POSACONAZOLE POLYMER CONJUGATES AND METHODS OF TREATMENT USING POSACONAZOLE AND POLYMER CONJUGATES THEREOF

• US 20100056543A1
• Filed: 11/13/2009
• Published: 03/04/2010
• Est. Priority Date: 01/16/2007
• Status: Abandoned Application

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: ZHAO, Hong
• Application Number:
  US12/618,260
• Publication Number:
  US 20100056543A1
• Time in Patent Office: Days
• US Class Current: 514/254.70
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/74 Synthetic polymeric materials
• 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 31/10 Antimycotics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C08G 65/331 containing oxygen cyclic ether compounds C08G65/26
• CPC Class Codes: C08G 65/3318 heterocyclic
• CPC Class Codes: C08G 65/3326 aromatic
• CPC Class Codes: C08G 65/33317 heterocyclic
• CPC Class Codes: C08G 65/33396 having oxygen in addition to nitrogen
• CPC Class Codes: C08L 2203/02 for biomedical use

Abstract

Improved posaconazole-based compositions and methods of treating and preventing fungal infections, cancer or metastatic diseases are disclosed. In preferred aspects, the conjugates are PEG-posaconazole conjugates in which the PEG has a molecular weight of about 20,000 daltons.

Claims

1. A polymeric conjugate comprising posaconazole and a substantially non-antigenic polymer.

2. The polymeric conjugate of claim 1, wherein the substantially non-antigenic polymer is a polyalkylene oxide.

3. The polymeric conjugate of claim 2, wherein the polyalkylene oxide is a polyethylene glycol.

4. The polymeric conjugate of claim 2, wherein the polyalkylene oxide has a weight average molecular weight of from about 1,000 to about 100,000 daltons.

5. The polymeric conjugate of claim 2, wherein the polyalkylene oxide has a weight average molecular weight of from about 5,000 to about 60,000 daltons.

6. The polymeric conjugate of claim 2, wherein the polyalkylene oxide has a weight average molecular weight of from about 12,000 to about 24,000 daltons.

7. A polymeric conjugate of claim 1 having Formula (I):

wherein

A is a capping group or

X is

Z₁, Z_1′

, Z₂ and Z_2′

are independently selected from the group consisting of O, S and NR₁;

R is a polyalkylene oxide;

Y₁ and Y_1′

are independently O, S, SO, SO₂, CR₂R₃ or NR₄; and

R₁, R₂, R₃ and R₄ are independently selected from the group consisting of hydrogen, C_1-6 alkyls, C_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, C_3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C_1-6 heteroalkyls, substituted C_1-6 heteroalkyls, C_1-6 alkoxy, phenoxy and C_1-6 heteroalkoxy.

8. The polymeric conjugate of claim 7 having Formula (II):

9. The polymeric conjugate of claim 7, wherein the capping group is selected from the group consisting of H, NH₂, OH, CO₂H, C_1-6 alkoxy and C_1-6 alkyl.

10. The polymeric conjugate of claim 7, wherein R comprises a linear, branched or multi-armed polyalkylene oxide.

11. The compound of claim 7, wherein R is selected from the group consisting of polyethylene glycol, polypropylene glycol, and copolymers thereof.

12. The polymeric conjugate of claim 7, wherein R is

—

Y₁1-(CH₂CH₂O)_n—

CH₂CH₂Y₁₁—

,

wherein;

Y₁₁ and Y_11′

are independently O, S, or NR₁₁;

R₁₁ is selected from the group consisting of hydrogen, C_1-6 alkyls, C_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, C_3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C_1-6 heteroalkyls, substituted C_1-6 heteroalkyls, C_1-6 alkoxy, phenoxy and C_1-6 heteroalkoxy;

(n) is an integer from about 20 to about 2300.

13. The polymeric conjugate of claim 7 having Formula (III):

wherein (n) is an integer from about 20 to about 2300.

14. The polymeric conjugate of claim 13, wherein Y₁, Y_1′

, Z₁, Z_1′

, Z₂ and Z_2′

are each O.

17. A pharmaceutical composition comprising an effective amount of the polymeric conjugate of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

18. A method of treating and/or preventing fungal infections in a mammal, comprising administering an anti-fungally effective amount of a polymeric conjugate of claim 1 to a mammal in need thereof.

19. The method of claim 18, wherein the polymeric conjugate is administered parenterally.

20. The method of claim 18, wherein the amount of posaconazole administered to the mammal is from about 10 to about 2,000 mg per day.

21. The method of claim 18, wherein the amount of posaconazole administered to the mammal is from about 50 to about 800 mg per day.

22. The method of claim 18, wherein the amount of posaconazole administered to the mammal is from about 5 to about 50 mg/kg/day.

23. The method of claim 18, wherein the amount of posaconazole administered is an amount effective to produce an arithmetic mean steady state average maximum plasma concentration of posaconazole that exceeds the majority of the Minimum Inhibitory Concentrations needed to kill 90% (“

MICs₉₀”

) of the clinically relevant pathogenic fungi.

24. A method of treating and/or preventing cancer or metastatic diseases in a mammal, comprising administering an effective amount of a polymeric conjugate of claim 1 to a mammal in need thereof.

25. The method of claim 24, wherein the polymeric conjugate is administered parenterally.

26. The method of claim 24, wherein the amount of posaconazole administered to the mammal is from about 10 to about 2,000 mg per day.

27. The method of claim 24, wherein the amount of posaconazole administered to the mammal is from about 50 to about 800 mg per day.

28. The method of claim 24, wherein the amount of posaconazole administered to the mammal is from about 5 to about 50 mg/kg/day.

15. A method of preparing a polymeric conjugate, comprising

a) reacting a compound of the structure

in the presence of a base

wherein

Z₂₁ and Z₂₂ are independently selected from the group consisting of O, S and NR₂₁;

Y₂₁ is O, S, SO, SO₂, CR₂₂R₂₃ or NR₂₄;

R₂₁, R₂₂, R₂₃ and R₂₄ are independently selected from the group consisting of hydrogen, C_1-6 alkyls, C_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, C_3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C_1-6 heteroalkyls, substituted C_1-6 hetero-alkyls, C_1-6 alkoxy, phenoxy and C_1-6 heteroalkoxy; and

b) reacting the resulting product of step a) with an amine-terminated polyalkylene oxide in the presence of a base and a coupling agent under conditions sufficient to form a polymeric conjugate.

16. The method of claim 15, wherein the base is 4-dimethylaminopyridine (DMAP) and the coupling agent is 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (EDC).