Pyridylether derivatives, their preparation and use

Abstract

The present invention relates to novel pyridylether derivatives which are cholinergic ligands at nicotinic Ach receptors. The compounds of the invention are useful for the treatment of conditions, disorders, or diseases involving the cholinergic system of the central nervous system, pain, inflammatory diseases, diseases caused by smooth muscle contractions and as assistance in the cessation of chemical substance abuse.

1 . A compound represented by the general formula  
     
       
         
         
             
             
         
       
     
     any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof;  
     wherein 
 m is 1, 2 or 3;  
 n is 1, 2 or 3;  
 R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; and  
 R 1  represents  
 a monocyclic 5 to 6 membered heterocyclic group which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF 3 , OCF 3 , CN, amino, nitro, —COOR 3 , —CONR 2 R 3 , —NH—CO 2 R 2 , NHCO—R 2 , —OCO—NR 2 R 3 ; wherein R 2 and R 3  independently represents hydrogen or alkyl; 
 aryl optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy,halogen, CF 3 , OCF 3 , CN, amino and nitro;  
 —X-alkyl—Y-alkyl wherein X and Y independently represents O, S, NH, N-alkyl or Se; and alkyl is optionally substituted with alkoxy or thioalkoxy;  
 —X-(alkyl) o -aryl- wherein o is 0 or 1 and X represents O, S, NH, N-alkyl or Se; optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF 3 , OCF 3 , CN, amino and nitro;  
 —X-(alkyl) o -5- or 6-membered heterocyclic monocyclic group wherein o is 0 or 1 and X represents O, S, NH, N-alkyl or Se; optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF 3 , OCF 3 , CN, amino and nitro;  
 a monocyclic 5 to 6 membered heterocyclic group optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF 3 , OCF 3 , CN, amino and nitro; or  
 
 or R 1  represents a bicyclic heterocyclic group, composed of a 5 to 6 membered monocyclic heterocyclic group fused to a benzene ring, and which may be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, alkoxy-alkoxy, cycloalkoxy, methylenedioxy, halogen, CF 3 , OCF 3 , CN, amino, nitro, aryl optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF 3 , OCF 3 , CN, amino and nitro; and a monocyclic 5 to 6 membered heterocyclic group optionally substituted one or more times with alkyl, cycloalkyl, cycloalkylalkyl alkenyl, alkynyl, alkoxy, cycloalkoxy, methylenedioxy, halogen, CF 3 , OCF 3 , CN, amino and nitro;  
 
   
   
       2 . A compound of formula (I), according to  claim 1 , wherein R and R 1  is attached to an azetidine, pyrrolidine, piperidine or homopiperidine;  
   
   
       3 . A compound of formula (I), according to  claim 1 , wherein n is 1 and m is 1 or 2; 
 R is hydrogen or C 1-4 -alkyl;    and R 1  represents a pyridyl or a substituted pyridyl;    
   
   
       4 . A compound of formula (I), according to  claim 1 , wherein R 1  is 3-pyridyl, 5-chloro-3-pyridyl, 2-chloro-3-pyridyl;  
   
   
       5 . A compound of formula (I), according to  claim 1 , said compound being:  
     (±)-1-Methyl-3-oxy-(3-pyridyl)-pyrrolidine;  
     (±)-1-Methyl-3-oxy-(3-pyridyl)-azetidine;  
     (±)-1-Methyl-3-oxy-(3-pyridyl)-piperidine;  
     (±)-1-Methyl-3-oxy-(5-chloro-3-pyridyl)-pyrrolidine;  
     (±)-1-Methyl-3-oxy-(5-chloro-3-pyridyl)-piperidine;  
     (±)-1-Methyl-3-oxy-(2-chloro-3-pyridyl)-piperidine;  
     (±)-1-Methyl-4-oxy-(3-pyridyl)-homopiperidine;  
     (±)-1-Methyl-4-oxy-(5-chloro-3-pyridyl)-homopiperidine;  
     (±)-3-Oxy-(3-pyridyl)-pyrrolidine;  
     (±)-3-Oxy-(3-pyridyl)-azetidine  
     (±)-3-Oxy-(3-pyridyl)-piperidine;  
     (±)-(5-Chloro-3-pyridyl)-3-oxy-pyrrolidine;  
     (±)-(5-Chloro-3-pyridyl)-3-oxy-piperidine;  
     (±)-(2-Chloro-3-pyridyl)-3-oxy-piperidine;  
     (±)-4-Oxy-(3-pyridyl)-homopiperidine; or  
     (±)-(5-Chloro-3-pyridyl)-4-oxy-homopiperidine;  
     or a pharmaceutically acceptable addition salt thereof;  
   
   
       6 . A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.  
   
   
       7 . The use of a compound according to  claim 1  for the manufacture of a medicament for the treatment of a disease of a living animal body, including a human, which disease is responsive to the activity of nicotinic ACh receptor modulators.  
   
   
       8 . The use according to  claim 7  wherein the disease to be treated is pain, a disease in the central nervous system, a disease caused by smooth muscle contraction, neurodegeneration, inflammation, chemical substance abuse or withdrawal symptoms caused by the cessation of intake of the chemical substance such as smoking cessation;  
   
   
       9 . The use of a compound according to  claim 8  wherein a disease in the central nervous system is Alzheimer's disease, Parkinson's disease, memory dysfunction or attention deficit hyperactivity disorder.  
   
   
       10 . A method of treating a disease of a living animal body, including a human, which disease is responsive to the activity of nicotinic ACh receptor modulators, comprising the step of administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of a compound according to  claim 1 .  
   
   
       11 . The method according to  claim 10 , wherein pain, a disease in the central nervous system, a disease caused by smooth muscle contraction, neurodegeneration, inflammation, chemical substance abuse or withdrawal symptoms caused by the cessation of intake of the chemical substance, such as smoking cessation, are treated.  
   
   
       12 . The method of  claim 11  wherein a disease in the central nervous system, said disease being Alzheimer's disease, Parkinson's disease, memory dysfunction or attention deficit hyperactivity disorder, is treated.