Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-06-12
2004-11-02
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...
C549S403000
Reexamination Certificate
active
06812246
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to novel 5-aminoflavone compounds, compositions, and methods of using these compounds as cytotoxic agents.
BACKGROUND OF THE INVENTION
Flavonoids, either natural or synthetic, have been recognized as exhibiting various biological activities. Such compounds, for example, may inhibit protein kinase C, aromatase, topoisomerase, or cyclin-dependent kinase activity or may exhibit antimitotic activity. In particular, 5,4′-diaminoflavones reportedly exhibit cytotoxicity against, for example, the human breast cancer cell line MCF-7. See Akama et al.,
J. Med. Chem.,
41, 2056-2067 (1998).
The mechanism of action and the target molecule of the 5,4′-diaminoflavone compounds remain largely unknown. Experiments incorporating various substituent groups at the 6, 7, 8, and 3′-positions on the flavone ring yielded some speculation as to the structure-activity relationship of the substituents, particularly at the 7-position of 5,4′-diamino-6,8,3′-trifluoroflavone. Although the real role of the various substituent groups remains unclear, it was demonstrated that certain physical properties of the parent flavone compound, such as solubility, could be improved by the presence of some, but not all, substituent groups at the 7-position. Some of the 7-substituted compounds also demonstrated cytotoxicity against human breast cancer cells. See Akama et al.,
J. Med. Chem., at
2061-62.
Despite the cytotoxicity of 5,4′-diamino-6,8,3′-trifluoroflavone against certain human cancer cells, the compound possesses poor solubility in organic solvents and hardly solubilizes in water. In fact, solubility data of 5,4′-diamino-6,8,3′-trifluoroflavone were found to be less than 0.2 &mgr;g/mL in water and 1.2 mg/mL in ethanol. See Akama et al.,
J. Med. Chem., at
2067.
Water solubility provides a critical advantage for a pharmaceutical compound, especially with respect to the formulation of the drug and oral absorption after administration. In most cases, the site of drug action is located in a region that is separated from the site of drug administration by a membrane. Drugs that are administered orally, intramuscularly, or subcutaneously must cross membranes to be absorbed and to enter the systemic circulation. Even drugs administered by intravenous injection must cross capillary membranes in order to leave the systemic circulation and enter intracellular and extracellular sites of action. See
Human Pharmacology
, Wingard et al., eds., St. Louis: Mosby-Year Book, Inc., 1991, pp. 50-51.
In this respect, most drugs must have an affinity for water in order to be transported-by blood and other body fluids to their sites of action. One solution to the low water solubility of an active ingredient is to compound the active ingredient with emulsifiers or complexing agents to prevent the drug from precipitating at the site of administration. See
Human Pharmacology
, pp. 50-51. Any manipulation of the active ingredient, however, in an attempt to improve a physical property should not detrimentally affect its biological activity. The use of emulsifiers and complexing agents, while an acceptable approach, may limit the modes of administering the drug and/or render the drug more difficult to use and store.
There remains a need, therefore, for novel 5-aminoflavone compounds and compositions which exhibit potent antitumor properties. There also remains a need for 5-aminoflavone compounds which have improved solubility in water and organic solvents. The present invention provides such compounds, compositions, and methods. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
BRIEF SUMMARY OF THE INVENTION
The invention provides trifluoroaminoflavone compounds which are substituted with amine-containing groups at the 5- and/or 4′-position on the flavone ring, and optionally substituted with an alkyl, hydroxyalkyl, alkanoyloxyalkyl, alkanoyloxy, alkoxy, or alkoxyalkyl at the 7-position of the flavone ring, or pharmaceutically acceptable salts thereof. The compounds of the present invention demonstrate desirable physical characteristics, such as solubility in aqueous solvents.
In addition to their desirable physical properties, the aminoflavone compounds of the present invention also exhibit anti-tumor activity against a variety of cancer cells.
The present invention also provides a pharmaceutical composition comprising an aminoflavone compound as defined generally above, and a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a method of inhibiting the growth of a tumor in a host by administering to the host a tumor growth-inhibiting amount of an aminoflavone compound as defined generally above. The host may be any mammal, including humans.
The invention may best be understood with reference to the accompanying drawings and in the following detailed description of the preferred embodiments.
REFERENCES:
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patent: 0 638 566 (1995-02-01), None
patent: 0 755 928 (1997-01-01), None
Phillips, L. R. et al, ‘Identification of the principal circulating metabolite of a synthetic 5,4′-diaminoflavone (NSC 686288), an antitumor agent, in the rat’ 133:68295 (2000).*
Akama et al.,J. Med. Chem., 41, 2056-2067 (1998).
Boyd et al.,Cytotoxic Anticancer Drugs: Models and Concepts for Drug Discovery and Development, Valeriote et al., eds., Amsterdam: Kluwer Academic Pulbishers, 11-34 (1990).
Boyd,Current Therapy in Oncology, ed. Niederhuber, Philadelphia: B.C. Decker, Inc., 11-22 (1993).
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Chabner and Collins,Cancer Chemotherapy: Principles and Practice, eds., J. B. Lippincott, Chapter 2 (1990).
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Grever and Chabner,Cancer: Principles and Practice of Oncology, 5th Ed., DeVita et al., eds, Philadelphia: Lippincott-Raven, 385-394 (1997).
Monks et al.,J. Natl. Cancer Inst., 83(11), 757-766 (1991).
Rubinstein et al.,J. Natl. Cancer Inst., 82(13), 1113-1118 (1990).
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Stinson et al.,Anticancer Res., 12, 1034-1035 (1992).
Weinstein et al.,Science, 275, 343-349 (1997).
Wingard et al.,Human Pharmacology, eds., St. Louis: Mosby-Year Book, Inc., 50-63 (1991).
Akama Tsutomu
Snader Kenneth M.
Vishnuvajjala B. Rao
Leydig , Voit & Mayer, Ltd.
Owens Amelia A.
The United States of America as represented by the Department of
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