Substituted polyesters by thiol-ene modification: rapid diversification for therapeutic protein stabilization

Patent metadata

Field	Value
Publication number	US-10273333-B2
Application number	US-201615394483-A
Country	US
Kind code	B2
Filing date	Dec 29, 2016
Priority date	Aug 13, 2014
Publication date	Apr 30, 2019
Grant date	Apr 30, 2019

Abstract

Structures and methods of making biodegradable trehalose co-polymers are disclosed. Specifically, biodegradable trehalose co-polymers consist of the general structure R 5 —[R 1 R 2 C—CR 3 R 4 ] n -[DG] m —R 6 , wherein R 1 -R 4 are independently selected from hydrogen or a side chain comprising at least one carbon atom, and wherein at least one of R 1 -R 4 is a side chain comprising -L-trehalose, wherein L is a linker molecule that links trehalose to the monomer through at least one of the trehalose hydroxyl groups (—OH), wherein DG is a biodegradable group, and wherein R 5 and R 6 are end groups.

First claim

What is claimed is:

1. A biodegradable trehalose or zwitterion polymer, wherein the polymer consists of the general structure:
R′-[DG-CR 1 R 2 —CR 3 R 4 —CR 5 R 6 —CR 7 R 8 —CR 9 R 10 ] m —R″

wherein R 1 -R 10 are independently selected from hydrogen or a side chain comprising at least one carbon atom, and wherein at least one of R 1 -R 10 is a side chain comprising trehalose, -L-trehalose, -zwitterion or -L-zwitterion, wherein L is a linker molecule that links trehalose or zwitterion to the polymer through the reaction of at least one of the trehalose hydroxyl groups (—OH) or through one end of the zwitterion, wherein DG is a biodegradable group, and
wherein R′ and R″ are end groups, and
wherein m≥1.

2. The polymer of claim 1 , wherein R′ and R″ are independently comprising —H, —Alkyl, -Alkenyl, -Alkynyl, -Aryl, disulfide, pyridyl disulfide, 5-thio-2-nitrobenzoic acid, disulfide reductants, Michael acceptors, maleimides, maleimide derivatives, dihalomaleimides, vinyl groups, vinyl sulfones, acryloyl derivatives, haloacetyl, alkyl halide derivatives, aziridines, arylating agents, isothiocyanates, isocyanates, acryl azides, activated esters, N-hydroxysuccinimide esters, para-nitrophenyl esters, sulfonyl chlorides, aldehydes and glyoxals (with or without reductive amination), epoxides (also called oxiranes), carbonates, arylating agents, imidoesters, carbodiimides, anhydrides, primary amines, secondary amines, tertiary amines, diazoalkanes, diazoacetyls, carbonyldiimidazoles, carbonates, chloroformates, alkyl halogens, isocyanates, aminooxy (hydroxylamines), hydrazines, azide or biomolecules.

3. The polymer of claim 1 , wherein R′ and R″ are independently comprising —H, -Alkyl, -Alkenyl, -Alkynyl, azide or biomolecules.

4. The polymer of claim 1 , wherein DG comprises at least one ester group.

5. The polymer of claim 1 , wherein DG is an ester group in the backbone of the polymer.

6. The polymer of claim 1 , the linking molecules L are methylene groups —(CH 2 ) n — (n=1-1000).

7. The polymer of claim 6 , wherein the linking molecules L are methylene groups —(CH 2 ) n — (n=1-10).

8. The polymer of claim 1 , wherein the polymer is

wherein n=1-10000.

9. The polymer of claim 1 , wherein the polymer is

wherein n=1-10000.

10. A biodegradable trehalose or zwitterion polymer, wherein the polymer consists of the general structure: R′—[OOC—CR 1 R 2 —(CH 2 ) m ] n —OR″,
wherein m=0-10, n=1-10000 and R 1 and R 2 are independently selected from hydrogen or a side chain comprising at least one carbon atom, wherein at least one of R 1 and R 2 is a side chain comprising -trehalose, -L-trehalose, -zwitterion or -L-zwitterion, wherein L is a linker molecule that links the trehalose or zwitterion to the polymer through the reaction of at least one of the trehalose hydroxyl groups (—OH) or through one end of the zwitterion,
wherein R′ and R″ are end groups.

11. The polymer of claim 10 , wherein R′ and R″ are independently comprising —H, -Alkyl, -Alkenyl, -Alkynyl, -Aryl, disulfide, pyridyl disulfide, 5-thio-2-nitrobenzoic acid, disulfide reductants, Michael acceptors, maleimides, maleimide derivatives, dihalomaleimides, vinyl groups, vinyl sulfones, acryloyl derivatives, haloacetyl, alkyl halide derivatives, aziridines, arylating agents, isothiocyanates, isocyanates, acryl azides, activated esters, N-hydroxysuccinimide esters, para-nitrophenyl esters, sulfonyl chlorides, aldehydes and glyoxals (with or without reductive amination), epoxides (also called oxiranes), carbonates, arylating agents, imidoesters, carbodiimides, anhydrides, primary amines, secondary amines, tertiary amines, diazoalkanes, diazoacetyls, carbonyldiimidazoles, carbonates, chloroformates, alkyl halogens, isocyanates, aminooxy (hydroxylamines), hydrazines, azide or biomolecules.

12. The polymer of claim 10 , wherein R′ and R″ are independently comprising —H, -Alkyl, -Alkenyl, -Alkynyl, azide or biomolecules.

13. The polymer of claim 10 , the linking molecules L are methylene groups —(CH 2 ) n — (n=1-1000).

14. The polymer of claim 13 , wherein the linking molecules L are methylene groups —(CH 2 ) n — (n=1-10).

15. A biodegradable zwitterion polymer, wherein the polymer consists of the general structure: R—[OOC—CR 1 R 2 —(CH 2 ) m ] n —OR″,
wherein m=0-10, n=1-10000 and R 1 and R 2 are independently selected from hydrogen or a side chain comprising at least one carbon atom, wherein at least one of R 1 and R 2 is a side chain comprising -zwitterion or -L-zwitterion, wherein L is a linker molecule that links zwitterion to the polymer through one end of the zwitterion electrical charges,
wherein R′ and R″ are end groups.

16. The polymer of claim 15 , wherein R′ and R″ are independently comprising —H, -Alkyl, -Alkenyl, -Alkynyl, -Aryl, disulfide, pyridyl disulfide, 5-thio-2-nitrobenzoic acid, disulfide reductants, Michael acceptors, maleimides, maleimide derivatives, dihalomaleimides, vinyl groups, vinyl sulfones, acryloyl derivatives, haloacetyl, alkyl halide derivatives, aziridines, arylating agents, isothiocyanates, isocyanates, acryl azides, activated esters, N-hydroxysuccinimide esters, para-nitrophenyl esters, sulfonyl chlorides, aldehydes and glyoxals (with or without reductive amination), epoxides (also called oxiranes), carbonates, arylating agents, imidoesters, carbodiimides, anhydrides, primary amines, secondary amines, tertiary amines, diazoalkanes, diazoacetyls, carbonyldiimidazoles, carbonates, chloroformates, alkyl halogens, isocyanates, aminooxy (hydroxylamines), hydrazines, azide or biomolecules.

17. The polymer of claim 15 , wherein R′ and R″ are independently comprising —H, -Alkyl, -Alkenyl, -Alkynyl, azide or biomolecules.

18. The polymer of claim 15 , the linking molecules L are methylene groups —(CH 2 ) n — (n=1-1000).

19. The polymer of claim 18 , wherein the linking molecules L are methylene groups —(CH 2 ) n — (n=1-10).

20. The polymer of claim 15 , where the zwitterion is an amino acid derivative.

Assignees

• Univ California

Inventors

• Maynard Heather D

Classifications

• C08F220/40

  Esters of unsaturated alcohols {, e.g. allyl (meth)acrylate} · CPC title

• A61K47/24

  containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids · CPC title

• A61K47/593

  Polyesters, e.g. PLGA or polylactide-co-glycolide · CPC title

• C08F220/285

  and containing a polyether chain in the alcohol moiety · CPC title

• A61K47/58

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin · CPC title