Phosphonate analogs for treating metabolic diseases

Abstract

The invention is related to phosphorus substituted compounds with activity for treating metabolic diseases and/or disorders, e.g., diabetes and hypercholesterolemia, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

1 . A conjugate of formula:
   [DRUG]-(A 0 ) nn ;   wherein:   DRUG is a compound of formula 518:   
     
       
         
         
             
             
         
       
       wherein: 
       nn is 1, 2, or 3; 
       A 0  is A 1 , A or W 3  with the proviso that the conjugate includes at least one A 1 ; 
       A 1  is: 
     
     
       
         
         
             
             
         
       
       A 2  is: 
     
     
       
         
         
             
             
         
       
       A 3  is: 
     
     
       
         
         
             
             
         
       
       Y 1  is independently O, S, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R x )(R x )); 
       Y 2  is independently a bond, O, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R x )(R x )), —S(O) M2 —, or —S(O) M2 —S(O) M2 —; and when Y 2  joins two phosphorous atoms Y 2  can also be C(R 2 )(R 2 ); 
       R x  is independently H, R 1 , R 2 , W 3 , a protecting group, or the formula: 
     
     
       
         
         
             
             
         
       
       wherein: 
       R 1  is independently H, W 3 , R 2  or a protecting group; 
       R 1  is independently H or alkyl of 1 to 18 carbon atoms; 
       R 2  is independently H, R 1 , R 3  or R 4  wherein each R 4  is independently substituted with 0 to 3 R 3  groups or taken together at a carbon atom, two R 2  groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3  groups; 
       R 3  is R 3a , R 3b , R 3c  or R 3d , provided that when R 3  is bound to a heteroatom, then R 3  is R 3c  or R 3d ; 
       R 3a  is F, Cl, Br, I, —CN, N 3  or —NO 2 ; 
       R 3b  is Y 1 ; 
       R 3c  is R x , —N(R x )(R x ), —SR x , —S(O)R x , —S(O) 2 R x , —S(O)(OR x ), —S(O) 2 (OR x ), —OC(Y 1 )R x , —OC(Y 1 )OR x , —OC(Y 1 )(N(R x )(R x )), —SC(Y 1 )R x , —SC(Y 1 )OR x , —SC(Y 1 )(N(R x )(R x )), —N(R x )C(Y 1 )R x , —N(R x )C(Y 1 )OR x , or —N(R x )C(Y 1 )(N(R x )(R x )); 
       R 3  is —C(Y 1 )R x , —C(Y 1 )OR x  or —C(Y 1 )(N(R x )(R x )); 
       R 4  is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; 
       R 5  is R 4  wherein each R 4  is substituted with 0 to 3 R 3  groups; 
       W 3  is W 4  or W 5 ; 
       W 4  is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO M2 R 5 , or —SO M2 W 5 ; 
       W 5  is carbocycle wherein W 5  is independently substituted with 0 to 3 R 2  groups; 
       W 6  is W 3  independently substituted with 1, 2, or 3 A3 groups; 
       M2 is 0, 1 or 2; 
       M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 
       M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 
       M1a, M1c, and M1d are independently 0 or 1; and 
       M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 
       or a pharmaceutically acceptable salt or solvate thereof. 
     
   
   
       2 . The conjugate of  claim 1  which is a compound of formula 42, 43, or 44: 
     
       
         
         
             
             
         
       
     
   
   
       3 . The conjugate of  claim 1  wherein each A 3  is of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       4 . The conjugate of  claim 1  wherein each A 3  is of the formula: 
     
       
         
         
             
             
         
       
     
     wherein Y 2b  is O or N(R x ). 
   
   
       5 . The conjugate of  claim 1  wherein each A 3  is of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       6 . The conjugate of  claim 1  wherein each A 3  is of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       7 . The conjugate of  claim 1  wherein each A 3  is of the formula: 
     
       
         
         
             
             
         
       
     
     wherein Y 2b  is O or N(R x ). 
   
   
       8 . The conjugate of  claim 1  wherein each A 3  is of the formula: 
     
       
         
         
             
             
         
       
     
     wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R 2  groups. 
   
   
       9 . The conjugate of  claim 1  wherein each A 3  is of the formula: 
     
       
         
         
             
             
         
       
     
     wherein:
 Y 1a  is O or S; 
 Y 2b  is O or N(R 2 ); and 
 Y 2c  is O, N(R y ) or S. 
 
   
   
       10 . The conjugate of  claim 1  wherein A 0  is of the formula: 
     
       
         
         
             
             
         
       
     
     wherein each R is independently alkyl. 
   
   
       11 . A pharmaceutical composition comprising a pharmaceutical excipient and a conjugate as described in  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.