Use of isatin derivatives as ion channel activating agents

Abstract

The present invention relates to ion channel activating agents. More particularly, the present invention relates to a particular class of chemical compounds that has proven useful as openers of SK Ca and IK Ca channels. In further aspects, the present invention relates to the use of these SK/IK channel activating agents for the manufacture of medicaments and pharmaceutical compositions comprising the SK/IK channel activating agents. The SK/IK channel activating agents of the invention are useful for the treatment or alleviation of diseases and conditions associated with the SK/IK channels, in particular 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 diarrhea, ischaemia, cerebral ischaemia, ischaemic heart disease, angina pectoris, coronary heart 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 labor, baldness, cancer, and immune suppression.

1 . Use of an isatin derivative represented by the general formula  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or an oxide or a hydrate thereof, wherein,  
         R 1  represents hydrogen; an alkyl group; a cycloalkyl 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 alkyl; a group of the formula —CH 2 CONR IV R V , wherein R IV  and R V  independently represents hydrogen, alkyl, phenyl or benzyl, which phenyl and benzyl groups may optionally be substituted one or more times with halogen and/or alkyl, or R IV  and R V  together with the N-atom to which they are attached form a heterocyclic 4 to 7 membered monocyclic group, which heterocyclic group may optionally be substituted one or more times with substituents selected from the group consisting of halogen, alkyl, cycloalkyl, alkyloxy, cycloalkyloxy, phenyl or benzyl; or a group of the formula —CH 2 C(═NOH)NH 2 ;  
         R 2  represents hydrogen; an alkyl group; a cycloalkyl group; a group of the formula —CH 2 CO 2 R′, wherein R′ represents hydrogen or an alkyl 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 , R 5 , and R 6  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  and R 6  are as defined above, and R 3  and R 4  together form an additional 4 to 7 membered fused ring, which fused ring may be aromatic, saturated or partially saturated, 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 , and a group of the formula —SO 2 NR″R′″, wherein R″ and R′″ independently of each another represents hydrogen or an alkyl group;  
         for the manufacture of a medicament for the treatment or alleviation of a disease or disorder or condition that is responsive to activation of SK Ca  and/or IK Ca  channels.  
       
     
     
         2 . The use according to  claim 1 , wherein R 1  of formula I represents hydrogen; a C 1-6 -alkyl group; a phenyl group; a benzyl group; a group of the formula —CH 2 CO 2 R′, wherein R′ represents hydrogen or a C 1-6 -alkyl group; a group of the formula —CH 2 NH-Z, wherein Z represents phenyl or benzyl, which phenyl and benzyl may optionally be substituted one or more times with halogen; or a group of the formula —CH 2 CO—Y, wherein Y represents a heterocyclic 6 membered monocyclic group containing at least one nitrogen atom as the heteroatom, and which heterocyclic group may optionally be substituted one or more times with a C 1-6 -alkyl group or a phenyl group.  
     
     
         3 . The use according to  claim 2 , wherein Y represents a piperidinyl or a piperazinyl group.  
     
     
         4 . The use according to either of claims  1 - 3 , wherein R 2  of formula I represents hydrogen, C 1-6 -alkyl, phenyl, benzyl, or a group of the formula —CH 2 COOH.  
     
     
         5 . The use according to any of claims  1 - 4 , wherein R 3 , R 4 , R 5 , and R 6  of formula I independently of each another represents hydrogen, F, Br, Cl, NO 2 , CN, CF 3 , or C 1-6 -alkyl.  
     
     
         6 . The use according to any of claims  1 - 4 , wherein the isatin derivative is represented by the general formula  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or an oxide or a hydrate thereof, wherein,  
         R 1 , R 2 , R 5  and R 6  are as defined above; and  
         X represents a substituent selected from the group consisting of hydrogen, halogen, —NO 2 , —CN, —CF 3 , and 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 use according to  claim 1 , wherein the isatin derivative is 
 5,7-dinitro-1-methyl-1 H-indole-2,3-dione-3-(O-methyloxime);    5-bromo-7-nitro-1 H-indole-2,3-dione-3-oxime;    5,7-dinitro-1 -methyl-1 H-indole-2,3-dione-3-oxime;    5-nitro-1 H-benz[g]indole-2,3-dione-3-oxime;    5-nitro-1 H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione-3-oxime;    5,7-dinitro-1-methyl-1 H-indole-2,3-dione-3-(O-methyloxime);    5,7-dinitro-1 H-indole-2,3-dione-3-(O-methyloxime);    5,7-dinitro-1-ethyl-1 H-indole-2,3-dione-3-(O-methyloxime);    5-nitro-3-(O-methyloxime)-1 H-indole-2,3-dione;    1-phenyl-1 H-indole-2,3-dione-3-(O-methyloxime);    1 H-indole-2,3-dione-3-(O-methyloxime);    5,7-dibromo-1-methyl-1 H-indole-2,3-dione-3-(O-methyloxime);    5,7-dibromo-1 H-indole-2,3-dione-3-(O-methyloxime);    1-methyl-5-nitro-1 H-indole-2,3-dione-3-(O-methyloxime);    5,6-dichloro-1-methyl-1 H-indole-2,3-dione-3-(O-methyloxime);    4,5-dichloro-1-methyl-1 H-indole-2,3-dione-3-(O-methyioxime);    5,7-dinitro-1-benzyl-1 H-indole-2,3-dione-3-(O-methyloxime);    4,6-ditrifluoromethyl-1-methyl-1 H-indole-2,3-dione-3-(O-methyloxime);    5-nitro-7-trifluoromethyl-1-methyl-1 H-indole-2,3-dione-3-(O-methyloxime);    5-nitro-7-trifluoromethyl-1 H-indole-2,3-dione-3-(O-methyloxime);    5,7-dinitro-6-methoxy-1-methyl-1 H-indole-2,3-dione-3-(O-methyloxime);    5,7-dinitro-1-(O-ethylcarboxymethyl)-1 H-indole-2,3-dione-3-(O-methyloxime);    5-nitro-1-methyl-1 H-benz[g]indole-2,3-dione-3-(O-methyloxime);    5-bromo-1-ethoxycarbonylmethyl)-1 H-indole-2,3-dione-3-(O-methyloxime);    5,7-dibromo-1-(ethoxycarbonylmethyl)-1 H-indole-2,3-dione-3-(O-methyloxime);    5-methyl-1-(methoxycarbonylmethyl)-1 H-indole-2,3-dione-3-(O-methyloxime);    5-nitro-1-methyl-1 H-6,7,8,9-tetrahydro-benz[g]-indole-2,3-dione-3-(O-methyloxime);    1 H-benz[g]indole-2,3-dione-3-oxime;    5,7-dinitro-1-methyl-1 H-indole-2,3-dione-3-oxime;    5,7-dibromo-1 H-indole-2,3-dione-3-oxime;    5-bromo-1-methyl-1 H-indole-2,3-dione-3-oxime;    5,7-dinitro-1 H-indole-2,3-dione-3-oxime;    5-bromo-7-nitro-1 H-indole-2,3-dione-3-oxime;    5-bromo-1 H-indole-2,3-dione-3-oxime;    5-nitro-1 H-indole-2,3-dione-3-oxime;    5-methyl-1 H-indole-2,3-dione-3-oxime;    1 H-indole-2,3-dione-3-oxime;    1-methyl-6,7,8,9-tetrahydro-1 H-benz[g]indole-2,3-dione-3-oxime;    5,6-dichloro-1-methyl-1 H-indole-2,3-dione-3-oxime;    4-phenyl-7-methoxy-1 H-indole-2,3-dione-3-oxime;    4,5-dichloro-1 H-indole-2,3-dione-3-oxime;    1-phenyl-1 H-indole-2,3-dione-3-oxime;    4,5-dichloro-1-methyl-1 H-indole-2,3-dione-3-oxime;    5-nitro-1 H-benz[g]indole-2,3-dione-3-oxime;    5-nitro-7-trifluoromethyl-1-methyl-1 H-indole-2,3-dione-3-oxime;    5-nitro-7-trifluorimethyl-1 H-indole-2,3-dione-3-oxime;    5-nitro-1 H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione-3-oxime;    5-fluoro-7-nitro-1 H-indole-2,3-dione-3-oxime;    5,7-dinitro-1-(ethoxycarbonylmethyl)-1 H-indole-2,3-dione-3-oxime;    1-(ethoxycarbonylmethyl)-1 H-indole-2,3-dione-3-oxime;    5-bromo-1-(ethoxycarbonylmethyl)-1 H-indole-2,3-dione-3-oxime;    5,7-dinitro-1 H-indole-2,3-dione-3-oxime;    5,7-dinitro-1 H-indole-2,3-dione-3-(O-benzyloxime);    5,7-dinitro-1 H-1-benzyl-indole-2,3-dione-3-(O-benzyloxime);    5,7-dinitro-1-methyl-1 H-indole-2,3-dione-3-(Obenzyloxime);    5,7-dinitro-1-(ethoxycarbonylmethyl)-1 H-indole-2,3-dione-3-(O-benzyloxime);    5-nitro-1-(ethoxycarbonylmethyl)-1 H-indole-2,3-dione-3-(O-benzyloxime);    1-methoxy-1 H-indole-2,3-dione-3-oxime;    1-acetyl-5-bromo-1 H-indole-2,3-dione;    1-hydroxy-1-H-indole-2,3-dione-3-oxime;    5-bromoisatin 3-oxime;    5,6-dichloro-1-methylisatin 3-oxime;    4,5-dichloroisatin 3-oxime;    4,5-dichloro-1-methylisatin 3-oxime;    O-methyl-4,5-dichloro-1-methylisatin 3-oxime;    benz[e]isatin 3-oxime;    6,7-dichloroisatin 3-oxime;    O-methyl 6,7-dichloroisatin 3-oxime;    O-methyl 6,7-dichloro-1-methylisatin 3-oxime;    6,7-dichloro-1-methylisatin 3-oxime;    potassium 2-(6,7-dichloroisatin-1-yl 3-oxime)acetate;    O-t-butyl 6,7-dichloroisatin 3-oxime;    O-((4-phenylpiperazin-1-yl)carbonylmethyl) 6,7-dichloroisatin 3-oxime;    O-(4-chlorobenzylamino)methyl 6,7-dichloroisatin 3-oxime;    6,7-difluoroisatin 3-oxime;    6,7-dimethylisatin 3-oxime;    5,6-dichloroisatin 3-oxime;    O-carboxymethyl 5-bromoisatin 3-oxime;    O-(ethoxycarbonylmethyl) 5-bromoisatin 3-oxime;    O-(carboxymethyl) 6,7-dichloroisatin 3-oxime;    6-chloro-7-methylisatin 3-oxime;    6-fluoro-7-methylisatin 3-oxime; or    6-fluoro-7-methoxyisatin 3-oxime;    or a pharmaceutically acceptable salt or an oxide or a hydrate thereof.    
     
     
         8 . The use according to any of claims  1 - 7 , wherein the disease or condition is a respiratory disease 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.  
     
     
         9 . An isatin derivative represented by the general formula  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or an oxide or a hydrate thereof, wherein,  
         R 1  represents hydrogen; a C 1-6 -alkyl group; a group of the formula —CH 2 CO 2 R′, wherein R′ represents hydrogen or C 1-3 -alkyl; a group of the formula —CH 2 NH-Z, wherein Z represents phenyl or benzyl, which phenyl and benzyl may optionally be substituted one or more times with halogen; or a group of the formula —CH 2 CO—Y, wherein Y represents a heterocyclic 6 membered monocyclic group containing at least one nitrogen atom as the heteroatom, and which heterocyclic group may optionally be substituted one or more times with a C 1-6 -alkyl group or a phenyl group;  
         R 2  represents hydrogen; a C 1-6 -alkyl group; a group of the formula —CH 2 CO 2 R′, wherein R′ represents hydrogen or an alkyl group; and  
         R 3 , R 4 , R 5 , and R 6  independently of each another represents hydrogen, halogen or a C 1-3 -alkyl group;  
         or R 5  and R 6  are as defined above, and R 3  and R 4  together form an additional 6 membered aromatic or heteroaromatic fused ring.  
       
     
     
         10 . The isatin derivative according to  claim 9 , which is 
 5-bromoisatin 3-oxime;    5,6-dichloro-1-methylisatin 3-oxime;    4,5-dichloroisatin 3-oxime;    4,5-dichloro-1-methylisatin 3-oxime;    O-methyl-4,5-dichloro-1-methylisatin 3-oxime;    benz[e]isatin 3-oxime;    6,7-dichloroisatin 3-oxime;    O-methyl 6,7-dichloroisatin 3-oxime;    O-methyl 6,7-dichloro-1-methylisatin 3-oxime;    6,7-dichloro-1-methylisatin 3-oxime;    potassium 2-(6,7-dichloroisatin-1-yl 3-oxime)acetate;    O-t-butyl 6,7-dichloroisatin 3-oxime;    O-((4-phenylpiperazin-1-yl)carbonylmethyl) 6,7-dichloroisatin 3-oxime;    O-(4-chlorobenzylamino)methyl 6,7-dichloroisatin 3-oxime;    6,7-difluoroisatin 3-oxime;    6,7-dimethylisatin 3-oxime;    5,6-dichloroisatin 3-oxime;    O-carboxymethyl 5-bromoisatin 3-oxime;    O-(ethoxycarbonylmethyl) 5-bromoisatin 3-oxime;    O-(carboxymethyl) 6,7-dichloroisatin 3-oxime;    6-chloro-7-methylisatin 3-oxime;    6-fluoro-7-methylisatin 3-oxime; or    6-fluoro-7-methoxyisatin 3-oxime;    or a pharmaceutically acceptable salt or an oxide or a hydrate thereof.    
     
     
         11 . A pharmaceutical composition comprising a therapeuticallly-effective amount of the isatin derivative according to any of claims  9 - 10 , or a pharmaceutically-acceptable addition salt thereof, together with at least one pharmaceutically-acceptable carrier or diluent.  
     
     
         12 . The pharmaceutical composition according to  claim 11 , for use in the treatment or alleviation of a disease or disorder or conditions responsive to activation of SK Ca  and/or IK Ca  channels.  
     
     
         13 . The pharmaceutical composition according to  claim 12 , for use in 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.  
     
     
         14 . A method of treatment or alleviation of a disease or disorder or condition of a living animal body, including a human, which disorder or disease or condition is responsive to activation of SK Ca  and/or IK 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  claim 9 .  
     
     
         15 . The method according to  claim 15 , in which the disease or disorder or condition is a respiratory disease 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.