Releasable polymeric conjugates based on biodegradable linkers

• US 7,413,738 B2
• Filed: 12/14/2004
• Issued: 08/19/2008
• Est. Priority Date: 08/13/2002
• Status: Expired due to Fees

• Current Assignee: Belrose Pharma, Inc.
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Zhao, Hong
• Primary Examiner(s): Saucier; Sandra
• Assistant Examiner(s): HANLEY, SUSAN MARIE
• Application Number:
  US11/011,818
• Publication Number:
  US 20050197290A1
• Time in Patent Office: 1,344 Days
• Field of Search: 424/179.1,181.1,193.1,194.1 514/668,716,715
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 207/46 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 277/16 Sulfur atoms
• CPC Class Codes: C07H 15/24 Condensed ring systems having three or more rings

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, d′

, g, m, n, o and pare each 1.

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

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

6. The compound of claim 1, wherein A is selected from the group consisting of an activating group, proteins, and enzymes, and A′

is selected from the group consisting of an alkyl group, an activating group, proteins, and enzymes.

7. The compound of claim 1 wherein R₁ further comprises a capping group J, selected from the group consisting of OH, NH₂, SH, CO₂H, C_1-6 alkyl moieties, and

8. A compound of claim 7, of the formula:

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

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

11. The compound of claim 1, wherein R₁ comprises a polymer residue of the formula

12. The compound of claim 1 wherein L₁ and L₃ are independently selected the group consisting of:

—

NR₁₉(CR₁₄R₁₅)_tO—

,

—

NR₁₉(CR₁₄R₁₅)_t(CR₁₆CR₁₇O)_sNR₁₉—

,

—

O(CR₁₄R₁₅)_tNR₁₉—

,

—

O(CR₁₄R₁₅)_tO—

,

—

NR₁₉(CR₁₄R₁₅)_tNR₁₉—

,

—

NR₁₉(CR₁₄R₁₅)_t(CR₁₆CR₁₇O)_s—

,

—

NR₁₉(CR₁₆CR₁₇O)_t—

,

—

NR₁₉(CR₁₆CR₁₇O)_t(CR₁₄R₁₅)_sNR₁₉—

,

—

O(CR₁₆CR₁₇O)_tNR₁₉—

,

13. The compound of claim 1 wherein L₂ is selected from the group consisting of:

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

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

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

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

18. A compound of claim 17, comprising the structure:

19. A compound of claim 18, comprising the structure:

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

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

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

25. A method of treatment of a condition, comprising administering to a mammal in need thereof, an effective amount of a compound of claim 1, wherein A′

is an alkyl group and A is a residue of a biologically active agent which is capable of treating the condition selected from the group consisting of proteins and enzymes.

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

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

1) reacting one equivalent of an extended blocked bifunctional linker with one equivalent of an acid protected bicine moiety to form an intermediate of the formula;