Substituted oxopyridine derivatives

Patent metadata

Field	Value
Publication number	US-10077265-B2
Application number	US-201515513853-A
Country	US
Kind code	B2
Filing date	Sep 22, 2015
Priority date	Sep 24, 2014
Publication date	Sep 18, 2018
Grant date	Sep 18, 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. A 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, difluoromethoxy, or trifluoromethoxy,
R 7 is bromine, chlorine, fluorine, cyano, nitro, hydroxyl, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, 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, hydroxycarbonyl, methylcarbonyl, or cyclopropyl,
R 3 is hydrogen, C 1 -C 5 -alkyl, C 1 -C 4 -alkoxy, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 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 is optionally substituted by a substituent selected from the group consisting of fluorine, cyano, hydroxyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C 3 -C 6 -cycloalkyl, 4- to 6-membered oxoheterocyclyl, 1,4-dioxanyl, oxazolyl, phenyl, and pyridyl,
in which cycloalkyl is optionally substituted by 1 to 2 substituents independently selected from the group consisting of fluorine, hydroxyl, methyl, ethyl, methoxy, ethoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy,
R 4 is hydrogen,
R 5 is a group of the formula

where # is the attachment point to the nitrogen atom,
R 9 is hydroxycarbonyl, aminocarbonyl, C 1 -C 3 -alkoxycarbonyl, or C 1 -C 3 -alkylaminocarbonyl,
where alkylaminocarbonyl is optionally substituted by a substituent selected from the group consisting of hydroxyl, trifluoromethyl, methoxy, and trifluoromethoxy,
R 10 is hydrogen, chlorine, fluorine, or methyl,
or one of the salts thereof, solvates thereof, or solvates of the salts thereof.

2. The 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, 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 is optionally substituted by a substituent selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, and 1, 4-dioxanyl,
in which cyclobutyl or cyclohexyl is optionally substituted by 1 to 2 substituents independently selected from the group consisting of hydroxyl and methoxy, and
where ethyl, n-propyl, or n-butyl is optionally 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 9 is hydroxycarbonyl, aminocarbonyl, C 1 -C 3 -alkoxycarbonyl, or C 1 -C 3 -alkylaminocarbonyl,
where alkylaminocarbonyl is optionally substituted by a substituent selected from the group consisting of hydroxyl, trifluoromethyl, methoxy and trifluoromethoxy,
R 10 is hydrogen, chlorine, fluorine, or methyl,
or one of the salts thereof, solvates thereof, or solvates of the salts thereof.

3. The 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 methoxy,
R 3 is ethyl,
where ethyl is optionally 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 9 is hydroxycarbonyl, aminocarbonyl, C 1 -C 3 -alkoxycarbonyl, or C 1 -C 3 -alkylaminocarbonyl,
where alkylaminocarbonyl is optionally substituted by a substituent selected from the group consisting of hydroxyl, trifluoromethyl, methoxy, and trifluoromethoxy,
R 10 is hydrogen,
or one of the salts thereof, solvates thereof or solvates of the salts thereof.

4. A 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 , wherein either:
[A] a compound of the formula

is reacted in the first stage with a compound of the formula

in the presence of a dehydrating reagent, and
optionally converted 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
X 1 is chlorine, bromine, or iodine,
is reacted with a compound of the formula
R 1 -Q  (V)

in which
Q is —B(OH) 2 , a boronic ester, or —BF 3 − K + ,
under Suzuki coupling conditions to give a compound of the formula (I).

5. A method of using a compound, a salt thereof, a solvate thereof, or a solvate of a salt thereof according to claim 1 for production of a pharmaceutical composition, the method comprising preparing the pharmaceutical composition comprising (i) the compound, the salt thereof, the solvate thereof, or the solvate of the salt thereof and (ii) inert, non-toxic pharmaceutically suitable excipients in a form suitable for oral administration.

6. A method of using a compound according to claim 1 for treatment of a thrombotic or thromboembolic disorder, the method comprising administering a therapeutically effective amount of the compound to a patient in need thereof.

7. A method of using a compound according to claim 1 for treatment of diabetic retinopathy or macular oedema, the method comprising administering a therapeutically effective amount of the compound to a patient in need thereof.

8. A method of using a compound according to claim 1 for treatment of hereditary angioedema, Crohn's disease, or ulcerative colitis, the method comprising administering a therapeutically effective amount of the compound to a patient in need thereof.

9. A pharmaceutical composition comprising a compound, a salt thereof, a solvate thereof, or a solvate of a salt the

Assignees

• Bayer Pharma AG

Inventors

• Röhrig Susanne
• Hillisch Alexander
• Straβburger Julia
• Heitmeier Stefan
• Schmidt Martina Victoria
• Schlemmer Karl-Heinz
• Tersteegen Adrian
• Buchmüller Anja
• Gerdes Christoph
• Schäfer Martina
• Teller Henrik
• Jiménez Núnez Eloisa
• Schirok Hartmut
• Klar Jürgen
• Lobell Mario

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title