PARTICLES OF IMIDAZO[4,5-b]PYRIDINE COMPOUND, PHARMACEUTICAL COMPOSITIONS, AND THEIR USE IN TREATING MEDICAL CONDITIONS
The invention provides particles of an imidazo[4,5-b]pyridine compound having a preferred particle size range, pharmaceutical compositions, methods of inhibiting tropomyosin-related kinase and/or c-FMS, methods of treating medical diseases and conditions, such as pain, and methods for preparing such particles.
1 . Particles of the compound 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate having a D50 particle size in the range of from 40 μm to 75 μm.
2 . (canceled)
3 . (canceled)
4 . (canceled)
5 . The particles of claim 1 , wherein the particles have a D50 particle size in the range of from 55 μm to 59 μm.
6 . The particles of claim 1 , wherein the particles have a D50 particle size in the range of from 56 μm to 57 μm.
7 . (canceled)
8 . (canceled)
9 . (canceled)
10 . The particles of claim 1 , wherein the particles have a D90 particle size in the range of from 121 μm to 141 μm.
11 . The particles of claim 1 , wherein the particles have a D90 particle size in the range of from 126 μm to 136 μm.
12 . The particles of claim 6 , wherein the particles have a D90 particle size in the range of from 129 μm to 133 μm.
13 . The particles of claim 6 , wherein the particles have a D90 particle size in the range of from 130 μm to 132 μm.
14 . (canceled)
15 . (canceled)
16 . (canceled)
17 . (canceled)
18 . The particles of claim 1 , wherein the particles have a D10 particle size in the range of from 16 μm to 22 μm.
19 . (canceled)
20 . The particles of claim 13 , wherein the particles have a D10 particle size in the range of from 18 μm to 19 μm.
21 . (canceled)
22 . (canceled)
23 . Particles of the compound 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate having a D90 particle size in the range of from 70 μm to 150 μm.
24 . The particles of claim 23 , wherein the particles have a D50 particle size in the range of from 35 μm to 45 μm.
25 . (canceled)
26 . (canceled)
27 . The particles of claim 23 , wherein the particles have a D90 particle size in the range of from 80 μm to 100 μm.
28 . The particles of claim 23 , wherein the particles have a D90 particle size in the range of from 85 μm to 95 μm.
29 . The particles of claim 23 , wherein the particles have a D90 particle size in the range of from 88 μm to 92 μm.
30 . The particles of claim 23 , wherein the particles have a D90 particle size of about 90 μm.
31 . The particles of claim 23 , wherein the particles have a D90 particle size in the range of from 110 μm to 130 μm.
32 . The particles of claim 23 , wherein the particles have a D90 particle size in the range of from 120 μm to 124 μm.
33 . The particles of claim 23 , wherein the particles have a D90 particle size of about 120 μm.
34 . (canceled)
35 . The particles of claim 23 , wherein the particles have a D10 particle size in the range of from 20 μm to 30 μm.
36 . The particles of claim 23 , wherein the compound 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate is in crystalline form.
37 . (canceled)
38 . (canceled)
39 . (canceled)
40 . The particles of claim 36 , wherein at least 90% by weight of the compound in the particles is in the form of plate-like crystals.
41 . (canceled)
42 . (canceled)
43 . The particles of claim 36 , wherein less than 5% by weight of the compound in the particles is in the form of needle-like crystals.
44 . The particles of claim 23 , wherein the compound is 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in crystalline form exhibiting an X-ray powder diffraction pattern comprising peaks at the following 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 . (canceled)
46 . (canceled)
47 . (canceled)
48 . The particles of claim 44 , wherein the X-ray powder diffraction pattern further comprises peaks at the following 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 . (canceled)
50 . (canceled)
51 . (canceled)
52 . The particles of claim 44 , wherein the compound is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):
Angle [2θ]
d-spacing [Å]
Relative Intensity [%]
12.78
6.93
7.3
13.19
6.71
8.1
14.87
5.96
100.0
16.62
5.33
19.3
17.34
5.12
8.9
19.03
4.66
11.8
20.19
4.40
49.1
20.67
4.30
31.0
21.40
4.15
40.7
22.56
3.94
28.6
22.90
3.88
26.1
23.93
3.72
14.4
25.09
3.55
64.4
26.53
3.36
7.4
28.00
3.19
41.6
28.35
3.15
10.5
28.83
3.10
6.2
29.95
2.98
42.4
53 . (canceled)
54 . (canceled)
55 . (canceled)
56 . (canceled)
57 . (canceled)
58 . A pharmaceutical composition comprising the particles of claim 23 and a pharmaceutically acceptable carrier.
59 . A method of treating a disease or condition selected from the group consisting of an inflammatory disease, autoimmune disease, pain, osteoarthritis, defect of bone metabolism, and cancer, comprising administering a therapeutically effective amount of the particles of claim 23 to a subject in need thereof to treat the disease or condition.
60 . (canceled)
61 . (canceled)
62 . (canceled)
63 . The method of claim 59 , wherein the disease or condition is pain due to osteoarthritis.
64 . (canceled)
65 . The method of claim 59 , wherein the disease or condition is osteoarthritis.
66 . (canceled)
67 . (canceled)
68 . A method of inhibiting the activity of a tropomyosin-related kinase, comprising contacting a tropomyosin-related kinase with an effective amount of the particles of claim 23 to inhibit the activity of said tropomyosin-related kinase.
69 . (canceled)
70 . (canceled)
71 . (canceled)
72 . A method of inhibiting the activity of a cellular receptor for colony stimulating factor-1, comprising contacting said cellular receptor for colony stimulating factor-1 with an effective amount of the particles of claim 23 to inhibit the activity of said cellular receptor for colony stimulating factor-1.
73 . A method of preparing the particles of claim 23 , comprising the steps of:
a. admixing (i) a first solution having a temperature of about 50° C. and containing acetone, water, and 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine and (ii) an aliquot of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine monohydrate in crystalline form to provide a first mixture;
b. maintaining the first mixture at a temperature in the range of from 42° C. to 48° C. for a duration of about 1 hour, then cooling the first mixture to a temperature in the range of from 37° C. to 42° C. and maintaining the first mixture at a temperature in the range of from 37° C. to 42° C. for about 1 hour, then cooling the first mixture to a temperature in the range of from 2° C. to 8° C. and maintaining the first mixture at a temperature in the range of from 2° C. to 8° C. for about 1 hour, to produce a second mixture;
c. heating the second mixture to a temperature in the range of from 48° C. to 53° C., maintaining the second mixture at a temperature in the range of from 48° C. to 53° C. for about 3 hours, then cooling the second mixture to a temperature in the range of from 43° C. to 47° C. and maintaining the second mixture at a temperature in the range of from 43° C. to 47° C. for about 1 hour, then cooling the second mixture to a temperature in the range of from 37° C. to 42° C. and maintaining the second mixture at a temperature in the range of from 37° C. to 42° C. for about 1 hour, then cooling the second mixture to a temperature in the range of from 2° C. to 8° C. and maintaining the second mixture at a temperature in the range of from 2° C. to 8° C. for about 1 hour, to produce a third mixture;
d. heating the third mixture to a temperature in the range of from 48° C. to 53° C., maintaining the third mixture at a temperature in the range of from 48° C. to 53° C. for about 3 hours, then cooling the third mixture to a temperature in the range of from 43° C. to 47° C. and maintaining the third mixture at a temperature in the range of from 43° C. to 47° C. for about 1 hour, then cooling the third mixture to a temperature in the range of from 37° C. to 42° C. and maintaining the third mixture at a temperature in the range of from 37° C. to 42° C. for about 1 hour, then cooling the third mixture to a temperature in the range of from 2° C. to 8° C. and maintaining the third mixture at a temperature in the range of from 2° C. to 8° C. for about 1 hour, to produce a crystallization mixture; and
e. isolating said particles of claim 1 from the crystallization mixture.
74 - 82 . (canceled)