Method for preparing water-soluble polymer derivatives bearing a terminal carboxylic acid
View Patent ↗A method is provided for preparing water-soluble polymer derivatives bearing a terminal carboxylic acid or ester thereof. The method involves the hydrolyzing an ortho ester of a water-soluble polymer so as provide the corresponding acid. In addition, the invention provides water-soluble polymers bearing a terminal carboxylic acid or ester thereof, intermediates and reagents useful in carrying out the method, as well as gels, pharmaceutical formulations, conjugates related to the described water-soluble polymer derivatives.
1. An ortho ester of a branched water-soluble polymer, wherein the branched water-soluble polymer has two or more polymer arms and the ortho ester (a) is attached to each of the two or more polymer arms, and (b) has the following structure,
wherein:
(a) is either zero or one;
X, when present, is a spacer moiety;
(z) is an integer from 1 to 24;
R 1 , in each occurrence, is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl;
R 2 , in each occurrence, is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl; and
each R 4 is a either (i) an organic radical independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl, or (ii) one or more atoms that combine with another R 4 or the remaining R 4 moieties to form a cyclic ortho ester structure.
2. The polymer of claim 1 , wherein the branched water-soluble polymer has three polymer arms and the ortho ester is attached to each one of the three polymer arms.
3. The polymer of claim 1 , wherein the branched water-soluble polymer has four polymer arms and the ortho ester is attached to each one of the four polymer arms.
4. The polymer of claim 1 , wherein (z) equals three and the ortho ester has the following structure:
5. The polymer of claim 4 , wherein each occurrence of R 1 and R 2 is H.
6. The polymer of claim 3 , wherein (z) equals three and the ortho ester has the following structure:
7. The polymer of claim 6 , wherein each occurrence of R 1 and R 2 is H.
8. The polymer of claim 1 , wherein each R 4 combines with another R 4 or the remaining R 4 moieties to faun an ortho ester cyclic structure.
9. The polymer of claim 8 , wherein each R 4 combines with another R 4 or the remaining R 4 moieties to form an ortho ester cyclic structure selected from the group consisting of
10. The polymer of claim 6 , wherein each R 4 combines with another R 4 or the remaining R 4 moieties to form an ortho ester cyclic structure.
11. The polymer of claim 10 , wherein each R 4 combines with another R 4 or the remaining R 4 moieties to form an ortho ester cyclic structure selected from the group consisting of
12. The polymer of claim 1 , wherein the ortho ester has the following structure:
13. The polymer of claim 12 , wherein (a) is zero and the ortho ester has the following structure:
14. The polymer of claim 10 , wherein the ortho ester cyclic structure has the following structure:
15. The polymer of claim 14 , wherein (a) is zero and the ortho ester cyclic structure has the following structure:
16. The polymer of claim 1 , wherein each of the two or more polymer arms is a polymer selected from the group consisting of a poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, poly(acryloylmorpholine), and poly(oxyethylated polyol).
17. The polymer of claim 16 , wherein each of the two or more polymer arms is a poly(alkylene oxide).
18. The polymer of claim 17 , wherein the poly(alkylene oxide) is a poly(ethylene glycol).
19. The polymer of claim 18 , wherein the poly(ethylene glycol) has a molecular weight of from about 5,000 daltons to about 100,000 daltons.
20. The polymer of claim 19 , wherein the poly(ethylene glycol) has a molecular weight of from about 5,000 daltons to about 25,000 daltons.
21. The polymer of claim 15 , wherein each of the four polymer arms is selected a polymer from the group consisting of a poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, poly(acryloylmorpholine), and poly(oxyethylated polyol).
22. The polymer of claim 21 , wherein each of the four more polymer arms is a poly(alkylene oxide).
23. The polymer of claim 22 , wherein the poly(alkylene oxide) is a poly(ethylene glycol).
24. The polymer of claim 23 , wherein the poly(ethylene glycol) has a molecular weight of from about 5,000 daltons to about 100,000 daltons.
25. The polymer of claim 24 , wherein the poly(ethylene glycol) has a molecular weight of from about 5,000 daltons to about 25,000 daltons.
26. A polymer selected from the group consisting of
wherein (m) is defined such as to provide —(CH 2 CH 2 O)— with a molecular weight of from about 1,000 Daltons to about 50,000 Daltons.
27. The polymer of claim 26 , wherein the molecular weight is about 30,000 Daltons.
28. The polymer of claim. 26 , wherein the molecular weight is about 40,000 Daltons.