Branched polymeric prodrugs of vancomycin
(19)AUSTRALIAN PATENT OFFICE(54) Title Branched polymeric prodrugs of vancomycin(51)6 International Patent Classification(s) A61K 038/12 COSH 001/00 C07K 009/00(21) Application No: 2003295433 (22) Application Date: 2003.11.11(87) WIPO No: WO04/044224(30) Priority Data (31) Number (32) Date 60/425,890 2002.11.12 (33) Country US 200511037(43) (43) Publication Date : 2004 .06.03 Publication Journal Date : 2004 .07.08(71) Applicant(s) ENZON PHARMACEUTICALS, INC.(72) Inventor(s) Greenwald, Richard B.; Zhao, Honq(-1-1) Application NoAU2003295433 A8(19)AUSTRALIAN PATENT OFFICE(54) Title Branched polymeric prodrugs of vancomycin(51)6 International Patent Classification(s) A61K 038/12 COSH 001/00 C07K 009/00(21) Application No: 2003295433 (22) Application Date: 2003.11.11(87) WIPO No: WO04/044224(30) Priority Data (31) Number (32) Date 60/425,890 2002.11.12 (33) Country US 200511037(43) (43) Publication Date : 2004 .06.03 Publication Journal Date : 2004 .07.08(71) Applicant(s) ENZON PHARMACEUTICALS, INC.(72) Inventor(s) Greenwald, Richard B.; Zhao, Honq-1- Methods of preparing branched polymer vancomycin conjugates are disclosed. In preferred aspects, the branched polymers contain several equivalents of a vancomycin selectively attached to the sugar amino group of the vancomycin. Multi-loaded vancomycin-polymer conjugates made by the methods and methods of treatment using the same are also disclosed. What is claimed : 1. A method of preparing a vancomycin-polymer conjugate, comprising: reacting a vancomycin compound of the formula : EMI36.1 wherein Ril and R12 are independently selected from the group consisting of hydrogen, C16 alkyls, C312 branched alkyls, G38 cycloalkyls, C16 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C16 heteroalkyls, C16 alkoxyalkyl, phenoxyalkyl and C1-6 heteroalkoxys ;R13 is OH, NH-aryl, NH-aralkyl, or NH-C112 alkyl ; and w is 1 or 2;STDC0272 with a branched polymer residue containing at least one leaving group capable of reacting with the sugar amino group of said vancomycin compound in the presence of at least about a twenty-fold molar excess of triethylamine and a sufficient amount of dimethylformamide.
2. The method of claim 1, wherein said activated polymer residue is selected from the group consisting of: <Desc/Clms Page number 37> EMI37.1 <Desc/Clms Page number 38> EMI38.1 EMI38.2 <Desc/Clms Page number 39> EMI39.1 wherein R1 is a polymeric residue; W is a bifunctional linker, selected from the group consisting of O, amino acids, EMI39.2 - (CH2) y, and-NH (CH2CH20) 2- ; z is 0, 1, 2, 3 or 4; y is a positive integer; and D is selected from the group consisting of: EMI39.3 EMI39.4 <Desc/Clms Page number 40> EMI40.1 <Desc/Clms Page number 41> EMI41.1 EMI41.2 EMI41.3 EMI41.4 3. The method of claim 2, wherein said vancomycin compound is: EMI41.5 <Desc/Clms Page number 42> 4.STDC0841 The method of claim 3, wherein said vancomycin-polymer conjugate is selected from the group consisting of: EMI42.1 <Desc/Clms Page number 43> EMI43.1 <Desc/Clms Page number 44> EMI44.1 wherein D is selected from the group consisting of EMI44.2 <Desc/Clms Page number 45> EMI45.1 EMI45.2 <Desc/Clms Page number 46> EMI46.1 EMI46.2 EMI46.3 EMI46.4 where Va is EMI46.5 <Desc/Clms Page number 47> 5. The method of claim 1, wherein said branched polymer containing said leaving group is selected from the group consisting of: EMI47.1 EMI47.2 <Desc/Clms Page number 48> EMI48.1 EMI48.2 and EMI48.3 wherein PEG is -O (-CH2CH20) x-; n is a positive integer, and x is a positive integer selected from about 10 to about 2300.
6. The method of claim 2, wherein Ri is a polyalkylene oxide residue. <Desc/Clms Page number 49> 7. The method of claim 2, wherein Ri is a polyethylene glycol residue.
8. The method of claim 1, wherein said vancomycin-polymer conjugate is selected from the group consisting of EMI49.1 EMI49.2 <Desc/Clms Page number 50> EMI50.1 wherein Xis EMI50.2 PEG is-O (-CH2CH20) x- ; n is a positive integer selected from about 10 to about 2300; and Va is EMI50.3 9. The product prepared by the method of claim 1. <Desc/Clms Page number 51> 10.STDC0710 A vancomycin polymer conjugate selected from the group consisting of: EMI51.1 <Desc/Clms Page number 52> EMI52.1 EMI52.2 <Desc/Clms Page number 53> EMI53.1 EMI53.2 wherein Rr is a polymeric residue; W is a bifunctional linker, selected from the group consisting of O, amino acids, EMI53.3 z is 0, 1,2, 3 or 4 ; y is a positive integer; and D is selected from the group consisting of EMI53.4 EMI53.5 <Desc/Clms Page number 54> EMI54.1 EMI54.2 <Desc/Clms Page number 55> EMI55.1 EMI55.2 EMI55.3 EMI55.4 wherein Va is EMI55.5 <Desc/Clms Page number 56> 11.STDC0685 A method of preparing a vancomycin polymer conjugate, comprising: a) reacting a vancomycin compound of the formula: EMI56.1 wherein Rit and R12 are independently selected from the group consisting of hydrogen, Ci. alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C16 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, Cri-6 heteroalkyls, substituted C16 heteroalkyls, C16 alkoxyalkyl, phenoxyalkyl and Ci-e heteroalkoxys ; R13 is OH, NH-aryl, NH-aralkyl, or NH-C1-12 alkyl ; and wis 1 or2 ;STDC0744 with a capping moiety containing a leaving group capable of reacting with the sugar amino group of said vancomycin compound in the presence of at least about a twenty-fold molar excess of triethylamine and a sufficient amount of dimethylformamide ; b) reacting the resultant sugar amino group capped vancomycin compound with a branched polymer residue containing at least one leaving group capable of reacting with the N-methyl amino group of said vancomycin compound in the presence of about a five-fold molar molar excess of dimethylaminopyridine (DMAP) and a sufficient amount of a <Desc/Clms Page number 57> solvent mixture comprising dichloromethane (DCM) and dimethyl formamide (DMF).
12. The method of claim 11, further comprising removing said capping group from the sugar amino group of said vancomycin polymer conjugate 13. The method of claim 11, wherein said vancomycin polymer conjugate is selected from the group consisting of: EMI57.1 <Desc/Clms Page number 58> EMI58.1 EMI58.2 <Desc/Clms Page number 59> EMI59.1 wherein Ri is a polymeric residue; W is a bifunctional linker, selected from the group consisting of O, amino acids, EMI59.2 z is 0, 1,2, 3 or 4 ; y is a positive integer; and D is selected from the group consisting of EMI59.3 <Desc/Clms Page number 60> EMI60.1 <Desc/Clms Page number 61> wherein Vb is: EMI61.1 wherein J is H or a polymer residue containing a capping group.
14. A method of treating a vancomycin susceptible disease in a mammal comprising administering an effective amount of a compound of claim 10, to a mammal in need of such treatment, whereby, the compound of claim 10 undergoes degradation and releases vancomycin or a vancomycin derivative in vivo.
15. A method of treating a vancomycin susceptible disease in a mammal comprising administering to a mammal in need of such treatment, an effective amount of a combination of vancomycin or a pharmaceutical acceptable salt, solvate or hydrate thereof, and a compound of claim 10.
16. A kit comprising in separate containers in a single package, pharmaceutical compositions for use in combination to treat a vancomycin susceptible disease which comprises in one container a therapeutical effective amount of vancomycin or a pharmaceutical acceptable salt, <Desc/Clms Page number 62> solvate or hydrate thereof in a pharmaceutical acceptable carrier and in a second container a therapeutically effective amount of a compound of claim 10 or a pharmaceutically acceptable salt, solvate or hydrate thereof in a pharmaceutical acceptable carrier.