Matthias Treu,^a Ulrich Jordis,*^a and Ving J. Lee^b

a Institute of Organic Chemistry, VUT, A-1060 Vienna, Getreidemarkt 9, Austria, ujordis@pop.tuwien.ac.at
^b Iconix Pharmaceuticals, Inc., 830 Maude Avenue, Mountain View, CA 94043

Mitogen-activated protein (MAP) kinases are key enzymes involved in signal transduction and the amplification of cellular responses to stumuli. P38 MAP kinase is a specific member of the MAP kinase family associated with the onset and progression of inflammation, and several groups are working to develop p38 MAP kinase inhibitors as potential treatments for inflammatory and neurological disease. Vertex discovered the 3D structure of p38MAP kinase in 1996 and computer modeling and testing suggested the design of VX-475 [1].

For comparison we needed a sample of VX-745 and followed the synthesis as described in a general procedure for the preperation of p38 inhibitor compounds by Bemis and coworkers [2,3]. As we had difficulties in duplicating some of the experiments and only few physical data were mentioned by the authors, we herein report our experiences and improvements in the synthesis of VX-745.

As the samples were nicely crystalline and exhibited distinct colors they are depicted below:

The authors thank Iconix Pharmaceuticals, Inc. for financial support.

Experimental Details

HPLC data

1. For biological data see: (a) Dillon, Susan B.; Griego, Sandra D. Use of CSAIDs (cytokine suppressive antiinflammatory drugs) in rhinovirus infection. WO 0119322. (b) Ferraccioli, G. F. VX-745 Vertex Pharmaceuticals. Curr. Opin. Anti-Inflammatory Immunomodulatory Invest. Drugs 2000, 2, 74 - 77.

2. Bemis, Guy W.; Salituro, Francesco Gerald; Duffy, John Patrick; Cochran, John E.; Harrington, Edmund Martin; Murcko, Mark A.; et al. Preparation of annelated pyrimidinones and analogs as p38 kinase inhibitors. WO 9827098.

3. Bemis, Guy W.; Salituro, Francesco Gerald; Duffy, John Patrick; Harrington, Edmund Martin. Preparation of pyrido[1,2-c]pyrimidin-3-ones or 1,2-dihydro-pyrido[1,2-c]pyrimidin-3-ones as inhibitors of p38. US 6147080.