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-10039746-B2
Publication Date
2018-08-07
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 methods of making 1-aryl-3-azabicyclo[3.1.0]hexanes of Formula IV or Formula V, including pharmaceutically acceptable salts thereof. The methods are defined by cyclizing or by reducing specific precursor compounds, with Ar being an unsubstituted naphthyl group or a naphthyl group having 1-4 substituents independently selected from a defined list, and with additional definition of R in Formula V. Related embodiments further describe precursor transformations, including reducing a compound of formula (ii), reacting a compound of formula (i) with epichlorohydrin, and optional deprotecting or dealkylating when R is methyl, ethyl, isopropyl, or a nitrogen protecting group.
The invention covers substituted 1-aryl-3-azabicyclo[3.1.0]hexane hydrochloride salts and their precursors, including cyclopropanecarbonitriles and hydroxymethylcyclopropyl derivatives. The disclosed material includes enantiomerically specified products and hydrochloride salt embodiments for selected stereochemical forms, together with characterization information including 1H NMR, 13C NMR, LC/MS, optical rotation, and yield.
Claims Coverage
The provided independent claims are directed to two distinct method frameworks for making 1-aryl-3-azabicyclo[3.1.0]hexanes: cyclizing a compound of formula (iii) to give Formula IV, and reducing a compound of formula (ix) to give Formula V. The inventive features center on the naphthyl substituent scope for Ar, and for Formula V the additional R scope.
Cyclizing a compound of formula (iii) to form formula IV products
A method of making a 1-aryl-3-azabicyclo[3.1.0]hexane of Formula IV or a pharmaceutically acceptable salt thereof, wherein Ar is an unsubstituted naphthyl group or a naphthyl group having 1-4 substituents independently selected from halogen, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo(C1-3)alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxy, nitro, amino, C1-3 alkylamino, and di(C1-3)alkylamino, comprising cyclizing a compound of formula (iii) wherein Ar is as defined above.
Reducing a compound of formula (ix) to form formula V products
A method of making a 1-aryl-3-azabicyclo[3.1.0]hexane of Formula V or a pharmaceutically acceptable salt thereof, wherein Ar is an unsubstituted naphthyl group or a naphthyl group having 1-4 substituents independently selected from halogen, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo(C1-3)alkyl, cyano, hydroxy, C3-5 cycloalkyl, C1-3 alkoxy, C1-3 alkoxy(C1-3)alkyl, carboxy(C1-3)alkyl, C1-3 alkanoyl, halo(C1-3)alkoxy, nitro, amino, C1-3 alkylamino, and di(C1-3)alkylamino, and R is hydrogen, methyl, ethyl, isopropyl or a nitrogen protecting group, comprising reducing a compound of formula (ix) wherein Ar and R are as defined above.
Claim coverage is directed to producing 1-aryl-3-azabicyclo[3.1.0]hexane scaffold products of Formula IV or Formula V, with Ar restricted to unsubstituted or 1-4 substituted naphthyl groups from a specified list. The Formula V route additionally restricts R to hydrogen, methyl, ethyl, isopropyl, or a nitrogen protecting group.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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