A large number of cytokines participate in the inflammatory response, including IL-1, IL-6, IL-8 and TNF-α. Overproduction of cytokines such as IL-1 and TNF-α are implicated in a wide variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, and congestive heart failure, among others [Henry et al., Drugs Fut., Vol. 24 (1999), at pp. 1345-54; Salituro et al., Curr. Med. Chem., Vol. 6 (1999), at pp. 807-823]. Evidence in human patients indicates that protein antagonists of cytokines are effective in treating chronic inflammatory diseases, such as, for example, monoclonal antibody to TNF-α (Enbrel) [Rankin et al., Br. J. Rheumatol., Vol. 34 (1995), at pp. 334-42], and soluble TNF-α receptor-Fc fusion protein (Etanercept) [Moreland et al., Ann. Intern. Med., Vol. 130 (1999), at pp. 478-86].
The biosynthesis of TNF-α occurs in many cell types in response to an external stimulus, such as, for example, a mitogen, an infectious organism, or trauma. Important mediators of TNF-α production include the mitogen-activated protein (MAP) kinases, a family of Ser/Thr protein kinases that activate their substrates by phosphorylation. The MAP kinases are activated in response to various stress stimuli, including but not limited to proinflammatory cytokines, endotoxin, ultraviolet light, and osmotic shock.
One important MAP kinase is p38 kinase, also known as cytokine suppressive anti-inflammatory drug binding protein (CSBP) or IK. Activation of p38 requires dual phosphorylation by upstream MAP kinase kinases (MKK3 and MKK6) on threonine and tyrosine within a Thr-Gly-Tyr motif characteristic of p38 isozymes. There are four known isoforms of p38, i.e., p38-α, p38β, p38γ, and p38δ. The α and β isoforms are expressed in inflammatory cells and are key mediators of TNF-α production. Inhibiting the p38α and β enzymes in cells results in reduced levels of TNF-α expression. Also, administering p38α and β inhibitors in animal models of inflammatory disease has proven that these inhibitors are effective in treating those diseases.
The present invention provides thiazolyl-based compounds, useful as kinase inhibitors, in particular, as inhibitors of p38 kinase. Thiazolyl derivatives that reportedly inhibit p38 kinase and TNF-α for use in treating inflammatory diseases are disclosed in WO 01/74811 and WO 01/10865 to Takeda Chem. Indus., WO 01/35959 to Astrazeneca AB, and WO 02/096905 to Vertex Pharmaceuticals. Tyrosine kinase inhibitors having a thiazolyl component are disclosed in WO 02/45652 to Merck & Co., Inc., and WO 00/62778 to Bristol-Myers Squibb Company. Thiazolyl compounds useful as cyclin dependent kinase inhibitors are described in U.S. Pat. Nos. 6,262,096, 6,596,746 B1, and U.S. application No. 2003/0114504 A1, each of which is assigned to the present assignee.
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USPTO Backgrounds