Tlr7 agonist maleate salt, crystalline forms c, d and e thereof, preparation methods and uses of maleate salt and crystalline forms

Abstract

The present invention relates to a maleate salt of a compound represented by formula I, a method for preparing the salt, a pharmaceutical composition containing the salt, and the use of the salt. The present invention also relates to crystalline forms C, D and E of the maleate salt of the compound represented by formula I, methods for preparing the crystalline forms, crystalline compositions and pharmaceutical compositions containing the crystalline forms, and uses thereof.

1 .- 10 . (canceled) 
     
     
         11 . A crystal form C of a maleate of a compound of formula I, wherein the crystal form C has diffraction peaks at 2θ=5.6°±0.2°, 7.6°±0.2°, 9.9°±0.2°, 17.8°±0.2°, 19.8°±0.2°, 22.8°±0.2°, 24.2°±0.2°, 25.0°±0.2°, 26.3°±0.2° in X-ray diffraction pattern 
       
         
           
           
               
               
           
         
       
     
     
         12 . The crystal form C according to  claim 11 , wherein the crystal form C has diffraction peaks at 2θ=5.6°±0.2°, 6.0°±0.2°, 7.6°±0.2°, 9.9°±0.2°, 12.0°±0.2°, 15.3°±0.2°, 17.8°±0.2°, 18.5°±0.2°, 19.8°±0.2°, 20.4°±0.2°, 22.8°±0.2°, 23.1°±0.2°, 24.2°±0.2°, 24.7°±0.2°, 25.0°±0.2°, 26.3°±0.2° in X-ray diffraction pattern. 
     
     
         13 . The crystal form C according to  claim 11 , wherein the crystal form C has a X-ray powder diffraction pattern substantially shown in  FIG. 1 . 
     
     
         14 . A process for preparing the crystal form C according to  claim 11 , comprising the following steps:
 1) dissolving the compound of formula I in a solvent;   2) adding maleic acid; and   3) cooling for crystallization, filtering, washing and drying to obtain the crystal form C, wherein the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tertiary butanol, acetone, ethyl acetate and mixed solvent thereof.   
     
     
         15 . The process according to  claim 14 , wherein the solvent is ethanol. 
     
     
         16 . A crystal form D of a maleate of a compound of formula I, wherein the crystal form D has diffraction peaks at 2θ=5.1°±0.2°, 9.5°±0.2°, 11.2°±0.2°, 17.6°±0.2°, 20.2°±0.2°, 20.7°±0.2°, 23.0°±0.2°, 23.7°±0.2° in X-ray diffraction pattern 
       
         
           
           
               
               
           
         
       
     
     
         17 . The crystal form D according to  claim 16 , wherein the crystal form D has diffraction peaks at 2θ=5.1°±0.2°, 5.6°±0.2°, 9.5°±0.2°, 11.2°±0.2°, 16.9°±0.2°, 17.6°±0.2°, 20.2°±0.2°, 20.7°±0.2°, 22.6°±0.2°, 23.0°±0.2°, 23.7°±0.2°, 24.5°±0.2° in X-ray diffraction pattern. 
     
     
         18 . The crystal form D according to  claim 16 , wherein the crystal form D has a X-ray powder diffraction pattern substantially shown in  FIG. 2 . 
     
     
         19 . A process for preparing the crystal form D according to  claim 16 , comprising the following steps:
 1) placing a crystal form C of the maleate of the compound of formula I in acetone solvent to form a suspension;   2) shaking at constant temperature; and   3) centrifugating, washing and drying to obtain the crystal form D, wherein the crystal form C has diffraction peaks at 2θ=5.6°±0.2°, 7.6°±0.2°, 9.9°±0.2°, 17.8°±0.2°, 19.8°±0.2°, 22.8°±0.2°, 24.2°±0.2°, 25.0°±0.2°, 26.3°±0.2° in X-ray diffraction pattern.   
     
     
         20 . A crystal form E of a maleate of a compound of formula I, wherein the crystal form E has diffraction peaks at 2θ=4.9°±0.2°, 5.3°±0.2°, 6.7°±0.2°, 9.0°±0.2°, 10.8°±0.2°, 16.5°±0.2°, 19.3°±0.2° in X-ray powder diffraction pattern 
       
         
           
           
               
               
           
         
       
     
     
         21 . The crystal form E according to  claim 20 , wherein the crystal form E has diffraction peaks at 2θ=4.9°±0.2°, 5.3°±0.2°, 6.7°±0.2°, 9.0°±0.2°, 10.8°±0.2°, 16.2°±0.2°, 16.5°±0.2°, 19.3°±0.2°, 22.0°±0.2°, 22.6°±0.2°, 25.9°±0.2° in X-ray powder diffraction pattern. 
     
     
         22 . The crystal form E according to  claim 20 , wherein the crystal form E has a X-ray powder diffraction pattern substantially shown in  FIG. 3 . 
     
     
         23 . A process for preparing the crystal form E according to  claim 20 , comprising the following steps:
 1) placing a crystal form C of the maleate of the compound of formula I in isopropanol solvent to form a suspension;   2) shaking at constant temperature; and   3) centrifugating, washing and drying to obtain the crystal form E, wherein the crystal form C has diffraction peaks at 2θ=5.6°±0.2°, 7.6°±0.2°, 9.9°±0.2°, 17.8°±0.2°, 19.8°±0.2°, 22.8°±0.2°, 24.2°±0.2°, 25.0°±0.2°, 26.3°±0.2° in X-ray diffraction pattern.   
     
     
         24 . A pharmaceutical composition comprising the crystal form C according to  claim 11  in an effective amount. 
     
     
         25 . A pharmaceutical composition comprising the crystal form D according to  claim 16  in an effective amount. 
     
     
         26 . A pharmaceutical composition comprising the crystal form E according to  claim 20  in an effective amount. 
     
     
         27 . A method for treating hepatitis B viral infection or hepatitis C viral infection comprising administering a subject in need thereof the crystal form C according to  claim 11 . 
     
     
         28 . A method for treating hepatitis B viral infection or hepatitis C viral infection comprising administering a subject in need thereof the crystal form D according to  claim 16 . 
     
     
         29 . A method for treating hepatitis B viral infection or hepatitis C viral infection comprising administering a subject in need thereof the crystal form E according to  claim 20 .