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.

1 . (canceled) 
     
     
         2 . A crystalline form of Raltegravir potassium selected from:
 a) crystalline Form V of Raltegravir potassium, characterized by data selected from: an X-ray powder diffraction pattern having peaks at 8.0, 11.9, 18.2 and 26.6 degrees two theta±0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in  FIG. 2 ; a solid-state  13 C NMR spectrum with signals at 121.9, 144.0, 149.3 and 170.3±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 111.9, 134.0, 139.3 and 160.3±0.1 ppm; a solid-state  13 C NMR spectrum substantially as depicted in  FIG. 31 ; and combinations thereof; and   b) crystalline Form IV of Raltegravir potassium, characterized by data selected from: an X-ray powder diffraction pattern having peaks at 6.5, 7.5, 8.1, 18.4 and 23.2 degrees two theta±0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in  FIG. 1 ; and combinations thereof.   
     
     
         3 . The crystalline Raltegravir potassium Form V according to  claim 2 , characterized by data selected from: an X-ray powder diffraction pattern having peaks at 8.0, 11.9, 18.2 and 26.6 degrees two theta±0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in  FIG. 2 ; a solid-state  13 C NMR spectrum with signals at 121.9, 144.0, 149.3 and 170.3±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 111.9, 134.0, 139.3 and 160.3±0.1 ppm; a solid-state  13 C NMR spectrum substantially as depicted in  FIG. 31 ; and combinations thereof. 
     
     
         4 . The crystalline Form V of Raltegravir potassium according to  claim 3 ; characterized by an X-ray powder diffraction pattern having peaks at 8.0, 11.9, 18.2 and 26.6 degrees two theta±0.2 degrees two theta. 
     
     
         5 . The crystalline Form IV of Raltegravir potassium according to  claim 2 , characterized by data selected from: an X-ray powder diffraction pattern having peaks at 6.5, 7.5, 8.1, 18.4 and 23.2 degrees two theta±0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in  FIG. 1 ; and combinations thereof. 
     
     
         6 . The crystalline Raltegravir potassium Form IV according to  claim 5 , characterized by an X-ray powder diffraction pattern having peaks at 6.5, 7.5, 8.1, 18.4 and 23.2 degrees two theta±0.2 degrees two theta, and further characterized by data selected from: X-ray powder diffraction pattern having additional peaks at 13.0, 17.5, 24.2 and 25.5 degrees two theta±0.2 degrees two theta; a DSC thermogram as depicted in  FIG. 27 ; a TGA thermogram as depicted in  FIG. 28 ; and combinations thereof. 
     
     
         7 . Crystalline Raltegravir sodium. 
     
     
         8 . A crystalline form of Raltegravir sodium according to  claim 7 , selected from:
 a) Form S1, characterized by data selected from: 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 data selected from: 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 data selected from: 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 . Crystalline Form S1 of Raltegravir sodium according to  claim 8 , characterized by data selected from: 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. 
     
     
         10 . The crystalline Form S1 of Raltegravir sodium according to  claim 9 , 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 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. 
     
     
         11 . Crystalline form S2 of Raltegravir sodium according to  claim 8 , characterized by data selected from: 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. 
     
     
         12 . The crystalline Form S2 of Raltegravir sodium according to  claim 11 , 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. 
     
     
         13 . The crystalline Form S2 of Raltegravir sodium according to  claim 12 , 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. 
     
     
         14 . Crystalline Form S3 of Raltegravir sodium according to  claim 7 , characterized by data selected from: 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. 
     
     
         15 . The crystalline Form S3 of Raltegravir sodium according to  claim 14 , 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. 
     
     
         16 . The crystalline Form S3 of Raltegravir sodium according to  claim 15 , 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. 
     
     
         17 . Raltegravir calcium salt. 
     
     
         18 . Raltegravir calcium salt according to  claim 17  in crystalline form. 
     
     
         19 . The crystalline Raltegravir calcium according to  claim 18 , characterized by data selected from: 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. 
     
     
         20 . Raltegravir tert-butyl amine salt. 
     
     
         21 . Raltegravir tert-butyl amine salt according to  claim 20  in crystalline form. 
     
     
         22 . The crystalline Raltegravir tert-butyl amine salt according to  claim 21 , characterized by data selected from: 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  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. 
     
     
         23 . The crystalline Raltegravir tert-butyl amine according to  claim 22 , 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. 
     
     
         24 . (canceled) 
     
     
         25 . A pharmaceutical composition comprising crystalline Form V or crystalline Form IV of Raltegravir potassium according to  claim 2  and at least one pharmaceutically acceptable excipient. 
     
     
         26 . A pharmaceutical composition comprising the Raltegravir salt according to any one of  claims 7 ,  17  or  20 , and at least one pharmaceutically acceptable excipient. 
     
     
         27 . A method of treating a patient with HIV, comprising administering to said patient an effective amount of the pharmaceutical composition according to  claim 26 . 
     
     
         28 . (canceled) 
     
     
         29 . A process for preparing Raltegravir potassium comprising: reacting at least one Raltegravir salt according to any one of  claim 7 ,  17  or  20 , with a potassium base. 
     
     
         30 . The process of  claim 29 , wherein said process comprises converting the at least one Raltegravir salt to Raltegravir free hydroxy prior to reacting with a potassium base. 
     
     
         31 . The process of  claim 30 , wherein the at least one Raltegravir salt is in solid state when converted to Raltegravir free hydroxy prior to reacting with a potassium base. 
     
     
         32 . The crystalline Raltegravir potassium Form V according to  claim 4 , further characterized by data selected from: X-ray powder diffraction pattern having additional peaks at 14.9, 19.8, 24.9, 27.7 and 28.9 degrees two theta±0.2 degrees two theta; a DSC thermogram as depicted in  FIG. 29 ; a TGA thermogram as depicted in  FIG. 30 ; an FT Raman spectrum as depicted in  FIG. 32 ; and combinations thereof. 
     
     
         33 . A method of treating a patient with HIV, comprising administering to said patient an effective amount of the pharmaceutical composition according to  claim 25 .