Small molecule inhibitors of superoxide dismutase expression

Abstract

Disclosed are new small molecules and the uses thereof for inhibiting superoxide dismutase (SOD) expression. Also disclosed are pharmaceutical compositions comprising the small molecule inhibitors which may be administered in methods of treating diseases or disorders associated with elevated SOD expression or activity, including neurological diseases and disorders such as amyotrophic lateral sclerosis (ALS).

We claim: 
     
         1 . A compound or a salt, ester, amide, or solvate thereof having a formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         A is O or S; 
         W is C1-C6 alkyl or a saturated or unsaturated homocycle or heterocycle comprising one 5- or 6-membered ring or two fused 5- or 6-membered rings, and W is optionally substituted at one or more positions with an amino group, a 4-fluorophenyl group, a hydroxyl group, a phenylamino group, a benzylamino group, or a tetrahydropuro-4-amino group; 
         X is S, S(O), S(O)(O), O, NH, CH, or CH 2 ; 
         Y is CH or CH 2 ; 
         n is 0, 1, or 2; and 
         Z is C1-C6 alkyl or a saturated or unsaturated homocycle or heterocycle comprising one 5- or 6-membered ring or two fused 5- or 6-membered rings, and Z is optionally substituted at one or more positions with a C1-6 alkyl group, a C1-6 alkoxy group, a halo group, an haloalkyl group, a cyano group, a nitro group, a 2-morpholino-ethoxy group, a phenyl group, a halophenyl group, a phenoxy group, an oxo group, a phenylamino group, a benzylamino group, a tetrahydropuran-4-methoxy group, or a 2-dimethyamino-ethoxy group. 
       
     
     
         2 . The compound of  claim 1  wherein X is S; m is 0; and Y is CH 2 . 
     
     
         3 . The compound of  claim 1 , wherein W is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein Z is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein W is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein Z is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1  having a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutical carrier. 
     
     
         9 . A method for treating a disease or disorder that is associated with elevated SOD1 expression or activity. 
     
     
         10 . The method of  claim 9 , wherein the disease or disorder is a neurological disease or disorder. 
     
     
         11 . The method of  claim 10 , wherein the neurological disease or disorder is a degenerative neurological disease or disorder. 
     
     
         12 . The method of  claim 11 , wherein the degenerative neurological disease or disorder is amyotrophic lateral sclerosis (ALS).