WO2002090344A1

WO2002090344A1 - Amido-diphenyl derivatives

Info

Publication number: WO2002090344A1
Application number: PCT/EP2002/004622
Authority: WO
Inventors: Helmut Haning; Michael Woltering; Gunter Schmidt; Christiane Faeste; Hilmar Bischoff; Axel Kretschmer; Verena Vöhringer
Original assignee: Bayer Aktiengesellschaft
Priority date: 2001-05-09
Filing date: 2002-04-26
Publication date: 2002-11-14
Also published as: DE10122443A1

Abstract

The invention relates to a amido-diphenyl derivatives of formula (I), whereby variables X, Z and R<1>-R<7> have the meanings as cited in Claim No. 1, to a method for the production thereof, and to their use in medicaments.

Description

AMIDO DIPHENY DERIVATIVES

The invention relates to new amido-diphenyl derivatives, processes for their preparation and their use in medicaments.

EP-A-580 550 describes oxamic acid derivatives which have cholesterol-lowering properties in mammals. The reduction in plasma a-cholesterol, in particular LDL cholesterol, is emphasized as a pharmacological property. Cholesterol-lowering effects are also described in EP-A-188 351 for certain diphenyl ethers with thyroid hormone-like effects.

Diphenyl ethers as thyroid receptor ligands are also disclosed in WO 99/00353 and WO 00/39077. Further diphenyl derivatives with thyroid hormone-like properties are described in the applications WO 98/57919, WO 99/26966, WO

00/51971 and WO 00/58279. Certain diphenyl sulfones for the treatment of hair loss are claimed in WO 00/72810 and WO 00/73265.

The object of the present invention is to provide new compounds with improved, in particular pharmaceutical, effects.

It has now been found that compounds of the general formula (I)

in which X represents O, S, SO, SO ₂ , CH ₂ , CHF, CF ₂ or NR ⁸ , in which R ^{8 is} hydrogen or (Cj-C) -alkyl,

R ¹ and R ^{2 are the} same or different and represent hydrogen or (QC ^ alkyl,

R ³ and R ^{4 are the} same or different and represent hydrogen, halogen, cyano, (C _r C ₆ ) alkyl, CF ₃ , CHF ₂ , CH ₂ F, vinyl or (C ₃ -C ₇ ) cycloalkyl, where at least one of the two substituents is not hydrogen,

R _> 5 represents hydrogen, (C _t -C ^ alkyl or halogen,

R ^{6 represents} a group of the formula -SR ⁹ , -S (O) _n -R ¹⁰ , -NR ^u -C (O) -R ¹² , -CH ₂ -R ¹³ or -MR ¹⁴ , in which

R ⁹ for (CrCιo) -Al yl, (C ₃ -C ₈ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl, (C ₆ -C ₁₀ ) aryl, (C ₆ -C ₁₀ ) arylmethyl or represents a saturated, partially unsaturated or aromatic 5- to 10-membered heterocycle having up to four identical or different heteroatoms from the series N, O and or S, the abovementioned radicals optionally being selected by one, two or three identical or different substituents from the group halogen, hydroxy, oxo, cyano, (CrC ^ alkyl, (CrC ₆ ) alkoxy, carboxyl and (dC ^ alkoxycarbonyl) are substituted,

n represents the number 1 or 2,

R ¹⁰ for OR ¹⁵ , KR ¹⁶ R ¹⁷ , (-C-C ₁₀ ) -Al yl, (C ₃ -C ₈ ) -cycloalkyl, (C ₂ -C ₆ ) -

Alkenyl, (C ₆ -C ₁₀ ) aryl, (C ₆ -C o) arylmethyl or for a saturated, partially unsaturated or aromatic 5- to 10-membered

Heterocycle with up to four identical or different hetero- atoms from the series N, O and or S, the abovementioned radicals optionally being selected from the group halogen, hydroxyl, oxo, cyano, nitro, amino, NR ¹⁸ R ¹⁹ , trifluoromethyl by one, two or three identical or different substituents, (C "-C ₆ ) alkyl optionally substituted by R ²⁰ (CrC - ^ - alkoxy, (C ₃ -C ₈ ) -

Cycloalkyl, (C _ö -C ^ aryl, which in turn is optionally substituted by halogen, (dG -alkyl, (-C-C ₄ ) alkoxy, trifluoromethyl, nitro or cyano, -OC (O) -R ²¹ , -C (O) -OR ²² , -C (O) -NR ²³ R ²⁴ , -SO ₂ -NR ²⁵ R ²⁰ , -NH-C (O) -R ²⁷ and -NH-C (O) -OR ^{28 are} substituted , in which

R ¹⁵ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ and R ^{28 are the} same or different and each represents hydrogen, phenyl, benzyl,

or (C -C ₈ ) -cycloalkyl, which in turn are optionally one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (dG -alkoxy, (-C ^ -alkoxycarbonyl, (-C ^ -alkoxycarbonylamino , (- C ₅ ) -alkanoyloxy, a heterocycle or, in turn, optionally substituted by halogen or hydroxy-substituted phenyl,

and

R ¹⁶ and R ^{17 are} identical or different and, independently of one another, represent hydrogen, straight-chain or branched (-C-Cö) alkyl, which one or more times, identical or different, by mono- (C _r C ₆ ) -alkylamino, di- (C _r C ₆ ) alkylamino, (C _r C4) alkoxy, (Cι-C ₆ ) alkoxycarbonyl, carboxyl, pyridyl or (C ₆ - C ₁₀ ) aryl, the latter in turn optionally being substituted by halogen, trifluoromethyl,

or (C _r C ₆ ) alkoxy is substituted, for (C ₆ -C ₁₀ ) aryl, which is optionally substituted by halogen, trifluoromethyl, (Cj-C ₆ ) alkyl or (Ci-Cg ^ alkoxy), or for (C _ß -Cgj-cycloalkyl or a 5- bis 7-membered heterocycle containing one to two nitrogen atoms, the cycloalkyl and heterocycle in turn optionally being substituted by (C 1 -C 4 -alkyl),

or

£ 1 17

R and R together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated, optionally benzo-fused heterocycle, which may be up to two more

Heteroatoms from the series N, O and / or S contain and by amino, (Cι-Cg) alkyl, (Ci-C ^ alkoxycarbonyl, (C _j -

C ₄ ) -alkoxycarbonylamino or phenyl may be substituted,

R ^{11 represents} hydrogen, straight-chain or branched (C ₁ -C ₆ ) -alkyl, which one or more times, identically or differently, by mono- (C _r C ₆ ) -alkylamino, di- (C _r C ₆ ) -alkylamino, (C _r C ₄ ) alkoxy, (C _r

Cö) alkoxycarbonyl, carboxyl, pyridyl or (C * ₅ -Cιo) aryl may be substituted, the latter in turn optionally substituted by halogen, trifluoromethyl, (C ₁ -Cö) alkyl or (C ₁ -C ₆ ) alkoxy is (C ₃ -Cg) cycloalkyl or a 5- to 7-membered heterocycle containing one to two nitrogen atoms, where

Cycloalkyl and heterocycle optionally substituted by (C _j -C ^ alkyl,

R ^{12 is} straight-chain or branched (C _j -C ^ alkyl, which can be substituted by (C ₃ -Cg) cycloalkyl, (Cj-C ₄ ) alkoxy, phenyl, phenoxy or benzyloxy, the aromatics mentioned in each case up to three times the same or different can be substituted by halogen, (C ^ C ^ ^ alkyl or (Ci-C ^ alkoxy,

for (C ₃ -Cg) cycloalkyl, which can be substituted by (Cι-C4) alkoxy or phenyl,

for (C6-Cιo) aryl, which can be substituted up to three times the same or different by (Ci-C ^ alkyl, (C ₁ -C ₆ ) alkoxy, halogen, cyano, amino, trifluoromethyl or phenyl,

or

represents a 5- to 6-membered saturated or aromatic, optionally benzo-fused heterocycle with up to two heteroatoms from the series N, O and / or S,

or

is a group of the formula -OR ²⁹ or -NR ³⁰ R ³¹ ,

wherein

R ^{29 stands} for straight-chain or branched (-CC6) -alkyl,

and

R ³⁰ and R ^{31 are the} same or different and independent of each other

for hydrogen, straight-chain or branched

Alkyl by aminocarbonyl, a group of formula -NR ³² R ³³ , 5- to 6-membered heteroaryl, which contains up to 3 heteroatoms selected from the series N, O and / or S, or can be substituted by phenyl, phenyl optionally up to two times the same or different is substituted by halogen, (-CC) alkyl, trifluoromethyl or (-C-C4) alkoxy,

for (C ₃ -Cg) cycloalkyl, which can be substituted by (Cι-C4) alkyl,

10 for (C6-Cιo) aryl, which can be substituted up to three times the same or different by halogen, (C _r C ₄ ) alkyl, trifluoromethyl, (C _r C ₄ ) alkoxy, amino, phenyl or phenoxy,

15 or

represent a 5- to 7-membered, saturated or unsaturated, one or two nitrogen atom-containing heterocycle which is optionally substituted by (-CC) -alkyl or an oxo group 20,

in which

R ³² and R ^{33 are} identical or different and independently of one another represent hydrogen, (C ₁ -C ₆ ) alkyl, phenyl or (C6-Cιo) arylsulfonyl,

or

30 together with the nitrogen atom to which they are attached, a 3- to 7-membered saturated heterocycle which optionally contains up to two further heteroatoms from the series, N, O and or S,

or

R ³⁰ and R ³¹ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle which contains up to two further heteroatoms from the series, N, O and / or S and are replaced by amino, ( C _j -Cg ^ alkyl, (C \ - C4) alkanoyl, aminocarbonyl, (C ₁ -C) alkoxycarbonyl, (Ci

C4) -alkoxycarbonylamino, phenyl or pyridyl can be substituted,

1 part

R represents a saturated, partially unsaturated or aromatic 5- to 10-membered heterocycle with up to three identical or different heteroatoms from the series N, O and / or S, which is optionally selected from one, two or three identical or different substituents the group (-G -alkyl, hydroxy, oxo, (CrC ^ -alkoxy, halogen, cyano, carboxyl and (CrC ₄ ) - alkoxycarbonyl,

or

R ^{1 ά stands} for the group -NR ^J4 R ^J:> , in which

R ³⁴ and R ^{35 are} identical or different and represent hydrogen, (Ci

C ₈ ) alkyl, which may be substituted by (C ₆ -C ₁₀ ) aryl, for

(C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or for 5- to 6-membered

Heteroaryl with up to three identical or different heteroatoms from the series N, O and / or S, where

Aryl and heteroaryl for their part, if appropriate, in each case to twice, the same or different, by hydroxy, amino, cyano, halogen, trifluoromethyl, (CC ₄ ) -alkyl, (Cι-C ₄ ) alkoxy, carboxyl, (dC ^ -alkoxycarbonyl or mono- or di- (C ₁ - C) alkylaminocarbonyl are substituted,

M represents CO, CH (OH), CHF or CF ₂ ,

and

R ^{14 has} the meaning of R ¹⁰ given above,

R ^{7 represents} hydrogen, (dC ₄ ) -alkyl or (dC ₄ ) -alkanoyl,

and

Z for a group of the formula

stands in what

R ^{36 represents} hydrogen or (CC ₄ ) -alkyl,

a means the number 0 or 1,

d denotes the number 0 or 1, with the proviso that the sum (a + d) is not equal to the number 0,

A stands for SO ₂ or C = O, D represents a straight-chain (dC ₄ ) alkylene group, which, if appropriate. is substituted one or more times, identically or differently, by (dC ₃ ) -alkyl, hydroxy, amino or fluorine,

B is SO ₂ or, if a is 1 and A is SO ₂ , is also C = O,

and

R ^{37 represents} OR ³⁸ or NR ³⁹ R ⁴⁰ , wherein

R ³⁸ , R ³⁹ and R ^{40 are the} same or different and each represents hydrogen, phenyl, benzyl, (dC ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, which in turn may be one or more, identical or different , by halogen, hydroxy, amino, carboxyl,

(dC ₄ ) -alkoxy, (dC) -alkoxycarbonyl, (dC) -alkoxy-carbonylamino, (C ₁ -C ₅ ) -alkanoyloxy, a heterocycle or, in turn, optionally substituted by halogen or hydroxy-substituted phenyl,

as well as their pharmaceutically acceptable salts, solvates, hydrates and hydrates of the salts,

show a pharmacological effect and can be used as pharmaceuticals or for the production of pharmaceutical formulations.

The following may preferably be mentioned as heterocycles in the definition of R ⁹ , R ¹⁰ or R ¹³ :

A 5- to 10-membered saturated, partially unsaturated or aromatic heterocycle with up to 4 heteroatoms from the series S, N and / or O, ie a mono- or bicyclic heterocycle which can contain one or more double bonds and which is linked via a ring carbon atom or optionally via a ring nitrogen atom. Examples include: tetrahydrofüryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, azepinyl, 1,4-diazepinyl, furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, Triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,

Pyrimidinonyl, pyridazinonyl, indolyl, benzo [b] thienyl, benzo [b] furyl, benzimidazolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl.

From this list, the following are preferred: pyridyl, pyrimidinyl, pyridazinyl, pyrimidinonyl, pyridazinonyl and thienyl.

In the context of the invention, alkyl represents a straight-chain or branched alkyl radical having preferably 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. Examples and preferably are:

Methyl, ethyl, n-propyl, isopropyl, n-, i-, s- or t-butyl, n-pentyl and n-hexyl.

In the context of the invention, alkenyl represents a straight-chain or branched alkenyl radical having preferably 2 to 6 or 2 to 4 carbon atoms. A straight-chain or branched alkenyl radical having 2 to 4 carbon atoms is preferred. The following may be mentioned by way of example and preferably: vinyl, allyl, isopropenyl and n-but-2-en-1-yi.

In the context of the invention, aryl stands for an aromatic radical having preferably 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

Cycloalkyl in the context of the invention represents a cycloalkyl group with preferably 3 to 8, 3 to 7 or 3 to 6 carbon atoms. Examples and preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In the context of the invention, alkoxy preferably represents a straight-chain or branched alkoxy radical having 1 to 6, 1 to 4 or 1 to 3 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is preferred. The following may be mentioned as examples and preferably: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.

Alkoxycarbonyl in the context of the invention preferably represents a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms, which is linked via a carbonyl group. A straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred. The following may be mentioned as examples and preferably: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.

Alkanoyl in the context of the invention preferably represents a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms, which carries a double-bonded oxygen atom in the 1 position and is linked via the 1 position. A straight-chain or branched alkanoyloxy radical having 1 to 4 carbon atoms is preferred. The following may be mentioned as examples and preferably: formyl, acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl and n-hexanoyl.

Alkanoyloxy in the context of the invention preferably represents a straight-chain or branched alkyl radical having 1 to 6, 1 to 5 or 1 to 3 carbon atoms, which bears a double-bonded oxygen atom in the 1-position and which is linked via a further oxygen atom in the 1-position is. A straight-chain or branched alkanoyloxy radical having 1 to 3 carbon atoms is preferred. Examples and preferably mentioned are: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy and n-hexanoyloxy.

In the context of the invention, monoalkylamino represents an amino group with a straight-chain or branched alkyl substituent which preferably has 1 to 6, 1 to 4 or 1 to 2 carbon atoms. A straight-chain or mixed branched monoalkylamino radical having 1 to 4 carbon atoms. The following may be mentioned as examples and preferably: methylamino, ethylamino, n-propylamino, isopropylamino, t-butylamino, n-pentylamino and n-hexylamino.

In the context of the invention, dialkylamino stands for an amino group with two identical or different straight-chain or branched alkyl substituents which preferably each have 1 to 6, 1 to 4 or 1 to 2 carbon atoms. Straight-chain or branched dialkylamino radicals each having 1 to 4 carbon atoms are preferred. The following may be mentioned by way of example and preferably: NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-

Isopropyl-N-n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexy 1-N-methylamino.

In the context of the invention, mono- or dialkylaminocarbonyl represents an amino group which is linked via a carbonyl group and which has a straight-chain or branched or two identical or different straight-chain or branched alkyl substituents, each preferably having 1 to 4 or 1 to 2 carbon atoms , The following may be mentioned by way of example and preferably: methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, t-butylaminocarbonyl, NN-dimethylaminocarbonyl, NN-diethylarninocarbonyl, N-ethyl-N-methylaminocarbonyl and N-t-

Butyl-N-methylaminocarbonyl.

In the context of the invention, monoacylamino represents an amino group with a straight-chain or branched alkanoyl substituent which preferably has 1 to 6, 1 to 4 or 1 to 2 carbon atoms and is linked via the carbonyl group. A monoacylamino radical having 1 to 2 carbon atoms is preferred. The following may be mentioned as examples and preferably: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.

In the context of the invention, alkoxycarbonylamino represents an amino group with a straight-chain or branched alkoxycarbonyl substituent, the preferred has 1 to 6 or 1 to 4 carbon atoms in the alkoxy radical and is linked via the carbonyl group. An alkoxycarbonylamino radical having 1 to 4 carbon atoms is preferred. Examples that may be mentioned are: methoxycarbonyl-a ino, ethoxycarbonylamino, n-propoxycarbonylamino and t-butoxycarbonylamino.

5- to 6-membered heteroaryl with up to 3 identical or different heteroatoms from the series S, N and / or O preferably stands for an aromatic heterocycle in the context of the invention which is via a ring carbon atom of the heteroaromatic, optionally also via a ring nitrogen atom of the heteroaromatic is linked. Examples include: furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl,

Imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl. Pyridyl, pyrimidinyl, pyridazinyl, furyl and thiazolyl are preferred.

A 3- to 7-, 4- to 7- or 5- to 7-membered saturated or partially unsaturated heterocycle with up to 3 identical or different heteroatoms from the series

S, N and / or O in the context of the invention preferably represents a heterocycle which can contain one or two double bonds and which is linked via a ring carbon atom or a ring nitrogen atom. A 5- to 7-membered saturated heterocycle with up to 2 identical or different heteroatoms from the S, N and / or O series is preferred. Examples include: tetrahydrofur-2-yl,

Tetrahydrofur-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolin-1-yl, piperidin-1-yl, pireridin-4-yl, 1,2-dihydropyridin-l- yl, 1,4-dihydropyridin-l-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, azepin-1-yl, 1,4-diazepin-l-yl. Piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl are preferred.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Fluorine, chlorine or bromine are preferred.

Depending on the substitution pattern, the compounds according to the invention can be expressed in stereoisomeric forms which are either like images and mirror images

(Enantiomers), or which do not behave like image and mirror image (diastereomers) hold, exist. The invention relates both to the enantiomers or diastereomers and to their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.

Furthermore, certain compounds can exist in tautomeric forms. This is known to those skilled in the art and such compounds are also within the scope of the invention.

The compounds according to the invention can also be present as salts. Physiologically acceptable salts are preferred in the context of the invention.

Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carbon or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid are preferred , Benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically acceptable salts can also be salts of the compounds according to the invention with bases, such as, for example, metal or ammonium salts. Preferred examples are alkali metal salts (for example sodium or potassium salts), alkaline earth salts (for example magnesium or calcium salts), and also ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, Di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine. The compounds according to the invention can also be present in the form of their solvates, in particular in the form of their hydrates.

The invention also includes prodrugs of the compounds according to the invention. According to the invention, “prodrugs” refer to those derivatives of the compounds of the general formula (I) which themselves may be less biologically active or also inactive but which, after application under physiological conditions, are converted into the corresponding biologically active form (for example metabolically, solvolytically or on other way).

Compounds of the general formula (I) are preferred

in which

X represents O, S, CH ₂ or CF ₂ ,

R ¹ and R ^{2 are the} same or different and represent hydrogen or methyl,

R ³ and R ^{4 are} identical or different and represent hydrogen, halogen, (C ₁ -C ₄ ) alkyl, CF ₃ , CHF ₂ , CH ₂ F, vinyl or (C ₃ -C ₅ ) cycloalkyl, at least one of the two substituents is not hydrogen,

R ^{5 represents} hydrogen, (d -C ₃ ) -alkyl, fluorine, chlorine or bromine,

R ⁶ for a group of the formula -S (O) ₂ -R ¹⁰ , -NR ^π -C (O) -R ¹² , -CH ₂ -R ¹³ or

-MR ¹⁴ is where

R ¹⁰ for NR ¹⁶ R ¹⁷ , (dC ₈ ) alkyl, (C ₅ -C ₇ ) cycloalkyl, phenyl, benzyl or for a saturated, partially unsaturated or aromatic 5- to 10-membered heterocycle with up to three of the same or various heteroatoms from the series N, O and / or S, where the the aforementioned radicals optionally by one, two or three identical or different substituents selected from the group halogen, hydroxy, oxo, cyano, nitro, amino, dimethylamino, trifluoromethyl, (dC ₄ ) -alkyl, (dC) -alkoxy, (C ₃ - C ₆ ) -cycloalkyl, phenyl, which in turn is optionally substituted by halogen, (dC ₄ ) - alkyl, (dC ₄ ) -

Alkoxy, trifluoromethyl, nitro or cyano is substituted, -C (O) - OR ²² , -C (O) -NR ²³ R ²⁴ , -SO ₂ -NR ²⁵ R ²⁶ , -NH-C (O) -R ²⁷ and -NH-C (O) - OR are substituted, wherein

R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ and R ^{28 are the} same or different and each represents hydrogen, phenyl, benzyl, (dC ^ alkyl or (C ₅ -C ₇ ) cycloalkyl, which in turn, if appropriate, one or more times, identically or differently, by halogen, hydroxy, amino, carboxyl, (dC ₄ ) alkoxy, (dC-alkoxycarbonyl, (dC ₄ ) alkoxycarbonylamino or (d-Cs) -

Alkanoyloxy are substituted,

and

R ¹⁶ and R ^{17 are the} same or different and independently of one another are hydrogen, straight-chain or branched (Cj-Cg) alkyl, which one or more times, the same or different, by (-C-C) alkoxy, (C1-C4) Alkoxycarbonyl, carboxyl, pyridyl or phenyl can be substituted, the latter in turn optionally being substituted by halogen, trifluoromethyl, (C 1 -C 4 -alkyl or (C 1 -C 4) -alkoxy),

for phenyl, which may be replaced by halogen, trifluoromethyl,

(C1-C4) alkyl or (C _j -d alkoxy) is substituted, or for (C ₅ -C ₇ ) cycloalkyl or a 5- to 7-membered one or two

Heterocycle containing nitrogen atoms, wherein Cycloalkyl and heterocycle are in turn optionally substituted by (-CC ₄ ) -alkyl,

or

R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle which contains up to two further heteroatoms from the series N, O and / or S and are replaced by amino, (C1 -C4) - alkyl, (C ^ - C4) - alkoxycarbonyl, (Cι-C4) alkoxycarbonylamino or

Phenyl may be substituted

R ^{π represents} hydrogen, straight-chain or branched (C1-C4) alkyl, benzyl, (C ₃ -C ₇ ) cycloalkyl or a 5- to 7-membered heterocycle containing one to two nitrogen atoms, cycloalkyl and heterocycle optionally are substituted by (C1-C4) alkyl,

R ¹² for straight-chain or branched (-C-Cg) alkyl, which by (C -C ₇ ) - cycloalkyl,

Phenyl, phenoxy or benzyloxy can be substituted, the aromatics mentioned in turn each being substituted up to three times in the same or different manner by halogen, (C1-C4) alkyl or (Cι-C4) alkoxy,

or

represents phenyl which can be substituted up to three times in the same or different manner by (C1-C4) alkyl, (C ₁ -C) alkoxy, halogen, cyano, amino or trifluoromethyl,

or is a group of the formula -OR ²⁹ or -NR ³⁰ R ³¹ ,

wherein

R ^{29 represents} straight-chain or branched (C1-C4) alkyl,

and

R ³⁰ and R ^{31 are the} same or different and independent of each other

for hydrogen, straight-chain or branched (C _j -Cg) alkyl, which may be substituted by phenyl, which in turn may be up to two times the same or different

Halogen, (C _r C ₄ ) alkyl, trifluoromethyl or (C _r C ₄ ) alkoxy is substituted,

for (C ₃ -C ₇ ) cycloalkyl which can be substituted by (C1-C4) alkyl,

or

for phenyl which is identical or different up to three times by halogen, (C _r C ₄ ) alkyl, trifluoromethyl, (C _r C ₄ ) alkoxy or

Amino may be substituted,

or

R ³⁰ and R ³¹ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, which contain up to two further heteroatoms from the series, N, O and / or S and are replaced by amino, (C ₁ -C4) - alkyl, (Cj- C4) - alkanoyl, aminocarbonyl, (C1-C4) - alkoxycarbonyl, ( C ~ ~ C4) alkoxycarbonylamino or phenyl may be substituted,

R ¹³ for a saturated, partially unsaturated or aromatic 5- to 6-membered heterocycle with up to three identical or different

Heteroatoms from the series N, O and / or S, which is optionally selected from the group (-C-C ₄ ) alkyl, hydroxy, oxo, (dC ₄ ) by one, two or three identical or different substituents -

Alkoxy, halogen, cyano, carboxyl and (dC ₄ ) - alkoxycarbonyl is substituted,

or

represents the group -NR ³⁴ R ³⁵ , wherein

R ³⁴ and R ^{5 are} identical or different and for hydrogen, (Cj-C ₆ ) alkyl, which may be substituted by phenyl, for (Cs-C) - cycloalkyl, phenyl or for 5- to 6-membered heteroaryl with bis stand for three identical or different heteroatoms from the series N, O and / or S, phenyl and heteroaryl in turn optionally, in each case once or twice, identically or differently, by hydroxyl, amino, cyano, halogen, (d-C ₄ ) - Alkyl, trifluoromethyl, (dC ₄ ) alkoxy, carboxyl or (d-

C ₄ ) alkoxycarbonyl are substituted,

M represents C = O, CH (OH) or CF ₂ ,

and R ^{14 has} the meaning of R ¹⁰ given above,

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

and

Z for a group of the formula

stands in what

A stands for SO ₂ or C = O,

a means the number 0 or 1,

D represents a straight-chain (dC ₄ ) alkylene group which is optionally substituted one or more times, identically or differently, by (dC ₃ ) alkyl, hydroxy, amino or fluorine,

B is SO ₂ or, if a is 1 and A is SO ₂ , is also C = O,

and

R ^{37 represents} OR ³⁸ or NR ³⁹ R ⁴⁰ , wherein R ^{38 represents} hydrogen, phenyl, benzyl, (-CC ₆ ) alkyl or (C ₃ -C ₇ ) - cycloalkyl, which in turn may be one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (dC ₄ ) alkoxy, (dC ₄ ) alkoxycarbonyl, (dC ^ alkoxycarbonylamino, (C ₁ -Cs) alkanoyloxy or a heterocycle are substituted,

and

R ³⁹ and R ^{40 are the} same or different and each represents hydrogen,

(dC ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl, which in turn are optionally one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (dC ₄ ) -alkoxy, (dC ₄ ) -Alkoxycarbonyl, (dC ₄ ) -alkoxycarbonylamino, (d- C ₅ ) -alkanoyloxy, a heterocycle or, in turn, optionally substituted by halogen or hydroxy-substituted phenyl,

and their pharmaceutically acceptable salts, solvates, hydrates and hydrates of the salts.

Compounds of the general formula (I) are particularly preferred

in which

X represents O, S or CH ₂ ,

R and R represent hydrogen,

R and R ^{4 are the} same or different and are methyl, ethyl, propyl, isopropyl,

Cyclopropyl, trifluoromethyl, chlorine or bromine, R _> 5 represents hydrogen,

R ⁶ for a group of the formula -S (O) ₂ -R ¹⁰ , -NH-C (O) -R ¹² , -CH ₂ -R ¹³ , -C (O) -R ¹⁴ or -CH (OH) - R ⁴¹ is what

R ^{10 stands} for phenyl or for 5- to 6-membered heteroaryl with up to three identical or different heteroatoms from the series N, O and / or S, which may be mono- or discrete, identical or different, by fluorine, chlorine, bromine , Hydroxy, cyano, trifluoromethyl, (dC ₄ ) -alkyl, (dC ₄ ) -alkoxy, carboxyl or (dC ₄ > alkoxycarbonyl) are substituted,

or

represents the group -NR ¹⁶ R ¹⁷ , wherein

R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 5- to 6-membered saturated heterocycle, which contain a further hetero atom from the series N, O or S and substituted by (C 1 -C 4) -alkyl can be,

R ^{12 stands} for straight-chain or branched (C C 1-4 alkyl which is optionally substituted by phenoxy or benzyloxy,

R ¹³ for 5- to 6-membered heteroaryl with up to three identical or different heteroatoms from the series N, O and / or S, which is optionally selected from the group (dC ₄ ) -alkyl by one or two identical or different substituents, Hydroxy, (dC ₄ ) -alkoxy, fluorine, chlorine, bromine, cyano, carboxyl and (dC) -alkoxycarbonyl is substituted, or stands for the group -NR ³⁴ R ³⁵ , wherein R, 3'4 ^{4 represents} (dC ₆ ) alkyl or (C ₅ -C ₇ ) cycloalkyl,

and

R ³⁵ stands for benzyl which is optionally substituted in the phenyl ring by hydroxy, (dC ₄ ) alkoxy, (dC ₄ ) alkyl, trifluoromethyl, fluorine, chlorine or cyano,

R ^{14 represents} a group of the formula -NR ⁴² R ⁴³ , wherein

R ^{42 represents} hydrogen, (dC ₆ ) -alkyl or (C ₅ -C ₇ ) -cycloalkyl,

R ^{43 represents} hydrogen or (dC ₄ ) -alkyl, which can be substituted by phenyl,

or

R and R together with the nitrogen atom to which they are attached form a 5- to 6-membered saturated heterocycle which contain a further heteroatom from the series N, O or S and which are substituted by (C _j -dt) - alkyl can

and

R ^{41 represents} phenyl which is optionally mono- or disubstituted, identical or different, by fluorine, chlorine, bromine, (dC) -alkyl, (dC) -alkoxy, cyano, trifluoromethyl or (CC ₄ ) -alkoxycarbonyl,

represents hydrogen, and

for a group of the formula

where R ^{37 is} hydroxy or the radical -SO ₂ -R ³⁷ or -C (O) -R ^{37 has} the meanings of R ³⁷ given above for a group which, in the sense of a prodrug to the sulfonic acid -SO ₂ - OH or to the carboxylic acid -C (O) -OH or their salts can be degraded,

Compounds of the general formula (I) are very particularly preferred,

in which

X represents CH ₂ or in particular oxygen,

R and R represent hydrogen,

R ³ and R ^{4 are} identical or different and represent methyl, ethyl, propyl, isopropyl, cyclopropyl, trifluoromethyl, chlorine or bromine, R ^{5 represents} hydrogen,

R ^{6 represents} a group of the formula -S (O) ₂ -R ¹⁰ , -CH ₂ -R ¹³ or -C (O) -R ¹⁴ , in which

R ^{10 stands} for phenyl, pyridyl, pyrimidinyl or pyridazinyl, which may be mono- or bivalent, identical or different, by fluorine, chlorine, bromine, hydroxy, cyano, trifluoromethyl, (dC ₄ ) - alkyl, (d- C ₄ ) - Alkoxy, carboxyl or (dC ₄ ) - alkoxycarbonyl are substituted,

or

for a group of the formula

-N NH -N N-Ch or ~ N

stands,

R ¹³ is pyridyl, pyrimidinyl or pyridazinyl, optionally substituted by one or two identical or different substituents selected from the group (dC ₄₎ - alkyl, hydroxy, (dC ₄₎ -alkoxy, fluorine, chlorine,

Bromine, cyano, carboxyl and (dC ₄ ) alkoxycarbonyl are substituted, or stands for the group -NR ³⁴ R ³⁵ , wherein

-RT represents (dC ₄ ) alkyl or (C ₅ -C ₇ ) cycloalkyl,

and R ^{35 represents} benzyl, which is optionally substituted in the phenyl ring by hydroxy, (dC ₄ ) alkoxy, (dC ₄ alkyl, trifluoromethyl, fluorine, chlorine or cyano,

and

R ^{14 represents} a group of the formula -NR ⁴² R ⁴³ , wherein

R ^{42 represents} hydrogen, (d -C ₄ ) alkyl or (C ₅ -C ₇ ) cycloalkyl,

and

R ^{43 represents} hydrogen or (dC) - alkyl, which can be substituted by phenyl,

R represents hydrogen,

and

Z for a group of the formula

in which R ^{38 is} hydrogen, (CC ₄ ) -alkyl or (C ₄ -C ₆ ) -cycloalkyl, and their pharmaceutically acceptable salts, solvates, hydrates and hydrates of the salts.

The general definitions given above or those specified in preferred ranges apply both to the end products of the formula (I) and correspondingly to the starting materials or intermediates required in each case for the preparation.

The radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of other combinations, regardless of the respectively specified combinations of the radicals.

Of particular importance are compounds of the formula (I) in which X represents oxygen.

Of particular importance are compounds of formula (I) in which Z represents a group of the formula

is where R ^{38 is} hydrogen, methyl or ethyl.

Of particular importance are compounds of formula (I) in which R ^{6 represents} a group of formula -S (O) ₂ -R ¹⁰ , in which R ^{10 stands} for phenyl or for 5- to 6-membered heteroaryl with up to two identical or different heteroatoms from the series N, O and / or S, which may be mono- or discrete, identical or different, by fluorine, chlorine, bromine , Hydroxy, cyano, trifluoromethyl, (dC) - alkyl, (dC ₄ ) - alkoxy, carboxyl or (dC) -alkoxycarbonyl are substituted,

or

represents the group -NR ¹⁶ R ¹⁷ , wherein

R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 5- to 6-membered saturated heterocycle, which contain a further hetero atom from the series N, O or S and substituted by (C 1 -C 4) -alkyl can be.

Compounds of the formula (Ia) are of particular importance

in which

X represents CH ₂ or O,

R ³ and R ^{4 are} identical or different and represent bromine, trifluoromethyl, ethyl, cyclopropyl and in particular methyl or chlorine,

Z for a group of the formula -NH-CH ₂ -SO ₂ -OH, -NH-SO ₂ -CH ₂ -C (O) -OH or -NH-C (O) -CH ₂ -SO ₂ -OH, and

R is a group of formula -S (O) ₂ - 10, wherein

R, 10 represents phenyl or pyridyl, which are optionally substituted once or twice, identically or differently, by fluorine, chlorine, cyano, trifluoromethyl, methyl, hydroxy or methoxy.

The following individual compounds are mentioned by way of example and preferably:

Compounds of formula 1 in which Z has the meanings given in Table 1 (* in the table means the point of attachment):

Table 1

Individual compounds of formula 2 in which Z has the meanings given in Table 1 and R ³ instead of methyl in Formula 1 for each of the individual compounds 1 to 4 has the meanings for R ³ given in Table 2:

Table 2

Individual compounds of the formula 3 in which Z and R ³ each have the meanings given in Tables 1 and 2 and R ⁴ instead of methyl in the formula 2 for each of the individual compounds 1 to 52 each have the meanings given in Table 3 for R ⁴ Has:

Table 3

Individual compounds of the formula 4 in which Z, R ³ and R ⁴ each have the meanings given in Tables 1, 2 and 3 and R ⁶ instead of p-fluorophenylsulfonyl in the formula 3 for each of the individual compounds 1 to 676 in each case in the Table 4 has the meanings given for R ⁶ :

Table 4

The compounds of the general formula (I) according to the invention can be prepared by reacting one of the following process variants [A], [B] or [C] with reactive phenol derivatives of the general formulas (Ila-c) with reactive phenyl derivatives of the general If necessary, formulas (IIla-c) are reacted in the presence of inert solvents and catalysts and, if appropriate, with isolation of the intermediates of the general formulas (IV), (IVa), (IVb) or (IVc) or to give compounds of the formula (I), where the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ and X and Z each have the meanings given above,

Z 'has the meaning given for Z or represents a nitro, amino, acetamido, benzyloxycarbonylamino or tert-butoxycarbonylamino group,

and

PG stands for a suitable protective group.

Process variant fA]:

V = F, CI, Br, I, B (OH) ₂ ; W = OH, SH, NH ₂ or V = OH, SH, NH ₂ ; W = F, CI, Br, I, B (OH) ₂

Process variant \]:

(Mb) (lllb) (IVa)

V = CHO; W = Li, MgCI, MgBr, Cu, Ce or Zn org. Group or V = Li, MgCI, MgBr, Cu, Ce or Zn org. Group; W = CHO

(IVb) (Ib) Process variant [C]:

Coupling catalysts such as Pd, Rh and / or Cu compounds may be mentioned as examples of catalysts.

Examples of the reactive groups V and W may be mentioned: halogen, hydroxy, CH2Br, mercapto, amino, CHO, Li, or magnesium, tin, boron, copper, cerium or zinc derivatives.

The phenol derivatives of the general formulas (Ila-c) which can be used according to the invention are known or can be prepared by known methods [compare e.g. Ogata et al., Tetrahedron 26: 731-736 (1970); Borsche et al., Justus Liebigs Ann. Chem. 450, 82 (1926); Pickholz, J. Chem. Soc, 685 (1946); Truce, J. Amer. Chem.

Soc. 73, 3013, 3015 (1951); Fraenkel et al., J. Amer. Chem. Soc. 102 (9), 2869-2880 (1980); Cacciola et al., Bioorg. Med. Chem. Lett. 6 (3), 301-306 (1996); Allen, synth. Commun. 29 (3), 447-456 (1999); WO 00/58279].

The phenyl derivatives of the general formulas (IIIa-c) are also known or can be prepared by known methods [compare, for example, van de Bunt, Recl. Trav. Chim. Pays-Bas 48, 131 (1929); Valkanas, J. Chem. Soc, 5554 (1963); Thea et al., J. Org. Chem. 50, 1867-1872 (1985); Baker et al., J. Chem. Soc, 2303-2306 (1948); Miller et al., J. Med. Chem. 23 (10), 1083-1087 (1980)].

The reaction of the starting compounds (Ila-c) with (Illa-c) generally takes place under normal pressure. However, it can also be carried out under increased or reduced pressure.

The reaction can be carried out in a temperature range from -100 ° C to + 200 ° C, preferably between -78 ° C and + 150 ° C in the presence of inert solvents. The following may be mentioned as inert solvents: dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N-methyl-2-pyrrolidinone (NMP), tetrahydrofuran (THF), diethyl ether, dichloromethane etc.

Depending on the specific substituent pattern, the implementation of (Ila-c) and

(Illa-c) intermediates of the formula (IV), (IVa), (IVb) or (INc) are also formed, in which e.g. the substituent Z 'represents a nitro, amino, acetamido, benzyloxycarbonylamino or tert-butoxycarbonylamino group or X represents a CH (OH) or C (O) group, which is then with or without Isolation of these intermediates can be further implemented by conventional methods to give compounds of the formula (I).

The processes according to the invention can be illustrated by the following formula schemes: Scheme 1:

Scheme 2:

Depending on the meaning of the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , it may be expedient or necessary to vary them at individual levels in the scope of the meaning given.

Protective groups (PG, PG ¹ , PG ² ) are used in the present

Registration understood such groups in starting materials and / or intermediates that present functional groups such as Protect carboxyl, amino, mercapto or hydroxy groups and which are common in preparative organic chemistry. The groups protected in this way can then be converted into free functional groups in a simple manner under known conditions.

The compounds of formula (I) according to the invention show a surprising and valuable spectrum of pharmacological activity and can therefore be used as versatile medicaments. In particular, they can be used for all indications that can be treated with natural thyroid hormones, such as, for example and preferably, depression, goiter or thyroid cancer. Arteriosclerosis, hypercholesterolemia and dyslipidemia can preferably be treated with the compounds of formula (I) according to the invention. In addition, obesity and heart failure can be treated and a postprandial reduction in triglycerides can be achieved.

The compounds are also suitable for the treatment of certain respiratory diseases, in particular pulmonary emphysema and for the medicinal promotion of pulmonary maturation.

The compounds are also suitable for the treatment of pain and migraines, for neuronal repair (remyelination) and for the treatment of Alzheimer's disease.

The compounds are also suitable for the treatment of osteoporosis, cardiac arrhythmias, hypothyroidisms and skin diseases. The compounds can also be used to promote and regenerate hair growth and to treat diabetes.

The active compounds according to the invention open up a further treatment alternative and represent an enrichment of the pharmaceutical industry. Compared to the known and previously used thyroid hormone preparations, the compounds according to the invention show an improved spectrum of activity. They are preferably characterized by great specificity, good tolerance and fewer side effects, especially in the cardiovascular area.

The activity of the compounds according to the invention can e.g. Test in vitro using the T3 promoter assay cell test described below:

The test is carried out with a stably transfected human HepG2 hepatocarcinoma cell which expresses a luciferase gene under the control of a thyroid hormone-regulated promoter. The vector used for transfection carries a minimal thymidine kinase promoter with a thyroid hormone responsive element (TRE), which consists of two inverted palindromes of 12 bp each and an 8 bp spacer, in front of the luciferase gene.

For the test, the cell cultures are sown in 96-well plates in Eagle's Minimal Essential Medium with the following additives: glutamine, tricine [N- (tris (hydroxymethyl) methyl) glycine], sodium pyruvate, non-essential amino acids (L- Ala, L-Asn, L-Asp, L-Pro, L-Ser, L-Glu, Gly), insulin, selenium and transferrin. At 37 ° C and

10% CO2 atmosphere, the cultures are grown for 48 hours. Serial dilutions of test substance or reference compound (T3, T4) and costimulator retinoic acid are then added to the test cultures and these are incubated for a further 48 or 72 hours as before. Each substance concentration is tested in four replicates. To determine those induced by T3 or other substances

The cells are then made luciferase by adding a Triton and Luci ferine-containing buffers (from Promega) lysed and immediately measured luminometrically. The EC50 values of each connection are calculated.

The compounds according to the invention also show surprisingly advantageous properties in the tests described below:

Test descriptions for the detection of pharmacologically active substances:

The substances that are to be tested for their serum cholesterol-lowering effect in vivo are administered orally to male mice with a body weight between 25 and 35 g. The animals are divided into groups with the same number of animals, usually n = 7-10, one day before the start of the experiment. During the entire experiment, drinking water and feed are available to the animals ad libitum. The substances are administered orally once a day for 7 days. For this purpose, the test substances are, for example, in a solution made from Solutol HS 15 +

Dissolved ethanol + saline (0.9%) in a 1 + 1 + 8 ratio or in a solution of Solutol HS 15 + saline (0.9%) in a 2 + 8 ratio. The dissolved substances are applied in a volume of 10 ml / kg body weight with a gavage. Animals that are treated in the same way but only receive the solvent (10 ml / kg body weight) without test substance serve as a control group.

Before the first substance application, blood is taken from each mouse to determine the serum cholesterol by puncturing the retroorbital venous plexus (previous value). The animals are then given the test substance for the first time using a pharyngeal tube. 24 hours after the last substance application, (on the 8th day after the start of treatment), blood is again taken from each animal for the determination of the serum cholesterol by puncturing the retroorbital venous plexus. The blood samples are centrifuged and after the serum has been obtained, the cholesterol is determined photometrically using an EPOS Analyzer 5050 (Eppendorf-Gerätebau, Netheler & Hinz GmbH, Hamburg). The determination is carried out using a commercially available enzyme test (Boehringer Mannheim, Mannheim). The effect of the test substances on the serum cholesterol concentration is determined by subtracting the cholesterol value of the 1st blood sample (previous value) from the cholesterol value of the 2nd blood sample (after treatment). The differences of all cholesterol values in a group are averaged and compared with the mean value of the differences in the control group.

Statistical evaluation is carried out with Student's t-test after the variances have been checked for homogeneity.

Substances that reduce the serum cholesterol of the treated animals statistically significantly (p <0.05) by at least 10% compared to that of the control group are considered to be pharmacologically active.

At the end of the experiment, the animals are weighed and killed after the blood is drawn.

To check for potential cardiovascular side effects under the influence of the substance, the hearts are removed and weighed. An effect on the cardiovascular system can be determined by a significant increase in heart weight. A change in body weight can be used as a further parameter for the substance effect.

Analogously, e.g. NMRI mice, whether ob mice, Wistar rats or fa, fa sugar rats are used as experimental animals for this test.

Another in vivo test in which the compounds according to the invention show surprisingly advantageous properties is the animal model of the cholesterol-fed rat [A. Taylor et al., Molecular Pharmacology 52, 542-547 (1997); Z. Stephan et al., Atherosclerosis 126, 53-63 (1996)]. Furthermore, the cholesterol-lowering effect of the compounds according to the invention can also be checked in normocholesterolemic dogs by oral administration of the test substances for 5-7 days.

For further investigation of potential cardiovascular side effects under

Influence of substances can be used, inter alia, to determine the expression of the mRNA of the "HCN2" ion channel ("hyperpolarization-activated cyclic nucleotide-gated channel") in mouse or rat hearts [cf. also: Trost et al., Endocrinology 141 (9), 3057-3064 (2000); Gloss et al., Endocrinology 142 (2), 544-550 (2001); Pachuki et al., Circulation Research 85, 498-503 (1999)]:

HCN2 assay:

The mRNA of the "hyperpolarization-activated cyclic nucleotide-gated" cation channel (HCN2) in rat hearts was determined using real-time PCR

(TaqMan PCR; Heid et al., Genome Res. 6 (10), 986-994). For this purpose, after preparation of the heart, the total RNA is isolated using RNaesy columns (Qiagen), digested with DNase and then rewritten into cDNA (SUPERS CRTPT-II RT cDNA synthesis kit, Gibco). The HCN2 mRNA determination is carried out on an ABI Prism 7700 device (from Applied Biosystems). The sequence of the "forward" and "reverse" primer was: 5'-GGGAATCGACTCCGAGGTC-3 'and 5'-GATCTTGGTGAAACGCACGA-3', that of the fluorescent sample 5'-6FAM-ACAAGACGGCCCGTGCACTACGC-TAMRA-3 (FAM = fluorescent 6-carboxyfluorescein; TAMRA = quencher 6-carboxytetramethylrhodamine). During the polymerase chain reaction, the 5'-exonuclease activity

Taq polymerase cleaved the fluorescent dye FAM and thereby obtained the previously quenched fluorescence signal. The number of cycles at which the fluorescence intensity was 10 standard deviations above the background fluorescence is recorded as the so-called “threshold cyle” (Ct value). The relative expression of the HCN2 mRNA calculated in this way is then based on the expression of the ribosomal

Protein L32 standardized. This assay can also be carried out in an analogous manner with mouse hearts. The sequence of the "forward" and "reverse" primer in this case was 5'-CGAGGTGCTGGAGGAATACC-3 'and 5'-CTAGCCGGTCAATAGCCACAG-3', that of the fluorescent sample 5'-6FAM-CATGATGCGGCGTGCCTTTGAG-

TAMRA-third

For the application of the compounds of the general formula (I), all customary application forms come into consideration, i.e. i.e. oral, parenteral, inhalative, nasal, sublingual, buccal, rectal or external, e.g. transdermally, particularly preferably orally or parenterally. In parenteral administration, intravenous, intramuscular, subcutaneous administration should be mentioned in particular, e.g. as a subcutaneous depot. Oral application is very particularly preferred.

The active ingredients can be administered alone or in the form of preparations. For oral application, suitable preparations include Tablets, capsules, pellets, dragees, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions. The active ingredient must be present in such an amount that a therapeutic effect is achieved. In general, the active ingredient can be present in a concentration of 0.1 to 100% by weight, in particular 0.5 to 90% by weight, preferably 5 to 80% by weight. In particular, the concentration of the active ingredient should be 0.5-90% by weight, i.e. the active substance should be present in amounts sufficient to achieve the dosage range indicated.

For this purpose, the active ingredients can be converted into the customary preparations in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable carriers, auxiliaries, solvents, vehicles, emulsifiers and / or dispersants. Examples of auxiliaries include: water, non-toxic organic solvents such as paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerol), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock powder (e.g. talc or silicates), Sugar (e.g. milk sugar), emulsifiers, dispersants (e.g. polyvinylpyrrolidone) and lubricants (e.g. magnesium sulfate).

In the case of oral administration, tablets can of course also contain additives such as sodium citrate together with additives such as starch, gelatin and the like. Aqueous preparations for oral administration can also be mixed with flavor enhancers or colorants.

In the case of oral administration, doses of 0.001 to 5 mg / kg, preferably 0.001 to 3 mg / kg of body weight are preferably administered per 24 hours.

The new active substances can be used alone and, if necessary, also in combination with other active substances, preferably from the group CETP inhibitors, antidiabetics, antioxidants, cytostatics, calcium antagonists, antihypertensive agents, thyroid hormones, inhibitors of HMG-CoA reductase, inhibitors of HMG-CoA reductase Gene expression, squalene synthesis inhibitors, ACAT inhibitors, circulatory agents, platelet aggregation inhibitors, anticoagulants, angiotensin II receptor antagonists, cholesterol absorption inhibitors, MTP inhibitors, aldose reductase inhibitors, fibrates, niacin, niacin Inhibitors and PPAR agonists are administered.

The examples below are intended to illustrate the invention by way of example without restricting the scope of protection. The following examples are prepared analogously to the processes specified above. starting compounds

Example I

4- (2,6-dimethyl-4-nitrophenoxy) -2- (phenylsulfonyl) phenol

0.32 g (7.99 mmol) sodium hydride (60%) are suspended in 15 ml N-methyl-2-pyrrolidinone. 1.0 g (4.0 mmol) of 2- (phenylsulfonyl) -1,4-dihydroxybenzene are added at 0.degree. Allow 45 min. Stir at room temperature and then add 0J4 g (4.4 mmol) of 2-fluoro-1,3-dimethyl-5-nitrobenzene. The mixture is stirred at 75 ° C. for one hour, then poured onto water and extracted twice with ethyl acetate. The organic phases are combined, washed once with water and dried with sodium sulfate. The solvent is removed in vacuo. The residue is crystallized from a solvent mixture consisting of diethyl ether, cyclohexane and ethyl acetate. The product is suctioned off and dried in vacuo. 1.0 g (63% of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 2.19 (s, 6H), 6.87 (d, 1H), 7.04 (dd, 1H), 7.20

(d, 1H), 7.54-7.72 (m, 3H), 7.85-7.89 (m, 2H), 8.16 (s, 2H). Example II

4- (4-amino-2,6-dimethylphenoxy) -2- (phenylsulfonyl) phenol

0.96 g (2.4 mmol) of 4- (2,6-dimethyl-4-nitrophenoxy) -2- (phenylsulfonyl) phenol (Example I) are dissolved in a mixture of 20 ml of ethanol and 12 ml of dichloromethane. A catalytic amount of palladium on activated carbon (10% strength) is added and the mixture is hydrogenated for 4 hours at 1.5 bar. The mixture is then filtered through Eaeselgur and freed from the solvent in vacuo. The product is in

Vacuum dried. 0.88 g (99% of theory) of the title compound are obtained.

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.93 (s, 6H), 5.17 (s, 2H), 6.38 (s, 2H), 6.83 (d, 1H), 7.01 (dd, 1H), 7.12 (d, 1H), 7.54-7.71 (m, 3H), 7.81-7.85 (m, 2H), 10.33 (s, 1H).

embodiments

example 1

Methyl [({4- [4-hydroxy-3- (phenylsulfonyl) phenoxy] -3,5-dimethylphenyl} amino) sulfonyl] acetate

Example 2

Ethyl {[(4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxyphenoxy} -3,5-dimethylphenyl) aminojsulfonyl} acetate

Example 3

Methyl {[(4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxyphenoxy} -3,5-dimethylphenyl) amino] sulfonyl} acetate

Example 4

Isopropyl {[(4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxyphenoxy} -3,5-dimethylphenyl) amino] sulfonyl} acetate

Example 5 [({4- [4-Hydroxy-3- (phenylsulfonyl) phenoxy] -3,5-dimethylphenyl} amino) sulfonyl] acetic acid

Example 6

{[(4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxyphenoxy} -3,5-dimethylphenyl) amino] sulfonyl} acetic acid

Example 7

{[(4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxybenzyl} -3,5-dimethylphenyl) amino] sulfonyl} acetic acid Example 8

2 - ({4- [4-Hydroxy-3- (phenylsulfonyl) phenoxy] -3,5-dimethylphenyl} amino) -2-oxoethanesulfonic acid

Example 9

2 - [(4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxyphenoxy} -3,5-dimethylphenyl) amino] -

2-oxoethansulfonsäure

Example 10

2 - [(4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxybenzyl} -3,5-dimethylphenyl) amino] -2-oxoethanesulfonic acid

Claims

Patentansprfiche

1. Compounds of the general formula (I)

in which

X represents O, S, SO, SO ₂ , CH ₂ , CHF, CF ₂ or NR ⁸ , in which R ^{s is} hydrogen or (CrC ₄ ) alkyl,

R ¹ and R ^{2 are the} same or different and represent hydrogen or (-) - alkyl,

R represents hydrogen, (-CC ₄ ) -alkyl or halogen,

R ⁶ for a group of the formula -SR ⁹ , -S (O) _n -R ¹⁰ , -NR ⁿ -C (O) -R ¹² ,

-CH ₂ -R ¹³ or -MR ¹⁴ , wherein

R ⁹ for (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl, (C ₆ - Ci _ö ) aryl, (C ₆ -C ₁₀ ) -Arylmethyl or for a saturated, partially unsaturated or aromatic 5- to 10-membered heterocycle with up to four identical or different Heteroatoms from the series N, O and / or S, the abovementioned radicals optionally being selected by one, two or three identical or different substituents from the group halogen, hydroxy, oxo, cyano, (Ci-Cβ) - alkyl, (- C ₆ ) alkoxy, carboxyl and (C ₁ -C ₄ ) alkoxycarbonyl are substituted,

n represents the number 1 or 2,

R ¹⁰ for OR ¹⁵ , NR ¹⁶ R ¹⁷ , (QC ^ alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂ -

C ₆ ) alkenyl, (C ₆ -C ₁₀ ) aryl, (C ₆ -Cιo) arylmethyl or for a saturated, partially unsaturated or aromatic 5- to 10-membered heterocycle with up to four identical or different heteroatoms from the Row N, O and or S stands, the abovementioned radicals optionally being selected from the group halogen, hydroxy, oxo, cyano, nitro, amino, NR ¹⁸ R ¹⁹ , trifluoromethyl, (dC ₆ by one, two or three identical or different substituents ) -Alkyl, optionally substituted by R ²⁰ (-C-C ₆ ) alkoxy, (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, which in turn optionally by halogen, (CC ₄ ) - alkyl , (CC) alkoxy, trifluoromethyl, nitro or cyano is substituted, -OC (O) -R, -C (O) -OR ²² , -C (O) -NR ²³ R ²⁴ , -SO ₂ -NR ²⁵ R ²⁶ , -NH-C (O) -R ²⁷ and -NH-C (O) -OR ^{28 are} substituted, wherein

R ^l R ^ιs , R ^ιy , RR \ R ^A RR \ R ^D , R ^zo , R ^/ and R are the same or different and each for

Hydrogen, phenyl, benzyl, (-C ^ alkyl or (C ₃ -

C ₈ ) -cycloalkyl, which in turn are optionally one or more, identical or different, by

Halogen, hydroxy, amino, carboxyl, (dC ^ alkoxy, (C i -C ₄ ) - alkoxycarbonyl, (C i -C ₄ ) - alkoxycarbonylamino, (Cι-C ₅ ) -alkanoyloxy, a heterocycle or, in turn, optionally substituted by halogen or hydroxy-substituted phenyl,

and

1 fi 17

R and R are the same or different and are independently hydrogen, straight-chain or mixed

10 branched (-C-C6) -alkyl, which one or more, the same or different, by mono- (-C-Cg) -alkylamino, di- (-C-C, 5) -alkylamino, (C _j -C ^ -Alkoxy, (C _j - Cg) - alkoxycarbonyl, carboxyl, pyridyl or (C _Ö -CJO) - aryl may be substituted, the latter in turn

15 optionally by halogen, trifluoromethyl, (Cj-

Cg ^ alkyl or (-C-C6) alkoxy is substituted,

for (C ₆ -C ₁₀ ) aryl which may be replaced by halogen,

Trifluoromethyl, (C _r C ₆ ) alkyl or (C _r C ₆ ) alkoxy

20 is substituted, or for (C3-Cg) -cycloalkyl or one

5- to 7-membered heterocycle containing one to two nitrogen atoms, the cycloalkyl and heterocycle in turn optionally being substituted by (C1-C4) alkyl,

25 or

R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated,

30 optionally form a benzo-fused heterocycle of up to two further heteroatoms from the series N, Contain O and or S and can be substituted by amino, (Cj-C ₆ ) -alkyl, (Cι-C) -alkoxycarbonyl, (Ci-C ^ -alkoxy-carbonylamino or phenyl,

R ^π for hydrogen, straight-chain or branched (C ^ C _Ö ) - alkyl, which one or more times, the same or different, by mono- (-C-C6) alkylamino, di- (-C-C6) alkylamino, (Cj -C.}) - Alkoxy, (Cj-Cg) - alkoxycarbonyl, carboxyl, pyridyl or (Cg-Cιo) -aryl can be substituted, the latter in turn optionally being replaced by halogen, trifluoromethyl, (C ₁ -C 6) -alkyl or ( C _j -Cg alkoxy is substituted for (C3-C8) cycloalkyl or for a 5- to 7-membered heterocycle containing one to two nitrogen atoms, the cycloalkyl and heterocycle optionally being substituted by (C _j -C ^ alkyl) .

R ¹² for straight-chain or branched (C ^ -015) - alkyl, which can be substituted by (C3-Cg) -cycloalkyl, (C _j -C ^ -alkoxy, phenyl, phenoxy or benzyloxy, the flavors mentioned for their part each up to three times the same or different can be substituted by halogen, (C _r C ₆ ) -alkyl or (C ₁ -C) -alkoxy,

for _(C3-C8) cycloalkyl which may be substituted by (Ci-C ^ alkoxy or phenyl,

for (Cg-Cio aryl, which can be substituted up to three times in the same or different manner by (C _r C ₆ ) -alkyl, (C _r C ₆ ) -alkoxy, halogen, cyano, amino, trifluoromethyl or phenyl,

or represents a 5- to 6-membered saturated or aromatic, optionally benzo-fused heterocycle with up to two heteroatoms from the series N, O and / or S,

or

is a group of the formula -OR ²⁹ or -NR ³⁰ R ³¹ ,

wherein

10

R ²⁹ represents straight-chain or branched (Ci-Cg) alkyl,

and

15 R ³⁰ and R ^{31 are the} same or different and are independent of each other

for hydrogen, straight-chain or branched (Cγ-Ci2) alkyl, which by aminocarbonyl, a group of

20 formula -NR ³² R ³³ , 5- to 6-membered heteroaryl, which contains up to 3 heteroatoms selected from the series N, O and / or S, or can be substituted by phenyl, phenyl optionally up to two times the same or different by halogen, (C1-C4) - alkyl,

25 trifluoromethyl or (-C-C4) alkoxy is substituted,

for (C ₃ -C ₈ ) cycloalkyl which can be substituted by (C _r C ₄ ) alkyl,

30 for (C ₆ -Cιo) aryl which is identical or different up to three times by halogen, (Ci ^) - alkyl, trifluoro methyl, (-C-C4) -Al oxy, amino, phenyl or phenoxy may be substituted,

or

represent a 5- to 7-membered, saturated or unsaturated heterocycle containing one or two nitrogen atoms, which is optionally substituted by (C ₁ -C 4) -alkyl or an oxo group,

10 where

R ³² and R ^{33 are the} same or different and are independently hydrogen, (CJ-C _Ö ) - 15 alkyl, phenyl or (C ₆ -C ₁₀ ) arylsulfonyl,

or

20 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated heterocycle which optionally contains up to two further heteroatoms from the series, N, O and / or S,

25 or

R ³⁰ and R ³¹ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle which contains up to two further heteroatoms from the series, N, O and / or S and by amino, (-CC ₆ ) - alkyl, (C _r C4) - alkanoyl, amino carbonyl, (C 1 -C ₄ ) - alkoxycarbonyl, (-C-C ₄ ) alkoxycarbonylamino, phenyl or pyridyl may be substituted .

R for a saturated, partially unsaturated or aromatic

5- to 10-membered heterocycle with up to three identical or different heteroatoms from the series N, O and / or S, which is optionally selected from the group by one, two or three identical or different substituents (Cr

C ₄ ) -alkyl, hydroxy, oxo, (-G -alkoxy, halogen, cyano, carboxyl and (dC ₄ ) - alkoxycarbonyl,

or

R ^{13 represents} the group -NR ³⁴ R ³⁵ , wherein

R ³⁴ and R ^{35 are the} same or different and represent hydrogen, (-CC ₈ ) - alkyl, which may be substituted by (C ₆ -C ₁₀ ) aryl, (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or for 5- to 6-membered heteroaryl with up to three identical or different heteroatoms from the series N, O and or S, where aryl and heteroaryl in turn, if appropriate, in each case once or twice, the same or different , by hydroxy, amino, cyano, halogen,

Trifluoromethyl, (-CC ₄ ) alkyl, (CC) alkoxy, carboxyl, (C ₁ -C ₄ ) alkoxycarbonyl or mono- or di- (C ₁ -C ₄ ) alkylaminocarbonyl are substituted,

M represents C = O, CH (OH), CHF or CF ₂ , and

R ^{14 has} the meaning of R ¹⁰ given above,

R ^{7 represents} hydrogen, (dC ₄ ) -alkyl or (dC ₄ ) -alkanoyl,

and

for a group of the formula

stands in what

R ^{36 represents} hydrogen or (dC ₄ ) alkyl,

a means the number 0 or 1,

A stands for SO ₂ or C = O,

B is SO ₂ or, if a is 1 and A is SO ₂ , is also C = O, and

R »3 ^J 7 ' _Λ for _S _r O _Y R _Γ » 3 ^J 8 ^δ o „d Je_„ r τ NvτRr.3 ^j 9 ^y Rn4 ^w 0, where

R ³⁸ , R ³⁹ and R ^{40 are the} same or different and are each for

Hydrogen, phenyl, benzyl, (dC ₆ ) -alkyl or (C ₃ -

C ₈ ) -cycloalkyl, which in turn are optionally one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (dC ₄ ) -alkoxy,

(C 1 -C ₄ ) -alkoxycarbonyl, (C _\ -C ₄ ) - alkoxycarbonyl-amino, (C ₁ -C ₅ ) -alkanoyloxy, a heterocycle or, in turn, optionally substituted by halogen or hydroxy-substituted phenyl,

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

X represents O, S, CH ₂ or CF ₂ ,

1

R and R are the same or different and represent hydrogen or methyl,

R ³ and R ^{4 are the} same or different and represent hydrogen, halogen, (C - C ₄ ) alkyl, CF ₃ , CHF ₂ , CH ₂ F, vinyl or (C ₃ -C ₅ ) cycloalkyl, at least one of the two substituents is not hydrogen,

R ^{5 represents} hydrogen, (dC ₃ ) alkyl, fluorine, chlorine or bromine, represents a group of the formula -S (O) ₂ -R ¹⁰ , -NR ⁿ -C (O) -R ¹² , -CH ₂ -R ¹³ or -MR ¹⁴ , wherein

R ¹⁰ for NR ¹⁶ R ¹⁷ , (dC ₈ ) alkyl, (C ₅ -C ₇ ) cycloalkyl, phenyl,

Benzyl or represents a saturated, partially unsaturated or aromatic 5- to 10-membered heterocycle with up to three identical or different heteroatoms from the series N, O and / or S, the abovementioned radicals optionally being replaced by one, two or three identical or various

Substituents selected from the group halogen, hydroxyl, oxo, cyano, nitro, amino, dimethylamino, trifluoromethyl, (dC ₄ ) alkyl, (dC ₄ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl, phenyl, which in turn, if appropriate is substituted by halogen, (dC ₄ ) alkyl, (dC ₄ ) alkoxy, trifluoromethyl, nitro or cyano, -C (O) -OR ²² , -C (O) -NR ²³ R ²⁴ , -SO ₂ -NR ²⁵ R ²⁶ , -NH-C (O) -R ²⁷ and -NH-C (O) -OR ^{28 are} substituted, wherein

R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ and R ^{28 are the} same or different and each represents hydrogen, phenyl, benzyl, (d-

C ₄ ) -alkyl or (C ₅ -C ₇ ) -cycloalkyl, which in turn are optionally one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (CrC ₄ ) -alkoxy, (dC ₄ ) - Alkoxycarbonyl, (CrC ₄ ) -alkoxycarbonylamino or (-C-C5) -alkanoyl-oxy are substituted,

and

R ¹⁶ and R ^{17 are the} same or different and are independently hydrogen, straight-chain or mixed branched (-C-Cg) alkyl, which one or more times, the same or different, by

C4) -alkoxycarbonyl, carboxyl, pyridyl or phenyl may be substituted, the latter in turn 5 optionally being substituted by halogen, trifluoromethyl, (Cj-d ^ -alkyl or (C _j -d ^ -alkoxy),

for phenyl, which is optionally substituted by halogen,

Trifluoromethyl, (C _r C ₄ ) alkyl or (C _r C ₄ ) alkoxy

10 is substituted, or for (C5-C7) cycloalkyl or one

5- to 7-membered heterocycle containing one to two nitrogen atoms, the cycloalkyl and heterocycle in turn optionally being substituted by (Ci-C4) -alkyl,

15 or

R and R together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle which contain up to two further heteroatoms from the series N, O and / or S and are substituted by amino, (Cι- C ₄ ) -alkyl, (-C-C) -alkoxycarbonyl, (-CC-C4) alkoxycarbonylamino or phenyl may be substituted, 25

R ^{11 represents} hydrogen, straight-chain or branched (C 1 -C 4) -alkyl,

Benzyl, (C ₃ -C ₇ ) cycloalkyl or represents a 5- to 7-membered heterocycle containing one to two nitrogen atoms, the cycloalkyl and heterocycle optionally being replaced by (Cj-

30 d ^ -Alky! are substituted, R ¹² for straight-chain or branched (-C-Cg) alkyl, which can be substituted by (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₄ ) alkoxy, phenyl, phenoxy or benzyloxy, the aromatics mentioned in turn each up to three times the same or different can be substituted by halogen, (C1-C4) alkyl or (C ₁ -C4) alkoxy,

or

10 for phenyl, which is up to three times the same or different

(C1-C4) alkyl, (-C-C ₄ ) alkoxy, halogen, cyano, amino or trifluoromethyl may be substituted,

or

15 represents a group of the formula -OR ²⁹ or -NR ³⁰ R ³¹ ,

wherein

20 R ^{29 stands} for straight-chain or branched (C ^ -d ^ -Alky!

and

R ³⁰ and R ^{31 are the} same or different and independent of each other

for hydrogen, straight-chain or branched (C _j - 5 Cg) alkyl, which may be substituted by phenyl, which in turn may be up to two times the same or different by halogen, (C ₁ -C ₄ ) alkyl, trifluoromethyl or (C ^ -C ₄ ) alkoxy is substituted,

10 for (C ₃ -C ₇ ) cycloalkyl, which can be substituted by (C _r C ₄ ) alkyl,

or

15 represents phenyl, which can be substituted up to three times in the same or different manner by halogen, (-CC ₄ ) -alkyl, trifluoromethyl, (C 1 -C ₄ ) -alkoxy or amino,

or

20

R ³⁰ and R ³¹ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle which contains up to two further heteroatoms from the series, N, O and / or S and 25 by amino, _(Cι-C4) alkyl, (C ₄ _-C?) - alkanoyl, amino aminocarbonyl, (C ₁ -C ₄₎ - alkoxycarbonyl, _(Cι-C4) alkoxy carbonylamino or phenyl may be substituted,

R ^{13 is} a saturated, partially unsaturated or aromatic 30 5- to 6-membered heterocycle with up to three identical or different heteroatoms from the series N, O and / or S. stands, optionally by one, two or three identical or different substituents selected from the group (d- C ₄ ) alkyl, hydroxy, oxo, (-C-C ₄ ) alkoxy, halogen, cyano, carboxyl and (dC ₄ ) Alkoxycarbonyl is substituted,

or

represents the group -NR ³⁴ R ³⁵ , wherein

R ³⁴ and R ^{35 are the} same or different and are hydrogen,

(Ci-Cβ) - alkyl, which can be substituted by phenyl, for (C ₅ -C ₇ ) cycloalkyl, phenyl or for 5- to 6-membered heteroaryl with up to three identical or different heteroatoms from the series N, O and / or S, where phenyl and heteroaryl in turn, if appropriate, in each case one or two times, identically or differently, by hydroxy, amino, cyano, halogen, (-C-C ₄ ) -alkyl, trifluoromethyl, (d-C ₄ ) -alkoxy , Carboxyl or (dC ₄ ) alkoxycarbonyl are substituted,

M represents C = O, CH (OH) or CF ₂ ,

and

R ^{14 has} the meaning of R ¹⁰ given above,

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

and for a group of the formula

stands in what

A stands for SO ₂ or C = O,

a means the number 0 or 1,

d means the number 0 or 1, with the proviso that the sum

(a + d) is not equal to the number 0,

B is SO ₂ or, if a is 1 and A is SO ₂ , is also C = O,

and

R ^{37 represents} OR ³⁸ or NR ³⁹ R ⁴⁰ , wherein

R ^{38 represents} hydrogen, phenyl, benzyl, (dC ₆ ) alkyl or (C ₃ -

C) -cycloalkyl, which in turn is optionally one or more, identical or different, by halogen,

Hydroxy, amino, carboxyl, (C ₁ -C) alkoxy, (dC ₄ ) alkoxycarbonyl, (dC ₄ ) alkoxycarbonylamino, (d- C ₅ ) -alkanoyloxy or a heterocycle are substituted,

and

R ³⁹ and R ^{40 are the} same or different and are each for

Are hydrogen, (dC ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl, which in turn are optionally one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (dC ₄ ) -alkoxy, (dC ) -

Alkoxycarbonyl, (dC ₄ ) -alkoxycarbonylamino, (d-Cs) -alkanoyloxy, a heterocycle or, in turn, optionally substituted by halogen or hydroxy-substituted phenyl,

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

X represents O, S or CH ₂ ,

R ¹ and R ^{2 represent} hydrogen,

R ³ and R ^{4 are the} same or different and are methyl, ethyl, propyl,

Isopropyl, cyclopropyl, trifluoromethyl, chlorine or bromine,

R represents hydrogen,

R ⁶ for a group of the formula -S (O) ₂ -R ¹⁰ , -NH-C (O) -R ¹² , -CH ₂ -R ¹³ , -C (O) -R ¹⁴ or -CH (OH) - R ⁴¹ is what R ^{10 stands} for phenyl or for 5- to 6-membered heteroaryl with up to three identical or different heteroatoms from the series N, O and / or S, which may be mono- or discrete, identical or different, by fluorine, chlorine, bromine , Hydroxy, cyano, trifluoromethyl, (dC ₄ ) -alkyl, (CC ₄ ) -alkoxy, carboxyl or (dC ₄ ) -alkoxycarbonyl are substituted,

or

represents the group -NR 1 ¹ 6 ⁰ -Rr, 1'7 ', wherein

R and R together with the nitrogen atom to which they are attached form a 5- to 6-membered saturated heterocycle which can contain a further heteroatom from the series N, O or S and can be substituted by (C1-C4) alkyl .

R ^{12 represents} straight-chain or branched (C 1 -C 4 -alkyl which is optionally substituted by phenoxy or benzyloxy,

R ¹³ for 5- to 6-membered heteroaryl with up to three identical or different heteroatoms from the series N, O and / or S, which is optionally selected from the group (dC ₄ ) by one or two identical or different substituents - alkyl,

Hydroxy, (dC ₄ ) alkoxy, fluorine, chlorine, bromine, cyano, carboxyl and (dC ₄ ) - alkoxycarbonyl is substituted, or stands for the group -NR ³⁴ R ³⁵ , wherein

R ^{34 represents} (dC ₆ ) alkyl or (C ₅ -C ₇ ) cycloalkyl, and

R ^{35 represents} benzyl which is optionally substituted in the phenyl ring by hydroxy, (C ₁ -C ₄ ) alkoxy, (dC ₄ ) alkyl, trifluoromethyl, fluorine, chlorine or cyano,

R ^{14 represents} a group of the formula -NR ⁴² R ⁴³ , wherein

R ^{42 represents} hydrogen, (dC ₆ ) -alkyl or (C ₅ -C ₇ ) -cycloalkyl,

or

R ⁴² and R ⁴³ together with the nitrogen atom to which they are attached form a 5- to 6-membered saturated

Form heterocycle, which contain another heteroatom from the series N, O or S and by (C1-C4) -

Alkyl may be substituted

and

R ^{41 represents} phenyl, which may be mono- or discrete, identical or different, by fluorine, chlorine, bromine, (C ₁ -C) alkyl, (dC ₄ ) alkoxy, cyano, trifluoromethyl or (dC) alkoxy carbonyl is substituted,

represents hydrogen, and

Z for a group of the formula

in which R ^{37 is} hydroxy or the radical -SO ₂ -R ³⁷ or

-C (O) -R ³⁷ the meanings of R ³⁷ given above for a

Has a group which can be degraded in the sense of a prodrug to the sulfonic acid -SO ₂ -OH or to the carboxylic acid -C (O) -OH or the salts thereof,

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

X represents CH ₂ or in particular oxygen,

R ¹ and R ^{2 represent} hydrogen,

R ³ and R ^{4 are} identical or different and represent methyl, ethyl, propyl, isopropyl, cyclopropyl, trifluoromethyl, chlorine or bromine,

R ^{5 represents} hydrogen, represents a group of the formula -S (O) ₂ -R ¹⁰ , -CH ₂ -R ¹³ or -C (O) -R ¹⁴ , wherein

R ^{10 stands} for phenyl, pyridyl, pyrimidinyl or pyridazinyl, which may be mono- or discrete, identical or different, by fluorine, chlorine, bromine, hydroxy, cyano, trifluoromethyl, (dC ₄ ) -alkyl, (dC ₄ ) -alkoxy, Carboxyl or (dC ₄ ) - alkoxycarbonyl are substituted,

or

for a group of the formula

stands,

R ^{13 represents} pyridyl, pyrimidinyl or pyridazinyl, which are optionally selected from the group (dC ₄ ) -alkyl, hydroxy, (C1-C4) by one or two identical or different substituents -

Alkoxy, fluorine, chlorine, bromine, cyano, carboxyl and (dC ₄ ) - alkoxycarbonyl are substituted, or stands for the group -NR ³⁴ R ³⁵ , wherein

R ^{34 represents} (CC ₄ ) alkyl or (C ₅ -C ₇ ) cycloalkyl,

and R represents benzyl which is optionally substituted in the phenyl ring by hydroxy, (dC ₄ ) alkoxy, (dC ₄ ) alkyl, trifluoromethyl, fluorine, chlorine or cyano,

and

R ^{14 represents} a group of the formula -NR ⁴² R ⁴³ , wherein

R ^{42 represents} hydrogen, (dC ₄ ) alkyl or (C ₅ -C ₇ ) cycloalkyl,

and

R ^{43 represents} hydrogen or (dC ₄ ) - alkyl, which is characterized by

Phenyl may be substituted

R ^{7 represents} hydrogen,

and

Z for a group of the formula

in which R ^{38 is} hydrogen, (dC) -alkyl or (C ₄ -C ₆ ) -cycloalkyl,

5. Medicaments containing at least one compound of formula (I), which are defined in claim 1, and inert, non-toxic, pharmaceutically suitable carriers, auxiliaries, solvents, vehicles, emulsifiers and / or dispersants.

6. Use of compounds of formula (I) and medicaments, which are defined in claims 1 to 5, for the prevention and treatment of diseases.

7. Compounds of formula (I), which are defined in claim 1, for the prevention and treatment of diseases.

8. Use of compounds of formula (I), which are defined in claim 1, for the manufacture of medicaments.

9. Use of compounds of formula (I), which are defined in claim 1, for the manufacture of medicaments for the treatment of arteriosclerosis.

10. A method for the prevention and treatment of diseases, characterized in that compounds of the formula (I), which are defined in claim 1, are administered to living beings.

11. A process for the preparation of compounds of formula (I), which are defined in claim 1, characterized in that reactive phenol derivatives with reactive phenyl derivatives of the general formula (Illa-c), if appropriate in the presence of inert solvents and catalysts and optionally isolating the intermediates of formula (I).