Emetine Derivatives, Prodrugs Containing Same, And Methods Of Treating Conditions Using Same

Abstract

Compounds are provided herein which are emetine derivatives that can be used as prodrugs which selectively undergo activation to release emetine in specific cellular conditions. In one aspect, a blocking group is incorporated onto the emetine molecule by the derivization of the N2′-position with moieties that can be selectively removed by hydrolysis in the cancer/tumor microenvironment. Such compounds are less cytotoxic than emetine and are substantially inactive in non-cancerous cells. In one aspect, the compounds described herein can be used for the treatment of metastatic and non-metastatic cancers, including, for example, breast cancer, prostate cancer, lung cancer, and leukemia.

1 - 15 . (canceled) 
     
     
         16 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         where M is: 
       
       
         
           
           
               
               
           
         
         and where 
       
       
         
           
           
               
               
           
         
         X 1 =H, —NO 2 , —CO 2 X 2 , —OX 3 , halogen, or C1-C4 alkyl, 
         X 2 =C1-C4 alkyl or H, 
         X 3 =C1-C4 alkyl or H, 
         Y=H or C1-C6 alkyl, and 
         p=0 to 8. 
       
     
     
         17 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         where M has the general formula: 
       
       
         
           
           
               
               
           
         
         where R 8  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       and (CH 3 ) m (CH) n (CH 2 ) p —
 where 
 L=H 2 N— and H 3 CO— 
 m=1-3. 
 n=0-1, 
 p=0 to 8, 
 X 1 =H, —NO 2 , —CO 2 X 2 , —OX 3 , halogen, or C1-C4 alkyl, 
 X 2 =C1-C4 alkyl or H, and 
 X 3 =C1-C4 alkyl or H. 
 
     
     
         18 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       where M is not hydrogen and comprises a substituent effective to be hydrolyzed by an enzyme preferentially expressed by cancer cells. 
     
     
         19 . The compound according to  claim 18 , wherein M comprises a peptide having the sequence His-Ser-Ser-Lys-Leu-Gln. 
     
     
         20 . The compound according to  claim 18 , wherein M comprises one of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       where X is a protecting group or one or more amino acids. 
     
     
         21 . The compound according to  claim 20 , wherein X is selected from the group consisting of 9-fluorenylmethyloxycarbonyl, tert-butyloxycarbonyl, acetyl, and morpholino groups.