Y shape branched hydrophilic polymer derivatives, their preparation methods, conjugates of the derivatives and drug molecules, and pharmaceutical compositions comprising the conjugates

• US 8,003,089 B2
• Filed: 03/12/2003
• Issued: 08/23/2011
• Est. Priority Date: 03/13/2002
• Status: Active Grant

• Current Assignee: Tianjin Jiankai Technology Company Limited
• Original Assignee: Tianjin Jiankai Technology Company Limited
• Inventors: Ji, Shishan, Zhu, Dequan
• Primary Examiner(s): Vivlemore; Tracy
• Assistant Examiner(s): WHEELER, THURMAN MICHAEL
• Application Number:
  US10/507,452
• Publication Number:
  US 20050180946A1
• Time in Patent Office: 3,086 Days
• Field of Search: None
• US Class Current: 424/78.38
• 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. A Y-shaped branched hydrophilic polymer derivative as set forth by formula I:

2. The hydrophilic polymer derivative of claim 1 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.

5. The derivative of claim 1, wherein P_a and P_b are the same or different polyethylene glycols (PEGs) of formula (V):

6. The derivative of claim 5, wherein R is selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl and benzyl.

7. The derivative of claim 5, wherein the molecular weight of PEG is from about 300 to 60000.

10. A conjugate formed by reacting the derivative of claim 1 with a drug molecule through the terminal group F.

11. The conjugate of claim 10 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.

12. The conjugate of claim 10 wherein the drug is an active component of a natural medicine.

13. The conjugate of claim 12 wherein the active component is cinobufagin, clycyrrhetinic acid or scopoletin.

14. The conjugate of claim 10 wherein the drug is an anti-tumor agent.

15. The conjugate of claim 14 wherein the anti-tumor agent is selected from the group consisting of paclitaxel, camptothecin, interferon and derivatives thereof.

16. The conjugate of claim 15 wherein the interferon is α

-, β

- or γ

-interferon.

17. A pharmaceutical composition comprising the conjugate according to claim 10 and a pharmaceutically acceptable carrier or excipient.

4. A Y-shaped branched polyethylene glycol (PEG) derivative as set forth by formula III:

8. A method to prepare the PEG derivative of claim 4, comprising:

reacting one methoxyl polyethylene glycol mesylate with an amino acid under basic conditions to produce a reactive product; and

reacting the reactive product obtained above with another methoxyl polyethylene glycol derivative.

9. The method of claim 8, wherein the another methoxyl polyethylene glycol derivative is mPEG-carboxyethyl NHS ester.

18. The derivative of claim 4, wherein P_a and P_b are the same or different polyethylene glycols (PEGs) of formula (V):

19. The derivative of claim 18, wherein R is selected from the group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl and benzyl.

20. The derivative of claim 19, wherein the molecular weight of PEG is from about 300 to 60000.

21. The method of claim 8, further comprising a step of derivatizing to incorporate the functional group F of claim 4.

22. A conjugate formed by reacting the derivative of claim 4 with drug molecules through the terminal group F.

23. The conjugate of claim 22 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, glycoside of the steroids and alkaloids of the steroids.

24. The conjugate of claim 22 wherein the drug is an active component of a natural medicine.

25. The conjugate of claim 22 wherein the active component is cinobufagin, clycyrrhetinic acid or scopoletin.

26. The conjugate of claim 22 wherein the drug is an anti-tumor agent.

27. The conjugate of claim 26 wherein the anti-tumor agent is selected from the group consisting of paclitaxel, camptothecin, interferon and derivatives thereof.

28. The conjugate of claim 27 wherein the interferon is α

-, β

- or γ

-interferon.

29. A pharmaceutical composition comprising the conjugate according to claim 22 and a pharmaceutically acceptable carrier or excipient.