Heterocyclic Substituted Aminoazacycles Useful as Central Nervous System Agents

Abstract

Heterocyclic substituted aminoazacyclic compounds of formula I Z-R 3   I, wherein Z is a defined aminoazacycle and R 3 is a defined heterocycle moiety, pharmaceutical compositions of these compounds, and use of said compositions to control synaptic transmission in mammals.

1 . A compound of formula I  
         Z-R 3   I,  or pharmaceutically acceptable salts thereof wherein,    Z is selected from the group consisting of                          R 1  and R 2  are independently selected from the group consisting of hydrogen and allyl;    A and B are independently absent or independently selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, carboxy, haloalkyl, halogen, hydroxy, and hydroxyalkyl;    R 3  is selected from the group consisting of                          R 4  is selected from the group consisting of hydrogen, alkyl, and halogen;    R 5  is selected from the group consisting of hydrogen, alkoxy, alkyl, halogen, nitro, and —NR 10 R 11  wherein R 10  and R 11  are independently selected from the group consisting of hydrogen and lower alkyl;    R 6  is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, 5-tetrazolyl, —NR 7 SO 2 R 8 , —C(NR 7 )NR 8 R 9 , —CH 2 C(NR 7 )NR 8 R 9 , —C(NOR 7 )R 8 , —C(NCN)R 7 , —C(NNR 7 R 8 )R 9 , —S(O) 2 OR 7 , and —S(O) 2 R 7 ; and    R 7 , R 8 , and R 9  are independently selected from the group consisting of hydrogen and alkyl.    
     
     
         2 . (canceled)  
     
     
         3 . A compound according to  claim 1  of formula II  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         4 . A compound according to  claim 3  wherein  
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound according to  claim 4  that is 1-(6-chloro-3-pyridinyl)-3-azetidinylamine.  
     
     
         6 - 11 . (canceled)  
     
     
         12 . A compound according to  claim 1  of formula V  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         13 . A compound according to  claim 12  wherein 
 R 3  is                          
     
     
         14 . A compound according to  claim 13  that is 1-(6-chloro-3-pyridinyl)-4-piperidinylamine.  
     
     
         15 . A compound according to  claim 1  of formula VI  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         16 . A compound according to  claim 15  wherein 
 R 3  is                          
     
     
         17 . A compound according to  claim 1  of formula VII  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         18 . A compound according to  claim 15  wherein 
 R 3  is                          
     
     
         19 . A compound according to  claim 1  selected from the group consisting of 
 (3S)-1-(3-pyridinyl)azepanylamine;    N-methyl-N-[(3S)-1-(3-pyridinyl)azepanyl]amine;    (3S)-1-(3-pyridinyl)azepanylamine;    N-methyl-N-[(3R)-1-(3-pyridinyl)azepanyl]amine;    (3S)-1-(6-chloro-3-pyridinyl)azepanylamine;    N-[(3R)-1-(6-chloro-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(6-chloro-3-pyridinyl)azepanylamine;    N-[(3R)-1-(6-chloro-3-pyridinyl)azepanyl]-N-methylamine;    (3S)-1-(5,6-dichloro-3-pyridinyl)azepanylamine;    N-[(3S)-1-(5,6-dichloro-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(5,6-dichloro-3-pyridinyl)azepanylamine;    N-[(3R)-1-(5,6-dichloro-3-pyridinyl)azepanyl]-N-methylamine;    (3S)-1-(6-chloro-5-methoxy-3-pyridinyl)azepanylamine;    N-[(3R)-1-(6-chloro-5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(6-chloro-5-methoxy-3-pyridinyl)azepanylamine;    N-[(3R)-1-(6-chloro-5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(6-chloro-5-methyl-3-pyridinyl)azepanylamine;    N-[(3S)-1-(6-chloro-5-methyl-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(6-chloro-5-methyl-3-pyridinyl)azepanylamine;    N-[(3R)-1-(6-chloro-5-methyl-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(5-methoxy-3-pyridinyl)azepanylamine;    N-[(3R)-1-(5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(5-methoxy-3-pyridinyl)azepanylamine;    N-[(3R)-1-(5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;    (3S)-1-(6-bromo-3-pyridinyl)azepanylamine;    N-[(3S)-1-(6-bromo-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(6-bromo-3-pyridinyl)azepanylamine;    N-[(3R)-1-(6-bromo-3-pyridinyl)azepanyl]-N-methylamine;    (3S)-1-(5-fluoro-3-pyridinyl)azepanylamine;    N-[(3S)-1-(5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(5-fluoro-3-pyridinyl)azepanylamine;    N-[(3R)-1-(5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;    (3S)-1-(6-chloro-5-fluoro-3-pyridinyl)azepanylamine;    N-[(3S)-1-(6-chloro-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(6-chloro-5-fluoro-3-pyridinyl)azepanylamine;    N-[(3R)-1-(6-chloro-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;    (3S)-1-(6-bromo-5-fluoro-3-pyridinyl)azepanylamine;    N-[(3S)-1-(6-bromo-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(6-bromo-5-fluoro-3-pyridinyl)azepanylamine;    N-[(3R)-1-(6-bromo-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;    (3S)-1-(5-bromo-6-chloro-3-pyridinyl)azepanylamine;    N-[(3S)-1-(5-bromo-6-chloro-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(5-bromo-6-chloro-3-pyridinyl)azepanylamine;    N-[(3R)-1-(5-bromo-6-chloro-3-pyridinyl)azepanyl]-N-methylamine;    (3S)-1-(6-bromo-5-chloro-3-pyridinyl)azepanylamine;    N-[(3S)-1-(6-bromo-5-chloro-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(6-bromo-5-chloro-3-pyridinyl)azepanylamine;    N-[(3R)-1-(6-bromo-5-chloro-3-pyridinyl)azepanyl]-N-methylamine;    (3S)-1-(6-bromo-5-ethoxy-3-pyridinyl)azepanylamine;    N-[(3S)-1-(6-bromo-5-ethoxy-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(6-bromo-5-ethoxy-3-pyridinyl)azepanylamine;    N-[(3R)-1-(6-bromo-5-ethoxy-3-pyridinyl)azepanyl]-N-methylamine;    (3S)-1-(5-cyano-3-pyridinyl)azepanylamine;    N-[(3S)-1-(5-cyano-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(5-cyano-3-pyridinyl)azepanylamine;    N-[(3R)-1-(5-cyano-3-pyridinyl)azepanyl]-N-methylamine;    (3S)-1-(5-ethynyl-3-pyridinyl)azepanylamine;    N-[(3S)-1-(5-ethynyl-3-pyridinyl)azepanyl]-N-methylamine;    (3R)-1-(5-ethynyl-3-pyridinyl)azepanylamine;    N-[(3R)-1-(5-ethynyl-3-pyridinyl)azepanyl]-N-methylamine;    (3S)-1-furo[3,2-b]pyridin-6-ylazepanylamine;    N-[(3S)-1-furo[3,2-b]pyridin-6-ylazepanyl]-N-methylamine;    (3R)-1-furo[3,2-b]pyridin-6-ylazepanylamine;    N-[(3R)-1-furo[3,2-b]pyridin-6-ylazepanyl]-N-methylamine;    (4S)-1-(3-pyridinyl)azepanylamine;    N-methyl-N-[(4S)-1-(3-pyridinyl)azepanyl]amine;    (4R)-1-(3-pyridinyl)azepanylamine;    N-methyl-N-[(4R)-1-(3-pyridinyl)azepanyl]amine;    (4S)-1-(6-chloro-3-pyridinyl)azepanylamine;    N-[(4S)-1-(6-chloro-3-pyridinyl)azepanyl]-N-methylamine;    (4R)-1-(6-chloro-3-pyridinyl)azepanylamine;    N-[(4R)-1-(6-chloro-3-pyridinyl)azepanyl]-N-methylamine;    (4S)-1-(5,6-dichloro-3-pyridinyl)azepanylamine;    N-[(4S)-1-(5,6-dichloro-3-pyridinyl)azepanyl]-N-methylamine;    (4R)-1-(5,6-dichloro-3-pyridinyl)azepanylamine;    N-[(4R)-1-(5,6-dichloro-3-pyridinyl)azepanyl]-N-methylamine;    (4S)-1-(6-chloro-5-methoxy-3-pyridinyl)azepanylamine;    N-[(4S)-1-(6-chloro-5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;    (4R)-1-(6-chloro-5-methoxy-3-pyridinyl)azepanylamine;    N-[(4R)-1-(6-chloro-5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;    (4S)-1-(6-chloro-5-methyl-3-pyridinyl)azepanylamine;    N-[(4S)-1-(6-chloro-5-methyl-3-pyridinyl)azepanyl]-N-methylamine;    (4R)-1-(6-chloro-5-methyl-3-pyridinyl)azepanylamine;    N-[(4R)-1-(6-chloro-5-methyl-3-pyridinyl)azepanyl]-N-methylamine;    (4S)-1-(5-methoxy-3-pyridinyl)azepanylamine;    N-[(4S)-1-(5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;    (4R)-1-(5-methoxy-3-pyridinyl)azepanylamine;    N-[(4R)-1-(5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;    (4S)-1-(6-bromo-3-pyridinyl)azepanylamine;    N-[(4S)-1-(6-bromo-3-pyridinyl)azepanyl]-N-methylamine;    (4R)-1-(6-bromo-3-pyridinyl)azepanylamine;    N-[(4R)-1-(6-bromo-3-pyridinyl)azepanyl]-N-methylamine;    (4S)-1-(5-fluoro-3-pyridinyl)azepanylamine;    N-[(4S)-1-(5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;    (4R)-1-(5-fluoro-3-pyridinyl)azepanylamine;    N-[(4R)-1-(5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;    (4S)-1-(6-chloro-5-fluoro-3-pyridinyl)azepanylamine;    N-[(4S)-1-(6-chloro-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;    (4R)-1-(6-chloro-5-fluoro-3-pyridinyl)azepanylamine;    N-[(4R)-1-(6-chloro-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;    (4S)-1-(6-bromo-5-fluoro-3-pyridinyl)azepanylamine;    N-[(4S)-1-(6-bromo-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;    (4R)-1-(6-bromo-5-fluoro-3-pyridinyl)azepanylamine;    N-[(4R)-1-(6-bromo-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;    (4S)-1-(5-bromo-6-chloro-3-pyridinyl)azepanylamine;    N-[(4S)-1-(5-bromo-6-chloro-3-pyridinyl)azepanyl]-N-methylamine;    (4R)-1-(5-bromo-6-chloro-3-pyridinyl)azepanylamine;    N-[(4R)-1-(5-bromo-6-chloro-3-pyridinyl)azepanyl]-N-methylamine;    (4S)-1-(6-bromo-5-chloro-3-pyridinyl)azepanylamine;    N-[(4S)-1-(6-bromo-5-chloro-3-pyridinyl)azepanyl]-N-methylamine;    (4R)-1-(6-bromo-5-chloro-3-pyridinyl)azepanylamine;    N-[(4R)-1-(6-bromo-5-chloro-3-pyridinyl)azepanyl]-N-methylamine;    (4S)-1-(6-bromo-5-ethoxy-3-pyridinyl)azepanylamine;    N-[(4S)-1-(6-bromo-5-ethoxy-3-pyridinyl)azepanyl]-N-methylamine;    (4R)-1-(6-bromo-5-ethoxy-3-pyridinyl)azepanylamine;    N-[(4R)-1-(6-bromo-5-ethoxy-3-pyridinyl)azepanyl]-N-methylamine;    (4S)-1-(5-cyano-3-pyridinyl)azepanylamine;    N-[(4S)-1-(5-cyano-3-pyridinyl)azepanyl]-N-methylamine;    (4R)-1-(5-cyano-3-pyridinyl)azepanylamine;    N-[(4R)-1-(5-cyano-3-pyridinyl)azepanyl]-N-methylamine;    (4S)-1-(5-ethynyl-3-pyridinyl)azepanylamine;    N-[(4S)-1-(5-ethynyl-3-pyridinyl)azepanyl]-N-methylamine;    (4R)-1-(5-ethynyl-3-pyridinyl)azepanylamine;    N-[(4R)-1-(5-ethynyl-3-pyridinyl)azepanyl]-N-methylamine;    (4S)-1-furo[3,2-b]pyridin-6-ylazepanylamine;    N-[(4S)-1-furo[3,2-b]pyridin-6-ylazepanyl]-N-methylamine;    (4R)-1-furo[3,2-b]pyridin-6-ylazepanylamine; and    N-[(4R)-1-furo[3,2-b]pyridin-6-ylazepanyl]-N-methylamine.    
     
     
         20 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in  claim 1 .  
     
     
         21 . A method for selectively controlling neurotransmitter release in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I in  claim 1 .  
     
     
         22 . A method of treating a disorder wherein the disorder is ameliorated by controlling neurotransmitter release in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula I in  claim 1 .  
     
     
         23 . The method according to  claim 22  wherein the disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, depression, nicotinic withdrawal syndrome, Tourette's syndrome, and schizophrenia.  
     
     
         24 . The method according to  claim 22  wherein the disorder is pain.  
     
     
         25 . A method of treating pain in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I in  claim 1  in combination with an opioid and a pharmaceutically acceptable carrier.  
     
     
         26 . A method of treating pain in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I in  claim 1  in combination with a non-steroid antiinflammatory agent and a pharmaceutically acceptable carrier.  
     
     
         27 . A method of treating pain in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I in combination with a tricyclic antidepressant and a pharmaceutically acceptable carrier.  
     
     
         28 . A method of treating pain in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I in combination with an anticonvulsant and a pharmaceutically acceptable carrier.  
     
     
         29 . A compound of formula VIII  
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof wherein,  
         R 3  is selected from the group consisting of  
         
           
             
             
                 
                 
             
           
         
         R 1  is alkyl;  
         R 2  is selected from the group consisting of hydrogen and alkyl;  
         A and B are independently absent or independently selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, carboxy, haloalkyl, halogen, hydroxy, and hydroxyalkyl;  
         R 5  is selected from the group consisting of hydrogen, alkoxy, alkyl, halogen, nitro, and —NR 10 R 11  wherein R 10  and R 11 , are independently selected from the group consisting of hydrogen and lower alkyl;  
         R 6  is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, 5-tetrazolyl, —NR 7 SO 2 R 8 , —C(NR 7 )NR 8 R 9 , —CH 2 C(NR 7 )NR 8 R 9 , —C(NOR 7 )R 8 , —C(NCN)R 7 , —C(NNR 7 R 8 )R 9 , —S(O) 2 OR 7 , and —S(O) 2 R 7 ; and  
         R 7 , R 8 , and R 9  are independently selected from the group consisting of hydrogen and alkyl.  
       
     
     
         30 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula VIII in  claim 29  in combination with a pharmaceutically acceptable carrier.  
     
     
         31 . A method for selectively controlling neurotransmitter release in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula VIII in  claim 29 .  
     
     
         32 . A method of treating a disorder wherein the disorder is ameliorated by controlling neurotransmitter release in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula VIII in  claim 29 .  
     
     
         33 . The method according to  claim 31  wherein the disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, depression, nicotinic withdrawal syndrome, Tourette's syndrome, and schizophrenia.  
     
     
         34 . The method according to  claim 31  wherein the disorder is pain.  
     
     
         35 . A method of treating pain in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula VIII in  claim 29  in combination with an opioid and a pharmaceutically acceptable carrier.  
     
     
         36 . A method of treating pain in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula VIII in  claim 29  in combination with a non-steroid antiinflammatory agent and a pharmaceutically acceptable carrier.  
     
     
         37 . A method of treating pain in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula VIII in  claim 29  in combination with a tricyclic antidepressant and a pharmaceutically acceptable carrier.  
     
     
         38 . A method of treating pain in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula VIII in  claim 29  in combination with an anticonvulsant and a pharmaceutically acceptable carrier.