(N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide

Patent metadata

Field	Value
Publication number	US-9469613-B2
Application number	US-201514736690-A
Country	US
Kind code	B2
Filing date	Jun 11, 2015
Priority date	Jun 12, 2014
Publication date	Oct 18, 2016
Grant date	Oct 18, 2016

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.

First claim

What is claimed:

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).

Assignees

• Gilead Sciences Inc

Inventors

• Brown Brandon H
• Carra Ernest A
• Hemenway Jeffrey N
• Morrison Henry
• Reynolds Troy
• Shi Bing
• Stefanidis Dimitrios
• Wang Fang
• Warr Matthew Robert
• Whitney James Andrew
• Xin Yan

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/535

  having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines · CPC title