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
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9737506-B2
Publication Date
2017-08-22
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 invention relates to substituted and multiply substituted 1-aryl-3-azabicyclo[3.1.0]hexane compounds and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, prodrugs, and isotopically labeled compounds. The disclosed compounds include substituted phenyl and naphthyl embodiments, with examples of halogen- and alkoxy-substituted aromatic groups and specific stereochemical forms, including resolved and racemic forms.
The compounds are defined by formula II with substituent selections for R1 and R2, R3, and R4 and R5. The document also describes related preparation of 1-aryl-3-azabicyclo[3.1.0]hexane scaffolds and corresponding hydrochloride salt forms, together with alternative synthetic routes to the same bicyclic scaffold family.
The invention is directed to treating attention deficit hyperactivity disorder (ADHD) in a human or mammalian subject by administering an effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof, including a pharmaceutical composition comprising such a compound. The compounds are also framed as CNS therapeutic agents for CNS disorders including depression and anxiety, with stated involvement in inhibition of norepinephrine reuptake, serotonin reuptake, and dopamine reuptake.
Claims Coverage
The claim coverage centers on two independent ADHD treatment methods: administering an effective amount of a formula II compound or pharmaceutically acceptable salt to a human, and administering an effective amount of a pharmaceutical composition comprising a formula II compound or pharmaceutically acceptable salt to a mammalian subject. Across the claims, the inventive scope is defined by the formula II scaffold and the allowed substituent selections for R1, R2, R3, and R4/R5, with dependent claims narrowing to specific named compounds, stereochemical forms, and at least one hydrochloride salt form.
Treating ADHD by administering a formula II compound or salt
A method for treating attention deficit hyperactivity disorder (ADHD) in a human in need thereof comprising administering to the human in need thereof an effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof, with defined substituent selections for R1 and R2, R3, and R4 and R5.
Formula II substituent constraints
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 listed substituent options; R3 is selected from hydrogen and specified alkyl, alkoxycarbonyl, alkanoyl, cycloalkyl, cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, alkenyl, alkynyl, and substituted variants; and R4 and R5 are independently hydrogen or specified substituents including halogen, alkyl, alkenyl, alkynyl, haloalkyl, cyano, hydroxy, cycloalkyl, alkoxy, alkoxyalkyl, carboxyalkyl, alkanoyl, haloalkoxy, nitro, amino, alkylamino, and dialkylamino.
Treating ADHD by administering a pharmaceutical composition
A method for treating attention deficit hyperactivity disorder (ADHD) in a mammalian subject in need thereof comprising administering to the mammalian subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula II or a pharmaceutically acceptable salt thereof, with defined substituent selections for R1 and R2, R3, and R4 and R5.
The claims collectively cover treatment of ADHD by administering formula II 1-aryl-3-azabicyclo[3.1.0]hexane compounds or pharmaceutically acceptable salts, either directly or as part of a pharmaceutical composition, with the covered compound set defined by the R1-R5 substituent framework.
Stated Advantages
Treating attention deficit hyperactivity disorder (ADHD) in a human or mammalian subject.
CNS therapeutic use for CNS disorders including depression and anxiety.
Inhibition of norepinephrine reuptake, serotonin reuptake, and dopamine reuptake.
Includes enantiomeric stereoisomers, resolved and racemic forms, and pharmaceutically acceptable salt, prodrug, metabolic product, and isotopically labeled embodiments.
Potent, non-uniform inhibition of cellular reuptake of biogenic amine neurotransmitters, including norepinephrine, dopamine, and serotonin.
Large and unpredictable changes in absolute potency and potency ratios across structurally varied compounds.
Differential transporter inhibition profiles supporting neurotransmitter-selective therapeutic potential for CNS and neuropsychiatric disorders, including ADHD, anxiety, and depression.
Documented Applications
Treatment of attention deficit hyperactivity disorder (ADHD) in a human by administering an effective amount of a formula II compound or a pharmaceutically acceptable salt thereof.
Treatment of attention deficit hyperactivity disorder (ADHD) in a mammalian subject by administering an effective amount of a pharmaceutical composition comprising a formula II compound or a pharmaceutically acceptable salt thereof.
CNS therapeutic use for CNS disorders including depression and anxiety.
Combination therapy within the therapeutic framework for CNS disorders.
In vitro neurotransmitter monoamine uptake inhibition in rat brain synaptosomes, including norepinephrine, dopamine, and serotonin uptake.
Neurobiological utility for modulating biogenic amine transport in mammalian subjects for CNS and neuropsychiatric disorders, including ADHD, anxiety, and depression.
Interested in licensing this patent?