Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-21
2003-10-14
Owens, Amelia A. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S452000, C549S280000
Reexamination Certificate
active
06632835
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a series of new chemical agents that demonstrate anti-proliferative effects against human endothelial cells for the treatment of a variety of diseases including cancer, in addition to an inhibitory effect directly on cancer cells for the treatment of solid tumors. More particularly, the present invention relates to molecules that demonstrate anti-proliferative capabilities against human endothelial cells and several epithelial cancer cells and their applications in treating a variety of disease states.
BACKGROUND OF THE INVENTION
Cancer is a disease state characterized by the uncontrolled proliferation of genetically altered tissue cells. There have been several chemotherapeutic approaches targeted against such proliferation including alkylating agents, antimitotics, antimetabolites, and antibiotics. These act preferentially on rapidly proliferating cells including cancer cells. Hormonal therapy with anti-estrogens or anti-androgens is another approach to attacking cancer cells that work by inhibiting the proliferative action of the required hormone. Although anti-cancer agents fall into specific classifications, it is not uncommon for agents to act by multiple modes of action. For example, the anti-estrogen tamoxifen has been shown to have anti-proliferative activity on cancer cells and endothelial cells by an estrogen independent mechanism. Taxol, an antimitotic agent acting on microtubules has also demonstrated antiangiogenic properties, possibly by inducing apoptosis through Bcl-2 phosphorylation.
Angiogenesis, the formation of new blood vessels, is a fundamental biological process involved in wound healing, tissue regeneration, embryogenesis and the female reproductive cycle. Blood vessel walls are formed by endothelial cells that have the ability to divide and migrate under specific stimuli, such as growth factors. The creation of new blood vessels follows a specific set of tightly regulated steps. Briefly, endothelial cells are stimulated by factors secreted by surrounding cells and secrete enzymes such as matrix metalloproteinases that break down the extra-cellular matrix and basement membrane, thus creating a space for the cells to migrate into and establish themselves. The endothelial cells then organize into hollow tubes that eventually form a new vascular network of blood vessels providing surrounding cells with nutrients and oxygen and the ability to eliminate toxic metabolic waste products. Under normal physiological conditions endothelial cells are dormant unless triggered to proliferate in localized parts of tissues. Many diseases are associated with the inappropriate proliferation of endothelial cells including arthritis, psoriasis, arteriosclerosis, diabetic retinopathy, and cancer.
In order for a tumor to grow beyond a few million cells, typically more than 1 or 2 mm
3
in volume, an increase in vascularization is required. Cells that are too distant from blood vessels cannot survive because of poor nutrient and oxygen supply. Clinically, tumors that are highly vascularized are the most metastatic and difficult to treat. It is also known that tumor cells produce and secrete the factors necessary for angiogenesis. It is widely held that agents inhibiting angiogenesis through direct competition with angiogenic factors, or by some other mechanism, would have a major clinical benefit in the treatment of many types of cancer and other diseases associated with inappropriate angiogenesis.
Many therapeutic agents are being targeted for development based on a variety of targeting strategies. One strategy is the use of natural inhibitors of angiogenesis such as angiostatin and endostatin. Another strategy is the use of agents that block the receptors required to stimulate angiogenesis, such as antagonists to the vitronectin receptor. Yet a third strategy is the inhibition of specific enzymes which allow new blood vessels to invade surrounding tissues, for example, inhibitors of matrix metalloproteinases.
Angiogenesis is an attractive therapeutic target for cancer treatment due to its selectivity of action. Blood vessels in growing tumors are rapidly proliferating and being replaced, whereas blood vessels in most normal tissues are static. This rapid turnover is believed to be the physiological difference that will allow the selective targeting of blood vessels in the tumor by anti-angiogenic agents. Anti-angiogenesis is also less likely to pose a drug resistance problem compared to conventional chemotherapeutics. Tumor cells are prone to mutations that render them resistant to standard chemotherapy. Since anti-angiogenic agents target normal but rapidly proliferating endothelial cells that are not genetically unstable, resistance to anti-angiogenic agents is not a major concern.
Anti-angiogenic therapy will likely be very effective at suppressing tumor growth by denying tumors a blood supply. However, anti-angiogenic therapy may prove more effective in combination with other therapies aimed directly at the tumor cells. Chemical agents that demonstrate both anti-angiogenic and tumor directed properties would obviously be greatly desired. There thus remains a need to develop a series of chemical agents that demonstrate anti-proliferative effects against human endothelial cells for the treatment of a variety of diseases including cancer, in addition to an inhibitory effect directly on cancer cells for the treatment of solid tumors.
The present invention seeks to meet these and other needs.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.
SUMMARY OF THE INVENTION
It has now been discovered that certain dibenzo[c]chromen-6-one derivatives have anti-proliferative abilities against both human endothelial cells and epithelial cancer cell lines and can be made as set forth herein.
The present invention relates to a series of chemical agents that demonstrate anti-proliferative effects against human endothelial cells for the treatment of a variety of diseases including cancer, in addition to an inhibitory effect directly on cancer cells for the treatment of solid tumors.
The present invention also relates to anti-cancer molecules that are derivatives of dibenzo[c]chromen-6-one.
As well, the present invention relates to a therapeutic composition of molecules useful in the treatment of cancer and other diseases, characterized by the undesired proliferation of endothelial or epithelial cells such as, but not limited to, pathological tissue growth, psoriasis, diabetic retinopathy, rheumatoid arthritis, hemangiomas, solid tumor formation and other malignancies.
In accordance with one embodiment of the present invention, there is provided a pharmaceutical composition, comprising a therapeutically effective amount of anti-cancer molecules specified herein. As used herein, the terms R
1
, R
2
, R
3
and R
4
refer to effective functional groups, whose location on the dibenzo[c]chromen-6-one backbone is illustrated below by Formula I:
wherein R
1
is one of, but not limited to the following: H, OH or OR
3
; wherein certain preferred substituents at R
2
are one of, but not limited to the following:
wherein certain preferred substituents at R
3
are one of, but not limited to the following: a lower alkyl chain ranging from 1 to 8 carbons; and wherein R
4
is selected from the group consisting of: hydrogen, hydroxy, methoxy, ethoxy and trifluoroethoxy.
In accordance with the present invention, there is therefore provided a compound of Formula I, or a pharmaceutically acceptable salt or ester thereof,
wherein R
1
represents a substituent selected from the group consisting of H, OH and OR
3
; wherein R
2
represents a substituent selected from the group consisting of
wherein R
3
is a C
1-8
lower alkyl chain and wherein R
4
is selected from the group consisting of: hydrogen, hydroxy, methoxy, ethoxy and trifluoroethoxy.
In accordance with the present invention, there is also provided a process for the preparation of
Lazarowych Natalie
Mercure Julie
Redden Peter
Schmidt Jonathan Martin
Whelan John
Fulbright & Jaworski L.L.P.
Nanodesign Inc.
Owens Amelia A.
LandOfFree
Dibenzo[c]chromen-6-one derivatives as anti-cancer... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Dibenzo[c]chromen-6-one derivatives as anti-cancer..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Dibenzo[c]chromen-6-one derivatives as anti-cancer... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3173639