Hydrolytically stable maleimide-terminated polymers
The present invention is directed to conjugates of hydrolytically stabilized maleimide-functionalized water soluble polymers and to methods for making and utilizing such polymers and their precursors.
1. A conjugate formed by reaction of a biologically active agent with a water-soluble polymer having the structure:
wherein:
POLY is a water-soluble polymer segment,
b is 0 or 1,
s is an integer selected from the group consisting of 3, 4, 5, 6, 7 and 8,
R 3 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, and
T is a hydrolytically stable linker comprising at least 4 contiguous saturated carbon atoms.
2. The conjugate of claim 1 , wherein R 3 is H.
3. The conjugate of claim 1 , wherein T is a saturated acyclic, cyclic or alicyclic hydrocarbon chain having a total of 4 to 20 carbon atoms.
4. The conjugate of claim 1 , wherein the water-soluble polymer has structure:
wherein R 1 and R 2 , in each occurrence, are each 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 y is an integer from 1 to 20.
5. The conjugate of claim 4 , wherein the water-soluble polymer has structure:
6. A conjugate formed by reaction of a biologically active agent with a water-soluble polymer having the structure:
wherein:
POLY is a water-soluble polymer segment,
b is 0 or 1,
s is an integer selected from the group consisting of 3, 4, 5, 6, 7 and 8,
R 3 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, and
T is a hydrolytically stable linker comprising at least 4 contiguous saturated carbon atoms.
7. The conjugate of claim 6 , wherein the water-soluble polymer has the structure:
wherein R 1 and R 2 , in each occurrence, are each 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 y is an integer from 1 to 20.