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Last Updated: March 8, 2021

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Claims for Patent: 8,193,204

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Summary for Patent: 8,193,204
Title:Solid forms of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1- (4-chloro-2-(3-methyl-1H-pyrazol-1-YL)phenyl)2,2,2-trifluoroethoxy)-pyrim- idin-4-YL)phenyl)propanoate and methods of their use
Abstract: Solid forms of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phen- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate and salts thereof are disclosed.
Inventor(s): Bednarz; Mark S. (Yardley, PA), De Paul; Susan (Zurich, CH), Kanamarlapudi; Ramanaiah C. (Bridgewater, NJ), Perlberg; Anett (Gunzgen, CH), Zhang; Haiming (Pennington, NJ)
Assignee: Lexicon Pharmaceuticals, Inc. (The Woodlands, TX)
Application Number:12/237,455
Patent Claims: 1. Crystalline (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phen- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate or a pharmaceutically acceptable salt thereof.

2. A compound, which is crystalline (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phen- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate.

3. The compound of claim 2, which has a melting point of about 104.degree. C.

4. The compound of claim 2, which has an X-ray powder diffraction pattern with peaks at one or more of about 10.7, 12.2, 12.8, 17.7 and/or 22.0 degrees 2 .theta..

5. The compound of claim 2, which has an X-ray powder diffraction pattern that is substantially the same as that shown in FIG. 1.

6. A crystalline salt of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phen- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl) phenyl)propanoate.

7. The crystalline salt of claim 6, which is a hippurate salt.

8. The crystalline salt of claim 7, which has a melting point of about 145.degree. C.

9. The crystalline salt of claim 7, which has an X-ray powder diffraction pattern comprising peaks at one or more of about 8.2, 9.5, 12.6, 16.9, 21.8, 22.0, 22.7, 24.3 and/or 29.1 degrees 2.theta..

10. The crystalline salt of claim 7, which has an X-ray powder diffraction pattern that is substantially the same as that shown in FIG. 2.

11. The crystalline salt of claim 7, which has a Raman spectrum that is substantially the same as that shown in FIG. 3.

12. The crystalline salt of claim 6, which is a succinate salt.

13. The crystalline salt of claim 12, which has an X-ray powder diffraction pattern comprising peaks at one or more of about 7.7, 11.5, 11.7, 15.7, 17.9, 21.1 and/or 23.2 degrees 2.theta..

14. The crystalline salt of claim 12, which has an X-ray powder diffraction pattern that is substantially the same as that shown in FIG. 4.

15. A method of preparing a crystalline salt of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phen- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate, which comprises: contacting a solution comprising (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phen- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate with pharmaceutically acceptable acid under conditions sufficient to provide a salt of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H -pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propano- ate; reducing the solubility of the salt in the solution under conditions sufficient to provide a crystalline salt of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phen- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate; and isolating the crystalline salt.

16. The method of claim 15, wherein the solution comprises isopropyl acetate, ethyl acetate, ethanol, isopropanol, methyl t-butyl ether, or methyl isobutylketone.

17. The method of claim 15, wherein the acid is hippuric or succinic acid.

18. The method of claim 15, wherein the solubility of the salt is reduced by cooling the solution.

19. The method of claim 15, wherein the amount of the dissolved salt is reduced by increasing the concentration of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phen- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate in the solution.

20. The method of claim 15, wherein the solubility of the salt is reduced by adding to the solution an anti-solvent.

21. The method of 20, wherein the anti-solvent is heptane.

22. A method of preparing crystalline (S)-ethyl 2-amino-3-(4-(2-amino-6-((R) -1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)py- rimidin-4-yl)phenyl)propanoate,which comprises: adding a basic aqueous solution to an organic suspension to provide a mixture having organic and aqueous components, wherein the organic suspension comprises a salt of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol- -1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate and an organic solvent; isolating the organic component from the mixture; and cooling and/or concentrating the organic component to provide crystalline (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol- -1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate; and isolating the crystalline free base.

23. The method of claim 22, wherein the salt of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phen- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate is a hippurate salt.

24. The method of claim 22, wherein the organic solvent is an ether.

25. The method of claim 22, wherein the basic aqueous solution comprises sodium bicarbonate.

26. The method of claim 22, which further comprises washing the crystalline (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phen- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate with an organic solvent.

27. A pharmaceutical dosage form comprising crystalline (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phen- yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate.

28. A pharmaceutical dosage form comprising a crystalline salt of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol- -1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate.

29. The dosage form of claim 28, wherein the salt is a hippurate salt.

30. The dosage form of claim 28, wherein the salt is a succinate salt.

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