Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-25
2001-02-20
Davis, Zinna Northington (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S371000, C514S447000, C514S507000, C546S308000, C548S195000, C549S069000, C562S621000
Reexamination Certificate
active
06191150
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, such compounds generally pharmacologically useful as agents in those disease states alleviated by the inhibition or antagonism of matrix metalloproteases, metalloproteases, and/or tumor necrosis factor-alpha (TNF), which pathologically involve aberrant extracellular matrix degradation, shedding of cell surface protein ectodomains, and/or TNF synthesis, such disease states including arthritis, tumor metastasis and diabetes. The aforementioned pharmacologic activities are useful in the treatment of mammals.
More specifically, the compounds of the present invention can be used in the treatment of rheumatoid arthritis, osteoarthritis, inflammatory bowel syndromes, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal ulceration and the complications of diabetes. At the present time, there is a need in the areas of rheumatology, oncology, dentistry, opththalmology, gastroenterology, cardiology, neurology, nephrology, infectious disease and endocrinology therapy for such agents.
BACKGROUND OF THE INVENTION
The matrix metalloprotease (MMP) family of zinc endoproteases includes fibroblast collagenase (MMP-1, collagenase-1), neutrophil collagenase (MMP-8, collagenase-2), chondrocyte collagenase (MMP-13, collagenase-3), gelatinases A and B (MMP's 2 and 9), and members of the stromelysin family such as stromelysin-1 (MMP-3), stromelysin-3 (MMP-11), and matrilysin (MMP-7). These enzymes accelerate breakdown of connective tissue by catalyzed resorption of the extracellular matrix. This is a feature of diverse pathologies; therefore, inhibitors of one or more of the matrix metalloproteases would have utility in a wide range of disease states such as in abrogating the initiation of tumor metastasis and angiogenesis and in halting the pathogenesis of demyelinating diseases of the nervous system, multiple sclerosis being one example. MMP inhibitors would also find utility in diseases involving connective tissue degradation in the joint, as occurs in osteoarthritis and rheumatoid arthritis. MMP's-1 and -3 have been found in elevated levels in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis.
Collagenase-3 (MMP-13) is a member of the family of MMP's which preferentially digest collagen. Collagenase-3 is one of the more newly characterized MMP's; biochemical studies on the recombinant protein have demonstrated that it cleaves type II collagen, the predominant matrix component of articular cartilage, more efficiently than either MMP-1 or MMP-2 and that it is expressed by chondrocytes in osteoarthritic cartilage. These data would implicate collagenase-3 as a significant target in rheumatoid arthritis and osteoarthritis for inhibition by MMP inhibitors.
Compounds which inhibit the activities of one or more of the matrix metalloproteases are recognized as having therapeutic benefit in one or more pathologies where MMP activity is upregulated, such as:
i) inflammatory/autoimmune diseases, including but not limited to rheumatoid arthritis, osteoarthritis, Crohn's disease and other inflammatory bowel diseases, periodontal disease, gingivitis, and corneal ulceration;
ii) cardiovascular diseases, including but not limited to atherosclerosis and restenosis;
iii) metabolic diseases, including but not limited to complications of diabetes, osteoporosis, and other disorders involving resorption of bone;
iv) neurologic diseases, including but not limited to multiple sclerosis and other demyelination ailments;
v) diseases of cancer and malignancy, including but not limited to cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pancreas, larynx, lung, bone, connective tissue, skin, colon, breast, cervix uteri, corpus endometrium, ovary, prostate, testis, bladder, kidney and other urinary tissues, eye, brain and central nervous system, thyroid and other endocrine gland, leukemias (lymphocytic, granulocytic, monocytic), Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, tumor invasion, and metastatic and angiogenic events thereof;
vi) renal diseases, including but not limited to nephrotic syndromes and glomerulonephritis; and
vii) infectious diseases, including but not limited to those mediated by viruses, bacteria, and fungi;
viii) respiratory diseases, including but not limited to emphysema and COPD.
Many inhibitors of matrix metalloproteases have been disclosed, including some structure activity relationships for a series of carboxylalkylamine inhibitors. These molecules are exemplary for MMP inhibitors in general. They generally embody a functional group capable of tightly binding the zinc cofactor at the enzyme active site, which is contained within a peptidic or pseudopeptide structure. Zinc binding groups among the MMP inhibitor art have included hydroxamic acid, reverse hydroxamic acid, thiol, carboxylate, and phosphinate.
Hydroxamate metalloprotease inhibitors disclosed in the art usually have the following general structure (I):
where W is a zinc-chelating acyl derivative group of the formula —C(O)NHOH (which by convention and in this application are referred to as “forward hydroxamates”) or a zinc-chelating substituted amine group of the formula —NH(OH)C(O)R (which by convention and in this application are referred to as “reverse hydroxamates”), where R is usually hydrogen or alkyl. The other substituents vary according to specifications expressed by the art disclosure. It is understood and demonstrated that variations in these substituents can have dramatic effects on potency and selectivities between the matrix metalloproteases.
Suppression of MMP activity in conditions characterized by its overproduction would be of benefit, and compounds which inhibit MMP's would act in this manner at a specific target and be useful and of benefit. The present invention fills this need by providing potent, specific, orally or parenterally active inhibitors of matrix metalloproteases.
Tumor necrosis factor-&agr; (TNF&agr;), hereinafter called “TNF”, is a mammalian protein capable of inducing cellular effects by virtue of its interaction with specific cellular receptors. It was initially characterized and so named due to its ability to cause death of cancerous cells. It is produced primarily by activated monocytes and macrophages. Human TNF is produced as a larger pro-form of 26 kD which is processed to a secreted 17 kD mature form by proteolytic processing of the alanine-76—valine-77 peptide bond.
Recently, certain compounds having matrix metalloprotease—inhibiting activity have been found to inhibit the release of mature 17 kD TNF from cells. Further, these inhibitors also protect mice from a lethal dose of endotoxin indicating that the compounds can inhibit TNF secretion in vivo. These compounds inhibit the cell-associated proteolytic processing of the 26 kD pro-TNF to the mature 17 kD form. The proteolytic activity is thought to reside in an intracellular or cell-associated specific enzyme or family of enzymes, which by convention is called a “TNF convertase”, distinct from the matrix metalloproteases but related in that both contain a zinc cation at the active site. TNF convertase enzymatic activity can be detected in monocyte membrane fractions, and the enzyme activity can be inhibited by certain matrix metalloprotease—inhibiting compounds.
A metalloprotease is thought to mediate the proteolysis of the cell—surface IgE receptor CD23. Certain of the CD23—derived peptides possess proinflammatory biological activities mimicking those of cytokines, including TNF&agr;.
Metalloprotease—like activity is also thought to contribute to the shedding of certain cell surface protein ectodomains such as L-selectin, fibronectin, thyrotropin stimulating hormone receptor, transforming growth factor alpha precursor, low density lipoprotein receptor, beta amyloid precursor pr
Andersen Marc Werner
Andrews Robert Carl
Bubacz Dulce Garrido
Chan Joseph Howing
Cowan David John
Davis Zinna Northington
Glaxo Wellcome Inc.
Lemanowicz John L.
Robinson Binta
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