Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor
View Patent ↗The dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine is a potent inhibitor of dipeptidyl peptidase-IV and is useful for the prevention and/or treatment of non-insulin dependent diabetes mellitus, also referred to as type 2 diabetes. The invention also relates to a crystalline monohydrate of the dihydrogenphosphate salt as well as a process for its preparation, pharmaceutical compositions containing this novel form and methods of use for the treatment of diabetes, obesity, and high blood pressure.
1. A dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine of structural formula I:
or a hydrate thereof.
2. The salt of claim 1 of structural formula II having the (R)-configuration at the chiral center marked with an *
3. The salt of claim 1 of structural formula III having the (S)-configuration at the chiral center marked with an *
4. The salt of claim 2 characterized in being a crystalline monohydrate.
5. The salt of claim 4 characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of 7.42, 5.48, and 3.96 angstroms.
6. The salt of claim 5 further characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of 6.30, 4.75, and 4.48 angstroms.
7. The salt of claim 6 further characterized by characteristic absorption bands obtained from the X-ray powder diffraction pattern at spectral d-spacings of 5.85, 5.21, and 3.52 angstroms.
8. The salt of claim 7 further characterized by the X-ray powder diffraction pattern of FIG. 1 .
9. The salt of claim 4 characterized by a solid-state carbon-13 CPMAS nuclear magnetic resonance spectrum showing signals at 169.1, 120.8, and 46.5 ppm.
10. The salt of claim 9 further characterized by a solid-state carbon-13 CPMAS nuclear magnetic resonance spectrum showing signals at 159.0, 150.9, and 40.7 ppm.
11. The salt of claim 10 further characterized by the solid-state carbon-13 CPMAS nuclear magnetic resonance spectrum of FIG. 2 .
12. The salt of claim 4 characterized by a solid-state fluorine-19 MAS nuclear magnetic resonance spectrum showing signals at −64.5, −114.7, −136.3, and −146.2 ppm.
13. The salt of claim 12 further characterized by a solid-state fluorine-19 MAS nuclear magnetic resonance spectrum showing signals at −96.5, −104.4, −106.3, and −154.5 ppm.
14. The salt of claim 13 further characterized by the solid-state fluorine-19 MAS nuclear magnetic resonance spectrum of FIG. 3 .
15. The salt of claim 4 characterized by the thermogravimetric analysis curve of FIG. 4 .
16. The salt of claim 4 characterized by the differential scanning calorimetric curve of FIG. 5 .
17. A pharmaceutical composition comprising a therapeutically effective amount of the salt according to claim 2 in association with one or more pharmaceutically acceptable carriers.
18. A pharmaceutical composition comprising a therapeutically effective amount of the salt according to claim 4 in association with one or more pharmaceutically acceptable carriers.
19. A method for the treatment of type 2 diabetes comprising administering to a patient in need of such treatment a therapeutically effective amount of the salt according to claim 2 or a hydrate thereof.
20. A method for the treatment of type 2 diabetes comprising administering to a patient in need of such treatment a therapeutically effective amount of the salt according to claim 4 .
21. A process for preparing the salt of claim 2 comprising the step of contacting one equivalent of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine in an organic solvent or aqueous organic solvent with about a one equivalent of phosphoric acid at a temperature in the range of about 25-100° C.
22. The process of claim 21 wherein said organic solvent is a C 1 -C 5 linear or branched alkanol.
23. The phosphoric acid salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine prepared according to the process of claim 21 .
24. A process for preparing the crystalline monohydrate of claim 4 comprising the steps of:
(a) crystallizing the dihydrogenphosphate salt of structural formula (II):
at 25° C. from a mixture of isopropanol and water, such that the water concentration is above 6.8 weight percent;
(b) recovering the resultant solid phase; and
(c) removing the solvent therefrom.