Enzyme-activating compounds and compositions

Patent metadata

Field	Value
Publication number	US-9249116-B2
Application number	US-201314417524-A
Country	US
Kind code	B2
Filing date	Aug 5, 2013
Priority date	Aug 3, 2012
Publication date	Feb 2, 2016
Grant date	Feb 2, 2016

Abstract

The invention provides compounds and compositions useful for the modulation of certain enzymes. 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.

First claim

What is claimed is:

1. A compound that directly activates procaspase-3 upon contacting procaspase-3, wherein the compound is 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 ), 2-propenyl, acetylene, N-alkyl-triazole, or N-benzyl-triazole; or two R 2 groups form an ortho-fused benzo group;
or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1 wherein n is 1 or 2.

3. The compound of claim 1 wherein R 2 is methyl, t-butyl, methoxy, hydroxy, fluoro, chloro, bromo, iodo, amino, ethylamino, diethylamino, trifluoromethoxy, benzyl, benzyloxy, nitro, 2-propenyl, acetylene, N-methyl-triazole, or N-benzyl-triazole.

4. The compound of claim 1 wherein n is 2 and two R 2 groups form an ortho-fused benzo group.

5. The compound of claim 1 wherein n is 2 and each R 2 is t-butyl.

6. The compound of claim 1 wherein n is 1 and R 2 is 2-propenyl.

7. The compound of claim 1 wherein R 1 is a methoxy-benzoyl; dimethoxy-benzoyl; benzyloxy-benzoyl; t-butyl-benzoyl; naphthylcarbonyl; or ethyl-benzoyl.

8. The compound of claim 1 wherein R 1 is 4 methoxy-benzoyl; 2,5-dimethoxy-benzoyl; 4-benzyloxy-benzoyl; 4-t-butyl-benzoyl; 2-naphthylcarbonyl; or 4-ethyl-benzoyl.

9. The compound of claim 1 wherein R 1 is:

10. The compound of claim 1 wherein the compound is:

11. The compound of claim 1 wherein the compound induces death of cancer cells in culture.

12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent, excipient, or carrier.

13. A method of inducing apoptosis in a cancer cell comprising administering to a cancer cell an effective amount of a compound of claim 1 .

14. A compound of claim 1 wherein the compound is a compound of Formula (X):

wherein
R 10 is H, F, Cl, Br, —NO 2 , —CN, —CF 3 , —OCF 3 , or —SO 2 NH 2 ;
R 20 is H, F, Cl, Br, —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.

15. The compound of claim 14 wherein R 30 is H, propyl, or 2-propenyl.

16. A pharmaceutical composition comprising a compound of claim 14 and a pharmaceutically acceptable diluent, excipient, or carrier.

17. A method of inducing apoptosis in a cancer cell comprising administering to a cancer cell an effective amount of a compound of claim 14 .

18. The method of claim 17 wherein the cancer cell is an adrenal cancer cell, a brain cancer cell, a breast cancer cell, a colon cancer cell, a kidney cancer cell, a lymphoma cell, a leukemia cell, a liver cancer cell, a lung cancer cell, a melanoma cell, a neuroblastoma cell, a pancreatic cancer cell, a prostate cancer cell, or a renal cancer cell.

19. The method of claim 13 wherein the cancer cell is an adrenal cancer cell, a brain cancer cell, a breast cancer cell, a colon cancer cell, a kidney cancer cell, a lymphoma cell, a leukemia cell, a liver cancer cell, a lung cancer cell, a melanoma cell, a neuroblastoma cell, a pancreatic cancer cell, a prostate cancer cell, or a renal cancer cell.

Assignees

• Univ Illinois

Inventors

• Hergenrother Paul J
• Roth Howard S

Classifications

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D295/15

  to an acyclic saturated chain · CPC title

• C07D295/16 Primary

  acylated on ring nitrogen atoms · CPC title

• A61K31/4965

  Non-condensed pyrazines · CPC title

• C07D295/192 Primary

  from aromatic carboxylic acids · CPC title