Crystalline fumarate salt of (s)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone

Abstract

This disclosure relates to the crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]methamine. The disclosure also relates to pharmaceutical compositions comprising the crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone. The disclosure also relates to methods of treating cancers comprising administering to a patient in need thereof the crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]methanone.

1 . A crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone. 
     
     
         2 . The crystalline fumarate salt of  claim 1 , designated as Form A, wherein the crystalline fumarate salt is characterized by at least one of the following:
 (i) a  1 H NMR spectrum in d 6  DMSO substantially as depicted in  FIG. 2 ;   (ii) a 13C NMR spectrum in d 6  DMSO substantially as depicted in  FIG. 3 ;   (iii) a solid state  13 C NMR spectrum with three or more peaks selected from 175.3, 173.6, 117.5, 155.5, and 153.5, ±0.2 ppm;   (iv) a solid state  13 C NMR spectrum substantially as depicted in  FIG. 4 ;   (v) a powder x-ray diffraction pattern (CuKαλ=1.5418 Å) comprising three or more 2θ values selected from 4.6, 12.1, 13.2, 13.6 and 14.5±0.2°2θ, wherein measurement of the crystalline form is at room temperature;   (vi) an x-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in  FIG. 10 ; and   (vii) a differential scanning calorimetry thermogram substantially in accordance with  FIG. 8 .   
     
     
         3 . The crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone of  claim 1 , designated as Form A, wherein said salt is characterized by a solid state  13 C NMR spectrum with three or more peaks selected from 175.3, 173.6, 117.5, 155.5, and 153.5, ±0.2 ppm. 
     
     
         4 . The crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone of  claim 1 , designated as Form A, wherein said salt is characterized by a powder x-ray diffraction pattern (CuKαλ=1.5418 Å) comprising three or more 20 values selected from 4.6, 12.1, 13.2, 13.6 and 14.5±0.2°2θ, wherein measurement of the crystalline form is at room temperature. 
     
     
         5 . The crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone of  claims 1 - 4 , wherein said salt is at least 90 weight % Form A, based on weight of said salt. 
     
     
         6 . A pharmaceutical composition comprising crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone of  claims 1 - 4 , designated as Form A; and a pharmaceutically acceptable excipient. 
     
     
         7 . Use of crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone of any one of  claims 1 - 4 , designated as Form A, for the manufacture of a medicament for the treatment of cancer. 
     
     
         8 . Use of the crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone of any one of  claims 1 - 4 , designated as Form A, for therapy in treating cancer. 
     
     
         9 . The crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone designated as Form A, for use as a medicament for treating cancer which is selected from the group consisting of melanoma (including BRAF V600 mutant melanoma), breast cancer (including triple negative breast cancer), colorectal cancer (including KRAS mutant colorectal cancer), non-small cell lung cancer, acute myeloid leukemia, and pancreatic cancer. 
     
     
         10 . The use of  claim 8 , wherein the cancer is BRAF V600 mutant melanoma. 
     
     
         11 . The crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone designated as Form A, in combination with vemurafenib for use as a medicament for treating melanoma. 
     
     
         12 . A method of treating BRAF V600 mutant melanoma in a subject, the method comprising administering to the subject in need of the treatment a therapeutically effective amount of the crystalline fumarate salt of Compound I alone or in combination with vemurafenib. 
     
     
         13 . The method of  claim 12 , wherein the crystalline fumarate salt of Compound I is administered prior or subsequent to, or concurrent with vemurafenib. 
     
     
         14 . A process for preparing the crystalline fumarate salt of Compound I designated as Form A, comprising:
 adding fumaric acid dissolved in a solvent to a mixture of Compound I dissolved in a solvent to form the crystalline fumarate salt of Compound I designated as Form A; and   collecting the resulting crystals of the crystalline fumarate salt of Compound I designated as Form A.