Substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity
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.
1. A compound of formula 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.
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-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.
3. 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.
4. 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.
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 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.
6. A pharmaceutical composition comprising a compound of formula 1 according to claim 1 or a pharmaceutically active salt thereof and a pharmaceutically acceptable carrier.