Benzamides-containing compounds and their use in the treatment of depression

Abstract

or pharmaceutically acceptable salts thereof which inhibit the P2X7 receptor, and their use in the treatment of depression.

1 - 18 . (canceled) 
     
     
         19 . A method of treating depression comprising administering a therapeutically effective amount of at least one compound of formula I 
       
         
           
           
               
               
           
         
         wherein R 1  is pyridyl, pyrazinyl, pyridazinyl, or pyrimidyl, each of which is optionally substituted with one or more C 1-6  alkyl, halogen, hydroxy, C 1-6  hydroxyalkyl, C 1-4  fluoroalkyl, C 3-6  cycloalkyl, C 1-4  alkoxy, C 1-4  fluoroalkoxy, cyano or —SO 2 R 8 ; 
         wherein R 2  is C 3-6  cycloalkyl, C 3-6  cyclohetalkyl, C 1-4  fluoroalkyl, C 1-4  fluoroalkoxy, C 1-4  alkoxy, C 1-6  alkenyl, C 1-6  alkynyl, 6 membered heteroaryl, phenyl or C 1-4  alkyl optionally substituted with one or more R 9 ; 
         wherein R 3  is hydrogen, fluorine, C 1-4  alkyl or C 1-4  fluoroalkyl; or 
         wherein R 2  and R 3  combine with the carbon to which they are attached to form cyclohexyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrrolo, imidazo, azetidinyl, homomorpholinyl, homopiperidinyl or homopiperazinyl each of which is optionally substituted with one or more C 1-6  alkyl, C 1-6  alkenyl, C 3-6 -cycloalkyl, C 1-6  alkoxy, oxo, —NR 6 R 7  or fluorine; 
         wherein R 4  is halogen, C 1-4  fluoroalkyl, cyano, cyclopropyl, C 1-4 alkyloxy, C 1-4  fluoroalkyloxy, —SO 2 R 8 , —NR 6 R 7  or C 1-6  alkyl; 
         wherein R 5  is halogen, C 1-6  alkyl, C 1-4  fluoroalkyl, cyano, —SO 2 R 8 , —NR 6 R 7 , C 1-6  alkoxy, C 1-4  fluoroalkoxy or C 3-6  cycloalkyl; 
         wherein R 6  and R 7  independently of each other are hydrogen or C 1-6  alkyl; 
         wherein R 8  is C 1-6  alkyl, C 3-6  cycloalkyl or C 1-4  fluoroalkyl; 
         wherein R 9  is C 1-6  alkyl, C 3-6  cycloalkyl, —NR 10 R 11 , C 1-4  fluoroalkyl or 3 to 7 membered heterocyclyl which is optionally substituted with one or more C 1-6  alkyl, halogen, hydroxy, C 1-4  fluoroalkyl, C 3-6  cycloalkyl, C 1-4  alkoxy, C 1-4  fluoroalkoxy or cyano; 
         wherein R 10  and R 11  independently of each other are hydrogen or C 1-6  alkyl; or 
         wherein R 10  and R 11  combine with the nitrogen to which they are attached to form piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, homomorpholinyl, homopiperidinyl or homopiperazinyl each of which is optionally substituted with one or more C 1-6  alkyl, C 1-6  alkoxy, oxo or fluorine; and 
         wherein n is 0-3; or a pharmaceutically acceptable salt thereof; 
         to a subject in need thereof. 
       
     
     
         20 . The method of  claim 19 , wherein the depression is major depressive disorder (MDD) including mild, moderate and severe depression. 
     
     
         21 . The method of  claim 19 , wherein the depression is treatment-resistant depression. 
     
     
         22 . The method of  claim 19 , wherein the depression is catatonic depression, melancholic depression, atypical depression, psychotic depression, postpartum depression. bipolar depression, mild, moderate or severe depression, wherein bipolar depression includes bipolar I and bipolar II. 
     
     
         23 . The method of  claim 19 , wherein the depression is associated with inflammatory disease. 
     
     
         24 . The method of  claim 19 , wherein the compound is 2-chloro-N-[3-cyclopropyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The method of  claim 24 , wherein the depression is major depressive disorder (MDD) including mild, moderate and severe depression. 
     
     
         26 . The method of  claim 24 , wherein the depression is treatment-resistant depression. 
     
     
         27 . The method of  claim 24 , wherein the depression is catatonic depression, melancholic depression, atypical depression, psychotic depression, postpartum depression. bipolar depression, mild, moderate or severe depression, wherein bipolar depression includes bipolar I and bipolar II. 
     
     
         28 . The method of  claim 24 , wherein the depression is associated with inflammatory disease. 
     
     
         29 . The method of  claim 19 , wherein the compound is (−)2-chloro-N-[3-cyclopropyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide or a pharmaceutically acceptable salt thereof. 
     
     
         30 . The method of  claim 29 , wherein the depression is major depressive disorder (MDD) including mild, moderate and severe depression. 
     
     
         31 . The method of  claim 29 , wherein the depression is treatment-resistant depression. 
     
     
         32 . The method of  claim 29 , wherein the depression is catatonic depression, melancholic depression, atypical depression, psychotic depression, postpartum depression. bipolar depression, mild, moderate or severe depression, wherein bipolar depression includes bipolar I and bipolar II. 
     
     
         33 . The method of  claim 29 , wherein the depression is associated with inflammatory disease. 
     
     
         34 . The method of  claim 19 , wherein the compound is (+)2-chloro-N-[3-cyclopropyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide or a pharmaceutically acceptable salt thereof. 
     
     
         35 . A method of treating depression comprising administering a therapeutically effective amount of (−)2-chloro-N-[3-cyclopropyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide or a pharmaceutically acceptable salt thereof. 
     
     
         36 . The method of  claim 35 , wherein the depression is major depressive disorder (MDD) including mild, moderate and severe depression. 
     
     
         37 . The method of  claim 35 , wherein the depression is treatment-resistant depression. 
     
     
         38 . The method of  claim 35 , wherein the depression is catatonic depression, melancholic depression, atypical depression, psychotic depression, postpartum depression. bipolar depression, mild, moderate or severe depression, wherein bipolar depression includes bipolar I and bipolar II. 
     
     
         39 . The method of  claim 35 , wherein the depression is associated with inflammatory disease.