Trifluoromethyl pyrazolyl guanidine F1F0-ATPase inhibitors and therapeutic uses thereof

Patent metadata

Field	Value
Publication number	US-9266839-B2
Application number	US-201414565463-A
Country	US
Kind code	B2
Filing date	Dec 10, 2014
Priority date	Dec 10, 2013
Publication date	Feb 23, 2016
Grant date	Feb 23, 2016

Abstract

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.

First claim

The invention claimed is:

1. A compound represented by Formula I:

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 compound of claim 1 , wherein the compound is a compound of Formula I or a geometric isomer or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

3. The compound of claim 1 , wherein the compound is in the form of a solvate.

4. The compound 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.

5. The compound of claim 1 , wherein the compound is represented by:

or a geometric isomer or tautomer; or a solvate of any of the foregoing.

6. The compound of claim 5 , wherein the compound is in the form of an acetone solvate.

7. The compound of claim 1 , wherein the compound is represented by:

or a geometric isomer or tautomer.

8. The compound of claim 1 , wherein the compound is represented by:

9. Crystalline compound 3-chloro-N-(((3-chloro-5-fluorophenyl)amino)((5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)methylene)benzamide.

10. The crystalline compound of claim 9 , wherein the crystalline compound 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.

11. The crystalline compound of claim 10 , wherein the relative intensity of the peak at said diffraction angles (2θ) is at least 30%.

12. The crystalline compound of claim 10 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 [%]

6.2
14.3
53.8

7.1
12.4
69.6

9.4
9.4
53.8

10.7
8.3
51.0

12.9
6.9
34.6

15.6
5.7
92.8

16.4
5.4
29.1

17.9
4.9
44.0

19.0
4.7
100.0 

20.0
4.4
62.6

21.9
4.1
38.9

23.6
3.8
51.4

25.2
3.5
57.8

27.3
3.3
24.0

28.4
3.1
15.8

35.0
2.6
  10.0.

13. The crystalline compound of claim 10 , wherein the X-ray powder diffraction pattern is substantially as shown in FIG. 3 .

14. The crystalline compound of claim 11 , wherein the crystalline compound has a melting point onset as determined by differential scanning calorimetry in the range of from about 157 degrees Celsius to about 161 degrees Celsius.

15. The crystalline compound of claim 11 , wherein the crystalline compound has a melting point onset as determined by differential scanning calorimetry at about 159 degrees Celsius.

16. The crystalline compound of claim 11 , wherein the crystalline compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 4 .

17. The crystalline compound of claim 9 , wherein the crystalline compound 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.

18. The crystalline compound of claim 17 , wherein the relative intensity of the peak at said diffraction angles (2θ) is at least 15%.

19. The crystalline compound of claim 17 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

Assignees

• Lycera Corp

Inventors

• Hurd Alexander R
• Taylor Clarke B
• Wang Jian
• Zhou Peng

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title