Methods for treating spinal muscular atrophy

Abstract

Described herein are methods for the identification or validation of compounds capable of causing ribosomal frameshifting and the use of said compounds to produce a stabilized SMNΔEx7 protein and treat Spinal Muscular Dystrophy.

1 .- 21 . (canceled) 
     
     
         22 . A method for producing a stabilized SMNΔ7Ex7 protein in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound of Formula (I) having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, racemate, enantiomer or tautomer thereof, wherein, 
         W is C(O), C(S), and CH 2 ; 
         B is CH 2  or CH(C n H 2n+1 ), wherein n is an integer from 1 to 8; 
         R 1  and R 2  are independently selected from the group consisting of H and C 1 -C 3  alkyl, or R 1  and R 2  may be taken together with the carbon atom to which they are attached to form a C 3 -C 6  cycloalkyl ring or a carbonyl group; 
         R 3  is selected from the group consisting of H, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, CN, NO 2 , heteroaryl, and phenyl optionally substituted with any combination of one to five halogen, NO 2 , CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy substituents; 
         R 4 , R 5 , R 6  and R 7  are independently selected from the group consisting of H, hydroxyl, halogen, CN, NO 2 , sulfonamide, C 1 -C 8  alkyl, C 3 -C 6  cycloalkyl, cycloalkyloxy, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 1 -C 4  haloalkyl, C 2 -C 8  alkenyl, amino, C 1 -C 4  alkylamino, C 1 -C 4  dialkylamino, C 3 -C 6  cycloalkylamino, morpholinyl, heteroaryl, arylamino, arylalkylamino, phenyl, C(O)R′, NR′(COR″), NR′SO 2 R″ and NR′(CONR″R′″), wherein R′, R″ and R′″ are independently H, C 1 -C 6  alkyl, phenyl, or substituted phenyl, and wherein C 1 -C 8  alkyl is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, C 1 -C 6  alkylamino, cycloalkylamino, and morpholinyl, and the phenyl is optionally substituted with one or more substituents selected from the group consisting of halogen, NO 2 , CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  alkoxy, or R 4  and R 5 , R 5  and R 6 , or R 6  and R 7 , taken together with the carbon to which they are attached, form a ring; 
         X is selected from the group consisting of H; CN; C(O)OR 8 , wherein R 8  is H or C 1 -C 8  alkyl, and C 1 -C 8  alkyl optionally is substituted with one or more substituents selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, C 1 -C 6  alkylamino, cycloalkylamino, phenyl, and morpholinyl; C(O)NR 9 R 10  or CH 2 NR 9 R 10 , wherein R 9  and R 10  are independently selected from the group consisting of H and C 1 -C 6  alkyl, or R 9  and R 10  together with the nitrogen to which they are attached form a heterocyclyl ring; CH 2 OR 11 , wherein R 11  is H, C 1 -C 8  alkyl, or C 3 -C 6  cycloalkyl, wherein C 1 -C 8  alkyl is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, C 1 -C 6  alkylamino, cycloalkylamino, and morpholinyl; CH 2 Z, wherein Z is halogen; C(O)NHOH; C(O)NHCN; C(O)N(R 1 )SO 2 R 13 , wherein R 13  is C 1 -C 4  alkyl, phenyl, or substituted phenyl; C 1 -C 8  alkyl, optionally substituted with one or more substituents selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, and C 1 -C 6  alkylamino; and C 2 -C 8  alkenyl, optionally substituted with one or more substituents selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, and C 1 -C 6  alkylamino. 
       
     
     
         23 . The method of  claim 22 , wherein the stabilized SMNΔ7Ex7 protein comprises the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5. 
     
     
         24 .- 31 . (canceled) 
     
     
         32 . The method of  claim 22 , wherein the compound is 2-(4-isopropylphenyl)-6-methoxyisoindolin-1-one. 
     
     
         33 . The method of  claim 22 , wherein:
 W is C(O);   B is CH 2 ;   R 1  and R 2  are independently C 1 -C 3  alkyl;   R 3  is H;   R 4 , R 5 , R 6  and R 6  are independently selected from the group consisting of H and C 1 -C 6  alkoxy; and   X is H.   
     
     
         34 . The method of  claim 33 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, racemate, enantiomer or tautomer thereof.