Camptothecin analogs and methods of preparation thereof
View Patent ↗A method of inhibiting topoisomerase I mediated DNA cleavage including administering a pharmaceutically effective amount of a compound having the following formula or a pharmaceutically acceptable salt thereof: wherein R 1 and R 2 are independently the same or different and are hydrogen, an alkyl group, an aminoalkyl group, an alkylaminoalkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxyl group, an aryloxy group, a carbamoyloxy group, a halogen, a hydroxyl group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, —C(O)R f , an amino group, an alkylamino group, a dialkylamino group, —SR c , 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 R3 together form —O(CH 2 ) n O— (n=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.
1. A method of inhibiting topoisomerase I mediated DNA cleavage in a mammal, comprising:
administering to the mammal a pharmaceutically effective amount of a compound having the following formula or a pharmaceutically acceptable salt thereof:
wherein R 1 and R 2 are independently the same or different and are hydrogen, an alkyl group, an aminoalkyl group, an alkylaminoalkyl group, a C 1 -C 3 perphaloalkyl group, hydroxyalkyl group an alkenyl group, an alkynyl group, an alkoxyl group, an aryloxy group, a carbamoyloxy group, a halogen, a hydroxyl group, a nitro group, a cyano group, an azido groups a formyl group, a hydrazino group, —C(O)R f , wherein R f is an alkyl group, a haloalkyl group, an alkoxyl group, an amino group or a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, —SR c , wherein R c is hydrogen, —C(O)R f , an alkyl group, or an aryl group, —OC(O)R d or —OC(O)OR d , wherein R d is an alkyl 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;
provided that at least one of R 1 , R 2 , R 3 and R 4 is not H, a halogen, an alkyl group, an amino group or a nitro group.
2. The method of claim 1 , wherein R 4 is H.
3. The method of claim 1 , wherein R 1 and R 2 are independently the same or different and are H, a hydroxy group, a halogen, an amino group, a nitro group, a cyano group, a C1-3 alkyl group, a C2-3 alkenyl group, a C2-3 alkynyl group or a C1-3 alkoxyl group.
4. The method of claim 1 , wherein R 1 and R 2 are independently the same or different and are a C1-3 perhaloalkyl group, a C1-3 aminoalkyl group, a C1-3 alkylamino group or a C1-3 dialkylamino group.
5. The method 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 method 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 method of claim 1 , wherein R 3 is F, an amino group, or a hydroxyl group.
8. The method of claim 1 , wherein R 5 is an ethyl group.
9. The method of claim 1 , wherein R 6 , R 7 and R 8 are independently the same or different and are a C1-6 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 method of claim 1 , wherein R 6 , R 7 and R 8 are methyl groups.
11. The method of claim 1 , wherein R 2 and R 3 form a methylenedioxy group, or a 1,2-ethylenedioxy group.
12. The method of claim 1 , wherein R 3 is F.
13. The method of claim 1 , wherein the compound is 7-trimethylsilyl-10-acetoxy camptothecin, 7-trimethylsilyl-10-hydroxy camptothecin, 7-tert-butyldimethylsilyl-10-acetoxy camptothecin, 7-tert-butyldimethylsilyl-10-hydroxy camptothecin.
14. The method of claim 1 , wherein R 2 is a hydroxy group and R 4 is H.
15. The method of claim 14 , wherein R 1 is 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.
16. The method of claim 14 , wherein R 1 is 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.
17. The method of claim 14 , wherein R 1 is H, a methyl group, an amino group, a nitro group, a cyano group, or a hydroxyl group.
18. The method of claim 14 , wherein R 1 is 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.
19. The method of claim 14 , wherein R 3 is F, an amino group, or a hydroxyl group.
20. The method of claim 14 , wherein R 5 is an ethyl group.
21. The method of claim 14 , 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 )NR 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.
22. The method of claim 14 , wherein R 2 and R 3 form a methylenedioxy group, or a 1,2-ethylenedioxy group.
23. The method of claim 14 , wherein the compound is 7-trimethylsilyl-10-hydroxy camptothecin or 7-tert-butyldimethylsilyl-10-hydroxy camptothecin.
24. The method of claim 14 , wherein the compound is 7-tert-butyldimethylsilyl-10-hydroxy camptothecin.
25. A compound having the formula:
wherein R 1 and R 2 are independently the same or different and are hydrogen, an alkyl group, an aminoalkyl group, an alkylaminoalkyl group, a C 1 -C 3 group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxyl group, an aryloxy group, a carbamoyloxy group, a halogen, a hydroxyl group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, —C(O)R f , wherein R f is an alkyl group, a haloalkyl group, an alkoxyl group, an amino group or a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, —SR c , wherein R c is hydrogen, —C(O)R f , an alkyl group, or an aryl group, —OC(O)R d or —OC(O)OR d , wherein
R d is an alkyl 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;
provided that at least one of R 1 , R 2 , R 3 and R 4 is not H, a halogen, an alkyl group, an amino group or a nitro group; and
pharmaceutically acceptable salts thereof.