Diamine crosslinking agents, crosslinked acidic polysaccharides and medical materials

Patent metadata

Field	Value
Publication number	US-10919840-B2
Application number	US-201916362208-A
Country	US
Kind code	B2
Filing date	Mar 22, 2019
Priority date	Jan 31, 2014
Publication date	Feb 16, 2021
Grant date	Feb 16, 2021

Abstract

The invention provides a diamine crosslinking agent for acidic polysaccharides consisting of a diamine compound having a primary amino group at both terminals and an ester or thioester bond in the molecule, wherein the number of atom in the linear chain between at least one of the amino groups and the carbonyl carbon in the ester or thioester is 1 to 5; in particular, a diamine crosslinking agent for acidic polysaccharides which is represented by the general formula (I) below:

[the symbols in the formula are as described in the specification]; a crosslinked acidic polysaccharide obtained by forming crosslinks by amide bonding between the amino groups in the diamine crosslinking agent and carboxyl groups in an acidic polysaccharide; and a medical material including the crosslinked product.

First claim

What is claimed is:

1. A crosslinked acidic polysaccharide obtained by forming crosslinks by amide bonding between primary amino groups in a diamine or a polyamine crosslinking agent and carboxyl groups in an acidic polysaccharide;
wherein the crosslinking agent has the general formula (I) below:

where the number of atoms in the linear chain between the primary amino groups at both terminals is 5 to 12, X and Y are each independently a single bond, a substituted or unsubstituted alkanediyl group, a substituted or unsubstituted alkenylene group, or a substituted or unsubstituted alkynylene group, with the proviso that X and Y are not single bonds at the same time;
Z is an oxygen atom or a sulfur atom;
R 1 is a hydrogen atom, a CONR 3 R 4 group, a COOR 5 group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group;
R 2 consists of a hydrogen atom, a —CONR 3 R 4 group, a —COOR 5′ group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group, wherein R 5′ is an alkyl group optionally substituted with phenyl group;
any —CH 2 — in X or Y, if present, is optionally substituted with one or more groups selected from the group consisting of an amide group (—CONH—), an ester group (—C(═O)—O—), an ether group (—O—), an imino group (—NH—) and a phenylene group, wherein the ester group, the amide group, the ether group or the imino group present in X or Y is not directly adjacent to —CO—Z— in the formula (I);
any —CH 2 — in R 1 or R 2 , if present, is optionally substituted with one or more groups selected from the group consisting of >C═O, —CONH—, arylene, —O—, —NR 6 — and —S—;
R 3 , R 4 , R 5 and R 6 are each independently a hydrogen atom or an alkyl group optionally substituted with phenyl group;
the substituent in X and Y is selected from the group consisting of an hydroxyl group, an alkyl group having 1 to 6 carbon atom and a halogen atom;
the substituent in R 1 and R 2 is selected from the group consisting of a hydroxyl group, an alkyl group having 1 to 6 carbon atom, a phenyl group, an indolyl group, a diazolyl group, a —(CH 2 ) n —NHMe group, a —(CH 2 ) n —NMe 2 group, a —(CH 2 ) n —CONR 3 R 4 group, a —(CH 2 ) n —COOR 5 group, a —S-Me group, and a —SH group, wherein n is, independently, an integer of 0 to 4, and
wherein the polyamine crosslinking agent has a structure in which at least one of the substituents in X and Y or at least one of R 1 and R 2 in the general formula (I) comprises a biodegradable site and a terminal primary amino group.

2. The crosslinked acidic polysaccharide according to claim 1 , wherein Z is an oxygen atom.

3. The crosslinked acidic polysaccharide according to claim 2 , wherein the number of atoms in the linear chain between the amino groups at both terminals is 5 to 8.

4. The crosslinked acidic polysaccharide according to claim 2 , wherein the number of atoms in the linear chain between the amino groups at both terminals is 5 or 6.

5. The crosslinked acidic polysaccharide according to claim 1 , wherein
R 1 is a hydrogen atom, or a substituted or unsubstituted alkyl group;
R 2 is a hydrogen atom, a —CONR 3 R 4 group or a —COOR 5′ group;
X is a single bond or an alkanediyl group which contains optionally a halogen substituent;
Y is a substituted or unsubstituted alkanediyl group;
the substituent(s) in R 1 is selected from the group consisting of a methyl group, a phenyl group, an indolyl group, a —COOR 5 group and a —S-Me group; and
the substituent(s) in Y is selected from the group consisting of a methyl group.

6. The crosslinked acidic polysaccharide according to claim 1 , wherein
X is a single bond; Y is a >CR 7 R 8 group; and
R 7 and R 8 are each independently a hydrogen atom, or an alkyl group having 1 to 6 carbon atom.

7. The crosslinked acidic polysaccharide according to claim 6 , wherein
R 2 is a —CONR 3 R 4 group or a —COOR 5′ group;
R 7 is a hydrogen atom; and
R 8 is a hydrogen atom or a methyl group.

8. The crosslinked acidic polysaccharide according to claim 3 , wherein at least one of X and Y contains a halogen atom substituent.

9. The crosslinked acidic polysaccharide according to claim 6 , wherein R 7 and R 8 are each independently a hydrogen atom or a methyl group.

10. The crosslinked acidic polysaccharide according to claim 9 , wherein R 1 is a hydrogen atom, a —(CH 2 ) 2 —S—CH 3 group, a —(CH 2 ) 3 or 4 —NHMe group, a —(CH 2 ) 3 or 4 —NMe 2 group or a —(CH 2 ) 1 or 2 —COOR 5 group.

11. The crosslinked acidic polysaccharide according to claim 10 , wherein R 2 is a —CONR 3 R 4 group or —COOR 5′ group, and R 7 and R 8 are hydrogen atoms.

12. The crosslinked acidic polysaccharide according to claim 11 , wherein R 1 is a hydrogen atom.

13. The crosslinked acidic polysaccharide according to claim 1 , wherein the acidic polysaccharide is glycosaminoglycan, carboxymethyl cellulose or alginic acid.

14. The crosslinked acidic polysaccharide according to claim 13 , wherein the acidic polysaccharide is glycosaminoglycan.

15. The crosslinked acidic polysaccharide according to claim 14 , wherein the glycosaminoglycan is chondroitin or chondroitin sulfate.

16. The crosslinked acidic polysaccharide according to claim 9 , wherein the acidic polysaccharide is glycosaminoglycan, carboxymethyl cellulose or alginic acid.

17. The crosslinked acidic polysaccharide according to claim 16 , wherein the acidic polysaccharide is glycosaminoglycan.

18. The crosslinked acidic polysaccharide according to claim 17 , wherein the glycosaminoglycan is chondroitin or chondroitin sulfate.

19. A medical material comprising the crosslinked acidic polysaccharide described in claim 1 .

20. A tissue bulking material comprising the crosslinked acidic polysaccharide described in claim 1 .

21. An adhesion preventing material comprising the crosslinked acidic polysaccharide described in claim 9 .

22. The crosslinked acidic polysaccharide of claim 9 , wherein the diamine crosslinked agent has the general formula (II) below:

wherein R 1 is a hydrogen atom, a —CONR 3 R 4 group, a —COOR 5 group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group;
R 2′ is a —CONR 3 R 4 group or a —COOR 5′ group;
any —CH 2 — in R 1 , if present, is optionally substituted with one or more groups selected from the group consisting of >C═O, —CONH—, an arylene, —O—, —NR 6 — and —S— (with the proviso that when R 5′ is a benzyl group, the —O— is excluded);
the substituent(s) in R 1 is selected from the group consisting of hydroxyl group, alkyl group having 1 to 6 carbon atom, indolyl group, diazolyl group, —(CH 2 ) n —NHMe group, —(CH 2 ) n —NMe 2 group, —(CH 2 ) n —CONR 3 R 4 group, —(CH 2 ) n —COOR 5 group and —SH group (with the proviso that when R 2′ is a —CONH 2 group, the —SH group is excluded) wherein n independently at each occurrence is an integer of 0 to 4;
R 3 , R 4 , R 5 and R 6 are each independently a hydrogen atom or an alkyl group optionally sub

Assignees

• Seikagaku Kogyo Co Ltd

Inventors

• Funayama Sho
• Yasuda Yosuke
• Takezawa Akihiro
• Takahashi Katsuya

Classifications

• C08B11/12 Primary

  substituted with carboxylic radicals {, e.g. carboxymethylcellulose [CMC]} · CPC title

• C08K5/16

  Nitrogen-containing compounds {(C08K5/0091 takes precedence)} · CPC title

• C07C219/06 Primary

  having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton · CPC title

• C08B37/0072

  Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates · CPC title

• C07C237/06

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title