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US 2008/0269348 A1Published application
Novel Arylbicyclo[3.1.0]Hexylamines And Methods And Compositions For Their Preparation And Use
OwnerPhil Skolnick, Zhengming Cheninventors
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Abstract
The invention provides novel arylbicyclo[3.1.0]hexylamines, 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 but not limited to depression and anxiety.
Claims34
A compound of the following formula I:
- and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, prodrugs, and combinations thereof, wherein:
- Ar is a phenyl, a naphthyl or an aryl heterocycle group which is unsubstituted or substituted with one or more substituents selected from fluoro, chloro, bromo, iodo, —NO2, —CN, —NH2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halo(C1-8)alkyl, hydroxy, trifluoromethyl, C3-8 cycloalkyl, C1-3 alkoxyl, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxyl, C1-8 alkylamino, and di(C1-8)alkylamino;
- and
- R1, R2, R3, R4 and R5 are independently hydrogen or
- wherein R6 and R7 are independently selected from hydrogen, unsubstituted C1-10 alkyl, C3-8 cycloalkyl, C2-10 alkenyl, and C3-10 alkynyl, and substituted C1-10 alkyl, C3-10 alkenyl and C3-10 alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C1-6 alkoxy, aryl substituted C1-6 alkoxy, aryloxy, aryloxy substituted with one or more halogens, C1-6 alkyl, C1-6 alkyl independently substituted with one or more of cyano and halogen, C1-4 alkoxy, and C1-4 haloalkoxy;
- with the proviso that only one of R1, R2, R3, R4 and R5 is and must be
3 more elements
A neurobiologically active composition effective to inhibit cellular uptake of one or more biogenic amine neurotransmitter(s) selected from norepinephrine, serotonin, and dopamine in a mammalian subject comprising a compound, or a pharmaceutically acceptable salt, enantiomer, polymorph, solvate, hydrate, prodrug, or combination thereof, selected from the group consisting of:
- 1-p-tolylbicyclo[3.1.0]hexan-2-amine;
- N-methyl-1-p-tolylbicyclo[3.1.0]hexan-2-amine;
- N,N-dimethyl-1-p-tolylbicyclo[3.1.0]hexan-2-amine;
- 1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-2-amine;
- 1-(3,4-dichlorophenyl)-N-methylbicyclo[3.1.0]hexan-2-amine;
- 1-(3,4-dichlorophenyl)-N,N-dimethylbicyclo[3.1.0]hexan-2-amine;
- 1-p-tolylbicyclo[3.1.0]hexan-3-amine;
- N-methyl-1-p-tolylbicyclo[3.1.0]hexan-3-amine;
- N,N-dimethyl-1-p-tolylbicyclo[3.1.0]hexan-3-amine;
- 1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-amine;
- 1-(3,4-dichlorophenyl)-N-methylbicyclo[3.1.0]hexan-3-amine;
- 1-(3,4-dichlorophenyl)-N,N-dimethylbicyclo[3.1.0]hexan-3-amine;
- 5-p-tolylbicyclo[3.1.0]hexan-2-amine;
- N-methyl-5-p-tolylbicyclo[3.1.0]hexan-2-amine;
- N,N-dimethyl-5-p-tolylbicyclo[3.1.0]hexan-2-amine;
- 5-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-2-amine;
- 5-(3,4-dichlorophenyl)-N-methylbicyclo[3.1.0]hexan-2-amine;
- and 5-(3,4-dichlorophenyl)-N,N-dimethylbicyclo[3.1.0]hexan-2-amine, and a pharmaceutically acceptable carrier or excipient.
15 more elements
A neurobiologically active composition effective to inhibit cellular uptake of one or more biogenic amine neurotransmitter(s) selected from norepinephrine, serotonin, and dopamine in a mammalian subject comprising a compound, or a pharmaceutically acceptable salt, enantiomer, polymorph, solvate, hydrate, prodrug, or combination thereof, selected from the group consisting of:
- N-methyl-1-(naphthalen-1-yl)bicyclo[3.1.0]hexan-3-amine;
- N,N-dimethyl-1-(naphthalen-1-yl)bicyclo[3.1.0]hexan-3-amine;
- N-methyl-1-(naphthalen-2-yl)bicyclo[3.1.0]hexan-3-amine;
- N-methyl-5-(naphthalen-1-yl)bicyclo[3.1.0]hexan-2-amine;
- N,N-dimethyl-5-(naphthalen-1-yl)bicyclo[3.1.0]hexan-2-amine;
- N-methyl-5-(naphthalen-2-yl)bicyclo[3.1.0]hexan-2-amine;
- and N,N-dimethyl-5-(naphthalen-2-yl)bicyclo[3.1.0]hexan-2-amine, and a pharmaceutically acceptable carrier or excipient.
4 more elements
A method of making an arylbicyclo[3.1.0]hexylamine of the following formula II,
- wherein Ar is a phenyl, a naphthyl or an aryl heterocycle group which is unsubstituted or substituted with one or more substituents selected from fluoro, chloro, bromo, iodo, —NO2, —CN, —NH2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halo(C1-8)alkyl, hydroxy, trifluoromethyl, C3-8 cycloalkyl, C1-3 alkoxyl, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxyl, C1-8 alkylamino, and di(C1-8)alkylamino, and
- R1 and R2 are independently selected from hydrogen, unsubstituted C1-10 alkyl, C3-8 cycloalkyl, C1-10 alkenyl, and C3-10 alkynyl, and substituted C1-10 alkyl, C3-10 alkenyl and C3-10 alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C1-6 alkoxy, aryl substituted C1-6 alkoxy, aryloxy, aryloxy substituted with one or more halogens, C1-6 alkyl, C1-6 alkyl independently substituted with one or more of cyano and halogen, C1-4 alkoxy, and C1-4 haloalkoxy, comprising the steps of:
- (a) coupling a compound of the following formula (i), Ar—I, wherein Ar is defined as above, with propargyl alcohol to produce a compound of the following formula (ii),
- (b) oxidizing the compound of formula (ii) to produce a compound of the following formula (iii),
- (c) reacting the compound of formula (iii) with
- to produce a compound of the following formula (iv),
- (d) causing acylation followed by cyclization and deprotection of the compound of formula (iv) to produce a compound of the following formula (v),
- (e) causing reductive amination of the compound of formula (v) by reacting the compound of formula (v) with NHR1R2, wherein R1 and R9 are defined as above, to produce the arylbicyclo[3.1.0]hexylamine.
5 more elements
A method of making an arylbicyclo[3.1.0]hexylamine of the following formula III,
- wherein Ar is a phenyl, a naphthyl or an aryl heterocycle group which is unsubstituted or substituted with one or more substituents selected from fluoro, chloro, bromo, iodo, —NO2, —CN, —NH2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halo(C1-8)alkyl, hydroxy, trifluoromethyl, C3-8 cycloalkyl, C1-3 alkoxyl, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxyl, C1-8 alkylamino, and di(C1-8)alkylamino, and
- R1 and R2 are independently selected from hydrogen, unsubstituted C1-10 alkyl, C3-8 cycloalkyl, C2-10 alkenyl, and C3-10 alkynyl, and substituted C1-10 alkyl, C3-10 alkenyl and C3-10 alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C1-6 alkoxy, aryl substituted C1-6 alkoxy, aryloxy, aryloxy substituted with one or more halogens, C1-6 alkyl, C1-6 alkyl independently substituted with one or more of cyano and halogen, C1-4 alkoxy, and C1-4 haloalkoxy, comprising the steps of:
- (a) coupling a compound of the following formula (I), Ar-1, wherein Ar is defined as above, with propargyl alcohol to produce a compound of the following formula (ii),
- (b) oxidizing the compound of formula (ii) to produce a compound of the following formula (iii),
- (c) reacting the compound of formula (iii) with
- to produce a compound of the following formula (iv),
- (d) causing cyclization of the compound of formula (iv) to produce a compound of the following formula (vi),
- (e) causing reductive amination of the compound of formula (vi) by reacting the compound of formula (vi) with NHR1R2, wherein R1 and R2 are defined as above, to produce the arylbicyclo[3.1.0]hexylamine.
5 more elements
A method of making an arylbicyclo[3.1.0]hexylamine of the following formula IV,
- wherein Ar is a phenyl, a naphthyl or an aryl heterocycle group which is unsubstituted or substituted with one or more substituents selected from fluoro, chloro, bromo, iodo, —NO2, —CN, —NH2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halo(C1-8)alkyl, hydroxy, trifluoromethyl, C3-8 cycloalkyl, C1-3 alkoxyl, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxyl, C1-8 alkylamino, and di(C1-8)alkylamino, and
- R1 and R2 are independently selected from hydrogen, unsubstituted C1-10 alkyl, C3-8 cycloalkyl, C2-10 alkenyl, and C3-10 alkynyl, and substituted C1-10 alkyl, C3-10 alkenyl and C3-10 alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C1-6 alkoxy, aryl substituted C1-6 alkoxy, aryloxy, aryloxy substituted with one or more halogens, C1-6 alkyl, C1-6 alkyl independently substituted with one or more of cyano and halogen, C1-4 alkoxy, and C1-4 haloalkoxy, comprising the steps of:
- (a) coupling a compound of the following formula (i), Ar—X, wherein Ar is defined as above and X is Br or I, with 3-methoxy-2-cyclopenten-1-one to produce a compound of the following formula (vii),
- (b) reducing the compound of formula (vii) to produce a compound of the following formula (viii),
- (c) causing cyclopropanation of the compound of formula (viii) to produce a compound of the following formula (ix),
- (d) oxidizing the compound of formula (ix) to produce a compound of the following formula (x),
- (e) causing reductive amination of the compound of formula (vi) by reacting the compound of formula (x) with NHR1R2, wherein R1 and R2 are defined as above, to produce the arylbicyclo[3.1.0]hexylamine.
4 more elements
A method of making an arylbicyclo[3.1.0]hexylamine of the following formula III,
- wherein Ar is a phenyl, a naphthyl or an aryl heterocycle group which is unsubstituted or substituted with one or more substituents selected from fluoro, chloro, bromo, iodo, —NO2, —CN, —NH2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halo(C1-8)alkyl, hydroxy, trifluoromethyl, C3-9 cycloalkyl, C1-3 alkoxyl, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxyl, C1-8 alkylamino, and di(C1-8)alkylamino, and
- R1 and R2 are independently selected from hydrogen, unsubstituted C1-10 alkyl, C3-8 cycloalkyl, C2-10 alkenyl, and C3-10 alkynyl, and substituted C1-10 alkyl, C3-10 alkenyl and C3-10 alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C1-6 alkoxy, aryl substituted C1-6 alkoxy, aryloxy, aryloxy substituted with one or more halogens, C1-6 alkyl, C1-6 alkyl independently substituted with one or more of cyano and halogen, C1-4 alkoxy, and C1-4 haloalkoxy, comprising the steps of:
- (a) reacting a compound of the following formula (xi),
- wherein Ar is defined as above, with epichlohydrin or an enantiomer thereof, to produce a compound of the following formula (xii),
- or an enantiomer or diastereomer thereof, or a compound of the following formula (xiii),
- (b) hydrolyzing and causing cyclization of the compound of formula (xii), or an enantiomer or diastereomer thereof, or the compound of formula (xiii) to produce a compound of the following formula (xiv),
- (c) reducing the compound of formula (xiv) to produce a compound of the following formula (xv),
- (d) brominating the compound of formula (xv) to produce a compound of the following formula (xvi),
- (e) reacting the compound of formula (xvi) with K9Fe(CO)4 to produce a compound of the following formula (vi),
- (f) causing reductive amination of the compound of formula (vi) by reacting the compound of formula (vi) with NHR1R2, wherein R1 and R2 are defined as above, to produce the arylbicyclo[3.1.0]hexylamine.
7 more elements
Dependencies are inferred from the claim text.