Degradable polyethylene glycol derivative

Patent metadata

Field	Value
Publication number	US-12187846-B2
Application number	US-201917042711-A
Country	US
Kind code	B2
Filing date	Mar 29, 2019
Priority date	Mar 29, 2018
Publication date	Jan 7, 2025
Grant date	Jan 7, 2025

Abstract

The invention provides a high-molecular-weight polyethylene glycol derivative that does not cause vacuolation of cells. The degradable polyethylene glycol derivative is represented by the following formula (1):

wherein m is 1-7, n1 and n2 are each independently 45-682, p is 1-4, R is an alkyl group having 1-4 carbon atoms, Z is an oligopeptide with 2-8 residues composed of neutral amino acids excluding cysteine, Q is a residue of a compound having 2-5 active hydrogens, X is a functional group capable of reacting with a bio-related substance, and L 1 , L 2 , L 3 , L 4 and L 5 are each independently a single bond or a divalent spacer.

First claim

The invention claimed is:

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

wherein m is 1-7, n1 and n2 are each independently 45-682, p is 1-4, R is an alkyl group having 1-4 carbon atoms, Z is an oligopeptide with 2-8 residues composed of neutral amino acids excluding cysteine, Q is a residue of a compound having 2-5 active hydrogens, X is a functional group capable of reacting with a bio-related substance, and L 1 , L 2 , L 3 , L 4 and L 5 are each independently a single bond or a divalent spacer, and
wherein the oligopeptide for Z is an oligopeptide having at least one hydrophobic neutral amino acid having a hydropathy index of not less than 2.5.

2. The degradable polyethylene glycol derivative according to claim 1 , wherein Q is a residue of ethylene glycol, lysine, aspartic acid, glutamic acid, glycerol, pentaerythritol, diglycerol or xylitol.

3. The degradable polyethylene glycol derivative according to claim 1 , wherein Q is a residue of an oligopeptide, and the oligopeptide has 4 to 8 residues and comprises any one of lysine, aspartic acid, and glutamic acid, and neutral amino acids excluding cysteine as the other amino acids.

4. The degradable polyethylene glycol derivative according to claim 3 , wherein the oligopeptide for Q is an oligopeptide having glycine as C-terminal amino acid.

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

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

7. The degradable polyethylene glycol derivative according to claim 1 , having a total molecular weight of not less than 30,000.

8. The degradable polyethylene glycol derivative according to claim 1 , wherein L 1 , L 2 , L 3 , L 4 and L 5 are each independently a urethane bond, an amide bond, an ether bond, a thioether bond, a secondary amino group, a urea bond, or an alkylene group optionally comprising such bond or group.

9. The degradable polyethylene glycol derivative according to claim 1 , wherein X is 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 vinylsulfone group, an acrylic group, a sulfonyloxy group, a carboxyl group, a thiol group, a dithiopyridyl group, an a-haloacetyl group, an alkynyl group, an allyl group, a vinyl group, an amino group, an oxyamino group, a hydrazide group and an azide group.

10. The degradable polyethylene glycol derivative according to claim 1 that is represented by the following formula (2):

wherein m is 1-7, n1 and n2 are each independently 45-682, p is 1-4, R is an alkyl group having 1-4 carbon atoms, Z 1 is an oligopeptide with 2-6 residues composed of neutral amino acids excluding cysteine, A is a hydrophobic neutral amino acid having a hydropathy index of not less than 2.5, a is 0 or 1, b is 1, Q is a residue of a compound having 2-5 active hydrogens, X is a functional group capable of reacting with a bio-related substance, and L 1 , L 2 , L 3 , L 4 and L 5 are each independently a single bond or a divalent spacer.

11. The degradable polyethylene glycol derivative according to claim 10 that is represented by the following formula (3):

wherein n3 and n4 are each independently 45-682, p is 1-4, R is an alkyl group having 1-4 carbon atoms, Z 1 is an oligopeptide with 2-6 residues composed of neutral amino acids excluding cysteine, A is a hydrophobic neutral amino acid having a hydropathy index of not less than 2.5, a is 0 or 1, b is 1, Q is a residue of a compound having 2-5 active hydrogens, X is a functional group capable of reacting with a bio-related substance, and L 1 , L 2 , L 3 , L 4 and L 5 are each independently a single bond or a divalent spacer.

12. The degradable polyethylene glycol derivative according to claim 1 that is represented by the following formula (4):

wherein m is 1-7, n5 and n6 are each independently 113-682, R is an alkyl group having 1 4 carbon atoms, Z is an oligopeptide with 2-8 residues composed of neutral amino acids excluding cysteine, X is a functional group capable of reacting with a bio-related substance, and L 2 , L 3 , L 4 and L 5 are each independently a single bond or a divalent spacer, and
wherein the 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. The degradable polyethylene glycol derivative according to claim 10 that is represented by the following formula (5):

wherein m is 1-7, n5 and n6 are each independently 113-682, R is an alkyl group having 1-4 carbon atoms, Z 1 is an oligopeptide with 2-6 residues composed of neutral amino acids excluding cysteine, A is a hydrophobic neutral amino acid having a hydropathy index of not less than 2.5, a is 0 or 1, b is 1, X is a functional group capable of reacting with a bio-related substance, and L 2 , L 3 , L 4 and L 5 are each independently a single bond or a divalent spacer.

14. The degradable polyethylene glycol derivative according to claim 11 that is represented by the following formula (6):

wherein n7 and n8 are each independently 226-682, R is an alkyl group having 1-4 carbon atoms, Z 1 is an oligopeptide with 2-6 residues composed of neutral amino acids excluding cysteine, A is a hydrophobic neutral amino acid having a hydropathy index of not less than 2.5, a is 0 or 1, b is 1, X is a functional group capable of reacting with a bio-related substance, and L 2 , L 3 , L 4 and L 5 are each independently a single bond or a divalent spacer.

15. The degradable polyethylene glycol derivative according to claim 1 that is represented by the following formula (2):

wherein m is 1-7, n1 and n2 are each independently 45-682, p is 1-4, R is an alkyl group having 1-4 carbon atoms, Z 1 is an oligopeptide with 2-6 residues composed of neutral amino acids excluding cysteine and has at least one hydrophobic neutral amino acid having a hydropathy index of not less than 2.5, A is a neutral amino acid excluding cysteine, a is 1, b is 0 or 1, Q is a residue of a compound having 2-5 active hydrogens, X is a functional group capable of reacting with a bio-related substance, and L 1 , L 2 , L 3 , L 4 and L 5 are each independently a single bond or a divalent spacer.

16. The degradable polyethylene glycol derivative according to claim 15 that is represented by the following formula (3):

wherein n3 and n4 are each independently 45-682, p is 1-4, R

Assignees

• Nof Corp
• Tokyo Inst Tech

Inventors

• Yoshioka Hiroki
• Kamiya Masaki
• Yamamoto Yuji
• Hirai Midori
• Sasaki Akiko
• Nishiyama Nobuhiro
• Matsui Makoto
• Takemoto Hiroyasu
• Miyauchi Kazuki
• Nomoto Takahiro
• Tomoda Keishiro

Classifications

• C08G65/325

  containing nitrogen · CPC title

• A61K47/65

  Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers · CPC title

• C08G2230/00

  Compositions for preparing biodegradable polymers · CPC title

• A61K47/62

  the modifying agent being a protein, peptide or polyamino acid · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title