EP1370523A1 - 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

Diphenyl derivatives

The invention relates to new 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 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 WO 98/57919, WO 99/26966 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 stands for O, S, SO, SO ₂ , CH ₂ , CHF, CF ₂ or for NR ⁸ , in which R ^{8 is} hydrogen or (-CC ₄ ) -alkyl, R ¹ and R ^{2 are the} same or different and represent hydrogen or (C _t -C ^ alkyl,

R ³ and R ^{4 are the} same 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 ^{3 represents} hydrogen, (-C-C ₄ ) alkyl or halogen,

R ^{6 represents} 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 , in which

R ⁹ for (-C-Cιo) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl, (C ₆ -C ₁₀ ) aryl, (C ₆ -Cι ₀ ) 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 replaced by one, two or three identical or different ones Substituents selected from the group halogen, hydroxy, oxo, cyano, (-CC ₆ ) -alkyl,

(-C-C ₆ ) alkoxy, carboxyl and (-C-C ₄ ) alkoxycarbonyl are substituted,

n represents the number 1 or 2,

R ¹⁰ is OR ^15, NR ¹⁶ R ^17, _(C. -Cιo) _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, the aforementioned

Residues, if necessary, by one, two or three identical or different various substituents selected from the group halogen, hydroxy, oxo, cyano, nitro, amino, NR ¹⁸ R ¹⁹ , trifluoromethyl, (Cι-C6) -Aϊkyl, optionally substituted by R ^2D (Ci-Cβ) - alkoxy, (C ₃ - C ₈ ) -cycloalkyl, (C ₆ -Cι ₀ ) aryl, which in turn is optionally substituted by halogen, (Cι.-C ₄ ) alkyl, (CC 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, (Cι -C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, which in turn, if appropriate, one or more times, identically or differently, by halogen, hydroxy, amino, carboxyl, (Cι.-C) -alkoxy, (Cι -C ₄ ) alkoxycarbonyl, (-C-C) alkoxycarbonylamino, (-

C5) -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 (-CC ₆ ) -alkyl, which one or more times the same or different by mono- (C ₁ -Cg) -alkylamino, di- ( C ₁ -C ₆ ) alkylamino, (C ₁ -C ₄ ) -

Alkoxy, (CpC ^ alkoxycarbonyl, carboxyl, pyridyl or (C ₆ -Cιo) aryl may be substituted, the latter in turn optionally substituted by halogen, trifluoromethyl, (Cj-Cg) - alkyl or (Cι-C ₆ ) alkoxy is

for (C ₃ -C ₈ ) cycloalkyl or for a 5- to 7-membered one are up to two nitrogen atoms containing heterocycle, where cycloalkyl and heterocycle are optionally substituted by (-CC) -A_kyl,

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-Cg) -alkyl, (-C-C ₄ ) -alkoxycarbonyl, (Cι-C) -alkoxycarbonylamino or phenyl may be substituted,

R ¹¹ for hydrogen, straight-chain or branched (-C-Cg) alkyl, which is one or more, identical or different, by mono- (C ₁ -C ₆ ) alkylamino, di- (C ₁ -C ₆ ) alkylamino , (-C-C ₄ ) alkoxy, (-C-C ₆ ) alkoxycarbonyl, carboxyl, pyridyl or (C ₆ -Cιo) aryl may be substituted, the latter in turn optionally being substituted by halogen, trifluoromethyl, (C _r C ₆ ) Alkyl or (C _r C ₆ ) alkoxy is substituted for (C ₃ -C ₈ ) cycloalkyl or for a 5- to 7-membered heterocycle containing one to two nitrogen atoms, cycloalkyl and heterocycle optionally being substituted by (Cι -C4) alkyl are substituted,

R ¹² for straight-chain or branched (-CC ₅ ) -alkyl, which by (C ₃ -Cg) -

Cycloalkyl, (C _j -C ₄ ) alkoxy, phenyl, phenoxy or benzyloxy may be substituted, the aromatics mentioned in turn each being up to three times the same or different by halogen, (C _j -C ₆ ) alkyl or (C j - C ₄ ) - alkoxy can be substituted, for (C ₃ -C ₈ ) cycloalkyl, which can be substituted by (-C ₄ ) alkoxy or phenyl,

for (C ₆ -Cιo) aryl which can be substituted up to three times the same or different by (Cι-C ₆ ) alkyl, (Cι-Cg) 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 for straight-chain or branched stands,

and

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

for hydrogen, straight-chain or branched (C ^ C ^) -

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, where phenyl is given - if up to two times the same or different is substituted by halogen, (-CC ₄ ) -alkyl, trifluoromethyl or (C ₁ -C ₄ ) -alkoxy,

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

for (C ₆ -C o) aryl which is identical or different up to three times by halogen, Trifluoromethyl, (C _! -C ₄ ) -10 alkoxy, amino, phenyl or phenoxy may be substituted,

or

represent a 5- to 7-membered, saturated or unsaturated heterocycle containing 15 or two nitrogen atoms, which is optionally substituted by (C ₁ -C) -alkyl or an oxo group,

in which

20

R ₍₆ -Cιo C) are ³² and R ³³ are identical or different and are each independently hydrogen, (Cι-C6) alkyl, phenyl or arylsulfonyl,

25 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 30 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 contain up to two further heteroatoms from the series, N, O and or S and by amino, (Cι -C ₆ ) -alkyl, (C ₁ -C ₄ ) -alkanoyl, aminocarbonyl, (C C4) -alkoxycarbonyl, (-C-C ₄ ) -alkoxycarbonylamino, 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 (Ci-C ^ alkyl, hydroxy,

Oxo, (C ₁ -C ₄ ) alkoxy, halogen, cyano, carboxyl and (dC) - alkoxycarbonyl is substituted, 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 the} same or different and represent hydrogen, (-CC ₈ ) -alkyl, which may be substituted by (C ₆ -C -o) -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 one to two times the same or differently, by hydroxy, amino, cyano, halogen, trifluoromethyl, (-CC ₄ ) alkyl, (CrC ₄ ) -alkoxy, carboxyl, (dG -alkoxycarbonyl or mono- or DKd-C ^ -allcylaminocarbonyl 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, (-CC ₄ ) -alkyl or (CC ₄ ) -alkanoyl,

and

for a group of the formula

stands in what

represents O or S,

the number 0 or 1 means

D represents a straight-chain (C 1 -C ₄ ) alkylene group which can be substituted one or more times, identically or differently, by (C ₃ -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-C ₆ ) -A_kyl or (C ₃ -C ₈ ) cycloalkyl, which in turn may be one or more, the same or different, by halogen, hydroxy, amino, carboxyl, (QG -alkoxy, (Cι-C) -

Alkoxycarbonyl, (Cι.-C ₄ ) -alkoxycarbonylamino, (C ₁ -Cs) -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

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, i.e. 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: 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 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-l-yl.

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 has a

Carbonyl group is linked. A straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred. Exemplary and preferred may be mentioned: 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 branched monoalkylamino radical having 1 to 4 carbon atoms is preferred. 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. Examples and preferably mentioned are: NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N- Isopropyl-Nn-propylamino, Nt-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-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 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-diethylaminocarbonyl, 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. Examples and preferably mentioned are: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.

In the context of the invention, alkoxyearbonylamino represents an amino group with a straight-chain or branched alkoxycarbonyl substituent which preferably 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: methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonyl__rnino and t-butoxycarbonylamino.

5- to 6-membered heteroaryl with up to 3 identical or different heteroatoms from the series S, Ν 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 series S, N and / or O 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, piperidin-4-yl, 1,2-dihydropyridin-l- yl, 1,4-dihydropyridin-l-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholine-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 that do not behave like image and mirror image (diastereomers) 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 metal salts (for example magnesium or calcium salts), and also ammonium salts which are derived from ammonia or organic amines, 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 and R ^{4 are the} same or different and are hydrogen, halogen, (-CC ₄ ) alkyl,

CF ₃ , CHF ₂ , CH ₂ F, vinyl or (C ₃ -C ₅ ) cycloalkyl, at least one of the two substituents not being hydrogen,

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

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

-MR ¹⁴ is where

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 aforementioned radicals optionally being selected from the group halogen, hydroxy, oxo, cyano by one, two or three identical or different substituents , Nitro, amino, dimethylamino, trifluoromethyl, (Cι.-C ₄ ) -alkyl, (CrG -alkoxy, (C ₃ -C ₆ ) -cycloalkyl, phenyl, which in turn by halogen, (QQ) - alkyl, (CrC 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, (-CC) alkyl or (C ₅ -C) cycloalkyl , which in turn may be one or more, the same or different, by halogen, hydroxy, amino, carboxyl, (C Carb-C ^ alkoxy, (Cι-C4) alkoxycarbonyl, (QC ^ alkoxycarbonylamino or (Ct-Cs ) - Alkanoyloxy are substituted,

and

R ¹⁶ and R ^{17 are the} same or different and are independently hydrogen, straight-chain or branched (-C-C ₆ ) alkyl, which is one or more times the same or different

(-C-C ₄ ) alkoxy, (-C-C) alkoxycarbonyl, carboxyl, pyridyl or phenyl may be substituted, the latter in turn optionally being replaced by halogen, trifluoromethyl, (Cι-C) alkyl or (Cι-C ₄ ) - Alkoxy is substituted,

represent (C ₅ -C7) 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 _j -C ₄ ) alkoxycarbonyl, (-C-C4) alkoxycarbonylamino or

Phenyl may be substituted R ^{11 represents} hydrogen, straight-chain or branched (C ₁ -C ₄ ) alkyl, benzyl, (C ₃ -C7) cycloalkyl or a 5- to 7-membered heterocycle containing one to two nitrogen atoms, cycloalkyl and heterocycle optionally through are substituted,

R ¹² for straight-chain or branched (C ₁ -C ₃ ) alkyl which is substituted by (C ₃ -C ₇ ) -

Cycloalkyl, (C ₁ -C ₄ ) alkoxy, phenyl, phenoxy or benzyloxy may be substituted, the aromatics mentioned in turn each being up to three times the same or different by halogen, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy may be substituted,

or

represents phenyl, which can be substituted up to three times in the same or different manner by (C1-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) alkyl,

and

R ³⁰ and R ^{31 are the} same or different and independent of each other for hydrogen, straight-chain or branched (C ^ -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) alkyl, trifluoromethyl or (Cι-C) Alkoxy is substituted,

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

or

phenyl up to three times identically or differently by halogen, (C1-C ₄₎ - may be substituted alkyl, trifluoromethyl, (Cι-C4) alkoxy or amino, are provided,

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, _(Cι-C4) alkanoyl, aminocarbonyl, _(Cι-C4) -alkoxycarbonyl, (C ₁ -C ₄₎ alkoxycarbonylamino or phenyl may be substituted,

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 from the group by one, two or three identical or different substituents Group (-C-C) alkyl, hydroxy, oxo, (C ₁ -C4) - Alkoxy, halogen, cyano, carboxyl and (QG -alkoxycarbonyl is substituted,

or

represents the group -NR ³⁴ R ³⁵ , wherein

R ³⁴ and R ^{35 are the} same or different and for hydrogen, (-C.-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, where phenyl and heteroaryl in turn are optionally one to two times, identical or different, by hydroxyl, amino, cyano, halogen, (C] - C ₄ ) - alkyl, trifluoromethyl, (dC ^ alkoxy,

Carboxyl or (-CC) 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 O or S,

a means the number 0 or 1,

D represents a straight-chain (-C-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, (-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, (CrC ₄ ) -

Alkoxy, (C! -C ₄ ) -alkoxycarbonyl, (-C-C ₄ ) -alkoxycarbonylamino, (C _! -C ₅ ) -alkanoyloxy or a heterocycle are substituted,

and

R ³⁸ and R ^{39 are the} same or different and each represents hydrogen, (-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, (CrC ₄ ) alkoxy, (CrC) alkoxycarbonyl, (Q-Qyalkoxycarbonylamino, (C ₁ -C ₅ ) alkanoyl- oxy, a heterocycle or, in turn, phenyl which is optionally substituted by halogen 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 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 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, (-CC 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 can be substituted by (CC ₄ ) - alkyl can

R ^{12 represents} straight-chain or branched (Ct-Cg) alkyl which is optionally substituted by phenoxy or benzyloxy,

R 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, hydroxy by one or two identical or different substituents , (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> 3 "4 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, (dC ₄ ) alkoxy, (dC ₄ ) alkyl, trifluoromethyl, fluorine, chlorine or cyano,

R represents a group of the formula -NR ^4I R ⁴² , wherein

R ^{41 represents} hydrogen, (dC ₆ ) alkyl or (C ₅ -C ₇ ) cycloalkyl, R ^{42 represents} hydrogen or (dC 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 contain a further hetero atom from the series N, O or S and can be substituted by (CC ₄ ) alkyl can

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 (dC) Alkoxycarbonyl are substituted,

R ^{7 represents} hydrogen,

and

for a group of the formula

in which R ^{36 is} hydroxyl or the radical -C (O) -R ^{36 has} the meanings given above of R for a group which degrades to a carboxylic acid -C (O) -OH or its salts in the sense of a prodrug 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} 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 1Ö stands for phenyl, pyridyl, pyrimidinyl or pyridazinyl, which may be mono- or discrete, identical or different, by fluorine, chlorine, bromine, hydroxy, cyano, trifluoromethyl, (dC) - alkyl, (dC ₄ ) -alkoxy, carboxyl or (C ₁ -C 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, (dC ₄ ) -alkoxy, fluorine, chlorine, bromine, cyano, carboxyl and (by one or two identical or different substituents) 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 ⁴¹ R, wherein

R ^{41 represents} hydrogen, (-CC ₄ ) -alkyl or (C ₅ -C ₇ ) -cycloalkyl,

and

R ^{42 represents} hydrogen or (dC ₄ ) -alkyl, which can be substituted by phenyl,

R represents hydrogen,

and

Z for a group of the formula

in which R ^{37 is} hydrogen, (dC ₄ ) -alkyl or (C ₄ -C ₆ ) -cycloalkyl,

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

The general or preferred radical definitions given above 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 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

R> 37 means hydrogen, methyl or ethyl.

Of particular importance are compounds of formula (I) in which R ^{6 is} for a

Group of the formula -S (O) -R 10, wherein

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 ₄ ) -alkyl, (dC ₄ ) -alkoxy, carboxyl or (dC ₄ ) - alkoxycarbonyl are substituted,

or

represents the group -NR ^I6 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 by (C _j -C) 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 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 (* means the linkage point in the table):

Table 1

Individual compounds of formula 2, in which Z in each case those given in Table 1

Has meanings and R ³ instead of methyl in formula 1 for each of the individual

Compounds 1 to 19 each have the meanings for R 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 247 each have the meanings given for R in Table 3 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 each R ⁶ has the meanings given in Table 4:

Table 4

R6 R6 R6 R6

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 stands for OH, O-PG, SH, S-PG, or for a nitro, aldehyde, cyano, carboxyl or (d-C) alkoxycarbonyl group,

and

PG stands for a suitable protective group. Driving method [AI:

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

(I)

Process variant [B]:

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

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

(IIc) (IIIc) (IVc)

V or W = halogen

(IVb) (Ib)

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, CH ₂ Br, mercapto, amino, CHO, Li, magnesium, tin, boron or copper 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. 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 (IIla-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)].

The reaction of the starting compounds (Ila-c) with (Illa-c) generally takes place at 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, intermediates of the formulas (IV), (IVa), (IVb) and (IVc) can also be formed in the reaction of (Ila-c) and (ffla-c), in which e.g. the substituent Z 'represents 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 according to the usual Methods to compounds of formula (I) are further implemented.

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

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 in the scope of meaning given on individual process stages.

Protective groups (PG, PG ¹ , PG ² ) are understood in the present application to mean those groups in starting materials and / or intermediates which contain functional groups such as, for example, carboxyl, amino, mercapto or

Protect 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 the formula (I) according to the invention have a surprising and valuable spectrum of pharmacological activity and can therefore be used as versatile medicaments for the treatment of humans and mammals, such as in particular dogs and cats. 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. With the compounds of the formula (I) according to the invention, arteriosclerosis, Treat hypercholesterolemia, dyslipidemia, obesity and obesity. In addition, cardiac insufficiency can also be treated with the compounds according to the invention and a postprandial "reduction in triglycerides can be achieved.

The compounds are also suitable for the treatment of certain respiratory diseases, in particular of emphysema of the lungs, and for the medication of the lung.

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, 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 are an enrichment for the pharmaceutical industry. Compared to the known and previously used thyroid hormone preparations, the compounds according to the invention show an improved spectrum of action. They are preferably characterized by great specificity, good tolerance and fewer side effects, especially in the cardiovascular area.

The effectiveness of the compounds according to the invention can be 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 contains a luciferase gene under the control of a thyroid hormone. mon-regulated promoters. 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. 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 ₅ 0 values of each connection are calculated. The compound of Example 2 shows an EC ₅₀ value of 2 nM in this test.

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 examined 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 (normal 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 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, Νetheler & 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 (Norwert) 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 using Student's t-test after checking the variants 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 test, the animals are weighed and killed after the blood is drawn. To check for potential cardiovascular side effects under the influence of substances, 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-jerking rats are used as test 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.

As a parameter for the effectiveness of the compounds according to the invention in the treatment of obesity (obesity), for example, body weight development after four weeks of test substance administration can be used in mice in which obesity was previously induced by pre-feeding with fatty food.

For further investigation of potential cardiovascular side effects under the influence of substances, the determination of the expression of the mRNA of the "HCN2" ion channel ("hyperpolarization-activated cyclic nucleotide-gated channel") in mouse or rat hearts can be used [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 was isolated using RNaesy columns (Qiagen), digested with DNase and then rewritten into cDNA (SUPERSCRIPT-II RT cDNA synthesis kit, Gibco). The HCN2 mRNA determination was 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 dye -Carboxyfluorescein; TAMRA = Quencher 6-Carboxytetramethylrhodamin). During the polymerase chain reaction, the 5'-exonuclease activity of the Taq polymerase cleaves the fluorescent dye FAM and thereby the previously quenched fluorescence signal is obtained. The number of cycles, in which the fluorescence intensity was 10 standard deviations above the background fluorescence, was recorded as the so-called “threshold cycle” (Ct value). The relative expression of the HCN2 mRNA calculated in this way was 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 'and 5'-CTAGCCGGTCAATAGCCACAG-

3 'that of the fluorescent sample 5'-6FAM-CATGATGCGGCGTGCCTTTGAG-TAMRA-3.

For the application of the compounds of the general formula (I), all customary forms of application come into consideration, that is to say orally, parenterally, by inhalation, nasally, sublingually, buccally, rectally or externally, for example transdermally, particularly preferably orally or parenterally. In parenteral administration, intravenous, intramuscular, subcutaneous administration should be mentioned in particular, for example 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 auxiliary substances are: water, non-toxic organic solvents such as e.g. Paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerin), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock flour (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, preferably dosages of 0.001 to 5 mg / kg, preferably 0.001 to 3 mg / kg body weight are 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, lipase inhibitors, fibrate Inhibitors and PP AR agonists can be administered.

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

Starting Compounds:

Example I

[4- (Ben__yloxy) -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 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- (Ber ___ yloxy) -3-bromophenyl] methanol are obtained.

1H-NMR (200 MHz, CDC1 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 dissolved in

30 ml DMF submitted. 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 washed. The organic phase is dried with sodium sulfate and the solvent is removed in vacuo. 4.02 g (86% of theory) of {[4- (benzyloxy) -3-bromobenzyl] oxy} (tert-butyl) dimethylsilane are obtained.

1H-NMR (200 MHz, CDC1 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- (Benzylo-χy) -3 - [(4 - fluorohenyl) sulfar_yl] benzyl} σxy) (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.

1H-NMR (200 MHz, CDC1 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 IN

({4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} 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 overnight at room temperature. 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.

1H-NMR (200 MHz, CDC1 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 N

{4- (Ben__yloxy) -3 - [(4-fluoφhenyl) sulfonyl] phenyl} methanol

3.4 g (6.99 mmol) ({4- (Benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} oxy) (tert-butyl) dimethylsilane (Example IN) 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.

1H-NMR (200 MHz, CDC1 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.

1H-NMR (200 MHz, CDC1 ₃ ): δ = 5.12 (s, 2H), 6.87-6.99 (m, 2H), 7.1 (d, IH), 7.24- 7.30 (m, 2H), 7.41-7.46 (m , 3H), 7.72-7.82 (m, 2H), 8.08 (dd, IH), 8.7 (d, IH), 9.98 (s, IH).

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.

1H-NMR (200 MHz, CDC1 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 - [(triisopropylsilyl) oxy] phenyl} methanol

810 mg (2.27 mmol) of 4-bromo-3,5-dimethylphenyltrüsopropylsilylether (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 a constant temperature, the mixture is stirred for an 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. It 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 ,

1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.04-1.35 (m, 21H), 2.2 (s, 6H), 3.68 (s, IH), 4.99 (s, 2H), 6.25 (d, IH), 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, IH).

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 are then added dropwise. sulfonate too. After the reaction mixture has been stirred for 1.5 hours, saturated ammonium chloride solution is added. The mixture is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. 611 mg (53% of theory) (4- {4- (ben__yloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} -3,5-dimethylphenoxy) (friisopropyl) silane are obtained.

1H-NMR (200 MHz, CDC1 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, IH).

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 , At room temperature, 359 mg (1.14 mmol) of tetrabutylammonium fluoride are added and the mixture is stirred for a further thirty minutes. Then you remove that

Solvent in vacuo and the product is purified chromatographically 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. 1H-NMR (200 MHz, CDC1 ₃ ): δ = 2.18 (s, 6H), 3.97 (s, 2H), 4.48 (s, IH), 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, IH).

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.

1H-NMR (200 MHz, CDCI 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, IH). Example XII

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

This compound was obtained in a manner analogous to Example XI, starting from 4- {4- (benzyloxy) -3 - [(4-fluorophenyl) sulfonyl] benzyl} -3,5-dimethylphenol (Example X) and ethyl dimethylbromoacetate.

1H-NMR (200 MHz, CDC1 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, IH).

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.

1H-NMR (200 MHz, CDC1 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, IH), 6.98-7.05 (m, IH), 7.16-7.23 (m, 3H), 7.84-7.90 (m, 2H), 8.94 (s, IH).

Example 2

(4- {3 - [(4-Fluoφhenyl) 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-Fluoφhenyl) sulfonyl] -4-hydroxybenzyl} - 3,5-dimethylphenoxy) acetic acid are obtained.

1H-NMR (200 MHz, CDC1 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, IH).

Example 3

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

This compound was prepared in a manner analogous to Examples 1 and 2 starting from ethyl 2- (4- {4- (benzyloxy) -3 - [(4-fluoro-phenyl) sulfonyl] benzyl} -3,5-dimethylphenoxy) -2-methylpropanoate ( Example XII) obtained.

1H-NMR (200 MHz, CDC1 ₃ ): δ = 1.60 (s, 6H), 2.11 (s, 6H), 3.88 (s, 2H), 6.66 (s,

2H), 6.85-7.30 (m, 5H), 7.84-7.91 (m, 2H), 8.94 (broad s, IH).

The following examples are produced analogously to the processes specified above:

Example 4

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

Example 5

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

Example 6 3- (4- {3 - [(4-Fluoφhenyl) sulfonyl] -4-hydroxyphenoxy} -3,5-dimethylphenoxy) propionic acid Example 7

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

Example 8

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

Example 9 Fluoro (4- {3 - [(4-fluorophene) sulfonyl] -4-hydroxybenzyl} -3,5-dimethylphenyl) acetic acid

Example 10

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

Example 11

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

Example 12

Fluoro (4- {3 - [(4-fluoφhenyl) 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-fluoφhenyl) sulfonyl] -4-hydroxyphenoxy} phenyl) acetic acid Example 15

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

Example 16

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

Example 17 3- [4- {3 - [(4-Fluophenyl) sulfonyl] -4-hydroxyphenoxy} -3, 5-bis (trifluoromethyl) phenylpropionic acid

Example 18

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

Claims

claims

Compounds of the general formula (I)

in which

X stands for O, S, SO, SO ₂ , CH ₂ , CHF, CF ₂ or for NR ⁸ , in which R ⁸ denotes hydrogen or (dC ₄ ) alkyl,

R ¹ and R ^{2 are} identical or different and represent hydrogen or (dC ₄ ) 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 represents hydrogen, (dC 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 for (-C-Cιo) 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 Heteroatoms from the series N, O and / or S, the abovementioned radicals optionally being selected from the group halogen, hydroxy, oxo, cyano, (dC ₆ ) -alkyl, (d-) by one, two or three identical or different substituents 5 C ₆ ) -alkoxy, carboxyl and (C ₁ -C ₄ ) -alkoxycarbonyl are substituted,

n represents the number 1 or 2,

10 R ¹⁰ for OR ¹⁵ , NR ¹⁶ R ¹⁷ , (dC 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 heteroatoms of the series N, O and / or S

15, the abovementioned radicals optionally being selected from the group halogen, hydroxyl, oxo, cyano, nitro, amino, NR ¹⁸ R ¹⁹ , trifluoromethyl, (dC ₆ ) alkyl, optionally by one, two or three identical or different substituents R ²⁰ substituted (-C-C ₆ ) alkoxy, (C ^* 3-C ₈ ) -

20 cycloalkyl, (C6-Cι ₀ ) aryl, which in turn is optionally substituted by halogen, (Cι-C ₄ ) alkyl, (dC ₄ ) alkoxy, trifluoromethyl, nitro or cyano, -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

25

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, (dC ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, which in turn may be

30 or more times, the same or different, by halogen,

Hydroxy, amino, carboxyl, (Cι-C ₄ ) -A_koxy, (Cι-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, 5 and

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

10 branched (-C-Cö) -alkyl, which one or more times the same or different by mono- (-C-C ₆ ) alkylamino, di- (Cι-Cg) alkylamino, (-C-C ₄ ) alkoxy , (C ₁ -C ₆ ) alkoxycarbonyl, carboxyl, pyridyl or (Cg-Cιo) aryl may be substituted, the latter

15 is in turn optionally substituted by halogen, trifluoromethyl, (C _r C ₆ ) -alkyl or (CC ₆ ) -alkoxy,

represent (C ₃ -Cg) cycloalkyl or a 5- to 7-membered heterocycle containing 20 to two nitrogen atoms, the cycloalkyl and heterocycle optionally being substituted by (C _j -C ₄ ) alkyl,

or

25

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 contains up to two further heteroatoms from the series N, O 30 and / or S and through Amino, (C _j -C ₆ ) alkyl,

(C ι -C) alkoxycarbonyl, (C ι -C) alkoxycarbonyl- amino or phenyl may be substituted,

R ¹¹ for hydrogen, straight-chain or branched (Cj-Cg) - alkyl, which one or more times, the same or different, by mono- (-C-C ₆ ) alkylamino, di (C ₁ -Cg) alkylamino, ( Cι-C) -

Alkoxy, (Ci-C ^ alkoxycarbonyl, carboxyl, pyridyl or (C ₆ -Cιo) aryl may be substituted, the latter in turn optionally halogen, trifluoromethyl, (CJ-C _Ö ) - alkyl or (C Cg) - alkoxy is substituted for (C ₃ -C ₈ ) cycloalkyl or for a 5- to 7-membered, one to two

Heterocycle containing nitrogen atoms, where cycloalkyl and heterocycle are optionally substituted by (C 1 -C ₄ ) alkyl,

R ¹² for straight-chain or branched (C _j -C ₁ 5) alkyl, which by

(C ₃ -C ₈ ) -cycloalkyl, (C _r C ₄ ) - alkoxy, phenyl, phenoxy or benzyloxy may be substituted, the aromatics mentioned in turn each being up to three times the same or different by halogen, (-C-C ₆ ) - Alkyl or (Cj-C ₄ ) - alkoxy can be substituted,

for (C ₃ -C ₈ ) cycloalkyl which can be substituted by (C _j -C ₄ ) alkoxy or phenyl,

for (C ₆ -Cιo) aryl, which can be substituted up to three times the same or different by (Ci-CgJ-alkyl, (C ^ Cg) - 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 ⁰ and R ^{31 are the} same or different and are independent of one another

for hydrogen, straight-chain or branched (Ci-C ι ₂ ) - alkyl by aminocarbonyl, a group

20 of the 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 being up to twice the same or differentiated by halogen, (-CC ₄ ) - alkyl,

25 trifluoromethyl or (Cj-C ₄ ) - alkoxy is substituted,

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

30 for (Cg-C _j o ^ aryl which is up to three times the same or different by halogen, (C1-C4) - alkyl, trifluoro- methyl, (Cι ~ C) - alkoxy, amino, phenyl or phenoxy may be substituted,

or

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

10 where

R ³² and R ^{33 are the} same or different and independently of one another represent hydrogen, (Cj-Cg) - alkyl, phenyl or 15 (Cg-Cιo) arylsulfonyl,

or

together with the nitrogen atom to which they are attached, 20 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

25

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 30 by amino, (C _r C ₆ ) alkyl, (C ₁ -C ₄ ) alkanoyl, aminocarbonyl, (C ₁ -C) alkoxycarbonyl, (C ₁ -C ₄ ) alkoxy carbonylamino, phenyl or pyridyl can be substituted,

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 (dC ₄ ) alkyl, hydroxy, oxo, (dC ₄ ) alkoxy, halogen, cyano, carboxyl and (dC ₄ ) alkoxycarbonyl, with the proviso that X in this case is not SO or SO ₂ stands,

or

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

R ³⁴ and R are identical or different and for hydrogen, (dC ₈ ) alkyl, which can be substituted by (C ₆ -Cι ₀ ) 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 each optionally one to two times, identical or different, by Hydroxy, amino, cyano, halogen,

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

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

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

A stands for O or S,

the number 0 or 1 means

D represents a straight-chain (dC ₄ ) alkylene group which can be substituted one or more times, identically or differently, by (dd) 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-C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, which in turn may be one or more, the same or different, by Halogen, hydroxy, amino, carboxyl, (dC ₄ ) - alkoxy, (C ι -C ₄ ) - alkoxycarbonyl, (C ι -C ₄ ) - alkoxycarbonylamino, (C ₁ -C ₅ ) alkanoyloxy, a heterocycle or are in turn substituted by phenyl optionally substituted by halogen or hydroxy,

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

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 the} same 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 which of the two substituents is not hydrogen,

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

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

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 the same or different heteroatoms from the series N, O and / or S, the abovementioned radicals optionally being selected from the group halogen, hydroxy, 5 oxo, cyano, nitro, amino, dimethylamino by one, two or three identical or different substituents , Trifluoromethyl,

(dC ₄ ) alkyl, (dC ₄ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl, phenyl, which in turn may be halogen, (dC ₄ ) alkyl, (Cj-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 , 10 -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,

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

15 in turn, optionally one or more times, the same or different, by halogen, hydroxy, amino, carboxyl, (dC ₄ ) - alkoxy, (C ₁ -C ₄ ) -alkoxycarbonyl, (dC ^ -alkoxycarbonylamino or (dC ₅ ) -alkanoyl - are oxy substituted,

20 and

R ¹⁶ and R ^{17 are the} same or different and are independently hydrogen, straight-chain or mixed

25 branched (-C-Cg) alkyl, which can be substituted one or more times the same or different by (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, carboxyl, pyridyl or phenyl, the latter for its part optionally by halogen, trifluoromethyl, (Cj-

30 C ₄ ) -alkyl or (C _\ -C ₄ ) - alkoxy is substituted, 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 one

Form heterocycle, which contain up to two further heteroatoms from the series N, O and / or S and by amino, (-CC ₄ ) alkyl, (-C-C ₄ ) alkoxycarbonyl, (Ci-d -alkoxycarbonylamino or phenyl can be substituted

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, cycloalkyl and heterocycle optionally passing through

(C ₁ -C ₄ ) alkyl are substituted,

R for straight-chain or branched (C _j -Cg ^ alkyl, which by

(C ₃ -C ₇ ) cycloalkyl, (C _r C ₄ ) alkoxy, phenyl, phenoxy or benzyloxy may be substituted, the above

Aromatics in turn can each be substituted up to three times in the same or different manner by halogen, (C _j - i) 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, (d-dt) alkoxy, halogen, cyano, amino or trifluoromethyl,

or

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

wherein

10

R ^{29 represents} straight-chain or branched (C ₁ -C ₄ ) alkyl,

and

15 R ³⁰ and R ³ * are the same or different and are independent of one another

for hydrogen, straight-chain or branched

(C Cg) alkyl, which may be substituted by phenyl,

20 which in turn is optionally up to two times the same or differently substituted by halogen, (C ₁ -C ₄ ) alkyl, trifluoromethyl or (C _j -G alkoxy),

for (C ₃ -C ₇ ) cycloalkyl which can be substituted by (C ₁ -C ₄ ) alkyl,

or

for phenyl which is identical or different up to three times by halogen, (C ₁ -C ₄ ) alkyl, trifluoromethyl, (C ₁ -C ₄ ) alkoxy or amino may be substituted,

or 5

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 10 by amino, (C ₁ -C 4) - alkyl, _(Cι-C4) alkanoyl, aminocarbonyl amino, (Cι-C4) alkoxycarbonyl, (Ci-e alkoxy carbonylamino or phenyl may be substituted,

1 "

R represents a saturated, partially unsaturated or aromatic 15 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 (dC ₄ ) alkyl, hydroxy, oxo, (dC ₄ ) alkoxy, halogen, 20 cyano, carboxyl and (C ₁ -C) alkoxycarbonyl,

or

represents the group -NR ³⁴ R ³⁵ , wherein

25

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

(dC 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

30 different heteroatoms from the series N, O and / or

S are, with phenyl and heteroaryl in turn optionally substituted one to two times, identically or differently, by hydroxy, amino, cyano, halogen, (d-C ₄ ) -alkyl, trifluoromethyl, (dC ₄ ) -alkoxy, carboxyl or (dC) -alkoxycarbonyl,

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 O or S,

a means the number 0 or 1,

D represents a straight-chain (dC 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, (dC ₆ ) alkyl or (C ₃ -C ₇ cycloalkyl, which in turn, if appropriate, one or more times, identically or differently, by halogen, hydroxyl, amino, carboxyl, (dC) - Alkoxy, (dC) -alkoxycarbonyl, (dC ₄ ) -alkoxycarbonylamino, (d-C5) -alkanoyloxy or a heterocycle are substituted,

and

R and R are the same or different and each represents hydrogen, (-CC ₆ ) alkyl or (dC) -cycloalkyl, which in turn may be one or more, identical or different, by halogen, hydroxy, amino, carboxyl, ( dC ₄ ) - alkoxy, (C ι -C ₄ ) - alkoxycarbonyl, (C ι -C ₄ ) - alkoxycarbonylamino,

(-C-Cs) -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) 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} identical 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, (dC) - alkyl, (dC ₄ ) - alkoxy, carboxyl or (dC ₄ ) -alkoxycarbonyl are substituted,

or

represents the group -NR 16π Rl7, 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 substituted by (Cj-Gt) - alkyl can be,

R represents straight-chain or branched (Ci-Cg ^ Alk l, 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 ) - alkyl, hydroxy, (dC ₄ ) - alkoxy, fluorine, chlorine, bromine, cyano, carboxyl and (C ₁ -C ₄ ) by one or two identical or different substituents Alkoxycarbonyl is substituted, or represents the group -NR ³⁴ R ³⁵ , wherein

R ^{34 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 ⁴¹ R ⁴² , wherein

R ^{41 represents} hydrogen, (dC ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,

R ^{42 represents} hydrogen or (-C-C ₄ ) alkyl, which by

Phenyl may be substituted

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 contain a further hetero atom from the series N, O or S and are replaced 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, (dC ₄ ) -alkyl, (-C-C ₄ ) alkoxy, cyano, trifluoromethyl or (dC ₄ ) Alkoxycarbonyl are substituted,

R ^{7 represents} hydrogen,

and

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 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 discrete, identical or different, by fluorine, chlorine, bromine, hydroxy, cyano, trifluoromethyl,

(dC ₄ ) -alkyl, (C _r C ₄ ) -alkoxy, carboxyl or (CC 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-C) - alkyl, hydroxy, (dC ₄ ) - 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} (dC ₄ ) 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,

and

R ^{14 represents} a group of the formula -NR ⁴¹ R ⁴² , wherein

R ^{41 represents} hydrogen, (dC ₄ ) -alkyl or (C ₅ -C ₇ ) -cycloalkyl,

and

R ^{42 represents} hydrogen or (dC ₄ ) -alkyl, which can be substituted by phenyl,

represents hydrogen, and

for a group of the formula

in which R ^{37 is} hydrogen, (CC) 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} 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 or -S-CH ₂ -C (O) -OH,

and

R 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.

Compounds of formula (Ia)

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,

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 substituted once or twice, identically or differently, 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. Medicament containing at least one compound of the general formula (I) as defined in claims 1 to 6.

9. A process for the preparation of medicaments, characterized in that at least one compound of the general formula (I) as defined in claims 1 to 6 is converted into a suitable application form with auxiliaries and / or carriers.

10. Use of compounds of general formula (I) as defined in claims 1 to 6 for the manufacture of medicaments.

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 which can be treated with natural thyroid hormone.

13. A method for the treatment and / or prophylaxis of diseases, characterized in that compounds as defined in claims 1 to 6 are used.

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

2. has the meaning given for Z or stands for OH, O-PG, SH, S-PG, or for an aldehyde, cyano, carboxyl or (dC ₄ ) alkoxycarbonyl 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).