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 to form a target molecule-POZ conjugate wherein all the linkages between the target molecule and the POZ compound are stable in a biological system; 
 P is a linking group selected from the group consisting of —O—, NH or —NR 11 —; 
 Q is an optional 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 from 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 
 
     
     
         2 . The compound of  claim 1 , wherein the active functional group is protected. 
     
     
         3 . The compound of  claim 1 , wherein R 7  is methyl, ethyl or n-propyl. 
     
     
         4 . 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. 
     
     
         5 . The compound of  claim 1 , wherein NR 11  together form a substituted or unsubstituted piperazinyl or a substituted or unsubstituted piperidinyl group. 
     
     
         6 . The compound of  claim 1 , wherein the POZ polymer has a polydispersity value of less than or equal to 1.2, less than or equal to 1.1 or less than or equal to 1.05. 
     
     
         7 . The compound of  claim 1 , wherein Q is an unsubstituted or substituted alkyl, alkenyl, aralkyl, heterocyclyl or aryl group, —(CH 2 ) m —CONH—(CH 2 ) m —, —NH—(CH 2 ) m —NHCO—(CH 2 ) m —, —CO—(CH 2 ) m —, —CO—C 6 H 4 —, or —CO—R 8 , —(R 15 ) m — or —(CR 3 R 4 ) m —, where R 3 -R 4  and R 15  are each independently selected from hydrogen, unsubstituted or substituted alkyl, alkenyl or aralkyl group, R 8  is —C 6 H 10 —CH 2 — and m is an integer from 1 to 10. 
     
     
         8 . A target molecule POZ conjugate of the general formula A-B-TM, wherein
 A is a POZ compound of  claim 1  minus any leaving groups eliminated during the reaction of the active functional group on the POZ compound with a binding partner on a target molecule;   TM is the target molecule, said target molecule containing the binding partner; and   B is a linkage formed between the POZ compound and the binding partner, the linkage being stable in a biological system.   
     
     
         9 . The conjugate of  claim 8 , wherein the active functional group is a tresylate, the binding partner is SH and B is a thioether linkage. 
     
     
         10 . The conjugate of  claim 8 , wherein the active functional group is a maleimide, the binding partner is SH and B is a thioether linkage. 
     
     
         11 . The conjugate of  claim 8 , wherein the active functional group is an active carbonate, the binding partner is NH 2  and B is a urethane linkage. 
     
     
         12 . The conjugate of  claim 8 , wherein the active functional group is an active ester, the binding partner is NH 2  and B is an amide linkage. 
     
     
         13 . The conjugate of  claim 8 , wherein the active functional group is an aldehyde, the binding partner is NH 2  and B is an amine linkage. 
     
     
         14 . The conjugate of  claim 8 , wherein the POZ compound has a polydispersity value of less than or equal to 1.2, less than or equal to 1.1 or less than or equal to 1.05. 
     
     
         15 . The conjugate of  claim 8 , wherein the in vivo half-life of the target molecule-POZ conjugate is increased under physiological conditions. 
     
     
         16 . The conjugate of  claim 15 , wherein the POZ polymer has a polydispersity value of less than or equal to 1.2, less than or equal to 1.1 or less than or equal to 1.05.