Novel Arylbicyclo[3.1.0]Hexylamines And Methods And Compositions For Their Preparation And Use
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.
1 . 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, —NO 2 , —CN, —NH 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo(C 1-8 )alkyl, hydroxy, trifluoromethyl, C 3-8 cycloalkyl, C 1-3 alkoxyl, C 1-3 alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3 alkanoyl, halo(C 1-3 )alkoxyl, C 1-8 alkylamino, and di(C 1-8 )alkylamino; and
R 1 , R 2 , R 3 , R 4 and R 5 are independently hydrogen or
wherein R 6 and R 7 are independently selected from hydrogen, unsubstituted C 1-10 alkyl, C 3-8 cycloalkyl, C 2-10 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;
with the proviso that only one of R 1 , R 2 , R 3 , R 4 and R 5 is and must be
2 . The compound according to claim 1 wherein Ar is 4-methylphenyl or 3,4-dichlorophenyl, R 4 and R 5 are hydrogen and R 1 , R 2 and R 3 are independently hydrogen or
wherein R 6 and R 7 are independently selected from hydrogen and methyl, with the proviso that only one of R 1 , R 2 and R 3 is and must be
3 . The compound according to claim 2 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 pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, prodrugs, and combinations thereof.
4 . The compound according to claim 3 which is selected from 1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-amine, and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, prodrugs, and combinations thereof.
5 . The compound according to claim 1 wherein Ar is a napthyl group, R 2 , R 4 and R 5 are hydrogen and R 1 and R 3 are independently hydrogen or
wherein R 6 and R 7 are independently selected from hydrogen and methyl, with the proviso that only one of R 1 and R 3 is and must be
6 . The compound according to claim 5 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 pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, prodrugs, and combinations thereof.
7 . The compound according to claim 6 which is selected from N-methyl-1-(naphthalen-2-yl)bicyclo[3.1.0]hexan-3-amine, and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, prodrugs, and combinations thereof.
8 . The compound according to claim 6 which is selected from N-methyl-1-(naphthalen-1-yl)bicyclo[3.1.0]hexan-3-amine, and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, prodrugs, and combinations thereof.
9 . The compound according to claim 6 which is selected from N,N-dimethyl-1-(naphthalen-1-yl)bicyclo[3.1.0]hexan-3-amine, and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, prodrugs, and combinations thereof.
10 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier or vehicle.
11 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 3 and a pharmaceutically acceptable carrier or vehicle.
12 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 6 and a pharmaceutically acceptable carrier or vehicle therefore.
13 . An isolated (+) enantiomer of the compound of claim 1 substantially free of its corresponding (−) enantiomer.
14 . An isolated (−) enantiomer of the compound of claim 1 substantially free of its corresponding (+) enantiomer.
15 . 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.
16 . The neurobiologically active composition of claim 15 , wherein the cellular uptake is inhibited in a mammalian cell or tissue.
17 . 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.
18 . The neurobiologically active composition of claim 17 , wherein the cellular uptake is inhibited in a mammalian cell or tissue.
19 . A method for treating or preventing a central nervous system (CNS) disorder in a mammalian subject comprising administering to said subject an effective amount of a compound according to claim 3 or claim 6 sufficient to treat or prevent said CNS disorder, or to alleviate one or more symptom(s) associated with the CNS disorder.
20 . The method of claim 19 , wherein the CNS disorder is depression
21 . The method of claim 19 , wherein the CNS disorder is an anxiety disorder.
22 . The method according to claim 19 , wherein the CNS disorder is an attention deficit disorder.
23 . A method for treating or preventing a central nervous system (CNS) disorder in a mammalian subject comprising administering to said subject an effective amount of a composition according to claim 11 , 12 , 15 or 17 sufficient to treat or prevent said CNS disorder, or to alleviate one or more symptom(s) associated with the CNS disorder.
24 . The method of claim 23 , wherein the CNS disorder is depression.
25 . The method of claim 23 , wherein the CNS disorder is an anxiety disorder.
26 . The method according to claim 23 , wherein the CNS disorder is an attention deficit disorder.
27 . 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, —NO 2 , —CN, —NH 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo(C 1-8 )alkyl, hydroxy, trifluoromethyl, C 3-8 cycloalkyl, C 1-3 alkoxyl, C 1-3 alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3 alkanoyl, halo(C 1-3 )alkoxyl, C 1-8 alkylamino, and di(C 1-8 )alkylamino, and
R 1 and R 2 are independently selected from hydrogen, unsubstituted C 1-10 alkyl, C 3-8 cycloalkyl, C 1-10 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, 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 NHR 1 R 2 , wherein R 1 and R 9 are defined as above, to produce the arylbicyclo[3.1.0]hexylamine.
28 . The method according to claim 27 further comprising:
(f) converting the arylbicyclo[3.1.0]hexylamine to a pharmaceutically acceptable salt.
29 . 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, —NO 2 , —CN, —NH 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo(C 1-8 )alkyl, hydroxy, trifluoromethyl, C 3-8 cycloalkyl, C 1-3 alkoxyl, C 1-3 alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3 alkanoyl, halo(C 1-3 )alkoxyl, C 1-8 alkylamino, and di(C 1-8 )alkylamino, and
R 1 and R 2 are independently selected from hydrogen, unsubstituted C 1-10 alkyl, C 3-8 cycloalkyl, C 2-10 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, 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 NHR 1 R 2 , wherein R 1 and R 2 are defined as above, to produce the arylbicyclo[3.1.0]hexylamine.
30 . The method according to claim 29 further comprising:
(f) converting the arylbicyclo[3.1.0]hexylamine to a pharmaceutically acceptable salt.
31 . 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, —NO 2 , —CN, —NH 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo(C 1-8 )alkyl, hydroxy, trifluoromethyl, C 3-8 cycloalkyl, C 1-3 alkoxyl, C 1-3 alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3 alkanoyl, halo(C 1-3 )alkoxyl, C 1-8 alkylamino, and di(C 1-8 )alkylamino, and
R 1 and R 2 are independently selected from hydrogen, unsubstituted C 1-10 alkyl, C 3-8 cycloalkyl, C 2-10 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, 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 NHR 1 R 2 , wherein R 1 and R 2 are defined as above, to produce the arylbicyclo[3.1.0]hexylamine.
32 . The method according to claim 31 further comprising:
(f) converting the arylbicyclo[3.1.0]hexylamine to a pharmaceutically acceptable salt.
33 . 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, —NO 2 , —CN, —NH 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo(C 1-8 )alkyl, hydroxy, trifluoromethyl, C 3-9 cycloalkyl, C 1-3 alkoxyl, C 1-3 alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3 alkanoyl, halo(C 1-3 )alkoxyl, C 1-8 alkylamino, and di(C 1-8 )alkylamino, and
R 1 and R 2 are independently selected from hydrogen, unsubstituted C 1-10 alkyl, C 3-8 cycloalkyl, C 2-10 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, 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 K 9 Fe(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 NHR 1 R 2 , wherein R 1 and R 2 are defined as above, to produce the arylbicyclo[3.1.0]hexylamine.
34 . The method according to claim 33 further comprising:
(g) converting the arylbicyclo[3.1.0]hexylamine to a pharmaceutically acceptable salt.