Fatty acid conjugates of statin and fxr agonists: compositions and methods of use

Abstract

The invention relates to fatty acid statin conjugates and fatty acid FXR agonist conjugates; compositions comprising an effective amount of a fatty acid statin conjugate or a fatty acid FXR agonist conjugate; and methods for treating or preventing a metabolic disease comprising the administration of an effective amount of a fatty acid statin conjugate or a fatty acid FXR agonist conjugate.

1 . A molecular conjugate comprising a statin and a fatty acid. 
     
     
         2 - 11 . (canceled) 
     
     
         12 . A compound of the Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer or stereoisomer thereof; 
         wherein R a1  is 
       
       
         
           
           
               
               
           
         
         W 1  and W 2  are each independently null, O, S, NH, NR, or W 1  and W 2  can be taken together to form an imidazolidine or piperazine group; 
         each a, b, c, and d is independently —H, -D, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —C(O)OR, —O—Z, or benzyl, or two of a, b, c, and d can be taken together, along with the single carbon to which they are bound, to form a cycloalkyl or heterocycle; 
         each n, o, p, and q is independently 0, 1, or 2; 
         each L is independently —O—, —S—, —S(O)—, —S(O) 2 , —S—S—, —(C 1 -C 6  alkyl)-, —(C 3 -C 6  cycloalkyl)-, a heterocycle, a heteroaryl, 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the representation of L is not limited directionally left to right as is depicted, rather either the left side or the right side of L can be bound to the W 1  side of the compound of Formula II; 
         R 6  is independently —H, -D, —C 1 -C 4  alkyl, halogen, cyano, oxo, thiooxo, —OH, —C(O)C 1 -C 4  alkyl, —O-aryl, —O-benzyl, —OC(O)C 1 -C 4  alkyl, C 2 -C 3  alkene, C 2 -C 3  alkyne, —NH 2 , —NH(C 1 -C 3  alkyl), —N(C 1 -C 3  alkyl) 2 , —NH(C(O)C 1 -C 3  alkyl), —N(C(O)C 1 -C 3  alkyl) 2 , —SH, —S(C 1 -C 3  alkyl), —S(O)C 1 -C 3  alkyl, or —S(O) 2 C 1 -C 3  alkyl; 
         each g is independently 2, 3 or 4; 
         each h is independently 1, 2, 3 or 4; 
         m is 0, 1, 2, or 3; if m is more than 1, then L can be the same or different; 
         m1 is 0, 1, 2 or 3; 
         k is 0, 1, 2, or 3; 
         z is 1, 2, or 3; 
         each R 3  is independently H or C 1 -C 6  alkyl, or both R 3  groups, when taken together with the nitrogen to which they are attached, can form a heterocycle; 
         each R 4  is independently e, H or straight or branched C 1 -C 10  alkyl which can be optionally substituted with OH, NH 2 , CO 2 R, CONH 2 , phenyl, C 6 H 4 OH, imidazole or arginine; 
         each e is independently H or any one of the side chains of the naturally occurring amino acids; 
         each Z is independently —H, 
       
       
         
           
           
               
               
           
         
         with the proviso that there is at least one 
       
       
         
           
           
               
               
           
         
          in the compound; 
         each r is independently 2, 3, or 7; 
         each s is independently 3, 5, or 6; 
         each t is independently 0 or 1; 
         each v is independently 1, 2, or 6; 
         each f 1  is independently 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26; 
         each f2 is independently 3, 4, 5, 6, 7, 8, 9, 10 or 11; 
         each f3 is independently 2, 3, 4 or 5; 
         each f4 is independently 3, 7, 8, 9, 11 or 13; 
         each f5 is independently 1 or 3; 
         R 1  and R 2  are each independently —H, -D, —C 1 -C 4  alkyl, -halogen, —OH, —C(O)C 1 -C 4  alkyl, —O-aryl, —O-benzyl, —OC(O)C 1 -C 4  alkyl, C 2 -C 3  alkene, C 2 -C 3  alkyne, —NH 2 , —NH(C 1 -C 3  alkyl), —N(C 1 -C 3  alkyl) 2 , —NH(C(O)C 1 -C 3  alkyl), —N(C(O)C 1 -C 3  alkyl) 2 , —SH, —S(C 1 -C 3  alkyl), —S(O)C 1 -C 3  alkyl, or —S(O) 2 C 1 -C 3  alkyl; and 
         each R is independently —H, or straight or branched C 1 -C 4  alkyl optionally substituted with OH, or halogen;
 provided that 
 when each of m, n, o, p, and q, is 0, W 1  and W 2  are each null, and Z is 
 
       
       
         
           
           
               
               
           
         
         
            then t must be 0; and 
           when each of m, n, o, p, and q is 0, and W 1  and W 2  are each null, then Z must not be 
         
       
       
         
           
           
               
               
           
         
       
     
     
         13 . (canceled) 
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 12  and a pharmaceutically acceptable carrier. 
     
     
         15 - 20 . (canceled)