Releasable polymeric conjugates based on aliphatic biodegradable linkers

• US 7,897,647 B2
• Filed: 08/09/2006
• Issued: 03/01/2011
• 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., Pendri, Annapurna
• Primary Examiner(s): Wityshyn; Michael G
• Assistant Examiner(s): HANLEY, SUSAN MARIE
• Application Number:
  US11/502,108
• Publication Number:
  US 20060286065A1
• Time in Patent Office: 1,665 Days
• Field of Search: 514/668, 514/715, 514/716, 424/179.1, 424/181.1, 424/193.1, 424/194.1
• US Class Current: 514/668
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 271/16 to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 271/20 to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 317/28 with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
• CPC Class Codes: C07D 207/452 with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 277/16 Sulfur atoms
• CPC Class Codes: C07D 333/34 Sulfur atoms
• CPC Class Codes: C07K 14/43595 from coelenteratae, e.g. medusae

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:

2. The compound of claim 1, wherein A is selected from the group consisting of cardiovascular agents, anti-neoplastic agents, anti-infective agents, anti-fungal agents, anti-anxiety agents, gastrointestinal agents, central nervous system-activating agents, analgesic agents, fertility agents, contraceptive agents, anti-inflammatory agents, and steroidal agents.

3. The compound of claim 1, wherein R₁ is a polyethylene glycol;

R₂ is C_1-6 alkyl; and

both c and d are zero.

4. The compound of claim 1, wherein R₃-R₁₀, R₂₄ and R₂₅ are each hydrogen.

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

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

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

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

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

10. 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,

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

12. 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—

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_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, 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.

13. The compound of claim 1, wherein R₁ and R₂ 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—

CH₂CH₂S—

wherein x is the degree of polymerization.

14. 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—

CH₂CH₂S—

,

—

OC(O)CH₂—

O—

(CH₂CH₂O)_X—

CH₂C(O)—

O—

,

—

NR₁₃CH₂CH₂—

O—

(CH₂CH₂O)_X—

CH₂CH₂NR₁₃— and

—

SCH₂CH₂—

O—

(CH₂CH₂O)_X—

CH₂CH₂S—

,

wherein;

x is the degree of polymerization;

R₁₃ is selected from the group consisting of hydrogen, C_1-6 alkyls, C_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, 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 R₁ and R₂ each comprise a polymer residue of the formula —

O—

(CH₂CH₂O)_x and x is the degree of polymerization.

16. The compound of claim 15, wherein R₁ and R₂ each have a weight average molecular weight of from about 2,000 Da to about 25,000 Da.

17. The compound of claim 1, wherein L₁ is selected from the group consisting of:

—

NH(CH₂CH₂O)₂CH₂C(O)—

,

—

NH(CH₂)₃OC(O)—

,

—

(CH₂)_tC(O)—

,

—

C(O)NH(CH₂)_tC(O)—

,

—

NH(CH₂)_tC(O)—

,

—

NR₁₉(CH₂)_t(CH₂CH₂O)_qNHC(O)—

,

—

(CH₂CH₂O)_tNHC(O)—

,

—

O(CR₁₄R₁₅)_tNHC(O)—

,

—

NR₁₉(CR₁₄R₁₅)_qC(O)NH(CR₁₆R₁₇)_tC(O)—

,

—

O(CH₂)_tOC(O)—

,

—

NR₁₉(CR₁₄R₁₅)_tC(O)—

,

—

NR₁₉(CH₂CH₂O)_t—

OC(O)—

,

—

O(CR₁₄R₁₅)_tOC(O)—

,

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

—

NH(CH₂CH₂O)₂CH₂C(O)—

,

—

NH(CH₂)₃OC(O)—

,

—

(CH₂)_vC(O)—

,

—

C(O)(CH₂)_vNHC(O)—

,

—

NH(CH₂)_vC(O)—

,

—

NR₂₅(CH₂)_v(CH₂CH₂O)_wNHC(O)—

,

—

(CH₂CH₂O)_vNHC(O)—

,

—

O(CR₂₀R₂₁)_vNHC(O)—

,

—

NR₂₅(CR₂₀R₂₁)_w(O)CNH(CR₂₂R₂₃)_vC(O)—

,

—

O(CH₂)_vOC(O)—

,

—

NR₂₅(CR₂₀R₂₁)_vC(O)—

,

—

NR₂₅(CH₂CH₂O)_v—

OC(O)—

,

—

O(CR₂₀R₂₁)_vOC(O)—

,

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

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

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

22. The compound of claim 1, wherein R₃-R₁₀, R₂₄ and R₂₅ are each hydrogen;

Y₁ is oxygen; and

R₁ is a polyethylene glycol.

23. The compound of claim 22, wherein a, b, c, d, m, n, o and p are each 1;

and e is 0 or 1.

24. A method of treatment of a condition that is treatable by a moiety A of claim 2, comprising administering to a mammal in need thereof, an effective amount of a compound of claim 4, wherein R₁ is a polyethylene glycol.

25. A compound comprising the formula:

26. The compound of claim 25, wherein A is selected from the group consisting of cardiovascular agents, anti-neoplastic agents, anti-infective agents, anti-fungal agents, anti-anxiety agents, gastrointestinal agents, central nervous system-activating agents, analgesic agents, fertility agents, contraceptive agents and anti-inflammatory agents.

27. The compound of claim 25, wherein R₃-R₁₀, R₂₄ and R₂₅ are each hydrogen.

28. The compound of claim 25, wherein a, b, c, d, m, n, o and p are each 1 and e is 0 or 1.

29. The compound of claim 25, wherein R₁ comprises a polyalkylene oxide.

30. The compound of claim 25, wherein R₂ comprises a polyalkylene oxide.

31. The compound of claim 25, wherein R₁ comprises a polyethylene glycol.

32. The compound of claim 25, wherein R₂ comprises a polyethylene glycol.

33. The compound of claim 25, 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,

34. A compound of claim 33, selected from the group consisting of:

35. The compound of claim 25, 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—

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_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, 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.

36. The compound of claim 25, wherein R₁ and R₂ 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—

CH₂CH₂S—

wherein x is the degree of polymerization.

37. The compound of claim 35, 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—

CH₂CH₂S—

,

—

OC(O)CH₂—

O—

(CH₂CH₂O)_X—

CH₂C(O)—

O—

,

—

NR₁₃CH₂CH₂—

O—

(CH₂CH₂O)_X—

CH₂CH₂NR₁₃— and

—

SCH₂CH₂—

O—

(CH₂CH₂O)_X—

CH₂CH₂S—

,

wherein;

x is the degree of polymerization;

R₁₃ is selected from the group consisting of hydrogen, C_1-6 alkyls, C_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, 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.

38. The compound of claim 25, wherein R₁ and R₂ each comprise a polymer residue of the formula —

O—

(CH₂CH₂O)_x and x is the degree of polymerization.

39. The compound of claim 30, wherein R₁ and R₂ each have a weight average molecular weight of from about 2,000 Da to about 25,000 Da.

40. The compound of claim 25, wherein L₁ is selected from the group consisting of:

—

NH(CH₂CH₂O)₂CH₂C(O)—

,

—

NH(CH₂)₃OC(O)—

,

—

(CH₂)_tC(O)—

,

—

C(O)NH(CH₂)_tC(O)—

,

—

NH(CH₂)_tC(O)—

,

—

NR₁₉(CH₂)_t(CH₂CH₂O)_qNHC(O)—

,

—

(CH₂CH₂O)_tNHC(O)—

,

—

O(CR₁₄R₁₅)_tNHC(O)—

,

—

NR₁₉(CR₁₄R₁₅)_qC(O)NH(CR₁₆R₁₇)_tC(O)—

,

—

O(CH₂)_tOC(O)—

,

—

NR₁₉(CR₁₄R₁₅)_tC(O)—

,

—

NR₁₉(CH₂CH₂O)_t—

OC(O)—

,

—

O(CR₁₄R₁₅)_tOC(O)—

,

41. The compound of claim 25, wherein L₂ is selected from the group consisting of:

—

NH(CH₂CH₂O)₂CH₂C(O)—

,

—

NH(CH₂)₃OC(O)—

,

—

(CH₂)_vC(O)—

,

—

C(O)(CH₂)_vNHC(O)—

,

—

NH(CH₂)_vC(O)—

,

—

NR₂₅(CH₂)_v(CH₂CH₂O)_wNHC(O)—

,

—

(CH₂CH₂O)_vNHC(O)—

,

—

O(CR₂₀R₂₁)_vNHC(O)—

,

—

NR₂₅(CR₂₀R₂₁)_w(O)CNH(CR₂₂R₂₃)_vC(O)—

,

—

O(CH₂)_vOC(O)—

,

—

NR₂₅(CR₂₀R₂₁)_vC(O)—

,

—

NR₂₅(CH₂CH₂O)_v—

OC(O)—

,

—

O(CR₂₀R₂₁)_vOC(O)—

,

42. The compound of claim 25, wherein said terminal branching group comprises the formula:

43. A compound of claim 42, comprising the structure:

44. A compound of claim 42, comprising the structure: