Activated Polyoxazolines and Conjugates and Compositions Comprising the Same

Abstract

The present disclosure provides POZ derivatives having a range of active functional groups allowing conjugation of POZ derivatives to a variety of target molecules under a wide range of reaction conditions to produce a hydrolytically stable target molecule-POZ conjugate. Furthermore, the present disclosure provides novel methods of synthesis for the disclosed POZ derivatives and hydrolytically stable target molecule-POZ conjugates created using the disclosed terminally activated monofunctional POZ derivatives. In one embodiment, the POZ derivative is a terminally activated monofunctional POZ derivative.

What is claimed: 
     
         1 . A terminally activated polyoxazoline (POZ) compound of the general structure
   R 1 —[N(COR 7 )CH 2 CH 2 ] n —P p -Q q -X,
   wherein:   X is an active functional group capable of forming a linkage with a target molecule wherein all the linkages between the target molecule and the POZ compound are stable in a biological system;   P is NH or —NR 11 —;   Q is a linking group;   R 7  is independently selected for each repeating unit of POZ from an unsubstituted or substituted alkyl, alkenyl or aralkyl group;   R 1  and R 11  are each independently hydrogen, unsubstituted or substituted alkyl, alkenyl or aralkyl group or R 11  and the N to which it is connected form a 5 or 6 membered heterocycle ring, which may be further substituted with 1 additional N atom;   n is an integer from 3 to 1000; and   p and q are integers independently selected from zero or one, wherein all the linkages in the POZ compound are stable in a biological system.   
     
     
         2 . The compound of  claim 1 , wherein R 7  is methyl, ethyl or n-propyl. 
     
     
         3 . The compounds of  claim 1 , wherein the active functional group is selected from the group consisting of: aldehydes, active carbonates, maleimides, sulfonate esters, tresylate, mesylate, hydrazide, epoxides, iodoacetamides, alkynes, azides, isocyanates, cyanates isothiocyanates, thiocyanates, nitriles, carbonyldiimidazole derivatives, vinylsulfones, carboxylic acid halides, active esters and carboxylic acids. 
     
     
         4 . The compound of  claim 1 , wherein NR 11  forms a substituted or unsubstituted piperazinyl or a substitutedor unsubstituted piperidinyl group. 
     
     
         5 . The compound of  claim 1 , wherein the POZ polymer has a polydispersity value selected from the group consisting of: less than or equal to 1.2, less than or equal to 1.1 and less than or equal to 1.05. 
     
     
         6 . The compound of  claim 1 , wherein the compound is terminally activated. 
     
     
         7 . The compound of  claim 1  linked to the target molecule. 
     
     
         8 . A polyoxazoline (POZ) compound of the general structure
   R 1 -[N(COR 7 )CH 2 CH 2 ] n —O-Q q -X,
   wherein:   X is an active functional group capable of forming a linkage with a target molecule;   Q is a linking group;   R 7  is independently selected for each repeating unit of POZ from an unsubstituted or substituted alkyl, alkenyl or aralkyl group;   R 1  is hydrogen, unsubstituted or substituted alkyl, alkenyl or aralkyl;   n is an integer from 3 to 1000; and   q is an integer from zero or one,   wherein all the linkages in the POZ compound are stable in a biological system.   
     
     
         9 . The compound of  claim 8 , wherein R 7  is methyl, ethyl or n-propyl. 
     
     
         10 . The compounds of  claim 8 , wherein the active functional group is selected from the group consisting of: aldehydes, active carbonates, maleimides, sulfonate esters, tresylate, mesylate, hydrazide, epoxides, iodoacetamides, alkynes, azides, isocyanates, cyanates isothiocyanates, thiocyanates, nitriles, carbonyldiimidazole derivatives, vinylsulfones, carboxylic acid halides, active esters and carboxylic acids. 
     
     
         11 . The compound of  claim 8 , wherein the POZ polymer has a polydispersity value selected from the group consisting of: less than or equal to 1.2, less than or equal to 1.1 and less than or equal to 1.05. 
     
     
         12 . The compound of  claim 8 , wherein the compound is terminally activated. 
     
     
         13 . The compound of  claim 8  linked to the target molecule. 
     
     
         14 . The compound of  claim 8 , wherein Q is —C(O)—O—, C(O)—NH—(CH 2 ) m , (CH 2 ) m —C(O)O— or C(O)O—NH—(CH 2 ) m . 
     
     
         15 . The compound of  claim 8  having the structure