4-Heteroaryl-tetrahydroquinolines and their use as inhibitors of the cholesterin-ester transfer protein
Hetero-tetrahydroquinolines can be prepared either by condensing correspondingly substituted hetero-tetrahydroquinoline aldehydes with the desired substituent or by reducing the corresponding keto-substituted hetero-tetrahydroquinolines, followed by introduction of the desired substituent by customary methods. The hetero-tetrahydroquinolines are suitable for use as active compounds in medicaments, in particular in medicaments for treating artheriosclerosis and dyslipidaemias.
1. A pyridinyl-tetrahydroquinolin-5-one compound of the formula:
in which
A represent pyridinyl, which is optionally substituted up to 5 times by identical or different substituents from the group consisting of halogen, nitro, hydroxyl, trifluorometbyl, trifluoromethoxy and straight-chain or branched alky, acyl, hydroxyalkyl or alkoxy having in each case up to 7 carbon atoms, or by a group of the formula —NR 3 R 4 , in which
R 3 and R 4 are identical or different and represent hydrogen, pheny or straight-chain or branched alkyl having up to 6 carbon atoms,
D represents aryl having 6 to 10 carbon atoms which is optionally substituted by phenyl, nitro, halogen, trifluorornethyl or trifluoromethoxy, or
represents a radical of the formula
in which
R 5 , R 6 and R 9 independently of one another represent cycloalkyl having 3 to 6 carbon atoms, or
represent aryl having 6 to 10 carbon atoms, which optionally substituted up to 5 times by identical or different substituents from the group consisting of halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, and straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, by aryl or by trifluoromethyl-substituted aryl having in each case 6 to 10 carbon atoms,
and/or by a group of the formula —OR 10 , —SR 11 , —SO 2 R 12 or —NR 13 R 14
in which
R 10 , R 11 and R 12 independently of one another represent aryl having 6 to 10 carbon atoms which for its part is substituted up to 2 times by identical or different substituents from the group consisting of phenyl, halogen and straight-chain or branched alkyl having up to 6 carbon atoms,
R 13 and R 14 are identical or different and have the meaning of R 3 and R 4 given above,
R 7 represents hydrogen or halogen, and
R 8 represents hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having in each case up to 6 carbon atoms or a radical of the formula —NR 15 R 16 ,
in which
R 15 and R 16 are identical or different and have the meaning of R 3 and R 4 given above, or
R 7 and R 8 together form a radical of the formula ═O or ═NR 17 ,
in which
R 17 represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 6 carbon atoms,
L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 8 carbon atoms which are optionally substituted up to 2 times by hydroxyl,
T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 8 carbon atoms, or
T or X represents a bond,
V represents an oxygen or sulphur atom or represents an —NR 18 group,
in which
R 18 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, and
E represents cycloalkyl having 3 to 8 carbon atoms, or
represents straight-chain or branched alkyl having up to 8 carbon atoms which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or hydroxyl, or represents phenyl which is optionally substituted by halogen or trifluoromethyl, and
wherein the tetrahydroquinolin-5-yl moiety is optionally substituted by one or more alkyl groups having a collective total of 1–3 carbon atoms,
or a salt of said compound or an N-oxide of said compound or said salt.
2. The compound according to claim 1 ,
in which
A represents pyridinyl, which is optionally substituted up to 2 times by identical or different substituents from, the group consisting of fluorine, chlorine, bromine, amino, hydroxyl, trifluoromethyl, trifluoromethoxy and straight-chain or branched alkyl, and alkoxy having in each case up to 6 carbon atoms,
D represents phenyl which is optionally substituted by nitro, fluorine, chlorine, bromine. phenyl, trifluoromethyl or trifluoromethoxy, or
represents a radical of the formula
in which
R 5 , R 6 and R 9 independently of one another represent cyclopropyl, cyclopentyl or cyclohexyl, or
represent phenyl, which is optionally substituted up to 3 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, trifluoromethyl-substituted phenyl and phenyl,
R 7 represents hydrogen, fluorine, chlorine or bromine, and
R 8 represents hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having in each case up to 5 carbon atoms or a radical of the formula —NR 5 R 6 ,
in which
R 15 and R 16 are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, or
R 7 and R 8 together form a radical of the formula ═O or ═NR 17 ,
in which
R 17 represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each ease up to 4 carbon atoms,
L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 6 carbon atoms which are optionally substituted up to 2 times by hydroxyl,
T and X are identical or different and represent a sfraight-chain or branched alkylene chain having up to 6 carbon atoms, or
T or X represents a bond,
V represents an oxygen or sulphur atom or represents a group of the formula —NR 18 ,
in which
R 18 represents hydrogen or straight-chain or branched aikyl having up to 4 carbon atoms or phenyl,
E represents cyclopropyl, -butyl, -pentyl, -hexyl or -heptyl, or
represents straight-chain or branched all having up to 6 carbon atoms which is optionally substituted by cyclopropyl, -butyl, -hexyl, -pentyl, -heptyl or by hydroxyl, or represents phenyl which is optionally substituted by fluorine, chlorine or trifluoromethyl, and
wherein the tetrahydroquinolin-5-yl moiety is optionally substituted by one or more alkyl groups having a collective total of 1–3 carbon atoms,
or a salt of said compound or an N-oxide of said compound or said salt.
3. The compound according to claim 1 ,
in which
A represents pyridyl, which is optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy and straight-chain or branched all or alkoxy having in each case up to 5 carbon atoms,
D represents phenyl which is optionally substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or
represents a radical of the formula
in which
R 5 , R 6 and R 9 independently of one another represent cyclopropyl, cyclopentyl or cyclohexyl, or
represent phenyl or naphthyl, which are optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy and straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,
R 7 represents hydrogen or fluorine, and
R 8 represents hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, or straight-chain or branched alkoxy or alkyl having in each case up to 4 carbon atoms or a radical of the formula —NR 15 R 16 ,
in which
R 15 and R 16 are identical or different and represent hydrogen or straight-chain or branched all having up to 3 carbon atoms, or
R 7 and R 8 together represent a radical of the formula ═O,
L represents a straight-chain or branched alkylene or alkenylene chain having in each case tip to 5 carbon atoms which are optionally substituted up to 2 times by hydroxyl,
T and X are identical or different and represent a straight-chain or branched alkylene chain having up to 3 carbon atoms, or
T or X represents a bond,
V represents an oxygen or sulphur atom or a group of the formula —NR 18 ,
in which
R 8 represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl which is optionally substituted by fluorine or trifluoromethyl, or
represents straight chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, and
wherein the tetrahydroquinolin-5-yl moiety is optionally substituted by one or more alkyl groups having a collective total of 1–3 carbon atoms,
or a salt of said compound or an N-oxide of said compound or said salt.
4. The compound according to claim 1 ,
in which
A represents pyridinyl,
D represents phenyl which is optionally substituted by trifluoromethyl, fluorine, or
represents a radical of the formula
in which
R 6 represents phenyl which is optionally substituted by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl having in each case up to 4 carbon atoms.
R 7 represents hydrogen or fluorine, and
R 8 represents hydrogen, fluorine, chlorine, hydroxyl, methoxy, or
R 7 and R 8 together represent a radical of the formula ═O,
E represents cyclopropyl, cyclopentyl or cyclohexyl, or
represents straight-chain or branched all having up to 4 carbon atoms, and
wherein the tetrahydroquinolin-5-yl moiety is optionally substituted by one or more alkyl groups having a collective total of 1–3 carbon atoms,
or a salt of said compound or an N-oxide of said compound or said salt.
5. The compound according to claim 1 , which has the formula:
or a salt of said compound or an N-oxide of said compound or said salt.
6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the pyridinyl-tetrahydroquinolin-5-one compound according to claim 1 , or a salt or an N-oxide of said compound or said salt.
7. A method of treating hyperlipoproteinanaemia comprising administering to a patient in need thereof an effective amount therefor of the composition according to claim 6 .
8. A method of treating arteriosclerosis comprising administering to a patient in need thereof an effective amount therefor of the composition according to claim 6 .
9. A method of treating dislipidaemia comprising administering to a patient in need thereof an effective amount therefor of the composition according to claim 6 .