Branched polymers and their conjugates
DC CAFCFirst Claim
Patent Images
1. A branched reactive polymer having the structure:
-
Y—
(X)p-R(—
X′
-POLY)qwherein;
R is an aliphatic hydrocarbon having a length of at least three carbon atoms;
each POLY is a water soluble and non-peptide polymer, wherein the molecular weight of each POLY is selected such that the total molecular weight or the branched reactive polymer is independently selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), polysaccharides, poly(α
-hydroxy acid), poly(vinyl alcohol), plyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof is at least about 5,000 Da;
X′
is a heteroatom linkage;
X is a linker;
p is 0 or 1;
q is 2 to about 10; and
Y is a functional group reactive with an electrophilic or nucleophilic group.
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Abstract
The present invention is directed to branched reactive water-soluble polymers comprising at least two polymer arms, such as poly(ethylene glycol), attached to a central aliphatic hydrocarbon core molecule through heteroatom linkages. The branched polymers bear at least one functional group for reacting with a biologically active agent to form a biologically active conjugate. The functional group of the branched polymer can be directly attached to the aliphatic hydrocarbon core or via an intervening linkage, such as a heteroatom, -alkylene-, —O-alkylene-O—, -alkylene-O-alkylene-, -aryl-O—, —O-aryl-, (—O-alkylene-)m, or (-alkylene-O—)m linkage, wherein m is 1–10.
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Citations
35 Claims
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1. A branched reactive polymer having the structure:
-
Y—
(X)p-R(—
X′
-POLY)qwherein; R is an aliphatic hydrocarbon having a length of at least three carbon atoms; each POLY is a water soluble and non-peptide polymer, wherein the molecular weight of each POLY is selected such that the total molecular weight or the branched reactive polymer is independently selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), polysaccharides, poly(α
-hydroxy acid), poly(vinyl alcohol), plyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof is at least about 5,000 Da;X′
is a heteroatom linkage;X is a linker; p is 0 or 1; q is 2 to about 10; and Y is a functional group reactive with an electrophilic or nucleophilic group. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 32, 33, 34, 35)
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21. A method of preparing a branched poly(alkylene glycol) polymer, comprising:
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providing an aliphatic hydrocarbon substituted with at least two nucleophilic groups and at least one protected functional group; polymerizing alkylene oxide monomer units onto the aliphatic hydrocarbon at the site of the nucleophilic groups to form at least two poly(alkylene glycol) polymers attached to the aliphatic hydrocarbon via heteroatom linkages; end-capping the poly(alkylene glycol) polymers with an alkyl group to form alkoxy-terminated polymers; and deprotecting the protected hydroxyl group. - View Dependent Claims (22, 23, 24, 25, 26, 27, 28)
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29. A branched reactive polymer having the structure:
-
Y—
(X)p-R(—
X′
-POLY)qwherein; R is an aliphatic hydrocarbon having a length of at least three carbon atoms; each POLY is a water soluble and non-peptide polymer is independently selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), polysaccharides, poly(α
-hydroxy acid), poly(vinyl alcohol), plyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof covalently attached to a methoxy capping group;X′
is —
NH—
, —
O—
, or —
S—
;X is a linker; p is 0 or 1; q is 2 to about 10; and Y is a functional group.
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30. A branched reactive polymer having the structure:
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—
HO—
R(—
X′
-POLY)qwherein; R is an aliphatic hydrocarbon having a length of at least three carbon atoms; each POLY is a water soluble and non-peptide polymer is independently selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), polysaccharides, poly(α
-hydroxy acid), poly(vinyl alcohol), plyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof;X′
is —
NH—
, —
O—
, or —
S—
; andq is 2 to about 10.
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31. A biologically active conjugate, comprising a biologically active molecule covalently attached to a branched reactive polymer having the structure:
-
Y—
(X)p-R(—
X′
-POLY)qwherein; R is an aliphatic hydrocarbon having a length of at least three carbon atoms; each POLY is a water soluble and non-peptidic polymer is independently selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), polysaccharides, poly(α
-hydroxy acid), poly(vinyl alcohol), plyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof;X′
is —
NH—
, —
O—
, or —
S—
;X is linker ; p is 0 or 1; q is 2 to about 10; and Y is a functional group.
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Specification