7-Substituted camptothecin and camptothecin analogs and methods for producing the same

Abstract

Methods of forming camptothecin compounds which are effective anti-tumor compounds are disclosed. These compounds inhibit the enzyme topoisomerase I and may alkylate DNA of the associated topoisomerase I-DNA cleavable complex.

1 . A method for the preparation of 7-substituted camptothecin compounds of formula (I) or (11):  
       
         
           
           
               
               
           
         
       
       where 
 X is H, NH 2 , H, F, Cl, Br, O—C 1-6  alkyl, S-C 1-6 alkyl, NH—C 1-6 alkyl, N(C 1-6 alkyl) 2 , or C 1-8  alkyl,  
 or X is -Z—(CH 2 ) a —N—(C 1-6  alkyl) 2  wherein Z is selected from the group consisting of O, NH and S, and a is an integer of 2 or 3,  
 or X is —CH 2 NR 2 R , where (a) R 2  and R 3  are, independently, hydrogen, C 1-6 alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-6 alkyl, C 2-6  alkenyl, C 1-6  alkoxy-C 1-6  COR 4  where R 4  is hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-6  alkyl, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkoxy-C 1-6  alkyl, or (b) R 2  and R 3  taken together with the nitrogen atom to which they are attached form a saturated 3-7 membered heterocyclic ring which may contain a O, S or NR 5  group, where R 5  is hydrogen, C 1-6  alkyl, alkyl, aryl, aryl substituted with one or more groups selected from the group consisting of C 1-6  alkyl, amino, C 1-6  alkylamino, C 1-6  alkoxy, C 1-6  alkoxy-C 1-6  alkyl C 1-6  alkyl C 1-6  alkoxy, aryl, and aryl substituted with one or more C 1-6  alkyl, or C 1-6  alkoxy-C 1-6  alkyl groups;  
 R is C 1-30  alkyl, substituted C 1-30  alkyl, C 1-30  alkenyl, substituted C 1-30  alkenyl, C 1-30  alkynyl, substituted, C 1-30  alkynyl, C 3-30  cycloalkyl, substituted C 3-30  cycloalkyl, C 6-18  aryl, substituted C 6-18  aryl, C 6-18  aryalkyl, (C 1-30  alkyl) 3  silyl or (C 1-30  alkyl) 3  silyl C 1-30  alkyl,  
 Y is independently H or F, and  
 n is an integer of 1 or 2,  
 and salts thereof  
 comprising:  
 i) reacting an ortho amino cyano aromatic compound of formula (II) or (IV)  
                     
 with an organometallic reagent R-M and  
 ii) condensing a resulting product with a 20(S)tricyclic ketone of formula (VII)  
                     
 
     
     
         2 . The method of  claim 1 , wherein R-M is selected from the group consisting of cyclohexylmagnesium halide, allyl magnesium halide, vinyl magnesium halide, ethyl magnesium halide, 4-fluorophenylmagnesium halide, isopropenyl magnesium halide, isopropyl magnesium halide, methyl magnesium halide, ethynyl magnesium halide, cyclopentyl magnesium halide, phenyl magnesium halide, benzyl magnesium halide, propyl magnesium halide, 1-propynyl magnesium halide, p-tolyl magnesium halide, o-tolyl magnesium halide, 1-trimethylsilymethyl magnesium halide, hexyl magnesium halide, 2-thiophenyl magnesium halide, 4-dimethylaminophenyl magnesium halide, 4-chloro 1-butenyl 2-magnesium halide, p-methoxylbenzyl magnesium halide, methoxymethyl magnesiumhalide, and p-chloro phenylmagnesium halide, n-butyl magnesium halide, s-butyl magnesium halide, t-butyl magnesium halide and p-trifluoromethylphenylmagnesium halide.  
     
     
         3 . The method of  claim 2 , wherein said ortho amino cyano aromatic compound is a compound of formula (III), R-M is n-butyl magnesium halide, and R 7  is n-butyl.  
     
     
         4 . The method of  claim 2 , wherein said ortho amino cyano aromatic compound is a compound of formula (III), R-M is benzyl magnesium halide, and R 7  is benzyl.  
     
     
         5 . The method of  claim 2 , wherein said ortho amino cyano aromatic compound is a compound of formula (III), R-M is p-tolyl magnesium halide, and R 7  is p-tolyl.  
     
     
         6 . The method of  claim 2 , wherein said ortho amino cyano aromatic compound is a compound of formula (III), R-M is 4-fluorophenyl magnesium halide, and R 7  is 4-fluorophenyl.  
     
     
         7 . The method of  claim 2 , wherein said ortho amino cyano aromatic compound is a compound of formula (III), R-M is p-chlorophenyl magnesium halide, and R 7  is p-chlorophenyl.  
     
     
         8 . The method of  claim 2 , wherein said ortho amino cyano aromatic compound is a compound of formula (III), R-M is p-trifluoromethylphenyl magnesium halide, and R 7  is p-trifluoromethylphenyl.  
     
     
         9 . The method of  claim 2 , wherein said ortho amino cyano aromatic compound is a compound of formula (IV), R-M is n-butyl magnesium halide, and R 7  is n-butyl.  
     
     
         10 . The method of  claim 2 , wherein said ortho amino cyano aromatic compound is a compound of formula (IV), R-M is s-butyl magnesium halide, and R 7  is s-butyl.  
     
     
         11 . The method of  claim 2 , wherein said ortho amino cyano aromatic compound is a compound of formula (IV), R-M is t-butyl magnesium halide, and R 7  is t-butyl.  
     
     
         12 . A 7-substituted camptothecin compound of formula (I) or (II):  
       
         
           
           
               
               
           
         
       
       wherein 
 X is H, NH 2 , H, F, Cl, Br, O—C 1-6  alkyl, S—C 1-6  alkyl, NH—C 1-6  alkyl, N(C 1-6  alkyl) 2 , or C 1-8  alkyl,  
 or X is -Z—(CH 2 ) a —N—(C 1-6  alkyl) 2  wherein Z is selected from the group consisting of O, NH and S, and a is an integer of 2 or 3,  
 or X is —CH 2 NR 2 R 3 , where (a) R 2  and R 3  are, independently, hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-6  alkyl, C 2-6  alkenyl, C 1-6  alkoxy-C 1-6  COR 4  where R 4  is hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-6  alkyl, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkoxy-C 1-6  alkyl, or (b) R 2  and R 3  taken together with the nitrogen atom to which they are attached form a saturated 3-7 membered heterocyclic ring which may contain a O, S or NR 5  group, where R 5  is hydrogen, C 1-6  alkyl, alkyl, aryl, aryl substituted with one or more groups selected from the group consisting of C 1-6  alkyl, amino, C 1-6  alkylamino, C 1-6  alkoxy, C 1-6  alkoxy-C 1-6  alkyl C 1-6  alkyl C 1-6  alkoxy, aryl, and aryl substituted with one or more C 1-6  alkyl, or C 1-6  alkoxy-C 1-6  alkyl groups;  
 R is C 1-30  alkyl, substituted C 1-30  alkyl, C 1-30  alkenyl, substituted C 1-30  alkenyl, C 1-30  alkynyl, substituted , C 1-30  alkynyl, C 3-30  cycloalkyl, substituted C 3-30  cycloalkyl, C 6-18  aryl, substituted C 6-18  aryl, C 6-18  aryalkyl, (C 1-30  alkyl) 3  silyl or (C 1-30  alkyl) 3  silyl C 1-30  alkyl,  
 Y is independently H or F, and  
 n is an integer of 1 or 2,  
 and salts thereof.  
 
     
     
         13 . The 7-substituted camptothecin compound of  claim 12 , wherein R is selected from the group consisting of cyclohexyl, allyl, vinyl, 4-fluorophenyl, ethynyl, cyclopentyl, phenyl, benzyl, 1-propynyl, p-tolyl, o-tolyl, 1-trimethylsilymethyl, hexyl, 2-thiophenyl, 4-dimethylaminophenyl, 2-(4-chloro 1-butenyl), p-methoxylbenzyl, methoxymethyl, p-chloro phenyl, s-butyl, t-butyl, and p-trifluoromethylphenyl.  
     
     
         14 . The 7-substituted camptothecin compound of  claim 13 , wherein R is benzyl.  
     
     
         15 . The 7-substituted camptothecin compound of  claim 13 , wherein R is p-tolyl.  
     
     
         16 . The 7-substituted camptothecin compound of  claim 13 , wherein R is p-fluorophenyl.  
     
     
         17 . The 7-substituted camptothecin compound of  claim 13 , wherein R is p-chlorophenyl.  
     
     
         18 . The 7-substituted camptothecin compound of  claim 13 , wherein R is p-trifluoromethylphenyl.  
     
     
         19 . The 7-substituted camptothecin compound of  claim 13 , wherein R is s-butyl.  
     
     
         20 . The 7-substituted camptothecin compound of  claim 13 , wherein R is t-butyl.