Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-14
2002-11-19
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06482828
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to quinazoline compounds, compositions and therapeutic methods for the treatment of cancers by administering quinazoline compounds.
BACKGROUND OF THE INVENTION
Currently, there is a need for methods useful for preventing the development or recurrence of cancer in mammals. Quinazoline compounds have been suggested as useful compounds in the treatment of cell growth and differentiation characterized by activity of the human epidermal growth factor receptor type2 (HER2). See, for example, Myers et.al., U.S. Pat. No. 5,721,237. Some quinazoline derivatives have been suggested as useful as anti-cancer agents for the treatment of specific receptor tyrosine kinase-expressing cancers, especially those expressing epithelial growth factor (EGF) receptor tyrosine kinase. See, for example, Barker et. al., U.S. Pat. No. 5,457,105. It is generally taught that quinazolines exert their anti-tumor effects via tyrosine kinase inhibition. However, while some quinazoline compounds inhibit the growth of tumor cells, such as brain tumor cells, others with equally potent tyrosine kinase inhibitory activity fail to do so (Naria et.al., 1998
, Clin. Cancer Res.
4:1405-1414; Naria et.al., 1998
, Clin. Cancer Res.
4:2463-2471).
Some quinazoline derivatives have also been suggested as useful agents for treating precancerous legions and inhibiting the growth of neoplastic cells. See for example, Pamukeu et al., U.S. Pat. Nos. 5,990,117; 6,037,345; and 6,046,206. Although many of the disclosed quinazoline derivatives are useful for treating precancerous legions and inhibiting the growth of neoplastic cells, there still exists the need to discover better compounds for the treatment of cancer, in particular colorectal cancer.
Cancer of the colon and/or rectum is now the third most common cause of death from cancer in the United States. Over 150,000 new cases of colon and/or rectal cancer are diagnosed each year. In addition, the incidence of colon cancer reportedly increases with age, particularly after the age of 40. Since the mean ages of populations in America and Western Europe are increasing, the prevalence of colorectal cancer should increase in the future.
To date, the only effective cure for colorectal cancer is surgery at an extremely early stage. Unfortunately, most cases of colorectal cancer are discovered too late for surgical cure. In many cases, the patient does not experience symptoms until the cancer has progressed to a malignant stage. The search for drugs useful for treating and preventing colorectal cancer continues.
What is needed in the art is a useful therapeutic agent for the treatment of colorectal cancer.
SUMMARY OF THE INVENTION
It has been discovered that 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline is effective as a therapeutic agent for the treatment of colorectal cancer. The present invention demonstrates the improved chemopreventive activity of 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline compared to known therapeutic agents.
The present invention provides a method of preventing the development or recurrence of colorectal cancer in a mammal comprising administering to the mammal, an effective cancer preventative amount of 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, or a pharmaceutically acceptable salt thereof.
The present invention also provides the use of 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, or a pharmaceutically acceptable salt thereof, to prepare a medicament useful for preventing the development or recurrence of colorectal cancer in a mammal.
These and other features and advantages of the present invention will become apparent after a review of the following detailed description of the disclosed embodiments and the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
It has been discovered unexpectedly that 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline possesses increased activity against colorectal cancer. As such, 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline is particularly useful as an active agent for anticancer compositions and for methods of treating cancers, such as colorectal cancer.
Definitions
A number of terms are used throughout the present disclosure. Some of these terms are defined as shown below.
All scientific and technical terms used in this application have meanings commonly used in the art unless otherwise specified. As used in this application, the following words or phrases have the meanings specified.
As used herein, “pharmaceutically acceptable carrier” means any material which, when combined with 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, allows 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline to retain biological activity, such as the ability to potentiate antibacterial activity of mast cells and macrophages. Examples include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsions, and various types of wetting agents. Compositions comprising such carriers are formulated by well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, Chapter 43, 14th Ed., Mack Publishing Co., Easton, Pa.).
The term “conjugate” means a compound formed as a composite between two or more molecules. More specifically, in the present invention, 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline is bonded, for example, covalently bonded, to cell-specific targeting moieties forming a conjugate compound for efficient and specific delivery of 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline to a cell of interest.
The phrase “targeting moiety” means a molecule, which serves to deliver 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline to a specific site for the desired activity. Targeting moieties include, for example, molecules that specifically bind molecules on a specific cell surface. Such targeting moieties useful in the present invention include anti-cell surface antigen antibodies. Cytokines, including interleukins and factors such as granulocyte/macrophage stimulating factor (GMCSF) are also specific targeting moieties, known to bind to specific cells expressing high levels of their receptors.
The term “prodrug moiety” is a substitution group, which facilitates use of 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, for example by facilitating entry of 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline into cells or administration of 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline. The prodrug moiety may be cleaved from 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, for example by cleavage enzymes in vivo. Examples of prodrug moieties include phosphate groups, peptide linkers, and sugars, which moieties can be hydrolyzed in vivo.
As used herein, “inhibit” means to reduce by a measurable amount, or to prevent entirely.
As used herein, “to treat” means to inhibit or block at least one symptom that characterizes a pathologic condition, in a mammal threatened by, or afflicted with, the condition.
Compounds for Use in the Present Invention
Compounds for use in the present invention include 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, or pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline may include organic acid addition salts formed with acids, which form a physiological acceptable anion, including, but not limited to, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, and a-glycerophosphate. Suitable inorganic salts may also be formed, including, but not limited to, hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
Acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
Synthesis of 4-(
Henley III Raymond
Parker Hughes Institute
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