Phosphonate analogs of antimetabolites

Abstract

The invention is related to phosphorus substituted antimetabolites, 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 505: 
 
     
       
         
         
             
             
         
       
       wherein: 
       nn is 1, 2 or 3; 
       A 0  is A 1 , A 2  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 y  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 3d  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 A 3  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 selected from formulae 17-20 and 22-23: 
     
       
         
         
             
             
         
       
     
     wherein:
 A 0  is A 1 , A 2  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 y  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 3d  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 A 3  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. 
     
   
   
       3 . The conjugate of  claim 2  wherein R x  is not H. 
   
   
       4 . The conjugate of  claim 1  wherein A 3  is: 
     
       
         
         
             
             
         
       
     
   
   
       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: 
     
       
         
         
             
             
         
       
     
     wherein Y 2b  is O or N(R x ). 
   
   
       7 . The conjugate of  claim 1  wherein each A 3  is of the formula: 
     
       
         
         
             
             
         
       
     
   
   
       8 . The conjugate of  claim 1  wherein each A 3  is of the formula: 
     
       
         
         
             
             
         
       
     
     wherein Y 2b  is O or N(R x ). 
   
   
       9 . 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. 
   
   
       10 . 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. 
 
   
   
       11 . The conjugate of  claim 1  wherein A 0  is of the formula: 
     
       
         
         
             
             
         
       
     
     wherein each R is independently alkyl. 
   
   
       12 . A pharmaceutical composition comprising a pharmaceutical excipient and a conjugate as described in  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.