Y-SHAPE BRANCHED HYDROPHILIC POLYMER DERIVATIVES, THEIR PREPARATION METHODS, CONJUGATES OF THE DERIVATIVES AND DRUG MOLECULES, AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE CONJUGATES

• US 20100221213A1
• Filed: 05/17/2010
• Published: 09/02/2010
• Est. Priority Date: 03/13/2002
• Status: Abandoned Application

• Current Assignee: Dequan Zhu, Shishan Ji
• Original Assignee: Dequan Zhu, Shishan Ji
• Inventors: Ji, Shishan, Zhu, Dequan
• Application Number:
  US12/781,173
• Publication Number:
  US 20100221213A1
• Time in Patent Office: Days
• US Class Current: 424/85.400
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08L 2203/02 for biomedical use

Abstract

The present invention relates to Y-shape branched PEG derivatives of formulae (I) to (IV). The present invention also relates to conjugates of these Y-shape derivatives and drug molecules, pharmaceutical compositions comprising those conjugates.

Claims

1. (canceled)

4. (canceled)

5. (canceled)

6. A Y-shaped branched polyethylene glycol derivative represented by formula IV:

wherein

P_a and P_b are polyethylene glycols, which are the same or different;

n and j are independently an integer from 1 to 12;

R_i is selected from the group consisting of H, a C_1-12 substituted or unsubstituted alkyl, a substituted aryl, an aralkyl, and a heteroalkyl; and

F is a functional group capable of reacting with an amino group, a hydroxyl group, or a thiol group of a therapeutic agent or a substrate to form a covalent linkage, selected from the group consisting of a hydroxyl group, a carboxyl group, an ester group, carboxylic acid chloride, hydrazide, maleimide and pyridine disulfide.

2. The hydrophilic polymer derivative of claim 6 wherein the hydrophilic polymer is selected from the group consisting of polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyacrylmorpholine and copolymers thereof.

3. The hydrophilic polymer derivative of claim 2 wherein the hydrophilic polymer is polyethylene glycol.

7. The derivative of claim 6, wherein P_a and P_b are be the same or different PEGs of formula (V):

wherein

R is H, a C_1-12 alkyl, a cycloalkyl or an aralkyl; and

n is an integer, representing the degree of polymerization.

8. The derivative of claim 7, wherein R is selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl and benzyl.

9. The derivative of claim 7, wherein the molecular weight of PEG is from about 300 to 60000.

13. A conjugate formed by reacting the derivative of claim 6 with a drug molecule through the terminal group F.

15. The conjugate of claim 13 wherein the drug is selected from the group consisting of amino acids, proteins, enzymes, nucleosides, saccharides, organic acids, glycosides, flavonoids, anthraquinones, terpenoids, phenylpropanoid phenols, steroids, glycosides of the steroids and alkaloids of the steroids.

16. The conjugate of claim 13 wherein the drug is an active component of a natural medicine.

17. The conjugate of claim 16 wherein the active component is cinobufagin, clycyrrhetinic acid or scopoletin.

18. The conjugate of claim 13 wherein the drug is an anti-tumor agent.

19. The conjugate of claim 18 wherein the anti-tumor agent is selected from the group consisting of paclitaxel, camptothecin, interferon and derivatives thereof.

20. The conjugate of claim 19 wherein the interferon is α

-, β

- or γ

-interferon.

21. A pharmaceutical composition comprising the conjugate according to claim 13 and a pharmaceutically acceptable carrier or excipient.

10. (canceled)

11. (canceled)

12. (canceled)

14. (canceled)