Treatment of affective disorders by the combined action of a nicotinic receptor agonist and a monoaminergic substance

Abstract

This invention relates to use of the combined action of a nicotinic acetylcholine receptor agonist and a monoaminergic substance for the treatment of affective disorders, as well as to pharmaceutical compositions comprising these substances and chemical substances for use according to the invention.

1 . A chemical compound represented by Formula I  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 1, 2 or 3; and  
 m is 0, 1 or 2; and  
 R represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, acyl or benzyl; and  
 R 1  represents 5-bromo-3-pyridyl; 5-bromo-3pyridyl; 6-chloro3-pyridyl; 6-bromo-5-methoxy-3-pyridyl; 6-bromo-3-pyridyl; 6-bromo-5-chloro-3-pyridyl; 5,6-dibromo-3-pyridyl; 6-chloro-5-bromo-3-pyridyl; 6-iodo-5-methoxy-3-pyridyl; 5,6-dichloro-3-pyridyl; 5-bromo-6-chloro-2-pyrazinyl; 6-bromo-5-etynyl-3-pyridyl; 6-chloro-5-methoxy-3-pyridyl; 6-phenyl-3-pyridazinyl; 6-chloro-2-pyrazinyl; 6-chloro-3-pyridazinyl; 6-iodo-3-pyridazinyl; 6-(1-benzimidazolyl)-3-pyridazinyl; 2-pyrazinyl; 6-chloro-2-pyrazinyl; 6-phenyl-3-pyridyl; 5-chloro-6-phenyl-3-pyridyl; 5-chloro-6-methyl-3-pyridyl; 5-etynyl-3-pyridyl: 5-bromo-3-pyridyl; 5-methoxy-6-bromo-3-pyridyl; 6-bromo-3-pyridyl; 5-chloro-6-bromo-3-pyridyl; 5,6-dibromo-3-pyridyl; 5-bromo-6-chloro-3-pyridyl; 5-methoxy-6-iodo-3-pyridyl; or 5,6-dichloro-3-pyridyl.  
 
   
   
       2 . The chemical compound of  claim 1 , wherein 
 n and m are 1; and    R represents hydrogen, methyl, or 4-tert-butoxycarbonyl; and    R 1  represents 5-bromo-3-pyridyl; 5-bromo-3-pyridyl; 6-chloro-3-pyridyl; 6-bromo-5-methoxy-3-pyridyl; 6-bromo-3-pyridyl; 6-bromo-5-chloro-3-pyridyl; 5,6-dibromo-3-pyridyl; 6-chloro-5-bromo-3-pyridyl; 6-iodo-5-methoxy-3-pyridyl; 5,6-dichloro-3-pyridyl; 5-bromo-6-chloro-2-pyrazinyl; 6-bromo-5-etynyl-3-pyridyl; 6-chloro-5-methoxy-3-pyridyl; 6-phenyl-3-pyridazinyl; 6-chloro-2-pyrazinyl; 6-chloro-3-pyridazinyl; 6-iodo-3- pyridazinyl; 6-(1-benzimidazolyl)-3-pyridazinyl; 2-pyrazinyl; 6-chloro-2-pyrazinyl; 6-phenyl-3-pyridyl; 5-chloro-6-phenyl-3-pyridyl; 5-chloro-6-methyl-3-pyridyl; 5-etynyl-3-pyridyl; 5-bromo-3-pyridyl; 5-methoxy-6-bromo-3-pyridyl; 6-bromo-3-pyridyl; 5-chloro-6-bromo-3-pyridyl; 5,6-dibromo-3-pyridyl; 5-bromo-6-chloro-3-pyridyl; 5-methoxy-6-iodo-3-pyridyl; or 5,6-dichloro-3-pyridyl.    
   
   
       3 . The chemical compound of  claim 1 , which is 
 1-(5-bromo-3-pyridyl)-piperazine;    1-(6-chloro-3-pyridyl)-piperazine;    1-(6-bromo-5-methoxy-3-pyridyl)-piperazine;    1-(6-bromo-3-pyridyl)-piperazine;    1-(6-bromo-5-chloro-3-pyridyl)-piperazine;    1-(5,6-dibromo-3-pyridyl)-piperazine;    1-(6-chloro-5-bromo-3-pyridyl)-piperazine;    1-(6-iodo-5methoxy-3-pyridyl)-piperazine;    1-(5,6-dichloro-3-pyridyl)-piperazine;    1-(5-bromo-6-chloro-2-pyrazinyl)-piperazine;    1-(6-bromo-5-etynyl -3-pyridyl)-piperazine;    1-(6-chloro-5-methoxy-3-pyridyl)-piperazine;    1-(6-phenyl-3-pyridazinyl)-piperazine;    1-(6-chloro-2-pyrazinyl)-piperazine;    1-(6-chloro-3-pyridazinyl)-piperazine;    1-(6-iodo-3-pyridazinyl)-piperazine;    1-[6-(1-benzimidazolyl)-3-pyridazinyl]-piperazine;    1-(2-pyrazinyl)-piperazine;    1-(6-chloro-2-pyrazinyl)-4-methyl-piperazine;    1-(6-phenyl-3-pyridyl)-piperazine;    1-(5-chloro-6-phenyl-3-pyridyl)-piperazine;    1-(5-chloro-6-methyl-3-pyridyl)-4-tert-butoxycarbonyl-piperazine; or    1-(5-etynyl-3-pyridyl)-piperazine;    or an enantiomer or a mixture of its enantiomers, or an isotope thereof or a pharmaceutically acceptable salt thereof.    
   
   
       4 . The chemical compound of  claim 1 , wherein 
 n is 2; and    m is 1; and    R represents hydrogen, methyl, or 4-tert-butoxycarbonyl; and    R 1  represents 5-bromo-3-pyridyl; 5-bromo-3-pyridyl; 6-chloro-3-pyridyl; 6-bromo-5-methoxy-3-pyridyl; 6-bromo-3-pyridyl; 6-bromo-5-chloro-3-pyridyl; 5,6-dibromo-3-pyridyl; 6-chloro-5-bromo-3-pyridyl; 6-iodo -5-methoxy-3-pyridyl; 5,6-dichloro-3-pyridyl; 5-bromo-6-chloro-2-pyrazinyl; 6-bromo-5-etynyl-3-pyridyl; 6-chloro-5-methoxy-3-pyridyl; 6-phenyl-3-pyridazinyl; 6-chloro-2-pyrazinyl; 6-chloro-3-pyridazinyl; 6-iodo-3-pyridazinyl; 6-(1-benzimidazolyl)-3-pyridazinyl; 2-pyrazinyl; 6-chloro-2-pyrazinyl; 6-phenyl-3-pyridyl; 5-chloro-6-phenyl-3-pyridyl; 5-chloro-6-methyl-3-pyridyl; 5-etynyl-3-pyridyl; 5-bromo-3-pyridyl; 5-methoxy-6-bromo-3-pyridyl; 6-bromo-3-pyridyl; 5-chloro-6-bromo-3-pyridyl; 5,6-dibromo-3-pyridyl; 5-bromo-6-chloro-3-pyridyl; 5-methoxy-6-iodo-3-pyridyl; or 5,6-dichloro-3-pyridyl.    
   
   
       5 . The chemical compound of  claim 1 , which is 
 1-(5-bromo-3-pyridyl)-homopiperazine;    1-(6-chloro-3-pyridyl)-homopiperazine;    1-(5-methoxy-6-bromo-3-pyridyl)-homopiperazine;    1-(6-bromo-3-pyridyl)-homopiperazine;    1-(5-chloro-6-bromo-3-pyridyl)-homopiperazine;    1-(5,6-dibromo-3-pyridyl)-homopiperazine;    1-(5-bromo-6-chloro-3-pyridyl)-homopiperazine;    1-(5-methoxy-6-iodo-3-pyridyl)- homopiperazine; or    1-(5,6-dichloro-3-pyridyl)-homopiperazine;    or an enantiomer or a mixture of its enantiomers, or an isotope thereof or a pharmaceutically acceptable salt thereof.    
   
   
       6 . An 8-azabicyclo[3.2.1]oct-2-ene derivative of Formula VI,  
     
       
         
         
             
             
         
       
     
     any of its enantiomers or any mixture of its enantiomers, or a pharmaceutically acceptable salt thereof; 
 wherein  
 R is hydrogen, alkyl, alkenyl, cycloalkyl, cyanoalkyl, phenyl, naphthyl or benzyl; and  
 R 1  is  
                     
 wherein R 2  is hydrogen, alkyl, cycloalkyl, or amino; or  
 furanyl, thienyl, pyrrolyl, oxazolyl, isoaxzolyl, imidazolyl, pyridyl, pyrimidinyl or thiazolyl, which heteroaryl group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, cyanoalkyl, halogen, CF 3 , OCF 3 , CN, amino, nitro, and furyl; or  
 naphthyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl or thieno-thienyl, which bicyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, cyanoalkyl, halogen, CF 3 , OCF 3 , CN, amino, nitro and furyl.  
 
   
   
       7 . The 8-azabicyclo[3.2.1]oct-2-ene derivative of  claim 6 , wherein 
 R represents hydrogen, methyl, ethyl, allyl, cyanomethyl, or benzyl; and    R 1  represents acetyl, 3-pyridyl, 3-(6-methoxy)pyridyl, 3-(6-chloro)pyridyl, 2-thiazolyl, 3-thienyl, 2-thienyl, 2-(3-methoxymethyl)thienyl, 2-(3-bromo)thienyl, 2-(3,4-dibromo)thienyl, 2-furyl, 3-furyl, 2-(3-bromo)thienyl), 3-chloro-thien-2-yl, 5-indolyl, 3-(3-furyl)-2-thienyl, 3-quinolinyl, 3-benzofuryl, 2-benzofuryl, 3-benzothienyl, 2-benzothienyl, 2-benzothiazolyl, 2-thieno[3.2-b]thienyl, thieno[2.3-b]thienyl, 2-(3-bromo)benzofuryl or 2-(3-bromo)benzothienyl.    
   
   
       8 . The 8-azabicyclo[3.2.1]oct-2-ene derivative of  claim 6 , which is 
 (±)-3-(2-benzothienyl)-8-H-8-azabicyclo[3.2.1]oct-2-ene;    (±)-3-(2-benzothienyl)-8-ethyl-8-azabicyclo[3.2.1]oct-2-ene;    (±)-8-allyl-3-(2-benzothienyl)-8-azabicyclo[3.2.1]oct-2-ene;    (±)-8-allyl-3-(2-benzothienyl)-8-azabicyclo[3.2.1]oct-2-ene;    (±)-8-allyl-3-[2-(3-bromothienyl)]-8-azabicyclo[3.2.1]oct-2-ene;    (±)-3-(2-benzothienyl)-8-cyanomethyl-8-azabicyclo[3.2.1]oct-2-ene;    (±)-3-[2-(3,4-dibromothienyl)]-8-methyl-8-azabicyclo[3.2.1]oct-2-ene; or    (±)-3-(5-indolyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene;    or an enantiomer or a mixture of its enantiomers, or an isotope thereof or a pharmaceutically acceptable salt thereof.    
   
   
       9 . A method of treatment, prevention or alleviation of an affective disorder, disease or condition in a subject, which method comprises administering to said subject a therapeutically effective amount of one or more compounds having nicotinic acetylcholine agonistic activity and monoamine agonistic or antagonistic or reuptake inhibiting activity.  
   
   
       10 . The method of  claim 9 , wherein the therapeutically active substances are administered as a combination therapy comprising a substance acting as nicotinic acetylcholine agonist and a substance acting as a monoamine agonist or antagonist or reuptake inhibitor.  
   
   
       11 . The method of  claim 9 , wherein the therapeutic effect is achieved using a substance having the dual activity of a nicotinic acetylcholine agonist and a monoamine agonist or antagonist or reuptake inhibitor.  
   
   
       12 . The method of  claim 9 , wherein the monoamine reuptake inhibitor is a selective serotonin reuptake inhibitor (SSRI).  
   
   
       13 . The method of  claim 9 , wherein the affective disorder, disease or condition is depression, anxiety, obsessive compulsive disorder (OCD), panic disorder, or pain.  
   
   
       14 . A method of treatment, prevention or alleviation of an affective disorder, disease or condition in a subject, which method comprises administering to said subject a therapeutically effective amount of one or more compounds having nicotinic acetylcholine agonistic activity and monoamine agonistic or antagonistic or reuptake inhibiting activity, wherein said method comprises administering to said subject a therapeutically effective amount of a compound according to  claim 1 .  
   
   
       15 . A method of treatment, prevention or alleviation of an affective disorder, disease or condition in a subject, which method comprises administering to said subject a therapeutically effective amount of one or more compounds having nicotinic acetylcholine agonistic activity and monoamine agonistic or antagonistic or reuptake inhibiting activity, wherein said method comprises administering to said subject a therapeutically effective amount of a compound according to  claim 6 .  
   
   
       16 . A pharmaceutical composition comprising a therapeutically effective amount of a nicotinic acetylcholine agonist and a monoamine reuptake inhibitor, together with at least one pharmaceutically acceptable carrier or diluent.  
   
   
       17 . The pharmaceutical composition of  claim 16 , for use in the treatment, prevention or alleviation of an affective disorder, disease or condition in a subject.  
   
   
       18 . The pharmaceutical composition of  claim 16 , wherein the affective disorder, disease or condition is depression, anxiety, obsessive compulsive disorder (OCD), panic disorder, or pain.