Vesicular monoamine transporter-2 ligands and their use in the treatment of psychostimulant abuse

Patent metadata

Field	Value
Publication number	US-11999676-B2
Application number	US-202016848462-A
Country	US
Kind code	B2
Filing date	Apr 14, 2020
Priority date	Apr 21, 2016
Publication date	Jun 4, 2024
Grant date	Jun 4, 2024

Abstract

The present invention relates to methods of treatment of a disease or pathology of the central nervous system, an eating disorder, or substance use disorder, drug dependence/abuse and withdrawal therefrom comprising administering at least one N-phenylalkyl amphetamine derivative and pharmaceutical compositions comprising at least one N-phenylalkyl amphetamine derivative to an individual in need thereof.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein
m is an integer in the range from 1 to 3;
n is zero or an integer in the range from 1 to 5;
R 1 and R 2 are independently an aryl group or a heteroaryl group,
wherein R 1 is unsubstituted and R 2 is substituted with one or more substituents selected from the group consisting of mono-, di-, or tri-tritium; methyl; deuteromethyl (CD 3 ); tritiomethyl (CT 3 ); ethyl; propyl; isopropyl; C 4 -C 7 straight chain or branched alkyl; C 3 -C 6 cycloalkyl; C 4 -C 7 alkenyl (including cis and trans geometrical forms); alkylsulfonyl; alkylsulfinyl; phenylethyl; amino; cycloalkylamine, isopropylamino; N-methylamino; N,N-dimethylamino; carboxylate; methylcarboxylate; ethylcarboxylate; propylcarboxylate; isopropylcarboxylate; carboxaldehyde; acetoxy; propionyloxy; isopropionyloxy; cyano; aminomethyl; N-methylaminomethyl; N,N-dimethylaminomethyl; carboxamide; N-methylcarboxamide; N,N-dimethylcarboxamide; acetyl; propionyl; formyl; benzoyl; sulfate; phenyl; methylsulfate; hydroxyl; methoxy; difluoromethoxy; ethoxy; propoxy; isopropoxy; thiol; methylthio; ethylthio; propiothiol; chloro; bromo; iodo; trifluoromethyl; vinyl; allyl; propargyl; nitro; carbamoyl; ureido; azido; isocyanate; thioisocyanate; hydroxylamino; nitrile; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; an oxygen containing heterocyclic or heteroaryl moiety; a sulfur containing heterocyclic or heteroaryl moiety; a selenium containing heterocyclic or heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; and ortho-, meta-, or para-substituted benzene;
or wherein R 2 is unsubstituted and R 1 is substituted with one or more substituents selected from the group consisting of mono-, di-, or tri-tritium; methyl; deuteromethyl (CD 3 ); tritiomethyl (CT 3 ); ethyl; propyl; isopropyl; C 4 -C 7 straight chain or branched alkyl; C 3 -C 6 cycloalkyl; C 4 -C 7 alkenyl (including cis and trans geometrical forms); alkylsulfonyl; alkylsulfinyl; phenylethyl; amino; cycloalkylamine, isopropylamino; N-methylamino; N,N-dimethylamino; carboxylate; methylcarboxylate; ethylcarboxylate; propylcarboxylate; isopropylcarboxylate; carboxaldehyde; acetoxy; propionyloxy; isopropionyloxy; cyano; aminomethyl; N-methylaminomethyl; N,N-dimethylaminomethyl; carboxamide; N-methylcarboxamide; N,N-dimethylcarboxamide; acetyl; propionyl; formyl; benzoyl; sulfate; phenyl; methylsulfate; methoxy; difluoromethoxy; ethoxy; propoxy; isopropoxy; thiol; methylthio; ethylthio; propiothiol; fluoro; chloro; bromo; iodo; vinyl; allyl; propargyl; nitro; carbamoyl; ureido; azido; isocyanate; thioisocyanate; hydroxylamino; nitrile; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; an oxygen containing heterocyclic or heteroaryl moiety; a sulfur containing heterocyclic or heteroaryl moiety; a selenium containing heterocyclic or heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; and ortho-, meta-, or para-substituted benzene;
or wherein R 1 and R 2 are substituted with one or more substituents independently selected from the group consisting of mono-, di-, or tri-tritium; methyl; deuteromethyl (CD 3 ); tritiomethyl (CT 3 ); ethyl; propyl; isopropyl; C 4 -C 7 straight chain or branched alkyl; C 3 -C 6 cycloalkyl; C 4 -C 7 alkenyl (including cis and trans geometrical forms); alkylsulfonyl; alkylsulfinyl; phenylethyl; amino; cycloalkylamine, isopropylamino; N-methylamino; N,N-dimethylamino; carboxylate; methylcarboxylate; ethylcarboxylate; propylcarboxylate; isopropylcarboxylate; carboxaldehyde; acetoxy; propionyloxy; isopropionyloxy; cyano; aminomethyl; N-methylaminomethyl; N,N-dimethylaminomethyl; carboxamide; N-methylcarboxamide; N,N-dimethylcarboxamide; acetyl; propionyl; formyl; benzoyl; sulfate; phenyl; methylsulfate; hydroxyl; methoxy; difluoromethoxy; ethoxy; propoxy; isopropoxy; thiol; methylthio; ethylthio; propiothiol; fluoro; chloro; bromo; iodo; trifluoromethyl; vinyl; allyl; propargyl; nitro; carbamoyl; ureido; azido; isocyanate; thioisocyanate; hydroxylamino; nitrile; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; an oxygen containing heterocyclic or heteroaryl moiety; a sulfur containing heterocyclic or heteroaryl moiety; a selenium containing heterocyclic or heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; and ortho-, meta-, or para-substituted benzene,
wherein one or more of the benzyl; phenyl; saturated or unsaturated hydrocarbon ring; nitrogen containing heterocyclic or heteroaryl moiety; oxygen containing heterocyclic or heteroaryl moiety; sulfur containing heterocyclic or heteroaryl moiety; selenium containing heterocyclic or heteroaryl moiety; mixed heterocyclic or heteroaryl moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; or ortho-, meta-, or para-substituted benzene substituent on R 1 or R 2 may be independently fused to R 1 or R 2 or linked to R 1 or R 2 ;

R 3 is a methyl; ethyl; propyl; isopropyl; hydroxymethyl; 2-hydroxyethyl; 1-hydroxyethyl; methoxymethyl; 2-methoxyethyl; 1-methoxyethyl; aminomethyl; 2-aminoethyl; 1-aminoethyl; N-methylaminomethyl; 2-N-methylaminoethyl; 1-N-methylaminoethyl; N,N-dimethylaminomethyl; 2-N,N-dimethylaminoethyl; 1-N,N-dimethylaminoethyl; methyl, ethyl, propyl, or isopropyl substituted with one or more fluoro; or benzyl;
R 4 is an ethyl, propyl, isopropyl, or carbonyl group; or a methyl, ethyl, propyl or isopropyl group substituted with a hydroxyaryl group; and
R 5 is hydrogen or methyl; or
an enantiomer; racemate; or pharmaceutically acceptable salt thereof; or

wherein
m is an integer in the range from 1 to 3;
n is zero or an integer in the range from 1 to 5;
R 1 and R 2 are independently an aryl group or a heteroaryl group,
wherein R 2 is unsubstituted and R 1 is substituted with one or more substituents selected from the group consisting of mono-, di-, or tri-tritium; methyl; deuteromethyl (CD 3 ); tritiomethyl (CT 3 ); ethyl; propyl; isopropyl; C 4 -C 7 straight chain or branched alkyl; C 3 -C 6 cycloalkyl; C 4 -C 7 alkenyl (including cis and triflcycloalkylamine, isopropylamino; N-methylamino; N,N-dimethylamino; carboxylate; methylcarboxylate; ethylcarboxylate; propylcarboxylate; isopropylcarboxylate; carboxaldehyde; acetoxy; propionyloxy; isopropionyloxy; cyano; aminomethyl; N-methylaminomethyl; N,N-dimethylaminomethyl; carboxamide; N-methylcarboxamide; N,N-dimethylcarboxamide; acetyl; propionyl; formyl; benzoyl; sulfate; phenyl; methylsulfate; difluoromethoxy; ethoxy; propoxy; isopropoxy; thiol; methylthio; ethylthio; propiothiol; chloro; iodo; vinyl; allyl; propargyl; carbamoyl; ureido; azido; isocyanate; thioisocyanate; hydroxylamino; nitrile; a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic or heteroaryl moiety; an oxygen containing heterocyclic or heteroaryl moiety; a sulfur containing heterocyclic or heteroaryl moiety; a selenium containing heterocyclic or heteroaryl moiety; a mixed heterocyclic or heteroaryl moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; and ortho-, meta-, or para-substituted benzene;
or wherein R 1 and R 2 are substituted with one or more substituents independently selected from the group consisting of mono-, di-, or tri-tritium; methyl; deuteromethyl (CD 3 ); tritiomethyl (CT 3 ); ethyl; propyl; i

Assignees

• Univ Kentucky Res Found

Inventors

• Dwoskin Linda P
• Watt David
• Thorson Jon
• Leggas Mark
• Guy Kip
• Hammill Jared
• Kwiatkowski Stefan
• Ding Derong
• Zheng Guangrong
• Crooks Peter Anthony
• Lee Na-Ra

Classifications

• C07C211/53 Primary

  having the nitrogen atom of at least one of the amino groups further bound to a hydrocarbon radical substituted by amino groups · CPC title

• C07C233/43

  having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton · CPC title

• C07D209/14

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title

• C07D213/38

  having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom · CPC title

• C07D215/12 Primary

  with substituted hydrocarbon radicals attached to ring carbon atoms · CPC title