Fumagillol derivatives and preparing method thereof

Abstract

The disclosure relates to a fumagillol compound which can be usefully used not only as an angiogenesis inhibiting agent showing a superior angiogenesis inhibitory effect with less toxicity, but also as a cancer metastasis inhibitor and a therapeutic agent against cancer and other various inflammatory diseases such as rheumatic disease, psoriasis, etc., and diabetic retinopathy related to angiogenesis, and also a method for preparing the same.

1 : A pharmaceutical composition for inhibition of angiogenesis, comprising a therapeutically effective amount of a fumagillol compound represented by the following formula I or a pharmaceutically acceptable salt thereof, as an effective ingredient:  
     
       
         
         
             
             
         
       
     
     wherein, 
 X is —OH and Y is halogen, or X and Y are linked together to form an oxyrane ring,  
 B represents —(C═O)— or —CH 2 —,  
 R 1  represents hydroxy; —CN; —NO 2 ; —CF 3 ; formyl; C 1 -C 4  thioalkyl; acetamido; acetoxy; C 1 -C 6  alkoxy; C 1 -C 6  aminoalkoxy; C 1 -C 4  alkylaminoalkoxy; C 1 -C 4  dialkylaminoalkoxy; amino; C 1 -C 6  alkylamino; C 1 -C 4  dialkylamino; C 1 -C 4  alkyloxycarboxylic acid; C 3 -C 6  cycloalkyl or  
                     
 in which R 2 , R 3 , R 4 , R 5  and R 6 , which are the same or different, each represents hydrogen; hydroxy; —CN; —NO 2 ; —CF 3 ; formyl; C 1 -C 4  thioalkyl; acetamido; acetoxy; C 1 -C 6  alkyl; C 1 -C 4  aminoalkyl; C 1 -C 4  alkylaminoalkyl; C 1 -C 4  dialkylaminoalkyl; C 1 -C 6  alkoxy; C 1 -C 6  aminoalkoxy; C 1 -C 4  alkylaminoalkoxy; C 1 -C 4  dialkylaminoalkoxy; amino; C 1 -C 6  alkylamino; C 1 -C 4  dialkylamino; C 1 -C 4  hydroxyalkyl; or C 1 -C 4  alkyloxycarboxylic acid; or, R 2  and R 3 , R 3  and R 4 , R 4  and R 5 , or R 5  and R 6 , are linked together to form a C 1 -C 3  alkylene dioxy ring, and  
 Z 1 , Z 2 , Z 3 , Z 4  and Z 5  each represent carbon or nitrogen.  
 
   
   
       2 : A pharmaceutical compound for treatment of cancer, rheumatoid arthritis, psoriasis or diabetic retinopathy, or for inhibition of cancer metastasis, comprising a therapeutically effective amount of a fumagillol compound represented by the following formula I or a pharmaceutically acceptable salt thereof, as an effective ingredient:  
     
       
         
         
             
             
         
       
     
     wherein, 
 X is —OH and Y is halogen, or X and Y are linked together to form an oxyrane ring,  
 B represents —(C═O)— or —CH 2 —,  
 R 1  represents hydroxy; —CN; —NO 2 ; —CF 3 ; formyl; C 1 -C 4  thioalkyl; acetamido; acetoxy; C 1 -C 6  alkoxy; C 1 -C 6  aminoalkoxy; C 1 -C 4  alkylaminoalkoxy; C 1 -C 4  dialkylaminoalkoxy; amino; C 1 -C 6  alkylamino; C 1 -C 4  dialkylamino; C 1 -C 4  alkyloxycarboxylic acid; C 3 -C 6  cycloalkyl or  
                     
 in which R 2 , R 3 , R 4 , R 5  and R 6 , which are the same or different, each represents hydrogen; hydroxy; —CN; —NO 2 ; —CF 3 ; formyl; C 1 -C 4  thioalkyl; acetamido; acetoxy; C 1 -C 6  alkyl; C 1 -C 4  aminoalkyl; C 1 -C 4  alkylaminoalkyl; C 1 -C 4  dialkylaminoalkyl; C 1 -C 6  alkoxy; C 1 -C 6  aminoalkoxy; C 1 -C 4  alkylaminoalkoxy; C 1 -C 4  dialkylaminoalkoxy; amino; C 1 -C 6  alkylamino; C 1 -C 4  dialkylamino; C 1 -C 4  hydroxyalkyl; or C 1 -C 4  alkyloxycarboxylic acid; or, R 2  and R 3 , R 3  and R 4 , R 4  and R 5 , or R 5  and R 6 , are linked together to form a C 1 -C 3  alkylene dioxy ring, and  
 Z 1 , Z 2 , Z 3 , Z 4  and Z 5  each represent carbon or nitrogen.