Triazolophthalazines

Abstract

The compounds of formula (I) in which R1, R2 and R3 have the meanings as given in the description are novel effective PDE2 inhibitors.

1 - 11 . (canceled) 
     
     
         12 . A method for treating an acute or chronic airway disorder in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
       
       in which
 R1 is —U-A, in which 
 U is a direct bond, or methylene (—CH 2 —), 
 A is phenyl, pyridinyl, thienyl or R11- and/or R111-substituted phenyl, in which 
 R11 is 1-4C-alkyl, halogen, trifluoromethyl, hydroxyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, phenoxy, 1-4C-alkoxycarbonyl, morpholino, or di-1-4C-alkylamino, 
 R111 is 1-4C-alkoxy, halogen, hydroxyl, or 1-4C-alkyl, 
 R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, phenyl-1-4C-alkoxy, phenoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, halogen, trifluoromethyl, nitro, phenyl, R21-substituted phenyl, completely or predominantly fluorine-substituted 1-4C-alkoxy, 1-4C-alkylthio, cyano-1-4C-alkyl, or —N(R22)R23, in which 
 R21 is 1-4C-alkoxy, halogen or 1-4C-alkyl, 
 R22 and R23 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het1, in which 
 Het1 is optionally substituted by R24, and is a 3- to 7-membered monocyclic fully saturated heterocyclic ring radical comprising the nitrogen atom, to which R22 and R23 are bonded, and optionally one further heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, in which 
 R24 is 1-4C-alkyl, 
 R3 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         13 . The method of  claim 12 , wherein the acute or chronic airway disorder is selected from the group consisting of acute respiratory distress syndrome (ARDS) in septic shock, pneumonia, rhinitis, bronchitis, bronchial asthma, emphysema and chronic obstructive pulmonary disease (COPD). 
     
     
         14 . The method of  claim 12 , wherein the acute or chronic airway disorder is selected from the group consisting of pneumonia and acute respiratory distress syndrome (ARDS) in septic shock. 
     
     
         15 . The method of  claim 12 , wherein, in the compound of formula I,
 R1 is —U-A, in which   U is a direct bond, or methylene (—CH 2 —),   A is phenyl, pyridinyl, thienyl, dimethoxyphenyl, or R11-substituted phenyl, in which   R11 is methyl, tert-butyl, chlorine, fluorine, bromine, trifluoromethyl, hydroxyl, methoxy, ethoxy, trifluoromethoxy, phenoxy, methoxycarbonyl, morpholino, or dimethylamino,   R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, phenyl-1-4C-alkoxy, phenoxy, halogen, phenyl, R21-substituted phenyl, completely or predominantly fluorine-substituted 1-4C-alkoxy, 1-4C-alkylthio, cyano-1-4C-alkyl, or —N(R22)R23, in which   R21 is 1-4C-alkoxy,   R22 and R23 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het1, in which   Het1 is pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, or 4N-(1-4C-alkyl)-piperazin-1-yl,   R3 is hydrogen or 1-4C-alkoxy,   or a pharmaceutically acceptable salt thereof.   
     
     
         16 . The method of  claim 12 , wherein, in the compound of formula I,
 R1 is —U-A, in which   U is a direct bond, or methylene (—CH 2 —),   A is phenyl, 4-methoxy-phenyl, 2-methoxy-phenyl, 2-hydroxy-phenyl, 2-bromo-phenyl, 4-bromo-phenyl, 2-fluoro-phenyl, 2-(trifluoromethyl)-phenyl, 2-methyl-phenyl, 3-methoxy-phenyl, 3-bromo-phenyl, 3-fluoro-phenyl, 2-dimethylamino-phenyl, methoxycarbonyl, phenoxy, or 3-(trifluoromethyl)-phenyl,   R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, phenyl-1-4C-alkoxy, phenoxy, halogen, phenyl, R21-substituted phenyl, completely or predominantly fluorine-substituted 1-4C-alkoxy, 1-4C-alkylthio, cyano-1-4C-alkyl, or —N(R22)R23, in which   R21 is 1-4C-alkoxy,   R22 and R23 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het1, in which   Het1 is morpholin-4-yl, or 4N-(1-4C-alkyl)-piperazin-1-yl,   R3 is hydrogen or 1-4C-alkoxy,   or a pharmaceutically acceptable salt thereof.   
     
     
         17 . The method of  claim 12 , wherein, in the compound of formula I,
 R1 is 4-methoxy-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 2-bromo-phenyl, 3-bromo-phenyl, 4-bromo-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 2-(trifluoromethyl)-phenyl, or 3-(trifluoromethyl)-phenyl;   R2 is hydrogen, methyl, methoxy, ethoxy, benzyloxy, chlorine, phenoxy, phenyl, 4-methoxy-phenyl, trifluoromethoxy, difluoromethoxy, methylthio, cyanomethyl, or —N(R22)R23, in which   R22 and R23 together and with inclusion of the nitrogen atom, to which they are attached, form a heterocyclic ring Het1, in which   Het1 is morpholin-4-yl, or 4N-methyl-piperazin-1-yl,   R3 is hydrogen, methoxy or ethoxy,   or a pharmaceutically acceptable salt thereof.   
     
     
         18 . The method of  claim 12 , wherein the compound of formula I is selected from the group consisting of:
 (4-Methoxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   (3,4-Dimethoxy-phenyl)-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   [3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-phenyl-amine,   (3-Benzyloxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   (4-Chlorophenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   (4′-Methoxybiphenyl-4-yl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   (3-Methoxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   [3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4-phenoxyphenyl)-amine,   [3-(4-Methoxyphenyl)-]1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(3-phenoxyphenyl)-amine,   (4-Benzyloxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   [3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-p-tolyl-amine,   (4-Ethoxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   [3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4-morpholin-4-yl-phenyl)-amine,   [3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4-trifluoromethoxyphenyl)-amine,   {4-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetonitrile,   [3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4-methylsulfanylphenyl)-amine,   (4-Morpholin-4-yl-phenyl)-[3-(4-phenoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   [3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-[4-(4-methylpiperazin-1-yl)-phenyl]-amine,   3-[6-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[3,4-a]phthalazin-3-yl]-benzoic acid methyl ester,   (4-Morpholin-4-yl-phenyl)-[3-(4-morpholin-4-yl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   [3-(4-Methoxy-benzyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(4-morpholin-4-yl-phenyl)-amine,   4-[6-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[3,4-a]phthalazin-3-yl]-benzoic acid methyl ester,   (3-Ethoxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   [3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-(3-trifluoromethoxyphenyl)-amine,   (4-Morpholin-4-ylphenyl)-(3-phenyl-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)-amine,   2-[6-(4-Morpholin-4-yl-phenylamino)-[1,2,4]triazolo[3,4-a]phthalazin-3-yl]-phenol,   (3,5-Dimethoxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   [3-(1,1-Difluoromethoxy)-phenyl]-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   (3,4-Diethoxyphenyl)-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   [4-(1,1-Difluoromethoxy)-phenyl]-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   (4-Bromo-phenyl)-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-amine,   and the pharmaceutically acceptable salts of these compounds.