EP1654227A1

EP1654227A1 - Bicyclic indoline sulfonamide derivatives

Info

Publication number: EP1654227A1
Application number: EP04763344A
Authority: EP
Inventors: Elke Dittrich-Wengenroth; Hilmar Bischoff; Stephan Siegel; Michael Woltering
Original assignee: Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2003-08-02
Filing date: 2004-07-20
Publication date: 2006-05-10
Also published as: WO2005016881A1; CA2534171A1; DE10335449A1; JP2007501195A; US20070117860A1

Abstract

The invention relates to novel bicyclic indoline sulfonamide derivatives of general formula (I), methods for the production thereof, and the use thereof in medicaments, especially as potent PPAR delta agonists for preventing and/or treating cardiovascular diseases, particularly dyslipidemia, arteriosclerosis, and coronary heart diseases.

Description

Bicyclic indoline sulfonamide derivatives

The present application relates to new bicyclic indoline sulfonamide 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 hypertriglyceridemia. ^'

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. Endocrinok 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 can result.

WO 00/23407 discloses PPAR modulators for the treatment of obesity, atherosclerosis and / or diabetes. WO 93/15051 and EP 636 608-A1 describe 1-benzenesulfonyl-1,3-dihydroindol-2-one derivatives as vasopressin and / or oxytocin antagonists for the treatment of various diseases.

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

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-C ₆ ) alkoxy, trifluoromethyl, trifluoromethoxy, (Cι-C ₆ ) alkylsulfonyb (CC ₆ ) alkanoyb (CC ₆ ) -Alkoxy-carbonyb-carboxyb amino, (-C-C ₆ ) -acylamino, mono- and di- (-C-C ₆ ) -alkylamino may be substituted,

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

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

R ^s and R ^{6 are the} same or different and independently of one another represent hydrogen or (-CC ₄ ) - alkyl,

R ^{7 represents} hydrogen or a hydrolyzable group which can be broken down into the corresponding carboxylic acid,

and

n represents the number 1 or 2,

and their salts, solvates and solvates of the salts.

In the context of the invention, in the definition of R ^7, a hydrolyzable group means a group which leads in particular in the body to a conversion of the -C (0) OR ^{7 group} into the corresponding carboxylic acid (R ⁷ = hydrogen). Such groups are exemplary and preferably: benzyb (CC ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyb, each optionally one or more times, identically or differently, by halogen, hydroxyl, amino, (CC ₆ ) alkoxy, Carboxyb (CC ₆ ) alkoxycarbonyb (-C-C ₆ ) alkoxycarbonylamino or (Cι-C ₆ ) alkanoyloxy are substituted, or in particular (C _r C ₄ ) -alky which may be one or more, identical or different, by halogen , Hydroxy, amino, (CC ₄ ) alkoxy, carboxyb (CC ₄ ) alkoxycarbonyl (CC) alkoxycarbonylamino or (C] -C) alkanoyloxy. In the context of the invention, C 1 -C 6 -alkyl and (CC ₄ ) -alkyl stand for a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. A straight-chain or is preferred branched alkyl radical with 1 to 4 carbon atoms. The following may be mentioned as examples and preferably: methyl, ethyl n-propyb isopropyl and tert-butyb

In the context of the invention, (C Cg) cycloalkyl stands for a monocyclic cycloalkyl group with 3 to 8 carbon atoms. Examples and preferably mentioned are: Cyclopropyb Cyclobutyb Cyclopentyl and Cyclohexyb

In the context of the invention, (Cr-) alkoxy and (Cv-CHAlkoxY) stand for a straight-chain or branched alkoxy radical with 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched alkoxy radical with 1 to 4 carbon atoms is preferred called: methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy.

In the context of the invention, (C ₁ -Cg) -alkoxycarbonyl and (-G -alkoxycarbonyl) 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 is preferred with 1 to 4 carbon atoms, and examples which may be mentioned are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl

(-CfiVAlkoxycarbonylamino and (CC ^ -alkoxycarbonylamino) 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. Preferred an alkoxycarbonylamino radical having 1 to 4 carbon atoms, and examples which may be mentioned are: methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino and tert-butoxycarbonylamino.

In the context of the invention, fCq-Cg) -alkanoyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, which carries a double-bonded oxygen atom in the 1 position and is linked via the 1 position. A straight-chain or branched alkanoyl radical having 1 to 4 carbon atoms is preferred. Examples and preferably mentioned are: Formyb Acetyb Propionyb n-Butyryb i-Butyryb Pivaloyl and n-Hexanoyb

In the context of the invention, (Cr-CsValkanoyloxy and (Cr-C balkanoyloxy) stand 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 which Position is linked via a further oxygen atom. An alkanoyloxy radical having 1 to 4 carbon atoms is preferred. Examples and preferably mentioned are: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy, n-hexanoyloxy. Mono- (C ₁ -C _≤ -alkylamino and mono- (C ₁ -C 4) alkylamino are in the context of the invention an amino group having 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, and examples which may be mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

Di- (C ₁ -C _≤) -All / lamino and DIJG-CaVAlkylamino are in the context of the invention an amino group having two identical or different straight-chain or branched alkyl substituents having in each case 1 to 6 or 1 to 4 carbon atoms. Straight-chain or ^'branched dialkylamino radicals are preferably each having 1 to 4 carbon atoms. Examples that may be mentioned are: NN-dimethylamino, N / V-diethylamino, H-ethyl-H-methylamino, N-methyl-H-n-propylamino, TV-isopropyl-Nn-propylamino, N-tert-butyl -H-memylamino, N-ethyl-Nn-pentylamino and Nn- hexyl-H-memylanjJ.no.

(C 1 -C 6 -acylamino 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, for example and preferably the following are mentioned: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.

In the context of the invention, (C Cfi) alkylsulfonyl 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. The following may be mentioned as examples and preferably: methylsulfonyb ethylsulfonyb n-propylsulfonyb isopropylsulfonyb tert.-butylsulfonyb n-pentylsulfonyl and n-hexylsulfonyb

5- to 6-membered heteroaryl with up to 2 identical or different heteroatoms from the series N, O and / or S in the context of the invention represents a monocyclic aromatic heterocycle (heteroaromatics) which has a ring carbon atom or optionally a ring nitrogen atom of the heteroaromatic is linked. Examples which may be mentioned are: Furanyb Pyrrolyb Thieme nyb Pyrazolyb Imidazolyb Thiazolyb Oxazolyb Isoxazolyb Isothiazolyb Pyridyb Pyrimidinyb Pyridazinyb Pyrazinyb are preferably 5- to 6-membered heteroaryl radicals having up to two nitrogen atoms, such as Imidazolyb Pyridyb Pyrimidinyb Pyridazinyb Pyrazinyb

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. 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. 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, for example ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine , Di- or triethanolamine, dicyclohexylamine, dimethylaminoethanob dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.

The compounds according to the invention can also be in the form of their solvates, in particular 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 fluorine, chlorine, cyano, (C _r C ₄ ) alkylb (C 1 -C ₄ ) alkoxy, trifluoromethyl Trifluoromethoxy, methylsulfonyb ^' . Acetyb Propionyb (-C-C ₄ ) -alkoxycarbonyl amino, acetylamino, mono- and di- (-C-C ₄ ) -alkylamino can be substituted, R ² and R ^{3 are the} same or different and independently of one another represent hydrogen or (-C) alkyl or together with the carbon atom to which they are attached form a 5- to 6-membered, spiro-linked cycloalkyl ring,

R ^{4 represents} hydrogen or methyl,

R ⁵ and R ^{6 are the} same or different and are independently hydrogen or methyl,

R ^{7 represents} hydrogen,

and

n stands for the number 1 or 2.

Compounds of the general formula (I) in which

R ^{1 represents} phenyl, which can be substituted one to two times, identically or differently, by substituents selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl and trifluoromethoxy,

R ^{2 represents} methyl,

R ^{3 represents} methyl,

or

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

R ^{4 represents} hydrogen or methyl,

R ⁵ and R ⁶ each represent hydrogen,

R ^{7 represents} hydrogen,

and

n stands for the number 1 or 2.

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 as desired by radical definitions of other combinations, irrespective of the respectively specified combinations of the radicals.

Combinations of two or more of the preferred ranges mentioned above are very particularly preferred.

Compounds of the formula (I-A) are of particular importance

in which

R represents phenyl which is substituted by fluorine, chlorine or trifluoromethyl,

and

n stands for the number 1 or 2.

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 (U)

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

Y represents chlorine or bromine,

initially using methods customary in the literature in compounds of the formula (rQ)

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

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

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

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

R ^{8 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 (V)

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

implements [cf. e.g. W. Hahnfeld, M. Jung, Pharmazie 1994, 49, 18-20; idem, Liebigs Ann. Chem. 1994, 59-64], then the protective group PG according to methods customary in the literature to form compounds of the formula (VI)

in which R> lb τ R> ² , r R> 3 and R each have the meanings given above,

removed again, then with a compound of formula (VII)

in which R> s, R and n each have the meanings given above and

T represents benzyl or (CC ₆ ) alkyl,

in an inert solvent in the presence of a base in compounds of the formula (VIII)

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

transferred, the compounds of the formula (V1TJ) then with acids or bases or, if T is benzyl, also hydrogenolytically to give the corresponding carboxylic acids of the formula (LX)

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

if appropriate, these carboxylic acids (LX) are further modified to give compounds of the formula (I) by known esterification methods, and the resulting compounds of the formula (LX) or (I) are optionally reacted with the corresponding (i) solvents and / or (ii) bases or acids to give their solvates, salts and / or solvates of the salts.

Inert solvents for process step (ITJ) + (IV) - »(V) 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-propanob n-butanol or tert. -Butanob hydrocarbons such as benzene, xylob toluob 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. Toluob dimethylformamide or acetonitrile are preferred.

The usual inorganic or organic bases are suitable as bases for the process step (HI) + (IV) - »(V). These preferably 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 phosphates such as sodium or potassium phosphate, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine. Sodium or potassium carbonate or potassium phosphate are particularly preferred.

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

Suitable palladium catalysts for process step (ITJ) + (TV) - »(V) are preferably palladium (O) - or palladium (ITj compounds which are used preformed, such as, for example, [1,1'-bis (diphenylphosphino) ferrocenyl] palladium (π) chloride, bis (triphenylphosphine) - palladium (π) chloride or tetrakis (triphenylphosphine) palladium (0), or those obtained in situ from a suitable palladium source such as bis (dibenzylidene acetone) palladium (0) and a suitable phosphine ligand 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.

Inert solvents for process step (VI) + (VU) -> (VI-LT) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran , Glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylobotoluene hexane, cyclohexane or petroleum fractions, or other solvents such as nitro methane, ethyl acetate, acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile, N-methylpyrrolidinone or pyridine. It is also possible to use mixtures of the solvents mentioned. Dichloromethane or tetrahydrofuran are preferred.

The usual inorganic or organic bases are suitable as bases for process step (VI) + (VII) - »(VITJ). These preferably 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, ethyldiisopropylamine, N-methylmorpholine or N methylpiperidine. Amine bases such as triethylamine, pyridine or ethyldiisopropylamine are particularly preferred, optionally in the presence of catalytic amounts (approx. 10 mol%) of 4-NN-dimethylaminopyridine or 4-pyrrolidinopyridine.

The base is used here in an amount of 1 to 5, preferably 1 to 2.5 mob based on 1 mol of the compound of the formula (VIT).

The reaction generally takes place in a temperature range from -20 ° C to + 100 ° C, preferably from 0 ° C to +75 ° C. The reaction can be normal, increased or reduced

Pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

Inert solvents for process step (VITI) - »(LX) 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, ethanob n-propanob isopropane n-Butanol or tert-butanob hydrocarbons such as benzene, xylobotoluene hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, acetone, dimethylformamide, dimethyl sulfoxide, acetonitrib N-methylpyrrolidine or water. It is also possible to use mixtures of the solvents mentioned. Alcohols such as methanol or ethanol and mixtures thereof with tetrahydrofuran are preferred.

The usual inorganic bases are suitable as bases for process step (VITJ) - (LX). 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 mob based on 1 mol of the compound of formula (VWL). Suitable acids for process step (NIJJ) - »(LX) 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 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 normal, increased or reduced

Pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

The compounds of the formula (11) are known or can be prepared analogously to processes known from the literature, for example by

in which Y has the meaning given above,

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

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

in the case that R ² and R ³ in (XI) are both not hydrogen, to compounds of the formula (XJI) or in the case that R ³ in (XI) is hydrogen to compounds of the formula (XITJ)

(XU) (XIII)

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

and the compounds of the formula (XII) or (Xiπ) are then reacted using 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-Nickeb reduced [for process steps (X) + (XI) → (XU) → (IT) cf. e.g. PE Maligres, I. Houpis, K. Rossen, A. Molina, b Sager, V. Upadhyay, KM Wells, RA Reamer, JE Lynch, D. Askin, RP Volante, P J. Reider, Tetrahedron 1997, 53, 10983 -10992].

Inert solvents for process step (X) + (XI) → (XU) or (XITJ) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as dioxane, tetrahydrofuran, Glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanob n-propanob iso-propanob n-butanol or tert-butanob or hydrocarbons such as benzene, xylob 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 (XITJ), 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 (XJJ) performed.

The usual inorganic or organic acids are suitable as acids for process step (X) + (XI) → (XU) or (XIII). 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 trichlo- are also suitable. rid or zinc chloride. The acid is used in an amount of 1 to 10 mob based on 1 mol of the compound of formula (X). In the event that R ^{3 is} hydrogen, the reaction is preferably with 1 to 2 moles of zinc chloride to the product (XITJ), and in the event that R ² and R ^{3 are} both not hydrogen, preferably with 2 to 5 moles of trifluoroacetic acid to the product ( XU).

The reaction generally takes place in a temperature range from 0 ° C to + 250 ° C. If R ^{3 is} hydrogen, the reaction is preferably carried out in a temperature range from + 130 ° C to + 200 ° C to the product (XTJI), if R ² and R ^{3 are} both not hydrogen, the reaction is preferred in a temperature range from 0 ° C to + 50 ° C to the product (XU). 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 (XU) or (XUI) -> (U) are boron, aluminum or silicon hydrides, such as, for example, borane, diborane, sodium borohydride, sodium cyano- borohydride, lithium aluminum hydride or triethylsilane, optionally in the presence of an acid or Lewis acid such as, 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 (XUI), preference is given to reduction using sodium cyanoborohydride; in the case of compounds of the formula (XU), sodium borohydride is preferably used.

Suitable solvents for process step (XU) or (XUI) - (U) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanob n-propanob iso-propanob n-butanol or tert-butanob or Hydrocarbons such as benzene, xylobium 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 formula (XUI) 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 (XU), a mixture of methanol and toluene / acetonitrile [from the reaction (X) - (XU), with the addition of 2 to 5 mol of trifluoroacetic acid] in a ratio of 1: 1 to 1:10 used.

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 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 (VU) are known or can be prepared analogously to processes known from the literature, for example by the fact that compounds of the formula (XIV)

in which n has the meaning given above,

initially in a Wittig or Wittig-Horner reaction [see, for example, J. Heterocycl. Chem. 1986, 747; J. Org. Chem. 1991, 6717] or via Zinkorganyle [see, for example, J. Amer. Chem. Soc. 1958, 4360] in compounds of the formula (XV)

in which R ⁵ , n and T each have the meanings given above,

converted, this then in the presence of a suitable catalyst, such as palladium on activated carbon, to compounds of the formula (XVI)

in which R ⁵ , n and T each have the meanings given above,

hydrogenated and finally reacted with chlorosulfonic acid [cf. e.g. P. D. Edwards, R.C. Mauger, K.M. CottreH, F.X. Morris, K.K. Pine, M.A. Sylvester, C.W. Scott, S.T. Furlong, Bioorg. Med. Chem. Lett. 2000, 10, 2291-2294].

The compounds of the formulas (IV), (X), (XI) and (XTV) 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 and 2:

Scheme 1

Scheme 2

The compounds of formula (I) according to the invention have a surprising and valuable pharmacological spectrum of activity and can therefore be used as versatile medicaments. In particular, they are 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 formula (I) 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, dyslipidaemia and high blood pressure 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, aldolate inhibitor, redibrase inhibitor , Anoretics, lipase inhibitors and PPAR-α and / or PPAR-γ agonists can be administered.

The effectiveness of the compounds according to the invention can e.g. Check in vitro using the transactivation assay described in the sample 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 (I), all customary application forms are possible, i.e. i.e. oral, parenteral inhalation, nasal, sublinguab rectal, external as e.g. transdermab or local such as for 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 in a concentration of 0.1 to 100 wt .-%, in particular in particular 0.5 to 90% by weight, preferably 5 to 80% by weight, are present. 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. ethanob glycerol), 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 and dispersants (e.g. polyvinylpyrrolidone) and lubricants (e.g. magnesium sulfate).

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

In the case of oral administration, doses of 0.001 to 5 mg / kg, preferably 0.005 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

Used abbreviations:

CI chemical ionization (for MS)

TLC thin layer chromatography

DCI direct chemical ionization (for MS)

DMAP 4-NN-dimethylaminopyridine

DMF NN-dimethylformamide

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

EI electron impact ionization (for MS)

ESI electrospray ionization (for MS)

Et Ethyb

GC gas chromatography h hour (s)

HPLC high pressure, high performance liquid chromatography min minute (s)

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy

Rf retention index (at DC)

RT room temperature

THF tetrahydrofuran

GC-MS method:

Instrument: Micromass GCT, GC6890; Column: Restek RTX-35MS, 30 x 250 μm x 0.25 μm; constant flow with helium: 0.88 ml / min; Oven: 60 ° C; Inlet: 250 ° C; Gradient: 60 ° C (hold for 0.30 min), 50 ° C / min → 120 ° C, 16 ° C / min → 250 ° C, 30 ° C / min → 300 ° C (hold 1.7 min). Ausfährungsbeispiele:

example 1

[7 - ({3,3-Dimethyb5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indobl-yl} sulfonyl) -b2,3,4-tetrahydro-1-naphthalinyl] acetic acid

Stage a):

5-bromo-3, 3-dimethylindoline

A mixture of 45 ml of toluene / acetonitrile (49: 1) is flushed with argon for 5 minutes and then mixed with 3.00 g (13.4 mmol) of 4-bromophenylhydrazine. Then 3.71 ml (48.1 mmol) of trifluoroacetic acid are slowly added, taking care that the temperature does not exceed 35 ° C. 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 over 100 g of silica gel. First the by-products are eluted with cyclohexane, then the product is eluted with a mixture of cyclohexane / diethyl ether (20: 1). 1.78 g (54% of theory) of the product are obtained as an oil. R _f (petroleum ether / ethyl acetate 5: 1) = 0.47

MS (ESIpos): m / z = 226 [M + H] ⁺

'H NMR (200 MHz, DMSO-d ₆ ): δ = 1.20 (s, 6H), 3.18 (d, 2H), 5.66 (broad s, IH), 6.42 (d, IH), 7.02 (dd, IH ), 7.10 (d, IH).

Level b):

5-bromo-3,3-dimethyl-l- (4-nitrophenylsulfonyl) -2,3-dihydro-7H-indole

17 g (75.18 mmol) of the bromoindoline from stage a), 5.22 g (150.37 mmol) of triethylamine and 0.46 g (3.76 mmol) of DMAP are dissolved in 100 ml of dichloromethane and cooled to 5-10 ° C. A solution of 17.5 g (78.94 mmol) of 4-nitrobenzenesulfonyl chloride in 150 ml of dichloromethane is added dropwise and the mixture is stirred at RT for 16 h. It is washed once with 2 M hydrochloric acid, water and saturated sodium chloride solution and the organic phase is dried over sodium sulfate. After removal of the solvent, 31 g (98% of theory) of the product are obtained as a yellow solid.

MS (CI): m / z = 430 [M + NΗ ₄ ] ⁺

Η NMR (200 MHz, CDC1 ₃ ): δ = 8.32 (d, 2H), 8.0 (d, 2H), 7.51 (d, IH), 7.34 (d, IH), 7.15 (d, IH), 3.66 ( s, 2H), 1.13 (s, 6H).

Stage c):

3,3-dimethyl-1 - (4-nitrophenylsulfonyl) -5 - [4- (trifluoromethyl) phenyl] -2,3-dihydroJH-indole

31 g (75.38 mmol) of the protected bromoindoline from stage b), 21.47 g (113.06 mmol) of 4- (trifluoromethyl) phenylboronic acid and 15.63 g (113.06 mmol) of potassium carbonate are suspended in 500 ml of toluene. Argon is passed through the solution for 30 min and then 1.74 g (1.51 mmol) of tetrakis (triphenylphosphine) palladium (0) are added. The mixture is heated under reflux for 16 h, then cooled and filtered through an approx. 1000 ml column with silica gel 60. Elution is carried out first with approx. 1.5 1 cyclohexane and then with approx. 2 1 dichloromethane. The dichloromethane phase is concentrated. 30 g (84% of theory) of the product are obtained as a yellow solid.

MS (EI): m / z = 475.9 [M] ⁺

'H NMR (200 MHz, CDC1 ₃ ): δ = 8.32 (d, 2H), 8.05 (d, 2H), 7.71 (d, IH), 7.66 (d, 2H), 7.61 (d, 2H), 7.46 (dd, IH), 7.26 (s, IH), 3.73 (s, 2H), 1.21 (s, 6H).

Stage d):

3,3-Dimethyb5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-7H-indole

68 g (142.72 mmol) of the indoline derivative from stage c) are initially introduced together with 25.12 g (0.628 mol) of sodium hydroxide in 300 ml of DMF at RT. 28.92 g (0.314 mol) of thioacetic acid are rapidly added dropwise and the reaction mixture is heated to 45 ° C. for 5 h. 1000 ml of ethyl acetate are added and the mixture is washed twice with sodium carbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated. The residue is filtered through silica gel 60 (1 kg) with cyclohexane / ethyl acetate (7: 1) as the eluent. 27.1 g (61% of theory) of the product are obtained as a light yellow solid.

MS (EI): mz = 292.1 [M] ⁺

Η-NMR (200 MΗz, CDCb): δ = 7.62 (s, 4Η), 7.31 (d, IH), 7.27 (m, 2H), 6.69 (d, IH), 3.39 (s, 2H), 1.36 (s , 6H).

Stage e):

Ethyl 3,4-dihydro-l (2H) -naphthalenetide ethanoate

13 g (40.22 mmol) of sodium ethanolate are placed in a 100 ml round-bottomed flask and 6.7 ml (33.5 mmol) of triethylphosphonoacetate are added dropwise. 10 ml of anhydrous ethanol are added and, after stirring for 5 minutes, 5 g (33.5 ml) of 1-tetralone are slowly added dropwise within 10 minutes. The dark brown solution is heated under reflux for 18 h. The solvent is completely removed and the residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane ethyl acetate 30 + 1 - »7 + 1). The product thus obtained (mixture of the E / Z Isomers), which is still slightly contaminated with 1-tetralone, is hydrogenated in the manner described below without further purification.

Level f):

Ethyl 1,2,3,4-tetrahydro-1-naphthalenyl acetate

4.2 g (19.4 mmol) of the unsaturated ester from stage e) are dissolved in 300 ml of ethanol, 2 g of palladium on activated carbon (10%) are added and the mixture is hydrogenated for 4 h at 3 bar hydrogen pressure. The catalyst is filtered off and the solvent is removed. The residue is fractionally distilled in an oil pump vacuum and the fractions are analyzed by GC-MS. The fraction that passes at 160-170 ° C and about 1 mbar contains 99% of the desired product.

Yield: 0.7 g (17% of theory)

GC-MS (CI): mz = 219 [M + H] ⁺

'H-NMR (200 MHz, DMSO-d ₆ ): δ = 7.18-6.99 (m, 4H), 4.09 (q, 2H), 3.20 (m, IH), 2.75-2.65 (m, 2H), 2.53- 2.40 (m, 2H), 1.85-1.54 (m, 4H), 1.89 (t, 3H).

Level ε):

Ethyl [7- (chlorosulfonyl) b2,3,4-tetrahydro-l-naphthalinyl] acetate

393 mg (1,787 mmol) of the tetrahydronaphthalene derivative from stage f) are placed in 13 ml of trichloromethane at 0 ° C. and 831 mg (7.13 mmol) of chlorosulfonic acid are added dropwise. The mixture is stirred at RT for 3 h, then ice is added and the mixture is extracted three times with ethyl acetate. The united organic Phases are dried over magnesium sulfate and the solvent is completely removed. The crude product thus obtained is used in the next stage without further purification.

Yield: 292 mg (52% of theory)

MS (DCL NH ₃ ): m / z = 333 [M + NH ₃ + NH ₄ ] ⁺

'H NMR (300 MHz, CDC1 ₃ ): δ = 7.69 (s, IH), 7.60 (d, IH), 7.12 (d, IH), 4.14 (q, 2H), 3.33-3.24 (m, IH) , 2.89-2.48 (m, 4H), 1.90-1.65 (m, 4H), 1.24 (t, 3H).

Level h):

Ethyl [7 - ({3,3-dimethyb5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indobl-yl} sulfonyl) -b2,3,4-tetrahydro-1-naphthalinyl] acetate

94 mg (0.324 mmol) of the indoline derivative from stage d) are placed in 3 ml of dichloromethane. 0.052 ml (0.65 mmol) of triethylamine and 4 mg (0.032 mmol) of DMAP are added. A solution of 113 mg (0.357 mmol) of the sulfonyl chloride from stage g) in 2 ml of dichloromethane is slowly added dropwise at RT and the mixture is stirred at RT for 5 h. The solvent is completely removed and the residue is purified by preparative HPLC. The product is isolated as a yellow solid.

Yield: 129 mg (63% of theory)

MS (DCI, NΗ ₃ ): m / z = 589 [M + NH ₄ ] ⁺

'H NMR (500 MHz, CDC1 ₃ ): δ = 7.70 (d, IH), 7.66-7.61 (m, 4H), 7.56 (d, IH), 7.45 (d, IH), 7.23 (s, 2H) , 7.15 (d, IH), 4.13 (m, 2H), 3.68 (q, 2H), 3.34 (m, IH), 2.82-2.72 (m, 2H), 2.54-2.41 (m, 2H), 1.93-1.62 (m, 4H), 1.24 (t, 3H), 1.23 (s, 3H), 1.17 (s, 3H).

Stage i):

[7 - ({3,3-Dimethyb5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-mdol-l-yl} sulfonyl) -b2,3,4-tetrahydro-1-naphthalinyl] acetic acid

100 mg (0.175 mmol) of the ester derivative from stage h) are dissolved in 1 ml of THF and 1 ml of methanol and then a solution of 8.4 mg (0.35 mmol) of lithium hydroxide in 0.4 ml of water is added. The mixture is stirred at 50 ° C. for 1 h and then the cooled solution is adjusted to pH 5 with 1 M hydrochloric acid. The mixture is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulfate and the solvent is removed completely. The residue is purified by means of preparative HPLC.

Yield: 45 mg (38% of theory)

MS (DCL NH ₃ ): m / z = 561 [M + NH ₄ ] ⁺

Η NMR (300 MHz, DMSO-d ₆ ): δ = 12.27 (broad s, IH), 7.83 (d, 2H), 7.75 (d, 2H), 7.72 (d, IH), 7.61-7.50 (m, 4H), 7.26 (d, IH), 3.71 (s, 2H), 3.22 (m, IH), 2.73 (dd, 2H), 2.57-2.34 (m, 2H), 1.88-1.53 (m, 4H), 1.15 (s, 6H).

Example 2

[6 - ({3,3-Dimethyb5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indobl-yl} sulfonyl) -2,3-dihydro-1H-inden-1-ybiacetic acid

Stage a):

Ethyl 2,3-dihydro-1H-indene-1-ylidene ethanoate

19.9 g (88.9 mmol) of triethylphosphonoacetate in 30 ml of THF are placed in a 100 ml round-bottomed flask and 3.9 g (97.9 mmol) of sodium hydride (60% in mineral oil) are added in portions. The temperature should not rise above 30 ° C. After the addition, the mixture is stirred for 10 min and then 4 g (29J mmol) of 1-indanone are added. The solution is heated under reflux for 18 h. After cooling, water is added and extracted three times with ethyl acetate. The combined organic phases are washed once with sodium chloride solution and then dried over sodium sulfate. After removing the solvent, the crude product is chromatographed on silica gel (mobile phase: cyclohexane / ethyl acetate 1 + 0 -> 10 + 1). 5.53 g (70% of theory) of the product (as a mixture of the E / Z isomers) are obtained, which according to GC-MS is approx. 76% pure.

MS (DCI, NH ₃ ): m / z = 220 [M + NH ₄ ] ⁺ .

Level b):

Ethyl 2, 3 -dihydro-1H-indene-1-ethyl acetate

Analogously to the procedure for Example 1, stage f), 1.88 g (9.34 mmol) of the unsaturated ester from stage a) are hydrogenated on activated carbon in the presence of 10% palladium.

Yield: 1.84 g (90% of theory)

GC-MS (CI): m / z = 222 [M + NΗ ₄ ] ⁺

'H-NMR (200 MHz, CDC1 ₃ ): δ = 7.35-7.09 (m, 4H), 4.18 (q, 2H), 3.59 (m, IH), 3.0-2J0 (, 3H), 2.50-2.30 (, 2H), 1.85-1.65 (, IH), 1.28 (t, 3H). Stage c):

Ethyl [6- (chlorosulfonyl) -2,3-dihydro-lH-inden-l-yl] acetate

1.4 g (12.24 mmol) of chlorosulfonic acid are placed in 15 ml of chloroform and heated to 70 ° C. A solution of 500 mg (2.45 mmol) of the indane derivative from stage b) is added dropwise at this temperature and the mixture is stirred for 30 min. After cooling, water is added and extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulfate. After removing the solvent, the crude product is used for sulfonamide formation without further purification.

Yield: 437 mg (59% of theory)

MS (DCI, NΗ ₃ ): m / z = 320 [M + NH ₄ ] ⁺ .

Stage d):

Ethyl [6 - ({3 ₎ 3-dimethyb5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indobl-yl} sulfonyl) -2,3-dihydro-lH-inden-1-yl acetate

44 mg (0.15 mmol) of the indoline derivative from Example 1, step d) are dissolved in 2 ml of anhydrous dichloromethane and 0.024 ml (0.3 mmol) of triethylamine and 1.8 mg (0.015 mmol) of DMAP are added. A solution of 50 mg (0.165 mmol) of the sulfonyl chloride from stage c) in 2 ml of dichloromethane is added dropwise and the mixture is stirred at RT for 24 h. Water and ethyl acetate are added and the aqueous phase is extracted three more times with ethyl acetate. The United organic phases are dried over sodium sulfate and the solvent is removed. The residue is purified by means of preparative HPLC.

Yield: 17 mg (20% of theory)

MS (ESIpos): m z = 558 [M + H]

Η NMR (500 MHz, CDC1 ₃ ): δ = 7.73-7.59 (m, 7H), 7.44 (d, IH), 7.32-7.20 (m, 2H), 4.15 (q, 2H), 3.69 (s, 2H ), 3.59 (m, IH), 3.02-2.82 (m, 2H), 2J0 (dd, IH), 2.45-2.33 (m, 2H), 1.76 (m, IH), 1.26 (t, 3H), 1.21 ( s, 3H), 1.20 (s, 3H).

Stage e):

[6 - ({3,3-Dimethyb5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indobl-yl} sulfonyl) -2,3-dihydro-lH-inden-1-yl] acetic acid

16 mg (0.029 mmol) of the ester derivative from stage d) are dissolved in 0.5 ml TΗF and 0.5 ml methanol and then a solution of 2 mg (0.08 mmol) lithium hydroxide in 0.1 ml water is added. The mixture is stirred at 50 ° C. for 1 h and then the cooled solution is adjusted to pH 5 with 1 M hydrochloric acid. The mixture is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulfate and the solvent is removed completely.

Yield: 14 mg (91% of theory)

MS (DCL NΗ ₃ ): m / z = 547 [M + NH ₄ ] ⁺

'H NMR (300 MHz, CDC1 ₃ ): δ = 7.74-7.57 (m, 7H), 7.45 (dd, IH), 7.33-7.21 (m, 2H), 3.70 (d, 2H), 3.62 (m, IH), 3.0-2.88 (m, 2H), 2.73 (dd, IH), 2.52-2.40 (m, 2H), 1.81 (m, IH), 1.22 (s, 3H), 1.18 (s, 3H). Example 3

[5 - ({3,3-Dimethyl-5- [4- (1xifluoromethyl) phenyl] -2,3-dihydro-1H-indobl-yl} sulfonyl) -2,3-dihydro-1H-inden-2-yl ]acetic acid

Stage a):

Ethyl b3-dihydro-2H-inden-2-ylidene acetate

31.2 g (136.2 mmol) of triethylphosphonoacetate in 225 ml TΗF are placed in a 100 ml round-bottomed flask and 5.99 g (149.8 mmol) of sodium hydride (60% in mineral oil) are added in portions. The temperature should not rise above 30 ° C. After the addition, the mixture is stirred for 10 min and then 6 g (45.4 mmol) of 2-indanone are added. The solution is heated under reflux for 18 h. After cooling, water is added and extracted three times with ethyl acetate. The combined organic phases are washed once with sodium chloride solution and then dried over sodium sulfate. After the solvent has been removed, the crude product is chromatographed on silica gel (mobile phase: cyclohexane / ethyl acetate 10 + 1).

Yield: 2.83 g (24% of theory)

MS (EIpos): m / z = 202 [M] ⁺

'Η NMR (300 MΗz, CDC1 ₃ ): δ = 7.39 (d, 1Η), 7.30 (d, 1Η), 7.22 (m, 1Η), 7.14 (dt, 1Η), 6.69 (s, 1Η), 4.17 (q, 2Η), 3.51 (s, 2H), 3.45 (s, 2H), 1.28 (t, 3H). Level b):

Ethyl 2,3-dihydro-1H-inden-2-ylacetate

Analogously to the procedure for Example 1, stage f), 2.83 g (14 mmol) of the unsaturated ester from stage a) are hydrogenated on activated carbon in the presence of 10% palladium.

Yield: 2.66 g (93% of theory)

MS (EIpos): m / z = 204 [M] ⁺

Η-NMR (300 MΗz, CDC1 ₃ ): δ = 7.22-7.09 (m, 4Η), 4.15 (q, 2H), 3.13 (dd, 2H), 2.89 (quin, IH), 2.65 (dd, 2H), 2.48 (d, 2H), 1.27 (t, 3H).

Stage c):

Ethyl [5- (chlorosulfonyl) -2,3-dihydro-1H-inden-2-yl] acetate

2.65 g (12.97 mmol) of the indane derivative from stage b) are initially introduced into trichloromethane at 0 ° C. and 15.12 g (0.137 mol) of chlorosulfonic acid are slowly added dropwise. The mixture is stirred at RT for 2 h and the reaction mixture is poured onto ice. The mixture is extracted three times with ethyl acetate and the combined organic phases are dried over sodium sulfate. After removing the solvent, the crude product is used for sulfonamide formation without further purification.

Yield: 3.56 g (55% of theory)

MS (DCb NΗ ₃ ): m / z = 320 [M + NH ₄ ] ⁺

Η NMR (300 MHz, CDC1 ₃ ): δ = 7.22-7.09 (m, 3H), 4.15 (q, 2H), 3.13 (dd, 2H), 2.89 (quin, IH), 2.65 (dd, 2H), 2.48 (d, 2H), 1.27 (t, 3H). Stage d):

Ethyl [5 - ({3,3-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indobl-yl} sulfonyl) -2,3-dihydro-lH-inden-2- yl] acetate

Analogously to the procedure for Example 2, stage d), 150 mg (0.515 mmol) of the indoline derivative from Example 1, stage d) are converted into 120 mg (40% of theory) by reaction with 311 mg (1.03 mmol) of the sulfonyl chloride from stage c) . Th.) Of the title compound.

MS (DCI, NΗ ₃ ): m / z = 575 [M + NH ₄

Η NMR (300 MHz, CDC1 ₃ ): δ = 7.72-7.58 (m, 7H), 7.43 (dd, IH), 7.28-7.22 (m, 2H), 4.12 (q, 2H), 3.70 (s, 2H ), 3.15 (dd, 2H), 2.90 (quin, IH), 2.66 (dd, 2H), 2.45 (d, 2H), 1.26 (s, 3H), 1.25 (s, 3H), 1.23 (t, 3H) ,

Stage e):

[5 - ({3,3-Dimethyb5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-lH-indobl-yl} sulfonyl) -2,3-dihydro-lH-inden-2-yl] acetic acid

100 mg (0.179 mmol) of the ester derivative from stage d) are dissolved in 5 ml of TΗF and 5 ml of methanol and then a solution of 9 mg (0.359 mmol) of lithium hydroxide in 1 ml of water is added. The mixture is stirred at 50 ° C. for 16 h and then the cooled solution is adjusted to pH 5 with 2 M hydrochloric acid. The solvent is removed completely and the residue is purified by preparative HPLC. Yield: 90 mg (95% of theory)

'H NMR (300 MHz, DMSO-d ₆ ): δ = 12.06 (broad s, IH), 7.85 (d, 2H), 7J6 (d. 2H), 7J2 (s, IH), 7.66-7.52 (m , 4H), 7.39 (d, IH), 3.71 (s, 2H), 3.09 (m, 2H), 2.77-2.59 (m, 3H), 2.37 (d, 2H), 1.99 (s, 6H).

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 different endogenous nuclear receptors which may complicate an unambiguous interpretation of the results, an established chimera system is used in which the ligand-binding domain ^"of the human PPAR delta 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 thymidine 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 (GTBCO) supplemented with 2.5% fetal calf serum and 1% penicillin / streptomycin (GEBCO), at a cell density ^'of from 2 x 10 ³ cells per well in a 384 well plate (Greiner) is 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 _S o values are calculated with the help of the computer program GraphPad PRISM (version 3.02). In this test, examples 1-3 show EC ₅₀ values in a range from 10 to 100 nM.

Example B

Test descriptions for the detection 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 ob, affect ob 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).

Human mouse ApoAl is sandwiched by ELISA using a polyclonal anti-human ApoAl and a monoclonal anti-human ApoAl antibody (Biode- sign Internationab USA). The quantification is carried out by UV photometry (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 with Student's t-test after checking the variances 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.

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

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 compressed with a conventional tablet press (tablet format see above). A pressing force of 15 kN is used as a guideline for the pressing.

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 connection according to the invention has completely dissolved.

Claims

claims

1. 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, which in turn can be substituted by hydroxy, (CC ₆ ) -alkoxy, trifluoromethyl, trifluoromethoxy, (Cι-C ₆ ) -alkylsulfonyl, (CC ₆ ) - alkanoyb (CC ₆ ) -alkoxycarbonyl carboxyb amino, (Cι-C ₆ ) - Acylamino, mono- and di- (CC ₆ ) -alkylamino can be substituted,

R ² and R ^{3 are the} same or different and independently of one another represent hydrogen or (C] -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 (C, -C ₄ ) -alkyl,

R ⁵ and R ^{6 are the} same or different and independently of one another represent hydrogen or (-CC ₄ ) -alkyl,

R ^{7 represents} hydrogen or a hydrolyzable group which can be broken down to the corresponding carboxylic acid and represents the number 1 or 2, and the pharmaceutically acceptable salts, solvates and solvates thereof.

2. Compounds of general formula (I) according to claim 1, in which R ^{1 represents} phenyl, the one or two, identical or different, by substituents selected from the group fluorine, chlorine, cyano, (CC ₄ ) alkylb (C _r C ₄ ) alkoxy, trifluoromethyl trifluoromethoxy, methylsulfonyb acetyb Propionyb (- C) -alkoxycarbonyl amino, acetylamino, mono- and di- (CC) -alkylamino can be substituted,

R ² and R ^{3 are} identical or different and independently of one another represent hydrogen or (Cj-O-alkyl or together with the carbon atom to which they are attached form a 5- to 6-membered, spiro-linked cycloalkyl ring,

R ^{4 represents} hydrogen or methyl,

R ⁵ and R ^{6 are the} same or different and independently represent hydrogen or methyl,

R ^{7 represents} hydrogen,

and

n stands for the number 1 or 2.

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

R ^{1 represents} phenyl, which can be substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl and trifluoromethoxy,

R ^{2 represents} methyl,

R ^{3 represents} methyl,

or

R ^{4 represents} hydrogen or methyl,

R ⁵ and R ⁶ each represent hydrogen,

R ^{7 represents} hydrogen, and n represents the number 1 or 2.

4. Compounds of formula (I-A)

in which

R represents phenyl which is substituted by fluorine, chlorine or trifluoromethyl and represents the number 1 or 2.

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 (U)

in which R, R and R each have the meanings given in claim 1 and

Y represents chlorine or bromine, initially by methods customary in the literature, in compounds of the formula (UJ)

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

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

in which R ^{1 has} the meaning given in claim 1 and

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

- then, using methods customary in the literature, the protective group PG to give compounds of the formula (VI)

in which R, R, R and R each have the meanings given in claim 1,

removed again, then with a compound of formula (VU)

in which R, R and n each have the meanings given in claim 1 and

T represents benzyl or (CC ₆ ) alkyl,

in an inert solvent in the presence of a base in compounds of the formula

(Vm)

in which n, T, R ¹ , R ² , R ³ , R ⁴ , R and R ^δ each have the meanings given in claim 1,

transferred, the compounds of the formula (VUI) then with acids or bases or, if T is benzyl, also hydrogenolytically to the corresponding carboxylic acids of the formula (LX) in which n, R ¹ , R ² , R ³ , R ⁴ , R and R each have the meanings given in claim 1, optionally converting these carboxylic acids (LX) further by known methods of esterification to give compounds of the formula (I ) modified, and the resulting compounds of formula (LX) or (I) optionally reacted with the corresponding (i) solvents and / or (ii) bases or acids to give 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 (I-A) 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 (I) 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.