USRE49445EActiveUtilityPatentIndex 71
N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide

Assignee: SIERRA ONCOLOGY INCPriority: Jun 12, 2014Filed: Sep 4, 2020Granted: Mar 7, 2023
Est. expiryJun 12, 2034(~7.9 yrs left)· nominal 20-yr term from priority
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
C07D 239/42C07D 265/30A61P 7/00A61P 35/02A61P 35/00A61K 31/535C07B 2200/13A61P 43/00A61K 31/5377C07D 413/12
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Cited by
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References
Claims
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.
Claims

exact text as granted — not AI-modified
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-4yl)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 having the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or diluent; 
         wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by a deuterium atom.  
       
     
     
       25. A pharmaceutical composition comprising a compound having the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or diluent; 
         wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.  
       
     
     
       26. A pharmaceutical composition comprising a compound having the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or diluent; 
         wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.  
       
     
     
       27. A compound selected from the group consisting of:
 N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II;   N-(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;   wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.    
     
     
       28. The compound of claim 27 in a crystalline form.  
     
     
       29. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II.  
     
     
       30. The crystalline form of claim 28, 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=87.649(2)°, y=67.445(2)°, and a triclinic P-1 space group.  
     
     
       31. The crystalline form of claim 28, 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.  
     
     
       32. The crystalline form of claim 28, 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° −θ.  
     
     
       33. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II and is characterized by a differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 8.  
     
     
       34. The crystalline form of claim 28, 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.  
     
     
       35. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I.  
     
     
       36. The crystalline form of claim 28, 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.  
     
     
       37. The crystalline form of claim 28, 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.  
     
     
       38. The crystalline form of claim 28, 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.  
     
     
       39. The crystalline form of claim 28, wherein the crystalline form is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III.  
     
     
       40. The crystalline form of claim 28, 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.  
     
     
       41. The crystalline form of claim 28, 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°, 19.7°, and 23.3° 2−θ±0.2° 2−θ.  
     
     
       42. The crystalline form of claim 28, 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.  
     
     
       43. A pharmaceutical composition comprising a compound of claim 27, wherein the pharmaceutical composition is in a solid form.  
     
     
       44. The pharmaceutical composition of claim 43, wherein the compound is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II.  
     
     
       45. The pharmaceutical composition of claim 43, wherein N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II is present in an amount equivalent to 50 mg, 100 mg, 150 mg, or 200 mg of free base N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide.  
     
     
       46. The pharmaceutical composition of claim 43, wherein the compound is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I.  
     
     
       47. The pharmaceutical composition of claim 43, wherein N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form I is 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.  
     
     
       48. The pharmaceutical composition of claim 43, wherein the compound is N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III.  
     
     
       49. The pharmaceutical composition of claim 43, wherein N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide monohydrochloride anhydrous Form III is 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.  
     
     
       50. The pharmaceutical composition of claim 43 in the form of a tablet.  
     
     
       51. The pharmaceutical composition of claim 43, 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.    
     
     
       52. The pharmaceutical composition of claim 51, 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.  
     
     
       53. A method for the treatment of a disease associated with Janus Kinase (JAK) which comprises administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 51, wherein the disease is a myeloproliferative disease selected from the group consisting of thrombocythemia, idiopathic myelofibrosis, systemic mastocystosis (SM), myelodysplastic syndrome (MDS) and systemic mast cell disease (SMCD).  
     
     
       54. A method for the treatment of a disease associated with Janus Kinase (JAK) which comprises administering to a subject in need thereof:
 an effective amount of a therapeutic agent that inhibits or modulates the activity of a bromodomain-containing protein; and   an effective amount of N-(cyanomethyl)-4-(2-(4-morpholinophenylamino) pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II.    
     
     
       55. The method of claim 54, wherein the therapeutic agent is a bromodomain-containing protein (BRD) inhibitor.  
     
     
       56. The method of claim 55, wherein the therapeutic agent is a BRD4 inhibitor.  
     
     
       57. The method of claim 54, wherein the N-(cyanomethyl)-4-(2-(4-morpholinophenylamino) pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II is crystalline.  
     
     
       58. The method of claim 54, wherein the N-(cyanomethyl)-4-(2-(4-morpholinophenylamino) pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II is crystalline and
 (a) 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;   (b) is characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 5;   (c) is characterized by a differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 8; or   (d) is characterized by a dynamic vapor sorption (DVS) pattern substantially as set forth in FIG. 14.    
     
     
       59. The method of claim 54, wherein the disease is a myeloproliferative disease selected from the group consisting of thrombocythemia, idiopathic myelofibrosis, systemic mastocystosis (SM), myelodysplastic syndrome (MDS) and systemic mast cell disease (SMCD).  
     
     
       60. The method of claim 54, wherein the N-(cyanomethyl)-4-(2-(4-morpholinophenylamino) pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II is provided in a pharmaceutical composition that is in a solid form.  
     
     
       61. The method of claim 60, wherein N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II is present in an amount equivalent to 50 mg, 100 mg, 150 mg, or 200 mg of free base N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide.  
     
     
       62. The method of claim 61, wherein N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate Form II is in the form of a tablet.
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