Releasable polymeric conjugates based on aliphatic biodegradable linkers

• US 8,192,743 B2
• Filed: 07/25/2008
• Issued: 06/05/2012
• 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, Greenwald, Richard B.
• Primary Examiner(s): HANLEY, SUSAN MARIE
• Application Number:
  US12/180,187
• Publication Number:
  US 20080305070A1
• Time in Patent Office: 1,411 Days
• Field of Search: 424/179.1, 424/181.1, 424/193.1, 424/194.1, 514/668, 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 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 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 p are each 1.

4. The compound of claim 1, wherein A is a biologically active moiety, and A′

is an alkyl group.

5. 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

6. A compound of claim 5, of the formula:

7. 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—

(C₂CH₂O)_x—

CH₂CH₂S—

,

—

OC(O)CH₂—

O—

(CH₂CH₂O)_X—

CH₂C(O)—

O—

,

—

NR₁₂CH₂CH₂—

O—

(CH₂CH₂O)_X—

CH₂CH₂NR₁₂— and

—

SCH₂CH₂—

O—

(CH₂CH₂O)_X—

CH₂CH₂S—

wherein;

x is the degree of polymerization;

R₁₂ is selected from the group consisting of hydrogen, C_1-6 alkyls, C_2-6 alkenyls, C_2-6 alkynyls, C_3-19 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_1-6 heteroalkyls, C_1-6 alkoxy, phenoxy and C_1-6 heteroalkoxy; and

J is a capping group.

8. The compound of claim 1, wherein R₁ is 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—

CH₂CH₂S—

wherein x is the degree of polymerization.

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

10. The compound of claim 1 wherein L₁ and L₃ are independently selected from 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—

,

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

—

C(O)CR₃₀R₃₁OCR₃₂R₃₃C(O)NR₃₅—

,

—

C(O)CR₃₀R₃₁NR₃₄CR₃₂R₃₃C(O)NR₃₅—

,

—

C(O)CR₃₀R₃₁SCR₃₂R₃₃C(O)NR₃₅— and

—

C(O)(CR₃₀R₃₁)_n′

C(O)NR₃₅—

wherein;

R_30-34 are independently selected from the group consisting of H, C_1-6 alkyls, C_2-6 alkenyls, C_2-6 alkynyls, C_1-6 heteroalkyls and aryls; and

n′

is a positive integer from 1 to 3.

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

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

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

15. A compound of claim 14, comprising the structure:

16. A compound of claim 15, comprising the structure:

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

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

20. A method of treatment, 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 moiety selected from the group consisting of a residue of hydroxyl- or amine-containing organic compounds, peptides and nucleic acids.

21. The compound of claim 1, wherein a, b, c, d, m, n, o and p are each 1.

22. The compound of claim 1, wherein A′

is an alkyl group and A is a residue of a biologically active moiety selected from the group consisting of a residue of hydroxyl- or amine-containing organic compounds, peptides and nucleic acids.

23. The compound of claim 1, wherein d′

and g are 0.

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