Polymorphs and solid forms of (s)-2-((2-((s)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide, and methods of production

Abstract

The present invention relates to crystalline polymorph forms of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide (GDC-0077), having the structure, Formula I: or stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, and processes of preparing the polymorph forms.

1 . A crystalline, anhydrate polymorph of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide designated the Form A polymorph that exhibits an X-ray powder diffraction pattern having a characteristic peak expressed in degrees 2-theta at approximately 5.7. 
     
     
         2 . The Form A polymorph of  claim 1 , wherein Form A polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.7, 11.4, and 19.0. 
     
     
         3 . The Form A polymorph of  claim 1 , wherein Form A polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.7, 11.4, 17.2, 19.0, 19.7, and 24.4. 
     
     
         4 . The Form A polymorph of  claim 1  characterized by the X-ray powder diffraction pattern substantially as shown in  FIG. 4 . 
     
     
         5 . The Form A polymorph of  claim 1  characterized by the X-ray powder diffraction peaks shown in Table 2. 
     
     
         6 . The Form A polymorph of  claim 1  wherein a differential scanning calorimetry DSC shows a melting endotherm at approximately 212 to 215° C. 
     
     
         7 . The Form A polymorph of  claim 1  characterized by the  13 C SSNMR (solid-state nuclear magnetic resonance) spectra substantially as shown in  FIG. 7A . 
     
     
         8 . The Form A polymorph of  claim 1  characterized by the  19 F SSNMR (solid-state nuclear magnetic resonance) spectra substantially as shown in  FIG. 7B . 
     
     
         9 . A crystalline, anhydrate polymorph of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide designated the Form D polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 7.5, 10.8, 16.8, and 20.4. 
     
     
         10 . The Form D polymorph of  claim 9 , wherein Form D polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 7.5, 8.6, 10.8, 16.8, 19.2, and 20.4. 
     
     
         11 . A crystalline, trihydrate polymorph of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide designated the Form B polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.4, 10.5, and 25.2. 
     
     
         12 . A pharmaceutical composition comprising a therapeutically effective amount of the crystalline, anhydrate polymorph of  claim 1 , and a pharmaceutically acceptable carrier, glidant, diluent, or excipient. 
     
     
         13 . A pharmaceutical composition comprising a therapeutically effective amount of the crystalline, anhydrate polymorph of  claim 9 , and a pharmaceutically acceptable carrier, glidant, diluent, or excipient. 
     
     
         14 . A pharmaceutical composition comprising a therapeutically effective amount of the crystalline, trihydrate polymorph of  claim 11 , and a pharmaceutically acceptable carrier, glidant, diluent, or excipient. 
     
     
         15 . The pharmaceutical composition of  claim 12  in the form of a tablet. 
     
     
         16 . The pharmaceutical composition of  claim 12  wherein the therapeutically effective amount is from about 1 to about 100 mg. 
     
     
         17 . The pharmaceutical composition of  claim 12  wherein the crystalline, anhydrate polymorph is milled. 
     
     
         18 . A process for preparing a crystalline polymorph comprising heating a slurry of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide in ethanol or n-propanol, and then cooling the mixture whereby a Form A crystalline polymorph that exhibits an X-ray powder diffraction pattern having a characteristic peak expressed in degrees 2-theta at approximately 5.7 is formed. 
     
     
         19 . The process of  claim 18 , whereby a Form A crystalline polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.7, 11.4, 17.2, 19.0, 19.7, and 24.4 is formed. 
     
     
         20 . The process of  claim 18  wherein ethanol or n-propanol are used with water. 
     
     
         21 . The process of  claim 18  wherein ethanol or n-propanol are used without water. 
     
     
         22 . The process of  claim 18  comprising heating a slurry of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide in ethanol in the presence of less than 40% of water. 
     
     
         23 . A method for the treatment of cancer in a subject in need thereof comprising administering to the subject an effective amount of a crystalline polymorph of  claim 1 . 
     
     
         24 . A method for the treatment of cancer in a subject in need thereof comprising administering to the subject an effective amount of a crystalline polymorph of  claim 9 . 
     
     
         25 . A method for the treatment of cancer in a subject in need thereof comprising administering to the subject an effective amount of a crystalline polymorph of  claim 11 .