WO1999015487A1

WO1999015487A1 - Benzyl-biphenyls and analogous compounds and the application thereof in order to treat arteriosclerosis and dyslipidaemia

Info

Publication number: WO1999015487A1
Application number: PCT/EP1998/005731
Authority: WO
Inventors: Michael Lögers; Arndt Brandes; Gunter Schmidt; Jürgen Stoltefuss; Klaus-Dieter Bremm; Hilmar Bischoff; Delf Schmidt
Original assignee: Bayer Aktiengesellschaft
Priority date: 1997-09-19
Filing date: 1998-09-09
Publication date: 1999-04-01
Also published as: EP1017658A1; DE19741400A1; AU1145899A; JP2001517646A; CA2304274A1

Abstract

The invention relates to benzyl-biphenyls and analogous compounds thereof which are produced first by reacting α and β-unsaturated ketones to form corresponding substituted and conjugated dienes, and afterwards said dienes are cyclized with acetylene derivatives. The resulting cyclohexane dienes are oxidized to form aromatic compounds and/or are varied in available substituents through usual methods. The compounds are suited for additives in medicaments, especially in medicaments for treating arteriosclerosis and dyslipidaemia.

Description

BENZYL-BIPHENYLE AND ANALOG COMPOUNDS AND THEIR USE FOR TREATING ARTERIOSCLEROSIS AND DIYLIPIDEMIA

The present invention relates to benzyl biphenyls and analogous compounds, processes for their preparation and their use in medicaments.

Publication US Pat. No. 5,169,857-A2 discloses 7- (polysubstituted pyridyl) -6-heptenoate for the treatment of arteriosclerosis, lipoprotein anemia and hyperprotein anemia. In addition, the preparation of 7- (4-aryl-3-pyridyl) -3,5-dihydroxy-6-heptenoate is described in the publication EP-325 130-A2.

The present invention relates to benzyl biphenyls and analogous compounds of the general formula (I),

in which

A represents cycloalkyl having 3 to 8 carbon atoms, or

represents aryl having 6 to 10 carbon atoms, or

represents a 5- to 7-membered, saturated, partially unsaturated or unsaturated, optionally benzocondensed heterocycle with up to 4 heteroatoms from the series S, N and / or O,

where aryl and the heterocyclic ring systems listed above, if appropriate, up to 5 times the same or different by cyano, halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each having up to 7 carbon atoms, or are substituted by a group of the formula -NR ³ R ⁴ ,

woπn

R ³ and R ^{4 are} identical or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,

for a rest of the formula

R ⁷ R ⁸ R ⁵ - L—, R ⁶ V ^/ A or _R ⁹ _ _τ _ _v _χ_

stands,

woπn

R ⁵ , R ⁶ and R ⁹ independently of one another

Aryl having 6 to 10 carbon atoms or a 5- to 7-membered, optionally benzo-fused, saturated or unsaturated, mono-, bi- or tricyclic heterocycle with up to 4 heteroatoms from the series S, N and / or O,

where the cycles, optionally, in the case of the nitrogen-containing rings also via the N function, up to 5 times the same or different by halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoro- methoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, aryl substituted by aryl or trifluoromethyl each having 6 to 10 carbon atoms or by an optionally benzo-condensed aromatic 5- to 7- structure

Heterocycle with up to 3 heteroatoms from the series S, N and / or O are substituted,

and / or are substituted by a group of the formula -OR ¹⁰ , -SR ", -SO ₂ R ¹² or - NR ¹³ R ¹⁴ ,

wherein

R ¹⁰ , R "and R ¹² independently of one another are aryl having 6 to 10 carbon atoms, which in turn is substituted up to 2 times in the same or different manner by phenyl, halogen or by straight-chain or branched alkyl having up to 6 carbon atoms,

R ¹³ and R ^{14 are the} same or different and are those given above

Have the meaning of R ³ and R ⁴ ,

or

R ⁵ and / or R ^{6 is} a radical of the formula

F ₃ C mean

R ^{7 represents} hydrogen, halogen or methyl, and

R ^{8 is} hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkyl each having up to 6 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ ,

wherein

R ¹⁵ and R ^{! 6 are the} same 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 ,

wherein

R ^{17 is} hydrogen or straight-chain or branched alkyl,

Alkoxy or acyl each having up to 6 carbon atoms,

L is a straight-chain or branched alkylene or alkenylene chain each having up to 8 carbon atoms, which are optionally substituted up to 2 times by hydroxy,

T and X are identical or different and represent a straight-chain or branched alkylene chain with up to 8 carbon atoms,

or T or X represents a bond,

V represents an oxygen or sulfur atom or an -NR ¹⁸ group,

wherein

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

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 hydroxy, or represents phenyl which is optionally substituted by halogen or trifluoromethyl,

R ^{1 represents} straight-chain or branched alkyl having up to 6 carbon atoms, which is by hydroxy or by a group of the formula

is substituted,

R ^{2 represents} hydrogen or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which may optionally be hydroxyl, halogen, phenyl, cycloalkyl having 3 to 6 carbon atoms or a group of the formula

are substituted,

woπn

R ^{19 represents} a radical of the formula -Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , or

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

is a 5- to 7-membered saturated, partially unsaturated or unsaturated heterocycle having up to 3 heteroatoms from the series S, N and / or O, or

Phenyl or benzyl, where all ring systems listed under R ¹⁹ optionally up to 2 times the same or different by trifluoromethyl, fluorine, nitro, hydroxy, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms or by straight-chain or branched alkyl having up to are substituted to 4 carbon atoms, which is optionally substituted by hydroxy,

and their salts. The compounds according to the invention can also be in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.

Physiologically acceptable salts are preferred in the context of the present invention. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. For example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.

For example, particular preference is given to Sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which are derived from ammonia, or organic amines, such as ethylamine, di- or. Triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylene diamine or 2-phenylethylamine.

The compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.

Heterocycle, optionally benzocondensed, in the context of the invention generally represents a saturated, partially unsaturated or unsaturated 5- to 7-membered, preferably 5- to 6-membered, heterocycle of up to 4 heteroatoms from the series S, N and / or O can contain. Examples include: indolyl, isoquinolyl, quinolyl, benzo [b] thiophene, benzo [b] furanyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, mopholinyl or piperidyl. Quinolyl, furyl, pyridyl and thienyl are preferred.

The compounds of the general formula (I) according to the invention are preferred

in which

A stands for naphthyl, phenyl, pyridyl, thienyl, imidazolyl, pyrryl or Moφholin, which are optionally up to 2 times the same or different by fluorine, chlorine, bromine, amino, hydroxy, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, or alkoxy are each substituted with up to 6 carbon atoms,

D represents phenyl, which may be replaced by nitro, fluorine, chlorine, bromine, phenyl,

Trifluormethyl or Trifluormethoxy is substituted, or

for a rest of the formula

stands,

wherein

R, R and R independently of one another Phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, mopholinyl, imidazolyl, benzothiazolyl, phenoxathi-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl,

the cycles, optionally up to 3 times in the case of the nitrogen-containing rings also via the N function, the same or different by fluorine, chlorine, bromine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio , Alkylalkoxy, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, triazolyl, tetrazolyl, benzoxathiazolyl, or trifluoromethyl-substituted phenyl or phenyl are substituted,

and / or are substituted by a group of the formula -OR ¹⁰ , -SR ¹¹ or -SO ₂ R ¹² ,

wherein

R ¹⁰ , R ¹¹ and R ^{12 are} identical or different and are phenyl, which in turn is up to 2 times identical or different due to phenyl,

Fluorine, chlorine or substituted by straight-chain or branched alkyl having up to 4 carbon atoms,

or

R ⁵ and / or R ^{6 is} a radical of the formula

^F 3 ^C mean R ⁷ denotes hydrogen, fluorine, chlorine or bromine,

and

R ^{8 is} hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkyl each having up to 5 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ ,

wherein

R ¹⁵ and R ^{16 are} identical or different and denote 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 ,

wherein

R ¹⁷ denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms,

is a straight-chain or branched alkylene or alkenylene chain each having up to 6 carbon atoms, which are optionally substituted up to 2 times by hydroxy,

T and X are the same or different and are straight or branched

Mean alkylene chain with up to 6 carbon atoms, or

T or X represents a bond,

V for an oxygen or sulfur atom or for a group of

Formula -NR ¹⁸ - stands,

wherein

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

E represents cyclopropyl, butyl, pentyl, hexyl or heptyl, or

represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cyclopropyl, butyl, hexyl, pentyl, heptyl or by hydroxy, or represents phenyl which is optionally substituted by fluorine, chlorine or trifluoromethyl,

R ¹ for a group of the formula -CH ₂ OH or

stands,

R ^{2 represents} hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, which is optionally by hydroxy, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or by a group of the formula

is substituted,

wherein

R is a radical of the formula -Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , or

straight-chain or branched alkyl having up to 5 carbon atoms, or

Tetrahydropyranyl, pyridyl, phenyl or benzyl means, optionally up to 2 times the same or different

Trifluoromethyl, fluorine, nitro, hydroxy, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 3 carbon atoms or substituted by straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by hydroxy,

and their salts.

Compounds of the general formula (I) according to the invention are particularly preferred

in which A represents phenyl or pyridyl, which are optionally substituted up to twice in the same or different manner by fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,

D represents phenyl which may be replaced by nitro, trifluoromethyl, phenyl,

Fluorine, chlorine or bromine is substituted, or for a radical of the formula

R ⁷ R ⁸ R ⁵ - L-, R ⁶ V ^ A or _R ⁹ _ _τ _ _V -χ-

stands,

wherein

R ⁵ , R ⁶ and R ⁹ independently of one another

Phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, mopholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl,

the cycles, optionally up to 3 times, in the case of the nitrogen-containing rings also via the N function, identically or differently by fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, Alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, triazolyl, tetrazolyl, benzothiazolyl, trifluoromethyl-substituted phenyl or phenyl are substituted and / or are substituted by a group of the formula -OR ¹⁰ , -SR ¹¹ or -SO ₂ R ¹² ,

wherein

R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and represent phenyl, which in turn is substituted up to 2 times the same or different by phenyl, fluorine, chlorine or by straight-chain or branched alkyl having up to 3 carbon atoms,

or

R ⁵ and / or R is a radical of the formula

mean,

R ^{7 represents} hydrogen or fluorine,

and

R ^{8 is} hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy, trifluoromethoxy, or straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ ,

wherein R ¹⁵ and R ^{16 are} identical or different and are 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 = 0 or = NR ¹⁷ ,

wherein

L is a straight-chain or branched alkylene or alkenylene chain each having up to 5 carbon atoms, which are optionally substituted up to 2 times by hydroxy,

T and X are identical or different and represent a straight-chain or branched alkylene chain with up to 3 carbon atoms,

or

T or X represents a bond,

V for an oxygen or sulfur atom or for a group of

Formula -NR ¹⁸ stands,

woπn R ¹⁸ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

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 hydroxy,

R ¹ for a group of the formula -CH ₂ OH or

stands,

R ^{2 stands} for hydrogen or for straight-chain or branched alkyl or alkenyl each having up to 5 carbon atoms, which is optionally by

Hydroxy, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or through a group of the formula

or ° - ^N γ ° is substituted,

wherein R denotes straight-chain or branched alkyl having up to 4 carbon atoms, or

is a radical of the formula -Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , or

Tetrahydropyranyl, pyridyl, phenyl or benzyl, which optionally up to 2 times the same or different by trifluoromethyl, fluorine, chlorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 3 carbon atoms or by straight-chain or branched alkyl having up to are substituted to 3 carbon atoms, which is optionally substituted by hydroxy,

and their salts.

Compounds of the general formula (I) according to the invention are very particularly preferred

A for phenyl, fluorine, chlorine, bromine, trifluoromethyl,

D for a residue of the formula

stands,

wherein

R, R and R independently of one another Phenyl, mean

which is optionally up to 3 times the same or different substituted by fluorine, chlorine or trifluoromethyl,

R ^{7 represents} hydrogen or fluorine,

and

R ^{8 is} hydrogen, fluorine, chlorine, bromine or alkyl, each with up to 4 carbon atoms

or

R ⁷ and R ⁸ together form a radical of the formula = or = NR ¹⁷ ,

wherein

or T or X represents a bond,

V represents an oxygen or sulfur atom or a group of the formula -NR ¹⁸ ,

woπn

R ¹⁸ denotes 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,

R ¹ for a group of the formula -CH ₂ OH or

stands,

R ^{2 represents} hydrogen or straight-chain or branched alkyl or alkenyl each having up to 5 carbon atoms, which may optionally be hydroxyl, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or a group of the formula

or is substituted,

wherein

R ¹⁹ denotes straight-chain or branched alkyl having up to 4 carbon atoms, or

is a radical of the formula -Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , or

and their salts.

In addition, processes for the preparation of the compounds of the general formula (I) according to the invention were found, characterized in that

Compounds of the general formula (II)

in which

A, D and E have the meaning given above,

in the system (C ₆ H ₅ ) ₃ PCH ₃ Br / n-butyllithium first to the compounds of the general formula (III)

in which

A, D and E have the meaning given above,

implements

then with compounds of the general formula (IV) or (IVa)

R ²⁰ - O ₂ C - Ξ≡ - CO ₂ R ²⁰ (IV)

R ²¹ IZZI CO _? R ^{20 "} (IVa)

in which R ²⁰ , R ²⁰ and R ^{20 "are} identical or different and represent straight-chain or branched alkyl having up to 4 carbon atoms,

and

R 21 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxy, phenyl, straight-chain or branched alkoxy having up to 6 carbon atoms, amino, alkyl- or dialkylamines having up to 4 carbon atoms in the alkyl part,

into the compounds of the general formula (V)

in which

A, D and E have the meaning given above,

R includes the scope of R and R given above,

and

R ²² either represents hydrogen or the radical -CO, R ²⁰ , or

includes the scope of R ²¹ given above, convicted,

by oxidation the compounds of the general formula (VI)

in which

A, D, E, R, R and R have the meaning given above,

manufactures,

and finally reduced the carbonyl functions to the hydroxymethyl function,

and derivatization on the substituent R ² by starting from

Compounds of the general formula (Ia)

in which

A, D and E have the meaning given above, depending on the abovementioned meaning of R ² in the system P (C ₆ H ₅ ) ₃ / diethylazodicarboxylic acid ethyl ester and the corresponding alcohols or amines defined under R ¹⁹ ,

or

performs etherification by reaction with alkyl halides in the presence of a base,

and finally cleaves the hydroxy protective group with acids in both derivatizations,

or in the case R ² = alkenyl, the compounds of the general formula (Ia) first to the aldehydes of the general formula (VII)

in which

A, D and E have the meaning given above,

implemented and in a further step carries out a Wittig reaction by customary methods, cleaves the hydroxyl protective group as described above and finally reduces it to the corresponding alkyl compounds (R ² = alkyl) by hydrogenation in the presence of a catalyst. The process according to the invention can be illustrated by the following formula scheme:

Xylene, 140 ° C

LiAIH ₄

H2, Pt / C

Suitable solvents for the reaction step (II) - (III) are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether. It is also possible to use mixtures of the solvents mentioned. Diethyl ether is preferred.

The bases used for the reaction step (II) - »(III) are the usual strongly basic ones

Connections in question. These preferably include organolithium compounds such as N-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride. N-Butyllithium is particularly preferred.

The base is generally used in an amount of 1 mol to 2 mol, preferably 1.05 mol to 1.2 mol, based on 1 mol of the compounds of the general formula (II).

The reaction generally takes place at a temperature from -30 ° C to room temperature, preferably from -20 ° C to 0 ° C.

The reaction generally takes place at normal pressure, but it is also possible to work at elevated or reduced pressure.

Suitable solvents for the preparation of the compounds of the general formula (V) according to the invention are hydrocarbons such as benzene, toluene, xylene, chlorobenzene, ethylbenzoate, decalin, benzonitrile, hexane, cyclohexane or petroleum fractions. It is also possible to use mixtures of the solvents mentioned. Xylene is preferred.

The reaction can also be carried out without a solvent, or alkyne can be used as the solvent. The reaction generally takes place at a temperature of from -30 ° C. to +250, preferably from 80 ° C. to 180 ° C.

The reaction generally takes place without a catalyst, but it is also possible to use Lewis acids as catalysts. Examples include: BF ₃ , BF ₃ x OEt ₂ , A1C1 ₃ TiCl ₄ , A1 (CH ₃ ) ₃ , A1 (C ₂ H ₅ ) ₃ , (C ₂ H ₅ ) ₂ A1C1, MgCl ₂ , ZnCl ₂ and BC1 _3rd

Suitable solvents for the oxidation are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, chlorobloromethylene , Ethyl acetate, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Toluene is preferred.

Suitable oxidizing agents are, for example, potassium permanganate, bromine, cerium (IV) ammonium nitrate, 2,3-dichloro-5,6-dicyano-benzoquinone, pyridinium chlorochromate (PCC), pyridinium chlorochromate on basic aluminum oxide, osmium tetroxide, sodium acetate / iodine and manganese dioxide. 2,3-Dichloro-5,6-di-cyanobenzoquinone is preferred.

The oxidizing agent is used in an amount of 1 mol to 10 mol, preferably from

2 mol to 5 mol, based on 1 mol of the compounds of the general formula (V), are used.

The oxidation generally takes place in a temperature range from 0 ° C. to + 100 ° C., preferably from room temperature to 80 ° C. The oxidation generally takes place at normal pressure. However, it is also possible to carry out the oxidation at elevated or reduced pressure.

The hydrocarbons listed above are suitable as solvents for the reduction, with toluene being preferred.

The reduction of the compounds of the general formula (VI) is generally carried out using reducing agents, preferably those which are suitable for the reduction of alkoxycarbonyl to hydroxy compounds. Reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane, is particularly suitable. The reduction is preferably carried out with complex metal hydrides such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoboranate, diisobutylaluminium hydride or lithium aluminum hydride. The reduction is very particularly preferably carried out using diisobutylaluminum hydride.

The reducing agent is generally used in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, based on 1 mol of the compounds to be reduced.

The reduction generally takes place in a temperature range from -78 ° C. to + 50 ° C., preferably from -78 ° C. to 0 ° C., particularly preferably at -78 ° C., in each case depending on the choice of the reducing agent and solvent.

The reduction generally proceeds at normal pressure, but it is also possible to work at elevated or reduced pressure.

Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene,

Xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichlorethylene, trichlorethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric acid triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Toluene and dichloromethane are preferred.

The protecting group is generally split off in one of the alcohols and THF listed above, preferably methanol / THF in the presence of hydrochloric acid in a temperature range from 0 ° C. to 50 ° C., preferably at room temperature, and normal pressure. In special cases, the deprotection with tetrabutylammonium fluoride (TBAF) in THF at room temperature is preferred.

The compounds of the general formula (VI) are reacted in one of the ethers listed above, preferably in tetrahydrofuran under a protective gas atmosphere in a temperature range from -78 ° C. to -10 ° C., preferably at

-25 ° C.

The derivatization of the hydroxy function in the compounds of the general formula (VII) takes place, for example, by oxidations, sulfonations,

Alkylation, hydrogenation, halogenation, Wittig / Grignard reactions, aldol reactions, reductive amination and sulfoamidation.

The usual strongly basic connections can be used as bases for the individual steps. These preferably include organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride. N-Butyllithium, sodium hydride or lithium diisopropylamide is particularly preferably used. The usual inorganic bases are also suitable as bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate. Sodium hydroxide or potassium hydroxide is particularly preferably used.

I also use alcohols such as methanol, ethanol, propanol, butanol or tert-butanol as solvents for the individual reaction steps. Tert is preferred. Butanol.

The alkylation with alkyl halides is generally carried out in inert solvents in the presence of a base.

Suitable solvents are, depending on the nature of the alkylating agent, all inert organic solvents. These preferably include ethers such as diethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene or xylene, or

Dimethylformamide or Hexamethylphosphorsäuretriamid, or mixtures of the solvents mentioned.

The usual basic compounds are suitable as bases for the alkylation. These preferably include alkali hydrides such as sodium hydride, alkali amides such as

Sodium amide or lithium diisopropyl amide, alkali alcoholates such as sodium methanolate, sodium ethanolate, potassium methoxide, potassium ethanolate or potassium ter.butylate, or organic amines such as trialkylamines, e.g. Triethylamine, or organolithium compounds such as butyllithium or phenyllithium. Lithium diisopropylamide is preferred.

The alkylation generally takes place in a temperature range from -70 ° C. to + 110 ° C., preferably from 20 ° C. to 80 ° C. The alkylation is generally carried out at normal pressure. However, it is also possible to carry out the process under reduced pressure or elevated pressure (for example in a range from 0.5 to 5 bar).

The compounds of the general formula (II) are partly new and can be prepared, for example, by

Compounds of the general formula (VIII)

D-CH ₂ -CO-CH (CH ₃ ) ₂ (VIII)

in which

D has the meaning given above,

with compounds of the general formula (IX)

A-CHO (IX)

in which

A has the meaning given above,

in the presence of lithium diisopropylamide to the compounds of the general formula (X)

in which

A and D have the meaning given above,

implements

and finally in two stages in the system mesyl chloride / triethylamine and diazabicycloundecane in tetrahydrof ran.

Some of the compounds of the general formula (VIII) are known or new and can be prepared by first reacting with N, N-dimethylhydrazine and finally with compounds of the general formula (XI)

D-Br (XI)

in which

D has the meaning given above,

in inert solvents, in the presence of a base and then mixed with hydrochloric acid.

The compounds of the general formula (XI) are reacted in ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether. Preferred in tetrahydrofuran.

The bases which are customary for the individual steps are the customary strongly basic compounds. These preferably include organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropylamide, sodium amide or Potassium amide, or lithium hexamethylsilyl amide, or alkali hydrides such as sodium hydride or potassium hydride. N-Butyllithium, sodium hydride or lithium diisopropylamide is particularly preferably used.

The base is used in an amount of 0.1 mol to 10 mol, preferably from 1 mol to

5 mol, based in each case on 1 mol of the starting compound.

The reaction is generally carried out in a temperature range from -10 ° C to + 10 ° C, preferably from 5 ° C to 10 ° C and normal pressure.

The reaction with the aldehydes of the general formula (IX) takes place as follows:

Xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichlorethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethyl or acetonitrile triamonitrilethane. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran is preferred.

The bases which are customary for the individual steps are the customary strongly basic compounds. These preferably include organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride. N-Butyllithium, sodium hydride or lithium diisopropylamide is particularly preferably used. The base is used in an amount of 0.1 mol to 10 mol, preferably 1 mol to 5 mol, in each case based on 1 mol of the starting compound.

The compounds of the general formula (XI) are known per se or can be prepared by customary methods.

The compounds of the general formula (IX) are known per se or can be prepared by customary methods.

The compounds of general formula (X) are new and can be described as described above.

The compounds of the general formula (III), (V) and (VI) are new and can be prepared as described above.

The compounds of the general formula (IV) are known per se or can be prepared by customary methods.

The compounds of the general formula (VII) are largely new and can be prepared as described above.

The compounds of the general formula (Ia) are new and can be prepared as described above.

The compounds of general formula (I) according to the invention have an unforeseeable spectrum of pharmacological activity. The compounds of the general formula (I) according to the invention have valuable pharmacological properties which are superior in comparison with the prior art, in particular they are highly effective inhibitors of cholesterol ester transfer protein (CETP) and stimulate the reverse cholesterol transport. The active substances according to the invention bring about a reduction in the LDL cholesterol level in the blood with a simultaneous increase in the HDL cholesterol level. They can therefore be used to treat and prevent hypolipoproteinemia, dyslipidaemia, hypertriglyceridaemia, hyperlipidaemia or arteriosclerosis.

The pharmacological effect of the substances according to the invention was as follows

Test determines:

CETP inhibition testing

Obtaining CETP

CETP is obtained from human plasma by differential centrifugation and column chromatography in a partially purified form and used for the test. For this purpose, human plasma is adjusted to a density of 1.21 g per ml with NaBr and centrifuged at 50,000 rpm at 4 ° C. for 18 h. The bottom fraction (d> 1.21 g / ml) is applied to a Sephadex®Phenyl-Sepharose 4B (Pharmacia) column, washed with 0.15 m NaCl / 0.001 m TrisHCl pH 7.4 and then with dist. Water eluted. The CETP -type active fractions are pooled, dialyzed against 50 mM Na acetate pH 4.5 and applied to a CM-Sepharose ^® (Fa. Pharmacia) column. With a linear

Gradient (0-1 M NaCl) is then eluted. The pooled CETP fractions are dialyzed against 10 mM TrisHCl pH 7.4 and then further purified by chromatography on a Mono Q® column (from Pharmacia). Obtaining radioactively labeled HDL

50 ml of fresh human EDTA plasma is adjusted to a density of 1.12 with NaBr and centrifuged at 4 ° C. in a Ty 65 rotor for 18 h at 50,000 rpm. The upper phase is used to obtain cold LDL. The phase is dialyzed against 3 * 4 1 PDB buffer (10 mM Tris / HCl pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN ₃ ). 20 μl 3H-cholesterol (Dupont NET-725; 1 -μC / μl dissolved in ethanol!) Are then added per 10 ml retentate volume and incubated for 72 h at 37 ° C. under N ₂ .

The mixture is then adjusted to a density of 1.21 with NaBr and centrifuged in a Ty 65 rotor for 18 h at 50,000 rpm at 20 ° C. The upper phase is obtained and the lipoprotein fractions are purified by gradient centrifugation. For this purpose, the isolated, labeled lipoprotein fraction is adjusted to a density of 1.26 with NaBr. 4 ml of this solution are overlaid in centrifuge tubes (SW 40 rotor) with 4 ml of a solution with a density of 1.21 and 4.5 ml with a solution of 1.063 (sealing solutions made of PDB buffer and NaBr) and then added for 24 h 38,000 rpm and 20 ° C centrifuged in the SW 40 rotor. The intermediate layer between the density 1.063 and 1.21, containing the marked HDL, becomes 3 * 100 volume

PDB buffer dialyzed at 4 ° C.

The retentate contains radioactively labeled ³ H-CE-HDL, which is set to approx. 5x10 ⁶ cmp per ml and used for the test.

CETP test

To test the CETP activity, the transfer of ³ H-cholesterol ester from human HD lipoproteins to biotinylated LD lipoproteins is measured. The reaction is ended by adding streptavidin-SPA®beads (from Amersham) and the radioactivity transferred is determined directly in the liquid scintillation counter.

In the test mixture, 10 μl HDL- ³ H-cholesterol esters (~ 50,000 cpm) with 10 μl biotin-LDL (from Amersham) in 50 mM Hepes / 0.15 m NaCl / 0.1% bovine serum albumin / 0.05% NaN ₃ pH 7.4 with 10 μl CETP (1 mg / ml) and 3 μl solution of the substance to be tested (dissolved in 10% DMSO / 1% RSA), incubated for 18 h at 37 ° C. Then 200 μl of the SPA-streptavidin-bead solution (TRKQ 7005) are added, incubated for 1 h while shaking and then measured in a scintillation counter. Corresponding incubations with 10 μl buffer, 10 μl CETP at 4 ° C. and 10 μl CETP at 37 ° C. serve as controls.

The activity transferred in the control batches with CETP at 37 ° C. is rated as 100%) transfer. The substance concentration at which this transfer is reduced to half is given as the IC ₅₀ value.

The following Table A shows the IC ₅₀ values (mol / 1) for CETP inhibitors:

Table A:

Ex vivo activity of the compounds according to the invention

Syrian golden hamsters from in-house breeding are anesthetized after a 24-hour fast (0.8 mg / kg atropine, 0.8 mg / kg Ketavet® sc, 30 'later 50 mg / kg Nembutal ip). The jugular vein is then dissected and cannulated. The test substance is dissolved in a suitable solvent (usually Adalat placebo solution: 60 g glycerol, 100 ml H ₂ O, ad 1000 ml PEG-400) and administered to the animals via a PE catheter inserted into the jugular vein. The control animals receive the same volume of solvent without test substance. The vein is then tied off and the wound closed.

The administration of the test substances can also p.o. are carried out by dissolving the substances in DMSO and suspending 0.5% tylose by oral gavage. The control animals receive identical ones

Volume of solvent without test substance.

At various times - up to 24 hours after application - blood is drawn from the animals by puncturing the retro-orbital venous plexus (approx. 250 μl). The coagulation is terminated by incubation at 4 ° C. overnight, followed by centrifugation at 6000 × g for 10 minutes. In the serum obtained in this way, the CETP activity is determined by the modified CETP test. As described for the CETP test above, the transfer of ³ H-cholesterol esters from HD lipoproteins to biotinylated LD lipoproteins is measured.

The reaction is terminated by adding streptavidin-SPA ^R beads (from Amersham) and the radioactivity transferred is determined directly in the liquid scintlation counter. The test batch is carried out as described under "CETP test". Only 10 μl CETP are replaced by 10 μl of the corresponding serum samples for testing the serum. Appropriate incubations with sera from untreated animals serve as controls.

The activity transferred in the control batches with control sera is rated as 100%) transfer. The substance concentration at which this transfer is reduced to half is given as the ED ₅₀ value.

Activity of the compounds according to the invention

In tests to determine the oral effect on lipoproteins and triglycerides, Syrian golden hamsters from in-house breeding test substance is dissolved in DMSO and 0.5%) tylose suspended is administered orally using a pharyngeal tube. To determine the CETP activity, blood is taken by retro-orbital puncture (approx. 250 μl) before the start of the experiment. The test substances are then administered orally using a gavage. The control animals receive identical volumes of solvent without test substance. The animals are then deprived of their feed and carried out at various times - up to 24 hours after substance application

Puncture of the retroorbital venous plexus is taken from blood.

The coagulation is terminated by incubation at 4 ° C. overnight, followed by centrifugation at 6000 × g for 10 minutes. The content of cholesterol and triglycerides in the serum obtained in this way is determined using modified commercially available enzyme tests (cholesterol enzymatically 14366 Merck, triglycerides 14364 Merck). Serum is appropriately diluted with physiological saline.

100 μl of serum dilution are mixed with 100 μl of test substance in 96-well plates and incubated for 10 minutes at room temperature. Then will determined the optical density at a wavelength of 492 nm with an automatic plate reader. The triglyceride or cholesterol concentration contained in the samples is determined using a standard curve measured in parallel.

The HDL cholesterol content is determined after precipitation of the ApoB-containing lipoproteins using a reagent mixture (Sigma 352-4 HDL cholesterol reagent) according to the manufacturer's instructions.

Efficacy in vivo in transgenic hCETP mice

Transgenic mice from our own breeding (Dinchuck, Hart, Gonzalez, Karmann, Schmidt, Wirak; BBA (1995), 1295, 301) were administered the substances to be tested in the feed. Before the start of the experiment, blood was taken from the mice retroorbitally in order to determine cholesterol and triglycerides in the serum. The serum was obtained as described above for hamsters by incubation at 4 ° C. overnight and subsequent centrifugation at 6000 × g. After a week, blood was again drawn from the mice to determine lipoproteins and triglycerides. The change in the measured parameters is shown as a percentage change compared to the

Output value expressed.

The invention also relates to the combination of benzyl biphenyls of the general formula (I) with a glucosidase and / or amylase inhibitor for the treatment of familial hyperlipidemia, obesity and obesity

Diabetes mellitus. Glucosidase and / or amylase inhibitors in the context of the invention are, for example, acarbose, adiposins, Voglibose, Miglitol, Emiglitate, MDL-25637, Camiglibose (MDL-73945), Tendamistate, AI-3688, Trestatin, Pradimicin-Q and Salbostatin. The combination of acarbose, miglitol, emiglitate or Voglibose with one of the above-mentioned compounds of the general formulas (I) according to the invention is preferred.

Furthermore, the compounds according to the invention can be used in combination with

Cholesterol-lowering Vastatinen or ApoB-lowering principles can be combined to treat dyslipidemics, combined hyperlipidemics, hypercholesterolemics or hypertriglyceridemics.

The combinations mentioned can also be used for primary or secondary prevention of coronary heart diseases (e.g. myocardial infarction).

Vastatins in the context of the invention are, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin. ApoB-lowering agents are, for example, MTP inhibitors.

The combination of cerivastatin or ApoB inhibitors with one of the above-mentioned compounds of the general formulas (I) and (Ia) is preferred.

The new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. Here, the therapeutically active compound should be in a concentration of about 0.5 to

90% by weight of the total mixture is present, i.e. in amounts sufficient to achieve the dosage range indicated.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, for example in the case of use of water as a diluent, organic solvents can optionally be used as auxiliary solvents.

The application takes place in the usual way intravenously, orally, parenterally or perlingually, in particular orally.

In the case of parenteral use, solutions of the active ingredient can be used using suitable liquid carrier materials.

In general, it has proven to be advantageous for intravenous administration

To administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight to achieve effective results, and in the case of oral administration the dosage is about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of route of administration, on the individual behavior towards the medication, the type of its formulation and the time or interval at which the submission takes place. In some cases it may be sufficient to make do with less than the above-mentioned minimum quantity, while in other cases the above-mentioned upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day. Output connections

Example I

4-methyl-1 - (4-trifluoromethylphenyl) pentan-3-one

To 40 g (0.312 mol) of NN-dimethyl-N- {2-methyl-1- [2- (4-trifluoromethylphenyl) ethyl] propylidene} hydrazine (SD Sharma et al, J. Org. Chem. 1990, 55, 2196) in

400 ml abs. THF is added dropwise at 0 ° C over 30 min, 131 ml (0.328 mol) of a 2.5M solution of nBuLi in n-hexane and stirred at 15-20 ° C for 30 min. Then a solution of 67.9 g (0.284 mol) of 4-trifluoromethyl-benzyl bromide in 100 ml of abs. THF was added dropwise and the mixture was stirred at 20 ° C. for 2 hours. The reaction mixture is concentrated to about 80 ml and carefully hydrolyzed with 200 ml of H ₂ O. After extraction with

You wash ethyl acetate with sat. NaCl solution, dries over Na ₂ SO ₄ and concentrated. 82 g of NN-dimethyl-N- {2-methyl-1- [2- (4-trifluoromethyl-phenyl) -ethyl] propylidene-hydrazine are obtained as a red oil.

The hydrazone is dissolved in 150 ml of THF and mixed with 170 ml of 2M HCl and stirred at 20 ° C. for 1 hour. It is extracted with EtOAc, washed with water and sat. ΝaCl solution, dries over Νa ₂ SO ₄ and evaporates. Distillation gives a colorless oil (bp 95-98 ° C / 0.7 mbar). Yield: 51.5 g (78%) R _f = 0.25 (EtOAc / PE 1:20) Example II

1 - (4-Fluoro-phenyl) -1-hydroxy-4-methyl-2- (4-trifluoromethyl-benzyl) pentan-3 -one

To 184 g (0.753 mol) of the compound from Example I in 1.2 1 abs. THF is added at - 70 ° C 400 ml (0.791 mol) of a 2.0M solution of LDA in THF / heptane over 50 min and stirred for 60 min at -70 ° C. Then 81 ml (0.753 mol) of 4-fluorobenzaldehyde are added and the mixture is stirred at -70 ° C. for 60 min. It is quenched with 100 ml of a 10% NH ₄ C1 solution, allowed to warm to -10 ° C. and a further 400 ml of a 10% is added.

NH ₄ C1 solution. The phases are separated, extracted with EtOAc, washed with sat. NaCl solution dries over Na ₂ SO ₄ and concentrates. The crude product is purified on silica gel 60 (EtOAc / PE 1: 5). Yield: 253 g (91%) R _f = 0.31 (EtOAc / PE 1: 5)

Example III

1 - (4-fluorophenyl) -4-methyl-2- (4-trifluoromethyl-benzyl) -pent-1-en-3-one

To 279 g (0.76 mol) of the compound from Example II in 2.5 1 abs. CH ₂ C1 ₂ is added at 0 ° C to 231 ml (1.672 mol) of triethylamine and 118 ml (1.52 mol) of methanesulfonyl chloride. The mixture is stirred overnight at 20 ° C. and 456 ml (3.04 mol) of DBU dissolved in 1 liter of abs are added at -30 ° C. CH ₂ C1 ₂ . After 90 minutes, the mixture is quenched with 500 ml of water. The phases are separated and the aqueous phase is extracted with CH ₂ C1 ₂ . The combined organic phases are washed with 0.5 M HCl, dried over Na ₂ SO ₄ and concentrated. The crude product is purified on silica gel 60 (cyclohexane / EtOAc 40: 1 to 10: 1). Yield: 220 g (83%) R _f = 0.27 (EtOAc / PE 1:20).

Example IV

1 -Fluoro-4- (3-isopropyl-2- (4-trifluoromethyl-benzyl) -buta- 1, 3-dienyl) -benzene

To 20 g (5.71 mmol) of the compound from Example III in 100 ml of abs. Ether is added at 0 ° C 47.6 g (114.2 mmol) of a mixture of methyl triphenylphosphonium bromide and sodium amide in 200 ml abs. Ether. After 90 minutes, add 300 ml

Petroleum ether and sucks off over a little silica gel. It is washed with 2 1 PE and concentrated. The crude product is purified on silica gel 60 (cyclohexane / EtOAc 20: 1 to

10: 1).

Yield: 9.1 g (44%)

R _f = 0.35 (PE).

Example V

6- (4-fluorophenyl) -4-isopropyl-5- (4-trifluoromethyl-benzyl) cyclohexa-l, 4-diene-carboxylic acid methyl ester

To 3.0 g (8.61 mmol) of the compound from Example IV in 15 ml of abs. One gives xylene

7.66 ml (86.1 mmol) of methyl propiolate and heated in a closed autoclave at 180 ° C. for 20 h. The mixture is then concentrated in vacuo with silica gel and purified over 80 g of silica gel (elution with cyclohexane and cyclohexane / EtOAc 20: 1, 10: 1). Yield: 2.68 g (70%)

R _f = 0.36 (EtOAc / PE 1:20)

Example VI

4'-Fluoro-5-isopropyl-6- (4-trifluoromethyl-benzyl) biphenyl-2-carboxylic acid, methyl ester

149 mg (0.34 mol) of the compound from Example V and 472 mg (2.08 mmol) of DDQ are dissolved in 10 ml of toluene and refluxed overnight. The mixture is concentrated and purified on silica gel (cyclohexane / EtO Ac 20: 1)

Yield: 122 mg (82%) R _f = 0.22 (EtOAc / PE 1:20)

Example VII

[4'-Fluoro-5-isopropyl-6- (4-trifluoromethyl-benzyl) biphenyl-2-yl] methanol

46 mg (0.11 mmol) of the compound from Example VI are dissolved in 5 ml of abs. Dissolved toluene and mixed with 600μl (0.9 mmol) of a 1.5M solution of DIBAH in toluene at -78 ° C. The mixture is stirred at this temperature for 1 h, allowed to warm to room temperature and stirred for 1 h. It is quenched with water and extracted with EtOAc. The combined organic phases are dried over Na ₂ SO ₄ and concentrated. The crude product is purified on silica gel 60 (petroleum ether / EtOAc 2: 1). Yield: 25 mg (58%)

R _f = 0.28 (EtOAc / petroleum ether 1: 5). Example VIII

3- (4-fluorophenyl) -5-isopropyl-4- (4-trifluoromethyl-benzyl) -cyclohexa-l, 4-diene-l, 2-dicarboxylic acid dimethyl ester

To 22.25 g (63.9 mmol) of the compound from Example IV in 400 ml abs. Toluene is added to 36.3 g (255 mmol) of dimethylacetylene dicarboxylate and refluxed for 48 hours. The mixture is concentrated and excess dimethylacetylenedicarboxylate is distilled off in vacuo. The crude product is then purified on silica gel (CH ₂ C1 ₂ ) yield: 23.9 g (77%)

R _f = 0.39 (CH ₂ Cl ₂ ).

Example IX

4'-Fluoro-5-isopropyl-6- (4-trifluoromethyl-benzyl) biphenyl-2,3-dicarboxylic acid dimethyl ester

23.9 g (50 mol) of the compound from Example VIII and 22.2 g (100 mmol) of DDQ are dissolved in 250 ml of toluene and refluxed overnight. The mixture is concentrated and purified on silica gel (CH ₂ C1 ₂ ).

Yield: 19.9 g (81%) R _f = 0.37 (CH ₂ Cl ₂ ). Example X

[4'-Fluoro-5-isopropyl-2- (tetrahydro-pyran-2-yloxymethyl) -6- (4-trifluoromethyl-benzyl) biphenyl-3-yl] carbaldehyde

To 2.10 g (4.06 mmol) of the compound from Example 2, dissolved in 100 ml of abs. CH ₂ C1 ₂ , 830 mg Al ₂ O ₃ (neutral) and 1.31 g (6.11 mmol) pyridinium chlorochromate are added in 3 portions over 60 minutes. After 1 h it is filtered through Al ₂ O ₃ and with

Washed CH ₂ C1 ₂ . Further purification is carried out on silica gel 60 (CH ₂ C1 ₂ ). Yield: 1.84 g (87%) R _f = 0.39 (EtOAc / PE 1: 5).

Manufacturing examples

example 1

[4'-fluoro-3-hydroxymethyl-5-isopropyl-6- (4-trifluoromethyl-benzyl) biphenyl-2-yl] methanol

2.2 g (4.5 mmol) of the compound from Example IX are abs in 60 ml. Dissolved toluene and mixed with 60 ml (90 mmol) of a 1.5M solution of DIBAH in toluene at -78 ° C. 1 is stirred at this temperature, allowed to warm to room temperature and stirred for 1 hour. Pour on ice and extract with EtOAc. The combined organic phases are dried over Na ₂ SO ₄ and concentrated. The crude product is purified on silica gel 60 (CH ₂ Cl ₂ / MeOH 100: 3). Yield: 1.82 g (93%)

R _f = 0.20 (CH ₂ Cl ₂ / MeOH 100: 3).

Example 2

[4'-Fluoro-5-isopropyl-2- (tetrahydro-pyran-2-yloxymethyl) -6- (4-trifluoromethyl-benzyl) biphenyl-3-yl] methanol

15.5 g (35.2 mmol) of the compound from Example 1, 7.2 g (105 mmol) of imidazole and 11 ml (42 mmol) of tert-butyl-diphenylchlorosilane (TBDPS) are dissolved in 300 ml of CH ₂ C1 ₂ dissolved and stirred for 90 min at room temperature. It is quenched with water, extracted with CH ₂ C1 ₂ , dried over Na ₂ SO ₄ and concentrated. The crude product is purified on silica gel 60 (cyclohexane / EtOAc 100: 1 to 20: 1). 17.8 g (26.4 mmol,

75%>) [3-tert-butyl-diphenylsiloxymethyl-4'-fluoro-5-isopropyl-6- (4-trifluoromethyl-benzyl) biphenyl-2-yl] methanol (Rf = 0.52 in CH ₂ C1 ₂ ).

This compound is dissolved in 220 ml of abs. CH ₂ C1 ₂ and add 3.32 g (13.2 mmol) pyridinium p-toluenesulfonate (PPTS) and 12.1 ml (132 mmol) 3,4-dihydropyran.

After 60 min at room temperature, water is added and extracted with CH ₂ C1 ₂ . The combined organic phases are saturated with sat. Washed NaHCO ₃ solution and water, dried over Na ₂ SO ₄ and concentrated. 19.6 g (26 mmol, 98%) of the THP-protected compound (Rf = 0.22 EtOAc / PE 1:20) are obtained.

This compound is abs in 250 ml. THF solved. 24.3 g (77 mmol) of tetra-n-butylammonium fluoride trihydrate (TBAFx3H ₂ O) are added and the mixture is stirred for 90 min at room temperature. Water is added and extracted with EtOAc. The combined organic phases are saturated with sat. Washed NaHCO ₃ solution and water, dried over Na ₂ SO ₄ and concentrated. The cleaning is done on silica gel 60

(Cyclohexane / EtOAc 20: 1 to 2: 1). Yield: 11.3 g (85%) R _f = 0.54 (EtOAc / PE 1: 2)

Example 3

[3-Benzyloxymethyl-4'-fluoro-5-isopropyl-6- (4-trifluoromethyl-benzyl) biphenyl-2-yl] methanol

12 mg (0.48 mmol) of sodium hydride and 8 mg of tetra-n-butylammonium iodide are suspended in 3 ml of abs. THF and a solution of 50 mg (0.1 mmol) of the compound from Example 2 in 1 ml of abs. THF added. After 30 minutes, add up

14 µl (0.115 mmol) benzyl bromide and stir overnight. After adding water, the mixture is extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated. The purification is carried out on silica gel 60 (cyclohexane / EtOAc 5: 1). 70 mg of the THP-protected compound are obtained. This is dissolved in methanol and 300 mg of pyridinium p-toluenesulfonate (PPTS) are added. After stirring for ₂ h at room temperature, water is added, extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated. The purification is carried out on silica gel 60 (cyclohexane / EtOAc 5: 1). Yield: 35 mg (58%) R _f = 0.56 (EtOAc / PE 1: 5)

Example 4

[4'-Fluoro-3- (4-fluoro-phenoxymethyl) -5-isopropyl-6- (4-trifluoromethyl-benzyl) biphenyl-2-yl] methanol

150 mg (0.29 mmol) of the compound from Example 2, 99 mg (0.38 mmol) triphenylphosphine and 49 mg (0.435 mmol) 4-fluorophene are dissolved in 4 ml ether / THF (3: 1) and added dropwise 59 µl (0.38 mmol) of diethyl azodicarboxylate over 15 minutes. After 30 minutes at room temperature, the mixture is concentrated in vacuo and purified on silica gel 60 (cyclohexane / EtOAc 20: 1). 156 mg (83%) of the THP-protected compound are obtained. This is dissolved in methanol and 300 mg of pyridinium p-toluenesulfonate (PPTS) are added. After stirring for ₂ h at room temperature, water is added, extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated. The purification is carried out on silica gel 60 (cyclohexane / EtOAc 5: 1). Yield: 75 mg (79%) R _f = 0.40 (EtOAc / PE 1: 5)

Example 5

2- [4'-Fluoro-2-hydroxymethyl-5-isopropyl-6- (4-trifluoromethyl-benzyl) biphenyl-3-ylmethyl] isoindole-1,3-dione

150 mg (0.29 mmol) of the compound from Example 2, 99 mg (0.38 mmol) triphenylphosphine and 64 mg (0.435 mmol) phthalimide are dissolved in 4 ml ether / THF (3: 1) and 59 μl (0 , 38 mmol) of diethyl azodicarboxylate over 15 minutes. After 30 minutes at room temperature, the mixture is concentrated in vacuo and 60 on silica gel

(Cyclohexane / EtOAc 5: 1). 134 mg (72%) of the THP-protected compound are obtained. This is dissolved in 12 ml of acetic acid / THF / water (4: 2: 1) and stirred at 45 ° C for 18 h. It is concentrated in vacuo and purified on silica gel 60 (CH ₂ Cl ₂ / MeOH 100: 3). Yield: 74 mg (69%)

R _f = 0.39 (CH ₂ Cl ₂ / MeOH 100: 3). Example 6

[3-Cyclopentylidenemethyl-4'-fluoro-5-isopropyl-6- (4-trifluoromethyl-benzyl) biphenyl-2-yl] methanol

To 480 mg (1.16 mmol) methyl triphenylphosphonium bromide in 40 ml abs. Ether is added at 0 ° C to 0.63 ml (1.0 mmol) of a 1.6M solution of n-BuLi in n-hexane and stirred at 20 ° C for 2 h. 100 mg (0.19 mmol) of the compound are added

Example X dissolved in 10 ml abs. Ether. After 90 minutes, petroleum ether is added and the mixture is suctioned off through a little silica gel. Wash with petroleum ether and concentrate. The crude product is purified on silica gel 60 (toluene). 88 mg (80%), Rf = 0.42 (toluene) of the THP-protected compound are obtained. 70 mg of this are dissolved in methanol and 300 mg of pyridinium p-toluenesulfonate (PPTS) are added. After stirring for ₂ h at room temperature, water is added, extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated. The purification is carried out on silica gel 60 (cyclohexane / EtOAc 10: 1). Yield: 49 mg (81%) 0.19 (EtOAc / PE 1:10)

Example 7

[3-Cyclopentylmethyl-4 ^, -fluoro-5-isopropyl-6- (4-trifluoromethyl-benzyl) biphenyl-2-yl] methanol

20 mg Pt / C (5%) are added to 20 mg (0.04 mmol) of the compound from Example 6, dissolved in 5 ml EtOAc, and the mixture is hydrogenated in the presence of hydrogen at atmospheric pressure for 5 h. It is filtered through a membrane filter and concentrated. Further purification is carried out on silica gel 60 (EtOAc / Pe 1:10). Yield: 19 mg (96%) R _f = 0.20 (EtOAc / PE 1:10)

The compounds listed in Table 1 are prepared in analogy to the instructions in Examples 1-7:

Table 1:

Claims

claims

1. Compounds of the general formula (I)

in which

A represents cycloalkyl having 3 to 8 carbon atoms, or

represents aryl having 6 to 10 carbon atoms, or

where aryl and the above-mentioned heterocyclic ring systems optionally up to 5 times the same or different by cyano, halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each having up to 7 carbon atoms, or are substituted by a group of the formula -NR ³ R ⁴ ,

woπn R ³ and R ^{4 are} identical or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,

D for a residue of the formula

stands,

wherein

R ⁵ , R ⁶ and R ⁹ independently of one another

Aryl having 6 to 10 carbon atoms or a 5- to 7-membered, optionally benzocondensed, saturated or unsaturated, mono-, bi- or tricyclic heterocycle with up to 4 heteroatoms from the series S, N and / or O,

where the cycles, optionally, in the case of the nitrogen-containing rings, also via the N function, up to 5 times identically or differently by halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, Alkylalkoxy, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, aryl substituted by aryl or trifluoromethyl each having 6 to 10 carbon atoms or by an optionally benzo-condensed aromatic 5- to 7-membered heterocycle are substituted with up to 3 heteroatoms from the series S, N and / or O,

and / or are substituted by a group of the formula -OR ¹⁰ , -SR ", -SO ₂ R ¹² or -NR ¹³ R ¹⁴ ,

wherein

R ¹⁰ , R ¹¹ and R ¹² independently of one another denote aryl having 6 to 10 carbon atoms, which in turn is substituted up to 2 times identically or differently by phenyl, halogen or by straight-chain or branched alkyl having up to 6 carbon atoms,

R ¹³ and R ^{14 are the} same or different and have the meaning of R ³ and R ⁴ given above,

or

R ⁵ and / or R ^{6 is} a radical of the formula

mean,

R ^{7 represents} hydrogen, halogen or methyl,

and

R ^{8 is} hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkyl with because up to 6 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ ,

wherein

R ¹⁵ and R ^{16 are} identical or different and have the meaning of R ³ and R ⁴ given above,

or

R and R together form a radical of the formula = O or = NR

woπn

R ^{17 is} hydrogen or straight-chain or branched alkyl,

Alkoxy or acyl each having up to 6 carbon atoms,

or

T or X represents a bond,

V represents an oxygen or sulfur atom or an -NR ^I8 group, woπn

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

E represents cycloalkyl having 3 to 8 carbon atoms, or

R ^{1 represents} straight-chain or branched alkyl having up to 6 carbon atoms, which is by hydroxyl or by a group of the formula

is substituted,

R ^{2 represents} hydrogen or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which may be hydroxyl, halogen, phenyl, cycloalkyl having 3 to 6 carbon atoms or a group of the formula

or are substituted,

wherein

R is a radical of the formula -Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , or

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

Phenyl or benzyl, where all ring systems listed under R ¹⁹ optionally up to 2 times the same or different by trifluoromethyl, fluorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms or by straight-chain or branched alkyl having up to are substituted to 4 carbon atoms, which is optionally substituted by hydroxy, or

and their salts.

2. Compounds of formula (I) according to claim 1,

in which

D represents phenyl, which is optionally substituted by nitro, fluorine, chlorine, bromine, phenyl, trifluoromethyl or trifluoromethoxy, or

for a rest of the formula

R ⁷ R ⁸ R ⁵ - L -, R ⁶ V ^/ A or _R ⁹ _ _τ _ _v _χ_

stands.

woπn

R ⁵ , R ⁶ and R ⁹ independently of one another

Phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, mopholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl, the cycles, optionally up to 3 times in the case of the nitrogen-containing rings, also via the N function, identically or differently by fluorine, chlorine, bromine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio , Alkylalkoxy, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, triazolyl, tetrazolyl, benzoxathiazolyl, or trifluoromethyl-substituted phenyl or phenyl,

and / or by a group of the formula -OR ¹⁰ , -SR "or

-SO ₂ R ^{12 are} substituted,

wherein

R ¹⁰ , R "and R ^{12 are the} same or different and are phenyl, which in turn is substituted up to 2 times the same or different by phenyl, fluorine, chlorine or by straight-chain or branched alkyl having up to 4 carbon atoms,

or

R ⁵ and / or R ^{6 is} a radical of the formula

mean

R ⁷ denotes hydrogen, fluorine, chlorine or bromine,

and R ^{8 is} hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkyl each having up to 5 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ ,

wherein

or

R ⁷ and R ⁸ together form a radical of the formula = O or = NR ¹⁷ ,

wherein

L is a straight-chain or branched alkylene or alkenylene chain each having up to 6 carbon atoms, which are optionally substituted up to 2 times by hydroxy,

T and X are the same or different and represent a straight-chain or branched alkylene chain with up to 6 carbon atoms,

or T or X represents a bond,

V represents an oxygen or sulfur atom or a group of the formula -NR ¹⁸ -,

wherein

E represents cyclopropyl, butyl, pentyl, hexyl or heptyl, or

R ¹ for a group of the formula -CH ₂ OH or

stands,

R ^{2 stands} for hydrogen or for straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, optionally by hydroxy, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or by a group of the formula

or is substituted,

wherein

straight-chain or branched alkyl having up to 5 carbon atoms, or

Tetrahydropyranyl, pyridyl, phenyl or benzyl, which optionally up to 2 times the same or different by trifluoromethyl, fluorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 3 carbon atoms or by straight-chain or branched alkyl having up to 3 Carbon atoms are substituted, which is optionally substituted by hydroxy, -u

and their salts.

3. Compounds of formula (I) according to claim 1,

D represents phenyl, which is optionally substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or

for a rest of the formula

R ⁷ R ⁸ R ⁵ - L-, R ⁶ V ^/ \ ^or R ⁹ -TVX-

stands,

wherein

R ⁵ , R ⁶ and R ⁹ independently of one another

Phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyπolidinyl, mopholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl,

where the cycles, optionally up to 3 times, in the case of the nitrogen-containing rings also via the N function, identically or differently by fluorine, chlorine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, Alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, triazolyl, Tetrazolyl, benzothiazolyl, trifluoromethyl substituted phenyl or phenyl are substituted

wherein

R ¹⁰ , R ^π and R ^{12 are the} same or different and are phenyl, which in turn is substituted up to 2 times the same or different by phenyl, fluorine, chlorine or by straight-chain or branched alkyl having up to 3 carbon atoms,

or

R ⁵ and / or R ^{6 is} a radical of the formula

F ₃ C mean

R ^{7 represents} hydrogen or fluorine,

and

R ^{8 is} hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy, trifluoromethoxy, or straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ , woπn

R ¹⁵ and R ^{16 are} identical or different and are 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 or = NR ¹⁷ ,

wonn

or

T or X represents a bond,

V represents an oxygen or sulfur atom or a group of the formula -NR ¹⁸ ,

wherein R ¹⁸ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

R ¹ for a group of the formula -CH ₂ OH or

stands,

R ² for hydrogen or for straight-chain or branched alkyl or

Alkenyl each having up to 5 carbon atoms, optionally by hydroxy, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or by a group of the formula

is substituted,

wherein R ¹⁹ denotes straight-chain or branched alkyl having up to 4 carbon atoms, or

is a radical of the formula -Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , or

Trifluoromethyl, fluorine, chlorine, nitro, hydroxy, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 3 carbon atoms or substituted by straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by hydroxy

and their salts.

4. Compounds of formula (I) according to claim 1, in which

A represents phenyl or pyridyl, which may be up to 2 times identical or different by fluorine, chlorine, bromine, hydroxy, trifluoromethyl,

Trifluoromethoxy or substituted by straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,

D represents phenyl, which is optionally substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or a radical of the formula

R ⁵ - L-, RV ⁶ - ^ A or _R ^Q _ _τ _ _v _χ_ stands,

wherein

R ⁵ , R ⁶ and R ⁹ independently of one another

the cycles, optionally up to 3 times, in the case of the nitrogen-containing rings also via the N function, identically or differently by fluorine, chlorine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, Alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, triazolyl, tetrazolyl, benzothiazolyl, trifluoromethyl-substituted phenyl or phenyl are substituted

and / or by a group of the formula -OR ¹⁰ , -SR ¹¹ or

-SO ₂ R ^{12 are} substituted,

wherein

R ¹⁰ , R ^u and R ^{12 are the} same or different and are phenyl, which in turn is substituted up to 2 times the same or different by phenyl, fluorine, chlorine or by straight-chain or branched alkyl having up to 3 carbon atoms, or

R ⁵ and / or R ^{6 represent} a radical of the formula

R ^{7 represents} hydrogen or fluorine,

and

wherein

or

R ⁷ and R ⁸ together form a radical of the formula = O or ^ NR ¹⁷ ,

wherein

R ¹⁷ denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms, L is a straight-chain or branched alkylene or alkenylene chain each having up to 5 carbon atoms, which are optionally substituted up to 2 times by hydroxy,

or

T or X represents a bond,

V for an oxygen or sulfur atom or for a group of

Formula -NR ¹⁸ stands,

wherein

R ¹ for a group of the formula -CH ₂ OH or

stands. represents hydrogen or straight-chain or branched alkyl or alkenyl each having up to 5 carbon atoms, which may be by hydroxyl, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or by a group of the formula

or is substituted,

wherein

R ' ⁹ denotes straight-chain or branched alkyl having up to 4 carbon atoms, or

is a radical of the formula -Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , or

Tetrahydropyranyl, pyridyl, phenyl or benzyl, which optionally up to 2 times the same or different by trifluoromethyl, fluorine, chlorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 3 carbon atoms or by straight-chain or branched alkyl having up to are substituted to 3 carbon atoms, which is optionally substituted by hydroxy, and their salts.

5. Compounds according to claim 1 for use in combating diseases.

6. A process for the preparation of compounds according to claim 1, characterized in that

Compounds of the general formula (II)

in which

A, D and E have the meaning given above,

in which

A, D and E have the meaning given above, implements

then with compounds of the general formula (IV) or (IVa)

₂ o

R ²⁰ -O ₂ C- -CO ₂ R (IV)

21 20 "

R -CO ₂ R (IVa)

in which

R ²⁰ , R ²⁰ and R ^{20 are} identical or different and stand for straight-chain or branched alkyl having up to 4 carbon atoms,

and

R ^{21 represents} hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxy, phenyl, straight-chain or branched alkoxy having up to 6 carbon atoms, amino, alkyl- or dialkylamino having up to 4 carbon atoms in the alkyl part.

into the compounds of the general formula (V)

in which A, D and E have the meaning given above,

R ^{20 '} ^" includes the scope of R ²⁰ and R ^20" given above,

and

R ²² either represents hydrogen or the radical -CO ₂ R ²⁰ , or includes the scope of R ²¹ given above,

convicted,

by oxidation the compounds of the general formula (VI)

in which

A, D, E, R ² , R ²⁰ and R ^{22 have} the meaning given above,

manufactures,

and finally reduced the carbonyl functions to the hydroxymethyl function,

and derivatization on the substituent R ² by starting from compounds of the general formula (Ia)

in which

A, D and E have the meaning given above,

depending on the abovementioned meaning of R ² in the system P (C ₆ H ₅ ) ₃ / diethylazodicarboxylic acid ethyl ester and the corresponding alcohols or amines defined under R ¹⁹ ,

or

or in the case of R ² = alkenyl, the compounds of the general formula (Ia) first give the aldehydes of the general formula (VII)

in which

A, D and E have the meaning given above,

implemented and in a further step carries out a Wittig reaction by customary methods, cleaves the hydroxyl protective group as described above and finally reduces it to the corresponding alkyl compounds (R ² = alkyl) by hydrogenation in the presence of a catalyst.

7. Medicament containing at least one compound according to claim 1 and pharmacologically acceptable formulation auxiliaries.

8. Medicament according to claim 7 for the treatment of hyperlipoproteinemia.

9. Medicament according to claim 7 for the treatment of arteriosclerosis.

10. Use of compounds according to claim 1 for the manufacture of medicaments.

11. Use according to claim 10 for the manufacture of medicaments for the treatment of arteriosclerosis, in particular dyslipidemia.