N-Substituted (Benzoimidazol-2-yl)phenylamines, Processes for Their Preparation, Their Use as a Medicament or Diagnostic Aid, and a Medicament Comprising Them

Abstract

This invention is directed to the compound of formula (I), compositions containing said compounds to inhibit the sodium-proton exchanger of subtype 3 (NHE3) which are useful in the prevention or treatment of various disorders in a patient suffering from a disease state, such as, renal disorders including acute or chronic renal failure, disorders of biliary function and for respiratory disorders such as snoring or sleep apnea or for stroke.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein,
 R1 and R4 are independently selected from the group consisting of H, F, Cl, Br, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy wherein, the C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy are optionally substituted independently of one another by 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms; 
 R2 and R3 are independently selected from the group consisting of H, F, OH, C 1 -C 3 -alkyl, and C 1 -C 3 -alkoxy wherein, the C 1 -C 3 -alkyl and C 1 -C 3 -alkoxy are optionally substituted independently of one another by 1, 2, 3, 4, 5, 6 or 7 fluorine atoms; 
 R5 is independently selected from the group consisting of C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl and C 3 -C 5 -cycloalkyl, wherein, the C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl and C 3 -C 5 -cycloalkyl are optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms; and 
 R6 and R7 are independently selected from the group consisting of H, F, Cl, Br, C 1 -C 4 -alkyl and C 1 -C 3 -alkoxy, wherein, the C 1 -C 4 -alkyl and C 1 -C 3 -alkoxy are optionally substituted independently of one another by 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms, 
 provided that R6 and R7 are not simultaneously hydrogen; 
 or the pharmaceutically acceptable salt, or trifluoroacetic acid salt thereof. 
 
     
     
         2 . The compound according to  claim 1  wherein, R1 and R4 are independently selected from the group consisting of H, F, Cl, Br, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy, wherein, the C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy are optionally substituted independently of one another by 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms;
 R2 and R3 are independently selected from the group consisting of H, F, OH, C 1 -C 3 -alkyl, or C 1 -C 3 -alkoxy, wherein, the C 1 -C 3 -alkyl and C 1 -C 3 -alkoxy are optionally substituted independently of one another by 1, 2, 3, 4, 5, 6 or 7 fluorine atoms;   R5 is independently selected from C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl and C 3 -C 5 -cycloalkyl wherein, the C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl and C 3 -C 5 -cycloalkyl are optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms; and   R6 and R7 are independently selected from the group consisting of F, Cl, Br, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy, wherein, the C 1 -C 3 -alkyl and C 1 -C 3 -alkoxy are optionally substituted independently of one another by 1, 2, 3, 4, 5, 6 or 7 fluorine atoms,   provided that R6 or R7 does not correspond to hydrogen.   
     
     
         3 . The compound according to  claim 1 , which is:
 (1H-benzoimidazol-2-yl)(2,6-dichlorophenyl)methylamine;   (1H-benzoimidazol-2-yl)(2,6-dichlorophenyl)ethylamine;   (2,6-dichlorophenyl)(5-fluoro-1H-benzoimidazol-2-yl)methylamine;   (1H-benzoimidazol-2-yl)(2,6-dichlorophenyl)isopropylamine;   allyl(1H-benzoimidazol-2-yl)(2,6-dichlorophenyl)amine;   (1H-benzoimidazol-2-yl)cyclopentyl(2,6-dichlorophenyl)amine; or   the pharmaceutically acceptable salt, or trifluoroacetic acid salt thereof.   
     
     
         4 . A method of inhibiting the activity of sodium-proton exchanger of subtype 3 (NH3) comprising contacting an inhibitory amount of a pharmaceutically effective amount of a compound according to  claim 1  to a patient in need thereof. 
     
     
         5 . A method of treatment or prophylaxis with a pharmaceutical composition comprising a compound of formula I and/or a pharmaceutically acceptable salt thereof, of  claim 1 , for a disorder of the respiratory drive, a respiratory disorder, a sleep-related respiratory disorder, sleep apnea, snoring, an acute renal disorder, a chronic renal disorder, an acute renal failure, a chronic renal failure, a disorder of an intestinal function, a disorder of high blood pressure, a disorder of essential hypertension, a disorder of the central nervous system, a disorder resulting from central nervous system overexcitability, epilepsy and centrally induced convulsions, a disorder of an anxiety state, depressions and psychoses, an ischemic state of the peripheral and central nervous system, a stroke, a disorder of acute and chronic damage to a peripheral organ and limb caused by an ischemic event, a disorder of a peripheral organ and limb caused by a reperfusion event, a disorder of atherosclerosis, a disorder of lipid metabolism, a disorder of thromboses, a disorder of biliary function, a disorder of infestation by ectoparasites, a disorder resulting from endothelial dysfunction, a protozoal disorder, malaria, for the preservation and storage of a transplant for a surgical procedure, for use in a surgical operation and an organ transplant, for the treatment of shock, for the treatment of diabetes and late damage from diabetes, for the treatment of a disease in which cellular proliferation represents a primary or secondary cause, and for maintaining health and prolonging life. 
     
     
         6 . The method of  claim 5  wherein, the compound or salt is used in combination with one or more other drugs or active ingredients. 
     
     
         7 . The method of  claim 5  wherein, the drug is for the treatment or prophylaxis of a disorder of the respiratory drive and/or of a sleep-related respiratory disorder. 
     
     
         8 . The method of  claim 7  wherein, the sleep-related respiratory disorder is sleep apnea. 
     
     
         9 . The method of  claim 5  wherein, the drug is for the treatment or prophylaxis of snoring. 
     
     
         10 . The method of  claim 5  wherein, the drug is for the treatment or prophylaxis of an acute renal disorder, a chronic renal disorder, an acute renal failure, or a chronic renal failure. 
     
     
         11 . The method of  claim 5  wherein, the drug is for the treatment or prophylaxis of a disorder of an intestinal function. 
     
     
         12 . A pharmaceutical composition for human, veterinary or phytoprotective use comprising a pharmaceutically effective amount of one or more compounds or a salt according to  claim 1 . 
     
     
         13 . The composition of  claim 12  further comprising one or more other pharmacologically active ingredients or drugs.