Conjugates of biologically active molecules to functionalized polymers

Abstract

This document relates to conjugates of a biologically active molecule or a derivative thereof and functionalized (e.g., mono- or bi-functional) polymers (e.g., polyethylene glycol and related polymers) as well as methods and materials for making and using such conjugates.

What is claimed is: 
     
         1 . A conjugate, or a pharmaceutically acceptable salt thereof, comprising a structure of formula (10): 
       
         
           
           
               
               
           
         
         or a salt form thereof, wherein: 
         polymer is poly(ethylene glycol), wherein said poly(ethylene glycol) has an average molecular weight from about 500 Da to about 100,000 Da, wherein each linking group is bonded at a different terminus of said polymer; 
         E is O; 
         E 1  is O; 
         K and K 1  are independently selected from the group consisting of: alkylene, alkyleneoxyalkylene, and oligomeric alkyleneoxyalkylene; 
         G and G 1  are independently absent or are selected from the group consisting of: alkoxy and a hydrophobic separation handle; 
         Z 1  is O; 
         Z 2  is O; 
         Z 3  is O; 
         Z 4  are O; 
         L and L 1  are independently selected from the group consisting of: a divalent radical of a nucleoside, alkylene, alkyleneoxyalkylene, oligomeric alkyleneoxyalkylene, and unsubstituted and substituted arylene; 
         L 2  is a covalent linking moiety between L on the polymer backbone and B; 
         L 3  is a covalent linking moiety between L on the polymer backbone and B 1 ; 
         B is a TNF inhibitor or a derivative thereof; and 
         B 1  is a TNF inhibitor or a derivative thereof. 
       
     
     
         2 . The conjugate of  claim 1 , wherein B is a TNF inhibitor. 
     
     
         3 . The conjugate of  claim 1 , wherein B 1  is a TNF inhibitor. 
     
     
         4 . The conjugate of  claim 1 , wherein K is selected from the group consisting of: methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, and hexylene, or a residue from diethylene glycol, triethylene glycol, tetraethylene glycol or hexaethylene glycol. 
     
     
         5 . The conjugate of  claim 1 , wherein K 1  is selected from the group consisting of: methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, and hexylene, or a residue from diethylene glycol, triethylene glycol, tetraethylene glycol or hexaethylene glycol. 
     
     
         6 . The conjugate of  claim 1 , wherein G is substituted or unsubstituted trityloxy. 
     
     
         7 . The conjugate of  claim 1 , wherein G is alkoxy. 
     
     
         8 . The conjugate of  claim 1 , wherein G 1  is substituted or unsubstituted trityloxy. 
     
     
         9 . The conjugate of  claim 1 , wherein G 1  is alkoxy. 
     
     
         10 . The conjugate of  claim 1 , wherein L is a divalent radical of a nucleoside. 
     
     
         11 . The conjugate of  claim 1 , wherein L 1  is a divalent radical of a nucleoside. 
     
     
         12 . The conjugate of  claim 1 , wherein L is alkylene. 
     
     
         13 . The conjugate of  claim 1 , wherein L 1  is alkylene. 
     
     
         14 . The conjugate of  claim 1 , wherein:
 B is a TNF inhibitor;   B 1  is a TNF inhibitor;   K is selected from the group consisting of: methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, and hexylene, or a residue from diethylene glycol, triethylene glycol, tetraethylene glycol or hexaethylene glycol;   K 1  is selected from the group consisting of: methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, and hexylene, or a residue from diethylene glycol, triethylene glycol, tetraethylene glycol or hexaethylene glycol;   G is alkoxy;   G 1  is alkoxy;   L is alkylene; and   L 1  is alkylene.   
     
     
         15 . The conjugate of  claim 1 , wherein:
 B is a TNF inhibitor;   B 1  is a TNF inhibitor;   K is selected from the group consisting of: methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, and hexylene, or a residue from diethylene glycol, triethylene glycol, tetraethylene glycol or hexaethylene glycol;   K 1  is selected from the group consisting of: methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, and hexylene, or a residue from diethylene glycol, triethylene glycol, tetraethylene glycol or hexaethylene glycol;   G is substituted or unsubstituted trityloxy;   G 1  is substituted or unsubstituted trityloxy;   L is a divalent radical of a nucleoside; and   L 1  is a divalent radical of a nucleoside.   
     
     
         16 . A composition comprising the conjugate of  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
         17 . A method of treating a patient diagnosed with an inflammatory disease, said method comprising administering to said patient an effective amount of the conjugate of  claim 1 . 
     
     
         18 . A conjugate, or a pharmaceutically acceptable salt thereof, comprising a compound of formula (11): 
       
         
           
           
               
               
           
         
         or a salt form thereof, 
         wherein: 
         polymer is poly(ethylene glycol wherein said poly(ethylene glycol) has an average molecular weight from about 500 Da to about 100,000 Da, wherein L 4  and the phosphonate-derived functional group are bonded at a different terminus of said polymer; 
         E and E 1  are O; 
         K is selected from the group consisting of: alkylene, alkyleneoxyalkylene, and oligomeric alkyleneoxyalkylene; 
         G is selected from the group consisting of: hydrogen, alkoxy, and a hydrophobic separation handle; 
         Z 1  and Z 2  are independently 0; 
         L is selected from the group consisting of: a divalent radical of nucleoside, alkylene, alkyleneoxyalkylene, oligomeric alkyleneoxyalkylene, and unsubstituted and substituted arylene; 
         L 2  is a covalent linking moiety between L on the polymer backbone and B; 
         L 4  is a covalent linking moiety between L on the polymer backbone and B 1 ; and 
         B and B 1  are independently a TNF inhibitor, a derivative of a TNF inhibitor, a biologic other than a TNF inhibitor, a drug, a detectable group, a separation moiety, wherein at least one of B and B 1  is a TNF inhibitor or a derivative of a TNF inhibitor. 
       
     
     
         19 . A composition comprising the conjugate of  claim 18 , and a pharmaceutically acceptable excipient. 
     
     
         20 . A method of treating a patient diagnosed with an inflammatory disease, said method comprising administering to said patient an effective amount of the conjugate of  claim 18 .