Dopamine Transporter Inhibitors for Use in Treatment of Movement Disorders and Other CNS Indications

Abstract

The invention provides a class of dopamine transporter inhibitors of formula (I) (DAS inhibitors), packaged pharmaceuticals comprising such inhibitors, and their uses treating, or the manufacturing medicaments for treating disease conditions, including Parkinson's disease, Hoehn and Yahr Staging of Parkinson's Disease. Unified Parkinson Disease Rating Scale (UPDRS), and Schwab and England Activities of Daily Living Scale. Related business methods such as marketing the inhibitors to healthcare providers are also provided.

1 . A method of treating a CNS disorder selected from the group consisting of a movement disorder, a depressive disorder, a sleep disorder, obesity, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), sexual dysfunction, and substance abuse; the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula I, or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
       wherein, as valence and stability permit,
 Ar, independently for each occurrence, represents a substituted aryl or heteroaryl ring, and Ar is substituted with one or more groups selected from halogen, cyano, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, silyloxy, amino, nitro, thiol, imino, amido, phosphoryl, phosphonate, carboxyl, carboxamide, silyl, thioether, alkylsulfonyl, arylsulfonyl, sulfoxide, selenoether, ketone, aldehyde, ester, and —(CH 2 ) m R 2 , wherein in is an integer from 0 to 4 and R 2 , independently for each occurrence, represents H or substituted or unsubstituted lower alkyl, cycloalkyl, heterocyclyl heteroaralkyl, aryl, or heteroaryl; 
 X represents —H or —OR; 
 Y represents —O—; 
 R, independently for each occurrence, represents —H or lower alkyl; 
 R 1  represents one or more substituents positioned at the 4- and/or 6-position of the piperidine ring; 
 n is an integer from 0 to 2; 
 p is 0 or 1; and 
 q is 1. 
 
     
     
         2 . The method of  claim 1 , wherein
 R 1 , independently for each occurrence, represents halogen, amino, acylamino, amidino, cyano, nitro, azido, ether, thioether, sulfoxido, -J-R 2 , -J-OH, -J-lower alkyl, -J-lower alkenyl, -J-R 2 , -J-SH, -J-NH 2 , or substituted or unsubstituted lower alkyl, lower alkenyl, cycloakyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, or protected forms of the above;   R 2 , independently for each occurrence, represents H or substituted or unsubstituted lower alkyl, cycloalkyl, heterocyclyl, aralkyl, heteroaralkyl, aryl, or heteroaryl; and   J represents, independently for each occurrence, a Chain having from 0-8 units selected from —C(R) 2 —, —N(R)—, —O—, and —S—.   
     
     
         3 . The method of  claim 1 , wherein Ar is substituted with at least one halogen, cyano, hydroxyl, alkoxy, alkenyl, aryl, nitro, thiol, imino, amido, carboxyl, thioether, alkylsulfonyl, arylsulfonyl, ketone, aldehyde, or ester group. 
     
     
         4 . The method of  claim 1 , wherein Ar is substituted with at least one halogen, cyano, alkyl, alkenyl, nitro, amido, carboxyl, alkylsulfonyl, ketone, aldehyde, or ester group. 
     
     
         5 . The method of  claim 1 , wherein Ar is substituted at the para position. 
     
     
         6 . The method of  claim 1 , wherein each occurrence of Ar is phenyl. 
     
     
         7 . The method of  claim 1 , wherein each occurrence of Ar is a phenyl substituted by one or more electron-withdrawing substituents. 
     
     
         8 . The method of  claim 7 , Wherein the electron-withdrawing substituent is halogen, cyano, nitro, perfluoroalkyl or acyl group. 
     
     
         9 . The method of  claim 1 , wherein R 1 , independently for each occurrence, represents a lower alkyl group. 
     
     
         10 . The method of  claim 1 , wherein the movement disorder is Parkinson's disease, restless leg syndrome, or tardive dyskinesia/dystonia. 
     
     
         11 . The method of  claim 1 , wherein the CNS disorder is a sleep disorder. 
     
     
         12 . The method of  claim 1 , further comprising administering, conjointly With the compound represented by Formula I or a pharmaceutically acceptable salt thereof, a second therapeutic agent, a physical therapy, an occupational therapy, or a speech/language therapy. 
     
     
         13 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . A method of treating a CNS disorder selected from the group consisting of a movement disorder, depression, a sleep disorder, obesity, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), sexual dysfunction, and substance abuse; the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula 1, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein, as valence and stability permit,
 Ar, independently for each occurrence, represents a substituted aryl or heteroaryl ring, and Ar is substituted with one or more groups selected from halogen, cyano, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, silyloxy, amino, nitro, thiol, imino, amido, phosphoryl, phosphonate, carboxyl, carboxamide, silyl, thioether, alkyl sulfonyl, arylsulfonyl, sulfoxide, selenoether, ketone, aldehyde, ester, and —(CH 2 ) m R 2 , wherein m is an integer from 0 to 4 and R 2 , independently for each occurrence, represents H or substituted or unsubstituted lower alkyl, cycloalkyl, heterocyclyl, aralkyl, heteroaralkyl, aryl, or heteroaryl; 
 X represents —H or —OR; 
 Y represents —O—; 
 R, independently for each occurrence, represents —H or lower alkyl; 
 R 1  represents one or more lower alkyl groups positioned at the 4- and/or 6-position of the piperidine ring; 
 n is an integer from 0 to 2; 
 p 0 or 1; and 
 q is 1. 
 
     
     
         15 . The method of  claim 1 , wherein Ar is substituted with at least one halogen, cyano, hydroxyl, alkoxy, alkenyl, alkynyl, aryl, nitro, thiol, imino, amido, carboxyl, thioether, alkylsulfonyl, arylsulfonyl, ketone, aldehyde, or ester group. 
     
     
         16 . The method of  claim 1 , wherein Ar is substituted with at least one halogen, cyano, alkenyl, alkynyl, nitro, amido, carboxyl, alkylsulfonyl, ketone, aldehyde, or ester group. 
     
     
         17 . The method of  claim 1 , wherein Ar is substituted at the para position. 
     
     
         18 . The method of  claim 1 , wherein each occurrence of Ar is phenyl. 
     
     
         19 . The method of  claim 1 , wherein each occurrence of Ar is a phenyl substituted by one or more electron-withdrawing substituents. 
     
     
         20 . The method of  claim 1 , wherein the electron-withdrawing substituent is halogen, cyano, nitro, perfluoroalkyl or acyl group.