Drug compound and purification methods thereof

Abstract

The invention provides a method of preparing a lyophilized pharmaceutical composition containing a compound described herein or a pharmaceutically-acceptable salt thereof. The process comprises dissolving the compound in a solvent comprising dimethylsulfoxide and optionally one or more co-solvents to form a solution, and then removing the solvent and any co-solvents by a freeze-drying process. Also provided by the invention are lyophilized pharmaceutical compositions and their use in medicine and in particular in the treatment of cancer.

1 .- 28 . (canceled) 
     
     
         29 . A method of treating a condition, comprising mixing a lyophilized pharmaceutical composition with a pharmaceutically acceptable solvent to provide a mixture, and administering an effective amount of the mixture to a subject in need thereof, wherein the lyophilized pharmaceutical composition is prepared by a process, wherein the process comprises removing a portion of a solvent by a freeze-drying process from a solution, thereby generating the lyophilized pharmaceutical product, wherein the solution comprises:
 a) a compound of Formula (1):   
       
         
           
           
               
               
           
         
          or a pharmaceutically-acceptable salt thereof; and 
         b) the solvent, wherein the solvent comprises DMSO, and 
         wherein the freeze-drying process comprises:
 (i) a first freezing stage in which the solution is frozen by reducing a temperature of the solution to about −45° C. to form a frozen solution; 
 (ii) a first annealing stage in which the temperature of the solution is raised from about −4° C. to about 0° C., Wherein the solution remains frozen when the temperature of the solution is about 0° C.; 
 (iii) a second freezing stage in which the temperature of the solution is lowered from about 0° C. to about −45° C.; 
 (iv) a primary drying stage in which the temperature of the solution is raised from about −45° C. to about −6° C., wherein the primary drying stage comprises a sublimation step in which the DMSO is removed by sublimation from the solution in a frozen state of the solution under reduced pressure to give a partially dried product; and 
 (v) a secondary drying stage in which the temperature of the solution is raised from about −6° C. to about 40° C., wherein in the secondary drying stage the DMSO is removed by evaporation from the partially dried product in a non-frozen state under reduced pressure to give the lyophilized pharmaceutical product, wherein the lyophilized pharmaceutical product comprises a compound of formula (2): 
 
       
       
         
           
           
               
               
           
         
         
           
             or a pharmaceutically-acceptable salt thereof, wherein:
 R 1  is 4-amino-2H-1λ 2 ,3,5-triazin-2-one or a carbamide, each of which is independently substituted or unsubstituted; 
 each R 2  and R 3  is independently alkyl, which is substituted or unsubstituted; or hydrogen; and 
 R 4  is hydrogen or an acyl group, each of which is independently substituted or unsubstituted. 
 
           
         
       
     
     
         30 . The method of  claim 29 , wherein the condition is cancer. 
     
     
         31 . The method of  claim 30 , wherein the cancer is chronic myelogenous leukaemia, myelodysplastic syndrome, or promyelocytic leukaemia. 
     
     
         32 . The method of  claim 29 , wherein the condition is a chronic inflammatory disease. 
     
     
         33 . The method of  claim 32 , wherein the chronic inflammatory disease is Crohn's disease, ulcerative colitis, psoriasis, sarcoidosis, or rheumatoid arthritis. 
     
     
         34 . The method of  claim 29 , wherein the condition is a disease associated with abnormal hemoglobin synthesis. 
     
     
         35 . The method of  claim 34 , wherein the disease associated with abnormal hemoglobin synthesis is sickle cell anemia or β-thalassemia. 
     
     
         36 . A lyophilized pharmaceutical product, wherein the lyophilized pharmaceutical product is prepared by removing a portion of solvent by a freeze-drying process from a solution, wherein the solution comprises:
 a) a compound of Formula (1)   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 b) the solvent, wherein the solvent comprises DMSO, and 
 c) a nucleotide-based compound that is not a compound of Formula (1), 
 
       wherein in an amount of the lyophilized composition obtained from 1 gram of the solution, a residual DMSO content is no greater than 20 mg. 
     
     
         37 . The method of  claim 36 , wherein the freeze-drying process comprises:
 (i) a first freezing stage in which the solution is frozen by reducing a temperature of the solution to about −45° C. to form a frozen solution;   (ii) a first annealing stage in which the temperature of the solution is raised from about −45° C. to about 0° C., wherein the solution remains frozen when the temperature of the solution is about 0° C.;   (iii) a second freezing stage in which the temperature of the solution is lowered from about 0° C. to about −45° C.;   (iv) a primary drying stage in which the temperature of the solution is raised from about −45° C. to about −6° C., wherein the primary diving stage comprises a sublimation step in which the DMSO is removed by sublimation from the solution in a frozen state of the solution under reduced pressure to give a partially dried product; and   (v) a secondary drying stage in which the temperature of the solution is raised from about −6° C. to about 40° C., wherein in the secondary drying stage the DMSO is removed by evaporation from the partially dried product in a non-frozen state under reduced pressure to give the lyophilized pharmaceutical product.   
     
     
         38 . The method of  claim 36 , wherein the nucleotide-based compound is a compound of Formula (2): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is a heteroaryl or a carbamide, each of which is independently substituted or unsubstituted; 
 each R 2  and R 3  is independently alkyl, which is substituted or unsubstituted; or hydrogen; and 
 R 4  is hydrogen or an acyl group, each of which is independently substituted or unsubstituted. 
 
     
     
         39 . The composition of  claim 38 , wherein R 1  is heteroaryl. 
     
     
         40 . The composition of  claim 39 , wherein R 1  is 4-amino-2H-1λ 2 ,3,5-triazin-2-one. 
     
     
         41 . The composition of  claim 38 , wherein each R 2  and R 3  is substituted alkyl or hydrogen. 
     
     
         42 . The composition of  claim 41 , wherein R 2  is H and R 3  is methyl substituted with methoxy. 
     
     
         43 . The composition of  claim 38 , wherein R 4  is hydrogen.