MXPA00002771A - Benzyl-biphenyls and analogous compounds and the application thereof in order to treat arteriosclerosis and dyslipidaemia - Google Patents

Abstract

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

Description

Benzyl biphenyls and analogous compounds and their use for the treatment of arteriosclerosis and dyslipidemia. Description of the invention: The present invention relates to benzyl biphenyls and analogous compounds, to processes for their preparation and their use in medicaments. US Pat. No. 5,169,857-A2 discloses 7- (polysubstituted pyridyl) -6-heptenoates for the treatment of arteriosclerosis, lipoproteinemia and hyperproteinemia. In addition, the preparation of 7- (4-aryl-3-pyridyl) -3,5-dihydroxy-6-heptenoates is described in EP-325 130-A2.

The present invention relates to benzyl biphenyls and analogous compounds of general formula (I), wherein A represents cycloalkyl of 3 to 8 carbon atoms, or represents aryl of 6 to 10 carbon atoms, or represents a 5- to 7-membered heterocycle, saturated, partially unsaturated or unsaturated, optionally benzo-condensed, with up to 4 heteroatoms of the series of S, N and / or 0, where appropriate, aryl and ring systems REF .: 32928 previously indicated heterocyclics up to pentasubstituted in the same or different manner with cyano, halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoromethoxy or with alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy, straight chain or branched, of up to 7 carbon atoms each, or with a group of formula -NR3R4, wherein R3 and R4 are the same or different and mean hydrogen, phenyl or straight or branched chain alkyl of up to 6 carbon atoms, represents a residue of formula in which Rf, Rc and Rc mean independently from each other aryl of 6 to 10 carbon atoms or a 5- to 7-membered heterocycle, optionally benzo-condensed, saturated or unsaturated, mono, bi or tricyclic with up to 4 heteroatoms of the series of S, N and / or 0, the cycles being, if necessary, also through the function N in the case of rings containing nitrogen, until pentasubstituted in the same or different manner with halogen, trifluoromethyl, nitro, hydroxy, cyano, carboxyl, trifluoromethoxy, acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or straight chain or branched alkoxycarbonyl with up to 6 carbon atoms each, with aryl or aryl substituted with trifluoromethyl of 6 to 10 carbon atoms in each case or with an aromatic heterocycle of 5-7 links, optionally benzocondensate, with up to 3 heteroatoms of the S, N and / or O series, and / or with a group of the formula -OR10, -SR11, -S02R12 or -NR13R14, where R10, R11 and R12 mean independent in each case aryl of 6 to 10 carbon atoms, which in turn is even disubstituted in the same or different way with phenyl, halogen or with straight or branched chain alkyl of up to 6 carbon atoms, R13 and R14 are the same or different and have the above-indicated meaning of R3 and R4, or R5 and / or Re mean a remainder of formula >; F3C yO R7 means hydrogen, halogen or methyl, and R8 means hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromethoxy, alkoxy or straight-chain or branched alkyl with up to 6 carbon atoms each or a residue of formula -NR15R16, in that R15 and R16 are the same or different and have the aforementioned meaning of R3 and R4, R7 and R8 together form a residue of formula = 0 or = NR17, in which R17 means hydrogen or straight chain or branched alkyl, alkoxy or acyl with up to 6 carbon atoms each, L means a linear or branched alkylene or alkenylene chain with up to 8 carbon atoms each, which if appropriate they are even disubstituted with hydroxy, T and X are the same or different and mean a linear or branched alkylene chain with up to 8 carbon atoms, or T or X means a bond, V represents an oxygen or sulfur atom or represents a group -NR18, wherein R18 means hydrogen or straight or branched chain alkyl with up to 6 carbon atoms or phenyl, E represents cycloalkyl of 3 to 8 carbon atoms, or represents straight or branched chain alkyl with up to 8 carbon atoms which are optionally substituted by cycloalkyl of 3 to 8 carbon atoms or hydroxy, or represents phenyl which is optionally substituted by halogen or trifluoromethyl, R: represents alkyl straight or branched chain with up to 6 carbon atoms that is substituted with hydroxy or with a group of formula R: represents hydrogen or straight-chain or branched alkyl or alkenyl with up to 8 carbon atoms in each case, which optionally are substituted with hydroxy, halogen, phenyl, cycloalkyl of 3 to 6 carbon atoms or with a group of formula wherein R 19 signifies a residue of formula -Si (CH 3) 2 C (CH 3) 3, or means straight or branched chain alkyl with up to 6 carbon atoms, or means a saturated, partially unsaturated or unsaturated 5- to 7-membered heterocycle unsaturated with up to 3 heteroatoms from the series S, N and / or O, or represents phenyl or benzyl, all ring systems listed under R19 optionally up to disubstituted identically or differently by trifluoromethyl, fluorine, nitro, hydroxy being, straight chain or branched alkoxy or alkoxycarbonyl with up to 4 carbon atoms in each case or with straight or branched chain alkyl of up to 4 carbon atoms, which optionally is substituted with hydroxy, and their salts. The compounds according to the invention can also be present in the form of their salts. In general, it is here to mention salts with organic or inorganic bases or acids.

In the context of the present invention, physiologically acceptable salts are preferred. Physiologically innocuous salts of the compounds according to the invention can be the salts of the substances according to the invention with mineral, carboxylic or sulphonic acids. Particularly preferred are, eg, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, etanosul phonic, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid. Equally physiologically acceptable salts may be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Especially preferred are, eg, salts of sodium, potassium, magnesium or calcium and ammonium salts, derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethyl ina. The compounds according to the invention can exist in stereoisomeric forms which behave as an object and its mirror image (enantiomers), or which do not behave as an object and its mirror image (diastereomers). The invention relates to both the enantiomers or diastereomers as well as their respective mixtures. These mixtures of enantiomers and diastereomers can be separated in known manner into the unit stereoisomeric components. Heterocycle, optionally benzo-fused, generally depicted in the context of the invention a saturated, partially unsaturated or unsaturated 5- to 7-membered, preferably 5- to 6-membered ring which can contain up to 4 heteroatoms from the series S, N and / or O. examples which may be mentioned are: indolyl, isoquinolyl, benzo [b] thiophene, benzo [b] furanyl, pyridyl, thienyl, furyl, pyrrolyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Preferred are quinolinyl, furyl, pyridyl and thienyl. Preferred are the compounds according to the invention of the general formula (I), in which A represents naphthyl, phenyl, pyridyl, thienyl, imidazolyl, pyrrhyl or morpholine, which are optionally disubstituted in the same or different manner with fluorine, chlorine , bromo, amino, hydroxy, trifluoromethyl, trifluoromethoxy or alkyl or alkoxy straight chain or branched having up to 6 carbon atoms each, represents phenyl which is optionally substituted by nitro, fluorine, chlorine, bromine, phenyl, trifluoromethyl or trifluoromethoxy, or represents a residue of formula wherein R5, R6 and R9 independently stand for phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl, the cycles being, if appropriate, also through the N-function in the case of the rings containing nitrogen, until trisubstituted in the same or different manner with fluorine, chlorine, bromine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or straight chain or branched alkoxycarbonyl with up to 4 carbon atoms each, triazolyl, tetrazolyl, benzoxathiazolyl, or phenyl substituted with trifluoromethyl or phenyl, and / or are substituted with a group of formula -OR10, -SR11 or -S02R12, wherein R10, R11 and R12 are the same or different and mean phenyl, which in turn is disubstituted 'in the same or different way with phenyl, fluorine, chlorine or with straight or branched chain alkyl of up to 4 carbon atoms, or R5 and / or R6 mean a radical of formula R7 means hydrogen, fluorine, chlorine or bromine, and means hydrogen, fluorine, chlorine, bromine, azide, trifluoromethyl, hydroxy, trifluoromethoxy, alkoxy or straight-chain or branched alkyl with up to 5 carbon atoms each or a radical of formula NRlbRif, wherein R15 and R1É are the same or different and mean hydrogen, phenyl or straight or branched chain alkyl with up to 4 carbon atoms, R and Ry together form a residue of formula = 0 or = NRA in which R 17 is hydrogen or straight chain or branched alkyl, alkoxy or acyl with up to 4 carbon atoms each, L means a linear alkylene or alkenylene chain or branched with up to 6 carbon atoms each, which are optionally disubstituted with hydroxy, T and X are the same or different and mean a straight or branched alkylene chain with up to 6 carbon atoms, or T or X means a bond , V represents an oxygen or sulfur atom or represents a group of formula -NR18, in which R18 means hydrogen or straight or branched chain alkyl with up to 4 carbon atoms or phenyl, E represents cyclopropyl, -butyl, -pentyl , -hexyl or -heptyl, or represents straight or branched chain alkyl with up to 6 carbon atoms which is optionally substituted with cyclopropyl, -butyl, -hexyl, -pentyl, -heptyl or with hydroxy, or represents phenylene which gives If the case is substituted with fluorine, chlorine or trifluoromethyl, R1 represents a group of formula -CH2OH or R 2 represents hydrogen or straight-chain or branched alkyl or alkenyl with up to 6 carbon atoms in each case, which optionally are substituted with hydroxy, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or with a group of formula wherein R19 means a residue of the formula -Si (CH3) 2C (CH3) 3, or means straight or branched chain alkyl with up to 5 carbon atoms, or means tetrahydropyranyl, pyridyl, phenyl or benzyl, which may be even disubstituted in the same or different manner with straight chain or branched trifluoromethyl, fluoro, nitro, hydroxy, alkoxy or alkoxycarbonyl with up to 3 carbon atoms in each case or with straight or branched chain alkyl of up to 3 carbon atoms given the case is substituted with hydroxy, and its salts. Especially preferred are compounds according to the invention of general formula (I), in which A represents phenyl or pyridyl, which are optionally disubstituted in the same or different manner with fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy or straight chain or branched alkyl or alkoxy with up to 5 carbon atoms each, D represents phenyl which is optionally substituted with nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or represents a radical of formula wherein R5, R6 and R9 independently signify phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxythyn-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8- ilo, the cycles being, if necessary, also through the function N in the case of rings containing nitrogen, until trisubstituted in the same or different way with fluorine, chlorine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, alkyl , straight-chain or branched alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl with up to 4 carbon atoms each, triazolyl, tetrazolyl, benzothiazolyl, phenyl substituted with trifluoromethyl or phenyl, and / or are substituted with a group of formula -OR10, -SRa : or -S0R?, in which R10, R11 and R !: are the same or different and mean phenyl, which in turn is even disibstituted in the same or different way with phenyl, fluorine, chlorine or with straight chain alkyl or branched of up to 3 carbon atoms, R- and / or R "mean a remainder of formula R7 means hydrogen or fluorine, and R8 means hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy, trifluoromethoxy, or alkoxy or straight-chain or branched alkyl with up to 4 carbon atoms each or a radical of formula -NR15R? e, wherein R 15 and R are the same or different and denote hydrogen or straight or branched chain alkyl with up to 3 carbon atoms, or R 7 and R 8 together form a moiety of formula = 0 or = NR 1 \ wherein R 17 means hydrogen or straight-chain or branched alkyl, alkoxy or acyl with up to 4 carbon atoms each, L means a straight or branched alkylene or alkenylene chain with up to 5 carbon atoms each, which, if any, are up to disubstituted with hydroxy, T and X are the same or different and mean a linear or branched alkylene chain with up to 3 carbon atoms, or T or X means a bond, V represents an oxygen or sulfur atom or represents a group of formula -NR18, in which R18 is hydrogen or straight or branched chain alkyl with up to 3 carbon atoms, E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl, which optionally is substituted with fluorine or trifluoromethyl, or represents straight-chain alkyl or branched with up to 4 carbon atoms which optionally is substituted with hydroxy, R 1 represents a group of formula -CH 2 OH or R- represents hydrogen or straight-chain or branched alkyl or alkenyl with up to 5 carbon atoms in each case, which optionally are substituted with hydroxy, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or with a formula group wherein R1Q means straight or branched chain alkyl with up to 4 carbon atoms, or means a residue of the formula -Si (CH3) 2C (CH3) 3, or means tetrahydropyranyl, pyridyl, phenyl or benzyl, which are optionally even disubstituted in the same or different manner with straight chain or branched trifluoromethyl, fluoro, chloro, nitro, hydroxy, alkoxy or alkoxycarbonyl with up to 3 carbon atoms in each case or with straight or branched chain alkyl of up to 3 carbon atoms if necessary, it is substituted with hydroxy, and its salts.

Especially preferred are compounds according to the invention of general formula (I), wherein A represents phenyl, fluorine, chlorine, bromine, trifluoromethyl, D represents a radical of formula in which R5, R6 and R9 stand for phenyl independently, which is optionally trisubstituted in the same or different manner with fluorine, chlorine or trifluoromethyl, means hydrogen or fluorine, YR * means hydrogen, fluorine, chlorine, bromine or alkyl straight chain "or branched chain with up to 4 carbon atoms, or R7 and R8 together form a moiety of formula = 0 or = NRA wherein R1" 7 means hydrogen or straight chain or branched alkyl, alkoxy or acyl with up to 4 carbon atoms each, L means a linear or branched alkylene or alkenylene chain with up to 5 carbon atoms each, which optionally are disubstituted with hydroxy, T and X are the same or different and mean a linear alkylene chain or branched with up to 3 carbon atoms, or T or X means a bond, V represents an oxygen or sulfur atom or represents a group of formula -NR18, in which R18 means hydrogen or cad alkyl linear or branched with up to 3 carbon atoms, E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl, which optionally is substituted with fluorine or trifluoromethyl, or represents straight or branched chain alkyl with up to 4 carbon atoms, R represents a group of formula -CH2OH or R 2 represents hydrogen or straight-chain or branched alkyl or alkenyl with up to 5 carbon atoms in each case, which optionally are substituted with hydroxy, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or with a group of formula wherein R19 means straight or branched chain alkyl with up to 4 carbon atoms, or means a residue of the formula -Si (CH3) 2C (CH3) 3, or means tetrahydropyranyl, pyridyl, phenyl or benzyl, which are optionally even disubstituted in the same or different manner with trifluoromethyl, fluoro, chloro, nitro, hydroxy, alkoxy or straight chain or branched alkoxycarbonyl groups with up to 3 carbon atoms in each case or with straight or branched chain alkyl of up to 3 carbon atoms carbon that is substituted, if necessary, with hydroxy, and its salts. In addition, processes have been found for the preparation of the compounds of general formula (I), characterized in that compounds of general formula (II) are reacted, wherein A, D and E have the meaning indicated above, in the system (C¿H5) 3PCH3Br / n-butyllithium to obtain first the compounds of general formula (III), wherein A, D and E have the meaning indicated above, they are then transformed with compounds of general formula (IV) or (IVa), wherein R 2o R 20 'and R 20"are the same or different and represent straight or branched chain alkyl with up to 4 carbon atoms, and R 21 represents hydrogen or straight or branched chain alkyl with up to 6 carbon atoms, which given the case is substituted with hydroxy, phenyl, straight or branched chain alkoxy with up to 6 carbon atoms, amino, alkyl or dialkylamines with up to 4 carbon atoms in the alkyl part, in the compounds of general formula (V), where A, D and E have the meaning indicated above, R20"'comprises the above-indicated significance range of R20' and R20", and R22 represents either hydrogen or the residue -CO; R20", or comprises the aforementioned significance range of R21, by oxidation the compounds of formula (VI) are obtained wherein A, D, E, R2, R20"'and R2-' have the meaning indicated above, and finally the carbonyl functions are reduced to the hydroxymethyl function, and derivatizations are carried out in the substituents R2 starting from compounds of the general formula (the) wherein A, D and E have the meaning indicated above, in function of the aforementioned meaning of R2 in the system P (C6H5) 3 / diethyl azodicarboxylate and the correspondingly defined alcohols or amines are transformed under R19, or a etherification by reaction with alkyl halides in the presence of a base, and finally in both derivatizations the hydroxy protecting group with acids is eliminated, or in the case of R2 = alkenyl, the compounds of general formula (Ia) are firstly transformed in the aldehydes of general formula (VII) wherein A, D and E have the meaning indicated above, and in a second step a Wittig reaction is carried out by customary methods, the hydroxy protecting group is removed as described above and finally reduced to the corresponding alkyl compounds (R2 = alkyl) by hydrogenation in the presence of a catalyst.

The process according to the invention can be illustrated by way of example by means of the following formula scheme: H2.Pt/C As solvent for the reaction step (II) - > (III) ethers such as diethyl ether, dioxane, tetrahydrofuran, glycidimethyl ether are suitable. It is also possible to use mixtures of the indicated solvents. Diethyl ether is preferred. As bases for the reaction step (II) - > (III) The usual strong basic compounds are considered. These preferably include organolithium compounds such as, for example, 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. Especially preferred is n-butyl lithium. The base is generally used in an amount of 1 mol to 2 mol, preferably from 1.05 mol to 1.2 mol, referred to 1 mol of the compounds of general formula (II). The reaction proceeds in general at a temperature of -30 ° C to room temperature, preferably -20 ° C to 0 ° C. The reaction generally proceeds at normal pressure, but it is also possible to work at elevated or reduced pressure. As the solvent for the preparation of the compounds according to the invention of the general formula (V), hydrocarbons such as benzene, toluene, xylene, chlorobenzene, ethyl benzoate, decalin, benzonitrile, hexane, cyclohexane or petroleum fractions are suitable. It is also possible to use mixtures of the indicated solvents. Xylene is preferred.

The reaction can also be carried out without solvent or using the alkyne as the solvent. The reaction generally proceeds at a temperature of from -30 ° C to + 250 ° C, preferably from 80 ° C to 180 ° C. The reaction proceeds in general at normal pressure, but it is also possible to work at elevated or reduced pressure. The reaction proceeds in general without catalyst, but it is also possible to use Lewis acids as catalysts, for example: BF3, BF3 x OEt2 / A1C13, TiC4, A1 (CH3) 3, A1 (C2H5) 3, (C2H5) 2A1C1, MgCl2, ZnCl2 and BC13 Ethers such as diethyl ether, dioxane, tetrahydrofuran, glycid dimethyl ether or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane are suitable as the solvent for oxidation. , dichloroethylene, trichlorethylene, chlorobenzene, ethyl acetate, dimethylsulfoxide, dimethylformamide, hexamethylphosphorotriamide, acetonitrile, acetone or nitromethane It is also possible to use mixtures of the indicated solvents. Toluene is preferred. Suitable oxidants are, for example, potassium permanganate, bromine, ammonium nitrate and Ce (IV), 2,3-dichloro-5,6-dicyanobenzoquinone, pyridinium chlorochromate (PCC), pyridinium chlorochromate on basic aluminum oxide. , osmium tetroxide, sodium acetate / iodine and manganese dioxide. 2,3-dichloro-5, β-dicyanobenzoquinone is preferred. The oxidant is used in an amount of 1 mol to 10 mol, preferably 2 mol to 5 mol, referred to 1 mol of the compounds of general formula (V). The oxidation proceeds in general at a temperature of from 0 ° C to + 100 ° C, preferably from room temperature to 80 ° C. Oxidation generally proceeds at normal pressure, but it is also possible to perform oxidation at elevated or reduced pressure. As the solvent for the reduction, the abovementioned hydrocarbons are suitable, with toluene being preferred. The reduction of the compounds of general formula (VI) is generally carried out with reductants, preferably with those which are suitable for the reduction of alkoxycarbonyl compounds to hydroxyls. The reduction with metal hydrides or complex metal hydrides in inert solvents is particularly suitable in this respect. Preferably, the reduction is carried out with complex metal hydrides such as, for example, lithium borohydride, sodium borohydride, potassium boranate, zinc boranate, lithium trialkyl hydruroborates, diisobutylaluminium hydride or lithium aluminum hydride. With very special preference the reduction is carried out with diisobutylaluminum hydride. The reductant is used in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, referred to 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, with particular preference to -78 ° C, respectively depending on the choice of reducing agent and solvent. The reduction generally takes place at normal pressure, but it is also possible to work at high or reduced pressure. Ethers such as diethylether, dioxane, tetrahydrofuran, glycidimethyl ether or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichlorethylene or chlorobenzene, are suitable as the solvent for all processes. or ethyl acetate, or triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphorotriamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the indicated solvents. Toluene and dichloromethane are preferred. The removal of the protective group is generally carried out in one of the alcohols indicated above and tetrahydrofuran, preferably in methanol / THF in the presence of hydrochloric acid in a temperature range of 0 ° C to 50 ° C, preferably at room temperature, and under pressure normal. In special cases the removal of the protective group with tetrabutylammonium fluoride (TBAF) in THF at room temperature is preferred. The reaction of the compounds of formula (VI) is carried out in one of the aforementioned ethers, preferably in tetrahydrofuran under protective gas atmosphere in a temperature range from -78 ° C to -10 ° C, preferably at -25 ° C. The derivatization of the hydroxy function in the compounds of general formula (VII) is carried out, for example, by oxidations, sulphonations, alkylations, hydrogenations, halogenations, Wittig / Grignard reactions, aldol reactions, reductive amination and sulfoamidations. The usual strong basic compounds are considered as bases for the different steps. These preferably include organditic compounds such as, for example, n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides, such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or hexaethylsilylamide. lithium, or alkali hydrides such as sodium hydride or potassium hydride. Particular preference is given to using n-butyl lithium, sodium hydride or lithium diisopropylamide. In addition, the usual inorganic bases are suitable as bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkaline carbonates such as sodium or potassium carbonate or sodium hydrogencarbonate. Sodium hydroxide or potassium hydroxide are particularly preferably used. As the solvent for the various reaction steps, alcohols such as methanol, ethanol, propanol, butanol or tert-butanol are also suitable. Tert-butanol is preferred. Alkylation with alkyl halides is generally carried out in inert solvents in the presence of a base. As the solvent, all inert organic solvents are suitable in this respect according to 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 hexamethylphosphorotriamide, or mixtures of the indicated solvents. The usual basic compounds are suitable as bases for the alkylation. These preferably include alkali hydrides such as sodium hydride, alkali metal amides such as sodium amide or lithium diisopropylamide, alkali metal alcoholates such as sodium methanolate, sodium ethanolate, potassium methanolate, potassium ethanolate or potassium tert-butylate, or organic amines such as trialkylamines. , eg triethylamine, or organolithic compounds such as butyl lithium 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. However, it is also possible to carry out the process under reduced or high pressure (for example in a range of 0.5 to 5 bar). The compounds of the general formula (II) are partially novel and can be prepared, for example, by reacting compounds of the general formula (VIII) D-CH2-CO-CH (CH3). (VIII) wherein D has the meaning indicated above, with compounds of general formula (IX) A-CHO (IX) wherein A has the meaning indicated above, in the presence of lithium diisopropylamide to obtain the compounds of general formula (X) wherein A and D have the meaning indicated above, and finally are agitated in two steps in the mesyl chloride / triethylamine and diazabicycloundecane system in tetrahydrofuran. The compounds of the general formula (VIII) are partially known or new and can be prepared by first reaction with N, N-dimethylhydrazine and finally with compounds of the general formula (XI) D-Br (XI) wherein D has the meaning indicated above, in inert solvents, in the presence of a base and final mixture with hydrochloric acid. The reaction of the compounds of the general formula (XI) is carried out in ethers such as diethyl ether, dioxane, tetrahydrofuran, glycidimethyl ether. It is preferred in tetrahydrofuran. The usual strong basic compounds are considered as bases for the different steps. These preferably include organolytic compounds such as, for example, n-butyl lithium., sec-butyl lithium, tert-butyl lithium 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 hydride and lithium diisopropylamide are particularly preferably used. The base is used in an amount of 0.1 mol to 10 mol, preferably 1 mol to 5 mol, based on 1 mol of the starting compound. The reaction is generally carried out in a temperature range from -10 ° C to + 10 ° C, preferably from 5 ° C to 10 ° C and at normal pressure. The reaction with the aldehydes of the general formula (IX) is carried out as follows: Ethers such as diethyl ether, dioxane, tetrahydrofuran, glycidimethyl ether or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions are suitable as the solvent for all processes. , or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichlorethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphorotriamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the indicated solvents. Tetrahydrofuran is preferred. The usual strong basic compounds are considered as bases for the different steps. These preferably include organolithium compounds such as, for example, 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. Particular preference is given to n-butyl lithium, sodium hydride or lithium diisopropylamide. The base is used in an amount of 0.1 mol to 10 mol, preferably 1 mol to 5 mol, respectively referred to 1 mol of the starting compound. The reaction is generally carried out in a temperature range from -10 ° C to + 10 ° C, preferably from 5 ° C to 10 ° C and at normal 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 general formula (III), (V) and (VI) are new and can be prepared as described above.

The compounds of general formula (IV) are known per se or can be prepared by customary methods. The compounds of general formula (VII) are mostly novel and can be prepared as described above.

The compounds of general formula (Ia) are new and can be prepared as described above. The compounds according to the invention of general formula (I) have a spectrum of pharmacological activity which is not foreseeable.

The compounds according to the invention of general formula (I) possess valuable pharmacological properties, superior in comparison with the state of the art, especially they are very effective inhibitors of the cholesterol-ester transfer protein (CETP) and stimulate the transport of the inverted cholesterol. The active ingredients according to the invention cause a decrease in the level of LDL cholesterol in the blood with a simultaneous increase in the level of HDL cholesterol. Therefore they can be used for the treatment and prevention of hypolipoproteinemias, dyslipidemias, hypertriglyceridemia, hyperlipidemias or arteriosclerosis. The pharmacological activity of the substances according to the invention were determined in the following assay: CETP inhibition assay CETP extraction CETP was obtained from human plasma by differential centrifugation and column chromatography in partially purified form and used for the assay. For this, human plasma was adjusted with NaBr to a density of 1.21 g per ml and centrifuged for 18 h at 50,000 rpm at 4 ° C. The bottom fraction (d> 1, 21 g / ml) was applied to a column of Sephadex® Phenyl-Sepharose 4B (Fa Pharmacia), washed with 0.15 M NaCl / 0.001 M tris HCl, pH 7.4 and then eluted with distilled water. Active fractions of CETP were pooled, dialyzed against 50 mM Na acetate, pH 4.5 and applied to a column of CM-Sepharose® (Fa Pharmacia). It was then eluted with a linear gradient (0-1 M NaCl). The pooled CETP fractions were dialyzed against tris HCl, pH 7.4 and then further purified through a Mono QR column (Fa Pharmacia). Obtaining radiolabeled HDL 50 ml of fresh human plasma EDTA was adjusted with NaBr to a density of 1.12 and centrifuged for 18 h at 50,000 rpm at 4 ° C in a Ty 65 rotor. The upper phase was used to obtain of the cold LDL. The lower phase was dialyzed against 3 * 4 1 of PDB buffer (10 mM tris / HCl, pH 7.4, 0.15 M NaCl, 1 mM EDTA, 0.02% NaN3). 20 μl of 3H-cholesterol was added per 10 ml of retained volume (Dupont NET-725, 1-μC / μl dissolved in ethanol!) And incubated for 72 h at 37 ° C under N2. The mixture was then adjusted with NaBr to the density of 1.21 and centrifuged for 18 h at 50,000 rpm at 20 ° C in a Ty 65 rotor. The upper phase was collected and the lipoprotein fractions were purified by gradient centrifugation. For this, the isolated labeled lipoprotein fraction was adjusted with NaBr to a density of 1.26. Each 4 ml of this solution were coated in centrifuge tubes (rotor SW-40) with 4 ml of a 1.21 density solution as well as 4.5 ml of a solution of 1.063 (buffer density solutions PDB and NaBr). ) and centrifuged for 24 h at 38,000 rpm and 20 ° C in the SW-40 rotor. The intermediate layer containing the labeled HDL that was between the 1.063 and 1.21 density was dialyzed against 3 * 100 volumes of PDB buffer at 4 ° C.

The retentate contained radiolabelled 3H-CE-HDL that was adjusted to ca. 5 x 106 cpm for me to be used in the trial. CETP assay For the assay of CETP activity, the transfer of H3-cholesterol ester from HD human lipoproteins to LDL-biotinylated lipoproteins was measured. The reaction was terminated by adding streptavidin-SPAR beads (Fa.Amershan) and the radioactivity transferred directly was determined in a liquid scintillation counter. The test mixture of 10 μl of HDL-3H-cholesterol ester (approximately 50,000 cpm) with 10 μl of biotin-LDL (Fa.Amershan) in 50 mM Hepes / NaCl 0, 15 M / 0, 1% bovine serum albumin / 0.05% NaN3, pH 7.4 was incubated for 18 h at 37 ° C with 10 μl of CETEP (1 mg / ml) and 3 μl of the substance to be tested (dissolved in 10% DMSO / 1% RSA). Next, 200 μl of the solution of SPS-streptavidin beads (TRKQ 7005) was added, incubation was continued with stirring for 1 h and then measured in a scintillation counter. Controls serve corresponding incubations with 10 μl of buffer, 10 μl of CETEP at 4 ° C as well as 10 μl of CETEP at 37 ° C.

The activity transferred in the control mixtures with CETEP at 37 ° C was evaluated as 100% transfer. The concentration of substance to which this transfer was reduced by half is indicated as CIS0 value. The IC50 values (mol / 1) for CETP inhibitors are indicated in Table A below. Table A: Ex vivo activity of the compounds according to the invention Drug (0.8 mg / kg of atropine, 0.8 mg / kg Ketavet® sc, 30% later 50 mg / kg of nembutal ip) Syrian golden hamsters of own breeding of 24 hours of fasting. Then he prepared himself by leaving the jugular vein free and he was cannulated. The test substance was dissolved in a suitable solvent (as a rule, Adalat placebo solution: 60 g of glycerin, 100 ml of H0, ad 1000 ml of PEG-400) and administered to the animals through a PE catheter. introduced into the jugular vein. The control animals receive the same volume of solvent without test substance. The vein is then ligated and the wound closed. The administration of the test substances can also be carried out p.o. orally administered the dissolved substances in DMSO and with 0.5% of suspended tylose by means of an esophageal probe. The control animals received identical volume of solvent without test substance. After various time lapses - up to 24 hours after administration - blood was taken from the animals of the retro-orbital venous plexus by puncture (approximately 250 μl). The coagulation was completed by incubation at 4 ° C overnight, then centrifuged for 10 minutes at 6000 x g. In the serum thus obtained, the CETP activity was determined by the modified CETP assay. The transfer of H3-cholesterol ester of HD-lipoproteins to LD-biotinylated lipoproteins was measured, as in the CETP assay described above. The reaction was terminated by adding streptavidin-SPAR beads (Fa.Amershan) and the radioactivity transferred directly was determined in a liquid scintillation counter. The test mixture was prepared as described in the "CETP'A assay Only 10 μl of CETP were substituted for the serum assay by 10 μl of the corresponding serum sample.As appropriate controls, incubations with animal sera were used. The activity transferred in the control mixtures with control sera was evaluated as 100% transfer The concentration of substance to which this transfer is reduced by half is indicated as DE50 value In vivo activity of the compliant compounds In the tests for the determination of the oral activity on lipoproteins and triglycerides, the test substances dissolved in DMSO and with 0.5% of tylose suspended by means of an esophageal tube were perorally administered to Syrian golden hamsters of their own rearing. determination of CETP activity was taken before the start of the blood test by retro-orbital puncture (approximately 250 μl). The test substances were administered perorally by an esophageal probe. The control animals receive identical volume of solvent without test substance. Then the food is removed from the animals and at different time intervals - up to 24 hours after the administration of the substance - blood was taken from the animals of the retro-orbital venous plexus by puncture. The coagulation was completed by incubation at 4 ° C overnight, then centrifuged for 10 minutes at 6000 x g. In the serum thus obtained, the content of cholesterol and triglycerides was determined by modified commercial enzymatic assays (enzymatic cholesterol 14366 of Merck, triglycerides 14364 of Merck). The serum was diluted adequately with normal salt solution. 100 μl of serum dilution was mixed with 100 μl of test substance in 96-well plates and incubated for 10 min at room temperature. Next the optical density was determined at a wavelength of 492 nm with an automatic plate reader apparatus. The concentration of triglycerides or cholesterol contained in the samples was determined using a standard curve measured in parallel. The determination of the cholesterol content of HDL was carried out after precipitation of the lipoproteins containing ApoB by means of a reaction mixture (HDL cholesterol reagent Sigma 352-4) following the manufacturer's instructions. In vivo activity in transgenic hCETP mice. Transgenic mice of their own breeding were administered (Dinchuck, Hart, González, Karmann, Schmidt, Wirak; BBA (1995), 1295, 301) the substances to be tested with the feed.

Retroorbital blood was taken from the mice to determine cholesterol and triglycerides in the serum before the test was started. Serum was obtained as described above for hamsters by incubation at 4 ° C overnight and subsequent centrifugation at 6000 x g. After a week, the mice were again bled to determine lipoproteins and triglycerides. The variation of the measured parameters was expressed as a percentage variation compared to the starting value. The invention also relates to the combination of benzylbiphenylenes of general formula (I) with a glucosidase and / or amylase inhibitor for the treatment of familial hyperlipidemias, obesity (adiposity) and diabetes mellitus. They are inhibitors of the glucosidases and / or amylases in the framework of the invention, for example, acarbose, adiposine, voglibose, miglitol, emiglitato, MDL-25637, camiglibose (MDL-73945), tendamistate, AI-3688, trestatin, pradimicine Q and salbostatin. The combination of acarbose, miglitol, emiglitate or voglibose with one of the aforementioned compounds according to the invention of general formula (I) is preferred.

In addition, the compounds according to the invention can be combined with vastatins that reduce cholesterol or with principles that reduce ApoB to treat dyslipidemias, combined hyperlipidemias, hypercholesterolemias or hypertriglyceridemia. The combinations indicated can also be used for the prevention of primary or secondary coronary heart diseases (eg myocardial infarction). They are vastatins within the scope of the invention, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin. They are agents that reduce ApoB, for example, inhibitors of MTP. The combination of cerivastatin or ApoB inhibitors with one of the compounds according to the invention of general formula (I) and (la) is preferred. The new active ingredients can be transferred in a known manner to the usual formulations, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable vehicles or solvents. In this regard, the therapeutically active compound should be present at a respective concentration of about 0.5 to 90% by weight of the total mixture, ie in amounts that are sufficient to reach the indicated dosage range. The formulations are prepared, for example, by cutting the active principle with solvents and / or excipients, optionally using emulsifiers and / or dispersants, and can be used, for example, in the case of using water as a diluent, if necessary, solvents. organic as adjuvant solvents. Administration is usually carried out intravenously, orally, parenterally or perlingually, especially orally. In the case of parenteral use, solutions of the active principle can be used using suitable liquid vehicles. In general it has been found advantageous in intravenous administration to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight to achieve effective results, and in oral administration dosage reaches from about 0.01 to 20 mg / kg, preferably from 0.1 to 10 mg / kg of body weight. However, if necessary, it may be necessary to deviate from the indicated amounts, specifically depending on the body weight or type of route of administration, the individual behavior against the drug, the type of formulation and the time or interval at which it is administered. perform the administration. Thus, in some cases, less than the aforementioned minimum amount may suffice, while in other cases the limits indicated above must be exceeded. In the case of the administration of larger quantities it is advisable to divide this into several individual doses throughout the day.

Starting compounds Example I 4-Methyl-1- (4-trifluoromethyl-phenyl) -pentan-3-one At 40 g (0.312 mol) of N, N-dimethyl-N-. { 2-methyl-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -propylidene} -hydrazine (S. D. Sharma et al., J. Org. Chem. 1990, 55, 2196) in 400 ml of THF abs. at 0 ° C was added dropwise over the course of 30 min 131 ml (0.328 mol) of a 2.5 M solution of nBuLi in n-hexane and was stirred for 30 min at 15-20 ° C. 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 was stirred for 2 h at 20 ° C. The reaction mixture was concentrated to ca. 80 ml and hydrolyzed carefully with 200 ml of H20. After extraction with ethyl acetate, it was washed with saturated NaCl solution, dried over Na 2 SO 4 and concentrated. 82 g of N, N-dimethyl-N- were obtained. { 2-methyl-1- [2- (4-trifluoromethyl-phenyl) -ethyl] -propylidene} -hydrazine in the form of a red oil. The hydrazone was dissolved in 150 ml of THF and mixed with 170 ml of 2 M HCl and stirred for 1 h at 20 ° C. It was extracted with EtOAc, washed with water and saturated NaCl solution, dried over Na2SO4 and concentrated. Distillation gave a colorless oil (b.p. 95-98 ° C / 0.7 mbar). Yield: 51.5 g (78%) Rf = 0.25 (EtOAC / EP 1:20) Example II 1- (4-Fluoro-phenyl) -l-hydroxy-4-methyl-2- (4-trifluoromethyl- benzyl) -pentan-3-one To 184 g (0.753 mol) of the compound of Example I in 1.2-1 of THF abs. 400 ml of a 2.0 M solution of LDA in THF / heptane was added at -70 ° C over the course of 50 min and stirred for 60 min at -70 ° C. Subsequently, 81 ml (0.753 mol) of 4-fluorobenzaldehyde were added and the mixture was stirred for a further 60 minutes at -70 ° C. It was quenched with 100 ml of a 10% NH 4 Cl solution, allowed to warm to -10 ° C and another 400 ml of a 10% NH 4 Cl solution was added. The phases were separated, extracted with EtOAc, washed with sat. NaCl, dried over Na2SO4 and concentrated. The crude product was purified through silica gel 60 (EtOAc / EP 1: 5). Yield: 253 g (91%) Rf = 0.31 (EtOAc / EP 1: 5) Example III 1- (4-Fluoro-phenyl) -4-methyl-2- (4-trifluoromethyl-benzyl) -pent-1 -3-in-3-one To 279 g (0.76 mmol) of the compound of Example II in 2.5 1 of CHC1_ abs. 231 ml (1,672) mol) of tritylamine and 118 ml (1.52 mol) of methanesulfonyl chloride were added at 0 ° C. It was stirred overnight at 20 ° C and 456 ml (3.04 mol) of DBU dissolved in 1 1 of CH2C12 abs were added at -30 ° C. After 90 min it was extinguished with 500 ml of water. The phases were separated and the aqueous phase was extracted with CH2C12. The combined organic phases were washed with 0.5 M HCl, dried over Na 2 SO 4 and concentrated. The crude product was purified on silica gel 60 (cyclohexane / EtOAc 40: 1 to 10: 1). Yield: 220 g (83%) Rf = 0.27 (EtOAc / EP 1:20). Example IV l-Fluoro-4- (3-isopropyl-2- (4-trifluoromethyl-benzyl) -buta-1,3-dienyl) -benzene To 20 g (5.71 mmol) of the compound of Example III in 100 ml of abs. 47.6 g (114.2 mmol) of a mixture of methyltriphenylphosphonium bromide and sodium amide in 200 ml of abs. ether were added at 0 ° C. After 90 min 300 ml of petroleum ether were added and filtered with suction through a little silica gel. It was then washed with 2 1 of PE and concentrated. The crude product was purified on silica gel 60 (cyclohexane / EtOAc 20: 1 to 10: 1). Yield: 9.1 g (44%) R ^ f - 0.35 (EP) Example V 6- (4-Fluoro-phenyl) -4-isopropyl-5- (4-trifluoromethyl-benzyl) - methyl ester cyclohexa-1,4-diene carboxylic acid To 3.0 g (8.61 mmol) of the compound of Example IV in 15 ml of xylene abs. 7.66 ml (86.1 mmol) of methyl propiolate were added and heated in a closed autoclave for 20 h at 180 ° C. The mixture was then concentrated with silica gel in vacuo and purified through 80 g of silica gel (elution with cyclohexane and cyclohexane / EtOAc 20: 1, 10: 1). Yield: 2.68 g (70%) Rf = 0.36 (EtOAc / EP 1:20). EXAMPLE VI 4'-Fluoro-5-isopropyl-6- (4-trifluoromethyl-1-benzyl) -biphenyl-2-carboxylic acid methyl ester In 10 ml of toluene 149 mg (0.34 mol) of the compound of Example V and 472 mg (2.08 mmol) of DDQ were dissolved and refluxed overnight. Concentrate and purify on silica gel (cyclohexane / EtOAc 20: 1). Yield: 122 mg (82%) Rf = 0.22 (EtOAc / EP 1:20). Example VII [4'-Fluoro-5-isopropy1-6- (4-trifluoromethyl-1-benzyl) -biphenyl-2-yl] -methanol They were dissolved in 5 ml of toluene abs. 46 mg (0.11 mmol) of the compound of Example VI and mixed at -78 ° C with 600 μl (0.9 mmol) of a 1.5 M solution of DIBAH in toluene. It was stirred for 1 h at this temperature, allowed to warm to room temperature and then stirred for 1 h. It was quenched with water and extracted with EtOAc. The combined organic phases were dried over Na 2 SO and concentrated. The crude product was purified on silica gel 60 (petroleum ether / EtOAc 2: 1). Yield: 25 mg (58%) Rf = 0.28 (EtOAc / petroleum ether 1: 5). Example VIII 3- (4-Fluoro-phenyl) -5-isopropyl-4- (4-trifluoromethyl-benzyl) -cyclohexa-1,4-dien-1,2-dicarboxylic acid dimethyl ester To 22.25 g (63.9 mmol) of the compound of Example IV in 400 ml of abs. Toluene. 36.3 g (255 mmol) of dimethyl acetylenedicarboxylate were added and heated to reflux for 48 h. The remaining dimethyl acetylenedicarboxylate was concentrated and distilled in vacuo. The crude product was then purified on silica gel (CHC12). Yield: 23.9 g (77%) Rf = 0.39 (CH2C12) Example IX Dimethyl ester of 4 '-fluoro-5-isopropyl-β- (4-trifluoroethyl-benzyl) -biphenyl-2, 3- acid dicarboxylic 250 ml of toluene, 23.9 g (50 mmol) of the compound of Example VIII and 22.2 g (100 mmol) of DDQ were dissolved and refluxed overnight. Concentrate and purify on silica gel (CH, C1) Yield: 19.9 g (81%) Rf = 0.37 (CH_C1 Example X [4'-Fluoro-5-isopropyl-2- (tetrahydro-pyran 2-yloxymethyl) -6- (4-trifluoromethyl-benzyl) -bifinyl-3-yl] -carbaldehyde To 2.10 g (4.06 mmol) of the compound of Example 2 dissolved in 100 ml of abs. CH2C12. 830 mg of Al203 (neutral) and 1.31 g (6.11 mmol) of pyridinium chlorochromate were added in 3 portions over the course of 60 minutes. After 1 h, it was filtered through A1203 and then washed with CH2C12. The subsequent purification was carried out on silica gel 60 (CH2C12). Yield: 1.84 g (87%) Rf 0.39 (EtOAc / EP 1: 5).

Preparation examples Example 1 [4'-Fluoro-3-hydroxymethyl-5-isopropyl-6- (4-trifluoromethyl-benzyl) -bifinyl-2-yl] -methanol They were dissolved in 60 ml of abs. Toluene. 2.2 g (4.5 mmol) of the compound of Example IX were added and mixed at -78 ° C with 60 ml (90 mmol) of a 1.5 M solution of DIBAH in toluene. It was stirred for 1 h at this temperature, allowed to warm to room temperature and then stirred for 1 h. It was poured onto ice and extracted with EtOAc. The combined organic phases were dried over Na 2 SO 4 and concentrated. The crude product was purified on silica gel 60 (CH2Cl2 / MeOH 100: 3). Yield: 1.82 g (93%) Rf = 0.20 (CH2Cl2 / MeOH 100: 3). Example 2 [4'-Fluoro-5-isopropyl-2- (tetrahydro-pyran-2-yloxymethyl) -6- (4-trifluoromethyl-benzyl) -biphenyl-3-yl] -methanol 300 ml of CH2C12 were dissolved in 15.5 g (35.2 mmol) of the compound of Example 1, 7.2 g (105 mmol) of imidazole and 11 ml (42 mol) of tert-butyl-diphenyl-chlorosilane (TBDPS). ) and was stirred for 90 min at room temperature. It was quenched with water, extracted with CH2C12, dried over Na2SO4 and concentrated. The crude product was purified on silica gel 60 (cyclohexane / EtOAc 100: 1 to 20: 1). There were obtained 17.8 g (26.4 mmol, 75%) of [3-tert-butyl-diphenylsiloxymethyl-4'-fluoro-5-isopropyl-6- (4-trifluoromethyl-benzyl) -biphenyl-2-yl] -metanol (Rf = 0.52 in CH2C1). This compound was dissolved in 220 ml of CH2C12 abs. and 3.32 g (13.2 mmol) of pyridinium p-toluenesulfonate (PPTS) and 12.1 ml (132 mmol) of 3,4-dihydropyran were added. After 60 min at room temperature, water was added and extracted with CH2C12. The combined organic phases were washed with sat. of NaHCO3 and water, dried over NaSO4 and concentrated. 19.6 g (26 mmol, 98%) of the compound protected with THP were obtained (Rf = 0.22, EtOAc / EP 1:20). This compound was dissolved in 250 ml of THF abs. 24.3 g (77 mmol) of tetra-n-butylammonium fluoride, trihydrate, (TBAFx3H20) were added and stirred for 90 min at room temperature. Water was added and extracted with EtOAc. The combined organic phases were washed with sat. NaHCO 3 and water were dried over Na 2 SO 4 and concentrated. The purification was carried out on silica gel 60 (cyclohexane / EtOAc 20: 1 to 2: 1). Yield: 11.3 g (85%) Rf = 0.54 (EtOAc / EP 1: 2) Example 3 [3-Benzyloxymethyl-4'-fluoro-5-isopropyl-β- (4-trifluoromethyl-benzyl) -biphenyl -2-il] -methanol They were suspended in 3 ml of THF abs. 12 mg (0.48 mmol) of sodium hydride and 8 mg of tetra-n-butyl-ammonium iodide and a solution of 50 mg (0.1 mmol) of the compound of Example 2 was added dropwise in 1 ml of THF abs. After 30 minutes, 14 μl (0.115 mmol) of benzyl bromide was added and stirred overnight. After adding water, it was extracted with EtOAc, dried over Na2SO4 and concentrated. The purification was carried out on silica gel 60 (cyclohexane / EtOAc 5: 1). 70 mg of the compound protected with THP were obtained. This was dissolved in methanol and mixed with 300 mg of pyridinium p-toluenesulfonate (PPTS). After 2 h of stirring at room temperature, water was added, extracted with EtOAc, dried over Na 2 SO 4 and concentrated. The purification was carried out on silica gel 60 (cyclohexane / EtOAc 5: 1). Yield: 35 mg (58%) Rf = 0.56 (EtOAc / EP 1: 5) Example 4 [4'-Fluoro-3- (4-fluoro-phenoxymethyl) -5-isopropy1-6- (4-trifluoromethyl- benzyl) -biphenyl-2-yl] -methanol To the ether. THF (3: 1) 150 mg (0.29 mmol) of the compound of Example 2, 99 mg (0.38 mmol) of triphenylphosphine and 49 mg (0.435 mmol) of 4-flurophenol were dissolved in ether. and 59 μl (0.38 mmol) of diethyl azodicarboxylate was added dropwise over the course of 15 minutes. After 30 minutes at room temperature, it was concentrated in vacuo and purified on silica gel 60 (cyclohexane / EtOAc 20: 1). 156 mg (83%) of the compound protected with THP were obtained. This was dissolved in methanol and mixed with 300 mg of pyridinium p-toluenesulfonate (PPTS). After 2 h of stirring at room temperature, water was added, extracted with EtOAc, dried over Na 2 SO 4 and concentrated. The purification was carried out on silica gel 60 (cyclohexane / EtOAc 5: 1). Yield: 75 mg (79%) Rf = 0.40 (EtOAc / EP 1: 5) Example 5 2- [4'-Fluoro-2-hydroxymethyl-5-isopropyl-6- (-trifluoromethyl-benzyl) -biphenyl- 3-ylmethyl] -isoindole-1,3-dione 4 ml of ether / THF (3: 1) were dissolved in 150 ml (0.29 mmol) of the compound of Example 2, 99 mg (0.38 mmol) of triphenylphosphine and 64 mg (0.435 mmol) of phthalimide were added. dropwise 59 μl (0.38 mmol) of diethyl azodicarboxylate over the course of 15 minutes. After 30 minutes at room temperature, it was concentrated in vacuo and purified on silica gel '60 (cyclohexane / EtOAc 5: 1). 134 mg (72%) of the compound protected with THP was obtained. This was dissolved in 12 ml of acetic acid / THF / water (4.2: 1) and stirred for 18 h at 45 ° C. Concentrate in vacuo and purify on silica gel 60 (CH2Cl2 / MeOH 100: 3). Yield: 74 mg (69%) Rf = 0.39 (CH2Cl2 / MeOH 100: 3). Example 6 [3-Cyclopentylidenemethyl-4'-fluoro-5-isopropyl-1-6- (4-trifluoromethyl-benzyl) -bifinyl-3-yl] -methanol To 480 mg (1.16 mmol) of methyltriphenylphosphonium bromide in 40 ml of abs. 0,63 ml (1.0 mmol) of a 1.6 M solution of n-BuLi in n-hexane was added at 0 ° C and then stirred for 2 h at 20 ° C. 100 mg (0.19 mmol) of the compound of Example X dissolved in 10 ml of abs ether were added. After 90 min petroleum ether was added and filtered with suction through a little silica gel. It was washed with petroleum ether and concentrated. The crude product was purified on silica gel 60 (toluene). 88 mg (80%), Rf = 0.42 (toluene) of the compound protected with THP were obtained. 70 mg of this were dissolved in methanol and mixed with 300 mg of pyridinium p-toluenesulfonate (PPTS). After 2 h of stirring at room temperature, water was added, extracted with EtOAc, dried over Na 2 SO 4 and concentrated. The purification was carried out on silica gel 60 (cyclohexane / EtOAc 10: 1). Yield: 49 mg (81%) Rf = 0.19 (EtOAc / EP 1:10). Example 7 [3-Cyclopentylmethyl-4'-fluoro-5-isopropyl-6- (4-trifluoromethyl-benzyl) -biphenyl-3-yl] -methanol To 20 mg (0.04 mmol) of the compound of Example 6, dissolved in 5 ml of EtOAc, was added 20 mg of Pt / C (5%) and hydrogenated in the presence of hydrogen at normal pressure for 5 h. It was filtered through a membrane filter and concentrated. The subsequent purification was carried out on silica gel 60 (EtOAc / EP 1:10). Yield: 19 mg (96%) Rf = 0.20 (EtOAc / EP 1:10).

Analogously to that described in Examples 1-7, the compounds listed in Table 1 were prepared: It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (11)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Compounds of general formula (1), characterized because; A represents cycloalkyl of 3 to 8 carbon atoms, or represents aryl of 6 to 10 carbon atoms, or represents a 5- to 7-membered heterocycle, saturated, partially unsaturated or unsaturated, optionally benzo-condensed, with up to 4 heteroatoms of the series of S, N and / or O, where appropriate, aryl and the above-mentioned heterocyclic ring systems up to pentasubstituted in the same or different manner with cyano, halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoromethoxy or with alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy, straight-chain or branched, of up to 7 carbon atoms each, or with a group of formula -NR3R4, wherein R3 and R4 are the same or different and mean hydrogen, phenyl or straight or branched chain alkyl of up to 6 carbon atoms, represents a residue of formula in which R5, R6 and R9 stand for independently from each other aryl of 6 to 10 carbon atoms or a 5- to 7-membered heterocycle, optionally benzo-condensed, saturated or unsaturated, mono, bi or tricyclic with up to 4 heteroatoms of the series of S, N and / or O, the cycles being, if necessary, also through the function N in the case of rings containing nitrogen, until pentasubstituted in the same or different manner with halogen, trifluoromethyl, nitro, hydroxy, cyano, carboxyl, trifluoromethoxy, acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or straight chain or branched alkoxycarbonyl with up to 6 carbon atoms each, with aryl or aryl substituted with trifluoromethyl of 6 to 10 carbon atoms in each case or with an aromatic heterocycle of 5-7 links, optionally benzo-condensed, with up to 3 heteroatoms of the S, N and / or O series, and / or with a group of the formula -OR10, -SR11, -S02R12 or -NR13R14, where R10, R11 and R12 stand independently With each other aryl of 6 to 10 carbon atoms, which in turn is even disubstituted in the same or different way with phenyl, halogen or with straight or branched chain alkyl of up to 6 carbon atoms, R13 and R14 are the same or different and have the above-indicated meaning of R3 and R4, or R5 and / or R6 mean a residue of formula R means hydrogen, halogen or methyl, and R "means hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromethoxy, alkoxy or straight-chain or branched alkyl with up to 6 carbon atoms each or a residue of formula -NR15RA wherein R15 and R are the same or different and have the above-indicated meaning of R3 and R4, or R7 and R8 together form a residue of formula = 0 or = NR17, in which R17 means hydrogen or straight chain or branched alkyl, alkoxy or acyl with up to 6 carbon atoms each, L means a straight or branched alkylene or alkenylene chain with up to 8 carbon atoms each, which if appropriate they are even disubstituted with hydroxy, T and X are the same or different and mean a linear or branched alkylene chain with up to 8 carbon atoms, or T or X means a bond, V represents an oxygen or sulfur atom or represents a group -NR1S, wherein R1"signifies hydrogen or straight or branched chain alkyl with up to 6 carbon atoms or phenyl, E represents cycloalkyl of 3 to 8 carbon atoms, or represents straight or branched chain alkyl with up to 8 carbon atoms which, if appropriate, are substituted by cycloalkyl of 3 to 8 carbon atoms or hydroxy, or represents phenyl which is optionally substituted with halogen or trifluoromethyl, R 1 represents alkyl linear or branched DNA with up to 6 carbon atoms that is substituted with hydroxy or with a group of formula R 2 represents hydrogen or straight-chain or branched alkyl or alkenyl with up to 8 carbon atoms in each case, which optionally are substituted with hydroxy, halogen, phenyl, cycloalkyl of 3 to 6 carbon atoms or with a group of formula wherein R19 means a residue of the formula -Si (CH3) 2C (CH3) 3, or means straight or branched chain alkyl with up to 6 carbon atoms, or means a saturated, partially unsaturated or unsaturated, 5- to 7-membered heterocycle with up to 3 heteroatoms of the series of S, N and / or 0, or means phenyl or benzyl, all the cyclic systems listed under R19 possibly being disubstituted in the same or different way with trifluoromethyl, fluorine, nitro, hydroxy, alkoxy or straight chain or branched alkoxycarbonyl with up to 4 carbon atoms in each case or with straight or branched chain alkyl of up to 4 carbon atoms, which optionally is substituted with hydroxy, and their salts.

2. Compounds of formula (I) according to claim 1, characterized in that; A represents naphthyl, phenyl, pyridyl, thienyl, imidazolyl, pyrryl or morpholine, which optionally are disubstituted in the same or different manner with fluorine, chlorine, bromine, amino, hydroxy, trifluoromethyl, trifluoromethoxy or with alkyl or chain alkoxy. linear or branched with up to 6 carbon atoms each, represents phenyl which is optionally substituted with nitro, fluoro, chloro, bromo, phenyl, trifluoromethyl or trifluoromethoxy, or represents a radical of formula wherein R5, R6 and R9 independently signify phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl, quinolyl or purin-8- ilo, the cycles being, if necessary, also through the function N in the case of rings containing nitrogen, up to trisubstituted in the same or different way with fluorine, chlorine, bromine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy , acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or straight chain or branched alkoxycarbonyl with up to 4 carbon atoms each, triazolyl, tetrazolyl, benzoxathiazolyl, or phenyl substituted with trifluoromethyl or phenyl, and / or are substituted with a group of formula -OR10, -SR11 or -S02R12, in which R10, R11 and R12 are the same or different and means -phenyl, which in turn is even disubstituted in the same or different way with phenyl, fluorine, chlorine or with alkyl ilo of straight or branched chain of up to 4 carbon atoms, R5 and / or R6 mean a residue of the formula R means hydrogen, fluorine, chlorine or bromine, and Re means hydrogen, fluorine, chlorine, bromine, azide, trifluoromethyl, hydroxy, trifluoromethoxy, alkoxy or straight-chain or branched alkyl with up to 5 carbon atoms each or a radical of formula - RI5R1,:, wherein R1- and R1- are the same or different and denote hydrogen, phenyl or straight or branched chain alkyl with up to 4 carbon atoms, or R-1 and R9 together form a radical of formula = 0 or = NR17, wherein R17 means hydrogen or straight chain or branched alkyl, alkoxy or acyl with up to 4 carbon atoms each, L means a straight or branched alkylene or alkenylene chain with up to 6 carbon atoms each, which, if appropriate, are even disubstituted with hydroxy, T and X are the same or different and mean a linear or branched alkylene chain with up to 6 carbon atoms, or T or X means a bond, V represents an oxygen or sulfur atom or represents u n group of formula -NR18, wherein R18 means hydrogen or straight or branched chain alkyl with up to 4 carbon atoms or phenyl, E represents cyclopropyl, -butyl, -pentyl, -hexyl or -heptyl, or represents chain alkenyl linear or branched with up to 6 carbon atoms which may be substituted with cyclopropyl, -butyl, -hexyl, • -pentyl, -heptyl or with hydroxy, or represents phenyl which is optionally substituted with fluorine, chlorine or trifluoromethyl, R1 represents a group of formula -CH20H or R 2 represents hydrogen or straight-chain or branched alkyl or alkenyl with up to 6 carbon atoms in each case, which optionally are substituted with hydroxy, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or with a group of formula wherein R19 means a residue of the formula -Si (CH3) 2C (CH3) 3, or means straight or branched chain alkyl with up to 5 carbon atoms, or means tetrahydropyranyl, pyridyl, phenyl or benzyl, which may be even disubstituted in the same or different manner with straight chain or branched trifluoromethyl, fluoro, nitro, hydroxy, alkoxy or alkoxycarbonyl with up to 3 carbon atoms in each case or with straight or branched chain alkyl of up to 3 carbon atoms given the case is substituted with hydroxy, and its salts.

3. Compounds of formula (I) according to the claim 1, characterized in that; A represents phenyl or pyridyl, which, if appropriate, are disubstituted in the same or different manner with fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy or with straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, D represents phenyl which is optionally substituted with nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or represents a radical of formula R5-L- R9-TV ~ X- in which R5, R6 and R9 stand for phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxythyn-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl, the cycles being, if appropriate, also through the N function in the case of rings containing nitrogen, up to trisubstituted in the same or different way with fluorine, chlorine, trifluoromethyl , hydroxy, cyano, carboxyl, trifluoromethoxy, alkyl, alkylthio, alkylalkoxy, alkoxy or straight chain or branched alkoxycarbonyl with up to 4 carbon atoms each, triazolyl, tetrazolyl, benzothiazolyl, phenyl substituted with trifluoromethyl or phenyl, and / or are substituted with a group of formula -OR10, in which R10, Rn and R ?: are the same or different and mean phenyl, which in turn is even disubstituted in the same or different way with phenyl, fluorine, chlorine or with chain alkyl eal or branched of up to 3 carbon atoms, or R5 and / or R6 mean a residue of formula R7 is hydrogen or fluorine, and R8 is hydrogen, fluorine, chlorine, bromine, azide, trifluoromethyl, hydroxy, trifluoromethoxy, or straight or branched chain alkoxy or alkyl with up to 4 carbon atoms each or a radical of formula -NR15R16, wherein R15 and R16 are the same or different and mean hydrogen or straight or branched chain alkyl with up to 3 carbon atoms, R1 and R9 together form a moiety of formula = 0 or = NR in which R17 means hydrogen or straight chain or branched alkyl, alkoxy or acyl with up to 4 carbon atoms each, L means a linear alkylene or alkenylene chain or branched with up to 5 carbon atoms each, which, if appropriate, are even disubstituted with hydroxy, T and X are the same or different and mean a linear or branched alkylene chain with up to 3 carbon atoms, T or X means a bond, V represents an oxygen or sulfur atom or represents a group of formula -NR18, in which R18 means hydrogen or straight or branched chain alkyl with up to 3 carbon atoms, E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl, which optionally is substituted with fluorine or trifluoromethyl, or represents straight or branched chain alkyl with up to 4 carbon atoms which optionally is substituted with hydroxy, represents a group of formula -CH20H or R- represents hydrogen or straight-chain or branched alkyl or alkenyl with up to 5 carbon atoms in each case, which optionally are substituted with hydroxy, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or with a formula group wherein R19 means straight or branched chain alkyl with up to 4 carbon atoms, or means a radical of formula -Si (CH3) 2C (CH3) 3, or means tetrahydropyranyl, pyridyl, phenyl or benzyl, which are optionally until disubstituted in the same or different manner with straight chain or branched trifluoromethyl, fluoro, chloro, nitro, hydroxy, alkoxy or alkoxycarbonyl with up to 3 carbon atoms in each case or with straight or branched chain alkyl of up to 3 carbon atoms which, if necessary, is substituted with hydroxy, and its salts.

4. Compounds of formula (I) according to claim 1 characterized in that; A represents phenyl or pyridyl, which, if appropriate, are disubstituted in the same or different manner with fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy or with straight-chain or branched alkyl or alkoxy with up to 5 carbon atoms each, D represents phenyl which is optionally substituted with nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or represents a radical of formula wherein R-, R- and R "signify independently phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl, the cycles being, if appropriate, also through the N function in the case of rings containing nitrogen, up to trisubstituted in the same or different way with fluorine, chlorine, trifluoromethyl, hydroxy, cyano, carboxyl , trifluoromethoxy, alkyl, alkylthio, alkylalkoxy, alkoxy or straight chain or branched alkoxycarbonyl with up to 4 carbon atoms each, triazolyl, tetrazolyl, benzothiazolyl, phenyl substituted with trifluoromethyl or phenyl, and / or are substituted with a group of formula OR10, -SR11 or -S02R12, in which R10, R11 and R12 are the same or different and mean phenyl, which in turn is even disubstituted in the same or different way with phenyl, fluorine, chlorine or with alkyl of the chain neal or branched of up to 3 carbon atoms, or R5 and / or Re mean a radical of formula, R7 represents hydrogen or fluorine, and Re means hydrogen, fluorine, chlorine, bromine, azide, trifluoromethyl, hydroxy, trifluoromethoxy, or alkoxy or straight chain or branched alkyl with up to 4 carbon atoms each or a radical of formula -NR 15 R 6 e, wherein R 15 and R 1c are the same or different and mean hydrogen or straight or branched chain alkyl with up to 3 carbon atoms , R7 and R8 together form a residue of formula = 0 or = NR17, wherein R17 means hydrogen or straight or branched chain alkyl, alkoxy or acyl with up to 4 carbon atoms each, L means a straight or branched alkylene or alkenylene chain with up to 5 carbon atoms each, which if appropriate they are even disubstituted with hydroxy, T and X are the same or different and mean a linear or branched alkylene chain with up to 3 carbon atoms, or T or X means a bond, V represents an oxygen or sulfur atom or represents a group of the formula -NR18, in which R18 is hydrogen or straight or branched chain alkyl with up to 3 carbon atoms, E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl, which optionally is substituted with fluorine or trifluoromethyl, or represents straight or branched chain alkyl with up to 4 carbon atoms which is optionally substituted with hydroxy, R 1 represents a group of formula -CH 2 H or R 2 represents hydrogen or straight-chain or branched alkyl or alkenyl with up to 5 carbon atoms in each case, which optionally are substituted with hydroxy, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or with a group of formula 0? ? > wherein R19 means straight or branched chain alkyl with up to 4 carbon atoms, or means a radical of formula -Si (CH3) 2C (CH3) 3, or means tetrahydropyranyl, pyridyl, phenyl or benzyl, which are optionally even disubstituted in the same or different way with straight chain or branched trifluoromethyl, fluoro, chloro, nitro, hydroxy, alkoxy or alkoxycarbonyl with up to 3 carbon atoms in each case or with straight or branched chain alkyl of up to 3 carbon atoms if necessary, it is substituted with hydroxy, and its salts.

5. Compounds according to claim 1 for use in the treatment of diseases.

6. Processes for the preparation of compounds according to claim 1, characterized in that compounds of general formula (II) are reacted, wherein A, D and E have the meaning indicated above, in the system (C6H5) 3PCH3Br / n-butyl lithium to obtain first the compounds of general formula (III), wherein A, D and E have the meaning indicated above, they are then transformed with compounds of general formula (IV) or (IVa), 20 R20-O2C- -CO2R (IV) wherein R- R20 'and R: r "are the same or different and represent straight or branched chain alkyl with up to 4 carbon atoms, and R: represents hydrogen or straight or branched chain alkyl with up to 6 carbon atoms, which is optionally substituted with hydroxy, phenyl, straight or branched chain alkoxy with up to 6 carbon atoms, amino, alkyl or dialkylamino with up to 4 carbon atoms in the alkyl part, in the compounds of general formula (V), wherein A, D and E have the meaning indicated above, R20"'comprises the above-indicated significance range of R20' and R20", and R22 represents either hydrogen or the residue -C02 R20", or comprises the scope of meanings above indicated of R21, by oxidation the compounds of formula (VI) are obtained wherein A, D, E, R-, R20"'and R- have the above-mentioned meaning, and finally the carbonyl functions are extruded to the hydroxymethyl function, and derivatizations are carried out in the substituent R2 starting from compounds of the general formula (the) wherein A, D and E have the meaning indicated above, depending on the above-mentioned meaning of R 2 in the system P (HC 5) 3 / diethyl azodicarboxylate and the correspondingly defined alcohols or amines are transformed under R 19, or a etherification by reaction with alkyl halides in the presence of a base, and finally in both derivatizations the hydroxy protecting group with acids is eliminated, or in the case of R- = alkenyl, the compounds of general formula (a) are transformed in the first place in aldehydes of general formula (VII) wherein A, D and E have the meaning indicated above, and in a second step a Wittig reaction is carried out by customary methods, the hydroxy protecting group is removed as described above and finally reduced to the corresponding alkyl compounds (R2 = alkyl) by hydrogenation in the presence of a catalyst.

7. Medicaments containing at least one compound according to claim 1 as well as pharmacologically acceptable formulation adjuvants.

8. Medicaments according to claim 7 for the treatment of hyperlipoproteinemias.

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

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

11. Use according to claim 10 for the manufacture of medicaments for the treatment of arteriosclerosis, in particular of dyslipidemias. Benzyl-biphenyls and analogous compounds and their use for the treatment of arteriosclerosis and dyslipidemias Summary of the invention The benzyl biphenyls and their analogous compounds are prepared by first reacting ketones, β-unsaturated to obtain the corresponding substituted conjugated dienes and then cyclizing them with acetylenic derivatives, the cyclohexanedienes thus formed are oxidized to the corresponding aromatic compounds and optionally the substituents present are varied by customary methods. The compounds are suitable as active ingredients in medicaments, especially in medicaments for the treatment of arteriosclerosis and dyslipidemias.