Di-ester prodrugs of camptothecin, process for their preparation and their therapeutical applications

Abstract

The present invention is related to 10,20-di-O ester derivatives of camptothecin and pharmaceutical formulations thereof. The compounds and pharmaceutical formulations of the present invention possess increased biological life span and bioavailability and reduced toxicity, while maintaining anti-cancer activity.

1 .- 54 . (canceled) 
     
     
         55 . A di-ester compound having the following structure: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1 , R 2 , R 3 , and R 4 , which can be the same or different, are hydrogen, halogen, C 1 -C 20  alkyl, C 1 -C 8  alkoxyl, C 4 -C 20  aryl or C 1 -C 20  silyl, 
 R, which can be the same or different, is C 2 -C 30  alkyl, C 2 -C 22  alkenyl, C 4 -C 30  aryl, (CH 2 ) n OR 5 , (CH 2 ) n SR 5 , (CH 2 ) n NR 5 R 6  or (CH 2 ) n COR 7 , 
 R 5  and R 6 , which can be the same or different, are C 1 -C 8  alkyl or C 2 -C 6  alkenyl, 
 R 7  is hydroxy, C 1 -C 20  alkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkoxy, C 4 -C 20  aryl, or NR 8 R 9 , 
 R 8  and R 9 , which can be the same or different, are C 1 -C 6  alkyl, 
 and n is an integer of 1 to 8, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         56 . The di-ester compound of  claim 55 , wherein each of R 1 , R 2 , R 3  and R 4  is H, and R is (CH 2 ) n SR 5 , R 5  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 4 -C 10  aryl, and n is 1 or 2. 
     
     
         57 . The di-ester compound of  claim 55 , wherein each of R 1 , R 2  and R 3  is H, R 4  is CH 2 CH 3 , and R is (CH 2 ) n SR 5 , R 5  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 4 -C 10  aryl, and n is 1 or 2. 
     
     
         58 . The di-ester compound of  claim 55 , wherein each of R 1 , R 2  and R 3  is H, R 4  is Si(CH 3 ) 2 C(CH 3 ) 3 , and R is (CH 2 ) n SR 5 , R 5  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl or C 4 -C 10  aryl, and n is 1 or 2. 
     
     
         59 . The di-ester compound of  claim 55 , wherein R 1  is CH 2 N(CH 3 ) 2 , each of R 2 , R 3  and R 4  is H, and R is (CH 2 ) n SR 5 , R 5  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl or C 4 -C 10  aryl, and n is 1 or 2. 
     
     
         60 . A method to inhibit the enzyme topoisomerase I in an animal in need thereof comprising administering to the animal an effective amount of a composition comprising at least one di-ester compound of  claim 55 . 
     
     
         61 . A method to treat cancer in a patient comprising administering a composition comprising at least one di-ester compound of  claim 55  to said patient in an amount effective to treat said cancer. 
     
     
         62 . The method of  claim 61 , wherein said cancer is lung, breast, colon, prostate, melanoma, pancreas, stomach, liver, brain, kidney, uterus, cervix, ovaries, urinary tract, gastrointestinal, or leukemia. 
     
     
         63 . The method of  claim 61 , wherein said cancer is solid tumor or blood borne tumor. 
     
     
         64 . The method of  claim 61 , wherein said composition is administered orally, parenterally, intramuscularly, transdermally or by an airborne delivery system. 
     
     
         65 . The method of  claim 61 , wherein said composition is a nanoparticle containing said at least one di-ester compound. 
     
     
         66 . A method to treat breast cancer in a patient comprising administering a composition comprising at least one di-ester compound of  claim 55  to said patient in an amount effective to treat said cancer.