Patent EA-001551-B1 (EA)
Title: Benzonaphthyridines as bronchial therapeutics.
Inventor: GUTTERER BEATE
IPC: C07D471/04
Filed: 1997-11-05
Abstract: 1. A compound of formula I   in which R1 is C1-C4alkyl, R2 is hydroxyl, C1-C4alkoxy, C3-C7cycloalkoxy, C3-C7cycloalkylmethoxy or C1-C4alkoxy which is completely or predominantly substituted by fluorine, R3 is hydroxyl, C1-C4alkoxy, C3-C7cycloalkoxy, C3-C7cycloalkylmethoxy or C1-C4alkoxy which is completely or predominantly substituted by fluorine, or in which R2 and R3 together are a C1-C2alkylenedioxy group, R4 is a phenyl radical which is substituted by R5 and R6, where R5 is hydrogen, hydroxyl, halogen, nitro group, C1-C4alkyl, trifluoromethyl or C1-C4alkoxy, R6 is CO-R7 or CO-R8, where R7 is hydroxyl, C1-C8alkoxy, C3-C7cycloalkoxy or C3-C7cycloalkylmethoxy and R8 is N(R81)R82, where each of R81 and R82 independently of one another are hydrogen, C1-C7alkyl, C3-C7cycloalkyl or C3-C7cycloalkylmethyl, or where R81 and R82, together with the nitrogen atom to which both are bonded, are 1-pyrrolidinyl, 1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical, or salts thereof. 2. The compounds of formula I according to claim 1, in which R1 is C1-C4alkyl, R2 is C1-C4alkoxy, C3-C7cycloalkoxy, C3-C7cycloalkylmethoxy or C1-C2alkoxy which is completely or predominantly substituted by fluorine, R3 is C1-C4alkoxy, C3-C7cycloalkoxy, C3-C7cycloalkylmethoxy or C1-C2alkoxy which is completely or predominantly substituted by fluorine, R4 is a phenyl radical which is substituted by R5 and R6, where R5 is hydrogen, hydroxyl, halogen, nitro group, C1-C4alkyl, trifluoromethyl or C1-C4alkoxy, R6 is CO-R7 or CO-R8, where R7 is hydroxyl, C1-C8alkoxy, C3-C7cycloalkoxy or C3-C7cycloalkylmethoxy and R8 is N(R81)R82, where R81 and R82 independently of one another are hydrogen, C1-C7alkyl, C3-C7cycloalkyl or C3-C7cycloalkylmethyl, or where R81and R82, together with the nitrogen atom to which both are bonded, are 1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical, or salts thereof. 3. The compounds of formula I according to claim 1, in which R1 is methyl, R2 is C1-C4alkoxy, C3-C7cycloalkoxy or C1-C2alkoxy which is completely or predominantly substituted by fluorine, R3 is C1-C4alkoxy, C3-C7cycloalkoxy or C1-C2alkoxy which is completely or predominantly substituted by fluorine, R4 is a phenyl radical which is substituted by R5 and R6, where R5 is hydrogen, hydroxyl, C1-C4alkyl or C1-C4alkoxy, R6 is CO-R7 or CO-R8, where R7 is hydroxyl, C1-C8alkoxy or C3-C7cycloalkoxy and R8 is N(R81)R82, where R81and R82 independently of one another are hydrogen, C1-C7alkyl or C3-C7cycloalkyl, or where R81 and R82, together with the nitrogen atom to which both are bonded, are 1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical, or salts thereof. 4. The compounds of formula I according to claim 1, in which R1 is methyl, R2 is methoxy or ethoxy, R3 is methoxy or ethoxy, R4 is a phenyl radical which is substituted by R5 and R6, where R5 is hydrogen, R6 is CO-R7 or CO-R8, where R7 is hydroxyl or C1-C8alkoxy and R8 is N(R81)R82, where R81 and R82 independently of one another are hydrogen or C1-C4alkyl or C5-C7cycloalkyl, or where R81 and R82, together with the nitrogen atom to which both are bonded, are 1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical, or salts thereof. 5. The compounds of formula I according to claim 1, in which R1 is methyl, R2 is ethoxy, R3 is methoxy or ethoxy, R4 is a phenyl radical which is substituted by R5 and R6, where R5 is hydrogen, R6 is CO-R7 or CO-R8, where R7 is hydroxyl or C1-C4alkoxy and R8 is N(R81)R82, where R81 and R82 independently of one another are C1-C4alkyl or C5-C7cycloalkyl, or where R81 and R82, together with the nitrogen atom to which both are bonded, are 1-piperidyl or 1-hexahydroazepinyl radical, or salts thereof. 6. The compounds of formula I according to claim 1, in which the hydrogen atoms in positions 4a and 10b are in the cis position relative to one another, and salts thereof. 7. The compounds of formula I according to claim 1, which in the positions 4a and 10b have the same absolute configuration as the compound (-)-cis-4-amino-3-(3,4-dimethoxyphenyl)-1-methylpiperidine dihydrochloride having the angle of rotation of optical polarization plane [α]<22>D=-57.1 degree  (c=1, methanol) which can be used as source material. 8. A compound selected from the group consisting of cis-8,9-diethoxy-6-(4-isopropoxycarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine; cis-8,9-diethoxy-6-(4-diisopropylaminocarbonylphenyl-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine; cis-8,9-diethoxy-6-(4-N-cyclohexyl-N-isopropylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine; cis-8,9-diethoxy-6-(4-dibutylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine; cis-8,9-diethoxy-6-[4-(hexahydroazepin-1-ylcarbonyl)phenyl]-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine; cis-8,9-diethoxy-6-[4-(piperidin-1-ylcarbonyl)phenyl]-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridine; cis-9-ethoxy-8-methoxy-6-(4-diisopropylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine; cis-9-ethoxy-8-methoxy-6-(4-dibutylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine; cis-9-ethoxy-8-methoxy-6-[4-(hexahydroazepin-1-yl-carbonyl)phenyl]-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine; cis-9-ethoxy-8-methoxy-6-[4-(piperidin-1-ylcarbonyl)phenyl]2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine and salts thereof which can be obtained using (-)-cis-4-amino-3-(3,4-diethoxyphenyl)-1-methylpiperidinedihydrochloride or (-)-cis-4-amino-3-(3-ethoxy-4-methoxy)-1-methylpiperidinedihydrochloride as source material. 9. A medicament composition comprising one or more compounds according to claim 1 together with customary pharmaceutical auxiliaries and/or excipients. 10. The use of compounds according to claim 1 for producing of medicaments for treating of an airway disorders and/or dermatosis. 11. The compounds of formula I according to claim 1, in which R1 is methyl, R2 is ethoxy, R3 is methoxy, R4 is a phenyl radical which is substituted by R5 and R6, where R5 is hydrogen, R6 is CO-R8, where R8 is N(R81)R82 and R81 and R82 are isopropyl, or salts thereof. 12. The compound of formula I according to claim 7, which is (-)-cis-9-ethoxy-8-methoxy-6-(4-diisopropylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine or salts thereof.