Benzimidazolone-, benzoxazolone-, or benzothiazolone derivatives as ion channel modulating agents

Abstract

The present invention relates to ion channel modulating agents. More particularly, the present invention relates to a particular class of chemical compounds that has proven useful as modulators of SK Ca , IK Ca and BK Ca channels. In further aspects, the present invention relates to the use of these SK/IK/BK channel modulating agents for the manufacture of medicaments, and pharmaceutical compositions comprising the SK/IK/BK channel modulating agents. The SK/IK/BK channel modulating agents of the invention are useful for the treatment or alleviation of diseases and conditions associated with the SK/IK/BK channels.

1 . A chemical compound represented by the general formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or an oxide or a hydrate thereof, wherein, 
 X represents N, O, or S; and  
 R 1  represents hydrogen; an alkyl group; a cycloalkyl group; hydroxy; an alkoxy group; an acyl group; a phenyl or a benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halogen, —NO 2 , —CN, —CF 3 , alkyl, cycloalkyl, hydroxy, and alkoxy; a group of the formula —CH 2 CN; a group of the formula —CH 2 CO 2 R′, wherein R′ represents hydrogen or an alkyl group; a group of the formula —CH 2 CONR IV R V , wherein R IV  and R V  independently represents hydrogen or an alkyl group; or a group of the formula —CH 2 C(═NOH)NH 2 ;  
 R 2  represents hydrogen, an alkyl group, a cycloalkyl group, a phenyl or a benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halogen, —NO 2 , —CN, —CF 3 , alkyl, cycloalkyl, hydroxy, and alkoxy; and  
 R 3 , R 4  and R 5  independently of each another represents hydrogen; halogen; —NO 2 ; —CN; —CF 3 ; an alkyl group; an alkoxy group; a phenyl or a benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halogen, —NO 2 , —CN, —CF 3 , alkyl, cycloalkyl, hydroxy, and alkoxy; or a group of the formula —SO 2 NR″R′″, wherein R″ and R′″ independently of each another represents hydrogen or an alkyl group;  
 or R 5  is as defined above and R 3  and R 4  together form an additional 4 to 7 membered fused ring, which fused ring may be a heterocyclic ring, it may be an aromatic, saturated or partially saturated ring, and which fused ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, —NO 2 , —CN, —CF 3 , or a group of the formula —SO 2 NR″R′″, wherein R″ and R′″ independently of each another represents hydrogen or an alkyl group.  
 
     
     
         2 . The chemical compound according to  claim 1 , wherein R 1  represents hydrogen or an alkyl group.  
     
     
         3 . The chemical compound according to either of claims  1 - 2 , wherein R 2  represents hydrogen or an alkyl group.  
     
     
         4 . The chemical compound according to any of claims  1 - 3 , wherein R 3 , R 4  and R 5  independently of each another represents hydrogen or an alkyl group.  
     
     
         5 . The chemical compound according to  claim 1  which is 
 1-Ethyl-4,5-dichlorobenzimidazolone;  
 1,3-diethyl-4,5-dichlorobenzimidazolone; or  
 3-Ethyl-5-chlorobenzoxazolone;  
 or a pharmaceutically acceptable salt or an oxide or a hydrate thereof.  
 
     
     
         6 . The chemical compound according to any of claims  1 - 3 , wherein R 3  and R 4  together form a 5- or 6-membered fused ring, which fused ring may be a heterocyclic ring, it may be an aromatic, saturated or partially saturated ring, and which fused ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, —NO 2 , —CN, —CF 3 , or a group of the formula —SO 2 NR″R′″, wherein R″ and R′″ independently of each another represents hydrogen or an alkyl group.  
     
     
         7 . The chemical compound according to  claim 6 , which is represented by the general formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or an oxide or a hydrate thereof, wherein, 
 X, R 1 , R 2  and R 5  are as defined above; and  
 Y represents hydrogen, halogen, —NO 2 , —CN, —CF 3 , or a group of the formula —SO 2 NR″R′″, wherein R″ and R′″ independently of each another represents hydrogen or an alkyl group.  
 
     
     
         8 . The chemical compound according to  claim 7 , wherein R 1  represents hydrogen or an alkyl group.  
     
     
         9 . The chemical compound according to either of claims  7 - 8 , wherein R 2  represents hydrogen or an alkyl group.  
     
     
         10 . The chemical compound according to any of claims  7 - 9 , wherein Y represents hydrogen.  
     
     
         11 . The chemical compound according to  claim 7 , which is 
 1,3-diethyl-5,6,7,8-tetrahydronaphto[1,2-d]imidazolinone; or    1-ethyl-5,6,7,8-tetrahydronaphto[1,2-d]imidazolinone;    or a pharmaceutically acceptable salt or an oxide or a hydrate thereof.    
     
     
         12 . The chemical compound according to  claim 6 , which is represented by the general formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or an oxide or a hydrate thereof, wherein, 
 X, R 1 , R 2  and R 5  are as defined above; and  
 Y represents hydrogen, halogen, —NO 2 , —CN, —CF 3 , or a group of the formula —SO 2 NR″R′″, wherein R″ and R′″ independently of each another represents hydrogen or an alkyl group.  
 
     
     
         13 . The chemical compound according to  claim 12 , wherein R 1  represents hydrogen or an alkyl group.  
     
     
         14 . The chemical compound according to either of claims  12 - 13 , wherein R 2  represents hydrogen or an alkyl group.  
     
     
         15 . The chemical compound according to any of claims  12 - 14 , wherein Y represents hydrogen.  
     
     
         16 . The chemical compound according to  claim 12 , wherein the chemical compound is 
 3-Ethyl-naphto[1,2-d]oxazolinone;    3-Ethyl-naphto[1,2-d]imidazolinone; or    3-Ethyl-quinolino[5,6-d]imidazolinone;    or a pharmaceutically acceptable salt or an oxide or a hydrate thereof.    
     
     
         17 . The chemical compound according to  claim 6 , in which R 3  and R 4  together form a 5-membered heterocyclic fused ring, which fused ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, —NO 2 , —CN, —CF 3 .  
     
     
         18 . The chemical compound according to  claim 17 , in which the heterocyclic ring is a 1,2 or 4-imidazolyl, 1,2,3,4- or 2,1,3,4-tetrazolyl, thiadiazol-3,4 or 5-yl, thiazol-2,4 or 5-yl, or 2 or 3-thienyl.  
     
     
         19 . The chemical compound according to  claim 18 , which is 
 3-Benzyl-(2,1,3-thiadiazolo)[4,5-g]benzimidazolone;    or a pharmaceutically acceptable salt or an oxide or a hydrate thereof.    
     
     
         20 . A pharmaceutical composition comprising a therapeuticallly-effective amount of a chemical compound of claims  1 - 19 , or a pharmaceutically-acceptable addition salt thereof, together with at least one pharmaceutically-acceptable carrier or diluent, for the treatment or alleviation of a disease or a disorder or a condition responsive to modulation of SK Ca , IK Ca  and/or BK Ca  channels.  
     
     
         21 . The pharmaceutical composition according to  claim 20 , for the treatment or alleviation of respiratory diseases such as asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic hearth disease, angina pectoris, coronary hearth disease, traumatic brain injury, psychosis, anxiety, depression, dementia, memory and attention deficits, Alzheimer's disease, dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia, premature labour, baldness, cancer, and immune suppression.  
     
     
         22 . Use of a chemical compound according to any of claims  1 - 19  for the manufacture of a pharmaceutical composition for the treatment or alleviation of a disorder or a disease or a condition of a mammal, including a human, which disorder, disease or condition is responsive to modulation of SK Ca , IK Ca  and/or BK Ca  channels.  
     
     
         23 . The use according to  claim 22 , wherein the disease, disorder or condition is asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic hearth disease, angina pectoris, coronary hearth disease, traumatic brain injury, psychosis, anxiety, depression, dementia, memory and attention deficits, Alzheimer's disease, dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia, premature labour, baldness, cancer, and immune suppression.  
     
     
         24 . A method of treatment or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disease, disorder or condition is responsive to modulation of SK Ca , IK Ca  and/or BK Ca  channels, comprising the step of administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of a compound according to any of claims  1 - 19 .  
     
     
         25 . The method of  claim 24 , in which the disease, disorder or condition is asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic hearth disease, angina pectoris, coronary hearth disease, traumatic brain injury, psychosis, anxiety, depression, dementia, memory and attention deficits, Alzheimer's disease, dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia, premature labour, baldness, cancer, and immune suppression.