Novel synthesis of C-13 labeled pyrazinone thrombin inhibitors and elucidation of metabolic activation pathways

ORGN 121

Jonathan Z. Ho1, Matthew P. Braun1, Raju Subramanian2, Ying-Duo Gao3, Dennis C. Dean1, and David G. Melillo1. (1) Department of Drug Metabolism, Merck Research Laboratories, 126 East Lincoln Ave, Rahway, NJ 07065, (2) Department of Drug Metabolism at West Point, PA, Merck & Co., Inc, P.O. Box 4 Sumneytown Pike, West Point, PA 19486, (3) Medicinal Chemistry, Merck & Co., Inc, P.O. Box 2000, Rahway, NJ 07065

In support of a research program aimed at discovering orally bioavailable thrombin inhibitors, carbon-13 labeled 3-aminopyrazinone acetamide thrombin inhibitors have been prepared to aid in the structural elucidation of key metabolites during preclinical and clinical studies. A method for the carbon-13 labeling of pyrazinones utilizing 13C-glycine as a building block has been developed with a good overall yield. Two targets with labels at different positions have been prepared. NMR studies not only determined the structure of a major metabolite but also revealed a likely metabolic pathway, which will provide structural guidance for the design and synthesis of future thrombin inhibitors as well as other pyrazinone containing compounds.

New Reactions and Methodology, Metal-Mediated Reactions, Heterocycles and Aromatics 8:00 PM-10:00 PM, Sunday, March 28, 2004 Anaheim Convention Center -- Hall A, Poster Division of Organic Chemistry The 227th ACS National Meeting, Anaheim, CA, March 28-April 1, 2004