4-(2-Pyridyl) piperizines having 5HT7 receptor agonist activity

Abstract

The present invention relates to compounds of the formula I wherein R 1 , R 2 , R 3 , X and Y are defined as in the specification. Those compounds are 5HT7 partial agonists and are useful in the treatment of several disorders of the central nervous system.

1 . A compound of the compounds of the formula I  
       
         
           
           
               
               
           
         
       
       wherein R 1  is hydrogen, (C 1 -C 6 )alkyl, aryl, heteroaryl, arylmethyl or heteroarylmethyl, wherein said aryl and heteroaryl and the aryl and heteroaryl moieties of said arylmethyl and said heteroarylmethyl can optionally be substituted with one or more substituents, preferably with from zero to two substituents, independently selected from hydrogen, halo, hydroxy, nitro, amino, cyano —C(═O)—O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-C(═O)—(C 1 -C 6 )alkyl, —C(═O)H, —C(═O)NR 4 R 5 ), (C 1 -C 6 )alkyl optionally substituted with from one to three fluorine atoms, and (C 1 -C 6 )alkoxy optionally substituted with from one to three fluorine atoms; 
 R 2  and R 3  are independently selected from hydrogen and (C 1 -C 6 )alkyl; or R 2  and R 3 , taken together, may form a saturated carbocyclic ring containing from 3 to 6 ring carbon atoms;  
 R 4  and R 5  are independently selected from hydrogen and (C 1 -C 6 )alkyl; or R 4  and R 5 , taken together, may form a saturated carbocyclic ring containing from 3 to 6 ring carbon atoms; and  
 X and Y are independently selected from hydrogen, halo, hydroxy, nitro, amino, cyano —C(═O)—O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-C(═O)—(C 1 -C 6 )alkyl, —C(═O)H, —C(═O)NR 4 R 5 ), (C 1 -C 6 )alkyl optionally substituted with from one to three fluorine atoms, and (C 1 -C 6 )alkoxy optionally substituted with from one to three fluorine atoms;  
 and the pharmaceutically acceptable salts of such compounds:  
 
     
     
         2 . A compound according to  claim 1 , wherein R 1  is hydrogen and X and Y are selected from hydrogen and methyl.  
     
     
         3 . A compound according to  claim 1  wherein X and Y are selected from hydrogen and (C 1 -C 6 )alkyl.  
     
     
         4 . A compound according to  claim 1 , wherein such compound is selected from the following compounds and their pharmaceutically acceptable salts: 
 1-[6-(Pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-[6-(Pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    3-{4-[6-(Pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazin-1-yl}-propan-1-ol;    1-Methyl-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-Ethyl-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-Benzyl-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-Propyl-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-(2-Methoxy-ethyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-Benzo[1,3]dioxol-5-ylmethyl-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-(2-Phenoxy-ethyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-(3-Phenoxy-propyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-(3-Phenyl-propyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-Butyl-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    3-{4-[6-(Pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazin-1-yl}-propionitrile;    4-{4-[6-(Pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazin-1-yl}-butyronitrile;    1-(3-Methyl-benzyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-(3-Chloro-benzyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    3-{4-[6-(Pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazin-1-ylmethyl}-benzonitrile;    2-{4-[6-(Pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazin-1-ylmethyl}-benzonitrile;    4-{4-[6-(Pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazin-1-ylmethyl}-benzonitrile;    1-(3-Fluoro-benzyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-(4-Fluoro-benzyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-(3-Methoxy-benzyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-(2-Chloro-benzyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-(4-tert-butyl-benzyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-(2-Fluoro-benzyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-(2-Bromo-benzyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-Isopropyl-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-Cyclporopyl-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-(1-Methyl-hexyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-[6-(2Methyl-pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-[6-(2-Methyl-pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    4-(6-Piperazin-1-yl-pyridin-2-yloxymethyl)-quinoline;    1-[6-(3-Methyl-pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-[6-(2-Phenyl-pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine;    1-[6-(2,6-Dimethyl-pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine; and    1-(4-Fluoro-benzyl)-4-[6-(pyridin-4-ylmethoxy)-pyridin-2-yl]-piperazine.    
     
     
         5 . A pharmaceutical composition for treating a disorder or condition selected from depression, anxiety, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), migraine, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder bipolar disorder, jet lag, sleep disorders such as circadian sleep rhythms disorder, sleep deprivation, REM sleep disorders, hypersomnia, parasomnias, sleep-wake cycle disorders, sleep disorders associated with blindness, sleep disorders associated with obesity, narcolepsy and sleep disorders associated with shift work or irregular work schedules; nocturnal enuresis, and restless legs syndrome in a mammal, comprising an amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier.  
     
     
         6 . A method for treating a disorder or condition selected from depression, anxiety, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), migraine, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, jet lag, sleep disorders such as circadian sleep rhythms disorder, sleep deprivation, REM sleep disorders, hypersomnia, parasomnias, sleep-wake cycle disorders, sleep disorders associated with blindness, sleep disorders associated with obesity, narcolepsy and sleep disorders associated with shift work or irregular work schedules; nocturnal enuresis, and restless legs syndrome in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.  
     
     
         7 . A pharmaceutical composition for treating a disorder or condition selected from depression, anxiety, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), migraine, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, jet lag, sleep disorders such as circadian sleep rhythms disorder, sleep deprivation, REM sleep disorders, hypersomnia, parasomnias, sleep-wake cycle disorders, sleep disorders associated with blindness, sleep disorders associated with obesity, narcolepsy and sleep disorders associated with shift work or irregular work schedules; nocturnal enuresis, and restless legs syndrome in a mammal, comprising a serotonin 7 receptor partial agonizing effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
     
     
         8 . A method for treating a disorder or condition selected from depression, anxiety, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), migraine, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, jet lag, sleep disorders such as circadian sleep rhythms disorder, sleep deprivation, REM sleep disorders, hypersomnia, parasomnias, sleep-wake cycle disorders, sleep disorders associated with blindness, sleep disorders associated with obesity, narcolepsy and sleep disorders associated with shift work or irregular work schedules; nocturnal enuresis, and restless legs syndrome in a mammal, comprising administering to a mammal requiring such treatment a serotonin 7 receptor partial agonizing effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof.