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 . A compound of the following formula I:  
     
       
         
         
             
             
         
       
     
     and enantiomers and pharmaceutically acceptable salts thereof, wherein: 
 Ar is a phenyl group substituted with two 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;  
 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; and  
 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;  
 with the proviso that when the substituted phenyl group is 3,4-dichlorophenyl, R 3  cannot be hydrogen.  
 
   
   
       2 . The compound according to  claim 1  wherein the phenyl group is substituted with two substituents independently selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, nitro, and trifluoromethoxy.  
   
   
       3 . The compound according to  claim 2  wherein R 1  and R 2  are hydrogen or methyl and R 3  is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or cyclopropyl.  
   
   
       4 . The compound according to  claim 3  selected from the group consisting of: 1-(2,4-difluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 3-ethyl-1-(2,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(2,4-difluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-difluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-difluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-3-ethyl-1-(3,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-3-ethyl-1-(3,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-difluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; 1-(3-chloro-4-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3-chloro-4-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3-chloro-4-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(3-chloro-4-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3-chloro-4-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3-chloro-4-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(3-chloro-4-fluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3-chloro-4-fluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3-chloro-4-fluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; 1-(3-chloro-4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3-chloro-4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3-chloro-4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(4-chloro-3-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(4-chloro-3-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(4-chloro-3-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(4-chloro-3-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(2,4-dichlorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(2,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; 1-(2,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; 1-(4-fluoro-3-methylphenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(4-fluoro-3-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 3-ethyl-1-(4-fluoro-3-methylphenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(4-fluoro-3-methylphenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; 1-(3-fluoro-4-methylphenyl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3-fluoro-4-methylphenyl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3-fluoro-4-methylphenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(3-fluoro-4-methylphenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; 1-(3-fluoro-4-methylphenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; 1-(3-fluoro-4-methoxyphenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; and 1-(3-chloro-4-nitrophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates and prodrugs thereof.  
   
   
       5 . The compound according to  claim 4  which is (1R,5S)-1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof.  
   
   
       6 . The compound according to  claim 4  which is (1S,5R)-1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof.  
   
   
       7 . The compound according to  claim 4  which is 3-ethyl-1-(3,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts and enantiomers thereof.  
   
   
       8 . The compound according to  claim 4  which is 1-(3-chloro-4-fluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts and enantiomers thereof.  
   
   
       9 . The compound according to  claim 4  which is 1-(3-chloro-4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts and enantiomers thereof.  
   
   
       10 . The compound according to  claim 4  which is (1R,5S)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof.  
   
   
       11 . The compound according to  claim 3  selected from the group consisting of: Cis-1-(3,4-dichlorophenyl)-2-methyl-3-aza-bicyclo[3.1.0]hexane; Cis-1-(3,4-dichlorophenyl)-2,3-dimethyl-3-aza-bicyclo[3.1.0]hexane; Trans-1-(3,4-dichlorophenyl)-2-methyl-3-aza-bicyclo[3.1.0]hexane; Trans-1-(3,4-dichlorophenyl)-2,3-dimethyl-3-aza-bicyclo[3.1.0]hexane; Cis-1-(3,4-dichlorophenyl)-4-methyl-3-aza-bicyclo[3.1.0]hexane; Trans-1-(3,4-dichlorophenyl)-4-methyl-3-aza-bicyclo[3.1.0]hexane; Trans-1-(3,4-dichlorophenyl)-3,4-dimethyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3,4-dichlorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3,4-dichlorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-dichlorophenyl)-3-propyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3,4-dichlorophenyl)-3-propyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3,4-dichlorophenyl)-3-propyl-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-dichlorophenyl)-3-cyclopropyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3,4-dichlorophenyl)-3-cyclopropyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3,4-dichlorophenyl)-3-cyclopropyl-3-aza-bicyclo[3.1.0]hexane; 3-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-3-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-3-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-dichlorophenyl)-3-isobutyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3,4-dichlorophenyl)-3-isobutyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3,4-dichlorophenyl)-3-isobutyl-3-aza-bicyclo[3.1.0]hexane; 3-tert-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-3-tert-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane; and (1S,5R)-3-tert-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates and prodrugs thereof.  
   
   
       12 . The compound according to  claim 11  which is (1R,5S)-1-(3,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof.  
   
   
       13 . A compound of the following formula II:  
     
       
         
         
             
             
         
       
     
     and enatiomers and pharmaceutically acceptable salts 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.  
 
   
   
       14 . The compound according to  claim 13  wherein R 4  and R 5  are independently hydrogen or 1-4 substituents independently selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, nitro, methoxy, ethoxy and trifluoromethoxy.  
   
   
       15 . The compound according to  claim 14  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.  
   
   
       16 . The compound according to  claim 15  selected from the group consisting of: 
 1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; 3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; 3-ethyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; 3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; 1-(2-methoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane; 1-(2-methoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(2-ethoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane; and 1-(2-ethoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane, and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates and prodrugs thereof.    
   
   
       17 . The compound according to  claim 16  which is 1-(2-methoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts and enantiomers thereof.  
   
   
       18 . The compound according to  claim 16  which is (1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof.  
   
   
       19 . The compound according to  claim 16  which is (1S,5R)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof.  
   
   
       20 . The compound according to  claim 16  which is (1R,5S)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof.  
   
   
       21 . The compound according to  claim 16  which is (1S,5R)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof.  
   
   
       22 . The compound according to  claim 16  which is 3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts and enantiomers thereof.  
   
   
       23 . The compound according to  claim 16  which is 3-ethyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts and enantiomers thereof.  
   
   
       24 . A compound of the following formula III:  
     
       
         
         
             
             
         
       
     
     and enatiomers and pharmaceutically acceptable salts 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.  
 
   
   
       25 . The compound according to  claim 24  wherein R 4  and R 5  are independently hydrogen or 1-4 substituents independently selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, nitro, methoxy, ethoxy and trifluoromethoxy.  
   
   
       26 . The compound according to  claim 25  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.  
   
   
       27 . The compound according to  claim 26  selected from the group consisting of: 1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; (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; 3-methyl-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; (1S,5R)-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; and 3-methyl-1-(1-methylnaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane, and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates and prodrugs thereof.  
   
   
       28 - 93 . (canceled)