Cell division inhibitor and a production method thereof

Abstract

The present invention relates to a cell division inhibitor comprising various dehydrodiketopiperazines such as dehydrophenylahistin, or analogs thereof as an active ingredient, and a dehydrogenase and a method for producing the same inhibitor.

1 - 14 . (canceled)  
   
   
       15 . A compound of formula (I) or pharmaceutically acceptable salt thereof:  
     
       
         
         
             
             
         
       
     
     wherein: 
 each of X 1  and X 2  is independently oxygen or sulfur;  
 Y 3  is oxygen, sulfur, —NR 3 —, or —CR 31 R 32 —;  
 Y 4  is oxygen, sulfur, —NR 4 —, or —CR 41 R 42 —;  
 R 10  is an aryl or aralkyl and is optionally substituted with other substituent(s) and optionally comprises one or more heteroatoms;  
 R 20  is an aryl or aralkyl and is optionally substituted with other substituent(s) and optionally comprises one or more heteroatoms, with the proviso that R 20  does not include a phenyl group;  
 each of R 3  and R 4  is independently selected from the group consisting of hydrogen, halogen, C 1-25  alkyl, C 2-25  alkenyl, C 2-25  alkynyl, C 1-25  alkoxy, aralkyl, hydroxyl, amino, nitro, and aryl, each of which is optionally substituted with other substituent(s), wherein any part of a carbon chain in R 3  and R 4  may be branched or cyclized, and may comprise one or more heteroatoms;  
 each of R 31 , R 32 , R 41 , and R 42  is independently selected from the group consisting of hydrogen, halogen, C 1-25  alkyl, C 2-25  alkenyl, C 2-25  alkynyl, C 1-25  alkoxy, aralkyl, hydroxyl, amino, nitro, and aryl, each of which is optionally substituted with other substituent(s), wherein any part of a carbon chain in R 31 , R 32 , R 41 , and R 42  may be branched or cyclized, and may comprise one or more heteroatoms;  
 R 10  and any of R 3 , R 31 , or R 32  may together from a ring;  
 R 20  and any of R 4 , R 41 , or R 42  may together from a ring;  
 each bond depicted by a solid line and dashed line represents a carbon-carbon single bond or a carbon-carbon double bond with E or Z configurations; and  
 at least one of said groups may have a protecting group capable of decomposing in vivo;  
 with the proviso that the compound of formula I does not include the compound having the following structure:  
                     
 
   
   
       16 . The compound of  claim 15 , wherein each bond depicted by a solid line and dashed line represents a carbon-carbon double bond.  
   
   
       17 . The compound of  claim 16 , wherein each of X 1  and X 2  is oxygen, Y 3  is —NR 3 —, and Y 4  is —NR 4 —.  
   
   
       18 . The compound of  claim 17 , wherein each of Y 3  and Y 4  is —NH—.  
   
   
       19 . The compound of  claim 15 , wherein at least one of R 10  and R 20  is substituted with 1,1-dimethyl-2-propenyl.  
   
   
       20 . The compound of  claim 15 , wherein at least one of R 10  and R 20  has the following structure:  
     
       
         
         
             
             
         
       
     
     and is optionally substituted with other substituent(s).  
   
   
       21 . The compound of  claim 15 , wherein: 
 R 10  is a phenyl or phenylalkyl and is optionally substituted with other substituent(s); and    R 20  is an imidazolyl or imidazolylalkyl and is optionally substituted with other substituent(s).    
   
   
       22 . The compound of  claim 15  selected from the group consisting of: 
 3-(imidazole-4-ylmethylene)-6-(phenylmethylene)piperazine-2,5-dione;    3-[(5-methylimidazole-4-yl)methylene]-6-(phenylmethylene)piperazine-2,5-dione;    3-[(5-ethylimidazole-4-yl)methylene]-6-(phenylmethylene)piperazine-2,5-dione;    3-[(5-butylimidazole-4-yl)methylene]-6-(phenylmethylene)piperazine-2,5-dione;    3-[(5-pentylimidazole-4-yl)methylene]-6-(phenylmethylene)piperazine-2,5-dione; and    3-{[5-(1, 1-dimethyl-2-propenyl)imidazole-4-yl]methylene}-6-(phenylmethylene) piperazine-2,5-dione.    
   
   
       23 . A method of inhibiting cell division in a subject, comprising administering to the subject a compound of  claim 15 .  
   
   
       24 . The method of  claim 23 , wherein the compound is selected from the group consisting of: 
 3-(imidazole-4-ylmethylene)-6-(phenylmethylene)piperazine-2,5-dione;    3-[(5-methylimidazole-4-yl)methylene]-6-(phenylmethylene)piperazine-2,5-dione;    3-[(5-ethylimidazole-4-yl)methylene]-6-(phenylmethylene)piperazine-2,5-dione;    3-[(5-butylimidazole-4-yl)methylene]-6-(phenylmethylene)piperazine-2,5-dione; and    3-[(5-pentylimidazole-4-yl)methylene]-6-(phenylmethylene)piperazine-2,5-dione.    
   
   
       25 . The method of  claim 23 , wherein the compound is 3-{[5-(1,1-dimethyl-2-propenyl)imidazole-4-yl]methylene}-6-(phenylmethylene)piperazine-2,5-dione.  
   
   
       26 . A method of treating a subject having a tumor, comprising administering to the subject a compound of  claim 15 .  
   
   
       27 . The method of  claim 26 , wherein the compound is selected from the group consisting of: 
 3-(imidazole-4-ylmethylene)-6-(phenylmethylene)piperazine-2,5-dione;    3-[(5-methylimidazole-4-yl)methylene]-6-(phenylmethylene)piperazine-2,5-dione;    3-[(5-ethylimidazole-4-yl)methylene]-6-(phenylmethylene)piperazine-2,5-dione;    3-[(5-butylimidazole-4-yl)methylene]-6-(phenylmethylene)piperazine-2,5-dione; and    3-[(5-pentylimidazole-4-yl)methylene]-6-(phenylmethylene)piperazine-2,5-dione.    
   
   
       28 . The method of  claim 26 , wherein the compound is 3-{[5-(1,1-dimethyl-2-propenyl)imidazole-4-yl]methylene}-6-(phenylmethylene)piperazine-2,5-dione.