Substituted oxopyridine derivatives

Patent metadata

Field	Value
Publication number	US-10414731-B2
Application number	US-201515513982-A
Country	US
Kind code	B2
Filing date	Sep 22, 2015
Priority date	Sep 24, 2014
Publication date	Sep 17, 2019
Grant date	Sep 17, 2019

Abstract

The invention relates to substituted oxopyridine derivatives of formula (I) 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 ompound 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, methylcarbonyl or cyclopropyl,
R 3 is hydrogen, C 1 -C 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, difluoromethoxy, trifluoromethoxy, C 3 -C 6 -cycloalkyl, 4- to 6-membered oxoheterocyclyl, 1,4-dioxanyl, oxazolyl, 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, difluoromethoxy 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,

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

where # is the attachment point to the oxygen atom,
R 10 is hydrogen or methyl,
R 11 is hydrogen or methyl,
R 12 is amino, —N + (CH 3 ) 3 , a 5- or 6-membered nitrogen-containing heterocyclyl or —NH(C═O)R 14 ,
in which heterocyclyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of C 1 -C 3 -alkyl,
and
in which
R 14 is C 1 -C 4 -alkyl, a 5- or 6-membered nitrogen-containing heterocyclyl or cyclopropyl,
in which alkyl may be substituted by a substituent selected from the group consisting of amino, methylamino, dimethylamino and a 5- or 6-membered nitrogen-containing heterocyclyl,
 in which the heterocyclyl may in turn be substituted by 1 to 2 substituents independently of one another selected from the group consisting of C 1 -C 3 -alkyl,
and
in which heterocyclyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of C 1 -C 3 -alkyl,
and
in which cyclopropyl may be substituted by a substituent selected from the group consisting of amino, methylamino and dimethylamino,

R 13 is hydrogen or hydroxycarbonyl,
R 15 is hydrogen or hydroxycarbonyl,
R 16 is hydrogen or methyl,
R 17 is hydrogen or hydroxycarbonyl,
R 18 is hydrogen or methyl,

R 9 is hydrogen or fluorine,
or a salt thereof, a solvate thereof, or a solvate of the salt thereof.

2. A 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 or fluorine,

R 2 is chlorine, cyano, ethoxy, methoxy or difluoromethoxy,
R 3 is methyl, ethyl, n-propyl, 2-methylprop-1-yl or n-butyl,
where methyl may be substituted by a substituent selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, oxazolyl 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
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 oxygen atom,
R 10 is hydrogen or methyl,
R 11 is hydrogen or methyl,
R 12 is amino, —N + (CH 3 ) 3 , pyrrolidinyl, piperidinyl, piperazinyl or —NH(C═O)R 14 ,
in which pyrrolidinyl, piperidinyl and piperazinyl may be substituted by a methyl substituent,
and
in which
R 14 is C 1 -C 4 -alkyl, pyrrolidinyl, piperidinyl, piperazinyl or cyclopropyl, in which alkyl may be substituted by a substituent selected from the group consisting of amino, methylamino, dimethylamino, pyrrolidinyl, piperidinyl and piperazinyl,
in which pyrrolidinyl, piperidinyl and piperazinyl may in turn be substituted by a methyl substituent,

and
in which pyrrolidinyl, piperidinyl and piperazinyl may be substituted by a methyl substituent,
and
in which cyclopropyl may be substituted by a substituent selected from the group consisting of amino, methylamino and dimethylamino,

R 13 is hydrogen or hydroxycarbonyl,
R 15 is hydrogen or hydroxycarbonyl,
R 16 is hydrogen or methyl,
R 17 is hydrogen or hydroxycarbonyl,
R 18 is hydrogen or methyl,

R 9 is hydrogen,
or a salt thereof, a solvate thereof, or a solvate of the salt thereof.

3. A 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 methyl or ethyl,
where methyl may be substituted by a tetrahydro-2H-pyranyl 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 oxygen atom,
R 10 is hydrogen or methyl,
R 11 is hydrogen or methyl,
R 12 is amino, pyrrolidinyl, piperidinyl, piperazinyl or —NH(C═O)R 14 ,
in which piperazinyl may be substituted by a methyl substituent,
and
in which
R 14 is C 1 -C 4 -alkyl, pyrrolidinyl, piperidinyl or cyclopropyl,
in which alkyl may be substituted by a substituent selected from the group consisting of amino, dimethylamino and pyrrolidinyl,
and
in which pyrrolidinyl and piperidinyl may be substituted by a methyl substituent,
and
in which cyclopropyl may be substituted by a dimethylamino substituent,

R 13 is hydrogen or hydroxycarbonyl,
R 15 is hydrogen or hydroxyca

Assignees

• Bayer Pharma AG

Inventors

• Röhrig Susanne
• Hillisch Alexander
• Heitmeier Stefan
• Schmidt Martina Victoria
• Schlemmer Karl-Heinz
• Tersteegen Adrian
• Teller Henrik

Classifications

• A61K31/00

  Medicinal preparations containing organic active ingredients · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61K9/2027

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title

• A61K9/0095

  Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006) · CPC title

• A61K47/36

  Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin · CPC title