Granted Patent E1

US 50,497 · App. 18/159,328 · Granted Jul 22, 2025

Inventors: Brandon H. Brown (Burlingame, CA); Ernest A. Carra (Foster City, CA); Jeffrey N. Hemenway (San Mateo, CA); Henry Morrison (Dublin, CA); Troy Reynolds (San Francisco, CA); Bing Shi (Redwood City, CA); Dimitrios Stefanidis (Mountain View, CA); Fang Wang (Foster City, CA); Matthew Robert Warr (Madison, CT); James Andrew Whitney (Guilford, CT); Yan Xin (San Carlos, CA)

Assignee: GlaxoSmithKline LLC

C07D239/42A61K31/535A61K31/5377C07D265/30C07B2200/13

Abstract

Claims (64)

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).

24. A pharmaceutical composition comprising:

a compound (i) N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II;

a compound (ii) N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl) benzamide dihydrochloride monohydrate Form II, wherein one or more hydrogen atoms attached to a carbon atom of the compound are replaced by a deuterium atom; and

a pharmaceutically acceptable excipient.

25. The pharmaceutical composition of claim 24 , wherein the pharmaceutical composition is in a tablet form.

26. The pharmaceutical composition of claim 24 , wherein the compound (i) has 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.

27. The pharmaceutical composition of claim 24 , wherein the compound (i) is characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 5.

28. The pharmaceutical composition of claim 24 , wherein the compound (i) 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.

29. The pharmaceutical composition of claim 24 , wherein the compound (i) is characterized by differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 8.

30. The pharmaceutical composition of claim 24 , wherein the compound (i) is characterized by a thermogravimetric analysis (TGA) pattern substantially as set forth in FIG. 11.

31. The pharmaceutical composition of claim 24 , wherein the compound (i) is characterized by a dynamic vapor sorption (DVS) pattern substantially as set forth in FIG. 14.

32. The pharmaceutical composition of claim 24 , wherein the compound (i) and the compound (ii) are collectively present in an amount equivalent to 100 mg, 150 mg, or 200 mg of free base N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide.

33. The pharmaceutical composition of claim 24 , wherein the excipient comprises microcrystalline cellulose.

34. The pharmaceutical composition of claim 24 , wherein the excipient comprises lactose monohydrate.

35. The pharmaceutical composition of claim 24 , wherein the excipient comprises sodium starch glycolate.

36. The pharmaceutical composition of claim 24 , wherein the excipient comprises silicon dioxide.

37. The pharmaceutical composition of claim 24 , wherein the excipient comprises magnesium stearate.

38. The pharmaceutical composition of claim 24 , wherein the excipient comprises propyl gallate.

39. The pharmaceutical composition of claim 24 , wherein the excipient comprises polyethylene glycol.

40. The pharmaceutical composition of claim 24 , wherein the excipient comprises talc.

41. A method for the treatment of a myeloproliferative disease, which comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises:

a compound (i) N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II;

a compound (ii) N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II, wherein one or more hydrogen atoms attached to a carbon atom of the compound are replaced by a deuterium atom; and

a pharmaceutically acceptable excipient.

42. The method of claim 41 , wherein the myeloproliferative disease is myelofibrosis, polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis, thrombocythemia, chronic myelogenous leukemia, systemic mastocystosis, chronic neutrophilic leukemia, myelodysplastic syndrome, or systemic mast cell disease.

43. The method of claim 41 , wherein the myeloproliferative disease is myelofibrosis.

44. The method of claim 43 , wherein the myelofibrosis is primary myelofibrosis.

45. The method of claim 43 , wherein the myelofibrosis develops from post-polycythemia (PV) vera or post-essential thrombocythemia (ET).

46. The method of claim 41 , wherein the subject is an adult with anemia.

47. 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 a therapeutic agent that inhibits or modulates the activity of a bromodomain-containing protein; and

an effective amount of a pharmaceutical composition that comprises:

a compound (i) N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II;

a compound (ii) N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II, wherein one or more hydrogen atoms attached to a carbon atom of the compound are replaced by a deuterium atom; and

a pharmaceutically acceptable excipient.

Assignments (8)

Continuity (5)

References Cited (233)