Substituted piperazinyl acetohydrazide procaspase-activating compounds
View Patent ↗The invention provides compounds and compositions useful for the modulation of certain enzymes. The compounds are of Formula I The compounds and compositions can induce of cell death, particularly cancer cell death. The invention also provides methods for the synthesis and use of the compounds and compositions, including the use of compounds and compositions in therapy for the treatment of cancer and selective induction of apoptosis in cells.
1. A compound of Formula I:
wherein
R 1 is an optionally substituted benzoyl;
n is 1, 2, 3, or 4; and
each R 2 is independently H, alkyl, alkoxy, hydroxy, carboxy, halo, amino, alkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy, nitro, cyano (—CN), sulfonamide
(—SO 2 NH 2 ), alkenyl, acetylene, N-alkyl-triazole, or N-benzyl-triazole;
or a pharmaceutically acceptable salt or solvate thereof.
2. The compound of claim 1 wherein R 1 is Ph(C═O)—.
3. The compound of claim 1 wherein R 1 is a benzoyl substituted by one or more alkyl, alkoxy, hydroxy, carboxy, halo, amino, alkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy, nitro, cyano (—CN), sulfonamide (—SO 2 NH 2 ), alkenyl, acetylene, N-alkyl-triazole, or N-benzyl-triazole groups.
4. The compound of claim 3 wherein R 1 is benzoyl substituted by —CN.
5. The compound of claim 3 wherein R 1 is benzoyl substituted by halo.
6. The compound of claim 5 wherein R 1 is benzoyl substituted by —F.
7. The compound of claim 3 wherein R 1 is benzoyl substituted by —CF 3 .
8. The compound of claim 3 wherein R 1 is benzoyl substituted by —SO 2 NH 2 .
9. The compound of claim 1 wherein n is 1, 2, or 3.
10. The compound of claim 1 wherein each R 2 is independently methyl, t-butyl, methoxy, hydroxy, fluoro, chloro, bromo, iodo, amino, ethylamino, diethylamino, trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy, nitro, alkenyl, acetylene, N-methyl-triazole, or N-benzyl-triazole.
11. The compound of claim 1 wherein n is 2, wherein one R 2 is alkenyl and the other R 2 is halo.
12. The compound of claim 1 wherein n is 2, wherein one R 2 is alkyl and the other R 2 is halo.
13. The compound of claim 1 wherein n is 1 and R 2 is alkenyl.
14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent, excipient, or carrier.
15. A pharmaceutical composition comprising a compound of Formula (X):
wherein
R 10 is H, F, Cl, Br, Me, —OMe, —NO 2 , —CN, —CF 3 , —OCF 3 , or —SO 2 NH 2 ;
R 20 is H, F, Cl, Br, Me, —OMe, —NO 2 , —CN, —CF 3 , —OCF 3 , or —SO 2 NH 2 ; and
R 30 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, or (C 1 -C 6 )alkoxy;
or a pharmaceutically acceptable salt or solvate thereof; in combination with a pharmaceutically acceptable diluent, excipient, or carrier.
16. The composition of claim 15 wherein R 30 is H, propyl, or 2-propenyl.
17. A method of treating a cancer in a patient in need thereof comprising administering an effective anti-cancer amount of a compound of claim 1 to the patient, wherein the cancer is lymphoma and the cancer is thereby treated.
18. A method of treating a cancer in a patient in need thereof comprising administering an effective anti-cancer amount of a composition of claim 15 to the patient, wherein the cancer is lymphoma and the cancer is thereby treated.