4-heteroaryl-tetrahydroquinolines and their use as inhibitors of the cholesterin-ester transfer protein

1. A hetero-tetrahydroquinoline according to the formula:

in which A represents a radical of the formula:

and wherein

D represents aryl having 6 to 10 carbon atoms, which is optionally substituted one or more times by phenyl, nitro, halogen, trifluoromethyl, trifluoromethoxy,

or

represents a radical of the formula:

in which

R 5 , R 6 and R 9 independently represent cycloalkyl having 3 to 6 carbon atoms, or aryl having 6 to 10 carbon atoms,

which are 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 having up to 6 carbon atoms, straight-chain or branched alkyl having up to 6 carbon atoms, straight-chain or branched alkylthio having up to 6 carbon atoms, straight-chain or branched alkylalkoxy having up to 6 carbon atoms, straight-chain or branched alkoxy having up to 6 carbon atoms or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, aryl having 6 to 10 carbon atoms, trifluoromethyl-substituted aryl having 6 to 10 carbon atoms, radicals of the formula —OR 10 , radicals of the formula —SR 11 , radicals of the formula —SO 2 R 12 and radicals of the formula:

—NR 13 R 14 ,

in which

R 10 , R 11 and R 12 represent aryl having 6 to 10 carbon atoms which is substituted up to 2 times by identical or different substituents selected from the group consisting of phenyl, halogen and straight-chain or branched alkyl having up to 6 carbon atoms;

R 13 and R 14 represent hydrogen, phenyl, or straight-chain or branched alkyl having up to 6 carbon atoms;

R 7 represents hydrogen or halogen, and

R 8 represents hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, straight-chain or branched alkoxy having up to six carbon atoms, straight-chain or branched alkyl having up to six 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, phenyl, or

straight-chain or branched alkyl having up to 6 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 having up to 6 carbon atoms, straight-chain or branched alkoxy having up to 6 carbon atoms or straight-chain or branched acyl having up to 6 carbon atoms,

L represents a straight-chain or branched alkylene having up to 8 carbon atoms or straight-chain or branched alkenylene chain having up to 8 carbon atoms, each of which alkylene or alkenylene 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 sulfur atom or represents an —NR 18 group,

in which

R 18 represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,

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

R 19 represents hydrogen; or represents cycloalkyl having 3 to 7 carbon atoms; or

represents straight-chain or branched silylalkyl having up to 8 carbon atoms;

or represents straight-chain or branched alkyl having up to 8 carbon atoms,

which alkyl is optionally substituted by hydroxyl; or straight-chain or branched alkoxy having up to 6 carbon atoms; a radical of the formula —OR 22 ; or phenyl, which phenyl is optionally substituted by halogen, nitro, trifluoromethyl, trifluoromethoxy, phenyl or tetrazole-substituted phenyl;

in which R 22 represents straight-chain or branched acyl having up to 4 carbon atoms or benzyl;

or

R 19 represents straight-chain or branched acyl having up to 20 carbon atoms or benzoyl which is optionally substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or

represents straight-chain or branched fluoroacyl having up to 8 carbon atoms and 9 fluorine atoms

or a salt of said compound or or an N-oxide of said compound or said salt.

2. The hetero-tetrahydroquinoline according to claim 1 , in which

A is optionally substituted up to 2 times by one or more substituents selected from the group consisting of fluorine, chlorine, bromine, amino, hydroxyl, trifluoromethyl, trifluormethoxy, straight-chain or branched alkyl having up to 6 carbon atoms, and straight-chain or branched alkoxy having up to 6 carbon atoms;

D represents aryl having 6 to 10 carbon atoms, which is optionally substituted one or more times by phenyl, nitro, chlorine, bromine, fluorine, trifluoromethyl, trifluoromethoxy, or represents a radical of the formula:

in which,

R 5 , R 6 and R 9 independently represent cyclopropyl, cyclopentyl, cyclohexyl, phenyl or napththyl, each of which are optionally substituted up to 3 times by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl having up to 4 carbon atoms, straight-chain or branched alkyl having up to 4 carbon atoms, straight-chain or branched alkylthio having up to 4 carbon atoms, straight-chain or branched alkylalkoxy having up to 4 carbon atoms, straight-chain or branched alkoxycarbonyl having 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 having up to 5 carbon atoms, or straight-chain or branched alkoxy alkyl having up to 5 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, 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, straight-chain or branched alkyl having up to 4 carbon atoms, straight-chain or branched alkoxy having up to 4 carbon atoms, straight-chain or branched acyl having up to 4 carbon atoms;

L represents a straight-chain or branched alkylene having up to 6 carbon atoms, or straight-chain or branched alkenylene having to 6 carbon atoms, each of which alkylene or alkenylene 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 6 carbon atoms;

or

T or X represents a bond,

V represents an oxygen or sulfur atom or represents an —NR 18 group;

in which

R 18 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl,

E represents cyclopropyl, cyclobutyl, cylcopentyl, cyclohexyl, cycloheptyl, or

represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by cyclopropyl, cylcopentyl, cyclohexyl, cycloheptyl, or hydroxyl; or

represents phenyl which is optionally substituted by fluorine, chlorine or trifluoromethyl;

and,

R 19 represents hydrogen, or represents cyclopropyl, cyclopentyl, cyclohexyl, or represents straight-chain or branched silylalkyl having up to 7 carbon atoms, or

represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, straight-chain or branched alkoxy having up to 4 carbon atoms, a radical of the formula —OR 22 or by phenyl which is optionally substituted by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy or by phenyl or tetrazole-substituted phenyl,

in which

R 22 represents straight-chain or branched acyl having up to 3 carbon atoms or benzyl;

or,

R 19 represents straight-chain or branched acyl having up to 18 carbon atoms or benzoyl which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or trifluoromethoxy, or

represents straight-chain or branched fluoroacyl having up to

6 carbon atoms, or a salt of said compound or an N-oxide of said compound or said salt.

3. The hetero-tetrahydroquinoline according to claim 1 , wherein

D represents aryl having 6 to 10 carbon atoms which is optionally substituted one or more times by nitro, trifluoromethyl, trifluoromethoxy, fluorine, chlorine or bromine, or represents a radical of the formula:

in which

R 5 , R 6 and R 9 independently represent cyclopropyl, cyclopentyl or cyclohexyl, phenyl, or naphthyl each of 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, straight-chain or branched alkyl having up to 4 carbon atoms, straight-chain or branched alkylthio having up to 4 carbon atoms, straight-chain or branched alkylalkoxy having up to 4 carbon atoms, straight-chain or branched alkoxy having up to 4 carbon atoms, or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms;

R 7 represents hydrogen or fluorine;

and

R 6 represents hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, or straight-chain or branched alkoxy or straight chain or branched alkyl having 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 alkyl having up to 3 carbon atoms,

or

R 7 and R 8 together form a radical of the formula ═O,

L represents a straight-chain or branched alkylene or alkenylene each having up to 5 carbon atoms, each alkylene or alkenylene 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 sulfur atom or represents a group of the formula —NR 18

in which

R 18 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; or

R 19 represents hydrogen;

or represents cyclopropyl, cyclopentyl or cyclohexyl;

or represents straight-chain or branched acyl having up to 15 carbon atoms or benzoyl which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or trifluoromethoxy; or

represents a radical of the formula —Si(CH 3 ) 2 C(CH 3 ) 3 ;

or a salt of said compound or an N-oxide of said compound

represents straight-chain or branched fluoroacyl having up to 8 carbon atoms and 9 fluorine atoms

or a salt of said compound or or an N-oxide of said compound or said salt.

4. The hetero-tetrahydroquinoline according to claim 1 , wherein

D represents aryl having 6 to 8 carbon atoms which is optionally substituted one or more times by trifluoromethyl and/or fluorine, or trifluoromethoxy 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 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 straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl;

or a salt of said compound or an N-oxide of said compound or said salt.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the hetero-tetrahydroquinoline compound of claim 1 , or a, salt or N-oxide, thereof.

6. A method for treating hyperlipoproteinanaemia, said method comprising administering to a patient in need thereof an effective amount therefor of a composition according to claim 5 .

7. A method for treating arteriosclerosis, said method comprising administering to a patient in need thereof an effective amount therefor of a composition according to claim 5 .

8. A method for treating dyslipidaemia, said method comprising administering to a patient in need thereof an effective amount therefor of a composition according to claim 5 .