Aminoacyl prodrug derivatives and medicaments for the treatment of thromboembolitic disorders
View Patent ↗The present application relates to prodrug derivatives of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, especially of thromboembolic disorders.
1. A pharmaceutical composition comprising (a) a compound of the formula (I)
in which
R 1 is hydrogen or (C 1 -C 4 )-alkyl which may be substituted by hydroxy or (C 1 -C 4 )-alkoxy,
R 2 is hydrogen or (C 1 -C 4 )-alkyl,
and
L is a (C 1 -C 4 )-alkanediyl group in which one CH 2 group may be replaced by an O atom, or is a group of the formula
in which
* means the point of linkage to the N atom,
R 3 is the side group of a natural α-amino acid or its homologues or isomers,
or
R 3 is linked to R 1 and the two together form a (CH 2 ) 3 or (CH 2 ) 4 group,
R 4 is hydrogen or methyl,
R 5 is (C 1 -C 4 )-alkyl,
and
R 6 is hydrogen or (C 1 -C 4 )-alkyl,
or a salt thereof, and (b) a pharmaceutically acceptable excipient.
2. The pharmaceutical composition according to claim 1 , wherein
R 1 is hydrogen or (C 1 -C 4 )-alkyl,
R 2 is hydrogen,
and
L is a (C 2 -C 4 )-alkanediyl group or is a group of the formula
in which
* means the point of linkage to the N atom,
R 3 is hydrogen, methyl, propan-2-yl, propan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl, 2-carbamoylethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl or 3-guanidinopropan-1-yl,
or
R 3 is linked to R 1 and the two together form a (CH 2 ) 3 or (CH 2 ) 4 group,
R 4 is hydrogen or methyl,
R 5 is methyl,
and
R 6 is hydrogen or methyl.
3. The pharmaceutical composition according to claim 1 , wherein
R 1 is hydrogen, methyl or n-butyl,
R 2 is hydrogen,
and
L is a CH 2 CH 2 group or is a group of the formula
in which
* means the point of linkage to the N atom,
R 3 is hydrogen, methyl, propan-2-yl, propan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl, 2-carbamoylethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl or 3-guanidinopropan-1-yl,
or
R 3 is linked to R 1 and the two together form a (CH 2 ) 3 or (CH 2 ) 4 group,
R 4 is hydrogen or methyl,
and
R 6 is hydrogen or methyl.
4. The pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition is suitable for intravenous use.
5. The pharmaceutical composition according to claim 1 , further comprising a second active ingredient.
6. The pharmaceutical composition according to claim 5 , wherein the second active ingredient is selected from lipid-lowering agents, coronary therapeutics/vasodilators, plasminogen activators and compounds which increase thrombolysis/fibrinolysis, anticoagulants, platelet aggregation-inhibiting substances, fibrinogen receptor antagonists, and antiarrhythmics.
7. A method of treating and/or preventing a thromboembolic disorder comprising administering to a human or animal in need thereof a therapeutically effective amount of a compound of the formula (I)
in which
R 1 is hydrogen or (C 1 -C 4 )-alkyl which may be substituted by hydroxy or (C 1 -C 4 )-alkoxy,
R 2 is hydrogen or (C 1 -C 4 )-alkyl,
and
L is a (C 1 -C 4 )-alkanediyl group in which one CH 2 group may be replaced by an O atom, or is a group of the formula
in which
* means the point of linkage to the N atom,
R 3 is the side group of a natural α-amino acid or its homologues or isomers,
or
R 3 is linked to R 1 and the two together form a (CH 2 ) 3 or (CH 2 ) 4 group,
R 4 is hydrogen or methyl,
R 5 is (C 1 -C 4 )-alkyl,
and
R 6 is hydrogen or (C 1 -C 4 )-alkyl,
or a salt thereof.
8. The method according to claim 7 , wherein
R 1 is hydrogen or (C 1 -C 4 )-alkyl,
R 2 is hydrogen,
and
L is a (C 2 -C 4 )-alkanediyl group or is a group of the formula
in which
* means the point of linkage to the N atom,
R 3 is hydrogen, methyl, propan-2-yl, propan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl, 2-carbamoylethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl or 3-guanidinopropan-1-yl,
or
R 3 is linked to R 1 and the two together form a (CH 2 ) 3 or (CH 2 ) 4 group,
R 4 is hydrogen or methyl,
R 5 is methyl,
and
R 6 is hydrogen or methyl.
9. The method according to claim 7 , wherein
R 1 is hydrogen, methyl or n-butyl,
R 2 is hydrogen,
and
L is a CH 2 CH 2 group or is a group of the formula
in which
* means the point of linkage to the N atom,
R 3 is hydrogen, methyl, propan-2-yl, propan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl, 2-carbamoylethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl or 3-guanidinopropan-1-yl,
or
R 3 is linked to R 1 and the two together form a (CH 2 ) 3 or (CH 2 ) 4 group,
R 4 is hydrogen or methyl,
and
R 6 is hydrogen or methyl.
10. A method of treating and/or preventing a thromboembolic disorder comprising administering to a human or animal in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 1 .
11. A method of treating and/or preventing a thromboembolic disorder comprising administering to a human or animal in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 2 .
12. A method of treating and/or preventing a thromboembolic disorder comprising administering to a human or animal in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 3 .
13. A method of treating and/or preventing a thromboembolic disorder comprising administering to a human or animal in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 4 .
14. A method of treating and/or preventing a thromboembolic disorder comprising administering to a human or animal in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 5 .
15. A method of treating and/or preventing a thromboembolic disorder comprising administering to a human or animal in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 6 .