4-phenylpiperazine derivatives with functionalized linkers as dopamine d3 receptor selective ligands and methods of use

Abstract

Dopamine D 3 receptor antagonists and partial agonists are known to modulate the reinforcing and drug-seeking effects induced by cocaine and other abused substances. By introducing functionality into the butylamide linking chain of the 4-phenylpiperazine class of ligands, improved D 3 receptor affinity and selectivity, as well as water solubility, is achieved. A series of linking-chain derivatives are disclosed wherein functionality such as OH, OAc, and cis or trans-cyclopropyl groups have been introduced into the linking chain. In general, these modifications are well tolerated at D 3 receptors and achieve high selectivity over D 2 and D 4 receptors.

We claim: 
     
         1 . A method of treating an addiction comprising: administering a pharmaceutically effective amount of a compound of the following chemical formula: 
       
         
           
           
               
               
           
         
         wherein:
 A=CHR 4  or trans CH═CH; 
 n=0 or 1; 
 R 1  and R 2 =independently represent hydrogen, halogen, or alkoxy; 
 R 3  and R 4 =H, OH, OAc, alkoxy, halogen, amino, nitro, alkyl having from 2-8 carbons, or pyridyl; 
 R 5 =phenyl, indole, thiophene, benzofuran, fluorenyl, or 2-pyridylphenyl; and R 5  is optionally substituted with one or more of hydrogen, halogen, amino, nitro, hydroxyl, alkoxy, alkyl, and pyridyl, substitution may occur at any of the ortho, meta, or para positions; 
 including all enantiomers and pharmaceutical salts thereof, 
 wherein alkyl is a branched or unbranched, saturated or unsaturated, monovalent hydrocarbon radical having from 1-8 carbons, optionally substituted with one or more C 1  to C 3  alkyl, halogen, hydroxyl, amino, alkoxyl, or mercapto groups, and 
 wherein alkoxy is —OR group, wherein R is a C 1  to C 3  alkyl optionally substituted with one or more C 1  to C 3  alkyl, halogen, hydroxyl, amino, alkoxyl, or mercapto groups; 
 wherein when A=trans CH═CH, then R 3 =OH, OAc, alkoxy, halogen, amino, nitro, alkyl, or pyridyl; and 
 wherein when A=CHR 4 , then one of R 3  or R 4 =OH, OAc, alkoxy, halogen, amino, nitro, alkyl, or pyridyl, 
 to a patient in need thereof. 
 
       
     
     
         2 . The method of  claim 1 , in which A is CHR 4 . 
     
     
         3 . The method of  claim 1 , wherein the compound is:
 N-(3-hydroxy-4-(4-(2-methoxyphenyl)-piperazin-1-yl)-butyl)-4-pyridin-2-yl-benzamide;   N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)-butyl)-9H-fluorene-2-carboxamide;   N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide;   N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indole-2-carboxamide;   N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-5-iodo-benzofuran-2 carboxamide;   N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-5-fluorobenzo furan-2 carboxamide;   5-fluoro-N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indole-2-carboxamide;   N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-5-methoxy-1H-indole-2-carboxamide;   (R)—N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide; or   (S)—N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide.   
     
     
         4 . The method of  claim 1 , wherein R 3 =OH, OAc, alkoxy, halogen, amino, nitro, alkyl having from 2-8 carbons, or pyridyl. 
     
     
         5 . The method of  claim 1 , wherein R 4 =OH, OAc, alkoxy, halogen, amino, nitro, alkyl having from 2-8 carbons, or pyridyl. 
     
     
         6 . The method of  claim 1 , wherein
 A=CHR 4 ;   n=1;   R 1  and R 2 =independently represent hydrogen, halogen, or alkoxy;   R 3 =OH or halogen;   R 4 =H; and   R 5 =indole or fluorenyl, and R 5  is optionally substituted with alkoxy.   
     
     
         7 . The method of  claim 1 , wherein
 A=CHR 4 ;   n=1;   R 1  and R 2 =Cl;   R 3 =F;   R 4 =H; and   R 5 =indole or fluorenyl, and R 5  is optionally substituted with methoxy.   
     
     
         8 . The method of  claim 1 , wherein
 A=CHR 4 ;   n=1;   R 1 =H;   R 2 =methoxy;   R 3 =OH;   R 4 =H; and   R 5 =indole substituted with methoxy.   
     
     
         9 . A method of treating schizophrenia or Parkinson's disease or dyskinesias associated with these diseases comprising: administering a pharmaceutically effective amount of a compound of the following chemical formula: 
       
         
           
           
               
               
           
         
         wherein:
 A=CHR 4  or trans CH═CH; 
 n=0 or 1; 
 R 1  and R 2 =independently represent hydrogen, halogen, or alkoxy; 
 R 3  and R 4 =H, OH, OAc, alkoxy, halogen, amino, nitro, alkyl having from 2-8 carbons, or pyridyl; 
 R 5 =phenyl, indole, thiophene, benzofuran, fluorenyl, or 2-pyridylphenyl; and R 5  is optionally substituted with one or more of hydrogen, halogen, amino, nitro, hydroxyl, alkoxy, alkyl, and pyridyl, substitution may occur at any of the ortho, meta, or para positions; 
 including all enantiomers and pharmaceutical salts thereof, 
 wherein alkyl is a branched or unbranched, saturated or unsaturated, monovalent hydrocarbon radical having from 1-8 carbons, optionally substituted with one or more C 1  to C 3  alkyl, halogen, hydroxyl, amino, alkoxyl, or mercapto groups, and 
 wherein alkoxy is —OR group, wherein R is a C 1  to C 3  alkyl optionally substituted with one or more C 1  to C 3  alkyl, halogen, hydroxyl, amino, alkoxyl, or mercapto groups; 
 wherein when A=trans CH═CH, then R 3 =OH, OAc, alkoxy, halogen, amino, nitro, alkyl, or pyridyl; and 
 
         wherein when A=CHR 4 , then one of R 3  or R 4 =OH, OAc, alkoxy, halogen, amino, nitro, alkyl, or pyridyl, 
         to a patient in need thereof. 
       
     
     
         10 . The method of  claim 9 , in which A is CHR 4 . 
     
     
         11 . The method of  claim 9 , wherein the compound is:
 N-(3-hydroxy-4-(4-(2-methoxyphenyl)-piperazin-1-yl)-butyl)-4-pyridin-2-yl-benzamide;   N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)-butyl)-9H-fluorene-2-carboxamide;   N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide;   N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indole-2-carboxamide;   N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-5-iodo-benzofuran-2 carboxamide;   N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-5-fluorobenzofuran-2 carboxamide;   5-fluoro-N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indole-2-carboxamide;   N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-5-methoxy-1H-indole-2-carboxamide;   (R)—N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide; or   (S)—N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide.   
     
     
         12 . The method of  claim 9 , wherein R 3 =OH, OAc, alkoxy, halogen, amino, nitro, alkyl having from 2-8 carbons, or pyridyl. 
     
     
         13 . The method of  claim 9 , wherein R 4 =OH, OAc, alkoxy, halogen, amino, nitro, alkyl having from 2-8 carbons, or pyridyl. 
     
     
         14 . The method of  claim 9 , wherein
 A=CHR 4 ;   n=1;   R 1  and R 2 =independently represent hydrogen, halogen, or alkoxy;   R 3 =OH or halogen;   R 4 =H; and   R 5 =indole or fluorenyl, and R 5  is optionally substituted with alkoxy.   
     
     
         15 . The method of  claim 9 , wherein
 A=CHR 4 ;   n=1;   R 1  and R 2 =Cl;   R 3 =F;   R 4 =H; and   R 5 =indole or fluorenyl, and R 5  is optionally substituted with methoxy.   
     
     
         16 . The method of  claim 9 , wherein
 A=CHR 4 ;   n=1;   R 1 =H;   R 2 =methoxy;   R 3 =OH;   R 4 =H; and   R 5 =indole substituted with methoxy.   
     
     
         17 . A method of selectively imaging dopamine D 2  family binding sites of the central nervous system to detect or monitor a disease resulting from abnormal distribution and/or density of dopamine D 3  receptor in the central nervous system of a patient comprising:
 contacting central nervous system tissue with a compound of the following chemical formula:   
       
         
           
           
               
               
           
         
         
           wherein: 
           A=CHR 4  or trans CH═CH; 
           n=0 or 1; 
           R 1  and R 2 =independently represent hydrogen, halogen, or alkoxy; 
           R 3  and R 4 =H, OH, OAc, alkoxy, halogen, amino, nitro, alkyl having from 2-8 carbons, or pyridyl; 
           R 5 =phenyl, indole, thiophene, benzofuran, fluorenyl, or 2-pyridylphenyl; and R 5  is optionally substituted with one or more of hydrogen, halogen, amino, nitro, hydroxyl, alkoxy, alkyl, and pyridyl, substitution may occur at any of the ortho, meta, or para positions; 
           including all enantiomers and pharmaceutical salts thereof, 
           wherein alkyl is a branched or unbranched, saturated or unsaturated, monovalent hydrocarbon radical having from 1-8 carbons, optionally substituted with one or more C 1  to C 3  alkyl, halogen, hydroxyl, amino, alkoxyl, or mercapto groups, and 
           wherein alkoxy is —OR group, wherein R is a C 1  to C 3  alkyl optionally substituted with one or more C 1  to C 3  alkyl, halogen, hydroxyl, amino, alkoxyl, or mercapto groups; 
           wherein when A=trans CH═CH, then R 3 =OH, OAc, alkoxy, halogen, amino, nitro, alkyl, or pyridyl; and 
           wherein when A=CHR 4 , then one of R 3  or R 4 =OH, OAc, alkoxy, halogen, amino, nitro, alkyl, or pyridyl; and 
           detecting the binding of the compound to the central nervous system tissue. 
         
       
     
     
         18 . The method of  claim 17 , further comprising:
 determining the distribution and/or density of the dopamine D 3  receptor in the central nervous system tissue;   comparing the distribution and/or density obtained with the distribution and/or density of dopamine D3 receptor in a corresponding normal tissue; and   diagnosing a disease state by a difference in the distribution and/or density between the normal tissue and the subject tissue.