Methods and compositions for treating beta-thalassemia and sickle cell disease

Abstract

Compounds, pharmaceutical compositions, and methods for treating anemia β-thalassemia anemia or sickle cell anemia.

1 .- 27 . (canceled) 
     
     
         28 . A compound of the formula selected from the group consisting of: Formula (VI), Formula (VII), and Formula (VIII): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 R 8 , R 9 , R 10 , R 11 , R 12  and R 13  are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, —N(R B ) 2 , and —N(R A )C(O)R A ; provided that in Formula (VI), R 10  is optionally substituted alkyl, —N(R B ) 2 , or —N(R A )C(O)R A . 
 R 14  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; 
 each instance of R A  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; and 
 each instance of R B  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; 
 
     
     
         29 . The compound of  claim 28 , wherein the compound is selected from the group consisting of Formula (VI-a), (VII-a), and (VIII-a): 
       
         
           
           
               
               
           
         
       
       in which each of R 10 , R 11 , and R 14  is as defined in  claim 28 . 
     
     
         30 . The compound of  claim 29 , wherein R 14  is optionally substituted alkyl. 
     
     
         31 . The compound of  claim 30 , wherein R 14  is —(CH 2 ) n —N(R B ) 2 , wherein:
 n is 1, 2, 3, 4, or 5; and 
 R B  is independently optionally substituted C 1-6  alkyl. 
 
     
     
         32 . The compound of  claim 31 , wherein R 14  is —(CH 2 ) 2 N(CH 3 ) 2 . 
     
     
         33 . The compound of  claim 29 , wherein R 10  is —N(R B ) 2  or —N(R A )C(O)R A , wherein:
 R A  is independently hydrogen or optionally substituted alkyl; and 
 R B  is independently hydrogen or optionally substituted alkyl. 
 
     
     
         34 . The compound of  claim 33 , wherein (i) each R B  is methyl or hydrogen, or (ii) one instance of R B  is optionally substituted C 1 -C 5  alkyl and the other instance of R B  is hydrogen. 
     
     
         35 . The compound of  claim 33 , wherein one instance of R A  is optionally substituted alkyl and the other instance of R A  is hydrogen. 
     
     
         36 . The compound of  claim 29 , wherein R 11  is hydrogen. 
     
     
         37 . The compound of  claim 29 , wherein the compound is selected from the group consisting of the compounds of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         38 . A pharmaceutical composition comprising a compound of  claim 28 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         39 . A method of inducing γ globin production, comprising: contacting a cell with an effective amount of a compound of  claim 28 . 
     
     
         40 . The method of  claim 39 , wherein the contacting step is performed by administering an effective amount of the compound of Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable salt thereof to a subject in need thereof. 
     
     
         41 . The method of  claim 40 , wherein the subject is a human patient who suffers from or is suspected of having anemia. 
     
     
         42 . The method of  claim 41 , wherein the anemia is β-thalassemia or sickle cell anemia. 
     
     
         43 . The method of  claim 40 , wherein the compound is administered orally. 
     
     
         44 . The method of  claim 40 , wherein the pharmaceutical composition is administered in combination with an additional therapeutic agent. 
     
     
         45 . A method of treating anemia, comprising: administering to a subject in need thereof an effective amount of a compound of  claim 28 . 
     
     
         46 . The method of  claim 45 , wherein the subject is a human patient who suffers from or is suspected of having β-thalassemia or sickle cell anemia.