Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-11-05
2001-10-23
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S467000
Reexamination Certificate
active
06306901
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a pharmaceutical agent containing an ascorbic acid and the like as an active ingredient, which is for the prophylaxis and/or treatment of diseases caused by unnecessary or pathogenic cells, a method for the prophylaxis and/or treatment of said diseases, and to use of an ascorbic acid and the like for the production of a pharmaceutical agent for the prophylaxis and/or treatment of said diseases.
BACKGROUND ART
With regard to the death of cells and tissues, apoptosis (active death of cells which is programmed in genes) has been drawing attention in recent years. Different from necrosis which is a pathological cell death, the apoptosis is considered to be the death incorporated from the first in the gene of the cell itself. That is, some external or internal factor triggers to activate the genes which program apoptosis, and apoptotic proteins biosynthesized by these genes or activation of existing apoptotic proteins cause active degeneration of the cells per se, thus resulting in cell death.
DISCLOSURE OF THE INVENTION
In view of the above situation, the present inventor has conducted intensive studies with the aim of developing a new pharmaceutical agent having an apoptosis inductive activity, and found that an ascorbic acid, a derivative thereof and a salt thereof (hereinafter also generally referred to as ascorbic acids) selectively induce apoptosis of unnecessary or pathogenic cells, and that they are useful for the prophylaxis and/or treatment of diseases caused by said cells, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following. 1. A pharmaceutical agent containing an ascorbic acid, a derivative thereof or a salt thereof as an active ingredient, for selectively inducing apoptosis of unnecessary or pathogenic cells to thereby prevent and/or treat diseases caused by said cells. 2. A method for the prophylaxis and/or treatment of diseases caused by unnecessary or pathogenic cells, comprising selectively inducing apoptosis of said cells by the use of an ascorbic acid, a derivative thereof or a salt thereof. 3. Use of an ascorbic acid, a derivative thereof or a salt thereof for the production of a pharmaceutical agent for selectively inducing apoptosis of unnecessary or pathogenic cells to thereby prevent and/or treat diseases caused by said cells.
The ascorbic acid to be used in the present invention is a known compound. The derivative thereof is exemplified by benzylidene-ascorbic acid. The benzylidene-ascorbic acid is also a known compound which is specifically exemplified by 5,6-O-benzylidene-L-ascorbic acid of the following formula, and the like. The method of preparation thereof is described in Steroids, 12, p. 309 (1968) and others.
Other derivatives of ascorbic acid include, for example, an acylated compound of hydroxy at the 6-position of ascorbic acid [Japanese Patent Unexamined Publication No.4103/1985 (WPI Acc, NO: 85-046633/08), Expl. Cell Biol., 54, p. 245(86), Vitamin, 61, p. 199(87) etc.], ethylidene compound, undecylidene compound [Japanese Patent Unexamined Publication No. 131978/1983 (=U.S. Pat. No. 4,552,888, GB 2114571)], benzylidene compound [Japanese Patent Unexamined Publication No. 313476/1989 (WPI Acc NO: 90-034400/05)], and the like, wherein the 5-position hydroxy and 6-position hydroxy are combined.
Specific examples thereof include 6-propionylascorbic acid, 6-octanoylascorbic acid, 6-palmitoylascorbic acid, 6-benzoylascorbic acid, 5,6-O-(1-methylethylidene)ascorbic acid, 5,6-O-(1-benzyl-2-phenylethylidene) ascorbic acid, 5,6-O-undecylidene-ascorbic acid, 5,6-O-p-nitrobenzylidene-ascorbic acid and the like. These derivatives can be prepared by the methods disclosed in the above-mentioned references.
Examples of the salts of ascorbic acid and derivatives thereof include pharmaceutically acceptable salts such as alkali metal salts (e.g., lithium, sodium and potassium); alkaline earth metal salts (e.g., calcium, magnesium and berillium); aluminum salts; organic salts (e.g., triethylamine and pyridine); and the like. These salts can be prepared by the methods disclosed in Japanese Patent Unexamined Publication No. 139619/1985 (=U.S. Pat. No. 5,036,103, EP 148094) and the like.
Inasmuch as the ascorbic acids to be used for the agent for the prophylaxis and therapy of diseases of the present invention are low toxic and selectively induce apoptosis of unnecessary or pathogenic cells, they are useful for the prophylaxis and/or treatment of the diseases caused by said cells. Specifically, they are useful as an anticancer drug and carcinostatic agent, as well as for the prophylaxis and/or treatment of many diseases caused by various viral infections. Particularly, since they selectively induce apoptosis of unnecessary or pathogenic cells, they are useful for the prophylaxis and/or treatment of HIV infections, and further for the prophylaxis and/or treatment of acquired immune deficiency syndrome (AIDS).
The agent for the prophylaxis and therapy of diseases of the present invention is provided as solid preparations, semi-solid preparations or liquid preparations in admixture with organic or inorganic carriers and/or excipients suitable for external, oral or local administration. The agent for the prophylaxis and therapy of diseases of the present invention is used to provide a suitable dosage form such as powders, granules, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, injections, syrups, external agents and the like, together with pharmacologically acceptable auxiliary ingredients.
Examples of such auxiliary ingredients include those effectively used for the production of solid, semi-solid or liquid preparations, such as water, glucose, lactose, gelatin, mannitol, starch paste, magnesium trisilicate, corn starch, keratin, colloidal silica, potato starch, urea and the like. Moreover, auxiliaries such as stabilizers, extenders, colorants and aromatic agents are also encompassed. For a retained activity of the ascorbic acids, a preservative may be added. The agent should contain a sufficient amount of the ascorbic acids to bring the desired therapeutic effects on the progress or symptom of the related diseases.
When the inventive agent for prophylaxis and therapy of diseases is administered to human, an effective amount of the ascorbic acids is preferably administered parenterally by, for example, injection, or orally administered. While the dose of the inventive agent for prophylaxis and therapy of diseases varies depending on sex, age, body weight, symptom, therapeutic effects, administration route, administration period and the like, it is typically about 100-3,000 mg/day to an adult patient.
The present invention is described in more detail by referring to Experimental Examples and Formulation Examples, which are not to be construed as limiting the invention.
REFERENCES:
patent: 5036103 (1991-07-01), Kochi
patent: 5130145 (1992-07-01), Oftebro et al.
patent: 5135948 (1992-08-01), Borretzen et al.
patent: WO9301817A1 (1993-02-01), None
patent: WO9535106A1 (1995-12-01), None
Academic Press dictionary of Science and Technology, 1995. Definitions of tumor, neoplasm, malignant, and pathogenic. (4 sheets printed).
“Benzylideneascorbate Induces Apoptosis in L929 Tumor Cells” by Tanuma et al, Biochemical and Biophysical Research Communications, vol. 194, No. 1, 1993, pp. 29-35.
“Effects of Sodium Benzylideneascorbate on Chemically-Induced Tumors in Rats” by Sakagami et al, Anticancer Research vol. 13, pp. 65-71 (1993).
Jariwalla et al., Nutr. AIDS, 117-39 (1994) (Abstract only).
Goldberg Jerome D.
Sughrue Mion Zinn Macpeak & Seas, PLLC
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