Di-ester prodrugs of camptothecin, process for their preparation and their therapeutical applications
View Patent ↗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. 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.
2. A di-ester compound of claim 1 wherein each R can be the same or different and is C 2 -C 20 alkyl, C 2 -C 6 alkenyl or C 4 -C 20 aryl.
3. A pharmaceutical composition comprising an effective amount of the di-ester compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
4. A pharmaceutical composition comprising an effective amount of the di-ester compound of claim 2 and a pharmaceutically acceptable carrier or diluent.
5. The di-ester compound of claim 1 , wherein each of R 1 , R 2 , R 3 , R 4 is H, and R is C 2 -C 30 alkyl.
6. The di-ester compound of claim 2 , wherein each of R 1 , R 2 , R 3 , R 4 is H, and R is C 2 -C 20 alkyl.
7. The di-ester compound of claim 1 , wherein each of R 1 , R 2 , R 3 , R 4 is H, and R is C 2 -C 22 alkenyl.
8. The di-ester compound of claim 1 , wherein each of R 1 , R 2 , R 3 , and R 4 is H, and R is C 2 -C 6 alkenyl.
9. The di-ester compound of claim 1 , wherein each of R 1 , R 2 , R 3 R 4 is H, and R is (CH 2 ) n OR 5 , R 5 is C 1 -C 6 alkyl or C 2 -C 6 alkenyl, and n is 1 or 2.
10. The di-ester compound of claim 1 , 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 or C 2 -C 6 alkenyl and n is 1 or 2.
11. The di-ester compound of claim 1 , wherein each of R 1 , R 2 , R 3 R 4 is H, and R is (CH 2 ) n NR 5 R 6 , R 5 and R 6 are independently C 1 -C 6 alkyl or C 2 -C 6 alkenyl, and n is 1 or 2.
12. The di-ester compound of claim 1 , wherein each of R 1 , R 2 , R 3 R 4 is H, R is (CH 2 ) n COR 7 R 7 , is hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 4 -C 10 aryl, and n is 2 to 4.
13. The di-ester compound of claim 1 , wherein each of R 1 , R 2 and R 3 is H, R 4 is CH 2 CH 3 , and R is C 2 -C 30 alkyl.
14. The di-ester compound of claim 2 , wherein each of R 1 , R 2 and R 3 is H, R 4 is CH 2 CH 3 , and R is C 2 -C 20 alkyl.
15. The di-ester compound of claim 1 , wherein each of R 1 , R 2 and R 3 is H, R 4 is CH 2 CH 3 , and R is C 2 -C 22 alkenyl.
16. The di-ester compound of claim 2 , wherein each of R 1 , R 2 and R 3 is H, R 4 is CH 2 CH 3 , and R is C 2 -C 6 alkenyl.
17. The di-ester compound of claim 1 , wherein each of R 1 , R 2 and R 3 is H, R 4 is CH 2 CH 3 , and R is C 4 -C 30 aryl.
18. The di-ester compound of claim 2 , wherein each of R 1 , R 2 and R 3 is H, R is CH 2 CH 3 , and R is C 4 -C 20 aryl.
19. The di-ester compound of claim 1 , wherein each of R 1 , R 2 and R 3 is H, R 4 is CH 2 CH 3 , R is (CH 2 ) n OR 5 , R 5 is C 1 -C 6 alkyl or C 2 -C 6 alkenyl, and n is 1 or 2.
20. The di-ester compound of claim 1 , 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 a C 2 -C 6 alkenyl and n is 1 or 2.
21. The di-ester compound of claim 1 or a salt thereof, 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 NR 5 R 6 , R 5 and R 6 are independently C 1 -C 6 alkyl or C 2 -C 6 alkenyl, and n is 1 or 2.
22. The di-ester compound of claim 1 , wherein each of R 1 , R 2 and R 3 is H, R 4 is CH 2 CH 3 , R is (CH 2 ) n COR 7 , R 7 is hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 4 -C 10 aryl, and n is 2 to 4.
23. The di-ester compound of claim 1 , wherein each of R 1 , R 2 and R 3 is H, R is Si(CH 3 ) 2 C(CH 3 ) 3 , and R is C 2 -C 30 alkyl.
24. The di-ester compound of claim 2 , 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 C 2 -C 20 alkyl.
25. The di-ester compound of claim 1 , 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 C 2 -C 22 alkenyl.
26. The di-ester compound of claim 2 , 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 C 2 -C 6 alkenyl.
27. The di-ester compound of claim 1 , 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 C 4 -C 30 aryl.
28. The di-ester compound of claim 2 , 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 C 4 -C 20 aryl.
29. The di-ester compound of claim 1 , wherein each of R 1 , R 2 and R 3 is H, R 4 is Si(CH 3 ) 2 C(CH 3 ) 3 , R is (CH 2 ) n OR 5 , R 5 is C 1 -C 6 alkyl or C 2 -C 6 alkenyl, and n is 1 or 2.
30. The di-ester compound of claim 1 , 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 or C 2 -C 6 alkenyl and n is 1 or 2.
31. The di-ester compound of claim 1 or a salt thereof, wherein each of R 1 , R 2 and R 3 is H, R 4 is Si(CH 3 ) 2 C(CH 3 ) 3 , R is (CH 2 ) n NR 5 R 6 , R 5 and R 6 are independently, C 1 -C 6 alkyl or C 2 -C 6 alkenyl, and n is 1 or 2.
32. The di-ester compound of claim 1 , wherein each of R 1 , R 2 and R 3 is H, R 4 is Si(CH 3 ) 2 C(CH 3 ) 3 , R is (CH 2 ) n COR 7 , R 7 is hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 4 -C 10 aryl, and n is 2 to 4.
33. The di-ester compound of claim 1 , wherein R 1 is CH 2 N(CH 3 ) 2 , each of R 2 , R 3 and R 4 is H, and R is C 2 -C 30 alkyl.
34. The di-ester compound of claim 2 , wherein R 1 is CH 2 N(CH 3 ) 2 , each of R 2 , R 3 and R 4 is H, and R is C 2 -C 20 alkyl.
35. The di-ester compound of claim 1 , wherein R 1 is CH 2 N(CH 3 ) 2 , each of R 2 , R 3 and R 4 is H, and R is C 2 -C 22 alkenyl.
36. The di-ester compound of claim 2 , wherein R 1 is CH 2 N(CH 3 ) 2 , each of R 2 , R 3 and R 4 is H, and R is C 2 -C 6 alkenyl.
37. The di-ester compound of claim 1 , wherein R 1 is CH 2 N(CH 3 ) 2 , each of R 2 , R 3 and R 4 is H, and R is C 4 -C 30 aryl.
38. The di-ester compound of claim 2 , wherein R 1 is CH 2 N(CH 3 ) 2 , each of R 2 , R 3 and R 4 is H, and R is C 4 -C 20 aryl.
39. The di-ester compound of claim 1 , wherein R 1 is CH 2 N(CH 3 ) 2 , each of R 2 , R 3 and R 4 is H, R is (CH 2 ) n OR 5 , R 5 is C 1 -C 6 alkyl or C 2 -C 6 alkenyl, and n is 1 or 2.
40. The di-ester compound of claim 1 , 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 or alkenyl and n is 1 or 2.
41. The di-ester compound of claim 1 , wherein R 1 is CH 2 N(CH 3 ) 2 , each of R 2 , R 3 and R 4 is H, R is (CH 2 ) n NR 5 R 6 , R 5 and R 6 are independently, C 1 -C 6 alkyl or C 2 -C 6 alkenyl, and n is 1 or 2.
42. The di-ester compound of claim 1 , wherein R 1 is CH 2 N(CH 3 ) 2 , each of R 2 , R 3 R 4 is H, and R is (CH 2 ) n COR 7 , R 7 is hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 4 -C 10 aryl, and n is 2 to 4.
43. 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 1 .
44. 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 2 .
45. A method to treat cancer in a patient comprising administering a composition comprising at least one di-ester compound of claim 1 to said patient in an amount effective to treat said cancer.
46. A method to treat cancer in a patient comprising administering a composition comprising at least one di-ester compound of claim 2 to said patient in an amount effective to treat said cancer.
47. The method of claim 45 , wherein said cancer is lung, breast, colon, prostate, melanoma, pancreas, stomach, liver, brain, kidney, uterus, cervix, ovaries, urinary tract, gastrointestinal, or leukemia.
48. The method of claim 46 , wherein said cancer is lung, breast, colon, prostate, melanoma, pancreas, stomach, liver, brain, kidney, uterus, cervix, ovaries, urinary tract, gastrointestinal, or leukemia.
49. The method of claim 45 , wherein said cancer is solid tumor or blood borne tumor.
50. The method of claim 46 , wherein said cancer is solid tumor or blood borne tumor.
51. The method of claim 45 , wherein said composition is administered orally, parenterally, intramuscularly, transdermally or by an airborne delivery system.
52. The method of claim 46 , wherein said composition is administered orally, parenterally, intramuscularly, transdermally or by an airborne delivery system.
53. The method of claim 45 , wherein said composition is a nanoparticle containing said at least one di-ester compound.
54. The method of claim 46 , wherein said composition is a nanoparticle containing said at least one di-ester compound.
55. A method to treat breast cancer in a patient comprising administering a composition comprising at least one di-ester compound of claim 1 to said patient in an amount effective to treat said cancer.
56. A method to treat breast cancer in a patient comprising administering a composition comprising at least one di-ester compound of claim 2 to said patient in an amount effective to treat said cancer.