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  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P3/00—Drugs for disorders of the metabolism
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  • A61P5/00—Drugs for disorders of the endocrine system
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
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• • A—HUMAN NECESSITIES
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  • A61P9/00—Drugs for disorders of the cardiovascular system
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/12—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Definitions

• the present application relates to new substituted indole-phenylsulfonamide derivatives, processes for their preparation and their use in medicaments, in particular as potent PPAR-delta activating compounds for the prophylaxis and / or treatment of cardiovascular diseases, in particular dyslipidemias and coronary heart diseases.
• CAD coronary artery disease
• fibrates are the only form of therapy for patients in these risk groups. They act as weak agonists of the peroxisome proliferator-activated receptor (PPAR) -alpha (Nature 1990, 347, 645-50). A disadvantage of previously approved fibrates is their poor interaction with the receptor, which leads to high daily doses and significant side effects.
• PPAR peroxisome proliferator-activated receptor
• WO 00/23407 discloses PPAR modulators for the treatment of obesity, atherosclerosis and / or diabetes.
• WO 93/15051 and EP 636 608-A1 describe l-benzenesulfonyl-l, 3-dihydroindol-2-one derivatives as vasopressin and / or oxytocin antagonists for the treatment of various diseases.
• Substituted indole-phenylsulfonamide derivatives with antiviral activity are described in WO 01/34146.
• the object of the present invention was to provide new compounds which can be used as PPAR delta modulators.
• X represents O, S or CH 2 ,
• R 1 stands for (C 6 -C 1 o) aryl or for 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, which are in each case one to three times, identical or different, by substituents selected from the group halogen, cyano, nitro, (-CC 6 ) -alkyl, which in turn can be substituted by hydroxy or amino, (-CC 6 ) -alkoxy, trifluoromethyl, trifluoromethoxy, (C 2 - C 6 ) -alkenyl, (-C-C 6 ) -alkylthio, (-C-C 6 ) -alkylsulfonyl, (Ci--C 6 ) -alkanoyl, (dC ⁇ -alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, amino, (-C ⁇ -C 6 ) Acylamino, mono- and di- (-C 6 ) alky
• R 2 for phenyl or 5- to 6-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, each one to three times, identical or different different, can be substituted by substituents selected from the group halogen, cyano, nitro, trifluoromethyl, (C 1-4 alkyl, hydroxy, trifluoromethoxy and (C 1 -C 4 ) alkoxy,
• R 3 represents hydrogen or (-CC 4 ) alkyl
• R 4 represents hydrogen or (dC ⁇ alkyl
• R 5 represents hydrogen, (-CC 6 ) alkyl, (-CC 6 ) alkoxy or halogen,
• R 6 and R 7 are identical or different and independently of one another represent hydrogen or (dC 4 ) -alkyl
• R 8 represents hydrogen or a hydrolyzable group which can be broken down into the corresponding carboxylic acid
• Such groups are exemplary and preferably: benzyl, (QC ⁇ alkyl or (C 3 - C 8 ) cycloalkyl, each optionally one or more times, identically or differently, by halogen, hydroxy, amino, (C 1 -C 6 ) -Alkoxy, carboxyl, (-C-C 6 ) - alkoxycarbonyl, (CrC 6 ) -alkoxycarbonylamino or (QC ⁇ -alkanoyloxy) are substituted, or in particular (-CC) -alkyl, which may be one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (-C-C 4 ) alkoxycarbonylamino or (Q-C4) - alkanoyloxy is substituted.
• (CrCCl-alkyl and (CrC 4 -alkyl) stand for a straight-chain or branched alkyl radical with 1 to 6 or 1 to 4 carbon atoms.
• a straight-chain or branched alkyl radical with 1 to 4 carbon atoms is preferred. Examples and preferably are mentioned : Methyl, ethyl, n-propyl, isopropyl and t-butyl.
• Cz-CfiVAlkenyl stands for a straight-chain or branched alkenyl radical with 2 to 6 carbon atoms.
• a straight-chain or branched alkenyl radical with 2 to 4 carbon atoms is preferred. Examples and, preferably, are: vinyl, allyl, isopropenyl and n-but- 2-en-l-yl.
• (C 3 -Cg) cycloalkyl stands for a monocyclic cycloalkyl group with 3 to 8 carbon atoms. Examples and preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• (C 6 -C_ ⁇ n) aryl in the context of the invention represents an aromatic radical having preferably 6 to 10 carbon atoms.
• Preferred aryl radicals are phenyl and naphthyl.
• (C 1 -C 6 ) -alkoxy and (C 1 -C 4 -alkoxy) stand for a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms.
• a straight-chain or branched alkoxy radical with 1 to 4 carbon atoms is preferred .
• the following may be mentioned as examples and preferably: methoxy, ethoxy, n-propoxy, isopropoxy and t-butoxy.
• (C ⁇ -C 6 -alkoxycarbonyl and (CrC -alkoxycarbonyl in the context of the invention represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms which is linked via a carbonyl group.
• a straight-chain or branched alkoxycarbonyl radical having 1 up to 4 carbon atoms, and examples which may be mentioned are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.
• (-C-C 6 -alkoxycarbonylamino and (-CC> alkoxycarbonylamino are within the scope of the invention for an amino group with a straight-chain or branched alkoxycarbonyl substituent which has 1 to 6 or 1 to 4 carbon atoms in the alkoxy radical and is linked via the carbonyl group
• An alkoxycarbonylamino radical having 1 to 4 carbon atoms is preferred, and examples which may be mentioned are: methoxycarbonylamino, emoxycarbonylamino, n-propoxycarbonylamino and t-butoxycarbonylamino.
• a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms which carries a double bonded oxygen atom in the 1 position and is linked via the 1 position.
• a straight-chain or branched alkanoyl radical having 1 to 4 carbon atoms is preferred. The following may be mentioned as examples and preferably: formyl, acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl and n-hexanoyl.
• (C ⁇ -Cfi -alkanoyloxy and (-CC 4 -alkanoyloxy are within the scope of the invention for a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon- atoms which carry a double bonded oxygen atom in the 1 position and which is linked via a further oxygen atom in the 1 position.
• An alkanoyloxy radical having 1 to 4 carbon atoms is preferred. Examples that may be mentioned are: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy, n-hexanoyloxy.
• Mono-fC C ⁇ VAlkylamino and mono-fC VAll- lamino stand in the context of the invention for an amino group with a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms.
• a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms is preferred. Examples and preferably mentioned are: methylamino, emylamino, n-propylamino, isopropylamino and t-butylamino.
• di- (CrC 6 ) -all-yl-u-ino and di- (Cj-C 4 VA-k ⁇ lamino) represent an amino group with two identical or different straight-chain or branched alkyl substituents, each of which has 1 up to 6 or 1 to 4 carbon atoms are preferred.
• Straight-chain or branched dialkylamino radicals each having 1 to 4 carbon atoms.
• NN-dimethylamino NN-diethylamino, N-emyl-N-memylamino, N-methyl -Nn-propylamino, N-isopropyl-Nn-propylamino, Nt-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-memylamino.
• an amino group with a straight-chain or branched alkanoyl substituent which has 1 to 6 carbon atoms and is linked via the carbonyl group.
• An acylamino radical having 1 to 2 carbon atoms is preferred. The following may be mentioned by way of example and preferably: foramido, acetamido, propionamido, n-butyramido and pivaloylamido.
• (CrC ⁇ VAlkylthio stands in the context of the invention for a straight-chain or branched alkylthio radical with 1 to 6 carbon atoms.
• a straight-chain or branched alkylthio radical with 1 to 4 carbon atoms is preferred. Examples and Mention should preferably be made of: methylthio, ethylthio, n-propylthio, isopropylthio, t-butylthio, n-pentylthio and n-hexylthio.
• C ⁇ _-Cfi) -Alkylsulfonyl stands in the context of the invention for a straight-chain or branched alkylsulfonyl radical having 1 to 6 carbon atoms.
• a straight-chain or branched alkylsulfonyl radical having 1 to 4 carbon atoms is preferred.
• the following may be mentioned as examples and preferably: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, t-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.
• 5- to 10-membered or 5- to 6-membered heteroaryl with up to 3 or up to 2 identical or different heteroatoms from the series N, O and / or S in the context of the invention is a mono- or optionally bicyclic aromatic heterocycle (heteroaromatic), which is linked via a ring carbon atom or optionally via a ring nitrogen atom of the heteroaromatic.
• heteroaromatic aromatic heterocycle
• Examples include: furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, indolylinyl, indolylinyl, indolylinyl, indolylinyl Quinazolinyl, quinoxalinyl.
• 5- to 6-membered heteroaryl radicals having up to two heteroatoms from the series N, O and / or S such as, for example, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, are preferred.
• 5- to 6-membered heterocyclyl having up to 2 heteroatoms from the series N, O and / or S represents a saturated heterocycle which is linked via a ring carbon atom or optionally via a ring nitrogen atom of the heterocycle.
• the following are mentioned by way of example and preferably: tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
• Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred.
• the Neritatien according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or which do not behave like image and mirror image (diastereomers).
• the invention relates both to the enantiomers or diastereomers and to their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
• the compounds according to the invention can also be present as salts, physiologically acceptable salts are preferred within the scope of the invention.
• Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid are preferred, or salts with organic carbon or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid , Benzenesulfonic acid, toluenesulfonic acid or ⁇ aphthalenedisulfonic acid.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid are preferred, or salts with organic carbon or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methane
• Physiologically acceptable salts can also be salts of the compounds according to the invention with bases, such as metal or ammonium salts.
• bases such as metal or ammonium salts.
• alkali metal salts for example sodium or potassium salts
• alkaline earth metal salts for example magnesium or calcium salts
• ammonium salts which are derived from ammonia or organic amines, for example ethylamine, di- or triemylamine, ethyldiisopropylamine, monoethanolamine, di- or Triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methyl morpholine, dihydroabietylamine, 1-ephenamine, N-methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.
• the compounds according to the invention and their salts can also be present in the form of their solvates, in particular in the form of their hydrates.
• X represents O or S
• R 1 represents phenyl or 5- to 6-membered heteroaryl with up to two heteroatoms from the series N, O and / or S, each of which is one to two times, identical or different, by substituents selected from the group fluorine, chlorine, Bromine, cyano, (C] . -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, trifluoromethyl, trifluoromethoxy, methylthio, acetyl, (C ⁇ -C) alkoxycarbonyl, amino, mono- and di- (-C-C 4 ) alkylamino can be substituted,
• R> 3 represents hydrogen or methyl
• R 4 represents hydrogen or methyl
• R 5 represents hydrogen, (-CC 4 ) -alkyl, (-CC 4 ) -alkoxy, fluorine or chlorine,
• R 6 and R 7 are identical or different and independently of one another represent hydrogen or methyl
• R 8 represents hydrogen
• R 1 represents phenyl, which can be substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine, chlorine, methyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, methylthio and dimethylamino,
• R 2 represents thiazolyl, (CrC - ⁇ - alkyl, acetyl or a group of the formula -CH 2 NR 9 R 10 , in which
• R 9 and R 10 are the same or different and represent (Ci-C- alkyl, or together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine or N ' -Methylpiperazin ring form,
• R 3 represents hydrogen, R represents hydrogen or methyl
• R 5 represents methyl
• R ⁇ represents hydrogen
• R 9 and R 10 are the same or different and represent (-CC 4 ) alkyl, or together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine or N Form a methylpiperazine ring,
• R 11 represents fluorine, chlorine, methyl, tert-butyl, trifluoromethyl, methoxy or trifluoromethoxy.
• Y represents chlorine or bromine
• T represents benzyl or (-C f -alkyl
• R 12 represents hydrogen or methyl or both radicals together form a -CH 2 CH 2 - or -C (CH 3 ) 2 -C (CH 3 ) 2 bridge, in an inert solvent in the presence of a suitable palladium catalyst and a base to give compounds of the general formula (IB)
• the coupling reaction step [cf. (IV) + (V) - »(I-B)] and the ester cleavage [cf. (I-B) - »(I-C)] can optionally also take place in reverse order in the reaction sequence described above; it is also possible to carry out a basic ester cleavage in situ in the coupling reaction.
• Inert solvents for process step (II) + (IH) - »(IV) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran or diethylene dimethyl ether - Dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, 2-butanone, dimethylformamide, dimethyl sulfoxide, acetonitrile, N-methylpyrrolidinone or pyridine. It is also possible to use mixtures of the solvents mentioned.
• the usual inorganic or organic bases are suitable as bases for process step (II) + (III) -> (IN).
• These preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate, alkali metal hydrides such as sodium hydride, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmo-holin or N- methylpiperidine.
• Potassium carbonate or amine bases such as triethylamine, pyridine or ethyldiisopropylamine are particularly preferred, optionally in the presence of catalytic amounts (approx. 10 mol%) of 4-N, N-dimethylaminopyridine or 4-pyrrolidinopyridine.
• the base is used here in an amount of 1 to 5, preferably 1 to 2.5, mol, based on 1 mol of the compound of the general formula (IH).
• the reaction generally takes place in a temperature range from 0 ° C. to + 150 ° C., preferably from + 25 ° C. to + 100 ° C.
• the reaction can be carried out under normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.
• Inert solvents for process step (IN) + (N) - »(IB) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert Butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, acetonitrile or water. It is also possible to use mixtures of the solvents mentioned. Toluene, dimethylformamide or acetonitrile are preferred.
• the usual inorganic or organic bases are suitable as bases for the process step (IV) + (V) -> • (I-B).
• bases preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate, alkali metal phosphates such as sodium or potassium phosphate, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine.
• alkali metal hydroxides such as lithium, sodium or potassium hydroxide
• alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate
• alkali metal phosphates such as sodium or potassium phosphate
• organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine.
• the base is used in an amount of 1 to 5, preferably 2 to 3, moles, based on 1 mole of the compound of the general formula (IV).
• Suitable palladium catalysts for process step (IV) + (V) - »(IB) are preferably palladium (O) - or palladium (II) compounds which are used preformed, such as, for example, [l, -bis (diphenylphosphino) ferrocenyl ] palladium (II) chloride or bis (ttiphenylphosphine) palladium (II) chloride, or those obtained in situ from a suitable palladium source such as, for example, bis (dibenzylidene acetone) palladium (0) or tetrakis (triphenylphosphine) palladium (0), and a suitable phosphine ligand.
• a suitable palladium source such as, for example, bis (dibenzylidene acetone) palladium (0) or tetrakis (triphenylphosphine) palladium (0), and a suitable phosphine ligand.
• the reaction generally takes place in a temperature range from 0 ° C. to + 150 ° C., preferably from + 20 ° C. to + 100 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
• Inert solvents for process step (IB) -_> are, for example, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n- Propanol, iso-propanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidinone. It is also possible to use mixtures of the solvents mentioned. Alcohols such as methanol or ethanol are preferred.
• the usual inorganic bases are suitable as bases for process step (I-B) - »(I-C). These preferably include alkali hydroxides such as lithium, sodium or potassium hydroxide, or alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate. Lithium or sodium hydroxide are particularly preferred.
• the base is used in an amount of 1 to 5, preferably 1 to 3, mol, based on 1 mol of the compound of the general formula (I-B).
• Suitable acids for process step (IB) - »(IC) are the customary inorganic acids such as, for example, hydrochloric acid or sulfuric acid, or sulfonic acids such as toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, or carboxylic acids such as trifluoroacetic acid.
• the reaction generally takes place in a temperature range from -20 ° C. to + 100 ° C., preferably from 0 ° C. to + 30 ° C.
• the reaction can be carried out under normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.
• Inert solvents for process step (VI) - (VII) are, for example, ethers such as dioxane, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or other solvents such as dimethylformamide , Dimethyl sulfoxide, N-methylpyrrolidinone or water. It is also possible to use mixtures of the solvents mentioned.
• the preferred solvent is water.
• the usual inorganic or organic acids are suitable as acids for process step (VI) - (VII). 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. Semi-concentrated to concentrated aqueous hydrochloric acid, which also serves as a solvent, is particularly preferred.
• the reaction generally takes place in a temperature range from -30 ° C. to + 80 ° C., preferably from -10 ° C. to + 25 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
• Inert solvents for process step (VII) + (VHI) - »(II) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene dimethyl ether ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetonitrile or water. It is also possible to use mixtures of the solvents mentioned. It is also possible to carry out the reaction
• the usual inorganic or organic acids are suitable as acids for process step (VII) + (VIII) - (II). 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.
• the usual Lewis acids such as boron trifluoride, aluminum trichloride or zinc chloride are also suitable.
• the acid is used in an amount of 1 to 10 mol, based on 1 mol of the compound of the general formula (VII).
• the use of zinc chloride preferably in an amount of 1 to 2 moles based on 1 mole of the compound (VII), is preferred.
• the reaction generally takes place in a temperature range from + 20 ° C to + 250 ° C, preferably in a temperature range from + 130 ° C to + 200 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
• chlorosulfonic acid cf. e.g. P. D. Edwards, R.C. Mauger, K.M. Cottrell, F.X. Morris, K.K. Pine, M.A. Sylvester, C.W. Scott, S.T. Furlong, Bioorg. Med. Chem. Lett. 2000, 10, 2291-2294].
• Inert solvents for process step (IX) + (X) -> (XI) are, for example, ethers such as diethyl ether, dioxane, tefrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone , Dimethylformamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidinone. Just- it is possible to use mixtures of the solvents mentioned. Dimethylformamide or acetone is preferred.
• the usual inorganic or organic bases are suitable as bases for process step (IX) + (X) - »(XI).
• bases preferably include alkali hydroxides such as lithium, sodium or potassium hydroxide, alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate, alkali hydrides such as sodium hydride, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine , Potassium carbonate is particularly preferred.
• the base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compound of the general formula (IX).
• the reaction generally takes place in a temperature range from -20 ° C. to + 150 ° C., preferably from 0 ° C. to + 80 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
• R 2 represents a group of the formula -CH 2 ⁇ R 9 R 10 , wherein
• R 9 and R 10 are the same or different and stand for (-CC 4 ) -alkyl, or together with the nitrogen atom to which they are attached Form a pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine or N'-methylpiperazine ring,
• R 3 represents hydrogen
• Inert solvents for process step (XIII) + (V) - »(XTV) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert .
• Butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, acetonitrile or water. It is also possible to use mixtures of the solvents mentioned. Toluene, dimethylformamide or acetonitrile are preferred.
• the usual inorganic or organic bases are suitable as bases for process step (XIII) + (V) - »(XIV).
• bases preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate, alkali metal phosphates such as sodium or potassium phosphate, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine.
• alkali metal hydroxides such as lithium, sodium or potassium hydroxide
• alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate
• alkali metal phosphates such as sodium or potassium phosphate
• organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine.
• the base is used in an amount of 1 to 5, preferably 2 to 3, moles, based on 1 mole of the compound of the general formula (XIII).
• Suitable palladium catalysts for process step (XHI) + (V) - »(XTV) are preferably palladium (O) - or palladium (II) compounds which are used preformed, such as, for example, [l, l'-bis (diphenylphosphino ) ferrocenyl] palladium (II) chloride or bis (triphenylphosphine) palladium (II) chloride, or those obtained in situ from a suitable palladium source, such as, for example, bis (dibenzylidene acetone) palla- dium (0) or tetrakis (triphenylphosphine) palladium (0), and a suitable phosphine ligand can be generated.
• a suitable palladium source such as, for example, bis (dibenzylidene acetone) palla- dium (0) or tetrakis (triphenylphosphine) palladium (0), and a
• the reaction generally takes place in a temperature range from 0 ° C. to + 150 ° C., preferably from + 20 ° C. to + 100 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
• Inert solvents for the process step (XTV) + (III) - »(XN) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydethyl ether or diethylene glycol - Glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as omitromethane, ethyl acetate, acetone, 2-butanone, dimethylformamide, dimethyl sulfoxide, acetonitrile, ⁇ -methylpyrrolidinone or pyridine. It is also possible to use mixture
• Suitable bases for process step (XIV) + (III) -> (XV) are the customary inorganic or organic bases. These preferably include alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate, alkali metal hydrides such as sodium hydride, or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine , Potassium carbonate or amine bases such as triethylamine, pyridine or ethyldiisopropylamine are particularly preferred, optionally in the presence of catalytic amounts (approx. 10 mol%) of 4-N, N-dimethylaminopyridine or 4-pyrrolidinopyridine.
• alkali metal hydroxides such as lithium, sodium or potassium hydroxide
• alkali metal or alkaline earth metal carbonates such as sodium,
• the base is used here in an amount of 1 to 5, preferably 1 to 2.5, mol, based on 1 mol of the compound of the general formula (HI).
• the reaction generally takes place in a temperature range from 0 ° C. to + 150 ° C., preferably from + 25 ° C. to + 100 ° C.
• the reaction can be carried out under normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.
• reaction (XV) + (XVI) - »(XVII) takes place in the solvents customary for reductive amination, which are inert under the reaction conditions, optionally in the presence of an acid, such as acetic acid, and / or a dehydrating agent, such as sodium sulfate, Magnesium sulfate or molecular sieve.
• an acid such as acetic acid
• a dehydrating agent such as sodium sulfate, Magnesium sulfate or molecular sieve.
• the usual solvents include, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloromethane or carbon tetrachloride, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions. It is also possible to use mixtures of the solvents mentioned. Methanol, dichloromethane, 1,2-dichloroethane or trichloromethane are preferred, optionally with the addition of acetic acid.
• ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol di
• the reducing agent is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compound of the general formula (XV).
• the amine of the general formula (XVI) is preferably used in an amount of 1 to 2 moles based on 1 mole of the compound (XV).
• the reaction generally takes place in a temperature range from 0 ° C. to + 100 ° C., preferably from + 20 ° C. to + 80 ° C. With normal, be carried out at elevated or reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.
• Solvents and bases or acids suitable for process step (XVII) - (I-D) correspond to those previously mentioned in process step (I-B) - »(I-C).
• the compounds according to the invention are preferably suitable for the treatment of arteriosclerosis and hypercholesterolemia, for increasing morbidly low HDL levels and for lowering increased triglyceride and LDL levels. They can also be used to treat obesity, diabetes, metabolic syndrome (glucose intolerance, hyperinsulinemia, dyslipidemia and high blood pressure due to insulin resistance), liver fibrosis and cancer.
• the new active substances can be used alone or, if necessary, in combination with other active substances, preferably from the group CETP inhibitors, antidiabetics, antioxidants, cytostatics, calcium antagonists, antihypertensive agents, thyroid hormones and / or thyroid mimetics, inhibitors of HMG-CoA reductase, Inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors, ACAT inhibitors, blood circulation-promoting agents, platelet aggregation inhibitors, anticoagulants, angiotensin II receptor antagonists, cholesterol absorption inhibitors, MTP inhibitors, aldolase redulants , Niacin, anoretics, lipase inhibitors and PPAR- ⁇ and / or PPAR- ⁇ agonists can be administered.
• active substances preferably from the group CETP inhibitors, antidiabetics, antioxidants, cytostatics, calcium antagonists, antihypertensive agents, thyroid hormones and / or thyroid mimetics, inhibitors
• the activity of the compounds according to the invention can e.g. Check in vitro using the transactivation assay described in the example section.
• the activity of the compounds according to the invention in vivo can be e.g. check by the examinations described in the example section.
• all customary forms of application come into consideration, that is to say orally, parenterally, by inhalation, nasally, sub- lingually, rectally, externally such as transdermally, or locally such as in the case of implants or stents.
• parenteral administration intravenous, intramuscular or subcutaneous administration, for example as a subcutaneous depot, should be mentioned in particular.
• Oral or parenteral administration is preferred.
• Oral application is very particularly preferred.
• the active ingredients can be administered alone or in the form of preparations.
• suitable preparations include Tablets, capsules, pellets, coated tablets, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions.
• the active ingredient must be present in such an amount that a therapeutic effect is achieved.
• the active ingredient can be present in a concentration of 0.1 to 100% by weight, in particular 0.5 to 90% by weight, preferably 5 to 80% by weight.
• the concentration of the active ingredient should be 0.5 to 90% by weight, i.e. the active substance should be present in amounts sufficient to achieve the dosage range indicated.
• the active ingredients can be converted into the customary preparations in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable carriers, auxiliaries, solvents, vehicles, emulsifiers and / or dispersants.
• auxiliaries include: water, non-toxic organic solvents such as e.g. Paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerin), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock flour (e.g. talc or silicates), sugar (e.g. milk sugar), emulsifiers, dispersants (e.g. polyvinylpyrrolidone) and lubricants (e.g. magnesium sulfate).
• non-toxic organic solvents such as e.g. Paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerin), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock flour (e.g. talc or silicates), sugar (e.g. milk sugar), emulsifiers, dispersants (e.g. polyvinylpyrrolidone)
• tablets can of course also contain additives such as sodium citrate together with additives such as starch, gelatin and the like. Chen included.
• Aqueous preparations for oral application can also be mixed with flavor enhancers or colorants.
• doses of 0.001 to 5 mg / kg, preferably 0.005 to 3 mg / kg of body weight are preferably administered per 24 hours.
• the product (purified by preparative HPLC YMC gel ODS-AQ S 5/15 micron; mobile phase A: water, mobile phase B: acetonitrile; gradient:. 0 min 30% B, 5 min 3 0% B, 50 min 95% B ). 44 mg (83% of theory) of the desired product are obtained.
• a cellular assay is used to identify activators of the
• PAR-delta Peroxisome proliferator-activated receptor delta
• the GAL4-PPAR ⁇ expression construct contains the ligand binding domain of PPAR ⁇ (amino acids 414-1326), which is PCR-amplified and cloned into the vector pcDNA3.1. This vector already contains the GAL4-DNA binding domain (amino acids 1-147) of the vector pFC2-dbd (Stratagene).
• the reporter construct which contains five copies of the GAL4 binding site upstream of a thymidine kinase promoter, leads to the expression of Firefly luciferase (Photinus pyralis) after activation and binding of GAL4-PPAR ⁇ .
• CHO (Chinese hamster ovary) cells are in CHO-A-SFM medium (GIBCO), supplemented with 2.5% fetal calf serum and 1% penicillin / streptomycin (GIBCO), with a cell density of 2 x 10 3 cells per well in one 384 well plate (Greiner) sown. After culturing at 37 ° C. for 48 h, the cells are stimulated. For this purpose, the substances to be tested are taken up in the medium mentioned above and added to the cells. After a stimulation time of 24 hours, the luciferase activity is measured using a video camera. The measured relative light units result in a sigmoid stimulation curve depending on the substance concentration. The EC 50 values are calculated using the GraphPad PRISM computer program (version 3.02).
• the embodiments 1-22 show in this test EC 5 o values in the range of 5 nM to 5 uM.
• the substances which are to be investigated for their HDL-C-increasing effect in vivo are administered orally to male transgenic hApo AI mice.
• the substances are administered orally once a day for 7 days.
• the test substances are dissolved in a solution of Solutol HS 15 + ethanol + saline (0.9%) in a ratio of 1 + 1 + 8 or in a solution of Solutol HS 15 + saline (0.9%) in a ratio of 2 + 8.
• the dissolved substances are applied in a volume of 10 ml / kg body weight with a gavage. Animals that are treated in the same way but only receive the solvent (10 ml / kg body weight) without test substance serve as a control group.
• each mouse is used to determine ApoAl
• the non-HDL-C fraction is precipitated with 20% PEG 8000 in 0.2 M glycine buffer pH 10.
• the cholesterol is determined from the supernatant in a 96-well perforated plate using commercially available reagent (Ecoline 25, Merck, Darmstadt) using UN photometry (BIO-TEK Instruments, USA).
• Human mouse ApoAl is determined using a sandwich ELISA method using a polyclonal anti-human ApoAl and a monoclonal anti-human Apo AI antibody (Biodesign International, USA). The quantification is carried out using UV photometry (BIO-TEK Instruments, USA) with peroxidase-coupled anti-mouse IGG antibodies (KPL, USA) and peroxidase substrate (KPL, USA).
• the effect of the test substances on the HDL-C concentration is determined by subtracting the measured value of the first blood sample (previous value) from the measured value of the second blood sample (after treatment).
• the differences of all HDL-C values in a group are averaged and compared with the mean value of the differences in the control group.
• mice with insulin resistance and increased blood glucose levels are used.
• C57B1 / 6J Lep ⁇ ob> mice are treated according to the same protocol as the transgenic ApoAl mice.
• Serum lipids are determined as described above.
• serum glucose is determined as a parameter for blood glucose in these animals. The serum glucose is determined enzymatically on an EPOS Analyzer 5060 (see above) using commercially available enzyme tests (Boehringer Mannheim).
• a blood glucose-lowering effect of the test substances is determined by subtracting the measured value of the 1st blood withdrawal from an animal (norwert) from the measurement value of the 2nd blood withdrawal from the same animal (after treatment). The differences of all serum glucose values in a group are averaged and compared with the mean value of the differences in the control group.
• Substances that reduce the serum glucose concentration of the treated animals statistically significantly (p ⁇ 0.05) by at least 10% compared to that of the control group are considered to be pharmacologically active.

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