Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-12-17
2000-10-17
Powers, Fiona T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514422, 514432, 514443, 514469, 514546, 514731, 514733, 514734, 546 17, 548525, 549 13, 549 51, 549344, 549345, 549462, 560130, 560138, 568644, 568650, A61K 31085, A61K 3122, A61K 3134, A61K 3138, C07D30779
Patent
active
061332798
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to therapeutic agents for renal diseases or organ preservatives. More specifically, it relates to therapeutic agents, which contain a 2,6-di-t-butylphenol derivative as an active ingredient, for renal diseases such as chronic renal failure, diabetic nephropathy, glomerular nephritis, immunocomplex nephritis, acute renal failure, nephropathies caused by platinum complex-based anticancer agents such as cisplatin or other drugs such as gentamicin, nephropathies caused by agrichemicals such as Paracort, uremia, etc. or organ preservatives.
BACKGROUND ART
Kidney is one of organs involving potential oxidative stress in the living organism. The importance of radical injury caused by active oxygen species or free radicals has long been pointed out in the formation and progression of various renal diseases such as acute renal failure, drug-induced nephropathies, glomerular nephritis, diabetic nephropathy, chronic renal failure, and renal transplantation. In recent years, the role of lipids in cell injury has attracted particular attention (Keane W. F., Lipids and the kidney. Kidney Int., 46:910-920, 1994; Higuchi and Sanaka, "Renal Diseases", Antioxidants--Free radicals and biological defense (Niki, Shimazaki and Mino, eds.) Gakkai Shuppan Center, 223-229, 1994; Aoyagi "Therapy with Antioxidants/Scavenger, No. 3, Renal Diseases", Biomedicine & Therapeutics, 26:592-596, 1992). However, the effect of antioxidants, particularly inhibitors against lipid peroxidation has not been well explained on renal diseases, and no useful compound that inhibits the lipid peroxidation has been reported as a therapeutic or preventive agent or organ preservative.
Vitamin E (.alpha.-tocopherol) is a natural potent inhibitor against lipid peroxidation and its use in renal transplantation and renal ischemic models has been reported (Marubayashi, Dohi and Kawasaki "Renal maintenance and active oxygen species", Kidney and Dialysis, 24:785-790, 1988; Takenaka M., Tatsukawa Y., Dohi K., Ezaki H., Matsukawa K., Kawasaki T., Transplantation, 32:137-141, 1981), but its effect is not sufficient. This is because it acts on only the surfaces of membranes and lipid and can not show inhibitory effect against lipid peroxidation in the deep inside of membranes and lipids (Niki E., Chem. Phys. Lipids, 44:227-253, 1987). Because Vitamin E endogenously exists in a significant amount (Nakamura "Absorption, Distribution and Excretion of Vitamin E", Vitamin E--Basic and Clinical Study (Igarashi, eds.), Ishiyaku Shuppan, 33-58, 1985), the endogenous Vitamin E is expected to have an inhibitory effect against lipid peroxidation near the surfaces of membranes and lipid. On the other hand, an insufficient protection mechanism against lipid peroxidation exists in the deep inside of membranes and lipids and, therefore, the inhibition of lipid peroxidation in the deep inside of membranes and lipids seems to be important for treatment and prevention of renal diseases. Additionally, the effects of probucol, one of lipid-soluble antioxidants, have been reported on various renal disease models (Modi K. S., Schreiner G. F., Purkerson M. L., J. Lab. Clin. Med., 120:310-317, 1992; Bird J. E., Milhoan K., Wilson C. B., Young S. G., Mundy C. A., Parthasarathy S., Blantz R. C., J. Clin. Invest., 81:1630-1638, 1988; Hirano T., Mamo J. C. L., Nagano S., Sugisaki T., Nephron, 58:95-100, 1991). However, the simple phenolic compounds such as probucol and butylated hydroxytoluene have a 10 or 100 fold lower reactivity with lipid peroxyl radicals than .alpha.-tocopherol (Gotoh N., Shimizu K., Komuro E., Tsuchiya J., Noguchi N., Niki E., Biochem. Biophys. Acta, 1128:147-154, 1992; Burton G. W., Ingold K. U., J. Am. Chem. Soc., 103:6472-6477, 1981). Thus, probucol has not shown sufficient protective effect for renal functions.
Thus, a potent cytoprotective agent that inhibits the lipid peroxidation hardly inhibited by Vitamin E is expected to be effective for the prevention and treatment of various renal diseases and preservati
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Cynshi Osamu
Ishikawa Akira
Kato Yoshiaki
Takashima Yoshiaki
Tamura Kunio
Chugai Seiyaku Kabushiki Kaisha
Powers Fiona T.
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