Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor

• US 7,326,708 B2
• Filed: 06/23/2004
• Issued: 02/05/2008
• Est. Priority Date: 06/24/2003
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck & Co., Inc.
• Inventors: Hansen, Karl, Vydra, Vicky K., Cypes, Stephen Howard, Chen, Alex Minhua, Wenslow, Robert M. Jr., Lee, Ivan, Ferlita, Russell R.
• Primary Examiner(s): Wilson; James O.
• Assistant Examiner(s): SACKEY, EBENEZER O
• Application Number:
  US10/874,992
• Publication Number:
  US 20050032804A1
• Time in Patent Office: 1,322 Days
• Field of Search: 514/249, 544/350
• US Class Current: 514/249
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

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.

Claims

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:

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 C₁-C₅ 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);