Polymeric alpha-hydroxy aldehyde and ketone reagents and conjugation method

Patent metadata

Field	Value
Publication number	US-11634540-B2
Application number	US-202117538885-A
Country	US
Kind code	B2
Filing date	Nov 30, 2021
Priority date	Sep 11, 2008
Publication date	Apr 25, 2023
Grant date	Apr 25, 2023

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 a structure IV:

where
R 1 is selected from H, lower alkyl, and alkoxyalkyl;
R 4 is a two- or three-carbon chain which may be substituted with one or more groups selected from alkyl, alkenyl, aryl, alkoxy, halo, cyano, and a water soluble polymer, wherein the carbon adjacent to the carbonyl carbon is not substituted with hydroxy, and wherein two substituents on R 4 may together form an aliphatic or aromatic ring;
NR 5 is a secondary or tertiary amino group which is linked to a water soluble polymer, POLY, via an optional spacer group Z, where R 5 is hydrogen or an alkyl group which may form a ring with spacer group Z when present; and
—NH—B represents the residue of an amine-containing biologically active compound.

2. The conjugate of claim 1 , where POLY is a polyethylene glycol, and R 1 is H or methyl.

3. The conjugate of claim 2 , where R 1 is H.

4. The conjugate of claim 1 , where R 4 is unsubstituted.

5. The conjugate of claim 1 , where R 5 is lower alkyl.

6. The conjugate of claim 5 , where R 5 is methyl.

7. The conjugate of claim 1 , where NR 5 together with Z forms a piperazine ring to which POLY is linked via a ring nitrogen atom.

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

9. The conjugate of claim 1 , wherein R 4 is a three-carbon chain which may be substituted with one or more groups selected from alkyl, alkenyl, aryl, alkoxy, halo, cyano, and a water soluble polymer, wherein the carbon adjacent to the carbonyl carbon is not substituted with hydroxy, and wherein two substituents on R 4 may together form an aliphatic or aromatic ring.

10. The conjugate of claim 9 , having a structure:

where POLY is a polyethylene glycol, and each of the substituents R c , R c′ , R d , and R d′ is independently selected from hydrogen, alkyl, alkenyl, aryl, alkoxy, halo, cyano, and a water soluble polymer, and each of the substituents R b and R b′ is independently selected from hydrogen, alkyl, alkenyl, aryl, alkoxy, halo, cyano, and a water soluble polymer, wherein at most one of these substituents is a water soluble polymer, and wherein any two of these substituents can together form an aliphatic ring.

11. The conjugate of claim 10 , wherein the substituents R b , R b′ , R c , R c′ , R d , and R d′ are independently selected from hydrogen and alkyl, and further wherein any two such alkyl substituents can together form a 5- to 7-membered aliphatic ring.

12. The conjugate of claim 11 , wherein R 5 is methyl and R b , R b′ , R c , R c′ , R d , and R d′ are each hydrogen.

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

14. The conjugate of claim 13 , wherein POLY is linear.

15. The conjugate of claim 13 , wherein POLY is branched and has two polymer arms.

16. The conjugate of claim 13 , wherein POLY has a weight average molecular weight of from about 100 daltons to about 150,000 daltons.

17. The conjugate of claim 16 , wherein POLY has a weight average molecular weight of from greater than about 5,000 daltons to about 100,000 daltons.

Assignees

• Nektar Therapeutics

Inventors

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

Classifications

• C07K17/08

  the carrier being a synthetic polymer · CPC title

• C08G65/3318

  heterocyclic · CPC title

• C08G65/33313

  aromatic · CPC title

• C08G65/33317

  heterocyclic · CPC title

• C08G65/331

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