Substituted benzoxazoles
The invention relates to substituted benzoxazoles and to processes for their preparation and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular of cardiovascular disorders, preferably of thrombotic or thromboembolic disorders.
1. A compound of the formula
in which
R 1 represents a group of the formula
where * is the point of attachment to the carbonyl group,
X represents an oxygen atom, a sulphur atom or CH—R 6 , where
R 6 represents hydroxyl,
R 2 represents hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl or phenyl,
where alkyl and cycloalkyl may be substituted by a substituent selected from the group consisting of hydroxy, methoxy, cyano, hydroxycarbonyl, aminocarbonyl, methylsulphonyl, difluoromethoxy and trifluoromethoxy,
or
where alkyl and cycloalkyl may be substituted by 1 to 3 fluorine substituents,
R 3 represents hydrogen or C 1 -C 4 -alkyl,
or
R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring,
where the cyclobutyl ring and the cyclopentyl ring may be substituted by a
hydroxyl substituent,
R 4 represents hydrogen or C 1 -C 6 -alkyl,
where alkyl may be substituted by a hydroxyl substituent,
R 5 represents C 1 -C 4 -alkyl,
or
R 4 and R 5 together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring,
where the cyclobutyl ring and the cyclopentyl ring may be substituted by a
hydroxyl substituent,
R 7 represents hydrogen or C 1 -C 6 -alkyl,
where alkyl may be substituted by a hydroxyl or cyano substituent, or
where alkyl may be substituted by 1 to 3 fluorine substituents,
R 8 represents hydrogen,
R 9 represents hydrogen or C 1 -C 6 -alkyl,
where alkyl may be substituted by a hydroxyl or cyano substituent,
or
where alkyl may be substituted by 1 to 3 fluorine substituents,
R 10 represents hydrogen,
R 11 represents C 1 -C 4 -alkyl,
where alkyl may be substituted by a hydroxyl substituent,
R 12 represents hydrogen or C 1 -C 4 -alkyl,
or
R 11 and R 12 together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring,
where the cyclobutyl ring and the cyclopentyl ring may be substituted by a hydroxyl substituent,
R 13 represents hydroxymethyl or hydroxyethyl,
R 14 represents methoxy or ethoxy,
or one of the salts thereof, solvates thereof or solvates of the salts thereof.
2. The compound of claim 1 , characterized in that
R 1 represents a group of the formula
where * is the point of attachment to the carbonyl group,
X represents an oxygen atom or CH—R 6 ,
where
R 6 represents hydroxyl,
R 2 represents hydrogen, C 1 -C 4 -alkyl or C 3 -C 6 -cycloalkyl,
where alkyl may be substituted by a hydroxyl or hydroxycarbonyl substituent,
and
where cycloalkyl may be substituted by a hydroxyl substituent,
R 3 represents hydrogen or C 1 -C 4 -alkyl,
or
R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl ring,
where the cyclobutyl ring may be substituted by a hydroxyl substituent,
R 4 represents hydrogen or C 1 -C 4 -alkyl,
where alkyl may be substituted by a hydroxyl substituent,
R 5 represents C 1 -C 4 -alkyl,
R 7 represents hydrogen or C 1 -C 4 -alkyl,
R 8 represents hydrogen,
R 9 represents hydrogen or C 1 -C 4 -alkyl,
where alkyl may be substituted by a hydroxyl substituent,
R 10 represents hydrogen,
R 11 and R 12 together with the carbon atom to which they are attached form a cyclobutyl ring,
R 13 represents hydroxymethyl or hydroxyethyl,
R 14 represents methoxy or ethoxy,
or one of the salts thereof, solvates thereof or solvates of the salts thereof.
3. The compound of claim 1 , characterized in that
R 1 represents a group of the formula
where * is the point of attachment to the carbonyl group,
X represents an oxygen atom,
R 2 represents methyl, ethyl or cyclobutyl,
where methyl and ethyl are substituted by a hydroxyl substituent,
and
where cyclobutyl is substituted by a hydroxyl substituent,
R 3 represents hydrogen,
R 4 represents hydrogen or methyl,
and
R 5 represents methyl,
or
R 2 represents methyl,
R 3 represents hydrogen or methyl,
R 4 represents methyl, ethyl or propyl,
where methyl, ethyl and propyl are substituted by a hydroxyl substituent,
and
R 5 represents methyl,
or
R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl ring,
where the cyclobutyl ring is substituted by a hydroxyl substituent,
R 4 represents hydrogen or methyl,
and
R 5 represents methyl,
or one of the salts thereof, solvates thereof or solvates of the salts thereof.
4. The compound of claim 1 , characterized in that
R 1 represents a group of the formula
where * is the point of attachment to the carbonyl group,
X represents an oxygen atom,
R 2 represents methyl or ethyl,
where methyl and ethyl are substituted by a hydroxyl substituent,
R 3 represents hydrogen,
or
R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl ring,
where the cyclobutyl ring is substituted by a hydroxyl substituent,
R 4 represents hydrogen or methyl,
R 5 represents methyl,
R 7 represents hydrogen or methyl,
R 8 represents hydrogen,
or one of the salts thereof, solvates thereof or solvates of the salts thereof.
5. The compound of claim 1 , characterized in that
R 1 represents a group of the formula
where * is the point of attachment to the carbonyl group,
X represents an oxygen atom,
R 2 represents methyl or ethyl,
where methyl and ethyl are substituted by a hydroxyl substituent,
R 3 represents hydrogen,
or
R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl ring,
where the cyclobutyl ring is substituted by a hydroxyl substituent,
R 4 represents hydrogen or methyl,
R 5 represents methyl,
or one of the salts thereof, solvates thereof or solvates of the salts thereof.
6. (2-{[(1S)-1-(3-Chlorophenyl)-2-fluoroethyl]amino}-7-methoxy-1,3-benzoxazol-5-yl)[(2S,5S)-5-(2-hydroxyethyl)-2-methylmorpholin-4-yl]methanone according to claim 1 of the formula below
or one of the salts thereof, solvates thereof or solvates of the salts thereof.
7. (2-{[(1S)-1-(3-Chlorophenyl)-2-fluoroethyl]amino}-7-methoxy-1,3-benzoxazol-5-yl)[(2S,5S)-5-(2-hydroxyethyl)-2-methylmorpholin-4-yl]methanone according to claim 1 of the formula below
8. A method of making a compound of the formula (I) or one of the salts thereof, solvates thereof or solvates of the salts thereof according to claim 1 , characterized in that a compound of the formula
is reacted with a compound of the formula
R 1 —H (III)
in which
R 1 has the meaning given in claim 1
with dehydrating agents.
9. A method for the treatment and/or prophylaxis of cardiovascular diseases comprising administering an effective amount of the compound of claim 1 .
10. A method of making a medicament for the treatment and/or prophylaxis of diseases comprising combining the compound of claim 1 with an inert, nontoxic, pharmaceutically suitable excipient.
11. A method of making a medicament for the treatment and/or prophylaxis of thromboembolic disorders comprising combining the compound of claim 1 with an inert, nontoxic, pharmaceutically suitable excipient.
12. A medicament for the treatment and/or prophylaxis of acute coronary syndrome (ACS), venous thromboembolisms, venous thromboses, pulmonary embolisms, stroke and/or thrombosis prophylaxis in the context of surgical interventions comprising the compound of claim 1 in combination with an inert, nontoxic, pharmaceutically suitable excipient.
13. A medicament comprising the compound of claim 1 , in combination with an inert, nontoxic, pharmaceutically suitable excipient.
14. The medicament of claim 13 for the treatment and/or prophylaxis of thromboembolic disorders.
15. A compound comprising
(A) (2-{[1S)-1-(3-chlorophenyl)-2-fluoroethyl]amino}-7-methoxy-1,3-benzoxazol-5-yl)[(2S,5S)-5-(2-hydroxyethyl)-2-methylmorpholin-4-yllmethanone of the formula below
or one of the salts thereof, solvates thereof or solvates of the salts thereof and
(B) 5-chloro-N-({(5S)-2-oxo-3 [4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (rivaroxaban) having the structural formula
16. A medicament for the treatment and/or prophylaxis of deep leg venous thromboses and kidney venous thromboses comprising the compound of claim 1 in combination with an inert, nontoxic, pharmaceutically suitable excipient.
17. A medicament for the treatment and/or prophylaxis of acute coronary syndrome (ACS), venous thromboembolisms, venous thromboses, pulmonary embolisms, stroke and/or thrombosis prophylaxis in the context of surgical interventions in patients suffering from cancer comprising the compound of claim 1 in combination with an inert, nontoxic, pharmaceutically suitable excipient.