Xinafoate salt of a substituted 5-oxazol-2-yl-quinoline compound
View Patent ↗The present invention relates to the compound of the formula To methods of treating upper and lower obstructive airway diseases using said compound, to formulations comprising it, and to polymorphs and processes of synthesis of the polymorphic forms.
1. The compound having the structural formula
2. A method of treating upper or lower obstructive diseases of the airways in a patient in need of such treatment comprising administering to said patient by inhalation an effective amount of the compound of claim 1 .
3. The method of claim 2 wherein the disease treated is asthma or chronic obstructive pulmonary disease.
4. A method of treating upper or lower obstructive diseases of the airways in a patient in need of such treatment comprising administering to said patient by inhalation an effective amount of a combination of the compound of claim 1 and at least one additional agent useful for treating upper or lower obstructive diseases of the airway.
5. The method of claim 4 wherein the disease treated is asthma or chronic obstructive pulmonary disease.
6. The method of claim 4 wherein the additional agent is selected from the group consisting of beta-agonists, muscarinic antagonists and corticosteroids.
7. An inhalable pharmaceutical composition comprising an effective amount of the compound of claim 1 .
8. An inhalable pharmaceutical composition comprising an effective amount of a combination of the compound of claim 1 and at least and at least one additional agent useful for treating upper or lower obstructive diseases of the airway.
9. A composition of claim 8 wherein the additional agents are selected from the group consisting of beta-agonists: muscarinic antagonists and corticosteroids.
10. A crystalline polymorph of a compound of the formula:
wherein, said polymorph is selected from the group consisting of:
Form 1 that exhibits a powder x-ray diffraction pattern substantially the same as the pattern shown in FIG. 1 ;
Form 2 that exhibits a powder x-ray diffraction pattern substantially the same as the pattern shown in FIG. 2 ; and
Dihydrate Form 1: that exhibits a powder x-ray diffraction pattern substantially the same as the pattern shown in FIG. 3 ;
Form 3 that exhibits a powder x-ray diffraction pattern substantially the same as the pattern shown in FIG. 10 .
11. A crystalline polymorph Form 1 of the compound of claim 10 that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 6.1, 7.7, 13.0 and 15.9 degrees 2θ.
12. The crystalline polymorph of claim 11 that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 5.6, 6.1, 7.7, 13.0, 15.9, 17.8, 18.4 and 26.1 degrees 2θ.
13. The crystalline polymorph of claim 11 that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 5.6, 6.1, 7.7, 9.2, 13.0, 14.2, 15.9, 17.8, 18.4, 20.5, 22.9 and 26.1 degrees 2θ.
14. The crystalline polymorph Form 1 of claim 10 .
15. A crystalline polymorph Form 2 of the compound of claim 10 that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 10.6, 13.6, 19.1 and 21.2 degrees 2θ.
16. The crystalline polymorph of claim 15 that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 10.6, 13.6, 17.9, 18.8, 19.1, 20.2, 21.2 and 23.9 degrees 2θ.
17. The crystalline polymorph of claim 15 that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 9.4, 10.6, 13.6, 17.9, 18.8, 19.1, 20.2, 21.2, 23.9, 26.0, 26.6 and 28.1 degrees 2θ.
18. The crystalline polymorph Form 2 of claim 10 .
19. A crystalline Dihydrate Form 1 of the compound of claim 10 that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 8.2, 16.5, 18.5 and 24.9 degrees 2θ.
20. The crystalline dihydrate of claim 19 that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 5.5, 8.2, 14.3, 16.5, 16.9, 18.5, 20.6, and 24.9 degrees 2θ.
21. The crystalline dihydrate of claim 19 that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 5.5, 7.2, 8.2, 14.3, 14.7, 16.5, 16.9, 18.5, 20.6, 24.1, 24.9 and 26.8 degrees 2θ.
22. The crystalline Dihydrate Form 1 of claim 10 .
23. A crystalline polymorph Form 3 of the compound of claim 10 that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 4.6, 7.9, 12. 1, and 18.9 degrees 2θ.
24. The crystalline polymorph of claim 23 that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 4.6, 7.9, 9.1, 12.1, 13.7, 15.8, 16.5, and 18.9 degrees 2θ.
25. The crystalline polymorph of claim 23 that exhibits a powder x-ray diffraction pattern having characteristic peak locations of 4.6, 7.9, 9.1, 12.1, 13.7, 15.8, 16.5, 18.9, 20.0, 23.9, 24.3 and 25.7 degrees 2θ.
26. The crystalline polymorph Form 3 of claim 10 .
27. A process for preparing the polymorph Form 1 of claim 10 from
comprising the steps of:
a) dissolving compound of Compound A, in hot ethanol and adding xinafoic acid while continuing to heat the mixture;
b) adding additional ethanol and water, and heating the mixture to near boiling;
c) filtering the hot mixture, then cooling slowly to room temperature and allowing the mixture to stand at room temperature overnight until Form 1 crystals precipitate; and
d) cooling the filtrate to 0° C. and filtering the Form 1 crystals.
28. A process for preparing the polymorph Form 1 of claim 10 from
comprising the steps of:
e) adding toluene and methanol to Compound A and xinafoic acid and mixing, forming a slurry;
f) heating said slurry to about 62° C. while mixing, affording a homogeneous mixture;
g) distilling said homogeneous mixture atmospherically, cooling distilled mixture to about 50° C., seeding said distilled mixture with Compound A Form 1 seeds, resulting in crystals in a slurry;
h) stirring said slurry for about 30 minutes at about 50° C. and cooling the slurry to about 10° C.;
i) adding additional toluene to the cooled slurry and vacuum distilling, then adding additional toluene and stirring for about 20 minutes at about 20° C. forming solid material;
j) collecting resulting solids using agitated dryer under vacuum forming a wet cake; washing said wet cake with toluene and drying: at about 50° C. for about 3 hours without agitation, then about 80° C. for about 12 hours with about 20 R.P.M. agitation, then about 80° C. for about 12 hours with about 60 R.P.M. agitation, all under vacuum.
29. A process for preparing the polymorph Form 1 of claim 10 from
k) comprising the steps of: dissolving Compound A and xinafoic acid in hot methanol separately;
l) filtering both of the hot solutions and mixing the two solutions;
m) refluxing the mixture and distilling out the excess methanol; and
n) cooling the mixture to 0° C. forming a precipitate and filtering the Form 1 crystals.
30. An inhalable pharmaceutical composition comprising a crystalline polymorph of Form 1 of claim 10 and at least one pharmaceutically acceptable excipient or carrier.
31. A purified form of the polymorph of Form 1 of claim 10 .
32. A method of treating upper or lower obstructive diseases of the airways in a patient in need of such treatment comprising administering to said patient by inhalation an effective amount of a polymorph of Form 1 of claim 10 .
33. A process for preparing the polymorph Form 2 of claim 10 from
comprising the steps of:
o) dissolving Compound A in hot methanol and adding xinafoic acid while continuing to heat the mixture;
p) adding water, and heating the mixture to near boiling;
q) filtering the hot mixture, then cooling slowly to room temperature and allowing the mixture to stand at room temperature overnight until Form 2 crystals precipitate; and
r) cooling the filtrate to 0° C. and filtering the Form 1 crystals.
34. An inhalable pharmaceutical composition comprising a crystalline polymorph of Form 2 of claim 10 and at least one pharmaceutically acceptable excipient or carrier.
35. A purified form of the polymorph of Form 2 of claim 10 .
36. A method of treating upper or lower obstructive diseases of the airways in a patient in need of such treatment comprising administering to said patient by inhalation an effective amount of a polymorph of Form 2 of claim 10 .
37. A process for preparing the Dihydrate Form 1 of claim 10 from xinafoate salt polymorph Form 1 of Compound A:
comprising the steps of:
r) Suspending Form I polymorph xinafoate salt of Compound A in a mixture of water and methanol;
s) the suspension was stirred for 21 hours, solids were isolated by centrifugation of the suspension then decanting off the supernatant;
t) Solids were dried under vacuum at room temperature.
38. An inhalable pharmaceutical composition comprising a crystalline of Dihydrate Form 1 of claim 10 and at least one pharmaceutically acceptable excipient or carrier.
39. A purified form of the crystalline Dihydrate Form 1 of claim 10 .
40. A method of treating upper or lower obstructive diseases of the airways in a patient in need of such treatment comprising administering to said patient by inhalation an effective amount of Dihydrate Form 1 of claim 10 .
41. A process for preparing the polymorph Form 3 of claim 10 from
comprising the steps of:
u) combining a mixture of compound A and xinafoic acid in 2-propanol;
v) heat mixture to reflux and add more 2-propanol; hold mixture at reflux for 1 hour then cooled to room temperature;
w) filter mixture, wash solids with 2-propanol, dry under vacuum.
42. An inhalable pharmaceutical composition comprising a crystalline polymorph of Form 3 of claim 10 and at least one pharmaceutically acceptable excipient or carrier.
43. A purified form of the polymorph of Form 3 of claim 10 .
44. A method of treating upper or lower obstructive diseases of the airways in a patient in need of such treatment comprising administering to said patient by inhalation an effective amount of a polymorph of Form 3 of claim 10 .