Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1996-12-18
2001-03-06
Fay, Zohreh (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
06197806
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to agents for eliminating active oxygen and free radicals containing a hydantoin derivative or a pharmaceutically acceptable salt thereof as an effective component. The reduction and elimination of free radicals and activated oxygen in living organisms and the treatment and prevention of a variety of diseases or conditions in which active oxygen and free radicals play a role are also provided by the present invention.
BACKGROUND OF THE INVENTION
Strong concern has been given in recent years to damage of molecules, membranes and tissues of living organisms by free radicals or by active oxygen and also to various diseases caused by such damage. Free radicals are chemical species having unpaired electrons and they are unstable and highly reactive. Activated oxygen species include superoxides, the hydroxyl radical, hydrogen peroxide and singlet oxygen. The superoxides and hydroxyl radical are radical species and, particularly, the hydroxyl radical has been known as a free radical having a very high reactivity. There are many target molecules in living organisms damaged by free radicals and active oxygen. Exemplary of such target molecules are lipids, nucleic acids, enzymes, proteins and sugars. Among these target molecules, highly unsaturated fatty acids, which are usually confined to lipids of cells, are especially apt to be attacked resulting in an oxidative degradation whereby lipid peroxides are produced. As a result of the production of lipid peroxides, cell membranes are damaged whereupon not only the membrane structure is destroyed but also enzymatic action and acceptor function of the proteins which are present and active there are greatly damaged. In addition, it has been known that the resulting lipid peroxides flow out from the topical region to blood causing a secondary pathology such as blood vessel pathology.
There have been many reports on the correlation of free radicals and active oxygen with diseases. The usefulness of substances having an ability to eliminate free radicals and active oxygen as pharmaceuticals has greatly attracted public attention. SOD (superoxide dismutase), which is a substance for eliminating the superoxides in living organisms, is a representative substance which eliminates free radicals and active oxygen and its development as a pharmaceutical agent is now under way. Therapeutic targets of SOD cover a wide variety of diseases including myocardial infarction, reperfusion disturbance, autoimmune diseases (such as collagen disease, Behçet disease and ulcerative colitis), fibrosis, pulmonary diseases (such as pulmonary edema and pulmonary fibrosis), dermatological diseases (such as burn injury, external wounds, keloid, hypersensitivity to sunlight and dermatitis), arthropathy, side effects of anticancer agents, radiation diseases, septic shock, inflammatory diseases and cataracts. See, for example, “Pathologic Biochemistry and Clinics of Free Radicals, Inflammation and Antiinflammation,”
Nippon Rinsho
, volume 46, number 10, pages 93-97 (1988).
SOD is a protein preparation which problematically exhibits a short half life period in blood and minimal incorporation into cells. Therefore, various investigations on techniques for manufacturing preparations containing it are now being conducted. Consequently, there has been a demand for a novel agent for eliminating free radicals and active oxygen which can be easily made into pharmaceutical preparations and has little side effects.
Japanese Laid Open (Kokai) Nos. 61/122275 (published Jun. 10, 1986) and 62/14 (published Jan. 6, 1987) and their corresponding U.S. Pat. Nos. 4,647,574 and 4,683,240 each to Ienaga et al, respectively, disclose hydantoin derivatives and pharmaceutical compositions which contain them as having hypoglycemic, hypolipidemic and diuretic effects but do not disclose any eliminating action for free radicals or activated oxygen.
The present invention provides pharmaceutical compositions comprising pharmaceutically effective amounts of one or more hydantoin derivatives for eliminating free radicals and active oxygen which are readily produced, exhibit little or no side effects, and which may be administered orally. The compositions of the present invention may be used for the treatment and prevention of a variety of diseases or conditions in which active oxygen and free radicals play a role, such as myocardial infarction, reperfusion disturbance, autoimmune diseases, fibrosis, pulmonary diseases, dermatological diseases, arthropathy, side effects of anticancer agents, radiation diseases, septic shock, inflammatory diseases and cataracts.
SUMMARY OF THE INVENTION
The hydantoin derivatives and their pharmaceutically acceptable salts of the present invention exhibit substantial inhibitory action towards free radicals and active oxygen, such as superoxides, the hydroxyl radical, hydrogen peroxide and singlet oxygen, which can cause damage to molecules, membranes and tissues of living organisms. The derivatives and their salts at least substantially reduce or eliminate free radicals and active oxygen in living cells and organisms which can cause damage to target molecules such as lipids, highly unsaturated fatty acids, nuclei acids, enzymes, proteins, and sugars. The eliminating agents of the present invention include at least one hydantoin derivative represented by the general formula (I) or pharmaceutically acceptable salts of the derivatives represented by the general formula (I):
wherein each of R
1
and R
2
, which may be the same or different, is hydrogen, an alkyl group or a cycloalkyl group; and each of X and Y, which may be the same or different, is hydrogen, a hydroxyl group, an allyl group or an alkoxy group, or X and Y together represent an oxo group.
The present invention also provides pharmaceutical compositions containing at least one of the derivatives of formula (I) or at least one salt thereof in a pharmaceutically acceptable amount with a pharmaceutically acceptable carrier or diluent.
The compounds and pharmaceutical compositions of the present invention may be used in pharmaceutically effective amounts to prevent damage to target molecules and cells caused by free radicals and activated oxygen in animals and humans. In accordance with the methods of the present invention, hydantoin derivatives and their pharmaceutically acceptable salts may be used to treat and prevent diseases in which active oxygen or free radicals are involved such as myocardial infarction, reperfusion disturbance, autoimmune diseases, fibrosis, pulmonary diseases, dermatological diseases, arthropathy, side effects of anticancer agents, radiation diseases, septic shock, inflammatory diseases and cataracts. The hydantoin derivatives may be administered orally to patients in need of treatment in effective, anti-oxidative amounts with little, if any side effects, low toxicity, and high safety.
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Endou Hitoshi
Ienaga Kazuharu
Fay Zohreh
Hollander Law Firm, P.L.C.
Nippon Zoki Pharmaceutical Co. Ltd.
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