Erg channel openers for the treatment of cardiac arrhythmias

Abstract

This invention relates to the use of ERG channel openers for the treatment of cardiac arrhythmias, and to the use of specific compounds for such treatment. In a separate aspect the invention provides novel compounds useful as ERG channel openers.

1 . A method of treatment or alleviation of an abnormal rhythm of the heart of a living animal body, including a human, which method comprises the step of administering to such a living animal body in need thereof, a therapeutically effective amount of a compound capable of activating an ERG channel, wherein the compound capable of activating an ERG channel is a diphenyl urea derivative of Formula I, 
       
         
           
           
               
               
           
         
       
       or an enantiomer or a mixture of its enantiomers, or a pharmaceutically acceptable salt thereof, wherein
 X represents hydroxy, alkoxy, amino, carboxy, alkyl-carbonyl, hydroxyaminocarbonyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl, tetrazolyl, 2,4-dihydro-[1,2,4]triazol-3-one, 4H-[1,2,4]oxadiazol-5-one, or 1,2-dihydro-[1,2,4]triazol-3-one; and 
 at least one of R 1 , R 2 , R 3  and R 4 , and independently of each other, represent halo, hydroxy, alkyl, alkoxy, thioalkoxy, nitro, cyano, haloalkyl, haloalkoxy, amino, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl and/or phenyl, which phenyl may optionally be substituted with one or two substituents selected from the group consisting of halo, hydroxy, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, and N,N-di-alkyl-sulfamoyl; and the remainder of R 1 , R 2 , R 3  and R 4  represent hydrogen. 
 
     
     
         2 . The method according to  claim 1 , wherein
 X represents hydroxy, amino, carboxy, hydroxyaminocarbonyl, sulfamoyl, tetrazolyl, 2,4-dihydro-[1,2,4]triazol-3-one, 4H-[1,2,4]oxadiazol-5-one, or 1,2-dihydro-[1,2,4]triazol-3-one; and   at least one of R 1 , R 2 , R 3  and R 4 , and independently of each other, represent halo, hydroxy, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, amino, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl and/or phenyl, which phenyl may optionally be substituted with a substituent selected from the group consisting of halo, haloalkyl, haloalkoxy, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, and N,N-di-alkyl-sulfamoyl; and the remainder of R 1 , R 2 , R 3  and R 4  represent hydrogen.   
     
     
         3 . The method according to  claim 1 , wherein the ERG channel activating compound is a compound of Formula I, wherein
 X represents hydroxy; and   at least one of R 1 , R 2 , R 3  and R 4 , and independently of each other, represent halo, hydroxy, alkyl, alkoxy, thioalkoxy, nitro, cyano, haloalkyl, haloalkoxy, amino, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl and/or phenyl, which phenyl may optionally be substituted with one or two substituents selected from the group consisting of halo, hydroxy, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, and N,N-di-alkyl-sulfamoyl; and the remainder of R 1 , R 2 , R 3  and R 4  represent hydrogen.   
     
     
         4 . The method according to  claim 3 , wherein
 at least one of R 1 , R 2 , R 3  and R 4 , independently of each other, represent halo, hydroxy, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl and/or phenyl.   
     
     
         5 . The method according to  claim 4 , wherein the ERG channel activating compound is
 1-(2-trifluoromethyl-phenyl)-3-(2-hydroxy-5-trifluoromethyl-phenyl)-urea; or   1-(2-trifluoromethyl-phenyl)-3-(2-hydroxy-5-chloro-phenyl)-urea;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method according to  claim 1 , wherein
 X represents carboxy; and   at least one of R 1 , R 2 , R 3  and R 4 , and independently of each other, represent halo, hydroxy, alkyl, alkoxy, thioalkoxy, nitro, cyano, haloalkyl, haloalkoxy, amino, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl and/or phenyl, which phenyl may optionally be substituted with one or two substituents selected from the group consisting of halo, hydroxy, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, and N,N-di-alkyl-sulfamoyl; and the remainder of R 1 , R 2 , R 3  and R 4  represent hydrogen.   
     
     
         7 . The method according to  claim 6 , wherein the ERG channel activating compound is a compound of Formula I, wherein
 X represents carboxy; and   at least one of R 1 , R 2 , R 3  and R 4 , independently of each other, represent halo, hydroxy, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, acyl, alkoxy-carbonyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl and/or phenyl, which phenyl may optionally be substituted with one or two substituents selected from the group consisting of halo, hydroxy, alkoxy, acyl, alkoxy-carbonyl and haloalkyl; and the remainder of R 1 , R 2 , R 3  and R 4  represent hydrogen.   
     
     
         8 . The method according to  claim 7 , wherein
 at least one of R 1 , R 2 , R 3  and R 4 , and independently of each other, represent halo, hydroxy, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, and/or phenyl.   
     
     
         9 . The method according to  claim 8 , wherein the ERG channel activating compound is
 1-(2-fluoro-phenyl)-3-(2-carboxy-5-chloro-phenyl)-urea;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method according to  claim 1 , wherein
 X represents tetrazolyl; and   at least one of R 1 , R 2 , R 3  and R 4 , and independently of each other, represent halo, hydroxy, alkyl, alkoxy, thioalkoxy, nitro, cyano, haloalkyl, haloalkoxy, amino, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl and/or phenyl, which phenyl may optionally be substituted with one or two substituents selected from the group consisting of halo, hydroxy, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, and N,N-di-alkyl-sulfamoyl; and the remainder of R 1 , R 2 , R 3  and R 4  represent hydrogen.   
     
     
         11 . The method according to  claim 10 , wherein
 X represents 1H-tetrazolyl; and   at least one of R 1 , R 2 , R 3  and R 4 , and independently of each other, represent Cl, Br, F, hydroxy, alkyl, alkoxy, nitro, CF 3 , OCF 3 , amino, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl and/or phenyl, which phenyl may optionally be substituted with a substituent selected from the group consisting of Cl, Br, F, CF 3 , OCF 3 , carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, and N,N-di-alkyl-sulfamoyl; and the remainder of R 1 , R 2 , R 3  and R 4  represent hydrogen.   
     
     
         12 . The method according to  claim 11 , wherein the ERG channel activating compound is
 1-(3-chloro-4-trifluoromethyl-phenyl)-3-[2-(1H-tetrazol-5-yl)-4-(2-N,N-dimethylcarbamoyl-ethyl)-phenyl]-urea;   1-(4-chloro-3-trifluoromethyl-phenyl)-3-[2-(1H-tetrazol-5-yl)-4-chloro-phenyl]-urea; or   1-(3,5-dichloro-phenyl)-3-[2-(1H-tetrazol-5-yl)-4-chloro-phenyl]-urea;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method according to  claim 1 , wherein
 X represents 2,4-dihydro-[1,2,4]triazol-3-one; and   at least one of R 1 , R 2 , R 3  and R 4 , and independently of one another, represent halo, hydroxy, alkyl, alkoxy, thioalkoxy, nitro, cyano, haloalkyl, haloalkoxy, amino, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl and/or phenyl, which phenyl may optionally be substituted with one or two substituents selected from the group consisting of halo, hydroxy, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, and N,N-di-alkyl-sulfamoyl; and the remainder of R 1 , R 2 , R 3  and R 4  represent hydrogen.   
     
     
         14 . The method according to  claim 13 , wherein
 at least one of R 1 , R 2 , R 3  and R 4 , and independently of one another, represent halo, haloalkyl, haloalkoxy, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl and/or phenyl, which phenyl may optionally be substituted with a substituent selected from the group consisting of halo, haloalkyl, haloalkoxy, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, and N,N-di-alkyl-sulfamoyl; and the remainder of R 1 , R 2 , R 3  and R 4  represent hydrogen.   
     
     
         15 . The method according to  claim 14 , wherein the ERG channel activating compound is
 1-(3-trifluoromethyl-phenyl)-3-[2-(5-oxo-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)-4-(4′-N,N-dimethyl-carbamoyl)-biphenyl]-urea;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method according to  claim 1 , wherein
 X represents 4H-[1,2,4]oxadiazol-5-one; and   at least one of R 1 , R 2 , R 3  and R 4 , and independently of one another, represent halo, hydroxy, alkyl, alkoxy, thioalkoxy, nitro, cyano, haloalkyl, haloalkoxy, amino, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl and/or phenyl, which phenyl may optionally be substituted with one or two substituents selected from the group consisting of halo, hydroxy, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, and N,N-di-alkyl-sulfamoyl; and the remainder of R 1 , R 2 , R 3  and R 4  represent hydrogen.   
     
     
         17 . The method according to  claim 16 , wherein
 at least one of R 1 , R 2 , R 3  and R 4 , and independently of one another, represent halo, haloalkyl, haloalkoxy, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl and/or phenyl, which phenyl may optionally be substituted with a substituent selected from the group consisting of halo, haloalkyl, haloalkoxy, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, and N,N-di-alkyl-sulfamoyl; and the remainder of R 1 , R 2 , R 3  and R 4  represent hydrogen.   
     
     
         18 . The method according to  claim 17 , wherein the ERG channel activating compound is
 1-(3-trifluoromethyl-phenyl)-3-[2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-4-(4′-N,N-dimethyl-carbamoyl)-biphenyl]-urea;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method according to  claim 1 , wherein
 X represents sulfamoyl, N-alkyl-sulfamoyl or N,N-di-alkyl-sulfamoyl; and   at least one of R 1 , R 2 , R 3  and R 4 , and independently of each other, represent halo, hydroxy, alkyl, alkoxy, thioalkoxy, nitro, cyano, haloalkyl, haloalkoxy, amino, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl and/or phenyl, which phenyl may optionally be substituted with one or two substituents selected from the group consisting of halo, hydroxy, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, and N,N-di-alkyl-sulfamoyl; and the remainder of R 1 , R 2 , R 3  and R 4  represent hydrogen.   
     
     
         20 . The method according to  claim 19 , wherein
 X represents sulfamoyl; and   at least one of R 1 , R 2 , R 3  and R 4 , and independently of each other, represent halo, CF 3 , OCF 3 ; and the remainder of R 1 , R 2 , R 3  and R 4  represent hydrogen.   
     
     
         21 . The method according to  claim 20 , wherein the ERG channel activating compound is
 1-(3-trifluoromethyl-phenyl)-3-(2-sulfamoyl-5-chloro-phenyl)-urea;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The method according to  claim 1 , wherein the abnormal rhythm of the heart is cardiac arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, bradyarrhythmia. 
     
     
         23 . The method according to  claim 1 , wherein the abnormal rhythm of the heart is cardiac ishemia, ishcemic heart disease, hypertrophic heart, cardiomyopathia or failing heart. 
     
     
         24 . The method according to  claim 1 , wherein the abnormal rhythm of the heart is cardiac arrhythmia, atrial fibrillation and/or ventricular tachyarrhythmia. 
     
     
         25 . The method according to  claim 1 , wherein the abnormal rhythm of the heart is cardiac arrhythmia. 
     
     
         26 . The method of treatment or alleviation of an abnormal rhythm of the heart of a living animal body according to  claim 1 , wherein said living animal body is a human body. 
     
     
         27 . A method of treatment or alleviation of an abnormal rhythm of the heart of a living animal body, including a human, which method comprises the step of administering to such a living animal body in need thereof, a therapeutically effective amount of a compound capable of activating an ERG channel, wherein the compound capable of activating an ERG channel is a urea derivative of Formula III, 
       
         
           
           
               
               
           
         
       
       or an enantiomer or a mixture of its enantiomers, or a pharmaceutically acceptable salt thereof, or an N oxide thereof, wherein
 A and B, independently of each other, represent a monocyclic carbocyclic or heterocyclic group, optionally substituted with one or more of X, R 1  and/or R 2 , wherein 
 X represents hydroxy, alkoxy, amino, carboxy, alkyl-carbonyl, hydroxyaminocarbonyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl, tetrazolyl, 2,4-dihydro-[1,2,4]triazol-3-one, 4H-[1,2,4]oxadiazol-5-one, or 1,2-dihydro-[1,2,4]triazol-3-one; and 
 R 1  and R 2 , independently of each other, represent halo, hydroxy, alkyl, alkoxy, thioalkoxy, oxo, nitro, cyano, haloalkyl, haloalkoxy, amino, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl and/or phenyl, which phenyl may optionally be substituted with one or two substituents selected from the group consisting of halo, hydroxy, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, and N,N-di-alkyl-sulfamoyl. 
 
     
     
         28 . The method according to  claim 27 , wherein
 A represents a monocyclic carbocyclic group selected from cyclohexyl and phenyl, which monocyclic carbocyclic group is optionally substituted with R 1  and/or R 2 ; and   B represents phenyl or a monocyclic heterocyclic group selected from pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, or an N oxide thereof, which carbocyclic or heterocyclic group is optionally substituted with one or more of X, R 1  and/or R 2 .   
     
     
         29 . The method according to  claim 28 , wherein
 A represents phenyl, which is optionally substituted with R 1  and/or R 2 ; and   B represents pyridyl or pyrimidinyl, or an N oxide thereof, which carbocyclic or heterocyclic group is optionally substituted with one or more of X, R 1  and/or R 2 .   
     
     
         30 . The method according to  claim 27 , wherein
 A represents pyridyl, optionally substituted with R 1  and/or R 2 ; and   B represents phenyl or a monocyclic heterocyclic group selected from pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, or an N oxide thereof, which carbocyclic or heterocyclic group is optionally substituted with one or more of X, R 1  and/or R 2 .   
     
     
         31 . The method according to  claim 27 , wherein
 X represents hydroxy, carboxy or tetrazolyl.   
     
     
         32 . The method according to  claim 27 , wherein
 R 1  and R 2 , independently of each other, represent halo, hydroxy, alkyl, alkoxy, thioalkoxy, oxo, nitro, cyano, haloalkyl, haloalkoxy, amino, carboxy and/or alkoxy-carbonyl.   
     
     
         33 . The method according to  claim 27 , wherein the urea derivative is
 1-pyrimidin-2-yl-3-(3-trifluoromethyl-phenyl)-urea;   1-(2-hydroxy-6-methoxy-pyridin-3-yl)-3-(3-fluoromethyl-phenyl)-urea;   1-(1-oxy-pyridin-2-yl)-3-(3-trifluoromethyl-phenyl)urea;   1-(3,5-dihydroxy-phenyl)-3-(3-trifluoromethyl-phenyl)urea;   1-(1,2,3,6-tetrahydro-2,6-dioxo-4-carboxy-pyrimidin-5-yl)-3-(3-trifluoromethyl-phenyl)-urea; or   1-(2-carboxy-pyrazin-3-yl)-3-(3-trifluoromethyl-phenyl)-urea;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         34 . The method according to  claim 27 , wherein the abnormal rhythm of the heart is cardiac arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, bradyarrhythmia. 
     
     
         35 . The method according to  claim 27  wherein the abnormal rhythm of the heart is cardiac ishemia, ishcemic heart disease, hypertrophic heart, cardiomyopathia or failing heart. 
     
     
         36 . The method according to  claim 27 , wherein the abnormal rhythm of the heart is cardiac arrhythmia, atrial fibrillation and/or ventricular tachyarrhythmia. 
     
     
         37 . The method according to  claim 27 , wherein the abnormal rhythm of the heart is cardiac arrhythmia. 
     
     
         38 . The method of treatment or alleviation of an abnormal rhythm of the heart of a living animal body according to  claim 27 , wherein said living animal body is a human body. 
     
     
         39 . A method of treatment or alleviation of an abnormal rhythm of the heart of a living animal body, including a human, which method comprises the step of administering to such a living animal body in need thereof, a therapeutically effective amount of a compound capable of activating an ERG channel, wherein the compound capable of activating an ERG channel is a benzamide derivative of Formula IV, 
       
         
           
           
               
               
           
         
       
       or an enantiomer or a mixture of its enantiomers, or a pharmaceutically acceptable salt thereof, wherein
 A represents a monocyclic carbocyclic or heterocyclic group, optionally substituted with one or more of X, R 1  and/or R 2 , wherein 
 X represents hydroxy, alkoxy, amino, carboxy, alkyl-carbonyl, hydroxyaminocarbonyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl, tetrazolyl, 2,4-dihydro-[1,2,4]triazol-3-one, 4H-[1,2,4]oxadiazol-5-one, or 1,2-dihydro-[1,2,4]triazol-3-one; and 
 R 1 , R 2 , R 3  and R 4 , independently of each other, represent halo, hydroxy, alkyl, alkoxy, thioalkoxy, oxo, nitro, cyano, haloalkyl, haloalkoxy, amino, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, N,N-di-alkyl-sulfamoyl phenyl and/or anilino, which phenyl or anilino may optionally be substituted with one or two substituents selected from the group consisting of halo, hydroxy, alkyl, alkoxy, nitro, haloalkyl, haloalkoxy, acyl, alkoxy-carbonyl, alkoxy-carbonyl-alkyl, alkoxy-carbonyl-alkenyl, N-(alkyl-carbonyl)-amino, carbamoyl, N-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl, N,N-di-alkyl-carbamoyl-alkyl, N,N-di-alkyl-carbamoyl-alkenyl, N-(carboxy-alkyl)-carbamoyl, sulfamoyl, N-alkyl-sulfamoyl, and N,N-di-alkyl-sulfamoyl. 
 
     
     
         40 . The method according to  claim 39 , wherein
 A represents phenyl or pyridinyl, optionally substituted with one or more of X, R 1  and/or R 2 .   
     
     
         41 . The method according to  claim 39 , wherein
 X represents hydroxy, carboxy or tetrazolyl.   
     
     
         42 . The method according to  claim 39 , wherein
 R 1 , R 2 , R 3  and R 4 , independently of each other, represent halo, hydroxy, alkyl, alkoxy, thioalkoxy, oxo, nitro, cyano, haloalkyl, haloalkoxy, amino, carboxy and/or alkoxy-carbonyl, phenyl and/or anilino, which phenyl or anilino may optionally be substituted with one or two substituents selected from the group consisting of halo, haloalkyl, and haloalkoxy.   
     
     
         43 . The method according to  claim 42 , wherein
 R 1  and R 2 , independently of each other, represent halo, hydroxy, nitro, CF 3 , phenyl and/or anilino, which phenyl and anilino is optionally substituted with halo and/or CF 3 ; and   R 3  and R 4 , independently of each other, represent halo, hydroxy, nitro and/or CF 3 .   
     
     
         44 . The method according to  claim 43 , wherein the benzamide derivative is
 N-[3-chloro-4-(4-chloro-phenylamino)-phenyl]-2-hydroxy-5-nitro-benzamide; or   N-[3-(1H-tetrazol-5-yl)-biphenyl-4-yl]-3,5-bis-trifluoromethyl-benzamide;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         45 . The method according to  claim 39 , wherein the abnormal rhythm of the heart is cardiac arrhythmia, atrial arrhythmia, ventricular arrhythmia, atrial fibrillation, ventricular fibrillation, tachyarrhythmia, atrial tachyarrhythmia, ventricular tachyarrhythmia, bradyarrhythmia. 
     
     
         46 . The method according to  claim 39 , wherein the abnormal rhythm of the heart is cardiac ishemia, ishcemic heart disease, hypertrophic heart, cardiomyopathia or failing heart. 
     
     
         47 . The method according to  claim 39 , wherein the abnormal rhythm of the heart is cardiac arrhythmia, atrial fibrillation and/or ventricular tachyarrhythmia. 
     
     
         48 . The method according to  claim 39 , wherein the abnormal rhythm of the heart is cardiac arrhythmia. 
     
     
         49 . The method of treatment or alleviation of an abnormal rhythm of the heart of a living animal body according to  claim 39 , wherein said living animal body is a human body.