Salts of Indazole Derivative and Crystals Thereof

• US 20190144419A1
• Filed: 11/27/2017
• Published: 05/16/2019
• Est. Priority Date: 11/28/2016
• Status: Active Grant

• Current Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated)
• Original Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated)
• Inventors: Onuma, Keiko
• Granted Patent: US 10,640,483 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention provides salts of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)but-2-enamide represented by the formula I and acids, and crystals thereof, possessing a potential to be used as drug substance in pharmaceuticals.

Claims

1. A salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)but-2- enamide represented by the formula I, and an acid selected from the group consisting of hydrobromic acid, maleic acid, mandelic acid and benzenesulfonic acid.

75. A pharmaceutical composition comprising the salt or the crystal thereof according to any one of claims 1 to 5 and 43 to 74.

2. A crystal of hydrochloride salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having one or more diffraction peaks at diffraction angles (2θ

±

0.2°

) selected from the group consisting of 6.1°

, 11.8°

, 16.8°

, 18.1° and

19.5°

in a powder X-ray diffractometry.

3. The crystal according to claim 2, characterized by having a diffraction peak at a diffraction angle (2θ

±

0.2°

) of 18.1°

in a powder X-ray diffractometry.

4. The crystal according to claim 2, characterized by having diffraction peaks at diffraction angles (2θ

±

0.2°

of 6.1°

, 11.8° and

18.1°

in a powder X-ray diffractometry.

5. A crystal of hydrochloride salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having peaks at chemical shifts (±

0.5 ppm) of 164.3 ppm, 162.2 ppm and 111.9 ppm in a solid state ¹³C NMR spectrum.

6-42. -42. (canceled)

43. A crystal of hydrochloride salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 1.

44. A crystal of hydrochloride salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having a solid state ¹³C NMR spectrum substantially the same as the solid state ¹³C NMR spectrum shown in FIG. 7.

45. A crystal of hydrobromide salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having one or more diffraction peaks at diffraction angles (2θ

±

0.2°

selected from the group consisting of 6.2°

, 11.7°

, 18.7°

, 20.4° and

22.5°

in a powder X-ray diffractometry.

46. The crystal according to claim 45, characterized by having a diffraction peak at a diffraction angle (2θ

±

0.2°

) of 18.7°

in a powder X-ray diffractometry.

47. The crystal according to claim 45, characterized by having diffraction peaks at diffraction angles (2θ

±

0.2°

) of 6.2°

, 18.7° and

22.5°

in a powder X-ray diffractometry.

48. A crystal of hydrobromide salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, which is characterized by having peaks at chemical shifts (±

0.5 ppm) of 164.5 ppm, 162.2 ppm and 111.7 ppm in a solid state ¹³C NMR spectrum.

49. A crystal of hydrobromide salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 2.

50. A crystal of hydrobromide salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having a solid state ¹³C NMR spectrum substantially the same as the solid state ¹³C NMR spectrum shown in FIG. 8.

51. A crystal form A of maleate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having one or more diffraction peaks at diffraction angles (2θ

±

0.2°

) selected from the group consisting of 16.7°

, 17.9°

, 21.2°

, 22.9° and

24.9°

in a powder X-ray diffractometry.

52. The crystal according to claim 51, characterized by having a diffraction peak at a diffraction angle (2θ

±

0.2°

of 24.9°

in a powder X-ray diffractometry.

53. The crystal according to claim 51, characterized by having diffraction peaks at diffraction angles (2θ

±

0.2°

of 17.9°

, 22.9° and

24.9°

in a powder X-ray diffractometry.

54. A crystal form A of maleate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having peaks at chemical shifts (±

0.5 ppm) of

55. A crystal form A of maleate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 3.

56. A crystal form A of maleate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having a solid state ¹³C NMR spectrum substantially the same as the solid state ¹³C NMR spectrum shown in FIG. 9.

57. A crystal form B of maleate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having one or more diffraction peaks at diffraction angles (2θ

±

0.2°

) selected from the group consisting of 14.8°

, 20.2°

, 22.3° and

26.5°

in a powder X-ray diffractometry.

58. The crystal according to claim 57, characterized by having a diffraction peak at a diffraction angle (2θ

±

0.2°

) of 22.3°

in a powder X-ray diffractometry.

59. The crystal according to claim 57, characterized by having diffraction peaks at diffraction angles (2θ

±

0.2°

) of 14.8°

, 20.2° and

22.3°

in a powder X-ray diffractometry.

60. A crystal form B of maleate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having peaks at chemical shifts (±

0.5 ppm) of 171.4 ppm, 108.6 ppm and 48.8 ppm in a solid state ¹³C NMR spectrum.

61. A crystal form B of maleate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 4.

62. A crystal form B of maleate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having a solid state ¹³C NMR spectrum substantially the same as the solid state ¹³C NMR spectrum shown in FIG. 10.

63. A crystal of L-mandelate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having one or more diffraction peaks at diffraction angles (2θ

±

0.2°

) selected from the group consisting of 5.1°

, 8.8°

, 10.3°

, 16.9° and

18.3°

in a powder X-ray diffractometry.

64. The crystal according to claim 63, characterized by having a diffraction peak at a diffraction angle (2θ

±

0.2°

) of 18.3°

in a powder X-ray diffractometry.

65. The crystal according to claim 63, characterized by having diffraction peaks at diffraction angles (2θ

±

0.2°

) of 5.1°

, 10.3° and

18.3°

in a powder X-ray diffractometry.

66. A crystal of L-mandelate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having peaks at chemical shifts (±

0.5 ppm) of 165.9 ppm, 160.7 ppm and 110.5 ppm in solid state ¹³C NMR spectrum.

67. A crystal of L-mandelate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 5.

68. A crystal of L-mandelate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having a solid state ¹³C NMR spectrum substantially the same as the solid state ¹³C NMR spectrum shown in FIG. 11.

69. A crystal of benzenesulfonate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having one or more diffraction peaks at diffraction angles (2θ

±

0.2°

) selected from the group consisting of 5.2°

, 9.5°

, 10.5°

, 21.4° and

24.4°

in a powder X-ray diffractometry.

70. The crystal according to claim 69, characterized by having a diffraction peak at a diffraction angle (2θ

±

0.2°

) of 9.5°

in a powder X-ray diffractometry.

71. The crystal according to claim 69, characterized by having diffraction peaks at diffraction angles (2θ

±

0.2°

) of 5.2°

, 9.5° and

10.5°

in a powder X-ray diffractometry.

72. A crystal of benzenesulfonate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having peaks at chemical shifts (±

0.5 ppm) of 163.0 ppm, 147.2 ppm and 145.0 ppm in a solid state ¹³C NMR spectrum.

73. A crystal of benzenesulfonate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 6.

74. A crystal of benzenesulfonate salt of (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2- yl)oxy)ethyl)amino)but-2-enamide represented by the formula I, characterized by having a solid state ¹³C NMR spectrum substantially the same as the solid state ¹³C NMR spectrum shown in FIG. 12.

169. 6 ppm, 107.3 ppm and 50.3 ppm in a solid state ¹³C NMR spectrum.