METHODS AND COMPOSITIONS FOR PRODUCTION, FORMULATION AND USE OF 1 ARYL-3-AZABICYCLO[3.1.0]HEXANES
The invention provides novel compositions and methods of making (−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and other 1-aryl-3-azabicyclo[3.1.0]hexanes, including synthetic methods that form novel intermediate compounds of the invention for producing)-(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and other 1-aryl-3-azabicyclo[3.1.0]hexanes and pharmaceutically acceptable salts thereof.
1 . A method for making (1S,5R)-(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane comprising:
(a) reacting a compound of the following formula (i),
with (R)-(−)-epichlorohydrin to produce a compound of the following formula (ii),
(b) reducing the compound of the formula (ii) to produce a compound of the following formula (iii),
(c) causing cyclization of the compound of formula (iii) to produce (1S,5R)-(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
2 . The method according to claim 1 further comprising:
(d) converting the (1S,5R)-(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane to a pharmaceutically acceptable salt.
3 . The method according to claim 1 wherein in step (b) the compound of formula (ii) is reduced using lithium aluminum hydride, sodium aluminum hydride, NaBH 4 with ZnCl 2 or catalytic hydrogenation.
4 . The method according to claim 1 wherein in step (b) the compound of formula (ii) is reduced using lithium aluminum hydride.
5 . The method according to claim 1 wherein in step (c) the cyclization of the compound of formula (iii) is performed using SOCl 2 or POCl 3 .
6 . The method according to claim 1 wherein in step (c) the cyclization of the compound of formula (iii) is performed using SOCl 2 .
7 . The method according to claim 2 wherein the pharmaceutically acceptable salt is the hydrochloride salt.
8 . A compound selected from the group consisting of compounds having the following formulas:
9 . A compound selected from the group consisting of compounds having the following formulas and pharmaceutically acceptable salts thereof:
10 . A method for making (1S,5R)-(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane comprising:
(a) reacting a compound of the following formula (i),
with
(R)-(−)-epichlorohydrin to produce a compound of the following formula (ii),
(b) reducing the compound of the formula (ii) to produce a compound of the following formula (iii)
(c) reacting the compound of the formula (iii) with (Boc) 2 O to produce a compound of the following formula (iv),
(d) deprotecting and causing cyclization of the compound of the formula (iv) to produce a compound of the following formula (v)
(e) reducing the compound of the formula (v) to produce (1S,5R)-(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
11 . The method according to claim 10 further comprising:
(f) converting the (1S,5R)-(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane to a pharmaceutically acceptable salt.
12 . The method according to claim 10 wherein in step (b) the compound of formula (ii) is reduced using lithium aluminum hydride, sodium aluminum hydride, NaBH 4 with ZnCl 2 or catalytic hydrogenation.
13 . The method according to claim 10 wherein in step (b) the compound of formula (ii) is reduced using lithium aluminum hydride.
14 . The method according to claim 10 wherein in step (d) the cyclization is performed using TFA.
15 . The method according to claim 10 wherein in step (e) the compound of formula (v) is reduced using lithium aluminum hydride, sodium aluminum hydride, NaBH 4 with ZnCl 2 or catalytic hydrogenation.
16 . The method according to claim 11 wherein the pharmaceutically acceptable salt is the hydrochloride salt.
17 . A compound having the formula:
18 . A compound having the formula:
19 . A method of making a 1-aryl-3-azabicyclo[3.1.0]hexane of the following formula I,
wherein Ar is a phenyl or napthyl group which is either unsubstituted or substituted with one or more 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 the steps of:
(a) reacting a compound of the following formula v(i),
wherein Ar is defined as above, with epichlohydrin or an enantiomer thereof, to produce a compound of the following formula (vii),
or an enantiomer or diastereomer thereof;
(b) oxidizing the compound of formula (vii) to produce a compound of the following formula (viii),
or an enantiomer or diastereomer thereof;
(c) causing esteration of the compound of formula (viii) to produce a compound of the following formula (ix),
or an enantiomer or diastereomer thereof; and
(d) reducing the compound of formula (ix) to produce the 1-aryl-3-azabicyclo[3.1.0]hexane, or an enantiomer or diastereomer thereof.
20 . The method according to claim 19 further comprising:
(e) converting the 1-aryl-3-azabicyclo[3.1.0]hexane, or an enantiomer or diastereomer thereof, to a pharmaceutically acceptable salt.
21 . The method according to claim 19 wherein the epichlorohydrin or enantiomer thereof is S-(+)-epichlorohydrin and the 1-aryl-3-azabicyclo[3.1.0]hexane, or the enantiomer or diastereomer thereof, is (1R,5S)-(+)-1-aryl-3-azabicyclo[3.1.0]hexane.
22 . The method according to claim 19 wherein the epichlorohydrin or enantiomer thereof is R-(−)-epichlorohydrin and the 1-aryl-3-azabicyclo[3.1.0]hexane, or the enantiomer or diastereomer thereof, is (1S,5R)-(−)-1-aryl-3-azabicyclo[3.1.0]hexane.
23 . The method according to claim 19 wherein Ar is 3,4-dichlorophenyl and the 1-aryl-3-azabicyclo[3.1.0]hexane, or the enantiomer or diastereomer thereof, is 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, or an enantiomer or diastereomer thereof.
24 . The method according to claim 23 wherein the epichlorohydrin or enantiomer thereof is R-(−)-epichlorohydrin and the 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, or the enantiomer or diastereomer thereof, is (1S,5R)-(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
25 . The method according to claim 19 wherein the epichlorohydrin or enantiomer thereof is S-(+)-epichlorohydrin and the 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, or the enantiomer or diastereomer thereof, is (1R,5S)-(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
26 . A method of making 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane comprising:
(a) reacting a compound of the following formula (i),
with epichlohydrin or an enantiomer thereof, to produce a compound of the following formula (x),
or an enantiomer or diastereomer thereof;
(b) oxidizing the compound of formula (x) to produce a compound of the following formula (xi),
or an enantiomer or diastereomer thereof;
(c) causing esteration of the compound of formula (xi) to produce a compound of the following formula (xii),
or an enantiomer or diastereomer thereof;
(d) reducing the compound of formula (xii) in the presence of a Raney nickel catalyst to produce a compound of the following formula (xiii),
or an enantiomer or diastereomer thereof; and
(e) reducing the compound of formula (xiii) to produce the 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, or an enantiomer or diastereomer thereof.
27 . The method according to claim 26 further comprising:
(e) converting the 1-aryl-3-azabicyclo[3.1.0]hexane, or an enantiomer or diastereomer thereof, to a pharmaceutically acceptable salt.
28 . The method according to claim 26 wherein the epichlorohydrin or enantiomer thereof is R-(−)-epichlorohydrin and the 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, or the enantiomer or diastereomer thereof, is (1S,5R)-(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
29 . The method according to claim 26 wherein the epichlorohydiin or enantiomer thereof is S-(+)-epichlorohydrin and the 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, or the enantiomer or diastereomer thereof, is (1R,5S)-(−)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
30 . A compound selected from the group consisting of compounds having the following formulas and pharmaceutically acceptable salts thereof:
wherein R 1 and R 2 are independently selected from hydrogen, halogen, C 1-3 alkyl, C 2-4 alkenyl, C 1-4 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.