Novel crystalline forms of an antiviral benzimidazole compound

Abstract

The invention relates to crystalline forms of 5,6-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1Hbenzimidazole, pharmaceutical compositions comprising the same, processes for preparing the same, and their use in medical therapy.

1 . Form II 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole having substantially the same X-ray powder diffraction pattern as  FIG. 2 , wherein said X-ray powder diffraction pattern is obtained with a diffractometer equipped with a diffracted beam curved graphite monochromator using copper Kα X-radiation. 
     
     
         2 . A crystalline form of 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole characterized by an X-ray powder diffraction pattern expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a diffracted beam curved graphite monochromator using copper Kα X-radiation, wherein said X-ray powder diffraction pattern comprises 2 theta angles at five or more positions selected from the group consisting of at five or more of the following positions: 7.91±0.09, 17.33±0.09, 18.23±0.95, 19.60±0.09, 21.88±0.09, 23.24±0.09, 23.92±0.09, 25.27±0.09, 27.70±0.09, and 29.21±0.09 degrees. 
     
     
         3 . 5,6,-Dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole ethanol solvate having substantially the same X-ray powder diffraction pattern as  FIG. 3 , wherein said X-ray powder diffraction pattern is obtained with a diffractometer equipped with a diffracted beam curved graphite monochromator using copper Kα X-radiation. 
     
     
         4 . Ethanol solvate of 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole characterized by an X-ray powder diffraction pattern expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a diffracted beam curved graphite monochromator using copper Kα X-radiation, wherein said X-ray powder diffraction pattern comprises 2 theta angles at five or more positions selected from the group consisting of at five or more of the following positions: 9.07±0.05, 10.38±0.05, 15.95±0.05, 17.72±0.05, 20.75±0.05, 21.37±0.05, 22.96±0.05, 23.93±0.05, 25.40±0.05, and 29.05±0.05 degrees. 
     
     
         5 . Form V 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole having substantially the same X-ray powder diffraction pattern as  FIG. 5 , wherein said X-ray powder diffraction pattern is obtained with a diffractometer equipped with a diffracted beam curved graphite monochromator using copper Kα X-radiation. 
     
     
         6 . A crystalline form of 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole characterized by an X-ray powder diffraction pattern expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a diffracted beam curved graphite monochromator using copper Kα X-radiation, wherein said X-ray powder diffraction pattern comprises 2 theta angles at five or more positions selected from the group consisting of at five or more of the following positions: 13.30±0.05, 18.13±0.05, 18.78±0.05, 20.41±0.05, 21.75±0.05, 23.02±0.05, 26.87±0.05, 28.34±0.05, 28.55±0.05, and 30.22±0.05 degrees. 
     
     
         7 . A composition comprising an admixture of two or more forms or solvates of 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole according to any of  claims 1 - 6 . 
     
     
         8 . A composition comprising Form II 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole according to  claim 1  and amorphous 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole. 
     
     
         9 . A composition comprising Form I 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole having substantially the same X-ray powder diffraction pattern as  FIG. 1  and Form V 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole having substantially the same X-ray powder diffraction pattern as  FIG. 5 , wherein said X-ray powder diffraction patterns are obtained with a diffractometer equipped with a diffracted beam curved graphite monochromator using copper Kα X-radiation. 
     
     
         10 . The composition according to  claim 9 , further comprising Form IV 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole characterized by the X-ray powder diffraction pattern expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a diffracted beam curved graphite monochromator using copper Kα X-radiation, wherein said X-ray powder diffraction pattern comprises 2 theta angles at five or more positions selected from the group consisting of at five or more of the following positions: 9.29±0.05, 16.04±0.05, 18.67±0.05, 22.06±0.05, 22.68±0.05, 23.34±0.05, 24.40±0.05, 29.64±0.05, 30.92±0.05, and 31.62±0.05 degrees. 
     
     
         11 . A pharmaceutical composition comprising a compound as claimed in any one of  claims 1  to  6  and at least one pharmaceutically acceptable carrier therefor. 
     
     
         12 . 5,6,-Dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole as claimed in any one of  claims 1 - 6  for use in medical therapy. 
     
     
         13 . Use of 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole as claimed in any one of  claims 1  to  6  in the preparation of a medicament for the treatment of a viral infection. 
     
     
         14 . A method for the treatment of a viral infection a human which comprises administering to the human host, an effective antiviral amount of a solvate or crystalline form of 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole as claimed in any one of  claims 1  to  6 . 
     
     
         15 . A process for the production of 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole in an anhydrous crystalline form said process comprising the steps of:
 a) providing 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole in solution either in free base or salt form; 
 b) isolating 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole from the solution and optionally removing unbound solvent leaving the 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole in substantially dry form; 
 c) treating 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole with a solubilising solvent serving to convert an amount of said optionally dried 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole into said 5,6,-dichloro-2-(isopropylamino)-1-β-L-ribofuranosyl-1H-benzimidazole anhydrous crystalline form; and 
 d) isolating said anhydrous crystalline form.