NF-κB is a protein which regulates the gene expression and is one of the so-called transcription factors. When normal cells are stimulated by an inflammatory cytokine such as interleukin-1 (IL-1) and TNF-α or by lipopolysaccharide, or ultraviolet rays, NF-κB is activated and migrates from the cytosol into the nucleus to bind to its specific nucleotide sequences on the genome DNA and thereby participate in the expression of various genes (Blackwell, T. S. and Christman, J. W. (1997) Am. J. Respir. Cell. Mol. Biol., 17, 3–9).
Among the genes of which the expression is under the control of NF-κB, many genes participate in an immunoinflammatory reaction, such as inflammatory cytokines (e.g., IL-1, IL-6, IL-8 and TNF-α), cell adhesion molecules (e.g., ICAM-1, VCAM-1 and ELAM-1) and inducible NO-synthase (iNOS) (Collins, T., Read, M. A., Neish, A. S., Whitley, M. Z., Thanos, D. and Maniatis, T. (1995) Faseb. J., 9, 899–909). It is further known that, when inflammatory cytokine binds to its receptor, it transmits the signal which activates NF-κB through various pathways and it is believed to be a cause for more exacerbation of inflammation. As such, activation of NF-κB in inflammation is understood as a cause and an exacerbating factor of a diseases (Baeuerle, P. A. and Baichwal, V. R. (1997) Adv. Immunol., 65, 111–137).
Further, it has been reported in recent years that HIV, HTLV-1, CMV, adenovirus, etc. activate NF-κB in host cells (Dezube, B. J., Pardee, A. B., Beckett, L. A., Ahlers, C. M., Ecto, L., Allen-Ryan, J., Anisowicz, Z. A., Sager, R. and Crumpacker, C. S. (1992) J. Acquir. Immune Defic. Syndr., 5, 1099–1104; Nabel, G. and Baltimore, D. (1987) Nature, 326, 711–713; Fazely, F., Dezube, B. J., Allen-Ryan, J., Pardee, A. B. and Ruprechet, R. M. (1991) Blood, 77, 1653–1656; Munoz, E. and Israel, A. (1995) Immunobiology, 193, 128–136) and it is believed that activation of NF-κB participates in self-replication and proliferation of virus in the infected host cells.
Accordingly, when activation of NF-κB is suppressed, it is possible to suppress expression and induction of all of those inflammatory cytokines, cell adhesion molecule gene and virus and suppressors for NF-κB activation is promising as a therapeutic agent for diseases directly or indirectly caused by activation of NF-κB, particularly for various inflammatory diseases and autoimmune diseases, or as a immunosuppressant or as a therapeutic agent for viral diseases.
At present, many anti-inflammatory agents are clinically used for the purpose of treating osteoarthritis, lumbago, rheumatoid arthritis, etc. However, with regard to an agent which suppresses production of various inflammatory cytokines and expression of cell adhesion molecules, no effective one has been available yet. A frequently-used NSAIDs (nonsteroidal anti-inflammatory drugs) suppresses production of prostaglandins by inhibition of cyclooxigenase in a metabolic pathway of arachidonic acid cascade but, generally, they do not directly inhibit the production of cytokines. Although steroids suppress the production of cytokines, they have been known to cause severe adverse actions such as undesirable harmonic action, exacerbation of infectious diseases, generation of peptic ulcer, central action, etc. and therefore not amenable to a long-term administration.
However, among those anti-inflammatory agents, several drugs which suppress the activation of NF-κB by high dose have been reported in recent years (Auphan, N., DiDonato, J. A., Rosette, C., Helmberg, A. and Karin, M. (1995) Science, 270, 286–290; Shackelford, R. E., Alford, P. B., Xue, Y., Thai, S. F., Adams, D. O. and Pizzo, S. (1997) Mol. Pharmacol., 52, 421–429; Bitko, V., Valazquez, A., Yang, L., Yang, Y. C. and Barik, S. (1997) Virology, 232, 369–378). For example, benzoic acid derivatives such as salicylic acid and aspirin have been reported to suppress the activation of NF-κB (Science, 265, 956–959, 1994) but insufficient effect, expression of adverse action caused by various pharmacological actions, etc. have been pointed out as the problems.
Accordingly, there has been a demand for development of medicines which inhibit the activation of NF-κB in more specific manner having higher safety. And investigation and molecular design of inhibitors for NFKB activation have been carried out by many investigators.
In recent years, as inhibitors for activation of NFKB, there have been reported isocarbazole derivatives (JP-A-08-319238; JP-A-2000-169479), isoquinoline derivatives (JP-A-10-87491; JP-A-11-180873), benzoquinone derivatives (JP-A-7-291859; JP-A-11-266872), β-lactam derivatives (JP-A-11-71278), lignan derivatives (JP-A-10175861), benzylidene derivatives (PCT/JP98/04774), pyrimidine-5-carboxamide derivatives (WO97/09315; WO97/09325), cyclopentabenzofuran derivatives (WO00/08007), benzene derivatives (WO00/15603), pyrrolidone dithiocarbonate (PDTC) (Eur. J. Immunol. (1999) 29, 1890–1900), 3-deazaadenosine (DZA) (J. Biol. Chem. (1999) 274, 27, 18981–18988), 2,21-bi-1H-pyrrole derivatives (J. Immunol. (1999) 162, 7102–7109), etc.
With regard to the action mechanism of those substances for suppressing the activation of NF-κB, there are many ambiguous points but, with respect to substances which are believed to inhibit the activation by antioxidant effects or activities of inhibiting protein phosphorylation, it is believed that stability as a substance or specificity of action will become problems. Further, at the present time, drugs exhibiting a enough potency as an inhibitor for the transcription factor NF-κB.
As an example for the fact that substituted benzoic acid derivatives act on transcription factor and receptor of an transcription factor type, there have been reported that retino-benzoic acid derivatives which are substituted benzoic acid derivatives act on receptors of a transcription factor type such as retinoic acid receptor (RAR) or retinoic acid X receptor (RXR) resulting in agonistic action or antagonistic action (Kagechika H., Kawachi E., Hashimoto Y., Himi T., Shudo K., J. Med. Chem., 1989, 31, 2182; Boehm M. F., Zhang L., Badea B. A., White S. K., Mais D. E., Suto C. M., Goldman M. E., Heyman R. A., J. Med. Chem., 1994, 37, 2930; Boehm M. F., Zhang L., Zhi L. McClurg M. R., Berger E., Wagoner M., Mais D. E., Suto C. M., Davis P. J. A., Heyman R. A., Nadzan A. M., J. Med. Chem., 1995, 38, 3146). However, NF-κB inhibiting activity of those retino-benzoic acid derivatives has not been reported.
On the other hand, in JP-A-7-291859, the following benzoquinone derivative (A) is disclosed as an NF-κB activiation inhibitor.

Further, in JP-A-11-266872, a novel screening method for substances which suppress the activation of NF-κB is disclosed and the following benzoquinone derivative (B) is listed as a substance which suppresses the activation of NF-κB which is able to be found by that method.

However, it cannot be said to be a compound having a sufficient effect as an NF-κB inhibiting substance and there has been a demand for investigation of substances having stronger inhibiting activity for NF-κB.