DE19741400A1 - New benzyl-biphenyl derivatives - Google Patents

Abstract

Hydroxylated benzyl-biphenyl derivatives (I) and their salts are new. Benzyl-biphenyl derivatives of formula (I) and their salts are new: A = cycloalkyl, or aryl or heterocyclyl containing up to 4 S, N and/or O atoms (both optionally substituted by 15 groups), D = -L-R<5>; -CR<6>R<7>R<8>; or -X-V-T-R<9>; R<5>, R<6> and R<9> = aryl or heterocyclyl (both optionally substituted by 15 groups); or R<5> and/or R<6> = difluoromethylenedioxy-phenyl or 2-trifluoromethyl-benzofuran-4-, -5-, -6- or -7-yl; R<7> = H, halo or methyl; and R<8> = H, halo, N3, CF3, OH, OCF3, 1-6C alkyl, 1-6C alkoxy or optionally mono- or disubstituted amino; or R<7>+R<8> = O or optionally substituted imino; L = alkylene or alkenylene optionally substituted by OH; T and X = alkylene; or T or X = a bond; V = O, S or optionally substituted imino; E = cycloalkyl, alkyl optionally substituted by cycloalkyl or OH, or phenyl optionally substituted by halo or CF3; R<1> = alkyl substituted by OH or tetrahydropyran-2-yloxy; R<2> = H or alkyl or alkenyl optionally substituted by 8 groups. The full definitions are given in the DEFINITIONS (Full Definitions) Field. An Independent claim is included for the preparation of (I).

Description

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

Publication US-5 169 857-A2 discloses 7- (polysubstituted pyridyl) -6-heptenoates Treatment of atherosclerosis, lipoproteinemia and hyperproteinemia known. In addition, the preparation of 7- (4-aryl-3-pyridyl) -3,5-dihydroxy-6-heptenoate in of publication EP-325 130-A2.

The present invention relates to benzyl biphenyls 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, optionally up to 5-fold, identically or differently, with cyano, halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoromethoxy or with straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each have up to 7 carbon atoms, or are substituted by a group of the formula -NR ³ R ⁴ ,
wherein
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
R ⁵ -L-,

or R ⁹ -TVX-
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 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 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 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 ¹¹ , -SO ₂ R ¹² or - NR ¹³ R ¹⁴ ,
wherein
R ¹⁰ , R ¹¹ and R ¹² independently of one another are aryl having 6 to 10 carbon atoms, which in turn is up to 2 times the same or different substituted 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 each having 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 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 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 the same 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,
E represents cycloalkyl having 3 to 8 carbon atoms, or 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

or

are substituted, wherein
R ^{19 is} a radical of the formula -Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , or straight-chain or branched alkyl having up to 6 carbon atoms, or a 5- to 7-membered saturated, partially unsaturated or unsaturated heterocycle with bis to 3 heteroatoms from the series S, N and / or O means, 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.

The benzyl biphenyls according to the invention can also be present in the form of their salts. in the general here are salts with organic or inorganic bases or acids called.

In the context of the present invention, physiologically acceptable salts prefers. Physiologically acceptable salts of the compounds according to the invention can salts of the substances according to the invention with mineral acids, carboxylic acids or Be sulfonic acids. Z are particularly preferred. B. salts with hydrochloric acid, bromine hydrochloric 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 compounds of the invention which have a free carboxyl group. Z are particularly preferred. B. sodium, potassium, magnesium or calcium salts, and Ammonium salts derived from ammonia, or organic amines such as for example ethylamine, di- or triethylamine, di- or triethanolamine,  Dicyclohexylamine, dimethylaminoethanol, alginine, lysine, ethylenediamine or 2- Phenylethylamine.

The compounds according to the invention can exist in stereoisomeric forms either like image and mirror image (enantiomers), or which are not like image and Mirror image (diastereomers) behave, exist. The invention relates to both the enane tiomers or diastereomers and their respective mixtures. These blends of Enantiomers and diastereomers can be stereoisomerized in a known manner separate uniform components.

Heterocycle, optionally benzocondensed, is within the scope of the invention in general for a saturated, partially unsaturated or unsaturated 5- to 7- membered, preferably 5- to 6-membered heterocycle, which consists of up to 4 heteroatoms the series S, N and / or O may contain. Examples include: indolyl, Isoquinolyl, quinolyl, benzo [b] thiophene, benzo [b] furanyl, pyridyl, thienyl, furyl, Pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Are preferred Quinolyl, furyl, pyridyl and thienyl.

The compounds of the general formula (I) according to the invention are preferred
in which
A represents naphthyl, phenyl, pyridyl, thienyl, imidazolyl, pyrryl or morpholine, which may optionally be identical or different up to 2 times through fluorine, chlorine, bromine, amino, hydroxy, trifluoromethyl, trifluoromethoxy or through straight-chain or branched alkyl, or alkoxy are each substituted with up to 6 carbon atoms,
D represents phenyl, which is optionally substituted by nitro, fluorine, chlorine, bromine, phenyl, trifluoromethyl or trifluoromethoxy, or
for a radical of the formula R ⁵ -L-,

or R ⁹ -TVX-
stands,
wherein
R ⁵ , R ⁶ and R ⁹ independently of one another are phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, iridolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, 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, 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,
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 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 is} hydrogen; Means 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,
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
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 may optionally be hydroxyl, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or a group of the formula

or

is substituted,
wherein
R ^{19 represents} 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, 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, or
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 2 times, identically or differently, 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 is optionally substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or a radical of the formula
R ⁵ -L-,

or R ⁹ -TVX-
stands,
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 ,
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, 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 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 ^{6 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 the} same 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 ,
wherein
R ¹⁷ denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms,
L denotes 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 the same 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 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,
E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl, which is optionally substituted by fluorine or trifluoromethyl, or
represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxy,
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 is tetrahydropyranyl, pyridyl, phenyl or benzyl, which may optionally be identical or different up to 2 times through 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.

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)

in which
R ²⁰ , R ^{20 '} and R ^{20''are the} same 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,
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 comprises 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
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 protecting 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:

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

The bases used for the reaction step (II) → (III) are the customary strongly basic Ver ties in question. These preferably include organolithium compounds such as for example 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. Sodium amide is special.

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) used.

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

The reaction generally takes place under normal pressure, but it is also possible with it to work at high or low pressure.

As a solvent for the preparation of the compounds of the general Formula (V) are suitable hydrocarbons such as benzene, toluene, xylene, chlorobenzene, Ethyl benzoate, decalin, benzonitrile, hexane, cyclohexane or petroleum fractions. Likewise it is possible to use mixtures of the solvents mentioned. Xylene is preferred.

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 under normal pressure, but it is also possible with it to work at high or low pressure.  

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 , AlCl ₃ , TiCl ₄ , Al (CH ₃ ) ₃ , Al (C ₂ H ₅ ) ₃ , (C ₂ H ₅ ) ₂ AlCl, MgCl ₂ ZnCl ₂ and BCl _3rd

Suitable solvents for the oxidation are ethers such as diethyl ether, dioxane, tetrahydro furan, 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 triamide, acetonitrile, acetone or nitromethane. It is the same possible to use mixtures of the solvents mentioned. Toluene is preferred.

Examples of suitable oxidizing agents are cerium (IV) ammonium nitrate, 2,3-dichloro-5,6- dicyanobenzoquinone, pyridinium chlorochromate (PCC), pyridinium chlorochromate basic aluminum oxide, osmium tetroxide, sodium acetate / iodine and manganese dioxide. Be 2,3-dichloro-5,6-dicyanobenzoquinone is preferred.

The oxidizing agent is used in an amount of 1 mol to 10 mol, preferably 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. But it is also possible that To carry out oxidation at elevated or reduced pressure.

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

The reduction of the compounds of the general formula (VI) is generally carried out with Reducing agents, preferably those used for the reduction of alkoxycarbonyl Hydroxy compounds are suitable to be carried out. It is particularly suitable here  reduction with metal hydrides or complex metal hydrides in inert solvents, optionally in the presence of a trialkylborane. The reduction with is preferred complex metal hydrides such as lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoboronate, diisobutylaluminium hydride or Lithium aluminum hydride performed. The reduction with is very particularly preferred Diisobutylaluminium hydride performed.

The reducing agent is generally preferred in an amount of 1 mol to 6 mol from 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, depending on the choice of reducing agent and solvent.

The reduction generally takes place at normal pressure, but it is also possible at to work under increased or reduced pressure.

Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetra hydrofuran, glycol dimethyl ether, or hydrocarbon such as benzene, toluene, xylene, Hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichlor methane, trichloromethane, carbon tetrachloride, dichlorethylene, trichlorethylene or chlorine benzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, Hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is the same possible to use mixtures of the solvents mentioned. Toluene and Dichloromethane.

The protective group is generally split off in one of the above Alcohols and THF, preferably methanol / THF in the presence of hydrochloric acid in one Temperature range from 0 ° C to 50 ° C, preferably at room temperature, and normal pressure. In special cases, the protective group is split off with tetrabutylammo nium fluoride (TBAF) preferred in WVW at room temperature.  

The compounds of the general formula (VI) are reacted in one of the above listed ethers, preferably in tetrahydrofuran under a protective gas atmosphere in one 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) is carried out, for example, by oxidation, sulfonation, alkylation, hydration stations, halogenation, Wittig / Grignard reactions, aldol reactions, reductive ami nation and sulfoamidation.

The usual strongly basic compounds come in as bases for the individual steps Question. These preferably include organolithium compounds such as n- Butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as for example lithium diisopropylamide, sodium amide or potassium amide, or lithium hexa methylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride. Especially N-butyllithium, sodium hydride or lithium diisopropylamide is preferably used.

The usual inorganic bases are also suitable as bases. This includes preferably alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, Potassium hydroxide or barium hydroxide, or alkali carbonates such as sodium or potassium carbonate or sodium bicarbonate. Sodium hydroxide is particularly preferred or potassium hydroxide used.

Alcohols such as are also suitable as solvents for the individual reaction steps Methanol, ethanol, propanol, butanol or tert-butanol. Tert is preferred. Butanol.

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

Suitable solvents are, depending on the type of alkylating agent, all inert orga African solvents. These preferably include ethers such as diethyl ether, dioxane or Tetrahydrofuran, or hydrocarbons such as benzene, toluene or xylene, or dimethyl formamide or hexamethylphosphoric triamide, or mixtures of the solutions mentioned medium.  

The usual basic compounds are suitable as bases for the alkylation. For this preferably include alkali hydrides such as sodium hydride, alkali amides such as sodium amide or Lithium diisopropylamide, alkali alcoholates such as sodium methoxide, sodium ethoxide, Potassium methanolate, potassium ethanolate or potassium ter.butylate, or organic amines such as Trialkylamines, e.g. B. triethylamine, or organolithium compounds such as butyllithium or phenyllithium. Lithium diisopropylamide is preferred.

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 carried out at normal pressure. It is also possible to carry out the process under vacuum or overpressure (e.g. in a Range from 0.5 to 5 bar).

The reaction with the compounds of general formula (III) takes place in generally with hydrocarbons such as benzene, toluene, xylene, hexane and Cyclohexane. Xylene is preferred.

The reaction generally takes place at a temperature of 100 ° C to 140 ° C preferably at 140 ° C.

The reaction generally takes place under normal pressure, but it is also possible with it to work at high or low pressure.

Suitable solvents for the oxidation are ethers such as diethyl ether, dioxane and tetra hydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, Hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichlor methane, trichloromethane, carbon tetrachloride, dichlorethylene, trichlorethylene or Chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, Dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or Nitromethane. It is also possible to use mixtures of the solvents mentioned. Toluene is preferred.  

Examples of suitable oxidizing agents are cerium (IV) ammonium nitrate, 2,3-dichloro-5,6- dicyanobenzoquinone, pyridinium chlorochromate (PCC), pyridinium chlorochromate basic aluminum oxide, osmium tetroxide, sodium acetate / iodine and manganese dioxide. Be 2,3-dichloro-5,6-dicyanobenzoquinone is preferred.

The oxidizing agent is used in an amount of 1 mol to 10 mol, preferably 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. But it is also possible that To carry out oxidation at elevated or reduced pressure.

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 two-stage stirring in the system mesyl chloride / triethylamine and and diazabicycloundecane in tetrahydrofuran.

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 tetrahydro furan.

The usual strongly basic compounds come in as bases for the individual steps Question. These preferably include organolithium compounds such as n- Butyllithium, sec. Butyllithium, tert.butyllithium or phenyllithium, or amides as for for example lithium diisopropylamide, sodium amide or potassium amide, or lithium hexa methylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride. Especially N-butyllithium, sodium hydride or lithium diisopropylamide is preferably used.

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

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:
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, dichloro or chlorobenzene, trichlorethylene , or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran is preferred.

The usual strongly basic compounds come in as bases for the individual steps Question. These preferably include organolithium compounds such as n- Butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as for example 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 preferred used.

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

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 compounds of the general formula (XI) are known per se or according to usual methods can be produced.

The compounds of the general formula (IX) are known per se or according to usual methods can be produced.

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

The compounds of 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 according to usual methods can be produced.

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

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

The compounds of the general formula (I) according to the invention do not have one predictable pharmacological spectrum of action.  

The compounds of general formula (I) according to the invention have valuable im Pharmacological properties superior to the prior art, in particular, they are highly effective inhibitors of the cholesterol ester transfer protein (CETP) and stimulate reverse cholesterol transport. The invention Active ingredients cause a lowering of the LDL cholesterol level in the blood at the same time Increase in HDL cholesterol. You can therefore treat and Prevention of hypolipoproteinemia, dyslipidemia, hypertriglyceridaemia, hyperlipi demia or arteriosclerosis.

The pharmacological effect of the substances according to the invention was tested in the following test certainly:

CETP inhibition testing Obtaining CETP

CETP is made from human plasma by differential centrifugation and columns Chromatography obtained in 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 soil 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 active fractions are pooled against 50 mM Dialyzed NaAcetat pH 4.5 and onto a CM-Sepharose® (Pharmacia) column applied. Then use a linear gradient (0-1 M NaCl) eluted. The pooled CETP fractions are against 10 mM TrisHCl pH 7.4 dialyzed and then by chromatography on a Mono Q® column (Pharmacia) further cleaned.

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 lower phase is dialyzed against 3 * 4 l PDB buffer (10 mM Tris / HCl pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN ₃ ). Then 20 µl of 3H cholesterol (Dupont NET-725; 1 µC / µl dissolved in ethanol!) Is added per 10 ml of retentate volume and incubated for 72 h at 37 ° C under N ₂ .

The mixture is then adjusted to the density 1.21 with NaBr and in the Ty 65 Centrifuged rotor at 50,000 rpm at 20 ° C for 18 h. You win the upper phase and purifies the lipoprotein fractions by gradient centrifugation. This will the isolated, labeled lipoprotein fraction with NaBr to a density of 1.26 set. 4 ml each of this solution are placed in centrifuge tubes (SW 40 rotor) with 4 ml of a solution of density 1.21 and 4.5 ml of a solution of 1.063 overlaid (sealing solutions from PDB buffer and NaBr) and then 24 h Centrifuged at 38,000 rpm and 20 ° C in the SW 40 rotor. The between the density 1,063 and 1,21 lying, the marked HDL-containing intermediate layer dialyzed against 3 * 100 volumes of PDB buffer at 4 ° C.

The retentate contains radioactively labeled ³ H-CE-HDL, which is set to approx. 5 × 10 ⁶ cmp per ml and used for the test.

CETP test

To test the CETP activity, the transfer of ³ H-cholesterol esters from human HD lipoproteins to biotinylated LD lipoproteins is measured.

The reaction is carried out by adding streptavidin-SPA®beads (from Amersham) ended and the transmitted radioactivity directly in the Liquid Scintillation Counter certainly.  

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. 200 μl of the SPA streptavidin bead solution (TRKQ 7005) are then 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. be done by sub punch dissolved in DMSO and 0.5% Tylose suspended using a pharyngeal tube to be administered orally. The control animals receive identical volumes 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. The transfer of ³ H-cholesterol esters from HD lipoproteins to biotinylated LD lipoproteins is measured as described for the CETP test above.

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 used for testing the serum by 10 µl of the corresponding Serum samples replaced. Corresponding incubations also serve as controls Sera from untreated animals.

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.

In vivo activity of the compounds according to the invention

In attempts to determine the oral effect on lipoproteins and tri glyceride is Syrian golden hamster from the company's own breeding test substance dissolved in DMSO and 0.5% tylose suspended orally using a pharyngeal tube administered. The CETP activity is determined before the start of the experiment Blood was withdrawn by retro-orbital puncture (approx. 250 µl). Subsequently the test substances are 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 differentiated Time points - up to 24 hours after substance application - by puncture of the retroorbital venous plexus.

The coagulation is terminated by incubation at 4 ° C. overnight, then centrifuged at 6000 x g for 10 minutes. So preserved The serum content of cholesterol and triglycerides is modified with the help commercially available enzyme tests (cholesterol enzymatic 14366 Merck, triglycerides 14364 Merck). Serum is used appropriately diluted with physiological saline.

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

The HDL cholesterol content is determined after precipitation 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 the ones to be tested Substances administered in the feed. Before the start of the experiment, the mice were retroorbital blood drawn to serum cholesterol and triglycerides determine. The serum was determined as described above for hamsters Incubation at 4 ° C overnight and subsequent centrifugation at 6000 x g won. After a week, blood was drawn from the mice again, to determine lipoproteins and triglycerides. The change in Measured parameters are shown as a percentage change compared to the Output value expressed.

The invention also relates to the combination of benzyl biphenyls general formula (I) with a glucosidase and / or amylase inhibitor Treatment of familial hyperlipidaemia, obesity and Diabetes mellitus. Glucosidase and / or amylase inhibitors within the scope of the invention Examples are acarbose, adiposins, Voglibose, Miglitol, Emiglitate, NIDL-25637, Camiglibose (MDL-73945), Tendamistate, AI-3688, Trestatin, Pradimicin-Q and Salbostatin.

The combination of acarbose, miglitol, emiglitate or voglibose is preferred one of the above-mentioned compounds of the general Formulas (I).

Furthermore, the compounds according to the invention can be used in combination with Combined cholesterol-lowering Vastatinen or ApoB-lowering principles to be dyslipidemic, combined hyperlipidemic, hypercholesterolemic or to treat hypertriglyceridemics.

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

Vastatins within the scope of the invention are, for example, lovastatin, simvastatin, Pravastatin, Fluvastatin, Atorvastatin and Cerivastatin. ApoB are reducing agents for example MTP inhibitors.

The combination of cerivastatin or ApoB inhibitors with one of the Compounds according to the invention of the general formulas (I) and listed above (Ia).

The new active ingredients can be introduced into the usual formulations in a known manner are transferred, such as tablets, dragees, pills, granules, aerosols, syrups, emuls ions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents. This is where the therapeu table active compound in a concentration of about 0.5 to 90- % By weight of the total mixture is present, d. H. in amounts that are sufficient to achieve the specified dosage range.

The formulations are prepared, for example, by stretching the active ingredients substances with solvents and / or carriers, optionally using Emulsifiers and / or dispersants, z. B. in the case of using Water as a diluent and optionally organic solvents as an auxiliary solvents can be used.

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

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

In general, it has proven to be advantageous for intravenous administration Amounts from about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight to give effective results, and oral appli  cation, 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 quantities mentioned give way, depending on the body weight or the type of Application route, from individual behavior towards the drug, the type of its formulation and the time or interval at which the Administration takes place. So in some cases it may be sufficient with less than the aforementioned minimum quantity, while in other cases the mentioned upper limit must be exceeded. Larger in the case of application Quantities, it may be advisable to add these in several single doses throughout the day to distribute.  

Output connections Example I

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

To 40 g (0.312 mol) of N, N-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 2.5 M 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 ethyl acetate, the mixture is washed with sat. NaCl solution, dries over Na ₂ SO ₄ and concentrated. 82 g of N, N-dimethyl-N- {2-methyl-1- [2- (4-trifluoromethylphenyl) 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 h. It is extracted with EtOAc, washed with water and sat. NaCl solution, dries over Na ₂ SO ₄ and concentrated. 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-fluorophenyl) -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 to 400 ml (0.791 mol) of a 2.0 M 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 Cl solution, allowed to warm to -10 ° C. and a further 400 ml of a 10% NH ₄ Cl solution are added. 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-fluoro-phenyl) -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 l of abs. CH ₂ Cl 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 at 20 ° C. overnight and 456 ml (3.04 mol) of DBU dissolved in 1 l of abs are added at -30 ° C. CH ₂ Cl 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 Cl 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 to 47.6 g (114.2 mmol) of a mixture of methyl triphenylphosphonium bromide and sodium amide in 200 ml abs. Ether. After 90 min, 300 ml of petroleum ether are added and the mixture is suctioned off through a little silica gel. Wash with 2 l PE and concentrate. 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-Fluoro-phenyl) -4-isopropyl-5- (4-trifluoromethyl-benzyl) cyclohexa-1,4-dienecarboxylic acid, methyl ester

To 3.0 g (8.61 mmol) of the compound from Example IV in 15 ml of abs. Xylene is added to 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. Concentrate and purify on silica gel (cyclohexane / EtOAc 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. Toluene dissolved and at -78 ° C with 600 ul (0.9 mmol) of a 1.5 M solution of DIBAH in toluene. 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-Fluoro-phenyl) -5-isopropyl-4- (4-trifluoromethyl-benzyl) cyclohexa-1,4-diene-1,2-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 Cl 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 Cl 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 Cl 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, the mixture is filtered through Al ₂ O ₃ and washed with CH ₂ Cl ₂ . Further purification is carried out on silica gel 60 (CH ₂ Cl ₂ ).
Yield: 1.84 g (87%)
R _f = 0.39 (EtOAc / PE 1: 5).

Manufacturing examples Example I

[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 1.5 M solution of DIBAH in toluene at -78 ° C. 1 is stirred at this temperature, allowed to warm to room temperature and stirred for 1 h. 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 Cl ₂ dissolved and stirred for 90 min at room temperature. It is quenched with water, extracted with CH ₂ Cl 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%) of [3-tert-butyl-diphenylsiloxymethyl-4'-fluoro-5-isopropyl-6- (4-trifluoromethyl-benzyl) -biphenyl-2-yl] -methanol are obtained (R _f = 0.52 in CH ₂ Cl ₂ ).

This compound is dissolved in 220 ml of abs. CH ₂ Cl 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 Cl 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 are obtained (R _f = 0.22 EtOAc / PE 1:20).

This compound is abs in 250 ml. THF solved. 24.3 g (77 mmol) of tetra-n-butylammonium fluoride trihydrate (TBAF × 3H ₂ O) are added and the mixture is stirred at room temperature for 90 min. 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 takes place 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-butyl ammonium 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, 14 μl (0.115 mmol) of benzyl bromide are added and the mixture is stirred 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-fluorophenoxymethyl) -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) of triphenylphosphine and 49 mg (0.435 mmol) of 4-fluorophenol are dissolved in 4 ml of ether / THF (3: 1) and 59 μl are added dropwise (0.38 mmol) 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 purified on silica gel 60 (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 1.6 M solution of n-BuLi in n-hexane and the mixture is stirred at 20 ° C for 2 h. 100 mg (0.19 mmol) of the compound from Example X dissolved in 10 ml of abs are added. Ether. After 90 minutes, petroleum ether is added and the mixture is filtered off with suction through a little silica gel. Wash with petroleum ether and concentrate. The crude product is purified on silica gel 60 (toluct). 88 mg (80%), R _f = 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%)
R _f = 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)

In analogy to the instructions of Examples 1-7, those in Table 1 are listed led connections made:

Table 1

Claims (10)

1. Benzyl biphenyls 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, optionally up to 5-fold, identically or differently, with cyano, halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoromethoxy or with straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each have up to 7 carbon atoms, or are substituted by a group of the formula -NR ³ R ⁴ ,
wherein
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
R ⁵ -L-,
or R ⁹ -TVX-
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 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, hydroxy, 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 having up to 3 heteroatoms from the S series, N and / or O are substituted,
and / or are substituted by a group of the formula -OR ¹⁰ , -SR ¹¹ , -SO ₂ R ¹² or -NR ¹³ R ¹⁴ ,
wherein
R ¹⁰ , R ¹¹ and R ¹² independently of one another are aryl having 6 to 10 carbon atoms, which in turn is up to 2 times the same or different substituted 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 each having 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 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 6 carbon atoms,
L denotes 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 the same 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,
E represents cycloalkyl having 3 to 8 carbon atoms, or
represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or 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 be by hydroxy, halogen, phenyl, cycloalkyl having 3 to 6 carbon atoms or by a group of the formula
or
are substituted,
wherein
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, or
and their salts. 2. benzyl biphenyls of the formula according to claim 1,
in which
A represents naphthyl, phenyl, pyridyl, thienyl, imidazolyl, pyrryl or morpholine, which may optionally be identical or different up to 2 times through fluorine, chlorine, bromine, amino, hydroxy, trifluoromethyl, trifluoromethoxy or through straight-chain or branched alkyl, or alkoxy are each substituted with up to 6 carbon atoms,
D represents phenyl, which is optionally substituted by nitro, fluorine, chlorine, bromine, phenyl, trifluoromethyl or trifluoromethoxy, or
for a rest of the formula
R ⁵ -L-,
or R ⁹ -TVX-
stands,
wherein
R ⁵ , R ⁶ and R ⁹ independently of one another phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8- yl mean
where the cycles, optionally up to 3 times in the case of nitrogen-containing rings also via the N function, are the same or different from 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 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 4 carbon atoms,
or
R ⁵ and / or R ^{6 is} a radical of the formula
mean,
R ^{7 is} hydrogen; Means 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 the} same or different and are hydrogen; Is 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 is 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 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
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, if appropriate by hydroxy, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or by a group of the formula
or
is substituted,
wherein
R ^{19 represents} 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, 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, or
and their salts. 3. benzyl biphenyls of the formula according to claim 1,
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 is optionally substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or
for a radical of the formula R ⁵ -L-,
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, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl,
the cycles, optionally up to 3 times, in the case of nitrogen-containing rings also via the N function, the same or different 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 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 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
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 the} same 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 ,
wherein
R ¹⁷ denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms,
L represents 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 the same 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 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,
E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl, which is optionally substituted by fluorine or trifluoromethyl, or
represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxy,
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 be by hydroxy, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or by 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
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. 4. Benzyl biphenyls according to Claims 1 to 3 as medicaments. 5. A process for the preparation of benzyl biphenylene according to claim 1 to 3, 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)
in which
R ²⁰ , R ^{20 '} and R ^{20''are the} same 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,
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 comprises 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
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, splits off 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. 6. Medicament containing at least one benzyl biphenyl according to claim 1 to 3 as well as pharmacologically acceptable formulation aids. 7. Medicament according to claim 6 for the treatment of hyperlipoproteinemia. 8. Medicament according to claim 6 and 7 for the treatment of arteriosclerosis. 9. Use of benzyl biphenylene according to claim 1 to 3 for the preparation of Medicines. 10. Use according to claim 9 for the manufacture of medicaments for treatment of arteriosclerosis, especially dyslipidemia.