Polymorphs and solid forms of a pyrimidinylamino-pyrazole compound, and methods of production

• US 10,370,361 B2
• Filed: 11/20/2018
• Issued: 08/06/2019
• Est. Priority Date: 11/21/2017
• Status: Active Grant

• Current Assignee: Denali Therapeutics Inc.
• Original Assignee: Denali Therapeutics Inc.
• Inventors: Remarchuk, Travis, Sudhakar, Anantha
• Primary Examiner(s): Habte, Kahsay
• Application Number:
  US16/197,037
• Publication Number:
  US 20190194170A1
• Time in Patent Office: 259 Days
• Field of Search: 544324
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links

Abstract

The present disclosure relates to crystalline polymorph and amorphous forms of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile or solvates, tautomers, and pharmaceutically acceptable salts or cocrystals thereof, and processes for their preparation.

Claims

1. A crystalline compound, 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile, selected from:

a Form B polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 7.0, 7.3, 16.1, 16.3, 24.1, 25.1, and 26.6;

a Form C polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.4, 15.1, 21.2, 25.7, and 27.8; and

a Form D polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 9.2, 14.0, 14.8, 19.7, and 20.0.

2. The crystalline compound of claim 1, selected from:

a Form C polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.4, 8.1, 8.6, 8.8, 9.9, 10.2, 12.9, 13.8, 15.1, 15.4, 16.5, 19.8, 21.2, 22.1, 23.7, 25.7, and 27.8; and

a Form D polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 8.0, 8.7, 9.2, 9.8, 10.4, 12.9, 13.4, 14.0, 14.8, 16.4, 18.5, 19.7, 20.0, 20.8, 23.1, 23.3, 23.9, 25.5, and 25.7.

3. The crystalline compound of claim 1, wherein the compound is in substantially pure form.

4. The crystalline compound of claim 1, wherein the X-ray powder diffraction pattern is made using CuKα

1 radiation.

5. The crystalline compound of claim 1, wherein the compound is the Form B polymorph having an X-ray powder diffraction pattern substantially free of peaks at approximately 12.9 and 14.8±

0.05 degrees 2-theta.

6. The crystalline compound of claim 1, wherein the Form B polymorph is a cyclohexanol solvate.

7. The Form B polymorph of claim 1 wherein a differential scanning calorimetry DSC shows two melting endotherms at about 87.9 and 103.2°

C. onset.

8. The crystalline compound of claim 1, wherein the compound is the Form C polymorph having an X-ray powder diffraction pattern substantially free of peaks at 13.6 and 14.8±

0.05 degrees 2-theta.

9. The crystalline compound of claim 1, wherein the compound is the Form C polymorph further comprising peaks at 16.5 and 22.1±

0.05 degrees 2-theta.

10. The crystalline compound of claim 1, wherein the Form C polymorph is an anhydrate.

11. The Form C polymorph of claim 1 characterized by the X-ray powder diffraction pattern shown in FIG. 10.

12. The Form C polymorph of claim 1 wherein a differential scanning calorimetry DSC shows a melting endotherm at about 127.8°

C. onset.

13. The crystalline compound of claim 1, wherein the compound is the Form D polymorph having an X-ray powder diffraction pattern substantially free of peaks at 13.6±

0.05 degrees 2-theta.

14. The crystalline compound of claim 1, wherein the Form D polymorph is an anhydrate.

15. The Form D polymorph of claim 1 characterized by the X-ray powder diffraction pattern shown in FIG. 12.

16. The Form D polymorph of claim 1 wherein a differential scanning calorimetry DSC shows a melting endotherm at about 129.1°

C. onset.

17. The crystalline compound of claim 1, exhibiting a mass increase of less than about 1% when subjected to an increase in relative humidity from about 0% to about 95% relative humidity for about 180 minutes.

18. The crystalline compound of claim 1, which is stable upon exposure to about 40°

C. and about 75% relative humidity for at least 6 months.

20. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline polymorph of claim 1, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

21. The pharmaceutical composition of claim 20 in the form of a tablet.

22. The pharmaceutical composition of claim 20 wherein the therapeutically effective amount is from 1 to 200 mg.

23. The pharmaceutical composition of claim 20 wherein the crystalline polymorph is milled.

19. A crystalline compound, 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile exhibiting an X-ray powder diffraction pattern having characteristic peaks expressed in ±

0.3 degrees 2-theta at approximately 6.4, 15.1, 21.2, 25.7, and 27.8.

24. A process for preparing a crystalline polymorph comprising heating at 50°

C. or above 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile in methyl tert-butyl ether, cyclopentyl methyl ether, ethyl acetate, isopropyl acetate, or combinations thereof and a non-polar solvent such as heptane, and then cooling the mixture whereby a Form C crystalline polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.4, 15.1, 21.2, 25.7, and 27.8 degrees 2-theta is formed.

25. The process of claim 24 wherein the mixture is seeded.

26. A process for preparing a crystalline polymorph comprising heating at 50°

C. or above, an anhydrous solution of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile in methyl tert-butyl ether, cyclopentyl methyl ether, ethyl acetate, isopropyl acetate, or combinations thereof, and a non-polar solvent such as heptane, and then cooling the mixture whereby a Form D crystalline polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 9.2, 14.0, 14.8, 19.7, and 20.0 degrees 2-theta is formed.

27. The process of claim 26 wherein the mixture is seeded.