Phosphonate analogs of hiv inhibitor compounds

Abstract

The invention is related to phosphorus substituted anti-viral inhibitory compounds, 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 - 103 . (canceled) 
     
     
         104 . An in vivo metabolic product of a compound of Formula A: 
       
         
           
           
               
               
           
         
         wherein A 0  is H or A 1 , provided that at least one of A 0  is A 1 , 
         K is R y , 
         K′ is R y ; 
         R y  is H; 
         A 1  is: 
       
       
         
           
           
               
               
           
         
         Y 2  is O; 
         R 2  is H; 
         M12a is 1; 
         M12b is 1; and 
         W 6  is carbocycle. 
       
     
     
         105 . The metabolic product of  claim 104  which is substantially isolated. 
     
     
         106 . A method of preparing the in vivo metabolic product of  claim 104  comprising contacting the compound of Formula A with a mammal for a period of time sufficient to yield the in vivo metabolic product. 
     
     
         107 . The method of  claim 106  wherein the compound of Formula A is radiolabeled. 
     
     
         108 . The method of  claim 107  wherein the radiolabel comprises C 14  or H 3 . 
     
     
         109 . A method of determining the optimal therapeutic dose of the compound of Formula A in a mammal comprising measuring the quantity of the in vivo metabolic product of  claim 104  produced upon contacting the mammal with a radiolabeled the compound of Formula A and correlating the measured quantity of the in vivo metabolic product with therapeutic effectiveness of the compound of Formula A. 
     
     
         110 . A prodrug of a compound of Formula A: 
       
         
           
           
               
               
           
         
         wherein A 0  is H or A 1 , provided that at least one of A 0  is A 1 , 
         K is R y , 
         K′ is R y ; 
         R y  is H; 
         A 1  is: 
       
       
         
           
           
               
               
           
         
         Y 2  is O; 
         R 2  is H; 
         M12a is 1; 
         M12b is 1; and 
         W 6  is carbocycle. 
       
     
     
         111 . A pharmaceutical composition comprising the prodrug of  claim 110 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         112 . A method of improving the pharmacokinetics of a drug, comprising administering to a patient treated with said drug, a therapeutically effective amount of the prodrug of  claim 110 , or a pharmaceutically acceptable salt thereof 
     
     
         113 . A solvate of a compound of Formula A: 
       
         
           
           
               
               
           
         
         wherein A 0  is H or A 1 , provided that at least one of A 0  is A 1 , 
         K is R y , 
         K′ is R y ; 
         R y  is H; 
         A 1  is: 
       
       
         
           
           
               
               
           
         
         Y 2  is O; 
         R 2  is H; 
         M12a is 1; 
         M12b is 1; and 
         W 6  is carbocycle. 
       
     
     
         114 . A pharmaceutical composition comprising the solvate of  claim 113 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         115 . A method of improving the pharmacokinetics of a drug, comprising administering to a patient treated with said drug, a therapeutically effective amount of the solvate of  claim 113 , or a pharmaceutically acceptable salt thereof.