Dihydroartemisinin and dihydroartemisitene dimers as anti-cancer and anti-infective agents

Abstract

This invention comprises compositions containing dihydroartemisinin and dihydroartemisitene dimers with activity as anticancer agents and anti-protozal, including anti-malarial and anti-leishmanial properties. This invention also describes methods of preparation of these compositions and methods of use of such compositions for the treatment of cancer, and protozoal infections, including malaria, or leishmaniasis. The compounds of this invention represent a potential new class of anti-tumor agents, one that has shown promising activity against solid tumors, and with a pattern of selectivity that suggests a possible new mechanism of action.

1 . A method of treating cancer comprising administering to a subject suffering from cancer an effective amount of at least one compound of the formula:  
       
         
           
           
               
               
           
         
       
       where R is  
       
         
           
           
               
               
           
         
       
       or a compound of the formula  
       
         
           
           
               
               
           
         
       
       where R is selected from one of the substituents described above or a simple (C 2 -C 4 ) alkyl residue.  
     
     
         2 . A method of treating a protozoal infection comprising administering to a subject suffering from an infection an effective amount of at least one compound of the formula:  
       
         
           
           
               
               
           
         
       
       where R is  
       
         
           
           
               
               
           
         
       
       or a compound of the formula  
       
         
           
           
               
               
           
         
       
       where R is selected from one of the substituents described above or a simple (C 2 -C 4 ) alkyl residue.  
     
     
         3 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       where R is  
       
         
           
           
               
               
           
         
       
       or a compound of the formula  
       
         
           
           
               
               
           
         
       
       where R is selected from one of the substituents described above or a simple (C 2 -C 4 ) alkyl residue.  
     
     
         4 . A pharmaceutical composition comprising at least of one compound according to  claim 3  and pharmaceutically acceptable carrier and/or excipient.  
     
     
         5 . A method of preparing compounds of the formulas:  
       
         
           
           
               
               
           
         
       
       where R is  
       
         
           
           
               
               
           
         
       
       or a compound of the formula  
       
         
           
           
               
               
           
         
       
       where R is selected from one of the substituents described above or a simple (C 2 -C 4 ) alkyl residue; 
 comprising reacting dihydroartemisin or dihydroartemistene with an appropriate optionally substituted 1, 2 or 1, 3 or 1, 4 glycol under acidic conditions such as borontrifluoride etherate followed by additional functionallization of the resulting dimer as necessary.  
 
     
     
         6 . The method of  claim 5  where R is a glycerol residue comprising reaction of dihydroartemisinin with glycerol in the presence of an acid catalyst such as boron trifluoride etherate followed by purification of the reaction mixture.  
     
     
         7 . The method of  claim 5  where R is a cyclohexane diol residue comprising the reaction of dihydroartemisinin with cis- or trans-cycloheane diols or a mixture thereof in the presence of an acid catalyst such as boron trifluoride etherate followed by purification of the reaction mixture and separation of the appropriate isomer.  
     
     
         8 . The method of  claim 5  where R is a dihydroxy acetone residue in the presence of an acid such as boron trifluoride etherate followed by purification of the reaction mixture.  
     
     
         9 . The method of  claim 6  by sodium borohydride reduction of the compound of  claim 8  followed by purification of the reaction mixture.  
     
     
         10 . The method of preparing the hemisuccinate ester of the compound of  claim 6  by reacting the compound of  claim 6  with succinic anhydride in the presence of a base catalyst such as a mixture of dimethylaminopyridine and triethylamine followed by the purification of the reaction mixture.  
     
     
         11 . The method of preparing compounds of  claim 5  by reacting dihydroartemisitene with the appropriate 1, 2 or 1, 3 or 1, 4 glycol in the presence of an acid catalyst such as borontrifluride etherate followed by the purification of the reaction mixture.  
     
     
         12 . The method of  claim 11  where the 1, 2 glycol is ethylene glycol.  
     
     
         13 . The method of  claim 11  where the 1, 2 glycol is 1, 2 propane-diol.  
     
     
         14 . The method of  claim 11  where the 1, 3 glycol is glycerol.  
     
     
         15 . The method of  claim 11  where the 1, 3 glycol is dihydroxy acetone.  
     
     
         16 . The method of  claim 11  where the 1,4 glycol is 1, 4-butane-diol.  
     
     
         17 . The method of preparing a compound of  claim 11  where the 1, 4 glycol is selected from 1, 4-cis-cyclohexanediol, 1, 4-trans-cyclohexanediol or a mixture thereof, followed by the purification of the reaction mixture and separation of the desired product.