Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-22
2004-05-11
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S280000, C544S277000, C544S255000, C544S254000, C544S279000, C544S117000, C514S258100, C514S261100
Reexamination Certificate
active
06734180
ABSTRACT:
TECHNICAL FIELD
The present invention relates to indan derivatives and pharmaceutically acceptable salts thereof, as well as NF-&kgr;B inhibitors. More specifically, the present invention relates to preventive or therapeutic agents for diseases caused by the activation of NF-&kgr;B, said agent having as an active ingredient an indan derivative or a pharmaceutically acceptable salt thereof.
BACKGROUND ART
Nitric oxide (NO) is biosynthesized from L-arginine as a substrate by NO synthase (NOS). Currently three isozymes of NOS have been found: a brain isozyme (bNOS), an endothelial isozyme (eNOS), and an inducible isozyme (iNOS) (Moncada, S. and Higgs, A. (1993) N. Engl. J. Med. 329: 2002-2012). The gene of iNos is induced by endotoxins and cytokines on macrophages, vascular smooth muscle cells, hepatocytes, chondrocytes, gliacytes, etc. and then its expression comes to be observed (Forstermann, U., Gath, I., Schwarz, P., Closs, E. I. and Kleinert, H. (1995) Biochem. Pharmacol. 50: 1321-1332).
The iNOS has been reported to be induced by inflammatory conditions regardless of the species, and the suppression of the enzymatic activity and the expression has been shown to be useful for amelioration of the disease states (Cattell, V. and Jansen, A. (1995) Histochem. J. 27: 777-784; Nussler, A. K. and Billiar, T. R. (1993) J. Leukoc. Biol. 54: 171-178).
It has been reported that arginine derivatives or aminoguanidine exhibit pharmacological effects in model animals of myocarditis, cerebral infarction, arthritis, sepsis, multiple sclerosis, systemic lupus erythematosus, and insulin-dependent diabetes mellitus (Moncada, S. and Higgs, E. A. (1995) Faseb. J. 9: 1319-1330). Though L-N-monomethyl arginine, a NOS inhibitor, is highly toxic at high doses, it not only improves low blood pressure in sepsis but has a marked preventive effect, on which a clinical trial is under way (Moncada, S. and Higgs, E. A. (1995) Faseb. J. 9: 1319-1330).
Furthermore, resistance against sepsis or inflammation induced by carrageenin has been shown in experiments using knockout mice of iNOS, revealing that the expression of iNOS causes these pathological states (Wei, X. Q., Charles, I. G., Smith, A., Ure, J., Feng, G. J., Huang, F. P., Xu, D., Muller, W., Moncada, S. and Liew, F. Y. (1995) Nature 375: 408-411).
An excess of NO produced by the induction of iNOS expression is believed to damage normal cells and cause various disease states. On the other hand, the constitutively occurring NOS (cNOS) termed eNOS or bNOS is required to suppress an increase in blood pressure and to maintain it. Thus, inhibitors that do not inhibit the activity of cNOS and that inhibit iNOS specifically are required. However, since the regions of the proteins that regulate the enzymatic activity of isozymes are very similar to one another in the primary structure, no NOS inhibitors have yet been found which are sufficiently specific (Ogden, J. E. and Moore, P. K. (1995) Trends Biotechnol. 13: 70-78, Manning, R., Jr., Hu. L., Mizelle, H. L., Montani, J. P. and Norton, M. W. (1993) Hypertension 22: 40-48).
As enzyme inhibitors, L-arginine (and amino acid) derivatives have mainly been developed but many of them are low in isozyme specificity. Although aminoguanidine and amidine derivatives, though weakly effective, have been reported to have relatively iNOS-specific inhibitory effects (Southan, G. J. and Szabo, C. (1996) Biochem. Pharmacol. 51: 383-394), pharmaceutical agents having adequate specificity have yet not to be found.
On the other hand, TNF-&agr;, a cytokine produced by various cells including macrophage, is believed to be an important mediator of inflammation (Vassalli, P. (1992) Annu. Rev. Immunol. 10: 411-452). There is growing evidence that the excessive production of TNF-&agr; damages normal cells and causes various pathological conditions (Muto, Y., Nouri-Aria, K. T., Meager, A., Alexander, G. J., Eddleston, A. L. and Williams, R. (1988) Lancet 2: 72-74, Sharief, M. R. and Hentges, R. (1991) N. Engl. J. Med. 325; 467-472).
Increases in TNF-&agr; have been observed in the synovial fluid and the blood of patients with, for example, rheumatoid arthritis (Tetta, C., Camussi, G., Modena, V., Di Vittorio C. and Baglioni, C. (1990) Ann. Rheum. Dis 49: 665-667; Venn, G., Nietfeld, J. J., Duits, A. J., Brennan, F. M., Arner, E., Covington, M., Billingham, M. E. and Mardingham, T. E. (1993) Arthritis Rheum. 36: 819-826). Antibody against TNF-&agr; has also been demonstrated to be effective in clinical trials (Elliott, M. J., Maini, R. N., Feldmann, M., Long-Fox, A., Charles, P., Bijl, H. and Woody, J. N. (1994) Lancet 344: 1125-1127; Elliott, M. J., Maini, R. N., Feldmann, M., Kalden. J. R., Antoni, C., Smolen, J. S., Leeb, B., Breedveld, F. C., Macfarlane, J. D., Bijl, H. and et al. (1994) Lancet 344: 1105-1110; Rankin, E. C., Choy, E. H., Kassimos, D., Kingsley, G. H., Sopwith, A. M., Isenberg, D. A. and Panayi, G. S. (1995) Br. J. Rheumatol. 34: 334-342).
Furthermore, the involvement of TNF-&agr; in sepsis or inflammatory bowel diseases has been pointed out and the ameliorating effects of anti-TNF-&agr; antibody on these diseases have been observed (Vincent, J. L., Bakker, J., Marecaux, G., Schandene, L., Kahn, R. J. and Dupont, E. (1992) Chest 101: 810-815; Hinshaw, L. B., Tekamp-Olson, P., Chang, A. C., Lee, P. A., Taylor, F., Jr., Murray, C. K., Peer, G. T., Emerson, T., Jr., Passey, R. B. and Kuo, G. C. (1990) Circ. Shock 30: 279-292).
These findings expressly indicate that the excessive production of TNF-&agr; causes and aggravates various inflammations, therefore the development of pharmaceutical agents that can inhibit the production of TNF-&agr; (Nyman, U., Mussener, A., Larsson, E., Lorentzen, J. and Klareskog, L. (1997) Clin. Exp. Immunol. 108: 415-419) is required.
Thus, iNOS or TNF-&agr; have been recognized to be one of the causes of various inflammations. However, the fact that many other mediators have been demonstrated to cause inflammation and thereby the cause of the diseases cannot be attributed to any one particular mediator makes the development of therapeutic agents difficult. Under these circumstances, there is a great need for low molecular weight compounds that not only suppress the expression of particular proteins but inhibit widely the production and expression of proteins involved as causative factor in the inflammation.
NF-&kgr;B is a protein that regulates gene expression and is one of the so-called transcription factors. Normal cells, when stimulated with inflammatory cytokines such as interleukin-1 (IL-1) and TNF-&agr;, a lipopolysaccharide, or ultraviolet rays, NF-&kgr;B is activated and then it translocates from the cytoplasm into the nucleus where it binds to specific nucleotide sequences on the genomic DNA and thereby become involved in the expression of various genes (Blackwell, T. S. and Christman, J. W. (1997) Am. J. Respir. Cell Mol. Biol. 17: 3-9).
Genes encoding iNOS and TNF-&agr;, though entirely different from one another, have regions to which NF-&kgr;B binds on the expression control region of the genomic gene thereof, and there is growing evidence that the activation of NF-&kgr;B is important for the expression of these proteins in common (Jongeneel, C. V. (1994) Prog. Clin. Biol. Res. 388: 367-381; Xie, Q. w., Kashiwabara, Y. and Nathan, C. (1994) J. Biol. Chem. 269: 4705-4708; Nunokawa, Y., Oikawa, S. and Tanaka, S. (1996) Biochem. Biophys. Res. Commun. 223: 347-352).
Many genes that are involved in immunological inflammatory reactions under expression control by NF-&kgr;B are recognized, in addition to iNOS and TNF-&agr;, ones for inflammatory cytokines such as IL-1, IL-6 and IL-8, as well as cell adhesion factors such as ICAM-1, VCAM-1 and ELAM-1 or the like (Collins, T., Read, M. A., Neish, A. S., Whitley, M. Z., Thanos, D. and Maniatis, T. (1995) Faseb. J. 9: 899-909). Furthermore, it is known that inflammatory cytokines, when bound to receptors, transduce NF-&kgr;B-activating signals via various routes, and this fact is believed to be cause that further aggravates inflammati
Abe Keiichi
Nakatsuka Takashi
Nunokawa Yoichi
Saitoh Masayuki
Daiichi Suntory Pharma Co., Ltd.
Liu Hong
Raymond Richard L.
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