EP1675825A2

EP1675825A2 - Indoline derivatives as ppar-delta modulators

Info

Publication number: EP1675825A2
Application number: EP04764167A
Authority: EP
Inventors: Elke Dittrich-Wengenroth; Stephan Siegel; Michael Woltering
Original assignee: Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2003-08-18
Filing date: 2004-08-16
Publication date: 2006-07-05
Also published as: DE10337839A1; US20070197626A1; JP2007502797A; WO2005019169A2; CA2535960A1; WO2005019169A3

Abstract

The invention relates to novel indoline derivatives, a method for the preparation and use thereof for drugs, in particular in the form of powerful compounds activating PPAR-delta for preventing and/or treating cardiovascular diseases, in particular dyslipidemias, arteriosclerosis and coronaropathy.

Description

Indoline derivatives

The present application relates to new indoline derivatives, processes for their preparation and their use in medicaments, in particular as potent PPAR-delta activating compounds for the prophylaxis and / or treatment of cardiovascular diseases, in particular dyslipidemias, arteriosclerosis and coronary heart diseases.

Despite multiple therapeutic successes, coronary artery disease (CAD) remains a serious public health problem. While treatment with statins by inhibiting HMG-CoA reductase very successfully lowers the plasma concentration of LDL cholesterol and this leads to a significant reduction in the mortality of high-risk patients, today there are no convincing treatment strategies for the therapy of patients with unfavorable HDL / LDL Cholesterol ratio and / or hypertriglyceridaemia.

Today fibrates are the only form of therapy for patients in these risk groups. They act as weak agonists of the peroxisome proliferator-activated receptor (PPAR) -alpha (Nature 1990, 347, 645-50). A disadvantage of previously approved fibrates is their poor interaction with the receptor, which leads to high daily doses and significant side effects.

For the peroxisome proliferator-activated receptor (PPAR) delta (Mol. Endocrinol. 1992, 6, 1634-41), the first pharmacological findings in animal models indicate that potent PPAR delta agonists also improve HDL / LDL Cholesterol ratio and hypertriglyceridemia.

The object of the present invention was to provide new compounds which can be used as PPAR delta modulators.

Indoline derivatives as phospholipase inhibitors for the treatment of inflammatory diseases are claimed in WO 99/43672, WO 99/43654 and WO 99/43651.

The present invention relates to compounds of the general formula (I)

in which R ^{1 represents} phenyl or 5- to 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, which in turn are each one to three times, identical or different, by substituents selected from the group halogen, Cyano, nitro, (-CC ₆ ) - alkyl, which in turn can be substituted by hydroxy, (-C ₆ ) alkoxy, trifluoromethyl, trifluoromefhoxy, (-C ₆ ) alkylsulfonyl, (C _r C ₆ ) alkanoyl, _(Cι-C6) alkoxy carbonyl, carboxyl, A ino, (C ₁ -C ₆₎ acylamino, mono- and di- _(Cι-C6) alkylamino can be substituted,

R ² and R ^{3 are the} same or different and independently of one another represent hydrogen or (C ₁ -C ₄ ) alkyl or, together with the carbon atom to which they are attached, a 3- to 7-membered, spiro-linked cycloalkyl- Forming a ring,

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

R ⁵ and R ^{6 are} hydrogen or together with the carbon atom to which they are attached form a carbonyl group,

R ^{7 represents} hydrogen, (C, -C ₄ ) -alkyl, (C, -C ₄ ) -alkoxy or halogen,

R ⁸ and R ^{9 are} identical or different and are independently hydrogen or (C ₁ -C ₄ ) alkyl,

R ^{10 represents} hydrogen or a hydrolyzable group which can be broken down into the corresponding carboxylic acid,

X for O, S or NR ¹¹

and

Y stands for a bond

or

X for a bond

and

Y represents O, S or NR ¹ ', wherein

R ¹ 'each represents hydrogen, (CC) -alkyl or (-C-C ₄ ) -alkanoyl,

and their salts, solvates and solvates of the salts. In the context of the invention, in the definition of R ^10, a hydrolyzable group means a group which leads in particular in the body to a conversion of the -C (O) OR ^I0 grouping into the corresponding carboxylic acid (R ¹⁰ = hydrogen). Such groups are exemplary and preferably: benzyl, (dC ₆ ) -alkyl or (C ₃ -C ₈ ) -cycloalkyl, each optionally one or more times, identically or differently, by halogen, hydroxy, amino, (-C-C ₆ ) -Alkoxy, carboxyl, (CC ₆ ) -alkoxycarbonyl, (-C-C ₆ ) -alkoxycarbonylamino or (-C-C ₆ ) -alkanoyloxy, or in particular (CC ₄ ) -alkyl, which may be one or more, the same or differently, by halogen, hydroxy, amino, (CC ₄ ) alkoxy, carboxyl, (CC ₄ ) alkoxycarbonyl, (Cι-C) alkoxycarbonylamino or (Cι-C ₄ ) alkanoyloxy is substituted. in the context of the invention for a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. The following may be mentioned by way of example and preferably: methyl, ethyl, n-propyl, isopropyl and tert-butyl.

(In the context of the invention, Cv-CgVCvcloalkyl stands for a monocyclic cycloalkyl group with 3 to 8 carbon atoms. Examples and preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

( ^" Ct-CfiValkoxy and (G-QValkoxy in the context of the invention represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. Examples and preferably are mentioned : Methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy.

( ^" G-CfiValkoxycarbonyl and (CrC ^ -alkoxycarbonyl in the context of the invention represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms which is linked via a carbonyl group. A straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms, examples and preferably are: mefhoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. stand in the context of the invention for an amino group with a straight-chain or branched alkoxycarbonyl substituent which 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. The following may be mentioned as examples and preferably: Me oxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino and tert-butoxycarbonylamino. (-C-Cfi) alkanoyl and (C _j -CaVAlkanoyl) stands for a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms within the scope of the invention, which carries a double bonded oxygen atom in the 1 position and via the 1-position is linked. A straight-chain or branched alkanoyl radical having 1 to 4 carbon atoms is preferred. Examples and preferably mentioned are: formyl, acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl and n-hexanoyl.

( ^" C-CfiVAlkanoyloxy and (-C-Gι) -alkanoyloxy stand in the context of the invention for 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 in the 1-position is linked via a further oxygen atom. An alkanoyloxy radical having 1 to 4 carbon atoms is preferred. Examples and preferably are: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy, n-hexanoyloxy.

In the context of the invention, mono- (-C-Cg) alkylamino and mono-fC _j -C _j Valkylamino stand for an amino group with a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms is preferred. The following may be mentioned by way of example and preferably: methylamines, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

In the context of the invention, di- (C 1 -C 8 -alkylamino and DKC-OV-alkylamino) stand for an amino group with two identical or different straight-chain or branched alkyl substituents, each having 1 to 6 or 1 to 4 carbon atoms. Straight-chain are preferred or branched dialkylamino radicals each having 1 to 4 carbon atoms, examples which may be mentioned as examples: Nn-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

(-CgVAcylamino in the context of the invention represents an amino group with a straight-chain or branched alkanoyl substituent which has 1 to 6 carbon atoms and is linked via the carbonyl group. An acylamino radical with 1 to 2 carbon atoms is preferred. Exemplary and preferably mentioned are: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.

(-Cg - alkylsulfonyl in the context of the invention represents a straight-chain or branched alkylsulfonyl radical having 1 to 6 carbon atoms. A straight-chain or branched alkylsulfonyl radical having 1 to 4 carbon atoms is preferred. Examples include and are preferably: methylsulfonyl, ethylsulfonyl, n Propyl sulfonyl, isopropyl sulfonyl, tert-butyl sulfonyl, n-pentyl sulfonyl and n-hexyl sulfonyl. In the context of the invention, 5- to 6-membered heteroaryl with up to 2 identical or different heteroatoms from the series N, O and or S stands for a monocyclic aromatic heterocycle (heteroaromatics) which is via a ring carbon atom or optionally via a ring nitrogen atom of the heteroaromatic is linked. Examples include: furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl. 5- to 6-membered heteroaryl radicals having up to two nitrogen atoms, such as, for example, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, are preferred.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Chlorine or fluorine 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 do not behave like image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. The racemic forms, like the diastereomers, 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. In the context of the invention, physiologically acceptable salts are preferred.

Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as, for example, 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 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, such as, for example, ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di - or triefhanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methyl morpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylefhylamine.

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

Compounds of the general formula (I) in which

R ^{1 represents} phenyl, the one or two, identical or different, by substituents selected from the group halogen, cyano, nitro, (-C-C ₄ ) alkyl, which in turn can be substituted by hydroxy, (CC) alkoxy , Trifluoromethyl, trifluoromefhoxy, (CpC ₄ ) -alkanoyl, amino, mono- and di- (C] -C ₄ ) -alkylamino can be substituted,

R ² and R ^{3 are the} same or different and stand for (-CC ₄ ) -alkyl or together with the carbon atom to which they are attached form a 4- to 6-membered, spiro-linked cycloalkyl ring,

R ^{4 represents} hydrogen,

R ^{7 represents} hydrogen, (C, -C ₄ ) -alkyl, (CC ₄ ) -alkoxy, fluorine or chlorine,

R ⁸ and R ⁹ independently of one another represent hydrogen or methyl,

R ^{10 represents} hydrogen,

X for O or S

and

Y stands for a bond

or

X for a bond

and

Y stands for O or S.

Compounds of the general formula (I) in which R ^{1 represents} phenyl, which can be substituted by fluorine, chlorine, cyano, methyl, ethyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, trifluoromorphhoxy, amino, dimethylamino or diethylamino,

R ² and R ³ each represent methyl or together with the carbon atom to which they are attached form a spiro-linked cyclopentane or cyclohexane ring,

R ^{4 represents} hydrogen,

R ^{7 represents} hydrogen, methyl, methoxy, ethoxy, fluorine or chlorine,

R ⁸ and R ⁹ each represent hydrogen,

R ¹ ° represents hydrogen,

X for O

and

Y stands for a bond

or

X for a bond

and

Y stands for O.

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 given in the respective combinations or preferred combinations of radicals are replaced independently of the radical combinations of the radicals given by radical definitions of other combinations.

Combinations of two or more of the preferred ranges mentioned above are very particularly preferred. Compounds of the formula (IA) are of particular importance

in which

R ^{1 represents} phenyl which is substituted by fluorine, chlorine or trifluoromethyl,

R ^{7 represents} hydrogen, methyl, methoxy, ethoxy, fluorine or chlorine,

X for O

and stands for a bond

or for a bond

and

Y stands for O,

and the group linked via Y is in the para or meta position of the phenyl ring marked in formula (I-A) relative to the substituent X.

In addition, a process for the preparation of the compounds of the general formula (I) or (I-A) according to the invention was found, characterized in that compounds of the formula (IT)

in which R, R, R and R each have the meanings given above,

either

[A] in an inert solvent in the presence of a condensing agent and optionally in the presence of an auxiliary base with a compound of the formula (III)

in which

X, Y, R, R and R each have the meanings given above and represents benzyl or (GC ₆ ) alkyl, to give compounds of the formula (IV)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , X, Y and T each have the meanings given above, couples them in the event that R ⁵ and R ⁶ in formula (I) or (IA) stand for hydrogen, further in compounds of the formula (V) in an inert solvent in the presence of a suitable reducing agent

in which R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , X, Y and T each have the meanings given above, the compounds of the formula (IV) or (V) are then converted with acids or bases or, if T is benzyl, also hydrogenolytically to the corresponding carboxylic acids of the formula (VI)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X and Y each have the meanings given above,

or

[B] in the case that in formula (I) or (IA) X is a bond and Y is O, S or NR ¹¹ , first in an inert solvent in the presence of a condensing agent and optionally in the presence of an auxiliary base with a compound of the formula (VE)

in which

R ^{7 has} the meanings given above and

Z for O, S or NR ^1! in which R ^{11 has} the meanings given above, to compounds of the formula (VIE)

in which R, R, R, R, R and Z each have the meanings given above,

couples, this then in an inert solvent in the presence of a base with a compound of formula (LX)

in which R, R and T each have the meanings given above and

Q represents a suitable leaving group such as halogen, mesylate or tosylate,

to compounds of the formula (X)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , T and Z each have the meanings given above,

in the event that R ⁵ and R ⁶ in formula (I) or (IA) are hydrogen, in an inert solvent in the presence of a suitable reducing agent, in compounds of the formula (XI) in which R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , T and Z each have the meanings given above, the compounds of the formula (X) or (XI) are then converted with acids or bases or, if T is benzyl, also hydrogenolytically to the corresponding carboxylic acids of the formula (XU)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and Z each have the meanings given above,

optionally the carboxylic acids of the formula (VI) or (XU) are further modified to give compounds of the formula (I) or (I-A) by known methods for esterification,

and the resulting compounds of formula (VI), (XII), (I) or (IA) optionally with the corresponding (i) solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts implements.

Inert solvents for process step (H) + (DT) → (IV) or (H) + (VET) → (VET) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene , Hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1, 2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as ethyl acetate, pyridine, dimethyl sulfoxide, dimethylformamide, N, N'-dimethylpropylene urea , N-methyl pyrrolidone (NMP), acetonitrile or acetone. It is also possible to mix to use the solvents mentioned. Dichloromethane, 1,2-dichloroethane or dimethylformamide are preferred.

Suitable condensation agents for the amide formation in process step (11) + (HT) → (IV) or (IT) + (VE) - »(VIÜ) are, for example, carbodiimides, e.g. N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), or carbonyl compounds such as N, N'-carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert.-butyl-5-methyl- isoxazolium perchlorate, or acylamino compounds such as 2-efhoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tris (dimethyl hexafluorophosphate, or O- (benzotriazol-1 -yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), 2- (2-oxo-l- (2H) -pyridyl) -l, 1,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), optionally in combination with other auxiliaries such as 1 -Hydroxybenzotriazol or N-hydroxysuccinimide, and as bases alkali carbon ate, e.g. Sodium or potassium carbonate or hydrogen carbonate, or organic bases such as trialkylamines, e.g. Triefhylamine, N-methylmorpholine, N-methylpiperidine or diisopropylethylamine. EDC is preferably used.

Process step (II) + (IH) - »(PV) or (IT) + (VH) -» (VIÜ) is generally in a temperature range from 0 ° C to + 100 ° C, preferably from 0 ° C to + 40 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

Suitable reducing agents for process step (IV) → (V) or (X) -> (XI) are, for example, borohydrides such as borane or diborane, including the complexes, for example with tetrahydrofuran or dimethyl sulfide, or also diphenylsilane in the presence of carbonyl tris ( triphenylphosphine) rhodium (r) hydride as catalyst [see R. Kuwano, M. Takahashi, Y. Ito, Tetrahedron Lett. 1998, 39, 1017-1020].

Inert solvents for process step (IV) - (V) or (X) -> (XI) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran is preferred. The reaction generally takes place in a temperature range from -20 ° C. to + 80 ° C., preferably from 0 ° C. to + 40 ° C. The reaction can be carried out under normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.

Inert solvents for process step (VIH) + (LX) -> (X) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone , 2-butanone, dimethylformamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidinone. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide or acetone is preferred.

The usual inorganic or organic bases are suitable as bases for the process step (VITJ) + (LX) - (X). These include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate, alkali metal hydrides such as sodium hydride, or organic amines such as pyridine, triethylamine, ethyl diisopropylamine, N-methylphorpholine or N-methylpiperidine , Potassium carbonate or sodium hydride is preferred.

The base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compound of the formula (VITJ).

The reaction generally takes place in a temperature range from -20 ° C. to + 150 ° C., preferably from 0 ° C. to + 80 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

Inert solvents for process step (IV) / (V) → (VI) or (X) / (XI) → (XU) are, for example, halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, Tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane , Acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile, N-methylpyrrolidinone or water. It is also possible to use mixtures of the solvents mentioned. In the case of basic ester hydrolysis, preference is given to alcohols such as methanol or ethanol and their mixtures with tetrahydrofuran and, in the case of acidic ester cleavage, dichloromethane. The usual inorganic bases are suitable as bases for process step (IV) / (V) → (VI) or (X) / (XI) → (Xu). These preferably include alkali hydroxides such as lithium, sodium or potassium hydroxide, or alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate. Lithium or sodium hydroxide are particularly preferred.

The base is used in an amount of 1 to 5, preferably 1 to 3, mol, based on 1 mol of the compound of the formula (IV), (V), (X) or (XI).

Suitable acids for process step (IV) / (V) → (VI) or (X) / (XI) → (XU) are the customary inorganic acids such as, for example, hydrochloric acid or sulfuric acid, or sulfonic acids such as toluenesulfonic acid, mefhan sulfonic acid or Trifluoromethanesulfonic acid, or carboxylic acids such as trifluoroacetic acid.

The reaction generally takes place in a temperature range from -20 ° C. to + 100 ° C., preferably from 0 ° C. to + 30 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

The compounds of the formula (H) can be prepared analogously to processes known from the literature in that compounds of the formula (XIH)

in which

A represents chlorine or bromine,

in the presence of an acid or Lewis acid, optionally in an inert solvent, with a compound of the formula (XTV)

in which R ² , R ³ and R ⁴ each have the meanings given above, in the event that R ² and R ³ in (XTV) are both not hydrogen, to compounds of the formula (XV) or in the case that R ³ in (XTV) is hydrogen to compounds of the formula (XVI)

(XV) (XVI)

in which A and R ⁴ each have the meanings given above,

then reacting the compounds of the formula (XV) or (XVI) with the aid of a boron, aluminum or silicon hydride, such as, for example, sodium borohydride or sodium cyanoborohydride, or by hydrogenation in the presence of a suitable catalyst, such as, for example, Raney nickel, to give compounds of the formula ( XVII)

in which A, R ² , R ³ and R ⁴ each have the meanings given above,

reduced [for process steps (XTH) + (XIV) → (XV) → (XVH) cf. e.g. P.E. Maligres, I. Houpis, K. Rossen, A. Molina, J. Sager, V. Upadhyay, K.M. Wells, R.A. Reamer, J.E. Lynch, D. Askin, R.P. Volante, P.J. Reider, Tetrahedron 1997, 53, 10983-10992], the compounds of the formula (XVJJ) then according to methods customary in the literature in compounds of the formula (XVITJ)

in which A, R, R and R each have the meanings given above and

PG stands for a suitable arnino protective group, preferably for 4-nitrophenylsulfonyl,

transferred, this then in a coupling reaction with a compound of formula (XLX)

in which R ^{1 has} the meanings given above and

R ^{12 represents} hydrogen or methyl or both radicals together form a CH ₂ CH ₂ or C (CH ₃ ) ₂ -C (CH ₃ ) ₂ bridge,

in an inert solvent in the presence of a suitable palladium catalyst and a base to give compounds of the formula (XX)

in which PG, R ¹ , R ² , R ³ and R ⁴ each have the meanings given above,

implements [cf. e.g. W. Hahnfeld, M. Jung, Pharmazie 1994, 49, 18-20; idetn, Liebigs Ann. Chem. 1994, 59-64] and finally the protective group PG to compounds of the formula (IT) removed again using methods customary in the literature.

Inert solvents for process step (XIO) + (XTV) - (XV) or (XVI) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichlorethylene, ethers such as dioxane, tetrahydro - Furan, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol, or hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetonitrile or water. It is also possible to use mixtures of the solvents mentioned. It is also possible to carry out the reaction without a solvent. In the event that R ^{3 is} hydrogen, the reaction is preferably carried out without solvent to the product (XVI), in the event that R ² and R ^{3 are} both not hydrogen, the reaction is preferably in a mixture of toluene and acetonitrile to the product (XV) performed.

The usual inorganic or organic acids are suitable as acids for process step (XTIf) + (XTV) - (XV) or (XVI). These preferably include hydrochloric acid, sulfuric acid or phosphoric acid, or carboxylic acids such as formic acid, acetic acid, or trifluoroacetic acid, or Sulfonic acids such as toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid. Alternatively, the usual Lewis acids such as boron trifluoride, aluminum trichloride or zinc chloride are also suitable. The acid is used here in an amount of 1 to 10 mol, based on 1 mol of the compound of the formula (XHI). In the event that R ^{3 is} hydrogen, the reaction is preferably with 1 to 2 mol of zinc chloride to the product (XVI), and in the event that R ² and R ^{3 are} both not hydrogen, preferably with 2 to 5 mol of trifluoroacetic acid to the product (XV).

The reaction generally takes place in a temperature range from 0 ° C to + 250 ° C. In the event that R ^{3 is} hydrogen, the reaction is preferably carried out in a temperature range from + 130 ° C to + 200 ° C to the product (XVI), in the event that R ² and R ^{3 are} both not hydrogen, the Reaction preferably carried out in a temperature range from 0 ° C to + 50 ° C to the product (XV). The reaction can be carried out under normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.

Reducing agents suitable for process step (XV) or (XVI) -> (XVII) are boron, aluminum or silicon hydrides, such as, for example, borane, diborane, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or triethylsilane, optionally in the presence of an acid or Lewis acid, for example Acetic acid, trifluoroacetic acid, aluminum trichloride or boron trifluoride, or hydrogenation with hydrogen in the presence of a suitable catalyst such as, for example, palladium on activated carbon, platinum oxide or Raney nickel. In the case of compounds of the formula (XVI), preference is given to reduction using sodium cyanoborohydride; in the case of compounds of the formula (XV), sodium borohydride is preferably used.

Suitable solvents for process step (XV) or (XVI) → (XVH) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol, or hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetonitrile, acetic acid or water. It is also possible to use mixtures of the solvents mentioned. Preferred for the reduction of the compounds of the formula (XVI) is the use of acetic acid, which serves as an acid additive to the reducing agent in large excess at the same time as a solvent. For the reduction of the compounds of the general formula (XV), a mixture of methanol and toluene / acetonitrile [from the reaction (XTU) - »(XV), with the addition of 2 to 5 mol of trifluoroacetic acid] in a ratio of 1: 1 used up to 1:10. The reaction generally takes place in a temperature range from -20 ° C to + 100 ° C, preferably from -10 ° C to + 50 ° C. The reaction can be carried out under normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.

Inert solvents for process step (XVEO) + (XLX) -> (XX) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert .- Butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, acetonitrile or water. It is also possible to use mixtures of the solvents mentioned. Toluene, dimethylformamide or acetonitrile are preferred.

The usual inorganic or organic bases are suitable as bases for process step (XVIJJ) + (XLX) → (XX). These preferably include alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate, alkali metal phosphates such as sodium or potassium phosphate, or organic airlines such as pyridine, triethylamine, ethyldiisopropylamine, N-mefhylmorpholine or N- methylpiperidine. Sodium or potassium carbonate or potassium phosphate are particularly preferred.

The base is used here in an amount of 1 to 5, preferably 2 to 3, mol, based on 1 mol of the compound of the formula (XVIJJ).

Suitable palladium catalysts for process step (XVJJJ) + (XIX) → (XX) are preferably palladium (O) or palladium (II) compounds which are used preformed, such as, for example, [1,1 'bis (diphenylphosphino) ferrocenyl] palladium (II) chloride, bis (triphenylphosphine) palladium (II) chloride or tetrakis (triphenylphosphine) palladium (0), or those in situ from a suitable palladium source such as bis (dibenzylidene acetone) palladium (0) and a suitable one Phosphine ligands can be generated.

The reaction generally takes place in a temperature range from 0 ° C. to + 150 ° C., preferably from + 20 ° C. to + 120 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

The compounds of the formula (IU) can be prepared analogously to processes known from the literature, for example by the fact that compounds of the formula (XXI)

in which R ⁷ and Z each have the meanings given above and represents benzyl or (-CC ₆ ) -alkyl,

in an inert solvent in the presence of a base with a compound of formula (XXU)

in which Q has the meanings given above and stands for benzyl or (-CC ₆ ) alkyl, but is different in its specific meaning from T ¹ ,

to compounds of the formula (XXUT)

in which R ⁷ , Z, T ¹ and T ² each have the meanings given above,

implemented and then under controlled, chemoselective reaction conditions with acids or bases or, if T ¹ or T ^{2 is} benzyl, also hydrogenolytically optionally in the corresponding carboxylic acids of the formula (XXIV) or (XXV)

in which R ⁷ , Z and T ¹ or T ² each have the meanings given above,

transferred.

Inert solvents for process step (XXI) + (XXU) - »(XXIJJ) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone , 2-butanone, dimethylformamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidinone. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide or acetone is preferred.

Suitable bases for process step (XXI) + (XXIT) - »(XXIJJ) are the usual inorganic or organic bases. These include alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate, alkali metal hydrides such as sodium hydride, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylphorpholine or N-methylpiperidine. Potassium carbonate or sodium hydride is preferred.

The base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compound of the formula (XXI).

Inert solvents for process step (XXIJJ) - »(XXIV) or (XXV) are, for example, halogenated hydrocarbons such as dichloromethane, 1, 2-dichlorofhan or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, Ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile, N-methylpyrrolidinone or water. It is also possible to use mixtures of the solvents mentioned. In basic ester hydrolysis, preference is given to alcohols such as thanol or ethanol and their mixtures with tetrahydrofuran and, in the case of an acidic ester cleavage, dichloromethane.

The usual inorganic bases are suitable as bases for process step (XXIH) -> (XXIV) or (XXV). These preferably include alkali hydroxides such as lithium, sodium or potassium hydroxide, or alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate. Lithium or sodium hydroxide are particularly preferred.

The base is used in an amount of 1 to 5, preferably 1 to 3, mol, based on 1 mol of the compound of the formula (XXIJJ).

Suitable acids for process step (XXIJJ) → (XXIV) or (XXV) are the customary inorganic acids such as, for example, hydrochloric acid or sulfuric acid, or sulfonic acids such as toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, or carboxylic acids such as trifluoroacetic acid.

The compounds of the formulas (VU), (IX), (XJJJ), (XTV), (XIX), (XXI) and (XXJJ) are commercially available, known from the literature or can be prepared analogously to processes known from the literature.

The process according to the invention can be illustrated by the following reaction schemes 1 to 3:

Scheme 1

a) trifluoroacetic acid, 35-40 ° C; b) NaBR ,, methanol, -10 ° C; c) Et ₃ N, cat. DMAP, dichloromethane, RT; d) Pd (PPh ₃ ) ₄ catalyst, K ₂ CO ₃ , toluene, 110 ° C; e) NaOH, thioacetic acid, DMF, 45 ° C.

Scheme 2

c)

a) EDC, 1,2-dichloroethane, RT; b) K ₂ CO ₃ , Br-CH ₂ -COOT, DMF, 50 ° C; c) NaOH, EtOH (T - Me or Et) or TFA, CH ₂ C1 ₂ (T = 'Bu), RT; d) Rh (PPh ₃ ) ₃ (CO) H, Ph ₂ SiH ₂ , THF, RT.

Scheme 3

a) K ₂ CO ₃ , DMF, 50 ° C; b) NaOH, EtOH (T ² = Me or Et, T ¹ = 'Bu) or TFA, CH ₂ C1 ₂ (T ² =' Bu, T ¹ = Me or Et), RT; c) NaOH, EtOH (T ¹ = Me or Et, T ² = * Bu) or TFA, CH ₂ C1 ₂ (T ¹ = 'Bu, T ² = Me or Et), RT; d) compound of the formula (Ua) [Scheme 1], EDC, 1,2-dichloroethane, RT; e) NaOH, EtOH (T ¹ or T ² = Me or Et) or TFA, CH ₂ C1 ₂ (T ¹ or T ² = 'Bu), RT; f) Rh (PPh ₃ ) ₃ (CO) H, Ph ₂ SiH ₂ , THF, RT; g) NaOH, EtOH (T ¹ or T ² = Me or Et) or TFA, CH ₂ C1 ₂ (T ¹ or T ² = 'Bu), RT.

The compounds of the formula (I) or (I-A) according to the invention have a surprising and valuable spectrum of pharmacological activity and can therefore be used as versatile medicaments. They are particularly suitable for the treatment of coronary heart disease, for the prevention of myocardial infarction and for the treatment of restenosis after coronary angioplasty or stenting. The compounds of the formula (I) or (I-A) according to the invention are preferably suitable for the treatment of arteriosclerosis and hypercholesterolemia, for increasing morbidly low HDL levels and for lowering increased triglyceride and LDL levels. They can also be used to treat obesity, diabetes, metabolic syndrome (glucose intolerance, hyperinsulinemia, dyslipidemia and hypertension due to insulin resistance), liver fibrosis and cancer.

The new active substances can be used alone or, if necessary, in combination with other active substances, preferably from the group CETP inhibitors, antidiabetics, antioxidants, cytostatics, calcium antagonists, antihypertensive agents, thyroid hormones and or thyroid mimetics, inhibitors of HMG-CoA reductase, inhibitors of HMG -CoA reductase expression, squalene synthesis inhibitors, ACAT inhibitors, blood circulation promoting agents, platelet aggregation inhibitors, anticoagulants, angiotensin U receptor antagonists, cholesterol absorption inhibitors, MTP inhibitors, aldolase reductase inhibitors, aldolase reductase inhibitors, Anoretics, lipase inhibitors and PPAR-α and or PPAR-γ agonists are administered.

The activity of the compounds according to the invention can e.g. Check in vitro using the transactivation assay described in the example section.

The activity of the compounds according to the invention in vivo can be e.g. check by the examinations described in the example section.

For the application of the compounds of the general formula (T) or (IA), all customary application forms come into consideration, that is to say orally, parenterally, inhalatively, nasally, sublingually, rectally, externally, such as, for example, transdermally, or locally, for example in the case of implants or stents , In parenteral administration, intravenous, intramuscular or subcutaneous administration, for example as a subcutaneous depot, should be mentioned in particular. Oral or parenteral administration is preferred. Oral application is very particularly preferred. The active ingredients can be administered alone or in the form of 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 to 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 auxiliaries include: 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. polyvinyl nylpyrrolidone) and lubricants (e.g. magnesium sulfate).

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

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

The following exemplary embodiments explain the invention. The invention is not limited to the examples.

The percentages in the following tests and examples are, unless stated otherwise, percentages by weight; Parts are parts by weight. Solvent ratios, dilution ratios and concentration details of liquid-liquid solutions each relate to the volume. A. Examples

Abbreviations:

'Bu tert-butyl

DCI direct chemical ionization (for MS)

DMAP 4-N, N-dimethylaminopyridine

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide d. Th. Of theory (with yield)

EDC N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide x HCl

ESI electrospray ionization (for MS)

Et ethyl h hour (s)

HPLC high pressure, high performance liquid chromatography

LC / MS liquid chromatography-coupled mass spectroscopy

Me methyl min minute (s)

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy

Ph phenyl

Rf retention index (at DC)

RT room temperature

TFA trifluoroacetic acid

THF tetrahydrofuran

UV ultraviolet spectrum

HPLC and LC / MS methods:

Method 1:

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Grom-Sil 120 ODS-4 HE, 50 mm x 2.0 mm, 3 μm; Eluent A: 1 1 water + 1 ml 50% formic acid, eluent B: 1 1 acetonitrile + 1 ml 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 nm.

Method 2:

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; Eluent A: 5 ml HCIO ₄ / I water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B -> 9 min 90% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm.

Method 3:

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; Eluent A: 5 ml HCIO ₄ l water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% o B → 6.5 min 90% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm.

Method 4:

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 125 mm x 2 mm, 3.5 μm; Eluent A: PIC B7 heptanesulfonic acid (from Waters, item no. WAT084282), eluent B: acetonitrile; Gradient: 0 min 2% B → 1 min 2% B → 9 min 90% B → 13 min 90% B; Flow: 2 ml / min; Oven: 30 ° C; UV detection: 210 nm.

Method 5:

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Column: Grom-Sil 120 ODS-4 HE, 50 mm x 2 mm, 3.0 μm; Eluent A: water + 500 ul 50% formic acid / 1, eluent B: acetonitrile + 500 ul 50% formic acid / 1; Gradient: 0.0 min 5% B → 2.0 min 40% B → 4.5 min 90% B - 5.5 min 90% B; Oven: 45 ° C; Flow: 0.0 min 0.75 ml / min → 4.5 min 0.75 ml / min - 5.5 min 1.25 ml min; UV detection: 210 nm. Method 6:

Instrument: Micromass Quattro LCZ, with HPLC Agilent Series 1100; Column: Grom-Sil 120 ODS-4 HE, 50 mm x 2.0 mm, 3 μm; Eluent A: 1 1 water + 1 ml 50% formic acid, eluent B: 1 1 acetonitrile + 1 ml 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 nm.

Starting Compounds:

Example 1A

5-bromo-3, 3-dimethylindoline

A mixture of 45 ml of toluene / acetonitrile (49: 1) is flushed with argon for 5 minutes and then 3.00 g (16.0 mmol) of 4-bromophenylhydrazine are added. Then 3.71 ml (48.1 mmol) of trifluoroacetic acid are slowly added, taking care that a temperature of 35 ° C. is not exceeded. The temperature is then kept at 35 ° C. and a solution of 1.05 g (14.6 mmol) of isobutyraldehyde in 4 ml of toluene / acetonitrile (49: 1) is slowly added dropwise within 2 h. The mixture is stirred for 4 h at 35 ° C. and 2 h at room temperature. The mixture is then cooled to -10 ° C., 4.0 ml of methanol are added and 819 mg (21.7 mmol) of solid sodium borohydride are added in portions in the course of 30 minutes. The temperature must not exceed -2 ° C. After the addition has ended, the mixture is stirred at 0 ° C. for 1 h. After adding 150 ml of a 6% by weight solution of ammonia in water, the phases are separated and the organic phase is mixed with 1.5 ml each of acetonitrile and methanol. The organic phase is then washed with 150 ml of a 15% solution of sodium chloride in water and dried over sodium sulfate. It is filtered through 100 g of silica gel and washed twice with 200 ml of diethyl ether. The organic filtrate is concentrated in vacuo and chromatographed on 100 g of silica gel. The by-products are first eluted with cyclohexane, then the desired product is eluted with a mixture of cyclohexane / diethylefher (20: 1).

Yield: 1.78 g (54% of theory)

R _f (petroleum ether / ethyl acetate 5: 1) = 0.47 UV [nm] = 200, 268, 276

MS (ESIpos): mz = 226 [M + H] ⁺

Η NMR (200 MHz, DMSO-d ₆ ): δ = 1.20 (s, 6H), 3.18 (d, 2H), 5.66 (br. S, 1H), 6.42 (d, 1H), 7.02 (dd, lH ), 7.10 (d, 1H).

Example 2A

5-bromo-3,3-dimethyl-l- (4-nitrobenzene) sulfonylindolin

A solution of 17.00 g (75.18 mmol) of 5-bromo-3,3-dimethylindoline, 0.46 g (3.76 mmol) of DMAP and 21 ml (15.22 g, 150.4 mmol) of triethylamine in 100 ml of dichloromethane is added at 5-10 ° C Solution of 17.50 g (78.94 mmol) of 4-nitrobenzenesulfonyl chloride in 150 ml of dichloromethane was added dropwise. The mixture is then stirred at room temperature overnight. 2 N aqueous hydrochloric acid is added to the reaction mixture, the phases are separated and the organic phase is washed with water and saturated sodium chloride solution. After drying over sodium sulfate and removal of the solvent in vacuo, 31 g (98% of theory) of the desired product are obtained.

HPLC (method 1): R, = 4.1 min.

MS (DCI): mz = 428 [M + NH ₄ ] ⁺

H-NMR (300 MHz, CDC1 ₃ ): δ = 1.14 (s, 6H), 3.68 (s, 2H), 7.15 (d, 1H), 7.34 (dd, 1H), 7.51 (d, 1H), 8.00 (d, 2H), 8.32 (d, 2H).

Example 3A

3, 3-dimethyl-1 - (4-nitrobenzene) sulfonyl-5 - (4-trifluoromethyl) phenylindoline

With a suspension of 31.00 g (75.38 mmol) 5-bromo-3,3-dimefhyl-l- (4-nitrobenzene) sulfonylindoline, 21.47 g (113.06 mmol) 4-trifluoromethylphenylboronic acid and 15.63 g (113.06 mmol) potassium carbonate in 500 ml of toluene is passed through a stream of argon for 15 minutes. Then 1.72 g (1.51 mmol) of tetrakis (triphenylphosphine) palladium are added and the reaction mixture is heated under reflux overnight. After cooling, the mixture is filtered through about 1000 ml of silica gel 60 and the column is then washed with about 1.5 l of cyclohexane and with 2 l of dichloromethane. Removing the solvent of the dichloromethane fraction in vacuo gives 30 g (84% of theory) of the desired product.

HPLC (method 2): R _t = 5.71 min.

MS (DCI): mz = 494 [M + NH ₄ ] ⁺

'H NMR (300 MHz, CDC1 ₃ ): δ = 1.21 (s, 6H), 3.72 (s, 2H), 7.26 (s, 1H), 7.47 (dd, 1H), 7.60 (d, 2H), 7.68 (d, 2H), 7.70 (d, 1H), 8.06 (d, 2H), 8.32 (d, 2H).

Example 4A

3,3-Dimethyl-5- (4-trifluoromethyl) phenylindolin

To a mixture of 68 g (142.7 mmol) of 3,3-dimethyl-l- (4-nitrobenzene) sulfonyl-5- (4-trifluoromethyl) phenylindoline and 25.1 g (627.9 mmol) of sodium hydroxide in 300 ml of N, N- Dimethylformamide is rapidly added dropwise 27.2 ml (28.9 g, 314.0 mmol) thioacetic acid with stirring at room temperature. The reaction mixture is then stirred at 45 ° C. for 5 hours, after cooling, 1 l of ethyl acetate is added and the organic phase is washed twice with saturated sodium carbonate solution and once with saturated sodium chloride solution. After drying over sodium sulfate, the solvent is removed in vacuo and the crude product obtained on 1 kg Silica gel 60 cleaned (mobile phase cyclohexane / efhylacetate 7: 1). The eluate is concentrated and the residue obtained is crystallized. 27.1 g (61% of theory) of the desired product are obtained.

HPLC (method 3): R _t = 4.46 min.

MS (ESIpos): m / z = 292 [M + H] ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.37 (s, 6H), 3.40 (s, 2H), 6.70 (d, IH), 7.27 (d, IH), 7.30 (dd, IH), 7.62 ( s, 4H).

Example 5A

Ethyl [4- (2-tert-butoxy-2-oxoethoxy) -3-ethoxyphenyl] acetate

3.39 g (24.526 mmol) of potassium carbonate are added to a solution of 5.0 g (22.3 mmol) of ethyl (3-efhoxy-4-hydroxyphenyl) acetate in 75 ml of DMF, and the mixture is then stirred at 50 ° C. for 1 h. 3.62 ml (24.53 mmol) of tert-butyl bromoacetate are then added and the reaction mixture is stirred at 50 ° C. overnight. After the reaction has ended, the solvent is distilled off in vacuo, the residue is taken up in 150 ml of ethyl acetate and washed three times with 75 ml of water each time. The organic phase is dried over sodium sulfate and concentrated. 7.5 g (99.4% of theory) of the desired product are obtained.

HPLC (method 3): R _t = 4.96 min.

MS (DCI): m / z = 356 [M + NH ₄ ] ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.22 (t, 3H), 1.42 (t, 3H), 1.48 (s, 9H), 3.5 (s, 2H), 4.12 (tt, 4H), 4.55 ( s, 2H), 6.75 (d, 2H), 6.85 (s, IH).

Example 6A

[2-ethoxy-4- (2-ethoxy-2-oxoethyl) phenoxy] acetic acid

7.7 ml (100.0 mmol) of trifluoroacetic acid are added at RT to a solution of 3.38 g (10.0 mmol) of ethyl [4- (2-tert-butoxy-2-oxoethoxy) -3-ethoxyphenyl] acetate in 25 ml of dichloromethane and then stirred at RT until the reaction is complete. The reaction mixture is freed from the solvent in vacuo, taken up in 100 ml of ethyl acetate and washed twice with 50 ml of water. The organic phase is dried over magnesium sulfate and freed from the solvent in vacuo. After purification on silica gel (mobile phase: cyclohexane / ethyl acetate 1: 1), 2.54 g (89% of theory) of the desired product are obtained.

HPLC (method 3): R, = 3.89 min.

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.25 (t, 3H), 1.48 (t, 3H), 3.55 (s, 2H), 4.15 (m, 4H), 4.65 (s, 2H), 6.88 ( m, 3H), 7.65 (br. s, IH).

Example 7A

[4- (2-tert-butoxy-2-oxoethoxy) -3-ethoxyphenyl] acetic acid

11 ml (11.0 mmol) of 1 M sodium hydroxide solution are added at RT to a solution of 3,384 g (10.0 mmol) of ethyl [4- (2-tert-butoxy-2-oxoethoxy) -3-ethoxyphenyl acetate in 50 ml of ethanol. The mixture is then stirred at RT until the reaction is complete. The equivalent amount of hydrochloric acid is added, the ethanol is distilled off in vacuo and the aqueous residue is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. The cleaning is carried out on silica gel (mobile phase: cyclohexane ethyl acetate 5: 1). 451 mg (96% of theory) of the desired product are obtained.

HPLC (method 4): R, = 3.06 min. MS (DCI): mz = 328 ΓM + NH ₄ ] ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.4 (t, 3H), 1.5 (s, 9H), 3.55 (s, 2H), 4.1 (q, 2H), 4.55 (s, 2H), 6.78 ( s, 2H), 6.85 (s, IH).

Example 8A

Ethyl [3- (2-tert-butoxy-2-oxoethoxy) phenyl] acetate

3,040 g (22.0 mmol) of potassium carbonate are added to a solution of 3,604 g (20.0 mmol) of ethyl (3-hydroxyphenyl) acetate in 25 ml of DMF and the mixture is stirred at 50 ° C. for 1 h. Then 3,248 ml (22.0 mmol) of tert-butyl bromoacetate are added and the mixture is stirred further at 50 ° C. overnight. After the reaction has ended, the solvent is distilled off in vacuo. The crude product is taken up in 100 ml of ethyl acetate and washed three times with 50 ml of water each. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. 5.6 g (95% of theory) of the desired product are obtained.

HPLC (method 3): R, = 4.75 min.

MS (DCI): m / z = 312 [M + NH ₄ ] ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.25 (t, 3H), 1.5 (s, 9H), 3.55 (s, 2H), 4.15 (q, 2H), 4.5 (s, 2H), 6.82 ( m, 3H), 7.25 (m, IH).

Example 9A

[3- (2-ethoxy-2-oxoethyl) phenoxy] acetic acid

2.7 g (9,173 mmol) of ethyl [3- (2-tert.-butoxy-2-oxoethoxy) phenyl] acetate are dissolved in 25 ml of dichloromethane, 7.07 ml (91.73 mmol) of trifluoroacetic acid are added at RT and the mixture is brought to a stirred reaction at RT. The reaction mixture is then concentrated in vacuo, the crude product is taken up in 100 ml of ethyl acetate and washed twice with 50 ml of water each time. The organic phase is dried over magnesium sulfate and freed from solvent in vacuo. Purification of the crude product on silica gel (mobile phase: cyclohexane / ethyl acetate 1: 1) gives 2 g (91% of theory) of the desired product.

HPLC (method 3): R _t = 3.89 min.

MS (DCI): m / z = 256 [M + NH ₄ ] ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.25 (t, 3H), 3.58 (s, 2H), 4.15 (q, 2H), 4.68 (s, 2H), 6.88 (m, 3H), 7.25 ( t, 2H).

Example 10A

Ethyl [4- (2-tert-butoxy-2-oxoethoxy) -3-fluorophenyl] acetate

844 mg (6.11 mmol) of potassium carbonate are added to a solution of 1.1 g (5.55 mmol) of ethyl (3-fluoro-4-hydroxyphenyl) acetate in 10 ml of DMF at RT and the suspension is stirred at 50 ° C. for 1 h. Then 0.90 ml (6.11 mmol) of tert-butyl bromoacetate are added and the mixture is stirred further at 50 ° C. overnight. After the reaction has ended, the solvent is distilled off in vacuo, the crude product is taken up in 100 ml of ethyl acetate and washed three times with 50 ml of water each time. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. 1.7 g (98% of theory) of the desired product are obtained.

HPLC (method 3): R _t = 4.93 min.

MS (DCI): m / z = 330 [M + NH ₄ ] ⁺

'H NMR (200 MHz, CDC1 ₃ ): δ = 1.25 (t, 3H), 1.48 (s, 9H), 3.5 (s, 2H), 4.15 (q, 2H), 4.58 (s, 2H), 6.95 (m, 3H). Example 11A

[4- (2-ethoxy-2-oxoethyl) -2-fluorophenoxy] acetic acid

To a solution of 800 mg (0.215 mmol) of ethyl [4- (2-tert-butoxy-2-oxoefhoxy) -3-fluorophenyl acetate in 5 ml of dichloromethane are added 1.97 ml (2.15 mmol) of trifluoroacetic acid and until the reaction is complete at RT touched. The reaction mixture is then concentrated in vacuo, the residue is taken up in 50 ml of ethyl acetate and washed twice with 20 ml of water each time. The organic phase is dried over magnesium sulfate, concentrated in vacuo and the crude product is purified on silica gel (mobile phase: cyclohexane / ethyl acetate 1: 1). 590 mg (89% of theory) of the desired product are obtained.

HPLC (method 2): R, = 5.17 min.

MS (DCI): m / z = 501 [M + NH ₄ ] ⁺

"H-NMR (200 MHz, DMSO-d ₆ ): δ = 1.35 (s, 6H), 2.0 (s, 2H), 3.85 (s, 2H), 4.65 (s, 2H), 6.85 (m, 3H) , 7.25 (t, IH), 7.6 (m, 2H), 7.8 (dd, 4H), 8.15 (d, IH), 13.0 (br. S, IH).

Example 12A

2-chloro-4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl} -2-oxoethyl) phenol

A solution of 218.5 mg (0.75 mmol) of 3,3-dimethyl-5- (4-trifluoromethyl) phenylindoline and 209.9 mg (1.13 mmol) of 3-chloro-4-hydroxyphenylacetic acid in 2 ml of 1, 2-dichloroethane are added to

0 ° C 287.6 mg (1.5 mmol) N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride and then the mixture was stirred at RT overnight. The reaction mixture is first filtered through silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1). The product fraction is concentrated and then finely cleaned by preparative HPLC (RP18 column; mobile phase: acetonitrile / water, gradient 30:70 → 90:10). 195 mg (56% of theory) of the desired product are obtained.

HPLC (method 5): R _t = 3.39 min.

'H-NMR (300 MHz, CDC1 ₃ ): δ = 1.4 (s, 6H), 2.05 (s, 2H), 3.62 (br. S, 2H), 3.85 (br. S, 2H), 5.5 (s, IH), 7.15 (d, IH), 7.35 (d, IH), 7.45 (d, IH), 7.68 (s, 4H), 8.3 (d, IH).

Example 13A

4- (2- {3,3-Dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} -2-oxoethyl) -2-mefhoxyphenol

A solution of 218.5 mg (0.75 mmol) of 3,3-dimethyl-5- (4-trifluoromethyl) phenylindoline and 204.9 mg (1.3 mmol) of 4-hydroxy-3-methoxyphenylacetic acid in 2 ml of 1,2-dichloroethane are added at 0 ° C 287.6 mg (1.5 mmol) of N ^, - (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride were added and the mixture was then stirred at RT overnight. The reaction mixture is purified directly on silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1). 280 mg (82% of theory) of the desired product are obtained.

HPLC (method 2): R, = 5.28 min.

MS (DCI): m / z = 473 [M + NH ₄ ] ⁺

Η NMR (400 MHz, CDC1 ₃ ): δ = 1.35 (s, 6H), 3.75 (s, 2H), 3.85 (s, 2H), 3.9 (s, 3H), 5.55 (s, IH), 6.75 ( d, IH), 6.85 (m, 2H), 7.32 (s, IH), 7.45 (d, IH), 7.68 (s, 4H), 8.3 (d, IH). EXAMPLES

example 1

Ethyl [4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} -2-oxoethoxy) -3-ethoxyphenyl] acetate

To a solution of 100 mg (0.343 mmol) of 3,3-dimethyl-5- (4-trifluoromethyl) phenylindoline and 145.4 mg (0.515 mmol) of [2-ethoxy-4- (2-ethoxy-2-oxoethyl) phenoxy ] Acetic acid in 2 ml of 1,2-dichloroethane are added at 0 ° C 131.6 mg (0.687 mmol) of N '- (3-dimethylaminopropyl) -N-ethyl-carbodiimide hydrochloride and then the reaction mixture is stirred overnight at RT. The reaction mixture is purified directly on silica gel (mobile phase: cyclohexane / ethyl acetate 3: 1). 161 mg (84% of theory) of the desired product are obtained.

HPLC (method 2): R _t = 5.68 min.

MS (ESIpos): mz = 556 [M + H] ⁺

'H NMR (300 MHz, CDC1 ₃ ): δ = 1.45 (s, 12H), 3.5 (s, 2H), 4.05 (s, 2H), 4.15 (m, 4H), 4.8 (s, 2H), 6.78 (d, IH), 6.85 (s, IH), 6.95 (d, IH), 7.35 (s, IH), 7.45 (d, IH), 7.68 (s, 4H), 8.28 (br. d, IH).

Example 2

tert-butyl [4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl} -2-oxoethyl) - 2-ethoxy-phenoxy] acetate

To a solution of 150 mg (0.515 mmol) of 3,3-dimethyl-5- (4-trifluoromethyl) phenylindoline and 239.7 mg (0.772 mmol) [4- (2-tert-butoxy-2-oxoethoxy) -3 -ethoxyphenyl] acetic acid in 2 ml of 1,2-dichloroethane, 159.9 mg (1.03 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodimide hydrochloride are added at 0 ° C. and the mixture is then stirred at RT overnight. The reaction mixture is purified directly on silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1). 279 mg (93% of theory) of the desired product are obtained.

HPLC (method 6): R _t = 4.82 min.

MS (ESIpos): m / z = 584 [M + H] ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.35 (s, 6H), 1.4 (t, 3H), 1.45 (s, 9H), 3.72 (s, 2H), 3.85 (s, 2H), 4.1 ( q, 2H), 4.55 (s, 2H), 6.8 (s, 2H), 6.9 (s, IH), 7.32 (s, IH), 7.45 (d, IH), 7.68 (s, 4H), 8.32 (d , IH).

Example 3

Ethyl [4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl} -2-oxoethoxy) -3-fluorophenyl] acetate

To a solution of 100 mg (0.343 mmol) of 3,3-dimethyl-5- (4-trifluoromethyl) phenylindoline and 131.9 mg (0.515 mmol) of [4- (2-ethoxy-2-oxoethyl) -2-fluoro-phenoxy] acetic acid in 2 ml of 1,2-dichloroethane are added at 0 ° C 131.6 mg (0.687 mmol) of N '- (3-dimethylaminopropyl) -N-ethyl-carbodiimide hydrochloride and then the mixture is stirred at RT overnight. It is purified directly on silica gel (mobile phase: cyclohexane / ethyl acetate 3: 1). 166 mg (91% of theory) of the desired product are obtained.

HPLC (method 2): R, = 5.64 min.

MS (ESIpos): m / z = 530 [M + H] ⁺

'H NMR (300 MHz, CDC1 ₃ ): δ = 1.25 (t, 3H), 1.42 (s, 6H), 3.52 (s, 2H), 3.98 (s, 2H), 4.15 (q, 2H), 4.82 (s, 2H), 7.05 (m, 3H), 7.35 (s, IH), 7.45 (d, IH), 7.68 (s, 4H), 8.28 (d, IH).

Example 4

Ethyl [3- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl} -2-oxoethoxy) phenyl acetate

To a solution of 100 mg (0.343 mmol) of 3,3-dimethyl-5- (4-trifluoromethyl) phenylindoline and 122.7 mg (0.515 mmol) of [3- (2-ethoxy-2-oxoethyl) phenoxy] acetic acid in 2 ml of 1,2-dichloroethane are added at 0 ° C to 131.6 mg (0.687 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride and the mixture is then stirred at RT overnight. The reaction mixture is purified directly on silica gel (mobile phase: cyclohexane / ethyl acetate 3: 1). 171 mg (97% of theory) of the desired product are obtained.

HPLC (method 2): R, = 5.63 min.

MS (ESIpos): m / z = 512 [M + H] ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.35 (t, 3H), 1.42 (s, 6H), 3.55 (s, 2H), 3.95 (s, 2H), 4.15 (q, 2H), 4.78 ( s, 2H), 6.92 (m, 4H), 7.35 (s, IH), 7.48 (d, IH), 7.68 (s, 4H), 8.28 (d, IH).

Example 5

[4- (2- {3,3-Dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} -2-oxoethyl) -2-ethoxyphenoxyacetic acid

A solution of 117 mg (0.20 mmol) of tert-butyl [4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl } -2-oxoethyl) -2-ethoxyphenoxy] acetate in 3 ml dichloromethane is mixed with 0.154 ml (2.005 mmol) trifluoroacetic acid at RT and stirred until the reaction is complete. The reaction mixture is then concentrated in vacuo and the crude product is purified on silica gel (mobile phase: cyclohexane / ethyl acetate 3: 1, 1: 1). 75 mg (70% of theory) of the desired product are obtained.

HPLC (method 3): R, = 5.20 min.

MS (ESI): mz = 528 [M + H] ⁺ Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.32 (t, 3H), 1.35 (s, 6H), 3.8 (s, 2H), 3.98 (s, 2H), 4.05 (q, 2H), 4.65 (s, 2H), 6.78 (m, 2H), 6.92 (s, IH), 7.55 (d, IH), 7.65 (s, IH), 7.85 (dd, 4H), 8.12 (d, IH), 12.88 (br. s, IH).

Example 6

[4- (2- {3,3-Dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} ethyl) -2-mefhoxyphenoxy] acetic acid

To a solution of 16 mg (0.029 mmol) tert-butyl [4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indole- l-yl} ethyl) -2-methoxyphenoxy] acetate in 0.5 ml dichloromethane are added at RT to 0.022 ml (0.288 mmol) trifluoroacetic acid and the mixture is then stirred until the reaction is complete. The reaction mixture is concentrated in vacuo and the crude product is purified on silica gel (mobile phase: dichloromethane - dichloromethane / mefhanol 10: 1). 13 mg (90% of theory) of the desired product are obtained.

MS (ESI): m / z = 500 [M + H] ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.32 (s, 6H), 2.85 (t, 2H), 3.2 (s, 2H), 3.38 (t, 2H), 3.88 (s, 3H), 4.6 ( s, 2H), 6.48 (d, IH), 6.8 (s, 2H), 6.9 (d, IH), 7.22 (s, IH), 7.35 (d, IH), 7.6 (s, 4H).

Example 7

tert -butyl [2-chloro-4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} -2-oxoethyl ) phenoxy] acetate

A solution of 100 mg (0.217 mmol) of 2-chloro-4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl} 30 mg (0.217 mmol) of potassium carbonate are added to -2-oxoethyl) phenol in 2 ml of DMF and the mixture is stirred at RT for 1 h. Then 0.035 ml (0.239 mmol) of tert-butyl bromoacetic acid are added. The mixture is first stirred at RT for 3 h and then at 50 ° C. overnight. After the reaction has ended, the solvent is distilled off in vacuo, the crude product is taken up in 30 ml of ethyl acetate and washed twice with 15 ml of water and once with saturated potassium carbonate solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. 117 mg (93% of theory) of the desired product are obtained.

MS (ESI): m / z = 575 [M + H] ⁺

'H NMR (300 MHz, CDC1 ₃ ): δ = 1.38 (s, 6H), 1.5 (s, 9H), 3.75 (s, 2H), 3.85 (s, 2H), 4.58 (s, 2H), 6.82 (d, IH), 7.15 (d, IH), 7.35 (d, 2H), 7.48 (d, IH), 7.68 (s, 4H), 8.3 (d, IH).

Example 8

tert-butyl [4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl} -2-oxoethyl) -2- methoxyphenoxy] acetate

A solution of 100 mg (0.22 mmol) of 4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl} -2-oxoethyl ) -2,3-methoxyphenol in 2 ml DMF is mixed with 30,343 mg (0.22 mmol) potassium carbonate and stirred for 1 h at RT. Then 0.036 ml (0.242 mmol) of tert-butyl bromoacetic acid are added. The mixture is initially stirred at RT for 3 h, then at 50 ° C. overnight. After the reaction has ended, the solvent is distilled off in vacuo, the crude product is taken up in 30 ml of ethyl acetate and washed twice with 15 ml of water and once with saturated potassium carbonate solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. After purification of the crude product on silica gel (mobile phase: cyclohexane / ethyl acetate 3: 1), 111 mg (88% of theory) of the desired product are obtained.

HPLC (method 2): R, = 5.62 min.

MS (ESI): m / z = 514 [M + H] ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 1.35 (s, 6H), 1.45 (s, 9H), 3.75 (s, 2H), 3.88 (s, 2H), 3.9 (s, 3H), 4.55 ( s, 2H), 6.78 (s, 2H), 6.9 (s, IH), 7.35 (s, IH), 7.45 (d, IH), 7.68 (s, 4H), 8.3 (d, IH).

Example 9

[4- (2- {3,3-Dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} -2-oxoethoxy) -3-ethoxyphenyl] acetic acid

To a solution of 130 mg (0.234 mmol) of ethyl [4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl } -2-oxoethoxy) -3-ethoxyphenyl] acetate in 5 ml of ethanol are added at RT 0.257 ml (0.257 mmol) of 1 M sodium hydroxide solution and then the mixture is stirred at RT until the reaction is complete. Then 0.3 ml of 1 N hydrochloric acid is added and the ethanol is distilled off in vacuo. A white precipitate precipitates, which is filtered off, washed with water and dried in vacuo. 117 mg (94% of theory) of the desired product are obtained.

HPLC (method 3): R, = 5.2 min.

MS (ESI): m / z = 528 [M + H] ⁺

Η NMR (200 MHz, DMSO-d ₆ ): δ = 1.35 (t, 3H), 1.4 (s, 6H), 3.5 (s, 2H), 4.0 (s, 2H), 4.05 (q, 2H), 4.95 (s, 2H), 6.75 (d, IH), 6.9 (s, 2H), 7.6 (d, IH), 7.7 (s, IH), 7.85 (dd, 4H), 8.12 (d, IH), 12.25 (br. s, IH).

Example 10

[3- (2- {3,3-Dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} -2-oxoethoxy) phenyl acetic acid

A solution of 87 mg (0.17 mmol) of ethyl [3- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl} -2 -oxoethoxy) phenyl] acetate in 5 ml of ethanol is mixed with RT at RT with 0.187 ml (0.187 mmol) of 1 M sodium hydroxide solution and stirred at RT until the reaction is complete. Then 0.25 ml of 1 N hydrochloric acid are added and the ethanol is distilled off in vacuo. A white precipitate precipitates, which is filtered off, washed with water and dried in vacuo. 75 mg (91% of theory) of the desired product are obtained.

HPLC (method 3): R, = 5.16 min.

MS (ESI): m / z = 484 [M + H] ⁺

Η NMR (200 MHz, DMSO-d ₆ ): δ = 1.4 (s, 6H), 3.55 (s, 2H), 4.0 (s, 2H), 4.95 (s, 2H), 6.88 (d, IH), 6.92 (s, 2H), 7.25 (t, IH), 7.6 (d, IH), 7.72 (s, IH), 7.85 (dd, 4H), 8.12 (d, IH), 12.35 (br. S, IH) ,

Example 11

Ethyl [4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} ethoxy) -3-fluorophenyl] acetate

A solution of 69 mg (0.13 mmol) of ethyl [4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl} -2 -oxoethoxy) -3-fluoφhenyl] acetate and 1.2 mg (0.001 mmol) of carbonyl tris (triphenylphosphine) rhodium (I) hydride in 1 ml of THF are mixed at RT with 0.06 ml (0.326 mmol) of diphenylsilane and stirred overnight at RT. The mixture is concentrated in vacuo and purified over silica gel (mobile phase: cyclohexane / ethyl acetate 7: 1). The product is used directly in the next stage.

Example 12

[4- (2- {3,3-Dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} ethoxy) -3-fluorophenyl acetic acid hydrochloride

A solution of 67 mg (0.13 mmol) of ethyl [4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl} ethoxy) -3-fluoφhenyl] acetate in 2 ml of ethanol is mixed with 1.43 ml (0.143mmol) 0.1 M sodium hydroxide solution and stirred at RT until the reaction is complete. Then an equivalent amount of hydrochloric acid is added, the aqueous phase is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated in vacuo. The crude product is purified on silica gel 60 (mobile phase: cyclohexane / ethyl acetate 5: 1). The product fractions are concentrated in vacuo, taken up in ethyl acetate and mixed with a solution of hydrogen chloride in dioxane. The mixture is evaporated to dryness in vacuo. 31 mg (45% of theory) of the desired product are obtained.

HPLC (method 3): R _t = 5.66 min.

MS (ESI): mz = 488 [M + H] ⁺

Η NMR (200 MHz, DMSO-d ₆ ): δ = 1.28 (s, 6H), 3.35 (s, 2H), 3.49 (s, 2H), 3.95 (br. S, 3H), 4.25 (t, 2H) ), 6.65 (d, IH), 7.1 (m, 3H), 7.42 (m, 2H), 7.75 (dd, 4H).

Example 13

Ethyl [3- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2 ₎ 3-dihydro-1H-indol-1-yl} ethoxy) phenyl] acetate

A solution of 75 mg (0.147 mmol) of ethyl [3- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl} -2 -oxoethoxy) phenyl] acetate and 1.3 mg (0.001 mmol) of carbonyltris (tri-phenylphosphine) rhodium (I) hydride in 1 ml of THF are mixed with 0.068 ml (0.367 mmol) of diphenylsilane at RT and stirred overnight at RT. The mixture is then concentrated in vacuo and purified over silica gel (mobile phase: cyclohexane / ethyl acetate 7: 1). The product is used directly in the next stage.

Example 14

[3- (2- {3,3-Dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} ethoxy) phenyl] acetic acid hydrochloride

To a solution of 73.14 mg (0.147 mmol) of ethyl [3- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl} ethoxy) phenyl] acetate in 2 ml of ethanol are added at RT to 1.62 ml (0.162 mmol) of 0.1 M sodium hydroxide solution and then the mixture is stirred at RT until the reaction is complete. Then the equivalent amount of hydrochloric acid is added, the aqueous phase is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated in vacuo. The crude product is purified over silica gel 60 (mobile phase: cyclo- hexane / ethyl acetate 5: 1). After concentrating the product fractions, taking up in ethyl acetate, adding a solution of hydrogen chloride in dioxane and again concentrating to dryness, 30 mg (40% of theory) of the desired product are obtained.

HPLC (method 3): R, = 5.67 min.

MS (ESI): m / z = 470 [M + H] ⁺

Η NMR (200 MHz, DMSO-d ₆ ): δ = 1.3 (s, 6H), 3.52 (s, 2H), 3.55 (s, 2H), 3.58 (t, 2H), 4.18 (t, 2H), 6.68 (d, IH), 6.85 (m, 3H), 7.25 (t, IH), 7.42 (m, 2H), 7.75 (dd, 4H), 12.3 (br. S, IH).

Example 15

tert-Butyl [4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl} ethyl) -2-methoxyphenoxy] acetate

A solution of 75 mg (0.132 mmol) of tert-butyl [4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl } -2-oxoethoxy) -2-methoxyphenoxy] acetate and 1.2 mg (0.001 mmol) carbonyltris (triphenylphosphine) rhodium (I) hydride in 1 ml THF are mixed at RT with 0.061 ml (0.329 mmol) diphenylsilane and stirred overnight at RT , The mixture is then concentrated in vacuo, pre-cleaned over silica gel (mobile phase: cyclohexane / ethyl acetate 7: 1) and finely cleaned by means of preparative HPLC (RP18 column; mobile phase: acetonitrile / water, gradient 30:70 - »90:10). 20 mg (27% of theory) of the desired product are obtained.

MS (ESI): mz = 555 [M + H] ⁺ 'H NMR (300 MHz, CDC1 ₃ ): δ = 1.35 (s, 6H), 1.45 (s, 9H), 2.88 (t, 2H), 3.22 (s, 2H), 3.4 (t, 2H), 3.88 (s, 3H), 4.55 (s, 2H), 6.52 (d, IH), 6.75 (s, 2H), 6.8 (s, IH), 7.22 (s, IH), 7.35 (d, IH), 7.62 ( s, 4H).

Example 16

tert-butyl [2-chloro-4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indol-l-yl} ethyl) phenoxy] acetate

A solution of 84 mg (0.146 mmol) of tert-butyl [2-chloro-4- (2- {3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H -indol-l-yl} -2-oxoethyl) phenoxy] acetate and 1.3 mg (0.001 mmol) carbonyltris (triphenylphosphine) rhodium (ι) hydride in 1 ml THF is mixed at RT with 0.068 ml (0.366 mmol) diphenylsilane and overnight stirred at RT. The mixture is then concentrated in vacuo, pre-cleaned over silica gel (mobile phase: cyclohexane / ethyl acetate 7: 1) and finely cleaned twice using preparative HPLC (RP18 column; mobile phase: acetonitrile / water, gradient 30:70 → 90:10). 29.5 mg (36% of theory) of the desired product are obtained.

MS (ESI): m / z = 559 [M + H] ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 1.35 (s, 6H), 1.48 (s, 9H), 2.88 (t, 2H), 3.25 (s, 2H), 3.38 (t, 2H), 4.55 ( s, 2H), 6.6 (d, IH), 6.78 (d, IH), 7.08 (d, IH), 7.3 (s, IH), 7.38 (d, IH), 7.6 (s, 4H), 7.65 (s , IH). B. Assessment of physiological effectiveness

Example A

Cellular Transactivation Assay:

Test principle:

A cellular assay is used to identify activators of the peroxisome proliferator-activated receptor delta (PPAR-delta).

Since mammalian cells contain various endogenous nuclear receptors, which could complicate a clear interpretation of the results, an established chimeric system is used in which the ligand binding domain of the human PPARδ receptor is fused to the DNA binding domain of the yeast transcription factor GAL4. The resulting GAL4-PPARδ chimera is co-transfected and stably expressed in CHO cells with a reporter construct.

cloning:

The GAL4-PPARδ expression construct contains the ligand binding domain of PPARδ (amino acids 414-1326), which is PCR-amplified and cloned into the vector pcDNA3.1. This vector already contains the GAL4 DNA binding domain (amino acids 1-147) of the vector pFC2-dbd (Stratagene). The reporter construct, which contains five copies of the GAL4 binding site, upstream of a thyridine kinase promoter, leads to the expression of Firefly luciferase (Photinus pyralis) after activation and binding of GAL4-PPARδ.

Transactivation Assay (Luciferase Reporter):

CHO (Chinese hamster ovary) cells are in CHO-A-SFM medium (GJBCO), supplemented with 2.5% fetal calf serum and 1% penicillin streptomycin (GJJ3CO), with a cell density of 2 x 10 ³ cells per well in a 384 well plate (Greiner) sown. After culturing at 37 ° C. for 48 h, the cells are stimulated. For this purpose, the substances to be tested are taken up in the medium mentioned above and added to the cells. After a stimulation time of 24 hours, the luciferase activity is measured using a video camera. The measured relative light units result in a sigmoid stimulation curve depending on the substance concentration. The EC ₅₀ values are calculated using the GraphPad PRISM computer program (version 3.02). In this test, exemplary embodiments 1-16 show EC 50 values in a range from 10 nM to 10 μM.

Example B

Test descriptions for the discovery of pharmacologically active substances which increase the HDL cholesterol (HDL-C) in the serum of transgenic mice transfected with the human ApoAl gene (hA-poAl) or the metabolic syndrome of obese whether or not - Affect mice and lower their blood glucose concentration:

The substances which are to be investigated for their HDL-C-increasing effect in vivo are administered orally to male transgenic hApoAl mice. The animals are randomly assigned to 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 dissolved 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. 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 for the determination of ApoAl, serum cholesterol, HDL-C and serum triglycerides (TG) 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, i.e. on the 8th day after the start of treatment, blood is again taken from each animal to determine the same parameters by puncturing the retroorbital venous plexus. The blood samples are centrifuged and, after the serum has been obtained, cholesterol and TG are determined photometrically using an EPOS Analyzer 5060 (Eppendorf-Gerätebau, Netheler & Hinz GmbH, Hamburg). The determination is carried out using commercially available enzyme tests (Boehringer Mannheim, Mannheim).

To determine the HDL-C, the non-HDL-C fraction is precipitated with 20% PEG 8000 in 0.2 M glycine buffer pH 10. The cholesterol is determined from the supernatant in a 96-well perforated plate using a commercially available reagent (Ecoline 25, Merck, Darmstadt) using UV photometry (BIO-TEK Instruments, USA).

The human mouse ApoAl is a sandwich ELISA method using a polyclonal anti-human ApoAl and a monoclonal anti-human ApoAl antibody (Biode- sign International, USA). The quantification is carried out UV-photometrically (BIO-TEK Instruments, USA) with peroxidase-coupled anti-mouse IGG antibodies (KPL, USA) and peroxidase substrate (KPL, USA).

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

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

Substances that increase the HDL-C of the treated animals statistically significantly (p <0.05) by at least 15% compared to that of the control group are considered to be pharmacologically active.

In order to be able to test substances for their influence on a metabolic syndrome, animals with insulin resistance and increased blood glucose levels are used. For this purpose, C57B1 / 6J Lep <ob> mice are treated according to the same protocol as the transgenic ApoAl mice. Serum lipids are determined as described above. In addition, serum glucose is determined as a parameter for blood glucose in these animals. The serum glucose is determined enzymatically on an EPOS Analyzer 5060 (see above) using commercially available enzyme tests (Boehringer Mannheim).

A blood glucose-lowering effect of the test substances is determined by subtracting the measured value of the first blood sample from an animal (previous value) from the measured value of the second blood sample from the same animal (after treatment). The differences of all serum glucose values in a group are averaged and compared with the mean value of the differences in the control group.

Substances that reduce the serum glucose concentration 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. C. Embodiments of pharmaceutical compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound from Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The mixture of compound according to the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. After drying, the granules are mixed with the magnesium stearate for 5 minutes. This mixture is veφresst with a conventional tablet press (format of the tablet see above). A pressing force of 15 kN is used as a guideline for the compression.

Oral suspension:

Composition:

1000 of the compound of Example 1, 1000 mg of ethanol mg (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.

production:

The Rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. The water is added with stirring. The mixture is stirred for about 6 hours until the swelling of the rhodel is complete. Orally applicable solution;

Composition:

500 mg of the compound from Example 1, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention corresponds to 20 g of oral solution.

production:

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring process is continued until the compound according to the invention has completely dissolved.

Claims

Patentanspräche

Compounds of the general formula (I)

in which

R ^{1 represents} phenyl or 5- to 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, which in turn are each one to three times, identical or different, by substituents selected from the group halogen, Cya-no, nitro, (-CC ₆ ) alkyl, which in turn can be substituted by hydroxy, (-C ₆ ) -alkoxy, trifluoromethyl, trifluoromethoxy, (CC ₆ ) -alkylsulfonyl, (CC ₆ ) -alkanoyl, (-CC ₆ ) alkoxycarbonyl, carboxyl, amino, (C ₁ -C ₆ ) acylamino, mono- and di- (C C6) alkylamino can be substituted,

R ² and R ^{3 are the} same or different and independently of one another represent hydrogen or (-CC ₄ ) -alkyl or together with the carbon atom to which they are attached, a 3- to 7-membered, spiro-linked cycloalkyl ring form,

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

R ^{7 represents} hydrogen, (C, -C ₄ ) -alkyl, (dC ₄ ) -alkoxy or halogen,

R ⁸ and R ^{9 are the} same or different and independently of one another represent hydrogen or (CC ₄ ) -alkyl,

R represents hydrogen or a hydrolyzable group which can be broken down into the corresponding carboxylic acid,

X for O, S or NR ¹¹ and Y stands for a bond or

X represents a bond and Y represents O, S or NR ¹¹ , wherein

R ¹¹ each represents hydrogen, (-CC ₄ ) -alkyl or (-CC ₄ ) -alkanoyl, and their pharmaceutically acceptable salts, solvates and solvates of the salts.

2. Compounds of the general formula (P according to claim 1, in which

R ¹ stands for phenyl, which is mono- or doubly, identical or different, by substituents selected from the group halogen, cyano, nitro, (-C-C ₄ ) -alkyl, which in turn can be substituted by hydroxy, (Cι- C ₄ ) alkoxy, trifluoromethyl, trifluoromethoxy, (C] -C ₄ ) alkanoyl, amino, mono- and di- (-C ₄ ) alkylamino can be substituted,

R ² and R ^{3 are the} same or different and stand for (CC ₄ ) -alkyl or together with the carbon atom to which they are attached form a 4- to 6-membered, spiro-linked cycloalkyl ring,

R ^{4 represents} hydrogen,

R ⁵ and R ^{6 are} hydrogen or together with the carbon atom to which they are attached form a carbonyl group, R ^{7 is} hydrogen, (CC ₄ ) -alkyl, (C, -C ₄ ) -alkoxy, fluorine or chlorine,

R ⁸ and R ⁹ independently of one another represent hydrogen or methyl,

R ^{10 represents} hydrogen,

X represents O or S and Y represents a bond or

X for a bond

and

Y stands for O or S.

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

R ^{1 represents} phenyl, which can be substituted by fluorine, chlorine, cyano, methyl, ethyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, amino, dimethylamino or diethylamino,

R ^{4 represents} hydrogen,

R ^{7 represents} hydrogen, methyl, methoxy, ethoxy, fluorine or chlorine,

R ⁸ and R ⁹ each represent hydrogen,

R ^{10 represents} hydrogen,

X for O

and

Y stands for a bond

or

X for a bond

and

Y stands for O. Compounds of formula (IA)

in which

R ^{7 represents} hydrogen, methyl, methoxy, ethoxy, fluorine or chlorine,

X for O

and stands for a bond

or

X for a bond

and

Y stands for O,

and the group linked via Y is located in the para or meta position of the phenyl ring in formula (I-A) relative to the substituent X.

Process for the preparation of the compounds of the general formula (I) or (I-A) as defined in claims 1 to 4, characterized in that compounds of the formula (JJ)

in which R ¹ , R ² , R ³ and R ⁴ each have the meanings given above,

either

[A] in an inert solvent in the presence of a condensing agent and optionally in the presence of an auxiliary base with a compound of the formula (JJJ)

in which

X, Y, R, R and R each have the meanings given above and represents benzyl or (CC ₆ ) -alkyl, to give compounds of the formula (IV)

or

[B] in the case that in formula (I) or (IA) X is a bond and Y is O, S or N-R ^u , initially in an inert solvent in the presence of a condensing agent and optionally in the presence of an auxiliary base a compound of the formula (VJJ)

in which

R ^{7 has} the meanings given above and

Z represents O, S or NR ⁿ , where R ^{u has} the meanings given above, to give compounds of the formula (VIJJ)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁷ and Z each have the meanings given above,

couples, this then in an inert solvent in the presence of a base with a compound of formula (JX)

in which R ⁸ , R ⁹ and T each have the meanings given above and

Q represents a suitable leaving group such as halogen, mesylate or tosylate,

to compounds of the formula (X)

in the event that R ⁵ and R ⁶ in formula (I) or (IA) are hydrogen, in an inert solvent in the presence of a suitable reducing agent, in compounds of the formula (XI) in which R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , T and Z each have the meanings given above, the compounds of the formula (X) or (XI) are then converted with acids or bases or, if T is benzyl, also hydrogenolytically to the corresponding carboxylic acids of the formula (XIJ)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and Z each have the meanings given above, optionally converting the carboxylic acids of the formula (VI) or (XU) further modified according to known esterification methods to give compounds of the formula (I) or (IA), and the resulting compounds of the formula (VI), (XU), (I) or (IA) optionally with the corresponding ( i) converting solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts.

6. Compounds of formula (I) or (I-A), as defined in claims 1 to 4, for the prevention and treatment of diseases.

7. Medicament containing at least one compound of formula (I) or (IA) as defined in claims 1 to 4, and inert, non-toxic, pharmaceutically suitable carriers, auxiliaries, solvents, vehicles, emulsifiers and / or dispersants.

8. Use of compounds of formula (T) or (I-A) and medicaments, which are defined in claims 1 to 7, for the prevention and treatment of diseases.

9. Use of compounds of formula (I) or (I-A), as defined in claims 1 to 6, for the manufacture of medicaments.

10. Use of compounds of formula (I) or (IA), as defined in claims 1 to 4, for the manufacture of medicaments for the prevention and treatment of stroke, arteriosclerosis, coronary heart diseases and dyslipidemia, for myocardial infarction prophylaxis and for treatment from restenosis after coronary angioplasty or stenting.

11. A method for the prevention and treatment of diseases, characterized in that compounds of the formula (I) or (I-A), as defined in claims 1 to 4, are allowed to act on living beings.