Crystalline forms of the sodium salt of (4--cyclohexyl)-acetic acid

Abstract

The present invention relates to novel crystalline forms of (4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid, sodium and their use in the treatment or prevention of a condition or a disorder associated with DGAT1 activity in animals, particularly humans. It also relates processes for making such novel crystalline forms.

1 . A crystalline form of the sodium salt of (4-{4-[5-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid of formula (II) 
       
         
           
           
               
               
           
         
       
       in the form of Modification B, C, D, F, I, L, N, or O. 
     
     
         2 . A crystalline form according to  claim 1  in the form of Modification C, N, or O. 
     
     
         3 . A crystalline form according to  claim 2  in the form of Modification C. 
     
     
         4 . A crystalline form according to  claim 1  which remains dry at 25° C. and at a relative humidity ranging from 0% to 70%. 
     
     
         5 . A crystalline form according to  claim 1  which remains dry at 25° C. and at a relative humidity ranging from 0% to 80%. 
     
     
         6 . A crystalline form according to  claim 1  comprising at least about 80% by weight of said Modification. 
     
     
         7 . A crystalline form according to  claim 6  comprising at least about 85% by weight of said Modification. 
     
     
         8 . A crystalline form according to  claim 1  in the form of Modification C, characterized by an X-ray powder diffraction pattern with peaks at 5.9 and 17.0 degrees two theta (±0.1 degree) (CuKα λ=1.5418 Å), or an X-ray powder diffraction pattern substantially in accordance with that shown in  FIG. 2.3 . 
     
     
         9 . A crystalline form according to  claim 1 , in the form of Modification C, characterized by a powder x-ray diffraction pattern comprising four or more 2θ values (±0.1 degree) (CuKα λ=1.5418 Å) selected from the group consisting of 5.9, 17.0, 19.6, 22.5, 23.6, 28.4 and 30.0, at a temperature of about 22° C. 
     
     
         10 . A crystalline form according to  claim 9 , in the form of Modification C, further characterized by a powder x-ray diffraction pattern comprising five or more 2θ values (±0.1 degree) (CuKα λ=1.5418 Å) selected from the group consisting of 5.9, 17.0, 19.6, 22.5, 23.6, 28.4 and 30.0, at a temperature of about 22° C. 
     
     
         11 . A crystalline form according to  claim 1 , in the form of Modification C characterized by a solid state  19 F NMR spectrum comprising a peak at −67.6 (±0.2) ppm. 
     
     
         12 . A crystalline form according to  claim 1 , in the form of Modification C characterized by a melting point with an onset at 246.0° C. (±2.4) and a maximum at 250.1° C. (±2.5). 
     
     
         13 . A crystalline form according to  claim 1 , in the form of Modification C characterized by a differential scanning calorimetry thermogram with an endotherm at 126° C. (±2.5). 
     
     
         14 . A pharmaceutical composition comprising a crystalline form, according to  claim 1 , and one or more pharmaceutically acceptable carrier or excipient. 
     
     
         15 . A composition according to  claim 14  comprising an additional therapeutic agent. 
     
     
         16 . A crystalline form according to  claim 1  for use in treating or preventing a condition or disorder associated with DGAT1 activity. 
     
     
         17 . A method for treating or preventing a condition or disorder associated with DGAT1 activity, which method comprises administering to a subject in need thereof a therapeutically effective amount of a crystalline form according to  claim 1 . 
     
     
         18 . The method according to  claim 17  wherein the subject is a mammal. 
     
     
         19 . A process for making Modification C comprising the steps of:
 (a) dissolving the compound of formula (II) in a solvent system, wherein said solvent system is either dimethyl sulfoxide (DMSO) or a mixture of tetrahydrofuran and ethanol;   (b) adding (i) a solvent which is selected from acetonitrile, toluene and methyl-t-butyl ether; or (ii) a mixture of and water and a solvent which is selected from acetonitrile, toluene and methyl-t-butyl ether, wherein the water content is 0.25 to 3% v/v; or (iii) an anti-solvent such as heptane;   (c) filtering the mixture obtained at the end of step (b);   (d) optionally drying the crystals.   
     
     
         20 . A crystalline form according to  claim 7  comprising at least about 90% by weight of said Modification. 
     
     
         21 . A crystalline form according to  claim 20  comprising at least about 95% by weight of said Modification. 
     
     
         22 . A crystalline form according to  claim 21  comprising at least about 99% by weight of said Modification. 
     
     
         23 . A crystalline form according to a pharmaceutical composition according to  claim 14 , for use in treating or preventing a condition or disorder associated with DGAT1 activity. 
     
     
         24 . A method for treating or preventing a condition or disorder associated with DGAT1 activity, which method comprises administering to a subject in need thereof a therapeutically effective amount of a crystalline form according to  claim 14 .