JP2001517646A - Benzylbiphenyl and similar compounds and their application for treating arteriosclerosis and dyslipidemia - Google Patents

Abstract

  (57) [Summary] The present invention relates to benzyl biphenyls and their analogous compounds, which are prepared by first reacting α and β-unsaturated ketones to form the corresponding substituted and conjugated dienes, and thereafter the said diene Is cyclized with an acetylene derivative. The resulting cyclohexanediene is oxidized to form an aromatic compound and / or varied with available substituents by conventional means. The compounds are suitable as excipients in medicaments, especially for treating arteriosclerosis and dyslipidemia.

Description

DETAILED DESCRIPTION OF THE INVENTION

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

The publication US-5 169 857-A2 discloses 7- (polysubstituted pyridyl) -6-heptenoates for treating arteriosclerosis, lipoproteinemia and hyperproteinemia. Further, 7- (4-aryl-3-pyridyl) -3,5-
The production of dihydroxy-6-heptenoate is described in the publication EP-325 130-A
2 is described.

The present invention relates to a compound represented by the general formula (I)

[0004]

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Wherein A represents cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms Or a 5- to 7-membered, saturated, partially unsaturated or unsaturated, optionally benzo-fused heterocycle having up to 4 heteroatoms from the group consisting of S, N and O. Wherein the aryl and the ring system of said heterocycle are cyano, halogen, nitro,
Straight or branched alkyl, acyl, hydroxyalkyl, alkylthio having the same or different substituents from the group consisting of carboxyl, hydroxyl, trifluoromethyl, trifluoromethoxy or in each case up to 7 carbon atoms , alkoxycarbonyl, by oxy alkoxycarbonyl or alkoxy, or optionally substituted up to 5 times by a group of the formula -NR ³ R ^4, wherein, R ³ and R ⁴ are identical or different and represent hydrogen, phenyl or 6 Represents a straight or branched alkyl having up to carbon atoms, wherein D is of the formula

[0006]

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Wherein R ⁵ , R ⁶ and R ⁹ independently of one another are aryl having 6 to 10 carbon atoms or 5- to 7-membered, optionally benzo-fused Represents a saturated, unsaturated, mono-, bi- or tricyclic heterocycle having up to 4 heteroatoms from the group consisting of S, N and O, wherein the ring is N-functional in the case of a nitrogen-containing ring Via the radicals also halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy having in each case up to 6 carbon atoms 6 to 1 in each case, depending on the same or different substituents from the group consisting of
5- to 7-membered aromatic, optionally benzo-fused, with aryl or trifluoromethyl-substituted aryl having 0 carbon atoms or with up to 3 heteroatoms from the group consisting of S, N and O of the hetero ring and / or the formula -OR ^10, -SR ^11, the group of -SO ₂ R ¹² or -NR ¹³ R ^14, optionally substituted up to 5 times, wherein R ^10, R ¹¹ and R ¹² Represents, independently of one another, an aryl having 6 to 10 carbon atoms, which for its part is the same or different from the group consisting of phenyl, halogen or has up to 6 carbon atoms Substituted up to twice by a straight-chain or branched alkyl, R ¹³ and R ¹⁴ are the same or different and R ³ and R ^Has the meaning of ⁴ or R ⁵ and / or R ⁶ are of the formula

[0008]

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R ⁷ represents hydrogen, halogen or methyl, and R ⁸ represents hydrogen, halogen, azide, trifluoromethyl, hydroxyl, trifluoromethoxy, in each case a straight chain having up to 6 carbon atoms. Represents a chain or branched alkoxy or alkyl, or a group of formula —NR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are the same or different and have the meanings of R ³ and R ⁴ given above. Or R ⁷ and R ⁸ together form a group of the formula ＯO or ＮＲNR ¹⁷ , wherein R ¹⁷ is hydrogen or a straight chain having up to 6 carbon atoms in each case. L represents a straight-chain or branched alkyl, alkoxy or acyl; L is a straight-chain or branched alkylene or alkenylene chain having in each case up to 8 carbon atoms. And they are optionally substituted up to twice by hydroxyl, T and X are the same or different and represent a straight or branched alkylene chain having up to 8 carbon atoms, or X represents a bond, V is either an oxygen or sulfur atom, or -NR ¹⁸ - represents a group wherein R ¹⁸ is a linear or branched carbon atoms hydrogen or up to 6, E represents alkyl, 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
R ¹ represents phenyl optionally substituted by cycloalkyl or hydroxyl having 3 to 8 carbon atoms or optionally substituted by halogen or trifluoromethyl;

[0010]

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Represents a straight-chain or branched alkyl having up to 6 carbon atoms, which is substituted by a radical of the formula: R ² represents hydrogen or in each case a straight-chain alkyl having up to 8 carbon atoms. Represents a chain or branched alkyl or alkenyl, which may be hydroxyl, halogen, phenyl, cycloalkyl having 3 to 6 carbon atoms, or

[0012]

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Wherein R ¹⁹ represents a group of the formula —Si (CH ₃ ) ₂ C (CH ₃ ) ₃ or a straight chain having up to 6 carbon atoms. Or a branched alkyl or a 5- to 7-membered saturated, partially unsaturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of S, N and O Or phenyl or benzyl, wherein all ring systems listed for R ¹⁹ are
By the same or different substituents from the group consisting of trifluoromethyl, fluorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl in each case having up to 4 carbon atoms, or optionally by hydroxyl Is optionally substituted up to twice with a straight or branched alkyl having up to 4 carbon atoms being substituted.

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

In the context of the present invention, preference is given to physiologically acceptable salts. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with inorganic acids, carboxylic acids or sulphonic acids. Particular preferences include, for example, 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, Given to salts with citric, fumaric, malic or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds of the present invention having a free carboxyl group. Particular preference is given, for example, to sodium, potassium, magnesium or calcium salts and also ammonia or, for example, ethylamine, di or triethylamine, di or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2 -Ammonium salts derived from organic amines such as phenylethylamine.

The compounds of the present invention may exist in stereoisomers, either image and mirror image (enantiomers) or non image and mirror image (diastereomers). The present invention relates to both enantiomers or diastereomers and their respective mixtures. These mixtures of enantiomers and diastereomers can be separated into stereoisomerically uniform components in a manner known per se.

In the context of the present invention, optionally benzofused heterocycles are generally S,
Represents a saturated, partially unsaturated or unsaturated 5- to 7-membered, preferably 5- to 6-membered heterocycle which may contain up to 4 heteroatoms from the group consisting of N and O. Examples which may be mentioned are: indolyl, isoquinolyl, quinolyl, benzo [
b] thiophene, benzo [b] furanyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Preference is given to quinolyl, furyl, pyridyl and thienyl.

Preferably, A is the same or different substituent from the group consisting of fluorine, chlorine, bromine, amino, hydroxyl, trifluoromethyl, trifluoromethoxy, or
A naphthyl, phenyl, pyridyl, thienyl, imidazolyl, pyryl or morpholine, optionally substituted up to twice by linear or branched alkyl or alkoxy having in each case up to 6 carbon atoms, D Represents phenyl optionally substituted by nitro, fluorine, chlorine, bromine, phenyl, trifluoromethyl or trifluoromethoxy, or

[0020]

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Wherein R ⁵ , R ⁶ and R ⁹ independently of one another are phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin -2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl, wherein the ring is fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, also via the N functional group in the case of a nitrogen-containing ring. , Cyano, carboxyl, trifluoromethoxy, linear or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl, triazolyl, tetrazolyl, benzoxatiazolyl having in each case up to 4 carbon atoms Or trif In some cases the same or different substituents from the group consisting of Oromechiru substituted phenyl or phenyl substituted up to 3 times, and / or substituted by a group of the formula -OR ^10, -SR ¹¹ or -SO ₂ R ^12, wherein In which R ¹⁰ , R ¹¹ and R ¹² are the same or different and represent phenyl, for which, by the same or different substituents from the group consisting of phenyl, fluorine, chlorine, or up to 4 carbon atoms Is substituted up to twice by a linear or branched alkyl having the formula: or R ⁵ and / or R ⁶ are of the formula

[0022]

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R ⁷ represents hydrogen, fluorine, chlorine or bromine; and R ⁸ represents hydrogen, fluorine, chlorine, bromine, azide, trifluoromethyl, hydroxyl, trifluoromethoxy, in each case Represents a straight-chain or branched alkoxy or alkyl having up to 5 carbon atoms or a group of formula -NR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, phenyl or 4 Represents linear or branched alkyl having up to carbon atoms, or R ⁷ and R ⁸ together form a group of formula ＯO or ＮＲNR ¹⁷ , wherein R ¹⁷ is Represents hydrogen or straight-chain or branched alkyl, alkoxy or acyl having in each case up to 4 carbon atoms, wherein L has in each case up to 6 carbon atoms Represents a straight-chain or branched alkylene or alkenylene chain, which is optionally substituted up to twice by hydroxyl, T and X are the same or different and are straight-chain or branched having up to 6 carbon atoms. or represents branched alkylene chain, or T or X represents a bond, V is or represents an oxygen or sulfur atom, or the formula -NR ¹⁸ - represents a group, wherein R ¹⁸ is hydrogen or 4, Represents a straight-chain or branched alkyl having up to 6 carbon atoms, or phenyl, E represents cyclopropyl, -butyl, -pentyl, -hexyl or -heptyl, or represents up to 6 carbon atoms. Represents a straight or branched alkyl having
Cyclopropyl, - butyl, - hexyl, - pentyl, - either optionally substituted by heptyl or hydroxyl, or, fluorine, represents phenyl which is optionally substituted by chlorine or trifluoromethyl, R ¹ has the formula —CH ₂ OH, or

[0024]

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R ² represents hydrogen or a straight-chain or branched alkyl or alkenyl having in each case up to 6 carbon atoms, which is hydroxyl,
By phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or of the formula

[0026]

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Wherein R ¹⁹ represents a group of formula —Si (CH ₃ ) ₂ C (CH ₃ ) ₃ or a straight chain having up to 5 carbon atoms Or a branched alkyl, or tetrahydropyranyl, pyridyl, phenyl or benzyl, which are trifluoromethyl, fluorine, nitro, hydroxyl, straight-chain in each case up to 3 carbon atoms Or twice with the same or different substituents from the group consisting of branched alkoxy or alkoxycarbonyl, or with straight-chain or branched alkyl having up to 3 carbon atoms, optionally substituted by hydroxyl. The compounds of general formula (I) of the present invention, and their salts, which are optionally substituted.

Particularly preferably, A is the same or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy or in each case 5
A phenyl or pyridyl, optionally substituted up to twice by a straight-chain or branched alkyl or alkoxy having up to 2 carbon atoms,
D represents phenyl optionally substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or

[0029]

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Wherein R ⁵ , R ⁶ and R ⁹ independently of one another are phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl , Morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl, wherein the ring is fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, also through the N functional group in the case of a nitrogen-containing ring. , Carboxyl, trifluoromethoxy, linear or branched alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl, in each case up to 4 carbon atoms, triazolyl, tetrazolyl, benzothiazolyl, trifluoromethyl-substituted phenyl Or substituted up to 3 times in some cases by identical or different substituents from the group consisting of phenyl, and / or formula -OR ^10, is replaced by a group of -SR ¹¹ or -SO ₂ R ^12, wherein R ¹⁰ , R ¹¹ and R ¹² are the same or different and, for that part, by the same or different substituents from the group consisting of phenyl, fluorine, chlorine, or linear or branched having up to 3 carbon atoms Represents phenyl substituted up to twice by alkyl, or R ⁵ and / or R ⁶ are of the formula

[0031]

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R ⁷ represents hydrogen or fluorine, and R ⁸ represents hydrogen, fluorine, chlorine, bromine, azide, trifluoromethyl, hydroxyl, trifluoromethoxy, or in each case up to 4 represents a straight-chain or branched alkoxy or alkyl or a group of the formula -NR ¹⁵ R ^16, carbon atoms, where identical or different R ¹⁵ and R ^16, and the carbon atom of hydrogen or up to three, Or R ⁷ and R ⁸ together form a group of formula ＯO or ＮＲNR ¹⁷ , wherein R ¹⁷ is hydrogen, or in each case Represents a straight-chain or branched alkyl, alkoxy or acyl having up to 4 carbon atoms, L is in each case a straight-chain or branched alkyl having up to 5 carbon atoms. Linear or branched alkylene or alkenylene chains, optionally substituted up to twice by hydroxyl, T and X being the same or different and having up to 3 carbon atoms or it represents, or T or X represents a bond, V is or represents an oxygen or sulfur atom, or represents a group of the formula -NR ^18, wherein R ¹⁸ is a carbon atom of hydrogen or up to three, Represents a straight or branched alkyl having, E represents cyclopropyl, cyclopentyl or cyclohexyl, or phenyl optionally substituted by fluorine or trifluoromethyl, or optionally substituted by hydroxyl Straight-chain or branched alkyl having up to 4 carbon atoms R ¹ is of the formula —CH ₂ OH, or

[0033]

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Wherein R ² represents hydrogen or, in each case, straight-chain or branched alkyl or alkenyl having up to 5 carbon atoms, which is hydroxyl, phenyl, By fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or of the formula

[0035]

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Wherein R ¹⁹ represents straight-chain or branched alkyl having up to 4 carbon atoms or has the formula Si (CH ₃ ) ₂ C (CH _{3 3} ) represents ₃ radicals or tetrahydropyranyl, pyridyl, phenyl or benzyl, which are trifluoromethyl, fluorine, chlorine, nitro, hydroxyl, straight-chain in each case up to 3 carbon atoms Or twice with the same or different substituents from the group consisting of branched alkoxy or alkoxycarbonyl, or with straight-chain or branched alkyl having up to 3 carbon atoms, optionally substituted by hydroxyl. And optionally substituted up to the compounds of general formula (I) of the present invention, and salts thereof. .

Very particularly preferably, A represents phenyl, fluorine, chlorine, bromine, trifluoromethyl and D is of the formula

[0038]

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Wherein R ⁵ , R ⁶ and R ⁹ independently of one another represent phenyl, which is the same or different by the same or different substituents from the group consisting of fluorine, chlorine and trifluoromethyl Up to three times optionally substituted, R ⁷ represents hydrogen or fluorine and R ⁸ represents hydrogen, fluorine, chlorine, bromine or alkyl in each case having up to 4 carbon atoms, or R ⁷ and R ⁸ together form a group of the formula ＯO or ＮＲNR ¹⁷ , wherein R ¹⁷ is hydrogen or straight-chain or branched alkyl having in each case up to 4 carbon atoms L represents an alkoxy or acyl; L represents a straight-chain or branched alkylene or alkenylene chain having in each case up to 5 carbon atoms, which are optionally Is substituted up to twice by hydroxyl, T and X are the same or different and represent a straight-chain or branched alkylene chain having up to 3 carbon atoms, or T or X represents a bond, and V is , or represents an oxygen or sulfur atom, or represents a group of the formula -NR ^18, wherein R ¹⁸ represents straight-chain or alkyl branched carbon atoms hydrogen or up to three,, E is, R ¹ represents cyclopropyl, cyclopentyl or cyclohexyl, or phenyl optionally substituted by fluorine or trifluoromethyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms; formula -CH ₂ OH, or

[0040]

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Wherein R ² represents hydrogen or, in each case, straight-chain or branched alkyl or alkenyl having up to 5 carbon atoms, which is hydroxyl, phenyl, By fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or of the formula

[0042]

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R ¹⁹ is optionally substituted by a group of the formula wherein R ¹⁹ represents straight-chain or branched alkyl having up to 4 carbon atoms, or has the formula —Si (CH ₃ ) ₂ C ( CH ₃ ) ₃ or tetrahydropyranyl, pyridyl, phenyl or benzyl, which have trifluoromethyl, fluorine, chlorine, nitro, hydroxyl and in each case up to 3 carbon atoms By the same or different substituents from the group consisting of straight-chain or branched alkoxy or alkoxycarbonyl, or by straight-chain or branched alkyl having up to 3 carbon atoms optionally substituted by hydroxyl, A compound of the general formula (I) of the present invention, and salts thereof, optionally substituted up to twice. is there.

Furthermore, a process for the preparation of the compounds of the general formula (I) according to the invention has been found, which comprises the steps of:

[0045]

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Wherein A, D and E are as defined above, in a system (C ₆ H ₅ ) ₃ PCH ₃ Br / n-butyllithium, first of the general formula ( III)

[0047]

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Wherein A, D and E are as defined above, converted to a compound of the general formula (IV) or (IVa)

[0049]

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Wherein R ²⁰ , R ²⁰ ′ and R ²⁰ ″ are the same or different and represent a straight-chain or branched alkyl having up to 4 carbon atoms, and R ²¹ represents hydrogen Or a straight or branched alkyl having up to 6 carbon atoms, which includes hydroxyl, phenyl, straight or branched alkoxy, amino, alkyl having up to 6 carbon atoms. Using a compound of the formula (V), optionally substituted by an alkyl or dialkylamine having up to 4 carbon atoms

[0051]

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Wherein A, D and E are as defined above, R ²⁰ ″ includes the aforementioned ranges of the meaning of R ²⁰ and R ²⁰ ″, and R ²² is hydrogen. or or or or either represents a group -CO ₂ R ²⁰ "represents or comprises the aforementioned range of meaning of R ^21, are converted to the compounds, by oxidation, formula (VI)

[0053]

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Wherein A, D, E, R ² , R ²⁰ ″ ′ and R ²² are as defined above, and then the carbonyl function is converted to a hydroxymethyl function And the general formula (Ia)

[0055]

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Wherein A, D and E are as defined above, starting from a compound of the formula P (C ₆ H ₅ ) ₃ / diethyl, depending on the aforementioned meaning of R ² Reacting in ethyl azodicarboxylate and the corresponding amine or alcohol as defined for R ¹⁹ , or performing the etherification by reaction with an alkyl halide in the presence of a base, and then using an acid To remove the hydroxyl protecting group in both derivatizations, or, if R ² = alkenyl, first replace the compound of general formula (Ia) with a compound of general formula (VII)

[0057]

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Wherein A, D and E are as defined above, converting to the aldehyde of and, in a further step, performing the Wittig reaction according to customary methods, as described above. Derivatization at the substituent R ² is performed by removing the hydroxyl protecting group and then reducing to the corresponding alkyl compound (R ² = alkyl) by hydrogenation in the presence of a catalyst. It is characterized by the following.

The method of the present invention may be illustrated in an illustrative manner by the following scheme. Ie

[0060]

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[0061]

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Suitable solvents for reaction steps (II) → (III) are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether. It is also possible to use mixtures of the solvents mentioned. Preference is given to diethyl ether.

Suitable bases for reaction steps (II) → (III) are customary strongly basic compounds. These are preferably organic lithium compounds such as, for example, N-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or, for example, lithium diisopropylamide, sodium amide or potassium amide or lithium hexamethylsilylamide. Amides, such as
Alternatively, it includes an alkali metal hydride such as sodium or potassium hydride. Particular preferences are given to N-butyllithium.

The base is generally from 1 mol to 2 mol, based on 1 mol of the compound of the general formula (II).
It is used in an amount of up to 1.0 mol, preferably from 1.05 mol to 1.2 mol.

The reaction generally proceeds at a temperature from −30 ° C. to room temperature, preferably from −20 ° C. to 0 ° C.

The reaction generally proceeds at atmospheric pressure; however, it is also possible to operate at elevated or reduced pressure.

Suitable solvents for preparing the compounds of the general formula (V) according to the invention include benzene, toluene, xylene, chlorobenzene, ethyl benzoate, decalin, benzonitrile, hexane, cyclohexane or mineral oil fractions. Hydrogen. It is also possible to use mixtures of the solvents mentioned. Preference is given to xylene.

The reaction may also be performed without a solvent, or the solvent used may be an alkyne.

The reaction is generally carried out from −30 ° C. to +250, preferably from 80 ° C. to 180 °.
Proceed at temperatures up to ° C.

The reaction generally proceeds at atmospheric pressure; however, it is also possible to operate at elevated or reduced pressure.

The reaction generally proceeds without a catalyst; however, it is also possible to use Lewis acids as catalysts. Examples which may be mentioned are: BF ₃ , BF ₃ × OEt ₂ , AlCl ₃ , TiCl ₄ , Al (CH ₃ ) ₃ , Al (C ₂ H ₅ ) ₃ , (C ₂ H ₅ ) ₂ Al
Cl, MgCl ₂ , ZnCl ₂ and BCl ₃ .

Suitable solvents for the oxidation are diethyl ether, dioxane, tetrahydrofuran,
Ethers such as glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethylene, trichloroethylene, chlorobenzene, acetic acid Ethyl, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Preference is given to toluene.

Suitable oxidizing agents are, for example, potassium permanganate, bromine, cerium (IV) ammonium nitrate, 2,3-dichloro-5,6-dicyanobenzoquinone, pyridinium chlorochromate (PCC), chloro on basic alumina Pyridinium chromate, osmium tetroxide, sodium acetate / iodine, and manganese dioxide.
Preference is given to 2,3-dichloro-5,6-dicyanobenzoquinone.

The oxidizing agent is used in an amount of from 1 mol to 10 mol, preferably from 2 mol to 5 mol, based on 1 mol of the compound of the general formula (V).

The oxidation generally proceeds in a temperature range from 0 ° C. to + 100 ° C., preferably from room temperature to 80 ° C.

The oxidation generally proceeds at atmospheric pressure. However, it is also possible to carry out the oxidation at elevated or reduced pressure.

Suitable solvents for the reduction are the hydrocarbons listed above, and preference is given to toluene.

The reduction of the compounds of general formula (VI) is generally carried out using a reducing agent, preferably one suitable for reducing an alkoxycarbonyl to a hydroxyl compound.
Here, reduction with a metal hydride or complex metal hydride in an inert solvent, if appropriate in the presence of a trialkylborane, is particularly suitable. The reduction is preferably carried out with a complex metal hydrogen such as, for example, lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylborohydride, diisobutylaluminum hydride or lithium aluminum hydride. Performed using a compound. The reduction is very particularly preferably carried out using diisobutylaluminum hydride.

The reducing agent is generally used in an amount of from 1 mol to 6 mol, preferably from 1 mol to 4 mol, based on 1 mol of the compound 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., depending in each case on the choice of the reducing agent and the solvent. proceed.

The reduction generally proceeds at atmospheric pressure; however, it is also possible to operate at elevated or reduced pressure.

Suitable solvents for all steps are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or benzene, toluene,
Hydrocarbons such as xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethylsulfoxide, dimethyl Formamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Preference is given to toluene and dichloromethane.

The protecting groups are generally in a temperature range from 0 ° C. to 50 ° C., preferably at room temperature, and
Cleavage at atmospheric pressure in the presence of hydrochloric acid in one of the above alcohols and THF, preferably methanol / THF. In certain cases, the protecting groups are preferably cleaved using tetrabutylammonium fluoride (TBAF) in THF at room temperature.

The reaction of the compound of general formula (VI) is carried out in one of the abovementioned ethers, preferably in tetrahydrofuran, in a temperature range from −78 ° C. to −10 ° C., preferably at −25 ° C., under an atmosphere of protective gas. Will be implemented.

Derivatization of the hydroxyl function to compounds of general formula (VII) includes, for example, oxidation, sulfonation, alkylation, hydrogenation, halogenation, Wittig / Grignard reaction, aldol reaction, reductive amination, and Performed by sulfamidation.

Suitable bases for the individual steps are customary strongly basic compounds. These are preferably organic lithium compounds such as, for example, n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or, for example, lithium diisopropylamide, sodium amide or potassium amide or lithium hexamethylsilylamide. Amides or alkali metal hydrides such as sodium or potassium hydride. Particular preference is given to using N-butyllithium, sodium hydride or lithium diisopropylamide.

Suitable bases are furthermore customary inorganic bases. These are preferably alkali metal hydroxides or alkaline earth metal hydroxides, for example sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates or carbonates, such as sodium carbonate or potassium carbonate. Sodium hydrogen. Particular preference is given to using sodium hydroxide or potassium hydroxide.

Suitable solvents for the individual reaction steps are also alcohols such as methanol, ethanol, propanol, butanol or tert-butanol. Preference is given to tert-butanol.

The alkylation with an alkyl halide is generally carried out in an inert solvent in the presence of a base.

Suitable solvents here are all inert organic solvents, depending on the type of alkylating agent. These preferably include ethers such as diethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene or xylene, or dimethylformamide or hexamethylphosphoric triamide, or mixtures of the solvents mentioned.

Suitable bases for the alkylation are the customary basic compounds. These are preferably alkali metal hydrides such as sodium hydride, alkali metal amides such as sodium amide or lithium diisopropylamide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide. Or an organic amine such as a trialkylamine such as triethylamine, or an organolithium compound such as butyllithium or phenyllithium. Preference is given to lithium diisopropylamide.

[0092] The alkylation is generally carried out in a temperature range from -70 ° C to + 110 ° C, preferably from 20 ° C to 80 ° C.

The alkylation is generally performed at atmospheric pressure. However, it is also possible to carry out the process under reduced or elevated pressure (for example in the range from 0.5 to 5 bar).

Some of the compounds of the general formula (II) are novel and are, for example, of the general formula (VIII) D—CH ₂ —CO—CH (CH ₃ ) ₂ (VIII) wherein D is Reacting a compound of the general formula (IX) A-CHO (IX), wherein A is as defined above, in the presence of lithium diisopropylamide , General formula (X)

[0095]

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Wherein A and D are as defined above, to give a compound of the formula and then, in two steps, stirring the diazabicycloundecane in mesyl chloride / triethylamine and tetrahydrofuran into the system , Can be manufactured.

Some of the compounds of the general formula (VIII) are known or new and are initially N, N-dimethylhydrazine and finally of the general formula (XI) D-Br (XI) Is as defined above, and can be prepared by reacting with a compound of the formula in an inert solvent in the presence of a base, and finally by treatment with hydrochloric acid.

The reaction of the compound of the general formula (XI) is carried out in an ether such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether. Preferably in tetrahydrofuran.

Suitable bases for the individual steps are customary strongly basic compounds. These are preferably organic lithium compounds such as, for example, n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or, for example, lithium diisopropylamide, sodium amide or potassium amide or lithium hexamethylsilylamide. Amides or alkali metal hydrides such as sodium or potassium hydride. Particular preference is given to using N-butyllithium, sodium hydride or lithium diisopropylamide.

The base is used in an amount of from 0.1 mol to 10 mol, preferably from 1 mol to 5 mol, in each case based on 1 mol of the starting materials.

The reaction is generally carried out from −10 ° C. to + 10 ° C., preferably from 5 ° C. to 10 ° C.
It is carried out in a temperature range up to and at atmospheric pressure.

The reaction with the aldehyde of the general formula (IX) is carried out as follows: Suitable solvents for the whole process are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or benzene, toluene,
Hydrocarbons such as xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethylsulfoxide, dimethyl Formamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Preference is given to tetrahydrofuran.

Suitable bases for the individual steps are customary strongly basic compounds. These are preferably organic lithium compounds such as, for example, n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or, for example, lithium diisopropylamide, sodium amide or potassium amide or lithium hexamethylsilylamide. Such amides or alkali metal hydrides such as sodium or potassium hydride. Particular preference is given to using N-butyllithium, sodium hydride or lithium diisopropylamide.

The base is used in an amount of from 0.1 mol to 10 mol, preferably from 1 mol to 5 mol, based in each case on 1 mol of the starting material.

The reaction is generally carried out from −10 ° C. to + 10 ° C., preferably from 5 ° C. to 10 ° C.
It is carried out in the temperature range up to and at atmospheric pressure.

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 prepared as described above.

The compounds of the general formulas (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.

Most of the compounds of the general formula (VII) are 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 the 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 when compared to the prior art; in particular, they represent a high degree of cholesterol ester transfer protein (CETP). Are effective inhibitors and they stimulate reverse cholesterol transfer. The active ingredients according to the invention effect a reduction in LDL cholesterol levels in the blood and at the same time increase HDL cholesterol levels. They can therefore be used for the treatment and prevention of hyperlipoproteinemia, dyslipidaemias, hypertriglyceridemia, hyperlipidemia or arteriosclerosis.

The pharmacological activity of the substances according to the invention was evaluated using the following test: CETP inhibition test Preparation of CETP CETP was partially produced from human plasma by differential centrifugation and column chromatography. And used for testing. For this purpose, human plasma was adjusted to a density of 1.21 g / ml using NaBr and 50,0
Centrifuge at 00 rpm at 4 ° C. for 18 hours. Bottom fraction (d> 1.21 g / ml)
With Sephadex ™ Phenyl Sepharose 4B (
Pharmacia column and 0.15 M NaCl /
Wash with 0.001 M Tris HCl, pH 7.4, and then elute using distilled water. The CETP active fractions were pooled and 50 mM sodium acetate pH 4.0.
5 and dialyzed against CM-Sepharose ™ (
Applies to Pharmacia columns. Elution is then performed using a linear gradient (0-1 M NaCl). The pooled CETP fraction was dialyzed against 10 mM Tris HCl, pH 7.4, and then monoQ [
Further purification by chromatography on a Mono Q] ™ column (Pharmacia). Production of Radioactively Labeled HDL 50 ml of fresh human EDTA plasma is adjusted to a density of 1.12 using NaBr and centrifuged at 50,000 rpm for 18 hours at 4 ° C. in a Ty 65 rotor. . The upper phase is used to obtain cold LDL. The lower phase was washed with 3 × 4 1 of PDB buffer (10 mM Tris / HCl, pH 7.4, 0.15 mM NaCl,
Dialysis against 1 mM EDTA, 0.02% NaN ₃ ). 20 μl ³ H-cholesterol (DuPont NET) per 10 ml volume of retained material
-725; 1 μCi / μl, dissolved in ethanol) is then added and the mixture is incubated at 37 ° C. under N ₂ for 72 hours.

The mixture was then adjusted to a density of 1.21 using NaBr and
Centrifuge in a 65 rotor at 20 ° C. and 50,000 rpm for 18 hours. The upper phase is collected and the lipoprotein fraction is purified by gradient centrifugation. For this purpose, the isolated labeled lipoprotein fraction was isolated using NaBr for 1.2 hours.
Adjust to a density of 6. In each case, 4 ml of this solution was added to a centrifuge tube (S
In a W40 rotor), 4 ml of a solution with a density of 1.21 and 4.5 ml of 1.
063 (PDB buffer and NaBr density solution) and the tubes are then centrifuged in a SW 40 rotor at 38,000 rpm and 20 ° C. for 24 hours. H found and labeled between 1.063 and a density of 1.21
The intermediate layer containing DL is dialyzed at 4 ° C. against 3 × 100 volumes of PDB buffer.

The material retained contains radioactively labeled ³ H-CE-HDL, adjusted to approximately 5 × 10 ⁶ cmp / ml and used for testing. CETP test To evaluate CETP activity, biotinylated LD from human HD lipoprotein
The transfer of ³ H-cholesterol ester to lipoprotein is measured.

The reaction was performed using Streptavidin-SPA [Streptavidin-SPA].
Stop by the addition of ™ beads (Amersham) and measure the transferred radioactivity directly on a liquid scintillation counter.

In the assay mixture, 10 μl of HDL containing 10 μl of biotin-LDL (Amersham) in 50 mM Hepes / 0.15 M NaCl / 0.1% bovine serum albumin / 0.05% NaN ₃ , pH 7.4. - the ³ H- cholesterol ester (~50,000cpm), 18 hours at 37 ° C., 10
μl of CETP (1 mg / ml) and 3 μl of a solution of the substance to be tested (1
(Dissolved in 0% DMSO / 1% BSA). 2
00 μl of SPA streptavidin bead solution (TRKQ 7005) is then added, the mixture is incubated with shaking for another hour and then measured with a scintillation counter. The controls used are the corresponding incubations with 10 μl buffer, 10 μl CETP at 4 ° C., and 10 μl CETP at 37 ° C.

The activity transferred in a control experiment using CETP at 37 ° C. is interpreted as 100% transfer. The substance concentration at which this shift is reduced by half is determined as the IC ₅₀ value.

Table A below gives the IC ₅₀ values (mol / l) for CETP inhibitors:

[0122]

[Table 1]

Ex Vivo Activity of the Compounds of the Invention Syrian gold hamsters bred in our own lab are anesthetized after a 24-hour fast (0.8 mg / kg atropine, 0.8 mg / kg ketabet). (Trademark) sc, 50 mg / kg Nembutal ip after 30 seconds). The jugular vein is then exposed and cannulated. The test substance, a suitable solvent to dissolve (usually, Adareto (Adalate) placebo solution, i.e. 60 g of glycerol, H ₂ O, PEG-400 to 1000ml of 100 ml), and via a PE catheter is introduced into the jugular vein To animals.
The same volume of vehicle without test substance is administered to control animals. The vein is then tied off to stop circulation and the wound is closed.

The test substances also consist of dissolving the substances in DMSO and adding them to 0.5% Tylose.
(tylose) and administering them orally using a pharyngeal tube, p. o. Can also be administered. The same volume of vehicle without test substance is administered to control animals.

At different intervals (up to 24 hours after administration), blood samples are taken from the animals by puncture of the retro-orbital venous plexus (approximately 250 μl). Clotting is completed by overnight incubation at 4 ° C., and the sample is then centrifuged at 6000 × g for 10 minutes. CETP activity is measured in the resulting serum using a modified CETP test. The transfer of ³ H-cholesterol ester from HD lipoprotein to biotinylated LD lipoprotein is measured as described above for the CETP test.

The reaction was performed using Streptavidin-SPA [Streptavidin-SPA].
Stop by the addition of ™ beads (Amersham) and measure the transferred radioactivity directly in a liquid scintillation counter.

The test protocol is performed as described in the “CETP test”. However, to test the serum, replace 10 μl of CETP with 10 μl of the appropriate serum sample. A corresponding incubation of untreated animal serum serves as a control.

The activity transferred in control experiments using control sera is classified as 100% transfer. The substance concentration at which this shift is reduced by half is defined as the ED ₅₀ value. In Vivo Activity of Compounds of the Invention In experiments to evaluate oral activity on lipoproteins and triglycerides, test substances dissolved in DMSO and suspended in 0.5% tylose were propagated in our own lab. Administer orally to Syrian golden hamsters using a pharyngeal tube. To measure CETP activity, a blood sample (approximately 250 μl) is collected by retro-orbital puncture before the start of the experiment. Test substance
Thereafter, it is administered orally using a pharyngeal tube. The same volume of vehicle without test substance is administered to control animals. Thereafter, the animals must be fasted and at different intervals (up to 24 hours after administration of the substance) blood samples are taken by puncture of the retro-orbital venous plexus.

The clotting is completed by overnight incubation at 4 ° C. and the samples are then centrifuged at 6000 × g for 10 minutes. The content of cholesterol and triglycerides in the resulting serum was determined by a modified commercially available enzyme test (cholesterol enzyme 14366).
Merck, triglyceride 14364 Merck)
Evaluate using The serum is diluted in a suitable manner with a physiological saline solution.

Transfer 100 μl of the serum dilution and 100 μl of the test substance into a 96-well plate and incubate for 10 minutes at room temperature. The optical density is then measured at a wavelength of 492 nm using an automatic plate reader. The triglyceride and cholesterol concentrations of the sample are determined with the help of a standard curve measured in parallel.

The measurement of the HDL-cholesterol content is performed after precipitation of the Apo-B-containing lipoprotein using a reagent mixture (Sigma 352-4 HDL cholesterol reagent) according to the manufacturer's instructions. In Vivo Activity in Transgenic hCETP Mice The substances to be tested were transfected via feed with transgenic mice (Dinchuk, Haat) bred in our own laboratory.
rt), Gonzalez (Gonzalez), Kalman (Karmann), Schmidt (Schmidt), Viraku (Wirak); BBA (1995) , was administered to 1 295, 301). Prior to the start of the experiment, blood samples were taken retro-orbitally from the mice to measure serum cholesterol and triglycerides. Serum was obtained by overnight incubation at 4 ° C. and subsequent centrifugation at 6000 × g as described above for hamsters. One week later, blood samples were again taken from the mice and lipoproteins and triglycerides were measured. The change in the measured parameter is expressed as a change in percent based on the initial value.

The present invention further relates to a combination of a benzylbiphenylene of the general formula (I) with a glucosidase and / or amylase inhibitor for the treatment of familial hyperlipidemia, obesity (hyperlipidemia) and diabetes. . Glycosidase and / or amylase inhibitors in the context of the present invention include, for example, acarbose, adiposine, voglibose, miglitol, emiglitate, MDL-25637, camiglibose (MDL-73945), tendamistate, AI-3688, trestatin, pradimicin-Q. And salbostatin.

Preference is given to combinations of acarbose, miglitol, emiglitate or voglibose with one of the aforementioned compounds of the general formula (I) according to the invention.

In addition, the compounds of the invention may be used in the treatment of dyslipidemia, combined hyperlipidemia, hypercholesterolemia or hypertriglyceridemia, with vastatin, which lowers cholesterol, or with a principal agent, which lowers ApoB. They can be jointly combined.

The above combinations may also be used for primary or secondary prevention of coronary heart disease (eg, myocardial infarction).

[0136] Vastatin in the context of the present invention is, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin. An agent that lowers ApoB is, for example, an MTP inhibitor.

Preference is given to combinations of cerivastatin or an ApoB inhibitor with one of the aforementioned compounds of the general formulas (I) and (Ia) according to the invention.

The novel active ingredients can be prepared in a known manner using tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, emulsions, inert and non-toxic pharmaceutically suitable carriers or solvents. It can be converted into customary formulations such as suspending agents and solutions. In this case, the therapeutically effective compound is in each case at a concentration of approximately 0.5 to 90% by weight of the total mixture, ie in an amount which is sufficient to achieve the indicated dosage range.
Should exist.

The formulations are prepared, for example, by diluting the active ingredient with solvents and / or carriers and, if appropriate, with emulsifiers and / or dispersants. When the agent is water, it is sometimes possible to use an organic solvent as an auxiliary solvent.

The administration is carried out in the customary manner, intravenously, orally, parenterally or sublingually, in particular orally.

For parenteral administration, solutions of the active ingredients may be employed by using suitable liquid carrier materials.

In general, for intravenous administration, in order to achieve effective results, no more than about 0.0
01 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg
It has proven advantageous to administer amounts of body weight, and in the case of oral administration, the dosage is approximately 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg.
/ Kg body weight.

Nevertheless, where appropriate, ie, depending on body weight or type of route of administration, individual response to the medicament, mode of formulation, and the time at which or during which administration occurs, or intervals therebetween, It may be necessary to deviate from the quantity. Therefore,
In some cases, less than the aforementioned minimum amount may be sufficient to manage, while in other cases, the upper limit listed must be exceeded. In the case of relatively large doses, it may be desirable to divide these into several distinct volumes over the course of the day.

Starting Materials Example I 4-Methyl-1- (4-trifluoromethylphenyl) pentan-3-one

[0145]

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At 0 ° C., 2 parts of nBuLi in 131 ml (0.328 mol) of n-hexane
. A 5M solution was added to 40 g (0%) in 400 ml of anhydrous THF over a period of 30 minutes.
. 312 mol) of N, N-dimethyl-N- {2-methyl-1- [2- (4-trifluoromethylphenyl) ethyl] propylidene} hydrazine (Sharma (S
. D Sharma) et al. Org. Chem. 1990, 55, 2196)
And the mixture is stirred for 30 minutes at 15-20 ° C. 100m
A solution of 67.9 g (0.284 mol) of 4-trifluoromethylbenzyl bromide in 1 l of anhydrous THF is then added dropwise and the mixture is stirred at 20 ° C. for 2 h. The reaction mixture was concentrated to about 80 ml, and carefully hydrolysed using H ₂ O in 200 ml. The mixture is extracted with ethyl acetate and the extract is
Wash with Cl solution, dry over Na ₂ SO ₄ and concentrate. This is 82g of N, N
-Dimethyl-N- {2-methyl-1- [2- (4-trifluoromethylphenyl) ethyl] propylidene} hydrazine is given as a red oil.

The hydrazone is dissolved in 150 ml of THF and mixed with 170 ml of 2M HCl and the mixture is stirred at 20 ° C. for 1 hour. The mixture is extracted with EtOAc, and the extracts are washed with water and saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated. Distillation gives a colorless oil (bp 95-98 ° C / 0.7 mbar). Yield: 51.5 g (78%) _Rf = 0.25 (EtOAc / PE 1:20) Example II 1- (4-Fluorophenyl) -1-hydroxy-4-methyl-2- (4-trifluoro Methylbenzyl) pentan-3-one

[0148]

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At −70 ° C., LDA in 400 ml (0.791 mol) of THF / heptane
Of a 2.0 M solution in 1.2 l of anhydrous THF over a period of 50 minutes.
To 184 g (0.753 mol) of the compound from
And stir for 60 minutes. 81 ml (0.753 mol) of 4-fluorobenzaldehyde are then added and the mixture is stirred at -70 ° C for 60 minutes. The reaction,
Quench with 100 ml of 10% NH ₄ Cl solution, allow the mixture to warm to −10 ° C., and add an additional 400 ml of 10% NH ₄ Cl solution. The phases are separated, the aqueous phase is extracted with EtOAc, and the extract is washed with a saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated. The crude product is purified on silica gel 60 (EtOAc / PE 1: 5). Yield: 253 g (91%) _Rf = 0.31 (EtOAc / PE 1: 5) Example III 1- (4-Fluorophenyl) -4-methyl-2- (4-trifluoromethylbenzyl) -pent- 1-en-3-one

[0150]

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At 0 ° C., 231 ml (1.672 mol) of triethylamine and 118 m
1 (1.52 mol) of methanesulfonyl chloride is added to 279 g (0.76 mol) of the compound from Example II in 2.5 l of anhydrous CH ₂ Cl ₂ . Mix 20
° C. overnight stirring at and at -30 ° C., it was dissolved in anhydrous CH ₂ Cl ₂ for 1l 456
Add ml (3.04 mol) of DBU. After 90 minutes, the reaction is quenched with 500 ml of water. The phases were separated and the aqueous phase is extracted with CH ₂ Cl _2. The combined organic phases are washed with 0.5M 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)
To purify. Yield: 220 g (83%) _Rf = 0.27 (EtOAc / PE 1:20).

Example IV 1-Fluoro-4- (3-isopropyl-2- (4-trifluoromethylbenzyl) -buta-1,3-dienyl) benzene

[0153]

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At 0 ° C., a mixture of 47.6 g (114.2 mmol) of methyltriphenylphosphonium bromide and sodium amide in 200 ml of anhydrous ether was treated with 10 ml of
20 g (5.71 mmol) of the compound from Example III in 0 ml of anhydrous ether are added. After 90 minutes, 300 ml of petroleum ether are added and the mixture is filtered off with suction through a little silica gel. 2 l of this silica gel
Wash with PE and concentrate the filtrate. The crude product is purified on silica gel 60 (cyclohexane / EtOAc 20: 1 to 10: 1). Yield: 9.1 g (44%) _Rf = 0.35 (PE).

Example V Methyl 6- (4-fluorophenyl) -4-isopropyl-5- (4-trifluoromethylbenzyl) cyclohexa-1,4-dienecarboxylate

[0156]

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7.66 ml (86.1 mmol) of methyl propiolate are added to 3.0 g (8.61 mmol) of the compound from Example IV in 15 ml of anhydrous xylene,
The mixture is then heated at 180 ° C. for 20 hours in a closed autoclave. The mixture is then concentrated under reduced pressure with silica gel and purified on 80 g of silica gel (cyclohexane and cyclohexane / EtOAc 20: 1, 1
Elution at 0: 1) Yield: 2.68 g (70%) _Rf = 0.36 (EtOAc / PE 1:20) Example VI Methyl 4'-fluoro-5-isopropyl-6- (4-trifluoro Methylbenzyl) biphenyl-2-carboxylate

[0158]

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149 mg (0.34 mol) of the compound from Example V, and 472 mg (
(2.08 mmol) DDQ are dissolved in 10 ml of toluene and the mixture is refluxed overnight. The mixture is concentrated and the residue is silica gel (cyclohexane / Et.
Purify with OAc 20: 1) Yield: 122 mg (82%) R = 0.22 (EtOAc / PE 1:20) Example VII [4'-fluoro-5-isopropyl-6- (4-trifluoromethylbenzyl) ) Biphenyl-2-yl] methanol

[0160]

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Dissolve 46 mg (0.11 mmol) of the compound from Example VI in 5 ml of anhydrous toluene and at −78 ° C. a 1.5 M solution of DIBAH in toluene 60
Mix with 0 μl (0.9 mmol). The mixture is stirred at this temperature for 1 hour,
Allow to warm to room temperature and stir for another hour. The reaction is quenched with water and the mixture is 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%) _Rf = 0.28 (EtOAc / petroleum ether 1: 5).

Example VIII Dimethyl 3- (4-fluorophenyl) -5-isopropyl-4- (4-trifluoromethylbenzyl) cyclohexa-1,4-diene-1,2-dicarboxylate

[0163]

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36.3 g (255 mmol) of dimethyl acetylenedicarboxylate are
22.25 g (63.9 m) of the compound from Example IV in 400 ml of anhydrous toluene
mol) and the mixture is refluxed for 48 hours. The mixture is concentrated and the excess dimethylacetylenedicarboxylate is distilled off under reduced pressure. The crude product is then purified on silica gel (CH ₂ Cl ₂ ) Yield: 23.9 g (77%) R _f = 0.39 (CH ₂ Cl ₂ ).

Example IX Dimethyl 4'-fluoro-5-isopropyl-6- (4-trifluoromethylbenzyl) biphenyl-2,3-dicarboxylate

[0166]

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23.9 g (50 mol) of the compound from Example VIII and 22.2 g (10
(0 mmol) DDQ is dissolved in 250 ml of toluene and the mixture is refluxed overnight. The mixture is concentrated and the product is purified on silica gel (CH ₂ Cl ₂ ). _{Yield: 19.9g (81%) R f} = 0.37 (CH 2 Cl 2).

Example X [4′-Fluoro-5-isopropyl-2- (tetrahydropyran-2-yloxymethyl) -6- (4-trifluoromethylbenzyl) biphenyl-3-yl] carbaldehyde

[0169]

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[0170] Al ₂ O ₃ of 830mg pyridinium chlorochromate (neutral) and 1.31 g (6.11 mmol), performed was dissolved in anhydrous CH ₂ Cl ₂ in 100ml Example 2
To 3.10 g (4.06 mmol) of the compound from in three portions over a period of 60 minutes. After 1 hour, the mixture was filtered through Al ₂ O _3, and the Al ₂ O ₃ C
Wash with H ₂ Cl ₂ . Further purification is performed on silica gel 60 (CH ₂ Cl ₂ ). Yield: 1.84 _g (87%) _Rf = 0.39 (EtOAc / PE 1: 5).

Production Examples Example 1 [4′-Fluoro-3-hydroxymethyl-5-isopropyl-6- (4-trifluoromethylbenzyl) biphenyl-2-yl] methanol

[0172]

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2.2 g (4.5 mmol) of the compound from Example IX are dissolved in 60 ml of anhydrous toluene and 60 m of a 1.5 M solution of DIBAH in toluene at −78 ° C.
1 (90 mmol). The mixture is stirred at this temperature for 1 hour, allowed to warm to room temperature and stirred for another hour. The mixture is poured on ice 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 (CH ₂ Cl ₂ / MeOH 100: 3). _{Yield: 1.82g (93%) R f} = 0.20 (CH 2 Cl 2 / MeOH 100: 3).

Example 2 [4′-Fluoro-5-isopropyl-2- (tetrahydropyran-2-yloxymethyl) -6- (4-trifluoromethylbenzyl) biphenyl-3-yl] methanol

[0175]

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15.5 g (35.2 mmol) of the compound from Example 1, 7.2 g (105
imidazole and 11ml of (42 mmol) tert-butyl diphenyl chlorosilane mmol) (TBDPS) was dissolved in CH ₂ Cl ₂ in 300 ml, and stirred for 90 minutes at room temperature the mixture. The reaction is quenched with water and the mixture is
Extract with H ₂ Cl ₂ and dry the extract over Na ₂ SO ₄ and concentrate. The crude product is purified on silica gel 60 (cyclohexane / EtOAc 100: 1 to 20: 1)
To purify. This gave 17.8 g (26.4 mmol, 75%) of [3-ter
t-butyldiphenylsiloxymethyl-4'-fluoro-5-isopropyl-6
- (4-trifluoromethylbenzyl) biphenyl-2-yl] gives methanol (R _f = CH ₂ Cl ₂ in 0.52).

This compound was dissolved in 220 ml of anhydrous CH ₂ Cl ₂ and 3.32 g (13
. 2 mmol) of pyridinium p-toluenesulfonate (PPTS) and 12.1 ml (132 mmol) of 3,4-dihydropyran are added. Water was added after 60 min at room temperature, and the mixture is extracted with CH ₂ Cl _2. The combined organic phases are washed with saturated NaHCO ₃ solution and water, dried over Na ₂ SO ₄ and concentrated. This gives 19.6 g (26 mmol, 98%) of the THP protected compound (R _f = 0.22 EtOAc / PE 1:20).

This compound is dissolved in 250 ml of anhydrous THF. 24.3 g (77 mmol
Fluoride tetra n- butylammonium trihydrate (TBAF × 3H ₂ O) was added pressure of), and the mixture is stirred for 90 minutes at room temperature. Water is added and the mixture is added to E
Extract with tOAc. The combined organic phases are washed with saturated NaHCO ₃ solution and water, dried over Na ₂ SO ₄ and concentrated. Purification is performed on silica gel 60 (cyclohexane / EtOAc 20: 1 to 2: 1). Yield: 11.3 g (85%) _Rf = 0.54 (EtOAc / PE 1: 2) Example 3 [3-benzyloxymethyl-4'-fluoro-5-isopropyl-6- (4-
Trifluoromethylbenzyl) biphenyl-2-yl] methanol

[0179]

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12 mg (0.48 mmol) of sodium hydride and 8 mg of tetra-n-butylammonium iodide are suspended in 3 ml of anhydrous THF and 50 mg (0%) of the compound from Example 2 in 1 ml of anhydrous THF. .1 mmol) is added dropwise. After 30 minutes, 14 μl (0.115 mmol) of benzyl bromide are added and the mixture is stirred overnight. Water is added and the mixture is then
Extract with OAc and dry the extract with Na ₂ SO ₄ and concentrate. Purification is performed on silica gel 60 (cyclohexane / EtOAc 5: 1). This is 70
This gives mg of the THP protected compound. This is dissolved in methanol and
Mix with 00 mg of pyridinium-p-toluenesulfonate (PPTS).
After stirring for 2 hours at room temperature, water is added, the mixture is extracted with EtOAc, and the extracts are dried over Na ₂ SO ₄ and concentrated. Purification is performed on silica gel 60 (cyclohexane / EtOAc 5: 1). Yield: 35 mg (58%) _Rf = 0.56 (EtOAc / PE 1: 5) Example 4 [4'-Fluoro-3- (4-fluorophenoxymethyl) -5-isopropyl-6- (4-tri) Fluoromethylbenzyl) biphenyl-2-yl] methanol

[0181]

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150 mg (0.29 mmol) of the compound from Example 2, 99 mg (0.3
8 mmol) of triphenylphosphine, and 49 mg (0.435 mmol)
) Is dissolved in 4 ml of ether / THF (3: 1) and 59 μl (0.38 mmol) of diethyl azodicarboxylate are added dropwise over 15 minutes. After 30 minutes at room temperature, the mixture was concentrated under reduced pressure,
The crude product is then purified on silica gel 60 (cyclohexane / EtOAc 20: 1). This gives 156 mg (83%) of the THP protected compound. This is dissolved in methanol and mixed with 300 mg of pyridinium-p-toluenesulfonate (PPTS). After stirring for 2 hours at room temperature, water is added, the mixture is extracted with EtOAc, and the extract is dried over Na ₂ SO ₄ and concentrated. Purification is performed on silica gel 60 (cyclohexane / EtOAC 5: 1). Yield: 75 mg (79%) _Rf = 0.40 (EtOAc / PE 1: 5) Example 5 2- [4'-Fluoro-2-hydroxymethyl-5-isopropyl-6- (4-
Trifluoromethylbenzyl) biphenyl-3-ylmethyl] isoindole-
1,3-dione

[0183]

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150 mg (0.29 mmol) of the compound from Example 2, 99 mg (0.3
8 mmol) of triphenylphosphine, and 64 mg (0.435 mmol)
) Is dissolved in 4 ml of ether / THF (3: 1) and
9 μl (0.38 mmol) of diethyl azodicarboxylate are added dropwise to 15
Add over minutes. After 30 minutes at room temperature, the mixture is concentrated under reduced pressure and the crude product is purified on silica gel 60 (cyclohexane / EtOAc 5: 1). This gives 134 mg (72%) of the THP protected compound. 12 ml of this
In acetic acid / THF / water (4: 2: 1) and the mixture is stirred at 45 ° C. for 18 hours. The mixture is concentrated under reduced pressure, and the crude product is purified on silica gel 60 (CH ₂ Cl ₂ / MeOH 100: 3). _{Yield: 74mg (69%) R f} = 0.39 (CH 2 Cl 2 / MeOH 100: 3).

Example 6 [3-Cyclopentylidenemethyl-4′-fluoro-5-isopropyl-6- (
4-trifluoromethylbenzyl) biphenyl-2-yl] methanol

[0186]

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At 0 ° C., 0.63 ml (1.0 mmol) of a 1.6 M solution of n-BuLi in n-hexane was added to 480 mg (1.16 mmol) in 40 ml of anhydrous ether.
Of methyltriphenylphosphonium bromide and the mixture is stirred at 20 ° C. for 2 hours. Compound 10 from Example X dissolved in 10 ml of anhydrous ether
0 mg (0.19 mmol) are added. After 90 minutes petroleum ether is added and the mixture is filtered through a little silica gel with suction. The silica gel is washed with petroleum ether and the filtrate is concentrated. The crude product is converted to silica gel 60
(Toluene). This gives 88 mg (80%), R _f = 0.42 (toluene) of the THP protected compound. 70 mg of this is dissolved in methanol and mixed with 300 mg of pyridinium-p-toluenesulfonate (PPTS). After stirring at room temperature for 2 hours, water is added, the mixture is extracted with EtOAc, and the extract is dried over Na ₂ SO ₄ and concentrated. Purification is performed on silica gel 60 (cyclohexane / EtOAc 10: 1). Yield: 49 mg (81%) _Rf = 0.19 (EtOAc / PE 1:10) Example 7 [3-cyclopentylmethyl-4'-fluoro-5-isopropyl-6- (4-
Trifluoromethylbenzyl) biphenyl-2-yl] methanol

[0188]

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20 mg of Pt / C (5%) are added to 20 mg (0.04 mmol) of the compound from Example 6 dissolved in 5 ml of EtOAc, and the mixture is added at atmospheric pressure in the presence of hydrogen for 5 hours at atmospheric pressure Hydrogenate. The mixture is filtered through a membrane filter and concentrated. Further purification was carried out on silica gel 60 (EtOAc / PE 1:10
). Yield: 19 mg (96%) R = 0.20 (EtOAc / PE 1:10) The compounds listed in Table 1 are prepared analogously to the procedure of Examples 1-7:

[0190]

[Table 2]

[0191]

[Table 3]

[0192]

[Table 4]

[0193]

[Table 5]

[0194]

[Table 6]

[0195]

[Table 7]

[0196]

[Table 8]

[0197]

[Table 9]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/216 A61K 31/216 4C204 31/351 31/351 4C206 31/4015 31/4015 4H006 31/4035 31 / 4035 4H049 31/44 31/44 31/45 31/45 31/695 31/695 A61P 3/06 A61P 3/06 9/10 101 9/10 101 C07C 29/44 C07C 29/44 33/46 33 / 46 41/16 41/16 43/178 43/178 69/76 69/76 A C07D 207/404 C07D 207/404 209/48 211/88 211/88 213/64 213/64 309/12 309/12 C07F 7/18 A // C07F 7/18 C07D 209 / 48Z (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU , MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, M, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY) , KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE , ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US , UZ, VN, YU, ZW (72) Inventor Schmidt, Gunther DE 42115 Buppertal-Palke-Kyujtrathe 63 (72) Inventor Schyturtehus, Jurgen Germany Day-42781 Hahn Parkjujtrathe 20 (72) Inventor Brem, Claus-Dator Germany-Dec-45661 Lechling Hausen Eberhardt Schutlase 20 (72) Inventor Bishjov, Hilmer Federal Republic of Germany Day-42113 Butuperthal Amröm 78 (72) Inventor Schymitt, Delft Federal Republic of Germany Day-42113 Buppertal Am Ekbutsche 55 B F-term (reference) 4C054 AA02 BB03 CC03 DD23 EE01 FF04 FF08 4C055 AA01 BA02 BA42 BB07 BB08 CA01 DA01 4C062 AA22 4C069 AC31 BB02 BB08 BB12 BB15 4C086 AA01 AA02 AA03 AA04 BC08 BC11 AC04 A04 CB04A04 A04 A04 CA11 CA21 CA26 CA27 DB15 MA01 MA04 NA14 ZA45 ZC33 4H006 AA01 AA02 AA03 AB23 AB27 AC11 AC12 AC25 AC28 AC4 1 FC22 FC52 FE11 FE71 FE73 FE74 FE75 GP01 GP10 GP20 GP22 4H049 VN01 VP01 VQ21 VR23 VR41 VU06 VW01

Claims (11)

[Claims] 1. A compound of the general formula (I) Wherein A represents cycloalkyl having 3 to 8 carbon atoms, or represents aryl having 6 to 10 carbon atoms, or 5 to 7-membered, saturated or partially unsaturated Or an unsaturated, optionally benzo-fused heterocycle having up to four heteroatoms from the group consisting of S, N and O, wherein the ring system of aryl and said heterocycle is cyano , Halogen, nitro,
Straight or branched alkyl, acyl, hydroxyalkyl, alkylthio having the same or different substituents from the group consisting of carboxyl, hydroxyl, trifluoromethyl, trifluoromethoxy or in each case up to 7 carbon atoms , alkoxycarbonyl, by oxy alkoxycarbonyl or alkoxy, or optionally substituted up to 5 times by a group of the formula -NR ³ R ^4, wherein, R ³ and R ⁴ are identical or different and represent hydrogen, phenyl or 6 Represents a straight or branched alkyl having up to carbon atoms, wherein D is of the formula Wherein R ⁵ , R ⁶ and R ⁹ independently of one another are aryl having 6 to 10 carbon atoms or 5- to 7-membered, optionally benzo-fused, saturated or unsubstituted Saturated mono-, bi- or tricyclic heterocycles having up to 4 heteroatoms from the group consisting of S, N and O, wherein the ring is also a N-functional group in the case of a nitrogen-containing ring. Via halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, in each case up to 6 carbon atoms, alkyl, alkylthio, alkylalkoxy, alkoxy or By the same or different substituents from the group consisting of alkoxycarbonyl, in each case 6 to 1
5- to 7-membered aromatic, optionally benzo-fused, with aryl or trifluoromethyl-substituted aryl having 0 carbon atoms or with up to 3 heteroatoms from the group consisting of S, N and O of the hetero ring and / or the formula -OR ^10, -SR ^11, the group of -SO ₂ R ¹² or -NR ¹³ R ^14, optionally substituted up to 5 times, wherein R ^10, R ¹¹ and R ¹² Represents, independently of one another, an aryl having 6 to 10 carbon atoms, which for its part is the same or different from the group consisting of phenyl, halogen or has up to 6 carbon atoms Substituted up to twice by a straight-chain or branched alkyl, R ¹³ and R ¹⁴ are the same or different and R ³ and R Having the meaning of ⁴ or alternatively R ⁵ and / or R ⁶ are of the formula R ⁷ represents hydrogen, halogen or methyl, and R ⁸ represents hydrogen, halogen, azide, trifluoromethyl, hydroxyl, trifluoromethoxy, in each case a straight or branched chain having up to 6 carbon atoms. Represents a branched alkoxy or alkyl or a group of formula —NR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are the same or different and have the meanings of R ³ and R ⁴ given above. Or R ⁷ and R ⁸ together form a group of the formula ＯO or ＝ NR ¹⁷ , wherein R ¹⁷ is hydrogen or a straight or branched chain having up to 6 carbon atoms in each case. L represents a straight-chain or branched alkylene or alkenylene chain having up to 8 carbon atoms in each case; Are optionally substituted up to twice by hydroxyl, T and X are the same or different and represent a straight or branched alkylene chain having up to 8 carbon atoms, or T or X is combine represents, V is either an oxygen or sulfur atom, or -NR ¹⁸ - represents a group wherein R ¹⁸ is a straight-chain or branched alkyl having carbon atoms of hydrogen or up to 6, Or represents 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
R ¹ represents phenyl optionally substituted by cycloalkyl or hydroxyl having 3 to 8 carbon atoms or optionally substituted by halogen or trifluoromethyl; ] Represents a straight-chain or branched alkyl having up to 6 carbon atoms, which is substituted by a radical of the formula: R ² represents hydrogen or in each case a straight-chain or straight-chain having up to 8 carbon atoms. Represents a branched alkyl or alkenyl, which is hydroxy,
By halogen, phenyl, cycloalkyl having 3 to 6 carbon atoms,
Or the formula Wherein R ¹⁹ represents a group of formula —Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , or a straight or branched chain having up to 6 carbon atoms. Or a 5- to 7-membered saturated, partially unsaturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, or Phenyl or benzyl, wherein all ring systems listed for R ¹⁹ are
Optionally by the same or different substituents from the group consisting of trifluoromethyl, fluorine, nitro, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl in each case having up to 4 carbon atoms, or optionally by hydroxyl Is a compound of the formula or a salt thereof, which is optionally substituted up to twice by a straight-chain or branched alkyl having up to 4 carbon atoms, or 2. A has the same or different substituents from the group consisting of fluorine, chlorine, bromine, amino, hydroxyl, trifluoromethyl, trifluoromethoxy or in each case up to 6 carbon atoms Represents naphthyl, phenyl, pyridyl, thienyl, imidazolyl, pyryl or morpholine, optionally substituted up to twice by straight-chain or branched alkyl or alkoxy, wherein D is nitro, fluorine, chlorine, bromine, phenyl Represents phenyl optionally substituted by trifluoromethyl or trifluoromethoxy or has the formula Wherein R ⁵ , R ⁶ and R ⁹ are each independently of the other phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2- Represents yl, benzoxazolyl, furyl, quinolyl or purin-8-yl, wherein the ring is also through a N-functional group in the case of a nitrogen-containing ring, fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, cyano, Carboxyl, trifluoromethoxy, linear or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl, triazolyl, tetrazolyl, benzoxthiazolyl or trifluoro, in each case up to 4 carbon atoms Methyl Substituted up to 3 times in some cases by identical or different substituents from the group consisting of conversion phenyl or phenyl, and / or formula -OR ^10, is replaced by a group of -SR ¹¹ or -SO ₂ R ^12, wherein R ¹⁰ , R ¹¹ and R ¹² are the same or different and represent phenyl, which means for that part by the same or different substituents from the group consisting of phenyl, fluorine, chlorine or by up to 4 carbon atoms It is substituted up to twice by a straight-chain or branched alkyl having, or R ⁵ and / or R ⁶ are of the formula R ⁷ represents hydrogen, fluorine, chlorine or bromine, and R ⁸ represents hydrogen, fluorine, chlorine, bromine, azide, trifluoromethyl, hydroxyl, trifluoromethoxy, in each case up to 5 of a straight-chain or branched alkoxy or alkyl or a group of the formula -NR ¹⁵ R ^16, carbon atoms, where identical or different R ¹⁵ and R ^16, and hydrogen, up to phenyl or 4 Represents linear or branched alkyl having carbon atoms, or R ⁷ and R ⁸ together form a group of formula ＯO or ＮＲNR ¹⁷ , wherein R ¹⁷ is hydrogen, or Represents a straight-chain or branched alkyl, alkoxy or acyl having in each case up to 4 carbon atoms, wherein L is a straight-chain or straight-chain having in each case up to 6 carbon atoms. Represents a branched alkylene or alkenylene chain, which is optionally substituted up to twice by hydroxyl, T and X are the same or different and are straight-chain or branched having up to 6 carbon atoms. It represents or represents an alkylene chain, or T or X is a bond, V is or represents an oxygen or sulfur atom, or the formula -NR ¹⁸ - represents a group, wherein R ¹⁸ is hydrogen or up to four, E represents cyclopropyl, -butyl, -pentyl, -hexyl or -heptyl, or represents a straight-chain or branched alkyl having carbon atoms, or phenyl, or a straight-chain having up to 6 carbon atoms. Or a branched alkyl, which is
Cyclopropyl, - butyl, - hexyl, - pentyl, - either optionally substituted by heptyl or hydroxyl, or, fluorine, represents phenyl which is optionally substituted by chlorine or trifluoromethyl, R ¹ has the formula —CH ₂ OH, or R ² represents hydrogen or a straight-chain or branched alkyl or alkenyl having in each case up to 6 carbon atoms, which is hydroxyl,
Phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, or a compound of the formula Wherein R ¹⁹ represents a group of formula —Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , or a straight or branched chain having up to 5 carbon atoms. Represents alkyl in the form of tetrahydropyranyl, pyridyl, phenyl or benzyl, which are trifluoromethyl, fluorine, nitro, hydroxyl, straight-chain or branched in each case up to 3 carbon atoms Up to twice as many times as possible with the same or different substituents from the group consisting of the alkoxy or alkoxycarbonyl in the form of a straight or branched alkyl having up to 3 carbon atoms, optionally substituted by the hydroxyl Is a compound of formula (I) according to claim 1 and salts thereof. 3. A wherein A is the same or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy or, in each case, straight-chain or up to 5 carbon atoms. Represents phenyl or pyridyl optionally substituted up to twice by branched alkyl or alkoxy, and D represents phenyl optionally substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine Or the formula Wherein R ⁵ , R ⁶ and R ⁹ independently of one another are phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, Represents benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl, wherein the ring is fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl, also through the N function in the case of a nitrogen-containing ring. Trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having up to 4 carbon atoms in each case, triazolyl, tetrazolyl, benzothiazolyl, trifluoromethyl-substituted phenyl or phenyl In some cases the same or different substituents from the group consisting of Le substituted up to 3 times, and / or formula -OR ^10, it is replaced by a group of -SR ¹¹ or -SO ₂ R ^12, wherein R ^10, R ¹¹ and R ¹² are the same or different and, for that part, by the same or different substituents from the group consisting of phenyl, fluorine, chlorine or by linear or branched alkyl having up to 3 carbon atoms Represents phenyl substituted up to twice, or R ⁵ and / or R ⁶ have the formula R ⁷ represents hydrogen or fluorine; and R ⁸ represents hydrogen, fluorine, chlorine, bromine, azide, trifluoromethyl, hydroxyl, trifluoromethoxy, or in each case up to 4 carbon atoms. linear or branched alkoxy or alkyl or a radical of the formula -NR ¹⁵ R ^16,, wherein the same or different R ¹⁵ and R ^16, and linear having carbon atoms of hydrogen or up to three, with R ⁷ and R ⁸ together form a group of formula ＯO or ＮＲNR ¹⁷ , wherein R ¹⁷ is hydrogen or in each case 4 Represents a straight-chain or branched alkyl, alkoxy or acyl having up to 5 carbon atoms, wherein L is a straight-chain or branched alkyl having in each case up to 5 carbon atoms. Or an alkenylene chain, which is optionally substituted up to twice by hydroxyl, T and X are the same or different and represent a straight-chain or branched alkylene chain having up to 3 carbon atoms or T or X represents a bond, straight V is or represents an oxygen or sulfur atom, or represents a group of the formula -NR ^18, wherein the carbon atoms of R ¹⁸ is hydrogen or up to three, E represents a chain or branched alkyl, E represents cyclopropyl, cyclopentyl or cyclohexyl, or phenyl optionally substituted by fluorine or trifluoromethyl, or 4 substituted by hydroxyl Represents a straight-chain or branched alkyl having up to R ¹ has the formula -CH ₂ OH or [of 12], R ² represents hydrogen or, in each case, straight-chain or branched alkyl or alkenyl having up to 5 carbon atoms, which is hydroxyl, phenyl, fluorine, chlorine With, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or of the formula Wherein R ¹⁹ represents straight-chain or branched alkyl having up to 4 carbon atoms, or has the formula Si (CH ₃ ) ₂ C (CH ₃ ) ₃ Represents a group or represents tetrahydropyranyl, pyridyl, phenyl or benzyl, which are trifluoromethyl, fluorine, chlorine, nitro, hydroxyl, straight-chain or branched in each case up to 3 carbon atoms. Up to twice as many times as possible with the same or different substituents from the group consisting of the alkoxy or alkoxycarbonyl in the form of a straight or branched alkyl having up to 3 carbon atoms, optionally substituted by the hydroxyl Is a compound of formula (I) according to claim 1 and salts thereof. 4. A wherein A is the same or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy or in each case straight-chain or up to 5 carbon atoms or Represents phenyl or pyridyl optionally substituted up to twice by branched alkyl or alkoxy, and D represents phenyl optionally substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine Or the formula Wherein R ⁵ , R ⁶ and R ⁹ independently of one another are phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, Represents benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl, wherein the ring is fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl, also through the N function in the case of a nitrogen-containing ring. Trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl having up to 4 carbon atoms in each case, triazolyl, tetrazolyl, benzothiazolyl, trifluoromethyl-substituted phenyl or phenyl In some cases the same or different substituents from the group consisting of Le substituted up to 3 times, and / or formula -OR ^10, it is replaced by a group of -SR ¹¹ or -SO ₂ R ^12, wherein R ^10, R ¹¹ and R ¹² are the same or different and, for that part, by the same or different substituents from the group consisting of phenyl, fluorine, chlorine or by linear or branched alkyl having up to 3 carbon atoms Represents phenyl substituted up to twice, or R ⁵ and / or R ⁶ represent a group of the formula: R ⁷ represents hydrogen or fluorine, and R ⁸ represents hydrogen, fluorine, chlorine, Bromine, azide, trifluoromethyl, hydroxyl, trifluoromethoxy, or straight-chain or branched alkyl groups having in each case up to 4 carbon atoms Alkoxy or alkyl, or a group of formula —NR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ¹⁶ are the same or different and are hydrogen or straight or branched alkyl having up to 3 carbon atoms. Or R ⁷ and R ⁸ together form a group of the formula ＯO or ＮＲNR ¹⁷ , wherein R ¹⁷ is hydrogen or straight-chain or branched having up to 4 carbon atoms in each case L represents a linear or branched alkylene or alkenylene chain having in each case up to 5 carbon atoms, which are optionally substituted up to twice by hydroxyl. T and X are the same or different and represent a straight-chain or branched alkylene chain having up to 3 carbon atoms, or It represents a X is a bond, V is or represents an oxygen or sulfur atom, or represents a group of the formula -NR ^18, wherein R ¹⁸ is a linear or branched carbon atoms hydrogen or up to three, E represents cyclopropyl, cyclopentyl or cyclohexyl, or phenyl optionally substituted by fluorine or trifluoromethyl, or up to 4 carbon atoms optionally substituted by hydroxyl Wherein R ¹ is a group of the formula —CH ₂ OH, or R ² represents hydrogen or, in each case, straight-chain or branched alkyl or alkenyl having up to 5 carbon atoms, which is hydroxyl, phenyl, fluorine, chlorine With, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or of the formula Wherein R ¹⁹ represents straight-chain or branched alkyl having up to 4 carbon atoms or has the formula —Si (CH ₃ ) ₂ C (CH ₃ ) Represents ₃ groups or represents tetrahydropyranyl, pyridyl, phenyl or benzyl, which are trifluoromethyl, fluorine, chlorine, nitro, hydroxyl, straight-chain or in each case up to 3 carbon atoms or Up to twice with the same or different substituents from the group consisting of branched alkoxy or alkoxycarbonyl, or with straight-chain or branched alkyl having up to 3 carbon atoms optionally substituted by hydroxyl 2. The compound of formula (I) according to claim 1 and salts thereof, which are optionally substituted. 5. The compound according to claim 1, for use in controlling a disease. 6. A compound of the general formula (II) Wherein A, D and E are as defined above, in a system (C ₆ H ₅ ) ₃ PCH ₃ Br / n-butyllithium, first of the general formula (III) ] Wherein A, D and E are as defined above, then converted to a compound of formula (IV) or (IVa) Wherein R ²⁰ , R ²⁰ ′ and R ²⁰ ″ are the same or different and represent straight-chain or branched alkyl having up to 4 carbon atoms, and R ²¹ represents hydrogen, or Represents a straight or branched alkyl having up to 6 carbon atoms, including hydroxyl, phenyl, straight or branched alkoxy, amino having up to 6 carbon atoms, amino, up to 4 in the alkyl moiety. Using a compound of the formula (V) optionally substituted by an alkyl or dialkylamino having a carbon atom of the formula (V) Wherein A, D and E are as defined above, R ²⁰ "'includes the aforementioned ranges of the meaning of R ²⁰ and R ²⁰ ", and R ²² represents hydrogen or Which either represents the group —CO ₂ R ²⁰ ″ or encompasses the aforementioned ranges of the meaning of R ²¹ , which, after oxidation, are converted to a compound of the general formula (VI) Wherein A, D, E, R ² , R ²⁰ ″ ′ and R ²² are as defined above, and then the carbonyl function is reduced to a hydroxymethyl function And the general formula (Ia): Where A, D and E are as defined above, starting from a compound of the formula P (C ₆ H ₅ ) ₃ / diethyl azodicarboxylic acid, depending on the aforementioned meaning of R ² Reacting in ethyl and the corresponding amine or alcohol as defined for R ¹⁹ , or performing the etherification by reaction with an alkyl halide in the presence of a base, and then using an acid to form both Elimination of the hydroxyl protecting group in the derivatization or, if R ² = alkenyl, first the compound of the general formula (Ia) is converted to a compound of the general formula (VII) Wherein A, D and E are as defined above; and converting, in a further step, a Wittig reaction according to customary methods, a hydroxyl protecting group as described above. , And subsequent reduction by hydrogenation in the presence of a catalyst to the corresponding alkyl compound (R ² = alkyl), whereby derivatization at the substituent R ² is carried out. The method for producing a compound according to claim 1, wherein: 7. A medicament comprising at least one compound according to claim 1 and a pharmacologically acceptable formulation auxiliary. 8. The medicament according to claim 7, for treating hyperlipoproteinemia. 9. The medicament according to claim 7, for treating arteriosclerosis. 10. Use of a compound according to claim 1 for the manufacture of a medicament. 11. Use according to claim 10, for the manufacture of a medicament for treating arteriosclerosis, especially dyslipidemia.