Mono-hydrochloric salts of an inhibitor of histone deacetylase

Abstract

This invention provides novel crystalline forms of mono-HCl salts and a mono-HCl salt hydrate of JNJ-26481585, an inhibitor of histone deacetylases. The invention also relates to processes for production of these forms, to intermediates used in these processes, to pharmaceutical compositions comprising these forms, and to the use of these forms in medical treatment for instance as a medicine to inhibit proliferative conditions, such as cancer and leukemia.

1 . A mono-hydrochloric salt of formula (XIX) 
     
       
         
         
             
             
         
       
     
   
   
       2 . The mono-hydrochloric salt of  claim 1  wherein said salt is in crystalline Form I, Form II or in a hydrate form. 
   
   
       3 . The mono-hydrochloric salt of  claim 1  in crystalline Form I wherein said crystalline form has an X-ray powder diffraction pattern comprising peaks at 15.1°±0.2°, 17.2°±0.2°, 23.4°±0.2°, 24.4°±0.2° and 27.7°±0.2°. 
   
   
       4 . The mono-hydrochloric salt of  claim 3  wherein the X-ray powder diffraction pattern further comprises peaks at 7.6°±0.2°, 12.0°±0.2° and 12.5°±0.2°. 
   
   
       5 . The mono-hydrochloric salt of  claim 1  wherein the crystalline form has an infrared spectrometry micro attenuated reflectance spectrum with peaks at 3119±1 cm −1 , 2756±1 cm −1 , 1634±1 cm −1 , 1475±1 cm −1 , 1371±1 cm −1 , 1333±1 cm −1 , 1275±1 cm −1 , 1226±1 cm −1 , 1128±1 cm −1  and 1066 cm −1 ±1 cm −1 . 
   
   
       6 . The mono-hydrochloric salt of  claim 1  wherein the crystalline form has a differential scanning calorimetry curve with an endothermic peak at about 216.8° C. 
   
   
       7 . The mono-hydrochloric salt of  claim 1  wherein the crystalline form adsorbs up to 0.6% water at high relative humidity. 
   
   
       8 . The mono-hydrochloric salt of  claim 1  in hydrate form wherein said hydrate form has an X-ray powder diffraction pattern comprising peaks at 10.0°±0.2°, 13.4°±0.2° and 26.5°±0.2°. 
   
   
       9 . The mono-hydrochloric salt of  claim 8  wherein the X-ray powder diffraction pattern further comprises peaks at 21.6°±0.2° and 24.9°±0.2°. 
   
   
       10 . The mono-hydrochloric salt of  claim 8  wherein the crystalline form has an infrared spectrometry micro attenuated reflectance spectrum with peaks at 3558±1 cm −1 , 3238±1 cm −1 , 1607±1 cm −1  and 997 cm −1 ±1 cm −1 . 
   
   
       11 . The mono-hydrochloric salt of  claim 1  wherein crystalline Form I is essentially pure. 
   
   
       12 . The mono-hydrochloric salt of  claim 1  wherein crystalline Form II is essentially pure. 
   
   
       13 . The mono-hydrochloric salt of  claim 1  wherein the hydrate form is essentially pure. 
   
   
       14 . A process for preparing the crystalline form according to  claim 1  comprising:
 a) dissolving compound of formula (XVIII) in an alcoholic solvent containing less than 0.1% w/w of water, while heating to between 50° C. and 70° C.;   b) adding hydrochloric acid to the reaction mixture; and   c) stirring the reaction mixture while maintaining the temperature at between 50° C. and 70° C.   
   
   
       15 . The process of  claim 14  comprising between step a) and b) seeding the mixture with Form I. 
   
   
       16 . A process for preparing the hydrate form according to  claim 2  comprising
 a) dissolving the compound of formula (XVIII), in an ethanol/water or methanol/water mixture comprising more than 5% of water, while heating to between 50° C. and 70° C., preferably 50° C. and 60° C. of the solvent;   b) adding hydrochloric acid to the reaction mixture; and   c) stirring the reaction mixture while maintaining the temperature at between 50° C. and 70° C., preferably between 50° C. and 60° C. more preferably at 55° C.   
   
   
       17 . A process for preparing the compound of formula (XVIII) comprising
 a) reacting the intermediate of formula (VIII) with the intermediate of formula (XI) in the presence of a suitable solvent,   
     
       
         
         
             
             
         
       
       b) reacting the intermediate of formula (I) with the intermediate of formula (II) in a suitable solvent followed by reduction and salt formation giving the intermediate of formula (XIII), 
     
     
       
         
         
             
             
         
       
       c) conversion of the intermediate of formula (XIII) by base neutralization, basic hydrolysis and acidification with hydrochloric acid into the intermediate of formula (XVII) and 
     
     
       
         
         
             
             
         
       
       d) reacting the intermediate of formula (XVII) with O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine, in the presence of an appropriate coupling reagents. 
     
     
       
         
         
             
             
         
       
     
   
   
       18 . The process of  claim 17  wherein the amount of water in intermediate (XVII) is between 15 and 25 v/v %. 
   
   
       19 . A process for the preparation of the compound of formula (XI) comprising
 reacting an intermediate of formula (IX) with an intermediate of formula (X) in the presence of a suitable solvent.   
     
       
         
         
             
             
         
       
     
   
   
       20 . A compound of formula (XI), (XIII), (XVII) or (XVIII). 
     
       
         
         
             
             
         
       
       an N-oxide, addition salt or stereochemically isomeric form thereof. 
     
   
   
       21 . (canceled) 
   
   
       22 . (canceled) 
   
   
       23 . (canceled) 
   
   
       24 . A pharmaceutical composition comprising the mono-hydrochloric salt of  claim 1  and a pharmaceutically acceptable excipient. 
   
   
       25 . Use of the mono-hydrochloric salt according to  claim 1  as seeding material for preparing Form I. 
   
   
       26 . A combination of the mono-hydrochloric salt of  claim 1  with another anticancer agent. 
   
   
       27 . The mono-hydrochloric salt of  claim 2  in crystalline Form I wherein said crystalline form has an X-ray powder diffraction pattern comprising peaks at 15.1°±0.2°, 17.2°±0.2°, 23.4°±0.2°, 24.4°±0.2° and 27.7°±0.2°. 
   
   
       28 . The mono-hydrochloric salt of  claim 27  wherein the X-ray powder diffraction pattern further comprises peaks at 7.6°±0.2°, 12.0°±0.2° and 12.5°±0.2°. 
   
   
       29 . The mono-hydrochloric salt of  claim 2  wherein the crystalline form has an infrared spectrometry micro attenuated reflectance spectrum with peaks at 3119±1 cm −1 , 2756±1 cm −1 , 1634±1 cm −1 , 1475±1 cm −1 , 1371±1 cm −1 , 1333±1 cm −1 , 1275±1 cm −1 , 1226±1 cm −1 , 1128±1 cm −1  and 1066 cm −1 ±1 cm −1 . 
   
   
       30 . The mono-hydrochloric salt of  claim 3  wherein the crystalline form has an infrared spectrometry micro attenuated reflectance spectrum with peaks at 3119±1 cm −1 , 2756±1 cm −1 , 1634±1 cm −1 , 1475±1 cm −1 , 1371±1 cm −1 , 1333±1 cm −1 , 1275±1 cm −1 , 1226±1 cm −1 , 1128±1 cm −1  and 1066 cm −1 ±1 cm −1 . 
   
   
       31 . The mono-hydrochloric salt of  claim 4  wherein the crystalline form has an infrared spectrometry micro attenuated reflectance spectrum with peaks at 3119±1 cm −1 , 2756±1 cm −1 , 1634±1 cm −1 , 1475±1 cm −1 , 1371±1 cm −1 , 1333±1 cm −1 , 1275±1 cm −1 , 1226±1 cm −1 , 1128±1 cm −1  and 1066 cm −1 ±1 cm −1 . 
   
   
       32 . The mono-hydrochloric salt of  claim 2  wherein the crystalline form has a differential scanning calorimetry curve with an endothermic peak at about 216.8° C. 
   
   
       33 . The mono-hydrochloric salt of  claim 3  wherein the crystalline form has a differential scanning calorimetry curve with an endothermic peak at about 216.8° C. 
   
   
       34 . The mono-hydrochloric salt of  claim 4  wherein the crystalline form has a differential scanning calorimetry curve with an endothermic peak at about 216.8° C. 
   
   
       35 . The mono-hydrochloric salt of  claim 5  wherein the crystalline form has a differential scanning calorimetry curve with an endothermic peak at about 216.8° C. 
   
   
       36 . The mono-hydrochloric salt of  claim 6  wherein the crystalline form has a differential scanning calorimetry curve with an endothermic peak at about 216.8° C. 
   
   
       37 . The mono-hydrochloric salt of  claim 2  in hydrate form wherein said hydrate form has an X-ray powder diffraction pattern comprising peaks at 10.0°±0.2°, 13.4°±0.2° and 26.5°±0.2°. 
   
   
       38 . The mono-hydrochloric salt of  claim 37  wherein the X-ray powder diffraction pattern further comprises peaks at 21.6°±0.2° and 24.9°±0.2°. 
   
   
       39 . The mono-hydrochloric salt of  claim 9  wherein the crystalline form has an infrared spectrometry micro attenuated reflectance spectrum with peaks at 3558±1 cm −1 , 3238±1 cm −1 , 1607±1 cm −1  and 997 cm −1 ±1 cm −1 .