Heterobifunctional poly(ethylene glycol) and uses thereof

• US 20060142506A1
• Filed: 10/24/2005
• Published: 06/29/2006
• Est. Priority Date: 10/25/2004
• Status: Active Grant

• Current Assignee: Intezyne Technologies
• Original Assignee: Intezyne Technologies
• Inventors: Skaff, Habib, Breitenkamp, Kurt, Sill, Kevin
• Granted Patent: US 7,612,153 B2
• Time in Patent Office: Days
• US Class Current: 525/482
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: C07C 205/34 having nitro groups bound to carbon atoms of six-membered aromatic rings and etherified hydroxy groups bound to acyclic carbon atoms of the carbon skeleton
• CPC Class Codes: C07C 213/08 by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
• CPC Class Codes: C07C 215/08 with only one hydroxy group and one amino group bound to the carbon skeleton
• CPC Class Codes: C07C 247/10 and containing rings
• CPC Class Codes: C07C 271/16 to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 319/14 of sulfides
• CPC Class Codes: C07C 323/12 the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07C 67/08 by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
• CPC Class Codes: C07C 67/31 by introduction of functional groups containing oxygen only in singly bound form
• CPC Class Codes: C07C 69/76 Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 69/92 with etherified hydroxyl groups
• CPC Class Codes: C07D 207/452 with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 213/71 to which a second hetero atom is attached
• CPC Class Codes: C07F 7/1892 by reactions not provided for in C07F7/1876 - C07F7/1888
• CPC Class Codes: C08G 65/2612 containing aromatic or arylaliphatic hydroxyl groups
• CPC Class Codes: C08G 65/2627 containing aromatic or arylaliphatic amine groups
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/33337 cyclic
• CPC Class Codes: C08G 65/33396 : having oxygen in addition to nitrogen
• CPC Class Codes: C08L 2203/02 : for biomedical use

Abstract

The present invention provides bifunctional polymers, methods of preparing the same, and intermediates thereto. These compounds are useful in a variety of applications including the PEGylation of biologically active molecules. The invention also provides methods of using said compounds and compositions thereof.

Claims

1. A method for preparing a compound of formula I:

2. The method according to claim 1, wherein said method comprises the steps of:

(1) providing a polymerization initiator of formula HX(CH₂CH₂Y)_m(CH₂)_nR³, wherein;

X is —

O—

, —

S—

, —

C≡

C—

, or —

CH₂—

;

each Y is independently —

O—

or —

S—

;

m is 0-10;

n is 0-10; and

R³ is —

N₃, —

CN, a mono-protected amine, a di-protected amine, a protected aldehyde, a protected hydroxyl, a protected carboxylic acid, a protected thiol, a 9-30-membered crown ether, or an optionally substituted group selected from aliphatic, a 5-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a detectable moiety;

(2) polymerizing ethylene oxide onto said polymerization initiator to provide a compound of formula II; and

(3) terminating the living polymer chain-end of the compound of formula II with a suitable polymerization terminator to afford a compound of formula I.

3. The method according to claim 1, wherein the R¹ and R² groups of formula I are different from each other.

4. The method according to claim 3, wherein R³ is an optionally substituted group selected from aliphatic or aryl.

5. The method according to claim 4, wherein R³ is an aliphatic group substituted with one or more groups independently selected from CN, N₃, trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, N-methyl propiolamido, N-methyl-4-acetylenylanilino, N-methyl-4-acetylenylbenzoamido, bis-(4-ethynyl-benzyl)-amino, dipropargylamino, di-hex-5-ynyl-amino, di-pent-4-ynyl-amino, di-but-3-ynyl-amino, propargyloxy, hex-5-ynyloxy, pent-4-ynyloxy, di-but-3-ynyloxy, N-methyl-propargylamino, N-methyl-hex-5-ynyl-amino, N-methyl-pent-4-ynyl-amino, N-methyl-but-3-ynyl-amino, 2-hex-5-ynyldisulfanyl, 2-pent-4-ynyldisulfanyl, 2-but-3-ynyldisulfanyl, or 2-propargyldisulfanyl.

6. The method according to claim 4, wherein R³ is an aryl group substituted with one or more groups independently selected from CN, N₃, NO₂, —

CH₃, —

CH₂N₃, —

CH═

CH₂, —

C≡

CH, Br, I, F, bis-(4-ethynyl-benzyl)-amino, dipropargylamino, di-hex-5-ynyl-amino, di-pent-4-ynyl-amino, di-but-3-ynyl-amino, propargyloxy, hex-5-ynyloxy, pent-4-ynyloxy, di-but-3-ynyloxy, 2-hex-5-ynyloxy-ethyldisulfanyl, 2-pent-4-ynyloxy-ethyldisulfanyl, 2-but-3-ynyloxy-ethyldisulfanyl, 2-propargyloxy-ethyldisulfanyl, bis-benzyloxy-methyl, [1,3]dioxolan-2-yl, or [1,3]dioxan-2-yl.

7. The method according to claim 3, wherein R³ is a group suitable for Click chemistry.

8. The method according to claim 7, wherein R³ is an azide-containing group or an alkyne-containing group.

9. The method according to claim 3, wherein R¹ is selected from the group consisting of:

10. The method according to claim 1, wherein said polymerization initiator is selected from:

11. The method according to claim 1, wherein the suitable polymerization terminator is one that is capable of Mistunobu coupling.

12. The method according to claim 11, wherein the suitable polymerization terminator is selected from the group consisting of:

14. A compound of formula IV:

15. A compound of formula I′

;

16. The compound according to claim 15, wherein the R¹ and R² groups of formula I′

are different from each other.

17. The compound according to claim 15, wherein R³ is an optionally substituted group selected from aliphatic or aryl.

18. The compound according to claim 17, wherein R³ is an aliphatic group substituted with one or more groups independently selected from CN, N₃, trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, N-methyl propiolamido, N-methyl-4-acetylenylanilino, N-methyl-4-acetylenylbenzoamido, bis-(4-ethynyl-benzyl)-amino, dipropargylamino, di-hex-5-ynyl-amino, di-pent-4-ynyl-amino, di-but-3-ynyl-amino, propargyloxy, hex-5-ynyloxy, pent-4-ynyloxy, di-but-3-ynyloxy, N-methyl-propargylamino, N-methyl-hex-5-ynyl-amino, N-methyl-pent-4-ynyl-amino, N-methyl-but-3-ynyl-amino, 2-hex-5-ynyldisulfanyl, 2-pent-4-ynyldisulfanyl, 2-but-3-ynyldisulfanyl, or 2-propargyldisulfanyl.

19. The compound according to claim 17, wherein R³ is an aryl group substituted with one or more groups independently selected from CN, N₃, NO₂, —

CH₃, —

CH₂N₃, —

CH═

CH₂, —

C≡

CH, Br, I, F, bis-(4-ethynyl-benzyl)-amino, dipropargylamino, di-hex-5-ynyl-amino, di-pent-4-ynyl-amino, di-but-3-ynyl-amino, propargyloxy, hex-5-ynyloxy, pent-4-ynyloxy, di-but-3-ynyloxy, 2-hex-5-ynyloxy-ethyldisulfanyl, 2-pent-4-ynyloxy-ethyldisulfanyl, 2-but-3-ynyloxy-ethyldisulfanyl, 2-propargyloxy-ethyldisulfanyl, bis-benzyloxy-methyl, [1,3]dioxolan-2-yl, or [1,3]dioxan-2-yl.

20. The compound according to claim 16, wherein R³ is a group suitable for Click chemistry.

21. The compound according to claim 20, wherein R³ is an azide-containing group or an alkyne-containing group.

22. The compound according to claim 15, wherein said compound has a polydispersity index of about 1.0 to about 1.2.

23. The compound according to claim 15, wherein n is about 200 to about 250.

24. The compound according to claim 15, wherein n is about 100 to about 150.

25. The compound according to claim 15, wherein n is about 400 to about 500.

26. The compound according to claim 21, wherein said compound is selected from the group consisting of: