Novel 1-Aryl-3-Azabicyclo[3.1.0]Hexanes: Preparation And Use To Treat Neuropsychiatric Disorders

Abstract

The invention provides novel, multiply-substituted 1-aryl-3-azabicyclo[3.1.0]hexanes, and related processes and intermediates for preparing these compounds, as well as compositions and methods employing these compounds for the treatment and/or prevention of central nervous system (CNS) disorders, including depression and anxiety.

1 - 93 . (canceled) 
     
     
         94 . A compound of the following formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  and R 2  are independently selected from hydrogen, unsubstituted C 1-10  alkyl, C 3-10  alkenyl and C 3-10  alkynyl, and substituted C 1-10  alkyl, C 3-10  alkenyl and C 3-10  alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C 1-6  alkoxy, aryl substituted C 1-6  alkoxy, aryloxy, aryloxy substituted with one or more halogens, C 1-6  alkyl, C 1-6  alkyl independently substituted with one or more of cyano and halogen, C 1-4  alkoxy, and C 1-4  haloalkoxy; 
         R 3  is selected from hydrogen, C 1-6  alkoxycarbonyl, C 2-6  alkanoyl, C 3-8  cycloalkyl, C 4-9  cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C 2-10  alkenyl, C 2-10  alkynyl, and substituted C 1-6  alkyl, C 2-10  alkenyl and C 2-10  alkynyl wherein the substituent is one or more of cyano, halogen, hydroxy, C 1-6  alkoxy, C 1-6  alkoxycarbonyl, C 2-6  alkyloxycarbonyloxy, C 1-6  alkanoyl, C 1-6  alkanoyloxy, C 3-8  cycloalkyl, C 3-8  cycloalkyloxy, C 4-9  cycloalkanoyl, aryl, aryloxy, heteroaryl and saturated heterocyclic; and 
         R 4  and R 5  are independently hydrogen or 1-4 substituents independently selected from halogen, C 1-3  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, halo(C 1-3 )alkyl, cyano, hydroxy, C 3-5  cycloalkyl, C 1-3  alkoxy, C 1-3  alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3  alkanoyl, halo(C 1-3 )alkoxy, nitro, amino, C 1-3  alkylamino, and di(C 1-3 )alkylamino. 
       
     
     
         95 . A compound of the following formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  and R 2  are independently selected from hydrogen, unsubstituted C 1-10  alkyl, C 3-10  alkenyl and C 3-10  alkynyl, and substituted C 1-10  alkyl, C 3-10  alkenyl and C 3-10  alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C 1-6  alkoxy, aryl substituted C 1-6  alkoxy, aryloxy, aryloxy substituted with one or more halogens, C 1-6  alkyl, C 1-6  alkyl independently substituted with one or more of cyano and halogen, C 1-4  alkoxy, and C 1-4  haloalkoxy; 
         R 3  is selected from hydrogen, C 1-6  alkyl, C 1-6  alkoxycarbonyl, C 2-6  alkanoyl, C 3-8  cycloalkyl, C 4-9  cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C 2-10  alkenyl, C 2-10  alkynyl, and substituted C 1-6  alkyl, C 2-10  alkenyl and C 2-10  alkynyl wherein the substituent is one or more of cyano, halogen, hydroxy, C 1-6  alkoxy, C 1-6  alkoxycarbonyl, C 2-6  alkyloxycarbonyloxy, C 1-6  alkanoyl, C 1-6  alkanoyloxy, C 3-8  cycloalkyl, C 3-8  cycloalkyloxy, C 4-9  cycloalkanoyl, aryl, aryloxy, heteroaryl and saturated heterocyclic; and 
         R 4  and R 5  are independently hydrogen or 1-4 substituents independently selected from halogen, C 1-3  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, halo(C 1-3 )alkyl, cyano, hydroxy, C 3-5  cycloalkyl, C 1-3  alkoxy, C 1-3  alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3  alkanoyl, halo(C 1-3 )alkoxy, nitro, amino, C 1-3  alkylamino, and di(C 1-3 )alkylamino. 
       
     
     
         96 . The compound according to  claim 95 , wherein R 4  and R 5  are independently hydrogen or 1-4 substituents independently selected from methyl, ethyl, propyl, fluoro, chloro, trifluoromethyl, cyano, nitro, methoxy, ethoxy and trifluoromethoxy. 
     
     
         97 . The compound according to  claim 96 , wherein R 1  and R 2  are hydrogen, R 3  is hydrogen, methyl, ethyl or isopropyl and R 4  and R 5  are independently selected from hydrogen, methyl, chloro, fluoro, propyl, methoxy and ethoxy. 
     
     
         98 . The compound according to  claim 97 , wherein the compound is:
 1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;   3-methyl-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;   1-(1-fluoronaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane;   1-(1-fluoronaphthalen-4-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;   1-(1-methylnaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane; or   3-methyl-1-(1-methylnaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane;   or a pharmaceutically acceptable salt thereof.   
     
     
         99 . The compound according to  claim 98 , wherein the compound is:
 (1R,5S)-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;   (1S,5R)-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;   (1R,5S)-3-methyl-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; or   (1S,5R)-3-methyl-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;   or a pharmaceutically acceptable salt thereof.   
     
     
         100 . A pharmaceutical composition, wherein the pharmaceutical composition comprises a compound or pharmaceutically acceptable salt thereof according to  claim 98  and a pharmaceutically acceptable carrier or vehicle therefor. 
     
     
         101 . A method for treating a central nervous system (CNS) disorder in a mammalian subject in need thereof, wherein the method comprises administering to the mammalian subject an effective amount of a compound or pharmaceutically acceptable salt thereof according to  claim 98 . 
     
     
         102 . The method according to  claim 101 , wherein the CNS disorder is depression. 
     
     
         103 . The method according to  claim 101 , wherein the CNS disorder is an anxiety disorder. 
     
     
         104 . The method according to  claim 101 , wherein the CNS disorder is attention deficit hyperactivity disorder (ADHD).