Use of a nitroxide or a prodrug thereof in the prophylactic and therapeutic treatment of cancer

Abstract

The present invention provides a method for the prophylactic and therapeutic treatment of cancer. The method comprises administering to an animal, preferably a mammal, more preferably a human, at risk for developing a cancer or having a cancer a nitroxide or a prodrug thereof, wherein the nitroxide or prodrug thereof preferably is alicyclic or heterocyclic and more preferably is a compound of Formula I or Formula II: in an amount sufficient to prevent or treat said cancer, wherein said cancer is susceptible to prevention or treatment by said nitroxide or prodrug thereof. Also provided is a composition for use in the method.

1 . A method for the prophylactic or therapeutic treatment of cancer in an animal, which method comprises administering to an animal at risk for developing a cancer or having a cancer a nitroxide or a prodrug thereof in an amount sufficient to prevent or treat said cancer, wherein said cancer is susceptible to prevention or treatment by said nitroxide or prodrug thereof.  
     
     
         2 . The method of  claim 1 , wherein said nitroxide or prodrug thereof is alicyclic or heterocyclic.  
     
     
         3 . The method of  claim 2 , wherein said nitroxide or prodrug thereof is a compound of Formula I or II:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of H, OH, OZ, O., ═O and Y, wherein Y is a leaving group, which can be converted to H, OH, O or ═O by reaction with a nucleophilic agent, and Z is selected from the group consisting of a C I 20  aliphatic group, a monocyclic aromatic group, a bicyclic aromatic group, a multicyclic aromatic group, a C 1-20  alicyclic group, a noncarbon/nonoxygen moiety, a carbohydrate, a lipid, a nucleic acid and a protein, wherein R 2 , R 3 , R 4  and R 5  are independently selected from the group consisting of a C 1-20  alkyl group, a C 2-20  alkenyl group, a C 2-20  alkynyl group, and —CH 2 —[CR′R″] m —CH 3 , wherein R′ is selected from the group consisting of hydrogen, a C 1-20  aliphatic group, a monocyclic aromatic group, a bicyclic aromatic group, and a multicyclic aromatic group, and R″ is selected from the group consisting of hydrogen, a C 1-20  aliphatic group, a monocyclic aromatic group, a bicyclic aromatic group, a multicyclic aromatic group, a C 1-20  alicyclic group, a noncarbon/nonoxygen moiety, a carbohydrate, a lipid, a nucleic acid, and a protein, m≦30, and R 2  and R 3  or R 4  and R 5  can be connected through one or more members, each of which is independently selected from the group consisting of carbon and a heteroatom, wherein R 6 , R 7 , R 8  and R 9  are independently selected from the group consisting of hydrogen, a hydroxyl group, a C 1-20  aldehydic group, a C 1-20  keto group, a primary amino group, a secondary amino group, a tertiary amino group, a sulfido group, a disulfido group, a sulfato group, a sulfito group, a sulfonato group, a sulfinato group, a sulfenato group, a sulfamato group, a metal-containing group, a silicone group, a halide, a C 1-20  ester-containing group, a carboxyl group, a phosphato group, a phosphino group, a phosphinato group, a phosphonato group, a C 1-20  alkyl group, a C 2-20  alkenyl group, a C 2-20  alkynyl group, and —CH 2 —[CR′R″] m —CH 3 , wherein R′ is selected from the group consisting of hydrogen, a C 1-20  aliphatic group, a monocyclic aromatic group, a bicyclic aromatic group, and a multicyclic aromatic group, and R″ is selected from the group consisting of hydrogen, a C 1-20  aliphatic group, a monocyclic aromatic group, a bicyclic aromatic group, a multicyclic aromatic group, a C 1-20  alicyclic group, a noncarbon/nonoxygen moiety, a carbohydrate, a lipid, a nucleic acid and a protein, and m≦30, and wherein any one of R 6 , R 7 , R 8  and R 9  can be attached covalently or noncovalently to a polymer of synthetic or natural origin, wherein in Formula I, one of R 6  and R 7  and one of R 8  and R 9  can be absent such that a double bond joins the two carbon atoms to which the remaining R groups are attached, wherein n=0-20 in Formula I, and n=1-20 in Formula II, wherein X is a heteroatom, and wherein R 10  and R 11  are independently selected from the group consisting of a C 1-20  aliphatic group, a monocyclic aromatic group, a bicyclic aromatic group, a multicyclic aromatic group, a C 1-20  aliphatic/aromatic group, a heteroatomic group, a C 1-20  ether-containing group, a C 1-20  keto group, a C 1-20  aldehydic group, a carboxamido group, a cyano group, an amino group, a carboxyl group, a selenium-containing group, a sulfato group, a sulfito group, a sulfenato group, a sulfinato group, and a sulfonato group, and wherein R 10  and R 11  can be connected through an aliphatic group and/or an aromatic group, or R 10  and/or R 11  can comprise a member selected from the group consisting of a carbohydrate, a lipid, a nucleic acid and a protein.  
     
     
         4 . The method of  claim 3 , wherein said aliphatic group is branched, substituted and/or unsaturated.  
     
     
         5 . The method of  claim 4 , wherein said aliphatic group is substituted with a member selected from the group consisting of oxygen, phosphorus, selenium, sulfur and nitrogen.  
     
     
         6 . The method of  claim 3 , wherein said aromatic group comprises a five- or six-membered ring, in which each of the five or six members is independently selected from the group consisting of carbon and a heteroatom.  
     
     
         7 . The method of  claim 6 , wherein said heteroatom is selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus and boron.  
     
     
         8 . The method of  claim 3 , wherein the metal of said metal-containing group is selected from the group consisting of a transition metal and a lanthanide.  
     
     
         9 . The method of  claim 6 , wherein said aromatic group is substituted.  
     
     
         10 . The method of  claim 9 , wherein said aromatic group is substituted with a heteroatom.  
     
     
         11 . The method of  claim 10 , wherein said heteroatom is selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus and boron.  
     
     
         12 . The method of  claim 3 , wherein said alicyclic group is substituted and/or unsaturated.  
     
     
         13 . The method of  claim 11 , wherein said alicyclic group is substituted with a heteroatom.  
     
     
         14 . The method of  claim 3 , wherein said amino group is substituted.  
     
     
         15 . The method of  claim 14 , wherein said amino group is substituted with up to three substituents selected from the group consisting of a C 1-20  aliphatic group, a monocyclic aromatic group, a bicyclic aromatic group, a multicyclic aromatic group, and a C 1-20  alicyclic group.  
     
     
         16 . The method of  claim 15 , wherein said aromatic group comprises a five- or six-membered ring, in which each of the five or six members is independently selected from the group consisting of carbon and a heteroatom.  
     
     
         17 . The method of  claim 16 , wherein said heteroatom is selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus and boron.  
     
     
         18 . The method of  claim 15 , wherein said aromatic group is substituted.  
     
     
         19 . The method of  claim 18 , wherein said aromatic group is substituted with a heteroatom.  
     
     
         20 . The method of  claim 19 , wherein said heteroatom is selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus and boron.  
     
     
         21 . The method of  claim 3 , wherein said noncarbon/nonoxygen moiety is selected from the group consisting of boron, sulfur, nitrogen and phosphorus.  
     
     
         22 . The method of  claim 1 , wherein said cancer is due to a genetic defect of a cancer regulatory gene or a tumor suppressor gene.  
     
     
         23 . The method of  claim 22 , wherein said tumor suppressor gene is the p53 gene.  
     
     
         24 . The method of  claim 2 , wherein said cancer is due to a genetic defect of a cancer regulatory gene or a tumor suppressor gene.  
     
     
         25 . The method of  claim 24 , wherein said tumor suppressor gene is the p53 gene.  
     
     
         26 . The method of  claim 3 , wherein said cancer is due to a genetic defect of a cancer regulatory gene or a tumor suppressor gene.  
     
     
         27 . The method of  claim 26 , wherein said tumor suppressor gene is the p53 gene.