Compositions of thienopyrimidine derivatives

1. A mixture comprising 1-{441-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea, or a salt or solvate thereof, and 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.

2. The mixture of claim 1 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 4.45% or less of the mixture, as determined by high performance liquid chromatography (HPLC).

3. The mixture of claim 1 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.25% or less of the mixture, as determined by HPLC.

4. The mixture of claim 1 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.23% or less of the mixture, as determined by HPLC.

5. The mixture of claim 1 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.22% or less of the mixture, as determined by HPLC.

6. The mixture of claim 1 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.20% or less of the mixture, as determined by HPLC.

7. The mixture of claim 1 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 4.45% to about 0.20% of the mixture, as determined by HPLC.

8. The mixture of claim 1 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 0.25% to about 0.20% of the mixture, as determined by HPLC.

9. The mixture of claim 1 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.16% or less of the mixture, as determined by HPLC.

10. The mixture of claim 1 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.07% or less of the mixture, as determined by HPLC.

11. The mixture of claim 1 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.05% of the mixture, as determined by HPLC.

12. The mixture of claim 1 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 0.16% to about 0.05% of the mixture, as determined by HPLC.

13. The mixture of claim 1 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 0.07% to about 0.05% of the mixture, as determined by HPLC.

14. The mixture of claim 1 , further comprising 1444142,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea.

15. The mixture of claim 14 , wherein the 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea is present in an amount of about 0.1% or less of the mixture, as determined by HPLC.

16. The mixture of claim 14 , wherein the 1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-2,4-dioxo-3-(6-oxo-1,6-dihydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea is present in an amount of from about 0.1% to about 0.02% of the mixture, as determined by HPLC.

17. The mixture of claim 14 , further comprising N-{441-(2,6-difluorobenzyl)-5-dimethylaminomethyl 3 (6 methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-dimethoxydicarbonimidic diamide.

18. The mixture of claim 1 , further comprising N-{441-(2,6-difluorobenzyl)-5-dimethylaminomethyl 3 (6 methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide.

19. The mixture of claim 18 , wherein the N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl 3 (6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide is present in an amount of about 0.08% or less of the mixture, as determined by HPLC.

20. The mixture of claim 18 , wherein the N-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl 3 (6 methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-N,N′-dimethoxydicarbonimidic diamide is present in an amount of from about 0.08% to about 0.02% of the mixture.

21. The mixture of claim 1 , further comprising 1-(2,6-Difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-6-(4-nitrophenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.

22. The mixture of claim 1 , further comprising ethyl (2,6-difluorobenzyl)- [4-dimethylaminomethyl-3-(6-methoxypyridazin-3-ylcarbamoyl)-5-(4-nitrophenyl)thiophen-2-yl]carbamate.

23. The mixture of claim 1 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 0.25% to about 0.05% of the mixture, as determined by HPLC.

24. The mixture of claim 1 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 0.25% to about 0.07% of the mixture, as determined by HPLC.

25. The mixture of claim 1 comprising 1-{441-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea and 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione.

26. The mixture of claim 1 , wherein the mixture is in solid form.

27. The mixture of claim 1 , wherein the mixture comprises crystals.

28. The mixture of claim 1 comprising 1-{441-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea in the form of crystals.

29. The mixture of claim 25 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of about 0.05% or less of the mixture, as determined by HPLC.

30. The mixture of claim 25 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 4.45% to about 0.05% of the mixture, as determined by HPLC.

31. The mixture of claim 25 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 4.45% to about 0.25% of the mixture, as determined by HPLC.

32. The mixture of claim 25 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 0.25% to about 0.16% of the mixture, as determined by HPLC.

33. The mixture of claim 25 , wherein the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione is present in an amount of from about 0.20% to about 0.05% of the mixture, as determined by HPLC.

34. The mixture of claim 2 , wherein the percentage composition of the mixture is determined by an HPLC method comprising:

a) contacting a stationary phase of a reverse phase chromatography column with the mixture;

b) eluting the mixture with a mobile phase such that the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno [2,3-d]pyrimidine-2,4(1H,3H)-dione traverses the column with a retention time that is different than the remainder of the mixture;

wherein the mobile phase comprises a first mixed solvent and a second mixed solvent, wherein the first mixed solvent comprises phosphorate buffer solution and acetonitrile, and the second mixed solvent comprises phosphorate buffer solution and acetonitrile; and

c) measuring the percentage composition of the mixture using an ultraviolet absorptiometer.

35. The mixture of claim 34 , wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume.

36. The mixture of claim 35 , wherein the ratio of phosphorate buffer solution to acetonitrile in the second mixed solvent is about 12:13 by volume.

37. The mixture of claim 34 , wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm.

38. The mixture of claim 36 , wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm.

39. The mixture of claim 34 , wherein the reverse phase chromatography column is a C18 column.

40. The mixture of claim 38 , wherein the reverse phase chromatography column is a C18 column.

41. The mixture of claim 40 , wherein the C18 column comprises particles of silica having a particle size of about 3.5 μm.

42. The mixture of claim 41 , wherein the C18 column has an inner diameter of about 4.6 mm and a length of about 100 mm.

43. The mixture of claim 8 wherein the percentage composition of the mixture is determined by an HPLC method comprising:

a) contacting a stationary phase of a reverse phase chromatography column with the mixture;

b) eluting the mixture with a mobile phase such that the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione traverses the column with a retention time that is different than the remainder of the mixture;

wherein the mobile phase comprises a first mixed solvent and a second mixed solvent, wherein the first mixed solvent comprises phosphorate buffer solution and acetonitrile, and the second mixed solvent comprises phosphorate buffer solution and acetonitrile; and

c) measuring the percentage composition of the mixture using an ultraviolet absorptiometer.

44. The mixture of claim 43 , wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume.

45. The mixture of claim 44 , wherein the ratio of phosphorate buffer solution to acetonitrile in the second mixed solvent is about 12:13 by volume.

46. The mixture of claim 43 , wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm.

47. The mixture of claim 45 , wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm.

48. The mixture of claim 43 , wherein the reverse phase chromatography column is a C18 column.

49. The mixture of claim 47 , wherein the reverse phase chromatography column is a C18 column.

50. The mixture of claim 49 , wherein the C18 column comprises particles of silica having a particle size of about 3.5 μm.

51. The mixture of claim 50 , wherein the C18 column has an inner diameter of about 4.6 mm and a length of about 100 mm.

52. The mixture of claim 23 , wherein the percentage composition of the mixture is determined by an HPLC method comprising:

a) contacting a stationary phase of a reverse phase chromatography column with the mixture;

b) eluting the mixture with a mobile phase such that the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno [2,3-d]pyrimidine-2,4(1H,3H)-dione traverses the column with a retention time that is different than the remainder of the mixture;

wherein the mobile phase comprises a first mixed solvent and a second mixed solvent, wherein the first mixed solvent comprises phosphorate buffer solution and acetonitrile, and the second mixed solvent comprises phosphorate buffer solution and acetonitrile; and

c) measuring the percentage composition of the mixture using an ultraviolet absorptiometer.

53. The mixture of claim 52 , wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume.

54. The mixture of claim 53 , wherein the ratio of phosphorate buffer solution to acetonitrile in the second mixed solvent is about 12:13 by volume.

55. The mixture of claim 52 , wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm.

56. The mixture of claim 54 , wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm.

57. The mixture of claim 52 , wherein the reverse phase chromatography column is a C18 column.

58. The mixture of claim 56 , wherein the reverse phase chromatography column is a C18 column.

59. The mixture of claim 58 , wherein the C18 column comprises particles of silica having a particle size of about 3.5 μm.

60. The mixture of claim 59 , wherein the C18 column has an inner diameter of about 4.6 mm and a length of about 100 mm.

61. The mixture of claim 30 , wherein the percentage composition of the mixture is determined by an HPLC method comprising:

a) contacting a stationary phase of a reverse phase chromatography column with the mixture;

b) eluting the mixture with a mobile phase such that the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione traverses the column with a retention time that is different than the remainder of the mixture;

wherein the mobile phase comprises a first mixed solvent and a second mixed solvent, wherein the first mixed solvent comprises phosphorate buffer solution and acetonitrile, and the second mixed solvent comprises phosphorate buffer solution and acetonitrile; and

c) measuring the percentage composition of the mixture using an ultraviolet absorptiometer.

62. The mixture of claim 61 , wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume.

63. The mixture of claim 62 , wherein the ratio of phosphorate buffer solution to acetonitrile in the second mixed solvent is about 12:13 by volume.

64. The mixture of claim 61 , wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm.

65. The mixture of claim 63 , wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm.

66. The mixture of claim 61 , wherein the reverse phase chromatography column is a C18 column.

67. The mixture of claim 65 , wherein the reverse phase chromatography column is a C18 column.

68. The mixture of claim 67 , wherein the C18 column comprises particles of silica having a particle size of about 3.5 μm.

69. The mixture of claim 68 , wherein the C18 column has an inner diameter of about 4.6 mm and a length of about 100 mm.

70. The mixture of claim 32 , wherein the percentage composition of the mixture is determined by an HPLC method comprising:

a) contacting a stationary phase of a reverse phase chromatography column with the mixture;

b) eluting the mixture with a mobile phase such that the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione traverses the column with a retention time that is different than the remainder of the mixture;

wherein the mobile phase comprises a first mixed solvent and a second mixed solvent, wherein the first mixed solvent comprises phosphorate buffer solution and acetonitrile, and the second mixed solvent comprises phosphorate buffer solution and acetonitrile; and

c) measuring the percentage composition of the mixture using an ultraviolet absorptiometer.

71. The mixture of claim 70 , wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume.

72. The mixture of claim 71 , wherein the ratio of phosphorate buffer solution to acetonitrile in the second mixed solvent is about 12:13 by volume.

73. The mixture of claim 70 , wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm.

74. The mixture of claim 72 , wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm.

75. The mixture of claim 70 , wherein the reverse phase chromatography column is a C18 column.

76. The mixture of claim 74 , wherein the reverse phase chromatography column is a C18 column.

77. The mixture of claim 76 , wherein the C18 column comprises particles of silica having a particle size of about 3.5 μm.

78. The mixture of claim 77 , wherein the C18 column has an inner diameter of about 4.6 mm and a length of about 100 mm.

79. The mixture of claim 33 , wherein the percentage composition of the mixture is determined by an HPLC method comprising:

a) contacting a stationary phase of a reverse phase chromatography column with the mixture;

b) eluting the mixture with a mobile phase such that the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione traverses the column with a retention time that is different than the remainder of the mixture;

wherein the mobile phase comprises a first mixed solvent and a second mixed solvent, wherein the first mixed solvent comprises phosphorate buffer solution and acetonitrile, and the second mixed solvent comprises phosphorate buffer solution and acetonitrile; and

c) measuring the percentage composition of the mixture using an ultraviolet absorptiometer.

80. The mixture of claim 79 , wherein the ratio of phosphorate buffer solution to acetonitrile in the first mixed solvent is about 31:9 by volume.

81. The mixture of claim 80 , wherein the ratio of phosphorate buffer solution to acetonitrile in the second mixed solvent is about 12:13 by volume.

82. The mixture of claim 79 , wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm.

83. The mixture of claim 81 , wherein the percentage composition of the mixture is measured by the ultraviolet absorptiometer at a wavelength of about 230 nm.

84. The mixture of claim 79 , wherein the reverse phase chromatography column is a C18 column.

85. The mixture of claim 83 , wherein the reverse phase chromatography column is a C18 column.

86. The mixture of claim 85 , wherein the C18 column comprises particles of silica having a particle size of about 3.5 μm.

87. The mixture of claim 86 , wherein the C18 column has an inner diameter of about 4.6 mm and a length of about 100 mm.