Novel 2-amino benzimidazole derivatives and their use as modulators of small-conductance calcium-activated potassium channels

Abstract

This invention relates to novel 2-amino benzimidazole derivatives useful as modulators of small-conductance calcium-activated potassium channels (SK channels). In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.

1 . A 2-amino benzimidazole derivative of Formula Ia: 
       
         
           
           
               
               
           
         
         or any of its isomers or any mixture of its isomers, 
         or a pharmaceutically acceptable salt thereof, wherein 
         m is 0, 1 or 2; 
         n is 0, 1 or 2; 
         R′ is hydrogen or alkyl; 
         R 1  and R 2  independent of each other represent a phenyl group, which phenyl group is optionally substituted with one or more substituents independently selected from the group consisting of:
 halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl, R a R b N— and R a R b N-alkyl; wherein R a  and R b  independent of each other are hydrogen or alkyl; and 
 
         R 4 , R 5 , R 6  and R 7  independent of each other are selected from the group consisting of:
 hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, alkyl and alkoxy. 
 
       
     
     
         2 . The chemical compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1. 
     
     
         3 . The chemical compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1. 
     
     
         4 . The chemical compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein
 R 1  and R 2  independent of each other represent a 4-halo-substituted phenyl group.   
     
     
         5 . The chemical compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein
 R 1  and R 2  independent of each other represent a 3,4-dihalo-substituted phenyl group.   
     
     
         6 . The chemical compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein
 R 4 , R 5 , R 6  and R 7  represent hydrogen.   
     
     
         7 . The chemical compound of  claim 1 , which is N-[1-(3,4-Difluorobenzyl)benzimidazol-2-yl]-3,4-difluoroaniline; N-[1-(4-Chlorobenzyl)benzimidazol-2-yl]-3,4-dichlorobenzylamine; N-[1-(3,4-Difluorobenzyl)benzimidazol-2-yl]-4-trifluoromethylaniline; N-[1-(4-Chloro-3-trifluoromethylbenzyl)benzimidazol-2-yl]-4-chloro-3-trifluoro-methylaniline; N-[1-(4-Chloro-3-trifluoromethylbenzyl)benzimidazol-2-yl]-3,4-difluorobenzylamine; N-[1-(3,4-Difluorobenzyl)benzimidazol-2-yl]-3,4-difluorobenzylamine; N-[1-(4-Chlorobenzyl)benzimidazol-2-yl]-4-chlorobenzylamine; N-[1-(3,4-Dichlorobenzyl)benzimidazol-2-yl]-3,4-dichlorobenzylamine; N-[1-(4-Fluorobenzyl)benzimidazol-2-yl]-4-fluorobenzylamine; (3,4-Difluorobenzyl)-[1-(3,4-difluorophenyl)-1H-benzoimidazol-2-yl]amine; or (3,4-Difluorophenyl)-[1-(3,4-difluorophenyl)-1H-benzoimidazol-2-yl]amine;
 or a pharmaceutically acceptable salt thereof.   
     
     
         8 . A pharmaceutical composition comprising:
 a therapeutically effective amount of the compound of  claim 1 , or any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof, and   at least one pharmaceutically acceptable carrier, excipient or diluent.   
     
     
         9 . A method for treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of SK channels, which method comprises:
 administering to such a living animal body in need thereof a therapeutically effective amount of the compound according to  claim 1 , or any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof.   
     
     
         10 . The method according to  claim 9 , wherein the disease, disorder or condition responsive to modulation of SK channels is: absence seizures, agerelated memory loss, Alzheimer's disease, angina pectoris, arrhythmia, asthma, anxiety, ataxia, attention deficits, baldness, bipolar disorder, bladder hyperexcitability, bladder outflow obstruction, bladder spasms, brain tumors, cerebral ischaemia, chronic obstructive pulmonary disease, cancer, cardiovascular disorders, cognitive dysfunction, colitis, constipation, convulsions, coronary artery spasms, coronary hearth disease, cystic fibrosis, dementia, depression, diabetes type II, dysmenorrhoea, epilepsy, gastrointestinal dysfunction, gastroesophageal reflux disorder, gastrointestinal hypomotility disorders gastrointestinal motility insufficiency, hearing loss, hyperinsulinemia, hypertension, immune suppression, inflammatory bowel disease, inflammatory pain, intermittent claudication, irritable bowel syndrome, ischaemia, ischaemic hearth disease, learning deficiencies, male erectile dysfunction, manic depression, memory deficits, migraine, mood disorders, motor neuron diseases, myokymia, myotonic dystrophy, myotonic muscle dystrophia, narcolepsy, neuropathic pain, pain, Parkinson's disease, polycystic kidney disease, postoperative ileus, premature labour, psychosis, psychotic disorders, renal disorders, Reynaud's disease, rhinorrhoea, secretory diarrhoea, seizures, Sjorgren's syndrome, sleep apnea, spasticity, sleeping disorders, stroke, traumatic brain injury, trigeminal neuralgia, urinary incontinence, urinogenital disorders, vascular spasms, vision loss, or xerostomia. 
     
     
         11 . A method for manufacturing the pharmaceutical composition of  claim 8 , said method comprising:
 mixing the therapeutically effective amount of the compound, or any of its isomers or any mixture of its isomers, or a pharmaceutically acceptable salt thereof, with the at least one pharmaceutically acceptable carrier, excipient or diluent to make the pharmaceutical composition.