&agr;v integrin receptor antagonists

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S212020, C514S300000, C544S316000, C544S333000, C544S335000, C546S115000, C546S118000, C546S122000, C546S123000, C546S135000, C540S521000, C540S543000, C540S577000, C540S580000

Reexamination Certificate

active

06693101

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to alkanoic acid derivatives, their synthesis, and their use as &agr;v integrin receptor antagonists. More particularly, the compounds of the present invention are antagonists of the integrin receptors &agr;v&bgr;3, &agr;v&bgr;5, and &agr;v integrin receptors associated with other &bgr;-subunits, and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth.
BACKGROUND OF THE INVENTION
It is believed that a wide variety of disease states and conditions can be mediated by acting on integrin receptors and that integrin receptor antagonists represent a useful class of drugs. Integrin receptors are heterodimeric transmembrane receptors through which cells attach and communicate with extracellular matrices and other cells. (See S. B. Rodan and G. A. Rodan, “Integrin Function In Osteoclasts,”
Journal of Endocrinology,
154: S47-S56 (1997), which is incorporated by reference herein in its entirety).
In one aspect of the present invention, the compounds herein are useful for inhibiting bone resorption. Bone resorption is mediated by the action of cells known as osteoclasts. Osteoclasts are large multinucleated cells of up to about 400 mm in diameter that resorb mineralized tissue, chiefly calcium carbonate and calcium phosphate, in vertebrates. Osteoclasts are actively motile cells that migrate along the surface of bone, and can bind to bone, secrete necessary acids and proteases, thereby causing the actual resorption of mineralized tissue from the bone. More specifically, osteoclasts are believed to exist in at least two physiological states, namely, the secretory state and the migratory or motile state. In the secretory state, osteoclasts are flat, attach to the bone matrix via a tight attachment zone (sealing zone), become highly polarized, form a ruffled border, and secrete lysosomal enzymes and protons to resorb bone. The adhesion of osteoclasts to bone surfaces is an important initial step in bone resorption. In the migratory or motile state, the osteoclasts migrate across bone matrix and do not take part in resorption until they again attach to bone.
Integrins are involved in osteoclast attachment, activation and migration. The most abundant integrin on osteoclasts, e.g., on rat, chicken, mouse and human osteoclasts, is an integrin receptor known as &agr;v&bgr;3, which is thought to interact in bone with matrix proteins that contain the RGD sequence. Antibodies to &agr;v&bgr;3 block bone resorption in vitro indicating that this integrin plays a key role in the resorptive process. There is increasing evidence to suggest that &agr;v&bgr;3 ligands can be used effectively to inhibit osteoclast mediated bone resorption in vivo in mammals.
The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid-induced osteoporosis. All of these conditions are characterized by bone loss, resulting from an imbalance between bone resorption, i.e. breakdown, and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site; for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
In the United States, there are currently about 20 million people with detectable fractures of the vertebrae due to osteoporosis. In addition, there are about 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture.
Individuals suffering from all the conditions listed above would benefit from treatment with agents which inhibit bone resorption.
Additionally, &agr;v&bgr;3 ligands have been found to be useful in treating and/or inhibiting restenosis (i.e. recurrence of stenosis after corrective surgery on the heart valve), atherosclerosis, diabetic retinopathy, macular degeneration, and angiogenesis (i.e. formation of new blood vessels), and inhibiting viral disease. Moreover, it has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor; thus, inhibition of angiogenesis can cause tumor regression in animal models (See
Harrison's Principles of Internal Medicine,
12th ed., 1991, which is incorporated by reference herein in its entirety). Therefore, &agr;v&bgr;3 antagonists which inhibit angiogenesis can be useful in the treatment of cancer by inhibiting tumor growth (See, e.g., Brooks et al.,
Cell,
79:1157-1164 (1994), which is incorporated by reference herein in its entirety).
Evidence has also been presented suggesting that angiogenesis is a central factor in the initiation and persistence of arthritic disease, and that the vascular integrin &agr;v&bgr;3 may be a preferred target in inflammatory arthritis. Therefore, &agr;v&bgr;3 antagonists which inhibit angiogenesis may represent a novel therapeutic approach to the treatment of arthritic disease, such as rheumatoid arthritis (see C. M. Storgard, et al, “Decreased angiogenesis and arthritic disease in rabbits treated with an &agr;v&bgr;3 antagonist,”
J. Clin. Invest.,
103: 47-54 (1999), which is incorporated by reference herein in its entirety).
Moreover, compounds of this invention can also inhibit neovascularization by acting as antagonists of the integrin receptor, &agr;v&bgr;5. A monoclonal antibody for &agr;v&bgr;5 has been shown to inhibit VEGF-induced angiogenesis in rabbit cornea and the chick chorioallantoic membrane model (See M. C. Friedlander, et al.,
Science
270: 1500-1502 (1995), which is incorporated by reference herein in its entirety). Thus, compounds that antagonize &agr;v&bgr;5 are useful for treating and preventing macular degeneration, diabetic retinopathy, viral disease, cancer, and metastatic tumor growth.
Additionally, compounds of the instant invention can inhibit angiogenesis and inflammation by acting as antagonists of &agr;&ngr; integrin receptors associated with other &bgr; subunits, suh as &agr;&ngr;&bgr;6 and &agr;&ngr;&bgr;8 (See, for example, Melpo Christofidou-Solomidou, et al., “Expression and Function of Endothelial Cell &agr;&ngr; Integrin Receptors in Wound-Induced Human Angiogenesis in Human Skin/SCID Mice Chimeras,”
American Journal of Pathology,
151: 975-83 (1997) and Xiao-Zhu Huang, et al., “Inactivation of the Integrin &bgr;6 Subunit Gene Reveals a Role of Epithelial Integrins in Regulating Inflammation in the Lungs and Skin,”
Journal of Cell Biology,
133: 921-28 (1996), which are incorporated by reference herein in their entirety).
In addition, certain compounds of this invention antagonize both the &agr;&ngr;&bgr;3 and &agr;&ngr;&bgr;5 receptors. These compounds, referred to as “dual &agr;&ngr;&bgr;3/&agr;&ngr;&bgr;5 antagonists,” are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammatory arthritis, cancer, and metastatic tumor growth.
Peptidyl as well as peptidomimetic antagonists of the &agr;&ngr;v&bgr;3 integrin receptor have been described both in the scientific and patent literature. For example, reference is made to W. J. Hoekstra and B. L. Poulter,
Curr. Med. Chem.
5: 195-204 (1998) and references cited therein; WO 95/32710; WO 95/37655; WO 97/01540; WO 97/37655

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