Releasable polymeric conjugates based on aliphatic biodegradable linkers

• US 7,087,229 B2
• Filed: 05/30/2003
• Issued: 08/08/2006
• Est. Priority Date: 05/30/2003
• Status: Expired due to Fees

• Current Assignee: Belrose Pharma, Inc.
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Zhao, Hong, Greenwald, Richard B.
• Primary Examiner(s): Witz, Jean C.
• Assistant Examiner(s): HANLEY, SUSAN MARIE
• Application Number:
  US10/449,849
• Publication Number:
  US 20050003448A1
• Time in Patent Office: 1,166 Days
• Field of Search: 424/91, 424/178.1, 424/179.1, 424/181.1, 424/193.1, 424/194, 514/663, 514/668, 514/7, 514/715, 514/716
• US Class Current: 424/179.1
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07D 207/404 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
• CPC Class Codes: C07D 277/16 Sulfur atoms

Abstract

Activated polymeric bicine derivatives such as,

as well as conjugates made therewith are disclosed. Methods of making and using the bicine derivatives are also disclosed.

Claims

1. A compound comprising the Formula (I):

2. The compound of claim 1, wherein R₃–

R₁₀, R_24-25 and R_30-34 are each hydrogen; and

Y₁₅ is O or NR₃₄.

3. The compound of claim 1, wherein a, b, c, d, f, g, m, n, o and p are each 1, and e is 0 or 1.

4. The compound of claim 1, wherein (c and g) are each 0.

5. The compound of claim 1, wherein (a and f) are each 0.

6. The compound of claim 1, wherein (c, g, and d) are each 0.

7. The compound of claim 1, wherein (a, b and f) are each 0.

8. The compound of claim 1, wherein R₁ comprises a polyalkylene oxide.

9. The compound of claim 1, wherein R₂ comprises a polyalkylene oxide.

10. The compound of claim 1, wherein R₁ comprises a polyethylene glycol.

11. The compound of claim 1 wherein R₂ comprises a polyethylene glycol.

12. The compound of claim 1 wherein R₁ or R₂ further include a capping group J, selected from the group consisting of OH, NH₂, SH, CO₂H, C_1-6 alkyl moieties,

13. A compound of claim 10, selected from the group consisting of:

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

J-O—

(CH₂CH₂O)_x—

,

J-O—

(CH₂CH₂O)_x—

CH₂C(O)—

O—

,

J-O—

(CH₂CH₂O)_x—

CH₂CH₂NR₁₂—

,

J-O—

(CH₂CH₂O)_x—

CH₂CH₂SH—

,

—

OC(O)CH₂—

O—

(CH₂CH₂O)_x—

CH₂C(O)—

O—

,

—

NR₁₂CH₂CH₂—

O—

(CH₂CH₂O)_x—

CH₂CH₂NR₁₂— and

—

SHCH₂CH₂—

O—

(CH₂CH₂O)_x—

CH₂CH₂SH—

wherein;

x is the degree of polymerization;

R₁₂ is selected from the group consisting of hydrogen, C_1-6 alkyls, C_2-6 alkenyl, C_2-6 alkynyl, C_3-19 branched alkyls, C_3-4 cycloalkyls, C_1-6 substituted alkyls, C_2-6 substituted alkenyls, C_2-6 substituted alkynyls, C_3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C_1-6 heteroalkyls, substituted C_1-6 heteroalkyls, C_1-6 alkoxy, phenoxy and C_1-6 heteroalkoxy; and

J is a capping group.

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

J-O—

(CH₂CH₂O)_x—

,

J-O—

(CH₂CH₂O)_x—

CH₂C(O)—

O—

,

J-O—

(CH₂CH₂O)_x—

CH₂CH₂NR₁₃—

,

J-O—

(CH₂CH₂O)_x—

CH₂CH₂SH—

,

—

OC(O)CH₂—

O—

(CH₂CH₂O)_x—

CH₂C(O)—

O—

,

—

NR₁₃CH₂CH₂—

O—

(CH₂CH₂O)_x—

CH₂CH₂NR₁₃— and

—

SHCH₂CH₂—

O—

(CH₂CH₂O)_x—

CH₂CH₂SH—

,

wherein;

x is the degree of polymerization;

R₁₃ is selected from the group consisting of hydrogen, C_1-6 alkyls, C_2-6 alkenyls, C_2-6 alkynyls, C_3-12 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, C_2-6 substituted alkenyls, C_2-6 substituted alkynyls, C_3-8 substituted cycloalkyls, aryls substituted aryls, aralkyls, C_1-6 heteroalkyls, substituted C_1-6heteroalkyls, C_1-6alkoxy, phenoxy and C_1-6heteroalkoxy, and

J is a capping group.

16. The compound of claim 1, wherein R_1-2 are individually selected from the group consisting of:

CH₃—

O—

(CH₂CH₂O)_x—

,

CH₃—

O—

(CH₂CH₂O)_x—

CH₂C(O)—

O—

,

CH₃—

O—

(CH₂CH₂O)_x—

CH₂CH₂NH— and

CH₃—

O—

(CH₂CH₂O)_x—

CH₂CH₂SH—

wherein x is the degree of polymerization.

17. The compound of claim 1, wherein R₁ and R₂ each comprise a polymer residue of the formula

—

OCH₂CH₂O_x

wherein x is the degree of polymerization.

18. The compound of claim 17, wherein R₁ and R₂each have a weight average molecular weight of from about 2,000 Da to about 25,000 Da.

19. The compound of claim 1 wherein L₁ and L₂ are independently selected from the group consisting of:

—

NR₁₉(CR₁₄R₁₅)_tO—

,

—

NR₁₉(CR₁₄R₁₅)_t(CR₁₆CR₁₇O)_qNR₁₉—

,

—

O(CR₁₄R₁₅)_tNR₁₉—

,

—

O(CR₁₄R₁₅)_tO—

,

—

NR₁₉(CR₁₄R₁₅)_tNR₁₉—

,

—

NR₁₉(CR₁₄R₁₅)_t(CR₁₆CR₁₇O)_q—

,

—

NR₁₉(CR₁₆CR₁₇O)_t—

,

—

NR₁₉(CR₁₆CR₁₇O)_t(CR₁₄R₁₅)_qNR₁₉—

,

—

NR₁₉(CR₁₆CR₁₇O)_t—

,

—

O(CR₁₄R₁₅)_t—

NR₁₉—

,

—

O(CR₁₄R₁₅)_tNR₁₉—

,

—

O(CR₁₆CR₁₇O)_tNR₁₉—

,

20. The compound of claim 1 wherein L₃ and L₄ are independently selected from the group consisting of:

—

C(O)CR₃₀R₃₁OCR₃₂R₃₃C(O)—

;

—

C(O)CR₃₀R₃₁NR₃₄CR₃₂R₃₃C(O)—

;

—

C(O)CR₃₀R₃₁SCR₃₂R₃₃C(O)—

, or

—

C(O)(CR₃₀R₃₁)_nC(O)—

;

wherein;

R_30-34 are independently selected from H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 heteroalkyl or aryl, and

n is a positive integer from about 2 to about 3.

21. A compound of claim 1, comprising the formula:

22. A compound of claim 1, selected from the group consisting of

23. The compound of claim 1, wherein A₁ is a leaving group selected from the group consisting of

24. The compound of claim 23, wherein A₁is:

25. The compound of claim 1, wherein A is selected from the group consisting of maleimidyl, vinyl sulfonyl, hydroxy, amino, carboxy, mercapto, hydrazide, and carbazate functional groups.

26. The compound of claim 1, wherein said terminal branching group comprises the formula:

27. A compound of claim 26, comprising the structure:

28. A compound of claim 26, comprising the structure:

29. A compound of claim 1, selected from the group consisting of

30. A compound of claim 1, selected from the group consisting of

31. A method of preparing a polymer conjugate, comprising reacting a compound of the formula:

32. A method of preparing a bicine-based polymer transport system, comprising:

a) reacting a blocked bifunctional linker with an anhydride to form an extended blocked bifunctional spacer of the formula;