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 DNA damage, including oxidative DNA damage resulting from ionizing radiation or other therapy are described herein.

1 .- 60 . (canceled) 
     
     
         61 . A method for treating neuronal toxicity in a host animal, the method comprising a) 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; 
         wherein the host animal comprises neuronal cells; and 
         wherein the compound of formula (I) increases the viability of the neuronal cells that have been exposed to the chemotoxicity. 
       
     
     
         62 . The method of  claim 61 , wherein each R A  is alkoxy. 
     
     
         63 . The method of  claim 61 , wherein R is selected from the group consisting of halo, alkyl, alkoxy, alkylthio, and heteroalkyl, each of which is optionally substituted. 
     
     
         64 . The method of  claim 61 , wherein X is CHCR X , and R X  is C 1 -C 10  alkyl. 
     
     
         65 . The method of  claim 61 , 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. 
     
     
         66 . The method of  claim 65 , 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. 
     
     
         67 . The method of  claim 65 , 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. 
     
     
         68 . The method of  claim 65 , wherein at least one R 2  is hydrogen. 
     
     
         69 . The method of  claim 65 , wherein at least one R 2  is optionally substituted alkyl. 
     
     
         70 . The method of  claim 61 , wherein the compound of the formula (I) is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         71 . A method for reducing ion radiation-induced toxicity in a host animal being treated for cancer, the method comprising a) administering to the host animal ionizing radiation 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; 
 wherein the host animal comprises neuronal cells; and 
 wherein the compound of formula (I) increases the viability of the neuronal cells; 
 that have been exposed to the ionizing radiation. 
 
     
     
         72 . The method of  claim 71 , wherein each R A  is alkoxy. 
     
     
         73 . The method of  claim 71 , wherein R is selected from the group consisting of halo, alkyl, alkoxy, alkylthio, and heteroalkyl, each of which is optionally substituted. 
     
     
         74 . The method of  claim 71 , wherein the compound of the formula (I) is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.