern. Moving the tBu group from the 3-position to the 4-position (12) resulted in an improvement in CYP3A4 selectivity, which also translated into the corresponding CF 3 analogue 1. With a favorable balance of cellular potency and CYP3A4 selectivity, 1 was selected for further investigation.…”