USRE48285EActiveUtilityPatentIndex 71

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

Assignee: SIERRA ONCOLOGY INCPriority: Jun 12, 2014Filed: Oct 18, 2018Granted: Oct 27, 2020

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

A61P 43/00A61P 35/00A61K 31/5377C07D 239/42A61P 7/00A61P 35/02C07D 413/12C07D 265/30A61K 31/535C07B 2200/13

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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)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 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 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.

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