2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof
The present invention relates generally to the compound: N-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octadecahydropicen-4a-yl)-2,2-difluoropropanamide, polymorphic forms thereof, methods for preparation and use thereof, pharmaceutical compositions thereof, and kits and articles of manufacture thereof.
1. An in vitro method of activating the antioxidant/anti-inflammatory Keap1/Nrf2/ARE pathway in a cell, the method comprising contacting the cell with an effective amount of
a compound of the formula or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the compound is a polymorphic form having an X-ray powder diffraction pattern (CuKα) comprising a halo peak at about 14° 2θ.
3. The method of claim 2 , wherein the X-ray powder diffraction pattern (CuKα) further comprises a shoulder peak at about 8° 2θ.
4. The method of claim 2 , wherein the X-ray powder diffraction pattern (CuKα) is substantially as shown in FIG. 59 .
5. The method of claim 2 , further having a Tg from about 150° C. to about 155° C.
6. The method of claim 2 , further having a differential scanning calorimetry (DSC) curve comprising an endotherm centered from about 150° C. to about 155° C.
7. The method of claim 2 , having a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 62 .
8. The method of claim 1 , wherein the compound is a solvate having an X-ray powder diffraction pattern (CuKα) comprising significant peaks at about 5.6, 7.0, 10.6, 12.7, and 14.6° 2θ.
9. The method of claim 8 , wherein the X-ray powder diffraction pattern (CuKα) is substantially as shown in FIG. 75 , top pattern.
10. The method of claim 1 , wherein the compound is a solvate having an X-ray powder diffraction pattern (CuKα) comprising significant peaks at about 7.0, 7.8, 8.6, 11.9, 13.9 (double peak), 14.2, and 16.0° 2θ.
11. The method of claim 10 , wherein the X-ray powder diffraction pattern (CuKα) is substantially as shown in FIG. 75 , second pattern from top.
12. The method of claim 1 , wherein the compound is an acetonitrile hemisolvate having an X-ray powder diffraction pattern (CuKα) comprising significant peaks at about 7.5, 11.4, 15.6, and 16.6 20.
13. The method of claim 12 , wherein the X-ray powder diffraction pattern (CuKα) is substantially as shown in FIG. 75 , second pattern from bottom.
14. The method of claim 12 , further having a Tg of about 196° C.
15. The method of claim 12 , further having a differential scanning calorimetry (DSC) curve comprising an endotherm centered at about 196° C.
16. The method of claim 12 , having a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 116 .
17. The method of claim 1 , wherein the compound is a solvate having an X-ray powder diffraction pattern (CuKα) comprising significant peaks at about 6.8, 9.3, 9.5, 10.5, 13.6, and 15.6° 2θ.
18. The method of claim 17 , wherein the X-ray powder diffraction pattern (CuKα) is substantially as shown in FIG. 75 , bottom pattern.