Solid Oral Formulations and Crystalline Forms of an Inhibitor of Apoptosis Protein

Abstract

The present disclosure relates to crystalline form of (S)—N—((S)-1-cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide, salts and hydrates thereof. This disclosure also relates to solid oral formulation of (S)—N—((S)-1-cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide, pharmaceutically acceptable salts, solvates (including hydrates) thereof, as well as methods of treatment using the same.

1 - 41 . (canceled) 
     
     
         42 . Crystalline Form B of (S)—N—((S)-1-cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide, described by compound (I): 
       
         
           
           
               
               
           
         
         characterized by a powder x-ray diffraction pattern comprising three or more 2θ values selected from the group consisting of 3.8±0.2, 7.7±0.2, 13.8±0.2, 14.6±0.2, 15.4±0.2, 17.6±0.2, 19.1±0.2, 19.2±0.2, 19.4±0.2, 20.0±0.2, 20.7±0.2, 20.9±0.2, and 22.8±0.2. 
       
     
     
         43 . Crystalline Form B of  claim 42  characterized by a powder x-ray diffraction pattern at ambient temperature substantially in accordance with that shown in  FIG. 1 . 
     
     
         44 . Crystalline Form B of  claim 42  characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with that shown in  FIG. 4 . 
     
     
         45 . Crystalline Form B of  claim 42  characterized by a thermo gravimetric analysis (TGA) diagram substantially in accordance with that shown in  FIG. 4 . 
     
     
         46 . Crystalline Form C of (S)—N—((S)-1-cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide, described by compound (I): 
       
         
           
           
               
               
           
         
         characterized by a powder x-ray diffraction pattern comprising three or more 2θ values selected from the group consisting of 5.8±0.2, 7.7±0.2, 9.9±0.2, 13.0±0.2, 14.3±0.2, 15.5±0.2, 17.5±0.2, 19.4±0.2, 20.0±0.2, 22.9±0.2, and 24.3±0.2, at ambient temperature. 
       
     
     
         47 . Crystalline Form C of  claim 46  characterized by a powder x-ray diffraction pattern at ambient temperature (i.e., at temperature from about 20° C. to 25° C.), substantially in accordance with that shown in  FIG. 1 . 
     
     
         48 . Crystalline Form C of  claim 46  characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with that shown in  FIG. 5 . 
     
     
         49 . Crystalline Form C of  claim 46  characterized by a thermo gravimetric analysis (TGA) diagram substantially in accordance with that shown in  FIG. 5 . 
     
     
         50 . Crystalline Form D of (S)—N—((S)-1-cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide, described by compound (I): 
       
         
           
           
               
               
           
         
         characterized by a powder x-ray diffraction pattern comprising three or more 2θ values selected from the group consisting of 6.5±0.2, 8.6±0.2, 11.3±0.2, 11.9±0.2, 13.1±0.2, 14.2±0.2, 15.1±0.2, 17.4±0.2, 19.6±0.2, 19.9±0.2, 20.4±0.2, 21.7±0.2, 25.6±0.2, and 31.7±0.2, at ambient temperature. 
       
     
     
         51 . Crystalline Form D of  claim 50  characterized by a powder x-ray diffraction pattern at ambient temperature, substantially in accordance with that shown in  FIG. 1 . 
     
     
         52 . Crystalline Form D of  claim 50  characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with that shown in  FIG. 6 . 
     
     
         53 . Crystalline Form D of  claim 50  characterized by a thermo gravimetric analysis (TGA) diagram substantially in accordance with that shown in  FIG. 6