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Synthesis 2008(2): 253-266  
DOI: 10.1055/s-2007-1000852
PAPER
© Georg Thieme Verlag Stuttgart · New York

Regiospecific and Highly Flexible Synthesis of 1,4,5-Trisubstituted 2-Sulfanylimidazoles from Structurally Diverse Ethanone Precursors

Stefan A. Laufer*, Dominik R. J. Hauser, Andy J. Liedtke
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
Fax: +49(7071)295037; e-Mail: stefan.laufer@uni-tuebingen.de; e-Mail: dominik.hauser@uni-tuebingen.de; e-Mail: andy.liedtke@uni-tuebingen.de;
Further Information

Publication History

Received 4 October 2007
Publication Date:
18 December 2007 (online)

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Abstract

Imidazoles represent important bioactive scaffolds in medicinal chemistry. More than 2,500 structures are listed in drug discovery databases and over 3,000 patents have been claimed for imidazole-based structures. Recent imidazole pharmacophores have targeted various MAP kinases. p38 Mitogen-activated protein (MAP) kinase plays a central role in the signaling network responsible for the upregulation of proinflammatory cytokines like IL-1β and TNFα and offers, therefore, a valid target for small molecule anti-inflammatory drugs. 2-Sulfanylimidazole derivatives offer some advantages over prototype inhibitors (SB203580), e.g. lower cytochrom P450 interactions and better kinetic properties. We report here three novel regioselective and, at the same time, highly flexible synthetic approaches towards 1,4,5-trisubstituted 2-sulfanylimidazoles starting from different ethanone regioisomers allowing maximum variability of all substituents introduced. As a result, a variety of selective and highly potent p38 MAPK inhibitors were prepared and selected for further preclinical development. Synthesis of structurally diverse inhibitor candidates, p38 inhibition data, and selectivity profiling of some selected compounds are specified. Furthermore, the benefits of the useful, brief synthetic sequences are outlined and contrasted with already published multistep routes.

Key words

medicinal chemistry - heterocycles - ring closure - nucleophilic aromatic substitutions - regioselectivity - p38 MAP kinase inhibitors

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