Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-11
2002-12-24
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S143000, C546S159000, C514S311000, C514S314000
Reexamination Certificate
active
06498167
ABSTRACT:
BACKGROUND
The present invention relates to the discovery of novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) and TNF-&agr; converting enzyme (TACE, tumor necrosis factor-&agr; converting enzyme) which are useful for the treatment of diseases in which these enzymes are implicated such as arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system and HIV infection.
Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes [Woessner, J. F., Jr.
FASEB J.
1991, 5, 2145; Birkedal-Hansen, H.; Moore, W. G. I.; Bodden, M. K.; Windsor, L. J.; Birkedal-Hansen, B.; DeCarlo, A.; Engler, J. A.
Crit. Rev. Oral Biol. Med.
1993, 4, 197; Cawston, T. E.
Pharmacol. Ther.
1996, 70, 163; Powell, W. C.; Matrisian, L. M.
Cur. Top. Microbiol. and Immunol.
1996, 213, 1]. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors, while the collagenases have been associated with the pathogenesis of osteoarthritis [Howell, D. S.; Pelletier, J.-P. In
Arthritis and Allied Conditions;
McCarthy, D. J.; Koopman, W. J., Eds.; Lea and Febiger: Philadelphia, 1993; 12
th Edition
Vol. 2, pp. 1723; Dean, D. D.
Sem. Arthritis Rheum.
1991, 20, 2; Crawford, H. C; Matrisian, L. M.
Invasion Metast.
1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G.
Exp. Opin. Invest. Drugs,
1996, 5, 323].
It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which may lead to tumor metastasis [Powell, W. C.; Matrisian, L. M.
Cur. Top. Microbiol. and Immunol.
1996, 213, 1; Crawford, H. C; Matrisian, L. M.
Invasion Metast.
1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G.
Exp. Opin. Invest. Drugs,
1996, 5, 323; Himelstein, B. P.; Canete-Soler, R.; Bernhard, E. J.; Dilks, D. W.; Muschel, R. J.
Invasion Metast.
1994-95, 14, 246; Nuovo, G. J.; MacConnell, P. B.; Simsir, A.; Valea, F.; French, D. L.
Cancer Res.
1995, 55, 267-275; Walther, M. M.; Levy, A.; Hurley, K.; Venzon, D.; Linehen, W. M.; Stetler-Stevenson, W.
J. Urol.
1995, 153 (
Suppl.
4), 403A; Tokuraku, M; Sato, H.; Murakami, S.; Okada, Y.; Watanabe, Y.; Seiki, M.
Int. J. Cancer,
1995, 64, 355; Himelstein, B.; Hua, J.; Bernhard, E.; Muschel, R. J.
Proc. Am. Assoc. Cancer Res. Ann. Meet.
1996, 37, 632; Ueda, Y.; Imai, K.; Tsuchiya, H.; Fujimoto, N.; Nakanishi, I.; Katsuda, S.; Seiki, M.; Okada, Y.
Am. J. Pathol.
1996, 148, 611; Gress, T. M.; Mueller-Pillasch, F.; Lerch, M. M.; Friess, H.; Buechler, M.; Adler, G.
Int. J. Cancer,
1995, 62, 407; Kawashima, A.; Nakanishi, I.; Tsuchiya, H.; Roessner, A.; Obata, K.; Okada, Y.
Virchows Arch.,
1994, 424, 547-552.]. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology [Crawford, H. C; Matrisian, L. M.
Invasion Metast.
1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G.
Exp. Opin. Invest. Drugs,
1996, 5, 323.]. Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis [Dollery, C. M.; McEwan, J. R.; Henney, A. M.
Circ. Res.
1995, 77, 863; Zempo, N.; Koyama, N.; Kenagy, R. D.; Lea, H. J.; Clowes, A. W.
Arterioscler. Thromb. Vasc. Biol.
1996, 16, 28; Lee, R. T.; Schoen, F. J.; Loree, H. M.; Lark, M. W., Libby, P.
Arterioscler. Thromb. Vasc. Biol.
1996, 16, 1070.]. Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis
eovascularization and corneal graft rejection.
The hypothesis that MMPs are important mediators of the tissue destruction that occurs in arthritis has long been considered, since it was first recognized that these enzymes are capable of degrading collagens and proteoglycans which are the major structural components of cartilage [Sapolsky, A. I.; Keiser, H.; Howell, D. S.; Woessner, J. F., Jr.;
J. Clin. Invest.
1976, 58, 1030; Pelletier, J.-P.; Martel-Pelletier, J.; Howell, D. S.; Ghandur-Mnaymneh, L.; Enis, J. E.; Woessner, J. F., Jr.,
Arthritis Rheum.
1983, 26, 63.], and continues to develop as new MMPs are identified. For example, collagenase-3 (MLMP-13) was cloned from breast cancer cells in 1994, and the first report that it could be involved in arthritis appeared in 1995 [Freiji, J. M.; Diez-Itza, I.; Balbin, M.; Sanchez, L. M.; Blasco, R.; Tolivia, J.; Lopez-Otin, C.
J. Biol. Chem.
1994,269, 16766; Flannery, C. R.; Sandy, J. D. 102-17, 41
st Ann. Meet. Orth. Res. Soc.
Orlando, Fla. Feb. 13-16, 1995.]. Evidence is accumulating that implicates MMP-13 in the pathogenesis of arthritis. A major structural component of articular cartilage, type II collagen, is the preferred substrate for MMP-13 and this enzyme is significantly more efficient at cleaving type II collagen than the other collagenases [Knauper, V.; Lopez-Otin, C.; Smith, B.; Knight, G.; Murphy, G.
J. Biol. Chem.,
1996, 271, 1544-1550; Mitchell, P. G.; Magna, H. A.; Reeves, L. M.; Lopresti-Morrow, L. L.; Yocum, S. A.; Rosner, P. J.; Geoghegan, K. F.; Hambor, J. E.
J. Clin. Invest.
1996, 97, 761.]. MMP-13 is produced by chondrocytes, and elevated levels of MMP-13 has been found in human osteoarthritic tissues [Reboul, P.; Pelletier, J-P.; Hambor, J.; Magna, H.; Tardif, G.; Cloutier, J-M.; Martel-Pelletier, J.
Arthritis Rheum.
1995, 38 (
Suppl.
9), S268;Shlopov, B. V.; Mainardi, C. L.; Hasty, K. A.
Arthritis Rheum.
1995, 38 (
Suppl.
9), S313; Reboul, P.; Pelletier, J-P.; Tardif, G.; Cloutier, J-M.; Martel-Pelletier, J.
J. Clin. Invest.
1996, 97, 2011]. Potent inhibitors of MMPs were described over 10 years ago, but the poor bioavailability of these early peptidic, substrate mimetic MMP inhibitors precluded their evaluation in animal models of arthritis. More bioavailable, non-peptidic MMP inhibitors may be preferred for the treatment of diseases mediated by MMPs.
TNF-&agr; converting enzyme catalyzes the formation of TNF-&agr; from membrane bound TNF-&agr; precursor protein. TNF-&agr; is a pro-inflammatory cytokine that is now thought to have a role in rheumatoid arthritis, septic shock, graft rejection, insulin resistance and HIV infection in addition to its well documented antitumor properties. For example, research with anti-TNF-&agr; antibodies and transgenic animals has demonstrated that blocking the formation of TNF-&agr; inhibits the progression of arthritis [Rankin, E. C.; Choy, E. H.; Kassimos, D.; Kingsley, G. H.; Sopwith, A. M.; Isenberg, D. A.; Panayi, G. S.
Br. J. Rheumatol.
1995, 34, 334;
Pharmaprojects,
1996, Therapeutic Updates 17 (Oct.), 197. This observation has recently been extended to humans as well. Other conditions mediated by TNF-&agr; are congestive heart failure, cachexia, anorexia, inflammation, fever, inflammatory disease of the central nervous system, and inflammatory
Albright Jay D.
Du Xuemei
Gu Yansong
Levin Jeremy I.
Zask Arie
American Cyanamid Company
Goudie Joy S.
Qazi Sabiha
LandOfFree
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