(N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide
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.
1. A compound selected from the group consisting of:
N-(cyanomethyl)-4-(2-(4-morpholinoohenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II;
N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrirnidin-4-yl)benzarnide 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 , wherein 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=87.649(2)° , y=67.445(2)° , and a triclinic P-1 space group.
5. The crystalline form of claim 3 , characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 5 .
6. The crystalline form of claim 3 , 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 , characterized by differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 8 .
8. The crystalline form of claim 3 , 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-(cyanomethyI)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I.
10. The crystalline form of claim 9 . characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 6 .
11. The crystalline form of claim 9 , 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 , 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 , characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 7 .
15. The crystalline form of claim 13 , characterized by an X-ray powder diffraction (XRPD) pattern having peaks at about 12.7° , 14.6° , 17,8° , 19.7° , and 23.3° 2−θ±0.2° 2−θ.
16. The crystalline form of claim 13 , 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 monohydrate Form II is present at 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.
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 C max in the range of 260 to 405 ng/mL of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide,
an AUC inf 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 C max in the range of 260 to 405 ng/ml of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide and an AUC inf 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 syndrome (MDS) and systemic mast cell disease (SMCD).