Fumagillol derivative and the medical use 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 method for inhibiting angiogenesis comprising administering to a subject in need of treatment, a fumagillol derivative represented by the following formula I or a pharmaceutically acceptable salt thereof.  
     
       
         
         
             
             
         
       
       wherein,  
       X is —OH and Y is halogen, or X and Y are linked together to form an oxirane ring, B represents —(C═O)— or —CH 2 —,  
       R 1  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; C 1 -C 4  alkyloxycarboxylic acid, 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 . The method according to  claim 1 , wherein X and Y of the fumagillol derivative are linked together to form the oxirane ring, and B of the fumagillol derivative is —(C═O)—.  
   
   
       3 . The method according to  claim 1 , wherein X and Y of the fumagillol derivative are linked together to form the oxirane ring, 
 B of the fumagillol derivative is —(C═O)—, 
 R 1  of the fumagillol derivative is hydrogen;  
   hydroxy; —CN; —NO 2 ; —CF 3 ; formyl; 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; C 1 -C 4  alkyloxycarboxylic acid; or 
 R 2 , R 3 , R 4 , R 5  and R 6  of the fumagillol derivative, which are the same or different, each represents hydrogen; hydroxy; —CN; —NO 2 ; —CF 3 ; formyl; 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  of the fumagillol derivative are linked together to form the C 1 -C 3  alkylene dioxy ring; and  
 Z 1 , Z 2 , Z 3 , Z 4  and Z 5  each represent carbon or nitrogen.  
   
   
   
       4 . The method according to  claim 1 , wherein X and Y of the fumagillol derivative are linked together to form the oxirane ring, 
 B of the fumagillol derivative is —(C═O)—   R 1  of the fumagillol derivative is selected from the group consisting of hydrogen; hydroxy; methyl; chlorine; methoxy; methylpropoxy; isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino; dimethylaminomethyl; methylpropoxy; dimethylethoxy; 3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy; nitro; acetoxy; trifluoromethyl; and hydroxyethoxy;    R 2 , R 3 , R 4 , R 5  and R 6  of the fumagillol derivative is independently selected from the group consisting of hydrogen; hydroxy; methyl; chlorine; methoxy; methylpropoxy; isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino; dimethylaminomethyl; methylpropoxy; dimethylethoxy; 3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy; nitro; acetoxy; trifluoromethyl; and hydroxyethoxy; and    Z 1 , Z 2 , Z 3  Z 4  and Z 5  each represent carbon or nitrogen.    
   
   
       5 . The method according to  claim 1 , wherein the fumagillol derivative is selected from the group consisting of: 
 1) 6-O-(4-methoxyaniline)acetyl fumagillol;    2) 6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol;    3) 6-O-(2,4-dimethoxyaniline)acetyl fumagillol;    4) 6-O-(3,4-dimethoxyaniline)acetyl fumagillol;    5) 6-O-(3,4-dimethoxy-6-nitroaniline)acetyl fumagillol;    6) 6-O-(3,4-dimethoxy-6-cyanoaniline)acetyl fumagillol;    7) 6-O-(4-allyloxyaniline)acetyl fumagillol;    8) 6-O-(4-(2-acetoxyethoxy)aniline)acetyl fumagillol;    9) 6-O-(3-cyano-4-methoxyaniline)acetyl fumagillol;    10) 6-O-(3-(dimethylaminomethyl)-4-methoxyaniline) acetyl fumagillol;    11) 6-O-(4-(2-methylpropoxyaniline)acetyl fumagillol;    12) 6-O-(3-isopropoxy-4-methoxyaniline)acetyl fumagillol;    13) 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol;    14) 6-O-(3,5-diisopropyl-4-methoxyaniline)acetyl fumagillol;    15) 6-O-(3,5-dimethyl-4-methoxyaniline)acetyl fumagillol;    16) 6-O-(3-isopropyl-4-ethoxy-6-methylaniline)acetyl fumagillol;    17) 6-O-(4-propyloxyaniline)acetyl fumagillol;    18) 6-O-(aniline)acetyl fumagillol;    19) 6-O-(4-chloroaniline)acetyl fumagillol;    20) 6-O-(4-dimethylaminoaniline)acetyl fumagillol;    21) 6-O-(4-hydroxyaniline)acetyl fumagillol;    22) 6-O-(4-aminoaniline)acetyl fumagillol;    23) 6-O-(3,4-methylenedioxyaniline)acetyl fumagillol;    24) 6-O-(4-nitroaniline)acetyl fumagillol;    25) 6-O-(2,3,4-trimethoxy-6-aminoaniline)acetyl fumagillol;    26) 6-O-(4-acetoxy-3,5-dimethoxyaniline)acetyl fumagillol;    27) 6-O-(3,4-dimethoxy-5-hydroxyaniline)acetyl fumagillol;    28) 6-O-(4-dimethylaminoethoxyaniline)acetyl fumagillol;    29) 6-O-(4-ethylaminoaniline)acetyl fumagillol;    30) 6-O-(4-ethylaminoethoxyaniline)acetyl fumagillol;    31) 6-O-(3-dimethylaminomethyl-4-methoxyaniline)acetyl fumagillol;    32) 6-O-(4-trifluoromethylaniline)acetyl fumagillol;    33) 6-O-(4-acetoxy aniline)acetyl fumagillol;    34) 6-O-(4-cyanoaniline)acetyl fumagillol;    35) 6-O-(4-hydroxyethoxyaniline)acetyl fumagillol;    36) 6-O-(5-amino-2-methoxypyridine)acetyl fumagillol;    37) 6-O-(5-methoxypyrimidine-2-amino)acetyl fumagillol;    38) 6-O-(3-methoxy-6-aminopyridazine)acetyl fumagillol;    39) 4-((4-methoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;    40) 4-((3,4,5-trimethoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;    41) 6-O-(ethylamino)acetyl fumagillol;    42) 6-O-(isopropyl amino)acetyl fumagillol;    43) 6-O-(1-propyl amino)acetyl fumagillol;    44) 6-O-(1-butyl amino)acetyl fumagillol;    45) 6-O-(sec-butyl amino)acetyl fumagillol;    46) 6-O-(2-methyl-butylamino)acetyl fumagillol;    47) 6-O-(t-butyl amino)acetyl fumagillol;    48) 6-O-(pentyl amino)acetyl fumagillol;    49) 6-O-(1-methyl-butyl amino)acetyl fumagillol;    50) 6-O-(1-ethyl-propyl amino)acetyl fumagillol;    51) 6-O-(1-methyl-pentylamino)acetyl fumagillol;    52) 6-O-(1,2-dimethyl-butylamino)acetyl fumagillol;    53) 6-O-(1,2,2-trimethyl-propylamino)acetyl fumagillol;    54) 6-O-(1-isopropyl-2-methylpropylamino)acetyl fumagillol;    55) 6-O-(3-methylbutylamino)acetyl fumagillol;    56) 6-O-(2-methylallylamino)acetyl fumagillol;    57) 6-O-(4-methyl-hepta-2,4-dienylamino)acetyl fumagillol;    58) 6-O-(1,5-dimethyl-4-hexenylamino)acetyl fumagillol;    59) 6-O-(1,1-dimethyl-2-propynylamino)acetyl fumagillol;    60) 6-O-(prop-2-enylamino)acetyl fumagillol;    61) 6-O-(2-bromo-ethylamino)acetyl fumagillol;    62) 6-O-(chloroethynylamino)acetyl fumagillol;    63) 6-O-(cyclopropylamino)acetyl fumagillol;    64) 6-O-(cyclobutylamino)acetyl fumagillol;    65) 6-O-(cyclopentylamino)acetyl fumagillol;    66) 6-O-(cyclohexylamino)acetyl fumagillol;    67) 6-O-(4-tert-butylcyclohexylamino)acetyl fumagillol;    68) 6-O-(2-dimethylamino-1-methylethylamino)acetyl fumagillol;    69) 6-O-(2-dimethylamino-propylamino)acetyl fumagillol;    70) 6-O-(2-methoxy-2-methyl-propylamino)acetyl fumagillol;    71) 6-O-(2-oxo-propylamine)acetyl fumagillol;    72) 6-O-(1,1-dimethyl-3-oxobutylamino)acetyl fumagillol;    73) 6-O-(ethyl-2-aminoacetate)acetyl fumagillol;    74) 6-O-(alanine-methylesteramino)acetyl fumagillol;    75) 6-O-(methyl-2-amino-3,3-dimethylbutanoate)acetyl fumagillol;    76) 6-O-(allylglycine-methylester)acetyl fumagillol;    77) 6-O-(2,2-dimethoxy-ehtylamino)acetyl fumagillol;    78) 4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol; and    79) 4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol.    
   
   
       6 . A method for treating cancer, rheumatoid arthritis, psoriasis or diabetic retinopathy, or for inhibiting cancer metastasis, comprising administering to a subject in need of treatment, a fumagillol derivative represented by the following formula I or a pharmaceutically acceptable salt thereof.  
     
       
         
         
             
             
         
       
       wherein,  
       X is —OH and Y is halogen, or X and Y are linked together to form an oxirane ring,  
       B represents —(C═O)— or —CH 2 —,  
       R 1  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; C 1 -C 4  alkyloxycarboxylic acid, 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.  
     
   
   
       7 . The method according to  claim 6 , wherein X and Y of the fumagillol derivative are linked together to form the oxirane ring, and B of the fumagillol derivative is —(C═O)—.  
   
   
       8 . The method according to  claim 6 , wherein X and Y of the fumagillol derivative are linked together to form the oxirane ring, 
 B of the fumagillol derivative is —(C═O)—,    R 1  of the fumagillol derivative is hydrogen; hydroxy; —CN; —NO 2 ; —CF 3 ; formyl; 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; C 1 -C 4  alkyloxycarboxylic acid; or    R 2 , R 3 , R 4 , R 5  and R 6  of the fumagillol derivative, which are the same or different, each represents hydrogen; hydroxy; —CN; —NO 2 ; —CF 3 ; formyl; 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  of the fumagillol derivative are linked together to form the C 1 -C 3  alkylene dioxy ring; and    Z 1 , Z 2 , Z 3 , Z 4  and Z 5  each represent carbon or nitrogen.    
   
   
       9 . The method according to  claim 6 , wherein X and Y of the fumagillol derivative are linked together to form the oxirane ring, 
 B of the fumagillol derivative is —(C═O)—   R 1  of the fumagillol derivative is selected from the group consisting of hydrogen; hydroxy; methyl; chlorine; methoxy; methylpropoxy; isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino; dimethylaminomethyl; methylpropoxy; dimethylethoxy; 3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy; nitro; acetoxy; trifluoromethyl; and hydroxyethoxy;    R 2 , R 3 , R 4 , R 5  and R 6  of the fumagillol derivative is independently selected from the group consisting of hydrogen; hydroxy; methyl; chlorine; methoxy; ethylpropoxy; isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino; dimethylaminomethyl; methylpropoxy; dimethylethoxy; 3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy; nitro; acetoxy; trifluoromethyl; and    hydroxyethoxy; and    Z 1 , Z 2 , Z 3  Z 4  and Z 5  each represent carbon or nitrogen.    
   
   
       10 . The method according to  claim 6 , wherein the fumagillol derivative is selected from the group consisting of: 
 1) 6-O-(4-methoxyaniline)acetyl fumagillol;    2) 6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol;    3) 6-O-(2,4-dimethoxyaniline)acetyl fumagillol;    4) 6-O-(3,4-dimethoxyaniline)acetyl fumagillol;    5) 6-O-(3,4-dimethoxy-6-nitroaniline)acetyl fumagillol;    6) 6-O-(3,4-dimethoxy-6-cyanoaniline)acetyl fumagillol;    7) 6-O-(4-allyloxyaniline)acetyl fumagillol;    8) 6-O-(4-(2-acetoxyethoxy)aniline)acetyl fumagillol;    9) 6-O-(3-cyano-4-methoxyaniline)acetyl fumagillol;    10) 6-O-(3-(dimethylaminomethyl)-4-methoxyaniline) acetyl fumagillol;    11) 6-O-(4-(2-methylpropoxyaniline)acetyl fumagillol;    12) 6-O-(3-isopropoxy-4-methoxyaniline)acetyl fumagillol;    13) 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol;    14) 6-O-(3,5-diisopropyl-4-methoxyaniline)acetyl fumagillol;    15) 6-O-(3,5-dimethyl-4-methoxyaniline)acetyl fumagillol;    16) 6-O-(3-isopropyl-4-ethoxy-6-methylaniline)acetyl fumagillol;    17) 6-O-(4-propyloxyaniline)acetyl fumagillol;    18) 6-O-(aniline)acetyl fumagillol;    19) 6-O-(4-chloroaniline)acetyl fumagillol;    20) 6-O-(4-dimethylaminoaniline)acetyl fumagillol;    21) 6-O-(4-hydroxyaniline)acetyl fumagillol;    22) 6-O-(4-aminoaniline)acetyl fumagillol;    23) 6-O-(3,4-methylenedioxyaniline)acetyl fumagillol;    24) 6-O-(4-nitroaniline)acetyl fumagillol;    25) 6-O-(2,3,4-trimethoxy-6-aminoaniline)acetyl fumagillol;    26) 6-O-(4-acetoxy-3,5-dimethoxyaniline)acetyl fumagillol;    27) 6-O-(3,4-dimethoxy-5-hydroxyaniline)acetyl fumagillol;    28) 6-O-(4-dimethylaminoethoxyaniline)acetyl fumagillol;    29) 6-O-(4-ethylaminoaniline)acetyl fumagillol;    30) 6-O-(4-ethylaminoethoxyaniline)acetyl fumagillol;    31) 6-O-(3-dimethylaminomethyl-4-methoxyaniline)acetyl fumagillol;    32) 6-O-(4-trifluoromethylaniline)acetyl fumagillol;    33) 6-O-(4-acetoxy aniline)acetyl fumagillol;    34) 6-O-(4-cyanoaniline)acetyl fumagillol;    35) 6-O-(4-hydroxyethoxyaniline)acetyl fumagillol;    36) 6-O-(5-amino-2-methoxypyridine)acetyl fumagillol;    37) 6-O-(5-methoxypyrimidine-2-amino)acetyl fumagillol;    38) 6-O-(3-methoxy-6-aminopyridazine)acetyl fumagillol;    39) 4-((4-methoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;    40) 4-((3,4,5-trimethoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;    41) 6-O-(ethylamino)acetyl fumagillol;    42) 6-O-(isopropyl amino)acetyl fumagillol;    43) 6-O-(1-propyl amino)acetyl fumagillol;    44) 6-O-(1-butyl amino)acetyl fumagillol;    45) 6-O-(sec-butyl amino)acetyl fumagillol;    46) 6-O-(2-methyl-butylamino)acetyl fumagillol;    47) 6-O-(t-butyl amino)acetyl fumagillol;    48) 6-O-(pentyl amino)acetyl fumagillol;    49) 6-O-(1-methyl-butyl amino)acetyl fumagillol;    50) 6-O-(1-ethyl-propyl amino)acetyl fumagillol;    51) 6-O-(1-methyl-pentylamino)acetyl fumagillol;    52) 6-O-(1,2-dimethyl-butylamino)acetyl fumagillol;    53) 6-O-(1,2,2-trimethyl-propylamino)acetyl fumagillol;    54) 6-O-(1-isopropyl-2-methylpropylamino)acetyl fumagillol;    55) 6-O-(3-methylbutylamino)acetyl fumagillol;    56) 6-O-(2-methylallylamino)acetyl fumagillol;    57) 6-O-(4-methyl-hepta-2,4-dienylamino)acetyl fumagillol;    58) 6-O-(1,5-dimethyl-4-hexenylamino)acetyl fumagillol;    59) 6-O-(1,1-dimethyl-2-propynylamino)acetyl fumagillol;    60) 6-O-(prop-2-enylamino)acetyl fumagillol;    61) 6-O-(2-bromo-ethylamino)acetyl fumagillol;    62) 6-O-(chloroethynylamino)acetyl fumagillol;    63) 6-O-(cyclopropylamino)acetyl fumagillol;    64) 6-O-(cyclobutylamino)acetyl fumagillol;    65) 6-O-(cyclopentylamino)acetyl fumagillol;    66) 6-O-(cyclohexylamino)acetyl fumagillol;    67) 6-O-(4-tert-butylcyclohexylamino)acetyl fumagillol;    68) 6-O-(2-dimethylamino-1-methylethylamino)acetyl fumagillol;    69) 6-O-(2-dimethylamino-propylamino)acetyl fumagillol;    70) 6-O-(2-methoxy-2-methyl-propylamino)acetyl fumagillol;    71) 6-O-(2-oxo-propylamine)acetyl fumagillol;    72) 6-O-(1,1-dimethyl-3-oxobutylamino)acetyl fumagillol;    73) 6-O-(ethyl-2-aminoacetate)acetyl fumagillol;    74) 6-O-(alanine-methylesteramino)acetyl fumagillol;    75) 6-O-(methyl-2-amino-3,3-dimethylbutanoate)acetyl fumagillol;    76) 6-O-(allylglycine-methylester)acetyl fumagillol;    77) 6-O-(2,2-dimethoxy-ehtylamino)acetyl fumagillol;    78) 4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol; and    79) 4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol.    
   
   
       11 . Use of a compound of formula I in the preparation of a medicament for inhibiting development of a hepatoma in a patient, wherein said compound of formula I is as represented by the  claim 1.