Active carbonates of polyalkylene oxides for modification of polypeptides

• US 5,324,844 A
• Filed: 01/08/1992
• Issued: 06/28/1994
• Est. Priority Date: 04/19/1989
• Status: Expired due to Term

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Zalipsky, Shmuel
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US07/817,757
• Time in Patent Office: 902 Days
• Field of Search: 546/208, 546/243, 548/435, 548/465, 548/475, 548/520, 548/542, 530/363, 530/389.1, 530/406, 530/410, 435/177, 435/188
• US Class Current: 548/520
• 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: C07D 207/46 with hetero atoms directly attached to the ring nitrogen atom

Abstract

Poly(ethylene glycol)-N-succinimide carbonate and its preparation are disclosed. Polyethylene glycol (PEG) is converted into its N-succinimide carbonate derivative. This form of the polymer reacts readily with amino groups of proteins in aqueous buffers. The modified proteins have PEG-chains grafted onto the polypeptide backbone by means of stable, hydrolysis-resistant urethane (carbamate) linkages.

Claims

1. A polyalkylene oxide having a molecular weight of less than about 20,000, where at least one end group of said polyalkylene oxide is an oxycarbonyl-oxy-N-dicarboximide group.

2. The polyalkylene oxide of claim 1, having the structure:

space="preserve" listing-type="equation">R.sub.1 --(O--R.sub.2).sub.a --(O--R.sub.3).sub.b --(O--R.sub.4).sub.c --O--CO--O--R.sub.5

wherein R₁ is H--, H₃ C-- or an carbonyl-oxy. N-dicarboximide group;

R₂, R₃ and R₄ are independently selected from the group consisting of straight and branched alkyl groups;

R₅ is an N-dicarboximide group; and

a is an integer between 1 and 1,000 and b and c are independently zero or an integer between 1 and 1,000.

3. The polyalkylene oxide of claim 2, wherein R₂, R₃ and R₄ are independently selected from the group consisting of --CH₂ CH₂ --, --CH₂ CH(CH₃)-- and --CH₂ CH₂ CH₂ CH₂ --.

4. The polyalkylene oxide of claim 2, wherein R₁ is a carbonyl-oxy-N-dicarboximide group and R₅ is an N-dicarboximide group and the N-dicarboximide of R₁ and R₅ are independently selected from the group consisting of N-succinimide, N-phthaliide, N-glutarimide, N-tetrahydrophthalimide and N-norborene-2,3-dicarboximide groups.

5. The polyalkylene oxide of claim 4, wherein R₅ is an N-succinimide group.

6. The polyalkylene oxide of claim 1, having the structure:

##STR8## wherein R₁ is H₃ C-- or H-- and a is an integer selected so that the molecular weight of said polyalkylene oxide is less than about 20,000.

7. The polyalkylene oxide of claim 1, having the structure:

##STR9## wherein a is an integer selected so that the molecular weight of said polyalkylene oxide is less than about 20,000.