EP0968162A1

EP0968162A1 - 5-hydroxyalkyl substituted phenyls and their use in medicaments for the treatment of arteriosclerosis and hyperlipoproteinaemia

Info

Publication number: EP0968162A1
Application number: EP98905338A
Authority: EP
Inventors: Matthias Müller-Gliemann; Rolf Angerbauer; Arndt Brandes; Michael Lögers; Carsten Schmeck; Gunter Schmidt; Klaus-Dieter Bremm; Hilmar Bischoff; Delf Schmidt
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1997-02-05
Filing date: 1998-01-23
Publication date: 2000-01-05
Also published as: AU6096698A; US6121330A; JP2001510477A; WO1998034895A1; DE19704244A1

Abstract

The invention relates to novel 5-hydroxyalkyl substituted phenyls, which are produced either by reacting corresponding benzaldehydes with Grignard compounds and then reduces the remaining functional groups, or by reducing corresponding benzoic acid esters according to the usual methods to the corresponding hydroxy compounds. The 5-hydroxyalkyl substituted phenyls are suitable as active substances in medicaments, especially for the treatment of dyslipidaemia.

Description

5-HYDROXY-ALKYL SUBSTITUTED PHENYLE AND THEIR USE IN MEDICINAL PRODUCTS FOR TREATING ARTERIOSCLEROSIS AND HYPERLEPOPROTEINEMIA

The present invention relates to 5-hydroxyalkyl substituted phenyls, processes for their preparation and their use in medicaments.

Publication US 5 169 857 A2 discloses 7- (polysubstituted pyridyl) 6-heptenoates for the treatment of arteriosclerosis, lipoproteinemia and hyperlipoproteinemia. In addition, the preparation of 7- (4-aryl-3-pyridyl) -3,5-dihydroxy-6-heptenoate is described in the publication EP 325 130 A2. Polyarylbenzene from the publication J.Org.Chem. (1979), 44 (26), 4749-52.

The present invention now relates to 5-hydroxyalkyl-substituted phenyls of the general formula (I),

in which

A represents aryl having 6 to 10 carbon atoms, optionally up to 5 times the same or different by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, nitro or by straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy each having 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, represents aryl having 6 to 10 carbon atoms, optionally by

Nitro, halogen, trifluoromethyl or trifluoromethoxy is substituted, or for a radical of the formula

stands,

wherein

R " ³ , R ⁶ and R ^{9 are} identical or different and mean cycloalkyl having 3 to 6 carbon atoms, or aryl having 6 to 10 carbon atoms or a 5- to 7-membered, optionally benzo-condensed, saturated or unsaturated, mono-, bi - or tricyclic heterocycle with up to 4 carbon atoms from the series S, N and / or O form, the cycles, in the case of nitrogen-containing rings also via the N function, optionally up to 5 times the same or different by halogen, trifluor - methyl, nitro, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl, each having up to 6 carbon atoms, by aryl having 6 to 10 carbon atoms or by an optionally benzo-condensed aromatic 5 - up to 7-membered heterocycle with 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 are the} same or different and are aryl having 6 to 10 carbon atoms, since in turn up to 2 times the same or different is substituted by phenyl, halogen or by straight-chain or branched alkyl having up to 4 carbon atoms, R ¹³ and R ^{14 are the} same or different and are those given above

Have the meaning of R and R,

or

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

mean

straight-chain or branched alkyl or alkenyl each having 2 to 10 carbon atoms, which are optionally substituted up to 2 times by hydroxy,

R represents hydrogen or halogen,

and

R is hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy 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 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, U and W are the same or different and represent straight-chain or branched alkyl having up to 8 carbon atoms,

or

U or W means a bond

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

Formula -NR ¹⁸ stands,

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 ,

L for hydrogen, hydroxy, straight-chain or branched alkoxy or

Alkyl each having up to 6 carbon atoms or for a radical of the formula -NR ¹⁹ R ²⁰ or

O - | ( stands, *

O "(CH ₂ ) _a

wherein

R ¹⁹ and R ^{20 have} the meaning of R ³ and R ⁴ given above and are identical or different with this,

and

a represents a number 1, 2 or 3, R ^{1 represents} straight-chain or branched alkyl having up to 6 carbon atoms which is substituted by hydroxy,

R ^{2 represents} aryl having 6 to 10 carbon atoms, which is optionally by

Halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, alkoxy, acyl or alkoxy carbonyl, each with up to 6

Carbon atoms, hydroxyl, carboxyl or by a group of the formula

-NR ²¹ R ^{22 is} substituted,

wherein

R ²¹ and R ^{22 are the} same or different and have the meaning given above for R ³ and R ⁴

and their salts.

The 5-hydroxyalkyl substituted phenyls according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.

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

Acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. For example, particular preference is given to Sodium, potassium, magnesium or

Calcium salts, as well as ammonium salts, which are derived from ammonia, or organic amines, such as ethylamine, di- or. Triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine. The compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). The invention relates to both the enantiomers or diastereomers or their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.

Heterocycle, optionally benzocondensed, in the context of the invention generally represents a saturated or unsaturated 5- to 7-membered, preferably 5- to 6-membered heterocycle which may contain up to 3 heteroatoms from the S, N and / or O series. Examples include: indolyl, isoquinolyl,

Quinolyl, benzo [b] thiophene, benzo [b] furaryl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Quinolyl, furyl, pyridyl and thienyl are preferred.

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

in which

A stands for naphthyl or phenyl, optionally up to 3 times the same or different by fluorine, chlorine, bromine, amino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro or by straight-chain or branched alkyl, or alkoxy each having up to 6 carbon atoms or by a group of the formula -NR ³ R ^{4 are} substituted,

wherein

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

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

Rest of the formula

stands,

wherein

R ⁵ , R ⁶ and R ⁹ independently of one another are cyclopropyl, cyclopentyl or cyclohexyl, or phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl Quinolyl or purin-8-yl, the cycles, optionally up to 3 times in the case of the nitrogen-containing rings, also via the N function, identically or differently, by fluorine, chlorine, bromine, trifluoromethyl, hydroxy, cyano, carboxyl , Trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, triazolyl, tetrazolyl, benzoxathiazolyl or phenyl, and / or by a group of the formula -OR, 10 SR ¹¹ or - SO ₂ R ^{12 are} substituted,

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

F, C JOO mean

R ⁷ denotes hydrogen, fluorine, chlorine or bromine,

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

wherein

R ¹⁵ and R ^{16 are} identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,

or

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

wherein

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

T denotes straight-chain or branched alkyl or alkenyl, each having up to 6 carbon atoms, which are optionally substituted up to 2 times by hydroxy,

U and W are identical or different and represent straight-chain or branched alkylene with up to 6 carbon atoms,

or

U or W mean a bond,

V is an oxygen or sulfur atom or a group of the formula

-NR ¹⁸ means

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 is phenyl which is optionally substituted by fluorine, chlorine or trifluoromethyl,

L for hydrogen, hydroxy, straight-chain or branched alkoxy or

Alkyl each having up to 5 carbon atoms or represents a radical of the formula NR ¹⁹ R ²⁰ , in which

R ^{1 represents} straight-chain or branched alkyl having up to 4 carbon atoms which is substituted by hydroxy,

R ^{2 represents} naphthyl or phenyl, which may be replaced by fluorine, chlorine,

Bromine, nitro, cyano, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, alkoxy, acyl or alkoxycarbonyl each having up to 4 carbon atoms, hydroxyl, carboxyl or substituted by a group of the formula -NR ²¹ R ²² ,

wherein

R ²¹ and R ^{22 are the} same or different and have the meaning of R ³ and R ⁴ given above

and their salts.

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

in which A represents phenyl, which is optionally up to 2 times identical or different by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy, nitro or by straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms or by a group of the formula - NR ³ R ^{4 is} substituted,

wherein

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

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

R ⁷ R ⁸

R ⁵ -T _f R ^{6 /} ^ ^ode r R ⁹ - U -V- W

stands,

wherein

R ⁵ , R ⁶ and R ⁹ independently of one another are cyclopropyl, cyclopentyl or cyclohexyl, or phenyl, naphthyl, pyridyl, tetrazolyl,

Pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl, quinolyl or purin-8-yl means, the cycles, optionally up to 3 times, also in the case of the nitrogen-containing rings via the N function, identical or different, by fluorine, chlorine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, triazolyl, tetrazolyl, benzothiazolyl or phenyl are substituted and / or are substituted by a group of the formula -OR ¹⁰ , -SR ^{1 1} 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 is hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy, trifluoromethoxy, or straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms or a radical of the formula -NR ¹⁵ R ¹⁶ ,

wherein

R ¹⁵ and R ^{16 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

or

R ⁷ and R ⁸ together form a radical of the formula = 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, T denotes straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, which are optionally substituted up to 2 times by hydroxy,

U and W are the same or different and represent straight-chain or branched alkyl having up to 3 carbon atoms,

or

U or W mean a bond,

V is an oxygen or sulfur atom or a group of the formula

-NR ¹⁸ means

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,

L for hydrogen, hydroxy, straight-chain or branched alkoxy or

Alkyl each having up to 4 carbon atoms or represents a radical of the formula -NR ¹⁹ R ²⁰ , wherein

R ^{1 represents} straight-chain or branched alkyl having up to 3 carbon atoms which is substituted by hydroxy,

R represents phenyl, which is optionally substituted by fluorine, chlorine, nitro, cyano, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl,

Alkoxy, acyl or alkoxycarbonyl each having up to 3 carbon atoms, Hydroxyl, carboxyl or substituted by a group of the formula -NR ²¹ R ²² ,

wherein

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

[A] into the compounds of the general formula (II)

in which

A, E, L and R ^{2 have} the meaning given above,

and

R »23 represents C ₁ -C ₄ alkoxycarbonyl,

first the radical D is generated in the sense of an organometallic reaction, optionally derivatized at this stage by conventional methods and the alkoxycarbonyl group is converted into the hydroxymethyl function by reduction,

or

[B] in the case where D represents the rest of the formula R ⁹ -UVW, in which V a

Oxygen atom means either compounds of the general formula (III)

A, E, L, W, R ¹ and R ^{2 have} the meaning given above,

with compounds of the general formula (IV)

R ⁹ -UY (IV),

in which

R ⁹ and U have the meaning given above,

and

Y represents halogen, preferably chlorine or bromine,

in inert solvents, optionally in the presence of a base and / or auxiliary,

or

[C] compounds of the general formula (III) first by reactions with compounds of the general formula (V)

O

24 ^sts

R ²⁴ - S - Cl (V),

II o in which R ^{24 represents} straight-chain alkyl having up to 4 carbon atoms,

into the compounds of the general formula (VI)

in which

A, E, L, W, R ¹ , R ² and R ^{24 have} the meaning given above,

transferred and then with compounds of the general formula (VII)

R ⁹ -UVH (VII),

in which

R ⁹ , U and V have the meaning given above,

implemented and, if necessary, splitting off protective groups,

and optionally the substituents listed under D, E, L and / or R ¹ and R ² are varied or introduced by customary methods

The method according to the invention can be exemplified by the following formula:

-10 ° -> RT

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, tetrachloromethane, dichlorethylene,

Trichlorethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric acid triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dichloromethane and toluene are preferred.

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

Sodium hydride or lithium diisopropylamide used.

The usual inorganic bases are also suitable for process [B]. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as for example sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate. Sodium hydride or potassium hydroxide are particularly preferably used.

Systems such as Mg bromobenzotrifluoride and p-trifluoromethylphenyllithium are, for example, suitable as organometallic reagents.

The usual reagents are suitable as Wittig reagents. 3-Trifluoromethylbenzyltriphenylphosphonium bromide is preferred.

Bases are generally one of the bases listed above, preferably sodium amide.

The base is used in an amount of 0.1 mol to 5 mol, preferably from 0.5 mol to

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

The reaction with Wittig reagents is generally carried out in a temperature range from 0 ° C. to 150 ° C., preferably at 25 ° C. to 40 ° C.

The Wittig reactions are generally carried out at normal pressure. However, it is also possible to carry out the process under negative pressure or under positive pressure (e.g. in a range from 0.5 to 5 bar).

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

The reducing agent is generally used in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, based on 1 mol of the compounds to be reduced. The reduction generally takes place in a temperature range from -78 ° C to + 50 ° C; preferably from -78 ° C. to 0 ° C., in the case of DIBAH and lithium aluminum hydride the reactions being carried out particularly preferably at 0 ° C.-room temperature.

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

The following reaction types may be mentioned as examples of derivatizations: reductions, hydrogenations, halogenation, Wittig / Grignard reactions and amidations.

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

Sodium hydride or lithium diisopropylamide used.

The usual inorganic bases are also suitable as bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate. Sodium hydroxide or potassium hydroxide are particularly preferably used.

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

It may be necessary to carry out a few reaction steps under a protective gas atmosphere.

The halogenations are generally carried out in one of the chlorinated hydrocarbons listed above, methylene chloride being preferred.

Suitable halogenating agents are, for example, diethylamino sulfur trifluoride (DAST) or SOCl ₂ . The halogenation generally takes place in a temperature range from -78 ° C. to + 50 ° C., preferably from -78 ° C. to 0 ° C., in each case depending on the choice of the halogenating agent and solvent.

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

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

Compounds of the general formula (VIII)

in which

A, E and L have the meaning given above

and

R and, 26 are the same or different and are C, -C ₄ alkyl

first by reaction with (F ₃ C-SO ₂ ) ₂ O in pyridine into the compounds of the general formula (IX)

in which

A, E, L, R> 25 and ..n. d R, 26 have the meaning given above, convicted,

then with the exclusion of oxygen in the triphenylphopine system, tris-di-benzylidene acetone-dipalladium chloroform complex with compounds of the general formula (X)

R ^! -Z (X)

in which

R ^{1 has} the meaning given above

and

Z represents B (OH) ₂ ,

to the compounds of the general formula (XI)

L in which

A, E, L, R ¹ , R ²⁵ and R ^{26 have} the meaning given above,

implements

in a further step the alkoxycarbonyl group (CO ₂ R ²⁵ ) is reduced to the hydroxy function and finally oxidized to the formyl group.

Suitable solvents for the oxidation are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 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. Methylene chloride is preferred.

Suitable oxidizing agents are, for example, cerium (IV) ammonium nitrate, thionyl chloride, 2,3-dichloro-5,6-dicyanobenzoquinone, pyridinium chlorochromate (PCC) or

Pyridinium chlorochromate on basic aluminum oxide, osmium tetroxide and manganese dioxide. Thionyl chloride and 2,3-dichloro-5,6-dicyanobenzoquinone are 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

(XII).

The oxidation generally takes place in a temperature range from -50 ° C. to + 100 ° C., preferably from room temperature to reflux.

The oxidation generally takes place at normal pressure. However, it is also possible to carry out the oxidation at elevated or reduced pressure.

The compounds of the general formulas (IV), (V), (VI), (VII) and (X) are known per se or can be prepared by customary methods.

Some of the compounds of the general formulas (IX) and (XI) are known or new and can then be prepared as described above.

Some of the compounds of the general formula (VIII) are known or new and can then be prepared by known methods.

The compounds of general formula (I) according to the invention have an unforeseeable spectrum of pharmacological activity.

The compounds of the general formula (I) according to the invention have valuable pharmacological properties which are superior compared to the prior art, in particular they are highly effective inhibitors of cholesterol ester transfer protein (CETP) and stimulate the reverse cholesterol transport. The active compounds according to the invention bring about a reduction in the LDL cholesterol level. gels in the blood while increasing the HDL cholesterol level. They can therefore be used to treat or prevent hyperlipoproteinaemia, hypolipoproteinaemia, dyslipidemia, hypertriglyceridaemia or arteriosclerosis.

The pharmacological effects of the substances according to the invention were determined in the following test:

CETP inhibition testing

Obtaining CETP

CETP is obtained from human plasma by differential centrifugation and column chromatography in a partially purified form and used for the test. For this purpose, human plasma is reduced to a density of NaBr

Set 1.21 g per ml and centrifuged at 50,000 rpm at 4 ° C for 18 h. The bottom fraction (d> 1.21 g / ml) is applied to a Sephadex®Phenyl-Sepharose 4B (Pharmacia) column, washed with 0.15 m NaCl / 0.001 m TrisHCl pH 7.4 and then with dist. Water eluted. The CETP-active fractions are pooled, dialyzed against 50 mM Na acetate pH 4.5 and applied to a CM-Sepharose® (from Pharmacia) column. Elution is then carried out using a linear gradient (0-1 M NaCl). The pooled CETP fractions are dialyzed against 10 mM TrisHCl pH 7.4 and then further purified by chromatography on a Mono Q® column (from Pharmacia).

Obtaining radioactively labeled HDL

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

The mixture is then adjusted to the density 1.21 with NaBr and in the Ty

65-rotor centrifuged for 18 h at 50,000 rpm at 20 ° C. The upper phase is won and the lipoprotein fractions are purified by gradient centrifugation. For this purpose, the isolated, labeled lipoprotein fraction is adjusted to a density of 1.26 with NaBr. 4 ml of this solution are overlaid in centrifuge tubes (SW 40 rotor) with 4 ml of a solution with a density of 1.21 and 4.5 ml with a solution of 1.063 (sealing solutions made of PDB buffer and NaBr) and then 24 hours at 38,000 rpm and centrifuged at 20 ° C in the SW 40 rotor. The between the density 1.063 and 1.21 lying intermediate layer containing the labeled HDL is 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. 5xl0 ⁶ cmp per ml and used for the test.

CETP test

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

Scintillation counter determined.

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 (in 10% DMSO / 1% RSA) dissolved, incubated for 18 h at 37 ° C. Then 200 μl of the SPA-streptavidin bead solution (TRKQ 7005) are added, incubated for 1 h while shaking and then measured in the 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:

Activity of the compounds according to the invention

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

The test substances can also be administered po by administering the substances dissolved in DMSO and suspended in 0.5% tylose by means of a pharyngeal tube. The control animals receive identical volumes of solvent without test substance

At various times - up to 24 hours after application - blood is withdrawn 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 serum obtained in this way, the CETP activity is determined by the modified CETP test. As described for the CETP test above, the transfer of H-cholesterol ester from HD lipoproteins to biotinylated LD lipoproteins is measured. The reaction is carried out by adding streptavιdιn -SPA ^R beads (Amersham) ended and the radioactivity transferred determined directly in the Liquid Scintlation Counter The test batch is carried out as described under "CETP test". Only 10 μl CETP are replaced by 10 μl of the corresponding serum samples for testing the serum. Appropriate incubations with sera from untreated animals serve as controls. The activity transferred in the control batches with control sera is rated as 100%) transfer. The substance concentration at which this transfer is reduced to half is given as the ED ₅₀ value.

Activity of the compounds according to the invention

In tests to determine the oral effect on lipoproteins and triglycerides, Syrian golden hamsters from the company's own breeding test substance are dissolved in DMSO and 0.5%> tylose suspended is administered orally using a pharyngeal tube. To determine the CETP activity, blood is taken by retro-orbital puncture (approx. 250 μl) before the start of the experiment. The test substances are then administered orally using a gavage. The control animals receive identical volumes of solvent without test substance. The animals are then deprived of their feed and blood is taken at various times - up to 24 hours after substance administration - by puncturing the retroorbital venous plexus. The coagulation is terminated by incubation at 4 ° C. overnight, followed by centrifugation at 6000 × g for 10 minutes. So preserved

The serum content of cholesterol and triglycerides is determined with the aid of modified commercially available enzyme tests (cholesterol enzymatically 14366 Merck, triglycerides 14364 Merck). Serum is appropriately diluted with physiological saline. 100 μl of serum dilution are mixed with 100 μl of test substance in 96-well plates and incubated for 10 minutes at room temperature. The optical density at a wavelength of 492 nM is then determined using an automatic plate reader. The triglyceride or cholesterol concentration contained in the samples is determined using a standard curve measured in parallel.

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

Efficacy in vivo in transgenic hCETP mice

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

The invention also relates to the combination of substances of the general formula (I) with a glucosidase and / or amylase inhibitor for the treatment of familial hyperlipidaemias, obesity (obesity) and diabetes mellitus. Glucosidase and / or amylase inhibitors in the context of the invention are, for example, acarbose, adiposins, Voglibose, Miglitol, Emiglitate, MDL-25637, Camiglibose (MDL-73945), Tendamistate, AI-3688, Trestatin, Pradimicin-Q and Salbostatin.

The combination of acarbose, miglitol, emiglitate or voglibose with one of the above-mentioned compounds of the general formula (I) according to the invention is preferred. Furthermore, the compounds according to the invention can be combined in combination with cholesterol-lowering vastatins or Apo B-lowering principles in order to treat dyslipidemics, combined hyperlipidemics, hypercholesterolemics or hypertriglyceridemics.

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

Vastatins in the context of the invention are, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin. Apo B lowering agents are e.g. MTP inhibitors.

The combination of cerivastatin or Apo B inhibitors with one of the above-mentioned compounds of the general formula according to the invention is preferred

(I) -

The new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. The therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.

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

In the case of parenteral use, solutions of the active ingredient can be used using suitable liquid carrier materials. In general, it has proven to be advantageous to administer amounts of approximately 0.001 to 1 mg / kg, preferably approximately 0.01 to 0.5 mg / kg of body weight in the case of intravenous administration in order to achieve effective results, and the dosage is approximately in the case of oral administration 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight.

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

used abbreviations

C cyclohexane

EE ethyl acetate

PE petroleum ether

THF = tetrahydrofuran

DAST ^* = dimethylamino sulfur trifluoride

PTS = para-toluenesulfonic acid

PDC ^**** - Py ri dinium di chromat

PE / EE = petroleum ether / ethyl acetate

DDQ = 2,3-dichloro-5,6-dicyano-benzoquinone

HC1 = hydrochloric acid

PCC = pyridinium chlorochromate

Output connections

Example I

1-Cyclopentyl-3- (4-fluorophenyl) -5-oxo-1-cyclohexene-2,3-dicarboxylic acid 2-methyl-3-ethyl ester

20 g (72.4 mmol) of l-cyclopentyl-3- (4-fluorophenyl) -1-oxo-2-propene-2-carboxylic acid methyl ester and 12.4 g (72.4 mmol) of 2- ( N-isopropyl) -2-propenecarboxylic acid ethyl ester refluxed overnight. 50 ml of semi-concentrated hydrochloric acid are stirred into the cooled solution and refluxed for 17 h.

The cooled solution is partitioned between CH ₂ C1 ₂ and water, the aqueous phase is re-extracted with CH ₂ C1 ₂ , the combined organic phases over Na ₂ SO ₄ dried, filtered and concentrated. The crude product is chromatographed on 1 kg of silica gel with EA: PE 1: 6. Yield: 8.4 g (29.8% of theory) 1 ^ = 0.73 tol: EA 5: 1

Example II

2-Cyclopentyl-4- (4-fluorophenyl) -6-hydroxy-phenyl-3,5-dicarboxylic acid 3-methyl-5-ethyl ester

7.3 g (18.8 mol) of the compound from Example I are dissolved in 100 ml of SOCl ₂ and refluxed for 18 h. The solution, cooled to room temperature, opens

Poured ice water, diluted with ethyl acetate, extracted, the organic phase with

NaHCO ₃ solution stirred and then dried with Na ₂ SO ₄ , filtered and concentrated.

9 g of crude product are chromatographed on 1 kg of silica gel with PE: EE 4: 1.

Yield: 1.12 g (15.4% of theory) R _f = 0.74 PE: EE 4: 1

Example m

2-Cyclopentyl-4- (4-fluorophenyl) -6-trifluoromethane-sulfonic acid-phenyl-3,5-dicarboxylic acid-3-methyl-5-ethyl ester

Under argon, 1.55 g (5.6 mmol) of trifluoromethanesulfonic anhydride are added dropwise to a solution of 1.2 g (3.1 mmol) of the compound from Example II in 4 ml of pyridine at 0 ° C. After stirring for 18 h at room temperature, the mixture is poured onto ice water and extracted 3 times with ethyl acetate. The combined organic phases are extracted with 10% HCl solution, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product is chromatographed on 150 g of silica gel using toluene. Yield: 1.04 g (65% of theory) R = 0.5 toluene

Example IV

2-Cyclopentyl-4- (4-fluorophenyl) -6- (fluorophenyl) phenyl-3,5-dicarboxylic acid 3-methyl-5-ethyl ester

Under strict exclusion of air, a solution of 1.08 g (2.1 mmol) of the compound is released after 15 minutes to a solution of 54 mg (0.05 mmol) of tridibenzylidene acetone dipalladium chloroform complex and 1 10 mg of triphenylphosphine dissolved in 40 ml of toluene Example III) added dropwise in 40 ml of toluene, then a solution of 292 mg (2.1 mmol) of p-fluorophenylboronic acid in 25 ml of methanol added dropwise and finally a solution of 221 mg (2.1 mmol) Na ₂ CO ₃ in 20 ml H ₂ O was added dropwise. It is refluxed for 18 hours. For working up, the mixture is partitioned between ethyl acetate and H ₂ O, the organic phase is extracted with saturated NaCl solution, dried over Na ₄ SO ₄ , filtered and concentrated. The crude product is chromatographed on 300 g of silica gel with toluene. Yield: 577 mg (59% of theory) R _f = 0.47 in toluene

Example V

2-Cyclopentyl-4,6-bis (4-fluorophenyl) -3-hydroxymethyl-5-carboxylic acid ethyl ester

1.8 ml of Red-Al solution (12 mmol) are added dropwise at room temperature to a solution of 927 mg (2 mmol) of the compound from Example IV in 30 ml of toluene under argon. After 14 h at 40 ° C is saturated hydrolyzed with 20 ml of Na, K-tartrate solution. It is extracted 3 times with ethyl acetate, the combined organic phases are dried over Na ₂ SO ₄ , filtered and concentrated. The crude product is chromatographed on 250 g of silica gel with 4: 1 PE: EE. Yield: 436 mg (50% of theory) R _f = 0.58 PE: EE 4: 1

Example VI

2-Cyclopentyl-4,6-bis (4-fluorophenyl) -3-formyl-5-carboxylic acid ethyl ester

A mixture of 210 mg Al ₂ O ₃ and 453 mg PCC (2 mmol) is added to a solution of 450 mg (1 mmol) of the compound from Example V in 20 ml CH ₂ C1 ₂ at room temperature and the mixture is stirred for 15 h. A little silica gel is added to the suspension and suction filtered over silica gel. The filtrate is concentrated. Yield: 417 mg (96% of theory) R _f = 0.84 in PE: EE 4: 1

Example VH

2-Cyclopentyl-4,6-bis (4-fluorophenyl) -3 - [(p-trifluoromethylphenyl) hydroxymethyl] phenyl - 5-carboxylic acid ethyl ester

57.4 mg of Mg chips are suspended in 10 ml of THF under argon and 566 mg (2.6 mmol) of p-trifluoromethylphenyl bromide are slowly added dropwise under reflux. After 1 h, the mixture is cooled. This solution is added dropwise at -70 ° C. to a solution of 400 mg (0.9 mmol) of the compound from Example VI in 10 m THF. It is slowly warmed to 10 ° C and after 30 minutes with saturated NH ₄ C1 solution solution added and ethyl acetate added. The aqueous phase is extracted again with ethyl acetate and the combined organic phases are dried over Na ₂ SO ₄ , filtered and concentrated. The crude product is chromatographed on 100 g of silica gel with PE: EE 6: 1. Yield: 475 mg (91% of theory) R _f = 0.68 in PE: EE 4: 1

Example VTH

2-Cyclopentyl-4,6-bis- (4-fluorophenyl) -3 - [(p-trifluoromethylphenyl) fluoromethyl] phenyl-5-carboxylic acid ethyl ester

42 mg (0.26 mmol) of diethylaminosulfur trifluoride are added dropwise under argon to a solution of 100 mg (0.17 mmol) of the compound from Example VII in 3 ml of CH ₂ C1 ₂ at -30 ° C. After 1 h, the mixture is poured onto 50 ml of saturated NaHCO ₃ solution and extracted 3 times with CH ₂ C1 ₂ . The combined organic phases are dried over Na ₂ SO ₄ , filtered and concentrated. Drying in a high vacuum.

Yield: 114 mg (115% of theory; solvent residues; used in the next step). R _f = 0.81 in toluene Manufacturing examples

example 1

2-Cyclopentyl-4,6-bis- (4-fluorophenyl) -3 - [(p-trifluoromethylphenyl) fluoromethyl-5-hydroxymethyl-benzene

A solution of 100 mg (0.17 mmol) of the compound from Example VIII in 2 ml of THF is added dropwise under argon to a solution of 0.38 ml of LiAlH ₄ (0.38 mmol) in 3 ml of THF. After 2 h of reflux, the mixture is hydrolyzed with Na, K-tartrate solution and extracted 3 times with CH ₂ Cl- _> . The combined organic phases are dried over Na ₂ SO ₄ , filtered and concentrated. The crude product is chromatographed on 20 g of silica gel with 4: 1 PE: EE. Yield: 65 mg (71% of theory) R _f = 0.64 ^* PE: EE 4: 1

The compounds listed in Table 1 were prepared analogously:

Table 1:

Claims

claims

1. 5-hydroxyalkyl substituted phenyls of the general formula (I)

in which

A represents aryl having 6 to 10 carbon atoms, optionally up to 5 times the same or different by halogen, hydroxy, trifluoromethyl, nitro, trifluoromethoxy or by straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy each having 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 represents aryl having 6 to 10 carbon atoms, which is optionally substituted by nitro, halogen, trifluoromethyl or trifluoromethoxy, or a radical of the formula

stands,

wherein R ⁵ , R ⁶ and R ^{9 are} identical or different and are cycloalkyl having 3 to 6 carbon atoms, or aryl having 6 to 10

Are carbon atoms or a 5- to 7-membered, optionally benzo-condensed, saturated or unsaturated

Form 5 saturated, mono-, bi- or tricyclic heterocycle with up to 4 carbon atoms from the series S, N and / or O, the cycles, in the case of the nitrogen-containing rings also via the N function, optionally up to 5 times identical or different by halogen, trifluoromethyl,

10 nitro, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, by aryl having 6 to 10 carbon atoms or by one, optionally benzo-condensing

15 substituted aromatic 5- to 7-membered heterocycle with up to 3 heteroatoms from the series S, N and / or O are substituted, and / or by a group of the formula -OR ¹⁰ , -SR ¹¹ , -SO ₂ R ¹² or -NR ¹³ R ^{14 are} substituted,

wherein

20 R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and aryl with

6 to 10 carbon atoms, since in turn up to 2 times the same or different is substituted by phenyl, halogen or by straight-chain or branched alkyl having up to 4 carbon atoms,

25 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 or R ^{6 is} a radical of the formula

mean

T denotes straight-chain or branched alkyl or alkenyl each having 2 to 10 carbon atoms, which are optionally substituted up to 2 times by hydroxy,

5 R ⁷ denotes hydrogen or halogen,

and

R ^{8 is} hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy having up to 5 carbon atoms or a radical of the formula 10 -NR ¹⁵ R ¹⁶ ,

wherein

or

15 R ⁷ and R ⁸ together form a radical of the formula = O or = NR ⁱ⁷ ,

wherein

R ¹⁷ denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 6 carbon atoms 20,

U and W are the same or different and represent straight-chain or branched alkyl having up to 8 carbon atoms,

or

U or W means a bond V represents an oxygen or sulfur atom or a radical of the formula -NR ¹⁸ ,

wherein

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 is substituted,

L for hydrogen, hydroxyl, straight-chain or branched alkoxy or alkyl each having up to 6 carbon atoms or for a radical of the formula -NR ¹⁹ R ²⁰ or

O -

<stands

wherein

and

a represents a number 1, 2 or 3,

R ^{1 represents} straight-chain or branched alkyl having up to 6 carbon atoms which is substituted by hydroxy,

R ^{2 represents} aryl having 6 to 10 carbon atoms, which may be replaced by halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, alkoxy, acyl or alkoxycarbonyl each having up to 6 carbon atoms, hydroxyl, carboxyl or substituted by a group of the formula -NR ²¹ R ²² ,

wherein

and their salts.

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

A stands for naphthyl or phenyl, optionally up to 3 times the same or different by fluorine, chlorine, bromine, amino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro or by straight-chain or branched alkyl, or alkoxy each having up to 6 carbon atoms or by a group of the formula -NR ^*** R ^{4 is} substituted,

wherein

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

Bromine, phenyl, trifluoromethyl or trifluoromethoxy is substituted, or for a radical of the formula

stands,

wherein R ⁵ , R ⁶ and R ⁹ independently of one another are cyclopropyl, cyclopentyl or cyclohexyl, or phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, morpholinyl, imidazolyl, benzothiazolyl, phenoxathiin-2-yl, benzoxazolyl, furyl Quinolyl or purin-8-yl, the cycles, optionally up to 3 times in the case of the nitrogen-containing rings, also via the N function, identically or differently by fluorine, chlorine, bromine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy , straight chain

10 or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl, each having up to 4 carbon atoms, triazolyl, tetrazolyl, benzoxathiazolyl or phenyl, and / or by a group of the formula -OR ¹⁰ , -SR ¹¹ or -SO ₂ R ^{12 are} substituted,

15 where

R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are phenyl, which in turn is up to 2 times the same or different through phenyl, fluorine, chlorine or through straight-chain or branched alkyl with up to 4

20 carbon atoms is substituted,

or

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

n,

R ⁷ denotes hydrogen, fluorine, chlorine or bromine,

25 and

R ^{8 is} hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched Alkoxy or alkyl 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, 5 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 ,

10 where

T straight or branched alkyl or alkenyl with

15 each means up to 6 carbon atoms which are optionally substituted up to twice by hydroxy,

U and W are identical or different and denote straight-chain or branched alkyl having up to 6 carbon atoms,

or

20 U or W mean a bond,

V is an oxygen or sulfur atom or a group of

Formula -NR ¹⁸ means

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

L represents hydrogen, hydroxyl, straight-chain or branched alkoxy or alkyl each having up to 5 carbon atoms or a radical of the formula NR ¹⁹ R ²⁰ ,

wherein

R and R have the meaning of R and R given above and are the same or different with this,

R ^{2 represents} naphthyl or phenyl, which may be replaced by fluorine,

Chlorine, bromine, nitro, cyano, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, alkoxy, acyl or

Alkoxy carbonyl each having up to 4 carbon atoms, hydroxyl, carboxyl or substituted by a group of the formula -NR ²¹ R ²² ,

wherein

R ²¹ and R ^{22 are the} same or different and are those given above

Have meaning of R ³ and R ⁴

and their salts.

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

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

Trifluoromethoxy, nitro or is substituted by straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms or by a group of the formula -NR ³ R ⁴ ,

wherein

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

Chlorine or bromine is substituted, or for a radical of the formula

R ⁷ R ⁸ R ⁵ -TR ^{6, /} ^ ^or R ⁹ - U -VW

stands,

wherein

R ⁵ , R ⁶ and R ⁹ independently of one another are cyclopropyl, cyclopentyl or cyclohexyl, or phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl Quinolyl or purin-8-yl, where the cycles, optionally up to 3 times, in the case of the nitrogen-containing rings also via the N function, identically or differently by fluorine, chlorine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, alkoxy or

Alkoxy carbonyl substituted with up to 3 carbon atoms, triazolyl, tetrazolyl, benzothiazolyl or phenyl are 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 ¹ "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

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

mean,

R ^{7 represents} hydrogen or fluorine,

and

15 R denotes 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

20 R ¹⁵ and R ^{16 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

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

wherein

T denotes straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, which are optionally substituted up to 2 times by hydroxy,

or

U or W mean a bond,

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

wherein

L represents hydrogen, hydroxyl, straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms or a radical of the formula -NR ¹⁹ R ²⁰ , woπn

R ^{2 represents} phenyl, which may be fluorine, chlorine, nitro, cyano, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, alkoxy, acyl or alkoxycarbonyl each having up to 3 carbon atoms, hydroxyl, carboxyl or by means of a group of the formula -NR ²¹ R ^{22 is} substituted,

wherein

and their salts.

A process for the preparation of compounds of general formula (I) according to claim 1, characterized in that

[A] into the compounds of the general formula (II)

in which

A, E, L and R ~ have the meaning given above,

and R> 23 represents C _r C ₄ alkoxycarbonyl,

or

[B] in the case where D represents the remainder of the formula R ⁹ -UVW, in which V represents an oxygen atom,

either compounds of the general formula (III)

in which

A, E, L, W, R ¹ and R ^{2 have} the meaning given above,

with compounds of the general formula (IV)

R ^y -UY (IV),

in which

R and U have the meaning given above,

and

represents halogen, preferably chlorine or bromine, in inert solvents, optionally in the presence of a base and / or auxiliary,

or

O

24 ^H

R ²⁴ S - Cl (V),

II

O in what

R ^{24 represents} straight-chain alkyl having up to 4 carbon atoms,

into the compounds of the general formula (VI)

in which

A, E, L, W, R ¹ , R ² and R ^{24 have} the meaning given above,

transferred and then with compounds of the general formula (VII)

R ⁹ -UVH (VII),

in which

R ⁹ , U and V have the meaning given above, implemented and, if necessary, splitting off protective groups,

and optionally the substituents listed under D, E, L and / or R ¹ and R ² are varied or introduced by customary methods.

5. Medicaments contain at least one 5-hydroxy-alkyl-substituted phenyl according to claim 1 to 3 and pharmacologically acceptable auxiliaries.

6. Medicament according to claim 5 for the treatment of arteriosclerosis.

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

8. Use of 5-hydroxy-alkyl-substituted phenylene according to claim 1 to 3 for the manufacture of medicaments.

9. Use according to claim 8 for the manufacture of medicaments for the treatment of arteriosclerosis.

10. Use according to claim 8 for the manufacture of medicaments for the treatment of hyperlipoproteinemia.