Claims for Patent: RE48285

Summary for Patent: RE48285

Title:	N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide
Abstract:	The present invention relates to stable novel salt forms of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide that are suitable for the preparation of pharmaceutical formulations thereof, and their therapeutic use.
Inventor(s):	Brandon H. Brown, Ernest A. Carra, Jeffrey N. Hemenway, Henry Morrison, Troy Reynolds, Bing Shi, Dimitrios Stefanidis, Fang Wang, Matthew Robert Warr, James Andrew Whitney, Yan Xin
Assignee:	GlaxoSmithKline LLC
Application Number:	US16/164,681
Patent Claims:	1. A compound selected from the group consisting of: N-(cyanomethyl)-4-(2-(4-morpholinoohenylamino)pyrimidin-4-yl)benzamideN-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II; N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrirnidin-4-yl)benzarnideN-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I; and N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III. 2. The compound of claim 1 in a crystalline form. 3. The crystalline form of claim 2, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylarnino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II. 4. The crystalline form of claim 3 2, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II and the crystals have unit cell parameters at T=100° K of: a=10.2837(6) Å, b=10.4981(6) Å, c=11.5143(7) Å, α=83.297(2)°,β β=87.649(2)°, y=67.445(2)°, and a triclinic P-1 space group. 5. The crystalline form of claim 3 2, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II and is characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 5. 6. The crystalline form of claim 3 2, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II and is characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 7.7°, 19.3°, 24.0°, 25.7°, and 29.6°2−θ±0.2° 2−θ. 7. The crystalline form of claim 3 2, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II and is characterized by differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 8. 8. The crystalline form of claim 3 2, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II and is characterized by a dynamic vapor sorption (DVS) pattern substantially as set forth in FIG. 14. 9. The crystalline form of claim 2, wherein the crystalline form is Crystalline N-(cyanomethyl)-4-(2-(4-morpholino-phenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I. 10. The crystalline form of claim 9. 2, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I and is characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 6. 11. The crystalline form of claim 9 2, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I and is characterized by an X-ray powder diffraction (“XRPD”) pattern having peaks at about 13.5°, 20.9°, 26.1°, 26.6°, and 28.3° 2−θ±0.2° 2−θ. 12. The crystalline form of claim 9 2, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I and is characterized by a differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 9. 13. The crystalline form of claim 2, wherein the crystalline form is crystalline N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrirnidin-4-yl)benzamide monohydrochloride anhydrous Form III. 14. The crystalline form of claim 13 2, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III and is characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 7. 15. The crystalline form of claim 13 2, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III and is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at about 12.7°, 14.6°, 17,8°17.8°, 19.7°, and 23.3° 2−θ±0.2° 2−θ. 16. The crystalline form of claim 13 2, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III and is characterized by a differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 10. 17. A pharmaceutical composition comprising a compound of claim 1, wherein the pharmaceutical composition is in a solid form. 18. The pharmaceutical composition of claim 17, wherein the compound of claim 1 is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II. 19. The pharmaceutical composition of claim 17 wherein N-(cyanornethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II is present at in an amount equivalent to 50 mg, 100 mg, 150 mg, or 200 mg of free base N-(cyanomethyl)-4-(2-(4-morpholinaphenybmino)pyrimidin-4-yl)benzamide N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide. 20. The pharmaceutical composition of claim 17 in the form of a tablet. 21. The pharmaceutical composition of claim 17, wherein after a single oral administration said composition provides: a Cmax in the range of 260 to 405 ng/mL of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide, an AUCinf in the range of 2,057 to 3,214 ng·hr/mL of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide, or both a Cmax in the range of 260 to 405 ng/ml of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide and an AUCinf in the range of 2,057 to 3,214 ng·hr/mL of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide. 22. The pharmaceutical composition of claim 21, wherein after a single oral administration said composition provides a pharmacokinetic profile substantially similar to that of a dosage form comprising N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride anhydrous Form I in an amount equivalent to 300 mg of free base N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide. 23. A method for the treatment of a disease associated with Janus Kinase (JAK) which comprises administering to a subject in need an effective amount of the pharmaceutical composition of claim 18, wherein the disease is a myeloproliferative disease selected from the group consisting of thrombocythemia, idiopathic myelofibrosis, systemic mastocystosis (SM), myelodispiastic myelodysplastic syndrome (MDS) and systemic mast cell disease (SMCD). 24. A pharmaceutical composition comprising a compound having the formula or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or diluent. 25. A pharmaceutical composition comprising a compound having the formula or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or diluent. 26. A pharmaceutical composition comprising a compound having the formula or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or diluent.