Substituted piperidines as Par-1 antagonists

Patent metadata

Field	Value
Publication number	US-8987248-B2
Application number	US-201013202707-A
Country	US
Kind code	B2
Filing date	Mar 12, 2010
Priority date	Mar 23, 2009
Publication date	Mar 24, 2015
Grant date	Mar 24, 2015

Abstract

The invention relates to novel substituted piperidines, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular of cardiovascular disorders and tumor disorders.

First claim

The invention claimed is:

1. A compound of formula (I)

in which
A represents a group of the formula

where
# is the point of attachment to the piperidine ring,
* is the point of attachment to R 2 ,
R 4 represents hydrogen or C 1 -C 3 -alkyl,
and
R 5 represents hydrogen or C 1 -C 3 -alkyl,

R 1 represents phenyl,
where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, methylsulphonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkoxycarbonyl,

R 2 represents phenyl
where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, hydroxyl, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino and phenyl,
where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen and trifluoromethyl,

R 3 represents 4- to 7-membered heterocyclyl,
where heterocyclyl, may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, oxo, hydroxyl, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl and cyclopropyl,
where alkyl may be substituted by a hydroxyl substituent,

or a salt thereof.

2. The compound of claim 1 , wherein
A represents a group of the formula

where
# is the point of attachment to the piperidine ring,
* is the point of attachment to R 2 ,
R 4 represents hydrogen or methyl,
and
R 5 represents hydrogen or methyl,

R 1 represents phenyl,
where phenyl is substituted by 1 or 2 substituents independently of one another selected from the group consisting of trifluoromethyl, trifluoromethoxy, methyl, ethyl, isopropyl, methoxy and ethoxycarbonyl,

R 2 represents phenyl,
where phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, cyano, hydroxyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy and phenyl,
where phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen and trifluoromethyl,

R 3 represents tetrahydrofuranyl, tetrahydropyranyl, morpholin-4-yl, thiomorpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl,
where tetrahydrofuranyl, morpholin-4-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, cyano, oxo, hydroxyl, amino, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, methyl, ethyl, methoxy, ethoxy, dimethylamino, methoxycarbonyl, ethoxycarbonyl, dimethylaminocarbonyl and cyclopropyl,
in which methyl and ethyl may be substituted by a hydroxyl substituent,

or a salt thereof.

3. The compound of claim 1 wherein
A represents a group of the formula

where
# is the point of attachment to the piperidine ring,
* is the point of attachment to R 2 ,

R 1 represents phenyl,
where phenyl is substituted by 1 or 2 substituents independently of one another selected from the group consisting of trifluoromethyl, trifluoromethoxy, methyl and ethyl,

R 2 represents phenyl,
where phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, methyl, methoxy and phenyl,
where phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of chlorine, fluorine and trifluoromethyl,

R 3 represents morpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl, 3-hydroxyazetidiny-1-yl, 3-hydroxypyrrolidin-1-yl, 4-cyanopiperidin-1-yl or 4-hydroxypiperidin-1-yl,
or a salt thereof.

4. The compound of claim 1 , wherein —R 1 and -A-R 2 are in a cis-position to one another.

5. A process for preparing a compound of claim 1 , comprising
[A] reacting a compound of the formula

in which
A, R 1 and R 2 have the meaning given in claim 1 ,
with a compound of the formula

in which
R 3 has the meaning given in claim 1 , and
X 1 represents halogen, preferably bromine or chlorine, or hydroxyl,
or
[B] reacting a compound of the formula (II) with a compound of the formula

in which
R 3a represents C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, 4- to 7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
where alkyl may be substituted by a substituent selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, C 3 -C 7 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl,
where alkoxy may be substituted by a C 1 -C 4 -alkoxy substituent, and

where cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, oxo, hydroxyl, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl and cyclopropyl,
where alkyl may be substituted by a hydroxyl substituent,

to give a compound of the formula

in which
A, R 1 , R 2 and R 3a have the meaning given in claim 1 ,
or
[C] reacting a compound of the formula

in which
R 1 and R 3 have the meaning given in claim 1 ,
with a compound of the formula

Assignees

• Jeske Mario
• Heimbach Dirk
• Röhrig Susanne
• Cancho Grande Yolanda
• Schneider Dirk
• Rester Ulrich
• Bender Eckhard
• Meininghaus Mark
• Zimmermann Katja
• Zubov Dmitry
• Buchmüller Anja
• Von Degenfeld Georges
• Gerdes Christoph
• Gerisch Michael
• Gnoth Mark Jean
• Gericke Kersten Matthias
• Bayer Ip Gmbh

Inventors

• Jeske Mario
• Heimbach Dirk
• Röhrig Susanne
• Cancho Grande Yolanda
• Schneider Dirk
• Rester Ulrich
• Bender Eckhard
• Meininghaus Mark
• Zimmermann Katja
• Zubov Dmitry
• Buchmüller Anja
• Von Degenfeld Georges
• Gerdes Christoph
• Gerisch Michael
• Gnoth Mark Jean
• Gericke Kersten Matthias

Classifications

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title

• C07D211/60 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D413/12

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