Y-shape branched hydrophilic polymer derivatives, their preparation methods, conjugates of the derivatives and drug molecules, and pharmaceutical compositions comprising the conjugates

Abstract

The present invention relates to Y-shape branched PEG derivatives of formulae (I) to (IV). The present invention also relates to conjugates of these Y-shape derivatives and drug molecules, pharmaceutical compositions comprising those conjugates.

1 . (canceled) 
     
     
         2 . The hydrophilic polymer derivative of  claim 4  wherein the hydrophilic polymer is selected from the group consisting of polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyacrylmorpholine and copolymers thereof. 
     
     
         3 . The hydrophilic polymer derivative of  claim 2  wherein the hydrophilic polymer is polyethylene glycol. 
     
     
         4 . A Y-shaped branched hydrophilic polymer derivative represented by formula II: 
       
         
           
           
               
               
           
         
         wherein 
         P a  and P b  are hydrophilic polymers, which are the same or different; 
         n and j are independently an integer from 1 to 12; 
         R i  is selected from the group consisting of H, a C 1-12  substituted or unsubstituted alkyl, a substituted aryl, an aralkyl, and a heteroalkyl; and 
         F is a functional group capable of reacting with an amino group, a hydroxyl group or a thiol group of a therapeutic agent or a substrate to form a covalent linkage, selected from the group consisting of a hydroxyl group, a carboxyl group, an ester group, carboxylic acid chloride, hydrazide, maleimide and pyridine disulfide. 
       
     
     
         5 - 6 . (canceled) 
     
     
         7 . The derivative of  claim 4 , wherein P a  and P b  are the same or different polyethylene glycols (PEGs) of formula (V): 
       
         
           
           
               
               
           
         
         wherein 
         R is H, a C 1-12  alkyl, a cycloalkyl or an aralkyl; and 
         n is an integer, representing the degree of polymerization. 
       
     
     
         8 . The derivative of  claim 7 , wherein R is selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl and benzyl. 
     
     
         9 . The derivative of  claim 7 , wherein the molecular weight of PEG is from about 300 to 60000. 
     
     
         10 . A method to prepare the hydrophilic polymer derivative of  claim 4 , comprising:
 initiating the polymerization of ethylene oxide with N,N-di-2-hydroxylethyl-2-benzyloxyethyl amine in the presence of a catalyst;   alkylating terminal hydroxyl groups; and   removing benzyl groups by catalytic hydrogenation; and   
     
     
         11 - 12 . (canceled) 
     
     
         13 . A conjugate formed by reacting the derivative of  claim 4  with a drug molecule through the terminal group F. 
     
     
         14 . (canceled) 
     
     
         15 . The conjugate of  claim 13  wherein the drug is selected from the group consisting of amino acids, proteins, enzymes, nucleosides, saccharides, organic acids, glycosides, flavonoids, anthraquinones, terpenoids, phenylpropanoid phenols, steroids, glycoside of the steroids and alkaloids of the steroids. 
     
     
         16 . The conjugate of  claim 13  wherein the drug is an active component of a natural medicine. 
     
     
         17 . The conjugate of  claim 16  wherein the active component is cinobufagin, clycyrrhetinic acid or scopoletin. 
     
     
         18 . The conjugate of  claim 13  wherein the drug is an anti-tumor agent. 
     
     
         19 . The conjugate of  claim 18  wherein the anti-tumor agent is selected from the group consisting of paclitaxel, camptothecin, interferon and derivatives thereof. 
     
     
         20 . The conjugate of  claim 19  wherein the interferon is α-, β- or γ-interferon. 
     
     
         21 . A pharmaceutical composition comprising the conjugate of  claim 13  and optionally a pharmaceutically acceptable carrier and excipient. 
     
     
         22 . The method of  claim 10 , further comprising derivatizing to incorporate the terminal group F of  claim 4 .