Azlactone activated polyalkylene oxides

• US 5,321,095 A
• Filed: 02/02/1993
• Issued: 06/14/1994
• Est. Priority Date: 02/02/1993
• Status: Expired due to Fees

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Greenwald, Richard B.
• Primary Examiner(s): KRASS, FREDERICK F
• Application Number:
  US08/012,447
• Time in Patent Office: 497 Days
• Field of Search: 525/404, 525/406, 525/408, 526/260, 548/146, 548/187, 548/204, 548/227, 548/228, 528/327, 528/354
• US Class Current: 525/404
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/332 containing carboxyl groups, or halides, or esters thereof
• CPC Class Codes: Y10S 530/815 Carrier is a synthetic polymer

Abstract

Water-soluble azlactone activated polyalkylene oxides having improved hydrolytic stability and conjugates of the azlactone activated polyalkylene oxides with biologically active nucleophiles are disclosed. Methods of forming and conjugating the activated polyalkylene oxides with biologically active nucleophiles are also disclosed.

Claims

1. A water-soluble, hydrolytically-stable, azlactone-activated polyalkylene oxide, comprising a structure represented by:

##STR9## wherein R represents the non-terminal portion of a water-soluble polyalkylene oxide having a number average molecular weight between about 600 and about 100,000 daltons;

L is selected from the group consisting of --O-- and --CH₂ --;

R₁ is a moiety selected from the group consisting of hydrogen, alkyl and cycloalkyl moieties, carbocyclic and heterocyclic aromatic rings and α

, β

-unsaturated alkyl moieties;

R₄ and R₅ are moieties independently selected from the group consisting of hydrogen, alkyl, aryl and alkylaryl moieties; and

X is a terminal moiety of said polyalkylene oxide selected from the group consisting of alkoxy moieties containing up to four carbon atoms.

2. The azlactone-activated polyalkylene oxide of claim 1, wherein R₁ is an aromatic ring selected from the group consisting of substituted and unsubstituted benzene, mapthalene, pyrene, biphenyl, thiophene, furan, pyrrole, indole, chromane, coumarone and thiazole rings.

3. The azlactone-activated polyalkylene oxide of claim 1, wherein X is a methoxy moiety.

4. The azlactone activated polyalkylene oxide of claim 1, wherein at least one of R₄ and R₅ is a moiety selected from the group consisting of alkyl, aryl and alkylaryl moieties.

5. The azlactone activated polyalkylene oxide of claim 1, wherein both R₄ and R₅ are hydrogen.

6. The azlactone-activated polyalkylene oxide of claim 1, wherein said polyalkylene oxide is selected from the group consisting of polyethylene glycol and block copolymers of polyethylene glycol and polypropylene glycol.

7. The azlactone-activated polyalkylene oxide of claim 6, wherein said polyalkylene oxide is polyethylene glycol.

8. The azlactone-activated polyalkylene oxide of claim 1, wherein said polyalkylene oxide has a number average molecular weight between about 2,000 and about 20,000 daltons.

9. The azlactone-activated polyalkylene oxide of claim 8, wherein said polyalkylene oxide has a 5,000 dalton number average molecular wight.