3-oxa-10-aza-phenanthrenes
View Patent ↗The compounds of formula I in which R1, R2 and R3 have the meanings as given in the description, are novel effective PDE4 inhibitors.
1. A compound of formula 1
in which
R1 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
or in which
R1 and R2 together are a 1-2C-alkylenedioxy group,
R3 is a phenyl radical which is substituted by R4 and R5, wherein
R4 is hydrogen, hydroxyl, halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy,
R5 is CO—R6 or CO—R7, wherein
R6 is hydroxyl, 1-8C-alkoxy, 3-7C-cycloalkoxy or 3-7C-cycloalkylmethoxy and
R7 is N(R71)R72, wherein R71 and R72 independently of one another are hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, or wherein R71 and R72, together and including the nitrogen atom to which both are bonded, are a 1-(1-4C-alkyl)-piperazin-4-yl, 1-pyrrolidinyl, 1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical,
or a hydrate, hydrate of a salt, solvate, solvate of a salt, salt, N-oxide, salt of an N-oxide, hydrate of an N-oxide or solvate of an N-oxide.
2. A compound of formula 1 according to claim 1 in which
R1 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R2 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R3 is a phenyl radical which is substituted by R4 and R5, wherein
R4 is hydrogen,
R5 is CO—R6 or CO—R7, wherein
R6 is hydroxyl, 1-8C-alkoxy, 3-7C-cycloalkoxy or 3-7C-cycloalkylmethoxy and
R7 is N(R71)R72, wherein R71 and R72 independently of one another are hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, or wherein R71 and R72, together and including the nitrogen atom to which both are bonded, are a 1-(1-4C-alkyl)-piperazin-4-yl, 1-pyrrolidinyl, 1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical,
or a hydrate, hydrate of a salt, solvate, solvate of a salt, salt, N-oxide, salt of an N-oxide, hydrate of an N-oxide or solvate of an N-oxide.
3. A compound of formula 1 according to claim 1 in which
R1 is methoxy or ethoxy,
R2 is methoxy or ethoxy,
R3 is a phenyl radical which is substituted by R4 and R5, wherein
R4 is hydrogen,
R5 is CO—R6 or CO—R7, wherein
R6 is hydroxyl or 1-4C-alkoxy and
R7 is N(R71)R72, wherein R71 and R72 independently of one another are hydrogen or 1-4C-alkyl, or wherein R71 and R72, together and including the nitrogen atom to which both are bonded, are a 1-methyl-piperazin-4-yl, 1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical,
or a hydrate, hydrate of a salt, solvate, solvate of a salt, salt, N-oxide, salt of an N-oxide, hydrate of an N-oxide or solvate of an N-oxide.
4. A compound of formula 1 according to claim 1 in which
R1 is methoxy or ethoxy,
R2 is methoxy or ethoxy,
R3 is a phenyl radical which is substituted by R4 and R5, wherein
R4 is hydrogen,
R5 is CO—R6 or CO—R7, wherein
R6 is hydroxyl or methoxy and
R7 is N(R71)R72, wherein R71 and R72 independently of one another are 1-4C-alkyl, or wherein R71 and R72, together and including the nitrogen atom to which both are bonded, are a 1-methyl-piperazin-4-yl or 4-morpholinyl radical,
or a hydrate, hydrate of a salt, solvate, solvate of a salt, salt, N-oxide, salt of an N-oxide, hydrate of an N-oxide or solvate of an N-oxide.
5. A compound of formula 1 according to claim 1 in which
R1 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
or in which
R1 and R2 together are a 1-2C-alkylenedioxy group,
R3 is a phenyl radical which is substituted by R4 and R5, where
R4 is hydrogen, hydroxyl, halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy,
R5 is CO—R6 or CO—R7, where
R6 is hydroxyl, 1-8C-alkoxy, 3-7C-cycloalkoxy or 3-7C-cycloalkylmethoxy and
R7 is N(R71)R72, where R71 and R72 independently of one another are hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, or where R71 and R72, together and including the nitrogen atom to which both are bonded, are a 1-pyrrolidinyl, 1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical,
or a hydrate, hydrate of a salt, solvate, solvate of a salt, salt, N-oxide, salt of an N-oxide, hydrate of an N-oxide or solvate of an N-oxide.
6. A compound of formula 1 according to claim 1 in which
R1 is methoxy or ethoxy,
R2 is methoxy or ethoxy,
R3 is a phenyl radical which is substituted by R4 and R5, where
R4 is hydrogen,
R5 is CO—R6 or CO—R7, where
R6 is 1-2C-alkoxy and
R7 is N(R71)R72, where R71 and R72 independently of one another are 1-4C-alkyl,
or a hydrate, hydrate of a salt, solvate, solvate of a salt, salt, N-oxide, salt of an N-oxide, hydrate of an N-oxide or solvate of an N-oxide.
7. A compound of formula 1 according to claim 1 , in which the hydrogen atoms in positions 4a and 10a are in the cis position relative to one another, or a hydrate, hydrate of a salt, solvate, solvate of a salt, salt, N-oxide, salt of an N-oxide, hydrate of an N-oxide or solvate of an N-oxide.
8. A compound of formula 1 according to claim 1 , which has with respect to the positions 4a and 10a the configuration shown in formula (1*):
or a hydrate, hydrate of a salt, solvate, solvate of a salt, salt, N-oxide, salt of an N-oxide, hydrate of an N-oxide or solvate of an N-oxide.
9. A process for the preparation of a compound of formula 4
comprising
(a) converting a tetrahydro-pyranone derivative of formula 7
with an optical pure 1-phenylethylamine to obtain an imine/enamine of formula 6,
(b) hydrogenating the obtained imine/enamine of formula 6 to obtain a secondary amine of formula 5
(c) separating the 1-phenylethyl radical of formula 5 by hydrogenation, and
(d) optionally converting the compound of formula 4 obtained in steps (a) to (c) into their salts, or converting salts of the compound of formula 4 obtained in the steps (a) to (c) then into free compounds, wherein in the compounds of formulae 4, 5, 6 and 7, R1 and R2 have the meanings given in claim 1 .
10. A compound of formula 4
in which
R1 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine and
R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
or in which
R1 and R2 together are a 1-2C-alkylenedioxy group,
or a hydrate, hydrate of a salt, solvate, solvate of a salt or salt thereof.
11. A compound of formula 4 according to claim 10 in which
R1 is methoxy or ethoxy,
R2 is methoxy or ethoxy,
or a hydrate, hydrate of a salt, solvate, solvate of a salt or salt thereof.
12. A compound of formulae 4a or 4b
in which
R1 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine and
R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
or in which
R1 and R2 together are a 1-2C-alkylenedioxy group,
or a hydrate, hydrate of a salt, solvate, solvate of a salt or salt thereof.
13. A compound of formulae 4a or 4b according to claim 12 , in which
R1 is methoxy or ethoxy,
R2 is methoxy or ethoxy,
or a hydrate, hydrate of a salt, solvate, solvate of a salt or salt thereof.
14. A process for the preparation of a compound of formula 7
comprising
(a) reacting a compound of formula 11
with concentrated hydrobromic acid under strictly anhydrous conditions,
(b) subjecting the resulting 1-bromo-1-(3,4-dialkoxyphenyl)ethane derivative of formula 10
to a bromo-lithium exchange reaction and then converting the reacted derivative of formula 10 with acrolein to yield a 2-(3,4-dialkoxyphenyl)-1,4-pentadien-3-ol derivative of formula 9
(c) oxidizing the 2-(3,4-dialkoxyphenyl)-1,4-pentadien-3-ol derivative of formula 9 to a corresponding 2-(3,4-dialkoxyphenyl)-1,4-pentadien-3-one derivative of formula 8
(d) and converting the 2-(3,4-dialkoxyphenyl)-1,4-pentadien-3-one derivative of formula 8 to a 3-(3,4-dialkoxy-phenyl)-tetrahydro-pyran-4-one derivative of formula 7 via a double Michael addition with KOH,
wherein in the compounds of formulae 7, 8, 9, 10 and 11, R1 and R2 have the meanings given in claim 1 .
15. A compound of formula 7
in which
R1 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine and
R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
or in which
R1 and R2 together are a 1-2C-alkylenedioxy group.
16. A compound of formula 7 according to claim 15 in which
R1 is methoxy or ethoxy and
R2 is methoxy or ethoxy.
17. A pharmaceutical composition comprising one or more compounds of formula 1 according to claim 1 , or a pharmaceutically acceptable hydrate, hydrate of a salt, solvate, solvate of a salt, salt, N-oxide, salt of an N-oxide, hydrate of an N-oxide or solvate of an N-oxide thereof, together with one or more pharmaceutical auxiliaries and/or excipients.
18. A method of treating or preventing a respiratory disease and/or dermatoses in a patient comprising administering to a patient in need thereof a compound of formula 1 according to claim 1 , or a pharmaceutically acceptable hydrate, hydrate of a salt, solvate, solvate of a salt, salt, N-oxide, salt of an N-oxide, hydrate of an N-oxide or solvate of an N-oxide thereof.