Substituted piperidines as Par-1 antagonists
View Patent ↗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.
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
in which
R 2 has the meaning given in claim 1 , and
X 2 represents halogen, preferably bromine or chlorine, or hydroxyl,
to give a compound of the formula
in which
R 1 , R 2 and R 3 have the meaning given in claim 1 ,
or
[D] reacting a compound of the formula (V) with a compound of the formula
in which
R 2 has the meaning given in claim 1 ,
to give a compound of the formula
in which
R 1 , R 2 and R 3 have the meaning given in claim 1 ,
or
[E] reacting a compound of the formula (V) with a compound of the formula
in which
R 2 and R 5 have the meaning given in claim 1 ,
to give a compound of the formula
in which
R 1 , R 2 , R 3 and R 5 have the meaning given in claim 1 ,
or
[F] reacting a compound of the formula (Id) with a compound of the formula
R 4 —X 3 (IX)
in which
R 4 has the meaning given in claim 1 , and
X 3 represents halogen, preferably iodine, bromine or chlorine,
to give a compound of the formula
in which
R 1 , R 2 , R 3 , R 4 and R 5 have the meaning given in claim 1 ,
or
[G] reacting a compound of the formula (V) with a compound of the formula
in which
R 2 has the meaning given in claim 1 , and
X 4 represents chlorine or hydroxyl,
to give a compound of the formula
in which
R 1 , R 2 and R 3 have the meaning given in claim 1 ,
or
[H] reacting a compound of the formula
in which
R 1 and R 3 have the meaning given in claim 1 ,
initially with disuccinimidyl carbonate and then with a compound of the formula
H 2 N—R 2 (XII),
in which
R 2 has the meaning given in claim 1 ,
to give a compound of the formula
in which
R 1 , R 2 and R 3 have the meaning given in claim 1 .
6. A pharmaceutical composition comprising a compound of claim 1 and an inert, nontoxic, pharmaceutically suitable excipient.
7. A method of inhibiting platelet aggregation in a thromboembolic disorders in a human or animal comprising administering thereto an anti-platelet aggregation effective amount of at least one compound of claim 1 .
8. A method of preventing blood coagulation, comprising adding an anticoagulatory amount of a compound according to claim 1 to an in vitro testing media.
9. A method of inhibiting platelet aggregation in a thromboembolic disorder in a human or animal comprising administering thereto an anti-platelet aggregation effective amount of at least one pharmaceutical composition according to claim 6 .