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 process for the preparation of a compound of formula 8
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, comprising:
(a) reacting a compound of formula 12
with concentrated hydrobromic acid under strictly anhydrous conditions,
(b) subjecting the resulting 1-bromo-1-(3,4-dialkoxyphenyl)ethane derivative of formula 11
to a bromo-lithium exchange reaction and then converting with acrolein to yield a 2-(3,4-dialkoxyphenyl)-1,4-pentadien-3-ol derivative of formula 10
(c) oxidizing the 2-(3,4-dialkoxyphenyl)-1,4-pentadien-3-ol derivative of formula 10 to the corresponding 2-(3,4-dialkoxyphenyl)-1,4-pentadien-3-one derivative of formula 9
(d) and converting the 2-(3,4-dialkoxyphenyl)-1,4-pentadien-3-one derivative of formula 9 to a 3-(3,4-dialkoxy-phenyl)-tetrahydro-thiopyran-4-one derivative of formula 8 via a double Michael addition with Na 2 S or NaHS.
2. A compound of formula 8
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.
3. 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.
4. A compound of formula 8 according to claim 2 in which
R1 is methoxy or ethoxy and
R2 is methoxy or ethoxy.
5. A compound of formula 8 according to claim 2 selected from
and
6. A compound of formula 7 according to claim 3 , in which
R1 is methoxy or ethoxy and
R2 is methoxy or ethoxy.
7. A compound of formula 7 according to claim 3 which is