Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-15
2003-06-17
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S183000, C514S217110, C514S237200, C514S423000, C540S482000, C540S604000, C546S221000, C548S559000
Reexamination Certificate
active
06579889
ABSTRACT:
SUMMARY OF THE INVENTION
The compounds of the present invention are antagonists of the VLA-4 integrin (“very late antigen-4”; CD49d/CD29; or &agr;
4
&bgr;1), the &agr;4&bgr;7 integrin (LPAM-1 and &agr;
4
&bgr;
p
), and/or the (&agr;9&bgr;1 integrin, thereby blocking the binding of VLA-4 to its various ligands, such as VCAM-1 and regions of fibronectin, &agr;4&bgr;7 to its various ligands, such as MadCAM-1, VCAM-1 and fibronectin, and/or (&agr;9&bgr;1 to its various ligands, such as tenascin, osteopontin and VCAM-1. Thus, these antagonists are useful in inhibiting cell adhesion processes including cell activation, migration, proliferation and differentiation. These antagonists are useful in the treatment, prevention and suppression of diseases mediated by VLA-4-, &agr;4&bgr;7-, and/or &agr;9&bgr;1-binding and cell adhesion and activation, such as AIDS-related dementia, allergic conjunctivitis, allergic rhinitis, Alzheimer's disease, aortic stenosis, asthma, atherosclerosis, autologous bone marrow transplantation, certain types of toxic and immune-based nephritis, contact dermal hypersensitivity, inflammatory bowel disease including ulcerative colitis and Crohn's disease, inflammatory lung diseases, inflammatory sequelae of viral infections, meningitis, multiple sclerosis, myocarditis, organ transplantation, psoriasis, restenosis, retinitis, rheumatoid arthritis, septic arthritis, stroke, tumor metastasis, type I diabetes, vascular occlusion following angioplasty.
BACKGROUND OF THE INVENTION
The present invention relates to isonipecotic acid amide derivatives which are useful for the inhibition and prevention of leukocyte adhesion and leukocyte adhesion-mediated pathologies. This invention also relates to compositions containing such compounds and methods of treatment using such compounds.
Many physiological processes require that cells come into close contact with other cells and/or extracellular matrix. Such adhesion events may be required for cell activation, migration, proliferation and differentiation. Cell-cell and cell-matrix interactions are mediated through several families of cell adhesion molecules (CAMs) including the selectins, integrins, cadherins and immunoglobulins. CAMs play an essential role in both normal and pathophysiological processes. Therefore, the targetting of specific and relevant CAMs in certain disease conditions without interfering with normal cellular functions is essential for an effective and safe therapeutic agent that inhibits cell-cell and cell-matrix interactions.
The integrin superfamily is made up of structurally and functionally related glycoproteins consisting of a and b heterodimeric, transmembrane receptor molecules found in various combinations on nearly every mammalian cell type. (for reviews see: E. C. Butcher,
Cell,
67, 1033 (1991); T. A. Springer,
Cell,
76, 301 (1994); D. Cox et al., “The Pharmacology of the Integrins.”
Medicinal Research Rev.
14, 195 (1994) and V. W. Engleman et al., “Cell Adhesion Integrins as Pharmaceutical Targets.” in
Ann. Repts. in Medicinal Chemistry
, Vol. 31, J. A. Bristol, Ed.; Acad. Press, NY, 1996, p. 191).
VLA-4 (“very late antigen-4”; CD49d/CD29; or &agr;
4
&bgr;
1
) is an integrin expressed on all leukocytes, except platelets and mature neutrophils, including dendritic cells and macrophage-like cells and is a key mediator of the cell-cell and cell-matrix interactions of of these cell types (see M. E. Hemler, “VLA Proteins in the Integrin Family: Structures, Functions, and Their Role on Leukocytes.”
Ann. Rev. Immunol.
8, 365 (1990)). The ligands for VLA-4 include vascular cell adhesion molecule-1 (VCAM-1) and the CS-1 domain of fibronectin (FN). VCAM-1 is a member of the Ig superfamily and is expressed in vivo on endothelial cells at sites of inflammation. (See R. Lobb et al. “Vascular Cell Adhesion Molecule 1.” in Cellular and Molecular Mechanisms of Inflammation, C. G. Cochrane and M. A. Gimbrone, Eds.; Acad. Press, San Diego, 1993, p. 151.) VCAM-1 is produced by vascular endothelial cells in response to pro-inflammatory cytokines (See A. J. H. Gearing and W. Newman, “Circulating adhesion molecules in disease.”,
Immunol. Today,
14, 506 (1993). The CS-1 domain is a 25 amino acid sequence that arises by alternative splicing within a region of fibronectin. (For a review, see R. O. Hynes “Fibronectins.”, Springer-Velag, NY, 1990.) A role for VLA-4/CS-1 interactions in inflammatory conditions has been proposed (see M. J. Elices, “The integrin &agr;
4
&bgr;
1
(VLA-4) as a therapeutic target” in
Cell Adhesion and Human Disease,
Ciba Found. Symp., John Wiley & Sons, NY, 1995, p. 79).
&agr;
4
&bgr;
7
(also referred to as LPAM-1 and &agr;
4
&bgr;
p
) is an integrin expressed on leukocytes and is a key mediator of leukocyte trafficking and homing in the gastrointestinal tract (see C. M. Parker et al.,
Proc. Natl. Acad. Sci. USA,
89, 1924 (1992)). The ligands for &agr;
4
&bgr;
7
include mucosal addressing cell adhesion molecule-1 (MadCAM-1) and, upon activation of &agr;
4
&bgr;
7
, VCAM-1 and fibronectin (Fn). MadCAM-1 is a member of the Ig superfamily and is expressed in vivo on endothelial cells of gut-associated mucosal tissues of the small and large intestine (“Peyer's Patches”) and lactating mammary glands. (See M. J. Briskin et al.,
Nature,
363, 461 (1993); A. Hamann et al.,
J. Immunol.,
152, 3282 (1994)). MadCAM-1 can be induced in vitro by proinflammatory stimuli (See E. E. Sikorski et al.
J. Immunol.,
151, 5239 (1993)). MadCAM-1 is selectively expressed at sites of lymphocyte extravasation and specifically binds to the integrin, &agr;
4
&bgr;
7
.
The &agr;9&bgr;1 integrin is found on airway smooth muscle cells, non-intestinal epithelial cells (see Palmer et al.,
J. Cell Biol.,
123, 1289 (1993)), and neutrophils, and, less so, on hepatocytes and basal keratinocytes (see Yokosaki et al.,
J. Biol. Chem.,
269,24144 (1994)). Neutrophils, in particular, are intimately involved in acute inflammatory repsonses. Attenuation of neutrophil involvement and/or activation would have the effect of lessening the inflammation. Thus, inhibition of &agr;9&bgr;1 binding to its respective ligands would be expected to have a positive effect in the treatment of acute inflammatory conditions.
Neutralizing anti-&agr;
4
antibodies or blocking peptides that inhibit the interaction between VLA-4 and/or &agr;
4
&bgr;
7
and their ligands have proven efficacious both prophylactically and therapeutically in several animal models of disease, including i) experimental allergic encephalomyelitis, a model of neuronal demyelination resembling multiple sclerosis (for example, see T. Yednock et al., “Prevention of experimental autoimmune encephalomyelitis by antibodies against &agr;
4
&bgr;
1
integrin.”
Nature,
356, 63 (1993) and E. Keszthelyi et al., “Evidence for a prolonged role of a
4
integrin throughout active experimental allergic encephalomyelitis.”
Neurology,
47, 1053 (1996)); ii) bronchial hyperresponsiveness in sheep and guinea pigs as models for the various phases of asthma (for example, see W. M. Abraham et al., “&agr;
4
-Integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep.”
J. Clin. Invest.
93, 776 (1993) and A. A. Y. Milne and P. P. Piper, “Role of VLA-4 integrin in leucocyte recruitment and bronchial hyperresponsiveness in the gunea-pig.”
Eur. J. Pharmacol.,
282, 243 (1995)); iii) adjuvant-induced arthritis in rats as a model of inflammatory arthritis (see C. Barbadillo et al., “Anti-VLA-4 mAb prevents adjuvant arthritis in Lewis rats.”
Arthr. Rheuma.
(Suppl.), 36 95 (1993) and D. Seiffge, “Protective effects of monoclonal antibody to VLA-4 on leukocyte adhesion and course of disease in adjuvant arthritis in rats.”
J. Rheumatol.,
23, 12 (1996)); iv) adoptive autoimmune diabetes in the NOD mouse (see J. L. Baron et al., “The pathogenesis of adoptive murine autoimmune diabetes requires an interaction between a4-integrins and vascular cell adhesion molecule-1
.”, J. Clin. Invest.,
93, 1700 (1994), A. Jakubowski e
de Laszlo Stephen E.
Gutteridge Clare E.
Hagmann William K.
Chang Ceila
Merck & Co. , Inc.
Rose David L.
Yang Mollie M.
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