Novel potentiating compounds

• US 20030050343A1
• Filed: 03/15/2002
• Published: 03/13/2003
• Est. Priority Date: 05/15/2001
• Status: Active Grant

• Current Assignee: Oasmia Pharmaceutical AB
• Original Assignee: Ardenia Investments Ltd. (Vivesto AB)
• Inventors: Aleksov, Julian, Strelchenok, Oleg
• Granted Patent: US 6,642,271 B2
• Time in Patent Office: Days
• US Class Current: 514/562
• CPC Class Codes: A61K 31/203 Retinoic acids ; Salts thereof
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07B 2200/09 Geometrical isomers
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07C 403/20 having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
• CPC Class Codes: C07C 403/22 having side-chains substituted by sulfur atoms

Abstract

This invention relates to novel compounds, capable of potentiating the efficacy of therapeutically active compounds, for example cytotoxic compounds used in the treatment of cancer. The novel compounds have been shown to increase the pharmacological activity of a conventional paclitaxel formulation and to make it possible to manufacture a new formulation of paclitaxel, exhibiting improved solubility, improved storage properties, and increased therapeutic efficacy as shown in the enclosed examples.

Claims

1. A compound having a structural formula chosen among the following (I-VI):

2. A pharmaceutically acceptable salt of a compound according to claim 1.

3. A pharmaceutical acceptable sodium salt of a compound according to claim 1.

4. Use of a compound according to claim 1, or a derivative thereof, for the manufacture of a medicament.

5. Use of a compound according to claim 1, or a derivative thereof, for the manufacture of a medicament for the treatment of cancer.

6. A pharmaceutical composition comprising an active substance in a therapeutically effective amount, characterized in that said composition further comprises a compound according to claim 1 or a derivative thereof.

7. A pharmaceutical composition according to claim 6, characterized in that the active substance is a cytotoxic or cytostatic compound.

8. A pharmaceutical composition according to claim 6, characterized in that the active substance is paclitaxel.

9. A pharmaceutical composition according to claim 6, characterized in that the active substance is paclitaxel present in the form of Taxol®

.

10. A pharmaceutical composition according to claim 6, characterized in that the compound of claim 1 is present in the form of its sodium salt.

11. A pharmaceutical composition according to claim 6, characterized in that the compound of claim 1 is present in acid form.

12. A method for potentiating the efficacy of a pharmaceutically active substance, characterized in that said substance is prepared in micellar form with a compound according to claim 1.

13. A method for increasing the solubility of a pharmaceutically active substance, characterized in that said substance is prepared in micellar form with a compound according to claim 1.

14. A method for improving the bio-availability of a pharmaceutically active substance, characterized in that said substance is prepared in micellar form with a compound according to claim 1.

15. A method for improving the storage properties of a pharmaceutically active substance, characterized in that said substance is prepared in micellar form with a compound according to claim 1.

16. A method for the treatment of cancer, characterized in that a cytotoxic substance is mixed with a compound according to claim 1 and delivered to a patient.

17. A method according to claim 16, characterized in that the cytotoxic substance is paclitaxel.

18. A method according to claim 16, characterized in that the cytotoxic substance is paclitaxel present in the form of Taxol®

.

19. A method according to claim 16, characterized in that the compound of claim 1 is present in the form of its sodium salt.

20. A method according to claim 16, characterized in that the compound of claim 1 is present in acid form.

21. A method for preparing a water-soluble formulation of paclitaxel, comprising the steps of dissolving paclitaxel in a first solvent, dissolving a compound according to claim 1 in a second solvent, mixing the aliquots of the resulting solutions of paclitaxel and said compound in a desired molar ratio, and evaporting the resulting mixture to dryness.

22. A method for preparing a water-soluble improved formulation of Taxol®

, comprising the steps of dissolving a compound according to claim 1 in a solvent, evaporation of a desired aliquot of the resulting solution to dryness, and dissolviong the residue in Taxol®

.

23. A method for preparing a stable storage formulation of paclitaxel, comprising the steps of dissolving paclitaxel in a first solvent, dissolving a compound according to claim 1 in a second solvent, mixing the aliquots of the resulting solutions of paclitaxel and said compound in a desired molar ratio.

24. A method for preparing a formulation of paclitaxel for administration to a patient, comprising the steps of dissolving paclitaxel in a first solvent, dissolving a compound according to claim 1 in a second solvent, mixing the aliquots of the resulting solutions of paclitaxel and said compound in a desired molar ratio, evaporting the resulting mixture to dryness forming a residue of paclitaxel and said compound, dissolving said residue in an aqueous solution, lyophilisation of the solution formed, followed by reconstitution of the lyophilised product using a vehicle suitable for administration to a patient.

25. A method according to claim 21, characterized in that said first and second solvent are at least one aliphatic alcohol.

26. A method according to claim 22, characterized in that said first and second solvent are at least one aliphatic alcohol.

27. A method according to claim 23, characterized in that said first and second solvent are at least one aliphatic alcohol.

28. A method according to claim 24, characterized in that said first and second solvent are at least one aliphatic alcohol.

29. A method according to claim 21, characterized in that said first and second solvent is a solvent chosen among ethanol, methanol, 2-propanol and butanol.

30. A method according to claim 22, characterized in that said first and second solvent is a solvent chosen among ethanol, methanol, 2-propanol and butanol.

31. A method according to claim 23, characterized in that said first and second solvent is a solvent chosen among ethanol, methanol, 2-propanol and butanol.

32. A method according to claim 24, characterized in that said first and second solvent is a solvent chosen among ethanol, methanol, 2-propanol and butanol.

33. A method according to claim 21, characterized in that said first and second solvent is methanol.

34. A method according to claim 22, characterized in that said first and second solvent is methanol.

35. A method according to claim 23, characterized in that said first and second solvent is methanol.

36. A method according to claim 24, characterized in that said first and second solvent is methanol.

37. A method according to claim 21, characterized in that paclitaxel is used in the form of Taxol®

.

38. A method according to claim 22, characterized in that paclitaxel is used in the form of Taxol®

.

39. A method according to claim 23, characterized in that paclitaxel is used in the form of Taxol®

.

40. A method according to claim 24, characterized in that paclitaxel is used in the form of Taxol®

.

41. A method for the synthesis of sodium salts of compounds according to claim 1 or analogues thereof, comprising the following consequtive steps:

direct acylation of the amino groups in water-organic medium in the presence of Na₂CO₃

separation of insoluble contaminants

separation of the sodium salts

42. A method according to claim 41, characterized in that the water-organic medium is a mixture of tetrahydrofuran-acetonitrile-water.

43. A method according to claim 41, characterized in that the separation is performed by the addition of a 2-propanol-water mixture to the water-organic medium.

44. A method according to claim 41, characterized in that the precipitation is performed by the addition of a 2-propanol-methanol mixture to a concentrated solution of the sodium salt of the compound in 2-propanol-water.