Camptothecin analogs and methods of preparation thereof

Abstract

The present invention provides generally a compound having the following general formula (1): wherein R 1 and R 2 are independently the same or different and are hydrogen, an alkyl group, an alkenyl group, a benzyl group, an alkynyl group, an alkoxyl group, an aryloxy group, an acyloxy group, a carbonyloxy group, a carbamoyloxy group, a halogen, a hydroxyl group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, an acyl group, an amino group, —SR c , wherein, R c is hydrogen, an acyl group, an alkyl group, or an aryl group, or R 1 and R 2 together form a group of the formula —O(CH 2 ) n O— wherein n represents the integer 1 or 2; R 3 is H, F, a halogen atom, a nitro group, an amino group, a hydroxyl group, or a cyano group; or 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; R 4 is H, F, a C 1-3 alkyl group, a C 2-3 alkenyl group, a C 2-3 alkynyl group, or a C 1-3 alkoxyl group; R 5 is a C 1-10 alkyl group, or a propargyl group; and R 6 , R 7 and R 8 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 9 group, wherein N is an integer within the range of 1 through 10 and R 9 is a hydroxyl group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group or a nitro group; and pharmaceutically acceptable salts thereof.

What is claimed is:  
     
         1 . A compound having the structure:  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently the same or different and are hydrogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxyl group, an aryloxy group, an acyloxy group, a carbonyloxy group, a carbamoyloxy group, a halogen, a hydroxyl group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, an acyl group, an amino group, —SR c , wherein R c  is hydrogen, an acyl group, an alkyl group, or an aryl group; or R 1  and R 2  together form a group of the formula —O(CH 2 ) n O— wherein n represents the integer 1 or 2;  
         R 3  is H, F, a halogen atom, a nitro group, an amino group, a hydroxyl group, or a cyano group; or 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;  
         R 4  is H, F, a C 1-3  alkyl group, a C 2-3  alkenyl group, a C 2-3  alkynyl group, or a C 1-3  alkoxyl group;  
         R 5  is a C 1-10  alkyl group, or a propargyl group; and  
         R 6 , R 7  and R 8  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 9  group, wherein N is an integer within the range of 1 through 10 and R 9  is a hydroxyl group, alkoxy group, an amino group, an alkylamino group, a dialkylamino group, a halogen atom, a cyano group or a nitro group;  
         and pharmaceutically acceptable salts thereof.  
       
     
     
         2 . The compound of  claim 1 , wherein R 4  is H.  
     
     
         3 . The compound of  claim 1 , wherein R 1  and R 2  are independently the same or different and are H, a hydroxyl group, a halogen, an amino group, a nitro group, a cyano group, a C 1-3  alkyl group, a C 2-3  alkenyl group, a C 2-3  alkynyl group or a C 1-3  alkoxyl group.  
     
     
         4 . The compound of  claim 1 , wherein R 1  and R 2  are independently the same or different and are a C 1-3  perhaloalkyl group, a C 1-3  aminoalkyl group, a C 1-3  alkylamino group or a C 1-3  dialkylamino group.  
     
     
         5 . The compound of  claim 1 , wherein R 1  and R 2  are independently the same or different and are H, a methyl group, an amino group, a nitro group, a cyano group, or a hydroxyl group.  
     
     
         6 . The compound of  claim 1 , wherein R 1  and R 2  are independently the same or different and are a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a hydroxymethyl group, an aminomethyl group, a methylaminomethyl group, or a dimethylaminomethyl group.  
     
     
         7 . The compound of  claim 1 , wherein R 3  is F, an amino group, or a hydroxyl group.  
     
     
         8 . The compound of  claim 1 , wherein R 5  is an ethyl group.  
     
     
         9 . The compound of  claim 1 , wherein R 6 , R 7  and R 8  are independently the same or different and are a C 1-6  alkyl group, a phenyl group or a —(CH 2 ) N R 9  group, wherein N is an integer within the range of 1 through 6 and R 9  is a hydroxyl group, alkoxy group an amino group, an alkylamino group a dialkylamino group, a halogen atom, a cyano group or a nitro group.  
     
     
         10 . The compound of  claim 1 , wherein R 6 , R 7  and R 8  are methyl groups.  
     
     
         11 . The compound of  claim 1 , wherein R 2  and R 3  form a methylenedioxy group, or a 1,2-ethylenedioxy group.  
     
     
         12 . The compound of  claim 1 , wherein R 3  is F.  
     
     
         13 . The compound of  claim 1 , wherein the compound is 7-trimethylsilyl camptothecin, 7-trimethylsilyl-10-acetoxy camptothecin, 7-trimethylsilyl-10-hydroxy camptothecin, 7-trimethylsilyl-11-fluoro camptothecin, 7-trimethylsilyl-9-fluoro camptothecin, 7-trimethylsilyl-10-fluoro camptothecin, 7-trimethylsilyl-10-amino camptothecin, 7-trimethylsilyl-11-amino camptothecin, 7-trimethylsilyl-11,12-diflouro camptothecin, 7-trimethylsilyl-9,10-diflouro camptothecin, 7-trimethylsilyl-10-amino-11-fluoro camptothecin, 7-tert-butyldimethylsilyl camptothecin, 7-tert-butyldimethylsilyl-10-acetoxy camptothecin, 7-tert-butyldimethylsilyl-10-hydroxy camptothecin, 7-dimethyl-3-cyanopropylsilyl camptothecin, 7-dimethyl-3-halopropylsilyl camptothecin, 7-triphenylsilyl camptothecin, 7-triethylsilyl camptothecin, 7-dimethylnorpinylsilyl camptothecin.  
     
     
         14 . A method of treating a patient, comprising the step of administering a pharmaceutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.