KR20050023388A - Indolin phenylsulfonamide derivatives - Google Patents

Abstract

The present invention provides novel substituted indolin phenylsulfonamide derivatives, methods for their preparation and their medicaments, in particular as PPAR-delta-active compounds effective for the treatment and / or prevention of cardiovascular diseases, in particular dyslipidemia and coronary heart disease. It is about.

Description

Indolin Phenylsulfonamide Derivatives {INDOLIN PHENYLSULFONAMIDE DERIVATIVES}

The present invention provides novel substituted indolin phenylsulfonamide derivatives, methods for their preparation and their medicaments, in particular PPAR-delta-activity, which is effective in the treatment and / or prevention of cardiovascular diseases, in particular dyslipidemia, arteriosclerosis and coronary heart disease. It relates to the use as a compound.

Despite many successful treatment regimens, coronary heart disease (CHD) remains a serious public health problem. Treatment with statins that inhibit HMG-CoA reductase has very successfully lowered LDL cholesterol plasma levels, significantly reducing the risk of death in patients. However, conviction of treatment methods in the treatment regimens of patients with undesirable HDL / LDL cholesterol ratios and / or hypertriglyceridemia is still not possible.

To date, fibrate is the only treatment therapy of choice for patients in these risk groups. It acts as a weak agent of peroxisome-prolifer-active receptor (PPAR) -alpha (Nature 1990, 347, 645-50). A disadvantage of the fibrates found to date is that their interaction with receptors is weak, requiring large daily doses and thereby having significant side effects.

For peroxide-prolifer-active receptor (PPAR) -delta (Mol. Endocrinol. 1992, 6, 1634-41), the first pharmacological finding in animal models is that the potent PPAR-delta-agonist is HDL / LDL cholesterol It also shows that it is possible to improve in rain and hypertriglyceridemia.

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.

It is an object of the present invention to provide novel compounds suitable for use as PPAR-delta modulators.

It has been found that the compounds of formula (I) below, and their pharmaceutically acceptable salts, solvates and solvates of the salts can be used for pharmacological action, or as a medicament or to prepare a pharmaceutical formulation.

Wherein A represents a CR ¹¹ group wherein R ¹¹ represents hydrogen or (C ₁ -C ₄ ) -alkyl or N

X represents O, S or CH ₂ ,

R ¹ represents (C ₆ -C ₁₀ ) -aryl or 5- to 10-membered heteroaryl having up to 3 heteroatoms from the group consisting of N, O and S wherein the groups are halogen, cyano, nitro, (C ₁ -C ₆ ) -alkyl (which may be substituted by hydroxyl in part thereof), (C ₁ -C ₆ ) -alkoxy, phenoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, (C ₂ -C ₆ ) -alkenyl, phenyl, benzyl, (C ₁ -C ₆ ) -alkylthio, (C ₁ -C ₆ ) -alkylsulfonyl, (C ₁ -C ₆ ) -alkanoyl, (C ₁ -C ₆ ) -alkoxycarbonyl, carboxyl, amino, (C ₁ -C ₆ ) -acylamino, mono- and di- (C ₁ -C ₆ ) -alkylamino the same or different substituents selected from the group May be substituted with a single to three in each part thereof; and 5- or 6-membered heterocyclyl having 2 or less heteroatoms from the group consisting of N, O and S, or a group represented by the following structural formula And,

R ² and R ³ are the same or different and each independently represent hydrogen or (C ₁ -C ₆ ) -alkyl or together with the carbon atom to which they are attached form a 3- to 7-membered spiro-bonded cycloalkyl ring and,

R ⁴ represents hydrogen or (C ₁ -C ₆ ) -alkyl,

R ⁵ represents hydrogen or (C ₁ -C ₆ ) -alkyl,

R ⁶ represents hydrogen or (C ₁ -C ₆ ) -alkyl,

R ⁷ represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy or halogen,

R ⁸ and R ⁹ are the same or different and each independently represent hydrogen or (C ₁ -C ₄ ) -alkyl,

R ¹⁰ represents hydrogen or a hydrolyzable group which can be decomposed to the corresponding carboxylic acid.

In the present invention, it means a group of the hydrolyzable group refers to in the definition of R ^10, especially to be converted in the body to the -C (O) carboxylic acid (R ¹⁰ = hydrogen) corresponding to the group OR ^10. Such groups are, by way of example, preferably benzyl, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₈ ) -cycloalkyl, which in each case are halogen, hydroxyl, amino, (C _1- From the group consisting of C ₆ ) -alkoxy, carboxyl, (C ₁ -C ₆ ) -alkoxycarbonyl, (C ₁ -C ₆ ) -alkoxycarbonylamino or (C ₁ -C ₆ ) -alkanoyloxy Optionally mono- or polysubstituted with the same or different substituents, in particular halogen, hydroxyl, amino, (C ₁ -C ₄ ) -alkoxy, carboxyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C _1- C ₄₎ - alkoxy-carbonyl or amino (C ₁ -C ₄₎ - alkyl - the same or by different substituents single arbitrarily from the group consisting of alkanoyloxy-substituted, or that multiple (C ₁ -C _4).

In the present invention, (C ₁ -C ₆ ) -alkyl and (C ₁ -C ₄ ) -alkyl represent straight or branched alkyl groups having 1 to 6 and 1 to 4 carbon atoms, respectively. Preferred are straight chain or branched alkyl groups having 1 to 4 carbon atoms. The following groups may preferably be mentioned by way of example: methyl, ethyl, n-propyl, isopropyl and t-butyl.

In the present invention, (C ₂ -C ₆ ) -alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms. Preferred are straight chain or branched alkenyl groups having 2 to 4 carbon atoms. The following groups may be mentioned preferably by way of example: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.

In the present invention, (C ₃ -C ₈ ) -cycloalkyl denotes a monocyclic cycloalkyl group having 3 to 8 carbon atoms. The following groups may preferably be mentioned by way of example: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the present invention, (C ₆ -C ₁₀ ) -aryl preferably represents an aromatic group having 6 to 10 carbon atoms. Preferred aryl groups are phenyl and naphthyl.

In the present invention, (C ₁ -C ₆ ) -alkoxy and (C ₁ -C ₄ ) -alkoxy represent straight or branched alkoxy groups having 1 to 6 and 1 to 4 carbon atoms, respectively. Preferred are straight chain or branched alkoxy groups having 1 to 4 carbon atoms. The following groups may be mentioned preferably by way of example: methoxy, ethoxy, n-propoxy, isopropoxy and t-butoxy.

In the present invention, (C ₁ -C ₆ ) -alkoxycarbonyl and (C ₁ -C ₄ ) -alkoxycarbonyl are straight chains bonded through a carbonyl group having 1 to 6 and 1 to 4 carbon atoms, respectively. Or a branched alkoxy group. Preferred are straight chain or branched alkoxycarbonyl groups having 1 to 4 carbon atoms. The following groups may be mentioned preferably by way of example: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.

In the present invention, the (C ₁ -C ₆ ) -alkoxycarbonylamino and the (C ₁ -C ₄ ) -alkoxycarbonylamino each have 1 to 6 and 1 to 4 carbon atoms in the alkoxy group, a carbonyl group Denotes an amino group having a straight or branched alkoxycarbonyl substituent bonded through. Preference is given to alkoxycarbonylamino groups having 1 to 4 carbon atoms. The following groups may preferably be mentioned by way of example: methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino and t-butoxycarbonylamino.

In the present invention, (C ₁ -C ₆ ) -alkanoyl refers to a straight or branched alkyl group having 1 to 6 carbon atoms bonded through 1 position with an oxygen atom double bonded at 1 position. Preferred are straight chain or branched alkanoyl groups having 1 to 4 carbon atoms. The following groups may be mentioned preferably by way of example: formyl, acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl and n-hexanoyl.

In the present invention, (C ₁ -C ₆ ) -alkanoyloxy and (C ₁ -C ₄ ) -alkanoyloxy are each double bonded to one position with 1 to 6 and 1 to 4 carbon atoms, respectively. A straight or branched alkyl group having an oxygen atom and bonded via an additional oxygen atom at position 1; Preference is given to alkanoyloxy groups having 1 to 4 carbon atoms. The following groups may preferably be mentioned by way of example: acetoxy, propionoxy, n-butyoxy, i-butyoxy, pivaloyloxy, n-hexanoyloxy.

In the present invention, mono- (C ₁ -C ₆ ) -alkylamino and mono- (C ₁ -C ₄ ) -alkylamino are linear or branched alkyl having 1 to 6 and 1 to 4 carbon atoms, respectively. The amino group which has a substituent is shown. Preferred are straight chain or branched monoalkylamino groups having 1 to 4 carbon atoms. The following groups may preferably be mentioned by way of example: methylamino, ethylamino, n-propylamino, isopropylamino and t-butylamino.

In the present invention, di- (C ₁ -C ₆ ) -alkylamino and di- (C ₁ -C ₄ ) -alkylamino are in each case 2 having 1 to 6 and 1 to 4 carbon atoms, respectively. Amino groups having the same or different straight or branched alkyl substituents. In each case a straight or branched dialkylamino group having 1 to 4 carbon atoms is preferred. The following groups may be mentioned preferably by way of example: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl- Nn-propylamino, Nt-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

In the present invention, (C ₁ -C ₆ ) -acylamino refers to an amino group having straight or branched alkanoyl substituents bonded via a carbonyl group having 1 to 6 carbon atoms. Preference is given to acylamino groups having one or two carbon atoms. The following groups may preferably be mentioned by way of example: formamido, acetamido, propionamido, n-butyramido and pivalolamido.

In the present invention, (C ₁ -C ₆ ) -alkylthio refers to a straight or branched alkylthio group having 1 to 6 carbon atoms. Preferred are straight chain or branched alkylthio groups having 1 to 4 carbon atoms. The following groups may be mentioned preferably by way of example: methylthio, ethylthio, n-propylthio, isopropylthio, t-butylthio, n-pentylthio and n-hexylthio.

In the present invention, (C ₁ -C ₆ ) -alkylsulfonyl refers to a straight or branched alkylsulfonyl group having 1 to 6 carbon atoms. Preference is given to straight or branched alkylsulfonyl groups having 1 to 4 carbon atoms. The following groups may be mentioned preferably by way of example: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, t-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.

In the present invention, 5- to 10-membered and 5- or 6-membered heteroaryl having up to 3 or up to 2 identical or different heteroatoms from the group consisting of N, O and S, respectively, are suitable via ring carbon atoms or If present, mono- or optionally bicyclic aromatic heterocycles (heteroaromatics) bonded via heteroaromatic ring nitrogen atoms. Examples that may be mentioned are furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl , Benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl. Preference is given to 5- or 6-membered heteroaryl groups having up to 2 nitrogen atoms, for example imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like.

In the present invention, a 5- or 6-membered heterocyclyl having 2 or less heteroatoms from the group consisting of N, O and S is a saturated heterocyclic ring bonded through a ring carbon atom or, if appropriate, through a heterocyclic ring nitrogen atom. Indicates. The following groups may be mentioned preferably by way of example: tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.

In the present invention, halogen includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.

Depending on the substitution pattern, the compounds according to the invention may exist in stereoisomeric forms, which are similar and enantiomers (enantiomers) or dissimilar and enantiomers (diastereomers). The present invention relates to both the enantiomers or diastereomers and their respective mixtures. Racemic forms, such as diastereomers, can be separated into homogeneous components into stereoisomers in known manner.

In addition, certain compounds may exist in tautomeric forms. It is known to those skilled in the art and such compounds are also within the scope of the present invention.

The compounds according to the invention may exist as salts. In the present invention, physiologically acceptable salts are preferred.

Physiologically acceptable salts may be salts of 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 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, Preference is given to salts with organic carboxylic acids or sulfonic acids, such as benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically acceptable salts may also be salts of the compounds according to the invention with bases such as, for example, metal salts or ammonium salts. Preferred examples include alkali metal salts (eg sodium or potassium salts), alkaline earth metal salts (eg magnesium salts or calcium salts), and ethylamine, di- or triethylamine, ethyldi, for example. Isopropylamine, monoethanolamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-ephenamine, methylpiperidine, arginine And ammonium salts derived from ammonia or organic amines such as lysine, ethylenediamine or 2-phenylethylamine.

In addition, the compounds according to the invention may exist in the form of their solvates, in particular their hydrates.

In the compound of formula (I), A represents a CR ¹¹ group, wherein R ¹¹ represents hydrogen or methyl, or represents N,

X represents O or S,

R ¹ represents phenyl or 5- or 6-membered heteroaryl having up to 2 heteroatoms from the group consisting of N, O and S, wherein the groups are fluorine, chlorine, cyano, (C ₁ -C ₄ ) -Alkyl, (C ₁ -C ₄ ) -alkoxy, phenoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, vinyl, phenyl, benzyl, methylthio, methylsulfonyl, acetyl, propionyl, (C ₁ -C ₄₎ - alkoxycarbonyl, amino, acetylamino, mono- and di - (C ₁ -C ₄₎ - in a single or parts thereof by the same or different substituents selected from the group consisting of alkylamino, each of which Can be substituted,

R ² and R ³ are the same or different and each independently represent hydrogen or (C ₁ -C ₄ ) -alkyl or together with the carbon atom to which they are attached form a 5- or 6-membered spiro-bonded cycloalkyl ring and,

R ⁴ represents hydrogen or methyl,

R ⁵ represents hydrogen, methyl or ethyl,

R ⁶ represents hydrogen or methyl,

R ⁷ represents hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, fluorine or chlorine,

R ⁸ and R ⁹ are the same or different and each independently represent hydrogen or methyl,

R ¹⁰ preferably represents hydrogen.

In the compound of formula (I), A represents CH or N,

X represents O,

R ¹ represents phenyl or is substituted by the same or different substituents selected from the group consisting of fluorine, chlorine, methyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, methylthio, amino and dimethylamino Each of these represents a single or pyridyl which may be substituted,

R ² represents hydrogen or methyl and R ³ represents methyl, isopropyl or tert-butyl, or R ² and R ³ together with the carbon atom to which they are attached form a spiro-bonded cyclohexane ring,

R ⁴ represents hydrogen or methyl,

R ⁵ represents hydrogen, methyl or ethyl,

R ⁶ represents hydrogen or methyl,

R ⁷ represents methyl,

R ⁸ and R ⁹ each represent hydrogen,

R ¹⁰ preferably represents hydrogen.

The general or preferred groups listed above apply to both the final product of the formula (I) and the corresponding starting materials and intermediates necessary for preparation in each corresponding case.

The definition of an individual group given in each combination or preferred combination of groups is also replaced by any group definition in other combinations independently of each given combination of groups.

In particular, compounds of formula (I-A) are important.

Wherein R ² represents hydrogen and R ³ represents methyl, isopropyl or tert-butyl, or R ² and R ³ both represent methyl or a spiro-bonded cyclohexane ring together with the carbon atom to which they are attached Form the

A, R ¹ , R ⁴ , R ⁵ and R ⁶ are each as defined above.

In addition, the inventors have discovered a process for the preparation of the compounds of formula (I) according to the invention, wherein the process of the compounds of formula (IV) is carried out using the compounds of formula (II) in Initial conversion to a compound,

(Wherein A, X, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each as defined above,

T represents benzyl or (C ₁ -C ₆ ) -alkyl,

Y represents chlorine or bromine)

Then reacting these compounds by coupling reaction with a compound of formula V in an inert solvent in the presence of a suitable palladium catalyst and base to give a compound of formula I-B,

Wherein R ¹ is as defined above,

R ¹² represents hydrogen or methyl or the two groups together form —CH ₂ CH ₂ — or —C (CH ₃ ) ₂ —C (CH ₃ ) ₂ — bridge)

Wherein A, T, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each as defined above.

[See, eg, W. Hahnfeld, M. Jung, Pharmazie 1994 , 49, 18-20; idem, Liebigs Ann. Chem. 1994 , 59-64].

Then reacting the compound (I-B) with an acid or a base or by hydrogenolysis when T represents benzyl to obtain the corresponding carboxylic acid of formula (I-C), and

Wherein A, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each as defined above.

The carboxylic acid (I-C), if appropriate, is further modified by known esterification methods to give the compound of formula (I).

In the reaction sequence described above, the steps of the coupling reaction [reference (IV) + (V) → (IB)] and the ester formation cleavage [reference (IB) → (IC)] are optionally performed in reverse order. It may be. In the coupling reaction, basic ester formation cleavage may be carried out in the same reactor.

Inert solvents in the process steps from (II) + (III) to (IV) are, for example, halogenated hydrocarbons (eg, dichloromethane, trichloroethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2). Dichloroethane or trichloroethylene), ethers (such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether), hydrocarbons (such as benzene, xylene, toluene, hexane, cyclohexane or Mineral oil fractions) or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile, N-methylpyrrolidinone or pyridine. Mixtures of the solvents mentioned may also be used. Preference is given to dichloromethane or tetrahydrofuran.

Suitable bases for the process steps from (II) + (III) to (IV) are conventional inorganic or organic bases. They are preferably alkali metal hydroxides (eg lithium hydroxide, sodium hydroxide or potassium hydroxide), alkali metal carbonates or alkaline earth metals (eg sodium carbonate, potassium carbonate or calcium carbonate), alkali metal hydrides (eg sodium hydride) or organic amines. (Eg, pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine). Particular preference is given to amine bases such as triethylamine, pyridine or ethyldiisopropylamine in the presence of a catalytic amount (about 10 mol%) of 4-N, N-dimethylaminopyridine or 4-pyrrolidinopyridine where appropriate.

Here, the base is used in an amount of 1 to 5, preferably 1 to 2.5 moles per mole of the compound of formula III.

In general, the reaction is carried out in a temperature range of -20 ° C to + 100 ° C, preferably 0 ° C to + 75 ° C. The reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.

Inert solvents in the process steps of (IV) + (V) → (IB) are, for example, ethers (eg diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether), alcohols (E.g. methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol), hydrocarbons (e.g. benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions) or other solvents (e.g. dimethylformamide , Acetonitrile or water). Mixtures of the solvents mentioned may also be used. Toluene, dimethylformamide or acetonitrile are preferred.

Suitable bases for the process steps of (IV) + (V) → (I-B) are conventional inorganic or organic bases. They are preferably alkali metal hydroxides (eg lithium hydroxide, sodium hydroxide or potassium hydroxide), alkali metal carbonates or alkaline earth metals (eg sodium carbonate, potassium carbonate or calcium carbonate), alkali metal phosphates (eg sodium phosphate or potassium phosphate) , Organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine. Particular preference is given to sodium carbonate or potassium carbonate or potassium phosphate.

The base is used herein in amounts of 1 to 5, preferably 2 to 3 moles per mole of the compound of formula IV.

Suitable palladium catalysts for the process step of (IV) + (V) → (IB) are preferably in preformed form, for example [1,1′-bis (diphenylphosphino) ferrocenyl] palladium (II) Used as chloride or bis (triphenylphosphine) palladium (II) chloride or as a suitable palladium source, for example bis (dibenzylideneacetone) palladium (0) or tetrakis (triphenylphosphine) palladium (0), And palladium (0) or palladium (II) compounds which can be produced in the same reactor from suitable phosphine ligands.

In general, the reaction is carried out in a temperature range of 0 ° C to + 150 ° C, preferably + 20 ° C to + 100 ° C. The reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.

Inert solvents in the process steps of (IB) to (IC) include, for example, halogenated hydrocarbons (eg dichloromethane, 1,2-dichloroethane or trichloroethylene), ethers (eg diethyl ether, dioxane, Tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether), alcohols (e.g. methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol), hydrocarbons (e.g. benzene, xylene, toluene, hexane, Cyclohexane or mineral oil fractions) or other solvents such as nitromethane, acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidinone. Mixtures of the solvents mentioned may also be used. Alcohols such as methanol or ethanol are preferred.

Suitable bases for the process steps from (I-B) to (I-C) are conventional inorganic bases. These preferably include alkali metal hydroxides (eg lithium hydroxide, sodium hydroxide or potassium hydroxide) or alkali metal carbonates or alkaline earth metals (eg sodium carbonate, potassium carbonate or calcium carbonate). Lithium hydroxide or sodium hydroxide is particularly preferred.

Here, the base is used in an amount of 1 to 5, preferably 1 to 3 moles per mole of the compound of formula I-B.

Suitable acids for the process step from (IB) to (IC) are conventional inorganic acids such as hydrochloric acid or sulfuric acid, or sulfonic acids (such as toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid), or carboxylic acids (such as trifluoroacetic acid). )to be.

In general, the reaction is carried out in a temperature range of -20 ° C to + 100 ° C, preferably 0 ° C to + 30 ° C. The reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.

Compounds of formula (II) are known or analogous to methods known in the literature, wherein compounds of formula (VI) are initially converted to hydrazine derivatives of formula (VII) with sodium nitrite and tin (II) in the presence of an acid ,

(Wherein A, Y and R ⁵ are each as defined above)

Then, an acid or Lewis acid suitable for them to formula VIII in the presence of an inert solvent a compound and, R ² and R ³ In this case, to R ³ in the compound of formula IX or formula (VIII) both other than hydrogen in formula VIII is hydrogen When represented by reacting with a compound of formula (X),

(Wherein A, Y, R ² , R ³ , R ⁴ and R ⁵ are each as defined above)

The compound of formula (IX) or (X) is then reduced by hydrogenation using boron hydride, aluminum hydride or silicon hydride such as sodium borohydride or sodium cyanoborohydride or by hydrogenation in the presence of a suitable catalyst such as Raney nickel. In the process steps of [(VII) + (VIII) → (IX) → (II), for example, PE Maligres, I. Houpis, K. Rossen, A. Molina, J. Sager, V. Upadhyay, KM Wells, RA Reamer, JE Lynch, D. Askin, RP Volante, PJ Reider, Tetrahedron 1997 , 53, 10983-10992].

Inert solvents in the process steps from (VI) to (VII) are, for example, ethers (eg dioxane, glycol dimethyl ether or diethylene glycol dimethyl ether), alcohols (eg methanol, ethanol, n-propanol, isopropanol) , n-butanol or tert-butanol) or other solvents such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidinone or water. Mixtures of the solvents mentioned may also be used. Preferred solvent is water.

Suitable acids for the process steps from (VI) to (VII) are conventional inorganic or organic acids. 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). Particular preference is given to semi-concentrated to concentrated hydrochloric acid aqueous solutions which simultaneously serve as solvents.

In general, the reaction is carried out in a temperature range of -30 ° C to + 80 ° C, preferably -10 ° C to + 25 ° C. The reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.

Inert solvents in the process steps of (VII) + (VIII) → (IX) or (X) are, for example, halogenated hydrocarbons (eg dichloromethane, trichloroethane, carbon tetrachloride, trichloroethane, tetrachloroethane , 1,2-dichloroethane or trichloroethylene), ethers (eg dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether), alcohols (eg methanol, ethanol, n-propanol, isopropanol, n -Butanol or tert-butanol) or hydrocarbons (eg benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions) or other solvents (eg acetonitrile or water). Mixtures of the solvents mentioned may also be used. The reaction may be carried out without any solvent. When R ³ represents hydrogen and A represents CH or N, the reaction is preferably carried out without any solvent to afford the product of (X). If both R ² and R ³ are not hydrogen and A represents CH, the reaction is preferably carried out in a mixture of toluene and acetonitrile to give the product of formula IX.

Suitable acids for the process steps of (VII) + (VIII) → (IX) or (X) are conventional inorganic or organic acids. 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, conventional Lewis acids such as boron trifluoride, aluminum trichloride or zinc chloride are also suitable. Here, the acid is used in an amount of 1 to 10 moles per mole of the compound of formula VII. When R ³ represents hydrogen and A represents CH or N, the reaction is preferably carried out using 1-2 moles of zinc chloride to give the product of formula X, wherein both R ² and R ³ are not hydrogen and A When is CH, the reaction is preferably carried out using 2 to 5 moles of trifluoroacetic acid to give the product of formula IX.

In general, the reaction is carried out in the temperature range of 0 ℃ to +250 ℃. When R ³ represents hydrogen and A represents CH or N, the reaction is preferably carried out at a temperature range of + 130 ° C. to + 200 ° C. to give the product of formula X, wherein both R ² and R ³ are not hydrogen When A represents CH, the reaction is preferably carried out at a temperature range of 0 ° C. to + 50 ° C. to give the product of formula IX. The reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.

Suitable reducing agents for the process steps of (IX) or (X) → (II) are boron hydride, aluminum hydride or silicon hydride such as borane, diborane, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or triethyl Silane or hydrogenation with hydrogen in the presence of a suitable catalyst such as palladium, palladium oxide or Raney nickel on activated carbon. In the case of compounds of formula (X), wherein A represents N, hydrogenation using Raney nickel as the catalyst is preferred, and when A represents CH in formula (X), reduction with sodium cyanoborohydride is preferred. In the case of compounds of formula (IX), preference is given to using sodium borohydride.

Suitable solvents for the process steps from (IX) or (X) to (II) are, for example, ethers (eg diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether), alcohols (E.g. methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol) or hydrocarbons (e.g. benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions) or other solvents (e.g. acetonitrile, Acetic acid or water). Mixtures of the solvents mentioned may also be used. In the hydrogenation of the compound of formula (X) in which A represents N, it is preferable to use ethanol, and in the case of reduction in case A represents CH in formula (X), it is preferable to use acetic acid, a large amount of which is added to the reducing agent. It is added as an acid and at the same time acts as a solvent. In the reduction of the compound of formula IX, a mixture of methanol and toluene / acetonitrile [add 2 to 5 moles of trifluoroacetic acid from the reaction of (VII) → (IX)] in a ratio of 1: 1 to 1:10] It is preferable to use.

In general, the reaction is carried out in the temperature range of -20 ℃ to +200 ℃. Here, the hydrogenation of the compound of formula X wherein A represents N is preferably carried out at a temperature range of + 150 ° C. to + 200 ° C., while the reduction of compounds of formula IX and X where A represents CH is preferably Is carried out in a temperature range of -10 ° C to + 50 ° C. The reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5 to 150 bar). The hydrogenation of the compound of formula X in which A represents N is preferably carried out at a pressure range of hydrogen of 50 to 150 bar, while the reduction of the compound of formula IX or X in which A represents CH is generally carried out at atmospheric pressure. .

Compounds of formula III are known or analogous to methods known in the literature, wherein compounds of formula XI are initially converted to compounds of formula XIII by using compounds of formula XII in an inert solvent in the presence of a base ,

Wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ , X and T are as defined above, respectively.

This compound is then reacted with chlorosulfonic acid [see, eg, PD Edwards, RC Mauger, KM Cottrell, FX Morris, KK Pine, MA Sylvester, CW Scott, ST Furlong, Bioorg. Med. Chem. Lett. 2000 , 10, 2291-2294].

Inert solvents in the process steps of (XI) + (XII) → (XIII) are, for example, ethers (eg diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether), hydrocarbons (Eg, benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions) or other solvents such as acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidinone. Mixtures of the solvents mentioned may also be used. Dimethylformamide or acetone is preferred.

Suitable bases for the process steps of (XI) + (XII) → (XIII) are conventional inorganic or organic bases. They are preferably alkali metal hydroxides (eg lithium hydroxide, sodium hydroxide or potassium hydroxide), alkali metal carbonates or alkaline earth metals (eg sodium carbonate, potassium carbonate or calcium carbonate), alkali metal hydrides (eg sodium hydride) or organic amines. (Eg, pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine). Potassium carbonate is particularly preferred.

Here, the base is used in an amount of 1 to 5, preferably 1 to 2 moles per mole of the compound of formula XI.

In general, the reaction is carried out in a temperature range of -20 ° C to + 150 ° C, preferably 0 ° C to + 80 ° C. The reaction can be carried out at atmospheric pressure, elevated pressure or reduced pressure (eg 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.

Compounds of formula (V), (VI), (VIII), (XI) and (XII) are commercially available, known from the literature, or prepared analogously to methods known in the literature.

The process according to the invention can be illustrated by the following schemes 1 and 2.

a) NaNO ₂ , SnCl ₂ , HCl; b) CH ₃ CH ₂ OH, RT; c) ZnCl ₂ , 170 ° C., 30 min; d) NaCNBH ₃ , CH ₃ COOH, 35 ° C., 16 hr; Raney Nickel for A = N, 180 ° C., 80 bar H ₂ ; e) DMAP, TEA, CH ₂ Cl ₂ , RT; f) Pd (PPh ₃ ) ₂ Cl, DMF, aq. Na ₂ CO ₃ , 100 ° C., 15 hr.

a) NaN0 ₂ , SnCl ₂ , HCl; b) TFA, 35 ° C .; c) NaBH ₄ , CH ₃ OH, -10 ° C; d) THF, TEA, -5 ° C; e) KOH, THF / H ₂ 0, RT; f) Pd catalyst, DME, Na ₂ CO ₃ , 60 ° C., 14 hr; For reaction steps b, c): PE Maligres, I. Houpis, K. Rossen, A. Molina, J. Sager, V. Upadhyay, KM Wells, RA Reamer, JE Lynch, D. Askin, RP Volante, PJ Reider, Tetrahedron 1997 , 53, 10983-10992.

The compounds of formula (I) according to the invention have a surprising and useful range of pharmacological activity and can therefore be used as multi-purpose pharmaceuticals, in particular for the treatment of diseases in which PPAR delta inhibitors are activated. In particular, it is suitable for the treatment of coronary heart disease, prevention of myocardial infarction, and treatment of restenosis after coronary angioplasty or stent. The compounds of formula (I) according to the invention are preferably suitable for the treatment of stroke, CNS disorders, Alzheimer's disease, osteoporosis, arteriosclerosis and hypercholesterolemia, an increase in pathologically low HDL levels and a decrease in high triglyceride and LDL levels. Do. In addition, it can be used for the treatment of obesity, diabetes, metabolic syndrome (hypertension due to glucose intolerance, hyperinsulinemia, dyslipidemia and insulin resistance), liver fibrosis and cancer.

The new active compound is administered alone or, if necessary, preferably a CETP inhibitor, an antidiabetic agent, an antioxidant, a cytostatic agent, a calcium antagonist, an antihypertensive agent, a thyroid hormone and / or a similar thyroid, an HMG-CoA reductase inhibitor, an HMG -CoA reductase expression inhibitor, squalene synthesis inhibitor, ACAT inhibitor, perfusion promoter, platelet aggregation inhibitor, anticoagulant, angiotensin II receptor antagonist, cholesterol absorption inhibitor, MTP inhibitor, aldolase reductase inhibitor, fibrate, niacin, appetite suppressant, It may be administered in combination with a lipase inhibitor and other active compounds from the group of PPAR-α and / or PPAR-γ agonists. Further combinations with anti-inflammatory agents such as COX-2 inhibitors, NEP inhibitors, ECE inhibitors, vasopeptidase inhibitors, aldose reduction inhibitors, antioxidants, cell proliferation inhibitors, perfusion promoters and appetite suppressants are also possible.

The compounds according to the invention are preferably combined in each case with the following.

One or more antidiabetic agents mentioned in Rote Liste 2002 / II, Chapter 12,

For example, preferably at least one antithrombotic agent from the group of platelet aggregation inhibitors or anticoagulants,

For example, preferably one or more antihypertensives from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, betablockers and diuretics and / or

Thyroid receptor agonists, cholesterol synthesis inhibitors, such as preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MPT inhibitors, PPAR agonists, fibrates, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid absorbers, lipoproteins (a) At least one lipid metabolism-modifying active compound from the group of antagonists.

Antidiabetic agents are understood to mean, for example or preferably insulins and insulin derivatives, also orally active hypoglycemic agents.

As used herein, insulin and insulin derivatives include both insulins of animal, human or biotechnological origin and mixtures thereof.

Orally active hypoglycemic agents include, for example, those disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A / S, for example, sulfonyl urea, biguadine, meglitinide Derivatives, oxodiazolidinones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, inhibitors of liver enzymes involved in the activity of insulin sensitizers, gluconeogenesis and / or glycogen degradation, glucose uptake and Potassium channel openers.

In a preferred embodiment of the invention, the compounds mentioned are administered with insulin.

In a preferred embodiment of the invention, the compounds mentioned are administered in combination with sulfonyl urea, for example, tolbutamide, glybenclamide, glymepiride, glipidide or glyclazide.

In a preferred embodiment of the invention, the compounds mentioned are administered in combination with meglitinide derivatives, for example lepaglinide or nateglinide.

In a preferred embodiment of the invention, the compounds mentioned are administered with PPAR gamma agonists, for example, preferably from a group of thiazolidinediones such as pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds mentioned are for example preferably GI-262570 (farglitazar), GW 2331, GW, 409544, AVE 8042, AVE 8134, AVE 0847, MK-0767 ( KRP-297), together with mixed PPAR alpha / gamma agents such as AZ-242.

Antithrombotic agents are understood to mean, for example, platelet aggregation inhibitors such as aspirin, clopidogrel, ticlopidine, dipyridamole, or compounds from the group of anticoagulants.

In a preferred embodiment of the invention, the compounds mentioned are preferably administered with thrombin inhibitors such as, for example, ximelagatran, melagatran, bivalirudin, lexic acid.

In a preferred embodiment of the invention, the compounds mentioned are administered, for example, in combination with GPIIb-IIIa antagonists, such as, for example, tyropiban, abciximab.

In a preferred embodiment of the invention, the compounds mentioned are preferably administered with factor Xa inhibitors, for example DX 9065a, DPC, 906, JTV 803.

In a preferred embodiment of the invention, the compounds mentioned are administered with heparin or low molecular weight heparin derivatives.

In a preferred embodiment of the invention, the mentioned compounds are administered, for example, together with vitamin K antagonists, such as coumarin.

Antihypertensive agents are, for example, preferably compounds from the group of calcium antagonists, such as, preferably, nipfedipine, verapamil, dilitazem, angiotensin AII antagonists, It is understood to mean compounds such as ACE inhibitors, beta-blockers and diuretics.

In a preferred embodiment of the invention, the compounds mentioned are administered with an antagonist of the alpha 1 receptor.

In a preferred embodiment of the invention, the compounds mentioned are reserpin, minoxidil, diazoxide, dihydralazine, hydralazine, and nitric oxide-emitting compounds such as, preferably, glycerol nitrate or It is administered in combination with sodium nitroprusside.

In a preferred embodiment of the invention, the compounds mentioned are administered, for example, preferably with angiotensin AII antagonists such as losartan, valsartan, telmisartan.

In a preferred embodiment of the invention, the compounds mentioned are administered together with ACE inhibitors, for example enalapril, captopril, preferably.

In a preferred embodiment of the invention, the compounds mentioned are administered, for example, together with betablocking agents, for example propranolol, athenol.

In a preferred embodiment of the invention, the compounds mentioned are administered together with a diuretic, such as, for example, furosemide.

Lipid metabolism-modifying agents are, for example, preferably thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR agonists, fibrates, cholesterol absorption inhibitors, lipase inhibitors Is understood to mean compounds from polymeric bile acid absorbers, lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds mentioned are thyroid receptor agonists, for example D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425, axitirome ) (CGS 26214).

In a preferred embodiment of the invention, the compounds mentioned are administered in combination with a squalene synthesis inhibitor, for example BMS-188494, TAK 457.

In a preferred embodiment of the invention, the compounds mentioned are administered in conjunction with an ACAT inhibitor, for example avasimibe.

In a preferred embodiment of the invention, the compounds mentioned are administered in combination with a cholesterol absorption inhibitor, for example, ezetimibe, tiqueside, pamaqueside.

In a preferred embodiment of the present invention, the compounds mentioned are administered in combination with an MTP inhibitor, for example, preferably impitapide, BMS-201038, R-103757.

In a preferred embodiment of the invention, the compounds mentioned are for example fibrate fenofibrate, clofibrate, bezafibrate, ciprofibrate, gemfibrozil ), Or preferably with a PPAR alpha agent such as, for example, GW 9578, GW 7647, LY-518674 or NS-220.

In a preferred embodiment of the invention, the compounds mentioned are administered in combination with a CEPT inhibitor, for example torcetrapib (CP-5239 414), JJT-705.

In a preferred embodiment of the invention, the compounds mentioned are, for example, preferably GI-262570 (paglitaza), GW # 2331, GW # 409544, AVE 8042, AVE 8134, AVE 0847, MK-0767 (KRP- 297), in combination with a mixed PPAR alpha / gamma agent such as AZ-242.

In a preferred embodiment of the invention, the compounds mentioned are administered, for example, in combination with lipase inhibitors, such as orlistat, for example.

In a preferred embodiment of the invention, the compounds mentioned are preferably, for example, cholestyramine, cholestipol, cholsolvam, cholestagel, cholesti It is administered with a polymeric bile acid absorbent such as colestimide.

In a preferred embodiment of the invention, the compounds mentioned are administered, for example, together with lipoprotein (a) antagonists such as gemcabene calcium (CI-1027) or nicotinic acid.

In a preferred embodiment of the invention, the compounds mentioned are administered in combination with antagonists of the niacin receptor.

In a preferred embodiment of the invention, the compounds mentioned are administered in conjunction with an LDL receptor inducer.

In addition, the present invention preferably contains, for example, HMG-CoA reductase inhibitors from the group of statins such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and cerivastatin, pitavastatin, Combinations of compounds of formulas I to III are provided.

The activity of the compounds according to the invention can be investigated in vitro by, for example, transcriptional assays described in the experimental section.

In vivo activity of the compounds according to the invention can be investigated, for example, by the tests described in the experimental section.

Suitable dosage forms for the administration of the compounds of formula (I) are all conventional dosage forms, namely oral, parenteral, inhalation, nasal, sublingual, rectal, external (eg transdermal) or topical (eg implantation or For stents). For parenteral administration, intravenous, intramuscular and subcutaneous administration, for example subcutaneous depots, is particularly mentioned. Oral or parenteral administration is preferred. Oral administration is particularly preferred.

Herein, the active compounds may be administered on their own or in the form of preparations. Formulations suitable for oral administration are, inter alia, tablets, capsules, pellets, dragees, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions. Herein, the active compound must be present in an amount to obtain a therapeutic effect. In general, the active compound may be present at 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 compound should be 0.5 to 90% by weight, ie the compound should be present in an amount sufficient to reach the stated dosage range.

To this end, the active compounds can be converted into conventional preparations in a manner known per se. This is done using inert and nontoxic pharmaceutically acceptable carriers, adjuvants, solvents, excipients, emulsifiers and / or dispersants.

Adjuvants which may be mentioned include, for example, water, non-toxic organic solvents such as paraffin, vegetable oils (eg sesame oil), alcohols (eg ethanol, glycerol), glycols (eg polyethylene) Glycols), solid carriers such as natural or synthetic minerals (eg talc or silicates), sugars (eg lactose), emulsifiers, dispersions (eg polyvinylpyrrolidone) and glidants (eg Magnesium sulfate).

For oral administration, tablets as well as additives such as sodium citrate may be included with additives such as starch, gelatin and the like. Aqueous formulations for oral administration may further comprise flavor enhancers or pigments.

For oral administration, it is preferred to administer a dose of 0.001 to 5 mg / kg body weight, preferably 0.005 to 3 mg / kg body weight per 24 hours.

The following examples illustrate the invention. The invention is not limited to these examples.

LC / MS method

Method A : Column: Waters Symmetry C18 50 × 2.1 mm, 3.5 μm; 0.5 ml / min; A: acetonitrile + 0.1% formic acid, B: water + 0.1% formic acid; 0 min 10% A, 4 min 90% A; 40 ° C.

Method B : Instrument: Fininnigan MAT 900S, TSP: P4000, AS3000, UV3000HR; Column: geometry C18, 150 mm × 2.1 mm, 5.0 μm; Mobile phase C: water, mobile phase B: water + 0.3 g / l 35% strength hydrochloric acid, mobile phase A: acetonitrile; Concentration gradient: 0.0 min 2% A → 2.5 min 95% A → 5 min 95% A; Oven: 70 ° C .; Flow rate: 1.2 ml / min; UV-detection: 210 nm.

Method C : Instrument: Micromass Quattro LCZ, HP1100; Column: geometry C18, 50 mm × 2.1 mm, 3.5 μm; Mobile phase A: acetonitrile + 0.1% formic acid, mobile phase B: water + 0.1% formic acid; Concentration gradient: 0.0 min 10% A → 4.0 min 90% A → 6.0 min 90% A; Oven: 40 ° C .; Flow rate: 0.5 ml / min; UV-detection: 208-400 nm.

Method D : Instrument: Micromass Platform LCZ, HP1100; Column: geometry C18, 50 mm × 2.1 mm, 3.5 μm; Mobile phase A: acetonitrile + 0.1% formic acid, mobile phase B: water + 0.1% formic acid; Concentration gradient: 0.0 min 10% A → 4.0 min 90% A → 6.0 min 90% A; Oven: 40 ° C .; Flow rate: 0.5 ml / min; UV-detection: 208-400 nm.

Method E : Instrument: Micromass Platform LCZ, HP1100; Column: geometry C18, 50 mm × 2.1 mm, 3.5 μm; Mobile phase A: acetonitrile + 0.5% formic acid, mobile phase B: water + 0.5% formic acid; Concentration gradient: 0.0 min 90% A → 4.0 min 10% A → 6.0 min 10% A; Oven: 50 ° C .; Flow rate: 0.5 ml / min; UV-detection: 208-400 nm.

Method F : Instrument: Micromass TOF-MUX-Interface / Waters 600; Column: YMC-ODS-AQ, 50 mm × 2.1 mm, 3.5 μm; Temperature: 20 ° C .; Flow rate: 0.8 ml / min; Mobile phase A: acetonitrile + 0.05% formic acid, mobile phase B: water + 0.05% formic acid; Concentration gradient: 0.0 min 0% A → 0.2 min 0% A → 2.9 min 70% A → 3.1 min 90% A.

GC / MS

Carrier gas: helium

Flow rate: 1.5 ml / min

Initial temperature: 60 ℃

Temperature gradient: 14 ° C./min up to 300 ° C., then 1 min constant 300 ° C.

Column: HP-5 30 m x 320 μm x 0.25 μm (film thickness)

Initial time: 2 min

Front injector temperature: 250 ℃

Abbreviations Used

abs .: absolute

aq .: aqueous

DMAP: 4-N, N-dimethylaminopyridine

DME: 1,2-dimethoxyethane

DMF: N, N-dimethylformamide

DMSO: Dimethyl Sulfoxide

ESI: Electrospray Ionization (MS)

GC: Gas Chromatography

LC-MS: liquid chromatography-bound mass spectrometry

MS: mass spectrometry

MW: Molecular Weight

NMR: nuclear magnetic resonance analysis

R _f : retention index (TLC)

RT: Room temperature

R _t : retention time (HPLC)

TEA: triethylamine

TFA: trifluoroacetic acid

THF: tetrahydrofuran

Example 1

[4-({3-isopropyl-7-methyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} -sulfonyl) -2- Methylphenoxy] acetic acid

Step a): 1- (4-Bromo-2-methylphenyl) hydrazine

50 g (267.7 mmol) of 4-bromo-2-methylaniline in 190 mL concentrated hydrochloric acid were heated at 80 ° C. for 30 minutes. After cooling to 5 ° C., 18.5 g (267.7 mmol) sodium nitrite in 95 mL water was added dropwise over 30 minutes. After stirring at 5 ° C. for 30 minutes, the reaction mixture was added dropwise to a solution of 384 g (2 mol) of tin chloride in 190 mL of concentrated hydrochloric acid over 45 minutes. After an additional 45 minutes at room temperature, the suspension was alkalized with 50% aqueous sodium hydroxide solution. The precipitate was filtered off and extracted repeatedly with dichloromethane and ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. The result was 43.6 g (81% theory) of the product as beige crystals.

LC-MS (Method B): R _t = 2.06 min

MS (ESIpos): m / z = 201 (M + H) ⁺

Step b): 5-Bromo-3-isopropyl-7-methyl-1 H-indole

7 g (34.8 mmol) of 1- (4-bromo-2-methylphenyl) hydrazine were suspended in 14 ml of ethanol and 3.9 g (45 mmol) of isovaleraldehyde was added. The mixture was stirred at room temperature for 30 minutes and the solvent was removed under reduced pressure and melted with 5.2 g (38 mmol) of anhydrous zinc chloride at 170 ° C. without further purification of the intermediate. After 30-45 minutes, the melt was cooled to room temperature, taken with dichloromethane and extracted with dilute hydrochloric acid and water. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was taken up in ethyl acetate and purified on silica gel (mobile phase: cyclohexane / ethyl acetate 9: 1). As a result, 4.2 g (48% in theory) were obtained.

LC-MS (method B): R _t = 3.15 min

Step c): 5-Bromo-3-isopropyl-7-methylindolin

4.1 g (16.3 mmol) of 5-bromo-3-isopropyl-7-methyl-1H-indole are dissolved in 30 mL of glacial acetic acid, and 5.1 g (81 mmol) of sodium cyanoborohydride at room temperature are added little at a time. Added. The reaction mixture was warmed at 35 ° C. for 16 h, hydrolyzed with water and extracted twice with ethyl acetate. The extract was dried over sodium sulfate and then the solvent was removed under reduced pressure. The crude product was dissolved in ethyl acetate and purified on silica gel (mobile phase: cyclohexane / ethyl acetate 9: 1). As a result, 1.6 g (39% of theory) were obtained.

LC-MS (Method C): R _t = 4.27 min

Step d): 2-methylphenoxyacetate

10.81 g (0.10 mol) of 2-methylphenol and 13.82 g (0.10 mol) of potassium carbonate were suspended in 100 mL of N, N-dimethylformamide and stirred at 50 ° C. for 1 hour. 18.37 g (0.11 mol) of ethyl bromoacetate was then added dropwise and the mixture was stirred at 50 ° C. overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure, taken up with ethyl acetate and washed three times with water. The organic phase was dried over sodium sulphate and the solvent was removed under reduced pressure. The residue was distilled by Kugelrohr to give 18.5 g (95% of theory) of the desired product.

GC-MS: R _t = 12.50 min.

Step e): ethyl [4- (chlorosulfonyl) -2-methylphenoxy] acetate

110 g (0.5 mol) of ethyl (2-methylphenoxy) acetate was initially charged in 250 mL of chloroform and cooled to 0 ° C. 330 g (2.8 mol) of chlorosulfonic acid were slowly added dropwise to this solution. The reaction solution was stirred at room temperature for 4 hours, poured into ice and extracted three times with dichloromethane. The organic phase was washed twice with water, once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution. This mixture was dried over sodium sulfate and the solvent was removed under reduced pressure. As a result, 153 g (93% of theory) were obtained.

LC-MS (Method C): R _t = 3.95 min

Step f): ethyl 4-[(5-bromo-3-isopropyl-7-methyl-2,3-dihydro-1H-indol-1-yl) sulfonyl] -2-methylphenoxy} acetate

2.5 g (9.8 mmol) of 5-bromo-3-isopropyl-7-methylindolin is dissolved in 20 mL of tetrahydrofuran, 3 mL (21 mmol) of triethylamine, 20 mg (0.16 mmol) DMAP and 2.8 g (9.8 mmol) of ethyl [4- (chlorosulfonyl) -2-methylphenoxy] acetate were added. The reaction mixture was stirred overnight at room temperature. After filtering the mixture, the solvent was removed under reduced pressure and the crude product was purified on silica gel (mobile phase: cyclohexane / ethyl acetate 9: 1). As a result, 4.8 g (96% of theory) were obtained.

LC-MS (method B): R _t = 3.29 min

Step g): [4-({3-isopropyl-7-methyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} sulfonyl) -2-methylphenoxy] acetic acid

0.1 g (0.19 mmol) of ethyl {4-[(5-bromo-3-isopropyl-7-methyl-2,3-dihydro-1H-indol-1-yl) sulfonyl] -2-methylphenoxy The acetate was dissolved in 6 mL of pure dimethylformamide, 7 mg (0.01 mmol) of bis (triphenylphosphine) palladium (II) chloride and 48.3 mg (0.25 mmol) of 4-trifluoromethylphenylboronic acid Was added under argon. The mixture was stirred at 70 ° C. for 30 minutes and then 1 mL of sodium carbonate 2 M solution was added. The reaction mixture was heated at 100 ° C for 16 h. After cooling to room temperature, the mixture was filtered through silica gel. The solvent was removed under reduced pressure and the crude product was preparative HPLC (YMC gel ODS-AQ S 5/15 μm; mobile phase A: water, mobile phase B: acetonitrile, concentration gradient 0 min 30% B, 5 min 30% B, 50 min Purified to 95% B). As a result, 65 mg (60% of theory) were obtained.

LC-MS (method B): R _t = 3.25 min

Example 2

[2-methyl-4-({2,3,7-trimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} sulfonyl) phenoxy Acetic acid

Step a) 5-Bromo-2,3,7-trimethyl-1H-indole

8 g (39.8 mmol) of 1- (4-bromo-2-methylphenyl) hydrazine (Example 1 / step a) were suspended in 14 mL of ethanol and 3.7 g (52 mmol) ethylmethylketone were added. After stirring for 30 minutes at room temperature, the solvent was removed under reduced pressure and the intermediate was melted with 5.9 g (43 mmol) of anhydrous zinc chloride at 170 ° C. without further purification. After 30-45 minutes the melt was cooled to room temperature, taken with dichloromethane and extracted with dilute hydrochloric acid and water. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was dissolved in ethyl acetate and purified on silica gel (mobile phase: cyclohexane / ethylacetate 9: 1). As a result, 3.8 g (40% in theory) were obtained.

LC-MS (Method D): R _t = 4.92 min

Step b): 5-Bromo-2,3,7-trimethylindolin

3.8 g (15.8 mmol) of 5-bromo-3,7-dimethyl-1H-indole was dissolved in 30 mL of glacial acetic acid, and 5 g (80 mmol) of sodium cyanoborohydride were added in portions at room temperature at a time. The reaction product was warmed at 35 ° C. for 16 h and then hydrolyzed with water and extracted twice with ethyl acetate. After drying over sodium sulfate, the solvent was removed under reduced pressure. The crude product was dissolved in ethyl acetate and purified on silica gel (mobile phase: cyclohexane / ethylacetate 9: 1). As a result, 1.4 g (37% of theory) were obtained.

LC-MS (method B): R _t = 2.66 min

Step c): Ethyl {4-[(5-bromo-2,3,7-trimethyl-2,3-dihydro-1H-indol-1-yl) sulfonyl] -2-methyl-phenoxy} acetate

1.3 g (5.7 mmol) of 5-bromo-2,3,7-trimethylindolin is dissolved in 4 mL tetrahydrofuran, 1.7 ml (12.5 mmol) triethylamine, 20 mg DMAP (0.16 mmol) And 1.6 g (5.7 mmol) of ethyl [4- (chlorosulfonyl) -2-methylphenoxy] acetate (Example 1 / step e). The reaction mixture was stirred overnight at room temperature. After filtration, the solvent was removed under reduced pressure and the crude product was purified on silica gel (mobile phase: cyclohexane / ethylacetate 9: 1). As a result, 0.6 g (23% in theory) was obtained.

LC-MS (method B): R _t = 3.15 min

MS (ESIpos): m / z = 496 (M + H) ⁺

Step d): [2-methyl-4-({2,3,7-trimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} Sulfonyl) phenoxy] acetic acid

0.08 g (0.16 mmol) of ethyl {4-[(5-bromo-2,3,7-trimethyl-2,3-dihydro-1H-indol-1-yl) -sulfonyl] -2-methylphenoxy The acetate was dissolved in 6 ml of pure dimethylformamide, 7 mg (0.01 mmol) of bis (triphenylphosphine) palladium (II) chloride and 40 mg (0.21 mmol) of 4-trifluoromethylphenylboronic acid Was added under argon. The mixture was stirred at 70 ° C. for 30 minutes and then 1 mL of sodium carbonate 2 M solution was added. The reaction mixture was heated at 100 ° C for 16 h. After cooling to room temperature, the mixture was filtered through silica gel. The solvent was removed under reduced pressure and the crude product was preparative HPLC (YMC gel ODS-AQ S 5/15 μm; mobile phase A: water, mobile phase B: acetonitrile, concentration gradient 0 min 30% B, 5 min 30% B, 50 min Purified to 95% B). As a result, 64 mg (74% of theory) were obtained.

LC-MS (Method C): R _t = 5.26 min

Example 3

[4-({3,7-dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} sulfonyl) -2-methylphenoxy] Acetic acid

Step a): 5-Bromo-3,7-dimethyl-1H-indole

5 g (24.8 mmol) of 1- (4-bromo-2-methylphenyl) hydrazine (Example 1 / step a) were suspended in 14 ml of ethanol and 1.8 g (32 mmol) propionaldehyde was added. The mixture was stirred at room temperature for 30 minutes, then the solvent was removed under reduced pressure and the intermediate was melted with 3.7 g (27 mmol) of anhydrous zinc chloride at 170 ° C. without further purification. After 30-45 minutes, the melt was cooled to room temperature, taken with dichloromethane and extracted with dilute hydrochloric acid and water. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was dissolved in ethyl acetate and purified on silica gel (mobile phase: cyclohexane / ethyl acetate 9: 1). As a result, 1.5 g (27% of theory) were obtained.

LC-MS (Method C): R _t = 4.65 min

MS (ESIpos): m / z = 224 (M + H) ⁺

Step b): 5-bromo-3,7-dimethylindolin

1.4 g (6.4 mmol) of 5-bromo-3,7-dimethyl-1H-indole was dissolved in 30 ml of glacial acetic acid, and 2 g (33 mmol) of sodium cyanoborohydride were added in portions at room temperature at a time. The reaction mixture was warmed at 35 ° C. for 16 hours, hydrolyzed with water and extracted twice with ethyl acetate. After drying over sodium sulfate, the solvent was removed under reduced pressure. The crude product was dissolved in ethyl acetate and purified on silica gel (mobile phase: cyclohexane / ethyl acetate 9: 1). As a result, 0.79 g (53% in theory) was obtained.

LC-MS (method B): R _t = 2.38 min

Step c): ethyl {4-[(5-bromo-3,7-dimethyl-2,3-dihydro-1H-indol-1-yl) sulfonyl] -2-methylphenoxy} acetate

0.7 g (3.4 mmol) of 5-bromo-3,7-dimethylindolin is dissolved in 4 ml of tetrahydrofuran, 1 ml (7.4 mmol) triethylamine, 20 mg DMAP and 1 g (3.4 mmol) ethyl [4- (chlorosulfonyl) -2-methylphenoxy] acetate (Example 1 / step e) was added. The reaction mixture was stirred overnight at room temperature. After filtration, the solvent was removed under reduced pressure and the crude product was purified on silica gel (mobile phase: cyclohexane / ethylacetate 9: 1). As a result, 1.5 g (90% of theory) were obtained.

LC-MS (method D): R _t = 5.25 min

Step d): [4-({3,7-Dimethyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-indol-1-yl} sulfonyl) -2- Methylphenoxy] acetic acid

0.1 g (0.2 mmol) ethyl {4-[(5-bromo-3,7-dimethyl-2,3-dihydro-1H-indol-1-yl) -sulfonyl] -2-methylphenoxy} Acetate was dissolved in 6 ml of pure dimethylformamide, and argon with 7 mg (0.01 mmol) of bis (triphenylphosphine) palladium (II) chloride and 51 mg (0.26 mmol) of 4-trifluoromethylphenylboronic acid Added under. The mixture was stirred at 70 ° C. for 30 minutes and 1 ml of 2 M sodium carbonate solution was added. The reaction solution was heated at 100 ° C. for 16 hours. After cooling to room temperature, the mixture was filtered through silica gel. The solvent was removed under reduced pressure and the crude product was preparative HPLC (YMC gel ODS-AQ S 5/15 μm; mobile phase A: water, mobile phase B: acetonitrile, concentration gradient 0 min 30% B, 5 min 30% B, 50 min Purified to 95% B). As a result, 87 mg (81% of theory) were obtained.

LC-MS (method D): R _t = 5.18 min

Example 4

4-({3-isopropyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-pyrrolo [3,2-b] pyridin-1-yl} sulfonyl) -2-methylphenoxy] acetic acid

Step a): 5-Chloro-3-isopropyl-1 H-pyrrolo [3,2-b] pyridine

0.2 g (1.39 mmol) of 2-chloro-5-hydrazinopyridine (prepared by GB-259 961 from 5-amino-2-chloro-pyridine) is dissolved in ethanol and 0.16 g (1.8 mmol) of 3 -Methylbutanal was added. The mixture was stirred at room temperature for 30 minutes, the solvent was removed under reduced pressure and the residue was dried under reduced pressure. 0.2 g (1.53 mmol) of anhydrous zinc chloride were then added to the intermediate and the mixture was heated to 170 ° C. in an oil bath. After stirring for 30 minutes at this temperature, the mixture was cooled to room temperature. The crude product was taken up with dichloromethane and washed with dilute hydrochloric acid. After drying over magnesium sulfate, the solvent was removed under reduced pressure and the crude product was filtered over silica gel (mobile phase: cyclohexane / ethyl acetate 1: 1). As a result, 133 mg (49% of theory) were obtained.

LC-MS (Method B): R _t = 2.62 min

Step b): 3-isopropyl-5- [4- (trifluoromethyl) phenyl] -1 H-pyrrolo [3,2-b] pyridine

Under argon, 0.1 g (0.51 mmol) of 5-chloro-3-isopropyl-1H-pyrrolo [3,2-b] pyridine, 0.13 g (0.67 mmol) of 4-trifluoromethylphenylboronic acid and 0.018 g (0.026 mmol) of bis (triphenylphosphine) palladium (II) chloride was first charged in 6 ml DMF and heated at 70 ° C. for 30 minutes. After addition of 1 ml 2 M sodium carbonate solution, the reaction mixture was heated at 100 ° C overnight. After cooling, the mixture was filtered through silica gel. The solvent was removed under reduced pressure and the crude product was preparative HPLC (YMC gel ODS-AQ S 5/15 μm; mobile phase A: water, mobile phase B: acetonitrile, concentration gradient 0 min 30% B, 5 min 30% B, 50 min Purified to 95% B). The result was 100 mg (64% theoretical).

LC-MS (Method C): R _t = 4.47 min

MS (ESIpos): m / z = 305 (M + H) ⁺

Step c): 3-isopropyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-pyrrolo [3,2-b] pyridine

0.085 g (0.279 mmol) 3-isopropyl-5- [4- (trifluoromethyl) phenyl] -1 H-pyrrolo- [3,2-b] -pyridine and 0.16 g (2.7 mmol) of Raney nickel Was first charged into 10 mL of decalin and hydrogenated at 80 bar, 180 ° C for 16 h. The product was extracted with methanol and used without further purification during the next reaction step.

LC-MS (method D): R _t = 5.00 min

MS (ESIpos): m / z = 307 (M + H) ⁺

Step d): ethyl [4-({3-isopropyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-pyrrolo [3,2-b] -pyridine- 1-yl} sulfonyl) -2-methylphenoxy] acetate

0.085 mg (0.277 mmol) of 3-isopropyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-pyrrolo [3,2-b] pyridine in 2 ml of pure water Dissolved in THF and 0.081 g (0.277 mmol) of ethyl [4- (chlorosulfonyl) -2-methylphenoxy] acetate (Example 1 / step e) and 0.085 ml (0.61 mmol) of triethylamine and 4 mg (0.028 mmol) DMAP was added. The reaction mixture was warmed at 45 ° C overnight. This mixture was filtered and the solvent removed under reduced pressure. The crude product was purified by preparative HPLC (YMC gel ODS-AQ S 5/15 μm; mobile phase A: water, mobile phase B: acetonitrile, concentration gradient 0 min 30% B, 5 min 30% B, 50 min 95% B) It was. As a result, 37 mg (24% in theory) were obtained.

LC-MS (method E): R _t = 4.78 min

Step e): [4-({3-isopropyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-pyrrolo- [3,2-b] pyridine-1 -Yl} sulfonyl) -2-methylphenoxy] acetic acid

0.029 g (0.052 mmol) of ethyl [4-({3-isopropyl-5- [4- (trifluoromethyl) phenyl] -2,3-dihydro-1H-pyrrolo [3,2-b] Pyridin-1-yl} sulfonyl) -2-methylphenoxy] acetate was dissolved in 1 ml THF and 0.5 ml of 1N aqueous sodium hydroxide solution was added. The reaction mixture was stirred overnight at room temperature. The mixture was acidified with concentrated hydrochloric acid and extracted with dichloromethane. The extract was dried over magnesium sulfate and the solvent was removed under reduced pressure. As a result, 27 mg (97% of theory) were obtained.

LC-MS (method E): R _t = 4.43 min

Example 5

(4-{[5- (4-trifluoromethylphenyl) -2,3-dihydro-3-spiro-1'-cyclohexyl-1H-indol-1-yl] -sulfonyl} -2-methylphenoxy Acetic acid

Step a): 4-bromophenylhydrazine hydrochloride

While stirring, a solution of 32.0 g (186 mmol) 4-bromoaniline in 200 mL of concentrated hydrochloric acid was cooled to 0 ° C. At this temperature, 12.8 g (186 mmol) of sodium nitrite solution in 150 mL water was added. The resulting diazonium solution with stirring at 0-4 ° C. was added dropwise to a solution of 42.7 g (225 mmol) of tin (II) chloride in 100 mL of concentrated hydrochloric acid. The resulting precipitate was aspirated and filtered, washed twice with 50 mL of water each and then recrystallized from isopropanol. As a result, 17.2 g (41% of theory) of a solid product were obtained.

R _f (dichloromethane / methanol 40: 1) = 0.46

UV [nm] = 198, 234, 284

Step b): 5-Bromo-2,3-dihydro-3-spiro-1'-cyclohexyl-1H-indole

90 ml of toluene / acetonitrile (49: 1) mixture was flushed with argon for 5 minutes and then 6.00 g (26.8 mmol) of 4-bromophenylhydrazine hydrochloride were added. Then, 7.41 ml (96.2 mmol) of trifluoroacetic acid was slowly added dropwise, taking care not to exceed the temperature of 35 ° C. The temperature was maintained at 35 ° C. and a solution of 3.27 g (29.2 mmol) of cyclohexanecarbaldehyde in 8.4 mL of toluene / acetonitrile (49: 1) was slowly added dropwise over 2 hours. The mixture was stirred at 35 ° C. for 4 hours and at room temperature for 2 hours. The mixture was then cooled to -10 ° C and 8.0 mL of methanol was added. 1.64 mg (43.3 mmol) of solid sodium cyanoborohydride was added little by little over 30 minutes, and the temperature was not allowed to exceed −2 ° C. during the addition. After the addition was complete, the mixture was stirred at 0 ° C for 1 hour. The phases were separated by adding 150 mL of a 6% by weight solution of ammonia in water, followed by 3 mL of acetonitrile and methanol each added to the organic phase. The organic phase was washed with 150 mL of a 15% solution of sodium chloride in water and dried over sodium sulfate. The organic phase was filtered through 150 g silica gel and the filter cake was washed twice with 200 ml of diethyl ether each. The organic filtrate was concentrated under reduced pressure and chromatographed on 200 g silica gel (70-230 mesh). First, the by-product was eluted with cyclohexane, then the product was eluted with a mixture of cyclohexane and diethyl ether (20: 1). As a result, 4.25 g (50% of theory) of solid were obtained.

R _f (petroleum ether / ethyl acetate 5: 1) = 0.4

Step c): ethyl {4-[(5-bromo-2,3-dihydro-3-spiro-1'-cyclohexyl-1H-indol-1-yl) sulfonyl] -2-methylphenoxy} acetate

4.5 g (16.9 mmol) of 5-bromo-2,3-dihydro-3-spiro-1'-cyclohexyl-1H-indole, 5.18 ml (37.2 mmol) triethylamine in 60 mL pure tetrahydrofuran And a solution of 210 mg (1.69 mmol) 4-dimethyl-aminopyridine is cooled to −5 ° C. and at this temperature 4.95 g (16.91 mmol) ethyl [4- (chlorosulfonyl) in 40 mL of pure tetrahydrofuran A solution of -2-methylphenoxy] acetate (Example 1 / step e) was added dropwise. The mixture was stirred at room temperature for 18 hours and 150 mL of distilled water was added. This mixture was extracted three times with 150 mL of ethyl acetate each. The combined organic phases were washed with 200 mL of saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography using 150 g silica gel (70-230 mesh). The mobile phase used was a mixture of cyclohexane and ethyl acetate (6: 1). As a result, 8.25 g (93% in theory) of a solid foam product were obtained.

R _f (petroleum ether / ethyl acetate 3: 1) = 0.6

Step d): {4-[(5-Bromo-2,3-dihydro-3-spiro-1'-cyclohexyl-1H-indol-1-yl) sulfonyl] -2-methyl-phenoxy} Acetic acid

3.3 g (6.32 mmol) ethyl {4-[(5-bromo-2,3-dihydro-3-spiro-1'-cyclohexyl-1H-indol-1-yl) sulphate in 16 mL of tetrahydrofuran To a solution of phonyl] -2-methylphenoxy} acetate was added 0.53 g (9.47 mmol) potassium hydroxide solution in 8 mL water. The mixture was stirred at room temperature for 1 hour and 0.49 g (3.16 mmol) sodium dihydrogen phosphate dihydrate was added. Tetrahydrofuran was removed under reduced pressure and the residue was diluted with 40 ml of water. This mixture was washed once with 40 mL of diethyl ether. This aqueous phase was adjusted to pH 2 with 1 N hydrochloric acid solution and extracted three times with 40 mL of dichloromethane each. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. As a result, 2.55 g (82% in theory) of a solid foam product were obtained.

R _f (petroleum ether / ethyl acetate 1: 3) = 0.14

Step e): (4-{[5- (4-Trifluoromethylphenyl) -2,3-dihydro-3-spiro-1'-cyclohexyl-1H-indol-1-yl] -sulfonyl}- 2-methylphenoxy) acetic acid

84.9 mg (0.45 mmol) of 4-trifluoromethylboronic acid under argon gas in 170 mg (0.34 mmol) of {4-[(5-bromo-2,3) in 3 mL of 1,2-dimethoxyethane. -Dihydro-3-spiro-1'-cyclohexyl-1H-indol-1-yl) sulfonyl] -2-methylphenoxy} acetic acid and 6.2 mg (8.5 μmol) of 1,1'-bis (diphenyl Phospho) ferrocenepalladium (II) chloride solution was added. 0.76 ml of 2 N sodium carbonate solution was added with vigorous stirring. The mixture was stirred at 60 ° C overnight. 8.50 mg (0.048 mmol) of 1,3,5-triazine-2,4,6-tritriol were added to the reaction solution at room temperature. The pH was adjusted to 4-5 with 5 N trifluoroacetic acid in water, and then the solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Kroma-Sil 50 × 20 mm, mobile phase A: water with 0.3% trifluoroacetic acid, mobile phase B: acetonitrile, 0 min A: B = 1: 1, 7 min A: B = 1: 4, 8 min A: B = 1: 9). As a result, 116 mg (61% of theory) of solid were obtained.

R _f (methylene chloride / methanol 10: 1) = 0.28

Example 6

(4-{[5- (4-methoxyphenyl) -2,3-dihydro-1H-indol-1-yl] sulfonyl} -2-methylphenoxy) -acetic acid

Step a): Ethyl {4-[(5-bromo-2,3-dihydro-1H-indol-1-yl) sulfonyl] -2-methylphenoxy} acetate

Of 792 mg (4.00 mmol) 5-bromoindoline, 1.23 ml (8.80 mmol) triethylamine and 48.9 mg (0.400 mmol) 4-dimethylaminopyridine in a 12 mL tetrahydrofuran at a temperature between -5 ° C and 0 ° C. To the solution was added dropwise a solution of 1.17 g (4.00 mmol) ethyl [4- (chlorosulfonyl) -2-methylphenoxy] acetate in 8 mL of tetrahydrofuran (Example 1 / step e). The mixture was warmed to room temperature and stirred for another 2 hours. 30 mL of water was added to the reaction solution, which was extracted three times with 20 mL of ethyl acetate each. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. 1.5 g of the crude product thus obtained were purified by flash chromatography (silica gel 70-230 mesh, mobile phase: cyclohexane / ethyl acetate 5: 1). As a result, 1.26 g (69% of theory) of a solid product were obtained.

R _f (petroleum ether / ethyl acetate 4: 1) = 0.25

Step b): 4-[(5-Bromo-2,3-dihydro-1H-indol-1-yl) sulfonyl] -2-methylphenoxyacetic acid

310 mg (0.682 mmol) ethyl {4-[(5-bromo-2,3-dihydro-1H-indol-1-yl) sulfonyl] -2-methylphenoxy} in 2 mL tetrahydrofuran} To a solution of acetate was added 57.4 mg (1.02 mmol) potassium hydroxide solution in 1 mL water. The mixture was stirred at room temperature for 45 minutes and the solvent was removed under reduced pressure. The residue was diluted with 3 mL of water and adjusted to pH 2 with 1 N hydrochloric acid. The resulting precipitate was filtered off by suction through a filter cartridge. The precipitates were washed twice with 2 mL of water each and dried under reduced pressure. As a result, 279 mg (96% of theory) of a solid product were obtained.

Step c): (4-{[5- (4-methoxyphenyl) -2,3-dihydro-1H-indol-1-yl] sulfonyl} -2-methylphenoxy) -acetic acid

Under argon gas, 54.7 mg (0.360 mmol) of 4-methoxyphenylboronic acid and 33.6 mg (0.792 mmol) of lithium chloride were first charged. 128 mg (0.300 mmol) 4-[(5-bromo-2,3-dihydro-1H-indol-1-yl) sulfonyl] -2-methylphenoxy in 3 mL of 1,2-dimethoxyethane Acetic acid and a solution of 3.5 mg (3.0 μmol) tetrakis (triphenylphosphine) -palladium (0) were added. While stirring vigorously, 660 μl of 2 M sodium carbonate solution in water was added. The mixture was heated at 60 ° C. overnight and then allowed to cool at room temperature. 8.50 mg (0.048 mmol) of 1,3,5-triazine-2,4,6-tritriol and 9.0 mg (0.041 mmol) of 2,2-bis (hydroxymethyl) -2,2 ', 2 " Nitrilotriethanol was added to the reaction solution and the mixture was concentrated under reduced pressure The residue was washed with 2 mL of cyclohexane / ethyl acetate (2: 1) solvent mixture and 3 mL of 1,2-dimethoxy Taken in a mixture of ethane and 0.6 ml of water and acidified with 0.66 ml of 5 N trifluoroacetic acid (pH ≦ 4) The solvent was removed under reduced pressure and the residue was taken up with tetrahydrofuran and preparative RP-HPLC (chroma-sil 50 x 20 mm, mobile phase A: water with 0.3% trifluoroacetic acid, mobile phase B: acetonitrile, 0 min A: B = 9: 1, 2 min A: B = 9: 1, 7 min A: B = 1: 9, 8 min A: B = 1: 9) to give 107 mg (79% of theory) of the freeze-dried product.

Example 7

(4-{[5- (4-trifluoromethylphenyl) -3,3-dimethyl-2,3-dihydro-1H-indol-1-yl] sulfonyl} -2-methylphenoxy) acetic acid

Step a): 5-bromo-3,3-dimethylindolin

45 ml of toluene / acetonitrile (49: 1) mixture was flushed with argon for 5 minutes and 3.00 g (13.4 mmol) 4-bromophenylhydrazine were added. Then, 3.71 ml (48.1 mmol) of trifluoroacetic acid was added slowly, taking care not to let the temperature exceed 35 ° C. The temperature was then maintained at 35 ° C., followed by the slow dropwise addition of 1.05 g (14.6 mmol) of isobutyraldehyde solution in 4 mL of toluene / acetonitrile (49: 1) over 2 hours. The mixture was stirred at 35 ° C. for 4 hours and at room temperature for 2 hours. The mixture was cooled to -10 [deg.] C. and 4.0 mL of methanol was added followed by 819 mg (21.7 mmol) of solid sodium cyanoborohydride in portions over 30 minutes at a time. The temperature should not exceed -2 ° C. After the addition was completed, the mixture was stirred at 0 ° C. for 1 hour. The phases were separated by adding 150 mL of a 6 wt% aqueous ammonia solution in water and 1.5 mL of acetonitrile and methanol were added to the organic phase, respectively. The organic phase was then washed with 150 mL of 15% sodium chloride solution in water and dried over sodium sulfate. The mixture was filtered through 100 g of silica gel and the filtercake was washed twice with 200 mL of diethyl ether each. The organic filtrate was concentrated under reduced pressure and chromatographed on 100 g of silica gel. The by-product was eluted first with cyclohexane and the product was then eluted with a mixture of cyclohexane / diethyl ether (20: 1). As a result, 1.78 g (54% of theory) oil product was obtained.

R _f (petroleum ether / ethyl acetate 5: 1) = 0.47

Step b): Ethyl {4-[(5-bromo-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) sulfonyl] -2-methylphenoxy} acetate

920 mg (4.07 mmol) of 5-bromo-3,3-dimethylindolin, 906 mg (8.95 mmol) of triethylamine and 49.7 mg (0.407 mmol) of 4-dimethylamino in 12.5 mL of pure tetrahydrofuran The solution of pyridine is cooled to −5 ° C. and a solution of 1.19 g (4.07 mmol) ethyl [4- (chlorosulfonyl) -2-methylphenoxy] acetate in 10 mL of pure tetrahydrofuran at this temperature (Example 1 / Step e) was added drop wise. The mixture was stirred at room temperature for 18 hours and then 100 mL of distilled water was added. This mixture was washed three times with 50 mL of ethyl acetate each. The combined organic phases were washed with 200 mL of saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by flash chromatography using 150 g silica gel. As a result, 1.74 g (89% in theory) of a solid foam product were obtained.

R _f (petroleum ether / ethyl acetate 3: 1) = 0.48

LC-MS (method A): R _t = 5.18 min

MS (ESIpos): m / z = 482 [M + H] ⁺

UV [nm] = 200, 238, 256

Step c): {4-[(5-Bromo-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) sulfonyl] -2-methylphenoxy} acetic acid

990 mg (2.05 mmol) ethyl {4-[(5-bromo-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) sulfonyl] -2- in 5 mL tetrahydrofuran] -2- To the methylphenoxy} acetate solution was added 173 mg (3.08 mmol) of potassium chloride and 2.5 mL of water solution, and the mixture was stirred at room temperature for 45 minutes. 160 mg (1.03 mmol) sodium dihydrogen phosphate dihydrate were added. The solvent was removed under reduced pressure. 40 mL of water was added to the residue and the mixture was washed with 20 mL of diethyl ether. The pH was then adjusted to 2 with 1N hydrochloric acid solution and the mixture was extracted three times with 20 mL of dichloromethane each. The organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. As a result, 805 mg (86% in theory) of a solid foam product were obtained.

R _f (dichloromethane / methanol 10: 1) = 0.31

Step d): (4-{[5- (4-Trifluoromethylphenyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-1-yl] sulfonyl} -2-methylphenoxy Acetic acid

77.2 mg (0.17 mmol) {4-[(5-bromo-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) in 1.5 mL of 1,2-dimethoxyethane under argon Sulfonyl] -2-methylphenoxy} acetic acid and 6.2 mg (8.5 μmol) 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride solution in 38.0 mg (0.20 mmol) of 4-trifluoro It was added to methylphenylboronic acid. With vigorous stirring, 374 μl of a 2 M sodium carbonate solution in water was added and the mixture was stirred at 60 ° C. for 17 h under argon. To remove palladium, 8.50 mg (0.048 mmol) of 1,3,5-triazine-2,4,6-tritriol are added to the reaction mixture and the mixture is added with 5 N trifluoroacetic acid in water. Neutralized. The mixture was concentrated under reduced pressure and the residue was taken up with 3 mL of a mixture of dichloromethane and methanol (5: 1) and filtered through a cartridge filled with 2 g of silica gel. The product was eluted with 20 mL of dichloromethane / methanol mixture (5: 1) and the solvent was removed under reduced pressure. The residue was dissolved in a mixture of 400 μl tetrahydrofuran and 200 μl dimethyl sulfoxide and reversed phase HPLC (chroma-sil, 50 × 20 mm, mobile phase A: water, mobile phase B: aceto with 0.3% trifluoroacetic acid) Nitrile, concentration gradient 0 min 50% A, 50% B; 7 min 20% A and 80% B; 8 min 10% A and 90% B). The solvent was removed under reduced pressure. As a result, 46.1 mg (52% of theory) of a solid product were obtained.

LC-MS (method A): R _t = 5.15 min

Examples 8-96 listed in the following table were obtained similar to the process described above.

Example A

Cell transcription promotion assay

Test principle:

Cellular assays were used to identify the activators of peroxide proliferator-active receptor delta (PPAR-delta).

Since mammalian cells contain different endogenous nuclear receptors that may make the interpretation of the results difficult, an established chimeric system was used in which the ligand binding domain of the human PPARδ receptor fuses with the DNA binding domain of yeast transcription factor GAL4. The resulting GAL4-PPARδ chimeras were co-transfected and stably expressed in CHO cells with reporter structure.

Cloning:

The GAL4-PPARδ expression construct contains the ligand binding domain of PPARδ (amino acids 414-1326) which is PCR amplified and cloned in vector pcDNA3.1. The vector already contains the GAL4-DNA binding domain (amino acids 1-147) of the vector pFC2-dbd (Stratagene). The reporter structure containing five copies of the GAL4 binding site on top of the thymidine kinase promoter expressed firefly luciferase (Photinuspyralis) after activation and binding of GAL4-PPARδ.

Transcription Assay (Luciferase Reporter):

CHO-A-SFM medium (GIBCO) added 2.5% fetal bovine serum and 1% penicillin / streptomycin (GIBCO) at a cell density of 2 × 10 ³ per well of 384-well plate (Greiner) CHO (Chinese hamster ovary) cells were seeded. Cells were stimulated after incubating at 37 ° C. for 48 hours. To this end, the material to be tested was taken in the above-mentioned medium and added to the cells. After 24 hours of stimulation, luciferase activity was measured with a video camera. Relatively bright units measured showed a sigmoidal stimulus curve as a function of material concentration. EC ₅₀ values were calculated using the computer program GraphPad PRISM (version 3.02).

In this test, Examples 1-96 showed EC ₅₀ values in the range of 1-200 nM.

Example B

Increasing HDL cholesterol (HDL-C) concentrations in serum of transgenic mice transfected with human ApoA1 gene (hApoA1) and / or affecting metabolic syndrome in lipid ob, ob mice and reducing blood glucose concentrations Description of the test for finding pharmacologically active substances

Substances to be investigated in vivo for HDL-C increasing activity were administered to orally genetically transformed male hApoA1 mice. One day before the start of the experiment, groups were randomized to have the same number of animals (usually n = 7 to 10). Animals were fed with drinking water and food throughout the experiment. The substances were administered orally once a day for 7 days. To this end, the test material was dissolved in a 1 + 1 + 8 ratio of Solutol HS 15 + Ethanol + Saline (0.9%) solution or in a 2 + 8 ratio of Solutol HS 15 + Saline (0.9%) solution. The dissolved material was administered at a volume of 10 mL / Kg body weight using the gavage. Animals treated in exactly the same manner but fed only solvent (10 mL / Kg body weight) without test substance administration were used as controls.

Blood samples from each mouse were collected by puncture of the orbital posterior vein prior to the initial administration of the material to determine ApoA1, serum cholesterol, HDL-C and serum triglycerides (TG). The test substance was then first administered to the animal using gavage. Twenty four hours after the last dose of the substance (ie, eight days after the start of treatment), another blood sample was collected by puncturing the orbital posterior vein to determine the same parameters. Blood samples were centrifuged, serum was obtained and cholesterol and TG were measured using EPOS Analyzer 5060 (Eppendorf-Geraetebau, Netheler & Hinz GmbH, Hamburg). This measurement was performed using a commercial enzyme test (Boehringer Mannheim, Mannheim).

To measure HDL-C, non-HDL-C fractions were precipitated using 20% PEG 8000 in 0.2 M glycine buffer pH 10. Cholesterol was measured from the supernatants (BIO-TEK Instruments, USA) by UV-photometry in 96-well plates using commercially available reagents (Ecoline 25, Merck, Darmstadt).

Human mouse-ApoA1 was measured by sandwich ELISA using a polyclonal anti-human-ApoA1 antibody and a monoclonal anti-human-ApoA1 antibody (Biodesign International, USA). Quantification was performed by UV-photometry (BIO-TEK Instruments, USA) using peroxidase-binding anti-mouse-IGG antibody (KPL, USA) and peroxidase substrate (KPL, USA).

The effect of the test substance on the HDL-C concentration was determined by subtracting the value measured for the first blood sample (zero value) from the value measured for the second sample (after treatment). The average of the differences of all HDL-C values in one group was determined and compared with the average of the differences in the control group.

After investigating the deviation for homogeneity, statistical evaluation was performed using the Student's t-test.

Compared to the control, the substances that statistically significantly (p <0.05) increase the HDL-C of the treated animals by 15% or more were considered pharmacologically effective.

To investigate substances that are effective in metabolic syndrome, animals with insulin resistance and increased blood glucose levels were used. To this end, C57Bl / 6J Lep <ob> mice were treated using the same protocol as the genetically transformed ApoA1 mice. Serum lipids were measured as described above. In these animals, serum glucose was additionally measured as a variable for blood glucose. Serum glucose was measured by EPOS Analyzer 5060 (see above) using a commercially available enzyme test (Boehringer Mannheim).

The blood glucose lowering effect of the test substance was determined by subtracting the value of the first blood sample of the animal (0 value) from the value of the second blood sample of the same animal (after treatment). The average of all the serum glucose values in one group was determined and compared with the average of the differences in the control group.

After investigating the deviation for homogeneity, statistical evaluation was performed using the Student's t-test.

Compared to the control, a substance that statistically significantly (p <0.05) reduced serum glucose concentrations of treated animals by at least 10% was considered pharmacologically effective.

Claims (11)

Compounds of formula (I) and their pharmaceutically acceptable salts, solvates and solvates of such salts. <Formula I> Wherein A represents a CR ¹¹ group wherein R ¹¹ represents hydrogen or (C ₁ -C ₄ ) -alkyl or N X represents O, S or CH ₂ , R ¹ represents (C ₆ -C ₁₀ ) -aryl or 5- to 10-membered heteroaryl having up to 3 heteroatoms from the group consisting of N, O and S wherein the groups are halogen, cyano, nitro, (C ₁ -C ₆ ) -alkyl (which may be substituted by hydroxyl in part thereof), (C ₁ -C ₆ ) -alkoxy, phenoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, (C ₂ -C ₆ ) -alkenyl, phenyl, benzyl, (C ₁ -C ₆ ) -alkylthio, (C ₁ -C ₆ ) -alkylsulfonyl, (C ₁ -C ₆ ) -alkanoyl, (C ₁ -C ₆ ) -alkoxycarbonyl, carboxyl, amino, (C ₁ -C ₆ ) -acylamino, mono- and di- (C ₁ -C ₆ ) -alkylamino the same or different substituents selected from the group May be substituted with a single to three in each part thereof; and 5- or 6-membered heterocyclyl having 2 or less heteroatoms from the group consisting of N, O and S, or a group represented by the following structural formula And, R ² and R ³ are the same or different and each independently represent hydrogen or (C ₁ -C ₆ ) -alkyl or together with the carbon atom to which they are attached form a 3- to 7-membered spiro-bonded cycloalkyl ring and, R ⁴ represents hydrogen or (C ₁ -C ₆ ) -alkyl, R ⁵ represents hydrogen or (C ₁ -C ₆ ) -alkyl, R ⁶ represents hydrogen or (C ₁ -C ₆ ) -alkyl, R ⁷ represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy or halogen, R ⁸ and R ⁹ are the same or different and each independently represent hydrogen or (C ₁ -C ₄ ) -alkyl, R ¹⁰ represents hydrogen or a hydrolyzable group which can be decomposed to the corresponding carboxylic acid. The compound of claim 1, wherein in formula (I), A represents a CR ¹¹ group, wherein R ¹¹ represents hydrogen or methyl, or represents N, X represents O or S, R ¹ represents phenyl or 5- or 6-membered heteroaryl having up to 2 heteroatoms from the group consisting of N, O and S, wherein the groups are fluorine, chlorine, cyano, (C ₁ -C ₄ ) -Alkyl, (C ₁ -C ₄ ) -alkoxy, phenoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, vinyl, phenyl, benzyl, methylthio, methylsulfonyl, acetyl, propionyl, (C ₁ -C ₄₎ - alkoxycarbonyl, amino, acetylamino, mono- and di - (C ₁ -C ₄₎ - in a single or parts thereof by the same or different substituents selected from the group consisting of alkylamino, each of which Can be substituted, R ² and R ³ are the same or different and each independently represent hydrogen or (C ₁ -C ₄ ) -alkyl or together with the carbon atom to which they are attached form a 5- or 6-membered spiro-bonded cycloalkyl ring and, R ⁴ represents hydrogen or methyl, R ⁵ represents hydrogen, methyl or ethyl, R ⁶ represents hydrogen or methyl, R ⁷ represents hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, fluorine or chlorine, R ⁸ and R ⁹ are the same or different and each independently represent hydrogen or methyl, R ¹⁰ represents hydrogen. The compound of claim 1, wherein in formula (I), A represents CH or N, X represents O, R ¹ represents phenyl or is substituted by the same or different substituents selected from the group consisting of fluorine, chlorine, methyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, methylthio, amino and dimethylamino Each of these represents a single or pyridyl which may be substituted, R ² represents hydrogen or methyl and R ³ represents methyl, isopropyl or tert-butyl, or R ² and R ³ together with the carbon atom to which they are attached form a spiro-bonded cyclohexane ring, R ⁴ represents hydrogen or methyl, R ⁵ represents hydrogen, methyl or ethyl, R ⁶ represents hydrogen or methyl, R ⁷ represents methyl, R ⁸ and R ⁹ each represent hydrogen, R ¹⁰ represents hydrogen. A compound of formula (I-A) <Formula I-A> Wherein R ² represents hydrogen and R ³ represents methyl, isopropyl or tert-butyl, or R ² and R ³ both represent methyl or a spiro-bonded cyclohexane ring together with the carbon atom to which they are attached Form the A, R ¹ , R ⁴ , R ⁵ and R ⁶ are as defined in claims 1 to 3, respectively. Initially converting a compound of formula II into a compound of formula IV using a compound of formula III in an inert solvent in the presence of a base, <Formula II> <Formula III> <Formula IV> (Wherein A, X, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each as defined in claim 1, T represents benzyl or (C ₁ -C ₆ ) -alkyl, Y represents chlorine or bromine) Then reacting these compounds by coupling reaction with a compound of formula V in an inert solvent in the presence of a suitable palladium catalyst and base to give a compound of formula I-B, <Formula V> Wherein R ¹ is as defined in claim 1, R ¹² represents hydrogen or methyl or the two groups together form —CH ₂ CH ₂ — or —C (CH ₃ ) ₂ —C (CH ₃ ) ₂ — bridge) <Formula I-B> (Wherein A, T, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each as defined in claim 1). Then reacting the compound (I-B) with an acid or a base or subjecting hydrogenation if T represents benzyl to obtain the corresponding carboxylic acid of formula (I-C), and <Formula I-C> (Wherein A, X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each as defined in claim 1). Further modifying the carboxylic acid (I-C), if appropriate, by known esterification methods to obtain the compound of formula (I) A process for preparing a compound of formula (I) or (I-A) as defined in claim 1. A compound of formula (I) or (I-A) as defined in claims 1 to 5 for the prevention and treatment of diseases. A medicament comprising at least one compound of formula (I) or (I-A) as defined in each of claims 1 and 5, and an inert and non-toxic pharmaceutically acceptable carrier, adjuvant, solvent, excipient, emulsifier and / or dispersant. Use of a compound of formula (I) or formula (I-A) and a medicament as defined in claims 1 to 7 for the prevention and treatment of diseases. Use of a compound of formula (I) or formula (I-A) as defined in claims 1 to 6 for the manufacture of a medicament. Definitions according to claims 1 to 5 for the preparation of a medicament for the prevention or treatment of stroke, atherosclerosis, coronary heart disease and dyslipidemia, the prevention of myocardial infarction, and the treatment of restenosis after coronary angioplasty or stent Use of a compound of formula (I) or (IA) as above. A method of preventing or treating a disease, characterized in that the compound of formula (I) or formula (I-A) as defined in claims 1 and 5 acts on an organism.