Substituted oxopyridine derivatives

Patent metadata

Field	Value
Publication number	US-10071995-B2
Application number	US-201515513930-A
Country	US
Kind code	B2
Filing date	Sep 22, 2015
Priority date	Sep 24, 2014
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

Abstract

The invention relates to substituted oxopyridine derivatives and to processes for preparation thereof, and also to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially of cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and oedemas, and also ophthalmic disorders.

First claim

The invention claimed is:

1. Compound of the formula

in which
R 1 is a group of the formula

where * is the attachment point to the oxopyridine ring,
R 6 is bromine, chlorine, fluorine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoronnethoxy or trifluoromethoxy,
R 7 is bromine, chlorine, fluorine, cyano, nitro, hydroxyl, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoronnethoxy, trifluoromethoxy, ethynyl, 3,3,3-trifluoroprop-1-yn-1-yl or cyclopropyl,
R 8 is hydrogen, chlorine or fluorine,

R 2 is hydrogen, bromine, chlorine, fluorine, cyano, C 1 -C 3 -alkyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, C 1 -C 3 -alkoxy, difluoromethoxy, trifluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, methylcarbonyl or cyclopropyl,
R 3 is hydrogen, C 1 - 5 -alkyl, C 1 -C 4 -alkoxy, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,1,2,2,2-pentadeuteroethyl, 3,3,3-trifluoro-2-hydroxyprop-1-yl, 3,3,3-trifluoro-2-methoxyprop-1-yl, 3,3,3-trifluoro-2-ethoxyprop-1-yl, prop-2-yn-1-yl, cyclopropyloxy or cyclobutyloxy,
where alkyl may be substituted by a substituent selected from the group consisting of fluorine, cyano, hydroxyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoronnethoxy, trifluoromethoxy, C 3 -C 6 -cycloalkyl, 4- to 6-membered oxoheterocyclyl, 1,4-dioxanyl, oxazolyl, pyrazolyl, phenyl and pyridyl,
in which cycloalkyl may be substituted by 1 to 2 substituents selected independently from the group consisting of fluorine, hydroxyl, methyl, ethyl, methoxy, ethoxy, difluoromethyl, trifluoromethyl, difluoronnethoxy and trifluoromethoxy,
and
in which oxoheterocyclyl may be substituted by 1 to 2 substituents selected independently from the group consisting of oxo, fluorine, methyl, ethyl, difluoromethyl and trifluoromethyl,
and
in which oxazolyl and pyrazolyl may be substituted by 1 to 2 substituents selected independently from the group consisting of methyl and ethyl,

R 4 is hydrogen,
R 5 is a group of the formula

where # is the attachment point to the nitrogen atom,
R 15 is hydrogen or fluorine,
R 16 is hydroxyl or —NHR 17 ,
in which
R 17 is hydrogen or C 1 -C 4 -alkyl,

or one of the salts thereof, solvates thereof or solvates of the salts thereof.

2. Compound according to claim 1 , wherein
R 1 is a group of the formula

where * is the attachment point to the oxopyridine ring,
R 6 is chlorine,
R 7 is fluorine, cyano, difluoromethyl or difluoromethoxy,
R 8 is hydrogen,

R 2 is chlorine, cyano, methoxy or difluoromethoxy,
R 3 is methyl, ethyl, n-propyl or n-butyl,
where methyl may be substituted by a substituent selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, tetrahydro-2H-pyranyl, oxazolyl, pyrazolyl and pyridyl,
in which cyclobutyl and cyclohexyl may be substituted by 1 to 2 substituents selected independently from the group consisting of hydroxyl and methoxy,
and
in which oxazolyl and pyrazolyl may be substituted by a methyl substituent,

and
where ethyl, n-propyl and n-butyl may be substituted by a substituent selected from the group consisting of methoxy and trifluoromethoxy,

R 4 is hydrogen,
R 5 is a group of the formula

where # is the attachment point to the nitrogen atom,
R 15 is hydrogen or fluorine,
R 16 is hydroxyl or —NHR 17 ,
in which
R 17 is hydrogen, methyl or ethyl,

or one of the salts thereof, solvates thereof or solvates of the salts thereof.

3. Compound according to claim 1 , wherein
R 1 is a group of the formula

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

R 2 is chlorine or methoxy,
R 3 is methyl or ethyl,
where methyl is substituted by a substituent selected from the group consisting of tetrahydro-2H-pyranyl, oxazolyl and pyridyl,
in which oxazolyl may be substituted by a methyl substituent,

and
where ethyl may be substituted by a methoxy substituent,

R 4 is hydrogen,
R 5 is a group of the formula

where # is the attachment point to the nitrogen atom,
R 15 is hydrogen or fluorine,
R 16 is hydroxyl or —NHR 17 ,
in which
R 17 is hydrogen or methyl,

or one of the salts thereof, solvates thereof or solvates of the salts thereof.

4. Process for preparing a compound of the formula (I) or one of the salts thereof, solvates thereof or solvates of the salts thereof according to claim 1 , comprising reacting either
[A] a compound of the formula

in which
R 1 , R 2 and R 3 have the definition given in claim 1
in a first stage with a compound of the formula

in which
R 4 R 5 have the definition given in claim 1
in the presence of a dehydrating reagent, and
optionally converting in a second stage by acidic or basic ester hydrolysis to a compound of the formula (I),
or
[B] a compound of the formula

in which
R 2 , R 3 , R 4 and R 5 have the definition given in claim 1 , and
X 1 is chlorine, bromine or iodine
with a compound of the formula
R 1 -Q   (V)

in which
R 1 has the definition given in claim 1 , and
Q is —B(OH) 2 , a boronic ester, preferably boronic acid pinacol ester, or —BF 3 − K + ,
under Suzuki coupling conditions to give a compound of the formula (I).

5. Method of using a compound according to claim 1 , a salt thereof, a solvate thereof, or a solvate of salt thereof for treatment a thrombotic or thromboembolic disorder, comprising administering a therapeutically effective amount of said compound, said salt thereof, said solvate thereof, or said solvate of the salt thereof.

6. Method of using a compound, a salt thereof, a solvate thereof, or a solvate of the salt thereof according to claim 1 , for treatment of an ophthalmic disorder, comprising administering a therapeutically effective amount of said compound, said salt thereof, said solvate thereof, or said solvate of the salt thereof to a patient.

7. Method of using a compound, a salt thereof, a solvate thereof, or a solvate of the salt thereof according to claim 1 , for treatment of hereditary angiooedema or an inflammatory di

Assignees

• Bayer Pharma AG

Inventors

• Röhrig Susanne
• Jimenez Núnez Eloisa
• Schlemmer Karl-Heinz
• Tersteegen Adrian
• Teller Henrik
• Hillisch Alexander
• Heitmeier Stefan
• Schmidt Martina Victoria
• Stampfuss Jan

Classifications

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · 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

• C07D409/14

  containing three or more hetero rings · CPC title