Polyglyoxylates, manufacture and use thereof

Patent metadata

Field	Value
Publication number	US-10214609-B2
Application number	US-201515309112-A
Country	US
Kind code	B2
Filing date	May 6, 2015
Priority date	May 6, 2014
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

Self-immolative polymers degrade by an end-to-end depolymerization mechanism in response to the cleavage of a stabilizing end-cap from the polymer terminus. Examples include homopolymers, mixed polymers including block copolymers, suitable for a variety of applications. A polyglyoxylate can be end-capped or capped with a linker as in a block copolymer.

First claim

The invention claimed is:

1. A capped polymer comprising a polyglyoxylate polymer having a polyacetal backbone with pendant esters and a terminal hydroxyl, an end capping molecule separate from the polymer that is a protecting group for the polyglyoxylate's terminal hydroxyl or a self-immolative spacer covalently linked to the protecting group, which is linked to an end thereof by a covalent linkage, wherein the end capping molecule is able to undergo selective cleavage from the polyglyoxylate polymer upon exposure to a preselected stimulus, wherein said selective cleavage is cleavage only of said covalent linkage of the end capping molecule to the end of the polymer thus leaving the polyacetal backbone and the pendant esters intact to produce the polyglyoxylate polymer without the end capping molecule.

2. The capped polymer of claim 1 , wherein the preselected stimulus is one or more of an aqueous solution, an enzyme, a reducing agent, an oxidizing agent, heat, and light.

3. The capped polymer of claim 2 , wherein the aqueous solution has a pH of between about 2 and 9.

4. The capped polymer of claim 2 , wherein the enzyme is selected from the group consisting of catalytic antibodies, esterases, and peptidases.

5. The capped polymer of claim 2 , wherein the reducing agent is a thiol, particularly glutathione.

6. The capped polymer of claim 2 , wherein the oxidizing agent is hydrogen peroxide.

7. The capped polymer of claim 1 , wherein the polyglyoxylate polymer has an average molecular weight in the range from 1000 Da to 10 6 Dabased on polystyrene standards.

8. The capped polymer of claim 1 , wherein the polyglyoxylate polymer has a polydispersity index in the range from 1.0 to 3.0.

9. The capped polymer of claim 1 , wherein the polymer has the structure of formula (A):

wherein n is between 10 and 2,000, R is selected from the group consisting of:
(i) H,
(ii) optionally substituted C 1-20 linear or branched alkyl,
(iii) optionally substituted C 3-20 cycloalkyl,
(iv) optionally substituted C 2-20 linear or branched alkenyl,
(v) optionally substituted C 5-20 cycloalkenyl
(vi) optionally substituted C 2-20 linear or branched alkynyl,
(vii) optionally substituted C 6-20 aromatic,
(viii) optionally substituted C 4-20 heteroaryl,
(ix) optionally substituted C 7-20 arylalkyl,
(x) optionally substituted C 2-20 cycloheteroalkyl,
(xi) cinnamoyl,
(xii) acrylyl,
(xiii) methacrylyl, and
(xiv) —CH 2 CH 2 OSi(R i )(R ii )(R iii ) wherein:
each of R i , R ii and R iii is, independently of the other, selected from foregoing groups (i) to (x) and at least one of R i , R ii and R iii is selected from foregoing groups (ii) to (x), and
salts of any of the foregoing; and

-Cap represents the end capping molecule covalently linked to the polymer having the polyacetal backbone.

10. The capped polymer of claim 9 , wherein -Cap represents the end capping molecule having the following formula

wherein R C is a group that is cleaved in response to a stimulus such as light, enzymes, heat, change in pH or redox potential.

11. The capped polymer of claim 9 , wherein a said optional substituent is 1, 2, 3, 4 or 5 independent substitution(s) of a hydrogen atom(s), substituent(s) being selected independently from the following:
C 1-20 alkoxy,
C 2-20 alkenyloxy,
C 7-20 aryloxy,
C 7-20 cycloalkyloxy,
halogen (F, Cl, Br, I),
—OH,
—OC(O)CH═CH 2 (acrylyl), —OC(O)CCH 3 ═CH 2 (methacrylyl),
NH 2 ,
N 3 (azido), and
—C(O)R 1 , —C(O)OR 1 , —OC(O)R 1 , NHR 1 , NR 1 R 2 , wherein each R 1 and R 2 is independently selected from the group consisting of:
C 1-20 linear or branched alkyl, C 3-20 cycloalkyl, C 2-20 linear alkenyl, C 4-20 branched alkenyl, C 5-20 cycloalkenyl, C 2-20 linear alkynyl, C 5-20 branched alkynyl, C 6-20 aromatic, C 7-20 alkyl-substituted aromatic, C 7-20 aryl-substituted alkyl, epoxy, mercapto (—SH), NHR 3 , NR 3 R 4 , wherein each each R 3 and R 4 is independently selected from the group consisting of C 1-20 linear alkyl, C 1-20 branched alkyl, C 3-20 cyclic alkyl, C 2-20 linear alkenyl, C 4-20 branched alkenyl, C 5-20 cyclic alkenyl, C 2-20 linear alkynyl, C 5-20 branched alkynyl, C 6-20 aromatic, C 7-20 alkyl-substituted aromatic, and C 7-20 aryl-substituted alkyl;
—C(O)OR 5 wherein each R 5 is independently selected from the group consisting of:
C 1-20 linear alkyl, C 1-20 branched alkyl, C 3-20 cycloalkyl, C 2-20 linear alkenyl, C 4-20 branched alkenyl, C 5-20 cycloalkenyl, C 2-20 linear alkynyl, C 5-20 branched alkynyl, C 6-20 aromatic, C 7-20 alkyl-substituted aromatic, C 7-20 aryl-substituted alkyl, and epoxy.

12. The capped polymer of claim 9 , wherein -Cap represents the end capping molecule selected from the group consisting of:

wherein each of rings A, B and C is, independently of the other of the rings, optionally substituted at one or more, including all, para- and ortho-positions with an electron-donating group;

wherein R 6 is optionally substituted C 1-20 linear or branched alkyl, optionally substituted C 6-20 aryl.

13. A block copolymer comprising first and second blocks, the first block being a polyglyoxylate polymer as defined in claim 1 , in which the end capping molecule is a linker that covalently links the first and second blocks.

14. The capped polymer of claim 13 , wherein the linker is of the formula:

in which L is a group that is cleaved in response to a stimulus such as light, enzymes, heat, change in pH or redox potential.

15. The capped polymer of claim 14 , wherein the linker is selected from the group consisting of:

wherein R 6 is optionally substituted C 1-20 linear or branched alkyl, optionally substituted C 6-20 aryl;

wherein each of rings D, E and F is, independently of the other of the rings, optionally substituted at one or more, including all, para- and ortho-positions with an electron-donating group.

16. The capped polymer of claim 15 , wherein each electron-donating group is selected from the group consisting of C 1 -C 20 alkoxy, and dialkylamino.

17. The block copolymer as defined in claim 14 , wherein said polyglyoxylate polymer is covalently linked to the carbon of the carbonyl group by an oxygen atom.

18. The polymer of claim 13 , wherein said second block comprises: a PEG, a PDMAEMA, a poly(lactic acid), a poly(glycolic acid), a poly(lactic acid-co-—glycolic acid), polycaprolactone, or a poly(glyoxylic acid).

Assignees

• Univ Western Ontario

Inventors

• Gillies Elizabeth R
• Fan Bo
• Wong Andrew D
• Trant John F

Classifications

• C07C69/716

  Esters of keto-carboxylic acids {or aldehydo-carboxylic acids} · CPC title

• C08G2/30 Primary

  Chemical modification by after-treatment · CPC title

• C07F7/1804

  Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896) · CPC title

• C07C67/30

  by modifying the acid moiety of the ester, such modification not being an introduction of an ester group · CPC title

• C07C69/86

  with esterified hydroxyl groups · CPC title