Crystalline forms of [(1R), 2S]-2-aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester

Abstract

Crystalline form, Form N-1, of [(1R), 2S]-2-aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester (Compound I) is provided. Also provided are a pharmaceutical composition and an oral dosage form comprising the Form N-1 of Compound I as well as a method of using the Form N-1 of Compound I in the treatment of cancer and other proliferative diseases.

1 . A crystalline form of Compound I:  
     
       
         
         
             
             
         
       
     
     comprising Form N-1.  
   
   
       2 . The crystalline form according to  claim 1  consisting essentially of said Form N-1.  
   
   
       3 . The crystalline form according to  claim 1 , wherein said Form N-1 is in substantially pure form.  
   
   
       4 . The crystalline form according to  claim 1  characterized by unit cell parameters substantially equal to the following:  
     Cell dimensions: 
       a=9.85 Å b=8.06 Å c=14.98 Å α=90.0° β=106.9° γ=90.0° 
     Space group: P2 1    
     Molecules/unit cell: 2  
     wherein measurement of said crystalline form is at a temperature of about 25° C.  
   
   
       5 . The crystalline form according to  claim 1  characterized by fractional atomic coordinates substantially as listed in Table 1.  
   
   
       6 . The crystalline form according to  claim 1  characterized by a powder x-ray diffraction pattern comprising four or more 2θ values (CuKα λ=1.5418 Å) selected from the group consisting of 9.4±0.2, 12.6±0.2, 13.2±0.2, 14.5±0.2, 16.6±0.2, 17.2±0.2, 18.2±0.2, 18.8±0.2, 21.3±0.2, 21.6±0.2, and 22.1±0.2, wherein measurement of said crystalline form is at a temperature of about 25° C.  
   
   
       7 . The crystalline form according to  claim 1  characterized by a powder x-ray diffraction pattern comprising five or more 2θ values (CuKα λ=1.5418 Å) selected from the group consisting of 9.4±0.2, 12.6±0.2, 13.2±0.2, 14.5±0.2, 16.6±0.2, 17.2±0.2, 18.2±0.2, 18.8±0.2, 21.3±0.2, 21.6±0.2, and 22.1±0.2, wherein measurement of said crystalline form is at a temperature of about 25° C.  
   
   
       8 . The crystalline form according to  claim 1  characterized by one or more of the following: 
 a) unit cell parameters substantially equal to the following:    Cell dimensions:     a=9.85 Å b=8.06 Å c=14.98 Å α=90.0° β=106.9° γ=90.0°   Space group: P2 1      Molecules/unit cell: 2    wherein measurement of said crystalline form is at a temperature of about 25° C.;    b) a powder x-ray diffraction pattern comprising five or more 2θ values (CuKα λ=1.5418 Å) selected from the group consisting of 9.4±0.2, 12.6±0.2, 13.2±0.2, 14.5±0.2, 16.6±0.2, 18.2±0.2, 18.8±0.2, 21.3±0.2, 21.6±0.2, and 22.1±0.2, wherein measurement of said crystalline form is at a temperature of about 25° C.; and/or    c) a melting point in the range of from about 138° C. to about 144° C.    
   
   
       9 . A pharmaceutical composition comprising the crystalline form according to  claim 1  and a pharmaceutically acceptable carrier or diluent.  
   
   
       10 . The pharmaceutical composition according to  claim 9  wherein said Form N-1 is in substantially pure form.  
   
   
       11 . An oral dosage form comprising Compound I  
     
       
         
         
             
             
         
       
     
     wherein Compound I is in crystalline form comprising Form N-1.  
   
   
       12 . The oral dosage form according to  claim 11 , wherein said Compound I consists essentially of said Form N-1.  
   
   
       13 . The oral dosage form according to  claim 11 , wherein said Form N-1 is in substantially pure form.  
   
   
       14 . The oral dosage form according to  claim 11 , comprising from about 1 to about 500 mg of said Compound I.  
   
   
       15 . The oral dosage form according to  claim 14 , wherein said Form N-1 is in substantially pure form.  
   
   
       16 . A method for treating a proliferative disease, comprising administering to a mammalian species in need thereof, a therapeutically effect amount of Compound I  
     
       
         
         
             
             
         
       
     
     wherein said Compound I is provided in a crystalline form comprising Form N-1.  
   
   
       17 . The method of  claim 16  wherein said mammalian species is human.  
   
   
       18 . The method of  claim 16  wherein said proliferative disease is selected from the group consisting of breast cancer, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer, and prostate cancer.