Indole compounds as an inhibitor of cellular necrosis

1. A method for hepatoprotection, hepatic functional improvement, and/or treatment of hepatic disease comprising administering a composition which comprises an indole compound of the following formula (1), pharmaceutically acceptable salt or stereoisomer thereof as an active ingredient together with a pharmaceutically acceptable carrier or diluent to a subject in need thereof:

in which

n denotes a number of 0 to 3,

A represents 5 membered heteroaryl or heterocycle each of which has 1 to 3 hetero atoms selected from N, O and S,

R 1 represents R 5 —X—B—X′—,

B represents a direct bond, or represents 3˜10 membered heterocycle or heteroaryl each of which has 1 to 4 hetero atoms selected from N, O and S,

X and X′ independently of one another represent a direct bond, or are selected from the group consisting of —NR 6 —, —CO—, —CONR 6 —, —CO 2 —, —OC(O)—, —S(O) m —, —O—(CH 2 ) m —O—, —(CH 2 ) m —, —NR 6 CO—, —(R 6 O) 2 P(O)— and —NHCO 2 —, wherein m denotes a number of 0 to 3, and R 6 represents hydrogen or C 1 -C 6 -alkyl,

R 5 represents hydrogen, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 4 -C 6 -cycloalkyl or phenyl, or represents 3˜10 membered monocyclic or fused cyclic heterocycle or heteroaryl each of which has 1 to 3 hetero atoms selected from N, O and S, and is optionally substituted by oxo or C 1 -C 6 -alkyl, or

R 2 represents —(CR 8 R 9 ) p —Y—R 7 ,

p denotes a number of 0 to 2,

R 8 and R 9 independently of one another represent hydrogen or C 1 -C 6 -alkyl,

Y represents a direct bond, or is selected from the group consisting of —O—, —S—, —NR 6 C(O)—, —NR 6 C(O)—, —C(O)NR 6 — and —S(O) q —, wherein q denotes a number of 0 to 2,

R 7 represents hydrogen, halogen, hydroxyl, C 1 -C 6 -alkyl, phenyl or represents 3˜10 membered heterocycle or heteroaryl each of which has 1 to 3 hetero atoms selected from N, S and O and which optionally contains oxo,

R 3 represents hydrogen, C 1 -C 6 -alkyl, or —(CH 2 ) q —C 4 -C 6 -cycloalkyl,

R 4 represents C 3 -C 6 -cycloalkyl,

where alkyl, alkoxy, phenyl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, and the substituents are one or more selected from the group consisting of hydroxy, halogen, nitrile, amino, C 1 -C 6 -alkylamino, di-C 1 -C 6 -alkylamino, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkylsulfonyl, carboxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyloxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkyloxycarbonyl, C 1 -C 6 alkylaminocarbonyl, and oxo.

2. The method of claim 1 , wherein the hepatic disease is selected from the group consisting of liver transplantation, alcoholic or non-alcoholic fatty liver, hepatic fibrosis, hepatocirrhoisis and hepatitis caused by virus or drugs.

3. The method of claim 1 , wherein the hepatic disease is alcoholic acute/chronic hepatic disease.

4. The method of claim 1 , wherein the hepatic disease is fatty acid-induced fatty liver or acute/chronic hepatic disease derived from fatty liver.

5. The method of claim 1 , wherein the hepatic disease is mediated by reactive oxygen species (ROS).

6. The method of claim 1 , wherein the hepatic disease is mediated by heavy metals.

7. The method of claim 1 , wherein a prophylactic or therapeutic agent for drug-derived necrosis and necrosis-associated diseases is co-administered.

8. The method of claim 7 , wherein the prophylactic or therapeutic agent for drug-derived necrosis and necrosis-associated diseases is selected from the group consisting of antibiotics, anti-cancer agents, anti-viral agents, anti-infectives, anti-inflammatory agents, anti-coagulants, lipid-improving agents, cell death inhibitors, anti-hypertensive agents, anti-diabetic/anti-obesity agents, therapeutic agents for cardiovascular disease, therapeutic agents for neurodegenerative disease, anti-aging agents, and therapeutic agents for metabolic disease.

9. The method of claim 1 , wherein an agent selected from the group consisting of hepatocyte regeneration promoters, hepatic functional adjuvants, anti-viral agents, immunosuppressants, and fibrosis inhibitors is co-administered.

10. A method of preparing a composition for hepatoprotection, hepatic functional improvement, and treatment of hepatic disease, which comprises mixing the compounds of formula (1), pharmaceutically acceptable salts or stereoisomers thereof as defined in claim 1 as an active ingredient together with a pharmaceutically acceptable carrier.