3-Substituted quinuclidines and their use

Abstract

This invention relates to novel 3-substituted quinuclidine derivatives, which are found to be cholinergic ligands at the nicotinic acetylcholine receptors and modulators of the monoamine receptors and transporters. Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

1 . A 3-substituted quinuclidine derivative represented by Formula II: 
       
         
           
           
               
               
           
         
         wherein 
         ---- represents an optional double bond; and 
         R 1  and R 2 , independently of one another, represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, alkoxycycloalkyl, cycloalkoxyalkoxy, hydroxyalkoxy, alkenyl, alkoxyalkenyl, alkynyl, alkoxyalkynyl, halo, haloalkyl, hydroxy, cyano, amino, nitro, phenyl, and/or a group of the formula —(CO)R 3 , —COOR 3 , —O(CO)R 3 , —CONR 2 R 3 , —NH—CO 2 R 2 , —NHCO—R 2  or —OCO—NR 2 R 3 ; in which formulas R 2  and R 3  independently of each another represents hydrogen or alkyl; 
         any of its enantiomers or any mixture of enantiomers, or a pharmaceutically acceptable salt thereof, or an aza-onium-salt thereof. 
       
     
     
         2 . The 3-substituted quinuclidine derivative of  claim 1 , represented by Formula III: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2 , independently of one another, represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, alkoxycycloalkyl, cycloalkoxyalkoxy, hydroxyalkoxy, alkenyl, alkoxyalkenyl, alkynyl, alkoxyalkynyl, halo, haloalkyl, hydroxy, cyano, amino, nitro, phenyl, and/or a group of the formula —(CO)R 3 , —COOR 3 , —O(CO)R 3 , —CONR 2 R 3 , —NH—CO 2 R 2 , —NHCO—R 2  or —OCO—NR 2 R 3 ; in which formulas R 2  and R 3  independently of each another represents hydrogen or alkyl; 
         any of its enantiomers or any mixture of enantiomers, or a pharmaceutically acceptable salt thereof, or an aza-onium-salt thereof. 
       
     
     
         3 . The quinuclidine derivative of  claim 1 , wherein R 1  and R 2 , independently of one another, represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, hydroxyalkoxy, halo, haloalkyl, hydroxy, haloalkoxy, cyano, amino, nitro or phenyl. 
     
     
         4 . The quinuclidine derivative of  claim 1 , wherein R 1  and R 2 , independently of one another, represent hydrogen, alkyl, alkoxy, halo, haloalkyl, hydroxy, cyano, amino, nitro or phenyl. 
     
     
         5 . The quinuclidine derivative of  claim 1 , wherein one of R 1  and R 2  represents hydrogen, and the other of R 1  and R 2  represents alkyl, alkoxy, halo, haloalkyl, hydroxy, cyano, amino, nitro or phenyl. 
     
     
         6 . The quinuclidine derivative of  claim 2 , which is 
       3-(3-Indolyl)-quinuclidine-2-ene; 
       3-(5-Bromo-3-indolyl)-quinuclidine-2-ene; 
       3-(5-Methoxy-3-indolyl)-quinuclidine-2-ene; 
       3-(5-Phenyl-3-indolyl)-quinuclidine-2-ene;
 any of its enantiomers or any mixture of enantiomers, or a pharmaceutically acceptable salt thereof, or an aza-onium-salt thereof.