Hydrolysable Polymeric FMOC- Linker

Abstract

The invention relates to Fmoc (9-fluorenyl-methoxycarbonyl)-based polymeric conjugates. These conjugates are useful for extending the in-vivo circulation of protein and peptide drugs.

1 .- 14 . (canceled) 
   
   
       15 . A compound of the formula 1 
     
       
         
         
             
             
         
       
     
     wherein Z a leaving group and at least one of position 1, 2, 3, 4, 5, 6, 7 or 8 is bound to radical Y;
 Y is a radical containing a biopolymer, which is bound to a N-succinimidyl moiety; 
 at least one of an available position 1, 2, 3, 4, 5, 6, 7 or 8 is optionally bound to radical X; 
 X is —SO 3 —R 3 ; 
 R 3  is independently selected from the group consisting of hydrogen, (C 1 -C 8 -alkyl and (C 1 -C 8 -alkyl-R 4 ; and 
 R 4  is a polymer. 
 
   
   
       16 . The compound according to  claim 15 , wherein Z is an N-succinimidyl ester;
 Y is:   
     
       
         
         
             
             
         
       
       POLYMER is a biopolymer; 
       R 1  is at each occurrence independently a (C 1 -C 8 )-alkyl; 
       R 2  is independently selected from the group consisting of —C(O)NR—, —C(O)NR—(C 1 -C 8 )-alkyl-NR—, —NRC(O)— and —NRC(O)—(C 1 -C 8 )-alkyl-NR; and 
       R is independently either hydrogen or (C 1 -C s )-alkyl. 
     
   
   
       17 . The compound according to  claim 16 , wherein R 2  is either —C(O)NR— or —NRC(O)— and wherein R is independently either hydrogen or (C 1 -C 8 )-alkyl. 
   
   
       18 . The compound according to  claim 17 , wherein said POLYMER is bound via a thioether linkage. 
   
   
       19 . The compound according to  claim 15 , wherein said biopolymer is a carbohydrate biopolymer. 
   
   
       20 . The compound according to  claim 19 , wherein said carbohydrate biopolymer is a polysaccharide. 
   
   
       21 . The compound according to  claim 20 , wherein said polysaccharide is polysialic acid (PSA). 
   
   
       22 . The compound according to  claim 20 , wherein said polysaccharide comprises at least 3 units of a monosaccharide. 
   
   
       23 . A compound of the formula 1 
     
       
         
         
             
             
         
       
     
     wherein Z a leaving group and at least one of position 1, 2, 3, 4, 5, 6, 7 or 8 is bound to radical Y;
 Y is a radical containing a polymer, which is bound to a N-succinimidyl moiety; 
 at least one of an available position 1, 2, 3, 4, 5, 6, 7 or 8 is optionally bound to radical X; 
 X is —SO 3 —R 3 ; 
 R 3  is independently selected from the group consisting of hydrogen, (C 1 -C s )-alkyl and (C 1 -C 8 )-alkyl-R 4 ; and 
 R 4  is a polymer. 
 
   
   
       24 . The compound according to  claim 23 , wherein Z is an N-succinimidyl ester;
 Y is:   
     
       
         
         
             
             
         
       
       R 1  is at each occurrence independently a (C 1 -C 8 )-alkyl; 
       R 2  is independently selected from the group consisting of —C(O)NR—, —C(O)NR—(C 1 -C 8 )-alkyl-NR—, —NRC(O)— and —NRC(O)—(C 1 -C 8 )-alkyl-NR; and 
       R is independently either hydrogen or (C 1 -C 8 )-alkyl. 
     
   
   
       25 . The compound according to  claim 24 , wherein R 2  is either —C(O)NR— or —NRC(O)— and wherein R is independently either hydrogen or (C 1 -C 8 )-alkyl. 
   
   
       26 . The compound according to  claim 25 , wherein said polymer is bound via a thioether linkage. 
   
   
       27 . A process for the preparation of a compound of formula (2) 
     
       
         
         
             
             
         
       
       said process comprising the step of subjecting a polymer having a thiol moiety and an intermediate compound having a formula 
     
     
       
         
         
             
             
         
       
     
     to a coupling reaction to form the compound of formula (2),
 wherein 
 R 1  is at each occurrence independently a (C 1 -C 8 -alkyl; 
 R 2  is independently selected from the group consisting of —C(O)NR—, —C(O)NR—(C 1 -C 8 )-alkyl-NR—, —NRC(O)— and —NRC(O)—(C 1 -C s )-alkyl-NR, 
 R is independently either hydrogen or (C 1 -C 8 )-alkyl; 
 X is —SO 3 —R 3 ; 
 R 3  is independently selected from the group consisting of hydrogen, (C 1 -C 8 -alkyl and (C 1 -C 8 -alkyl-R 4 ; 
 R 4  is a polymer, 
 n is an integer selected from 0, 1, 2, 3, or 4; and 
 m is an integer selected from 1, 2, 3, or 4. 
 
   
   
       28 . The process according to  claim 27 , wherein R 2  is either —C(O)NR— or —NRC(O)— and wherein R is independently either hydrogen or C 1 -C 8 -alkyl. 
   
   
       29 . The process according to  claim 27 , wherein the polymer having the thiol moiety comprises a biopolymer. 
   
   
       30 . The process according to  claim 27 , further comprising reacting the compound of formula (2) and a protein or peptide drug which contains one or more groups for displacement. 
   
   
       31 . The process according to  claim 30 , wherein the protein or peptide drug is selected from the group consisting of Factor VII, von Willebrand Factor (VWF), Factor VIIa, and Factor IX.