Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-15
2004-02-03
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252130, C514S255040, C514S253010, C540S575000, C544S359000, C544S398000, C544S403000, C544S360000, C544S379000, C544S396000
Reexamination Certificate
active
06686353
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel diarylalkyl cyclic diamine derivatives.
This invention also relates to chemokine receptor antagonists that may be effective as a therapeutic agent and/or preventive agent for diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, glomerulonephritis, multiple sclerosis, pulmonary fibrosis, and myocarditis, in which tissue infiltration of blood monocytes and lymphocytes plays a major role in the initiation, progression or maintenance of the disease.
BACKGROUND TECHNOLOGY
Chemokines are a group of inflammatory/immunomodulatory polypeptide factors produced by lymphatic tissues and by activated macrophages and leukocytes at inflammatory sites; they have a molecular weight of 6-15 kD, contain four cysteine residues, are basic and have heparin binding activity. The chemokines can be classified into two subfamilies, the CXC chemokines and CC chemokines, by the common location of the four cysteine residues and by the differences in the chromosomal locations of the genes encoding them. For example IL-8 (abbreviation for interleukin-8 is a CXC chemokine, while the CC chemokines include MIP-1&agr;/&bgr; (abbreviation for macrophage inflammatory protein-1&agr;/&bgr;), MCP-1 (abbreviation for monocyte chemotactic protein-1), and RANTES (abbreviation for regulated on activation, normal T-cell expressed and secreted cytokine). There also exists a chemokine called lymphotactin, which does not fall into either chemokine subfamily. These chemokines promote cell migration, increase the expression of cellular adhesion molecules such as integrins, and promote cellular adhesion, and are thought to be the protein factors intimately involved in the adhesion and infiltration of leukocytes into the pathogenic sites in such as inflammatory tissues (for references, see for example, Michiel, D., Biotechnology, 1993, 11, 739; Oppenheim, J. J., et al., Annual Review of Immuology, 1991, 9, 617-648; Schall, T. J., Cytokine, 1991, 3, 165-183; Springer, T. A., Cell, 1994, 76, 301-314; Furie, M. B., American Journal of Pathology, 1995, 146, 1287-1301; Kelner, G. S., et al.; Science, 1994, 266, 1395-1399).
For example, HIP-1&agr; induces cell migration and causes a transient increase in intracellular calcium ion concentration levels, an increase in the expression of integrins, adhesion molecules, and degranulation of monocytes and lymphocytes, and inhibits bone marrow stem cell proliferation (See for example, Wolpe, S. D., et al., Journal of Experimental Medicine, 1998, 167, 570-581; Wolpe, S. D., et al., Faseb Journal, 1989, 3, 2565-2573; Taub, D. D., at al., Science, 1993, 260, 355-358; Schall. T. J., at al., Journal of Experimental Medicine, 1993, 177, 1821-1825; Neote, K., et al., Cell, 1993, 72, 415-425; Vaddi, K., et al., The Journal of Immunology, 1994, 153, 4721-4732).
With respect to the activity of HIP-1&agr; in vivo and its role in the pathogenesis of disease, it has been reported that it is a pyrogen in rabbits (see for example Davatelis, G., et al., Science, 1989, 243, 1066-1068); that MIP-1&agr; injection into mouse foot pads results in an inflammatory reaction such as infiltration by neutrophils and mononuclear cells (see for example Alam, R., et al., The Journal of Immunology, 1994, 152, 1298-1303); that MIP-1&agr; neutralizing antibody has an inhibitory effect or a therapeutic affect in animal models of granuloma, multiple sclerosis and idiopathic pulmonary fibrosis (see for example Lukacs, N. W., et al., Journal of Experimental Medicine, 1993, 177, 1551-1559; Koprus, K. J., et al., The Journal of Immunology, 1995, 155, 5003-5010; Smith, R. E., et al., The Journal of Immunology, 1994, 153, 4704-4712); and that coxsackie virus induced myocarditis is inhibited in mice with a disrupted MIP-1&agr; gene (see for example Cook, D. N. et al., Science, 1995, 269, 1583-1585). These studies indicate that MIP-1&agr; is deeply involved in the local attraction of various subtypes of leukocytes and the initiation, progression and maintenance of resulting inflammatory response.
MCP-1 (also known as MCAF (abbreviation for macrophage chemotactic and activating factor) or JE) is a chemokine produced by macrophages, smooth muscle cells, fibroblasts, and vascular endothelial cells and causes cell migration and cell adhesion of monocytes, memory T cells, and natural killer cells, as well as mediating histamine release by basophils (For reference, see for example, Rollins, B. J., et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 3738-3742; Matsushima, K., at al., Journal of Experimental Medicine, 1989, 169, 1485-14907; Yoshimura, T. et al., Febs Letters, 1989, 244, 487-493; Rollins, B. J. et al., Blood, 1991, 78, 1112-1116; Carr, M. W., at al., Proc. Natl. Acad. Sci. USA, 1994, 91, 3652-3656; Jiang, Y., et al., American Journal of Physiology, 1994, 267, C1112-C1118; Allavena, P., et al., European Journal of Immunology, 1994, 24, 3233-3236; Alam, R., et al., The Journal of Clinical Investigation, 1992, 89, 723-728).
In addition, high expression of MCP-1 has been reported in diseases where accumulation of monocyte/macrophage and/or T cells is thought to be important in the initiation or progression of diseases, such as atherosclerosis, restenosis due to endothelial injury following angioplasty, rheumatoid arthritis, glomerulonephritis, pulmonary fibrosis, asthma and psoriasis (for reference, see for example, Firestein, G. S. et al., Arthritis and Rheumatism, 1990, 33, 768-773; Nikolic-Peterson, D. J., et al., Kidney International, 1994, 45, enlarged ed., 45, S79-S82; Thomas, P. D., et al., American Review of Respiratory Disease, 1987, 135, 747-760; Ross, R., Nature, 1993, 362, 801-809; Cooper, K. D., et al., The Journal of Investigative Dermatology, 1994, 102, 128-137; Sousa, A. R., et al., American Journal of Respiratory Cell And Molecular Biology, 1994). Furthermore, anti-MCP-1 antibody has been reported to inhibit delayed type hypersensitivity and hepatitis (for reference, see for example Rand, M. L., et al., American Journal of Pathology, 1996, 148, 855-864; Wada, T., et al., Faseb Journal, 1996, 10, 1418-1425).
These data indicate that chemokines such as MIP-1&agr; and MCP-1 attract monocytes and lymphocytes to disease sites and mediate their activation and thus are thought to be intimately involved in the initiation, progression and maintenance of diseases deeply involving monocytes and lymphocytes, such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, glomerulonephritis, multiple sclerosis, pulmonary fibrosis and myocarditis.
Therefore, drugs which inhibit the action of chemokines on target cells may be effective as a therapeutic and/or preventive drug in diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, glomerulonephritis, multiple sclerosis, pulmonary fibrosis, and myocarditis.
Genes encoding receptors of specific chemokines have been cloned, and it is now known that these receptors are G protein-coupled seven-transmembrane receptors present on various leukocyte populations (for reference, see for example, Holmes, W. E., et al., Science 1991, 253, 1278-1280; Murphy P. M., et al., Science, 253, 1280-1283; Neote, K. et al., Cell, 1993, 72, 415-425; Charo, I. F., et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 2752-2756; Yamagami, S., et al., Biochem. Biophys. Res. Commun., 1994, 202, 1156-1162; Combadier, C., et al., The Journal of Biological Chemistry, 1995, 270, 16491-16494, Power, C. A., et al., J. Biol. Chem., 1995, 270, 19495-19500; Samson, H., et al., Biochemistry, 1996, 35, 3362-3367; Murphy, P. M., Annual Review of Immunology, 1994, 12, 592-633). Therefore, compounds which inhibit the binding of chemokines such as MIP-1&agr; and/or MCP-1 to these receptors, that is, chemokine receptor antagonists, may be useful as drugs which inhibit the action of chemokines such as MIP-1&agr; and/or MCP-1 on the target cells, but there are no drugs known to have such effects.
Cyclic diamine derivatives containing diarylalkyl groups are known to have muscarine recept
Barnum Doug
Endo Noriaki
Greene Jonathan
Kataoka Ken-ichiro
Moree Wilna
Anderson Kill & Olick
Coleman Brenda
Lieberstein Eugene
Meller Michael N.
Teijin Intellectual Property Center Limited
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