Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-06
2004-11-23
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S412000, C544S281000, C546S176000, C546S276700, C548S126000, C548S181000, C548S248000, C548S266800, C548S453000
Reexamination Certificate
active
06821964
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to chemokine receptor antagonists, in particular, bicyclic diamine compounds that act as antagonists of chemokine CCR2 and CCR3 receptors including pharmaceutical compositions and uses thereof to treat or prevent diseases associated with monocyte accumulation, lymphocyte accumulation or leucocyte accumulation.
BACKGROUND
The local production and secretion of a family of 8-10 KD chemotactic cytokines (called chemokines) mediate the local accumulation of inflammatory cells in many pathological inflammatory and autoimmune disease states. Chemokines have been found to be highly expressed in a variety of pathological states, including atherosclerosis, pulmonary fibrosis, asthma, psoriasis and rheumatoid arthritis, coinciding with the chronic macrophage accumulation of inflamed tissue (see, e.g., Barker, J. N., et al.,
J. Immunol.,
146, 1192 (1991); Koch, A. E.
J. Clin. Invest,
90, 772 (1996); Nelken, N. A., et al.,
J. Clin. Invest.,
88, 1121 (1991); Gong, J. H.,
J. Exp. Med.,
186, 131 (1997); Yla-Herttuala, S., et al.,
Proc. Natl., Acad. Sci.,
88, 5252 (1991); Rovin, B. H., et al.,
Am. J. Kidney Dis.,
31, 1065 (1998); and Gong, J. H. et al.,
J. Exp. Med.,
186, 131 (1997)). Continuous local release of chemokines at sites of inflammation mediates the excessive migration of effector cells in chronic inflammation. Thus, blocking leukocyte recruitment to target tissues by inhibiting chemokine activity in inflammatory and autoimmune disease would be an effective therapeutic intervention.
The chemoattractant chemokines belong to a super family of pro-inflammatory mediators that promote the recruitment of multiple lineages of leukocytes and lymphocytes. The human chemokine polypeptides are 70-80 residues in length that share substantial sequence homology. These polypeptides share a common structural motif: a conserved set of four cysteine residues. Based on the position of the first two or four cysteine residues and the chromosomal location of the corresponding genes, two main chemokine families, CC and CXC, have been identified. Members of the CXC subfamily attract mainly neutrophils, except for platelet factor 4 (PF4) and gamma interferon inducible protein (IP10). The CC chemokines attract mainly monocytes, eosinophils, and lymphocytes but may also attract T lymphocytes. Monocyte chemoattractant protein-1 (MCP-1) is a member of the CC chemokine family that is a potent chemotactic and activating factor for monocytes and memory T cells. The other members of the of the CC chemokine family, MCP-2, MCP-3, MCP-4, MCP-5, macrophage inflammatory protein (MIP)-1&agr;, MIP-1&bgr;, RANTES (regulated on activation, normal T cell expressed and secreted) and eotaxin also mediate chemotaxis in distinct but overlapping leukocyte subsets.
The molecular targets for chemokines are their cell surface receptors that belong to the seven-transmembrane helix (STH), G-protein coupled receptors. This type of receptor consists of a single polypeptide chain with an extracellular amino-terminal domain and a cytoplasmic-terminal domain. The amino terminal and the third extracellular domain are important for receptor ligand interaction. The third intracellular loop (50-75 amino acids long) interacts directly with G-proteins. At least five CC chemokine receptors have been identified (CCR1-CC R5) and all five CC receptors belong to the STH G-coupled protein receptor family. Each of these receptors mediates the binding and signaling of more than one chemokine. For example, the CCR1 receptor is specific for MIP-1 &agr;, RANTES, and MCP-3. CCR2B recognizes both MCP-1 and MCP-3; CCR3 is expressed on eosinophils and recognizes eotaxin; and CCR4 is found on basophils and responds to MIP1-&agr;, RANTES and MCP-1. The MCP-1 receptor CCR2b signals through multiple G-proteins including G&agr;I, G&agr;q, and G&agr;16. See, e.g., Monteclaro, F. S.,
J. Biol. Chem.,
37, 23186 (1997). Thus, in addition to promoting the transmigration and emigration of circulating monocytes into tissues, MCP-1 interaction with the CCR2 receptor increases histamine release, calcium influx, cAMP activation, increases integrin expression and acts as a chemotactic factor for monocytes/macrophages. For further discussions, see Rollins, B. J.,
Blood,
78, 112 (1991); Neote, K., et al.,
Cell,
72, 415 (1993); Charo, I. F., et al.,
Proc Natl., Acad. Sci. USA,
91, 2752 (1994).
Various cell types including endothelial cells, smooth muscle cells, macrophages and fibroblasts produce MCP-1 and its murine homolog JE that was identified initially as a platelet-derived growth factor inducible gene. Although MCP-1 expression has been documented in a variety of human diseases that have inflammatory components, including atherosclerosis, multiple sclerosis, asthma and rheumatoid arthritis among many others, a direct cause and effect relationship has been difficult to prove. MCP-1 along with many other chemokines is expressed in many inflammatory lesions. Direct injection of MCP-1 into rodent's skin provides only a mild infiltrate or no infiltrate at all. See, Zachariae, C. O.,
J. Exp. Med.,
171, 2177 (1990). However, MCP-1 has been demonstrated to play a role in atherosclerosis. Overexpression of MCP-1 by macrophages in apolipoprotein E deficient mice increases monocytic infiltration and atherosclerosis. See, Aiello, R. J., et al.,
Arteriosclero Thromb Vasc Biol.,
19, 1518 (1999). Several studies using MCP-1 transgenic mice have suggested that the ability of MCP-1 to elicit monocyte infiltration depends on MCP-1 being expressed at specific sites. See, Fuentes, M. E.,
J. Immunology,
155, 5769 (1995). Recently MCP-1 deficient mice and MCP-1 receptor (CCR2) deficient mice were shown to have decreased atherosclerotic lesion formation. See, Boring, L.
Nature,
394, 894 (1998).
Leukocyte entry into tissue involves a cascade of molecular events including chemotactic signaling to circulating cells, interaction with endothelial cells and transmigration through tissues. Significant advances have been made in the identification of leukocyte adhesion molecules and their cellular and extracellular matrix legends. Leukocyte-endothelial interactions occur in several phases which include rolling, firm adhesion and transmigration. See, Traffic Signals for Lymphocyte Recirculation and Leukocyte Emigration: The Multistep Paradigm; Springer,
Cell,
76,301 (1994). Primarily a specific class of adhesion molecules mediates each of the phases of adhesion. Integrins are one of the specific classes and exist as heteromeric-cell surface proteins. Recent cell culture studies have shown that the expression of monocyte chemokines MCP-1, MIP-1 &agr;, and RANTES increases the expression of the &agr; chain of 2 members of the &bgr;2 family of integrins, CD11a and CD11b. CD11b (one of two subunits of the CD11b/CD18 (Mac-1, CR3 receptor) &bgr;2 integrin) is highly regulated and is expressed maximally in terminally differentiated myeloid cells. See, Corbi, A. J.,
Biol. Chem,
263, 12403 (1988). Additionally MCP-1 has been reported to selectively activate the &bgr;1 integrin family of leukocyte molecules, suggesting a role in leukocyte adhesion. See, Woldemar, et al.,
Immunity,
4, 179 (1996). Thus, in addition to acting as a chemoattractant, MCP-1 may further potentiate the inflammatory response by promoting integrin expression and cellular adhesion.
Chemoattractants appear to be required for the transendothelial migration both in vivo and in vitro and can induce many of the steps required for transmigration in vivo. MCP-1 is also abundantly expressed at the sites of inflammation, antigen challenge and autoimmune diseases and is an excellent candidate to inhibit tissue trafficking of monocytes during inflammation and autoimmune diseases. Therefore, compounds which inhibit the binding of MCP-1 to the chemokine CCR2 receptor (MCP-1 receptor antagonists) provide useful leads for drugs that will inhibit the action of MCP-1 on target cells.
PCT publications WO 97/44329; WO 99/25686; WO 00/07678; WO 99/07351; WO 99/09984; WO
Colon-Cruz Roberto
Didiuk Mary T.
Duffy Erin M.
Garigipati Ravi
Lau Wan F.
Benson Gregg C.
Pfizer Inc
Powers Fiona T.
Richardson Peter C.
Ronau Robert T.
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