Heteroaryl-substituted piperidines
View Patent ↗The invention relates to novel heteroaryl-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 diseases and tumor diseases.
1. A compound of the formula
in which
A represents a group of the formula
where
# is the point of attachment to the piperidine ring,
and
* is the point of attachment to R 2 ,
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, C 1 -C 4 -alkoxycarbonyl and C 3 -C 6 -cycloalkyl,
where C 2 -C 4 -alkoxy may be substituted by a substituent selected from the group consisting of methoxy and ethoxy, and
where cycloalkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen and C 1 -C 4 -alkyl,
R 2 represents hydrogen, trifluoromethyl, aminomethyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 1 -C 4 -alkoxycarbonyl, C 3 -C 6 -cycloalkyl, cyclopentenyl, 4- to 6-membered heterocyclyl, phenyl, 1,3-benzodioxolyl, 5- or 6-membered heteroaryl or pyridylaminocarbonyl,
where cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted by1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, 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, C 1 -C 4 -alkoxycarbonylamino, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl,
where alkylamino may be substituted by a substituent selected from the group consisting of C 1 -C 4 -alkoxy and C 1 -C 6 -alkylamino, and
where C 1 -C 4 -alkyl may be substituted by a substituent selected from the group consisting of halogen, hydroxyl, amino, aminocarbonyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkylcarbonyloxy, C 1 -C 4 -alkylsulphonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkoxycarbonylamino, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylamino, 4- to 6-membered heterocyclyl, phenyl, phenoxy, 5-or 6-membered heteroaryl and 5-or 6-membered heteroarylthio,
where cycloalkyl, heterocyclyl, phenyl, phenoxy, heteroaryl and heteroarylthio may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, hydroxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5-or 6-membered heteroaryl,
R 3 represents C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 3 -C 7 -cycloalkyl, 4-to 6-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
where alkyl, C 2 -C 6 -alkoxy and alkylamino may be substituted by a substituent selected from the group consisting of hydroxyl, amino, cyano and C 1 -C 4 -alkoxy, 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, nitro, oxo, hydroxyl, amino, aminomethyl, 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 and C 1 -C 4 -alkylaminocarbonyl,
or one of its salts.
2. A compound according to claim 1 , wherein
A represents a group of the formula
where
# is the point of attachment to the piperidine ring,
and
* 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, ethyl, isopropyl and methoxy,
R 2 represents methyl, ethyl, isopropyl, n-propyl, tert-butyl, methoxycarbonyl, ethoxycarbonyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydropyridinyl, phenyl, 1,3-benzodioxolyl, thienyl, furanyl, pyrrolyl, thiazolyl, isoxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl, where azetidinyl, oxetanyl, pyrrolidinyl, tetrahydropyridinyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, isoxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl and pyrazinyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy and ethylamino,
where ethylamino may be substituted by a substituent selected from the group consisting of methoxy and dimethylamino, and
where methyl and ethyl may be substituted by a substituent selected from the group consisting of hydroxyl, amino, methoxy, ethoxy, isopropoxy, dialkylamino, methylsulphonyl, cyclopropylamino, morpholinyl, phenyl and phenoxy,
where phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, hydroxymethyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy and ethoxy,
R 3 represents tert-butyl, N-methyl-N-ethylamino, methoxyalkylamino, cyclopropyl, cyclopentyl, azetidinyl, 3,3-difluoroazetidinyl, 3-hydroxyazetidinyl, 3-methylazetidinyl, 3-methoxyazetidinyl, 3-dimethylaminoazetidinyl, pyrroldinyl, 3,3-difluoropyrroldin-1-yl, 3-hydroxypyrroldin-1-yl, 3-aminopyrroldin-1-yl, 4,4-difluoropiperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-aminopiperidin-1-yl, 4-cyanopiperidin-1-yl, 3-methoxypiperidin-1-yl, thiazolidinyl, morpholin-4-yl, 2,2-dimethylmorpholin-4-yl, 2-oxopiperazin-1-yl or 3-oxo-4-methylpiperazin-1-yl,
or one of its salts.
3. A compound according to claim 1 , wherein
A represents a group of the formula
where
# is the point of attachment to the piperidine ring,
and
* 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 methyl, ethyl or isopropyl,
where methyl and ethyl may be substituted by a substituent methoxy,
R 3 represents 3-hydroxyazetidinyl, 3-hydroxypyrroldin-1-yl, 4-hydroxypiperidin-1-yl, 4-cyanopiperidin-1-yl or morpholin-4-yl,
or one of its salts.
4. A compound according to claim 1 , wherein the substituents -R 1 and -A-R 2 are in the cis-position to one another.
5. A process for preparing a compound of the formula (I) or one of its salts according to claim 1 , wherein either
[A] a compound of the formula
in which
R 1 and R 3 have the meaning given in claim 1 ,
is reacted with a compound of the formula
in which
R 2 has the meaning given in claim 1 ,
or
[B] a compound of the formula
in which
R 1 and R 3 have the meaning given in claim 1 ,
is reacted with a compound of the formula
in which
R 2 has the meaning given in claim 1 , and
X 1 represents bromine or chlorine,
or
[C] a compound of the formula (II) is reacted with a compound of the formula
R 2 CONHNH 2 (XVI),
in which
R 2 has the meaning given in claim 1 ,
in the presence of phosphoryl chloride or thionyl chloride
or
[D] a compound of the formula (II) is, in the first step, reacted with a compound of the formula
R 2 COCH 2 NH 2 (XVII),
in which
R 2 has the meaning given in claim 1 ,
in the presence of thionyl chloride or phosphoryl chloride,
and, in the second step, reacted with Lawesson reagent
or
[E] a compound of the formula (II) is reacted with a compound of the formula (XVII) in the presence of thionyl chloride or phosphoryl chloride
or
[F] a compound of the formula (II) is, in the first step, reacted with a compound of the formula (XVI) in the presence of thionyl chloride or phosphoryl chloride and, in the second step, reacted with Lawesson reagent
or
[G] a compound of the formula
in which
R 1 and R 3 have the meaning given in claim 1 , and
R 4 represents methyl or ethyl,
is reacted with a compound of the formula
in which
R 2 has the meaning given in claim 1 ,
in the presence of butyllithium
or
[H] a compound of the formula
in which
R 1 and R 3 have the meaning given in claim 1 ,
is reacted with a compound of the formula
in which
R 2 has the meaning given in claim 1 ,
or
[J] a compound of the formula
in which
A, R 1 and R 2 have the meaning given in claim 1 ,
is, in the first step, reacted with 4-nitrophenyl chloroformate and, in the second step, reacted with a compound of the formula
R 3 —H (XXII),
in which
R 3 has the meaning given in claim 1 .
6. A pharmaceutical composition, comprising a compound according to claim 1 in combination with an inert non-toxic pharmaceutically acceptable auxiliary.
7. The pharmaceutical composition of claim 6 , further comprising an active compound selected from the group consisting of calcium channel blockers, statins, cholesterol resorption inhibitors, cholesterol ester transfer protein inhibitors, low-molecular weight heparins, other anticoagulants, antiarrhythmics, alpha-adrenergic agonists, beta-adrenergic blockers, aldosterone antagonists, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, endothelin antagonists, inhibitors of neutral endopeptidase, phosphodiesterase inhibitors, fibrinolytics, GP IIb/IIIa antagonists, direct thrombin inhibitors, indirect thrombin inhibitors, direct and indirect factor Xa inhibitors, direct and indirect factor Xa/IIa inhibitors, lipoprotein-associated phospholipase A2 modulators, diuretics, nitrates, thromboxane antagonists, platelet aggregation inhibitors, cyclooxygenase inhibitors, B-type natriuretic peptides, NV1FGF modulators, HT1B/5-HT2A antagonists, guanylate cyclase activators, e-NOS transcription enhancers, antiatherogenic substances, CPU inhibitors, renin inhibitors, inhibitors of adenosine diphosphate-induced platelet aggregation, NHE-1 inhibitors, antibiotic therapies, and medicaments for proliferative disorders.
8. A method for the treatment of a thromboembolic disorder, comprising administering to a human or animal in need thereof an anticoagulatory amount of at least one compound according to claim 1 , wherein the thromboembolic disorder is selected from ST-segment elevation myocardial infraction (STEMI) and non-ST-segment elevation myocardial infraction (non-STEMI); stable angina pectoris; unstable angina pectoris; reocclusions and restenoses after coronary interventions, angioplasty, stent implantations or aortocoronary bypass; peripheral arterial occlusion diseases; pulmonary embolisms; deep venous thromboses and renal vein thromboses; transitory ischaemic attacks; and thrombotic and thromboembolic stroke.