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, 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 leaving groups, functional groups, and OH;

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 a and b are both not 0 when c and d are both 0.

2. The compound of claim 1 , wherein R 3 –R 10 , R 24 and R 25 are each hydrogen.

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

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

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

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

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

8. 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,

9. A compound of claim 8 , selected from the group consisting of:

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

10. 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 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.

11. 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 SH—

wherein x is the degree of polymerization.

12. The compound of claim 10 , 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 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 each comprise a polymer residue of the formula —O—(CH 2 CH 2 O) x .

14. The compound of claim 13 , wherein R 1 and R 2 each have a weight average molecular weight of from about 2,000 Da to about 25,000 Da.

15. 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 ) t (CH 2 CH 2 O) q NHC(O)—,

—NR 19 (CH 2 CH 2 O) t —OC(O)—,

—O(CR 14 R 15 ) t NHC(O)—,

—O(CR 14 R 15 ) t OC(O)—,

—(CH 2 CH 2 O) t NHC(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.

16. 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 C 23 ) v C(O)—,

—O(CH 2 ) v OC(O)—,

—NR 25 (CR 20 R 21 ) v C(O)—,

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

—NR 25 (CH 2 CH 2 O) v —O—C(O)

—O(CR 20 R 21 ) v NHC(O)—,

—O(CR 20 R 21 ) v OC(O)—,

—(CH 2 CH 2 O) v NHC(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.

17. A compound of claim 1 , comprising the formula:

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

where A 1 is a leaving group.

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

20. The compound of claim 1 , wherein A is selected from the group consisting of maleimidyl, vinyl, residues of sulfone, hydroxy, amino, carboxy, mercapto, hydrazide, and carbazate functional groups.

21. The compound of claim 20 , wherein A is:

22. 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;

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

23. A compound of claim 22 , comprising the structure:

24. A compound of claim 22 , comprising the structure:

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

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

27. 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, 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

 wherein L 3 is a bifunctional linker and Y4 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;

with an amine-containing, biologically active agent under conditions sufficient to form

wherein A 2 is a residue of an amine containing biologically active agent selected from the group consisting of proteins, enzymes, peptides, polypeptides, peptide nucleic acids and nucleic acids.

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

a) synthesizing an acid protected bicine;

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

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

d) deprotecting and activating the blocked acid of said acid protected bicine under coupling conditions.