Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide
The present invention relates to solid forms of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound 1) in substantially crystalline form (Form A) or amorphous form, pharmaceutical compositions thereof, and methods of treatment therewith.
1. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A characterized by one or more peaks at 19.3 to 19.7 degrees, 21.5 to 21.9 degrees, 16.9 to 17.3, and 20.2 to 20.6 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation.
2. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 1 characterized by one or more peaks at about 19.5, 21.7, and 17.1 degrees.
3. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 1 characterized by a peak at about 20.4 degrees.
4. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 1 further characterized by a peak at 18.6 to 19.0 degrees.
5. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 4 characterized by a peak at about 18.8 degrees.
6. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 1 further characterized by a peak at 24.5 to 24.9 degrees.
7. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 6 characterized by a peak at about 24.7 degrees.
8. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 1 further characterized by a peak at 9.8 to 10.2 degrees.
9. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 8 characterized by a peak at about 10.0 degrees.
10. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 1 further characterized by a peak at 4.8 to 5.2 degrees.
11. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 9 characterized by a peak at about 5.0 degrees.
12. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 1 further characterized by a peak at 24.0 to 24.4 degrees.
13. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 12 characterized by a peak at about 24.2 degrees.
14. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 1 further characterized by a peak at 18.3 to 18.7 degrees.
15. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 14 characterized by a peak at about 18.5 degrees.
16. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 1 characterized by a diffraction pattern substantially similar to that of FIG. 4 .
17. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 1 characterized by a diffraction pattern substantially similar to that of FIG. 5 .
18. (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A having a monoclinic crystal system, a C2 space group, and the following unit cell dimensions:
a = 21.0952(16) Å
α = 90°
b = 6.6287(5) Å
β = 95.867(6)°
c = 17.7917(15) Å
γ = 90°.
19. A pharmaceutical composition comprising (R)-1-(2,2-difluorobenzo[d][1,3]-dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 1 , and a pharmaceutically acceptable carrier.
20. The pharmaceutical composition of claim 19 , further comprising an additional therapeutic agent.
21. The pharmaceutical composition of claim 20 , wherein the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR potentiator, or a nutritional agent.
22. A process of preparing the Form A of claim 1 comprising slurrying (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide in a solvent for an effective amount of time.
23. The process of claim 22 , wherein the solvent is ethyl acetate, dichloromethane, MTBE, isopropyl acetate, water/ethanol, water/acetonitrile, water/methanol, or water/isopropyl alcohol.
24. The process of claim 22 , wherein the effective amount of time is 24 hours to 2 weeks.
25. A process of preparing the Form A of claim 1 comprising dissolving (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide in a solvent and evaporating the solvent.
26. The process of claim 25 , wherein the solvent is acetone, acetonitrile, methanol, or isopropyl alcohol.
27. A process of preparing the Form A of claim 1 comprising dissolving (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide in a first solvent and adding a second solvent that (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide is not soluble in.
28. The process of claim 27 , wherein the first solvent is ethyl acetate, ethanol, isopropyl alcohol, or acetone.
29. The process of claim 27 , wherein the second solvent is heptane or water.
30. The process of claim 27 , wherein the addition of the second solvent is done while stirring the solution of the first solvent and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide.
31. A method of treating a CFTR mediated disease in a subject comprising administering to the subject an effective amount of Form A of claim 1 , wherein the CFTR mediated disease is selected from cystic fibrosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), and dry-eye disease.
32. The method of claim 31 , wherein the CFTR mediated disease is cystic fibrosis.
33. The method of claim 31 , wherein the subject has cystic fibrosis transmembrane receptor (CFTR) with a ΔF508 mutation.
34. The method of claim 31 , wherein the subject has cystic fibrosis transmembrane receptor (CFTR) with a R117H mutation.
35. The method of claim 31 , wherein the subject has cystic fibrosis transmembrane receptor (CFTR) with a G551D mutation.
36. The method of claim 31 , wherein the method comprises administering an additional therapeutic agent.
37. The method of claim 36 , wherein the therapeutic agent is selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR potentiator, or a nutritional agent.
38. A kit comprising (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A of claim 1 , and instructions for use thereof.
39. The pharmaceutical composition of claim 21 , wherein the additional therapeutic agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
40. The method of claim 36 , wherein the additional therapeutic agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.