Particles, pharmaceutical compositions, and uses of imidazo[4,5-b]pyridine compounds in the treatment of medical conditions

Abstract

The present invention provides particles of imidazo[4,5-b]pyridine compounds having a preferred particle size range, pharmaceutical compositions, methods for inhibiting tropomyosin-related kinases and / or c-FMS, methods for treating medical diseases and conditions such as pain, and methods for preparing such particles.

Claims

1. D50 Particles of compound 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazole-4-yl)-3H-imidazo[4,5-b]pyridine-2-amine monohydrate with a particle size in the range of 40 μm to 75 μm.

2. The particle according to claim 1, wherein the particle has a D50 particle size in the range of 40 μm to 45 μm.

3. The particle according to claim 1, wherein the particle has a D50 particle size in the range of 47 μm to 67 μm.

4. The particle according to claim 1, wherein the particle has a D50 particle size in the range of 52 μm to 62 μm.

5. The particle according to claim 1, wherein the particle has a D50 particle size in the range of 55 μm to 59 μm.

6. The particle according to claim 1, wherein the particle has a D50 particle size in the range of 56 μm to 57 μm.

7. The particle according to claim 1, wherein the particle has a D50 particle size in the range of 55 μm to 65 μm.

8. The particle is the particle according to any one of claims 1 to 7, wherein the D90 particle size is in the range of 70 μm to 150 μm.

9. The particle is the particle according to any one of claims 1 to 7, wherein the D90 particle size is in the range of 110 μm to 150 μm.

10. The particle is the particle according to any one of claims 1 to 7, wherein the D90 particle size is in the range of 121 μm to 141 μm.

11. The particle is the particle according to any one of claims 1 to 7, wherein the D90 particle size is in the range of 126 μm to 136 μm.

12. The particle is the particle according to any one of claims 1 to 7, wherein the D90 particle size is in the range of 129 μm to 133 μm.

13. The particle is the particle according to any one of claims 1 to 7, wherein the D90 particle size is in the range of 130 μm to 132 μm.

14. The particle is the particle according to any one of claims 1 to 13, wherein the D10 particle size is in the range of 5 μm to 10 μm.

15. The particle is the particle according to any one of claims 1 to 13, wherein the D10 particle size is in the range of 7 μm to 9 μm.

16. The particle is the particle according to any one of claims 1 to 13, wherein the D10 particle size is in the range of 12 μm to 26 μm.

17. The particle is the particle according to any one of claims 1 to 13, wherein the D10 particle size is in the range of 14 μm to 24 μm.

18. The particle is the particle according to any one of claims 1 to 13, wherein the D10 particle size is in the range of 16 μm to 22 μm.

19. The particle is the particle according to any one of claims 1 to 13, wherein the D10 particle size is in the range of 17 μm to 21 μm.

20. The particle is the particle according to any one of claims 1 to 13, wherein the D10 particle size is in the range of 18 μm to 19 μm.

21. The particle is the particle according to any one of claims 1 to 13, wherein the D10 particle size is in the range of 20 μm to 30 μm.

22. The particle is the particle according to any one of claims 1 to 13, wherein the D10 particle size is in the range of 24 μm to 28 μm.

23. D90 Particles of compound 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazole-4-yl)-3H-imidazo[4,5-b]pyridine-2-amine monohydrate with a particle size in the range of 70 μm to 150 μm.

24. The particle according to claim 23, wherein the particle has a D50 particle size in the range of 35 μm to 45 μm.

25. The particle is the particle according to claim 1 or 23, wherein the particle has a D50 particle size of about 40 μm.

26. The particle is the particle according to any one of claims 1 to 7 or 23 to 25, wherein the D90 particle size is in the range of 80 μm to 130 μm.

27. The particles are those according to any one of claims 1 to 7 or 23 to 25, wherein the D90 particle size is in the range of 80 μm to 100 μm.

28. The particle is the particle according to any one of claims 1 to 7 or 23 to 25, wherein the D90 particle size is in the range of 85 μm to 95 μm.

29. The particle is the particle according to any one of claims 1 to 7 or 23 to 25, wherein the D90 particle size is in the range of 88 μm to 92 μm.

30. The particle is the particle according to any one of claims 1 to 7 or 23 to 25, wherein the D90 particle size is about 90 μm.

31. The particle is the particle according to any one of claims 1 to 7 or 23 to 25, wherein the D90 particle size is in the range of 110 μm to 130 μm.

32. The particle is the particle according to any one of claims 1 to 7 or 23 to 25, wherein the D90 particle size is in the range of 120 μm to 124 μm.

33. The particle is the particle according to any one of claims 1 to 7 or 23 to 25, wherein the D90 particle size is about 120 μm.

34. The particle is the particle according to any one of claims 23 to 33, wherein the D10 particle size is in the range of 5 μm to 10 μm.

35. The particle is the particle according to any one of claims 23 to 33, wherein the D10 particle size is in the range of 20 μm to 30 μm.

36. The particles according to any one of claims 1 to 35, wherein the compound 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazole-4-yl)-3H-imidazo[4,5-b]pyridine-2-amine monohydrate is in crystalline form.

37. The particle according to any one of claims 1 to 36, wherein at least 50% by weight of the compound in the particle is in the form of plate-like crystals.

38. The particle according to any one of claims 1 to 36, wherein at least 75% by weight of the compound in the particle is in the form of plate-like crystals.

39. The particle according to any one of claims 1 to 36, wherein at least 80% by weight of the compound in the particle is in the form of plate-like crystals.

40. The particle according to any one of claims 1 to 36, wherein at least 90% by weight of the compound in the particle is in the form of plate-like crystals.

41. The particle according to any one of claims 1 to 38, wherein at least less than 20% by weight of the compound in the particle is in the form of needle-shaped crystals.

42. The particle according to any one of claims 1 to 39, wherein at least less than 10% by weight of the compound in the particle is in the form of needle-shaped crystals.

43. The particle according to any one of claims 1 to 40, wherein at least less than 5% by weight of the compound in the particle is in the form of needle-shaped crystals.

44. The particle according to any one of claims 1 to 43, wherein the compound is 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazole-4-yl)-3H-imidazo[4,5-b]pyridine-2-amine monohydrate in crystalline form, exhibiting an X-ray powder diffraction pattern with peaks at diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0.2, 28.0±0.2, and 30.0±0.

2.

45. The particle according to claim 44, wherein the X-ray powder diffraction pattern further includes a peak at a diffraction angle (2θ): 16.6 ± 0.

2.

46. The particle according to claim 44 or 45, wherein the X-ray powder diffraction pattern further includes a peak at a diffraction angle (2θ): 22.6 ± 0.

2.

47. The particle according to any one of claims 44 to 46, wherein the X-ray powder diffraction pattern further includes a peak at a diffraction angle (2θ): 22.9 ± 0.

2.

48. The particle according to any one of claims 44 to 47, wherein the X-ray powder diffraction pattern further includes peaks at diffraction angles (2θ): 12.8±0.2, 13.2±0.2, 17.3±0.2, 19.0±0.2, 23.9±0.2, 26.5±0.2, 28.4±0.2, and 28.8±0.

2.

49. The particle according to any one of claims 44 to 48, wherein the relative intensity of the peak at the diffraction angle (2θ) is at least 15%.

50. The particle according to claim 44, wherein the relative intensity of the peak at the diffraction angle (2θ) is at least 20%.

51. The particle according to claim 44, wherein the relative intensity of the peak at the diffraction angle (2θ) is at least 30%.

52. The particle according to claim 44, characterized by the following X-ray powder diffraction pattern represented by the diffraction angle 2θ, interplane distance d, and relative intensity (expressed as a percentage of the strongest peak). Table 1

53. The particle according to claim 44, wherein the X-ray powder diffraction pattern is substantially as shown in Figure 1.

54. The particle according to any one of claims 44 to 53, wherein the compound has substantially the same differential scanning calorimetry curve as shown in Figure 2.

55. The particle according to any one of claims 1 to 43, wherein the compound is 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazole-4-yl)-3H-imidazo[4,5-b]pyridine-2-amine monohydrate in crystalline form, exhibiting an X-ray powder diffraction pattern with peaks at diffraction angles (2θ): 7.1±0.2, 10.4±0.2, 10.7±0.2, 12.4±0.2, and 14.3±0.

2.

56. The particle according to claim 55, wherein the X-ray powder diffraction pattern further includes a peak at a diffraction angle (2θ): 8.9 ± 0.

2.

57. The particle according to claim 55, wherein the X-ray powder diffraction pattern is substantially as shown in Figure 5.

58. A pharmaceutical composition comprising particles according to any one of claims 1 to 57 and a pharmaceutically acceptable carrier.

59. A method for treating a disease or condition selected from the group consisting of inflammatory diseases, autoimmune diseases, pain, osteoarthritis, bone metabolic disorders, and cancer, comprising administering a therapeutically effective amount of particles according to any one of claims 1 to 57 to a subject in need thereof to treat the disease or condition.

60. The method according to claim 59, wherein the disease or condition is an inflammatory disease.

61. The method according to claim 59, wherein the disease or condition is an autoimmune disease.

62. The method according to claim 59, wherein the disease or condition is pain.

63. The method according to claim 59, wherein the disease or condition is pain resulting from osteoarthritis.

64. The method according to claim 59, wherein the disease or condition is postoperative pain.

65. The method according to claim 59, wherein the disease or condition is osteoarthritis.

66. The method according to claim 59, wherein the disease or condition is cancer.

67. The method according to any one of claims 59 to 66, wherein the subject is a human.

68. A method for inhibiting the activity of a tropomyosin-related kinase, comprising contacting the tropomyosin-related kinase with an effective amount of particles described in any one of claims 1 to 57 to inhibit the activity of the tropomyosin-related kinase.

69. The method according to claim 68, wherein the tropomyosin-related kinase is tropomyosin-related kinase A.

70. The method according to claim 68, wherein the tropomyosin-related kinase is tropomyosin-related kinase B.

71. The method according to claim 68, wherein the tropomyosin-related kinase is tropomyosin-related kinase C.

72. A method for inhibiting the activity of a cell receptor for a colony-stimulating factor 1, comprising contacting the cell receptor for the colony-stimulating factor 1 with an effective amount of particles described in any one of claims 1 to 57 to inhibit the activity of the cell receptor for the colony-stimulating factor 1.

73. A method for preparing particles according to claims 1 to 23, a. (i) A first solution containing acetone, water, and 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazole-4-yl)-3H-imidazo[4,5-b]pyridine-2-amine at a temperature of approximately 50°C is mixed with (ii) an aliquot of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazole-4-yl)-3H-imidazo[4,5-b]pyridine-2-amine monohydrate in crystalline form to obtain a first mixture; b. Maintain the first mixture at a temperature in the range of 42°C to 48°C for about 1 hour, then cool the first mixture to a temperature in the range of 37°C to 42°C, maintain the first mixture at a temperature in the range of 37°C to 42°C for about 1 hour, then cool the first mixture to a temperature in the range of 2°C to 8°C, maintain the first mixture at a temperature in the range of 2°C to 8°C for about 1 hour to obtain the second mixture; c. Heat the second mixture to a temperature in the range of 48°C to 53°C and maintain the second mixture at a temperature in the range of 48°C to 53°C for about 3 hours; then cool the second mixture to a temperature in the range of 43°C to 47°C and maintain the second mixture at a temperature in the range of 43°C to 47°C for about 1 hour; then cool the second mixture to a temperature in the range of 37°C to 42°C and maintain the second mixture at a temperature in the range of 37°C to 42°C for about 1 hour; then cool the second mixture to a temperature in the range of 2°C to 8°C and maintain the second mixture at a temperature in the range of 2°C to 8°C for about 1 hour to obtain the third mixture; d. Heat the third mixture to a temperature in the range of 48°C to 53°C, maintain the third mixture at a temperature in the range of 48°C to 53°C for about 3 hours, then cool the third mixture to a temperature in the range of 43°C to 47°C, maintain the third mixture at a temperature in the range of 43°C to 47°C for about 1 hour, then cool the third mixture to a temperature in the range of 37°C to 42°C, maintain the third mixture at a temperature in the range of 37°C to 42°C for about 1 hour, then cool the third mixture to a temperature in the range of 2°C to 8°C, maintain the third mixture at a temperature in the range of 2°C to 8°C for about 1 hour to obtain a crystallized mixture; e. The method comprising the step of isolating the particles according to claim 1 from the crystallized mixture.

74. The method according to claim 73, further comprising the step between step (d) and step (e) of heating the crystallization mixture to a temperature in the range of 48°C to 53°C and maintaining the crystallization mixture at a temperature in the range of 48°C to 53°C for about 3 hours, then cooling the crystallization mixture to a temperature in the range of 43°C to 47°C and maintaining the crystallization mixture at a temperature in the range of 43°C to 47°C for about 1 hour, then cooling the crystallization mixture to a temperature in the range of 37°C to 42°C and maintaining the crystallization mixture at a temperature in the range of 37°C to 42°C for about 1 hour, and then cooling the crystallization mixture to a temperature in the range of 2°C to 8°C and maintaining the crystallization mixture at a temperature in the range of 2°C to 8°C for about 1 hour.

75. The method according to claim 73, further comprising the step between step (d) and step (e) of heating the crystallization mixture to a temperature of 50°C and maintaining the crystallization mixture at a temperature of 50°C for about 3 hours, then cooling the crystallization mixture to a temperature of 45°C and maintaining the crystallization mixture at a temperature of 45°C for about 1 hour, then cooling the crystallization mixture to a temperature of 40°C and maintaining the crystallization mixture at a temperature of 40°C for about 1 hour, and then cooling the crystallization mixture to a temperature of 5°C and maintaining the crystallization mixture at a temperature of 5°C for about 1 hour.

76. Between step (d) and step (e), the crystallization mixture is heated to a temperature in the range of 48°C to 53°C and maintained at a temperature in the range of 48°C to 53°C for about 3 hours, then the crystallization mixture is cooled to a temperature in the range of 43°C to 47°C and maintained at a temperature in the range of 43°C to 47°C for about 1 hour, then the crystallization mixture is cooled to a temperature in the range of 37°C to 42°C and maintained at a temperature in the range of 37°C to 42°C for about 1 hour, then the crystallization mixture is cooled to a temperature in the range of 2°C to 8°C and maintained at a temperature in the range of 2°C to 8°C for about 1 hour, then, The method according to claim 73, further comprising the steps of: heating the crystallization mixture to a temperature in the range of 48°C to 53°C and maintaining the crystallization mixture at a temperature in the range of 48°C to 53°C for about 3 hours; then cooling the crystallization mixture to a temperature in the range of 43°C to 47°C and maintaining the crystallization mixture at a temperature in the range of 43°C to 47°C for about 1 hour; then cooling the crystallization mixture to a temperature in the range of 37°C to 42°C and maintaining the crystallization mixture at a temperature in the range of 37°C to 42°C for about 1 hour; and then cooling the crystallization mixture to a temperature in the range of 2°C to 8°C and maintaining the crystallization mixture at a temperature in the range of 2°C to 8°C for about 1 hour.

77. The method according to claim 73, further comprising the step between step (d) and step (e) of heating the crystallization mixture to a temperature of 50°C and maintaining the crystallization mixture at a temperature of 50°C for about 3 hours, then cooling the crystallization mixture to a temperature of 45°C and maintaining the crystallization mixture at a temperature of 45°C for about 1 hour, then cooling the crystallization mixture to a temperature of 40°C and maintaining the crystallization mixture at a temperature of 40°C for about 1 hour, then cooling the crystallization mixture to a temperature of 5°C and maintaining the crystallization mixture at a temperature of 5°C for about 1 hour, then heating the crystallization mixture to a temperature of 50°C and maintaining the crystallization mixture at a temperature of 50°C for about 3 hours, then cooling the crystallization mixture to a temperature of 45°C and maintaining the crystallization mixture at a temperature of 45°C for about 1 hour, then cooling the crystallization mixture to a temperature of 40°C and maintaining the crystallization mixture at a temperature of 40°C for about 1 hour, and then cooling the crystallization mixture to a temperature of 5°C and maintaining the crystallization mixture at a temperature of 5°C for about 1 hour.

78. The method according to any one of claims 73 to 77, wherein the ratio of acetone to water in the first solution is approximately 5:1 by volume.

79. Step (a) is a first solution having a temperature of approximately 50°C and containing acetone, water, and 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazole-4-yl)-3H-imidazo[4,5-b]pyridine-2-amine, and (ii) diffraction angles (2θ): 14.9±0.2, 20.2±0.2, 20.7±0.2, 21.4±0.2, 25.1±0. The method according to any one of claims 73 to 78, comprising mixing an aliquot of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazole-4-yl)-3H-imidazo[4,5-b]pyridine-2-amine monohydrate in crystalline form, which exhibits an X-ray powder diffraction pattern including peaks at 2, 28.0 ± 0.2 and 30.0 ± 0.2, to obtain a first mixture.

80. The method according to any one of claims 73 to 79, wherein step (b) is to maintain the first mixture at a temperature of 45°C for about 1 hour, then cool the first mixture to a temperature of 40°C and maintain the first mixture at a temperature of 40°C for about 1 hour, then cool the first mixture to a temperature of 5°C and maintain the first mixture at a temperature of 5°C for about 1 hour to obtain a second mixture.

81. The method according to any one of claims 73 to 80, wherein step (c) is to heat the second mixture to a temperature of 50°C, maintain the second mixture at a temperature of 50°C for about 3 hours, then cool the second mixture to a temperature of 45°C, maintain the second mixture at a temperature of 45°C for about 1 hour, then cool the second mixture to a temperature of 40°C, maintain the second mixture at a temperature of 40°C for about 1 hour, then cool the second mixture to a temperature of 5°C, maintain the second mixture at a temperature of 5°C for about 1 hour to obtain a third mixture.

82. The method according to any one of claims 73 to 81, wherein step (d) is to heat the third mixture to a temperature of 50°C, maintain the third mixture at a temperature of 50°C for about 3 hours, then cool the third mixture to a temperature of 45°C, maintain the third mixture at a temperature of 45°C for about 1 hour, then cool the third mixture to a temperature of 40°C, maintain the third mixture at a temperature of 40°C for about 1 hour, then cool the third mixture to a temperature of 5°C, maintain the third mixture at a temperature of 5°C for about 1 hour to obtain a crystallized mixture.

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