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.

What is claimed is: 
     
         1 . A method for preventing or treating neuronal damage in a host animal, the method comprising the step of 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, wherein:
 R A  represents two substituents each independently selected from hydrogen, alkoxy, where R A  are not both hydrogen; or 
 R A  represents a fused aryl ring that is optionally substituted; 
 R is hydrogen or halo, or alkyl, heteroalkyl cycloalkyl, cycloheteroalkyl, alkoxy, heteroalkoxy cycloalkoxy, cycloheteroalkoxy, alkylthio, heteroalkylthio cycloalkylthio, or cycloheteroalkylthio, each of which is optionally substituted; 
 X is alkylene, alkenylene, or alkynylene, each of which is optionally substituted; and 
 Y forms a carboxylic acid, ester, or amide. 
 
       
     
     
         2 . The method of  claim 1  wherein each R A  is alkoxy. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1  wherein R A  represents optionally substituted benzo. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1  wherein R is halo, or alkyl, alkoxy, alkylthio, or heteroalkyl each of which is optionally substituted; 
     
     
         7 .- 11 . (canceled) 
     
     
         12 . The method of  claim 1  wherein X is optionally substituted alkylene. 
     
     
         13 . The method of  claim 1  wherein X is an epoxy alkylene. 
     
     
         14 . The method of  claim 1  wherein X is optionally substituted alkenylene. 
     
     
         15 .- 16 . (canceled) 
     
     
         17 . The method of  claim 1  wherein X is CHCR X , and R X  is C 1 -C 10  alkyl. 
     
     
         18 .- 22 . (canceled) 
     
     
         23 . The method of  claim 1  wherein Y forms an ester. 
     
     
         24 .- 25 . (canceled) 
     
     
         26 . The method of  claim 1  wherein Y is N(R 1 ) 2  or NR 2 OR 2 , where 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; where each R 2  is independently selected from the group consisting of hydrogen, alkyl heteroalkyl, cycloalkyl, and cycloheteroalkyl, each of which is optionally substituted, and a prodrug group, or both R 2  are taken together with the attached nitrogen and oxygen to form an optionally substituted heterocycle. 
     
     
         27 . The method of  claim 1  wherein one R 1  is optionally substituted alkyl. 
     
     
         28 . (canceled) 
     
     
         29 . The method of  claim 1  wherein each R 1  is optionally substituted alkyl. 
     
     
         30 .- 32 . (canceled) 
     
     
         33 . The method of  claim 1  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. 
     
     
         34 . (canceled) 
     
     
         35 . The method of  claim 1  wherein Y is NR 2 OR 2 , where each R 2  is independently selected from the group consisting of hydrogen, alkyl heteroalkyl, cycloalkyl, and cycloheteroalkyl, each of which is optionally substituted, and a prodrug group, or both R 2  are taken together with the attached nitrogen and oxygen to form an optionally substituted heterocycle. 
     
     
         36 . The method of  claim 1  wherein at least one R 2  is hydrogen. 
     
     
         37 . The method of  claim 1  wherein at least one R 2  is optionally substituted alkyl. 
     
     
         38 .- 39 . (canceled) 
     
     
         40 . The method of  claim 1  wherein both R 2  are taken together with the attached nitrogen and oxygen to form an optionally substituted heterocycle selected from the group consisting of oxazolidine, oxazine, oxazapine, oxazolidinone, oxazinone, and oxazapinone. 
     
     
         41 . The method of  claim 1  wherein the neuronal damage is peripheral neuropathy, or in the central nervous system, or causes or aggravates cognitive dysfunction. 
     
     
         42 .- 43 . (canceled) 
     
     
         44 . The method of  claim 1  wherein the neuronal damage results at least in part from a disease therapy selected from the group consisting of ionizing radiation, cancer therapy, or a combination thereof. 
     
     
         45 .- 46 . (canceled) 
     
     
         47 . A method for preventing or treating a disease mediated by iCGRP release inhibition, the method comprising the step of administering a therapeutically effective amount of the compound of  claim 1 , or a pharmaceutical composition thereof optionally further comprising one or more carriers, diluents, or excipients, or a combination thereof. 
     
     
         48 . (canceled)