DI-ESTER PRODRUGS OF CAMPTOTHECIN, PROCESS FOR THEIR PREPARATION AND THEIR THERAPEUTICAL APPLICATIONS
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.