Polymeric alpha-hydroxy aldehyde and ketone reagents and conjugation method

Patent metadata

Field	Value
Publication number	US-11220575-B2
Application number	US-202016937378-A
Country	US
Kind code	B2
Filing date	Jul 23, 2020
Priority date	Sep 11, 2008
Publication date	Jan 11, 2022
Grant date	Jan 11, 2022

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 polymeric conjugate having the structure VI:

wherein:
(i) R 7 is —C(═O)—CHR 1 —NH-B, and R 8 is selected from —C(═O)OH, —CH 2 OH, —C(═O)N(R 1 ) 2 , —CH 2 N(R 1 ) 2 , —OH, and —N(R 1 ) 2 ; or
(ii) R 7 is —CHR 1 —C(═O)—CHR 1 —NH-B, and R 8 is —OH or —N(R 1 ) 2 ;
POLY is a water-soluble polymer;
—NH-B represents the residue of an amine-containing biologically active compound; and
each R 1 is independently selected from H, lower alkyl, and alkoxyalkyl.

2. The conjugate of claim 1 , wherein each R 1 is independently H or methyl.

3. The conjugate of claim 1 , wherein each R 1 is H.

4. The conjugate of claim 1 , wherein R 7 is —C(═O)—CHR 1 —NH—B, where R 1 is H or methyl, and R 8 is —C(═O)OH or —CH 2 NH 2 .

5. The conjugate of claim 1 , wherein R 7 is —CHR 1 —C(═O)—CHR 1 —NH—B, where each R 1 is independently H or methyl, and R 8 is —OH or —NH 2 .

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

7. The conjugate of claim 1 , wherein POLY is a poly(ethylene glycol).

8. The conjugate of claim 7 , wherein POLY is methoxy poly(ethylene glycol).

9. A pharmaceutical composition comprising the polymeric conjugate of claim 1 and a pharmaceutical excipient.

10. The pharmaceutical composition of claim 9 , wherein the composition is a solid.

11. The pharmaceutical composition of claim 9 , wherein the composition is a liquid.

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

• C08G65/33317

  heterocyclic · CPC title

• C08G65/331

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

• C08G65/26

  from cyclic ethers and other compounds · CPC title

• C08G65/33306

  acyclic · CPC title