Benzonaphthyridines
View Patent ↗The compounds of formula I in which R1, R2, R3, R4, R5, R6 and n have the meanings as indicated in the description, are novel effective PDE3/4 inhibitors.
1. A method for inhibiting PDE3 and PDE4 in a patient comprising administering to said patient an inhibiting amount of a compound of formula 1
in which
R1 is methyl,
R2 is 1-4C-alkoxy,
R3 is 1-4C-alkoxy,
R4 is hydrogen,
R5 is 1-4C-alkyl,
R6 is hydrogen, 1-4C-alkylcarbonyl, Arylcarbonyl or Aryl-1-2C-alkylcarbonyl,
Aryl is phenyl or phenyl substituted by R7 and/or R8,
R7 is nitro, 1-2C-alkyl or 1-2C-alkoxy,
R8 is 1-2C-alkoxy,
n is 1 or 2,
or a pharmaceutically acceptable salt thereof.
2. The method according to claim 1 , wherein
R1 is methyl,
R2 is methoxy or ethoxy,
R3 is methoxy,
R4 is hydrogen,
R5 is isopropyl,
and in which either
R6 is hydrogen, phenylcarbonyl, benzylcarbonyl, 4-nitrophenylcarbonyl, 3-4-dimethoxyphenylcarbonyl, 3-5-dimethoxyphenylcarbonyl or acetyl and
n is 1,
or
R6 is phenylcarbonyl, benzylcarbonyl or 3,4-dimethoxy-benzylcarbonyl and
n is 2,
or a pharmaceutically acceptable salt thereof.
3. The method according to claim 1 , wherein
R1 is methyl,
R2 is methoxy or ethoxy,
R3 is methoxy,
R4 is hydrogen,
R5 is isopropyl,
and in which either
R6 is hydrogen, benzylcarbonyl, 4-nitrophenylcarbonyl, 3,4-dimethoxyphenylcarbonyl, 3,5-dimethoxyphenylcarbonyl or acetyl and
n is 1,
or
R6 is phenylcarbonyl, benzylcarbonyl or 3,4-dimethoxy-benzylcarbonyl and
n is 2,
or a pharmaceutically acceptable salt thereof.
4. The method according to claim 1 , wherein the compound of formula 1 is selected from the group consisting of
Phenyl-acetic acid (S)-2-({1-[4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)-phenyl]-methanoyl}-isopropyl-amino)-propyl ester,
Benzoic acid (S)-2-({1-[4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)-phenyl]-methanoyl}-isopropyl-amino)-propyl ester,
3,4-Dimethoxy-benzoic acid (S)-2-({1-[4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]-naphthyridin-6-yl)-phenyl]-methanoyl}-isopropyl-amino)-propyl ester,
3,5-Dimethoxy-benzoic acid (S)-2({1-[4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]-naphthyridin-6-yl)-phenyl]-methanoyl}-isopropyl-amino)-propyl ester,
Acetic acid (S)-2-({1-[4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)-phenyl]-methanoyl}-isopropyl-amino)-propyl ester,
Benzoic acid 3-({1-[4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)-phenyl]-methanoyl}-isopropyl-amino)-butyl ester,
Phenyl-acetic acid 3-({1-[4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)-phenyl]-methanoyl}-isopropyl-amino)-butyl ester,
(3,4-Dimethoxy-phenyl)-acetic acid 3-({1-[4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)-phenyl]-methanoyl}-isopropyl-amino)-butyl ester,
4-Nitro-benzoic acid (S)-2-({1-[4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)-phenyl]-methanoyl}-isopropyl-amino-propyl ester,
4-Nitro-benzoic acid (R)-2({1-[4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)-phenyl]-methanoyl}-isopropyl-amino)-propyl ester,
4-((4aR,10bS)-9-Ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)-N-((S)-2-hydroxy-1-methyl-ethyl-N-isopropyl-benzamide,
4-((4aR,10bS)-9-Ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)-N-((R)-2-hydroxy-1-methyl-ethyl-N-isopropyl-benzamide, and pharmaceutically acceptable salts thereof.
5. The method according to claim 1 , in which the hydrogen atoms of the compound of formula 1, in positions 4a and 10b, are in the cis position relative to one another, or a pharmaceutically acceptable salt thereof.
6. The method according to claim 1 wherein the compound of formula 1 has, with respect to the chiral centers, the configuration shown in formulae (1*) or (1**):