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, Beh.cedilla.et 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.