Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-03-04
2002-04-16
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
57, 57, 57, 57, C424S649000
Reexamination Certificate
active
06372719
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of pharmaceutical agents (compounds) which are known as &agr;hd v&bgr;
3
integrin antagonists in combination with chemotherapeutic agents and methods for using the same for treatment or prevention of neoplasia diseases.
BACKGROUND OF THE INVENTION
Integrins are a group of cell surface glycoproteins which mediate cell adhesion and therefore are useful mediators of cell adhesion interactions which occur during various biological processes. Integrins are heterodimers composed of noncovalently linked &agr; and &bgr; polypeptide subunits. Currently eleven different &agr; subunits have been identified and six different &bgr; subunits have been identified. The various a subunits can combine with various &bgr; subunits to form distinct integrins.
The integrin identified as &agr;
v
&bgr;
3
(also known as the vitronectin receptor) has been identified as an integrin associated with endothelial cells and smooth muscle cells. &agr;
v
&bgr;
3
integrins can promote the formation of blood vessels (angiogensis) in tumors. These vessels nourish the tumors and provide access routes into the bloodstream for metastatic cells.
The &agr;
v
&bgr;
3
integrin is known to play a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, angiogenesis, including tumor angiogenesis, retinopathy, including macular degeneration, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis). Thus, compounds which selectively inhibit or antagonize &agr;
v
&bgr;
3
would be beneficial for treating such conditions.
It has been shown that the &agr;
v
&bgr;
3
integrin and other &agr;
v
containing integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules. Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors. However, it is also known that RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides which bind to &agr;
v
&bgr;
3
also bind to &agr;
v
&bgr;
5
, &agr;
v
&bgr;
1
and &agr;
IIb
&bgr;
3
. Antagonism of platelet &agr;
IIb
&bgr;
3
(also known as the fibrinogen receptor) is known to block platelet aggregation in humans. In order to avoid bleeding side-effects when treating the conditions or disease states associated with the integrin &agr;
v
&bgr;
3
, it would be beneficial to develop compounds which are selective antagonists of &agr;
v
&bgr;
3
as opposed to &agr;
IIb
&bgr;
3
.
Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic dissolution of the matrix; and 3) movement of the cells through the dissolved barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor.
Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992) 1557-1561) have shown that the &agr;
v
&bgr;
3
integrin has a biological function in melanoma cell invasion. Montgomery et al., (Proc. Natl. Acad. Sci. USA, Vol. 91 (1994) 8856-60) have demonstrated that the integrin &agr;
v
&bgr;
3
expressed on human melanoma cells promotes a survival signal, protecting the cells from apoptosis. Mediation of the tumor cell metastatic pathway by interference with the &agr;
v
&bgr;
3
integrin cell adhesion receptor to impede tumor metastasis would be beneficial.
Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstrated that antagonists of &agr;
v
&bgr;
3
provide a therapeutic approach for the treatment of neoplasia (inhibition of solid tumor growth) since systemic administration of &agr;
v
&bgr;
3
antagonists causes dramatic regression of various histologically distinct human tumors.
The adhesion receptor integrin &agr;
v
&bgr;
3
was identified as a marker of angiogenic blood vessels in chick and man and therefore such receptor plays a critical role in angiogenesis or neovascularization. Angiogenesis is characterized by the invasion, migration and proliferation of smooth muscle and endothelial cells. Antagonists of &agr;
v
&bgr;
3
inhibit this process by selectively promoting apoptosis of cells in neovasculature. Therefore, &agr;
v
&bgr;
3
antagonists would be useful therapeutic targets for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571).
A neoplasm or tumor, is an abnormal, unregulated, and disorganized proliferation of cell growth. A neoplasm is malignant, or cancerous, if it has properties of destructive growth, invasiveness and metastasis. Invasiveness refers to the local spread of a neoplasm by infiltration or destruction of surrounding tissue, typically breaking through the basal laminas that define the boundaries of the tissues, thereby often entering the body's circulatory system. Metastasis typically refers to the dissemination of tumor cells by lymphotics or blood vessels. Metastasis also refers to the migration of tumor cells by direct extension through serous cavities, or subarachnoid or other spaces. Through the process of metastasis, tumor cell migration to other areas of the body establishes neoplasms in areas away from the site of initial appearance.
Cancer is now the second leading cause of death in the United States. However, cancer is not fully understood at the molecular level. It is known that exposure of a cell to a carcinogen leads to DNA alteration that inactivates a suppressive gene or activates an oncogene.
Suppressive genes are growth regulatory genes, which upon mutation, can no longer control cell growth. Oncogenes are initially normal genes (called prooncogenes) that by mutation or altered context of expression become transforming genes. The products of transforming genes cause inappropriate cell growth. More than twenty different normal cellular genes can become oncogenes by genetic alteration. Transformed cells differ from normal cells in many ways, including cell morphology, cell-to-cell interactions, membrane content, cytoskeletal structure, protein secretion, gene expression and mortality (transformed cells can grow indefinitely).
Cancer is now primarily treated with one or a combination of three types of therapies: surgery, radiation and chemotherapy. Surgery involves the bulk removal of diseased tissue. While surgery is sometimes effective in removing tumors located at certain sites, for example, in the breast, colon and skin, it cannot be used in the treatment of tumors located in other areas, such as the backbone, nor in the treatment of disseminated neoplastic conditions such as leukemia.
Chemotherapy involves the disruption of all replication or cell metabolism. It is used most often in the treatment of breast, lung and testicular cancer. Many adverse effects are experienced by patients undergoing systemic chemotherapy for treatment of neoplastic diseases. Chemotherapy-induced side effects significantly impact the quality of life of the patient and may dramatically influence patient compliance with treatment.
SUMMARY OF THE INVENTION
The present invention relates to the use of compounds of the following general formula
wherein X and Y are the same or different halo group; R is H or alkyl; and pharmaceutically acceptable salts thereof in combination with chemotherapeutic agents and methods for using the combinations for treatment or prevention of neoplasia diseases.
The compounds described above can exist in various isomeric forms and all such isomeric forms are meant to be included. Tautomeric forms are also included as well as pharmaceutically acceptable salts of such isomers and tautomers.
DETAILED DESCRIPTION
The present invention relates to a class of compounds known as &agr;
v
&bgr;
3
integrin antagonists represented by the following formulae I-XVIII, in combination with chemotherapeutic agents, more fully described below, and methods of using such combinations for treatment or prevention of neoplasia diseases.
wherein R is H or lower alky
Cunningham Jay
Gordon Gary B.
Nickols G. Allen
Rogers Thomas Edward
Ruminski Peter Gerrard
Goldberg Jerome D.
Polster Rachel
Scrivner Alan
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