Poly (ethylene glycol) derivatives with proximal reactive groups
AssigneeShearwater Corporation
InventorsJ. MILTON HARRIS, ANTONI KOZLOWSKI
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Abstract
An activated, substantially water soluble poly(ethylene glycol) is provided having of a linear or branched poly(ethylene glycol) backbone and at least one terminus linked to the backbone through a hydrolytically stable linkage, wherein the terminus is branched and has proximal reactive groups. The free reactive groups are capable of reacting with active moieties in a biologically active agent such as a protein or peptide thus forming conjugates between the activated poly(ethylene glycol) and the biologically active agent.
Claims48
An activated, water soluble polymer comprising a polymer backbone and at least one terminus linked to said polymer backbone through a stable linkage, wherein said at least one terminus comprises a branching moiety and proximal reactive groups linked to said branching moiety that are capable of forming covalent linkages with another molecule.
An activated water soluble polymer having the formula:
- POLY-Y—CHXX′
- wherein POLY is a polymer backbone, Y is a hydrolytically stable linkage, and X and X′ are reactive groups having a reactive moiety, which may be the same or different, and are selected from the group consisting of active esters, active carbonates, aldehydes, isocyanates, isothiocyanates, epoxides, alcohols, maleimides, vinylsulfones, hydrazides, dithiopyridines, and iodoacetamides.
An activated water soluble polymer having the formula:
- B-[POLY-Y—CHXX′]n
- wherein
- B is a central core;
- POLY is a polymer backbone;
- Y is a hydrolytically stable linkage;
- n is from 2 to 200;
- X and X′ are reactive groups having a reactive moiety selected from the group consisting of active esters, active carbonates, aldehydes, isocyanates, isothiocyanates, epoxides, alcohols, maleimides, vinylsulfones, hydrazides, dithiopyridines, and iodoacetamides.
A method for preparing an activated water soluble polymer, said polymer comprising of a polymer backbone and at least one branched terminus having proximal reactive groups thereon, said terminus linked to said polymer backbone through a stable linkage, said method comprising:
- providing a first intermediate polymer comprising said polymer backbone linked to a reactive end group;
- providing a reactive compound having three free reactive groups linked to a branching moiety, one of said three free groups being capable of reacting with said reactive end group of the first intermediate polymer to form said stable linkage;
- and
- reacting the reactive end group of said intermediate polymer with said one of said three free groups of the compound to form said stable linkage.
A method for preparing an activated water soluble polymer represented by mPEGO—CH(CH2SO2CH═CH2)2, where mPEG represents methyl poly(ethylene glycol), comprising the steps of:
- providing mPEG-O-Ms, wherein Ms represents mesylate;
- providing NaO—CH(CH2—O-Bz)2, wherein Bz represents a benzyl moiety;
- reacting mPEG-O-Ms with NaO—CH(CH2—O-Bz)2 to form mPEGO—CH(CH2OBz)2;
- converting mPEGO—CH(CH2OBz)2 to mPEGO—CH(CH2OH)2;
- substituting a mesylate group for both hydroxyl groups in mPEGO—CH(CH2OH)2 to form mPEGO—CH(CH2OMs)2;
- converting mPEGO—CH(CH2OMs)2 into mPEGO—CH(CH2SCH2CH2OH)2;
- oxidizing the sulfur atom into a sulfone group;
- and
- converting the sulfone alcohol group into a vinyl sulfone group, thus forming mPEGO—CH(CH2SO2CH═CH2)2.
A conjugate comprising:
- a biologically active agent;
- and
- an activated water soluble polymer comprising a polymer backbone having at least one terminus linked to said polymer backbone through a stable linkage, wherein said at least one terminus comprises a branching moiety having proximal reactive groups linked to said branching moiety,
- said biologically active agent being covalently linked to at least one of said proximal reactive groups.
Dependencies are inferred from the claim text.