Heterobifunctional poly(ethyleneglycol) containing acid-labile amino protecting groups and uses thereof

• US 20080188638A1
• Filed: 04/27/2007
• Published: 08/07/2008
• Est. Priority Date: 04/27/2006
• Status: Active Grant

• Current Assignee: Intezyne Technologies
• Original Assignee: Intezyne Technologies
• Inventors: Skaff, Habib, Breitenkamp, Kurt, Sill, Kevin N.
• Granted Patent: US 8,212,083 B2
• Time in Patent Office: Days
• US Class Current: 528/393
• CPC Class Codes: C07D 273/01 having one nitrogen atom
• CPC Class Codes: C07F 9/36 Amides thereof
• CPC Class Codes: C07F 9/46 Phosphinous acids [R2POH], [R2P(= O)H]: Thiophosphinous acids including[R2PSH]; [R2P(=S)H]; Aminophosphines [R2PNH2]; Derivatives thereof
• CPC Class Codes: C07F 9/572 Five-membered rings
• CPC Class Codes: C07F 9/6561 containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• CPC Class Codes: C08G 65/2612 containing aromatic or arylaliphatic hydroxyl groups
• CPC Class Codes: C08G 65/2624 containing aliphatic amine groups
• CPC Class Codes: C08G 65/263 containing heterocyclic amine groups
• CPC Class Codes: C08G 65/325 containing nitrogen
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/3344 containing oxygen in addition to sulfur
• CPC Class Codes: C08G 65/337 containing other elements organic compounds containing halogens only as halides of a carboxyl group C08G65/332
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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:

R^x and R^y are each independently phenyl optionally substituted with one or more groups independently selected from C_1-6 aliphatic, CN, N₃, NO₂, —

CH₃, —

CH₂N₃, t-butyl, 5-norbornene-2-yl, octane-5-yl, —

CH═

CH₂, —

C≡

CH, —

CH₂C≡

CH, —

CH₂CH₂C≡

CH, —

CH₂CH₂CH₂C≡

CH, Cl, Br, I, F, —

NH₂, —

OH, —

SH, —

CO₂H, —

C(O)H, —

CH₂NH₂, —

CH₂OH, —

CH₂SH, —

CH₂CO₂H, —

CH₂C(O)H, —

C(O)(C_1-6 aliphatic), —

NHC(O)(C_1-6 aliphatic), —

NHC(O)NH—

, —

NHC(O)NH(C_1-6 aliphatic), —

NHC(S)NH—

, —

NHC(S)N(C_1-6 aliphatic)₂, —

NHC(O)O(C_1-6 aliphatic), —

NHNH₂, —

NHNHC(O)(C_1-6 aliphatic), —

NHNHC(O)NH₂, —

NHNHC(O)NH(C_1-6 aliphatic), —

NHNHC(O)O(C_1-6 aliphatic), —

C(O)NH₂, —

C(O)NH(C_1-6 aliphatic)₂, —

C(O)NHNH₂, —

C(S)N(C_1-6 aliphatic)₂, —

OC(O)NH(C_1-6 aliphatic), —

C(O)C(O)(C_1-6 aliphatic), —

C(O)CH₂C(O)(C_1-6 aliphatic), —

S(O)₂(C_1-6 aliphatic), —

S(O)₂O(C_1-6 aliphatic), —

OS(O)₂(C_1-6 aliphatic), —

S(O)₂NH(C_1-6 aliphatic), —

S(O) (C_1-6 aliphatic), —

NHS(O)₂NH(C_1-6 aliphatic), —

NHS(O)₂(C_1-6 aliphatic), —

P(O)₂(C_1-6 aliphatic), —

P(O)(C_1-6 aliphatic)₂, —

OP(O)(C_1-6 aliphatic)₂, or —

OP(O)(OC_1-6 aliphatic)₂, or

R^x and R^y are each independently an aliphatic group optionally substituted with one or more of Cl, Br, I, F, —

NH₂, —

OH, —

SH, —

CO₂H, —

C(O)H, —

C(O)(C_1-6 aliphatic), —

NHC(O)(C_1-6 aliphatic), —

NHC(O)NH—

, —

NHC(O)NH(C_1-6 aliphatic), —

NHC(S)NH₂, —

NHC(S)N(C_1-6 aliphatic)₂, —

NHC(O)O(C_1-6 aliphatic), —

NHNH₂, —

NHNHC(O)(C_1-6 aliphatic), —

NHNHC(O)NH₂, —

NHNHC(O)NH(C_1-6 aliphatic), —

NHNHC(O)O(C_1-6 aliphatic), —

C(O)NH₂, —

C(O)NH(C_1-6 aliphatic)₂, —

C(O)NHNH₂, —

C(S)N(C_1-6 aliphatic)₂, —

OC(O)NH(C_1-6 aliphatic), —

C(O)C(O)(C_1-6 aliphatic), —

C(O)CH₂C(O)(C_1-6 aliphatic), —

S(O)₂(C_1-6 aliphatic), —

S(O)₂O(C_1-6 aliphatic), —

OS(O)₂(C_1-6 aliphatic), —

S(O)₂NH(C_1-6 aliphatic), —

S(O)(C_1-6 aliphatic), —

NHS(O)₂NH(C_1-6 aliphatic), —

NHS(O)₂(C_1-6 aliphatic), —

P(O)₂(C_1-6 aliphatic), —

P(O)(C_1-6 aliphatic)₂, —

OP(O)(C_1-6 aliphatic)₂, or —

OP(O)(OC_1-6 aliphatic)₂.

3. The compound according to claim 1, wherein:

G¹ is a valence bond or a -Cy-, -Cy-CH₂—

, —

CH₂-Cy-, -Cy-CH₂CH₂—

, —

NH—

, —

O-Cy-CH₂NH—

, —

OCH₂—

, —

OCH₂CH₂—

, —

OCH₂CH₂—

, —

OCH₂CH₂NH—

, —

CH₂—

, —

CH₂CH₂—

, or —

CH₂CH₂CH₂—

; and

L² is -Cy-, —

C(O)—

, —

C(O)NH—

, —

NH—

O—

, —

O-Cy-CH₂NH—

O—

, —

NHC(O)—

, —

OCH₂—

, —

OCH₂C(O)—

, —

OCH₂CH₂C(O)—

, —

OCH₂CH₂O—

, —

OCH₂CH₂S—

, —

OCH₂CH₂C(O)O—

, —

OCH₂CH₂NH—

, —

OCH₂CH₂NHC(O)—

, —

OCH₂CH₂C(O)NH—

, —

O-Cy-, —

O-Cy-NH—

, —

NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂CH₂C(O)O—

, —

O-Cy-CH₂—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)NH—

, —

CH₂C(O)NH—

, —

CH₂C(O)NHNH—

, —

OCH₂CH₂NHNH—

, —

OC(O)CH₂CH₂CH₂CH₂—

, —

OCH₂CH₂—

, —

NHC(O)CH₂CH₂—

, —

NHC(O)CH₂CH₂CH₂—

, —

OC(O)CH₂CH₂CH₂—

, —

O-Cy-C(O)—

, —

O-Cy-C(O)O—

, —

O-Cy-C(O)O-Cy-, —

O-Cy-OCH₂CH(CH₃)C(O)O—

, —

O-Cy-C(O)O—

, —

O-Cy-OCH(CH₃)CH₂C(O)O—

, —

OCH₂C(O)O—

, —

OCH₂C(O)NH—

, —

OCH₂O—

, —

OCH₂S—

, —

O-Cy-S—

, or —

OCH₂NH—

.

4. The compound according to claim 1, wherein R² is an azide-containing group, an alkyne-containing group, a group comprising a terminal alkyne moiety, an aldehyde-containing group, a group comprising a terminal hydrazine moiety, a group comprising a terminal oxyamine moiety, an epoxide-containing group, or a group comprising a terminal maleimide moiety.

14. The compound according to claim 1, wherein said compound is selected from the following formulae:

20. A method for preparing the compound according to claim 1, comprising the steps of:

(a) providing a polymerization initiator of formula A;

21. The method according to claim 20, further comprising the step of treating the compound of formula I with a suitable acid to form a compound of formula V:

22. The method according to claim 21, further comprising the step of treating the compound of formula V with a suitable base to form a compound of formula V-a:

24. The method according to claim 20, further comprising the step of treating the compound of formula II with a suitable acid to form a compound of formula V:

25. The method according to claim 24, further comprising the step of treating the compound of formula V with a suitable base to form a compound of formula V-a:

5. A compound of formula II:

6. The compound according to claim 5, wherein

G¹ is a valence bond or a -Cy-, -Cy-CH₂—

, —

CH₂-Cy-, -Cy-CH₂CH₂—

, —

NH—

, —

O-Cy-CH₂NH—

, —

OCH₂—

, —

OCH₂CH₂—

, —

OCH₂CH₂—

, —

OCH₂CH₂NH—

, —

CH₂—

, —

CH₂CH₂—

, or —

CH₂CH₂CH₂—

; and

L² is -Cy-, —

C(O)—

, —

C(O)NH—

, —

NH—

O—

, —

O-Cy-CH₂NH—

O—

, —

NHC(O)—

, —

OCH₂—

, —

OCH₂C(O)—

, —

OCH₂CH₂C(O)—

, —

OCH₂CH₂O—

, —

OCH₂CH₂S—

, —

OCH₂CH₂C(O)O—

, —

OCH₂CH₂NH—

, —

OCH₂CH₂NHC(O)—

, —

OCH₂CH₂C(O)NH—

, —

O-Cy-, —

O-Cy-NH—

, —

NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂CH₂C(O)O—

, —

O-Cy-CH₂—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)NH—

, —

CH₂C(O)NH—

, —

CH₂C(O)NHNH—

, —

OCH₂CH₂NHNH—

, —

OC(O)CH₂CH₂CH₂CH₂—

, —

OCH₂CH₂—

, —

NHC(O)CH₂CH₂—

, —

NHC(O)CH₂CH₂CH₂—

, —

OC(O)CH₂CH₂CH₂—

, —

O-Cy-C(O)—

, —

O-Cy-C(O)O—

, —

O-Cy-C(O)O-Cy-, —

O-Cy-OCH₂CH(CH₃)C(O)O—

, —

O-Cy-C(O)O—

, —

O-Cy-OCH(CH₃)CH₂C(O)O—

, —

OCH₂C(O)O—

, —

OCH₂C(O)NH—

, —

OCH₂O—

, —

OCH₂S—

, —

O-Cy-S—

, or —

OCH₂NH—

.

7. The compound according to claim 5, wherein R² is an azide-containing group, an alkyne-containing group, a group comprising a terminal alkyne moiety, an aldehyde-containing group, a group comprising a terminal hydrazine moiety, a group comprising a terminal oxyamine moiety, an epoxide-containing group, or a group comprising a terminal maleimide moiety.

15. The compound according to claim 5, wherein said compound is selected from the following formulae:

23. A method for preparing the compound according to claim 5, comprising the steps of:

(a) providing a polymerization initiator of formula C;

8. A compound of formula III:

9. The compound according to claim 8, wherein:

each Z is oxygen;

each R¹ is independently C_1-4 straight or branched alkyl, C_4-8 cycloalkyl, or optionally substituted phenyl;

G¹ is a valence bond or a -Cy-, -Cy-CH₂—

, —

CH₂-Cy-, -Cy-CH₂CH₂—

, —

NH—

, —

O-Cy-CH₂NH—

, —

OCH₂—

, —

OCH₂CH₂—

, —

OCH₂CH₂—

, —

OCH₂CH₂NH—

, —

CH₂—

, —

CH₂CH₂—

, or —

CH₂CH₂CH₂—

; and

L² is -Cy-, —

C(O)—

, —

C(O)NH—

, —

NH—

O—

, —

O-Cy-CH₂NH—

O—

, —

NHC(O)—

, —

OCH₂—

, —

OCH₂C(O)—

, —

OCH₂CH₂C(O)—

, —

OCH₂CH₂O—

, —

OCH₂CH₂S—

, —

OCH₂CH₂C(O)O—

, —

OCH₂CH₂NH—

, —

OCH₂CH₂NHC(O)—

, —

OCH₂CH₂C(O)NH—

, —

O-Cy-, —

O-Cy-NH—

, —

NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂CH₂C(O)O—

, —

O-Cy-CH₂—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)NH—

, —

CH₂C(O)NH—

, —

CH₂C(O)NHNH—

, —

OCH₂CH₂NHNH—

, —

OC(O)CH₂CH₂CH₂CH₂—

, —

OCH₂CH₂—

, —

NHC(O)CH₂CH₂—

, —

NHC(O)CH₂CH₂CH₂—

, —

OC(O)CH₂CH₂CH₂—

, —

O-Cy-C(O)—

, —

O-Cy-C(O)O—

, —

O-Cy-C(O)O-Cy-, —

O-Cy-OCH₂CH(CH₃)C(O)O—

, —

O-Cy-C(O)O—

, —

O-Cy-OCH(CH₃)CH₂C(O)O—

, —

OCH₂C(O)O—

, —

OCH₂C(O)NH—

, —

OCH₂O—

, —

OCH₂S—

, —

O-Cy-S—

, or —

OCH₂NH—

.

10. The compound according to claim 8, wherein R² is an azide-containing group, an alkyne-containing group, a group comprising a terminal alkyne moiety, an aldehyde-containing group, a group comprising a terminal hydrazine moiety, a group comprising a terminal oxyamine moiety, an epoxide-containing group, or a group comprising a terminal maleimide moiety.

16. The compound according to claim 8, wherein said compound is selected from any of the following formulae:

26. A method for preparing a compound according to claim 8, comprising the steps of:

(a) providing a polymerization initiator of formula E;

27. The method according to claim 26, further comprising the step of treating the compound of formula II with a suitable acid to form a compound of formula V:

28. The method according to claim 27, further comprising the step of treating the compound of formula V with a suitable base to form a compound of formula V-a:

11. A compound of formula IV:

12. The compound according to claim 11, wherein:

each Z is oxygen;

each R¹ is independently C_1-4 straight or branched alkyl, C_4-8 cycloalkyl, or optionally substituted phenyl;

G¹ is a valence bond or a -Cy-, -Cy-CH₂—

, —

CH₂-Cy-, -Cy-CH₂CH₂—

, —

NH—

, —

O-Cy-CH₂NH—

, —

OCH₂—

, —

OCH₂CH₂—

, —

OCH₂CH₂—

, —

OCH₂CH₂NH—

, —

CH₂—

, —

CH₂CH₂—

, or —

CH₂CH₂CH₂—

; and

L² is -Cy-, —

C(O)—

, —

C(O)NH—

, —

NH—

O—

, —

O-Cy-CH₂NH—

O—

, —

NHC(O)—

, —

OCH₂—

, —

OCH₂C(O)—

, —

OCH₂CH₂C(O)—

, —

OCH₂CH₂O—

, —

OCH₂CH₂S—

, —

OCH₂CH₂C(O)O—

, —

OCH₂CH₂NH—

, —

OCH₂CH₂NHC(O)—

, —

OCH₂CH₂C(O)NH—

, —

O-Cy-, —

O-Cy-NH—

, —

NHC(O)CH₂CH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂CH₂C(O)O—

, —

O-Cy-CH₂—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)O—

, —

OCH₂CH₂NHC(O)CH₂OCH₂C(O)NH—

, —

CH₂C(O)NH—

, —

CH₂C(O)NHNH—

, OCH₂CH₂NHNH—

, —

OC(O)CH₂CH₂CH₂CH₂—

, —

OCH₂CH₂—

, —

NHC(O)CH₂CH₂—

, —

NHC(O)CH₂CH₂CH₂—

, —

OC(O)CH₂CH₂CH₂—

, —

O-Cy-C(O)—

, —

O-Cy-C(O)O—

, —

O-Cy-C(O)O-Cy-, —

O-Cy-OCH₂CH(CH₃)C(O)O—

, —

O-Cy-C(O)O—

, —

O-Cy-OCH(CH₃)CH₂C(O)O—

, —

OCH₂C(O)O—

, —

OCH₂C(O)NH—

, —

OCH₂O—

, —

OCH₂S—

, —

O-Cy-S—

, or —

OCH₂NH—

.

13. The compound according to claim 11, wherein R² is an azide-containing group, an alkyne-containing group, a group comprising a terminal alkyne moiety, an aldehyde-containing group, a group comprising a terminal hydrazine moiety, a group comprising a terminal oxyamine moiety, an epoxide-containing group, or a group comprising a terminal maleimide moiety.

17. The compound according to claim 11, wherein said compound is selected from any of the following formulae:

29. A method for preparing a compound according to claim 11, comprising the steps of:

(a) providing a polymerization initiator of formula G;

30. The method according to claim 29, further comprising the step of treating the compound of formula II with a suitable acid to form a compound of formula V:

31. The method according to claim 30, further comprising the step of treating the compound of formula V with a suitable base to form a compound of formula V-a:

18. A compound of formula V:

19. The compound according to claim 18, wherein A⁻

is the anion of trifluoroacetic acid or HCl.

32. A compound selected from those depicted in Tables A, B, C, and D: