Polymeric thiol-linked prodrugs

1. A prodrug compound comprising the formula: (I) R 1 -E that releases an —SH-containing biologically active moiety

wherein:

R 1 is a straight or branched residue of a water soluble polymer;

 wherein:

D 1 is a residue of an —SH-containing biologically active moiety bonded through the sulfur;

(AA) is an amino acid residue;

E 2 and E 3 are independently H, E 1 or

Y 1 , Y 2 and Y 3 are independently O, S or NR 7 ;

X 1 and X 2 are independently OH or E;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are independently selected from the group consisting of H, C 1-6 alkyls, C 3-12 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;

n is zero or a positive integer; and

p is zero or a positive integer.

2. The compound of claim 1 , wherein R 1 further comprises a capping group selected from the group consisting of hydrogen, NH 2 , OH, CO 2 H, C 1-6 moieties and

E′-  (I′)

wherein:

 wherein:

D 1 ′ is a residue of an —SH-containing biologically active moiety bonded through the sulfur;

(AA) is an amino acid residue;

E 2 ′ and E 3 ′ are independently H, E 1 ′ or

Y 1 ′, Y 2 ′ and Y 3 ′ are independently O, S or NR 7 ′;

X 1 ′ and X 2 ′ are independently OH or E;

R 2 ′, R 3 ′, R 4 ′, R 5 ′, R 6 ′, R 7 ′, R 8 ′, R 9 ′, R 10 ′ and R 11 ′ are independently selected from the group consisting of H, C 1-6 alkyls, C 3-12 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;

n′ is zero or a positive integer; and

p′ is zero or a positive integer.

3. A prodrug compound of the formula: E′-R 1 -E that releases an —SH-containing biologically active moiety

wherein:

R 1 is a straight or branched residue of a water soluble polymer;

 wherein:

D 1 is a residue of an —SH containing biologically active moiety bonded through the sulfur;

(AA) is an amino acid residue;

E 2 and E 3 are independently H, E 1 or

Y 1 , Y 2 and Y 3 are independently O, S or NR 7 ;

X 1 and X 2 are independently OH or E;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are independently selected from the group consisting of H, C 1-6 alkyls, C 3-12 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;

n is zero or a positive integer;

p is zero or a positive integer;

 wherein:

D 1 ′ is a residue of a —SH containing moiety;

(AA)′ is an amino acid residue;

E 2 ′ and E 3 ′ are independently H, E 1 ′ or

Y 1 ′, Y 2 ′ and Y 3 ′ are independently O, S or NR 7 ′;

X 1 ′ and X 2 ′ are independently OH or E;

R 2 ′, R 3 ′, R 4 ′, R 5 ′, R 6 ′, R 7 ′, R 8 ′, R 9 ′, R 10 ′ and R 11 ′ are independently selected from the group consisting of H, C 1-6 alkyls, C 3-12 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;

n′ is zero or a positive integer; and

p′ is zero or a positive integer.

4. The compound of claim 2 , where n, n′, p and p′ are independently zero, one or two.

5. The compound of claim 1 , wherein R 2 and R 3 are both H, n and p are both 2, Y 1 is O and both E 1 and R 6 are H.

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

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

8. The compound of claim 1 , wherein R 1 is

—C(═Y 4 )—(CH 2 ) t —O—(CH 2 CH 2 O) x -A,

—C(═Y 4 )—Y 5 —(CH 2 ) t —O—(CH 2 CH 2 O) x -A,

—C(═Y 4 )—NR 14 —(CH 2 ) t —O—(CH 2 CH 2 O) x -A,

—(CR 15 R 16 ) e —O—(CH 2 ) t —O—(CH 2 CH 2 O) x -A,

—NR 14 —(CH 2 ) t —O—(CH 2 CH 2 O) x -A,

—C(═Y 4 )—(CH 2 ) t —O—(CH 2 CH 2 O) x —(CH 2 ) t —C(═Y 4 )—,

—C(═Y 4 )—Y 5 —(CH 2 ) t —O—(CH 2 CH 2 O) x —(CH 2 ) t —Y 5 —C(═Y 4 )—,

—C(═Y 4 )—NR 14 —(CH 2 ) t —O—(CH 2 CH 2 O) x —(CH 2 ) t —NR 14 —C(═Y 4 )—,

—(CR 15 R 16 ) e —O—(CH 2 ) t —O—(CH 2 CH 2 O) x —(CH 2 ) t —O—(CR 15 R 16 ) e —, or

—NR 14 —(CH 2 ) t —O—(CH 2 CH 2 O) x —(CH 2 ) t —NR 14 —

wherein:

x is the degree of polymerization;

R 14 , R 15 and R 16 are independently selected from the group consisting of H, C 1-6 alkyls, C 3-12 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;

e and t are independently zero, one or two;

Y 4 and Y 5 are independently O, S or NR 12 ; and

A is a capping group.

9. The compound of claim 8 , wherein A is selected from the group consisting of H, NH 2 , OH, CO 2 H and C 1-6 alkyls.

10. The compound of claim 1 , wherein R 1 comprises —O—(CH 2 CH 2 O) x and x is a positive integer so that the weight average molecular weight is at least about 20,000.

11. The compound of claim 10 , wherein R 1 has a weight average molecular weight of from about 20,000 to about 100,000.

12. The compound of claim 11 , wherein R 1 has a weight average molecular weight of from about 25,000 to about 60,000.

13. The compound of claim 2 , wherein D 1 and D 1 ′ are independently selected residues of SH-containing biologically active moieties.

14. The compound of claim 13 , wherein said SH-containing moieties are selected from the group consisting of 1-β-D-ribofuranosyl, 1-β-D-arabinofuranosyl, penicillamine, 2-thiouracil, captopril, tiopronin, vasopressin, deaminooxytocin, thiopental sodium, and

wherein

R 12 is H, a C 1-6 alkyl, alkoxy, or a carbohydrate of the formula:

wherein R 21-25 are independently selected from the group consisting of alkoxy, OR 19 , H, OH, N 3 , NHR 20 , NO 2 , CN, fluoro, chloro, bromo, iodo, wherein R 19-20 are independently selected from the group consisting of hydrogen, C 1-6 alkyls, C 3-12 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 3-8 substituted cycloalkyls, aryls, halo, substituted aryls, aralkyls, C 1-6 heteroalkyls and substituted C 1-6 heteroalkyls;

R 13 is H or NH 2 ; and

X 3 is CH or N.

15. A compound of claim 3 , selected from the group consisting of:

wherein:

R 1 is a straight or branched residue of a water soluble polymer and

D 1 and D 1 ′ are residues of —SH containing biologically active moiety.

16. A method of treatment, comprising:

administering to a mammal in need of such treatment an effective amount of a compound of claim 1 , wherein D 1 is a residue of a —SH containing biologically active moiety and the —SH containing biologically active moiety is released from R 1 .

17. A method of treatment, comprising:

administering to a mammal in need of such treatment an effective amount of a compound of claim 3 , wherein D 1 and D 1 ′ are residues of a —SH containing biologically active moiety and the —SH containing biologically active moiety is released from R 1 .

18. The compound of claim 1 , wherein R 2 and R 3 are both H, and Y 1 is O.

19. A compound of claim 3 having the structure: