Crystalline form of a BACE inhibitor, compositions, and use
The present invention provides a novel crystalline form of verubecestat (Crystalline Form II of Verubecestat) and pharmaceutically acceptable compositions thereof, each of which may be useful in treating, preventing, ameliorating, and/or delaying the onset of an Aβ pathology and/or a symptom or symptoms thereof. Non-limiting examples of such Aβ pathologies, including Alzheimer's disease and mild cognitive impairment, are disclosed herein.
1. A crystalline form of verubecestat characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/−0.2°) of 10.94 and 14.98 in a powder x-ray diffraction obtained using Cu K alpha radiation.
2. The crystalline form of verubecestat according to claim 1 , characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/−0.2°) of 10.94, 14.53, 14.98, 16.23, 16.63, and 26.18.
3. The crystalline form of verubecestat according to claim 2 , characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/−0.2°) of 10.94, 14.53, 14.98, 16.23, 16.63, 17.77, 21.77, 23.24, and 26.18.
4. The crystalline form of verubecestat according to claim 3 , characterized by a powder x-ray diffraction pattern with at least peaks at diffraction angles degrees 2 theta (+/−0.2°) of 10.94, 14.53, 14.98, 16.23, 16.63, 17.77, 20.84, 21.77, 23.24, 26.18, 30.88, and 33.39.
5. The crystalline form of verubecestat according to claim 4 characterized by substantially the same powder x-ray diffraction pattern as shown in FIG. 1 .
6. The crystalline form of verubecestat of claim 1 exhibiting a melting endotherm with a peak temperature at 183.5° C. (+/−1° C.), measured by differential scanning calorimetry.
7. A crystalline form of verubecestat according to claim 6 exhibiting a melting endotherm with an extrapolated onset temperature of 181.7° C. (+/−1° C.) and a peak temperature at 183.5° C. (+/−1° C.), measured by differential scanning calorimetry.
8. The crystalline form of verubecestat according to claim 6 that exhibits a melting point substantially the same as shown in the differential scanning calorimetry scan of FIG. 2 .
9. The crystalline form of verubecestat of claim 1 having a solid state 13 C NMR spectrum exhibiting any two of the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
10. The crystalline form of verubecestat according to claim 9 having a solid state 13 C NMR spectrum exhibiting any three of the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
11. The crystalline form of verubecestat according to claim 9 having a solid state 13 C NMR spectrum exhibiting any four of the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
12. The crystalline form of verubecestat according to claim 9 having a solid state 13 C NMR spectrum exhibiting any five of the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
13. The crystalline form of verubecestat according to claim 9 having a solid state 13 C NMR spectrum exhibiting the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
14. The crystalline form of verubecestat according to claim 9 having a solid state 13 C NMR substantially as shown in FIG. 4 .
15. The crystalline form of verubecestat of claim 1 having an ORTEP representation as shown in FIG. 5 .
16. The crystalline form of verubecestat according to claim 1 further characterized as exhibiting a peak temperature at 183.5° C. (+/−1° C.), measured by differential scanning calorimetry.
17. The crystalline form of verubecestat according to claim 16 , further characterized as exhibiting a melting endotherm with an extrapolated onset temperature of 181.7° C. (+/−1° C.) and a peak temperature at 183.5° C. (+/−1° C.), measured by differential scanning calorimetry.
18. The crystalline form of verubecestat according to claim 1 , further characterized by a solid state 13 C NMR spectrum exhibiting any two of the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
19. The crystalline form of verubecestat according to claim 16 , further characterized by a solid state 13 C NMR spectrum exhibiting any two of the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
20. The crystalline form of verubecestat according to claim 17 , further characterized by a solid state 13 C NMR spectrum exhibiting any two of the following peaks: 162.98, 160.46, 158.65, 156.39, 151.47, 145.63, 139.21, 133.72, 132.28, 125.50, 124.38, 122.10, 114.93, 57.11, 55.82, 29.22 and 25.66 ppm.
21. The crystalline form of verubecestat according to claim 1 , further having a ORTEP representation as shown in FIG. 5 .