N-maleimidyl polymer derivatives

Abstract

The invention is directed to multi-functional N-maleimidyl polymer derivatives comprising a water soluble and non-peptidic polymer backbone having a terminal carbon, such as a poly(alkylene glycol), the terminal carbon of the polymer backbone being directly bonded to the nitrogen atom of a N-maleimidyl moiety without a linking group therebetween. The invention also provides two methods of preparing such linkerless N-maleimidyl polymer derivatives.

That which is claimed is: 
     
       1. A homobifunctional N-maleimidyl polymer having a formula: 
       
         
           
           
               
               
           
         
         wherein 
         n is about 20 to about 4000. 
       
     
     
       2. The homobifunctional N-maleimidyl polymer of  claim 1 , wherein the polyethylene glycol backbone has an average molecular weight of from about 800 daltons to about 100,000 daltons. 
     
     
       3. A method of forming a homobifunctional N-maleimidyl polyethylene glycol polymer, the method comprising:
 (i) reacting a N-maleimidyl polyethylene glycol amine, 
 
       
         
           
           
               
               
           
         
       
       with maleic anhydride to form an open ring amide carboxylic acid intermediate, 
       
         
           
           
               
               
           
         
         wherein the polyethylene glycol backbone of the N-maleimidyl polyethylene glycol amine has an average molecular weight of from about 800 daltons to about 100,000 daltons, and 
         (ii) heating the open ring amide carboxylic acid intermediate in the presence of acetic anhydride and an acetate salt to thereby form the homobifunctional N-maleimidyl polyethylene glycol polymer, 
       
       
         
           
           
               
               
           
         
       
     
     
       4. The method of  claim 3 , wherein the acetate salt in step (ii) is sodium acetate. 
     
     
       5. The method of  claim 3 , wherein the acetate salt in step (ii) is potassium acetate. 
     
     
       6. The method of  claim 3 , wherein the heating in step (ii) is at a temperature from about 50° C. to about 140° C. 
     
     
       7. The method of  claim 3 , wherein the heating in step (ii) is carried out for about 0.2 hours to about 5 hours. 
     
     
       8. The method of  claim 3 , further comprising purifying the homobifunctional N-maleimidyl polyethylene glycol polymer formed in step (ii). 
     
     
       9. The method of  claim 8 , wherein the purifying comprises precipitation. 
     
     
       10. The method of  claim 8 , wherein the purifying comprises ion exchange chromatography.