Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1993-05-27
2003-06-10
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C514S533000
Reexamination Certificate
active
06576784
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new antiviral compounds and compositions and, more particularly, to compounds which are carboxylic ester analogs of hypericin. The invention also relates to methods of use of such compounds and compositions.
BACKGROUND OF THE INVENTION
Hypericin, a constituent of plants of the genus Hypericum, has been obtained in pure form from plants (Brockman et al.,
Annalen
553:1 (1942)), and has also been totally synthesized (Brockman et al.,
Chem. Ber
. 90:2480 (1957), U.S. Pat. No. 5,120,412, issued Jun. 9, 1992).
Hypericin has the following structure:
Hypericin, both from plant origin and prepared by synthesis, has been found to be a potent inhibitor of DNA and RNA containing enveloped viruses, and particularly of Human Immunodeficiency Virus (HIV), the presumed causative agent of AIDS and other conditions.
Meruelo et al.,
Proc. Natl. Acad. Sci. USA
85:5230 (1988) and U.S. Pat. No. 5,047,435 reported antiretroviral activity of hypericin and pseudohypericin in vitro and in vivo. The authors also reported that hypericin is able to inhibit HIV from infecting individual cells. U.S. Pat. No. 4,898,891, issued Feb. 6, 1990, discloses antiviral pharmaceutical compositions containing hypericin and pseudohypericin, as well as methods for using these compositions to treat viral infections.
U.S. Pat. No. 5,149,718, describes pharmaceutical formulations and methods for inactivating DNA and RNA viruses present in blood and other body fluids, more generally biological fluids. The pharmaceutical formulations include compounds structurally related to hypericin whose synthesis has been previously described in the literature.
PCT patent publication WO 90-10438 describes many compounds, many of which are analogs of hypericin, which also have antiviral activity. None of the hypericin analogs specifically disclosed therein were carboxylic acid or carboxylic acid ester analogs of hypericin in which one or both of the two methyl groups of hypericin were replaced by carboxylic acid or ester groups.
On the other hand, it has been described (G. Lavie et al,
J.N.Y. Acad. Sci
. 616:556, 1990) that a number of compounds related to hypericin possess very weak antiviral activity. These compounds include, among others, a dicarboxylic acid analog of hypericin whose two methyl groups were replaced by two carboxylic groups, and an octahydroxy analog of hypericin, whose two methyl groups are replaced by two hydroxyl groups. This publication demonstrates that not all compounds related to hypericin are active.
Thus, it is an object of the present invention to prepare other hypericin derivatives with enhanced antiviral and antiretroviral activity, and also to define the physical properties required for the above activity.
SUMMARY OF THE INVENTION
The present invention relates to novel compounds possessing naphthodianthrone skeletons whose structures are related to the structure of hypericin, in which one or both of the two methyl groups are replaced by carboxy ester groups. The present invention relates also to pharmaceutical compositions containing such compounds, and antiviral and antiretroviral methods of use thereof in significantly reducing or completely eliminating the infectivity of a virus or retrovirus that may be present in whole blood or other biological fluids, in vivo or in vitro.
It has now been discovered that certain compounds, structurally related to hypericin, are useful for the treatment and prevention of infections caused by viruses or retroviruses, and that some properties of the ester analogs may have advantages over those of hypericin. All of these new compounds bind to liposomes and produce singlet oxygen in the presence of visible light when bound to liposomes.
One aspect of the present invention comprises a method for preventing or treating a viral or retroviral infection in a mammal, comprising administering to such a mammal an effective amount of a compound selected from the group consisting of the hypericin analogs of the present invention, and mixtures thereof, wherein said compounds or mixtures are used as the sole antivirally- or antiretrovirally-active ingredients, or in conjunction with other antiviral or antiretroviral agents.
Another aspect of the present invention relates to a method for significantly reducing or completely eliminating the infectivitiy of a virus present in a retaining means for retaining a biological fluid by contacting the retaining means with an effective amount of at least one antiviral compound in accordance with the present invention.
The invention also relates to a method for significantly reducing or completely eliminating the infectivity of any virus or retrovirus which may be present on a non-biological surface after such surface has come into contact with a biological fluid contaminated with a virus or retrovirus by contacting such surface with an effective amount of at least one antiviral compound in accordance with the present invention.
The invention further relates to a method for treating a surface intended to come into contact with a biological fluid which may be infected with a virus or retrovirus in order to significantly reduce or completely eliminate the infectivity of any such virus or retrovirus which comes into contact with such surface by placing onto such surface an effective amount of at least one antiviral compound in accordance with the present invention.
Yet another aspect of the present invention comprises pharmaceutical compositions and formulations for treating or preventing viral or retroviral infections in mammals, such compositions and formulations comprising an effective amount of antiviral or antiretroviral agent, selected from the group consisting of the hypericin analogs of the present invention, and mixtures thereof, and a pharmaceutically acceptable carrier or diluent.
A further aspect of the present invention relates to an article of manufacture comprising a container for holding a biological fluid which may be contaminated with a virus and an effective amount for inactivating such virus of at least one antiviral compound in accordance with the present invention. The container for holding a biological fluid may be a blood bag, a blood vacuum storage tube, a condom, a test tube, a urine cup, etc. Indeed, any means for retaining such a biological fluid may be used. In fact any surface intended to come into contact with a biological fluid which may be contaminated with a virus or retrovirus may have an effective amount for inactivating such a virus or retrovirus of at least one antiviral compound in accordance with the present invention, such compound being present on the surface to contact the biological fluid no later than when such fluid contacts such surface.
Finally, yet another aspect of the present invention is a composition of matter including a spermicidal agent or a vaginal lubricating agent, in combination with an effective amount of at least one compound in accordance with the present invention. Any biological fluid treated with an antiviral effective amount of at least one compound in accordance with the present invention is also considered to be an aspect of the present invention.
These and other aspects of the present invention will be better understood by consideration of the following detailed description of the preferred embodiments.
REFERENCES:
patent: 9010438 (1990-09-01), None
patent: 9308797 (1993-05-01), None
patent: WO 93/08797 (1993-05-01), None
Banks, H. J et al Aust. J. Chem. 29(7) 1509-21 1976.
Lavie David
Lavie Gad
Mazur Yehuda
Meruelo Daniel
Browdy and Neimark , P.L.L.C.
Killos Paul J.
Yeda Research and Development Co. Ltd.
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