Azabicyclic, azatricyclic and azaspirocyclic derivatives of aminocyclohexane NMDA, 5HT3 and neuronal nicotinic receptor antagonists

Abstract

Azabicyclic, azatricyclic and azaspirocyclic derivatives of aminocyclohexanes which are systemically-active as NMDA, 5HT 3 , and nicotinic receptor antagonists, pharmaceutical compostions comprising the same, method of preparation thereof, and method of treating CNS disorders which involve disturbances of glutamatergic, serotoninergic, and nicotinic transmission, treating immunomodulatory disorders, and antimalaria, antitrypanosomal, anti-Borna virus, anti-HSV and anti-Hepatitis C virus activity.

1 . A method-of-treating a living animal for alleviation of a condition wherein the compound is selected for its immunomodulatory, anti-malarial, anti-Borna virus, or anti-Hepatitis C, anti-trypanosomal, and anti-HSV efficacy, or for alleviation of a condition treatable by an NMDA, 5HT 3  or neuronal nicotinic receptor antagonist comprising the step of administering to the living animal a therapeutically effective amount of a compound selected from those of formula 1,  
     
       
         
         
             
             
         
       
     
     wherein 
 R and R 1  together represent a C 3 -C 5  alkylene or alkenylene group, R 2 -R 5  are each independently selected from hydrogen atoms, C 1 -C 6  alkyl groups, C 2 -C 6  alkenyl groups, C 2 -C 6  alkynyl groups, C 6 -C 12  aryl-C 1 -C 4  alkyl groups, and optionally substituted C 6 -C 12  aryl groups;  
 Y is CH; and  
 Z represents hydrogen atoms attached to Y and N respectively;  
 and optical isomers and pharmaceutically-acceptable acid and base addition salts thereof.  
 
   
   
       2 . The method of  claim 1 , wherein the condition treatable by an NMDA antagonist is selected from the group consisting of excitotoxicity selected from ischaemia during stroke, trauma, hypoxia, hypoglycemia, glaucoma, and hepatic encephalopathy, 
 chronic neurodegenerative diseases selected from Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-neurodegeneration, olivopontocerebellar atrophy, Tourette's syndrome, motor neurone disease, mitochondrial dysfunction, Korsakoff syndrome, and Creutzfeldt-Jakob disease,    other disorders related to long term plastic changes in the central nervous system selected from chronic pain, drug tolerance, dependence and addiction (e.g., opioids, cocaine, benzodiazepines, nicotine, and alcohol), and    tardive dyskinesia, L-DOPA-induced dyskinesia, schizophrenia, anxiety, depression, acute pain, spasticity, and tinnitus.    
   
   
       3 . The method of  claim 1 , wherein the condition treatable by a 5HT 3  antagonist is selected from the group consisting of anxiety disorders, depressive disorders, Schizophrenia and treatment related psychosis, drug and alcohol abuse disorders, cognitive disorders, Alzheimer's disease, Parkinson's disease, cerebellar tremor, migraine, appetite disorders, inflammatory bowel syndrome (IBS), and emesis.  
   
   
       4 . The method of  claim 1 , wherein the condition treatable by a neuronal nicotinic receptor antagonist is selected from the group consisting of Tourette's syndrome, anxiety disorders, Schizophrenia, drug abuse, nicotine abuse, cocaine abuse, dyskinesia (Morbus Huntington, L-DOPA-induced), attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, Parkinson's disease, and pain.