Potent and selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 labeled with carbon-13 and carbon-14

(S)-6-(2-Hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4- yl) phenyl) ethyl)-6-phenyl-1,3-oxazinan-2-one (1) and (4aR, 9aS)-1-(1H-benzo[d] midazole-5-carbonyl)-2,3,4,4a, 9,9a-hexahydro-1-H-indeno[2,1-b] pyridine-6-carbonitrile hydrochloride (2) are potent and selective inhibitor of 11 beta-hydroxysteroid dehydrogenase type 1 enzyme. These 2 drug candidates developed for the treatment of type-2 diabetes were prepared labeled with carbon-13 and carbon-14 to enable drug metabolism, pharmacokinetics, bioanalytical, and other studies. In the carbon-13 synthesis, benzoic C-13(6) acid was converted in 7 steps and in 16% overall yield to [C-13(6)]-(1). Aniline-C-13(6) was converted in 7 steps to 1H-benzimidazole-1-2,3,4,5,6-C-13(6)-5-carboxylic acid and then coupled to a tricyclic chiral indenopiperidine to afford [C-13(6)]-(2) in 19% overall yield. The carbon-14 labeled (1) was prepared efficiently in 2 radioactive steps in 41% overall yield from an advanced intermediate using carbon-14 labeled methyl magnesium iodide and Suzuki-Miyaura cross coupling via in situ boronate formation. As for the synthesis of [C-14]-(2), 1H-benzimidazole-5-carboxylic-C-14 acid was first prepared in 4 steps using potassium cyanide-C-14, then coupled to the chiral indenopiperidine using amide bond formation conditions in 26% overall yield.