Dynamic urea bonds with fast hydrolytic kinetics for polymers

Patent metadata

Field	Value
Publication number	US-10822448-B2
Application number	US-201716082969-A
Country	US
Kind code	B2
Filing date	Mar 7, 2017
Priority date	Mar 8, 2016
Publication date	Nov 3, 2020
Grant date	Nov 3, 2020

Abstract

The present invention relates to polymers having dynamic urea bonds and more specifically to polymers having hindered urea bonds (HUBs) with fast hydrolytic kinetics. These urea bonds are aryl-substituted, i.e. aromatic-substituted hindered urea bonds, that demonstrate pH independent hydrolytic kinetics, such that they consistently and rapidly hydrolyze in water from pH 2 to 11. The urea bond dissociation for these materials is generally such that k−1>h−1, which is two orders of magnitudes faster than for aliphatic hindered ureas. The present invention also relates to hydrolytically reversible or degradable linear, branched or network polymers incorporating these HUBs and to precursors for incorporation of these HUBs into these polymers. The technology can be applied to and integrated into a variety of polymers, such as polyureas, polyurethanes, polyesters, polyamides, polycarbonates, polyamines, and polysaccharides to make linear, branched, and cross-linked polymers. Polymers incorporating these HUBs can be used in a wide variety of applications including for example, environmentally compatible packaging materials and biomedical applications, such as drug delivery systems and tissue engineering. In other embodiments, the HUBs can be used in self-healing polymers.

First claim

What is claimed is:

1. A hydrolysable polymer comprising a hindered urea bond functional group corresponding to the following Formula (I)

wherein R 1 is selected from —(C 1 -C 20 )alkyl, —(C 3 -C 10 )cyclolalkyl, —(C 1 -C 20 )alkyl(C 3 -C 10 )cycloalkyl, —(C 3 -C 10 )cycloalkyl(C 1 -C 20 )alkyl, —Ar 2 , —(C 1 -C 20 )alkyl-Ar 2 , —C 2 -C 20 )alkyl-PEG-(C 2 -C 20 )alkyl, and H;
R 4 is selected from H and —(C 1 -C 20 )alkyl;
Ar 1 and Ar 2 are independently selected from phenyl, naphthyl, a 5 or 6-membered heteroaromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof, and a 7 to 10-membered fused bicyclic heteroaromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof, wherein each Ar 1 or Ar 2 is optionally substituted with one or more substituents selected from F, Cl, Br, I, —(C 1 -C 8 )alkyl, —(C 3 -C 8 )cycloalkyl, —OR 5 , —CN, —SR 5 , —SOR 5 , —SO 2 R 5 , —COOR 5 , —COR 5 , —CONR 5 R 5 , and —NR 5 COR 5 —, wherein
R 5 is selected from H and —(C 1 -C 8 )alkyl.

2. A hydrolysable polymer according to claim 1 wherein R 1 , R 2 , R 3 , are each independently selected from —(C 1 -C 20 )alkyl, —(C 3 -C 10 )cycloalkyl, —(C 1 -C 20 )alkyl(C 3 -C 10 )cycloalkyl, —(C 3 -C 10 )cycloalkyl(C 1 -C 20 )alkyl, —Ar 2 , —(C 1 -C 20 )alkyl-Ar 2 , and —C 2 -C 20 )alkyl-PEG-(C 2 -C 20 )alkyl.

3. A hydrolysable polymer according to claim 2 wherein R 1 , R 2 , R 3 , are each methyl.

4. A hydrolysable polymer according to claim 3 wherein R 4 is selected from H, methyl, and ethyl.

5. A hydrolysable polymer according to claim 3 wherein R 4 is H.

6. A hydrolysable polymer according to claim 1 wherein Ar 1 is selected from phenyl, naphthyl, furyl, benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl, and imidazopyridyl.

7. A hydrolysable polymer according to claim 6 wherein Ar 1 is phenyl.

8. A hydrolysable polymer according to claim 1 wherein the hindered urea bond functional group has a K eq that is greater than or equal to 1×10 4 M −1 and less than or equal to 1×10 8 M −1 at 25° C.

9. A hydrolysable polymer according to claim 1 wherein the hindered urea bond functional group has a k −1 that is greater than or equal to 0.05 h −1 at 25° C.

10. A hydrolysable polymer according to claim 1 wherein the hindered urea bond functional group has a k 1 that is greater than or equal to 1×10 4 M −1 h −1 at 25° C.

11. A hydrolysable polymer according to claim 1 wherein the polymer exhibits at least 10% hydrolysis of the hindered urea bond functional groups at 24 hours at 37° C.

12. A hydrolysable polymer according to claim 1 wherein the polymer exhibits a hindered urea bond functional group hydrolysis half-life of less than or equal to 24 hours at 37° C.

13. A hydrolysable polymer according to claim 1 that is hydrolysable over the pH range from about 2 to about 11.

14. A biodegradable packaging material comprising a hydrolysable polymer according to claim 1 .

15. A drug delivery system comprising a hydrolysable polymer according to claim 1 .

16. A medical device comprising a hydrolysable polymer according to claim 1 .

17. A medical device according to claim 16 wherein the medical device is an implantable medical device.

18. A surgical suture comprising a hydrolysable polymer according to claim 1 .

19. A scaffold for tissue regeneration comprising a hydrolysable polymer according to claim 1 .

20. An environmentally degradable packaging, coating, or film comprising a hydrolysable polymer according to claim 1 .

21. A hydrolysable hindered urea bond-containing polymer comprising recurring units from:
(a) a hindered amine monomer containing two or more hindered amine functional groups, and
(b) an aromatic isocyanate monomer containing two or more aromatic isocyanate groups, wherein the hindered amine monomer corresponds to the following Formula (II)

wherein R 1 , R 2 , and R 3 are independently selected from —(C 1 -C 20 )alkyl, —(C 3 -C 10 )cycloalkyl, —(C 1 -C 20 )alkyl(C 3 -C 10 )cycloalkyl, —(C 3 -C 10 )cycloalkyl(C 1 -C 20 )alkyl, —Ar 2 , —(C 1 -C 20 )alkyl-Ar 2 , —C 2 -C 20 )alkyl-PEG-(C 2 -C 20 )alkyl, and H;
Ar 2 is selected from phenyl, naphthyl, a 5 or 6-membered heteroaromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof, and a 7 to 10-membered heteroaromatic ring or fused bicyclic heteroaromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof, wherein each Ar′ and Ar 2 is optionally substituted with one or more substituents selected from F, Cl, Br, I, —(C 1 -C 8 )alkyl, —(C 3 -C 8 )cycloalkyl, —OR 5 , —CN, —SR 5 , —SOR 5 , —SO 2 R 5 , —COOR 5 , —COR 5 , —CONR 5 R 5 , and —NR 5 COR 5 —, wherein
R 5 is selected from H and —(C 1 -C 8 )alkyl,
and n is an integer from 2 to 100; and
wherein the aromatic isocyanate monomer corresponds to the following Formula (III)

wherein Ar 1 is selected from phenyl, naphthyl, a 5 or 6-membered heteroaromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof, and a 7 to 10-membered heteroaromatic ring or fused bicyclic heteroaromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof, wherein each Ar is optionally substituted with one or more substituents selected from F, Cl, Br, I, —(C 1 -C 8 )alkyl, —(C 3 -C 8 )cycloalkyl, —OR 5 , —CN, —SR 5 , —SOR 5 , —SO 2 R 5 , —COOR 5 , —COR 5 , —CONR 5 R 5 , and —NR 5 COR 5 —, wherein
R 5 is selected from H and —(C 1 -C 8 )alkyl,
and m is an integer from 0 to 100.

22. A hydrolysable hindered urea bond-containing polymer made by a process comprising;
(a) reacting a hindered amine monomer containing two or more hindered amine functional groups, and
(b) an aromatic isocyanate monomer containing two or more aromatic isocyanate groups wherein the hindered amine monomer corresponds to the following Formula (II)

wherein R 1 , R 2 , and R 3 are independently selected from —(C 1 -C 20 )alkyl, —(C 3 -C 10 )cycloalkyl, —(C 1 -C 20 )alkyl(C 3 -C 10 )cycloalkyl, —(C 3 -C 10 )cycloalkyl(C 1 -C 20 )alkyl, —Ar 2 , —(C 1 -C 20 )alkyl-Ar 2 , —C 2 -C 20 )alkyl-PEG-(C 2 -C 20 )alkyl, and H;
Ar 2 is selected from phenyl, naphthyl, a 5 or 6-membered heteroaromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof, and a 7 to 10-membered heteroaromatic ring or fused bicyclic heteroaromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and combinations thereof, wherein each Ar is optionally substituted with one or more substitue

Assignees

• Univ Illinois

Inventors

• Cheng Jianjun
• Cai Kaimin
• Ying Hanze

Classifications

• C08G2220/00

  Compositions for preparing gels other than hydrogels, aerogels and xerogels · CPC title

• C08G18/325

  containing secondary or tertiary amino groups (C08G18/3228, C08G18/3234, C08G18/3246 take precedence) · CPC title

• C08G18/6685

  with compounds of group C08G18/3225 or polyamines of C08G18/38 · CPC title

• C08F290/06

  Polymers provided for in subclass C08G · CPC title

• C08G18/4825

  Polyethers containing two hydroxy groups (C08G18/4833 - C08G18/5096 take precedence) · CPC title