Structure determination, synthesis, and biological evaluation of a metabolite of the selective α1Dadrenoceptor antagonist TAK-259

Article abstract of DOI:10.1016/j.tet.2016.08.013

5-Chloro-1-(5-chloro-2-(methylsulfonyl)benzyl)-2-imino-1,2-dihydropyridine-3-carboxamide hydrochloride (TAK-259) is a novel, selective, and orally active α_1Dadrenoceptor antagonist with anti-urinary frequency effect. A metabolite (2) of TAK-259 was identified from monkey urine samples. To elucidate the structure of 2, extraction and purification of the metabolite from TAK-259-treated monkey urine was conducted. Structural analysis of the purified compounds using NMR indicated the compound to be 2-amino-5-chloro-1-[5-chloro-2-(methylsulfonyl)benzyl]-4-oxo-1,4-dihydropyridine-3-carboxamide (2a). An authentic sample of compound 2a was synthesized via regioselective alkylation of 4-methoxypyridin-2-amine. The biological activity of metabolite 2a was also evaluated, and the compound found not to possess affinity toward any known α₁adrenoceptor subtype.