Degradable imidazolium oligomer and polymer for antimicrobial applications

Patent metadata

Field	Value
Publication number	US-10927100-B2
Application number	US-201816617562-A
Country	US
Kind code	B2
Filing date	Jun 28, 2018
Priority date	Jun 30, 2017
Publication date	Feb 23, 2021
Grant date	Feb 23, 2021

Abstract

The present invention relates to an oligomer of formula (I)

where the various groups are as defined in the specification. The present invention also relates to an oligomer or a polymer of formula (II)

where the various groups are as defined in the specification. The present invention also relates to the methods for their preparation, antimicrobial composition, antimicrobial gel containing these oligomers and/or polymers of Formula (I) and (II), and uses of these oligomers and/or polymers in the treatment of a microbial infection or disease.

First claim

The invention claimed is:

1. An oligomer of formula (I)

wherein linker 1 is an alkyl-aryl-alkyl group or (C 2 -C 8 )alkene;
p and q are independently an integer from 2 to 6, that is, 2, 3, 4, 5, or 6;
linker 2 is

m is 0 or 1;
A is independently aryl or heteroaryl;
B is independently O, N or S;
C is independently aryl or heteroaryl;
R 1 is a bond, alkyl, or absent;
R 2 is a bond, alkoxy or amine;
R 3 is carbonyl, a bond or alkyl;
R 4 is a bond or alkyl; R 5 is alkyl; and
X is a halide selected from fluoride, chloride and bromide.

2. The oligomer of claim 1 , wherein linker 2 is selected from the group consisting of

3. The oligomer of claim 1 , wherein when linker 1 is alkyl-aryl -alkyl, said alkyl-aryl-alkyl is a C 1-6 alkyl-phenyl-C 1-6 alkyl.

4. The oligomer of claim 1 , wherein the oligomer has a terminal group, or the oligomer is selected from

5. An oligomer or a polymer of formula (II)

wherein linker 1 is an alkyl-aryl-alkyl group or (C 2 -C 8 )alkene;
n is an integer from 3 to 30, that is, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30;
linker 2 is

m is 0 or 1;
A is independently aryl or heteroaryl;
B is independently O, N or S;
C is independently aryl or heteroaryl;
R 1 is a bond or alkyl;
R 2 is a bond, alkoxy or amine;
R 3 is carbonyl, a bond or alkyl;
R 4 is a bond or alkyl;
R 5 is alkyl; and
X is a halide selected from fluoride, chloride and bromide.

6. The oligomer or the polymer of claim 5 , wherein linker 2 is selected from the group consisting of

7. The oligomer or the polymer of claim 5 , wherein when linker 1 is alkyl-aryl-alkyl, said alkyl-aryl-alkyl is a C 1-6 alkyl-phenyl-C 1-6 alkyl.

8. The oligomer or the polymer of claim 5 , wherein the polymer has a terminal group selected from the group consisting of linker 2, an imidazolium ring and a combination thereof.

9. An antimicrobial composition comprising the oligomer as defined in claim 1 .

10. The antimicrobial composition of claim 9 , wherein said antimicrobial composition inhibits the activity or treats the infection or disease caused by a microbe that is selected from the group consisting of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilius, Klebsiella pneumonia, Cryptococcus neoformans and Candida albicans , or wherein when said microbe is contacted with said antimicrobial composition at a defined concentration, microbial activity of said microbe is reduced to 1%, or to 0.5%, or to 0.1%, or wherein said defined concentration of said antimicrobial composition is in the range of about 1 μg/ml to about 100 μg/ml, or wherein the reduction of the microbial activity is achieved within a duration of about 0.5 minutes to about 120 minutes, or wherein the microbe is not resistant to said antimicrobial composition.

11. A method of treating a microbial infection or disease comprising administering the oligomer of claim 1 to a subject.

12. The method of claim 11 , wherein said oligomer inhibits the activity or treats the infection or disease caused by a microbe that is selected from the group consisting of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilius, Klebsiella pneumonia, Cryptococcus neoformans , and Candida albicans.

13. The method of claim 12 , wherein when said microbe is contacted with said oligomer at a defined concentration, microbial activity of said microbe is reduced to 1% or wherein said defined concentration of said oligomer is in the range of about 1 μg/ml to about 100 μg/ml.

14. A method of preparing an oligomer of formula (I)

wherein linker 1 is an alkyl-aryl-alkyl group or (C 2 -C 8 )alkene;
p and q are independently an integer from 2 to 6, that is 2, 3, 4, 5 or 6;
linker 2 is

m is 0 or 1;
A is independently aryl or heteroaryl;
B is independently O, N or S;
C is independently aryl or heteroaryl;
R 1 is a bond or alkyl;
R 2 is a bond, alkoxy or amine;
R 3 is carbonyl, a bond or alkyl;
R 4 is a bond or alkyl;
R 5 is alkyl;
X is halide selected from fluoride, chloride and bromide,
said method comprising the steps of:
a) providing a di-imidazole unit bearing linker 2 of Formula (III)

b) mixing the di-imidazole of Formula (Ill) with an imidazolium salt that is dissolved in a suitable solvent to form a mixture; and
c) stirring the mixture obtained in step (b) under conditions to obtain said oligomer.

15. The method of claim 14 , wherein the di-imidazole unit bearing linker 2 of Formula (III) is selected from the group consisting of

or wherein the imidazolium salt is selected from the group consisting of bisimidazolium salt, trisimidazolium salt, tetraimidazolium salt, pentaimidazolium salt and hexaimidazolium salt, or wherein the solvent is selected from the group consisting of dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone and acetonitrile.

16. The method of claim 14 , wherein said condition in step (c) comprises a temperature of about 20° C. to about 30° C., or wherein said step (c) is undertaken for a time period in the range of about 18 hours to 60 hours.

17. A method of preparing the oligomer or the polymer of Formula (II)

wherein linker 1 is an alkyl-aryl-alkyl group or (C 2 -C 8 )alkene;
n is an integer from 3 to 30, that is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30;
linker 2 is

m is 0 or 1;
A is independently aryl or heteroaryl;
B is independently O, N or S;
C is independently aryl or heteroaryl;
R 1 is a bond or alkyl;
R 2 is a bond, alkoxy or amine;
R 3 is carbonyl, a bond or alkyl;
R 4 is a bond or alkyl;
R 5 is alkyl; and
X is halide selected from fluoride, chloride and bromide,
said method comprising the steps of:

Assignees

• Agency Science Tech & Res

Inventors

• Zhang Yugen
• Yuan Yuan
• Lim Shu Wen Diane

Classifications

• C08G73/0616

  with only two nitrogen atoms in the ring · CPC title

• A01N47/06

  containing —O—CO—O— groups; Thio analogues thereof · CPC title

• A01N47/34

  containing the groups [IMAGE cpc-sch-A01N-0947.gif], e.g. biuret; Thio analogues thereof; Urea-aldehyde condensation products · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07D233/61 Primary

  with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms · CPC title