Nitrogen-containing cyclic compound and pharmaceutical composition containing the compound

Abstract

The present invention provides a novel compound having a superior calcium antagonism, in particular, a neuron-selective calcium antagonism. Namely, it provides a compound represented by the following formula, a salt thereof or a hydrate of them. In the formula, Ar indicates an optionally substituted 5- to 14-membered aromatic ring etc.; the ring A indicates any one ring selected from a piperazine, a homopiperazine, a piperidine and the like; the ring B indicates an optionally substituted C 3-14 hydrocarbon ring etc.; E indicates a single bond, a group represented by the formula —CO—, etc.; X indicates a single bond, an oxygen atom etc.; R 1 indicates a hydrogen atom, a halogen atom, a hydroxyl group etc.; and D 1 , D 2 , W 1 and W 2 are the same as or different from each other and each represents a single bond or an optionally substituted C 1-6 alkylene chain.

1 . A method for treating stroke, inhibiting neural cell death or protecting cerebral neurons, wherein said method comprises: 
 applying an effective amount of a pharmaceutical composition to a patient in need thereof;    wherein said pharmaceutical composition comprises: 
 a compound, a salt thereof or the hydrate of the compound or salt, said compound represented by the following formula (I):  
                     
 wherein r is a hydrogen atom or a nitrile; and  
 a pharmaceutically acceptable carrier.  
   
     
     
         2 . The method of  claim 1 , wherein said compound, salt thereof or hydrate of them in the pharmaceutical composition is selected from the group consisting of: 
 1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine; and    1-[4-cyano-4-(3-cyano-5-thienyl)-5-methylhexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine.    
     
     
         3 . A method for treating or improving a neural disease or condition, wherein said method comprises: 
 applying an effective amount of a pharmaceutical composition to a patient in need thereof;    wherein said pharmaceutical composition comprises: 
 a compound, a salt thereof or the hydrate of the compound or salt, said compound represented by the following formula (I):  
                     
 wherein R is a hydrogen atom or a nitrile; and  
 a pharmaceutically acceptable carrier.  
   
     
     
         4 . The method of  claim 3 , wherein the neural disease or condition is at least one selected from the group consisting of 
 wherein said disease is acute ischemic stroke, cerebral apoplexy, cerebral infarction, head trauma, cerebral neural cell death, cerebral circulation metabolic affection, cerebral dysfunction, spasm, schizophrenia, migraine, epilepsy, manic-depression, AIDS dementia complications, edema, anxiety disorder, diabetic neuropathy, cerebral vascular dementia, and multiple sclerosis.    
     
     
         5 . The method according to  claim 3 , wherein the neural disease or condition is at least one selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and neural degenerative diseases.  
     
     
         6 . The method according to  claim 3 , wherein the neural disease or condition is multiple sclerosis.  
     
     
         7 . The method of  claim 3 , wherein said compound, salt thereof or hydrate of them in the pharmaceutical composition is selected from the group consisting of: 
 1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;      1 -[4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine; and    1-[4-cyano-4-(3-cyano-5-thienyl)-5-methylhexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine.    
     
     
         8 . A method for treating stroke, inhibiting neural cell death or protecting cerebral neurons, said method comprising: 
 administering a pharmacologically effective amount of a compound, a salt thereof or a hydrate of them to a patient in need thereof;    wherein said compound is represented by the following formula (I):                          wherein R is a hydrogen atom or a nitrile.    
     
     
         9 . The method of  claim 8 , wherein said compound, salt thereof or hydrate of them is selected from the group consisting of: 
 1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine; and    1-[4-cyano-4-(3-cyano-5-thienyl)-5-methylhexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine.    
     
     
         10 . A method for suppressing a neural cell death or protecting a cerebral neural cell, said method comprising: 
 administering a pharmacologically effective amount of a compound, a salt thereof or a hydrate of them to a patient in need thereof;    wherein said compound is represented by the following formula (I):                          wherein R is a hydrogen atom or a nitrile.    
     
     
         11 . The method of  claim 10 , wherein said compound, salt thereof or hydrate of them in the pharmaceutical composition is selected from the group consisting of: 
 1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine; and    1-[4-cyano-4-(3-cyano-5-thienyl)-5-methylhexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine.    
     
     
         12 . A method for treating or improving a neural disease or condition, said method comprising: 
 administering a pharmacologically effective amount of a compound, a salt thereof or a hydrate of them to a patient in need thereof;    wherein said compound is represented by the following formula (I):                          wherein R is a hydrogen atom or a nitrile;    wherein said disease or condition is at least one selected from the group consisting of acute ischemic stroke, cerebral apoplexy, cerebral infarction, head trauma, cerebral neural cell death, cerebral circulation metabolic affection, cerebral dysfunction, spasm, schizophrenia, migraine, epilepsy, manic-depression, AIDS dementia complications, edema, anxiety disorder, diabetic neuropathy and cerebral vascular dementia.    
     
     
         13 . The method of  claim 12 , wherein said compound, salt thereof or hydrate of them in the pharmaceutical composition is selected from the group consisting of: 
 1-(4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine; and    1-[4-cyano-4-(3-cyano-5-thienyl)-5-methylhexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine.    
     
     
         14 . A method for treating a disease, wherein said method comprises: 
 applying a pharmacologically effective amount of a compound, a salt thereof or a hydrate of them to a patient in need thereof;    wherein said compound is represented by the following formula (I):                          wherein R is a hydrogen atom or a nitrile; and    the neural disease is selected from the group consisting of acute ischemic stroke, cerebral apoplexy, head trauma, migraine, epilepsy and diabetic neuropathy.    
     
     
         15 . The method of  claim 14 , wherein said compound, salt thereof or hydrate of them in the pharmaceutical composition is selected from the group consisting of: 
 1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine; and    1-[4-cyano-4-(3-cyano-5-thienyl)-5-methylhexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine.    
     
     
         16 . A method for treating multiple sclerosis, wherein said method comprises: 
 administering a pharmacologically effective amount of a compound, a salt thereof or a hydrate of them to a patient in need thereof;    wherein said compound is represented by the following formula (I):                          wherein R is a hydrogen atom or a nitrile.    
     
     
         17 . The method of  claim 16 , wherein said compound, salt thereof or hydrate of them in the pharmaceutical composition is selected from the group consisting of: 
 1-[4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine;    1-[4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine; and    1-[4-cyano-4-(3-cyano-5-thienyl)-5-methylhexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine.