1-azatricyclic-4-benzylpiperazines

Abstract

Disclosed are 1-Azatricyclic-4-benzylpiperazine compounds which are useful for the treatment and/or prevention of neuropsychological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents. Pharmaceutical compositions, including packaged pharmaceutical compositions, are further provided. Compounds of the invention are also useful as probes for the localization of GABA A receptors in tissue samples.

What is claimed is:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 A represents phenyl optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, mono- or di (C 1 -C 6 ) hydrocarbylamino, aminosulfonyl, C 1 -C 6  hydrocarbylaminosulfonyl, di(C 1 -C 6 )hydrocarbylaminosulfonyl, cyano, nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl, C 1 -C 6  hydrocarbyl, trifluoromethoxy, C 3 -C 6  cyclohydrocarbyl, and C 1 -C 6  alkoxy;  
 R 5  and R 6  are the same or different and represent hydrogen or C 1 -C  6  hydrocarbyl; and  
 R 2  represents hydrogen, halogen, hydroxy, amino, mono- or di (C 1 -C  6 ) hydrocarbylamino, aminosulfonyl, C 1 -C 6  hydrocarbylaminosulfonyl, di(C 1 -C 6 )hydrocarbylaminosulfonyl, cyano, nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl, C 1 -C 6  hydrocarbyl, trifluoromethoxy, C 3 -C 6  cyclohydrocarbyl, or C 1 -C 6  alkoxy; and  
 n is 0, 1, or 2.  
 
     
     
         2 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 A represents phenyl optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, mono- or di(C 1 -C 6 ) alkylamino, aminosulfonyl, C 1 -C 6  alkylaminosulfonyl, di (C 1 -C 6 ) alkylaminosulfonyl, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C 1 -C 6 )alkyl, trifluoromethoxy, C 3 -C 6  cycloalkyl, and C 1 -C 6  alkoxy;  
 R 5  and R 6  are the same or different and represent hydrogen or C 1 -C 6  alkyl; and  
 R 2  represents hydrogen, halogen, hydroxy, amino, mono- or di(C 1 -C 6 ) alkylamino, aminosulfonyl, C 1 -C 6  alkylaminosulfonyl, di(C 1 -C 6 )alkylaminosulfonyl, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C 1 -C 6 )alkyl, trifluoromethoxy, C 3 -C 6  cycloalkyl, and C 1 -C 6  alkoxy; and  
 n is 2.  
 
     
     
         3 . A compound according to  claim 2  wherein A is a group of the formula:  
       
         
           
           
               
               
           
         
       
       where R 3  and R 4  independently represent hydrogen, halogen, hydroxy, amino, mono- or di (C 1 -C 6 )alkylamino, aminosulfonyl, C 1 -C 6  alkylaminosulfonyl, di (C 1 -C 6 )alkylaminosulfonyl, cyano, nitro, cycloalkylalkyl, trifluoromethyl, C 1 -C 6  alkyl, trifluoromethoxy, C 3 -C 6  cycloalkyl, or C 1 -C 6  alkoxy.  
     
     
         4 . A compound according to  claim 2  wherein R 3  and R 4  are the same or different and are C 1 -C 3  alkyl, chloro, fluoro, bromo, or C 1 -C 3  alkoxy.  
     
     
         5 . A compound according to  claim 2 , wherein at least ore of R 3  and R 4  is attached at the ortho or para position of the phenyl ring.  
     
     
         6 . A compound according to  claim 1 , wherein R 2  is hydrogen, fluoro, chloro, or C 1 -C 2  alkyl.  
     
     
         7 . A compound according to  claim 5  wherein R 2  is hydrogen.  
     
     
         8 . A compound according to  claim 6  wherein A is a group of the formula:  
       
         
           
           
               
               
           
         
       
       where R 3  and R 4  independently represent hydrogen, halogen, hydroxy, amino, mono- or di(C 1 -C 6 )alkylamino, aminosulfonyl, C 1 -C 6  alkylaminosulfonyl, di (C 1 -C 6 )alkylaminosulfonyl, cyano, nitro, cycloalkylalkyl, trifluoromethyl, C 1 -C 6  alkyl, trifluoromethoxy, C 3 -C 6  cycloalkyl, or C 1 -C 6  alkoxy.  
     
     
         9 . A compound according to  claim 7  wherein R 3  and R 4  are the same or different and are C 1 -C 3  alkyl, chloro, fluoro, bromo, or C 1 -C 3  alkoxy.  
     
     
         10 . A compound according to  claim 8 , wherein at least one of R 3  and R 4  is in the ortho or para position of the phenyl ring.  
     
     
         11 . A compound according to  claim 9 , wherein R 5  and R 6  independently represent hydrogen or C 1 -C 2  alkyl.  
     
     
         12 . A compound according to  claim 9 , wherein at least one of R 5  and R 6  is methyl.  
     
     
         13 . A compound according to  claim 9 , wherein both R 5  and R 6  are methyl.  
     
     
         14 . A compound according to  claim 1  which is 5-[(4-Methylbenzyl)piperazin-1-yl]-1,2,4,5, 6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk] [1]benzazepine.  
     
     
         15 . A compound according to  claim 1  which is 5-[(4-Chlorobenzyl)piperazin-1-yl]-2,2-dimethyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk] [1]benzazepine.  
     
     
         16 . A compound according to  claim 1  which is cis- 5-[(4-Chlorobenzyl)piperazin-1-yl]-2-methyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk] [1]benzazepine.  
     
     
         17 . A compound according to  claim 1  which is trans-5-[(4-Chlorobenzyl)piperazin-1-yl]-2-methyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk] [1]benzazepine.  
     
     
         18 . A compound according to  claim 1  which is 5-[(2-Methoxy-5-methylbenzyl)piperazin-1-yl]-2,2-dimethyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk] [1]benzazepine.  
     
     
         19 . A compound according to  claim 1  which is 5-[(2-Methoxy-5-chlorobenzyl)piperazin-1-yl]-2,2-dimethyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk] [1]benzazepine.  
     
     
         20 . A compound according to  claim 1  which is 5-[(2-Methoxy-4-methylbenzyl)piperazin-1-yl]-2,2-dimethyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk] [1]benzazepine.  
     
     
         21 . A pharmaceutical composition comprising a compound according to  claim 1 , together with at least one pharmaceutically acceptable carrier or excipient.  
     
     
         22 . A method for the treatment or prevention of a disease or disorder associated with pathogenic dopamine receptor activation, said method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound of  claim 1 .  
     
     
         23 . A method according to  claim 22  wherein the disease or disorder is schizophrenia, psychotic depression, mania, Parkinson's disease, or tardive dyskinesia.  
     
     
         24 . A method according to  claim 22  wherein the disease or disorder is attention deficit disorder or Alzheimer's disease.  
     
     
         25 . A method according to  claim 22  wherein the disease or disorder is extrapyramidyl side effects associated with the use of a neuroleptic agent.  
     
     
         26 . The use of a compound according to  claim 1  for the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with pathogenic dopamine receptor activation.  
     
     
         27 . A method for localizing dopamine receptors in a tissue sample comprising: 
 contacting with the sample a detectably-labeled compound of  claim 1  under conditions that permit binding of the compound to dopamine receptors,    washing the sample to remove unbound compound, and detecting the bound compound.    
     
     
         28 . The method of  claim 27  wherein the dopamine receptor is a D 4  receptor.  
     
     
         29 . A method of inhibiting the binding of a dopamine to a dopamine receptor, said method comprising contacting a compound of  claim 1  with cells expressing such a receptor in the presence of a dopamine, wherein the compound is present at a concentration sufficient to inhibit dopamine binding to cells expressing a cloned human dopamine receptor in vitro.  
     
     
         30 . The method of  claim 29  wherein the dopamine receptor is a dopamine D 4  receptor.  
     
     
         31 . A packaged pharmaceutical composition comprising the pharmaceutical composition of  claim 21  in a container and instructions for using the composition to treat a patient suffering from a disorder responsive to dopamine receptor antagonism.  
     
     
         32 . The packaged pharmaceutical composition of  claim 31 , wherein said patient is suffering from schizophrenia, psychotic depression, mania, Parkinson's disease, or tardive dyskinesia, attention deficit disorder, Alzheimer's disease, or the extrapyramidyl side effects associated with the use of a neuroleptic agent.  
     
     
         33 . A compound according to  claim 1  wherein in a assay of dopamine receptor binding the compound exhibits a K i  of 1 micromolar or less.  
     
     
         34 . A compound according to  claim 1  wherein the compound exhibits a K i  of 100 nanomolar or less.  
     
     
         35 . A compound according to  claim 1  wherein the compound exhibits a K i  of 10 nanomolar or less.  
     
     
         36 . A compound according to  claim 1  wherein the compound exhibits a 20-fold greater affinity for the dopamine D 4  receptor than for the dopamine D 2  receptor in an assay of dopamine receptor binding.  
     
     
         37 . A compound according to  claim 1  wherein the compound exhibits a 100-fold greater affinity for the dopamine D 4  receptor than for the dopamine D 2  receptor in an assay of dopamine receptor binding.