Polymeric prodrugs of vancomycin

1. A method of preparing a vancomycin-polymer conjugate wherein the polymer is conjugated to the suger amino group of a vancomycin, comprising:

reacting a vancomycin compound of the formula:

wherein

R 11 and R 12 are independently selected from the group consisting of hydrogen, C 1-6 alkyl[s], C 3-12 branched alkyl[s], C 3-8 cycloalkyl[s], C 1-6 substituted alkyl[s], C 3-8 substituted cycloalkyl[s], aryl[s], substituted aryl[s], aralkyl[s], C 1-6 heteroalkyl[s], substituted C 1-6 heteroalkyl[s], C 1-6 alkoxyalkyl, phenoxyalkyl and C 1-6 heteroalkoxy[s];

R 13 is OH, NH-aryl, NH-aralkyl, or NH—C 1-12 alkyl; and

w is 1 or 2;

in the presence of at least about a ten-fold molar excess of triethylamine and a sufficient amount of dimethylformamide with a polyalkylene oxide residue containing at least one leaving group that reacts with the sugar amino group NR 11 H of said vancomycin compound.

2. The method of claim 1 , wherein said polyalkylene oxide residue is activated, wherein the said activated polyalkylene oxide residue is selected from the group consisting of:

wherein:

R 1 and R 2 are independently selected from polyalkylene oxide residues;

R′ 1 and R′ 2 are independently selected from branched polyalkylene oxide residues;

Y 1-6 are independently selected from the group consisting of O, S or NR 9 ;

R 3-10 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-12 branched alkyl, C 3-8 cycloalkyl, C 1-6 substituted alkyl, C 3-8 substituted cyloalkyl, aryl, substituted aryl, aralkyl, C 1-6 heteroalkyl, substituted C 1-6 heteroalkyl, C 1-6 alkoxyalkyl, phenoxyalkyl and C 1-6 heteroalkoxy;

Ar is a moiety which forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;

L 1 and L 2 are independently selected from bifunctional linkers;

B 1 and B 2 are independently selected from leaving groups;

p and t are independently selected from positive integers;

n, q and s are independently either zero or a positive integer; and

o and r are independently zero or one.

3. The method of claim 2 , wherein said activated polyalkylene oxide residue is selected from the group consisting of

4. The method of claim 1 , wherein said polyalkylene oxide residue is activated, and wherein said activated polyalkylene oxide is selected from the group consisting of:

wherein B 1 is selected from the group consisting of:

5. The method of claim 1 , wherein said vancomycin compound is:

6. The method of claim 2 , wherein said vancomycin polymer conjugate is selected from the group consisting of

7. The method of claim 1 , wherein said polyalkylene oxide containing said leaving group is selected from the group consisting of

8. The method of claim 2 , wherein R 1 and R 2 are independently selected from polyethylene glycol residues and R′ 1 and R′ 2 are independently selected from branched polyethylene glycol residues.

9. The method of claim 1 , wherein said vancomycin-polymer conjugate is selected from the group consisting of

wherein

PEG is —O(—CH 2 CH 2 O) x —;

mPEG is H 3 CO(—CH 2 CH 2 O) x —;

x is a positive integer selected from about 10 to about 2300, and

U-PEG is selected from the group consisting of

10. The method of claim 1 , wherein said molar excess of triethylamine is at least about 30-fold.

11. The method of claim 1 , wherein said molar excess of triethylamine is at least about 20-fold.

12. The method of claim 1 , wherein said sufficient amount of dimethylformamide ranges from about 10 ml/g vancomycin to about 500 ml/g vancomycin.

13. The method of claim 1 , wherein said sufficient amount of dimethylformamide ranges from about 100 ml/g vancomycin to about 200 ml/g vancomycin.

14. The method of claim 4 , wherein said vancomycin polymer conjugate is selected from the group consisting of