Hydrolytically stable maleimide-terminated polymers
View Patent ↗The present invention is directed to hydrolytically stabilized maleimide-functionalized water soluble polymers and to methods for making and utilizing such polymers and their precursors.
1. A conjugate comprising the following structure:
wherein:
POLY is a water-soluble polymer segment,
b is 0 or 1,
X is a hydrolytically stable linker comprising at least 3 contiguous saturated carbon atoms adjacent to the ring nitrogen atom,
“POLY-[O] b —C(O)—NH—X—” is absent aromatic groups and ester linkages, and
“—S-biologically active agent” represents a residue of a biologically active agent comprising a thiol (—SH) group.
2. A composition comprising the conjugate of claim 1 , wherein said composition comprises a single polymer conjugate species.
3. The conjugate of claim 1 , where b is 0.
4. The conjugate of claim 1 , where b is 1.
5. The conjugate of claim 1 , wherein X is a saturated acyclic, cyclic or alicyclic hydrocarbon chain having a total of about 3 to about 20 carbon atoms.
6. The conjugate of claim 5 , wherein X is a saturated acyclic, cyclic, or alicyclic hydrocarbon chain having a total number of carbon atoms selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.
7. The conjugate of claim 5 , wherein X is a linear saturated acyclic hydrocarbon chain.
8. The conjugate of claim 5 , wherein X is a branched saturated acyclic hydrocarbon chain.
9. The conjugate of claim 8 , wherein X is branched at the carbon α to the maleimidyl group.
10. The conjugate of claim 8 , wherein X is branched at the carbon β to the maleimidyl group.
11. The conjugate of claim 8 , wherein X is branched at the carbon γ to the maleimidyl group.
12. The conjugate of claim 5 , having the structure:
wherein:
y is an integer from 3 to about 20;
R 1 , in each occurrence, is independently H or an organic radical that is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkylenecycloalkyl, and substituted alkylenecycloalkyl, and
R 2 , in each occurrence, is independently H or an organic radical that is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkylenecycloalkyl, and substituted alkylenecycloalkyl.
13. The conjugate of claim 12 , wherein R 1 and R 2 in each occurrence is independently H or an organic radical selected from the group consisting of lower alkyl and lower cycloalkyl.
14. The conjugate of claim 13 , wherein R 1 and R 2 are both H, and y is selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, and 10.
15. The conjugate of claim 12 having the structure:
wherein at least one of R 1 or R 2 on C α is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkylenecycloalkyl, and substituted alkylenecycloalkyl.
16. The conjugate of claim 15 , wherein each of R 1 and R 2 on C α is independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkylenecycloalkyl, and substituted alkylenecycloalkyl, and all other non-C α R 1 and R 2 variables are H.
17. The conjugate of claim 15 , wherein R 2 on C α is H.
18. The conjugate of claim 17 , wherein R 1 on C α is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl.
19. The conjugate of claim 1 , wherein X is a saturated cyclic or alicyclic hydrocarbon chain.
20. The conjugate of claim 19 , wherein X has the structure:
and
CYC a is a cycloalkylene group having “a” ring carbons, where the value of “a” ranges from 3 to 12;
p and q are each independently 0 to 20, and p+q+a≦20,
R 1 , in each occurrence, is independently H or an organic radical that is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkylenecycloalkyl, and substituted alkylenecycloalkyl, and
R 2 , in each occurrence, is independently H or an organic radical that is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkylenecycloalkyl, and substituted alkylenecycloalkyl.
21. The conjugate of claim 20 , wherein p and q are each independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8.
22. The conjugate of claim 20 , wherein R 1 , in each occurrence, is independently H or an organic radical that is either lower alkyl or lower cycloalkyl, and R 2 , in each occurrence, is independently H or an organic radical that is either lower alkyl or lower cycloalkyl.
23. The conjugate of claim 20 , wherein a is selected from the group consisting of 5, 6, 7, 8 and 9.
24. The conjugate of claim 23 , wherein a is 6 and CYC a is a 1,1-, 1,2-, 1,3- or 1,4-substituted cyclohexyl ring.
25. The conjugate of claim 24 , wherein p and q each independently range from 0 to 4.
26. The conjugate of claim 24 , wherein the substituents on said substituted cyclohexyl ring are cis.
27. The conjugate of claim 24 , wherein the substituents on said substituted cyclohexyl ring are trans.
28. The conjugate of claim 20 , wherein R 1 and R 2 are H in every occurrence.
29. The conjugate of claim 1 , wherein POLY is selected from the group consisting of a poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, poly(acryloylmorpholine), and poly(oxyethylated polyol).
30. The conjugate of claim 29 , wherein POLY is a poly(alkylene oxide).
31. The conjugate of claim 30 , wherein POLY is a poly(ethylene glycol).
32. The conjugate of claim 31 , wherein the poly(ethylene glycol) is terminally capped with an end-capping moiety.
33. The conjugate of claim 32 , wherein the end-capping moiety is independently selected from the group consisting of alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, alkynyloxy, substituted alkynyloxy, aryloxy, and substituted aryloxy.
34. The conjugate of claim 33 , wherein the end-capping moiety is selected from the group consisting of methoxy, ethoxy, and benzyloxy.
35. The conjugate of claim 31 , wherein the poly(ethylene glycol) has a nominal average molecular mass of from about 100 daltons to about 100,000 daltons.
36. The conjugate of claim 35 , wherein the poly(ethylene glycol) has a nominal average molecular mass of from about 1,000 daltons to about 50,000 daltons.
37. The conjugate of claim 36 , wherein the poly(ethylene glycol) has a nominal average molecular mass of from about 2,000 daltons to about 30,000 daltons.
38. The conjugate of claim 31 , wherein said poly(ethylene glycol) has a structure selected from the group consisting of linear, branched and forked.
39. The conjugate of claim 1 having the structure:
wherein X and b are as previously defined,
b′ is 0 or 1, and
X′ is a hydrolytically stable linker comprising at least 3 contiguous saturated carbon atoms adjacent to the ring nitrogen atom.
40. The conjugate of claim 39 , wherein said POLY is linear and the conjugate is homobifunctional.