Methods and compositions for production, formulation and use of 1-aryl-3-azabicyclo[3.1.0]hexanes

A method for making a (1R, 5S) enantiomer of a 1-aryl-3-azabicyclo[3.1.0]hexane of the following formula 1 ml

• wherein R1 is halogen, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo(C1-3)alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxy, amino, C1-3 alkylamino, di(C1-3)alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, nitro, phenyl or trifluoromethoxy and R is hydrogen, and pharmaceutically acceptable salts thereof, comprising the steps of:
• (a) reacting a compound of the following formula (i),
• with (S)-(+)-epichlorohydrin to produce a compound of the following formula (ii),
• formula (iii),
• and formula (Iv),
• (b) reducing the compounds produced in step (a) to produce a compound of the following formula (v),
• (c) causing cyclization of the compound of formula (v) to produce the (1R, 5S) enantiomer of the compound of Formula III;
• and
• (d) optionally converting the (1R, 5S) enantiomer of the compound of Formula III to a pharmaceutically acceptable salt.

A method for making a (1S, 5R) enantiomer of a 1-aryl-3-azabicyclo[3.1.0]hexane of the following formula III

• wherein R1 is halogen, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo(C1-3)alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxy, amino, C1-3 alkylamino, di(C1-3)alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, nitro, phenyl or trifluoromethoxy and R is hydrogen, and pharmaceutically acceptable salts thereof, comprising the steps of:
• (a) reacting a compound of the following formula (i),
• with (R)-(−)-epichlorohydrin to produce a compound of the following formula (vi),
• formula (vii),
• and formula (viii),
• (b) reducing the compounds produced in step (a) to produce a compound of the following formula (ix),
• (c) causing cyclization of the compound of formula (ix) to produce the (1S, 5R) enantiomer of the compound of Formula III;
• and
• (d) optionally converting the (1S, 5R) enantiomer of the compound of Formula III to a pharmaceutically acceptable salt.

A method for making (1R,5S)-(+)-1-p-tolyl-3-azabicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof, comprising the steps of:

• (a) reacting 1-p-tolylacetonitrile with S-(+)-epichlorohydrin to produce (1R,2S)-2-(hydroxymethyl)-1-p-tolylcyclopropanecarbonitrile;
• (b) reducing the (1R, 2S)-2-(hydroxymethyl)-1-p-tolylcyclopropanecarbonitrile to produce ((1S, 2R)-2-(aminomethyl)-2-p-tolylcyclopropyl)methanol;
• (c) causing cyclization of the ((1S, 2R)-2-(aminomethyl)-2-p-tolylcyclopropyl)methanol to produce (1R, 5S)-(+)-1-p-tolyl-3-azabicyclo[3.1.0]hexane;
• and
• (d) optionally converting the (1R, 5S)-(+)-1-p-tolyl-3-azabicyclo[3.1.0]hexane into a pharmaceutically acceptable salt.

A method for making (1S, 5R)-(−)-1-p-tolyl-3-azabicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof, comprising the steps of:

• (a) reacting 1-p-tolylacetonitrile with R-(−)-epichlorohydrin to produce (1S, 2R)-2-hydroxymethyl-1-p-tolyl-cyclopropancarbonitrile;
• (b) reducing the (1S, 2R)-2-hydroxymethyl-1-p-tolyl-cyclopropancarbonitrile to produce ((1R,2S)-2-(aminomethyl)-2-p-tolylcyclopropyl)methanol;
• (c) causing cyclization of the ((1R,2S)-2-(aminomethyl)-2-p-tolylcyclopropyl)methanol to produce (1S, 5R)-(−)-1-p-Tolyl-3-azabicyclo[3.1.0]hexane;
• and
• (d) optionally converting the (1S, 5R)-(−)-1-p-tolyl-3-azabicyclo[3.1.0]hexane into a pharmaceutically acceptable salt.

A method for making a 1-aryl-3-azabicyclo[3.1.0]hexane of the following formula II,

• wherein R is hydrogen, C1-6 alkyl, halo(C1-6)alkyl, C3-9 cycloalkyl, C1-5 alkoxy(C1-6)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, carbamate, halo(C1-3)alkoxy(C1-6)alkyl, C1-3 alkylamino(C1-6)alkyl, di(C1-3)alkylamino(C1-6)alkyl, cyano(C1-6)alkyl, methyl, ethyl, trifluoromethyl, trifluoroethyl or 2-methoxyethyl and Ar is a monosubstituted phenyl group of the following formula (x),
• wherein R1 is halogen, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo(C1-3)alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxy, amino, C1-3 alkylamino, di(C1-3)alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, nitro, phenyl or trifluoromethoxy, and enantiomers, diastereomers and pharmaceutically acceptable salts thereof, comprising the steps of:
• (a) coupling a compound of the following formula (xi),
• wherein R is as defined above or a nitrogen protecting group, with a compound of the following formula (xii), ArB(OH)2, wherein Ar is as defined above, to produce a compound of the following formula (xiii),
• (b) causing cyclopropanation of the compound of formula (xiii) to produce a compound of the following formula (xiv),
• wherein Ar is as defined above and R is as defined above or a nitrogen protecting group;
• (c) reducing the compound of formula (xiv) to produce a compound of the following formula (xv),
• wherein Ar is as defined above and R is as defined above or a nitrogen protecting group;
• (d) deprotecting the compound of formula (xv) when R is a nitrogen protecting group to produce the 1-aryl-3-azabicyclo[3.1.0]hexane;
• and
• (e) optionally converting the 1-aryl-3-azabicyclo[3.1.0]hexane to a pharmaceutically acceptable salt.

A method for making a 1-aryl-3-azabicyclo[3.1.0]hexane of the following formula III

• wherein R1 is halogen, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo(C1-3)alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxy, amino, C1-3 alkylamino, di(C1-3)alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, nitro, phenyl or trifluoromethoxy and R is hydrogen, and enantiomers, diastereomers and pharmaceutically acceptable salts thereof, comprising the steps of:
• (a) reacting a compound of the following formula (xvii),
• wherein R1 is as defined above, Me is methyl and X is chlorine or bromine, with acrylonitrile to produce a compound of the following formula (xviii),
• (b) reducing the compound of the formula (xviii) to produce a compound of the following formula (xix),
• (c) causing cyclization of the amino alcohol of the compound of formula (xix) to produce the compound of Formula III;
• and
• (d) optionally converting the compound of Formula III to a pharmaceutically acceptable salt.

A method for making a 1-aryl-3-azabicyclo[3.1.0]hexane of the following formula III

• wherein R1 is halogen, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo(C1-3)alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxy, amino, C1-3 alkylamino, di(C1-3)alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, nitro, phenyl or trifluoromethoxy and R is hydrogen, and enantiomers, diastereomers and pharmaceutically acceptable salts thereof, comprising the steps of:
• (a) reacting a compound of the following formula (xvii),
• wherein R1 is as defined above, Me is methyl and X is chlorine or bromine, with acrylonitrile to produce a compound of the following formula (xviii),
• (b) hydrolyzing the compound of the formula (xviii) to produce a compound of the following formula (xx),
• (c) acidifying the compound of the formula (xx) to produce a compound of the following formula (xxi),
• (d) either reducing and then causing cyclization of the compound of formula (xxi) or hydrogenating, then causing cyclization of and then reducing the compound of formula (xxi) to produce the the compound of Formula III;
• and
• (e) optionally converting the compound of Formula III to a pharmaceutically acceptable salt.

A method for making a 1-aryl-3-azabicyclo[3.1.0]hexane of the following formula III

• wherein R1 is halogen, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo(C1-3)alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxy, nitro, amino, C1-3 alkylamino, di(C1-3)alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, phenyl or trifluoromethoxy and R is hydrogen, and enantiomers, diastereomers and pharmaceutically acceptable salts thereof, comprising the steps of:
• (a) hydrogenating and then causing cyclization of a compound of the following formula (xviii),
• wherein R1 is as defined above and Me is methyl, to produce a compound of the following formula (xxii),
• (b) reducing the compound of the formula (xxii) to produce the compound of Formula III;
• and
• (c) optionally converting the compound of Formula III to a pharmaceutically acceptable salt.

A method for making a 1-aryl-3-azabicyclo[3.1.0]hexane of the following formula III

• wherein R1 is halogen, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo(C1-3)alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxy, nitro, amino, C1-3 alkylamino, di(C1-3)alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, phenyl or trifluoromethoxy and R is hydrogen, and enantiomers, diastereomers and pharmaceutically acceptable salts thereof, comprising the steps of:
• (a) reacting a compound of the following formula (xi),
• wherein R1 is as defined above, with epichlorohydrin to produce a compound having the following formula (xii),
• (b) oxidizing the compound of the formula (xii) to produce a compound of the following formula (xxiii),
• (c) hydrogenating and causing cyclization of the compound of the formula (xxiii) to produce a compound having the following formula (xxiv),
• (d) reducing the compound of the formula (xxiv) to produce the compound of Formula III;
• and
• (e) optionally converting the the compound of Formula III to a pharmaceutically acceptable salt.

A method for making a 1-aryl-3-azabicyclo[3.1.0]hexane of the following formula III

• wherein R1 is halogen, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo(C1-3)alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxy, nitro, amino, C1-3 alkylamino, di(C1-3)alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, phenyl or trifluoromethoxy and R is hydrogen, and enantiomers, diastereomers and pharmaceutically acceptable salts thereof comprising the steps of:
• (a) reacting a compound of the following formula (xxv),
• wherein R1 is as defined above and Me is methyl, with epichlorohydrin to produce a compound of the following formula (xxvi),
• (b) converting the compound of the formula (xxvi) to a compound of the following formula (xxvii),
• wherein R3 is selected from the group consisting of mesylate, tosylate, nosylate, brosylate and trifluoromethanesulfonate;
• (c) replacing the OR3 group of the compound of formula (xxvii) with a primary amine having the formula NH2R4, wherein R4 is a nitrogen protecting group, followed by cyclization of the resulting compound to produce a compound of the following formula (xxviii),
• (d) reducing the compound of the formula (xxviii) to produce a compound of the following formula (xxix),
• (e) deprotecting the compound of formula (xxix) to produce the compound of Formula III;
• and
• (f) optionally converting the compound of Formula III to a pharmaceutically acceptable salt.

A method for making a 1-aryl-3-azabicyclo[3.1.0]hexane of the following formula III

• wherein R1 is halogen, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo(C1-3)alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxy, nitro, amino, C1-3 alkylamino, di(C1-3)alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, phenyl or trifluoromethoxy and R is hydrogen, and enantiomers, diastereomers and pharmaceutically acceptable salts thereof, comprising the steps of:
• (a) reacting a compound of the following formula (xvii),
• wherein R1 is as defined above, X is either chlorine or bromine and Me is methyl, with
• to produce a compound of the following formula (xxx),
• (b) reducing the compound of the formula (xxx) to produce a compound of the following formula (xxxi),
• (c) converting the compound of the formula (xxxi) to a compound of the following formula (xxxii),
• wherein R3 is selected from the group consisting of mesylate, tosylate, nosylate, brosylate and trifluoromethanesulfonate;
• and
• (d) replacing the OR3 groups of the compound of formula (xxxii) with primary amines having the formula NH2R6, wherein R6 is a nitrogen protecting group, followed by cyclization of the resulting compound to produce a compound of the following formula (xxxiii),
• (e) deprotecting the compound of formula (xxxiii) to produce the compound of Formula III;
• and
• (f) optionally converting the compound of Formula III to a pharmaceutically acceptable salt.

A method for resolving a 1-aryl-3-aza-bicyclo[3.1.0]hexane of the following formula III

• wherein R1 is halogen, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo(C1-3)alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxy, nitro, amino, C1-3 alkylamino, di(C1-3)alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, phenyl or trifluoromethoxy and R is hydrogen, C1-6 alkyl, halo(C1-6)alkyl, C3-9 cycloalkyl, C1-5 alkoxy(C1-6)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, carbamate, halo(C1-3)alkoxy(C1-6)alkyl, C1-3 alkylamino(C1-6)alkyl, di(C1-3)alkylamino(C1-6)alkyl, cyano(C1-6)alkyl, methyl, ethyl, trifluoromethyl, trifluoroethyl or 2-methoxyethyl to a (+)- or (−)-enantiomer of the compound of Formula III, and pharmaceutically acceptable salts thereof, comprising the following steps:
• (a) reacting the compound of Formula III with either a (+) or (−) enantiomer of tartaric acid to produce a tartrate salt of the compound of Formula III;
• (b) crystallizing the tartrate salt of the compound of Formula III produced in step (a);
• (c) reacting the tartrate salt of the compound of Formula III produced in step (b) with a base to produce a free base of the (+) or (−) enantiomer of the compound of Formula III;
• and
• (d) optionally converting the free base of the (+) or (−) enantiomer of the compound of Formula III to a pharmaceutically acceptable salt.

A method for making a 1-aryl-3-azabicyclo[3.1.0]hexane of the following Formula III

• wherein R1 is halogen, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo(C1-3)alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxy, nitro, amino, C1-3 alkylamino, di(C1-3)alkylamino, methyl, ethyl, fluoro, chloro, trifluoromethyl, phenyl or trifluoromethoxy and R is hydrogen, and enantiomers, diastereomers and pharmaceutically acceptable salts thereof, comprising the steps of:
• (a) reacting a compound of the following formula (xi),
• wherein R1 is as defined above, with
• epichlorohydrin to produce a compound of the following formula (xii),
• (b) reducing the compound of the formula (xii) to produce a compound of the following formula (xiii),
• (c) reacting the compound of the formula (xiii) with (Boc)2O to produce a compound of the following formula (xiv),
• (d) causing cyclization of the compound of the formula (xiv) to produce a compound of the following formula (xv),
• (e) deprotecting the compound of the formula (xv) to produce the compound of the following formula (xvi),
• (f) reducing the compound of the formula (xvi) to produce the compound of Formula III;
• and
• (g) optionally converting the compound of Formula III to a pharmaceutically acceptable salt.

A compound selected from the group consisting of:

• (1R,5S)-3-methyl-1-p-tolyl-3-aza-bicyclo[3.1.0]hexane;
• (1S,5R)-3-methyl-1-p-tolyl-3-aza-bicyclo[3.1.0]hexane;
• (1R,5 S)-3-ethyl-1-p-tolyl-3-aza-bicyclo[3.1.0]hexane;
• (1S,5R)-3-ethyl-1-p-tolyl-3-aza-bicyclo[3.1.0]hexane;
• 3-propyl-1-p-tolyl-3-aza-bicyclo[3.1.0]hexane;
• 3-isopropyl-1-p-tolyl-3-aza-bicyclo[3.1.0]hexane;
• (1R,5S)-3-isopropyl-1-p-tolyl-3-aza-bicyclo[3.1.0]hexane;
• (1S,5R)-3-isopropyl-1-p-tolyl-3-aza-bicyclo[3.1.0]hexane;
• 3-isobutyl-1-p-tolyl-3-aza-bicyclo[3.1.0]hexane;
• 3-(2-methoxyethyl)-1-p-tolyl-3-aza-bicyclo[3.1.0]hexane;
• 3-(2,2,2-trifluoroethyl)-1-p-tolyl-3-aza-bicyclo[3.1.0]hexane;
• 1-(4-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;
• 3-ethyl-1-(4-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane;
• 1-(4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane;
• 1-(4-(trifluoromethyl)phenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;
• 3-ethyl-1-(4-(trifluoromethyl)phenyl)-3-aza-bicyclo[3.1.0]hexane;
• 1-(4-(trifluoromethyl)phenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane;
• (1R,5S)-1-(4-(trifluoromethyl)phenyl)-3-aza-bicyclo[3.1.0]hexane;
• (1S,5R)-1-(4-(trifluoromethyl)phenyl)-3-aza-bicyclo[3.1.0]hexane;
• (1R,5S)-1-(4-(trifluoromethyl)phenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;
• (1S,5R)-1-(4-(trifluoromethyl)phenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane, and active salts, enantiomers, polymorphs, solvates, hydrates and prodrugs thereof.