3-thia-10-aza-phenanthrene derivatives
View Patent ↗The compounds of formula I in which A, 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
A is S, S(O) or S(O) 2 ,
R1 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R2 is 1-4C-alkoxy or 1-4C-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, 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-pyrrolidinyl, 1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical,
or a salt thereof, an N-oxide thereof, or a salt of an N-oxide thereof.
2. A compound of formula 1 according to claim 1 in which
A is S or S(O),
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-pyrrolidinyl, 1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical,
or a salt thereof.
3. A compound of formula 1 according to claim 1 in which
A is S or S(O),
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-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical,
or a salt thereof.
4. A compound of formula 1 according to claim 1 in which
A is S or S(O),
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, wherein
R6 is 1-2C-alkoxy and
R7 is N(R71)R72, wherein R71 and R72 independently of one another are 1-4C-alkyl,
or a salt thereof.
5. A compound of formula 1 according to claim 1 in which
A is S or S(O),
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—R7, wherein
R7 is N(R71)R72, wherein R71 and R72 are isopropyl,
or a salt thereof.
6. A compound of formula 1 according to claim 1 in which
A is S(O) 2 ,
R1 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R2 is 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
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 salt thereof, an N-oxide thereof, or a salt, of an N-oxide thereof.
7. A compound of formula 1 according to claim 1 in which
A is S(O) 2 ,
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, where
R4 is hydrogen,
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 salt thereof, an N-oxide thereof, or a salt, of an N-oxide thereof.
8. A compound of formula 1 according to claim 1 in which
A is S(O) 2 ,
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 hydroxyl or 1-4C-alkoxy and
R7 is N(R71)R72, where R71 and R72 independently of one another are hydrogen or 1-4C-alkyl, or where R71 and R72, together and including the nitrogen atom to which both are bonded, are a 1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical,
or a salt thereof, an N-oxide thereof, or a salt, of an N-oxide thereof.
9. A compound of formula 1 according to claim 1 in which
A is S(O) 2 ,
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 salt thereof, an N-oxide thereof, or a salt, of an N-oxide thereof.
10. A compound of formula 1 according to claim 1 in which
A is S(O) 2 ,
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—R7, where
R7 is N(R71)R72, where R71 and R72 are isopropyl,
or a salt thereof.
11. 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 salt thereof, an N-oxide thereof, or a salt, of an N-oxide thereof.
12. A compound of formula 1 according to claim 2 , in which the hydrogen atoms in positions 4a and 10a are in the cis position relative to one another, or a salt thereof.
13. 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 salt thereof, an N-oxide thereof, or a salt, of an N-oxide thereof.
14. A compound of formula 1 according to claim 2 , which has with respect to the positions 4a and 10a the configuration shown in formula (1*):
or a salt thereof.
15. A pharmaceutical composition comprising one or more compounds of formula 1 according to claim 1 , or a pharmaceutically acceptable salt thereof, an N-oxide thereof, or a salt an N-oxide thereof, together with one or more pharmaceutical auxiliaries and/or excipients.
16. A pharmaceutical composition comprising one or more compounds of formula 1 according to claim 2 , or a pharmaceutically acceptable salt thereof together with one or more pharmaceutical auxiliaries and/or excipients.