DE10130835A1 - Diphenyl derivatives - Google Patents

Abstract

The invention relates to the novel diphenyl derivatives of formula (I), wherein the variables are defined as in the claims. The invention further relates to methods for producing the same and to their use in medicaments. The compounds of formula (I) are especially suitable for use in any indications that may be treated with natural thyroid hormones, such as, for example, depression, goiter or cancer of the thyroid. The inventive compounds of formula (I) are preferably used to treat arteriosclerosis, hypercholesterolemia, dyslipidemia as well as corpulence and obesity.

Description

The invention relates to new diphenyl derivatives, processes for their preparation as well as their use in medicines.

EP-A-580 550 describes oxamic acid derivatives which cholesterol-isolate have characteristic properties in mammals. As a pharmacological property is the reduction of plasma cholesterol, especially of LDL cholesterol pre-stressed. Cholesterol-lowering effects are also described in EP-A-188 351 wrote for certain diphenyl ethers with thyroid hormone-like effects.

Diphenyl ethers as thyroid receptor ligands are also described in WO 99/00353 and WO 00/39077 discloses. Other diphenyl derivatives with thyroid hormone-like Properties are described in WO 98/57919, WO 99/26966 and WO 00/58279 wrote. Certain diphenyl sulfones used to treat hair loss are found in WO 00/72810 and WO 00/73265 claimed.

The object of the present invention is to provide new connections with improved, especially 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 , where R ^{8 is} hydrogen or (C ₁ -C ₄ ) alkyl,
R ¹ and R ^{2 are} identical or different and represent hydrogen or (C ₁ -C ₄ ) alkyl,
R ³ and R ^{4 are} identical or different and represent hydrogen, halogen, cyano, (C ₁ -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 ₁ -C ₄ ) alkyl or halogen,
R ^{6 represents} a group of the formula -SR ⁹ , -S (O) _n -R ¹⁰ , -NR ¹¹ -C (O) -R ¹² , -CH ₂ -R ¹³ or -MR ¹⁴ , in which
R ^{9 is} for (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl, (C ₆ -C ₁₀ ) aryl, (C ₆ -C ₁₀ ) Arylmethyl or 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 having one, two or three identical or different substituents selected from the group halogen, hydroxy, oxo, cyano, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, carboxyl and (C ₁ -C ₄ ) alkoxycarbonyl are substituted .
n represents the number 1 or 2,
R ¹⁰ for OR ¹⁵ , OR ¹⁶ R ¹⁷ , (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl, (C ₆ -C ₁₀ ) 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 hetero atoms from the series N, O and / or S, where the aforementioned radicals optionally by one, two or three identical or different substituents selected from the group halogen, hydroxy, oxo, cyano, nitro, amino, NR ¹⁸ R ¹⁹ , trifluoromethyl, (C ₁ -C ₆ ) alkyl, optionally by R ²⁰ substituted (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, which in turn is optionally substituted by halogen, (C ₁ -C ₄ ) alkyl, ( C ₁ -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 ²⁶ , -NH-C (O) -R ²⁷ and -NH-C (O) -OR ^{28 are} substituted, wherein
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, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₈ ) -cycloalkyl, which in turn are optionally one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkoxycarbonylamino, (C ₁ - C ₅ ) alkanoyloxy, a heterocycle or phenyl which is optionally substituted by halogen or hydroxy,
and
R ¹⁶ and R ^{17 are the} same or different and independently of one another are hydrogen, straight-chain or branched (C ₁ -C ₆ ) -alkyl, which one or more times the same or different by mono- (C ₁ -C ₆ ) -alkylamino, Di - (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, carboxyl, pyridyl or (C ₆ -C ₁₀ ) aryl may be substituted, the latter it is optionally substituted by halogen, trifluoromethyl, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy,
represent (C ₃ -C ₈ ) cycloalkyl or a 5- to 7-membered heterocycle containing one to two nitrogen atoms, the cycloalkyl and heterocycle optionally being substituted by (C ₁ -C 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, optionally benzo-fused heterocycle, which contain up to two further heteroatoms from the series N, O and / or S and by amino , (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₁ -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 ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₆ ) -alkoxycarbonyl, carboxyl, pyridyl or (C ₆ -C ₁₀ ) -aryl may be substituted, the latter in turn optionally being halogen, trifluoromethyl, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy is substituted, represents (C ₃ -C ₈ ) cycloalkyl or a 5- to 7-membered heterocycle containing one or two nitrogen atoms , where cycloalkyl and heterocycle are optionally substituted by (C ₁ -C ₄ ) alkyl,
R ¹² for straight-chain or branched (C ₁ -C ₁₅ ) alkyl which can be substituted by (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₄ ) alkoxy, phenyl, phenoxy or benzyloxy, where the the aromatics mentioned may in turn each be substituted up to three times by halogen or (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₄ ) -alkoxy, the same or different,
for (C ₃ -C ₈ ) cycloalkyl which can be substituted by (C ₁ -C ₄ ) alkoxy or phenyl,
for (C ₆ -C ₁₀ ) aryl which is substituted up to three times the same or different by (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, halogen, cyano, amino, trifluoromethyl or phenyl can be,
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 represents} straight-chain or branched (C ₁ -C ₆ ) alkyl,
and
R ³⁰ and R ^{31 are the} same or different and independent of each other
for hydrogen, straight-chain or branched (C ₁ -C ₁₂ ) alkyl which is substituted by aminocarbonyl, a group of the formula -NR ³² R ³³ , 5- to 6-membered heteroaryl which has up to 3 hetero atoms selected from the series N, O and / or S contains, or may be substituted by phenyl, where phenyl optionally up to twice the same or different substituted by halogen, (C ₁ -C ₄ ) alkyl, trifluoromethyl or (C ₁ -C ₄ ) alkoxy is
for (C ₃ -C ₈ ) cycloalkyl which can be substituted by (C ₁ -C ₄ ) alkyl,
for (C ₆ -C ₁₀ ) aryl which can be substituted up to three times in the same or different manner by halogen, (C ₁ -C ₄ ) alkyl, trifluoromethyl, (C ₁ -C ₄ ) alkoxy, amino, phenyl or phenoxy can
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,
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 (C ₆ -C ₁₀ ) arylsulfonyl,
or
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,
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 ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkanoyl, aminocarbonyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkoxycarbonylamino, phenyl or pyridyl may be substituted,
R ^{13 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 may be ge by one, two or three identical or different Substituents selected from the group (C ₁ -C ₄ ) alkyl, hydroxy, oxo, (C ₁ -C ₄ ) alkoxy, halogen, cyano, carboxyl and (C ₁ -C ₄ ) alkoxycarbonyl is substituted, with the proviso that X in this case is not SO or SO ₂ ,
or
R ^{13 represents} the group -NR ³⁴ R ³⁵ , wherein
R ³⁴ and R ^{35 are} identical or different and are for hydrogen, (C ₁ -C ₈ ) -alkyl, which can 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 in turn, if appropriate, in each case once or twice , identical or different, by Hy droxy, amino, cyano, halogen, trifluoromethyl, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) 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, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -alkanoyl,
and
Z for a group of the formula

stands in what
A stands for O or S,
a means the number 0 or 1,
D represents a straight-chain (C ₁ -C ₄ ) alkylene group which can be substituted one or more times, identically or differently, by (C ₁ -C ₃ ) alkyl, hydroxy or fluorine,
and
R ^{36 represents} OR ³⁷ NR ³⁸ R ³⁹ , wherein
R ³⁷ , R ³⁸ and R ^{39 are the} same or different and each represents hydrogen, phenyl, benzyl, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, which in turn may be one or more times, identical or different, by halogen, hydroxy, amino, carboxyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkoxycarbonylamino, (C ₁ -C ₅ ) Alkanoyl oxy, a heterocycle or phenyl which is optionally substituted by halogen or hydroxy,
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 has one Ring carbon atom or optionally linked via a ring nitrogen atom. Examples include: tetrahydrofuryl, 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 stands for a straight-chain or branched Alkenyl radical with preferably 2 to 6 or 2 to 4 carbon atoms. Is preferred a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms. The following may be mentioned by way of example and preferably: vinyl, allyl, isopropenyl and n-but-2- en-1-yl.

In the context of the invention, aryl 1 is an aromatic radical with preferably 6 up to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

Cycloalkyl is preferred in the context of the invention for a cycloalkyl group example, 3 to 8, 3 to 7 or 3 to 6 carbon atoms. Exemplary and preferred may be mentioned: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Alkoxy preferably stands for a straight-chain or branched alkoxy radical having 1 to 6, 1 to 4 or 1 to 3 carbon atoms. before is a straight-chain or branched alkoxy radical with 1 to 3 carbon atoms. The following may be mentioned as examples and preferably: methoxy, ethoxy, n-propoxy, Isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.

In the context of the invention, alkoxycarbonyl preferably represents a straight-chain one or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms, which has a Carbonyl group is linked. A straight-chain or branched is preferred Alkoxycarbonylrest with 1 to 4 carbon atoms. Exemplary and preferred  may be mentioned: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxy carbonyl and t-butoxycarbonyl.

Alkanoyl preferably stands for a straight-chain or branched alkyl radical with 1 to 6 or 1 to 4 carbon atoms, in the 1-position carries a double bonded oxygen atom and is linked via the 1-position. A straight-chain or branched alkanoyloxy radical having 1 to 4 carbons is preferred atoms. 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 is preferably a straight-chain or branched alkyl radical having 1 to 6, 1 to 5 or 1 to 3 carbon atoms, which in in the 1 position carries a double bonded oxygen atom and in the 1 position via another oxygen atom is linked. A straight-chain or ver is preferred branched alkanoyloxy radical having 1 to 3 carbon atoms. Exemplary and preferred Wise may be mentioned: 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 substituents, which are preferably 1 to 6, 1 to 4 or has 1 to 2 carbon atoms. A straight-chain or ver is preferred branched monoalkylamino radical having 1 to 4 carbon atoms. Exemplary and before the following may also be mentioned: methylamino, ethylamino, n-propylamino, isopropylamino, t-butylamino, n-pentylamino and n-hexylamino.

In the context of the invention, dialkylamino represents an amino group with two same or different straight-chain or branched alkyl substituents which preferably each have 1 to 6, 1 to 4 or 1 to 2 carbon atoms. Be straight-chain or branched dialkylamino radicals each with 1 to 4 are preferred Carbon atoms. Examples include and are preferably: N, N-dimethyl amino, N, N-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-hexyl-N-methylamino.

In the context of the invention, mono- or dialkylaminocarbonyl represents an amino Group which is linked via a carbonyl group and which is a straight-chain or branched or two identical or different straight-chain or branched alkyl substituents with preferably 1 to 4 or 1 to 2 carbon atoms has. The following may be mentioned by way of example and preferably: methylaminocarbonyl, ethyl aminocarbonyl, isopropylaminocarbonyl, t-butylaminocarbonyl, N, N-dimethylamino carbonyl, N, N-diethylaminocarbony1, 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 substituents, preferably 1 to 6, 1 has up to 4 or 1 or 2 carbon atoms and linked via the carbonyl group is. A monoacylamino radical having 1 to 2 carbon atoms is preferred. exemplary and preferably the following are mentioned: formamido, acetamido, propionamido, n- Butyramido and Pivaloylamido.

In the context of the invention, alkoxycarbonylamino represents an amino group a straight-chain or branched alkoxycarbonyl substituent, the preferred example, has 1 to 6 or 1 to 4 carbon atoms in the alkoxy radical and via the Carbonyl group is linked. An alkoxycarbonylamino radical having 1 to 4 carbon atoms. Examples and preferably mentioned are: methoxycarbonyl amino, 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 one in the context of the invention aromatic heterocycle, which has a ring carbon atom of the heteroaromatic, optionally also linked via a ring nitrogen atom of the heteroaromatic. Examples include: furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl,  Imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl. Preferred are pyridyl, Pyrimidinyl, pyridazinyl, furyl and thiazolyl.

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 has a ring carbon atom or a ring nitrogen atom is linked. A 5- to 7- is preferred membered saturated heterocycle with up to 2 identical or different hetero atoms from the series S, N and / or O. Examples include: tetrahydrofur-2-yl, Tetrahydrofur-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolin-1-yl, Piperidin-1-yl, piperidin-4-yl, 1,2-dihydropyridin-1-yl, 1,4-dihydropyridin-1-yl, Piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, azepin-1-yl, 1,4-diazepin-1-yl. Piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl are preferred.

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

The compounds of the invention can, depending on the substituent tion patterns in stereoisomeric forms that are either like image and mirror image (Enantiomers), or which are not like image and mirror image (diastereomers) behave, exist. The invention relates to both the enantiomers or Diastereomers as well as their respective mixtures. The racemic forms can be as well as the diastereomers in a known manner in the stereoisomerically uniform Separate components.

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 Invention includes.  

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

Physiologically acceptable salts can be salts of the compound according to the invention with inorganic or organic acids. Salts are preferred with inorganic acids such as hydrochloric acid, bromine water Substance acid, phosphoric acid or sulfuric acid, or salts with organic carbon or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumarate acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphtha lindisulfonsäure.

Physiologically acceptable salts can also be salts of the invention Be compounds with bases, such as metal or ammonium salts. Be preferred examples are alkali metal salts (e.g. sodium or potassium salts), earth alkali salts (e.g. magnesium or calcium salts), as well as ammonium salts, the abge are guided by ammonia or organic amines, such as ethylamine, Di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di- or tri ethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methyl morpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine, Ethylenediamine or 2-phenylethylamine.

The compounds according to the invention can also be in the form of their solvates, in particular which are in the form of their hydrates.

The invention also includes prodrugs of the invention bonds. According to the invention, such derivatives of ver Bonds of the general formula (I), which itself is less biologically can be active or inactive, but after application under physiological Conditions are converted into the corresponding biologically active form (at for example metabolically, solvolytically or in some 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, (C ₁ -C ₃ ) -alkyl, fluorine, chlorine or bromine,
R ^{6 represents} a group of the formula -S (O) ₂ -R ¹⁰ , -NR ¹¹ -C (O) -R ¹² , -CH ₂ -R ¹³ or -MR ¹⁴ , in which
R ¹⁰ for NR ¹⁶ R ¹⁷ , (C ₁ -C 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 identical or different heteroatoms from the series N, O and / or S, the abovementioned radicals optionally being selected from the group halogen, hydroxy, oxo, cyano, nitro, amino, dimethylamino by one, two or three identical or different substituents , Tri fluoromethyl, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl, phenyl, which in turn may be replaced by halogen, (C ₁ -C ₄ ) - Alkyl, (C ₁ -C 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 ^{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, (C ₁ -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, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxy carbonyl, (C ₁ -C ₄ ) alkoxycarbonylamino or (C ₁ -C ₅ ) alkanoyloxy are substituted,
and
R ¹⁶ and R ^{17 are} identical or different and, independently of one another, represent hydrogen, straight-chain or branched (C ₁ -C ₆ ) -alkyl, which one or more times is identical or different by (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, carboxyl, pyridyl or phenyl may be substituted, the latter in turn optionally being substituted by halogen, trifluoromethyl, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy,
represent (C ₅ -C ₇ ) cycloalkyl or a 5- to 7-membered heterocycle containing one to two nitrogen atoms, the cycloalkyl and heterocycle optionally being substituted by (C ₁ -C 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, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonylamino or phenyl may be substituted,
R ^{11 represents} hydrogen, straight-chain or branched (C ₁ -C ₄ ) alkyl, benzyl, (C ₃ -C ₇ ) cycloalkyl or a 5- to 7-membered heterocycle containing one to two nitrogen atoms, cyclo alkyl and heterocycle are optionally substituted by (C ₁ -C ₄ ) -alkyl,
R ¹² for straight-chain or branched (C ₁ -C ₈ ) alkyl, which can be substituted by (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₄ ) alkoxy, phenyl, phenoxy or benzyloxy, where the mentioned aromatics can in turn each be substituted up to three times in the same or different manner by halogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -alkoxy,
or
represents phenyl which can be substituted up to three times in the same or different manner by (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) 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 (C ₁ -C ₄ ) -alkyl,
and
R ³⁰ and R ^{31 are the} same or different and independent of each other
for hydrogen, straight-chain or branched (C ₁ -C ₈ ) -alkyl, which may be substituted by phenyl, which in turn may optionally be up to twice the same or different by halogen, (C ₁ -C ₄ ) -alkyl, trifluoromethyl or (C ₁ -C ₄ ) alkoxy is substituted,
for (C ₃ -C ₇ ) cycloalkyl which can be substituted by (C ₁ -C ₄ ) alkyl,
or
represents phenyl which can be substituted up to three times in the same or different manner by halogen, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, (C ₁ -C ₄ ) -alkoxy or amino,
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 contains up to two further heteroatoms from the series, N, O and / or S and are replaced by amino, ( C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkanoyl, aminocarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonylamino or phenyl may be substituted,
R ^{13 stands} 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 optionally consists of one, two or three identical or different substituents selected from the group (C ₁ -C ₄ ) alkyl, hydroxy, oxo, (C ₁ -C ₄ ) alkoxy, halogen, cyano, carboxyl and (C ₁ -C ₄ ) alkoxycarbonyl is sub-substituted,
or
represents the group -NR ³⁴ R ³⁵ , wherein
R ³⁴ and R ^{35 are} identical or different and are hydrogen, (C ₁ -C ₆ ) -alkyl, which may be substituted by phenyl, for (C ₅ -C ₇ ) -cycloalkyl, phenyl or for 5- to 6-membered Hetero aryl with up to three identical or different heteroatoms from the series N, O and / or S, where phenyl and heteroaryl in turn are in each case optionally one to two times, identical or different, by hydroxyl, amino, cyano, halogen, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, (C ₁ -C ₄ ) -alkoxy, carboxyl or (C ₁ -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

where A is O or S,
a means the number 0 or 1,
D represents a straight-chain (C ₁ -C ₃ ) alkylene group which can be substituted one or more times, identically or differently, by methyl, hydroxy or fluorine,
and
R ^{36 represents} OR ³⁷ or NR ³⁸ R ³⁹ , wherein
R ^{37 represents} hydrogen, phenyl, benzyl, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₇ ) cycloalkyl, which in turn may be one or more, identical or different, by halogen, hydroxy, amino, carboxyl , (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkoxycarbonylamino, (C ₁ -C ₅ ) alkanoyloxy or a heterocycle,
and
R ³⁸ and R ^{39 are the} same or different and each represents hydrogen, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₇ ) cycloalkyl, which in turn may be one or more, identical or different, by halogen , Hydroxy, amino, carboxyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkoxycarbonylamino, (C ₁ -C ₅ ) alkanoyl oxy, a heterocycle or are in turn substituted by phenyl which is optionally substituted by halo or hydroxy,
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 ¹ and R ^{2 represent} hydrogen,
R ³ and R ^{4 are the} same or different and represent 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 ⁴⁰ is where
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, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, carboxyl or (C ₁ -C ₄ ) alkoxycarbonyl,
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 contains a further hetero atom from the series N, O or S and is replaced by (C ₁ -C ₄ ) -Alkyl can be substituted,
R ^{12 represents} straight-chain or branched (C ₁ -C ₆ ) 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 may be selected by one or two identical or different substituents from the group (C ₁ -C ₄ ) -alkyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, fluorine, chlorine, bromine, cyano, carboxyl and (C ₁ -C ₄ ) -alkoxycarbonyl, or for the group -NR ³⁴ R ³⁵ , wherein
R ^{34 represents} (C ₁ -C ₆ ) alkyl or (C ₅ -C ₇ ) cycloalkyl,
and
R ³⁵ stands for benzyl which is optionally substituted in the phenyl ring by hydroxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, trifluoromethyl, fluorine, chlorine or cyano,
R ^{14 represents} a group of the formula -NR ⁴¹ R ⁴² , wherein
R ^{41 represents} hydrogen, (C ₁ -C ₆ ) alkyl or (C ₅ -C ₇ ) cycloalkyl,
R ^{42 represents} hydrogen or (C ₁ -C ₄ ) -alkyl, which can be substituted by phenyl,
or
R ⁴¹ and R ⁴² together with the nitrogen atom to which they are attached form a 5- to 6-membered saturated heterocycle which contains a further hetero atom from the series N, O or S and is replaced by (C ₁ -C ₄ ) -Alkyl can be substituted,
and
R ^{40 represents} phenyl or naphthyl, which may be mono- or discrete, identical or different, by fluorine, chlorine, bromine, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, cyano, trifluoromethyl or (C ₁ -C ₄ ) alkoxycarbonyl are substituted,
R ^{7 represents} hydrogen,
and
Z for a group of the formula

stands in which R ^{36 is} hydroxy or the radical -C (O) -R ^{36 has} the meanings given above of R ³⁶ for a group which degrades in the sense of a prodrug to carboxylic acid -C (O) -OH or its salts can be,
and their pharmaceutically acceptable salts, solvates, hydrates and hydrates of the salts.

Compounds of the general formula (I) are very particularly preferred,
in which
X represents CH ₂ or in particular oxygen,
R ¹ and R ^{2 represent} hydrogen,
R ³ and R ^{4 are the} same 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 represents} phenyl, pyridyl, pyrimidinyl or pyridazinyl, which may be one or two, identical or different, by fluorine, chlorine, bromine, hydroxy, cyano, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) alkoxy, carboxyl or (C ₁ -C ₄ ) alkoxycarbonyl are substituted,
or
for a group of the formula

stands,
R ¹³ for pyridyl, pyrimidinyl or pyridazinyl, optionally selected from the group (C ₁ -C ₄ ) alkyl, hydroxy, (C ₁ -C ₄ ) alkoxy, fluorine, chlorine, bromine by one or two identical or different substituents , Cyano, carboxyl and (C ₁ -C ₄ ) alkoxycarbonyl are substituted, or stands for the group -NR ³⁴ R ³⁵ , wherein
R ^{34 represents} (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) cycloalkyl,
and
R ³⁵ stands for benzyl which is optionally substituted in the phenyl ring by hydroxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, trifluoromethyl, fluorine, chlorine or cyano,
and
R ^{14 represents} a group of the formula -NR ⁴¹ R ⁴² , wherein
R ^{41 represents} hydrogen, (C ₁ -C ₄ ) alkyl or (C ₅ -C ₇ ) cycloalkyl,
and
R ^{42 represents} hydrogen or (C ₁ -C ₄ ) -alkyl, which can be substituted by phenyl,
R ^{7 represents} hydrogen,
and
Z for a group of the formula

in which R ^{37 is} hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₄ -C ₆ ) -cycloalkyl,
and their pharmaceutically acceptable salts, solvates, hydrates and hydrates of the salts.

The radicals listed above or specified in preferred ranges Definitions apply both to the end products of the formula (I) and accordingly for the raw materials or intermediate products required for the production.

Those in the respective combinations or preferred combinations of residues radical definitions specified in detail are independent of the respective  specified combinations of the residues arbitrarily also by residue definitions and others rer combinations replaced.

Of particular importance are compounds of formula (I) in which X is Methylene or oxygen is available.

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

stands,
wherein
Means 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, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, carboxyl or (C ₁ -C ₄ ) alkoxycarbonyl,
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 contains a further hetero atom from the series N, O or S and is replaced by (C ₁ -C ₄ ) -Alkyl can be substituted.

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 -CH ₂ -C (O) -OH, -CH ₂ -CH ₂ -C (O) -OH, -O- CH ₂ -C (O) -OH, -OC [(CH ₃ ) ₂ ] -C (O) -OH or -S-CH ₂ -C (O) -OH,
and
R ^{6 represents} a group of the formula -S (O) ₂ -R ¹⁰ , wherein
R ^{10 represents} phenyl or pyridyl, which are optionally mono- or disubstituted, identical or different, 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 19 has the meanings given in Table 2 for R ³ :

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 247 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 3211 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 phenol derivatives of the general formulas (IIa-c) with reactive phenyl derivatives of the general formulas by one of the following process variants [A], [B] or [C] (IIIa-c) if appropriate 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 directly 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 stands for OH, O-PG, SH, S-PG, or for a nitro, aldehyde, cyano, carboxyl or (C ₁ -C ₄ ) alkoxycarbonyl group,
and
PG stands for a suitable protective group.

Process variant [A]

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

Process variant [B]

V = CHO; W = Li, MgCl, MgBr, cuprate
or V = Li, MgCl, MgBr, cuprate; W = CHO

Process variant [C]

Examples of catalysts are coupling catalysts such as Pd, Rh and / or Called Cu compounds.

Examples of the reactive groups V and W may be mentioned: halogen, hydroxy, CH ₂ Br, mercapto, amino, CHO, Li, magnesium, tin, boron or copper derivatives.

The phenol derivatives of the general formulas (IIa-c) which can be used according to the invention are known or can be produced by known methods [compare z. B. Gurumani et al .; Indian Journal of Chemistry 32B, 281-287 (1993); Riering et al., Chem. Ber. 127, 859-874 (1994)].

The phenyl derivatives of the general formulas (IIIa-c) are also known or can be produced by known methods [compare e.g. B. from 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)].

The reaction of the starting compounds (IIa-c) with (IIIa-c) proceeds in general mean at normal pressure. But it can also under increased or reduced pressure be performed.

The reaction can be in a temperature range from -100 ° C to + 200 ° C, preferably as between -78 ° C and + 150 ° C in the presence of inert solvents be performed. 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 (IIa-c) and (IIIa-c) intermediate products of the formulas (IV), (IVa), (IVb) and (IVc) also arise, in which z. B. the substituent Z 'for a nitro, aldehyde, cyano, carboxyl or Alkoxycarbonyl group or X represents a CH (OH) or C (O) group which then with or without isolation of these intermediates by conventional methods Compounds of formula (I) are further implemented.

The methods according to the invention can be exemplified by the following formula schemes are explained:  

Scheme 1

Scheme 2

Scheme 3

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 on individual process stages within the specified scope.

Protective groups (PG, PG ¹ , PG ² ) in the present application are understood to mean those groups in starting materials and / or intermediates which functional groups present, such as, for. B. 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 effects and can therefore be used as a variety use any medication. In particular, they can be used for all indications put that can be treated with natural thyroid hormones, such as exemplary and preferably depression, goiter or thyroid cancer. Prefers can be treated with the compounds of formula (I) according to the invention atherosclerosis,  Hypercholesterolemia, dyslipidemia, obesity and obesity act. In addition, the compounds according to the invention can also be used Treat heart failure and postprandial lowering of triglycerides pass.

The compounds are also suitable for the treatment of certain respiratory cranes kung and especially from emphysema and medication pulmonary maturation.

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

The compounds are also suitable for the treatment of osteoporosis, heart rhythm disturbances, hypothyroidisms and skin diseases.

The connections can also be used to promote and regenerate the Use hair growth and to treat diabetes.

The active substances according to the invention open up a further treatment alternative and represent an enrichment of pharmacy. In comparison to the known and Thyroid hormone preparations used to date show the inventive Connections an improved spectrum of activity. They prefer to excel due to great specificity, good tolerance and fewer side effects especially in the cardiovascular area.

The effectiveness of the compounds according to the invention can, for. B. Check 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 (hydroxy methyl) 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. The cultures are grown for 48 hours at 37 ° C. and 10% CO ₂ atmosphere. 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 the luciferase induced by T3 or other substances, the cells are then lysed by adding a buffer containing Triton and Luciferin (from Promega) and immediately measured luminometrically. The EC ₅₀ values of each connection are calculated. The compound of Example 2 shows an EC ₅₀ value of 2 nM in this test.

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

Test descriptions for the detection of pharmacologically active substances

The substances examined for their serum cholesterol lowering effects in vivo male mice with a body weight between 25 and and 35 g administered orally. The animals are brought to Grup one day before the start of the experiment pens with the same number of animals, usually n = 7-10. Throughout the whole Experimentally, 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 +  Ethanol + saline (0.9%) in the ratio 1 + 1 + 8 or in a solution Solutol HS 15 + saline (0.9%) dissolved in a ratio of 2 + 8. The application The dissolved substances are added in a volume of 10 ml / kg body weight a pharynx. Animals that are treated in the same way serve as a control group but only get the solvent (10 ml / kg body weight) without test substance.

Before the first substance application, each mouse is used to determine the serum Cholesterol blood drawn by puncturing the retroorbital venous plexus (Pre value). The animals are then given the test substance with a pharyngeal tube administered the first time. 24 hours after the last substance application, (on the 8th day after the start of treatment), each animal is used to determine the serum cholesterol Blood was drawn again by puncturing the retroorbital venous plexus. The blood Samples are centrifuged and after the serum is obtained, the cholesterol photometric with an EPOS Analyzer 5050 (Eppendorf-Gerätebau, Netheler & Hinz GmbH, Hamburg). The determination is made with a commercial standard Chen enzyme test (Boehringer Mannheim, Mannheim).

The effect of the test substances on the serum cholesterol concentration is determined by Subtraction of the cholesterol value of the 1st blood sample (pre-value) from the cholesterol rin value of the 2nd blood sample (after treatment) determined. There are differences All cholesterol values in a group averaged and with the mean of the differences boundaries of the control group compared.

Statistical evaluation is carried out with Student's t-test after prior checking the variants for homogeneity.

Substances that compared the serum cholesterol of the treated animals with that of the Control group, decrease statistically significant (p <0.05) by at least 10%, are considered 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 substance The hearts are removed and weighed under influence. An effect on the heart circle running system can be determined by a significant increase in heart weight become. A further parameter for the substance effect can be a body weight change can be used.

In an analogous manner, e.g. B. NMRI mice, whether-whether mice, Wistar rats or fa, fa sugar rats are used as test animals for this test.

Another in vivo test in which the compounds of the invention are based on The animal model of cholesterol gene shows surprisingly beneficial properties 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 ver Bindings also to normocholesterolemic dogs by oral administration of the test substances are checked for 5-7 days.

As a parameter for the effectiveness of the compounds according to the invention in loading The act of obesity, for example, can reduce body weight development after four weeks of test substance administration in mice who previously had obesity by pre-feeding them with fatty food was induced.

For further investigation of potential cardiovascular side effects under sub The influence of the punch can include determining the expression of the mRNA of the "HCN2" ion channel ("hyperpolarization-activated cyclic nucleotidegated channel") be used 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 quantification of the mRNA of the "hyperpolarization-activated cyclic nucleotide gated "cation channel (HCN2) in rat hearts was carried out by real-time PCR (TaqMan PCR; Heid et al., Genome Res. 6 (10), 986-994). This was done after Preparation of the hearts the total RNA using RNaesy columns (from Qiagen) isolated, digested with DNase and then rewritten into cDNA (SUPERSCRIPT-II RT cDNA synthesis kit, Gibco). The HCN2 mRNA Be mood was carried out on an ABI Prism 7700 device (from Applied Biosystems). The Sequence of the "forward" and "reverse" primer was: 5'- GGGAATCGACTCCGAGGTC-3 'or 5'-GATCTTGGTGAAACGCACGA-3', that of the fluorescent sample 5'-6FAM-ACAAGACGGCCCGTGCACTACGC- TAMRA-3 (FAM = fluorescent dye 6-carboxyfluorescein; TAMRA = Quencher 6-carboxytetramethylrhodamine). During the polymerase chain reaction becomes the fluorescent dye by the 5'-exonuclease activity of Taq polymerase Cleaved FAM and thereby obtained the previously quenched fluorescence signal. The so-called "threshold cyle" (Ct value) was the number of cycles at which the Fluorescence intensity 10 standard deviations above the background fluorescence was. The relative expression of the HCN2 mRNA calculated in this way was used then normalized to the expression of the ribosomal protein L32.

This assay can also be carried out in an analogous manner with mouse hearts. The sequence of the "forward" and "reverse" primers in this case was 5'- CGAGGTGCTGGAGGAATACC-3 'or 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 usual Chen application forms into consideration, d. H. also oral, parenteral, inhalative, nasal, sub lingual, buccal, rectal or external, e.g. B. transdermal, particularly preferred  orally or parenterally. In parenteral administration, intravenous, To name intramuscular, subcutaneous application, e.g. B. as a subcutaneous depot. All Oral application is particularly preferred.

The active ingredients can be administered alone or in the form of preparations become. For oral application are suitable as preparations u. a. Tablets, chap seln, pellets, dragees, pills, granules, solid and liquid aerosols, syrups, emuls sions, suspensions and solutions. Here, the active ingredient in such a Amount present that a therapeutic effect is achieved. In general can the active ingredient in a concentration of 0.1 to 100 wt .-%, in particular 0.5 up to 90% by weight, preferably 5 to 80% by weight. In particular, the Concentration of the active ingredient 0.5-90 wt .-%, d. H. the active ingredient should be in Amounts are available that are sufficient to give the specified dosage range to reach.

For this purpose, the active substances can be converted into the usual manner in a manner known per se Preparations are transferred. This is done using inert, not toxic, pharmaceutically suitable carriers, auxiliaries, solvents, Vehicles, emulsifiers and / or dispersants.

Examples of auxiliary substances are: water, non-toxic organic Solvents such as B. paraffes, vegetable oils (e.g. sesame oil), alcohols (e.g. Ethanol, glycerin), glycols (e.g. polyethylene glycol), solid carriers such as natural Liche or synthetic stone powder (e.g. talc or silicates), sugar (e.g. Milk sugar), emulsifier, dispersant (e.g. polyvinylpyrrolidone) and lubricant medium (e.g. magnesium sulfate).

In the case of oral administration, tablets can of course also contain additives like sodium citrate along with additives like starch, gelatin and the like Chen included. Aqueous preparations for oral administration can continue with flavor enhancers or colorants.  

When administered orally, doses of 0.001 to 5 mg / kg, preferably 0.001 to 3 mg / kg body weight applied per 24 hours.

The new active ingredients can be used alone and, if necessary, in combination with others ren active ingredients preferably from the group CETP inhibitors, antidiabetic agents, Antioxidants, cytostatics, calcium channel blockers, hypotensive agents, Thyroid hormones, inhibitors of HMG-CoA reductase, inhibitors of HMG-CoA Reductase gene expression, squalene synthesis inhibitors, ACAT inhibitors, by bleeding agents, platelet aggregation inhibitors, anticoagulants, Angiotensin II receptor antagonists, cholesterol absorption inhibitors, MTP-Inhi bittern, aldose reductase inhibitors, fibrates, niacin, anorectics, lipase-inhi bitters and PPAR agonists are administered.

The following exemplary embodiments are intended to explain the invention by way of example ters without restricting the scope of protection.

starting compounds

Example I

[4- (benzyloxy) -3-bromophenyl] methanol

1.0 g (3.43 mmol) of 4- (benzyloxy) -3-bromobenzaldehyde [Lit .: R. Baker et al., J. Chem. Soc. Chem. Commun. 14, 1102-1104 (1987)] are placed in 10 ml of tetrahydrofuran. At 0 ° C, 0.04 g (1.03 mmol) of sodium borohydride are added. The reaction mixture is stirred for three hours at room temperature. Saturated ammonium chloride solution is then added and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried with sodium sulfate and freed from the solvent in vacuo. 0.98 g (97% of theory) of [4- (benzyloxy) -3-bromophenyl] methanol are obtained.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.62 (broad s, 1H), 4.6 (s, 2H), 5.16 (s, 2H), 6.86-6.93 (m, 1H), 7.11-7.59 (m , 7H).

Example II

{[4- (benzyloxy) -3-bromobenzyl] oxy} (tert-butyl) dimethylsilane

3.0 g (10.23 mmol) of [4- (benzyloxy) -3-bromophenyl] methanol (Example I) are placed in 30 ml of DMF. 1.39 g (12.28 mmol) of 1H-imidazole (60%) and 2.01 g (13.3 mmol) of tert-butyl (chloro) dimethylsilane are added at room temperature. The reaction mixture is stirred overnight at room temperature. Then water is added and the mixture is extracted three times with diethyl ether. The combined organic phases are washed three times with water and once with saturated sodium chloride solution. The organic phase is dried with sodium sulfate and the solvent is removed in vacuo. 4.02 g (86% of theory) of {[4- (Benzyl oxy) -3-bromobenzyl] oxy} (tert-butyl) dimethylsilane are obtained.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 0.015 (m, 6H), 0.80-0.88 (m, 9H), 4.55 (s, 2H), 5.06 (s, 2H), 6.80 (d, 1H) , 7.08 (dd, 1H), 7.21-7.43 (m, 6H).

Example III

({4- (benzyloxy) -3 - [(4-fluorophenyl) sulfanyl] benzyl} oxy) (tert-butyl) dimethylsilane

0.5 g (1.23 mmol) {[4- (benzyloxy) -3-bromobenzyl] oxy} (tert-butyl) dimethylsilane (Example II) are dissolved in 12 ml of tetrahydrofuran. At -78 ° C, 0.55 ml (1.35 mmol) of tert-butyllithium (2.5 molar solution in hexane) is added dropwise and the mixture is left for 15 min. stirred. Then 0.34 g (1.35 mmol) of 4-fluorophenyl disulfide is added. The mixture is then left to stir at -78 ° C for 1 hour. Saturated ammonium chloride solution is added, the mixture is extracted three times with ethyl acetate and the combined organic phases are dried with sodium sulfate. The product is purified by chromatography on silica gel 60 (mobile phase: cyclohexane). 0.485 g (66% of theory) ({4- (Benzyloxy) -3 - [(4-fluorophenyl) sulfanyl] benzyl} oxy) (tert-butyl) dimethylsilane is obtained.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 0.00 (s, 6H), 0.85 (s, 9H), 4.55 (s, 2H), 5.11 (s, 2H), 6.83-7.04 (m, 6H) , 7.24-7.38 (m, 6H).

Example IV

({4- (Benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] b 13643 00070 552 001000280000000200012000285911353200040 0002010130835 00004 13524enzyl} oxy) (tert-butyl) dimethylsilane

4.2 g (9.24 mmol) ({4- (Benzyloxy) -3 - [(4-fluorophenyl) sulfanyl] benzyl} oxy) (tert-butyl) dimethylsilane (Example III) are dissolved in 25 ml dichloromethane and mixed with 7.33 g ( 21.25 mmol) of 3-chlorobenzene peroxycarboxylic acid. The reaction mixture is stirred at room temperature overnight. The mixture is then washed twice with saturated sodium bicarbonate solution, then dried with sodium sulfate and the solvent removed in vacuo. The residue is purified by chromatography on silica gel 60 (mobile phase: cyclohexane / ethyl acetate 4: 1). 3.4 g (68% of theory) ({4- (benzyloxy) -3- [(4-fluorophenyl) sulfonyl] benzyl} oxy) (tert-butyl) dimethylsilane are obtained.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 0.00 (s, 6H), 0.81 (s, 9H), 4.61 (s, 2H), 4.90 (s, 2H), 6.75-6.84 (m, 3H) , 7.07-7.18 (m, 2H), 7.23-7.28 (m, 3H), 7.40 (dd, 1H), 7.63- 7.7 (m, 2H), 7.98 (d, 1H).

Example V

{4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] phenyl} methanol

3.4 g (6.99 mmol) ({4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} oxy) (tert-butyl) dimethylsilane (Example IV) are dissolved in 10 ml of tetrahydrofuran. At room temperature, 7.68 mmol of tetrabutylammonium fluoride trihydrate (1 molar solution in THF) are added. The mixture is stirred at room temperature overnight. The solvent is then removed in vacuo and the product is purified by chromatography on silica gel 60 (mobile phase: cyclohexane / ethyl acetate 3: 2). 2.1 g (81% of theory) of {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] phenyl} methanol are obtained.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.77 (t, 1H), 4.72 (d, 2H), 5.05 (s, 2H), 6.86-6.96 (m, 3H), 7.22-7.40 (m, 2H), 7.35-7.40 (m, 3H), 7.55 (dd, 1H), 7.74-7.84 (m, 2H), 8.16 (d, 1H).

Example VI

4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzaldehyde

2.1 g (5.64 mmol) of {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] phenyl} methanol (Example V) are dissolved in 25 ml of dichloromethane. 4.9 g (56.39 mmol) of manganese (IV) oxide are added at room temperature. The mixture is stirred at room temperature overnight. The reaction mixture is then filtered through Celite and the solvent is removed in vacuo. 1.82 g (86% of theory) of 4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzaldehyde are obtained.
¹ H NMR (200 MHz, CDCl ₃ ): δ = 5.12 (s, 2H), 6.87-6.99 (m, 2H), 7.1 (d, 1H), 7.24- 7.30 (m, 2H), 7.41-7.46 ( m, 3H), 7.72-7.82 (m, 2H), 8.08 (dd, 1H), 8.7 (d, 1H), 9.98 (s, 1H).

Example VII

4-bromo-3,5-dimethylphenyl-triisopropylsilyl ether

5.0 g (24.87 mmol) of 4-bromo-3,5-dimethylphenol, 2.03 g (29.84 mmol) of imidazole and 6.23 g (32.33 mmol) of chlorine (triisopropyl) silane are stirred in 20 ml of dimethylformamide overnight at room temperature. Saturated sodium bicarbonate solution is then added and the mixture is extracted three times with diethyl ether. The combined organic phases are washed with water, dried with sodium sulfate and freed from the solvent in vacuo. 7.5 g (84% of theory) of 4-bromo-3,5-dimethylphenyl-triisopropylsilyl ether are obtained.
¹ H NMR (200 MHz, CDCl ₃ ): δ = 1.05-1.36 (m, 21H), 2.35 (s, 6H), 6.60 (s, 2H).

Example VIII

{4- (Benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] phenyl} {2,6-dimethyl-4 - [(triisopropyl silyl) oxy] phenyl) methanol

810 mg (2.27 mmol) of 4-bromo-3,5-dimethylphenyltriisopropylsilylether (Example VII) are dissolved in 10 ml of tetrahydrofuran. 147.3 mg (2.3 mmol) of butyllithium (2.4 molar in hexane) are added dropwise at -78 ° C. At constant temperature, the mixture is stirred for one hour and then 600 mg (1.62 mmol) of 4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzaldehyde (Example VI) dissolved in 4 ml of tetrahydrofuran are added dropwise. The mixture is stirred at -78 ° C. for one hour and then saturated ammonium chloride solution is added. The mixture is extracted three times with ethyl acetate, the combined organic phases are dried with sodium sulfate and concentrated. 580 mg (55% of theory) of {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] phenyl} {2,6-dimethyl-4 - [(triisopropylsilyl) oxy] phenyl} methanol are obtained ,
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.04-1.35 (m, 21H), 2.2 (s, 6H), 3.68 (s, 1H), 4.99 (s, 2H), 6.25 (d, 1H) , 6.55 (s, 2H), 6.80-7.96 (m, 3H), 7.20-7.43 (m, 6H), 7.70-7.81 (m, 2H), 8.20 (d, 1H).

Example IX

(4- {4- (Benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} -3,5-dimethylphenoxy) (triisopropyl) silane

575 mg (0.89 mmol) {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] phenyl} {2,6-dimethyl-4 - [(triisopropylsilyl) oxy] phenyl} methanol (Example VIII) are obtained in 10 ml of tetrahydrofuran dissolved. At 0 ° C., 1030.35 mg (8.86 mmol) of triethylsilane are first added, and 78.78 mg (0.35 mmol) of trimethylsilyltrifluoromethane sulfonate are then added dropwise. After the reaction mixture has been stirred for 1.5 hours, saturated ammonium chloride solution is added. It is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulfate and freed from the solvent in vacuo. 611 mg (53% of theory) (4- {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} -3,5-dimethylphenoxy) (triisopropyl) silane are obtained.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.04-1.35 (m, 21H), 2.16 (s, 6H), 3.97 (s, 2H), 4.94 (s, 2H), 6.60 (s, 2H) , 6.73-7.1 (m, 4H), 7.2-7.43 (m, 5H), 7.71-7.80 (m, 2H), 7.96 (d, 1H).

Example X

4- {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} -3,5-dimethylphenol

600 mg (9.95 mmol) (4- {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} -3,5-dimethylphenoxy) - (triisopropyl) silane (Example IX) are dissolved in 15 ml dichloroethane solves. At room temperature, 359 mg (1.14 mmol) of tetrabutyl ammonium fluoride are added and the mixture is stirred for a further thirty minutes. The solvent is then removed in vacuo and the product is purified by chromatography on silica gel (mobile phase cyclohexane / ethyl acetate 9: 1). 180 mg (40% of theory) of 4- {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} -3,5-dimethylphenol are obtained.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 2.18 (s, 6H), 3.97 (s, 2H), 4.48 (s, 1H), 4.95 (s, 2H), 6.57 (s, 2H), 7.02 -7.04 (m, 4H), 7.20-7.40 (m, 5H), 7.70-7.82 (m, 2H), 7.95 (d, 1H).

Example XI

Ethyl (4- {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} -3,5-dimethylphenoxy) acetate

85 mg (0.18 mmol) of 4- {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} -3,5-dimethylphenol (Example X) are dissolved in 2 ml of dimethylformamide. 30 mg (0.21 mmol) of potassium carbonate and 33 mg (0.20 mmol) of bromoethyl acetate are added. The mixture is stirred at room temperature overnight. Saturated ammonium chloride solution is then added and the mixture is extracted three times with diethyl ether. The combined organic phases are washed three times with water, dried with sodium sulfate and concentrated in vacuo. 80 mg (96.5% of theory) of ethyl (4- {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} -3,5-dimethylphenoxy) acetate are obtained.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.31 (t, 3H), 2.19 (s, 6H), 3.98 (s, 2H), 4.27 (q, 2H), 4.61 (s, 2H), 4.95 (s, 2H), 6.64 (s, 2H), 6.72-7.10 (m, 4H), 7.20-7.39 (m, 5H), 7.71-7.82 (m, 2H), 7.96 (d, 1H).

Example XII

Ethyl 2- (4- {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} -3,5-dimethylphen oxy) -2-methyl propanoate

This compound was obtained analogously to Example XI starting from 4- {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} -3,5-dimethylphenol (Example X) and dimethylbromoacetic acid ethyl ester.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.27 (t, 3H), 1.56 (s, 3H), 1.60 (s, 3H), 2.16 (s, 6H), 3.97 (s, 2H), 4.26 (q, 2H), 4.95 (s, 2H), 6.57 (s, 2H), 6.73-7.01 (m, 4H), 7.20- 7.39 (m, 5H), 7.73-7.80 (m, 2H), 7.96 (d , 1H).

Preparation Examples

example 1

Ethyl (4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxybenzyl} -3,5-dimethylphenoxy) acetate

50 mg (0.09 mmol) of ethyl (4- {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} -3,5-dimethylphenoxy) acetate (Example XI) are dissolved in 20 ml of ethanol. 10 mg of palladium on activated carbon (10% strength) are added and the mixture is hydrogenated for two hours at 1013 mbar and room temperature. The reaction mixture is then filtered through Celite and the solvent is removed in vacuo. 37 mg (86% of theory) of ethyl (4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxybenzyl} -3,5-dimethylphenoxy) acetate are obtained.
¹ H NMR (200 MHz, CDCl ₃ ): δ = 1.31 (t, 3H), 2.10 (s, 6H), 3.86 (s, 2H), 4.29 (q, 2H), 4.61 (s, 2H), 6.61 (s, 2H), 6.86 (m, 1H), 6.98-7.05 (m, 1H), 7.16-7.23 (m, 3H), 7.84-7.90 (m, 2H), 8.94 (s, 1H).

Example 2

(4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxybenzyl} -3,5-dimethylphenoxy) acetic acid

37 mg (0.08 mmol) of ethyl (4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxybenzyl} -3,5-dimethylphenoxy) acetate (Example 1) are dissolved in 1 ml of ethanol and mixed with a few drops of 1 N sodium hydroxide solution added. The mixture is stirred for thirty minutes at room temperature and then the solvent is removed in vacuo. The residue is mixed with water and extracted three times with ethyl acetate. The combined organic phases are dried with sodium sulfate and concentrated. 32 mg (90% of theory) of (4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxybenzyl} - 3,5-dimethylphenoxy) acetic acid are obtained.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 2.13 (s, 6H), 3.87 (s, 2H), 4.67 (s, 2H), 6.64 (s, 2H), 6.72-7.28 (m, 5H) , 7.77-7.92 (m, 2H), 8.94 (s, 1H).

Example 3

2- (4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxybenzyl} -3,5-dimethylphenoxy) -2-methylpropionic acid

This compound was prepared analogously to Examples 1 and 2 starting from ethyl 2- (4- {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} -3,5-dimethylphenoxy) -2-methyl propanoate ( Example XII) obtained.
¹ H-NMR (200 MHz, CDCl ₃ ): δ = 1.60 (s, 6H), 2.11 (s, 6H), 3.88 (s, 2H), 6.66 (s, 2H), 6.85-7.30 (m, SH) , 7.84-7.91 (m, 2H), 8.94 (broad s, 1H).

The following examples are analogous to the methods given above manufactured:

Example 4

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

Example 5

2- (4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxyphenoxy} -3,5-dimethylphenoxy) -2- methylpropionic

Example 6

3- (4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxyphenoxy} -3,5-dimethylphenoxy) propionic acid

Example 7

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

Example 8

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

Example 9

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

Example 10

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

Example 11

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

Example 12

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

Example 13

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

Example 14

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

Example 15

[3-Chloro-4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxyphenoxy} -5- (trifluoromethyl) phenyl] acetic acid

Example 16

[4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxyphenoxy} -3,5-bis (trifluoromethyl) phenyl] acetic acid

Example 17

3- [4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxyphenoxy} -3,5-bis (trifluoromethyl) phenyl] propionic acid

Example 18

3- [3-chloro-4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxyphenoxy} -5- (trifluoromethyl) phenyl] propionic acid

Example 19

3- (3,5-Dichloro-4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxyphenoxy} phenyl) propionic acid

Example 20

3- (3,5-dibromo-4- {3 - [(4-fluorophenyl) sulfonyl] -4-hydroxyphenoxy} phenyl) propionic acid

Claims (14)

1. Compounds of the general formula (I)
in which
X represents O, S, SO, SO ₂ , CH ₂ , CHF, CF ₂ or NR ⁸ , where R ^{8 is} hydrogen or (C ₁ -C ₄ ) alkyl,
R ¹ and R ^{2 are} identical or different and represent hydrogen or (C ₁ -C ₄ ) alkyl,
R ³ and R ^{4 are} identical or different and represent hydrogen, halogen, cyano, (C ₁ -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 ₁ -C ₄ ) alkyl or halogen,
R ^{6 is} a group of the formula -SR ⁹ , -S (O) _n -R ¹⁰ , -NR ¹¹ -C (O) -R ¹² , -CH ₂ - R ¹³ or -MR ¹⁴ , in which
R ⁹ for (C ₁ -C ₁₀ ) alkyl, (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 with up to four identical or different heteroatoms from the series N, O and / or S, the abovementioned radicals optionally being replaced by one, two or three identical ones or various substituents selected from the group halogen, hydroxy, oxo, cyano, (C ₁ -C ₆ ) alkyl, (C ₁ - 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 , (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂ - C ₆ ) alkenyl, (C ₆ -C ₁₀ ) aryl , (C ₆ -C ₁₀ ) arylmethyl or 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 substituted by one, two or three identical or different substituents from the group halogen, hydroxy, oxo, cyano, nitro, amino, NR ¹⁸ R ¹⁹ , trifluoromethyl, (C ₁ -C ₆ ) alkyl, optionally substituted by R ²⁰ (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl, which in turn is optionally substituted by halogen, (C ₁ -C ₄ ) alkyl, (C ₁ - C ₄ ) alkoxy, trifluoromethyl, nitro or cyano is substituted, -OC (O) -R ²¹ , -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 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 are each for hydrogen, phenyl, benzyl, ( C ₁ -C ₆ alkyl or (C ₃ -C ₈ ) cycloalkyl, which in turn may be one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (C ₁ -C ₄ ) alkoxy , (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonylamino, (C ₁ -C ₅ ) -alkanoyloxy, a heterocycle or, in turn, optionally substituted by halogen or hydroxy-substituted phenyl,
and
R ¹⁶ and R ^{17 are the} same or different and independently of one another are hydrogen, straight-chain or branched (C ₁ -C ₆ ) -alkyl, which one or more times the same or different by mono- (C ₁ -C ₆ ) -alkylamino , Di- (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, carboxyl, pyridyl or (C ₆ - C ₁₀ ) aryl can be substituted, the latter in turn being optionally substituted by halogen, trifluoromethyl, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy,
stand for (C ₃ -C ₈ ) cycloalkyl or for a 5- to 7-membered heterocycle containing one or two nitrogen atoms, the cycloalkyl and heterocycle optionally being substituted by (C ₁ -C ₄ ) alkyl,
or
R ¹⁶ R ¹⁷ and together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated, optionally benzo-fused heterocycle, which contain up to two further heteroatoms from the series N, O and / or S and through Amino, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₁ -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 ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, carboxyl, pyridyl or (C ₆ -C ₁₀ ) aryl, the latter of which may optionally be substituted by halogen, trifluoromethyl, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy is substituted, stands for (C ₃ -C ₈ ) cycloalkyl or for a 5- to 7-membered heterocycle containing one or two nitrogen atoms, where cyclo alkyl and heterocycle are optionally substituted by (C ₁ -C ₄ ) alkyl,
R ^{12 is} straight-chain or branched (C ₁ -C ₁₅ ) alkyl which can be substituted by (C ₃ -C ₈ ) cycloalkyl, (C ₁ -C ₄ ) alkoxy, phenyl, phenoxy or benzyloxy, the abovementioned Aromatics in turn can each be substituted up to three times in the same or different manner by halogen, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₄ ) alkoxy,
for (C ₃ -C ₈ ) cycloalkyl which can be substituted by (C ₁ -C ₄ ) alkoxy or phenyl,
for (C ₆ -C ₁₀ ) aryl which can be substituted up to three times in the same or different manner by (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, halogen, cyano, amino, trifluoromethyl or phenyl can
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 represents} straight-chain or branched (C ₁ -C ₆ ) alkyl,
and
R ³⁰ and R ^{31 are the} same or different and independent of each other
for hydrogen, straight-chain or branched (C ₁ -C ₁₂ ) alkyl, which by aminocarbonyl, a group of the formula -NR ³² R ³³ , 5- to 6-membered heteroaryl, which has up to 3 heteroatoms selected from the series N, O and / or S, or can be substituted by phenyl, where phenyl is optionally substituted up to twice the same or different by halogen, (C ₁ -C ₄ ) alkyl, trifluoromethyl or (C ₁ -C ₄ ) alkoxy,
for (C ₃ -C ₈ ) cycloalkyl which can be substituted by (C ₁ -C ₄ ) alkyl,
for (C ₆ -C ₁₀ ) aryl which is up to three times the same or different by halogen, (C ₁ -C ₄ ) alkyl, trifluoromethyl, (C ₁ -C ₄ ) alkoxy, amino, phenyl or phenoxy can 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,
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 (C ₆ -C ₁₀ ) arylsulfonyl,
or
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 5,
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 hetero atoms from the series, N, O and / or S and by amino, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkanoyl, amino carbonyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkoxy carbonylamino, phenyl or pyridyl may be substituted .
R ^{13 represents} a saturated, partially unsaturated or aromatic 5- to 10-membered heterocycle having up to three identical or different heteroatoms from the series N, O and / or S, which is optionally selected by one, two or three identical or different substituents from the group (C ₁ -C ₄ ) alkyl, hydroxy, oxo, (C ₁ -C ₄ ) alkoxy, halogen, cyano, carboxyl and (C ₁ -C ₄ ) alkoxycarbonyl, with the proviso that X in this case does not represent SO or SO ₂ ,
or
R ^{13 represents} the group -NR ³⁴ R ³⁵ , wherein
R ³⁴ and R ^{35 are} identical or different and are for hydrogen, (C ₁ -C ₈ ) -alkyl, which can be substituted by (C ₆ -C ₁₀ ) -aryl, for (C ₃ -C ₈ ) -cycloalkyl, ( C ₆ -C ₁₀ ) aryl or 5- to 6-membered heteroaryl with up to three identical or different heteroatoms from the series N, O and / or S, the aryl and heteroaryl in turn optionally being one to two times the same or different, by hydroxy, amino, cyano, halogen, trifluoromethyl, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) 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, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -alkanoyl,
and
Z for a group of the formula
stands in what
A stands for O or S,
a means the number 0 or 1,
D represents a straight-chain (C ₁ -C ₄ ) alkylene group which can be substituted one or more times, identically or differently, by (C ₁ -C ₃ ) alkyl, hydroxy or fluorine,
and
R ^{36 represents} OR ³⁷ or NR ³⁸ R ³⁹ , wherein
R ³⁷ , R ³⁸ and R ^{39 are the} same or different and each represents hydrogen, phenyl, benzyl, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, which in turn may be one or more times, identical or different, by halogen, hydroxy, amino, carboxyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkoxycarbonyl amino, (C ₁ -C ₅ ) -Alkanoyloxy, a heterocycle or phenyl which is optionally substituted by halogen or hydroxy,
and their pharmaceutically acceptable salts, solvates, hydrates and hydrates of the salts. 2. Compounds of the general formula (I), according to claim 1
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, (C ₁ -C ₃ ) -alkyl, fluorine, chlorine or bromine,
R ^{6 represents} a group of the formula -S (O) ₂ -R ¹⁰ , -NR ¹¹ -C (O) -R ¹² , -CH ₂ -R ¹³ or -MR ¹⁴ , in which
R ¹⁰ for NR ¹⁶ R ¹⁷ , (C ₁ -C 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 identical or different heteroatoms from the series N, O and / or S, the abovementioned radicals optionally being selected from the group halogen, hydroxy, oxo, cyano, nitro, amino, dimethylamino by one, two or three identical or different substituents, Trifluoromethyl, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl, phenyl, which in turn is optionally substituted by halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C 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 ^{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, (C ₁ -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, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkoxycarbonylamino or (C ₁ -C ₅ ) alkanoyl oxy are substituted,
and
R ¹⁶ and R ^{17 are} identical or different and independently of one another are hydrogen, straight-chain or branched (C ₁ -C ₆ ) -alkyl, which one or more times are identical or different by (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, carboxyl, pyridyl or phenyl may be substituted, the latter in turn optionally substituted by halogen, trifluoromethyl, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy, for (C ₅ -C ₇ ) cycloalkyl or a 5- to 7-membered heterocycle containing one to two nitrogen atoms, the cycloalkyl and heterocycle optionally being substituted by (C ₁ -C ₄ ) alkyl,
or
R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are bound form a 5- to 7-membered saturated heterocycle which contains up to two further hetero atoms from the series N, O and / or S and are replaced by amino, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkoxycarbonylamino or phenyl may be substituted,
R ^{11 represents} hydrogen, straight-chain or branched (C ₁ -C ₄ ) alkyl, benzyl, (C ₃ -C ₇ ) cycloalkyl or a 5- to 7-membered heterocycle containing one or two nitrogen atoms, cycloalkyl and Heterocycle optionally substituted by (C ₁ -C ₄ ) alkyl,
R ^{12 is} straight-chain or branched (C ₁ -C ₈ ) alkyl which can be substituted by (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₄ ) alkoxy, phenyl, phenoxy or benzyloxy, the abovementioned Aromatics in turn can each be substituted up to three times in the same or different manner by halogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -alkoxy,
or
represents phenyl which can be substituted up to three times in the same or different manner by (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -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 (C ₁ -C ₄ ) -alkyl,
and
R ³⁰ and R ^{31 are the} same or different and independent of each other
for hydrogen, straight-chain or branched (C ₁ -C ₈ ) -alkyl, which may be substituted by phenyl, which in turn may optionally be up to twice the same or different by halogen, (C ₁ -C ₄ ) -alkyl, trifluoromethyl or (C ₁ -C ₄ ) alkoxy is substituted,
for (C ₃ -C ₇ ) cycloalkyl which may be substituted by (C ₁ -C ₄ ) alkyl,
or
represents phenyl which can be substituted up to three times in the same or different manner by halogen, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, (C ₁ -C ₄ ) -alkoxy or amino,
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 contains up to two further hetero atoms from the series, N, O and / or S and by amino, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkanoyl, aminocarbonyl, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkoxy carbonylamino or phenyl may be substituted,
R ^{13 represents} a saturated, partially unsaturated or aromatic 5- to 6-membered heterocycle having up to three identical or different heteroatoms from the series N, O and / or S, which is optionally selected by one, two or three identical or different substituents from the group (C ₁ -C ₄ ) alkyl, hydroxy, oxo, (C ₁ -C ₄ ) alkoxy, halogen, cyano, carboxyl and (C ₁ -C ₄ ) alkoxycarbonyl,
or
represents the group -NR ³⁴ R ³⁵ , wherein
R ³⁴ and R ^{35 are} identical or different and are hydrogen, (C ₁ -C ₆ ) -alkyl, which may 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 are available, phenyl and heteroaryl in turn being optionally one to two times, identical or different, by hydroxyl, amino, cyano, halogen, ( C ₁ -C ₄ ) alkyl, trifluoromethyl, (C ₁ -C ₄ ) alkoxy, carboxyl or (C ₁ -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 O or S,
a means the number 0 or 1,
D represents a straight-chain (C ₁ -C ₃ ) alkylene group which can be substituted one or more times, identically or differently, by methyl, hydroxy or fluorine,
and
R ^{36 represents} OR ³⁷ or NR ³⁸ R ³⁹ , wherein
R ^{37 represents} hydrogen, phenyl, benzyl, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₇ ) cycloalkyl, which in turn may be one or more, identical or different, by halogen, hydroxyl, amino, carboxyl , (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkoxycarbonylamino, (C ₁ -C ₅ ) alkanoyloxy or a heterocycle are substituted,
and
R ³⁸ and R ^{39 are} identical or different and each represent hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl, which in turn may be one or more, identical or different, by halogen, Hydroxy, amino, carboxyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, (C ₁ -C ₄ ) alkoxycarbonylamino, (C ₁ -C ₅ ) alkanoyloxy, a heterocycle or through phenyl which is optionally substituted by halogen or hydroxy,
and their pharmaceutically acceptable salts, solvates, hydrates and hydrates of the salts. 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 represent 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 ⁴⁰ is where
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, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, carboxyl or (C ₁ -C 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 bound form a 5- to 6-membered saturated heterocycle which contain a further hetero atom from the series N, O or S and are substituted by (C ₁ -C ₄ ) Alkyl can be substituted,
R ^{12 represents} straight-chain or branched (C ₁ -C ₆ ) 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 (C ₁ -C _4. By one or two identical or different substituents ) Alkyl, hydroxy, (C ₁ -C ₄ ) alkoxy, fluorine, chlorine, bromine, cyano, carboxyl and (C ₁ -C ₄ ) alkoxycarbonyl, or represents the group -NR ³⁴ R ³⁵ , wherein
R ^{34 represents} (C ₁ -C ₆ ) alkyl or (C ₅ -C ₇ ) cycloalkyl,
and
R ³⁵ stands for benzyl which is optionally substituted in the phenyl ring by hydroxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, trifluoromethyl, fluorine, chlorine or cyano,
R ^{14 represents} a group of the formula -NR ⁴¹ R ⁴² , wherein
R ^{41 represents} hydrogen, (C ₁ -C ₆ ) alkyl or (C ₃ -C ₇ ) cycloalkyl,
R ^{42 represents} hydrogen or (C ₁ -C ₄ ) -alkyl, which can be substituted by phenyl,
or
R ⁴¹ and R ⁴² together with the nitrogen atom to which they are bound form a 5- to 6-membered saturated heterocycle which contain a further hetero atom from the series N, O or S and are substituted by (C ₁ -C 4) - Alkyl may be substituted
and
R ^{40 represents} phenyl or naphthyl, which may be mono- or discrete, identical or different, by fluorine, chlorine, bromine, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, cyano, trifluoromethyl or (C ₁ -C ₄ ) alkoxycarbonyl are substituted,
R ^{7 represents} hydrogen,
and
Z for a group of the formula
where R ^{36 is} hydroxy or the radical -C (O) -R ^{36 has} the meanings of R ³⁶ given above for a group which are degraded in the sense of a prodrug to the carboxylic acid -C (O) -OH or its salts can
and their pharmaceutically acceptable salts, solvates, hydrates and hydrates of the salts. 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 the} same 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 discrete, identical or different, by fluorine, chlorine, bromine, hydroxy, cyano, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₁ - C ₄ ) alkoxy, carboxyl or (C ₁ -C ₄ ) alkoxycarbonyl are substituted,
or
for a group of the formula
stands,
R ¹³ for pyridyl, pyrimidinyl or pyridazinyl, optionally selected from the group (C ₁ -C ₄ ) alkyl, hydroxy, (C ₁ -C ₄ ) alkoxy, fluorine, chlorine, bromine by one or two identical or different substituents , Cyano, carboxyl and (C ₁ -C ₄ ) - alkoxycarbonyl are substituted, or stands for the group -NR ³⁴ R ³⁵ , wherein
R ^{34 represents} (C ₁ -C ₄ ) alkyl or (C ₅ -C ₇ ) cycloalkyl,
and
R ³⁵ stands for benzyl which is optionally substituted in the phenyl ring by hydroxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, trifluoromethyl, fluorine, chlorine or cyano,
and
R ^{14 represents} a group of the formula -NR ⁴¹ R ⁴² , wherein
R ^{41 represents} hydrogen, (C ₁ -C ₄ ) alkyl or (C ₅ -C ₇ ) cycloalkyl,
and
R ^{42 represents} hydrogen or (C ₁ -C ₄ ) -alkyl, which can be substituted by phenyl,
R ^{7 represents} hydrogen,
and
Z for a group of the formula
in which R ^{37 is} hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₄ -C ₆ ) -cycloalkyl,
and their pharmaceutically acceptable salts, solvates, hydrates and hydrates of the salts. 5. Compounds of formula (Ia)
in which
X represents CH ₂ or O,
R ³ and R ^{4 are the} same or different and represent bromine, trifluoromethyl, ethyl, cyclopropyl and in particular methyl or chlorine,
Z for a group of the formula -CH ₂ -C (O) -OH, -CH ₂ -CH ₂ -C (O) -OH, -O-CH ₂ -C (O) -OH or -S-CH ₂ - C (O) -OH,
and
R ^{6 represents} a group of the formula -S (O) ₂ -R ¹⁰ , wherein
R ^{10 represents} phenyl or pyridyl, which are optionally substituted once or twice, identically or differently, by fluorine, chlorine, cyano, trifluoromethyl, methyl, hydroxyl or methoxy. 6. Compounds of formula (Ia)
in which
X represents CH ₂ or O,
R ³ and R ^{4 are the} same or different and represent bromine, trifluoromethyl, ethyl, cyclopropyl and in particular methyl or chlorine,
Z for a group of the formula -CH ₂ -C (O) -OH, -CH ₂ -CH ₂ -C (O) -OH, -O-CH ₂ -C (O) -OH, -OC [(CH ₃ ) ₂ ] -C (O) -OH or -S-CH ₂ -C (O) -OH,
and
R ^{6 represents} a group of the formula -S (O) ₂ -R ¹⁰ , wherein
R ^{10 represents} phenyl or pyridyl, which are optionally mono- or disubstituted, identical or different, by fluorine, chlorine, cyano, trifluoromethyl, methyl, hydroxy or methoxy. 7. Compounds as defined in claims 1 to 6 for prevention and Treatment of diseases. 8. Medicaments containing at least one compound of the general For mel (I) as defined in claims 1 to 6. 9. A process for the manufacture of medicaments, characterized in that at least one compound of the general formula (I) as in the Claims 1 to 6 defined with auxiliaries and / or carriers in a ge suitable application form transferred. 10. Use of compounds of general formula (I) as in the An Proverbs 1 to 6 defined for the manufacture of drugs. 11. Use according to claim 8 for the manufacture of medicaments for the Treatment and / or prophylaxis of arteriosclerosis, obesity and Obesity and / or hypercholesterolemia. 12. Use according to claim 8 for the manufacture of medicaments for the Prophylaxis and / or treatment of disease forms with natural Thyroid hormone can be treated.   13. A method for the treatment and / or prophylaxis of diseases, thereby characterized in that compounds as in claims 1 to 6 defined, applies. 14. A process for the preparation of compounds of the formula (I) as defined in claim 1, characterized in that reactive phenol derivatives of the general formulas (II)
in which
R ⁵ and R ^{6 have} the meanings given in claim 1 and
PG stands for a protective group and
V represents a bonding or leaving group,
with reactive phenyl derivatives of the general formulas (III)
in which
R ¹ , R ² , R ³ and R ^{4 have} the meanings given in claim 1 and
W stands for a bonding or leaving group and
Z 'has the meaning given for Z or stands for OH, O-PG, SH, S-PG, or for an aldehyde, cyano, carboxyl or (C ₁ -C ₄ ) alkoxy carbonyl group,
if appropriate in the presence of inert solvents and catalysts and if appropriate with isolation of the intermediates or directly to give compounds of the formula (I).