Crystalline oxalate salts of a diamide compound
The invention relates to crystalline oxalate salts of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]-methyl}phenylcarbamoyl)butyl]methylcarbamoyl}ethyl)piperidin-4-yl ester. This invention also relates to compositions containing such a crystalline oxalate salt; methods of using such a crystalline oxalate salt to, for example, treat a pulmonary disorder; and to processes for preparing such a crystalline oxalate salt.
1. A crystalline oxalate salt of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-phenylcarbamoyl)butyl]methylcarbamoyl}ethyl)piperidin-4-yl ester; wherein the crystalline oxalate salt is selected from:
(a) an isopropanol solvate characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 11.66±0.20, 15.75±0.20, 19.55±0.20, 23.00±0.20 and 23.45±0.20; and
(b) a hydrate characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 15.32±0.20, 16.90±0.20, 19.25±0.20 and 23.73±0.20.
2. A crystalline oxalate salt of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)butyl]methylcarbamoyl}-ethyl)piperidin-4-yl ester, wherein the crystalline oxalate salt is an isopropanol solvate characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 11.66±0.20, 15.75±0.20, 19.55±0.20, 23.00±0.20 and 23.45±0.20.
3. The crystalline oxalate salt of claim 2 , wherein the crystalline oxalate salt is characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 1 .
4. The crystalline oxalate salt of claim 2 , wherein the crystalline oxalate salt is characterized by a melting point in the range of about 162° C. to about 164° C.
5. The crystalline oxalate salt of claim 2 , wherein the crystalline oxalate salt is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG. 2 .
6. A crystalline oxalate salt of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}phenylcarbamoyl)butyl]methylcarbamoyl}-ethyl)piperidin-4-yl ester, wherein the crystalline oxalate salt is a hydrate characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 15.32±0.20, 16.90±0.20, 19.25±0.20 and 23.73±0.20.
7. The crystalline oxalate salt of claim 6 , wherein the crystalline oxalate salt is characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 4 .
8. The crystalline oxalate salt of claim 6 , wherein the crystalline oxalate salt is characterized by a melting point in the range of about 162° C. to about 164° C.
9. The crystalline oxalate salt of claim 6 , wherein the crystalline oxalate salt is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG. 5 .
10. A pharmaceutical composition comprising:
(a) a crystalline oxalate salt of claim 1 ; and
(b) a pharmaceutically-acceptable carrier.
11. A pharmaceutical composition comprising:
(a) crystalline oxalate salt of claim 1 ;
(b) a steroidal anti-inflammatory agent or a pharmaceutically acceptable salt or solvate thereof; and
(c) a pharmaceutically-acceptable carrier.
12. A method of treating a pulmonary disorder, the method comprising administering to a patient a crystalline oxalate salt of claim 1 .
13. The method of claim 12 , wherein the pulmonary disorder is chronic obstructive pulmonary disease or asthma.
14. A method of treating a pulmonary disorder, the method comprising administering to a patient (a) a crystalline oxalate salt of claim 1 ; and (b) a steroidal anti-inflammatory agent or a pharmaceutically acceptable salt or solvate thereof.
15. The method of claim 14 , wherein the pulmonary disorder is chronic obstructive pulmonary disease or asthma.
16. A method of producing bronchodilation in a mammal, the method comprising administering a crystalline oxalate salt of claim 1 to the mammal by inhalation.
17. A pharmaceutical composition comprising:
(a) a crystalline oxalate salt of claim 2 ; and
(b) a pharmaceutically-acceptable carrier.
18. A pharmaceutical composition comprising:
(a) a crystalline oxalate salt of claim 2 ;
(b) a steroidal anti-inflammatory agent or a pharmaceutically acceptable salt or solvate thereof; and
(c) a pharmaceutically-acceptable carrier.
19. A method of treating a pulmonary disorder, the method comprising administering to a patient a crystalline oxalate salt of claim 2 .
20. The method of claim 19 , wherein the pulmonary disorder is chronic obstructive pulmonary disease.
21. The method of claim 19 , wherein the pulmonary disorder is asthma.
22. A method of treating a pulmonary disorder, the method comprising administering to a patient (a) a crystalline oxalate salt of claim 2 ; and (b) a steroidal anti-inflammatory agent or a pharmaceutically acceptable salt or solvate thereof.
23. The method of claim 22 , wherein the pulmonary disorder is chronic obstructive pulmonary disease.
24. The method of claim 22 , wherein the pulmonary disorder is asthma.
25. A method of producing bronchodilation in a mammal, the method comprising administering a crystalline oxalate salt of claim 2 to the mammal by inhalation.
26. A pharmaceutical composition comprising:
(a) a crystalline oxalate salt of claim 6 ; and
(b) a pharmaceutically-acceptable carrier.
27. A pharmaceutical composition comprising:
(a) a crystalline oxalate salt of claim 6 ;
(b) a steroidal anti-inflammatory agent or a pharmaceutically acceptable salt or solvate thereof; and
(c) a pharmaceutically-acceptable carrier.
28. A method of treating a pulmonary disorder, the method comprising administering to a patient a crystalline oxalate salt of claim 6 .
29. The method of claim 28 , wherein the pulmonary disorder is chronic obstructive pulmonary disease.
30. The method of claim 28 , wherein the pulmonary disorder is asthma.
31. A method of treating a pulmonary disorder, the method comprising administering to a patient (a) a crystalline oxalate salt of claim 6 ; and (b) a steroidal anti-inflammatory agent or a pharmaceutically acceptable salt or solvate thereof.
32. The method of claim 31 , wherein the pulmonary disorder is chronic obstructive pulmonary disease.
33. The method of claim 31 , wherein the pulmonary disorder is asthma.
34. A method of producing bronchodilation in a mammal, the method comprising administering a crystalline oxalate salt of claim 6 to the mammal by inhalation.