Claims
- 1. A polymer conjugate of a triazine derivative comprising a water soluble and non-peptidic polymer backbone covalently attached to a non-heteroatom position of a triazine derivative comprising an s-triazine ring or an as-triazine ring.
- 2. The polymer conjugate of claim 1, wherein the triazine derivative comprises a 1,3,5-triazine ring, a 1,2,4-triazine ring or a benzotriazine ring.
- 3. The polymer conjugate of claim 1, wherein the triazine derivative is substituted at one or more non-heteroatom positions with a substituent selected from the group consisting of amino, substituted amino, aryl, and substituted aryl.
- 4. The polymer conjugate of claim 1, wherein the polymer backbone is selected from the group consisting of poly(alkylene glycol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof.
- 5. The polymer conjugate of claim 1, wherein the polymer backbone is poly(ethylene glycol).
- 6. The polymer conjugate of claim 5, wherein the poly(ethylene glycol) has an average molecular weight from about 100 Da to about 100,000 Da.
- 7. The polymer conjugate of claim 1, wherein the polymer backbone has about 2 to about 300 termini.
- 8. The polymer conjugate of claim 1, wherein the polymer backbone is covalently bonded to the structure:
- 9. The polymer conjugate of claim 8, wherein X is O or NR2, wherein R2 is H, C1-6alkyl, or substituted C1-6alkyl.
- 10. The polymer conjugate of claim 8, wherein Y1 and Y2 are each NRR1, wherein R is C1-6alkyl, substituted C1-6alkyl, or an electron withdrawing group, and R1 is H, C1-6alkyl, or substituted C1-6alkyl.
- 11. The polymer conjugate of claim 10, wherein R is methyl and R1 is —CH2OH. CH2OH.
- 12. The polymer conjugate of claim 8, having the structure:
- 13. The polymer conjugate of claim 12, wherein POLY is selected from the group consisting of poly(alkylene glycol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof.
- 14. The polymer conjugate of claim 12, wherein POLY is poly(ethylene glycol).
- 15. The polymer conjugate of claim 12, wherein X is O or NR2, wherein R2 is H, C1-6alkyl, or substituted C1-6alkyl.
- 16. The polymer conjugate of claim 12, wherein Z is selected from the group consisting of alkoxy, hydroxyl, protected hydroxyl, active ester, active carbonate, acetal, aldehyde, aldehyde hydrates, alkenyl, acrylate, methacrylate, acrylamide, active sulfone, amine, protected amine, hydrazide, protected hydrazide, thiol, protected thiol, carboxylic acid, protected carboxylic acid, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxals, diones, mesylates, tosylates, and tresylate.
- 17. The polymer conjugate of claim 12, wherein Z has the structure:
- 18. The polymer conjugate of claim 17, wherein X′ is O or NR2, wherein R2 is H, C1-6alkyl, or substituted C1-6alkyl.
- 19. The polymer conjugate of claim 17, wherein POLY is poly(ethylene glycol) and X and X′ are both O.
- 20. The polymer conjugate of claim 12, wherein POLY is poly(ethylene glycol) and Z is methoxy.
- 21. The polymer conjugate of claim 8, having the structure:
- 22. The polymer conjugate of claim 21, wherein n is about 3 to about 20.
- 23. The polymer conjugate of claim 21, wherein each X and Y are independently selected from the group consisting of O or NR2, wherein R2 is H, C1-6alkyl, or substituted C1-6alkyl.
- 24. The polymer conjugate of claim 21, wherein R′ is derived from a molecule selected from the group consisting of polyols, polyamines, and molecules having a combination of alcohol and amine groups.
- 25. The polymer conjugate of claim 21, wherein R′ is derived from a molecule selected from the group consisting of glycerol, glycerol oligomers, pentaerythritol, sorbitol, and lysine.
- 26. The polymer conjugate of claim 21, wherein each POLY is selected from the group consisting of poly(alkylene glycol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof.
- 27. The polymer conjugate of claim 21, wherein each POLY is poly(ethylene glycol).
- 28. The polymer conjugate of claim 21, having the structure:
- 29. The polymer conjugate of claim 8, wherein the polymer backbone is bonded to the structure:
- 30. The polymer conjugate of claim 29, wherein X1 and Y′ are independently selected from the group consisting of O or NR2, wherein R2 is H, C1-6alkyl, or substituted C1-6alkyl.
- 31. The polymer conjugate of claim 1, wherein the polymer backbone has the structure:
- 32. The polymer conjugate of claim 31, wherein polya and Polyb are both methoxy poly(ethylene glycol).
- 33. The polymer conjugate of claim 31, wherein R″ is H, methyl or a water-soluble and non-peptidic polymer backbone.
- 34. The polymer conjugate of claim 1, wherein the polymer backbone comprises methoxy poly(ethylene glycol) disubstituted lysine.
- 35. A method of forming a polymer conjugate of a triazine derivative, comprising:
providing a water soluble and non-peptidic polymer backbone bonded to a functional group reactive with cyanuric halide; reacting the polymer backbone with cyanuric halide, the cyanuric halide comprising a trihalo-substituted triazine ring, to form a dihalotriazine intermediate having a polymer backbone covalently attached at one of the non-heteroatom positions of the triazine ring; and replacing each of the two remaining halogen atoms of the dihalotriazine intermediate with a functional group.
- 36. The method of claim 35, wherein the cyanuric halide has the structure:
- 37. The method of claim 36, wherein Xh is chlorine.
- 38. The method of claim 35, wherein the functional group of the water-soluble and non-peptidic polymer backbone is selected from the group consisting of hydroxyl, alkoxide, and amine.
- 39. The method of claim 35, wherein said step of reacting the polymer backbone with the cyanuric halide occurs in the presence of a solvent selected from the group consisting of toluene, tetrahydrofuran, and dioxane.
- 40. The method of claim 35, wherein the polymer backbone is selected from the group consisting of poly(alkylene glycol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof.
- 41. The method of claim 35, wherein the polymer backbone is poly(ethylene glycol).
- 42. The method of claim 41, wherein the poly(ethylene glycol) has an average molecular weight from about 100 Da to about 100,000 Da.
- 43. The method of claim 35, wherein said step of replacing each of the two remaining halogen atoms of the dihalotriazine intermediate with a functional group comprises replacing each halogen atom with a functional group selected from the group consisting of amino, substituted amino, C1-6alkyl, substituted C1-6alkyl, aryl, or substituted aryl.
- 44. The method of claim 35, wherein said replacing step comprises reacting the triazine intermediate with an alkyl amine to form a diamino-substituted triazine polymer conjugate having the structure:
- 45. The method of claim 44, wherein the alkyl amine is methyl amine and R′ is methyl.
- 46. The method of claim 44, wherein the reaction with the alkyl amine occurs in the presence of a solvent selected from the group consisting of toluene, tetrahydrofaran, dioxane, acetonitrile, methylene chloride, and chloroform.
- 47. The method of claim 44, further comprising reacting the diamino-substituted triazine polymer conjugate with aqueous formaldehyde in the presence of an alkali metal carbonate to form a disubstituted amino triazine polymer conjugate having the structure:
- 48. A method of treating cancer in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a polymer conjugate of a triazine derivative comprising a water soluble and non-peptidic polymer backbone covalently attached to a non-heteroatom position of a triazine derivative comprising an s-triazine ring or an as-triazine ring.
- 49. The method of claim 48, wherein the triazine derivative comprises a 1,3,5-triazine ring, a 1,2,4-triazine ring or a benzotriazine ring.
- 50. The method of claim 48, wherein the triazine derivative is substituted at one or more non-heteroatom positions with a substituent selected from the group consisting of amino, substituted amino, aryl, and substituted aryl.
- 51. The method of claim 48, wherein the polymer backbone is selected from the group consisting of poly(alkylene glycol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof.
- 52. The method of claim 48, wherein the polymer backbone is poly(ethylene glycol).
- 53. The method of claim 52, wherein the poly(ethylene glycol) has an average molecular weight from about 100 Da to about 100,000 Da.
- 54. The method of claim 48, wherein the polymer backbone is covalently bonded to the structure:
- 55. The method of claim 54, wherein X is O or NR2, wherein R2 is H, C1-6alkyl, or substituted C1-6alkyl.
- 56. The method of claim 54, wherein Y1 and Y2 are each NRR1, wherein R is C1-6alkyl, substituted C1-6alkyl, or an electron withdrawing group, and R1 is H, C1-6alkly, or substituted C1-6alkyl.
- 57. The method of claim 54, wherein R is methyl and R1 is —CH2OH.
- 58. The method of claim 48, wherein said administering step comprises administering the compound buccally, subcutaneously, transdermally, intramuscularly, intravenously, orally, or by inhalation.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of Provisional Application Serial No. 60/250,483, filed Nov. 30, 2000, which is incorporated herein by reference in its entirety.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60250483 |
Nov 2000 |
US |