PYRROLO [3, 4-h] ISOQUINOLINE COMPOUNDS AND METHODS FOR MODULATING GATED ION CHANNELS

Abstract

The present invention relates to compositions and methods to modulate the activity of gated ion channels.

1 . A method of treating a clinical condition selected from the group consisting of inflammatory disorders, a disease or disorder associated with the genitourinary system, a disease or disorder associated with the gastrointestinal system, a disease or disorder of the musculoskeletal tissue and a disease or disorder of the connective tissue in a subject in need thereof comprising administering to the subject a compound represented by formula 1, 
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof; 
       wherein the dashed lines indicate a single or double bond; and 
       R 1  is selected from the group consisting of hydrogen, alkyl, alkoxy-alkyl, hydroxy-alkyl, alkoxy-carbonyl-alkyl, alkyl-carbonyl-oxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl, alkoxy, sulfonamide, amino, sulfonyl, sulfonic acid, urea, phenyl and benzyl, in which the phenyl or benzyl group is optionally substituted with one or more selected from the group consisting of halogen, CF 3 , nitro, amino, cyano, hydroxy-alkyl, alkoxy, sulfonamide, alkenyl, alkynyl, amino, sulfonyl, sulfonic acid and urea; 
       R 2  is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, —(CH 2 ) 1-4 S(O) 3 H, —C(O)C 1-4 alkyl and —S(O) 2 C 1-4 alkyl; 
       R 3  is selected from the group consisting of hydrogen, hydroxyl, alkyl, acyl, phenyl, benzyl, —COON, —C(O)N(CH 3 ) 2 , —O-phenyl, —OCF 3 , alkoxy, —O(CH 2 ) 0-4 OCH 3 , —C(O)H, —C(O)CH 3 , 
     
     
       
         
         
             
             
         
       
       and R 4  and R 5  are each, independently, selected from the group consisting of halogen, CF 3 , nitro, amino, cyano, hydroxyl, alkyl, alkoxy, phenoxy, phenyl and —SO 2 NR′R″, wherein R′ and R″ independently of each another represents hydrogen or alkyl. 
     
   
   
       2 . The method of  claim 1 , wherein the compound is represented by the Formula 2, 
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof; wherein 
       R 1  is selected from the group consisting of hydrogen, C 1-4 -alkyl, C 1-4 -alkenyl, and C 1-4 -alkynyl; 
       R 2  is selected from the group consisting of hydrogen, hydroxyl, C 1-4 -alkyl, C 1-4 -alkenyl and C 1-4 -alkynyl; and 
       R 4  and R 5  are each, independently, selected from the group consisting of halogen, CF 3 , nitro, amino, cyano, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, phenoxy and phenyl. 
     
   
   
       3 . The method of  claim 1 , wherein the compound is represented by the Formula 3, 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
       R 1  is selected from the group consisting of hydrogen, alkyl, alkoxy-alkyl, alkoxy-carbonyl-alkyl, alkyl-carbonyl-oxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl, alkoxy, sulfonamide, amino, sulfonyl, sulfonic acid, urea phenyl and benzyl, in which the phenyl or benzyl group is optionally substituted with one or more selected from the group consisting of halogen, CF 3 , nitro, amino, cyano, hydroxy-alkyl, alkoxy, sulfonamide, alkenyl, alkynyl, amino, sulfonyl, sulfonic acid and urea; and 
       R 4  and R 5  are each, independently, selected from the group consisting of halogen, phenoxy, CF 3 , nitro, amino, cyano, hydroxyl, alkyl, alkoxy, phenyl and SO 2 NR′R″, wherein R′ and R″ independently of each another represents hydrogen or alkyl. 
     
   
   
       4 . The method of  claim 3 , wherein R 5  is in the 2 position of the aryl ring and R 4  is in the 5 position of the aryl ring, or R 4  is in the 3 position of the aryl ring and R 5  is in the 5 position of the aryl ring. 
   
   
       5 . The method according to  claim 4 , wherein R 4  and R 5  each independently are selected from the group consisting of halogen, CF 3 , nitro, amino, cyano, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, phenoxy and phenyl. 
   
   
       6 . The method of  claim 3 , wherein R 1  is selected from the group consisting of hydrogen, C 1-4 -alkyl, C 1-4 -alkenyl, and C 1-4  alkynyl. 
   
   
       7 . The method of  claim 3 , wherein R 1  is selected from the group consisting of hydrogen, C 1-4 -alkyl, C 1-4 -alkenyl, and C 1-4 -alkynyl and R 4  and R 5  are each, independently, selected from the group consisting of halogen, CF 3 , nitro, amino, cyano, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, phenoxy and phenyl. 
   
   
       8 . The method of  claim 3 , wherein R 1  is selected from the group consisting of hydrogen and C 1-4 -alkyl; and R 4  and R 5  are each, independently, selected from the group consisting of halogen, CF 3 , C 1-4 -alkyl, phenoxy and C 1-4 -alkoxy. 
   
   
       9 . The method of  claim 3 , wherein R 1  is selected from the group consisting of C 1-4 -alkyl; and R 4  and R 5  are each, independently, selected from the group consisting of halogen, CF 3 , C 1-4 -alkyl, phenoxy and C 1-4 -alkoxy. 
   
   
       10 . The method of  claim 3 , wherein R 1  is selected from the group consisting of —CH 3  and —CH 2 CH 3 ; and R 4  and R 5  are each, independently, selected from the group consisting of halogen, phenoxy and C 1-4 -alkoxy. 
   
   
       11 . The method of  claim 1 , wherein the compound is selected from the group consisting of 5-(5-fluoro-2-methoxyphenyl)-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-methyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one; 5-(5-fluoro-2-methoxyphenyl)-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-ethyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one; 5-(5-chloro-2-methoxyphenyl)-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-methyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one; 5-(3,5-dimethylphenyl)-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-methyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one; 5-(3,5-dimethylphenyl)-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-ethyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one; 5-(2,5-dimethylphenyl)-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-ethyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one; 5-(2,3-dimethyl-phenyl)-8-ethyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione 3-oxime; and 5-(5-chloro-2-methoxyphenyl)-6,7,8,9-tetrahydro-3-(hydroxyimino)-8-ethyl-1H-pyrrolo[3,2-h]isoquinoline-2(3H)-one. 
   
   
       12 . The method of  claim 1 , wherein the disease or disorder is an inflammatory disorder of the genitourinary system and/or the gastrointestinal system. 
   
   
       13 . The method of  claim 1 , wherein the method is a method for treating pain associated with a disease or disorder of the genitourinary system and/or the gastrointestinal system. 
   
   
       14 . The method of  claim 12 , wherein the inflammatory disorder of the gastrointestinal system is selected from the group consisting of inflammatory bowel disorder, ulcerative colitis, Crohn's disease, diverticulitis, viral infection, bacterial infection, peptic ulcer, chronic hepatitis, gingivitis, periodentitis, stomatitis, gastritis and gastrointestinal reflux disease. 
   
   
       15 . The method of  claim 1 , wherein the method is a method for treating visceral pain associated with disorders of the oesophagus, stomach, duodenum, colon and/or intestines. 
   
   
       16 . The method of  claim 1 , wherein the method is a method of treating visceral pain associated with a disorder selected from the group consisting of ulcers, dyspepsia, oesophagitis, gastritis, duodenitis, diverticulitis, appendicitis, Crohn's disease paralytic ileus, intestinal obstruction, irritable bowel syndrome, neurogene bowel, megacolon, inflammatory bowel disease, ulcerative colitis, gastroenteritis, functional abdominal pain syndrome and gastrointestinal motility disorders. 
   
   
       17 . The method of  claim 1 , wherein the disease or disorder is selected from the group consisting of gastritis, duodenitis, irritable bowel syndrome, colitis, Crohn's disease, gastrointestinal reflux disease, ulcers and diverticulitis. 
   
   
       18 . The method of  claim 1 , wherein the clinical condition is a disease or disorder associated with the genitourinary system selected from the group consisting of inflammation of the kidney, inflammation of the bladder, inflammation of the urethra, inflammation of the male genital organs and inflammation of the female genital organs. 
   
   
       19 . The method of  claim 1 , wherein the method is a method of treating deep somatic pain associated with a disease or disorder of the musculoskeletal tissue and a disease or disorder of the connective tissue. 
   
   
       20 . The method according to  claim 15 , wherein the disease or disorder is selected from the group consisting of arthralgias, myalgias, fibromyalgias, myofascial pain syndrome, dental pain, lower back pain, pain during labor and delivery, surgical pain, post-operative pain, headaches, migraines, idiopathic pain disorder, sprains, bone fractures, bone injury, osteoporosis, severe burns, gout, arthritis, osteoarthithis, myositis, and dorsopathies. 
   
   
       21 . The method according to  claim 1 , wherein the clinical condition is an inflammatory condition selected from the group consisting of arthritis, osteoarthritis and myositis.