Inhibitors of proton-gated cation channels and their use in the treatment of ischaemic disorders

Abstract

This invention relates to the use of compounds capable of inhibiting the activity of a proton-gated cation channel in the treatment of alleviation of diseases or disorders associated with, or mediated by a drop in extra cellular pH.

1 . Use of a compound capable of inhibiting a mammalian proton-gated cation channel for the manufacture of a medicament for the treatment, prevention or alleviation of a disease, disorder or condition associated with, or mediated by a drop in extracellular pH.  
     
     
         2 . The use according to  claim 1 , wherein the compound is an isatin derivative represented by the general Formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein 
 R 1  represents hydrogen, alkyl, phenyl or benzyl; and  
 X represents oxygen, or a group of the formula NOR 2 , wherein R 2  represents hydrogen, alkyl, acyl, phenyl or benzyl; and  
 Y represents a group of the formula N—R 4 , wherein R 4  represents hydrogen, hydroxy or alkyl; and  
 n is 0 or 1; and  
 R 6  represents phenyl, naphthyl, thienyl, or pyridyl, all of which groups may be substituted one or more times with halogen, CF 3 , nitro, amino, cyano, hydroxy alkyl, alkoxy or phenyl, or a group of the formula —SO 2 NR′R″, wherein R′ and R″ independently of each another represents hydrogen or alkyl; and  
 “A” represents a ring holding of from five to seven atoms, which ring is fused to the benzo-ring at the positions marked “a” and “b”, and formed by one or the following bivalent radicals: 
 (a) —CH 2 —CH 2 —CH 2 — (b),  
 (a) —NR 12 —CH 2 —CH 2 — (b),  
 (a) —CH 2 —NR 12 —CH 2 — (b),  
 (a) —CH 2 —CH 2 —NR 12 — (b),  
 (a) —CH 2 —CH 2 —CH 2 —CH 2 — (b),  
 (a) —NR 12 —CH 2 —CH 2 —CH 2 — (b),  
 (a) —CH 2 —NR 12 —CH 2 —CH 2 — (b),  
 (a) —CH 2 —CH 2 —NR 12 —CH 2 — (b),  
 (a) —CH 2 —CH 2 —CH 2 —NR 12 — (b),  
 (a) —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 — (b),  
 (a) —NR 12 CH 2 —CH 2 —CH 2 —CH 2 — (b),  
 (a) —CH 2 —NR 12 —CH 2 —CH 2 — (b),  
 (a) —CH 2 —CH 2 —NR 12 —CH 2 —CH 2 — (b),  
 (a) —CH 2 —CH 2 —CH 2 —NR 12 —CH 2 — (b),  
 (a) —CH 2 —CH 2 —CH 2 —CH 2 —NR 12 — (b),  
 wherein  
 
 R 12  represents hydrogen, alkyl, alkyl substituted with hydroxy, alkoxy-alkyl, alkoxy-carbonyl-alkyl, alkyl-carbonyl-oxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl, phenyl or benzyl, which phenyl or benzyl group is optionally substituted with halogen, CF 3 , nitro, amino, cyano, hydroxy-alkyl, alkoxy, or a group of the formula —SO 2 NR′R″, wherein R′ and R″ independently of each another represents hydrogen or alkyl.  
 
     
     
         3 . The use according to  claim 2 , wherein the compound is represented by the general Formula II  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein R 1 , R 6 , R 12 , X, Y and n have the meanings set forth in  claim 1 .  
     
     
         4 . The use according to  claim 2 , wherein the compound is represented by the general Formula III  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein R 1 , R 6 , R 12  and X have the meanings set forth in  claim 1 .  
     
     
         5 . The use according to  claim 4 , wherein the compound is 
 8-ethyl-5-phenyl-6-7-8-9-tetrahydro-1H-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-oxim;    8-methyl-5-phenyl-6-7-8-9-tetrahydro-1H-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-oxim;    8-methyl-5-(4-nitrophenyl)-6,7,8,9-tetrahydro-1H-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-oxim;    8-methyl-5-phenyl-6-7-8-9-tetrahydro-1H-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-methyloxim;    5-phenyl-6-7-8-9-tetrahydro-1H-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-oxim;    8-ethyl-5-phenyl-6-7-8-9-tetrahydro-1-methyl-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-oxim;    8-methyl-5-(4-fluorophenyl)-6,7,8,9-tetrahydro-1H-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-oxim;    5-(4-chlorophenyl)-8-methyl-6-7-8-9-tetrahydro-1-H-pyrrolo-[3.2-h]-isoquinoline-2,3-dione-3-oxim;    5-(2-naphthyl)-8-methyl-6-7-8-9-tetrahydro-1-H-pyrrolo-[3.2-h]-isoquinoline-2,3-dione-3-oxim;    8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-acetyloxim;    8-methyl-5-(4-(N,N-dimethylsulfamoyl)-phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-oxime;    8-methyl-5-(4-toluyl)-6-7-8-9-tetrahydro-1-H-pyrrolo-[3.2-h]-isoquinoline-2,3-dione-3-oxim;    8-methyl-5-(4-methoxyphenyl)-6-7-8-9-tetrahydro-1-H-pyrrolo-[3.2-h]-isoquinoline-2,3-dione-3-oxim;    8-methyl-5-(3-methoxyphenyl)-6-7-8-9-tetrahydro-1-H-pyrrolo-[3.2-h]-isoquinoline-2,3-dione-3-oxim;    8-methyl-5-phenyl-6-7-8-9-tetrahydro-1-H-pyrrolo-[3.2-h]-isoquinoline-2,3-dione-3-O-2,2-dimethylpropanoyl-oxim;    8-methyl-5-(2-methoxyphenyl)-6-7-8-9-tetrahydro-1-H-pyrrolo-[3.2-h]-isoquinoline-2,3-dione-3-oxim;    8-benzyl-5-phenyl-6-7-8-9-tetrahydro-1H-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-oxim;    8-methoxycarbonylmethyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-oxime;    8-(2-propynyl)-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-oxime; or    8-cyclopropylmethyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-oxime;    8-ethyl-5-phenyl-6-7-8-9-tetrahydro-1-methyl-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-oxim;    8-ethyl-5-phenyl-6-7-8-9-tetrahydro-1-methyl-pyrrolo-[3,2-h]-isoquinoline-2,3-dione-3-O-methyloxim;    or a pharmaceutically acceptable salt thereof.    
     
     
         6 . The use according to  claim 2 , wherein the compound is represented by the general Formula IV  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein R 1 , R 6 , R 12 , X, Y and n have the meanings set forth in  claim 1 .  
     
     
         7 . The use according to  claim 2 , wherein the compound is represented by the general Formula V  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein R 1 , R 6 , R 12  and X have the meanings set forth in  claim 1 .  
     
     
         8 . The use according to  claim 2 , wherein the compound is represented by the general Formula VI  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein R 1 , R 6 , R 12 , X, Y and n have the meanings set forth in  claim 1 .  
     
     
         9 . The use according to  claim 2 , wherein the compound is represented by the general Formula VII  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein R 1 , R 6 , R 12  and X have the meanings set forth in  claim 1 .  
     
     
         10 . The use according to  claim 9 , wherein the compound is 
 7-ethyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo-[3,2-f]-isoquinoline-2,3-dione-3-oxim; or    5-phenyl-7-methyl-6-7-8-9-tetrahydro-1-methyl-pyrrolo-[3.2-f]-isoquinoline-2,3-dione-3-oxim;    or a pharmaceutically acceptable salt thereof.    
     
     
         11 . The use according to  claim 2 , wherein the compound is represented by the general Formula VIII  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein R 1 , R 6 , R 12 , X, Y and n have the meanings set forth in  claim 1 .  
     
     
         12 . The use according to  claim 2 , wherein the compound is represented by the general Formula IX  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein R 1 , R 6 , R 12  and X have the meanings set forth in  claim 1 .  
     
     
         13 . The use according to  claim 12 , wherein the compound is 
 7-methyl-5-phenyl-1-6-7-8-tetrahydrobenzo-[2,1-b:3,4-c]-dipyrrole-2,3-dione-3-oxime;    7-methyl-5-(1-naphthyl)-1-6-7-8-tetrahydrobenzo-[2,1-b:3,4-c]-dipyrrole-2,3-dione-3-oxime; or    7-ethyl-5-phenyl-1-6-7-8-tetrahydrobenzo-[2,1-b:3,4-c]-dipyrrole-2,3-dione-3-oxime;    or a pharmaceutically acceptable salt thereof.    
     
     
         14 . The use according to  claim 2 , wherein the compound is represented by the general Formula X  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein R 1 , R 6 , X, Y and n have the meanings set forth in  claim 1 .  
     
     
         15 . The use according to  claim 2 , wherein the compound is represented by the general Formula XI  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein R 1 , R 6 , and X have the meanings set forth in  claim 1 .  
     
     
         16 . The use according to  claim 15 , wherein the compound is 
 5-phenyl-6-7-8-9-tetrahydro-1-H-pyrrolo-[3.2-h]-naphthalene-2,3-dione-3-oxim; or    5-(4-chlorophenyl)-6-7-8-9-tetrahydro-1-H-pyrrolo-[3.2-h]-naphthalene-2,3-dione-3-oxim;    or a pharmaceutically acceptable salt thereof.    
     
     
         17 . The use according to  claim 2 , wherein the compound is represented by the general Formula XII  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein R 1 , R 6 , X, Y and n have the meanings set forth in  claim 1 .  
     
     
         18 . The use according to  claim 2 , wherein the compound is represented by the general Formula XIII  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein R 1 , R 6 , and X have the meanings set forth in  claim 1 .  
     
     
         19 . The use according to  claim 1 , in which the compound is N-amidino-3,5-diamino-6-chloropyrazine-2-carboxamide (Amiloride).  
     
     
         20 . The use according to  claim 1 , wherein the disease, disorder or condition is associated with reduced blood flow to the brain and other CNS tissue, or associated with instances of a temporary break in blood supply to the brain or to other CNS tissue.  
     
     
         21 . The use according to  claim 1 , wherein the disease, disorder or condition is an ischaemic disease, an anoxic episode, an injury to the brain and other parts of the CNS caused by trauma or other injury, a blow to the head, or a spinal injury, a tromboembolic or haemorrhagic stroke, a cerebral vasospasm, hypoglycaemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia, cerebral trauma, lathyrism, Alzheimer's disease, and Huntington's disease, cerebral ischaemia or cerebral infarction, ischaemic, hypoxic or anoxic brain damage, spinal cord injury, tissue ischaemia and reperfusion injury in a mammal at risk for such damage.  
     
     
         22 . The use according to  claim 1 , wherein the proton-gated cation channel is an ASIC1-, ASIC1A-, ASIC1B-, ASIC2—, ASIC2A-, ASIC2B-, ASIC3—, or ASIC-β-channel.  
     
     
         23 . The use according to  claim 1 , wherein the compound is used simultaneously with a pharmaceutically effective amount of an AMPA receptor antagonist.  
     
     
         24 . The use according to  claim 23 , wherein the AMPA receptor antagonising compound is 
 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo-(f)-quinoxaline (NBQX);    6,7-dinitroquinoxaline-2,3-dione; or    6-cyano-7-nitroquinoxaline-2,3-dione;    or a pharmaceutically acceptable salt thereof.    
     
     
         25 . A method for the treatment, prevention or alleviation of a disease, disorder or condition in a subject, including a human, which disease, disorder or condition is associated with, or mediated by a drop in extracellular pH, said method comprising administering to the subject a pharmaceutically effective amount of a compound capable of inhibiting a mammalian proton-gated cation channel.  
     
     
         26 . The method according to  claim 25 , in which the disease or disorder is a diseases associated with reduced blood flow to the brain and other CNS tissue, or associated with instances of a temporary break in blood supply to the brain or to other CNS tissue.  
     
     
         27 . The method according to  claim 25 , in which the disease or disorder is an ischaemic disease, an anoxic episode, an injury to the brain and other parts of the CNS caused by trauma or other injury, a blow to the head, or a spinal injury, a tromboembolic or haemorrhagic stroke, a cerebral vasospasm, hypoglycaemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia, cerebral trauma, lathyrism, Alzheimer's disease, and Huntington's disease, cerebral ischaemia or cerebral infarction, ischaemic, hypoxic or anoxic brain damage, spinal cord injury, tissue ischaemia and reperfusion injury in a mammal at risk for such damage.  
     
     
         28 . The method according to any of claims  25 - 27 , in which the proton-gated cation channel inhibiting compound is an ASIC1-, ASIC1A-, ASIC1B-, ASIC2-, ASIC2A-, ASIC2B-, ASIC3—, or ASIC-β-inhibiting compound.  
     
     
         29 . The method according to  claim 28 , which method comprises simultaneous administration of a pharmaceutically effective amount of the compound capable of inhibiting a mammalian proton-gated cation channel and a pharmaceutically effective amount of an AMPA receptor antagonist.  
     
     
         30 . The method according to  claim 29 , wherein the AMPA receptor antagonising compound is 
 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo-(f)-quinoxaline (NBQX);    6,7-dinitroquinoxaline-2,3-dione; or    6-cyano-7-nitroquinoxaline-2,3-dione;    or a pharmaceutically acceptable salt thereof.