Polymeric thiol-linked prodrugs employing benzyl elimination systems

1. A compound of the formula

wherein:

R 1 is a polymeric residue having an average molecular weight of from about 2,000 to about 100,000;

Y 1 is O, S or NR 10 ;

M is O, S or NR 11 ;

E 1 is

E 2-4 is are independently H, E 1 or

(a) is zero or one;

(m) is zero or a positive integer,

(w) is zero or one;

(n) and (p) are independently 0 or a positive integer;

Y 2-3 are independently O, S or NR 12 ;

R 2-11 and R 15 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, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy,

D 1 and D 2 are independently OH,

wherein:

R′ 4 and R′ 5 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, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy;

E 35 is

E 36-38 are independently H, E 35 , or

and

D′ 1 and D′ 2 are independently OH,

or,

wherein:

R″ 4 and R″ 5 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, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy;

E 45 is

E 46-48 are independently H, E 45 , or

and

D″ 1 and D″ 2 are independently OH,

(v) and (t) are independently 0 or 1;

L 1 and L 2 are independently selected linkers;

Y 4-5 are independently selected from the group consisting of O, S and NR 16 ;

R 12-14 and R 16 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, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy;

Ar is a moiety which when included in Formula (Ib) forms a multisubstituted aromatic hydrocarbon or a multi-substituted heterocyclic group; and

B 1 and B 2 are independently selected from the group consisting of OH, and residues of sulfhydryl-containing moieties

provided that w is not zero when

is CH 2 COOH.

2. The compound of claim 1 , wherein a terminal end of R 1 includes a cap group, which is selected from the group consisting of hydrogen, NH 2 , OH, CO 2 H, C 1-6 moieties and

wherein all variables are as previously defined.

3. A compound of claim 2 , of the formula:

4. The compound of claim 1 , wherein Y 1 -Y 5 are each O.

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

6. The compound of claim 5 , wherein R 1 comprises a polyethylene glycol residue.

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

—C(═Y′)—(CH 2 ) n3 —O—(CH 2 CH 2 O) x —A 2 ,

—C(═Y′)—Y″—(CH 2 ) n3 —O—(CH 2 CH 2 O) x —A 2 ,

and

C(═Y′)—NR′ 6 —(CH 2 ) n3 —O—(CH 2 CH 2 O) x —A 2 ,

wherein:

x is the degree of polymerization;

n3 is zero, or a positive integer;

R′ 6 is selected from the group which defines R 6 ;

Y′ and Y″ are independently O or S;

A 2 is a capping group.

8. The compound of claim 7 , 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.

9. The compound of claim 1 , wherein R 1 has a weight average molecular weight of from about 5,000 to about 50,000.

10. The compound of claim 1 , wherein B 1 and B 2 are independently selected residues of SH-containing moieties.

11. The compound of claim 10 , 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 30 is one of H, a C 1-6 alkyl, alkoxy, or a carbohydrate of the formula:

wherein R 32-36 are independently selected from alkoxy, OR 37 , H, OH, N 3 , NHR 38 , NO 2 , CN, fluoro, chloro, bromo, or iodo, wherein R 37-38 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 31 is H or NH 2 ; and

X 3 is CH or N.

12. The compound of claim 1 , wherein L 1 is (CH 2 CH 2 O) 2 .

13. The compound of claim 1 , wherein L 2 is selected from the group consisting of —CH 2 —, —CH(CH 3 )—, CH[CH 2 CH(CH 3 ) 2 ]—, —CH 2 C(O)NHCH(CH 3 )—, —(CH 2 ) 2 —, —CH 2 C(O)NHCH 2 —, CHC(O)NHCH[CH 2 CH(CH 3 ) 2 ], —(CH 2 ) 2 —NH— and —(CH 2 ) 2 —NH—C(O)(CH 2 ) 2 NH—.

14. A compound of claim 2 , selected from the group consisting of:

wherein R 1 is a straight or branched residue of a water soluble polymer and D is selected from the group comprising:

wherein B 1 are residues of a SH-containing moiety.

15. The compound of claim 1 , wherein R 1 is a water soluble polymer.

16. The compound of claim 1 , wherein w is not zero when E 2-4 are each H and D 1 and D 2 are both not simultaneously OH.