- p38 MAP kinase inhibitors. Part 5: Discovery of an orally bio-available and highly efficacious compound based on the 7-amino-naphthyridone scaffold
-
A new sub-class of p38 inhibitors represented by 7-amino-naphthyridone have been discovered. Benchmark compound 16 potently inhibited p38 in vitro, was functionally active, and displayed excellent pharmacokinetic profiles in two animal species. Compound 1
- Natarajan, Swaminathan R.,Liu, Luping,Levorse, Mark,Thompson, James E.,O'Neill, Edward A.,O'Keefe, Stephen J.,Vora, Kalpit A.,Cvetovich, Raymond,Chung, John Y.,Carballo-Jane, Ester,Visco, Denise M.
-
-
Read Online
- Synthesis of a naphthyridone p38 MAP kinase inhibitor
-
Compound 1 is a p38 MAP kinase inhibitor potentially useful for the treatment of rheumatoid arthritis and psoriasis. A novel six-step synthesis suitable for large-scale preparation was developed in support of a drug development program at Merck Research Laboratories. The key steps include a tandem Heck-lactamization, N-oxidation, and a highly chemoselective Grignard addition of 4-(N-tert-butylpiperidinyl)-magnesium chloride to a naphthyridone N-oxide. The N-oxide exerted complete chemoselectivity via chelation in directing the Grignard addition to the α position as opposed to 1,4-addition on the enelactam. The dihydropyridyl adduct was in situ aromatized with isobutylchloroformate followed by heating in pyridine. Syntheses of Grignard precursor, N-tert-butyl-4-chloro-piperidine, were accomplished via transamination with a quaternary ammonium piperidone or via addition of methylmagnesium chloride to an iminium ion. Utilizing this chemistry, multi-kilogram preparation of compound 1 was successfully demonstrated. American Chemical Society.
- Chung, John Y. L.,Cvetovich, Raymond J.,McLaughlin, Mark,Amato, Joseph,Tsay, Fuh-Rong,Jensen, Mark,Weissman, Steve,Zewge, Daniel
-
p. 8602 - 8609
(2007/10/03)
-