1-aryl-3-azabicyclo[3.1.0]hexanes: preparation and use to treat neuropsychiatric disorders
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 method for treating attention deficit hyperactivity disorder (ADHD) in a human in need thereof comprising administering to the human in need thereof an effective amount of 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 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.
2. A method for treating attention deficit hyperactivity disorder (ADHD) in a mammalian subject in need thereof comprising administering to the mammalian subject in need thereof an effective amount of a pharmaceutical composition comprising 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 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.
3. The method according to claim 1 , wherein the compound is 3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
4. The method according to claim 1 , wherein the compound is (1R,5S)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
5. The method according to claim 1 , wherein the compound is (1S,5R)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
6. The method according to claim 1 , wherein the compound is 3-ethyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
7. The method according to claim 1 , wherein the compound is 3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
8. The method according to claim 1 , wherein the compound is (1R,5S)-3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
9. The method according to claim 1 , wherein the compound is (1S,5R)-3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
10. The method according to claim 1 , wherein the compound is 1-(2-methoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
11. The method according to claim 1 , wherein the compound is 1-(2-methoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
12. The method according to claim 1 , wherein the compound is 1-(2-ethoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
13. The method according to claim 1 , wherein the compound is 1-(2-ethoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
14. The method according to claim 1 , wherein the compound is (1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane hydrochloride.
15. The method according to claim 2 , wherein the compound is 3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
16. The method according to claim 2 , wherein the compound is (1R,5S)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
17. The method according to claim 2 , wherein the compound is (1S,5R)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
18. The method according to claim 2 , wherein the compound is 3-ethyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
19. The method according to claim 2 , wherein the compound is 3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
20. The method according to claim 2 , wherein the compound is (1R,5S)-3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
21. The method according to claim 2 , wherein the compound is (1S,5R)-3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
22. The method according to claim 2 , wherein the compound is 1-(2-methoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
23. The method according to claim 2 , wherein the compound is 1-(2-methoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
24. The method according to claim 2 , wherein the compound is 1-(2-ethoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
25. The method according to claim 2 , wherein the compound is 1-(2-ethoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
26. The method according to claim 2 , wherein the compound is (1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane hydrochloride.