Raltegravir Salts And Crystalline Forms Thereof

Abstract

The present invention includes new salts of Raltegravir and crystalline forms thereof, pharmaceutical compositions containing the salts or crystalline forms, methods of using the salts or crystalline forms or the compositions to treat HIV infection or to prepare medicament for treating HIV infection, and a process for preparing Raltegravir potassium.

What is claimed is: 
     
         1 . Crystalline Raltegravir sodium. 
     
     
         2 . The crystalline form of Raltegravir sodium according to  claim 1 , selected from the group consisting of:
 a) Form S1, characterized by:
 an X-ray powder diffraction pattern having peaks at 7.9, 11.8, 17.0, 19.7 and 28.8 degrees two theta±0.2 degrees two theta; 
 an X-ray powder diffraction pattern substantially as depicted in  FIG. 12 ; 
 and combinations thereof; 
   b) Form S2, characterized by:
 an X-ray powder diffraction pattern having peaks at 7.8, 11.8, 19.6 and 26.3 degrees two theta±0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in  FIG. 13 ; 
 a solid-state  13 C NMR spectrum with signals at 134.3, 146.1, 149.0, 153.9 and 170.5±0.2 ppm; 
 a solid-state  13 C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of 124.3, 136.1, 139.0, 143.9 and 160.5±0.1 ppm; 
 a solid-state  13 C NMR spectrum substantially as depicted in  FIG. 33 ; 
 and combinations thereof; and 
   c) Form S3, characterized by:
 an X-ray powder diffraction pattern having peaks at 8.1, 13.6, 15.1, 16.1 and 22.6 degrees two theta±0.2 degrees two theta; 
 an X-ray powder diffraction pattern substantially as depicted in  FIG. 14 ; 
 and combinations thereof. 
   
     
     
         3 . The crystalline Form S1 of Raltegravir sodium according to  claim 2 , characterized by:
 an X-ray powder diffraction pattern having peaks at 7.9, 11.8, 17.0, 19.7 and 28.8 degrees two theta±0.2 degrees two theta;   an X-ray powder diffraction pattern substantially as depicted in  FIG. 12 ;   and combinations thereof.   
     
     
         4 . The crystalline Form S1 of Raltegravir sodium according to  claim 3 , characterized by an X-ray powder diffraction pattern having peaks at 7.9, 11.8, 17.0, 19.7 and 28.8 degrees two theta±0.2 degrees two theta, and further characterized by an X-ray powder diffraction pattern having additional peaks at 14.0, 15.0, 23.9 and 27.8 degrees two theta±0.2 degrees two theta. 
     
     
         5 . The crystalline Form S2 of Raltegravir sodium according to  claim 2 , characterized by:
 an X-ray powder diffraction pattern having peaks at 7.8, 11.8, 19.6 and 26.3 degrees two theta±0.2 degrees two theta;   an X-ray powder diffraction pattern substantially as depicted in  FIG. 13 ;   a solid-state  13 C NMR spectrum with signals at 134.3, 146.1, 149.0, 153.9 and 170.5±0.2 ppm;   a solid-state  13 C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of 124.3, 136.1, 139.0, 143.9 and 160.5±0.1 ppm;   a solid-state  13 C NMR spectrum substantially as depicted in  FIG. 33 ;   and combinations thereof.   
     
     
         6 . The crystalline Form S2 of Raltegravir sodium according to  claim 5 , characterized by an X-ray powder diffraction pattern having peaks at 7.8, 11.8, 19.6 and 26.3 degrees two theta±0.2 degrees two theta. 
     
     
         7 . The crystalline Form S2 of Raltegravir sodium according to  claim 6 , further characterized by X-ray powder diffraction pattern having additional peaks at 14.6, 17.2, 23.6, 28.1 and 29.1 degrees two theta±0.2 degrees two theta. 
     
     
         8 . The crystalline Form S3 of Raltegravir sodium according to  claim 1 , characterized by:
 an X-ray powder diffraction pattern having peaks at 8.1, 13.6, 15.1, 16.1 and 22.6 degrees two theta±0.2 degrees two theta;   an X-ray powder diffraction pattern substantially as depicted in  FIG. 14 ;   and combinations thereof.   
     
     
         9 . The crystalline Form S3 of Raltegravir sodium according to  claim 8 , characterized by:
 an X-ray powder diffraction pattern having peaks at 8.1, 13.6, 15.1, 16.1 and 22.6 degrees two theta±0.2 degrees two theta.   
     
     
         10 . The crystalline Form S3 of Raltegravir sodium according to  claim 9 , further characterized by X-ray powder diffraction pattern having additional peaks at 20.3, 23.1, 27.4, 30.2 and 32.5 degrees two theta±0.2 degrees two theta. 
     
     
         11 . Raltegravir calcium salt. 
     
     
         12 . Raltegravir calcium salt according to  claim 11  in crystalline form. 
     
     
         13 . The crystalline Raltegravir calcium salt according to  claim 12 , characterized by:
 an X-ray powder diffraction pattern with peaks at 6.5, 9.9, 18.0, 19.0 and 21.1 degrees two theta 0.2 degrees two theta;   an X-ray powder diffraction pattern substantially as depicted in  FIG. 16 ;   and combinations thereof.   
     
     
         14 . Raltegravir tert-butyl amine salt. 
     
     
         15 . The Raltegravir tert-butyl amine salt according to  claim 14  in crystalline form. 
     
     
         16 . The crystalline Raltegravir tert-butyl amine salt according to  claim 15 , characterized by:
 an X-ray powder diffraction pattern with peaks at 12.4, 16.7, 17.9, 18.6 and 20.9 degrees two theta 0.2 degrees two theta;   an X-ray powder diffraction pattern with peaks at 4.2, 6.6, 8.4, 16.9 and 21.1 degrees two theta 0.2 degrees two theta;   an X-ray powder diffraction pattern substantially as depicted in  FIG. 17  or  FIG. 26 ;   a solid-state  13 C NMR spectrum with signals at 121.7, 130.2, 141.6, 152.0±0.2 ppm;   a solid-state  13 C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of 110.4, 118.9, 130.3 and 140.7±0.1 ppm;   a solid-state  13 C NMR spectrum substantially as depicted in  FIG. 34 ;   and combinations thereof.   
     
     
         17 . The crystalline Raltegravir tert-butyl amine salt according to  claim 16 , further characterized by X-ray powder diffraction pattern having additional peaks at 9.2, 10.2, 12.6, 13.8, 15.2 and 18.0 degrees two theta±0.2 degrees two theta. 
     
     
         18 . A pharmaceutical composition comprising the Raltegravir salt according to any one of  claims 1 ,  11 , or  14  and at least one pharmaceutically acceptable excipient. 
     
     
         19 . A method of treating a patient with HIV, comprising administering to said patient an effective amount of the pharmaceutical composition according to  claim 18 . 
     
     
         20 . A process for preparing Raltegravir potassium comprising reacting at least one Raltegravir salt according to any one of  claims 1 ,  11 , or  14  with a potassium base. 
     
     
         21 . The process of  claim 20 , wherein said process comprises converting the at least one Raltegravir salt to Raltegravir free hydroxy prior to reacting with a potassium base. 
     
     
         22 . The process of  claim 21 , wherein the at least one Raltegravir salt is in solid state when converted to Raltegravir free hydroxy prior to reacting with a potassium base.