Taxane prodrugs

Abstract

Taxane prodrugs comprise a taxane joined by a hydrolyzable bond to one or more oligomers that comprise a polyethylene glycol moiety. The oligomer preferably further comprises a salt-forming moiety.

1 - 28 . (canceled)  
     
     
         29 . A polyethylene glycol polymer comprising a terminal hydroxyl group available for binding to a drug to form a prodrug, said polyethylene glycol polymer further comprising a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein n is from 1 to 7, m is from 2 to 25, and R is hydrogen or a lower alkyl;  
       
         
           
           
               
               
           
         
       
       wherein n is from 1 to 6, p is from 2 to 8, m is from 2 to 25, and R is hydrogen or a lower alkyl;  
       
         
           
           
               
               
           
         
       
       wherein n is from 1 to 6, m and r are each independently from 2 to 25, and R is hydrogen or a lower alkyl;  
       
         
           
           
               
               
           
         
       
       wherein n is from 1 to 6, p is from 2 to. 8, m is from 2 to 25, R is hydrogen or lower alkyl;  
       
         
           
           
               
               
           
         
       
       wherein n is from 1 to 6, p is from 2 to 8, m is from 2 to 25, R is hydrogen or lower alkyl, and X −  is a negative ion;  
       
         
           
           
               
               
           
         
       
       wherein n is from 1 to 6, p is from 2 to 8, m is from 2 to 25, and R 1  and R 2  are each independently hydrogen or a lower alkyl;  
       
         
           
           
               
               
           
         
       
       wherein n is from 1 to 6, p is from 2 to 8, and m is from 2 to 25;  
       
         
           
           
               
               
           
         
       
       wherein n and p are each independently from 1 to 6, m is from 2 to 25 and X +  is a positive ion;  
       
         
           
           
               
               
           
         
       
       wherein n is from 1 to 5, m is from 2 to 25, X is a negative ion, and wherein R 1  and R 2  are each independently hydrogen or lower alkyl;  
       
         
           
           
               
               
           
         
       
       wherein n is from 1 to 6, m is from 2 to 25 and X is a negative ion; and  
       
         
           
           
               
               
           
         
       
       wherein n is from 1 to 12, m is from 2 to 25, p is from 2 to 12, X +  is a positive ion and Z −  is a negative ion.  
     
     
         30 . The polyethylene glycol polymer of  claim 29 , wherein the terminal hydroxyl group can bind to a drug to form a bond that can undergo hydrolysis in vivo to release the drug from the polyethylene glycol polymer.  
     
     
         31 . The polyethylene glycol polymer according to  claim 29 , wherein the positive ion is selected from the group consisting of sodium cation, potassium cation, lithium cation, and calcium cation.  
     
     
         32 . The polyethylene glycol polymer according to  claim 29 , wherein the negative ion is selected from the group consisting of chloro anion, bromo anion, iodo anion, phosphate anion, acetate anion, carbonate anion, sulfate anion, tosylate anion, and mesylate anion.  
     
     
         33 . The polyethylene glycol polymer according to  claim 29 , having a structure represented by Formula 12, wherein the positive ion is selected from the group consisting of NH 3   +  and trisubstituted sulfur and the negative ion is selected from the group consisting of chloro anion, bromo anion, iodo anion, phosphate anion, acetate anion, trifluoracetate anion, carbonate anion, sulfate anion, and mesylate anion.  
     
     
         34 . The polyethylene glycol polymer according to  claim 29 , having a structure represented by formula 12, wherein n is 3, m is 2, p is 2, X +  is NH 3   + , and Z −  is −O 2 CCH 3 .  
     
     
         35 . An activated polyethylene glycol polymer of  claim 29 .  
     
     
         36 . The activated polyethylene glycol polymer according to  claim 35 , further characterized as an NHS ester.  
     
     
         37 . The polyethylene glycol polymer of  claim 29  having the formula of Formula 2.  
     
     
         38 . The polyethylene glycol polymer of  claim 29  having the formula of Formula 3.  
     
     
         39 . The polyethylene glycol polymer of  claim 29  having the formula of Formula 4.  
     
     
         40 . The polyethylene glycol polymer of  claim 29  having the formula of Formula 5.  
     
     
         41 . The polyethylene glycol polymer of  claim 29  having the formula of Formula 6.  
     
     
         42 . The polyethylene glycol polymer of  claim 29  having the formula of Formula 7.  
     
     
         43 . The polyethylene glycol polymer of  claim 29  having the formula of Formula 8.  
     
     
         44 . The polyethylene glycol polymer of  claim 29  having the formula of Formula 9.  
     
     
         45 . The polyethylene glycol polymer of  claim 29  having the formula of Formula 10.  
     
     
         46 . The polyethylene glycol polymer of  claim 29  having the formula of Formula 11.  
     
     
         47 . The polyethylene glycol polymer of  claim 29  having the formula of Formula 12.  
     
     
         48 . A method for preparing a taxane prodrug, comprising combining a taxane with one or more polyethylene glycol polymers of  claim 29 , wherein the polyethylene glycol polymers are activated and the combining occurs under conditions to promote a condensation reaction between the taxane and one or more polyethylene glycol polymers.  
     
     
         49 . The method of  claim 48 , wherein the taxane is paclitaxel, docetaxel or an analog or derivative thereof.  
     
     
         50 . The method of  claim 48 , wherein the taxane is paclitaxel or an analog or derivative thereof.  
     
     
         51 . The method of  claim 48 , wherein the taxane is paclitaxel.  
     
     
         52 . A method for enhancing microtubule formation in a mammalian subject, comprising administering to the subject an effective microtubule formation enhancing amount of a taxane prodrug comprising: 
 (a) a taxane, and    (b) from one to three polyethylene glycol polymers of  claim 29  joined to from one to three bonding sites on the taxane by a hydrolyzable bond,    wherein the microtubule formation is enhanced relative to the microtubule formation achieved by administration of the taxane alone.    
     
     
         53 . The method of  claim 52 , wherein the taxane is paclitaxel, docetaxel or an analog or derivative thereof.  
     
     
         54 . The method of  claim 52 , wherein the taxane is paclitaxel or an analog or derivative thereof.  
     
     
         55 . The method of  claim 52 , wherein the taxane is paclitaxel.  
     
     
         56 . The method of  claim 52 , wherein the taxane is paclitaxel and the polyethylene glycol polymer has a structure represented by Formula 12, wherein the positive ion is selected from the group consisting of NH 3   +  and trisubstituted sulfur and the negative ion is selected from the group consisting of chloro anion, bromo anion, iodo anion, phosphate anion, acetate anion, trifluoracetate anion, carbonate anion, sulfate anion, and mesylate anion.  
     
     
         57 . The method of  claim 52 , wherein the taxane is paclitaxel and the polyethylene glycol polymer has a structure represented by Formula 12, wherein n is 3, m is 2, p is 2, X +  is NH 3   + , and Z −  is  − O 2 CCH 3 .