Compounds, Compositions and Methods for Treating Oxidative DNA Damage Disorders

Abstract

Compounds, compositions, and formulations, and accompanying methods useful for treating disorders arising from oxidative damage, including oxidative DNA damage resulting from ionizing radiation or other therapy are described.

What is claimed is: 
     
         1 .- 48 . (canceled) 
     
     
         49 . A method for treating cancer in a host animal, the method comprising a) administering to the host animal a cancer therapy and b) administering to the host animal a therapeutically effective amount of a compound of the formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof comprising one or more carriers, diluents, or excipients, or a combination thereof, wherein:
 R A  represents two substituents each independently hydrogen or alkoxy, where R A  are not both hydrogen; or 
 R A  represents a fused aryl ring that is optionally substituted; 
 R is selected from the group consisting of hydrogen, halo, alkyl, heteroalkyl cycloalkyl, cycloheteroalkyl, alkoxy, heteroalkoxy cycloalkoxy, cycloheteroalkoxy, alkylthio, heteroalkylthio cycloalkylthio, and cycloheteroalkylthio, each of which is optionally substituted; 
 X is selected from the group consisting of alkylene, alkenylene, and alkynylene, each of which is optionally substituted; and 
 Y forms a carboxylic acid, ester, or amide. 
 
     
     
         50 . The method of  claim 49 , wherein each R A  is alkoxy. 
     
     
         51 . The method of  claim 49 , wherein R is selected from the group consisting of halo, alkyl, alkoxy, alkylthio, and heteroalkyl, each of which is optionally substituted; 
     
     
         52 . The method of  claim 49 , wherein X is CHCR X , and R X  is C 1 -C 10  alkyl. 
     
     
         53 . The method of  claim 49 , wherein Y is N(R 1 ) 2  or NR 2 OR 2 , wherein each R 1  is independently selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, and cycloheteroalkyl, each of which is optionally substituted, or both R 1  are taken together with the attached nitrogen to form an optionally substituted heterocycle; and each R 2  is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, and cycloheteroalkyl, each of which is optionally substituted, or R 2  is a prodrug group, or both R 2  are taken together with the attached nitrogen and oxygen to form an optionally substituted heterocycle. 
     
     
         54 . The method of  claim 53 , wherein both R 1  are taken together with the attached nitrogen to form an optionally substituted heterocycle selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, pyrrolidinone, piperidinone, piperazinone, and morpholinone. 
     
     
         55 . The method of  claim 53 , wherein Y is NR 2 OR 2 , and each R 2  is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, and cycloheteroalkyl, each of which is optionally substituted, or R 2  is a prodrug group, or both R 2  are taken together with the attached nitrogen and oxygen to form an optionally substituted heterocycle. 
     
     
         56 . The method of  claim 53 , wherein at least one R 2  is hydrogen. 
     
     
         57 . The method of  claim 53 , wherein at least one R 2  is optionally substituted alkyl. 
     
     
         58 . The method of  claim 49 , wherein the cancer therapy causes neuronal damage and the neuronal damage is peripheral neuropathy, or in the central nervous system, or causes or aggravates cognitive dysfunction. 
     
     
         59 . The method of  claim 49 , wherein the cancer therapy is a drug or ionizing radiation. 
     
     
         60 . The method of  claim 49 , wherein the cancer therapy causes neuronal damage and the compound of the formula (I) treats the neuronal damage. 
     
     
         61 . The method of  claim 60 , wherein the cancer therapy is a drug or ionizing radiation. 
     
     
         62 . The method of  claim 61 , wherein the drug is a platinum-containing drug or a taxane. 
     
     
         63 . The method of  claim 62 , wherein the drug is a cisplatin. 
     
     
         64 . The method of  claim 60 , wherein the cancer therapy is ionizing radiation. 
     
     
         65 . The method of  claim 49 , wherein the compound of the formula (I) is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         66 . A method for treating cancer in a host animal, the method comprising a) administering to the host animal a therapeutically effective amount of cisplatin or ionizing radiation and b) administering to the host animal a therapeutically effective amount of a compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof comprising one or more carriers, diluents, or excipients, or a combination thereof.