Trifluoromethyl pyrazolyl guanidine F
The invention provides trifluoromethyl pyrazolyl guanidine compounds that inhibit F 1 F 0 -ATPase, and methods of using trifluoromethyl pyrazolyl guanidine compounds as therapeutic agents to treat medical disorders, such as an immune disorder, inflammatory condition, or cancer.
1. A method of treating psoriasis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I in order to ameliorate a symptom of the psoriasis:
or a geometric isomer or tautomer; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein R 1 is a chloro group located at either the meta-position or para-position of the phenyl group to which it is attached.
2. The method of claim 1 , wherein the compound is represented by:
or a geometric isomer or tautomer; or a pharmaceutically acceptable salt of any of the foregoing.
3. The method of claim 1 , wherein the compound is represented by:
or a geometric isomer or tautomer; or a solvate of any of the foregoing.
4. The method of claim 1 , wherein the compound is represented by:
or a geometric isomer or tautomer.
5. The method of claim 1 , wherein the compound is represented by:
6. The method of claim 1 , wherein the compound is crystalline 3-chloro-N-(((3-chloro-5-fluorophenyl)amino)((5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)methylene)benzamide.
7. The method of claim 6 , wherein the compound that is crystalline exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 6.2±0.2, 7.1±0.2, 9.4±0.2, 10.7±0.2, 15.6±0.2, 19.0±0.2, 20.0±0.2, and 25.2±0.2.
8. The method of claim 7 , wherein the relative intensity of the peak at said diffraction angles (2θ) is at least 30%.
9. The method of claim 6 , wherein the compound that is crystalline exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 6.3±0.2, 7.3±0.2, 11.0±0.2, 12.8±0.2, 16.9±0.2, 19.2±0.2, 20.6±0.2, 22.2±0.2, 25.7±0.2, 26.0±0.2, and 35.7±0.2.
10. The method of claim 9 , wherein the relative intensity of the peak at said diffraction angles (2θ) is at least 15%.
11. The method of claim 9 , wherein the compound that is crystalline 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 [%]
6.33
13.95
65.8
7.32
12.06
100.0
9.73
9.08
14.8
11.03
8.01
55.9
12.76
6.93
18.3
13.27
6.67
9.7
14.75
6.00
9.3
16.07
5.51
12.7
16.91
5.24
27.2
18.45
4.80
9.9
19.18
4.62
42.0
19.53
4.54
8.3
20.56
4.31
19.8
22.20
4.00
88.4
22.51
3.95
43.5
23.11
3.85
56.1
23.55
3.77
29.0
25.65
3.47
48.8
25.96
3.43
100.0
26.75
3.33
26.2
28.03
3.18
52.6
29.03
3.07
44.7
29.51
3.02
29.3
30.45
2.93
20.0
31.49
2.84
17.8
31.82
2.81
20.4
32.27
2.77
29.9
33.15
2.70
16.8
34.18
2.62
12.9
35.66
2.52
59.6
36.03
2.49
17.7
36.84
2.44
13.5
37.75
2.38
14.8
38.27
2.35
10.9
38.99
2.31
13.6
39.71
2.27
13.5
42.15
2.14
11.2
43.46
2.08
13.7
44.19
2.05
8.3
44.55
2.03
13.1
45.96
1.97
16.3
46.46
1.95
16.6
48.33
1.88
9.4
49.33
1.85
9.9
50.27
1.81
9.3
50.48
1.81
9.9
51.25
1.78
8.2
51.45
1.77
9.5
53.86
1.70
9.1
55.63
1.65
9.8
56.54
1.63
6.5
57.53
1.60
8.8
59.28
1.56
6.4.
12. The method of claim 9 , wherein the compound that is crystalline has an X-ray powder diffraction pattern substantially as shown in FIG. 5 .
13. The method of claim 10 , wherein the compound that is crystalline has a melting point onset as determined by differential scanning calorimetry in the range of from about 158 degrees Celsius to about 165 degrees Celsius.
14. The method of claim 2 , wherein the patient is a human.
15. The method of claim 4 , wherein the patient is a human.
16. The method of claim 5 , wherein the patient is a human.
17. The method of claim 9 , wherein the patient is a human.
18. The method of claim 14 , wherein the compound is administered topically to the patient.
19. The method of claim 15 , wherein the compound is administered topically to the patient.
20. The method of claim 16 , wherein the compound is administered topically to the patient.
21. The method of claim 17 , wherein the compound is administered topically to the patient.
22. The method of claim 14 , wherein the compound is administered intradermally to the patient.
23. The method of claim 15 , wherein the compound is administered intradermally to the patient.
24. The method of claim 16 , wherein the compound is administered intradermally to the patient.
25. The method of claim 17 , wherein the compound is administered intradermally to the patient.
26. The method of claim 14 , wherein the compound is administered transdermally to the patient.
27. The method of claim 15 , wherein the compound is administered transdermally to the patient.
28. The method of claim 17 , wherein the compound is administered transdermally to the patient.
29. The method of claim 14 , wherein the compound is administered orally to the patient.
30. The method of claim 15 , wherein the compound is administered orally to the patient.
31. The method of claim 17 , wherein the compound is administered orally to the patient.