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Claims for Patent: 7,326,708

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Claims for Patent: 7,326,708

Title:Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor
Abstract: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.
Inventor(s): Cypes; Stephen Howard (Santa Clara, CA), Chen; Alex Minhua (Metuchen, NJ), Ferlita; Russell R. (Westfield, NJ), Hansen; Karl (Atlantic Highlands, NJ), Lee; Ivan (Piscataway, NJ), Vydra; Vicky K. (Fair Lawn, NJ), Wenslow, Jr.; Robert M. (East Windsor, NJ)
Assignee: Merck & Co., Inc. (Rahway, NJ)
Application Number:10/874,992
Patent Claims: 1. A dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8- H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine of structural formula I: ##STR00008## 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 * ##STR00009##

3. The salt of claim 1 of structural formula III having the (S)-configuration at the chiral center marked with an * ##STR00010##

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]pyrazi- n-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.degree. C.

22. The process of claim 21 wherein said organic solvent is a C.sub.1-C.sub.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]pyrazi- n-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): ##STR00011## at 25.degree. 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.
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