Substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity

Abstract

This invention relates to substituted 4-pyridones of formula 1 and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory diseases of the skin and the eye and other auto-immune and allergic disorders, allograft rejection, and oncological diseases.

What we claim: 
     
         1 . A compound of formula 1 
       
         
           
           
               
               
           
         
         wherein 
         A is phenyl or a five- or six-membered, aromatic heteroring, wherein one, two or three elements are replaced by an element selected independent from each other from the group consisting of N, (O − )—N + , O and S; 
         R 1a  is 
       
       
         
           
           
               
               
           
         
         
           R 1a.1  is C 1-4 -alkyl-, C 3-6 -cycloalkyl-, C 1-4 -haloalkyl-, H 2 N—, C 1-4 -alkyl-NH—, C 3-6 -cycloalkyl-NH—, (C 1-4 -alkyl) 2 N—, (C 3-6 -cycloalkyl)(C 1-4 -alkyl)N—, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, piperazinyl-C 1-4 -alkyl-, C 1-4 -alkyl-O—NH—, (C 1-4 -alkyl-O)(C 1-4 -alkyl)N—; 
           R 1a.2  is H, NC—, O 2 N—, C 1-4 -alkyl-SO 2 —, aryl-SO 2 —, (aromatic heteroring)-SO 2 —, C 1-4 -alkyl-O—(O)C—, C 1-4 -alkyl-(O)C—, C 3-6 -cycloalkyl-(O)C—, H 2 N—(O)C—, C 1-4 -alkyl-NH—(O)C—, C 3-6 -cycloalkyl-NH—(O)C—, (C 1-4 -alkyl) 2 N—(O)C—, (C 3-6 -cycloalkyl)(C 1-4 -alkyl)N—(O)C—, azetidinyl-(O)C—, pyrrolidinyl-(O)C—, piperidinyl-(O)C—, morpholinyl-(O)C—, piperazinyl-(O)C—, piperazinyl-C 1-4 -alkyl-(O)C—, C 1-4 -alkyl-, C 3-6 -cycloalkyl-, C 1-4 -haloalkyl-, aryl, heteroaryl; 
         
         R 1b  is H, C 1-4 -alkyl-, C 3-6 -cycloalkyl-, C 1-4 -haloalkyl- or halogen;
 or R 1a  and R 1b  are together C 2-4 -alkylene forming a carbocyclic heteroring; 
 
         R 2  is C 1-6 -alkyl or a residue selected from the group consisting of C 3-6 -cycloalkyl-, wherein one element of the ring is optionally replaced by O; phenyl-C 1-4 -alkyl-, (aromatic heteroring)-C 1-4 -alkyl- and a five- or six-membered, aromatic heteroring, wherein one, two or three elements are replaced by an element selected independent from each other from the group consisting of N, O and S; each element of one of the rings optionally substituted with one or two groups selected from C 1-4 -alkyl-, C 3-6 -cycloalkyl-, halogen, C 1-4 -haloalkyl-, C 1-4 -alkyl-O—, C 1-4 -alkyl-SO 2 — or NC—; 
         R 3  is H or C 1-4 -alkyl-; 
         R 4  is phenyl, a five- or six-membered, aromatic heteroring containing one, two or three atoms selected from N, O and S; each optionally substituted with one or two residues selected independently from each other from the group consisting of C 1-4 -alkyl-, C 3-6 -cycloalkyl-, halogen or C 1-4 -haloalkyl-; 
         R 5  is H, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-; 
         R 6  is H or C 1-4 -alkyl-; 
         R 7  is H or C 1-4 -alkyl-;
 or R 6  and R 7  are forming together a C 2-5 -alkylene, wherein one element of the formed ring is optionally replaced by O; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound of formula 1, according to  claim 1 , wherein
 A is phenyl or pyridinyl;   R 1a  is   
       
         
           
           
               
               
           
         
         
           R 1a.1  is C 1-4 -alkyl-; 
           R 1a.2  is NC—; 
         
         R 1b  is H; 
         R 2  is C 1-6 -alkyl or a residue selected from the group consisting of C 3-6 -cycloalkyl-, phenyl-C 1-4 -alkyl- and a five- or six-membered, aromatic heteroring containing one or two nitrogen atoms, each of the above rings optionally substituted with C 1-4 -alkyl-, halogen or NC—; 
         R 3  is methyl; 
         R 4  is phenyl, a five- or six-membered, aromatic ring containing one or two nitrogen atom, each ring optionally substituted with one or two residues selected independently from each other from the group consisting of C 1-4 -alkyl-, halogen or C 1-4 -haloalkyl-; 
         R 5  is H; 
         R 6  is H; 
         R 7  is H; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . A compound of formula 1, according to  claim 1 , wherein
 A is phenyl or pyridinyl;   R 1a  is   
       
         
           
           
               
               
           
         
         
           R 1a.1  is C 1-4 -alkyl-; 
           R 1a.2  is NC—; 
         
         R 1b  is H; 
         R 2  is C 1-6 -alkyl or a residue selected from the group consisting of C 3-6 -cycloalkyl-, phenyl-C 1-4 -alkyl- and a five-membered, aromatic ring containing two nitrogen atoms; each optionally substituted with methyl or NC—; 
         R 3  is methyl; 
         R 4  is phenyl or a six-membered, aromatic heteroring containing one or two nitrogen atom, each ring substituted with one or two residues selected independently from each other from the group consisting of C 1-4 -alkyl-, halogen or C 1-4 -haloalkyl-; 
         R 5  is H; 
         R 6  is H; 
         R 7  is H; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . A compound of formula 1, according to  claim 1 , wherein
 A is phenyl or pyridinyl;   R 1a  is   
       
         
           
           
               
               
           
         
         
           R 1a.1  is methyl, ethyl, i-propyl, n-propyl; 
           R 1a.2  is NC—; 
         
         R 1b  is H; 
         R 2  is ethyl, i-propyl, 2-butyl, cyclobutyl, 1-methylpyrazolyl, or benzyl or 4-NC-benzyl; 
         R 3  is methyl; 
         R 4  is phenyl or pyridinyl, each ring substituted with one or two residues selected independently from each other from the group consisting of methyl, ethyl, propyl, F, Br, Cl, F 2 HC— or F 3 C—; 
         R 5  is H; 
         R 6  is H; 
         R 7  is H; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . A compound of formula 1, according to  claim 1 , wherein
 A is phenyl;   R 1a  is   
       
         
           
           
               
               
           
         
         
           R 1a.1  is methyl; 
           R 1a.2  is NC—; 
         
         R 1b  is H; 
         R 2  is ethyl, i-propyl, cyclobutyl, 1-methylpyrazolyl, benzyl or 4-NC-benzyl; 
         R 3  is methyl; 
         R 4  is phenyl or pyridinyl, each ring substituted with one or two residues selected independently from each other from the group consisting of F, F 2 HC— or F 3 C—; 
         R 5  is H; 
         R 6  is H; 
         R 7  is H; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . A compound of formula 1, according to  claim 1 , wherein
 A is phenyl;   R 1a  is   
       
         
           
           
               
               
           
         
         
           R 1a.1  is methyl; 
           R 1a.2  is NC—; 
         
         R 1b  is H; 
         R 2  is selected from a group consisting of 
       
       
         
           
           
               
               
           
         
         R 3  is methyl; 
         R 4  is selected from a group consisting of 
       
       
         
           
           
               
               
           
         
         R 5  is H; 
         R 6  is H; 
         R 7  is H; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . A method for the treatment of asthma and allergic diseases, gastrointestinal inflammatory diseases, eosinophilic diseases, chronic obstructive pulmonary disease, infection by pathogenic microbes and rheumatoid arthritis which comprises administering to a host suffering from one of said conditions a therapeutically effective amount of a compound of formula 1, according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         8 . A pharmaceutical composition comprising a compound of formula 1 according to  claim 1  or a pharmaceutically active salt thereof and a pharmaceutically acceptable carrier.