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, S and (O − N + ); or 
  a ring system of two fused five- or six-membered, aromatic heterorings, wherein one, two or three elements are replaced by an element selected independent from each other from the group consisting of N, O, S, (O) 2 S and (O − N + ); 
 R 1a  is H, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cyloalkyl-, NC—, C 1-4 -alkyl-(O)S—, C 1-4 -alkyl-(O) 2 S—, C 3-6 -cycloalkyl-(O)S—, C 3-6 -cycloalkyl-(O) 2 S—, C 1-4 -haloalkyl-(O)S—, C 1-4 -haloalkyl-(O) 2 S—, H 2 N(O) 2 S—, R 1a.1 —C 1-4 -alkyl-, R 1a.1 ;
 R 1a.1  is a five- or six-membered, aromatic or non-aromatic heteroring, wherein one, two or three elements are replaced by an element selected independent from each other from the group consisting of N and O; optionally substituted with O═ or C 1-4 -Alkyl-; 
 
 R 1b  is H, O═, halogen, C 1-4 -alkyl-O— or C 1-4 -alkyl-; 
  or R 1a  and R 1b  are together C 2-4 -alkylene forming a carbocyclic heteroring, wherein one element of the ring is replaced by (O) 2 S; 
 R 2  is C 1-6 -alkyl-, C 1-6 -haloalkyl-, C 1-4 -alkyl-O—C 1-4 -alkyl- or a ring selected from the group consisting of C 3-6 -cycloalkyl-, C 3-6 -halocycloalkyl-, C 3-6 -cycloalkyl-C 1-4 -alkyl-, C 3-6 -halocycloalkyl-C 1-4 -alkyl-; wherein one element of the above mentioned rings is optionally replaced by O; 
 R 3  is C 1-4 -alkyl-; 
 R 4  is phenyl or a five- or six-membered, aromatic heteroring, wherein one or two 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 to substituted with a residue selected from the group consisting of C 1-4 -alkyl-, C 3-6 -cycloalkyl-, C 1-4 -haloalkyl- and halogen; 
 R 5  is H, C 1-4 -alkyl-, C 1-4 -haloalkyl- and C 3-6 -cycloalkyl-; 
 R 6  is H, C 1-4 -alkyl-; 
 R 7  is H, C 1-4 -alkyl-; 
  or R 6  and R 7  are together C 2-5 -alkylene forming a carbocyclic ring; 
 
       or a salt thereof. 
     
     
         2 . A compound of formula I, according to  claim 1 , wherein
 A is phenyl or a five- or six-membered, aromatic heteroring, wherein one or two or three elements are replaced by an element selected independent from each other from the group consisting of N, O, S and (O − N + ); or   R 1a  is H, C 1-4 -alkyl-, NC—, C 1-4 -alkyl-(O)S—, C 1-4 -alkyl-(O) 2 S—, H 2 N(O) 2 S—, R 1a.1 —C 1-4 -alkyl-, R 1a.1 ;
 R 1a.1  is a five- or six-membered, aromatic or non-aromatic heteroring, wherein one or two elements are replaced by an element selected independent from each other from the group consisting of N and O; optionally substituted with O═; 
   R 1b  is H, haolgen or C 1-4 -alkyl-;    or R 1a  and R 1b  are together C 2-4 -alkylene forming a carbocyclic ring, wherein one element of the ring is replaced by (O) 2 S;   R 2  is C 1-6 -alkyl-, C 1-6 -haloalkyl-, C 1-4 -alkyl-O—C 1-4 -alkyl- or a ring selected from the group consisting of C 3-6 -cycloalkyl-, C 3-6 -halocycloalkyl-, C 3-6 -cycloalkyl-C 1-4 -alkyl-, C 3-6 -halocycloalkyl-C 1-4 -alkyl-; wherein one element of the above mentioned rings is optionally replaced by O;   R 3  is C 1-4 -alkyl-;   R 4  is phenyl or a five- or six-membered, aromatic heteroring, wherein one or two elements are replaced by an element selected independent from each other from the group consisting of N and O; wherein one or two elements of one of the rings are optionally substituted with a residue selected from the group consisting of C 1-4 -alkyl-, C 1-4 -haloalkyl- and halogen;   R 5  is H;   R 6  is H;   R 7  is H;   
       or a salt thereof. 
     
     
         3 . A compound of formula 1, according to  claim 1 , wherein
 A is phenyl, pyrazolyl, oxadiazolyl, pyridinyl, pyridin-N-oxidyl, thiophenyl;   R 1a  is H, methyl, NC—, Me(O)S—, Me(O) 2 S—, Et(O) 2 S—, H 2 N(O) 2 S—, imidazolidin-onyl, pyrrolidinon-H 2 C—, imidazol-H 2 C—;   R 1b  is H;    or R 1a  and R 1b  are together C 3 -alkylene forming a carbocyclic ring, wherein one element of the ring is replaced by (O) 2 S;   R 2  is C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C 3-6 -cycloalkyl-H 2 C—, tetrahydrofuranyl, tetrahydrofuran-H 2 C—, each optionally substituted with one or two residues selected from the group consisting of F;   R 3  is methyl;   R 4  is phenyl or pyridinyl, both optionally substituted with a residue selected from the group consisting of F 2 HC—, F 3 C—;   R 5  is H;   R 6  is H;   R 7  is H;   
       or a salt thereof. 
     
     
         4 . A compound of formula I, according to  claim 1 , wherein
 A is phenyl, oxadiazolyl, pyridinyl, pyridin-N-oxidyl, thiophenyl;   R 1a  is H, methyl, NC—, Me(O)S—, Me(O) 2 S—, Et(O) 2 S—, H 2 N(O) 2 S—, imidazolidin-onyl, pyrrolidinon-H 2 C—, imidazol-H 2 C—;    or R 1a  and R 1b  are together C 3 -alkylene forming a carbocyclic ring, wherein one element of the ring is replaced by (O) 2 S;   R 2  is ethyl, n-propyl, i-propyl, 1-methyl-propyl, 1-ethyl-propyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, tetrahydrofuranyl, each optionally substituted with one or two F;   R 3  is methyl;   R 4  is phenyl or pyridinyl, both substituted with a residue selected from the group consisting of F 2 HC—, F 3 C—;   R 5  is H;   R 6  is H;   R 7  is H;   
       or a salt thereof. 
     
     
         5 . A compound of formula 1, according to  claim 1 , wherein
 A is phenyl, oxadiazolyl, pyridinyl, pyridin-N-oxidyl, thiophenyl;   R 1a  is H, methyl, NC—, Me(O)S—, Me(O) 2 S—, Et(O) 2 S—, H 2 N(O) 2 S—, imidazolidin-onyl, pyrrolidinon-H 2 C—, imidazol-H 2 C—;   R 1b  is H;   R 2  is i-propyl;   R 3  is methyl;   R 4  is phenyl or pyridinyl, both substituted with a residue selected from the group consisting of F 2 HC—, F 3 C—;   R 5  is H;   R 6  is H;   R 7  is H;   
       or a salt thereof. 
     
     
         6 . 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 the formula I according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         7 . A pharmaceutical composition comprising a compound of formula 1 according to  claim 1  or a pharmaceutically active salt thereof and a pharmaceutically acceptable carrier.