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1. WO2020118103 - INHIBITEURS D'HÉPARANASE ET LEUR UTILISATION COMME COMPOSÉS ANTICANCÉREUX

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

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CLAIMS

What is claimed is:

1. A method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a salt form of an anti-heparanase compound having the structure:


r^

wherein n = 2-100 repeating units of the structure; the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

2. A method of claim 1 wherein the salt form is sodium salt.

3. A method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a salt form of an anti- heparanase compound to the subject wherein the anti- heparanase compound comprises a glycopolymer linked to a disaccharide.

4. The method of claim 3 wherein the salt form of the anti-heparanase compound has 5-12 repeating units of the glycopolymer linked to the disaccharide.

5. The method of claim 3 wherein the glycopolymer is linked to the disaccharide through nitrogen bonding.

6. The method of claim 3 wherein the disaccharide comprises a glucosamine unit sulfated at the carbon 2 and carbon 6 nitrogen positions of the disaccharide.

7. The method of claim 3 wherein the disaccharide comprises a glucosamine unit fluorinated at the carbon 2 or carbon 3 positions of the disaccharide.

8. The method of claim 3 wherein the salt form of the anti-heparanase compound is a heparan sulfate mimicking glycopolymer having the structure:


linking group; Ra is a saccharide or disaccharide, which saccharide or disaccharide comprises a - SOsNa group; Q is -NSOsNa or -F; Z is either -OH or -F; the positioning of the carboxylic acid, or salt thereof, can either be axial or equatorial; and the dash bond— is a single bond or a double bond.

9. The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:


wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

10. The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:


wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

11. The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:


wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

12. The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:

wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

13. The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:


wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

14. The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:


wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

15. The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:


wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

16. The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:


wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

17. The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:


wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

18. The method of claim 8 wherein the heparan sulfate mimicking glycopolymer is a compound having the structure:


wherein the ring opening bonds designated as (*) are independently single or double bonds; and the salt form is selected from a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt.

19. The method of claim 3 wherein the salt form of the anti-heparanase compound has the structure:


linking group; Ra is a saccharide or disaccharide, which saccharide or disaccharide comprises a -SOsNa group; and the dash bond— is a single bond or a double bond.


20. The method of claim 19 wherein X is -O- and Y is -O-; or X is O and Y is -CH2-.

21. The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:


wherein R1 is OH or -N(H)-L-Ra; L is a linking group; and Ra is a saccharide or disaccharide, which saccharide or disaccharide comprises a -SOsNa group; and the carboxylic acid group is a salt thereof.

22. The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:


23. The method of claim 19 wherein the salt form of the anti-heparanase compound has the

structure:


24. The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:


25. The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:

26. The method of claim 19 wherein the salt for of the anti-heparanase compound has the structure:


27. The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:

wherein L is a linking group; Ra is a saccharide or disaccharide, which saccharide or disaccharide comprises a -SOsNa group.

28. The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:


29. The method of claim 19 wherein Ra is selected from:


30. The method of claim 19 wherein Ra is selected from:


31. The method of claim 19 wherein Ra is:


32. The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:


33. The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:


34. The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:


35. The method of claim 19 wherein the salt form of the anti-heparanase compound has the structure:


wherein n is 8.

36. The method of any one of claim 8-35 wherein n is an integer from 2-100

37. The method of any one of claim 8-35 wherein n is an integer from 5-55.

38. The method of any one of claim 8-35 wherein n is 5, 8, 9, 12, 27, or 51.

39. A compound having the structure:


wherein:


-100 repeating units; R1 is OH or -N(H)-L-Ra; L is a linking group; Ra is a saccharide or disaccharide, which saccharide or disaccharide comprises one or more -SO3H groups; the carboxylic acid group is a salt thereof; and the dash bond— is a single bond or a double bond.

40. The compound of claim 39, having the structure:


wherein: n = 2-100 repeating units; and the saccharide or disaccharide further comprises one or more F- groups.

41. The compound of claim 39, having the structure:


42. The compound of claim 39, having the structure:


43. The compound of claim 39, having the structure:


44. The compound of 40 wherein the one or more F- groups comprise axial 2-fluoro-glycoside.

45. The compound of 41 wherein the one or more F- groups comprise axial 2-fluoro-glycoside.

46. The compound of 42 wherein the one or more F- groups comprise axial 2-fluoro-glycoside.

47. The compound of 43 wherein the one or more F- groups comprise axial 2-fluoro-glycoside.

48. An anti-cancer composition comprising: (i) an anti-heparanase compound of any one of claims 1-35 and (ii) a pharmaceutically acceptable carrier.

49. The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to FGF-1 is more than the binding affinity of heparin to FGF-1.

50. The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to FGF-1 is at least 2000nM more than the binding affinity of heparin to FGF-1.

51. The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to FGF-2 is more than the binding affinity of heparin to FGF-2.

52. The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to FGF-2 is at least 530nM more than the binding affinity of heparin to FGF-2.

53. The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to VEGF is more than the binding affinity of heparin to VEGF.

54. The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to VEGF is at least 115nM more than the binding affinity of heparin to VEGF.

55. The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to PF4 is more than the binding affinity of heparin to PF4

56. The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to PF4 is at least 35nM more than the binding affinity of heparin to PF4.

57. The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to P-Selectin is more than or equal to the binding affinity of heparin to P-Selectin 58. The anti-cancer composition of claim 48 wherein the binding affinity of the anti-heparanase compound to P-Selectin is at least -570nM more than or equal to the binding affinity of heparin to P-Selectin.

59. The anti-cancer composition of claim 48 wherein the anti-heparanase compound has lower binding affinity to antithrombin III than heparin’s binding affinity to antithrombin III.

60. The anti-cancer composition of claim 48 wherein the pharmaceutically acceptable carrier is aqueous or alcoholic and comprises a viscous base.