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

• US 6,958,346 B2
• Filed: 10/31/2001
• Issued: 10/25/2005
• Est. Priority Date: 09/18/1997
• Status: Expired due to Fees

• Current Assignee: Bayer Schering Pharma AG (Bayer AG)
• Original Assignee: Bayer AG
• Inventors: Bischoff, Hilmar, Schmeck, Carsten, Schmidt, Gunter, Schmidt, Delf, Bremm, Klaus-Dieter, Brandes, Arndt, Stoltefuss, Jürgen, Lögers, Michael
• Primary Examiner(s): Morris, Patricia L
• Application Number:
  US09/999,233
• Publication Number:
  US 20020062024A1
• Time in Patent Office: 1,455 Days
• Field of Search: 546/15, 514/278
• US Class Current: 514/278
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 215/20 Oxygen atoms
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond

Abstract

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.

Claims

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

R⁵, R⁶ and R⁹ 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 —

OR¹⁰, radicals of the formula —

SR¹¹, radicals of the formula —

SO₂R¹² and radicals of the formula;

—

NR¹³R¹⁴,

in which

R¹⁰, R¹¹ and R¹² 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;

R¹³ and R¹⁴ represent hydrogen, phenyl, or straight-chain or branched alkyl having up to 6 carbon atoms;

R⁷ represents hydrogen or halogen, and

R⁸ 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 —

NR¹⁵R¹⁶,

in which

R¹⁵ and R¹⁶ are identical or different and represent hydrogen, phenyl, or

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

or

R⁷ and R⁸ together form a radical of the formula ═

O or ═

NR¹⁷,

in which

R¹⁷ 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 —

NR¹⁸ group,

in which

R¹⁸ 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

R¹⁹ 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 —

OR²²;

or phenyl, which phenyl is optionally substituted by halogen, nitro, trifluoromethyl, trifluoromethoxy, phenyl or tetrazole-substituted phenyl;

in which R²² represents straight-chain or branched acyl having up to 4 carbon atoms or benzyl;

or

R¹⁹ 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,

R⁵, R⁶ and R⁹ 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;

R⁷ represents hydrogen, fluorine, chlorine or bromine;

and

R⁸ 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 —

NR¹⁵R¹⁶,

in which

R¹⁵ and R¹⁶ are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,

or

R⁷ and R⁸ together form a radical of the formula ═

O or ═

NR¹⁷, in which R¹⁷ 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 —

NR¹⁸ group;

in which

R¹⁸ 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,

R¹⁹ 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 —

OR²² or by phenyl which is optionally substituted by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy or by phenyl or tetrazole-substituted phenyl,

in which

R²² represents straight-chain or branched acyl having up to 3 carbon atoms or benzyl;

or,

R¹⁹ 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

R⁵, R⁶ and R⁹ 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;

R⁷ represents hydrogen or fluorine;

and

R⁶ 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 —

NR¹⁵R¹⁶,

in which

R¹⁵ and R¹⁶ are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

or

R⁷ and R⁸ 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 —

NR¹⁸

in which

R¹⁸ 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

R¹⁹ 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(CH₃)₂C(CH₃)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

R⁶ represents phenyl which is optionally substituted by fluorine, chlorine, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl having up to 4 carbon atoms;

R⁷ represents hydrogen or fluorine; and

R⁸ represents hydrogen, fluorine, chlorine, hydroxyl, methoxy;

or

R⁷ and R⁸ 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.