Nuclear factor κB (hereinafter referred to as “NF-κB”) associated with signaling from the outside of a cell to the inside of a nucleous is a transcription factor associated with expression of many genes induced in immunological/inflammatory reactions. NF-κB as the transcription factor forms a complex with a control protein generally called IκB and is localized as being inactive in cytoplasm. When the IκB of the complex is phosphorylated by a kinase called IKKβ, degradation of IκB is developed. NF-κB that is released due to the IκB degradation becomes active and translocates from the cytoplasm to the nucleous to activate transcription of a target gene, thereby enhancing production of cytokines such as a tumor necrosis factor (hereinafter referred to as “TNF”), interleukin-1 (hereinafter referred to as “IL-1”), and interleukin-6 (hereinafter referred to as “IL-6”) and cell proliferation.
Therefore, it is possible to inhibit activation of NF-κB by way of control of IKKβ, which makes it possible to suppress the production of cytokines such as TNF, IL-1 and IL-6 and the cell proliferation, thereby realizing prevention and/or treatment of diseases associated with the factors.
Various diseases such as rheumatoid arthritis, asthma, diabetes, and cancer have been known as the diseases associated with IKKβ (see Journal of Molecular Medicine, 82, 434-448 (2004) and WO 06/036031).
As compounds having IKKβ inhibitory activity, condensed furan derivatives disclosed in WO 06/036031, aromatic heterocyclic 5-membered ring carboxamide derivatives disclosed in WO 01/58890, substituted thiophene carboxamide derivatives disclosed in WO 04/009582, and the like have been known.
Compounds having a urea structure at the 2-position of an indole ring are disclosed in Gazzete Chimica Italiana 48, II, 151-182 (1918), and compounds having an amide structure at the 3-position of an indole ring are disclosed in WO 96/020196. However, these publications do not contain any specific disclosure nor suggestion of compounds having a urea structure at the 2-position and an amide structure at the 3-position of an indole ring and do not refer to the IKKβ inhibitory effect of these compounds at all.
USPTO Backgrounds
USPTO Backgrounds