Camptothecin analogs and methods of preparation thereof

Abstract

A compound having the formula in racemic form, enantiomerically enriched form or enantiomerically pure form, and pharmaceutically acceptable salts thereof.

1 . A compound having the formula 
       
         
           
           
               
               
           
         
         in racemic form, enantiomerically enriched form or enantiomerically pure form; 
         wherein R 1  and R 2  are independently the same or different and are hydrogen, —C(O)R f  wherein R f  is an alkyl group, an alkoxy group, an amino group or a hydroxy group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryloxy group, an acyloxy group, —OC(O)OR d , wherein R d  is an alkyl group, —OC(O)NR a R b  wherein R a  and R b  are independently the same or different, H, —C(O)R f , an alkyl group or an aryl group, a halogen, a hydroxy group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, an amino group, —SR c , wherein R c  is hydrogen, —C(O)R f , an alkyl group or an aryl group; or R 1  and R 2  together form a chain of three or four members selected from the group of CH, CH 2 , O, S, NH, or NR 15 , wherein R 15  is an C 1 -C 6  alkyl group; 
         R 3  is H, a halogen atom, a nitro group, an amino group, a hydroxy group, or a cyano group; or R 2  and R 3  together form a chain of three or four members selected from the group of CH, CH 2 , O, S, NH, or NR 15 , wherein R 15  is an C 1 -C 6  alkyl group; 
         R 4  is H, F, an amino group, a C 1-3  alkyl group, a C 2-3  alkenyl group, a C 2-3  alkynyl group, a trialkylsilyl group or a C 1-3  alkoxy group; 
         R 5  is a C 1-10  alkyl group, an alkenyl group, an alkynyl group, or a benzyl group; 
         R 6  is —Si (R 8 R 9 R 10 ) or —(R 7 )Si(R 8 R 9 R 10 ), wherein R 7  is an alkylene group, an alkenylene group, or an alkynylene group; and R 8 , R 9  and R 10  are independently a C 1-10  alkyl group, a C 2-10  alkenyl group, a C 2-10  alkynyl group, an aryl group or a —(CH 2 ) N R 11  group, wherein N is an integer within the range of 1 through 10 and R 11  is a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, —SR c  or a nitro group; 
         R 12  is H or —C(O)R f , —C(O)OR d  or —C(O)NR a R b ; 
         R 13  is H, F or —CH 3 ; and 
         pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The compound of  claim 1  wherein R 2  and R 3  together form a group of the formula —O(CH 2 ) n O— wherein n represents the integer 1 or 2. 
     
     
         3 . The compound of  claim 1  wherein R 5  is an ethyl group, an allyl group, a benzyl group or a propargyl group. 
     
     
         4 . The compound of  claim 1  wherein R 13  is H. 
     
     
         5 . The compound of  claim 4  wherein R 5  is an ethyl group. 
     
     
         6 . The compound of  claim 5  wherein R 4  is H. 
     
     
         7 . The compound of  claim 6  wherein R 8  and R 9  are methyl groups, R 10  is a tert-butyl group or a methyl group, R 1  is H and R 3  is H. 
     
     
         8 . The compound of  claim 7  wherein R 2  is H, NH 2  or OH. 
     
     
         9 . A compound having the formula 
       
         
           
           
               
               
           
         
         wherein R 5  is a C 1-10  alkyl group, an alkenyl group, an alkynyl group, or a benzyl group; 
         R 12  is H or —C(O)R f , —C(O)OR d  or —C(O)NR a R b . 
       
     
     
         10 . The compound of  claim 9  wherein R 5  is an ethyl group, an allyl group, a benzyl group or a propargyl group. 
     
     
         11 . The compound of  claim 10  wherein R 5  is an ethyl group. 
     
     
         12 . A compound having the formula 
       
         
           
           
               
               
           
         
         wherein R 5  is a C 1-10  alkyl group, an alkenyl group, an alkynyl group, or a benzyl group; 
         R 13  is H, F or —CH 3 ; and 
         R 15  is a C 1 -C 6  alkyl group. 
       
     
     
         13 . The compound of  claim 12  wherein R 5  is an ethyl group, an allyl group, a benzyl group or a propargyl group. 
     
     
         14 . The compound of  claim 13  wherein R 13  is H. 
     
     
         15 . The compound of  claim 14  wherein R 5  is an ethyl group. 
     
     
         16 . A compound having the formula 
       
         
           
           
               
               
           
         
         in racemic form, enantiomerically enriched form or enantiomerically pure form; 
         wherein X is a radical precursor; 
         R 5  is a C 1-10  alkyl group, an alkenyl group, an alkynyl group, or a benzyl group; 
         R 6  is an alkyl group, —Si(R 8 R 9 R 10 ) or —(R 7 ) Si(R 8 R 9 R 10 ), wherein R 7  is an alkylene group, an alkenylene group, or an alkynylene group; and R 8 , R 9  and R 10  are independently a C 1-10  alkyl group, a C 2-10  alkenyl group, a C 2-10  alkynyl group, an aryl group or a —(CH 2 ) N R 11  group, wherein N is an integer within the range of 1 through 10 and R 11  is a hydroxy group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group, —SR c  or a nitro group; and 
         R 13  is H, F or —CH 3 . 
       
     
     
         17 . The compound of  claim 16  wherein R 5  is an ethyl group, an allyl group, a benzyl group or a propargyl group. 
     
     
         18 . The compound of  claim 17  wherein X is Br or I. 
     
     
         19 . The compound of  claim 18  wherein R 13  is H. 
     
     
         20 . The compound of  claim 19  wherein R 5  is an ethyl group.