Hydrophilic polymer derivative having cyclic benzylidene acetal linker

Patent metadata

Field	Value
Publication number	US-11530295-B2
Application number	US-202016887081-A
Country	US
Kind code	B2
Filing date	May 29, 2020
Priority date	Mar 31, 2014
Publication date	Dec 20, 2022
Grant date	Dec 20, 2022

Abstract

A hydrophilic polymer derivative having a cyclic benzylidene acetal linker represented by the following formula (1):wherein R1 and R6 are each independently a hydrogen atom or a hydrocarbon group; R2, R3, R4 and R5 are each independently an electron-withdrawing or electron-donating substituent or a hydrogen atom; X1 is a chemically reactive functional group; P is a hydrophilic polymer; s is 1 or 2, t is 0 or 1, and s+t is 1 or 2; w is an integer of 1 to 8; and Z1 and Z2 are each independently a selected divalent spacer.

First claim

The invention claimed is:

1. A method for chemical modification of a biofunctional molecule with a hydrophilic polymer compound for improving in vivo and intracellular kinetics in environments having different pH in a living body, which comprises reacting a functional group in the biofunctional molecule with a chemically reactive functional group in the hydrophilic polymer,
wherein the hydrophilic polymer compound has a cyclic benzylidene acetal linker represented by formula (1):

wherein R 1 and R 6 are each independently a hydrogen atom or a hydrocarbon group;
R 2 , R 3 , R 4 and R 5 are each independently an electron-withdrawing or electron-donating substituent or a hydrogen atom;
X 1 is the chemically reactive functional group and 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 epoxy group, a maleimide group, a vinyl sulfone group, an acryl group, a sulfonyloxy group, a carboxy 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;
P is a hydrophilic polymer;
s is 1 or 2, t is 0 or 1, and s+t is 1 or 2;
m is an integer of 1 to 8; and
Z 1 and Z 2 are each independently a selected divalent spacer.

2. The method as claimed in claim 1 , wherein s is 1 and t is 0, and R 2 and R 5 are each a hydrogen atom,
wherein the electron-withdrawing substituent is at least one selected from the group consisting of an acyl group having from 2 to 5 carbon atoms, an alkoxycarbonyl group having from 2 to 5 carbon atoms, a carbamoyl group having from 2 to 5 carbon atoms, an acyloxy group having from 2 to 5 carbon atoms, an acylamino group having from 2 to 5 carbon atoms, an alkoxycarbonylamino group having from 2 to 5 carbon atoms, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkylsulfanyl group having from 1 to 4 carbon atoms, an alkylsulfonyl group having from 1 to 4 carbon atoms, an arylsulfonyl group having from 6 to 10 carbon atoms, a nitro group, a trifluoromethyl group and a cyano group, and
the electron-donating substituent is at least one selected from the group consisting of an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atom and an aryloxy group having from 6 to 10 carbon atoms.

3. The method as claimed in claim 1 , wherein s is 1 and t is 0, and at least one of R 2 and R 5 is an electron-withdrawing or electron-donating substituent,
wherein the electron-withdrawing substituent is at least one selected from the group consisting of an acyl group having from 2 to 5 carbon atoms, an alkoxycarbonyl group having from 2 to 5 carbon atoms, a carbamoyl group having from 2 to 5 carbon atoms, an acyloxy group having from 2 to 5 carbon atoms, an acylamino group having from 2 to 5 carbon atoms, an alkoxycarbonylamino group having from 2 to 5 carbon atoms, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkylsulfanyl group having from 1 to 4 carbon atoms, an alkylsulfonyl group having from 1 to 4 carbon atoms, an arylsulfonyl group having from 6 to 10 carbon atoms, a nitro group, a trifluoromethyl group and a cyano group, and
the electron-donating substituent is at least one selected from the group consisting of an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atom and an aryloxy group having from 6 to 10 carbon atoms.

4. The method as claimed in claim 1 , wherein s is 1 and t is 1, or s is 2 and t is 0, R 2 and R 5 are each a hydrogen atom.

5. The method as claimed in claim 1 , wherein in formula (1), s is 1 and t is 1, or s is 2 and t is 0, and at least one of R 2 and R 5 is an electron-withdrawing or electron-donating substituent.

6. The method as claimed in claim 1 , wherein X 1 is selected from the group consisting of formula (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (1), formula (m) and formula (n):

wherein R 7 is a hydrogen atom or a sulfo group; R 8 and R 11 are each independently a hydrogen atom or a hydrocarbon group having from 1 to 5 carbon atoms; R 9 is a hydrocarbon group having from 1 to 10 carbon atoms which may contain a halogen atom; and R 10 is a halogen atom selected from a chlorine atom, a bromine atom and an iodine atom.

7. The method as claimed in claim 1 , wherein Z 1 and Z 2 are each independently an ether bond, an ester bond, a carbonate bond, a urethane bond, an amide bond, a secondary amino group, an alkylene group containing any of these bonds and group, a single bond or an alkylene group, and in a case where at least one of Z 1 and Z 2 is an ether bond, an ester bond, a carbonate bond, a urethane bond, an amide bond, a secondary amino group or an alkylene group containing any of these bonds and group and a plurality of identical structural units are connected, a number of the structural units is 2 or less.

8. The method as claimed in claim 1 , wherein P is a linear polyethylene glycol having a hydrocarbon group or a chemically reactive functional group at its terminal,
wherein the chemically reactive functional group 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 epoxy group, a maleimide group, a vinyl sulfone group, an acryl group, a sulfonyloxy group, a carboxy 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.

9. The method as claimed in claim 8 , wherein w is 1, and P is represented by formula (2):
Y—(OCH 2 CH 2 ) n   (2)

wherein Y is a hydrocarbon group having from 1 to 24 carbon atoms; and n is an integer of 3 to 2,000.

10. The method as claimed in claim 8 , wherein w is 1, and P is represented by formula (3):
X 2 —Z 3 —(OCH 2 CH 2 ) n   (3)

wherein X 2 is a chemically reactive functional group different from X 1 ; Z 3 is a divalent spacer; and n is an integer of 3 to 2,000.

11. The method as claimed in claim 1 , wherein P is a branched polyethylene glycol having a hydrocarbon group or a chemically reactive functional group different from X 1 at its terminal.

12. The method as claimed in claim 11 , wherein w is 1, and P is represented by formula (4):

wherein Y is a hydrocarbon group having from 1 to 24 carbon atoms; n is an integer of 3 to 1,000; and v is 0 or 2.

13. The method as claimed in claim 11 , wherein w is 1, and P is represented by formula (5):

wherein X 2 is a chemically reactive functional group different from X 1 ; Z 3 is a divalent spacer; n is an integer of 3 to 1,000; and v is 0 or 2.

14. The method as claimed in claim 11 , wherein w is v+2, and P is represented by formula (6):

Assignees

• Nof Corp

Inventors

• TSUBUSAKI Takuma
• Yamamoto Yuji

Classifications

• C07D405/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D317/22

  etherified · CPC title

• C08G65/33396 Primary

  having oxygen in addition to nitrogen · CPC title

• C07D317/24

  esterified · CPC title

• C07D317/20

  Free hydroxyl or mercaptan · CPC title