1-aryl-3-azabicyclo[3.1.0]hexanes: preparation and use to treat neuropsychiatric disorders
Inventors
Skolnick, Phil • Basile, Anthony • Chen, Zhengming • Epstein, Joseph W.
Assignees
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Publication Number
US-8461196-B2
Publication Date
2013-06-11
Expiration Date
Abstract
The invention provides novel, multiply-substituted 1-aryl-3-azabicyclo[3.1.0]hexanes, 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 depression and anxiety.
Core Innovation
The disclosure relates to substituted 3-aza-bicyclo[3.1.0]hexane derivatives bearing naphthyl substituents, including 1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and 1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane, and pharmaceutically acceptable salts thereof. The compounds include defined stereochemical variants such as (1R,5S) and (1S,5R), and compositions are described with stereochemical selection or exclusion using substantially free of corresponding stereoisomers.
The disclosed subject matter further frames these compounds as neurobiologically active compositions and pharmaceutical compositions. The compositions are effective to inhibit cellular uptake of one or more biogenic amine neurotransmitter(s) selected from norepinephrine, serotonin, and dopamine in a mammalian subject, and include pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, and prodrugs thereof.
The document also includes 1-aryl-3-azabicyclo[3.1.0]hexane derivatives and related synthetic schemes and intermediates, including hydrochloride salts and stereoisomeric forms. The described material refers to compounds intended for treating and/or preventing CNS disorders, including depression and anxiety.
Claims Coverage
The consolidated claim coverage includes three independent claim themes: a composition comprising a specific naphthyl-substituted 3-aza-bicyclo[3.1.0]hexane compound or pharmaceutically acceptable salts thereof, a neurobiologically active composition effective to inhibit cellular uptake of selected biogenic amine neurotransmitters in a mammalian subject, and a pharmaceutical composition formulated with a pharmaceutically acceptable carrier or vehicle. The inventive features center on the 3-aza-bicyclo[3.1.0]hexane scaffold, naphthyl substitution, stereochemical forms, and the stated functional and formulation contexts.
Naphthyl-substituted 3-aza-bicyclo[3.1.0]hexane composition
A composition comprising a compound selected from 1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof.
Neurobiologically active uptake-inhibiting composition
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 an effective amount of a compound, or a pharmaceutically acceptable salt, enantiomer, polymorph, solvate, hydrate, and prodrug thereof, selected from 1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane and its (1R,5S) and (1S,5R) forms.
Pharmaceutical composition with carrier or vehicle
A pharmaceutical composition comprising an effective amount of a compound selected from 1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof, formulated with a pharmaceutically acceptable carrier or vehicle.
Overall, the claims are directed to compositions and pharmaceutical formulations of naphthyl-substituted 3-aza-bicyclo[3.1.0]hexane compounds, including pharmaceutically acceptable salts and specified stereochemical variants. One independent claim additionally requires inhibition of cellular uptake of norepinephrine, serotonin, and/or dopamine, and another requires formulation with a pharmaceutically acceptable carrier or vehicle.
Stated Advantages
Inhibits cellular uptake of one or more biogenic amine neurotransmitter(s) selected from norepinephrine, serotonin, and dopamine in a mammalian subject.
Provides stereochemical selection through compositions including enantiomeric forms and substantially excluding corresponding stereoisomers.
Potential therapeutic use in CNS disorders, including neuropsychiatric disorders such as anxiety and depression, is stated.
Documented Applications
Use in a mammalian subject for inhibiting cellular uptake of biogenic amine neurotransmitters selected from norepinephrine, serotonin, and dopamine.
Pharmaceutical composition use comprising an effective amount of the specified compound formulated with a pharmaceutically acceptable carrier or vehicle.
Treating and/or preventing CNS disorders, including depression and anxiety.
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