IP Library › Patent Application 11936722

Patent Application

App. No. 11/936,722

Novel Arylbicyclo[3.1.0]Hexylamines And Methods And Compositions For Their Preparation And Use

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Patent No.: US None
App. No.: 11/936,722

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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.

Claims (44)

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 - 35 . (canceled)

36 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 35 and a pharmaceutically acceptable carrier or vehicle.

37 . 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,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; 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; 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; 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; 5-(3,4-dichlorophenyl)-N,N-dimethylbicyclo[3.1.0]hexan-2-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; N,N-dimethyl-5-(naphthalen-2-yl)bicyclo[3.1.0]hexan-2-amine; (1R,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-amine; (1S,5S)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-amine; (1R,3S,5R)-1-(3′,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-amine; (1R,3R,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-amine; (1R,5R)-1-(naphthalen-1-yl)bicyclo[3.1.0]hexan-3-amine; (1S,5S)-1-(naphthalen-1-yl)bicyclo[3.1.0]hexan-3-amine; (1R,3S,5R)-1-(naphthalen-1-yl)bicyclo[3.1.0]hexan-3-amine; and (1R,3R,5R)-1-(naphthalen-1-yl)bicyclo[3.1.0]hexan-3-amine, and a pharmaceutically acceptable carrier or excipient.

38 . The neurobiologically active composition of claim 37 , wherein the cellular uptake is inhibited in a mammalian cell or tissue.

39 . A compound selected from the group consisting of:

and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, prodrugs, and combinations thereof.

40 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 39 and a pharmaceutically acceptable carrier or vehicle.

41 . 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:

42 . The neurobiologically active composition of claim 41 , wherein the cellular uptake is inhibited in a mammalian cell or tissue.

43 . A compound selected from the group consisting of:

(1R,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-amine; (1S,5S)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-amine; (1R,3S,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-amine; (1R,3R,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-amine; (1R,5R)-1-(naphthalen-1-yl)bicyclo[3.1.0]hexan-3-amine; (1S,5S)-1-(naphthalen-1-yl)bicyclo[3.1.0]hexan-3-amine; (1R,3S,5R)-1-(naphthalen-1-yl)bicyclo[3.1.0]hexan-3-amine; and (1R,3R,5R)-1-(naphthalen-1-yl)bicyclo[3.1.0]hexan-3-amine,

and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, prodrugs, and combinations thereof.

44 . 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:

45 . The neurobiologically active composition of claim 44 , wherein the cellular uptake is inhibited in a mammalian cell or tissue.

46 - 52 . (canceled)

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 5, 2018

From: EUTHYMICS BIOSCIENCE, INC.

To: ETHISMOS RESEARCH, INC.

Reel/Frame 045252/0870 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 30, 2007

From: SKOLNICK, PHIL; CHEN, ZHENGMING; YANG, JI

To: DOV PHARMACEUTICAL, INC.

Reel/Frame 020183/0290 →