Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-09-14
2001-08-21
Berch, Mark L (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S578000
Reexamination Certificate
active
06277844
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds used in the treatment of cancer. More specifically, the present invention relates to a class of benzazepines which can be used for the treatment of cancers, including breast, prostate and glial cell cancer.
BACKGROUND OF THE INVENTION
Cancer is the second leading cause of death in the United States. In 1998, 564,800 Americans are expected to die of cancer (American Cancer Society). The National Cancer Institute estimates overall annual costs for cancer to be $107 billion. Thirty-seven billion dollars per year is spent in direct medical costs, with over half of the direct medical costs directly related to treatment of breast, lung, and prostate cancers.
Breast cancer is the second leading cause of cancer death in women, and the leading cause of cancer death among women age 40 to 55. In 1998, about 43,900 people (both men and women) are expected to die from breast cancer.
Chemotherapy is a common treatment for breast cancer, and a combination of anticancer drugs has proven more effective than a single drug. The effects of most chemotherapeutic agents are most profound on rapidly growing cells, such as cancer cells, although few agents have been found that exhibit a selective toxicity to cancer cells alone. The commonly known side effects of chemotherapy arise due to the cytotoxic effects of chemotherapeutic agents on normal cells.
The most commonly used chemotherapy combinations are cyclophosphamide, methotrexate, and fluorouracil (CMF) and cyclophosphamide, doxorubicin (Adriamycin), and fluorouracil (CAF). Recent data suggests that paclitaxel may also be useful for breast cancer treatment. Chemotherapy usually lasts three to six months and is given in cycles, with each period of treatment followed by a recovery period. The side effects of chemotherapy depend on the type of drugs, the amount taken, and the length of treatment. Typical side effects may include nausea and vomiting, loss of appetite, loss of hair, mouth sores, and changes in the menstrual cycle. Because chemotherapy can damage the blood-producing cells of the bone marrow, patients may have low blood cell counts, which can result in an increased chance of infection (due to a shortage of white blood cells), bleeding or bruising after minor cuts or injuries (due to a shortage of blood platelets), and fatigue (due to low red blood cell counts). Potential permanent complications of chemotherapy, particularly in older women, include premature menopause and infertility. Premature menopause may contribute to the development of osteoporosis and coronary artery disease, due to failure of the ovaries to produce estrogen. Adriamycin (doxorubicin) may cause permanent heart damage, so the dose of this drug must be carefully controlled. Very rarely, certain chemotherapeutic drugs may cause acute myeloid leukemia (AML) years after treatment.
Radiation therapy may be used to reduce the size of a tumor before surgery or to destroy cancer cells remaining in the breast, chest wall, or underarm area after surgery. The main side effects of radiation therapy are swelling and heaviness in the breast, sunburn-like skin changes in the treated area and possibly fatigue, but these changes to the breast tissue and skin usually go away in 6-12 months.
Another approach to treating breast cancer is to block the effect of estrogen or lower estrogen levels, often by the antiestrogen drug tamoxifen (Nolvadex). It is taken daily in pill form, for at least two years and usually for five years. Some studies have shown a slight increase of early stage endometrial cancer among women taking tamoxifen, with the risk increasing if the drug is taken for more than five years.
Megestrone (megace) is another drug used for hormonal treatment of advanced breast cancer, usually for women whose cancers do not respond to tamoxifen. Progestins (produced in the ovaries) or androgens (male hormones) also may used to treat advanced breast cancer. Side effects include fluid retention (progestin) and development of masculine characteristics (androgens).
Oophorectomy (surgery to remove the ovaries) may be used in pre-menopausal women to eliminate the body's main source of estrogen.
Prostate cancer is the second leading cause of cancer death in men. In 1998, 39,200 men are expected to die of prostate cancer in the United States. Recent advances in prostate cancer research include the discovery of a gene linked to prostate cancer, HPC1.
Treatment for prostate cancer follows a similar course to that taken in the treatment of breast cancer. Chemotherapy and hormone therapy figure prominently in the therapy regimen.
Chemotherapy, although helpful for decreasing the number of cancerous cells, has proven to be less satisfactory at producing remission from cancer than had been anticipated. The side effects of chemotherapy have made long-term treatment an unpleasant and harmful alternative. Furthermore, drug resistance to chemotherapeutic agents is common. A safe, effective chemotherapeutic agent, particularly one which could be combined with the chemotherapeutic agents presently available, would increase effectiveness of chemotherapy, while decreasing treatment time and decreasing the potential for the development of serious side effects.
SUMMARY OF THE INVENTION
The present invention relates to a novel class of benzazepine, exemplified by 2-amino-9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine (BBL22), and a method of using these compounds for the treatment of cancer, particularly breast and prostate cancer.
The present invention provides benzazepine compounds of formula (I)
wherein:
R1 is an amino or an alkyl group, optionally substituted with at least one C1-C6 alkyl group;
R2 is H or halogen;
R3 is H, halogen, hydroxyl group, or alkyl group;
R4 is H or halogen;
R5 is halogen;
and salts thereof. In certain embodiments, R5 is fluorine. In certain embodiments, R1 is an amino group. In certain embodiments, R2 is fluorine. In certain embodiments, R5 is chlorine. In a preferred embodiment, R1 is an amino group, R2 is fluorine, and R5 is chlorine.
In the method of the present invention, BBL22 is administered parenterally, orally, topically, intravenously, or by other means to inhibit growth of cancer cells.
BBL22 and related compounds can be used to selectively arrest cancer cells in G2/M phase. BBL22 can therefore be used to selectively inhibit cancer cell growth for the treatment of cancer.
BBL22, or analogs thereof, are administered either as an independent chemotherapy or in combination with other chemotherapeutic agents to reduce tumor size and eradicate cancerous cells. BBL22, or analogs thereof, can also be administered in conjunction with single-dose or fractionated radiotherapy for the treatment of solid tumors.
BBL22 can be used to decrease cellular levels of Bcl-2. The effect of BBL22 on Bcl-2 levels has important therapeutic and research uses. BBL22 and functionally related compounds can be used to decrease Bcl-2 levels to investigate cell cycle control mechanisms. BBL22 and functionally related compounds can be used to decrease Bcl-2 levels to reduce drug resistance to other chemotherapeutic agents. Furthermore, BBL22 can be used in conjunction with other chemotherapeutic agents to inhibit cancer cell growth for the treatment of cancer.
BBL22 can be used for the purpose of screening other pharmaceutical agents for therapeutic effect in the treatment of cancer. Use of labeled BBL22 in competitive binding assays provides a method for high-throughput screening of compound libraries for target compounds with similar activity to that demonstrated for BBL22.
BBL22 can also be used for prevention of cancer, particularly in individuals who are determined to have an increased risk, due to genetic of environmental factors, for the development of cancer.
REFERENCES:
patent: 3516988 (1970-06-01), Schmitt
patent: 3965151 (1976-06-01), Derieg
patent: 3996209 (1976-12-01), Chase
patent: 3997591 (1976-12-01), Derieg
patent: 4316829 (1982-02-01), Gerecke
patent: 4377522 (1983-03-01
Spector Neil L.
Spector Sydney
Berch Mark L
McCarthy Michael J.
McKenzie Thomas
Myers, Jr. Richard S.
Waddey & Patterson
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