Substituted oxopyridine derivatives and use thereof as factor xia/plasma

Patent metadata

Field	Value
Publication number	US-9475809-B2
Application number	US-201414906771-A
Country	US
Kind code	B2
Filing date	Jul 21, 2014
Priority date	Jul 23, 2013
Publication date	Oct 25, 2016
Grant date	Oct 25, 2016

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 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 C 1 -C 4 -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. The compound according to claim 1 , characterized in that
n represents the number 1 or 2,
A represents —N(R 2 )— or —CH 2 —,
wherein
R 2 represents hydrogen or methyl,

R 1 represents a group of the formula

where * is the point of attachment to the oxopyridine ring,
R 6 represents chlorine,
R 7 represents hydrogen, bromine, chlorine, cyano, methyl, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy,
R 8 represents hydrogen 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, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl,
where oxadiazolyl, pyrazolyl, imidazolyl and triazolyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, hydroxy, methyl and trifluoromethyl,

R 10 represents hydrogen.

3. The compound according to claim 1 , characterized in that
n represents the number 1 or 2,
A represents —CH 2 —,
R 1 represents a group of the formula

where * is the point of attachment to the oxopyridine ring,
R 6 represents chlorine,
R 7 is bromine or cyano,
R 8 represents hydrogen,

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, oxadiazolyl, pyrazolyl or tetrazolyl,
where oxadiazolyl and pyrazolyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, hydroxy and trifluoromethyl,

R 10 represents hydrogen.

4. A process for preparing a compound of the formula (I) according to claim 1 , characterized in that either
[A] a compound of the formula

in which
n, A , R 1 , R 3 , R 4 and R 10 are each as defined in claim 1 , and
R 14 represents tert-butyl,
is reacted with an acid to give a compound of the formula

in which
n, A, R 1 , R 3 , R 4 and R 10 are each as defined in claim 1 , and
R 9 represents hydroxycarbonyl,
or
[B] a compound of the formula

in which
n, A, R 1 , R 3 , R 4 and R 10 are each as defined in claim 1 , and
R 14 represents methyl or ethyl,
is reacted with a base to give a compound of the formula

in which
n, A, R 1 , R 3 , R 4 and R 10 are each as defined in claim 1 , and
R 9 represents hydroxycarbonyl,
or
[C] a compound of the formula

in which
n, A, R 1 and R 3 are each as defined in claim 1 ,
is reacted with a compound of the formula

in which
R 4 and R 5 are each as defined in claim 1 ,
in the presence of a dehydrating reagent to give a compound of the formula (I),
or
[D] a compound of the formula

in which
n, A,R 1 , R 3 , R 4 and R 5 are each as defined in claim 1 ,
is reacted with an oxidizing agent, wherein the oxidizing agent is ammonium cerium (IV) nitrate, 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (DDQ), manganese(IV) oxide, potassium permanganate, bromine, or N-bromosuccinimide/dibenzoyl peroxide.

5. A pharmaceutical composition comprising the Compound according to claim 1 .

6. A pharmaceutical composition comprising a compound according to claim 1 in combination with, a pharmaceutically suitable excipient.

7. A method of treating of thrombotic or thromboembolic disorders in a patient comprising administering a therapeutically effective amount of a pharmaceutical composition according to claim 6 .

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

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P29/00

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

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title