POLYMORPHS AND SOLID FORMS OF A PYRIMIDINYLAMINO-PYRAZOLE COMPOUND, AND METHODS OF PRODUCTION

• US 20190315723A1
• Filed: 06/20/2019
• Published: 10/17/2019
• Est. Priority Date: 11/21/2017
• Status: Active Grant

• Current Assignee: Denali Therapeutics Inc.
• Original Assignee: Denali Therapeutics Inc.
• Inventors: Remarchuk, Travis, Sudhakar, Anantha
• Granted Patent: US 10,851,088 B2
• Time in Patent Office: Days
• 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 pharmaceutical composition comprising a therapeutically effective amount of a crystalline polymorph of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient, wherein the crystalline polymorph is 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 pharmaceutical composition of claim 1, wherein the crystalline polymorph is 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 pharmaceutical composition of claim 1, wherein the crystalline compound is in substantially pure form.

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

1 radiation.

5. The pharmaceutical composition of claim 1, wherein the crystalline 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 pharmaceutical composition of claim 1, wherein the Form B polymorph is a cyclohexanol solvate.

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

C. onset.

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

0.05 degrees 2-theta.

10. The pharmaceutical composition of claim 1, wherein the Form C polymorph is an anhydrate.

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

12. The pharmaceutical composition of claim 1, wherein a differential scanning calorimetry (DSC) of the Form C polymorph shows a melting endotherm at about 127.8°

C. onset.

13. The pharmaceutical composition of claim 1, wherein the crystalline 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 pharmaceutical composition of claim 1, wherein the Form D polymorph is an anhydrate.

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

16. The pharmaceutical composition of claim 1, wherein a differential scanning calorimetry (DSC) of the Form D polymorph shows a melting endotherm at about 129.1°

C. onset.

17. The pharmaceutical composition of claim 1, which exhibits 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 pharmaceutical composition of claim 1, which is stable upon exposure to about 40°

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

19. A pharmaceutical composition of claim 1, wherein the crystalline compound exhibits 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.

20. The pharmaceutical composition of claim 1, in the form of a tablet.

21. The pharmaceutical composition of claim 1, wherein the crystalline polymorph is milled.