Polymer Derivatives Comprising an Imide Branching Point

A water-soluble polymer having one of the following structures:

• wherein:
• POLY1 is a first water-soluble polymer segment;
• POLY2 is a second water-soluble polymer segment;
• each of (a), (b) and (c) is independently either zero or one;
• X1, when present, is a first spacer moiety;
• X2, when present, is a second spacer moiety;
• X3, when present, is a third spacer moiety;
• and
• Z is a reactive group.

A conjugate comprising:

• (i) an imide group comprising a linking nitrogen atom, a first carbonyl group covalently attached to the linking nitrogen atom, and a second carbonyl group covalently attached to the linking nitrogen atom;
• (ii) a first water-soluble polymer segment covalently attached, either directly or through one or more atoms, to the first carbonyl group of the imide group;
• (iii) a second water-soluble polymer segment covalently attached, either directly or through one or more atoms, to the second carbonyl group of the imide group;
• and (iv) a pharmacologically active agent covalently attached, either directly or through one or more atoms, to the linking nitrogen atom.

A method of preparing a water-soluble polymer having an imide branching moiety comprising the steps of:

• (i) providing a first water-soluble polymer segment carrying a first reactive group, the first reactive group comprising a carbonyl group;
• (ii) reacting the first water-soluble polymer segment with ammonia to form a water-soluble polymer intermediate carrying an amide group (—C(O)—NH2);
• (iii) treating the water-soluble polymer intermediate with a strong base to remove a proton from the terminal amine of the amide group;
• (iv) reacting the water-soluble polymer intermediate with a second water-soluble polymer segment carrying a second reactive group comprising a carbonyl group to form an imide-linked water-soluble polymer, the imide linking group comprising a linking nitrogen atom, a first carbonyl group covalently attached to the linking nitrogen atom, and a second carbonyl group covalently attached to the linking nitrogen atom;
• and
• (v) optionally, attaching a reactive group to the linking nitrogen atom of the imide-linked water-soluble polymer.

A method of preparing a water-soluble polymer having an imide branching moiety comprising the steps of:

• (i) providing a first water-soluble polymer segment carrying a first reactive group, the first reactive group comprising a carbonyl group;
• (ii) reacting the first water-soluble polymer segment with a molecule comprising a second reactive group and an amine group, optionally separated by a spacer moiety, to form a water-soluble polymer intermediate comprising an amide linkage (—C(O)—NH—) between the water-soluble polymer segment and the second reactive group;
• (iii) treating the water-soluble polymer intermediate with a strong base to remove a proton from the nitrogen atom of the amide linkage;
• and
• (iv) reacting the water-soluble polymer intermediate with a second water-soluble polymer segment carrying a third reactive group comprising a carbonyl group to form an imide-linked water-soluble polymer, the imide linking group comprising a linking nitrogen atom, a first carbonyl group covalently attached to the linking nitrogen atom, and a second carbonyl group covalently attached to the linking nitrogen atom.