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 of making a 1-aryl-3-azabicyclo[3.1.0]hexane of Formula IV
or a pharmaceutically acceptable salt thereof, wherein Ar is an unsubstituted naphthyl group or a naphthyl group having 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, comprising cyclizing a compound of formula (iii)
wherein Ar is as defined above.
2. The method according to claim 1 further comprising reducing a compound of formula (ii)
formula (ii)
wherein Ar is an unsubstituted naphthyl group or a naphthyl group having 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 2 further comprising reacting a compound of formula (i)
with epichlorohydrin, wherein Ar is an unsubstituted naphthyl group or a naphthyl group having 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.
4. The method according to claim 3 , wherein the epichlorohydrin is S-(+)-epichlorohydrin.
5. The method according to claim 3 , wherein the epichlorohydrin is R-(−)-epichlorohydrin.
6. The method according to claim 1 , wherein the 1-aryl-3-azabicyclo[3.1.0]hexane is (1R,5S)-(+)-1-(2-naphthyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
7. The method according to claim 6 , wherein the pharmaceutically acceptable salt is (1R,5S)-(+)-1-(2-naphthyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
8. The method according to claim 1 , wherein the 1-aryl-3-azabicyclo[3.1.0]hexane is (1S,5R)-(−)-1-(2-naphthyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
9. The method according to claim 8 , wherein the pharmaceutically acceptable salt is (1S,5R)-(−)-1-(2-naphthyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
10. The method according to claim 4 , wherein the 1-aryl-3-azabicyclo[3.1.0]hexane is (1R,5S)-(+)-1-(2-naphthyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
11. The method according to claim 10 , wherein the pharmaceutically acceptable salt is (1R,5S)-(+)-1-(2-naphthyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
12. The method according to claim 5 , wherein the 1-aryl-3-azabicyclo[3.1.0]hexane is (1S,5R)-(−)-1-(2-naphthyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
13. The method according to claim 12 , wherein the pharmaceutically acceptable salt is (1S,5R)-(−)-1-(2-naphthyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
14. A method of making a 1-aryl-3-azabicyclo[3.1.0]hexane of Formula V
or a pharmaceutically acceptable salt thereof, wherein Ar is an unsubstituted naphthyl group or a naphthyl group having 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, and R is hydrogen, methyl, ethyl, isopropyl or a nitrogen protecting group, comprising reducing a compound of formula (ix)
wherein Ar and R are as defined above.
15. The method according to claim 14 further comprising cyclopropanating a compound of formula (viii)
wherein Ar is an unsubstituted naphthyl group or a naphthyl group having 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, and R is hydrogen, methyl, ethyl, isopropyl or a nitrogen protecting group.
16. The method according to claim 15 further comprising reacting a compound of formula (vii)
formula (vii)
wherein R is hydrogen, methyl, ethyl isopropyl or a nitrogen protecting group with
wherein Ar is an unsubstituted naphthyl group or a naphthyl group having 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.
17. The method according to claim 14 further comprising, when R is methyl, ethyl, isopropyl, or a nitrogen protecting group, deprotecting or dealkylating the compound of Formula V to remove the methyl, ethyl, isopropyl, or nitrogen protecting group.
18. The method according to claim 14 , wherein the 1-aryl-3-azabicyclo[3.1.0]hexane is selected from the group consisting of:
1-(6-methoxynaphthalen-2-yl)-3-azabicyclo[3.1.0]hexane;
1-(2-methoxynaphthalen-6-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;
1-(6-ethoxynaphthalen-2-yl)-3-azabicyclo[3.1.0]hexane;
1-(2-ethoxynaphthalen-6-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;
1-(naphthalen-2-yl)-3-ethyl-3-azabicyclo[3.1.0]hexane;
1-(2-naphthyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane; and
1-(4-methylnaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane;
or a pharmaceutically acceptable salt thereof.
19. The method according to claim 17 , wherein the 1-aryl-3-azabicyclo[3.1.0]hexane is 1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
20. The method according to claim 19 , wherein the pharmaceutically acceptable salt is 1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.
21. The method according to claim 6 further comprising isolating (1R,5S)-(+)-1-(2-naphthyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
22. The method according to claim 7 further comprising isolating (1R,5S)-(+)-1-(2-naphthyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
23. The method according to claim 10 further comprising isolating (1R,5S)-(+)-1-(2-naphthyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.
24. The method according to claim 11 further comprising isolating (1R,5S)-(+)-1-(2-naphthyl)-3-azabicyclo[3.1.0]hexane hydrochloride.