Polymeric alpha-hydroxy aldehyde and ketone reagents and conjugation method

Patent metadata

Field	Value
Publication number	US-10759906-B2
Application number	US-201815867524-A
Country	US
Kind code	B2
Filing date	Jan 10, 2018
Priority date	Sep 11, 2008
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

Provided herein are polymeric α-hydroxy aldehyde or α-hydroxy ketone reagents which can be conjugated to amine-containing compounds to form stable conjugates in a single-step reaction. In selected embodiments, the polymeric reagent itself incorporates an internal proton-abstracting (basic) functional group, to promote more efficient reaction. The substituent is appropriately situated, via a linker if necessary, to position the group for proton abstraction, preferably providing a 4- or 5-bond spacing between the abstracting atom and the hydrogen atom on the α-carbon. Also provided are methods of using the reagents and stable, solubilized conjugates of the reagents with biologically active compounds. In preferred embodiments, the polymeric component of the reagent or conjugate is a polyethylene glycol.

First claim

The invention claimed is:

1. A polymer conjugate having a structure V:

wherein:
POLY is a water-soluble polymer;
R 1 is selected from H, alkyl, hydroxyalkyl, and alkoxyalkyl;
m is 0-12;
each R 2 and R 3 is independently selected from H, alkyl, alkylene, hydroxy, amino, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkylene, aminoalkyl, iminoalkyl, carboxylic acid, alkylcarboxylic acid, phosphate, alkylphosphate, and a further water-soluble polymer,
and
—NH—B represents an amine-containing biologically active compound,
and further wherein (i) at most one of the R 2 and R 3 groups is a water-soluble polymer, (ii) two substituents, R 2 and R 3 , in —(CR 2 R 3 ) m — can together form a ring, and (iii) one R 2 or R 3 group is selected from hydroxy, amino, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkylene, aminoalkyl, iminoalkyl, carboxylic acid, alkylcarboxylic acid, phosphate, and alkylphosphate; and said group R 2 or R 3 and the value of m are selected such that an oxygen or nitrogen atom on R 2 or R 3 is separated from Cα by a four-bond path.

2. The conjugate of claim 1 , wherein m is 0 to 6.

3. The conjugate of claim 1 , where POLY is a polyethylene glycol.

4. The conjugate of claim 1 , where R 1 is H or methyl.

5. The conjugate of claim 1 , wherein one R 2 or R 3 group is selected from amino, aminoalkyl, iminoalkyl, carboxylic acid, and alkylcarboxylic acid.

6. The conjugate of claim 1 , wherein the amine-containing biologically active compound is a polypeptide or protein.

7. A composition comprising the polymer conjugate of claim 1 and a pharmaceutical excipient.

8. The composition of claim 7 , in the form of a liquid solution or suspension suitable for administration by injection.

9. The conjugate of claim 3 , wherein the polyethylene glycol is end-capped.

10. The conjugate of claim 1 , wherein m is 3-6.

Assignees

• Nektar Therapeutics

Inventors

• Culbertson Sean M
• Shen Xiaoming
• Kozlowski Antoni
• Mcmanus Samuel P

Classifications

• C07K1/003 Primary

  by transforming the C-terminal amino acid to amides · CPC title

• C07K17/08

  the carrier being a synthetic polymer · CPC title

• C08L71/02

  Polyalkylene oxides · CPC title

• C08G65/331

  containing oxygen {(cyclic ether compounds C08G65/26)} · CPC title

• C08G65/33317

  heterocyclic · CPC title