IP Library › Granted Patent US 7,897,647
Granted Patent B2
US 7,897,647 · App. 11/502,108 · Granted Mar 1, 2011

Releasable polymeric conjugates based on aliphatic biodegradable linkers

View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 7,897,647
App. No.
11/502,108
Granted
Mar 1, 2011
Kind
B2
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 (214)

1. A compound comprising the formula:

wherein:

R 1 and R 2 are independently selected from the group consisting of polyethylene glycol, C 1-6 alkyls, aralkyls, and terminal branching groups;

Y 1-3 are independently O, S or NR 11 ;

L 1 and L 2 are independently selected bifunctional linkers;

Z is selected from the group consisting of

wherein L 3 is a bifunctional linker and Y 4 is O, S or NR 11 , hydrophobic moieties, bifunctional linking moieties and combinations thereof;

R 3 -R 11 , R 24 and R 25 are independently 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;

A is an organic compound containing an amine;

a and c are each independently 0 or a positive integer;

b, d and e are independently 0 or 1; and

m, n, o, and p are independently selected positive integers,

provided that at least one of R 1 and R 2 is a polyethylene glycol and the weight average molecular weight thereof is about 40,000 Da.

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 R 1 is a polyethylene glycol; R 2 is C 1-6 alkyl; and both c and d are zero.

4. The compound of claim 1 , wherein R 3 -R 10 , R 24 and R 25 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 R 1 comprises a polyalkylene oxide.

7. The compound of claim 1 , wherein R 2 comprises a polyalkylene oxide.

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

9. The compound of claim 1 , wherein R 2 comprises a polyethylene glycol.

10. The compound of claim 1 , wherein R 1 or R 2 further include a capping group J, selected from the group consisting of OH, NH 2 , SH, CO 2 H, C 1-6 alkyl moieties,

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

wherein L 3 is a bifunctional linker and Y 4 is O, S or NR 11 .

12. The compound of claim 1 , wherein R 1 is selected from the group consisting of:

J-O—(CH 2 CH 2 O) x —,

J-O—(CH 2 CH 2 O) x —CH 2 C(O)—O—,

J-O—(CH 2 CH 2 O) x —CH 2 CH 2 NR 12 —,

J-O—(CH 2 CH 2 O) x —CH 2 CH 2 S—,

—OC(O)CH 2 —O—(CH 2 CH 2 O) X —CH 2 C(O)—O—,

—NR 12 CH 2 CH 2 —O—(CH 2 CH 2 O) X —CH 2 CH 2 NR 12 — and

—SCH 2 CH 2 —O—(CH 2 CH 2 O) X —CH 2 CH 2 S—

wherein:

x is the degree of polymerization;

R 12 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 R 1 and R 2 are individually selected from the group consisting of:

CH 3 —O—(CH 2 CH 2 O) x —,

CH 3 —O—(CH 2 CH 2 O) x —CH 2 C(O)—O—,

CH 3 —O—(CH 2 CH 2 O) x —CH 2 CH 2 NH— and

CH 3 —O—(CH 2 CH 2 O) x —CH 2 CH 2 S—

wherein x is the degree of polymerization.

14. The compound of claim 1 , wherein R 2 is selected from the group consisting of:

J-O—(CH 2 CH 2 O) x —,

J-O—(CH 2 CH 2 O) x —CH 2 C(O)—O—,

J-O—(CH 2 CH 2 O) x —CH 2 CH 2 NR 13 —,

J-O—(CH 2 CH 2 O) x —CH 2 CH 2 S—,

—OC(O)CH 2 —O—(CH 2 CH 2 O) X —CH 2 C(O)—O—,

—NR 13 CH 2 CH 2 —O—(CH 2 CH 2 O) X —CH 2 CH 2 NR 13 — and

—SCH 2 CH 2 —O—(CH 2 CH 2 O) X —CH 2 CH 2 S—,

wherein:

x is the degree of polymerization;

R 13 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 R 1 and R 2 each comprise a polymer residue of the formula —O—(CH 2 CH 2 O) x and x is the degree of polymerization.

16. The compound of claim 15 , wherein R 1 and R 2 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 L 1 is selected from the group consisting of:

—NH(CH 2 CH 2 O) 2 CH 2 C(O)—,

—NH(CH 2 ) 3 OC(O)—,

—(CH 2 ) t C(O)—,

—C(O)NH(CH 2 ) t C(O)—,

—NH(CH 2 ) t C(O)—,

—NR 19 (CH 2 ) t (CH 2 CH 2 O) q NHC(O)—,

—(CH 2 CH 2 O) t NHC(O)—,

—O(CR 14 R 15 ) t NHC(O)—,

—NR 19 (CR 14 R 15 ) q C(O)NH(CR 16 R 17 ) t C(O)—,

—O(CH 2 ) t OC(O)—,

—NR 19 (CR 14 R 15 ) t C(O)—,

—NR 19 (CH 2 CH 2 O) t —OC(O)—,

—O(CR 14 R 15 ) t OC(O)—,

wherein

R 14 -R 17 and R 19 are independently 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;

R 18 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, NO 2 , haloalkyl and halogen; and

t and q are individually selected positive integers.

18. The compound of claim 1 , wherein L 2 is selected from the group consisting of:

—NH(CH 2 CH 2 O) 2 CH 2 C(O)—,

—NH(CH 2 ) 3 OC(O)—,

—(CH 2 ) v C(O)—,

—C(O)(CH 2 ) v NHC(O)—,

—NH(CH 2 ) v C(O)—,

—NR 25 (CH 2 ) v (CH 2 CH 2 O) w NHC(O)—,

—(CH 2 CH 2 O) v NHC(O)—,

—O(CR 20 R 21 ) v NHC(O)—,

—NR 25 (CR 20 R 21 ) w (O)CNH(CR 22 R 23 ) v C(O)—,

—O(CH 2 ) v OC(O)—,

—NR 25 (CR 20 R 21 ) v C(O)—,

—NR 25 (CH 2 CH 2 O) v —OC(O)—,

—O(CR 20 R 21 ) v OC(O)—,

wherein

R 20 -R 23 and R 25 are independently 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;

R 24 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, C 1-6 heteroalkoxy, NO 2 , haloalkyl and halogen; and

v and w are individually selected positive integers.

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

wherein:

Y 5 is O, S or NR 46 ;

L 4 is a bifunctional linker;

R 40 -R 46 are independently 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;

j and k are each independently 0 or a positive integer;

q is 0 or 1;

g, h, v and w are independently selected positive integers;

R 50 is selected from the group consisting of substantially non-antigenic polymer residues, C 1-6 alkyls, C 1-6 aralkyls, and

wherein:

L 5 is a bifunctional linker; and

R 60 is selected from the group consisting of substantially non-antigenic polymer residues, C 1-6 alkyls and C 1-6 aralkyls.

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 R 3 -R 10 , R 24 and R 25 are each hydrogen; Y 1 is oxygen; and R 1 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 R 1 is a polyethylene glycol.

25. A compound comprising the formula:

wherein:

R 1 and R 2 are independently selected from the group consisting of substantially non-antigenic polymer residues, C 1-6 alkyls, aralkyls, and terminal branching groups;

Y 1-3 are independently O, S or NR 11 ;

L 1 and L 2 are independently selected bifunctional linkers;

Z is selected from the group consisting of

wherein L 3 is a bifunctional linker and Y 4 is O, S or NR 11 , hydrophobic moieties, bifunctional linking moieties and combinations thereof;

R 3 -R 11 , R 24 and R 25 are independently 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;

A is selected from the group consisting of proteins, and enzymes;

a and c are each independently 0 or a positive integer;

b, d and e are independently 0 or 1; and

m, n, o, and p are independently selected positive integers,

provided that at least one of R 1 and R 2 is a substantially non-antigenic polymer.

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 R 3 -R 10 , R 24 and R 25 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 R 1 comprises a polyalkylene oxide.

30. The compound of claim 25 , wherein R 2 comprises a polyalkylene oxide.

31. The compound of claim 25 , wherein R 1 comprises a polyethylene glycol.

32. The compound of claim 25 , wherein R 2 comprises a polyethylene glycol.

33. The compound of claim 25 , wherein R 1 or R 2 further include a capping group J, selected from the group consisting of OH, NH 2 , SH, CO 2 H, C 1-6 alkyl moieties,

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

wherein L 3 is a bifunctional linker and Y 4 is O, S or NR 11 .

35. The compound of claim 25 , wherein R 1 is selected from the group consisting of:

J-O—(CH 2 CH 2 O) x —,

J-O—(CH 2 CH 2 O) x —CH 2 C(O)—O—,

J-O—(CH 2 CH 2 O) x —CH 2 CH 2 NR 12 —,

J-O—(CH 2 CH 2 O) x —CH 2 CH 2 S—,

—OC(O)CH 2 —O—(CH 2 CH 2 O) X —CH 2 C(O)—O—,

—NR 12 CH 2 CH 2 —O—(CH 2 CH 2 O) X —CH 2 CH 2 NR 12 — and

—SCH 2 CH 2 —O—(CH 2 CH 2 O) X —CH 2 CH 2 S—

wherein:

x is the degree of polymerization;

R 12 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 R 1 and R 2 are individually selected from the group consisting of:

CH 3 —O—(CH 2 CH 2 O) x —,

CH 3 —O—(CH 2 CH 2 O) x —CH 2 C(O)—O—,

CH 3 —O—(CH 2 CH 2 O) x —CH 2 CH 2 NH— and

CH 3 —O—(CH 2 CH 2 O) x —CH 2 CH 2 S—

wherein x is the degree of polymerization.

37. The compound of claim 35 , wherein R 2 is selected from the group consisting of:

J-O—(CH 2 CH 2 O) x —,

J-O—(CH 2 CH 2 O) x —CH 2 C(O)—O—,

J-O—(CH 2 CH 2 O) x —CH 2 CH 2 NR 13 —,

J-O—(CH 2 CH 2 O) x —CH 2 CH 2 S—,

—OC(O)CH 2 —O—(CH 2 CH 2 O) X —CH 2 C(O)—O—,

—NR 13 CH 2 CH 2 —O—(CH 2 CH 2 O) X —CH 2 CH 2 NR 13 — and

—SCH 2 CH 2 —O—(CH 2 CH 2 O) X —CH 2 CH 2 S—,

wherein:

x is the degree of polymerization;

R 13 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 R 1 and R 2 each comprise a polymer residue of the formula —O—(CH 2 CH 2 O) x and x is the degree of polymerization.

39. The compound of claim 30 , wherein R 1 and R 2 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 L 1 is selected from the group consisting of:

—NH(CH 2 CH 2 O) 2 CH 2 C(O)—,

—NH(CH 2 ) 3 OC(O)—,

—(CH 2 ) t C(O)—,

—C(O)NH(CH 2 ) t C(O)—,

—NH(CH 2 ) t C(O)—,

—NR 19 (CH 2 ) t (CH 2 CH 2 O) q NHC(O)—,

—(CH 2 CH 2 O) t NHC(O)—,

—O(CR 14 R 15 ) t NHC(O)—,

—NR 19 (CR 14 R 15 ) q C(O)NH(CR 16 R 17 ) t C(O)—,

—O(CH 2 ) t OC(O)—,

—NR 19 (CR 14 R 15 ) t C(O)—,

—NR 19 (CH 2 CH 2 O) t —OC(O)—,

—O(CR 14 R 15 ) t OC(O)—,

wherein

R 14 -R 17 and R 19 are independently 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;

R 18 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, NO 2 , haloalkyl and halogen; and

t and q are individually selected positive integers.

41. The compound of claim 25 , wherein L 2 is selected from the group consisting of:

—NH(CH 2 CH 2 O) 2 CH 2 C(O)—,

—NH(CH 2 ) 3 OC(O)—,

—(CH 2 ) v C(O)—,

—C(O)(CH 2 ) v NHC(O)—,

—NH(CH 2 ) v C(O)—,

—NR 25 (CH 2 ) v (CH 2 CH 2 O) w NHC(O)—,

—(CH 2 CH 2 O) v NHC(O)—,

—O(CR 20 R 21 ) v NHC(O)—,

—NR 25 (CR 20 R 21 ) w (O)CNH(CR 22 R 23 ) v C(O)—,

—O(CH 2 ) v OC(O)—,

—NR 25 (CR 20 R 21 ) v C(O)—,

—NR 25 (CH 2 CH 2 O) v —OC(O)—,

—O(CR 20 R 21 ) v OC(O)—,

wherein

R 20 -R 23 and R 25 are independently 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;

R 24 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, C 1-6 heteroalkoxy, NO 2 , haloalkyl and halogen; and

v and w are individually selected positive integers.

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

wherein:

Y 5 is O, S or NR 46 ;

L 4 is a bifunctional linker;

R 40 -R 46 are independently 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;

j and k are each independently 0 or a positive integer;

q is 0 or 1;

g, h, v and w are independently selected positive integers;

R 50 is selected from the group consisting of substantially non-antigenic polymer residues, C 1-6 alkyls, C 1-6 aralkyls, and

wherein:

L 5 is a bifunctional linker; and

R 60 is selected from the group consisting of substantially non-antigenic polymer residues, C 1-6 alkyls and C 1-6 aralkyls.

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

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

Assignments (2)
CHANGE OF ADDRESS Recorded Feb 3, 2014
From: BELROSE PHARMA INC.
To: BELROSE PHARMA INC.
Reel/Frame 032152/0906 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 8, 2013
From: ENZON PHARMACEUTICALS, INC.
To: BELROSE PHARMA, INC.
Reel/Frame 030982/0692 →