Degradable multi-arm polyethylene glycol derivative

Patent metadata

Field	Value
Publication number	US-12404367-B2
Application number	US-202017763498-A
Country	US
Kind code	B2
Filing date	Sep 25, 2020
Priority date	Sep 26, 2019
Publication date	Sep 2, 2025
Grant date	Sep 2, 2025

Abstract

A multi-arm, degradable polyethylene glycol derivative with a high molecular weight that does not cause vacuolation of cells is provided. A degradable polyethylene glycol derivative represented by the following formula (1):

wherein n1 and n2 are each independently 45-950, W 1 and W 2 are each independently an oligopeptide of 2-47 residues, a1 and a2 are each independently 1-8, Q is a hydrocarbon chain having 2-12 carbon atoms and optionally containing an oxygen atom and/or a nitrogen atom, X 1 and X 2 are each independently a functional group capable of reacting with a bio-related substance, and L 1 , L 2 , L 3 , L 4 , L 5 and L 6 are each independently a divalent spacer.

First claim

The invention claimed is:

1. A degradable polyethylene glycol derivative represented by the following formula (1):

wherein n1 and n2 are each independently 45-950, W 1 and W 2 are each independently an oligopeptide of 2-47 residues, a1 and a2 are each independently 1-8, Q is a hydrocarbon chain having 2-12 carbon atoms and optionally containing an oxygen atom and/or a nitrogen atom, X 1 and X 2 are each independently a functional group capable of reacting with a bio-related substance, and L 1 , L 2 , L 3 , L 4 , L 5 and L 6 are each independently a divalent spacer.

2. The degradable polyethylene glycol derivative according to claim 1 , wherein the oligopeptide for W 1 and W 2 is an oligopeptide having glycine as a C-terminal amino acid.

3. The degradable polyethylene glycol derivative according to claim 1 , wherein the oligopeptide for W 1 and W 2 is an oligopeptide having at least one hydrophobic neutral amino acid having a hydropathy index of not less than 2.5.

4. The degradable polyethylene glycol derivative according to claim 1 , wherein the total molecular weight is not less than 20,000.

5. The degradable polyethylene glycol derivative according to claim 1 , wherein X 1 and X 2 are each independently selected from the group consisting of an active ester group, an active carbonate group, an aldehyde group, an isocyanate group, an isothiocyanate group, an epoxide group, a maleimide group, a vinylsulfonyl group, an acrylic group, a sulfonyloxy group, a carboxyl group, a thiol group, a dithiopyridyl group, an α-haloacetyl group, an alkynyl group, an allyl group, a vinyl group, an amino group, an oxyamino group, a hydrazide group, and an azide group.

6. A degradable polyethylene glycol derivative represented by the following formula (2):

wherein n3 and n4 are each independently 110-950, W 3 and W 4 are each independently an oligopeptide of 2-5 residues, Q is a hydrocarbon chain having 2-12 carbon atoms and optionally containing an oxygen atom and/or a nitrogen atom, X 1 and X 2 are each independently a functional group capable of reacting with a bio-related substance, and L 1 , L 2 , L 3 , L 4 , L 5 and L 6 are each independently a divalent spacer.

7. The degradable polyethylene glycol derivative according to claim 6 , wherein the oligopeptide for W 3 and W 4 is an oligopeptide composed only of a neutral amino acid and having glycine as a C-terminal amino acid.

8. The degradable polyethylene glycol derivative according to claim 6 , wherein the oligopeptide for W 3 and W 4 is an oligopeptide having at least one hydrophobic neutral amino acid having a hydropathy index of not less than 2.5.

9. A degradable polyethylene glycol derivative represented by the following formula (3):

wherein n1 and n2 are each independently 45-950, W 5 and We are each independently an oligopeptide consisting of 5 to 47 residues and having a symmetrical structure centered on glutamic acid, b1 and b2 are each independently 2-8, Q is a hydrocarbon chain having 2-12 carbon atoms and optionally containing an oxygen atom and/or a nitrogen atom, X 1 and X 2 are each independently a functional group capable of reacting with a bio-related substance, and L 1 , L 2 , L 3 , L 4 , L 5 and L 6 are each independently a divalent spacer.

10. The degradable polyethylene glycol derivative according to claim 9 , wherein the oligopeptide with a symmetrical structure centered on glutamic acid for W 5 and W 6 is an oligopeptide having a structure of the following v1 or v2 or v3:

wherein Glu is a glutamic acid residue, and Z is a degradable oligopeptide of 2-5 residues consisting of neutral amino acids excluding cysteine.

11. The degradable polyethylene glycol derivative according to claim 10 , wherein the degradable oligopeptide for Z is an oligopeptide having glycine as a C-terminal amino acid.

12. The degradable polyethylene glycol derivative according to claim 10 , wherein the degradable oligopeptide for Z is an oligopeptide having at least one hydrophobic neutral amino acid having a hydropathy index of not less than 2.5.

13. A degradable polyethylene glycol derivative-bonded bio-related substance represented by the following formula (4):

wherein n1 and n2 are each independently 45-950, W 1 and W 2 are each independently an oligopeptide of 2-47 residues, a1 and a2 are each independently 1-8, Q is a hydrocarbon chain having 2-12 carbon atoms and optionally containing an oxygen atom or a nitrogen atom, D 1 and D 2 are each independently a bio-related substance, and L 3 , L 4 , L 5 , L 6 , L 11 and L 12 are each independently a divalent spacer.

14. The bio-related substance according to claim 13 , wherein L 11 and L 12 are each independently a urethane bond, an amide bond, an ether bond, a thioether bond, a secondary amino group, a carbonyl group, a urea bond, a triazolyl group, a bond of maleimide and mercapto, an oxime bond, or an alkylene group optionally comprising such bond and group.

15. The bio-related substance according to claim 13 , wherein the bio-related substance for D is a hormone, a cytokine, an antibody, an aptamer or an enzyme.

Assignees

• Nof Corp
• Tokyo Inst Tech

Inventors

• Yoshioka Hiroki
• Hamura Ken
• Osakama Kazuki
• Nishiyama Nobuhiro

Classifications

• C08G83/003

  Dendrimers · CPC title

• C07K14/46

  from vertebrates · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title

• C07K5/1008

  the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala · CPC title

• C07K14/00 Primary

  Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof · CPC title