Hydrolytically stable maleimide-terminated polymers
AssigneeNektar Therapeutics AL, Corporation
InventorsAntoni Kozlowski, Remy F. Gross III, Samuel P. McManus
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Abstract
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.
Claims130
A water-soluble polymer having the structure:
- 91
- 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, and
- said polymer is absent aromatic groups and ester linkages.
A water-soluble polymer having the structure:
- 106
- 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, and
- said polymer is absent aromatic groups and ester linkages.
A method for forming a maleimide terminated polymer, said method comprising the steps of:
- a. reacting POLY-[O]b—C(O)-LG (IX) with NH2—X—NH2 (XII) under conditions effective to form POLY-[O]b—C(O)—H2N—X—NH2 (X), and
- b. converting POLY-[O]b—C(O)—H2N—X—NH2 (X) into POLY-[O]b—C(O)—HN—X-MAL (II),
- 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,
- LG is a leaving group,
- MAL is maleimide,
- and said maleimide terminated polymer is absent aromatic groups and ester linkages.
A conjugate comprising the following structure:
- 113
- 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,
- “POLY-[O]b—C(O)—NH—X-” is absent aromatic groups and ester linkages, and
- “—S-biologically active agent” represents a biologically active agent comprising a thiol (—SH) group.
A conjugate comprising the following structure:
- 114
- 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,
- “POLY-[O]b—C(O)—NH—X-” is absent aromatic groups and ester linkages, and
- “—NH-biologically active agent” represents a biologically active agent comprising an amino group.
A water soluble polymer having the structure:
- 116
- wherein:
- POLY is a water-soluble polymer segment,
- X is a hydrolytically stable linker that is a saturated cyclic or alicyclic hydrocarbon chain having a total of about 3 to about 20 carbon atoms, and
- said polymer is absent aromatic groups and ester linkages.
A method for forming a maleimide terminated polymer, said method comprising:
- a. reacting POLY-[O]b—C(O)-LG with H2N—X-MAL under conditions effective to form POLY-[O]b—C(O)—HN—X-MAL,
- 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,
- LG is a leaving group,
- MAL is maleimide,
- and said maleimide terminated polymer is absent aromatic groups and ester linkages.
Dependencies are inferred from the claim text.