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-8877798-B2
Publication Date
2014-11-04
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 compounds of formula II and formula IIa, enantiomers, and pharmaceutically acceptable salts thereof, based on a substituted 3-aza-bicyclo[3.1.0]hexane scaffold. The compounds are defined by variable substituent groups R1, R2, R3, and R4/R5, with R1 and R2 selected from hydrogen and specified substituted alkyl, alkenyl, and alkynyl groups, and R3 selected from hydrogen, alkyl, alkoxycarbonyl, alkanoyl, cycloalkyl, cycloalkanoyl, aryl, heteroaryl, and saturated heterocyclic options.
The disclosure further includes concrete embodiments of 1-aryl-3-azabicyclo[3.1.0]hexane derivatives, including naphthyl and substituted phenyl analogs, stereochemically defined (1R,5S) and (1S,5R) forms, and 3-position substituents such as methyl, ethyl, and isopropyl. Specific salt forms are also described, including hydrochloride salts, together with examples bearing fluoro, chloro, trifluoromethyl, methoxy, nitro, and dichloro substitution patterns.
The document also describes synthetic reaction schemes for preparing 1-aryl-3-azabicyclo[3.1.0]hexane derivatives and analog intermediates from substituted cyclopropane and epichlorohydrin-derived intermediates. The schemes include ring-forming transformations, functional-group interconversions, stereochemical access from chiral starting material, and salt formation, as well as characterization and comparative evaluation of substituted analogs.
Claims Coverage
The consolidated claim coverage includes two independent compound claims for formula II and formula IIa and an independent pharmaceutical composition claim. The inventive features center on the substituted 3-aza-bicyclo[3.1.0]hexane scaffold with variable R1, R2, R3, and R4/R5 definitions, with formula IIa narrowing R4/R5 to a smaller set of named substituents, plus a composition claim for 1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane hydrochloride with a pharmaceutically acceptable carrier or vehicle.
Formula II compound with variable substituent definitions
A compound of formula II, including enantiomers and pharmaceutically acceptable salts thereof, wherein R1 and R2 are independently selected from hydrogen, unsubstituted C1-10 alkyl, C3-10 alkenyl and C3-10 alkynyl, and substituted C1-10 alkyl, C3-10 alkenyl and C3-10 alkynyl with specified substituents; R3 is selected from hydrogen and groups including C1-6 alkyl, C1-6 alkoxycarbonyl, C2-6 alkanoyl, C3-8 cycloalkyl, C4-9 cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C2-10 alkenyl, C2-10 alkynyl, and substituted alkyl/alkenyl/alkynyl options; and R4 and R5 are independently hydrogen or 1-4 substituents selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, cyano, hydroxy, alkoxy, alkoxyalkyl, carboxyalkyl, alkanoyl, haloalkoxy, nitro, amino, alkylamino, and dialkylamino options.
Formula IIa compound with restricted R4 and R5 substituents
A compound of formula IIa, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from hydrogen, unsubstituted C1-10 alkyl, C3-10 alkenyl and C3-10 alkynyl, and substituted C1-10 alkyl, C3-10 alkenyl and C3-10 alkynyl with specified substituents; R3 is selected from hydrogen and groups including C1-6 alkyl, C1-6 alkoxycarbonyl, C2-6 alkanoyl, C3-8 cycloalkyl, C4-9 cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C2-10 alkenyl, C2-10 alkynyl, and substituted alkyl/alkenyl/alkynyl options; and R4 and R5 are independently hydrogen or 1-4 substituents independently selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, nitro, propyl, methoxy, ethoxy and trifluoromethoxy.
Pharmaceutical composition with 1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane hydrochloride
A pharmaceutical composition comprising 1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane hydrochloride and a pharmaceutically acceptable carrier or vehicle therefor.
Overall, the independent claims define broad Formula II and Formula IIa compound genera with enantiomers and pharmaceutically acceptable salts, together with a composition claim for a specific naphthyl-substituted hydrochloride. The formula IIa claim further restricts R4/R5 to a limited set of small substituents, while dependent embodiments identify stereochemically specific 3-aza-bicyclo[3.1.0]hexane derivatives and hydrochloride salt forms.
Stated Advantages
Intended to inhibit and/or reverse uptake of norepinephrine, serotonin, and dopamine.
Presented as therapeutic CNS agents for CNS disorders, including depression and anxiety.
The document states that modifying aryl and aza substituents yields distinct and sometimes non-uniform double/triple reuptake inhibition profiles.
The document states that exemplified compounds are potent (nM) inhibitors of neurotransmitter uptake.
Documented Applications
Therapeutic use as CNS agents for CNS disorders, including depression and anxiety.
Modulation of uptake of norepinephrine, serotonin, and dopamine for neuropsychiatric disorders.
CNS therapeutic use associated with dopamine/norepinephrine/serotonin reuptake inhibition for depression and anxiety.
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