Releasable polymeric conjugates based on aliphatic biodegradable linkers

1. A compound comprising the Formula (I):

wherein:

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

Z is selected from the group consisting of hydrophobics moieties, bifunctional linking moieties,

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

Y 1-3 may be the same or different and are selected from among O, S or NR 11 ;

L 1 and L 2 may be the same or different bifunctional linkers;

R 3 –R 11 , R 24 and R 25 may be the same or different and are 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 3-8 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;

L 3 and L 4 may be the same or different and are selected from:

—C(O)(CR 30 R 31 )Y 15 (CR 32 R 33 )C(O)— or

—C(O)(CR 30 R 31 )(CR 32 R 33 )C(O)—

 wherein:

Y 15 is selected from O, S, NR 34 or CH 2 , and

R 30-34 may be the same or different and are selected from H, alkyl, alkenyl, alkynyl, heteroalkyl or aryl;

A is selected from the group consisting of bioligically active proteins, leaving groups, functional groups, and OH;

a, b, c, d, and e are independently 0 or 1

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

f and g are 0 or 1, provided that

at least one of (f+a) or (g+c) is equal to 2.

2. The compound of claim 1 , wherein R 3 –R 10 , R 24-25 and R 30-34 are each hydrogen; and Y 15 is O or NR 34 .

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 R 1 comprises a polyalkylene oxide.

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

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

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

12. 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,

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

14. 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 SH—,

—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

—SHCH 2 CH 2 —O—(CH 2 CH 2 O) x —CH 2 CH 2 SH—

wherein:

x is the degree of polymerization;

R 12 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 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 SH—,

—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

—SHCH 2 CH 2 —O—(CH 2 CH 2 O) x —CH 2 CH 2 SH—,

wherein:

x is the degree of polymerization;

R 13 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 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy, and

J is a capping group.

16. The compound of claim 1 , wherein R 1-2 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 SH—

wherein x is the degree of polymerization.

17. 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

wherein x is the degree of polymerization.

18. The compound of claim 17 , wherein R 1 and R 2 each have a weight average molecular weight of from about 2,000 Da to about 25,000 Da.

19. The compound of claim 1 wherein L 1 and L 2 are independently selected from the group consisting of:

—NR 19 (CR 14 R 15 ) t O—,

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

—O(CR 14 R 15 ) t NR 19 —,

—O(CR 14 R 15 ) t O—,

—NR 19 (CR 14 R 15 ) t NR 19 —,

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

—NR 19 (CR 16 CR 17 O) t —,

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

—NR 19 (CR 16 CR 17 O) t —,

—O(CR 14 R 15 ) t —NR 19 —,

—O(CR 14 R 15 ) t NR 19 —,

—O(CR 16 CR 17 O) t NR 19 —,

wherein:

R 14 –R 17 and R 19 are independently 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 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy; and

R 18 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 1-6 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 from about 1 to about 4.

20. The compound of claim 1 wherein L 3 and L 4 are independently selected from the group consisting of:

—C(O)CR 30 R 31 OCR 32 R 33 C(O)—;

—C(O)CR 30 R 31 NR 34 CR 32 R 33 C(O)—;

—C(O)CR 30 R 31 SCR 32 R 33 C(O)—, or

—C(O)(CR 30 R 31 ) n C(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:

where A 1 is a leaving group.

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

wherein A 1 is a leaving group.

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

24. The compound of claim 23 , wherein A 1 is:

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:

wherein:

Y 5 is O, S or NR 46 ;

L 6 is a bifunctional linker selected from the same group as that which defines L 1 ;

L 8 is a bifunctional linker selected from the same group as that which defines L 3 ;

R 40 –R 46 may be the same or different and are 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 3-8 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;

j,j′, k 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 2-6 alkenyl, C 2-6 alkynyl, aralkyls, and

wherein:

L 7 is a bifunctional linker selected from the same group as that which defines L 1 ;

L 9 is a bifunctional linker selected from the same group as that which defines L 3 ; and

R 60 is selected from the group consisting of substantially non-antigenic polymer residues, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, and aralkyls.

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

wherein A is a leaving group.

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

wherein:

A 1 is a leaving group;

R 1 and R 2 are independently selected from the group consisting of substantially non-antigenic polymer residues, H, C 1-6 alkyls, C 2-6 alkenyl, C 2-6 alkynyl, aralkyls, and terminal branching groups, provided both R 1 and R 2 are not H;

Z is selected from hydrophobic moieties, bifunctional linking moieties,

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

Y 1-3 may be the same or different and are selected from among O, S or NR 11 ;

L 1 and L 2 may be the same or different bifunctional linkers;

R 3 –R 11 , R 24 and R 25 may be the same or different and are 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 3-8 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;

L 3 and L 4 may be the same or different and are selected from:

—C(O)(CR 30 R 31 )Y 15 (CR 32 R 33 )C(O)— or

—C(O)(CR 30 R 31 )(CR 32 R 33 )C(O)—

 wherein:

Y 15 is selected from O, S, NR 34 or CH 2 , and

R 30-34 may be the same or different and are selected from H, alkyl, alkenyl, alkynyl, heteroalkyl or aryl; wherein a, b, c, d, and e are independently 0 or 1 m, n, o, and p are independantly positive integers, f and g are 0 or 1, provided that at least one of (f+a) or (g+c) is equal to 2;

with a biologically active protein under conditions sufficient to form

wherein A 2 is a residue of a biologically active agent.

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:

b) attaching the blocked bifunctional spacer to each hydroxyl of an acid protected bicine molecule;

c) deblocking the resultant intermediate and reacting it with an activated polymer under basic coupling conditions, and

d) deprotecting the bicine acid and thereafter activating the acid with a suitable activating group under coupling conditions.