Substituted oxazolidinones and their use
View Patent ↗The invention relates to novel substituted oxazolidinones, to processes for preparation thereof, to the use thereof for treatment and/or prophylaxis of diseases, and to the use thereof for producing medicaments for treatment and/or prophylaxis of diseases, especially of thromboembolic disorders.
1. A compound of the formula
in which
R 1 is a group of the formula
where
# is the attachment site to the phenyl ring,
R 5 is hydrogen or C 1 -C 3 -alkyl,
in which alkyl may be substituted by a hydroxyl substituent,
R 6 is hydrogen, trifluoromethyl, trifluoromethoxy, difluoromethoxy, C 1 -C 3 -alkyl or C 1 -C 4 -alkoxy,
in which alkoxy may be substituted by a substituent, which substituent is selected from the group consisting of halogen, hydroxy, trifluoromethyl, aminocarbonyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylcarbonyl, C 1 -C 4 -alkylaminocarbonyl and morpholinocarbonyl,
R 7 is hydrogen, C 1 -C 3 -alkyl or C 1 -C 4 -alkoxy,
in which C 2 -C 3 -alkyl and C 2 -C 4 -alkoxy may be substituted by a hydroxyl substituent,
R 8 is hydrogen or C 1 -C 3 -alkyl,
in which C 2 -C 3 -alkyl may be substituted by a hydroxyl substituent,
R 9 is hydrogen or C 1 -C 3 -alkyl,
in which C 2 -C 3 -alkyl may be substituted by a hydroxyl substituent,
R 2 is chlorine, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl or cyclopropyl,
R 3 is hydrogen, C 1 -C 3 -alkoxy or C 1 -C 3 -alkylamino,
R 4 is hydrogen or methyl,
or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1 , characterized in that R 1 is a group of the formula
where
# is the attachment site to the phenyl ring,
R 5 is hydrogen or C 1 -C 3 -alkyl,
in which alkyl may be substituted by a hydroxyl substituent,
R 6 is hydrogen, trifluoromethyl, trifluoromethoxy, C 1 -C 3 -alkyl or C 1 -C 4 -alkoxy,
in which alkoxy may be substituted by a substituent, which substituent is selected from the group consisting of halogen, hydroxy, trifluoromethyl, aminocarbonyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylcarbonyl, C 1 -C 4 -alkylaminocarbonyl and morpholinocarbonyl,
R 7 is C 1 -C 4 -alkoxy,
R 8 is C 1 -C 3 -alkyl,
R 9 is hydrogen or C 1 -C 3 -alkyl,
in which C 2 -C 3 -alkyl may be substituted by a hydroxyl substituent,
R 2 is chlorine, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl or cyclopropyl,
R 3 is hydrogen, C 1 -C 3 -alkoxy or C 1 -C 3 -alkylamino, and
R 4 is hydrogen or methyl,
or a pharmaceutically acceptable salt thereof.
3. A compound as claimed in claim 1 , characterized in that
R 1 is a group of the formula
where
# is the attachment site to the phenyl ring,
R 5 is hydrogen or C 1 -C 3 -alkyl,
in which alkyl may be substituted by a hydroxyl substituent,
R 6 is hydrogen, trifluoromethyl, trifluoromethoxy, C 1 -C 3 -alkyl or C 1 -C 4 -alkoxy,
in which alkoxy may be substituted by a substituent, which substituent is selected from the group consisting of halogen, hydroxy, trifluoromethyl, aminocarbonyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylcarbonyl, C 1 -C 4 -alkylaminocarbonyl and morpholinocarbonyl,
R 7 is C 1 -C 4 -alkoxy,
R 9 is hydrogen or C 1 -C 3 -alkyl,
in which C 2 -C 3 -alkyl may be substituted by a hydroxyl substituent,
R 2 is chlorine, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl or cyclopropyl,
R 3 is hydrogen, C 1 -C 3 -alkoxy or C 1 -C 3 -alkylamino, and
R 4 is hydrogen or methyl,
or a pharmaceutically acceptable salt thereof.
4. A compound as claimed in claim 1 , characterized in that
R 1 is a group of the formula
where
# is the attachment site to the phenyl ring,
R 5 is hydrogen,
R 6 is hydrogen or C 1 -C 4 -alkoxy,
in which alkoxy may be substituted by a hydroxyl substituent,
R 7 is ethoxy,
R 9 is hydrogen, methyl or 2-hydroxyeth-1-yl,
R 2 is methyl, isopropyl, methoxy, ethoxy, methoxymethyl or cyclopropyl,
R 3 is hydrogen, and
R 4 is hydrogen or methyl,
or a pharmaceutically acceptable salt thereof.
5. A process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 , characterized in that
[A] the compound of the formula
is reacted in the first stage with a compound of the formula
in which R 1 , R 2 , R 3 and R 4 are each as defined in claim 1
to give a compound of the formula
in which R 1 , R 2 , R 3 and R 4 are each as defined in claim 1 ,
and, in the second stage, in the presence of phosgene or phosgene equivalents, the latter is cyclized to a compound of the formula (I),
or
[B] a compound of the formula
in which R 1 , R 2 , R 3 and R 4 are each as defined in claim 1
is reacted with a compound of the formula
in which
X is halogen or hydroxy.
6. A pharmaceutical composition comprising a compound as claimed in claim 1 in combination with an inert nontoxic pharmaceutically suitable excipient.
7. A method for treatment and/or prophylaxis of thromboembolic disorders in humans and animals using an anticoagulatory amount of at least one compound as claimed in claim 1 .
8. A method for preventing blood coagulation in vitro, characterized in that an anticoagulatory amount of a compound as claimed in claim 1 is added.