Substituted piperidines
The invention relates to novel substituted piperidines, to processes for preparation thereof, to the use thereof for treatment and/or prophylaxis of diseases and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially of cardiovascular disorders and tumour disorders.
1 . A compound of the formula
in which
A is an oxygen atom, a sulphur atom, —NR 4 —, —S(O═)— or —S(═O) 2 —,
where
R 4 is hydrogen or C 1 -C 3 -alkyl, or
R 2 and R 4 together with the nitrogen atom to which they are bonded form a 5- or 6-membered heterocycle,
in which the heterocycle may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen, cyano, hydroxyl, amino, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylamino, or
A is a group of the formula
where
# is the attachment site to the piperidine ring,
* is the attachment site of R 2 , and
R 5 is hydrogen or C 1 -C 3 -alkyl,
R 1 is phenyl,
where phenyl may be substituted by 1 to 3 substituents selected independently 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 is C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
where cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted by 1 to 3 substituents selected independently 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,
in which phenyl may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen and trifluoromethyl, and
where C 1 -C 6 -alkyl may be substituted by one substituent selected from the group consisting of C 1 -C 4 -alkoxy, C 1 -C 4 -alkylsulphonyl, C 3 -C 6 -cycloalkyl and phenyl,
in which cycloalkyl and phenyl may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy,
R 3 is C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 3 -C 7 -cycloalkyl, 4- to 7-membered heterocyclyl, phenyl, 5- or 6-membered heteroaryl, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkylamino, 4- to 7-membered heterocyclylamino, phenylamino or 5- or 6-membered heteroarylamino,
where alkyl, C 2 -C 6 -alkoxy and alkylamino may be substituted by one 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, and
where cycloalkyl, heterocyclyl, phenyl, heteroaryl, cycloalkyloxy, cycloalkylamino, heterocyclylamino, phenylamino and heteroarylamino may be substituted by 1 to 3 substituents selected independently 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,
in which alkyl may be substituted by one hydroxyl substituent,
or one of its salts, its solvates or the solvates of its salts.
2 . A compound according to claim 1 , wherein
A is an oxygen atom, a sulphur atom, —NR 4 —, —S(O═)— or —S(═O) 2 —,
where
R 4 is hydrogen, methyl or ethyl, or
R 2 and R 4 together with the nitrogen atom to which they are bonded form a 3-hydroxypyrrolidin-1-yl, or
A is a group of the formula
where
# is the attachment site to the piperidine ring,
* is the attachment site of R 2 , and
R 5 is hydrogen, methyl or ethyl,
R 1 is phenyl,
where phenyl is substituted by 1 to 2 substituents selected independently from the group consisting of trifluoromethyl, trifluoromethoxy, methyl, ethyl and methoxy,
R 2 is methyl, ethyl, propyl, isopropyl, 2-methylprop-1-yl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl or phenyl,
where phenyl may be substituted by 1 to 2 substituents selected independently from the group consisting of halogen, cyano, methyl, ethyl, methoxy and ethoxy, and
where methyl and ethyl may be substituted by one substituent selected from the group consisting of methoxy, methylsulphonyl and phenyl,
R 3 is morpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl, 3-hydroxyazetidin-1-yl, 3-hydroxypyrrolidin-1-yl, 4-cyanopiperidin-2-yl or 4-hydroxypiperidin-1-yl,
or one of its salts, its solvates or the solvates of its salts.
3 . A compound according to claim 1 , wherein
A is a group of the formula
where
# is the attachment site to the piperidine ring,
* is the attachment site to R 2 , and
R 5 is hydrogen, methyl or ethyl,
R 1 is phenyl,
where phenyl is substituted by 1 to 2 substituents selected independently from the group consisting of trifluoromethyl, trifluoromethoxy, methyl, ethyl and methoxy,
R 2 is methyl, ethyl, propyl, isopropyl, 2-methylprop-1-yl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl or phenyl,
where phenyl may be substituted by 1 to 2 substituents selected independently from the group consisting of halogen, cyano, methyl, ethyl, methoxy and ethoxy, and
where methyl and ethyl may be substituted by one substituent selected from the group consisting of methoxy, methylsulphonyl and phenyl,
R 3 is morpholin-4-yl, thiomorpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl, 3-hydroxyazetidin-1-yl, 3-hydroxypyrrolidin-1-yl, 4-cyanopiperidin-1-yl or 4-hydroxypiperidin-1-yl,
or one of its salts, its solvates or the solvates of its salts.
4 . A compound according to claim 1 , wherein the —R 1 and —CH 2 -A-R 2 substituents are in cis-positions to one another.
5 . A process for preparing a compound of the formula (I) or one of its salts, its solvates or the solvates of its salts according to claim 1 , wherein either
[A] a compound of the formula
in which
R 1 and R 3 are each as defined in claim 1
is reacted with a compound of the formula
H-A-R 2 (III),
in which
R 2 is as defined in claim 1
A is an oxygen atom, an sulphur atom or —NR 4 —, and
R 4 is as defined in claim 1
to give compounds of the formula
in which
A is an oxygen atom, a sulphur atom or —NR 4 —, and
R 1 , R 2 , R 3 and R 4 are each as defined in claim 1 , or
[B] compounds of the formula (I) in which A is sulphur atom and R′, R 2 and R 3 are each as defined above are reacted with an oxidizing agent
to give compounds of the formula
in which
A is —S(═O)— or —S(═O) 2 —, and
R 1 , R 2 and R 3 are each as defined in claim 1 , or
[C] a compound of the formula
in which
R 1 and R 3 are each as defined in claim 1 ,
is reacted with a compound of the formula
in which
R 2 and R 5 are each as defined in claim 1
To give a compound of the formula
in which
R 1 , R 2 , R 3 and R 5 are each as defined in claim 1 , or
[D] a compound of the formula
in which
R 1 and R 3 are each as defined in claim 1
are reacted with compounds of the formula
in which
R 2 is as defined in claim 1 and
X 1 is halogen, preferably bromine or chlorine, or hydroxyl
to give compounds of the formula
in which
R 1 , R 2 and R 3 are each as defined in claim 1 , or
[E] compounds of the formula (VI) are reacted with compounds of the formula
in which
R 2 is as defined in claim 1 and
X 2 is halogen, preferably bromine or chlorine,
to give compounds of the formula
in which
R 1 , R 2 and R 3 are each as defined in claim 1 , or
[F] compounds of the formula
in which
R 1 and R 3 are each as defined in claim 1
are reacted with compounds of the formula
R 2 —N — — O (X)
in which
R 2 is as defined in claim 1 ,
to give compounds of the formula
in which
R 1 , R 2 and R 3 are as defined in claim 1 .
6 . (canceled)
7 . (canceled)
8 . (canceled)
9 . (canceled)
10 . A pharmaceutical composition comprising a compound according to claim 1 in combination with an inert, non-toxic, pharmaceutically acceptable excipient.
11 . A pharmaceutical composition comprising a compound according to claim 1 in combination with a further active ingredient.
12 . (canceled)
13 . A method for the treatment and/or prophylaxis of a thromboembolic disorder comprising administering to a human or animal in need thereof an anticoagulatory amount of a compound according to claim 1 .
14 . A method for the prevention of blood coagulation in vitro, comprising adding to blood ex vivo an anticoagulatory amount of a compound according to claim 1 .
15 . A method for the treatment and/or prophylaxis of a cardiovascular disorder comprising administering to a human or animal in need thereof an effective amount of a compound according to claim 1 .
16 . A method for the treatment and/or prophylaxis of a tumour disorder comprising administering to a human or animal in need thereof an effective amount of a compound according to claim 1 .
17 . A method for the treatment and/or prophylaxis of a thromboembolic disorder comprising administering to a human or animal in need thereof an anticoagulatory amount of a pharmaceutical composition according to claim 10 .
18 . A method for the treatment and/or prophylaxis of a cardiovascular disorder comprising administering to a human or animal in need thereof an anticoagulatory amount of a pharmaceutical composition according to claim 10 .
19 . A method for the treatment and/or prophylaxis of a tumour disorder comprising administering to a human or animal in need thereof an anticoagulatory amount of a pharmaceutical composition according to claim 10 .