Heterobifunctional poly(ethylene glycol) and uses thereof

• US 7,612,153 B2
• Filed: 10/24/2005
• Issued: 11/03/2009
• Est. Priority Date: 10/25/2004
• Status: Expired due to Fees

• Current Assignee: Intezyne Technologies
• Original Assignee: Intezyne Technologies
• Inventors: Skaff, Habib, Breitenkamp, Kurt, Sill, Kevin
• Primary Examiner(s): Truong; Duc
• Application Number:
  US11/256,735
• Publication Number:
  US 20060142506A1
• Time in Patent Office: 1,471 Days
• Field of Search: 525/482, 525/523, 549/352, 549/223, 549/482, 548/518, 548/473, 546/255, 562/498, 556/449
• US Class Current: 525/523
• 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 compound of formula I′

;

2. The compound according to claim 1, wherein the R¹ and R² groups of formula I′

are different from each other.

3. The compound according to claim 1, wherein R³ is an optionally substituted group selected from aliphatic or aryl.

4. The compound according to claim 3, 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.

5. The compound according to claim 3, 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.

6. The compound according to claim 2, wherein R³ is a group suitable for Click chemistry.

7. The compound according to claim 6, wherein R³ is an azide-containing group or an alkyne-containing group.

8. The compound according to claim 1, wherein said compound has a polydispersity index of about 1.0 to about 1.2.

9. The compound according to claim 1, wherein n is about 200 to about 250.

10. The compound according to claim 1, wherein n is about 100 to about 150.

11. The compound according to claim 1, wherein n is about 400 to about 500.

12. The compound according to claim 1, wherein said compound is selected from the group consisting of:

13. The compound according to claim 1, wherein R³ is a mono-protected or di-protected amino group.

14. The compound according to claim 13, wherein R³ is a mono-protected amino group.

15. The compound according to claim 14, wherein R³ is a mono-protected amino group selected from t-butyloxycarbonylamino, ethyloxycarbonylamino, methyloxycarbonylamino, trichloroethyloxy-carbonylamino, allyloxycarbonylamino, benzyloxocarbonylamino, allylamino, benzylamino, fluorenylmethylcarbonyl, formamido, acetamido, chloroacetamido, dichioroacetamido, trichloroacetamido, phenylacetamido, trifluoroacetamido, benzamido, and t-butyldiphenylsilylamino.

16. The compound according to claim 13, wherein R³ is a di-protected amino group.

17. The compound according to claim 16, wherein R³ is a di-protected amino group selected from di-benzylamine, di-allylamine, phthalimide, maleimide, succinimide, pyrrole, 2,2,5,5-tetramethyl-[1,2,5]azadisilolidine, and azide.

18. The compound according to any one of claims 13-17, wherein R² is —

OS(O)₂R⁴, wherein R⁴ is an optionally substituted aliphatic group, or an optionally substituted 5-8-membered aryl ring.

19. The compound according to claim 18, wherein R² is p-toluenesulfonyloxy or methanesulfonyloxy.

20. The compound according to any one of claims 13-17, wherein R² is a group suitable for Click chemistry.

21. The compound according to claim 20, wherein R² is —

N₃.

22. The compound according to claim 1, wherein R² is selected from the group consisting of:

23. The compound according to claim 1, wherein R¹ is selected from the group consisting of: