Nk-1 and serotonin transporter inhibitors

Abstract

The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, their pharmaceutical compositions, and their use in treating disorders associated with an excess or imbalance of tachykinins or serotonin or both.

1 . A compound of Formula I  
     
       
         
         
             
             
         
       
       where:  
       R 1  is hydrogen, alkyl, cycloalkyl, or benzyl;  
       R 2  is hydrogen or alkyl;  
       R 3  is hydrogen or alkyl;  
       R 4  is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, or COR 6 ;  
       R 5  is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, or COR 6 ;  
       R 6  is hydroxy, alkoxy, benzyloxy, amino, alkylamino, dialkylamino, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, or morpholinyl;  
       Ar 1  is phenyl or pyridinyl, and is substituted with 0-2 substituents selected from the group consisting of halo, alkyl, haloalkyl, cyano, phenyl and furanyl;  
       Ar 2  is phenyl substituted with 1-5 substituents or is naphthyl substituted with 0-3 substituents where the substituents are selected from the group consisting of halo, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, haloalkoxy, benzyloxy, alkylthio, cyano, nitro, amino, alkylamino, dialkylamino, (alkylcarbonyl)amino, (alkoxycarbonyl)amino (benzyloxycarbonyl)amino, carboxy, alkoxycarbonyl, benzyloxycarbonyl, alkylSO 2 , phenyl, phenoxy, acetyl, and formyl;  
       or Ar 2  is furanyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrmidinyl, pyrazinyl, triazinyl, quinolinyl, or isoquinolinyl, and is substituted with 0-3 substituents selected from the group consisting of amino, alkylamino, dialkylamino, oxo, halo, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, and morpholinyl;  
       or Ar 2  is benzodioxolyl, dibenzofuranyl, thianthrenyl, or trimethylenedioxybenzen-yl;  
       or a pharmaceutically acceptable salt thereof.  
     
   
   
       2 . A compound of  claim 1  where: 
 R 1  is hydrogen or alkyl;    R 4  is hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano;    R 5  is hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano;    Ar 1  is phenyl substituted with 0-2 substituents selected from the group consisting of halo, alkyl, haloalkyl, and cyano;    Ar 2  is phenyl substituted with 1-3 substituents or is naphthyl substituted with 0-3 substituents where the substituents are selected from the group consisting of halo, alkyl, haloalkyl, hydroxyalkyl, hydroxy, alkoxy, alkoxyalkyl, haloalkoxy, alkylthio, cyano, nitro, amino, alkylamino, dialkylamino, phenyl, phenoxy, acetyl, and formyl;    or Ar 2  is furanyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrmidinyl, triazinyl, quinolinyl, or isoquinolinyl, and is substituted with 0-3 substituents selected from the group consisting of amino, alkylamino, dialkylamino, oxo, halo, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, or morpholinyl;    or Ar 2  is benzodioxolyl, dibenzofuranyl or thianthrenyl.    
   
   
       3 . A compound of  claim 1  where R 1  is hydrogen.  
   
   
       4 . A compound of  claim 1  where R 2  and R 3  are hydrogen.  
   
   
       5 . A compound of  claim 1  where R 2  is methyl and R 3  is hydrogen.  
   
   
       6 . A compound of  claim 1  where Ar 1  is phenyl.  
   
   
       7 . A compound of  claim 1  where Ar 2  is phenyl substituted with 1-5 substituents or is naphthyl substituted with 0-3 substituents where the substituents are selected from the group consisting of halo, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, haloalkoxy, benzyloxy, alkylthio, cyano, nitro, amino, alkylamino, dialkylamino, (alkylcarbonyl)amino, (alkoxycarbonyl)amino (benzyloxycarbonyl)amino, carboxy, alkoxycarbonyl, benzyloxycarbonyl, alkylSO 2 , phenyl, phenoxy, acetyl, and formyl.  
   
   
       8 . A compound of  claim 1  where Ar 2  is furanyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrmidinyl, pyrazinyl, triazinyl, quinolinyl, or isoquinolinyl, and is substituted with 0-3 substituents selected from the group consisting of amino, alkylamino, dialkylamino, oxo, halo, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, and morpholinyl.  
   
   
       9 . A compound of  claim 1  selected from the group consisting of  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof.  
     
   
   
       10 . A composition comprising a pharmaceutically acceptable amount of a compound of  claim 1  and at least one pharmaceutically acceptable carrier.  
   
   
       11 . A method for treating a disorder associated with aberrant levels of tachykinins or serotonin comprising administering an effective amount of a compound of  claim 1  to a patient afflicted with the disorder.  
   
   
       12 . The method of  claim 11  where the disorder is anxiety.  
   
   
       13 . The method of  claim 11  where the disorder is depression, obsessive compulsive disorder, bulimia, or panic disorder.