EP1307426A1

EP1307426A1 - Amino diphenyl ethers and amido diphenyl ethers

Info

Publication number: EP1307426A1
Application number: EP01956554A
Authority: EP
Inventors: Helmut Haning; Josef Pernerstorfer; Gunter Schmidt; Michael Woltering; Hilmar Bischoff; Verena Vöhringer; Axel Kretschmer; Christiane Faeste
Original assignee: Bayer AG; Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2000-08-04
Filing date: 2001-07-23
Publication date: 2003-05-07
Also published as: WO2002012169A1; DE10038007A1; CA2417880A1; US6555580B2; AU2001278502A1; US20030027862A1

Abstract

The invention relates to novel amino diphenyl ethers and amido diphenyl ethers, to methods for the production thereof, and to their use in medicaments, especially for the indications of arteriosclerosis and hypercholesterolemia.

Description

Amino and amido diphenyl ether

The invention relates to new amino and amido diphenyl ethers, processes for their preparation and their use in pharmaceuticals, in particular for the indications atherosclerosis and hypercholesterolemia.

European application 580 550 A (Ciba Geigy; 1994) describes oxamic acid derivatives which have cholesterol-lowering properties in mammals. This application describes an in vitro test based on the binding to

Thyroid hormone cell receptors (so-called T3 nuclear receptors) builds up. The reduction in plasma cholesterol, in particular LDL cholesterol, is emphasized as a pharmacological property. Cholesterol-lowering effects are also described in European application EP-A-188 351 (SKF; 1986) for certain diphenyl ethers with thyroid hormone-like effects.

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

wherein

R ^{1 represents} nitro, amino, acetamido or a group of the formula -NH-CO-CO-A or -NH-CH ₂ -CO-A,

wherein

A represents hydroxy or (C ι -C4) alkoxy, R ² and R ^{3 are} identical or different and are halogen, C _j -C4-alkyl or trifluoromethyl,

R ⁴ for a group of the formula

stands,

embedded image in which

E represents straight-chain or branched (C _j -C4) alkyl,

R ⁶ and R ^{7 are the} same or different and independently of one another for straight-chain or branched (C _j -Cιo) alkyl, that one or more times the same or different by (C3-Cg) -cycloalkyl, (C _j -Cg) - alkoxy , j nino, mono- or di- (C ₁ -C ₆ ) alkylamino, (Cι-C4) alk-oxycarbonylamino, aminocarbonyl, (Cι-C6) alkoxycarbonyl, or by (C6-Cιo) aryl or 5th up to 6-membered saturated or aromatic heterocyclyl with up to three heteroatoms from the series, N, O and / or S, where aryl and heterocyclyl in turn, if appropriate, one or more times identically or differently by (C 1 -C 4) -alkyl,

Aminocarbonyl, (-C-C4) alkanoylamido or halogen are substituted, can be substituted,

for (C ₆ -C ₁₀ ) aryl or (C ₃ -C ₈ ) cycloalkyl, which can be substituted by (C _r C ₄ ) alkoxy,

or for a 4- to 8-membered saturated heterocycle with up to two heteroatoms from the series N, O and / or S, the one or more of the same or different by (Cj-C4) alkoxycarbonyl, oxo or (Cι-C4) -Alkyl can be substituted,

or

R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle which optionally contains up to two further heteroatoms from the series, N, O and / or S,

R ⁸ for straight-chain or branched (-C-Cι _υ ) alkyl, which can be substituted by (C3 ~ Cg) - cycloalkyl, phenyl or phenoxy, or for (C3- C ₈ ) -cycloalkyl, (C ₆ -C ₁₀ ) Aryl, biphenyl or (C1 -C ₆ ) alkoxy,

R ⁹ for straight-chain or branched (C ₁ -Cg) alkyl, the carbon chain of which can be interrupted by -O- and which can be substituted by (C3-Cg) -cycloalkyl or phenyl, or for (C3-Cg) -cycloalkyl, ( C 2 -C ₆₎ alkenyl, phenyl or pyridyl,

where both the aromatic ring systems mentioned in R ⁸ and in R ^{9 may} each independently be substituted by trifluoromethyl, halogen, (C1-C4) -alkoxy, (Cι-C4) alkyl or amino,

or

R ⁸ and R ⁹ together with the nitrogen atom and the carbonyl group to which they are attached form a 4- to 7-membered saturated hetero- form a cycle which optionally contains up to two further heteroatoms from the series, N, O and / or S,

^ r straight-chain or branched (C _j -C ^ alkyl, which can be substituted by (C3 ~ Cg) - cycloalkyl, (C1-C4) - alkoxy, phenyl, phenoxy or benzyloxy, the aromatics mentioned in each case up to three times may be substituted identically or differently by halogen (-CC) alkyl or (Ci-Q ^ alkoxy,

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

for (C6-Cι ₀ ) aryl which can be substituted up to three times the same or different by (C _j -Cg ^ alkyl, (C _j -C ^ alkoxy, halogen, cyano, amino, trifluoromethyl or phenyl,

or

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

or

is a group of the formula -OR ¹³ or NR ¹⁴ R ¹⁵ ,

wherein

R13 fu _r straight or branched (C _j ^ Al -CG yl,

and R ¹⁴ and R ^{15 are the} same or different and are independent of one another

for hydrogen, straight-chain or branched 5 alkyl by aminocarbonyl, a group of formula

-NR ¹⁶ R ¹⁷ , 5- to 6-membered heteroaryl has up to 3 heteroatoms selected from the series N, O and / or S or can be substituted by phenyl, phenyl optionally up to two times the same or different by halogen, 10 (C1-C4) - alkyl, trifluoromethyl or (C _r C ₄ ) -alkoxy substitu- _. is,

for (C3-Cg) -cycloalkyl, which can be substituted by (C ₁ -C4) -alkyl, 15 for (C6-Cιo) -aryl, which are identical or different up to three times by halogen, (C _r C ₄ ) - Alkyl, trifluoromethyl, (C _r C ₄ ) - alkoxy, amino, phenyl or phenoxy may be substituted,

20 or

for a 5- to 7-membered, saturated or unsaturated heterocycle containing one or two nitrogen atoms, which can be bonded via a carbon or nitrogen atom and

25 is optionally substituted by (C 1 -C 4) -alkyl or an oxo group,

in which R ¹⁶ and R ^{17 are} identical or different and independently of one another represent hydrogen, (Ci-Cg) - alkyl, phenyl or (Cg-C - ^ - arylsulfonyl,

or

together with the nitrogen 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 ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated

Form heterocycle, which contain up to two further heteroatoms from the series, N, O and / or S and by amino, (C _r C ₆ ) -alkyl, (C _r C4) -alkanoyl, aminocarbonyl, (Cι-C4) - Alkoxycarbonyl, (-C-C4) alkoxycarbonylamino, phenyl or pyridyl can be substituted,

R ¹ ! and R ^{12 are the} same or different and independent of each other

for hydrogen, straight-chain or branched (-C-Cg) -alkyl, which one or more times the same or different by mono- (-C-C ₆ ) -alkylarnino, di- (C ₁ -C ₆ ) -alkylamino, (C1-C4 ) - Alkoxy, (C _j -C ^ alkoxycarbonyl, carboxyl, pyridyl or (C - Cι ₀ ) aryl may be substituted, the latter in turn optionally being replaced by halogen, trifluoromethyl, (C _j -Cό) alkyl or (Ci Cg) - alkoxy is substituted, represent (C3-Cg) -cycloalkyl or a 5- to 7-membered heterocycle containing one or two nitrogen atoms, which can be bonded via a carbon or nitrogen atom, the cycloalkyl and heterocycle optionally being substituted by (C1-C4) - Are alkyl substituted,

or

R ¹ and R ¹² 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 can be substituted by amino, (C _r C ₆ ) alkyl, (C ₁ -C) alkoxycarbonyl, (C _r C ₄ ) alkoxycarbonylamino or phenyl,

and

R ⁵ denotes hydrogen, (C _r C ₄ ) -alkyl or (C _r C ₄ ) -alkanoyl,

and their respective salts and hydrates have a pharmacological effect and can be used as medicaments or for the production of medicament formulations.

In the context of the invention, heteroaryl is generally intended to be a 5- to 8-membered aromatic, optionally benzocondensed, heterocycle of up to

4 heteroatoms from the series S, N and / or O can be understood. Examples include: pyridyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl,

Within the scope of the invention, a 5- to

8-membered saturated, partially unsaturated or aromatic optionally benzocondensed heterocycle with up to 4 heteroatoms from the series S, N and / or O are to be understood, ie a heterocycle which can contain one or more double bonds and which is linked via a ring carbon atom or a ring nitrogen atom. Examples include: tetrahydrofur-2-yl, tetrahydrofur-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolin-1-yl, piperidine-l-yl, Piperidin-3-yl, 1,2-dihydropyridin-l-yl, 1,4-dihydropyridin-l-yl, piperazine-l-yl, morpholin-1-yl, azepin-1-yl, 1,4- Diazepin-l-yl, furan-2-yl, furan-3-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, pyrimidyl, pyrazinyl, pyrimidinonyl, pyridazinonyl.

From this list, preference is given to: pyrimidyl, pyridazinyl, pyrimidinonyl, pyridazinyl.

(-C-Cι,) - alkyl, (CrC ^ alkyl, (C -, - Cιn) alkyl, (C -, - Cg) alkyl, (C-ι-) alkyl, (C ₁ -C ₄ ) - Alkyl and (-C ^ alkyl) in the context of the invention are a straight-chain or branched alkyl radical having 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4 and 1, respectively A straight-chain or branched alkyl radical having 1 to 3 carbon atoms is preferred, and examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-, i-, s- or t-butyl, n-pentyl and n-hexyl.

(C _f j-Cm aryl in the context of the invention is an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

In the context of the invention, (CyC _R ) cycloalkyl, (rC ₇ ) cyeloalkyl and (CC _fi ) cycloalkyl stand for a cycloalkyl group with 3 to 8, 3 to 7 and 3 to 6 carbon atoms. The following may preferably be mentioned: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the context of the invention, (C ₆ -C _fi ) alkenyl stands for straight-chain or branched

Alkenyl having 1 to 3 double bonds and 2 to 6 carbon atoms, preferably 1 or 2 double bonds and 2 to 4 carbon atoms, particularly preferably 1 double bond and 2 or 3 carbon atoms. Examples are: vinyl, allyl, prop-1-en-1-yl, isopropenyl, but-1-enyls, but-2-enyls, buta-1, 2-dienyls, buta-1,3-dienyls,

(-C-C ₆ ) monoalkylamino stands for a straight-chain or branched alkylamino radical having 1 to 6 carbon atoms. A straight-chain or branched alkylamino radical having 1 to 4 carbon atoms is preferred. Examples include: methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino and n-hexylamino. A straight-chain or branched alkylamino radical having 1 to 3 carbon atoms is particularly preferred.

(-CC ₆ ) -dialkylamino stands for a straight-chain or branched dialkylamino radical, where the alkyl radicals can be the same or different and each contain 1 to 6 carbon atoms. A straight-chain or branched dialkylamino radical is preferred, the alkyl radical each containing 1 to 4 carbon atoms. Examples include: dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-t-butylamino, di-n-pentylamino, di-n-hexylamino, ethylmethylamino, isopropylmethylamino, n-butylethylamino, n-hexyl i-pentylamino. A straight-chain or branched alkylamino radical having 1 to 3 carbon atoms is particularly preferred.

(-C-C ₆ ) alkoxycarbonylamino stands for a straight-chain or branched alkoxycarbonylamino radical having 1 to 6 carbon atoms. A straight-chain or branched alkoxycarbonylamino radical having 1 to 4 carbon atoms is preferred. Examples include: methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert.butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino. A straight-chain or branched alkoxycarbonylamino radical having 1 to 3 carbon atoms is particularly preferred.

(G; -C ₆ ) alkoxycarbonyl stands for a straight-chain or branched alkoxycarbonyl radical having 1 to 6 carbon atoms. A straight-chain or mixed branched alkoxy carbonyl radical having 1 to 4 carbon atoms. Examples include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. A straight-chain or branched alkoxycarbonyl radical having 1 to 3 carbon atoms is particularly preferred.

(Cy-C ^) - Alkoxy in the context of the invention represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is preferred. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.

In the context of the invention, (C ₎ -C ₄ ) -alkanoyl represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, which carries a double-bonded oxygen atom in the 1-position and is linked via the 1-position. Examples include: formyl, acetyl, propionyl, n-butyryl, i-butyryl.

(C i -C ₄ ) - Alkanoy lamido in the context of the invention represents a radical of the formula

Alk-CO-NH-

wherein the grouping Alk-CO- represents a (C1-C4) alkanoyl radical as defined above.

In the context of the invention, amino represents the NH ₂ groups.

In the context of the invention, aminocarbonyl represents the group H2NCO-.

(C-j -CaVAlkoxycarbonylamino stands for a radical of the formula in the context of the invention

AlkO-CO-NH- wherein the AlkO-CO- stands for a (C _j C4) alkoxycarbonyl radical as defined above.

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 exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or which do not behave like image and mirror image (diastereomers). 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 are preferred, 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, 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, ethanolamine, 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.

Preferred compounds of the general formula (I) are those in which

R ^{1 represents} acetamido or a group of the formula -NH-CO-CO-A or -NH-CH ₂ -CO-A,

embedded image in which

A represents hydroxy or (C 1 -C ₄ ) alkoxy,

R ² and R ^{3 are the} same or different and are halogen, methyl or trifluoromethyl,

R ⁴ for a group of the formula

stands in what

E represents straight-chain or branched (C1-C4) alkyl,

R and R are the same or different and independent of each other

for straight-chain or branched (-C-Cιo) alkyl, the one or more identical or different by (C ₃ -C ₈ ) cycloalkyl, (Cι-C ₄ ) - alkoxy, 5- to 6-membered saturated or aromatic heterocyclyl with up to three heteroatoms from the series N, O and / or S, or by (C ₆ -Cιo) aryl, which in turn may be substituted one or more times, identically or differently, by aminocarbonyl, (Cι-C) - alkanoylamido or halogen is, can be substituted,

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

or

represent a 4- to 8-membered saturated heterocycle with up to two heteroatoms from the series N, O and / or S, which can be substituted one or more times by the same or different substituents by (C 1 -C ₄ ) -alkyl,

R ^{8 represents} straight-chain or branched (-C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkylmethyl or phenyl, R ⁹ straight-chain or branched (-CC ₈ ) alkyl, the carbon chain of which can be interrupted by -O- and which can be substituted by phenyl, (C ₃ -C ₈ ) -cycloalkyl or phenyl which is substituted by halogen, trifluoromethyl or (C ] -C ₄ ) alkyl may be substituted means

R ¹⁰ for straight-chain or branched (Ci-Cio) - alkyl, which by (C ₃ -C ₈ ) ~

Cycloalkyl, (-CC) alkoxy, phenyl or phenoxy may be substituted, the aromatics mentioned in turn each being substituted up to three times the same or different by halogen, (-C-C ₃ ) -alkyl or (-C-C ₄ ) - alkoxy could be,

for (C ₃ -C ₈ ) cycloalkyl or for phenyl which can be substituted up to three times in the same or different manner by (C] -C ₄ ) alkyl, (C] -C) alkoxy, halogen 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 13 or "de" "r - -NNmR.14r R.15 i,

wherein

R ^{13 represents} straight-chain or branched (-CC ₆ ) -alkyl, and R ¹⁴ and R ^{15 are the} same or different and independent of each other

for hydrogen or straight-chain or branched (C] -C ₆ ) - alkyl, which may be substituted by phenyl, which in turn may be up to twice the same or different by halogen, (-C-C) - alkyl, trifluoromethyl or (-C-C ₄ ) - alkoxy is substituted,

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

or

represent phenyl, naphthyl or biphenyl,

R ¹¹ and R ^{12 are the} same or different and independent of each other

for hydrogen or straight-chain or branched (-CC ₆ ) -alkyl, which may be substituted by phenyl, which in turn is optionally substituted by halogen, trifluoromethyl, (-C-C ₄ ) -alkyl or (-C-C ₄ ) -alkoxy,

or

stand for (C ₃ -C ₈ ) cycloalkyl, which can be substituted by (C 1 -C ₄ ) alkyl,

and

R _{> is} hydrogen or (C 1 -C ₄ ) - alkanoy 1, and their respective salts and hydrates.

The compounds of the general formula (I) according to the invention in which

R ^{1 represents} a group of the formula -NH-CO-COOH or -NH-CH ₂ -COOH,

R ² and R ^{3 are the} same or different and are chlorine, bromine, methyl or trifluoromethyl,

R ⁴ for a group of the formula

stands in what

R ⁶ and R ^{7 are the} same or different and independent of each other

for straight-chain or branched (-CC ₈ ) - alkyl, which can be substituted by (C ₅ -C ₈ ) - cycloalkyl, pyridyl, furyl, tetrahydrofüryl or one to three times by methoxy or ethoxy, or by phenyl, which in turn optionally substituted once or twice identically or differently by fluorine, chlorine, aminocarbonyl or acetamido,

for (C ₃ -C ₈ ) cycloalkyl, which can be substituted by methoxy or ethoxy,

or represent pyrrolidinyl or piperidinyl, which can each be substituted one or more times by methyl,

R ^{8 represents} straight-chain (-C ₇ ) alkyl, (C ₃ -C ₆ ) cycloalkylmethyl, (C ₃ -C ₆ ) cycloalkyl or phenyl,

R ⁹ denotes straight-chain or branched (-CC) alkyl which can be substituted by phenyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl which can be substituted by chlorine or fluorine,

R ¹⁰ for straight-chain or branched (-CC ₄ ) - alkyl, which by (C ₃ -C ₆ ) -

Cycloalkyl, phenyl or phenoxy can be substituted, the aromatics mentioned in turn each being substituted up to three times in the same or different manner by fluorine, chlorine or (C ₁ -C ₃ ) -alkyl,

or

represents biphenyl, 2,3-dihydro-1-benzofuranyl, 3,4-dihydro-2H-1-benzopyranyl or 3,4-dihydro-1H-2-benzopyranyl,

or

represents a group of the formula -NR 14 * R-, 15,

embedded image in which

R ¹⁴ denotes hydrogen or straight-chain or branched (-C-C ₃ ) - alkyl,

and R ¹⁵ for straight-chain or branched (-C-C) - alkyl, which may be substituted by phenyl, which in turn is optionally substituted by methyl, methoxy, trifluoromethyl, fluorine or chlorine,

or

represents naphthyl, biphenyl or (C -C _ö ) cycloalkyl,

R »π is hydrogen or straight-chain or branched (Cι-C) - alkyl,

and

R ^{12 is} straight-chain or branched (C 1 -C ₄ ) alkyl, which can be substituted by phenyl, which in turn is optionally substituted by methyl, methoxy, trifluoromethyl, fluorine or chlorine,

or

represents cyclopentyl or cyclohexyl, which can be substituted by (-C ₃ -C ₃ ) -alkyl,

and

R ⁵ denotes (C i -C4) alkyl or in particular hydrogen,

and their respective salts and hydrates.

The compounds of the general formula (I) according to the invention in which R ^{1 represents} a group of the formula -NH-CO-COOH or -NH-CH ₂ -COOH,

R for a group of the formula

stands in what

fι 7

R and R are the same or different and independent of each other

for straight-chain or branched (-CC ₈ ) alkyl, which by

Phenyl, which in turn is optionally substituted once or twice identically or differently by fluorine, chlorine, aminocarbonyl or acetamido, by (C ₅ -C ₈ ) cycloalkyl, pyridyl, furyl, tetrahydrofuryl or once to three times by methoxy or ethoxy can

for (C ₅ -C ₈ ) cycloalkyl, which can be substituted by methoxy or ethoxy,

or

represent pyrrolidinyl or piperidinyl, which can each be substituted one or more times by methyl,

and R ¹⁰ for straight-chain or branched (-CC ₄ ) -alkyl, which can be substituted by (C ₃ -C ₆ ) - cycloalkyl, phenyl or phenoxy, the aromatics mentioned in turn each up to three times the same or different by fluorine, chlorine or (-CC ₃ ) - alkyl can be substituted

or

represents biphenyl, 2,3-dihydro-l-benzofyranyl, 3,4-dihydro-2H-l-benzopyranyl or 3,4-dihydro-lH-2-benzopyranyl,

and

R ^{5 represents} hydrogen,

and their respective salts and hydrates.

Compounds of the general formula (I) in which E represents methylene are particularly preferred.

Compounds in which R represents hydrogen are also particularly preferred.

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, irrespective of the respectively specified combinations of the radicals. Furthermore, a process for the preparation of the compounds of the general formula (I) according to the invention was found, which is characterized in that

(A) compounds of the formula (II)

wherein

PG ² for a Hydroxyschutzgmppe or a resin suitable for solid phase synthesis means and

R ^{4 has} the meaning given above,

in the presence of a base with compounds of the general formula (III)

wherein

R ² and R ^{3 have} the meaning given above and

R ¹ 'stands for a suitable group from the scope of meaning of R ¹ , preferably for the NO ₂ group, and

Shark stands for chlorine or fluorine

to compounds of the formula (IN) embedded image in which

R ¹ ', R ² , R ³ , R ⁴ and PG ^{2 have} the meaning given above,

implements, or

(B) compounds of the formula (V)

embedded image in which

PG ^{2 has} the meaning given above and

R for a suitable standard stage of group R ⁴ , preferably for CHO, (CJ-C _Ö ) -

Alkoxycarbonyl or Νitro stands,

in the presence of a base with a compound of formula (III)

embedded image in which

R ¹ ', R ² , shark and R ^{3 have} the meaning given above to a compound of formula (VI)

embedded image in which

R, R ¹ ', R ² , R ³ and PG ^{2 have} the meaning given above,

and converting them into compounds of the formula (IV) by converting the substituent R into the substituent R ⁴ in a suitable manner,

and that the protective group PG ² is finally split off from the compound of the formula (IV) and, if appropriate, the substituents are changed or derivatized in a suitable manner by means of standard reactions.

The coupling reaction of the compounds of the formulas (II) and (III) or (V) and (III) are usually carried out in a solvent which is inert under the reaction conditions. Examples include dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, acetonitrile and especially dimethyl sulfoxide.

Suitable bases are sodium carbonate, potassium carbonate, triethylamine, ethyldiisopropylamine, sodium hydrogen carbonate and in particular CS2CO3. The reaction is usually carried out at a temperature of 0 to 100 ° C, preferably 20 to 60 ° C.

Hydroxy protective groups as well as suitable conditions for their introduction or separation are explained in detail in TW Greene, PGM Wuts, "Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 2nd edition, 1991. Examples of hydroxy protecting groups include:

Trimethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, benzyl, benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl, tert-butoxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxycarbonyl, tetrahydropyranyyl, formyl

Trichloroacetyl, 2,2,2-trichloroethoxycarbonyl, methoxycarbonylmethyl, [2-trimethylsilyl) ethoxy] methyl, benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or 4-methoxybenzoyl.

Compounds of the formula (II) can be prepared by protecting the free OH group in a compound of the formula (VII) with a protective group PG ² or by attaching it to a resin suitable for solid phase synthesis and then by means of standard reactions the group R into the group R ⁴ transferred.

embedded image in which

R has the meaning given above and

PG ^{1 stands} for a hydroxy protective group, in particular benzoyl.

The compounds of the formula (V) are obtained analogously from compounds of the formula (VII) by introducing the group PG ² and then selectively cleaving off the group PG ¹ .

The procedure with its two variants is exemplified by the following scheme:

Transfer of

(X = COCOOEt, -CH ₂ COOEt, -COCH, etc.)

Compound of formula (I) The entire process can also be carried out as a solid phase synthesis. In this case, the compound of formula (VII) is linked to a suitable resin via its free OH group, PG ² standing for the corresponding resin in the previous explanation of the synthesis. The further reactions are carried out on a solid phase and the compound obtained is finally cleaved from the resin. If compounds of the general formula (I) are to be prepared in which R ^{5 is} not hydrogen, the compound obtained can be modified further.

Solid phase synthesis as well as the attachment and the cleavage from the resin are common standard techniques. As an example from the extensive literature, reference is made to the article "Linkers for Solid Phase Organic Synthesis, Ian W. James, Tetrahedron 55 (1999), 4855-4946".

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

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

The compounds are also suitable for the treatment of Alzheimer's disease. The compounds are also suitable for the treatment of osteoporosis.

The compounds can also be used to promote and regenerate hair growth and to treat glaucoma.

The active compounds according to the invention open up a further treatment alternative and represent an area of pharmaceutical rankings. 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.

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

The active ingredients can be administered alone or in the form of pharmaceutical preparations. Preparations suitable for oral administration 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, ie the active ingredient should be present in amounts which are 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

Lubricant (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 application can also be mixed with flavor enhancers or colorants.

In the case of oral administration, doses of 0.001 to 5 mg / kg, preferably 0.005 to 3 mg / kg of body weight are preferably administered per 24 hours.

The activity of the compounds according to the invention can e.g. Check in vitro using the known T 3 promoter assay cell test described below.

The following examples are intended to illustrate the invention by way of example without restricting the scope of protection.

List of abbreviations

DMF dimethylformamide DIEA ethyldiisopropylamine

DMSO dimethyl sulfoxide TBTU O- (benzotriazol-l-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate

DCM dichloromethane

TFA trifluoroacetic acid

HPLC High Performance Liquid Chromatography RP Reversed Phase

RT room temperature

ESI electrospray ionization

T 3 promoter assay cell test

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 bears a minimal thymidine kinase promoter with a thyroid hormone responsive element (TRE) consisting of two inverted palindromes each in front of the luciferase gene

12 bp and an 8 bp spacer.

For the test, the cell cultures are sown in 96-well plates in Eagle's Minimal Essential Medium with the following additives: glutamine, tricine, sodium pyravate, non-essential amino acids, insulin, selenium and transferrin. At 37 ° C and 10%

Cultures are grown in a CO 2 atmosphere for 48 hours. Serial dilutions of test substance or reference compound (triiodothyronine = T3, tyroxin = 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 and immediately measured luminometrically. The EC50 values of each connection are calculated (see Table 1). Table 1

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

Test description for the detection of pharmacologically active substances that lower serum cholesterol in mice:

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 in a solution of Solutol HS 15 + ethanol + saline (0.9%) in a ratio of 1 + 1 + 8 or in a solution of Solutol HS 15 + saline (0.9%) in a ratio of 2 + 8 solved. 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 serve as the control group, but they only receive the solvent (10 ml / kg body weight) without test substance. Before the first substance application, blood is taken from each mouse to determine the seramcholesterol by puncturing the retroorbital venous plexus (previous value). The animals are then given the test substance for the first time using a pharyngeal tube. 24 hours after the last substance application, (on the 8th day after the start of treatment), blood is again taken from each animal for the determination of the serum cholesterol by puncturing the retroorbital venous plexus. The blood samples are centrifuged and after the serum has been obtained, the cholesterol is determined photometrically using an EPOS Analyzer 5050 (Eppendorf-Gerätebau, Netheler & Hinz GmbH, Hamburg). The determination is carried out using a commercially available enzyme test (Boehringer Mannheim, Mannheim).

The effect of the test substances on the serum cholesterol concentration is determined by subtracting the cholesterol value of the 1st blood sample (previous value) from the cholesterol value of the 2nd blood sample (after treatment). The differences of all cholesterol values in a group are averaged and compared with the mean value of the differences in the control group.

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

Substances that lower the seramcholesterol 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.

Attachment of 5-benzoyloxy-2-hydroxybenzaldehyde to Wang bromide resin

Harz l Wang Bromidharz _(. 32.0 g, 45.8 mmol, NovaBiochem) is dissolved in acetonitrile / dioxane: Suspended, (g 17.7, 3:00 eq) with diisopropylethylamine, cesium iodide (5.94 g, 0:50 eq), 18-crown (1: 1, 300 ml) -6 (6.05 g, 0.50 eq) and and 5-benzoyloxy-2-hydroxybenzaldehyde (14.4 g, 1.3 eq) [JG Bruno, MN Chang, YM Choi-Sledeski, DM Green, DG McGarry, JR Regan, FA Volz , J.Org.Chem. (1997), 62, 5174-5190] and shaken at 55 ° C. for 20 h. The reaction mixture is filtered and the resin 1 obtained is washed repeatedly with water, methanol, DCM and diethyl ether and dried. To determine the load, a resin sample is split off with TFA / DCM, 1: 1. A loading of 1.35 mmol / g 5-benzoyloxy-2-hydroxybenzaldehyde is determined by quantitative HPLC.

Solid phase ester hydrolysis

Resin 2

Resin 1 (32.0 g) is suspended in dioxane (180 ml), a solution of KOH (5.13 g, 2 eq) in methanol (60 ml) is added and the mixture is shaken at room temperature for 15 minutes. The resin 2 obtained is filtered and washed repeatedly with methanol, water, methanol, DCM and diethyl ether and dried.

Formation of the phenyl ether on a solid phase

Resin 2 (32 g) is suspended in DMSO (300 ml), with Cs2CO3 (29.8 g, 2 eq), 18-crown-6 (12.1 g, 1 eq) and 2-fluoro-1,3-dimethyl-5 -nitrobenzene (11.6 g, 1.5 eq) at

40 ° C implemented for 1 h. The resin is then washed repeatedly with water / DMF (1: 1), water, DMF, methanol, DCM and diethyl ether and dried.

Creation of a library Ia

These and the following libraries are produced in MiniKans (IRORI) according to the mix and split method [K. C. Nicolaou, X.-Y. Xiao, Z. Parandoosh, A. Senyei, M. P. Nova, Angew. Chem. Int. Ed. Engl. (1995), 35, 2289-2290].

The preparation of the library Ia is shown as an example in Scheme 1.

Resin 3 is suspended as a suspension in DCM / DMF, 2: 1 in IRORI-MiniKans (each about 120 mg / Kan) and washed repeatedly with DCM and diethyl ether and dried.

The resin thus compartmentalized is in separate reaction vessels in

DCM / trimethyl orthoformate (1: 1) suspended, each with an amine, (5 eq, "amine A") at room temperature and shaken for 18 h. The resin is washed several times with DMF in the separate reaction vessels, suspended in DMF and at room temperature tetrabutylammonium borohydride (2 eq.) After shaking for 5 minutes at room temperature, the reaction mixture is cooled to -40 ° C., glacial acetic acid (100 eq) is added and the mixture is warmed to room temperature. The resin is repeated with water, methanol, DCM / 10%. DIEA, methanol, DCM and diethyl ether are washed and dried. The resin is resuspended in separate reaction vessels in dioxane, with DIEA (20 eq), tetrabutylammonium iodide (2 eq) and alkyl or benzyl halides (10 eq each, "halide B") offset and

Stirred at 70 ° C for 18 h. To synthesize secondary amines (R ⁷ = H), the resin is suspended in 3/1 in dioxane / 2-propanol instead of the alkylation, triethylamine (2 eq) and bis-tert-butyl pyrocarbonate (10 eq) are added, and 2 h shaken at RT.

The resin is filtered again and washed repeatedly with water, DMF, methanol, DCM and diethyl ether and dried. The resin is suspended in DMF / water, 9: 2, tin (II) chloride dihydrate (5 eq) is added, the mixture is reacted for 2 hours at 60 ° C. and washed repeatedly with water, DMF, methanol, DCM and diethyl ether. The resin compartments are again divided into separate reaction vessels, suspended in DCM, reacted with DIEA (10 eq) and various acid chlorides or chloroformic acid esters (5 eq each, "acid chloride C") at room temperature for 18 h. Analogously, the resin is reacted in a reaction vessel with ethyl bromoacetate ( 5 eq) overnight at 40 ° C. The resin is then washed repeatedly with methanol, DMF, water, DMF, methanol, DCM and diethyl ether and dried, and the products are then washed with TFA / dichloromethane (1: 1) the cleaved solid phase, the resin is filtered off and the reaction solutions are evaporated to give a set of amines Ia.

(Ia)

R> x ^Λ corresponds to a residue of the form CH ₃ CO-, C ₂ H ₅ OOCCH ₂ - or C ₂ H ₅ OOCCO-, Y corresponds to a sensible leaving group such as e.g. B. Cl, Br.

Scheme 1 Creation of a library Ib

The preparation of the library Ib is shown as an example in Scheme 2.

Resin 3 is suspended as a suspension in DCM / DMF, 2: 1 in IRORI-MiniKans

(each about 120 mg / Kan) and washed repeatedly with DCM and diethyl ether and dried.

The resin thus compartmentalized is suspended in separate reaction vessels in DCM / trimethyl orthoformate (1: 1), each with an amine (5 eq, “amine A”)

Room temperature added and shaken for 18 h. The resin is washed several times with DMF in the separate reaction vessels, suspended in DMF, and tetrabutylammonium borohydride (2 eq) is added at room temperature. After shaking for 5 minutes at room temperature, the reaction mixture is cooled to -40 ° C., glacial acetic acid (100 eq) is added and the mixture is warmed to room temperature again. The resin is washed repeatedly with 20% glacial acetic acid in methanol, water, DMF, 10% triethylmanine in DCM, DCM and diethyl ether and dried. The resin is again suspended in separate reaction vessels in DCM, DIEA (10 eq) and one acid chloride (5 eq, "acid chloride B") are added and the mixture is shaken for 2 hours at room temperature. The resin is filtered and repeated with methanol, DCM and Washed and dried diethyl ether, the resin was suspended in 9: 2 DMF / water, stannous chloride dihydrate (5 eq) was added, the mixture was reacted for 4 hours at 40 ° C. and washed repeatedly with water, DMF, methanol, DCM and diethyl ether The resin compartments are redistributed to separate reaction vessels, suspended in DCM, with DIEA (10 eq) and in each case one acid chloride or chloroformate (5 eq, "acid chloride C") at room temperature for 18 h. Analogously, the resin is reacted in a reaction vessel with ethyl bromoacetate (5 eq) overnight at 40 ° C. The resin is then washed and dried repeatedly with methanol, DMF, water, DMF, methanol, DCM and diethyl ether, the products are then cleaved from the solid phase with TF.A / dichloromethane (1: 1), the resin is filtered off and the reaction solutions evaporated to get a sentence from A iden Ib.

C "

(Ib)

R ^x corresponds to a residue of the form CH ₃ CO-, C ₂ H ₅ OOCCH - or C ₂ H ₅ OOCCO-, Y corresponds to a sensible leaving group such as B. Cl, Br.

Scheme 2 Binding of 4-benzoyloxy-2-nitroρhenyl to Wang bromide resin

Wang bromide resin (25.0 g, 35.0 mmol, NovaBiochem) is dissolved in dimethylacetamide

(150 ml) suspended with diisopropyethylamine (22.6 g, 5.0 eq), cesium iodide (4.55 g, 0.50 eq) and 4-hydroxy-3-nitrophenylbenzoate (27.2 g, 3.0 eq) [M. Svensson, B. Helgee, K. Skarp, G. Andersson, J.Mater.Chem. (1998), 8, 353-362] and shaken overnight at room temperature. The reaction mixture is filtered and the resin 4 is washed repeatedly with methanol, water, DMF, methanol, DCM and diethyl ether and dried. To determine the load, a resin sample is split off with TFA DCM, 1: 1. A loading of 0.87 mmol / g of 4-benzoyloxy-2-nitrophenol is determined by quantitative HPLC.

Reduction of the nitro group of resin 4

Resin 4 (60 g) is suspended with stannous chloride dihydrate (94.8 g, 420 mmol) in DMF / water, 9: 1 and stirred at 60 ° C. for 2 h. The reaction mixture is filtered and the resin 5 is washed repeatedly with water, methanol, DCM and diethyl ether and dried. Creation of a library Ic

Resin 5 is suspended as a suspension in DCM / DMF, 2: 1 in IRORI-MiniKans (each about 120 mg / Kan) and washed repeatedly with DCM and diethyl ether and dried.

a) Production of amides and urethanes (R ¹ ° ≠ NR ¹⁴ R ' ⁵ )

The preparation of the amide library Ic is shown as an example in Scheme 3.

The compartmented aniline resin is suspended in separate reaction vessels in DCM, with DIEA (10 eq) and one acid chloride (5 eq, "acid chloride A") at 0 ° C - room temperature. This reaction mixture is shaken at room temperature overnight Resin is washed repeatedly with methanol, DCM and diethyl ether and dried, and the solution is mixed with a solution of potassium hydroxide (2 eq) in dioxane-methanol (2: 1), shaken for 45 minutes at room temperature, filtered and repeated with methanol, DCM and diethyl ether The resin is suspended in DMSO and washed with cesium carbonate (3 eq), 18-crown-6 (1 eq) and 2-fluoro-1,3-dimethyl-5-nitrobenzene (5 eq) at 55 ° C. for 60 h, then the resin is washed repeatedly with water, DMF, methanol, DCM and diethyl ether and dried, and the resin is suspended in DMF / water, 9: 2, with Zimi-II chloride dihydrate (5 eq), 90 Minutes at 60 ° C and repeated m washed with methanol, DCM and diethyl ether. The resin compartments are again processed on separate reaction distributed vessels, suspended in DCM, reacted with DIEA (10 eq) and various acid chlorides or chloroformic acid esters (5 eq, "acid chloride B") at room temperature for 6 h. Analogously, the resin is reacted overnight in a reaction vessel with ethyl bromoacetate (5 eq) at 40 ° C. The resin is then washed repeatedly with methanol, DMF, water, DMF, methanol, DCM and diethyl ether and dried, and the products are then separated from the solid phase using TFA / dichloromethane (1: 1), the resin is filtered off and the reaction solutions are evaporated to give a set of amides Ic.

Resin 5

R ^x corresponds to a residue of the form CH ₃ CO-, C ₂ H ₅ OOCCH ₂ - or C ₂ H ₅ OOCCO-, Y corresponds to a reasonable leaving group such as e.g. B. Cl, Br.

Scheme 3 b) Production of ureas (R ¹⁰ = NR ¹⁴ R ¹⁵ ) Ic

The preparation of the urea library Ic is shown as an example in Scheme 4.

The compartmented aniline resin is suspended in separate reaction vessels in DCM, DIEA (15 eq) is added and the mixture is cooled to -20 to -30 ° C. Trichloromethylchloroformate (1.5 eq) is added and the mixture is stirred at -20 ° C. for 1 h. In the cold, primary or secondary amines (10 eq, "Amine 1") are added and shaken overnight at room temperature. The resin is washed repeatedly with methanol, DCM and diethyl ether and dried. The resin is washed with a solution of potassium hydroxide (2nd eq) in dioxane / methanol (2: 1) and shaken for 45 minutes at room temperature, filtered and washed repeatedly with methanol, DCM and diethyl ether and dried.The resin is suspended in DMSO and treated with cesium carbonate (3 eq), 18-crown-6 (1 eq) and 2-fluoro-1,3-dimethyl-5-nitrobenzene (5 eq) are reacted for 60 h at 55 ° C. The resin is then repeated with

Washed water, DMF, methanol, DCM xmd diethyl ether and dried. The resin is suspended in DMF / water, 9: 2, tin (II) chloride dihydrate (5 eq) is added, the mixture is reacted at 60 ° C. for 90 minutes and washed repeatedly with methanol, DCM and diethyl ether. The resin compartments are redistributed to separate reaction vessels, suspended in DCM, reacted with DIEA (10 eq) and in each case one acid chloride or chloroformate (5 eq, “acid chloride B”) at room temperature for 6 hours. The resin is reacted in an analogous manner in a reaction vessel Ethyl bromoacetate (5 eq) reacted overnight at 40 ° C. Finally, the resin is washed repeatedly with methanol, DMF, water, DMF, methanol, DCM and diethyl ether and dried. The products are then washed with TFA / dichloromethane (1: 1 ) split from the solid phase, the resin is filtered off xmd the reaction solutions are evaporated to give a set of ureas Ic.

Resin 5

R ^x corresponds to a residue of the form CH ₃ CO-, C ₂ H ₅ OOCCH ₂ - or C ₂ H ₅ OOCCO-, Y corresponds to a meaningful leaving group such as B. Cl, Br.

Scheme 4

5-Benzoyloxy-2-hydroxybenzoic acid ethyl ester 6

5-benzoyloxy-2-hydroxybenzoic acid [M. Bergmann, P. Dangschat, Chem Ber. (1919), 52, 371-387] (2.00 g, 7.74 mmol), is suspended in DMF (10 ml) and treated with diisoproylethylamine (1.20 g, 9.29 mmol), cesium iodide (0.201 g, 0.77 mmol) and iodoethane (2.42 g , 15.5 mmol) was added. The reaction mixture is stirred overnight at room temperature and taken up in diethyl ether. The organic phase is washed with water, saturated NaHCO ₃ solution, 1N HC1 and saturated NaCl solution, dried with MgSO4, decanted and evaporated. The crude product is purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate, 1: 0 - 9: 1). Yield: 1.96 g (89%) 6.

1H NMR (400 MHz, CDC1 ₃ ): 1.41, t, 3 H; 4.41, q, 2H; 7.03, d, 1H; 7.31, dd, 1H; 7.48 - 7.55, m, 2H; 7.61 - 7.68, 1H; 7.70, d, 1H; 8.19, d, 2H; 10.78, s, 1 H.

Binding of 5-benzoyloxy-2-hydroxybenzoic acid ethyl ester (6) to Wang bromide resin

Wang bromide resin (50.0 g, 70.0 mmol, NovaBiochem) is suspended in acetonitrile / dioxane (1: 1, 300 ml), with diisopropyethylamine (90.4 g, 10.0 eq), cesium iodide (1.82 g, 0.10 eq), 18-crown-6 (18.5 g, 1 eq) and and 5-benzoyloxy-2-hydroxybenzoic acid ethyl ester (5) (30.1 g, 1.5 eq) were added and shaken at 80 ° C. overnight.

The reaction mixture is filtered and the resin 7 is repeatedly washed with DMF, water, methanol, DCM and diethyl ether and dried. To determine the load, a resin sample is split off with TFA / DCM, 1: 1. A loading of 0.42 mmol / g of ethyl 5-benzoyloxy-2-hydroxybenzoate (6) is determined by quantitative HPLC. Selective ester hydrolysis on solid phase

Resin 8 Resin 7 (50 g) is suspended in dioxane (260 ml), a solution of KOH (4.94 g) in methanol (130 ml) is added and the mixture is shaken at room temperature for 5 minutes. The resin 8 obtained is filtered and washed repeatedly with DMF, 10% glacial acetic acid in DCM, methanol, DCM, diethyl ether and dried.

Formation of the phenyl ether on a solid phase

Resin 9

Resin 8 (33 g) is suspended in DMSO (300 ml) with Cs2CO3 (14.2 g), 18-crown-6 (3.84 g) and 2-fluoro-1,3-dimethyl-5-nitrobenzene (5 eq) at 90 ° C for 20 h. The resin 9 obtained is then washed repeatedly with water / DMF (1: 1), water, DMF, methanol, DCM and diethyl ether and dried.

Solid phase ester hydrolysis

Resin 10 Resin 9 (32 g) is suspended in dioxane (260 ml) and a solution of KOH (7.90 g) in methanol (130 ml) is added and the mixture is stirred at 50 ° C. for 1 h. The resin 10 obtained is filtered and washed three times with methanol, 10% glacial acetic acid in DCM, methanol, DCM and diethyl ether and dried xmd.

Creation of a library Id

The preparation of the library Id is shown as an example in Scheme 5.

Resin 10 is suspended as a suspension in DCM / DMF, 2: 1 in IRORI-MiniKans

The resin thus compartmentalized is suspended in separate reaction vessels in DCM, DIEA (10 eq), one amine (5 eq, "Amine A") and TBTU (5 eq) are added at room temperature and the mixture is shaken overnight. The resin is shaken Repeatedly washed with methanol, DCM and diethyl ether and dried, the resin is suspended in DMF / water, 9: 2, tin (II) chloride dihydrate (5 eq) is added, the mixture is reacted for 4 hours at 40 ° C. and repeated with methanol, DCM and The resin compartments are redistributed to separate reaction vessels, in

Suspended DCM, reacted with DIEA (10 eq) and in each case one acid chloride or chloroformate (5 eq, “acid chloride B”) at room temperature for 18 h. Analogously, the resin is reacted in a reaction vessel with ethyl bromoacetate (5 eq) overnight at 40 ° C. The resin is repeatedly washed with methanol, DMF, water, DMF, methanol, DCM and diethyl ether and dried

Products are cleaved from the solid phase with TFA / dichloromethane (1: 1), the resin is filtered off and the reaction solutions are evaporated to give a set of carboxamides Id.

Scheme 5

Preparation Examples

example 1

Ethyl {[4- (3 - {[benzyl (isopropyl) amino] methyl} -4-hydroxyphenoxy) -3, 5-dimethylphenyl] amino} (oxo) acetate

According to the general procedure for producing library Ia, 1.00 g of resin 3 is reacted with isopropylamine as "amine A", benzyl chloride as "halide B" and ethoxalyl chloride as "acid chloride C". The crude product obtained is prepared by preparative RP-HPLC with a water / Acetonitrile / TFA eluent is purified This product is partitioned between saturated NaHCO ₃ solution and DCM, the organic phase is salted out with NaCl, decanted and evaporated. Yield: 30 mg of ethyl {[4- (3 - {[benzyl (isopropyl ) amino] methyl} -4-hydroxyphenoxy] -3,5-dimethylphenyl] amino} (oxo) acetate

1H NMR (200 MHz, CDC1 ₃ ): 1.13, d, 6 H; 1.44, t, 3H; 2.11, s, 6H; 3.09, sept, 1H; 3.60, s, 2H; 3.71, s, 2H; 4.42, q, 2H; 6.40, d, 1H; 6.52, dd, 1H; 6.69, d, 1H; 7.20 - 7.40, m, 7H; 8.77, s, 1 H.

Example 2

Ethyl {[4- (3 - {[benzyl (cyclohexyl) amino] methyl} -4-hydroxyphenoxy) -3,5-dimethylphenyl] amino} (oxo) acetate

According to the general working instructions for the preparation of library Ia, 1.00 g of resin 3 is reacted with cyclohexylamine as "amine A", benzyl chloride as "halide B" and ethoxalyl chloride as "acid chloride C". The crude product obtained is prepared by preparative RP-HPLC with water / Acetonitrile / TFA eluent This product is partitioned between saturated NaHCO 3 solution and DCM, the organic phase is salted out with NaCl, decanted and evaporated. Yield: 30 mg ethyl {[4- (3 - {[benzyl (cyclohexyl ) amino] methyl} -4-hydroxyphenoxy] -3,5-dimethylphenyl] amino} (oxo) acetate 1H-NMR (200 MHz, CDC1 ₃ ): 1.00 - 1.95, m, 10 H; 1.43, t, 3 H; 2.12, s, 6 H; 2.61, m, 1 H; 3.64, s, 2 H; 3.75, s, 2 H; 4.42, q, 2 H; 6.39, d, 1 H; 6.52, dd, 1 H ; 6.67, d, 1 H; 7.20 - 7.40, m, 7 H; 8.77, s, 1 H.

Example 3

Ethyl {[4- (3 - {[cyclohexyl (4-fluorobenzyl) amino] methyl} -4-hydroxyphenoxy) -3,5-dimethylphenyl] amino} (oxo) acetate

According to the general procedure for producing library Ia, 1.00 g of resin 3 is reacted with cyclohexylamine as "amine A", 4-fluorobenzyl chloride as "halide B" and ethoxalyl chloride as "acid chloride C". The crude product obtained is prepared by preparative RP-HPLC with a water / acetonitrile / TFA-> eluent This product is partitioned between saturated NaHCO 3 solution and ethyl acetate, the ethyl acetate phase is salted out with NaCl, decanted and evaporated.

Yield: 30 mg of ethyl {[4- (3 - {[cyclohexyl (4-fluorobenzyl) amino] methyl} -4-hydroxyphenoxy) -3,5-dimethylphenyl] amino} (oxo) acetate

^ -NTVIR (200 MHz, CDC1 ₃ ): 1.20, d, 6H; 1.44, t, 3H; 2.11, s, 6H; 3.20, sept, 1H; 3.68, s, 2H; 3.76, s, 2H; 4.42, q, 2H; 6.40, d, 1H; 6.57, dd, 1H; 6.75, d, 1H; 6.95 - 7.10, m, 2H; 7.25 - 7.33, dd, 2H; 7.36, s, 2H; 8.79, s, 1 H.

Example 4

{[4- (3 - {[Benzyl (isopropyl) amino] methyl} -4-hydroxyphenoxy) -3,5-dimethylphenyl] - amino} (oxo) acetic acid

Ethyl {[4- (3 - {[benzyl (isopropyl) amino] methyl} -4-hydroxyphenoxy) -3,5-dimethyl 1-phenyl] amino} (oxo) acetate (50 mg, 0.10 mmol) and NaOH (40 mg, 1.02 mmol) is dissolved in dioxane / water (0.5 ml, 1: 1 v / v) and stirred at room temperature for 1 h. The reaction mixture is partitioned between ethyl acetate xmd potassium dihydrogenphosphate / disodium hydrogenphosphate buffer solution (pH 7), the organic phase becomes salted out with NaCl, filtered and evaporated. The crude product obtained is purified by preparative RP-HPLC with a water / acetonitrile / TFA eluent. Yield: 23 mg {[4- (3 - {[benzyl (isopropyl) amino] methyl} -4-hydroxyphenoxy) -3,5-dimethylphenyl] amino} (oxo) acetic acid MS: 463.2 [MH ⁺ ]

Example 5

Ethyl (4- {4-hydroxy-3 - [(2-phenoxybutanoyl) amino] phenoxy} -3,5-dimethylanilino) - (oxo) acetate

According to the general procedure for the preparation of the library Ic, 1.5 g (0.13 mmol) of resin 5 is reacted with 2-phenoxybutyric acid chloride as "acid chloride A" and ethoxalyl chloride as "acid chloride B". The crude product obtained is purified by preparative RP-HPLC with a water / acetonitrile / TFA eluent.

Yield: 0.305 g of ethyl (4- {4-hydroxy-3 - [(2-phenoxybutanoyl) amino] phenoxy} - 3,5-dimethylanilino) (oxo) acetate

1H NMR (400 MHz, CDC1 ₃ ): 1.09, t, 3 H; 1.43, t, 3H; 1.95 - 2.12, m, 2H; 2.10, s, 6H; 4.42, q, 2H; 4.71, dd, 1H; 6.43, d, 1H; 6.51, dd, 1H; 6.90, d, 1H; 6.97, d, 2H; 7.06, t, 1H; 7.31, d, 2H; 7.35, s, 2H; 8.33 s, 1H; 8.77, s, 1 H.

MS: 507 [MH ⁺ ].

Example 6

Ethyl (4- {3 - [([1,1'-biphenyl] -4-ylcarbonyl) amino] -4-hydroxyphenoxy} -3,5-dimethylanilino) (oxo) acetate

According to the general procedure for the preparation of library Ic, resin 5 is reacted with [l, l'-biphenyl] -4-carbonyl chloride as "acid chloride A" and ethoxalyl chloride as "acid chloride B". The crude product obtained is purified by preparative RP-HPLC with a water / acetonitrile eluent. Yield: 6.4 mg of ethyl (4- {3 - [([l, l'-biphenyl] -4-ylcarbonyl) amino] -4-hydroxyphenoxy} -3,5-dimethylanilino) (oxo) acetate

1H NMR (200 MHz, CDC1 ₃ ): 1.41, t, 3 H; 2.13, s, 6H; 4.42, q, 2H; 6.53, d, 1H; 6.69, dd, 1H; 7.01, d, 1H; 7.34, s, 2H; 7.38 - 7.75, m, 7H; 7.96, d, 2H; 8.18, s, 1H; 8.80, s, 1H. MS: 525 [MH ⁺ ].

Example 7

Ethyl (4- {3 - [(cyclopropylcarbonyl) amino] -4-hydroxyphenoxy} -3,5-dimethylanilino) (oxo) acetate

According to the general procedure for the preparation of the library Ic, the resin 5 is reacted with cyclopropylcarbonyl chloride as "acid chloride A" xmd ethoxalyl chloride as "acid chloride B". The crude product obtained is purified by preparative RP-HPLC with a water / acetonitrile eluent. Yield: 9.0 mg of ethyl (4- {3 - [(cyclopropylcarbonyl) amino] -4-hydroxyphenoxy} - 3,5-dimethylanilino) (oxo) acetate

1H NMR (200 MHz, CDC1 ₃ ): 0.83-0.97, m, 2H; 1.05 - 1.17, .2 H; 1.41, t, 3H; 1.52 - 1.68, m, 1H; 2.10, s, 6H; 4.40, q, 2H; 6.27, d, 1H; 6.66, dd, 1H; 6.93, d, 1H; 7.31, s, 2H; 7.93, s, 1H; 8.35, s, 1 H.

MS: 413 [MH ⁺ ].

Example 8

Ethyl (4- {4-hydroxy-3 - [(3-phenylpropanoyl) amino] phenoxy} -3,5-dimethylanilino) -

(Oxo) acetate

According to the general working procedure for the production of the library Ic

Resin 5 reacted with 3-phenylpropionic acid chloride as "acid chloride A" and ethoxalyl chloride as "acid chloride B". The crude product obtained is prepared by

RP-HPLC cleaned with a water / acetonitrile eluent.

Yield: 12.0 mg of ethyl (4- {4-hydroxy-3 - [(3-phenylpropanoyl) amino] phenoxy} -

3,5-dimethylanilino) (oxo) acetate

1H NMR (200 MHz, CDCI ₃ ): 1.38, t, 3 H; 2.09, s, 6H; 2.70, t, 2H; 3.03, t, 2H; 4.39, q, 2H; 6.10, d, 1H; 6.65, dd, 1H; 6.92 d, 1H; 7.12 - 7.33, m, 5H; 7.32, s,

2 H; 7.56, s, 1H; 8.83, s, 1 H. MS: 477 [Mit].

Example 9

Ethyl (4- {4-hydroxy-3 - [(2-phenylbutanoyl) amino] phenoxy} -3,5-dimethylanilino) -

(Oxo) acetate

According to the general procedure for the preparation of the library Ic, 1.5 g (0.13 mmol) of resin 5 is reacted with 2-phenylbutyric acid chloride as "acid chloride A" xmd ethoxalyl chloride as "acid chloride B". The crude product obtained is purified by preparative RP-HPLC with a water / acetonitrile eluent.

Yield: 4.2 mg of ethyl (4- {4-hydroxy-3 - [(2-phenylbutanoyl) amino] phenoxy} -3,5-dimethylanilino) (oxo) acetate

1H NMR (200 MHz, CDC1 ₃ ): 0.91, t, 3 H; 1.36, t, 3H; 1.73 - 2.00, m, 1H; 2.08, s, 6H; 2.12 - 2.33, m, 1H; 3.46, t, 1H; 4.35, q, 2H; 6.29, d, 1H; 6.55, dd, 1H; 6.89, d, 1H; 7.22 - 7.40, m, 5H; 7.35, s, 2H; 7.61, s, 1H; 8.23, br s, 1H; 8.80, s, 1 H.

MS: 491 [MH ⁺ ].

Example 10

Ethyl {4- [3- (hexanoylamino) -4-hydroxyphenoxy] -3,5-dimethylanilino} (oxo) acetate

According to the general procedure for producing the library Ic, 1.5 g (0.13 mmol) of resin 5 is reacted with hexanoyl chloride as “acid chloride A” and ethoxalyl chloride as “acid chloride B”. The crude product obtained is purified by preparative RP-HPLC with a water / acetonitrile eluent. Yield: 8.6 mg of ethyl {4- [3- (hexanoylamino) -4-hydroxyphenoxy] -3,5-dimethyl-anilino} (oxo) acetate 1H NMR (200 MHz, CDC1 ₃ ): 0.89, t, 3 H; 1.22-1.42, m, 4H; 1.40, t, 3H; 1.60 - 1.80, m, 2H; 2.10, s, 6H; 2.38, t, 2H; 4.40, q, 2H; 6.29, d, 1H; 6.66, dd, 1H; 6.93, d, 1H; 7.31, s, 2H; 7.72, s, 1H; 8.4, br s, 1H; 8.84, s, 1H. MS: 443 [MH ⁺ ].

Example 11

Ethyl (4- {4-hydroxy-3 - [(2-propylpentanoyl) amino] phenoxy} -3,5-dimexhylanilino) - (oxo) acetate

According to the general procedure for the production of the library Ic

1.5 g (0.13 mmol) of resin 5 with 2-propylpentanoyl chloride as “acid chloride A” and

Ethoxalyl chloride reacted as “acid chloride B”. The crude product obtained is purified by preparative RP-HPLC with a water / acetonitrile eluent. Yield: 11.5 mg of ethyl (4- {4-hydroxy-3 - [(2-propylpentanoyl) amino] phenoxy } -

3,5-dimethylanilino) (oxo) acetate

1H NMR (200 MHz, CDC1 ₃ ): 0.90, t, 6H; 1.20 - 1.80, m, 8H; 1.37, t, 3H; 2.23-2.43, m, 1H; 4.38, q, 2H; 6.32, d, 1H; 6.63, dd, 1H; 6.93, d, 1H; 7.32, s, 2H; 7.85, s, 1H; 8.85, s, 1 H. MS: 471 [MET].

Example 12

Ethyl (4- {4-hydroxy-3 - [(methoxyacetyl) amino] phenoxy} -3,5-dimethylanilmo) - (oxo) acetate

According to the general procedure for producing the library Ic, 1.5 g (0.13 mmol) of resin 5 is reacted with methoxyacetyl chloride as “acid chloride A” and ethoxalyl chloride as “acid chloride B”. The crude product obtained is purified by preparative RP-HPLC with a water / acetonitrile eluent.

Yield: 13.7 mg of ethyl (4- {4-hydroxy-3 - [(methoxyacetyl) amino] phenoxy} -3,5-dimethylanilino) (oxo) acetate

1H NMR (200 MHz, CDC1 ₃ ): 1.44, t, 3 H; 2.12, s, 6H; 3.51, s, 3H; 4.16, s, 2H; 4.42, q, 2H; 6.39, d, 1H; 6.61, dd, 1H; 6.93, d, 1H; 7.38, s, 2H; 8.28, s, 1H; 8.38, s, 1H; 8.80, s, 1 H.

MS: 417 [MH ⁺ ].

Example 13

N- {5- [4- (Acetylamino) -2,6-dimethylphenoxy] -2-hydroxyρhenyl} -2-phenoxybutanamide

According to the general procedure for the preparation of the library Ic, the resin 5 with 2-phenoxybutyric acid chloride as "acid chloride A" and acetyl chloride as

"Acid chloride B" implemented. The crude product obtained is purified by preparative RP-HPLC with a water / acetonitrile eluent. Yield: 11.3 mg of N- {5- [4- (acetylamino) -2,6-dimethylρhenoxy] -2-hydroxyphenyl} -2-phenoxybutanamide

1H NMR (200 MHz, CDC1 ₃ ): 1.08, t, 3H; 1.98 - 2.10, m, 2H; 2.05, s, 6H; 2.13, s, 3H; 4.70, dd, 1H; 6.47 - 6.57, m, 2H; 6.83 - 7.40, m, 8H; 7.97, s, 1H; 8.52, s, 1H. MS: 449 [MH ⁺ ].

Example 14

Ethyl {4- [4-hydroxy-3 - ({[(l-phenylethyl) amino] carbonyl} amino) phenoxy] -3,5-dimethylanilino} (oxo) acetate

According to the general working procedure for the production of the library Ic

Resin 5 reacted with 1-phenylethylamine as "amine A" and ethoxalyl chloride as "acid chloride B". The crude product obtained is purified by preparative RP-HPLC with a water / acetonitrile eluent.

Yield: 9.0 mg of ethyl {4- [4-hydroxy-3 - ({[(l-phenylethyl) amino] carbonyl} amino) phenoxy] -3,5-dimethyl lanilino} (oxo) acetate

1H NMR (200 MHz, CDC1 ₃ ): 1.41, t, 3 H; 1.46, t, 3H; 2.03, s, 6H; 4.41, q, 2H; 4.82, dq, 1H; 5.32, d, 1H; 5.95, d, 1H; 6.53, dd, 1H; 6.6, s, 1H; 6.85, d, 1H; 7.20

- 7.40, m, 7H; 8.88, s, 1 H.

MS: 492 [MH ⁺ ].

Example 15

Ethyl [4- (3 - {[(cyclohexylmethyl) amino] carbonyl} -4-hydroxyphenoxy) -3,5-dimethylanilino] (oxo) acetate

Analogously to the general procedure for the preparation of the library Id, 2.00 g of resin 10 is reacted with (cyclohexylmethyl) amine as "amine A" and ethoxalyl chloride as "acid chloride B". The crude product obtained is purified by preparative RP-HPLC with a water / acetonitrile eluent.

Yield: 95 mg of ethyl [4- (3 - {[(cyclohexylmethyl) amino] carbonyl} -4-hydroxyphenoxy) -3,5-dimethylanilino] (oxo) acetate

1H NMR (200 MHz, CDC1 ₃ ): 0.85-1.83, m, 11H; 1.44, t, 3H; 2.14, s, 6H; 3.27, t, 2H; 4.42, q, 1H; 6.29, t, 1H; 6.70 - 6.92.3 H; 7.40, s, 2H; 8.80, s, 1 H.

Example 16

Ethyl [4- (3 - {[cyclohexyl (methyl) amino] carbonyl} -4-hydroxyphenoxy) -3,5-dimethylanilino] (oxo) acetate

Analogously to that of the general working procedure for the preparation of the library Id, 2.00 g of resin 10 is reacted with cyclohexyl (methyl) amine as "amine A" and ethoxalyl chloride as "acid chloride B". The crude product obtained is purified by preparative RP-HPLC using a water / acetonitrile eluent.

Yield: 30 mg of ethyl [4- (3 - {[cyclohexyl (methyl) amino] carbonyl} -4-hydroxyphenoxy) -3,5-dimethylanilino] (oxo) acetate

1H-NMR (200 MHz, CDCI ₃ ): 0.95 - 1.83, m, 10 H; 1.44, t, 3H; 2.12, s, 6H; 2.89, s,

3 H; 4.42, q, 1H; 6.50, d, 1H; 6.86, dd, 1H; 6.93, d, 1H; 7.39, s, 2H; 8.80, s, 1 H. The connections listed below are made according to the general working instructions for libraries Ia - Id.

Analysis parameters All products are characterized by LC-MS. The following separation system is used as standard: HP 1100 with UV detector (208 - 400 nm), 40 ° C oven temperature, Waters-Symmetry C18 column (50 mm x 2.1 mm, 3.5 μm), solvent A: 99.9% acetonitrile / 0.1% formic acid, mobile phase B: 99.9% water / 0.1% formic acid: gradient:

Time A:% B:% flow

(min) (ml / min)

0.00 10.0 90.0 0.50

4.00 90.0 10.0 0.50

6.00 90.0 10.0 0.50

6, 10 10.0 90.0 1.00

7.50 10.0 90.0 0.50

The substances were detected using a Micromass Quattro LCZ MS, ionization: ESI positive / negative.

Claims

Patentansprtiche

1. Compounds of the general formula (I)

embedded image in which

R ^{1 represents} nitro, amino, acetamido or a Grappe of the formula -NH-CO-CO-A or -NH-CH ₂ -CO-A,

embedded image in which

A represents hydroxy or (Cj-Ci-alkoxy,

R ² and R ^{3 are the} same or different and halogen, C _j -C ^ alkyl or

Trifluoromethyl mean

R ⁴ for a group of the formula

embedded image in which

E represents straight-chain or branched (C ^ -C4) alkyl, R ⁶ and R ^{7 are the} same or different and independently of one another for straight-chain or branched (C _j -CK ^ alkyl) that one or more times the same or different by (Cß-Cg) - cycloalkyl, (C _j -Cg) - alkoxy , Amino, mono- or di- (-C-Cg) - alkylamino, (C C4) -alkoxycarbonylamino, aminocarbonyl,

(C _j -Cö ^ alkoxycarbonyl, or by (C5-C ₁₀ ) aryl or 5 to 6-membered saturated or aromatic heterocyclyl with up to three heteroatoms from the series, N, O and / or S, wherein aryl and heterocyclyl in turn optionally substituted one or more times, identically or differently, by (C1-C4) alkyl, aminocarbonyl, (C _j -C4) alkanoylamido or halogen,

or

for a 4- to 8-membered saturated heterocycle with up to two heteroatoms from the series N, O and / or S, which one or more times the same or different by (Cj-C4) -alkoxycarbonyl, oxo or (C1- C4) - alkyl can be substituted,

or

R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle which optionally contains up to two further heteroatoms from the series, N, O and / or S, R ⁸ for straight-chain or branched (CJ-CI _Q ) - alkyl, which can be substituted by (C ₃ -Cg) cycloalkyl, phenyl or phenoxy, or for (C ₃ -C ₈ ) cycloalkyl, (C ₆ -Cιo ) Aryl, biphenyl or (C _j -Cg) alkoxy,

R ⁹ for straight-chain or branched (Cj-Cg) alkyl, the

Carbon chain to be interrupted by -O- and that

(C ₃ -Cg) cycloalkyl or phenyl may be substituted, or for

(C ₃ -C ₈ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl, phenyl or pyridyl,

where both the aromatic ring systems mentioned in R ⁸ and in R ^{9 may} each independently be substituted by trifluoromethyl, halogen, (C ₁ -C 4) alkoxy, (C1-C ₄ ) alkyl or amino,

or

R ⁸ and R ⁹ together with the nitrogen atom and the carbonyl group to which they are attached form a 4- to 7-membered saturated heterocycle which optionally contains up to two further heteroatoms from the series, N, O and / or S contains

RIO fftj. straight-chain or branched (C ^ -C ₁ 5) - alkyl, which is substituted by (C ₃ -C ₈ ) -cycloalkyl, (C _r C ₄ ) - alkoxy, phenyl, phenoxy or

Benzyloxy may be substituted, where the aromatics mentioned may in turn each be substituted up to three times the same or different by halogen (C _j -Cg) alkyl or (C _r C4) alkoxy, for (C ₃ -C ₈ ) cycloalkyl which can be substituted by (C _r C ₄ ) alkoxy or phenyl,

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

or

10 represents a 5- to 6-membered saturated or aromatic, optionally benzo-amine-containing heterocycle having up to two heteroatoms from the series N, O and or S,

or

15 represents a group of the formula -OR ¹³ or NR ¹⁴ R ¹⁵ ,

embedded image in which

20 R ^{13 represents} straight-chain or branched (Ci-Cg) alkyl,

and

R ¹⁴ and R ^{15 are the} same or different and are independent of one another

for hydrogen, straight-chain or branched (Ci

Ci2) alkyl, which by aminocarbonyl, a Grappe of

Formula -NR ¹⁶ R ¹⁷ , 5- to 6-membered heteroaryl dast

Contains 30 to 3 heteroatoms selected from the series N, O and / or S or substituted by phenyl may, where phenyl is optionally substituted up to twice the same or different by halogen, (C1-C4) alkyl, trifluoromethyl or (C 2 -C4) alkoxy,

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

for (Cg-C _j o aryl, which can be substituted up to three times in the same or different manner by halogen, (Cj-C4) -alkyl, trifluoro-10 methyl, (C ₁ -C4) alkoxy, amino, phenyl or phenoxy,

or

15 for a 5- to 7-membered, saturated or unsaturated, one or two nitrogen atom-containing heterocycle which can be bonded via a carbon or nitrogen atom and optionally substituted by (-CC) alkyl or an oxo group

20 is standing

in which

R ¹⁶ and R ^{17 are the} same or different and independently of one another for hydrogen, (Ci-Cg) -

Are alkyl, phenyl or (C6-Cι ₀ ) arylsulfonyl,

or

30 together with the nitrogen 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 ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a 4- to 7-membered group

Form 10 saturated heterocycle, which contain up to two further heteroatoms from the series, N, O and / or S and by amino, (C- _[ - Cg) - alkyl, (Cj-C4) -alkanoyl, aminocarbonyl, (C _j -C4) alkoxycarbonyl, (C j -C4) alkoxy-

15 carbonylamino, phenyl or pyridyl can be substituted,

R ¹¹ and R ^{12 are the} same or different and independent of each other

20 for hydrogen, straight-chain or branched (C _} - Cg) -alkyl, which one or more times the same or different by mono- (Cι-C6) alkylamino, di - ^ - Cg) - alkylamino, (Cι-C ₄ ) -Alkoxy, (C _j -C ^ alkoxycarbonyl.

25 carboxyl, pyridyl or (C ₆ -C ₁₀ ) 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 for (C ₃ -Cg) cycloalkyl or for a 5- to 7-membered

30 gen, one to two nitrogen atoms containing heterocycle, which has a carbon or nitrogen atom can be bound, the cycloalkyl and heterocycle optionally being substituted by (C1-C4) alkyl,

or

R ¹¹ and R ¹² 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 _j -Cg) alkyl, (C ₁ -C) alkoxycarbonyl, (Cj-C4) alkoxycarbonylamino or phenyl may be substituted,

and

R ⁵ denotes hydrogen, (CC ₄ ) -alkyl or (C _r C ₄ ) -alkanoyl,

as well as their respective salts and hydrates have a pharmacological effect and can be used as medicaments or for the production of medicament formulas.

2. Compounds of general formula (I) according spoke 1, wherein

E represents straight-chain or branched (C _j -C ^ alkyl,

R ^{1 represents} acetamido or a Grappe of the formula -NH-CO-CO-A or -NH-CH ₂ -CO-A,

Wonn

Represents hydroxy or (-CC) alkoxy, R and R are identical or different and are halogen, methyl or Tπ-fluoromethyl,

R for a group of the formula

stands,

wherein

R and R are the same or different and independent of each other

for straight-chain or branched (Ci-Cio) - alkyl, the one or more identical or different by (C ₃ -C ₈ ) cycloalkyl, (-C-C ₄ ) - alkoxy, 5- to 6-membered saturated or aromatic heterocyclyl with up to three heteroatoms from the series N, O xmd / or S, or by (C ₆ -Cι ₀ ) aryl, which in turn, if appropriate, one or more times identically or differently by aminocarbonyl, (Cι-C ₄ ) - Alkanoylamido or halogen is substituted, can be substituted,

for (C ₃ -C ₈ ) cycloalkyl, which can be substituted by (Cι-C) - alkoxy,

or represent a 4- to 8-membered saturated heterocycle with up to two heteroatoms from the series N, O and / or S, which can be substituted one or more times by the same or different substituents by (C 1 -C ₄ ) -alkyl,

R ^{8 represents} straight-chain or branched (-CC ₈ ) -alkyl, (C ₃ -C ₈ ) -cycloalkyl, (C ₃ -C ₆ ) -cycloalkylmethyl or phenyl,

R ⁹ straight-chain or branched (-CC ₈ ) alkyl, the carbon chain of which can be interrupted by -O- and which can be substituted by phenyl, (C ₃ -C ₈ ) -cycloalkyl or phenyl by halogen, trifluoromethyl or (Cι ~ C ₄ ) alkyl may be substituted means

R ¹⁰ for straight-chain or branched (-CC) -alkyl, which by

(C ₃ -C ₈ ) -cycloalkyl, (CC ₄ ) - alkoxy, phenyl or phenoxy may be substituted, the aromatics mentioned in turn each being up to three times the same or different by halogen, (-C-C ₃ ) -alkyl or (Cι -C) - alkoxy may be substituted,

for (C ₃ -C ₈ ) cycloalkyl or for phenyl, which can be substituted up to three times the same or different by (Ci-C ₄ ) alkyl, (-C-C ₄ ) alkoxy, halogen 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 xmd / or S, or

is a Grappe of the formula -OR ¹³ or -NR ¹⁴ R ¹⁵ ,

embedded image in which

R, 13 represents straight-chain or branched (-CC ₆ ) alkyl,

and

10

R ¹⁴ and R ^{15 are the} same or different and independent of each other

for hydrogen or straight-chain or branched (-C-C ₆ ) - 15 alkyl, which may be substituted by phenyl, which in turn may be up to twice the same or different by halogen, (-C-C ₄ ) - alkyl, trifluoromethyl or (CrC) - Alkoxy is substituted,

20 for (C ₃ -C ₈ ) cycloalkyl, which can be substituted by (C ₁ -C ₄ ) alkyl,

or

25 represents phenyl, naphthyl or biphenyl,

R ¹¹ and R ^{12 are the} same or different and independent of each other

30 for hydrogen or straight-chain or branched (-C-C ₆ ) -

Alkyl, which may be substituted by phenyl, which of its is optionally substituted by halogen, trifluoromethyl, (-CC ₄ ) alkyl or (-C-C ₄ ) alkoxy,

or

stand for (C ₃ -C ₈ ) -cycloalkyl, which may be substituted by (-C-C ₄ ) -alkyl,

and

R »5 is hydrogen or (-C-C ₄ ) alkanoyl,

and their respective salts and hydrates.

Compounds of general formula (I) according spoke 1, wherein

E represents straight-chain or branched (C _J -C ₄ ) alkyl,

R ^{1 represents} a group of the formula -NH-CO-COOH or -NH-CH ₂ -COOH,

R ⁴ for a group of the formula

stands, wherein

R ⁶ and R ^{7 are the} same or different and independent of each other

for straight-chain or branched (-CC ₈ ) - alkyl, which can be substituted by (C ₅ -C ₈ ) cycloalkyl, pyridyl, furyl, tefrahydrofuryl or mono- to triple by methoxy or ethoxy, or by phenyl, which in turn optionally substituted once or twice identically or differently by fluorine, chlorine, aminocarbonyl or acetamido,

for (C ₃ -C ₈ ) cycloalkyl, which can be substituted by methoxy or ethoxy,

or

R ^{8 represents} straight-chain (-C ₇ ) alkyl, (C ₃ -C ₆ ) cycloalkylmethyl, (C -C ₆ ) cycloalkyl or phenyl,

R ⁹ denotes straight-chain or branched (-CC) alkyl, which can be substituted by phenyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, which can be substituted by chlorine or fluorine,

R ¹⁰ for straight-chain or branched (-CC ₄ ) alkyl, which by

(C ₃ -C ₆ ) cycloalkyl, phenyl or phenoxy may be substituted, the aromatics mentioned in turn each up to can be substituted three times the same or different by fluorine, chlorine or (Ci-C ₃ ) alkyl,

or

for biphenyl, 2,3-dihydro-l-benzofuranyl,

3,4-dihydro-2H-1-benzopyranyl or 3,4-dihydro-1H-2-benzopyranyl,

or

10 represents a grappe of the formula -NR 14τ R> l ₅ ,

embedded image in which

15 R ¹⁴ hydrogen or straight-chain or branched (Ci

C ₃ ) -alkyl means

and

20 R ¹⁵ for straight-chain or branched (-CC ₄ ) - alkyl, which may be substituted by phenyl, which in turn is optionally substituted by methyl, methoxy, trifluoromethyl, fluorine or chlorine,

25 or

represents naphthyl, biphenyl or (C ₃ -C ₆ ) cycloalkyl,

R ^{11 is} hydrogen or straight-chain or branched (C ₁ -C ₃ ) -alkyl 30, and

R ^{12 represents} straight-chain or branched (-CC) alkyl, which can be substituted by phenyl, which in turn is optionally substituted by methyl, methoxy, trifluoromethyl, fluorine or chlorine,

or

represents cyclopentyl or cyclohexyl, which may be substituted by (C] -C ₃ ) -alkyl,

and

R> 5 ^{D is} hydrogen or (C _r C ₄ ) -alkyl,

and their respective salts and hydrates.

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

R ^{1 represents} a group of the formula -NH-CO-COOH or -NH-CH ₂ -COOH,

R ⁴ for a group of the formula stands,

embedded image in which

R ⁶ and R ^{7 are the} same or different and independent of each other

for straight-chain or branched (-CC ₈ ) alkyl, which is substituted by phenyl, which in turn is optionally substituted once or twice identically or differently by fluorine, chlorine, aminocarbonyl or acetamido, by (C ₅ -C ₈ ) -cycloalkyl, pyridyl , Furyl, tetrahydrofrryl or can be substituted one to three times by methoxy or ethoxy,

for (C ₅ -C ₈ ) cycloalkyl, which can be substituted by methoxy or ethoxy,

or

and

R ¹⁰ for straight-chain or branched (-CC ₄ ) - alkyl, which can be substituted by (C ₃ -C ₆ ) cycloalkyl, phenyl or phenoxy, the aromatics mentioned in turn each up to may be substituted three times the same or different by fluorine, chlorine or (Cj-C ₃ ) -alkyl

or

represents biphenyl, 2,3-dihydro-l-benzoftyranyl, 3,4-dihydro-2H-l-benzopyranyl or 3,4-dihydro-lH-2-benzopyranyl,

and

R,

5 means hydrogen

and their respective salts and hydrates.

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

(A) compounds of the formula (II)

embedded image in which

PG ² for a hydroxy protective group or a resin suitable for solid-phase synthesis means and

R ^{4 has} the meaning given in spoke 1,

in the presence of a base with compounds of the general formula (III) embedded image in which

R ² and R ^{3 have} the meanings given in claim 1 xmd

R ¹ 'for a suitable Grappe from the scope of R ¹ , preferably for the Nθ2 group, xmd

Shark stands for chlorine or fluorine

to compounds of the formula (IV)

embedded image in which

R ¹ ', R ² , R ³ , R ⁴ and PG ^{2 have} the meaning given above,

implements, or

(B) compounds of the formula (V)

embedded image in which PG ^{2 has} the meaning given above and

R represents a suitable precursor of Grappe R ⁴ , preferably CHO, (C ₁ -Cg) alkoxycarbonyl or nitro,

in the presence of a base with a compound of formula (III)

embedded image in which

R ¹ ', R ² , shark and R ^{3 have} the meaning given above for a compound of the formula (VI)

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R, R ¹ ', R ² , R ³ and PG ^{2 have} the meaning given above,

xmd that the protective group PG ² is finally split off from the compound of the formula (IV) and, if appropriate, the substituents are changed or derivatized in a suitable manner by means of standard reactions.

6. Medicament containing at least one compound of the general formula (I) according to spoke 1.

7. Process for the preparation of medicaments, characterized in that at least one compound of the general formula (I) according to

Addressed 1 with auxiliaries and / or carriers converted into a suitable application form.

8. Use of compounds of general formula (I) according spoke 1 for the manufacture of medicaments.

9. Use according to spoke 8 for the manufacture of medicaments for the treatment and or prophylaxis of arteriosclerosis and / or hypercholesterolemia.

10. Use according to spoke 8 for the manufacture of medicaments for the prophylaxis and / or treatment of disease forms which can be treated with natural thyroid hormone.