Crystalline forms of an inhibitor of 11-β-hydroxysteroid dehydrogenase type 1
View Patent ↗Novel crystalline salts of 3-[4-(3-ethanesulfonyl-propyl)-bicyclo[2.2.2]oct-1-yl]-4-methyl-5-(2-trifluoromethyl-phenyl)-4H-1,2,4-triazole are potent inhibitors of 11β-hydroxysteroid dehydrogenase Type 1 and are useful for the treatment of conditions associated with Metabolic Syndrome as well as cognitive impairment. The invention also relates to pharmaceutical compositions containing these novel salts, processes to prepare these salts and their pharmaceutical compositions as well as uses thereof for the treatment of Type 2 diabetes, hyperglycemia, obesity, dyslipidemia, hypertension, and cognitive impairment.
1. A crystalline anhydrate of 3-[4-(3-ethanesulfonyl-propyl)-bicyclo[2.2.2]oct-1-yl]-4-methyl-5-(2-trifluoromethyl-phenyl)-4H-1,2,4-triazole of structural formula I:
characterized by characteristic reflections obtained from the X-ray powder diffraction pattern at spectral d-spacings of about 6.56, 6.33, 6.19, 5.63, 5.27, 4.93, 4.74, 4.65, 4.51 and 4.37 angstroms.
2. The crystalline anhydrate of claim 1 further characterized by the X-ray powder diffraction pattern of FIG. 1 .
3. A crystalline anhydrate of claim 1 characterized by a solid-state carbon-13 CPMAS nuclear magnetic resonance spectrum showing signals with chemical shift values of about 160.2, 153.6, 133.4, 129.8, 127.6, 48.0, 33.4, 32.7, 29.6, and 6.9 p.p.m.
4. The crystalline anhydrate of claim 3 characterized by the solid state carbon-13 CPMAS nuclear magnetic resonance spectrum of FIG. 2 .
5. A crystalline anhydrate of claim 1 characterized by the differential scanning calorimetric (DSC) curve of FIG. 3 .
6. A crystalline anhydrate of 3-[4-(3-ethanesulfonyl-propyl)-bicyclo[2.2.2]oct-1-yl]-4-methyl-5-(2-trifluoromethyl-phenyl)-4H-1,2,4-triazole of structural formula I:
characterized by characteristic reflections obtained from the X-ray powder diffraction pattern at spectral d-spacings of about 18.33, 9.37, 8.62, 6.28, 6.02, 8.08, 6.49, 5.43, 5.39, 4.38, 4.10, 3.18, and 2.74 angstroms.
7. The crystalline anhydrate of claim 6 further characterized by the X-ray powder diffraction pattern of FIG. 4 .
8. A crystalline anhydrate of claim 6 characterized by a solid-state carbon-13 CPMAS nuclear magnetic resonance spectrum showing signals with chemical shift values of about 153.2, 131.6, 129.0, 125.4, 54.4, 45.8, 32.3, 30.6, 29.4, and 4.8 p.p.m.
9. The crystalline anhydrate of claim 8 characterized by the solid-state carbon-13 CPMAS nuclear magnetic resonance spectrum of FIG. 5 .
10. A crystalline anhydrate of 3-[4-(3-ethanesulfonyl-propyl)-bicyclo[2.2.2]oct-1-yl]-4-methyl-5-(2-trifluoromethyl-phenyl)-4H-1,2,4-triazole of structural formula I:
characterized by characteristic reflections obtained from the X-ray powder diffraction pattern at spectral d-spacings of about 9.26, 5.90, 5.78, 5.33, 5.16, 5.10, 5.03, 4.69, 4.61, and 4.26 angstroms.
11. The crystalline anhydrate of claim 10 further characterized by the X-ray powder diffraction pattern of FIG. 6 .
12. A crystalline anhydrate of claim 10 characterized by a solid-state carbon-13 CPMAS nuclear magnetic resonance spectrum showing signals with chemical shift values of about 160.1, 153.9, 134.0, 131.4, 129.5, 127.0, 54.8, 51.5, 33.4, and 5.9 p.p.m.
13. The crystalline anhydrate of claim 12 characterized by the solid-state carbon-13 CPMAS nuclear magnetic resonance spectrum of FIG. 7 .
14. A crystalline anhydrate of claim 10 characterized by the differential scanning calorimetric (DSC) curve of FIG. 8 .
15. The crystalline methanol solvate of 3-[4-(3-ethanesulfonyl-propyl)-bicyclo[2.2.2]oct-1-yl]-4-methyl-5-(2-trifluoromethyl-phenyl)-4H-1,2,4-triazole of structural formula I:
characterized by characteristic reflections obtained from the X-ray powder diffraction pattern at spectral d-spacings of about 9.88, 6.13, 5.36, 4.65, 4.43, 4.39, 4.08, 3.98, 3.36, and 3.26 angstroms.
16. The crystalline methanol solvate of claim 15 further characterized by the X-ray powder diffraction pattern of FIG. 9 .
17. The crystalline methanol solvate of claim 15 characterized by the thermogravimetric analysis (TGA) curve of FIG. 10 .
18. The crystalline ethanol solvate of 3-[4-(3-ethanesulfonyl-propyl)-bicyclo[2.2.2]oct-1-yl]-4-methyl-5-(2-trifluoromethyl-phenyl)-4H-1,2,4-triazole of structural formula I:
characterized by characteristic reflections obtained from the X-ray powder diffraction pattern at spectral d-spacings of about 10.03, 6.66, 6.29, 5.38, 4.74, 4.46, 4.41, 4.15, 4.04, and 3.30 angstroms.
19. The crystalline ethanol solvate of claim 18 further characterized by the X-ray powder diffraction pattern of FIG. 11 .
20. The crystalline ethanol solvate of claim 18 characterized by the differential scanning calorimetric (DSC) curve of FIG. 12 .
21. The crystalline ethanol solvate of claim 18 characterized by the thermogravimetric analysis (TGA) curve of FIG. 13 .