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

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.

1 . A method of treating a disease or pathology of the central nervous system or an eating disorder in an individual in need thereof, wherein the method comprises the step of administering to the individual a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         m is an integer in the range from 1 to 3; 
         n is zero or an integer from 1 to 5; 
         R 1  and R 2  are each independently an aryl group, 
         wherein R 1  and R 2  are each independently unsubstituted or substituted by one or more substituents selected from the group consisting of 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; benzyl; phenylethyl; amino; 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; ethoxy; propoxy; isopropoxy; thiol; methylthio; ethylthio; propiothiol; fluoro; chloro; bromo; iodo; trifluoromethyl; vinyl; allyl; propargyl; nitro; carbamoyl; ureido; azido; isocyanate; thioisocyanate; hydroxylamino; nitroso; a saturated or unsaturated hydrocarbon ring; a nitrogen-containing heterocyclic moiety; an oxygen-containing heterocyclic moiety; a sulfur-containing heterocyclic moiety; a selenium-containing heterocyclic moiety; a mixed heterocyclic moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; and ortho, meta or para-substituted benzene; 
         R 3  is methyl, ethyl, propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl, 1-hyhydroxyethyl, 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, or 1-N,N-dimethylaminoethyl group; and 
         R 4  is a hydrogen atom or a methyl, ethyl, propyl, or isopropyl group; or 
         an enantiomer; racemate; or pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The method of  claim 1 , wherein:
 m is 1 or 2; and   n is an integer from 1 to 5; or   an enantiomer; racemate; or pharmaceutically acceptable salt thereof.   
     
     
         3 . The method of  claim 2 , wherein:
 R 3  is methyl, ethyl, propyl, or isopropyl; and   R 4  is a hydrogen atom or a methyl, ethyl, propyl, or isopropyl group; or   an enantiomer; racemate; or pharmaceutically acceptable salt thereof.   
     
     
         4 . The method of  claim 1 , wherein the compound of formula (I) is 3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine or an enantiomer; racemate; or pharmaceutically acceptable salt thereof. 
     
     
         5 . The method of  claim 1 , wherein the compound of formula (I) is (S)-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine hydrochloride. 
     
     
         6 . The method of  claim 1 , wherein the disease or pathology of the central nervous system is selected from the group consisting of cognitive disorders, brain trauma, memory loss, psychosis, sleep disorders, obsessive compulsive disorders, panic disorders, myasthenia gravis, Parkinson's disease, Alzheimer's disease, schizophrenia, Tourette's syndrome, Huntington's disease, attention deficit hyperactivity disorder, hyperkinetic syndrome, chronic nervous exhaustion, narcolepsy, pain, motion sickness, and depression. 
     
     
         7 . The method of  claim 1 , wherein the eating disorder is obesity. 
     
     
         8 . The method of  claim 1 , wherein the compound of formula (I), enantiomer, racemate, or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition further comprising a pharmaceutically acceptable excipient. 
     
     
         9 . The method of  claim 8 , wherein the pharmaceutical composition is administered to the individual by inhalation; topically; orally; intravenously as an infusion or injection; or subcutaneously as an infusion, injection, or depot formulation; transdermally; or rectally. 
     
     
         10 . A method of treating a substance use disorder, drug dependence/abuse or withdrawal from drug dependence/abuse in an individual in need thereof, wherein the method comprises the step of administering to the individual a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         m is an integer in the range from 1 to 3; 
         n is zero or an integer from 1 to 5; 
         R 1  and R 2  are each independently an aryl group, 
         wherein R 1  and R 2  are each independently unsubstituted or substituted by one or more substituents selected from the group consisting of 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; benzyl; phenylethyl; amino; 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; ethoxy; propoxy; isopropoxy; thiol; methylthio; ethylthio; propiothiol; fluoro; chloro; bromo; iodo; trifluoromethyl; vinyl; allyl; propargyl; nitro; carbamoyl; ureido; azido; isocyanate; thioisocyanate; hydroxylamino; nitroso; a saturated or unsaturated hydrocarbon ring; a nitrogen-containing heterocyclic moiety; an oxygen-containing heterocyclic moiety; a sulfur-containing heterocyclic moiety; a selenium-containing heterocyclic moiety; a mixed heterocyclic moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; and ortho, meta or para-substituted benzene; 
         R 3  is methyl, ethyl, propyl, isopropyl, hydroxymethyl, 2-hydroxyethyl, 1-hyhydroxyethyl, 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, or 1-N,N-dimethylaminoethyl group; and 
         R 4  is a hydrogen atom or a methyl, ethyl, propyl, or isopropyl group; or 
         an enantiomer; racemate; or pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The method of  claim 10 , wherein:
 m is 1 or 2; and   n is an integer from 1 to 5; or   an enantiomer; racemate; or pharmaceutically acceptable salt thereof.   
     
     
         12 . The method of  claim 11 , wherein:
 R 3  is methyl, ethyl, propyl, or isopropyl; and   R 4  is a hydrogen atom or a methyl, ethyl, propyl, or isopropyl group; or   an enantiomer; racemate; or pharmaceutically acceptable salt thereof.   
     
     
         13 . The method of  claim 10 , wherein the compound of formula (I) is 3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine or an enantiomer; racemate; or pharmaceutically acceptable salt thereof. 
     
     
         14 . The method of  claim 10 , wherein the compound of formula (I) is (S)-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine hydrochloride. 
     
     
         15 . The method of  claim 10 , wherein the drug is methamphetamine. 
     
     
         16 . The method of  claim 10 , wherein the compound of formula (I), enantiomer, racemate, or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition further comprising a pharmaceutically acceptable excipient. 
     
     
         17 . The method of  claim 16 , wherein the pharmaceutical composition is administered to the individual by inhalation; topically; orally; intravenously as an infusion or injection; or subcutaneously as an infusion, injection, or depot formulation; transdermally; or rectally.