# US 8,569,307 B2 · Indole compounds as an inhibitor of cellular necrosis

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- Number: US 8,569,307 B2
- Document ID: US8569307B2
- Status: Granted
- Kind: B2
- Application number: 13/493,045
- Filed: 2012-06-11
- Published: 2012-10-04
- Granted: 2013-10-29
- Earliest claimed: 2007-08-17
- Assignees: LG Life Sciences Ltd.
- Applicants: Soon Ha Kim; Hyoung Jin Kim; Sun Young Koo; Sung Bae Lee; Heui Sul Park; Seung Hyun Yoon; Seung Yup Paek; Hyo Shin Kwak; Dong Ook Seo; Eok Park
- Inventors: Soon Ha Kim; Hyoung Jin Kim; Sun Young Koo; Sung Bae Lee; Heui Sul Park; Seung Hyun Yoon; Seung Yup Paek; Hyo Shin Kwak; Dong Ook Seo; Eok Park
- Web page: https://patentgrep.com/patent/US8569307B2

## CPC

- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/416: condensed with carbocyclic ring systems, e.g. indazole
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/497: containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/38: of the suprarenal hormones
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/16: Central respiratory analeptics
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 17/16: Emollients or protectives, e.g. against radiation
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 25/32: Alcohol-abuse
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- A61P 31/12: Antivirals
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 39/02: Antidotes
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07F 9/65583: {each of the hetero rings containing nitrogen as ring hetero atom}
- C07F 9/65586: {at least one of the hetero rings does not contain nitrogen as ring hetero atom}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

The present invention relates to new indole compounds, pharmaceutically acceptable salts or isomers thereof which are useful for the prevention or treatment of cellular necrosis and necrosis-associated diseases. The present invention also relates to a method and a composition for the prevention or treatment of cellular necrosis and necrosis-associated diseases, comprising said indole compounds as an active ingredient.

## Claims

### Claim 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,
R1 represents R5—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 —NR6—, —CO—, —CONR6—, —CO2—, —OC(O)—, —S(O)m—, —O—(CH2)m—O—, —(CH2)m—, —NR6CO—, —(R6O)2P(O)— and —NHCO2—, wherein m denotes a number of 0 to 3, and R6 represents hydrogen or C1-C6-alkyl,
R5 represents hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, C4-C6-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 C1-C6-alkyl, or
R2 represents —(CR8R9)p—Y—R7,
p denotes a number of 0 to 2,
R8 and R9 independently of one another represent hydrogen or C1-C6-alkyl,
Y represents a direct bond, or is selected from the group consisting of —O—, —S—, —NR6C(O)—, —NR6C(O)—, —C(O)NR6— and —S(O)q—, wherein q denotes a number of 0 to 2,
R7 represents hydrogen, halogen, hydroxyl, C1-C6-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,
R3 represents hydrogen, C1-C6-alkyl, or —(CH2)q—C4-C6-cycloalkyl,
R4 represents C3-C6-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, C1-C6-alkylamino, di-C1-C6-alkylamino, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkylsulfonyl, carboxy-C1-C6-alkyl, C1-C6-alkylcarbonyloxy, C1-C6-alkylthio, C1-C6-alkyloxycarbonyl, C1-C6 alkylaminocarbonyl, and oxo.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 7)

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.

### Claim 9 (depends on 1)

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.

### Claim 10 (depends on 1)

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.