Treatment of oxidative stress disorders including contrast nephropathy, radiation damage and disruptions in the function of red cells

Abstract

Methods of treating or suppressing oxidative stress diseases and symptoms related to oxidative stress affecting normal electron flow in the cells or caused by reactive oxygen species with redox-active therapeutics. Use of redox-active therapeutics for the reduction, suppression or treatment of oxidative stress induced by chemical agents such as contrast agents and other nephrotoxic agents, by radiation exposure, and by disruptions in the transport of oxygen to tissues, is disclosed.

1 . A method for reducing, preventing or treating an oxidative stress disorder in a mammal having or prone to having an oxidative stress disorder said method comprising administering to the mammal a therapeutically effective amount of a redox-active therapeutic, wherein the redox-active therapeutic is selected from the group consisting of:
 (a) compounds of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein,
 the bonds indicated with a dashed line are all single or all double, R 1 , R 2 , and R 3  are independently selected from the group consisting of H, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-haloalkyl, CN, F, Cl, Br, and I; and 
 R 4  and R 5  are independently selected from the group consisting of hydroxy and (C 1 -C 4 )-alkyl, and R 6  is hydrogen; or 
 R 4  is (C 1 -C 4 )-alkyl, and R 5  and R 6  are hydrogen; or 
 R 4  is (C 1 -C 4 )-alkyl, and R 5  and R 6  together form a double bond; 
 or a stereoisomer, or a mixture of stereoisomers thereof; 
 (b) compounds of Formula II: 
 
       
         
           
           
               
               
           
         
       
       wherein,
 R 21 , R 22 , and R 23  are independently selected from the group consisting of H, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-haloalkyl, CN, F, Cl, Br, and I:, 
 R 24  is independently selected from the group consisting of (C 1 -C 20 )-alkyl, (C 2 -C 20 )-alkenyl, (C 2 -C 20 )-alkynyl, and (C 4 -C 20 ) containing at least one double bond and at least one triple bond; 
 or a stereoisomer, or a mixture of stereoisomers thereof; and 
 (c) compounds of Formula V: 
 
       
         
           
           
               
               
           
         
       
       wherein,
 R 51 , R 52 , and R 53  are independently selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl; 
 R 54  is (C 1 -C 6 )-alkyl; 
 R 55  and R 56  are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, (C 1 -C 40 )-alkyl, (C 2 -C 40 )-alkenyl, (C 2 -C 40 )-alkenyl, and aryl; where the alkyl, alkenyl, alkenyl and aryl groups are optionally substituted with
 —OR 501 , —S(O) 0-2 R 501 , —CN, —F, —Cl, —Br, —I, —NR 501 R 502 , oxo, (C 3 -C 6 )-cycloalkyl, aryl, aryl (C 1 -C6)-alkyl, heteroaryl, heterocyclyl, —C(═O)—R 503 , —C(═O)—(C 0 -C 6 )-alkyl-aryl, —C(═O)—O-R 503 , —C(═O)—O—(C 0 -C 6 )-alkyl-aryl, —C(═O)—N—R 503 R 504 , —C(═O)—NH—(C 0 -C 6 )-alkyl-aryl, —NH—C(═O)—R 503 , —NH—C(═O)—(C 0 -C 6 )-alkyl-aryl; where the aryl, heteroaryl and heterocyclyl ring substituents may be further substituted with (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, oxo, hydroxy, (C 1 -C 6 )-alkoxy, —C(═O)—(C 1 -C 6 )-alkyl, or —C(═O)—O—(C 1 -C 6 )-alkyl; and where one of the carbons of the alkyl, alkenyl, or alkynyl groups is optionally replaced with a heteroatom selected from the group consisting of 0, N and S; or 
 
 R 55  and R 56  together with the nitrogen atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating one or more additional heteroatoms which are independently N, O, or S, and optionally substituted with oxo, —OR 501 , —SR 501 , —CN, —F, —Cl, —Br, —NR 501 R 502 , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, hydroxy-(C 1 -C 6 )-alkyl-, —C(═O)—H, —C(═O)—(C 1 -C 6 )-alkyl, —C(═O)-aryl, —C(═O)—OH, or —C(═O)—O—(C 1 -C 6 )-alkyl; 
 or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof; and 
 wherein the oxidative stress disorder induces renal damage in the mammal due to the administration, ingestion, absorption of, or exposure to a nephrotoxic agent or wherein the oxidative stress is induced by exposure to radiation; or wherein the oxidative stress disorder is selected from the group consisting of hemoglobinopathy, sickle cell anemia, and thalassemia. 
 
     
     
         2 - 6 . (canceled) 
     
     
         7 . The method according to  claim 1 , wherein the oxidative stress disorder induces renal damage in the mammal due to the administration, ingestion, absorption of, or exposure to a nephrotoxic agent. 
     
     
         8 . The method according to  claim 7 , wherein the nephrotoxic agent is a contrast agent. 
     
     
         9 . The method according to  claim 8 , wherein the nephrotoxic agent is an iodinated, brominated, barium-containing, or gadolinium-containing contrast agent. 
     
     
         10 . The method according to  claim 8 , where the nephrotoxic agent is selected from the group of a non-steroidal anti-inflammatory drug, cisplatin, methotrexate, acyclovir, gentamicin, and an ACE inhibitor. 
     
     
         11 . The method according to  claim 1 , where the oxidative stress is induced by exposure to radiation. 
     
     
         12 . The method according to  claim 11 , where the radiation is selected from the group consisting of diagnostic X-rays, radiation therapy in cancer treatment, CAT-scans, mammograms, radionuclide scans, interventional radiological procedures under computed tomography or fluoroscopy guidance, tissue-incorporated radionuclides from ingestion of contaminated food or water, and uncontrolled exposure to ionizing radiation from nuclear weapons, radioactive spills, or cosmic radiation. 
     
     
         13 . The method according to  claim 1 , for preventing death of radiation-injured or radiation-damaged non-cancerous cells, comprising administering to a mammal in need thereof, prior to an exposure to radiation, a therapeutically effective amount of the redox-active therapeutic. 
     
     
         14 . The method according to  claim 1 , for reducing an effect of radiation on normal cells in a mammal at risk for incurring exposure to radiation, comprising administering to the mammal prior to an exposure to radiation, a therapeutically effective amount of the redox-active therapeutic. 
     
     
         15 . The method according to  claim 1 , for reducing an effect of radiation on normal cells in a mammal exposed to ionizing radiation, comprising administering to the mammal subsequent to an accidental or intentional release of radioactive materials, a therapeutically effective amount of [[a]] the redox-active therapeutic. 
     
     
         16 . The method according to  claim 1 , for protecting non-cancerous cells against radiation therapy, comprising administering to the mammal prior to an exposure to radiation therapy, a therapeutically effective amount of the redox-active therapeutic. 
     
     
         17 . The method according to  claim 1 , where the method is an improved radiotherapy for treatment of cancer, comprising administering the mammal a therapeutically effective amount of the redox-active therapeutic, and then administering to the mammal an effective amount of radiation, such that radiation injury to normal cells is decreased or eliminated. 
     
     
         18 . The method according to  claim 1 , wherein the redox-active therapeutic comprises a compound of Formula I
 or a stereoisomer, or a mixture of stereoisomers thereof.   
     
     
         19 . The method according to  claim 18 , wherein the redox-active therapeutic comprises the compound of Formula I wherein,
 the bonds indicated with a dashed line are all single or all double;   R 1 , R 2 , and R 3  are independently selected from (C 1 -C 4 )-alkyl;   R 4  is hydroxy;   R 5  is (C 1 -C4)-alkyl, and   R 6  is hydrogen;   or a stereoisomer, or a mixture of stereoisomers thereof   
     
     
         20 . The method according to  claim 1 , wherein the redox-active therapeutic comprises a compound of Formula II
 or a stereoisomer, or a mixture of stereoisomers thereof.   
     
     
         21 - 22 . (canceled) 
     
     
         23 . The method according to  claim 1 , wherein the redox-active therapeutic comprises a compound of Formula V;
 or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof.   
     
     
         24 . (canceled) 
     
     
         25 . The method according to  claim 1 , wherein the redox-active therapeutic is alpha-tocopherol quinone. 
     
     
         26 . The method according to  claim 1 , wherein the redox-active therapeutic is alpha-tocotrienol quinone. 
     
     
         27 . The method according to  claim 1 , wherein the redox-active therapeutic is 2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide.