Multi-armed forms of activated polyoxazoline and methods of synthesis thereof
The present disclosure provides novel POZ-2 derivatives, methods for synthesizing POZ-2 derivatives and intermediates useful in such methods. In one embodiment, the POZ-2 derivative comprises two linear POZ chains of the present disclosure linked directly or indirectly to a branching moiety that contains a functional group for linking the POZ-2 derivative to the target molecule. Target molecule-POZ-2 conjugates are also described. In certain embodiment, the POZ-2 derivatives have low polydispersity values and a decreased amount of impurities produced by unwanted side reactions, such as, but not limited to, chain transfer.
1. An activated polyoxazoline-2 (POZ-2) derivative of the general structure
Wherein
POZ a is a polyoxazoline of formula —[N(COR 2 )CH 2 CH 2 ] n —;
POZ b is a polyoxazoline of formula —[N(COR 2 )CH 2 CH 2 ] x —;
L(I), L(II) and L(III) are linking groups;
Br is a branching moiety that is linked with or without a linking group to POZ a , POZ b and is selected from the group consisting of a nitrogen atom, a substituted or unsubstituted aryl group or a carbon atom, provided that when Br is a carbon atom, at least one of c or d is 1 and the corresponding linking group contains a substituted or unsubstituted aryl group;
X is a functional group which is capable of forming a linkage with a target molecule or being converted to a group that is capable of forming a linkage with a target molecule;
A is a non-reactive group;
R 1 is independently selected for each of POZ a and POZ b from hydrogen, alkyl, substituted alkyl, aralkyl, or substituted aralkyl group;
R 2 is independently selected for each repeating unit of POZ from an unsubstituted or substituted alkyl, alkenyl, alkyl, aralkyl or aryl group;
c, d and e are independently selected from 1 or zero;
f is zero when Br is a nitrogen atom or substituted or unsubstituted aryl group and is 1 when Br is a carbon atom; and
n and x are independently selected for each of POZ a and POZ b from 3 to 1000.
2. The POZ-2 derivative of claim 1 wherein R 2 has from 1 to 12 carbon atoms.
3. The POZ-2 derivative of claim 1 wherein R 2 is methyl, ethyl or n-propyl.
4. The POZ-2 derivative of claim 1 wherein at least one of POZ a and POZ b of the POZ-2 derivative 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.
5. The POZ-2 derivative of claim 1 wherein the POZ-2 derivative is a monofunctional POZ-2 derivative.
6. The POZ-2 derivative of claim 1 wherein X is selected from the groups consisting of carboxylic acid, active esters, carbonates, aldehyde, oxyamine, acetylene, isocyanates, isothiocyanate, amines, alcohol, tresylate (2,2,2-trifluorethylsulfonate), vinylsulfone, iodoacetamide, pyridyldisulfide, ketones, azide, hydrazide and maleimide.
7. The POZ-2 derivative of claim 1 wherein the linkage with the target molecule is a hydrolytically stable linkage.
8. The POZ-2 derivative of claim 1 wherein the functional group is protected.
9. The POZ-2 derivative of claim 1 wherein L(I), L(II) and L(III) are each independently selected from —NH—, substituted or unsubstituted alkyl groups or substituted or unsubstituted alkenyl groups.
10. The POZ-2 derivative of claim 1 wherein A is H or a substituted or unsubstituted alkyl group.
11. The POZ derivative of claim 1 wherein Br is a C atom and c is 1 and L(I) contains a substituted or unsubstituted aryl group.
12. The POZ derivative of claim 1 wherein Br is a C atom and c is 1, d is 1 and at least one of L(I) and L(II) contains a substituted or unsubstituted aryl group.
13. A target molecule-POZ-2 conjugate of the general formula A-B-TM, wherein
A is a POZ-2 derivative of claim 1 minus any leaving groups eliminated during the reaction of the active functional group on the POZ-2 derivative with a binding partner on a target molecule;
TM is a target molecule, the target molecule containing the binding partner; and
B is a hydrolytically stable linkage formed between the active functional group and the binding partner.
14. The target molecule-POZ-2 conjugate of claim 13 wherein the active functional group is an Iodoacetamide, the binding partner is SH and B is a thioether linkage, the active functional group is a maleimide, the binding partner is SH and B is a thioether linkage, the active functional group is an active carbonate, the binding partner is NH 2 and B is a urethane linkage, the active functional group is an active ester, the binding partner is NH 2 and B is an amide linkage or the active functional group is an aldehyde, the binding partner is NH 2 and B is an amine linkage.
15. The target molecule POZ-2 conjugate of claim 13 wherein the in vivo half-life of the target molecule-POZ-2 conjugate is increased under physiological conditions.
16. The target molecule POZ-2 conjugate of claim 13 wherein at least one POZ chain of the POZ-2 derivative 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.