Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-13
2004-01-13
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S422000, C514S432000, C514S459000, C514S468000, C546S195000, C548S531000, C549S028000, C549S414000, C549S419000
Reexamination Certificate
active
06677355
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a group of hydroxamic acid compounds and derivatives which inhibit matrix metalloproteinase enzymes and thus are useful for treating diseases resulting from tissue breakdown, such as heart disease, multiple sclerosis, arthritis, atherosclerosis, and osteoporosis.
BACKGROUND OF THE INVENTION
Matrix metalloproteinases (sometimes referred to as MMPs) are naturally occurring enzymes found in most mammals. Over-expression and activation of MMPs or an imbalance between MMPs and inhibitors of MMPs have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues.
Stromelysin-1 and gelatinase A are members of the matrix metalloproteinases (MMP) family. Other members include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), gelatinase B (92 kDa gelatinase) (MMP-9), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), matrilysin (MMP-7), collagenase 3 (MMP-13), TNF-alpha converting enzyme (TACE), and other newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M.,
Nature,
1994;370:61-65). These enzymes have been implicated with a number of diseases which result from breakdown of connective tissue, including such diseases as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation which leads to restenosis and ischemic heart failure, and tumor metastasis. A method for preventing and treating these and other diseases is now recognized to be by inhibiting metalloproteinase enzymes, thereby curtailing and/or eliminating the breakdown of connective tissues that results in the disease states.
The catalytic zinc in matrix metalloproteinases is typically the focal point for inhibitor design. The modification of substrates by introducing zinc chelating groups has generated potent inhibitors such as peptide hydroxamates and thiol-containing peptides. Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat animal models of cancer and inflammation.
The ability of the matrix metalloproteinases to degrade various components of connective tissue makes them potential targets for controlling pathological processes. For example, the rupture of atherosclerotic plaques is the most common event initiating coronary thrombosis. Destabilization and degradation of the extracellular matrix surrounding these plaques by MMPs has been proposed as a cause of plaque fissuring. The shoulders and regions of foam cell accumulation in human atherosclerotic plaques show locally increased expression of gelatinase B, stromelysin-1, and interstitial collagenase. In situ zymography of this tissue revealed increased gelatinolytic and caseinolytic activity (Galla Z. S., Sukhova G. K., Lark M. W., and Libby P., “Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques,”
J. Clin. Invest.,
1994;94:2494-2503). In addition, high levels of stromelysin RNA message have been found to be localized to individual cells in atherosclerotic plaques removed from heart transplant patients at the time of surgery (Henney A. M., Wakeley P. R., Davies M. J., Foster K., Hembry R., Murphy G., and Humphries S., “Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization,”
Proc. Nat'l. Acad. Sci.,
1991;88:8154-8158).
Inhibitors of matrix metalloproteinases will have utility in treating degenerative aortic disease associated with thinning of the medial aortic wall. Increased levels of the proteolytic activities of MMPs have been identified in patients with aortic aneurysms and aortic stenosis (Vine N. and Powell J. T., “Metalloproteinases in degenerative aortic diseases,”
Clin. Sci.,
1991;81:233-239).
Heart failure arises from a variety of diverse etiologies, but a common characteristic is cardiac dilation which has been identified as an independent risk factor for mortality (Lee T. H., Hamilton M. A., Stevenson L. W., Moriguchi J. D., Fonarow G. C., Child J. S., Laks H., and Walden J. A., “Impact of left ventricular size on the survival in advanced heart failure,”
Am. J. Cardiol.,
1993;72:672-676). This remodeling of the failing heart appears to involve the breakdown of extracellular matrix. Matrix metalloproteinases are increased in patients with both idiopathic and ischemic heart failure (Reddy H. K., Tyagi S. C., Tjaha i.e., Voelker D. J., Campbell S. E., and Weber K. T., “Activated myocardial collagenase in idiopathic dilated cardiomyopathy,”
Clin. Res.,
1993;41:660A; Tyagi S. C., Reddy H. K., Voelker D., Tjara i.e., and Weber K. T., “Myocardial collagenase in failing human heart,”
Clin. Res.,
1993;41:681 A). Animal models of heart failure have shown that the induction of gelatinase is important in cardiac dilation (Armstrong P. W., Moe G. W., Howard R. J., Grima E. A., and Cruz T. F., “Structural remodeling in heart failure: gelatinase induction,”
Can. J. Cardiol.,
1994;10:214-220), and cardiac dilation precedes profound deficits in cardiac function (Sabbah H. N., Kono T., Stein P. D., Mancini G. B., and Goldstein S., “Left ventricular shape changes during the course of evolving heart failure,”
Am. J. Physiol.,
1992;263:H266-H270).
Congestive heart failure (CHF) is a significant health care problem which currently accounts for 7% of total health care expenditures in the USA. Approximately 400,000 new cases of heart failure are identified annually. The primary cause for development of heart failure is ischemic heart disease, and most new cases occur after myocardial infarction. The number of hospital discharges for heart failure has increased from 377,000 in 1979 to 875,000 in 1993, and the number of deaths during the same period has risen 82.5%. The average mortality rate eight years following initial diagnosis is 85% for men and 65% for women.
The development of CHF begins as an injurious process to the myocardium that reduces cardiac function (especially contractile or pump function) either in a specific region(s) or throughout its entire extent (i.e., globally). Heart failure is said to exist whenever the myocardial injury is of sufficient severity to reduce the heart's capacity to pump an adequate output of blood to satisfy the body's tissue requirements either at rest or during exercise. The disease state of heart failure is not a static situation, but instead progressively worsens until death occurs either suddenly (e.g., by cardiac arrhythmia or embolism to the brain or lung) or gradually from pump failure per se. The progressive decline in heart function in patients with CHF is characterized by progressive enlargement of the ventricular chambers (i.e., ventricular dilatation) and thinning and fibrosis of the ventricular muscle. The progressive ventricular enlargement and accompanying histologic changes in the ventricular muscle are termed “remodeling,” a process that involves changes in myocardiocyte structure as well as changes in the amount and composition of the surrounding interstitial connective tissue. An important constituent of the interstitial connective tissue is a matrix of fibrillar collagen, the “tissue scaffolding” that contributes to the maintenance of proper ventricular geometry and structural alignment of adjoining cardiomyocytes. The interstitial collagen matrix is subject to increased dissolution and repair during “remodeling” that leads to ventricular enlargement and progressive heart failure. The deterioration of the collagen matrix is effected by increased activity of matrix metalloproteinases, the inhibition of which is a new treatment for heart failure and ventricular dilatation. Ventricular dilatation, the severity of which is measured by the end-diastolic and end-systolic volumes, is a prognostic marker of the probability of subsequent morbidity and mortality. The larger the v
Conrad Christopher Alan
O'Brien Patrick Michael
Ortwine Daniel Fred
Picard Joseph Armand
Sliskovic Drago Robert
Baude Eric J.
Kifle Bruck
McKenzie Thomas
Purchase, Jr. Claude P.
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