Phospholipidation of imidazoquinolines and oxoadenines

Abstract

The present invention relates to a process for phospholipidation of imidazoquinolines and oxoadenines. More particularly, the present invention relates to a high-yielding and scalable procedure for the phospholipidation of imidazoquinolines and oxoadenines which obviates the need to isolate unstable phosphoramidite intermediates. This process may be used for the phospholipidation of toll-like receptor 7 (TLR7)—active and toll-like receptor (TLR8)—active imidazoquinolines and oxoadenines.

1 . A compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein 
         R 4  is C 1-6 alkyl; 
         d is 1; 
         m is 2; 
         A is 
       
       
         
           
           
               
               
           
         
         
           wherein 
           R 2  is H or a straight or branched, optionally unsaturated, C 4 -C 24  alkyl, or a straight or branched, optionally unsaturated, C 4 -C 24 , acyl; 
           R 3  is a straight or branched, optionally unsaturated, C 4 -C 24  alkyl or a straight or branched, optionally unsaturated, C 4 -C 24  acyl; 
           n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; 
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         2 . The compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof according to  claim 1 , wherein R 2  and R 3  are —C(O)-nC 11 H 23 . 
     
     
         3 . The compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof according to  claim 1 , wherein R 2  and R 3  are —C(O)-nC 13 H 27 . 
     
     
         4 . The compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof according to  claim 1 , wherein R 2  and R 3  are —C(O)-nC 15 H 31 . 
     
     
         5 . The compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof according to  claim 1 , wherein R 2  and R 3  are —C(O)—(CH 2 ) 7 CH═CH(CH 2 ) 7 CH 3 . 
     
     
         6 . The compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof according to  claim 2 , wherein n is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. 
     
     
         7 . The compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof according to  claim 3 , wherein n is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. 
     
     
         8 . The compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof according to  claim 4 , wherein n is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. 
     
     
         9 . The compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof according to  claim 5 , wherein n is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. 
     
     
         10 . The compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof according to  claim 1 , wherein A is: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof according to  claim 1 , wherein A is: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof according to  claim 1 , wherein A is: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof according to  claim 1 , wherein A is: