Substituted S-alaninate derivatives

Patent metadata

Field	Value
Publication number	US-11912692-B2
Application number	US-202318233031-A
Country	US
Kind code	B2
Filing date	Aug 11, 2023
Priority date	Sep 3, 2021
Publication date	Feb 27, 2024
Grant date	Feb 27, 2024

Abstract

The invention relates to substituted S-alaninate derivatives and to processes for their preparation, and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular vascular disorders, preferably thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications.

First claim

The invention claimed is:

1. 2-(1-Methyl-1H-imidazol-2-yl)ethyl 3-[(5-chlorothiophene-2-carbonyl)amino]-N-{2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]benzene-1-sulfonyl}-S-alaninate of formula (I)

or a salt thereof, a solvate thereof or a solvate of the salt thereof.

2. 2-(1-Methyl-1H-imidazol-2-yl)ethyl 3-[(5-chlorothiophene-2-carbonyl)amino]-N-{2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]benzene-1-sulfonyl}-S-alaninate according to claim 1 of the formula (I)

3. The salt of the compound of formula (I) according to claim 1 , wherein the salt is a physiologically acceptable salt of the compound of the formula (I).

4. The physiologically acceptable salt of the compound of the formula (I) according to claim 3 selected from the group consisting of:
2-(1-methyl-1H-imidazol-2-yl)ethyl 3-[(5-chlorothiophene-2-carbonyl)amino]-N-{2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]benzene-1-sulfonyl}-S-alaninate hydrochloride,
2-(1-methyl-1H-imidazol-2-yl)ethyl 3-{[(5-chloro-2-thienyl)carbonyl]amino}-N-({2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}sulfonyl)-S-alaninate sulfate,
2-(1-methyl-1H-imidazol-2-yl)ethyl 3-{[(5-chloro-2-thienyl)carbonyl]amino}-N-({2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}sulfonyl)-S-alaninate methanesulfonate,
2-(1-methyl-1H-imidazol-2-yl)ethyl 3-{[(5-chloro-2-thienyl)carbonyl]amino}-N-({2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}sulfonyl)-S-alaninate 4-methylbenzene-sulfonate,
2-(1-methyl-1H-imidazol-2-yl)ethyl 3-{[(5-chloro-2-thienyl)carbonyl]amino}-N-({2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}sulfonyl)-S-alaninate maleate,
2-(1-methyl-1H-imidazol-2-yl)ethyl 3-{[(5-chloro-2-thienyl)carbonyl]amino}-N-({2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}sulfonyl)-S-alaninate phosphate,
2-(1-methyl-1H-imidazol-2-yl)ethyl 3-{[(5-chloro-2-thienyl)carbonyl]amino}-N-({2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}sulfonyl)-S-alaninate (2R,3R)-tartrate,
and
2-(1-methyl-1H-imidazol-2-yl)ethyl 3-{[(5-chloro-2-thienyl)carbonyl]amino}-N-({2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}sulfonyl)-S-alaninate citrate.

5. A process for preparing the compound of the formula (I) or a salt thereof, a solvates thereof or a solvate of the salt thereof according to claim 1 , wherein a compound of the formula

is reacted with a compound of the formula

in the presence of a dehydrating agent to give the compound of the formula (I), and
the compound of formula (I) is optionally converted with the corresponding (i) solvents and/or (ii) bases or acids into solvates, salts and/or solvates of the salts of the compound of formula (I).

6. A method for the treatment and/or prophylaxis of thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications, and/or inflammatory disorders, comprising administering a therapeutic amount of compound of claim 1 to a subject in need thereof.

7. A pharmaceutical formulation comprising the compound of claim 1 and a pharmaceutically suitable excipient.

8. The method of 6 , wherein the subject is an animal or a human.

9. The compound of claim 1 , wherein the salt is 2-(1-methyl-1H-imidazol-2-yl)ethyl 3-[(5-chlorothiophene-2-carbonyl)amino]-N-{2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]benzene-1-sulfonyl}-S-alaninate hydrochloride.

10. The compound of claim 1 , wherein the salt is 2-(1-methyl-1H-imidazol-2-yl)ethyl 3-{[(5-chloro-2-thienyl)carbonyl]amino}-N-({2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}sulfonyl)-S-alaninate sulfate.

11. The compound of claim 1 , wherein the salt is 2-(1-methyl-1H-imidazol-2-yl)ethyl 3-{[(5-chloro-2-thienyl)carbonyl]amino}-N-({2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}sulfonyl)-S-alaninate methanesulfonate.

12. The compound of claim 1 , wherein the salt is 2-(1-methyl-1H-imidazol-2-yl)ethyl 3-{[(5-chloro-2-thienyl)carbonyl]amino}-N-({2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}sulfonyl)-S-alaninate 4-methylbenzene-sulfonate.

13. The compound of claim 1 , wherein the salt is 2-(1-methyl-1H-imidazol-2-yl)ethyl 3-{[(5-chloro-2-thienyl)carbonyl]amino}-N-({2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}sulfonyl)-S-alaninate maleate.

14. The compound of claim 1 , wherein the salt is 2-(1-methyl-1H-imidazol-2-yl)ethyl 3-{[(5-chloro-2-thienyl)carbonyl]amino}-N-({2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}sulfonyl)-S-alaninate phosphate.

15. The compound of claim 1 , wherein the salt is 2-(1-methyl-1H-imidazol-2-yl)ethyl 3-{[(5-chloro-2-thienyl)carbonyl]amino}-N-({2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}sulfonyl)-S-alaninate (2R,3R)-tartrate.

16. The compound of claim 1 , wherein the salt is 2-(1-methyl-1H-imidazol-2-yl)ethyl 3-{[(5-chloro-2-thienyl)carbonyl]amino}-N-({2-ethyl-3-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}sulfonyl)-S-alaninate citrate.

17. The method of claim 6 , wherein the thromboembolic complications is disseminated intravascular coagulation.

Assignees

• Bayer Ag

Inventors

• Beck Hartmut
• Mesch Stefanie
• Vakalopoulos Alexandros
• Pfaff Nils
• Zimmermann Stefanie
• Follmann Markus
• Kersten Elisabeth
• Levilain Guillaume
• Partikel Kartrin
• Broehl Andreas Peter
• Heitmeier Stefan
• Dietze-Torres Julia
• Lehmann Lutz
• Gericke Kersten Matthias
• Süssmeier Frank
• Bärfacker Lars
• Hillisch Alexander
• Tersteegen Adrian
• Buchmüller Anja
• Gerdes Christoph

Classifications

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title

• A61P7/02 Primary

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• C07D409/14 Primary

  containing three or more hetero rings · CPC title