Substituted oxopyridine derivatives and use thereof as factor XIa/plasma

Patent metadata

Field	Value
Publication number	US-9918969-B2
Application number	US-201615332893-A
Country	US
Kind code	B2
Filing date	Oct 24, 2016
Priority date	Jul 23, 2013
Publication date	Mar 20, 2018
Grant date	Mar 20, 2018

Abstract

The invention relates to substituted oxopyridine 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 cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and oedemas, and also ophthalmic disorders.

First claim

The invention claimed is:

1. A method of treating or preventing at least one of a thrombotic disorder and a thromboembolic disorder comprising administering a therapeutically effective amount of a compound of the formula

in which
n represents the number 1 or 2,
A represents —N(R 2 )- or —CH 2 —,
wherein

R 2 represents hydrogen or C1-C4-alkyl,
R 1 represents a group of the formula

where * is the point of attachment to the oxopyridine ring,

R 6 represents bromine, chlorine, fluorine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy,
R 7 represents hydrogen, bromine, chlorine, fluorine, cyano, nitro, hydroxy, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, ethynyl, 3,3,3-trifluoroprop-1-yn-1-yl or cyclopropyl,
R 8 represents hydrogen, chlorine or fluorine,
R 3 represents hydrogen,
R 4 represents hydrogen,
R 5 represents a group of the formula

where # is the attachment site to the nitrogen atom,

R 9 represents hydroxycarbonyl or 5-membered heterocyclyl, where heterocyclyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, hydroxy, thioxo, sulphanyl, methyl, difluoromethyl, trifluoromethyl, 2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl and 2-methoxycarbonyl-1,1,2,2-tetrafluoroethyl,
where methyl may be substituted by a methoxy substituent,

R 10 represents hydrogen, chlorine, fluorine or methyl,
R 11 and R 12 together with the carbon atoms to which they are bonded form a 5-membered heterocycle, where the heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, chlorine, hydroxy, hydroxycarbonyl, methyl, difluoromethyl, trifluoromethyl, 1,1,2,2,2-pentafluoroethyl, 2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl and 2-methoxycarbonyl- 1,1,2,2-tetrafluoroethyl,
R 13 represents hydrogen, chlorine, fluorine, methyl or methoxy, or one of the salts thereof.

2. A pharmaceutical composition comprising an active compound of the formula

in which
n represents the number 1 or 2,
A represents —N(R 2 )- or —CH2—,
wherein

R 2 represents hydrogen or C1-C4-alkyl,
R 1 represents a group of the formula

where * is the point of attachment to the oxopyridine ring,

R 6 represents bromine, chlorine, fluorine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy,
R 7 represents hydrogen, bromine, chlorine, fluorine, cyano, nitro, hydroxy, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, ethynyl, 3,3,3-trifluoroprop-1-yn-1-yl or cyclopropyl,
R 8 represents hydrogen, chlorine or fluorine,
R 3 represents hydrogen,
R 4 represents hydrogen,
R 5 represents a group of the formula

where # is the attachment site to the nitrogen atom,

R 9 represents hydroxycarbonyl or 5-membered heterocyclyl, where heterocyclyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, hydroxy, thioxo, sulphanyl, methyl, difluoromethyl, trifluoromethyl, 2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl and 2-methoxycarbonyl-1,1,2,2-tetrafluoroethyl,
where methyl may be substituted by a methoxy substituent,

R 10 represents hydrogen, chlorine, fluorine or methyl,
R 11 and R 12 together with the carbon atoms to which they are bonded form a 5-membered heterocycle, where the heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, chlorine, hydroxy, hydroxycarbonyl, methyl, difluoromethyl, trifluoromethyl, 1,1,2,2,2-pentafluoroethyl, 2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl and 2-methoxycarbonyl-1,1,2,2-tetrafluoroethyl,
R 13 represents hydrogen, chlorine, fluorine, methyl or methoxy,
or one of the salts thereof combined with one or more inert nontoxic pharmaceutically suitable excipients.

3. A method of treating or preventing at least one of a thrombotic disorder and a thromboembolic disorder comprising administering a therapeutically effective amount of the medicament of claim 2 .

Assignees

• Bayer Pharma AG

Inventors

• Röhrig Susanne
• Hillisch Alexander
• Straβburger Julia
• Heitmeier Stefan
• Schmidt Martina Victoria
• Schlemmer Karl-Heinz
• Buchmüller Anja
• Gerdes Christoph
• Teller Henrik
• Schäfer Martina
• Tersteegen Adrian

Classifications

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title