Intermediates useful in the preparation of maleimide functionalized polymers
View Patent ↗Methods for forming maleimide functionalized polymers are provided. In one such embodiment, a maleimide functionalized polymer is prepared in a method that includes a step of carrying out a reverse Diels-Alder reaction. Intermediates useful in the methods, as well as methods for preparing the intermediates, are also provided. Also provided are polymeric reagents, methods of using polymeric reagents, compounds and conjugates.
1. A Diels-Alder adduct-containing polymer of the following structure:
wherein:
POLY is a water soluble and non-peptidic polymer (i) terminating in either a hydroxyl group or end capping group selected from the group consisting of methoxy, ethoxy, butyloxy and benzyloxy, (ii) having a weight average molecular weight of greater than 4,000 Daltons and less than about 300,000 Daltons, and (iii) is selected from the group consisting of poly(alkylene glycol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(α-hydroxyacetic acid), poly(acrylic acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers or terpolymers thereof;
L is a linkage comprising -L 1 -L 2 -, wherein L 1 comprises a linkage selected from the group consisting of a heteroatom linkage, an amide linkage, an amine linkage, a urethane linkage and a urea linkage, and L 2 is a saturated acyclic or alicyclic hydrocarbon chain adjacent to the nitrogen atom of the Diels-Alder adduct, the hydrocarbon chain comprising a bivalent saturated cycloalkyl group, an alkylene group, or a combination thereof, and having a total number of carbons ranging from 1 to about 30;
X is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, —C(O)—, heteroatom, substituted heteroatom and two hydrogens, wherein one of the two hydrogens attached to the carbon bearing R 1 and the other to the carbon bearing R 4 ; and
each of R 1 , R 2 , R 3 and R 4 is independently selected from the group consisting of H, halo, hydroxyl, carboxyl, carboxylalkyl, thiol, alkylthio, acyl, acyloxy, nitro, cyano, azido, trihalomethyl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, and substituted heteroaryl.
2. The polymer of claim 1 , wherein the Diels-Alder adduct readily undergoes a retro Diels-Alder reaction.
3. The polymer of claim 1 , wherein the Diels-Alder adduct comprises about 10 to about 20 total ring atoms and 1 or 2 heteroatoms in the ring.
4. The polymer of claim 1 , wherein the polymer is capable of releasing a diene in a retro Diels-Alder reaction.
5. The polymer of claim 4 , wherein the diene is selected from the group consisting furan, pyrrole, and N-alkylated pyrroles.
6. The polymer of claim 1 , where in L 1 further comprises a moiety selected from the group consisting of alkylene chain, ethylene glycol oligomer and combinations thereof.
7. The polymer of claim 1 , wherein L 2 has the structure —(CR 5 R 6 ) m — or —(CR 5 R 6 ) p —C3-C12cycloalkyl-(CR 5 R 6 ) q —, wherein R 5 and R 6 are each independently H, alkyl, or cycloalkyl, m is 1 to about 20, and each of p and q is independently 0 to about 10.
8. The polymer of claim 1 , having the structure:
wherein n′ is 2 to about 10.
9. The polymer of claim 1 , wherein the polymer is a poly(ethylene glycol).
10. The polymer of claim 9 , wherein the poly(ethylene glycol) has a molecular weight of greater than 4,000 to about 100,000 Daltons.