Pharmaceutical composition comprising indole compound

Abstract

The present invention relates to a pharmaceutical composition comprising a compound of formula (1), (2) or (3) as defined in the specification for the prevention or treatment of diseases associated with oxidative stress, mitochondria dysfunction, hypoxic injury, necrosis and/or ischemic reperfusion injury, and a cosmetic composition comprising an indole compound having an antioxidant effect.

1 . A pharmaceutical composition for the prevention or treatment of diseases associated with oxidative stress, comprising a therapeutically-effective amount of a compound of the following formula (1), (2) or (3), pharmaceutically acceptable salt or isomer thereof as an active ingredient; and a pharmaceutically acceptable carrier: 
       
         
           
           
               
               
           
         
         in formula (1), 
         na denotes a number of 0 to 3, 
         A a  represents 5 membered heteroaryl or heterocycle each of which has 1 to 3 hetero atoms selected from N, O and S, 
         R 1a  represents R 5a —X a —B a —X′ a -, 
         B a  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 a  and X′ a  independently of one another represent a direct bond, or are selected from the group consisting of —NR 6a —, —CO—, —CONR 6a —, —OC(O)—, —S(O) ma —, —O—(CH 2 ) ma —, —(CH 2 ) ma —O—, -(CH 2 ) ma —, —NR 6a CO—, -(R 6a O) 2 P(O)— and —NHCO 2 —, wherein ma denotes a number of 0 to 3, and R 6a  represents hydrogen, alkyl or cycloalkyl, 
         R 5a  represents hydrogen, nitrile, hydroxy, alkyl, alkoxy, cycloalkyl or aryl, 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 alkyl, or 
         R 5a  and R 6a  may together form a 4˜8 membered cycle, 
         R 2a  represents -(CR 8a R 9a ) pa —Y a —R 7a , 
         pa denotes a number of 0 to 2, 
         R 8a  and R 9a  independently of one another represent hydrogen or alkyl, or may together faun a 4˜8 membered cycle, 
         Y a  represents a direct bond, or is selected from the group consisting of —O—, —S—, —NR 6a —, —NR 6a C(O)—, —C(O)—, —C(O)NR 6a —, —S(O) qa —, and —S(O) qa NR 6a —, wherein qa denotes a number of 0 to 2, 
         R 7a  represents hydrogen, halogen, cyano, hydroxy, nitro, alkyl, cycloalkyl or aryl, 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 3a  represents hydrogen, alkyl, —(CH 2 ) qa -cycloalkyl or —(CH 2 ) qa -heterocycle, 
         R 4a  represents —(CH 2 ) pa -D a -R 10a , 
         D a  represents a direct bond, represents cycloalkyl optionally containing oxo, represents aryl, or represents 3˜10 membered heterocycle or heteroaryl each of which has 1 to 3 hetero atoms selected from N, S and O, 
         R 10a  represents hydrogen, halogen, amino, cyano, nitro, hydroxy, alkyl, alkylcarbonyl, alkylsulfonyl or —(CH 2 ) pa —NR 8a R 9a , 
         where alkyl, alkoxy, aryl, 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, alkylamino, dialkylamino, alkyl, haloalkyl, alkylsulfonyl, carboxyalkyl, alkylcarbonyloxy, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl, arylalkoxy and oxo; 
       
       
         
           
           
               
               
           
         
         in formula (2), 
         nb denotes a number of 1 to 3, 
         mb denotes 0 or 1, 
         A b  represents a direct bond, represents phenyl, or represents 6 membered heteroaryl having 1 to 2 nitrogen atoms, 
         X b  represents C or N, with the proviso that mb is 0 when X b  is N, and mb is 1 when X b  is C, 
         R 1b  represent hydrogen, alkyl, —(CH 2 ) rb NR 7b R 8a , —(CH 2 ) rb CO 2 H, wherein rb denotes a number of 1 to 5, and R 7b  and R 8b  independently of one another represent hydrogen, alkyl or alkylcarbonyl, or may together form an optionally alkyl-substituted alkylene chain wherein optionally one methylene is replaced by N atom, 
         R 2b  represents hydrogen, halogen, cyano, nitro, hydroxy, alkyl, alkoxy or trialkylsilyl, represents —(CH 2 ) pb CO 2 R 7b , —(CH 2 ) pb OR 7b , —(CH 2 ) pb NR 7b R 8b , —NHR 10b , —N(H)S(O) 2 R 7b , —NHC(O)R 10b , —(CH 2 ) pb S(O) 2 R 7b  or (CH 2 ) pb -heterocycle-R 10b , wherein pb denotes a number of 0 to 3, R 7b  and R 8b  are as defined above, R 10b  represents hydrogen, oxo, alkylsulfonyl, alkylcarbonyl, alkyloxycarbonyl, alkylaminocarbonyl, alkoxy, alkyl or heterocycle, 
         R 3b  represents hydrogen, cyano, halogen, alkyl or phenyl, or represents —(CH 2 ) nb -heterocycle or —(CH 2 ) nb -aryl, wherein nb denotes a number of 0 to 3, 
         R 4b  represents —Y b R 11b , wherein Y b  represents a direct bond or —(CR 7b R 8b ) pb Y′ b -, wherein pb denotes a number of 0 to 3, R 7b  and R 8b  are defined as above, Y′ b  is selected from the group consisting of —O—, —S—, —NR 12b —, —NR 12b C(O)—, —C(O)—, —C(O)O—, —C(O)NR 12b -, —S(O) qb —, and —S(O) qb NR 12b —, wherein R 12b  represents hydrogen, alkyl, aryl or heteroaryl, qb denotes a number of 0 to 2, R 11b  is selected from the group consisting of hydrogen, cyano, halogen, hydroxy, thiol, carboxy, alkyl and —(CH 2 ) tb B b —R 13b , wherein tb denotes a number of 0 to 3, B b  represents heterocycle, heteroaryl or aryl, R 13b  represents hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy, carboxyalkyl, alkylcarbonyloxy, alkyl, alkoxy, alkylthio, alkylcarbonyl or alkylsulfonyl, 
         R 5b  represents hydrogen, alkyl, cycloalkyl, heterocycle or heterocyclylalkyl, 
         R 6b  represents -(CR 7b R 8b ) pb —Z b -D b -W b —R 14b , wherein Z b  represents a direct bond, or is selected from the group consisting of —C(O)—, —C(O)O—, —C(O)NR 12b —, and —S(O) yb —, yb denotes a number of 1 or 2, D b  represents a direct bond, or represents cycloalkyl, heteroaryl or heterocycle, W b  represents a direct bond, or represents —NR 7b —, —C(O)—, —C(O)O—, —C(O)NR 12b —, —S(O) yb —, —S(O) yb NR 12b - or —NR 12b S(O) yb —, wherein R 14b  represents hydrogen, hydroxy, alkyl, alkoxy, heterocycle, heteroaryl, aryl or aralkyl, 
         R 5b  and R 6b  together represent alkylene chain, 
         where alkyl, alkoxy, aryl, 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, alkylamino, dialkylamino, carboxy, alkyl, alkoxy, carboxyalkyl, alkylcarbonyloxy, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl, arylalkoxy and oxo; 
       
       
         
           
           
               
               
           
         
         in formula (3), 
         B c  represents aryl, or represents 4˜8 membered heterocycle or heteroaryl each of which has 1 to 2 hetero atoms selected from N, O and S, 
         R 7c  represents hydrogen, halogen, hydroxy, nitrile, nitro or alkoxy, 
         R 8c  represents C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, heterocyclyl, aryl, arylalkyl, cycloalkyl-alkyl or heterocyclyl-alkyl, 
         R 9c  represents hydrogen, halogen, hydroxy, nitrile, nitro, alkoxy, allyloxy, alkylamino or arylamino, 
         where alkyl, alkoxy, aryl, 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 -alkyl)amino, carboxy, C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, aryl-C 1 -C 6 -alkoxy and oxo. 
       
     
     
         2 . The pharmaceutical composition according to  claim 1  for the prevention and treatment of a disease caused by oxidative stress which is mediated by reactive oxygen species (ROS) or reactive nitrogen species (RNS). 
     
     
         3 . The pharmaceutical composition according to  claim 1 , which suppresses ischemic reperfusion injury. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , which suppresses mitochondrial dysfunction. 
     
     
         5 . The pharmaceutical composition according to  claim 4  for the prevention and treatment of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), MERRF syndrome (myoclonus epilepsy with ragged-red fibers) or Kearns-Sayre syndrome. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , which suppresses hypoxic injury. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , which suppresses necrotic cell death. 
     
     
         8 . The pharmaceutical composition according to  claim 7 , which suppresses necrosis of cells secreting HMGB1 (high-motility group box 1). 
     
     
         9 . The pharmaceutical composition according to  claim 8  for the prevention and treatment of a disease mediated by HMGB1. 
     
     
         10 . The pharmaceutical composition according to  claim 8  for the prevention and treatment of inflammation-mediated or inflammation-related diseases. 
     
     
         11 . The pharmaceutical composition according to  claim 8  for the prevention and treatment of sepsis, rheumatic arthritis, osteoarthritis, liver cirrhosis, hemorrhagic disease, various necrotizing diseases, a disease caused by virus or bacteria infection. 
     
     
         12 . The pharmaceutical composition according to  claim 1  for the prevention and treatment of liver disease, heart disease, vascular disease, degenerative brain disease, a disease caused by ischemic reperfusion injury, or an infectious disease by virus or bacteria. 
     
     
         13 . The pharmaceutical composition according to  claim 12  for the prevention and treatment of liver transplantation, hepatic resection, hepatic embolization, hepatic fibrosis, hepatic cirrhosis, alcoholic/non-alcoholic fatty liver and hepatitis caused by virus or drug. 
     
     
         14 . The pharmaceutical composition according to  claim 12  for the prevention and treatment of arrhythmia, cardioplegia or myocardial infarction. 
     
     
         15 . The pharmaceutical composition according to  claim 12  for the prevention and treatment of Lou Gehrig's disease, stroke, dementia, Parkinson's disease or Huntington's disease. 
     
     
         16 . The pharmaceutical composition according to  claim 12  for the prevention and treatment of a disease caused by influenza, HBV, HCV or HIV infection or bacteria infection. 
     
     
         17 . The pharmaceutical composition according to  claim 3 , wherein the ischemic reperfusion injury is caused by mitochondrial dysfunction, hypoxic injury, HMGB1 release or necrotic cell death. 
     
     
         18 . The pharmaceutical composition according to  claim 3  for the prevention and treatment of liver transplantation, hepatic resection, hepatic embolization, hepatic fibrosis, hepatic cirrhosis, alcoholic/non-alcoholic fatty liver, hepatitis caused by virus or drug. 
     
     
         19 . The pharmaceutical composition according to  claim 3  for the prevention and treatment of arrhythmia, cardioplegia or myocardial infarction. 
     
     
         20 . A compound of the following formula (3), pharmaceutically acceptable salt or isomer thereof: 
       
         
           
           
               
               
           
         
         in formula (3), 
         B c  represents aryl, or represents 4˜8 membered heterocycle or heteroaryl each of which has 1 to 2 hetero atoms selected from N, O and S, 
         R 7c  represents hydrogen, halogen, hydroxy, nitrile, nitro or alkoxy, 
         R 8c  represents C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, heterocyclyl, aryl, arylalkyl, cycloalkyl-alkyl or heterocyclyl-alkyl, 
         R 9c  represents hydrogen, halogen, hydroxy, nitrile, nitro, alkoxy, allyloxy, alkylamino or arylamino, 
         where alkyl, alkoxy, aryl, 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 -alkyl)amino, carboxy, C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, aryl-C 1 -C 6 -alkoxy and oxo. 
       
     
     
         21 . The compound according to  claim 20 , wherein
 B c  represents aryl, or represents 5˜6 membered heterocycle or heteroaryl each of which has 1 to 2 hetero atoms selected from N, O and S,   R 7c  represents hydrogen, halogen, nitrile or alkoxy,   R 8c  represents C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, heterocyclyl, arylalkyl, cycloalkyl-alkyl or heterocyclyl-alkyl,   R 9c  represents hydrogen, halogen, nitrile, alkoxy, allyloxy, alkylamino or arylamino.   
     
     
         22 . The compound according to  claim 20 , wherein
 B c  represents phenyl or pyridine,   R 7c  represents hydrogen, halogen or alkoxy,   R 8c  represents C 1 -C 6 -alkyl, heterocyclyl, cycloalkyl-alkyl, heterocyclyl-alkyl or arylalkyl,   R 9c  represents hydrogen, halogen or alkoxy.   
     
     
         23 . The compound according to  claim 20 , wherein
 R 8c  represents cyclopentyl or tetrahydropyran.   
     
     
         24 . The compound according to  claim 20  which is selected from the following group:
 cyclopentyl-(2-phenyl-3H-benzimidazol-4-yl)-amine 
 (2-phenyl-3H-benzimidazol-4-yl)-(tetrahydro-pyran-4-yl)-amine 
 cyclopentyl-(2-pyridin-2-yl-3H-benzimidazol-4-yl)-amine. 
 
     
     
         25 . A cosmetic composition having an antioxidant effect, comprising a compound of the following formula (1), (2) or (3), pharmaceutically acceptable salt or isomer thereof as an active ingredient; and an acceptable carrier: 
       
         
           
           
               
               
           
         
         in formula (1), 
         na denotes a number of 0 to 3, 
         A a  represents 5 membered heteroaryl or heterocycle each of which has 1 to 3 hetero atoms selected from N, O and S, 
         R 1a  represents R 5a —X a —B a —X′ a -, 
         B a  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 a  and X′ a  independently of one another represent a direct bond, or are selected from the group consisting of —NR 6a —, —CO—, —CONR 6a —, —CO 2 —, OC(O), —S(O) ma —, —O—(CH 2 ) ma —, -(CH 2 ) ma —O—, -(CH 2 ) ma —, —NR 6a CO—, -(R 6a O) 2 P(O)— and —NHCO 2 —, wherein ma denotes a number of 0 to 3, and R 6a  represents hydrogen, alkyl or cycloalkyl, 
         R 5a  represents hydrogen, nitrile, hydroxy, alkyl, alkoxy, cycloalkyl or aryl, 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 alkyl, or 
         R 5a  and R 6a  may together form a 4˜8 membered cycle, 
         R 2a  represents —(CR 8a R 9a ) pa —Y a —R 7a , 
         pa denotes a number of 0 to 2, 
         R 8a  and R 9a  independently of one another represent hydrogen or alkyl, or may together form a 4˜8 membered cycle, 
         Y a  represents a direct bond, or is selected from the group consisting of —O—, —S—, —NR 6a —, —NR 6a C(O)—, —CO 2 —, —C(O)—, —C(O)NR 6a —, —S(O) qa —, and —S(O) qa NR 6a —, wherein qa denotes a number of 0 to 2, 
         R 7a  represents hydrogen, halogen, cyano, hydroxy, nitro, alkyl, cycloalkyl or aryl, 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 3a  represents hydrogen, alkyl, —(CH 2 ) qa -cycloalkyl or —(CH 2 ) qa -heterocycle, 
         R 4a  represents —(CH 2 ) pa -D a R 10a , 
         D a  represents a direct bond, represents cycloalkyl optionally containing oxo, represents aryl, or represents 3˜10 membered heterocycle or heteroaryl each of which has 1 to 3 hetero atoms selected from N, S and O, 
         R 10a  represents hydrogen, halogen, amino, cyano, nitro, hydroxy, alkyl, alkylcarbonyl, alkylsulfonyl or —(CH 2 ) pa —NR 8a R 9a , 
         where alkyl, alkoxy, aryl, 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, alkylamino, dialkylamino, alkyl, haloalkyl, alkylsulfonyl, carboxyalkyl, alkylcarbonyloxy, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl, arylalkoxy and oxo; 
       
       
         
           
           
               
               
           
         
         in formula (2), 
         nb denotes a number of 1 to 3, 
         mb denotes 0 or 1, 
         A b  represents a direct bond, represents phenyl, or represents 6 membered heteroaryl having 1 to 2 nitrogen atoms, 
         X b  represents C or N, with the proviso that mb is 0 when X b  is N, and mb is 1 when X b  is C, 
         R 1b  represent hydrogen, alkyl, —(CH 2 ) rb NR 7b R 8b , —(CH 2 ) rb CO 2 H, wherein rb denotes a number of 1 to 5, and R 7b  and R 8b  independently of one another represent hydrogen, alkyl or alkylcarbonyl, or may together form an optionally alkyl-substituted alkylene chain wherein optionally one methylene is replaced by N atom, 
         R 2b  represents hydrogen, halogen, cyano, nitro, hydroxy, alkyl, alkoxy or trialkylsilyl, represents —(CH 2 ) pb CO 2 R 7b , —(CH 2 ) pb OR 7b , —(CH 2 ) pb NR 7b R 8b , —NHR 10b , —N(H)S(O) 2 R 7b , —NHC(O)R 10b , —(CH 2 ) pb S(O) 2 R 7b  or (CH 2 ) pb -heterocycle-R 10b , wherein pb denotes a number of 0 to 3, R 7b  and R 8b  are as defined above, R 10b  represents hydrogen, oxo, alkylsulfonyl, alkylcarbonyl, alkyloxycarbonyl, alkylaminocarbonyl, alkoxy, alkyl or heterocycle, 
         R 3b  represents hydrogen, cyano, halogen, alkyl or phenyl, or represents —(CH 2 ) nb -heterocycle or —(CH 2 ) nb -aryl, wherein nb denotes a number of 0 to 3, 
         R 4b  represents —Y b R 11b , wherein Y b  represents a direct bond or —(CR 7b R 8b ) pb Y′ b -, wherein pb denotes a number of 0 to 3, R 7b  and R 8b  are defined as above, Y′ b  is selected from the group consisting of —O—, —S—, —NR 12b -, —NR 12b C(O)—, —C(O)O—, —C(O)NR 12b —, —S(O) qb —, and —S(O) qb NR 12b —, wherein R 12b  represents hydrogen, alkyl, aryl or heteroaryl, qb denotes a number of 0 to 2, R 11b  is selected from the group consisting of hydrogen, cyano, halogen, hydroxy, thiol, carboxy, alkyl and —(CH 2 ) tb B b —R 13b , wherein tb denotes a number of 0 to 3, B b  represents heterocycle, heteroaryl or aryl, R 13b  represents hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy, carboxyalkyl, alkylcarbonyloxy, alkyl, alkoxy, alkylthio, alkylcarbonyl or alkylsulfonyl, 
         R 5b  represents hydrogen, alkyl, cycloalkyl, heterocycle or heterocyclylalkyl, 
         R 6b  represents —(CR 7b R 8b ) pb —Z b -D b -W b —R 14b , wherein Z b  represents a direct bond, or is selected from the group consisting of —C(O)—, —C(O)O—, —C(O)NR 12b —, and —S(O) yb —, yb denotes a number of 1 or 2, D b  represents a direct bond, or represents cycloalkyl, heteroaryl or heterocycle, W b  represents a direct bond, or represents —NR 7b —, —C(O)—, —C(O)O—, —C(O)NR 12b —, —S(O) yb —, —S(O) yb NR 12b — or —NR 12b S(O) yb —, wherein R 14b  represents hydrogen, hydroxy, alkyl, alkoxy, heterocycle, heteroaryl, aryl or aralkyl, 
         R 5b  and R 6b  together represent alkylene chain, 
         where alkyl, alkoxy, aryl, 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, alkylamino, dialkylamino, carboxy, alkyl, alkoxy, carboxyalkyl, alkylcarbonyloxy, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl, arylalkoxy and oxo; 
       
       
         
           
           
               
               
           
         
         in formula (3), 
         B c  represents aryl, or represents 4˜8 membered heterocycle or heteroaryl each of which has 1 to 2 hetero atoms selected from N, O and S, 
         R 7c  represents hydrogen, halogen, hydroxy, nitrile, nitro or alkoxy, 
         R 8c  represents C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, heterocyclyl, aryl, arylalkyl, cycloalkyl-alkyl or heterocyclyl-alkyl, 
         R 9c  represents hydrogen, halogen, hydroxy, nitrile, nitro, alkoxy, allyloxy, alkylamino or arylamino, 
         where alkyl, alkoxy, aryl, 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 -alkyl)amino, carboxy, C 1 -C 6 -alkyl, halogen-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, aryl-C 1 -C 6 -alkoxy and oxo.