Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • 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
  • C07D209/08—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
  • C07D209/56—Ring systems containing three or more rings
  • C07D209/96—Spiro-condensed ring systems

Definitions

• the present application relates to novel substituted indoline-phenylsulfonamide derivatives, to processes for their preparation and to their use in medicaments, in particular as potent PPAR-delta activating compounds for the prophylaxis and / or treatment of cardiovascular diseases, in particular dyslipidemias, arteriosclerosis and coronary heart diseases.
• HD coronary heart disease
• Fibrates are now the only form of therapy for patients in these risk groups. They act as weak agonists of the peroxisome proliferator-activated receptor (PPAR) -al ⁇ ha (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.
• Al are l-benzenesulfonyl-l, 3-dihydroindol-2-one derivatives as vasopressin and / or or oxytocin antagonists for the treatment of various diseases.
• the object of the present invention was to provide novel compounds which can be used as PPAR delta modulators.
• R 1 * is hydrogen or (C 1 -C 4 -alkyl
• X is O, S or CH 2 ,
• R 1 is (C 6 -C 10 ) -aryl or 5- to 10-membered heteroaryl of up to three
• Heteroatoms from the series N, O and / or S which in turn each one to three times, same or different, by substituents selected from the group halogen, cyano, nitro, (CrC ⁇ alkyl, which in turn may be substituted by hydroxy , (C 1 -C 6 ) -alkoxy, phenoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, (C 2 -C 6 ) -alkenyl, phenyl, benzyl, (C 1 -C 6 ) -
• Alkylthio, (C 1 -C 4 ) alkylsulfonyl, (C 1 -C 4 -alkanoyl, (C 1 -C 4 ) -alkoxycarbonyl, carboxyl, amino, (C 1 -C 6 ) -acylamino, mono- and di-CC C ⁇ ) - alkylamino and 5- to 6-membered heterocyclyl may be substituted by up to two heteroatoms from the series N, O and / or S,
• R 2 and R 3 are the same or different and independently of one another represent hydrogen or (C 1 -C 4) -alkyl or together with the carbon atom to which they are attached form a 3 to 7-membered, spiro-linked cycloalkyl ring,
• R 4 is hydrogen or (CC 6 ) -alkyl
• R 5 is hydrogen or (C 1 -C 4) -alkyl
• R 6 is hydrogen or (C 1 -C 6 ) -alkyl
• R 7 is hydrogen, (C 1 -C 4 -alkyl, (C 1 -C 6 ) -alkoxy or halogen,
• R 8 and R 9 are the same or different and independently of one another represent hydrogen or (C 1 -C 4 -alkyl
• R 10 is hydrogen or a hydrolyzable group which can be degraded to the corresponding carboxylic acid
• a hydrolyzable group means a group which, in particular in the body, converts the
• (C t -C ⁇ alkyl and (C ⁇ -alkyl in the context of the invention a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms.
• Preferred is a straight-chain or branched alkyl radical having 1 to 4 Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl and t-butyl.
• (C 2 -C 6 ) -alkenyl is a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms. Preference is given to a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms. Examples which may be mentioned are: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.
• (C 8 -C 8 ) -cycloalkyl in the context of the invention is a monocyclic cycloalkyl group having 3 to 8 carbon atoms.
• (C 6 -C ⁇ o) -Aryl is in the context of the invention 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 in the context of the invention represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms, preferably a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms
• methoxy, ethoxy, n-propoxy, isopropoxy and t-butoxy methoxy, ethoxy, n-propoxy, isopropoxy and t-butoxy.
• (C 1 -C 4 -alkoxycarbonyl and (C 1 -C 4 ) -alkoxycarbonyl represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms which is linked via a carbonyl group to 4 carbon atoms, by way of example and by way of preference: methoxycarbonyl, ethoxycarbonyL n-
• (C t -C alkoxycarbonylamino and (CrC ⁇ alkoxycarbonylamino are in the context of the invention an amino group having a straight-chain or comparable branched alkoxycarbonyl substituent which the alkoxy group 1 to 6 or 1 to 4
• (C 1 -C 4) -Alkanoyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms which carries a doubly bonded oxygen atom in the 1-position and is linked via the 1-position Alkanoyl radical having 1 to 4 carbon atoms, by way of example and preferably: formyl, acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl and n-hexanoyl.
• (C 1 -C 6 ) -alkanoyloxy and (C 1 -C 4 -alkanoyloxy in the context of the invention represent a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms which carries a doubly bound oxygen atom in the 1-position and is linked in the 1-position via a further oxygen atom
• Alkanoyloxy radical having 1 to 4 carbon atoms examples which may be mentioned by way of example include: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy, n-hexanoyloxy.
• Di (C 1 -C 6 ) -alkylamino and di- (C 1 -C 4 ) -alkylamino in the context of the invention are an amino group having two identical or different straight-chain or branched alkyl substituents, each of which has 1 to 6 or 1 have up to 4 carbon atoms. Preference is given to straight-chain or branched dialkylamino radicals each having 1 to 4 carbon atoms.
• N N-dimethylamino
• N N-ylamino
• N-emyl-N-memylamino N-methyl-n-propylamino
• N-isopropyl-Nn-propylamino N-t-butyl-N-methylamino
• N-ethyl -N-pentylamino Nn-hexyl-N-methylamino.
• (C t -C acylamino the purposes of the invention an amino group having a straight chain or branched alkanoyl substituent which has 1 to 6 Koblenstoffatome and is attached via the carbonyl group.
• C t -C ⁇ alkylthio is in the context of the invention a straight-chain or branched alkylthio radical having 1 to 6 carbon atoms is preferably mentioned a straight or branched alkylthio group having 1 to 4 carbon atoms, Examples which may preferably be:.. Methylthio, Ethylthio, n-propylthio, isopropylthio, t-butylthio, n-pentylthio and n-hexylthio.
• (C 1 -C 6 ) -alkylsulfonyl in the context of the invention is a straight-chain or branched alkylsulfonyl radical having 1 to 6 carbon atoms.
• Preferred is a straight-chain or branched alkylsulfonyl radical having 1 to 4 carbon atoms.
• 5- to 10-membered or 5- to 6-membered heteroaryl having 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 bicychschen aromatic
• Heterocycle which is linked via a ring carbon atom or optionally via a ring nitrogen atom of the heteroaromatic.
• Examples which 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- to 6-membered heteroaryl radicals having up to two nitrogen atoms, for example imidazolyl, pyridyl, pyrimidin
• 5- to 6-membered heterocyclyl having up to 2 heteroatoms from the series N, O and / or S is in the context of the invention a saturated heterocycle which is linked via a ring carbon atom or optionally via a ring nitrogen atom of the heterocycle.
• Examples which may be mentioned by way of example include tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
• Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
• the compounds according to the invention can be prepared in stereoisomeric forms which are either image-like or mirror-image-like
• Enantiomers or which do not behave like image and mirror image (diastereomers) exist.
• the invention relates to both the enantiomers or diastereomers as well as their respective mixtures.
• the racemic forms and the diastereomers can be separated in a known manner into the stereoisomerically uniform constituents.
• the compounds according to the invention can also be present as salts.
• physiologically acceptable salts are preferred.
• Physiologically acceptable salts may be salts of the compounds according to the invention with inorganic or organic acids.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid , Benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
• Physiologically acceptable salts may also be salts of the compounds according to the invention with bases, for example metal or ammonium salts.
• bases for example metal or ammonium salts.
• alkali metal salts for example sodium or potassium salts
• alkaline earth salts for example magnesium or calcium salts
• ammonium salts which have been removed.
• ammonia or organic amines for example ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, Argimn, lysine, ethylenediamine or 2-phenylethylamine.
• the compounds according to the invention can also be present in the form of their solvates, in particular in the form of their hydrates.
• A is the group CR 11 or N
• R 11 is hydrogen or methyl
• R 1 is phenyl or 5- to 6-membered heteroaryl having up to two heteroatoms from the series N, O and / or S, which in turn are each one to two times, identically or differently, by substituents selected from the group fluorine, Chlorine, cyano, (-G-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) -alkylamino may be substituted
• R 2 and R 3 are identical or different and independently of one another are hydrogen or (C 1 -C 4 ) -alkyl or, together with the carbon atom to which they are bonded, a 5- to 6-membered, spiro-linked cycloalkyl
• Form ring, R is hydrogen or methyl
• R 5 is hydrogen, methyl or ethyl
• R 6 is hydrogen or methyl
• R 7 is hydrogen, (QC ⁇ alkyl, (C r C4) -alkoxy, fluorine or chlorine,
• R 8 and R 9 are the same or different and independently of one another represent hydrogen or methyl
• R 10 is hydrogen
• A is CH or N
• R 1 is phenyl or pyridyl, which in turn is in each case one to two times, identical or different, by substituents selected from the group consisting of fluorine, chlorine, methyl, tert-butyl, methoxy, trifluoromethyl, trioromethoxy,
• Methylthio, amino and dimethylamino may be substituted
• R 2 is hydrogen or methyl
• R 3 is methyl, isopropyl or tert-butyl, or
• R 2 and R 3 together with the carbon atom to which they are attached form a spiro-linked cyclohexane ring
• R 4 is hydrogen or methyl
• R 5 is hydrogen, methyl or ethyl
• R 6 is hydrogen or methyl
• R 7 is methyl
• R 8 and R 9 are each hydrogen
• R, 10 is hydrogen
• radical definitions given in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of other combinations, irrespective of the particular combinations of the radicals indicated.
• R is hydrogen
• R, 3 is methyl, isopropyl or tert-butyl
• R and R are both methyl or together with the carbon atom to which they are attached form a spiro-linked cyclohexane ring
• R 2 , R 3 , R 4 and R 5 are each as defined above, and
• Y is chlorine or bromine
• T is benzyl or (C 1 -C 6 ) -alkyl
• R 12 is hydrogen or methyl or both radicals together form a CH 2 CH- or C (CH 3 ) 2 -C (CH 3 ) 2 bridge,
• the coupling reaction step [cf. (IV) + (V) - »(I-B)] and the ester cleavage [cf. (I-B) -> (I-C)] can optionally also be carried out in the above-described reaction sequence in an inverted order; it is also possible to carry out a basic ester cleavage in situ during the coupling reaction.
• Inert solvents for process step (II) + (III) - »(IV) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride,
• Trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, 'acetone , Dimethylformamide, dimethylsulfoxide, aeetonitrile, N-methylpyrrolidinone or pyridine. It is likewise possible to use mixtures of the solvents mentioned. Preferred are dichloromethane or tetrahydrofuran.
• Suitable bases for process step (II) + (III) - »(IV) are the customary inorganic or organic bases. These include preferably alkali 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.
• alkali hydroxides such as lithium, sodium or potassium hydroxide
• alkali metal or alkaline earth metal alkali metal or alkaline earth metal.
• carbonates such as sodium, potassium or calcium carbonate
• alkali metal hydrides such as sodium hydride
• organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine.
• amine bases such as triethylamine, pyridine or ethyldiisopropylamine, optionally in the presence of catalytic amounts (about 10 mol%) of 4-N, N-dimethylaminopyridine or 4-pyrrolidinopyridine.
• the base is used in this case in an amount of 1 to 5, preferably from 1 to 2.5, mol, based on 1 mol of the compound of the general formula (III).
• the reaction is generally carried out in a temperature range from -20 ° C to + 100 ° C, preferably from 0 ° C to + 75 ° C.
• the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). In general, one works at normal pressure.
• Inert solvents for process step (IV) + (V) -> • (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 likewise possible to use mixtures of the solvents mentioned. Preference is given to toluene, dimethylformamide or acetonitrile.
• Suitable bases for process step (IV) + (V) ⁇ (IB) are the customary inorganic or organic bases. These include preferably 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. Particularly preferred are sodium or potassium carbonate or potassium phosphate.
• the base is used here in an amount of 1 to 5, preferably from 2 to 3, mol, based on 1 mol of the compound of general formula (IV).
• Suitable palladium catalysts for process step (IV) + (V) - »(IB) are preferably palladium (O) or palladium (LI) compounds which are used preformed, such as, for example, [1-, bis (diphenylphosphino) ferrocenyl] palladium (II) chloride, bis (triphenylphosphine) palladium (II) chloride or in situ from a suitable palladium source such as bis (dibenzylideneacetone) palladium (O) or tetrakis (triphenylphosphine) palladium (0) and a suitable palladium source such as bis (dibenzylideneacetone) palladium (O) or tetrakis (triphenylphosphine) palladium (0) and a suitable palladium source such as bis (dibenzylideneacetone) palladium (O) or tetrakis (triphenylphosphine) pal
• Phosphine ligand can be generated.
• the reaction is generally carried out in a temperature range from 0 ° C to + 150 ° C, preferably from + 20 ° C to + 100 ° C.
• the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar).
• Inert solvents for process step (I-B) - »(I-C) are, for example, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or trichloro ethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or
• Diethylene glycol dimethyl ether Diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, acetone, dimethylformamide, dimethyl sulfoxide , Aeetonitrile or N-methylpyrrolidinone. It is likewise possible to use mixtures of the solvents mentioned. Alcohols such as methanol or ethanol are preferred.
• Suitable bases for process step (IB) - »(IC) are the customary inorganic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, or alkali metal or alkaline earth metal carbonates such as Sodium, potassium or calcium carbonate. Particularly preferred are lithium or sodium hydroxide.
• the base is used here in an amount of 1 to 5, preferably 1 to 3, mol, based on 1 mol of the compound of general formula (I-B).
• Suitable acids for process step (I-B) - »(I-C) are the customary 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.
• the reaction is generally carried out in a temperature range from -20 ° C to + 100 ° C, preferably from 0 ° C to + 30 ° C.
• the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). In general, one works at atmospheric 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 said solvents. Preferred solvent is water.
• Suitable acids for process step (VI) - (VII) are the customary inorganic or organic acids. These include preferably 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. Particularly preferred is half-concentrated to concentrated aqueous hydrochloric acid, which also serves as a solvent.
• the reaction is generally carried out in a temperature range from -30 ° C to
• reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). In general, one works at atmospheric pressure.
• Inert solvents for process step (VII) + (VIII) - »(IX) or (X) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers, such as dioxane, Tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or hydrocarbons such as benzene, xylene, toluene,
• halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachlor
• the reaction is preferably carried out without solvent to the product (X), in the case that R 2 and R 3 are both non-hydrogen and A is CH, is the reaction is preferably carried out in a mixture of toluene and acetonitrile to the product (IX).
• Suitable acids for process step (VII) + (VIII) - (IX) or (X) are the customary 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.
• the usual Lewis acids such as boron trifluoride, aluminum trichloride or zinc chloride are suitable.
• the acid is used here in an amount of 1 to 10 mol, based on 1 mol of the compound of general formula (VII). In the case that R for
• reaction is preferably with 1 to 2 moles of zinc chloride to the product (X), and in the case where R 2 and R 3 are both non-hydrogen and A is CH, is preferably 2 to 5 Mole of trifluoroacetic acid to product (IX).
• the reaction is generally carried out in a temperature range from 0 ° C to + 250 ° C.
• the reaction is preferably carried out in a temperature range of + 130 ° C to + 200 ° C to the product (X), in case R 2 and R 3 are both are not hydrogen and A is CH, the reaction is preferably in a temperature range of
• reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). In general, one works at atmospheric pressure.
• Suitable solvents for process step (IX) or (X) - »(II) 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, or hydrocarbons such as
• the reaction is generally carried out in a temperature range of -20 ° C to + 200 ° C.
• the hydrogenation of the compounds (X) in which A is N is preferably carried out in a temperature range from + 150 ° C to + 200 ° C
• the reduction of the compounds (IX) and (X), wherein A is CH is preferably carried out in a temperature range of -10 ° C to + 50 ° C.
• the Reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 150 bar). While the hydrogenation of the compounds (X), in which A is N, is preferably carried out in a pressure range of 50 to 150 bar hydrogen, the reduction of the compounds (IX) or (X), in which A is CH, is carried out generally at atmospheric pressure.
• Inert solvents for process step (XI) + (XII) ⁇ (XIII) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or
• hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidinone. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to dimethylformamide or acetone.
• Suitable bases for process step (XI) + (XII) -> (XTLI) are the customary inorganic or organic bases. These include preferably 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
• Na umhydrid or organic amines such as pyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine. Particularly preferred is potassium carbonate.
• the base is used here in an amount of 1 to 5, preferably 1 to 2 mol, based on 1 mol of the compound of the general formula (XI).
• the reaction is generally carried out 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 (for example from 0.5 to 5 bar). In general, one works at atmospheric pressure.
• the compounds of the formula (I) according to the invention exhibit a surprising and valuable pharmacological spectrum of action and can therefore be used as versatile medicaments, in particular for the treatment of diseases in which the PPAR delta inhibitor is activated. In particular, they are suitable for the treatment of coronary heart disease, for myocardial infarction prophylaxis and
• the compounds of the formula (I) according to the invention are preferably suitable for the treatment of stroke, CNS disorders, Alzheimer's disease, osteoporosis, arteriosclerosis and hypercholesterolemia, for increasing pathologically low HDL levels and for lowering elevated triglyceride and LDL levels.
• they can for
• the new agents can be used alone or as needed in combination with others
• Active substances preferably from the group consisting of CETP inhibitors, antidiabetic agents, antioxidants, cytostatic agents, 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, circulation-promoting agents, platelet aggregation inhibitors,
• Anticoagulants angiotensin II receptor antagonists, cholesterol absorption inhibitors, MTP inhibitors, aldolase redulase inhibitors, fibrates, niacin, anoretics, lipase inhibitors, and PPAR- ⁇ and / or PPAR- ⁇ agonists.
• Further combinations with anti-inflammatory agents e.g. COX-2 inhibitors, NEP inhibitors, ECE inhibitors, vasopeptidase inhibitors, aldose
• Reduction inhibitors antioxidants, cytostatics, Pperfusion Promoters and Anorectics are possible.
• the compounds according to the invention are preferably each with one antidiabetic agent or several antidiabetics which are in the red
• Antagonists include ACE inhibitors, beta-blockers and diuretics and / or with one or more lipid metabolism-modifying agents from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as, for example and preferably, HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP Inhibitors, PPAR
• Antidiabetics are understood by way of example and preferably as meaning insulin and insulin derivatives, as well as orally active hypoglycemic agents.
• Insulin and insulin derivatives here include both insulins of animal, human or biotechnological origin as well as mixtures thereof.
• the orally active hypoglycemic agents include, by way of example and by way of illustration, sulfonylureas, biguadins, meglitinide derivatives, oxadiazolidinones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, insulin sensitizers, inhibitors of liver enzymes that stimulate liver stimulation Gluconeogenesis and / or glycogenolysis are involved, modulators of glucose uptake and potassium channel opener, such as those in WO
• said compounds are administered in combination with insulin.
• the compounds mentioned are administered in combination with a sulphonylurea, by way of example and with preference tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.
• said compounds are administered in combination with a biguanide, such as by way of example and preferably metformin.
• a biguanide such as by way of example and preferably metformin.
• the compounds mentioned are administered in combination with a PPAR gamma agonist, for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
• a PPAR gamma agonist for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
• said compounds are used in combination with a mixed PPAR alpha / gamma
• Agonists as exemplified and preferably administered by GI-262570 (Farglitazar), GW 2331, GW 409544, AVE 8042, AVE 8134, AVE 0847, MK-0767 (KRP-297), AZ-242.
• antithrombotic agents are preferably compounds from the
• Group antiplatelet agents as exemplified and preferably aspirin, clopidogrel, ticlopidine, dipyridamole or anticoagulants understood.
• said compounds are administered in combination with a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin, Clexane.
• a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin, Clexane.
• the compounds mentioned are administered in combination with a GPIIb- ⁇ ia antagonist, such as, by way of example and by way of preference, tirofiban, abciximab.
• said compounds are administered in combination with a factor Xa inhibitor, such as by way of example and preferably DX 9065a, DPC 906, JTV 803.
• a factor Xa inhibitor such as by way of example and preferably DX 9065a, DPC 906, JTV 803.
• said compounds are administered in combination with a vitamin K antagonist such as by way of example and preferably coumarin.
• blood pressure lowering agents are exemplified and preferably compounds from the group of calcium antagonists, such as by way of example and preferably the compounds nifedipine, verapamil, diltiazem, angiotensin, AII-
• the compounds mentioned are administered in combination with an antagonist of the alpha 1 receptors.
• the compounds mentioned are administered in combination with reserpine, minoxidil, diazoxide, dihydralazine, hydralazine and nitric oxide-releasing substances such as, by way of example and by way of preference, glyceryl nitrate or nitroprusside sodium.
• said compounds are administered in combination with an angiotensin AII antagonist such as, for example and preferably, losartan, valsartan, telmisartan.
• Compounds in combination with an ACE inhibitor such as by way of example and preferably enalapril, captopril administered.
• said compounds are administered in combination with a beta-blocker, such as by way of example and preferably propranolol, atenolol.
• the compounds mentioned are administered in combination with a diuretic, such as by way of example and preferably with furosemide.
• lipid metabolizing agents are exemplified and preferably compounds from the group of 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, polymeric bile acid adsorbers, lipoprotein (a) antagonists understood.
• said compounds are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425, axitirome (CGS 26214).
• a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425, axitirome (CGS 26214).
• said compounds are administered in combination with a squalene synthesis inhibitor such as, for example and preferably, BMS-188494, TAK 457.
• a squalene synthesis inhibitor such as, for example and preferably, BMS-188494, TAK 457.
• said compounds are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe.
• said compounds are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside, pamaqueside.
• a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside, pamaqueside.
• the compounds mentioned in combination with a PPAR alpha agonists such.
• CETP inhibitor such as by way of example and preferably torcetrapib (CP-529 414), JJT-705.
• said compounds are used in combination with a mixed PPAR alpha / gamma
• Agonists as exemplified and preferably administered by GI-262570 (Farglitazar), GW 2331, GW 409544, AVE 8042, AVE 8134, AVE 0847, MK-0767 (KRP-297), AZ-242.
• said compounds are administered in combination with a lipase inhibitor such as, for example, and preferably orlistat.
• a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel, colestimide.
• a lipoprotein (a) antagonists such as exemplified and preferably gemcabene calcium (CI-1027) or nicotinic acid administered.
• said compounds are administered in combination with an LDL receptor inducer.
• Another object of the invention are combinations of the compounds of formulas (I) to (HI) with FfMG-CoA reductase inhibitors from the class of statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and cerivastatin, pitavastatin ,
• statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and cerivastatin, pitavastatin ,
• the activity of the compounds of the invention can be e.g. in vitro by the transactivation assay described in the Examples section.
• the active ingredients can be administered alone or in the form of preparations.
• preparations u.a. Tablets, capsules, pellets, dragees, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions.
• the active ingredient must be present in such an amount that a therapeutic effect is achieved.
• the active compound 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. the active substance should be present in sufficient quantities to reach the stated dose latitude.
• the active compounds may be converted into the customary preparations in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable excipients, adjuvants, solvents, vehicles, emulsifiers and / or dispersants.
• adjuvants include: water, non-toxic organic solvents such as paraffins, vegetable oils (eg sesame oil), alcohols (eg ethanol, glycerol), glycols (eg polyethylene glycol), solid carriers such as natural or synthetic minerals (eg talc or silicates), Sugar (eg milk sugar), emulsifying agent, dispersing agent (eg polyvinylpyrrolidone) and lubricant (eg magnesium sulphate).
• non-toxic organic solvents such as paraffins, vegetable oils (eg sesame oil), alcohols (eg ethanol, glycerol), glycols (eg polyethylene glycol), solid carriers such as natural or synthetic minerals (eg talc or silicates), Sugar (eg milk sugar), emulsifying agent, dispersing agent (eg polyvinylpyrrolidone) and lubricant (eg magnesium sulphate).
• tablets may also contain additives such as sodium citrate together with adjuvants such as star
• dosages of 0.001 to 5 mg / kg, preferably 0.005 to 3 mg / kg of body weight per 24 hours are preferably applied.
• Method A Column: Waters Symmetry C18 50 x 2.1 mm, 3.5 ⁇ m; 0.5 ml / min; A: aeetonitrile + 0.1% formic acid, B: water + 0.1% formic acid; 0 min 10% A, 4 min 90% A; 40 ° C.
• Method B Instrument: Finnigan MAT 900S, TSP: P4000, AS3000, UV3000HR; Column: Symmetry C 18, 150 mm x 2.1 mm, 5.0 ⁇ m; Eluent C: water, eluent B: water + 0.3 g / 1 35% hydrochloric acid, eluent A: acetonitrile; Gradient: 0.0 min 2% A ⁇ 2.5 min 95% A ⁇ 5 min 95% A; Oven: 70 ° C; Flow: 1.2 ml / min; UV detection:
• Method C Instrument: Micromass Quattro LCZ, HP1100; Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: acetonitrile + 0.1% formic acid, eluent B: water + 0.1% formic acid; Gradient: 0.0 min 10% A ⁇ 4.0 min 90% A ⁇ 6.0 min 90% A; Oven: '40 ° C; Flow: 0.5 ml / min; UV detection: 208-400 nm.
• Method D Instrument: Micromass Platform LCZ, HP1100; Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: acetonitrile + 0.1% formic acid, eluent B: water + 0.1% formic acid; Gradient: 0.0 min 10% A ⁇ 4.0 min 90% A ⁇ 6.0 min 90% A; Oven: 40 ° C; Flow: 0.5 ml / min; UV detection: 208-400 nm.
• Method E Instrument: Micromass Platform LCZ, HP1100; Column: Symmetry C18, 50 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: acetonitrile + 0.5% formic acid, eluent B: water + 0.5% formic acid; Gradient: 0.0 min 90% A - 4.0 min 10% A - 6.0 min 10% A; Oven: 50 ° C; Flow: 0.5 ml / min; UV detection: 208-400 nm.
• Method F Instrument: Micromass TOF-MUX Interface / Waters600; Column: YMC-ODS-AQ, 50 mm x 2.1 mm, 3.5 ⁇ m; Temperature: 20 ° C; Flow: 0.8 ml / min; Eluent A: acetonitrile + 0.05% formic acid, eluent B: water + 0.05% formic acid;
• Carrier gas helium
• reaction mixture is heated to 100 ° C for 16 h. After cooling to RT, it is filtered through silica gel. The solvent is removed in vacuo and the crude product purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 microns; Eluent A: water, eluent B: acetonitrile, gradient 0 min 30% B, 5 min 30% B, 50 min 95% B). 87 mg (81% of theory) are obtained.
• a mixture of 90 ml of toluene / acetonitrile (49: 1) is purged with argon for 5 minutes and then treated with 6.00 g (26.8 mmol) of 4-bromophenylhydrazine hydrochloride. 7.41 ml (96.2 mmol) of trifluoroacetic acid are then slowly added dropwise, care being taken that the temperature does not exceed 35 ° C. The temperature is then 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) is added dropwise slowly over the course of 2 hours.
• UV [nm] 200, 270, 276
• UV [nm] 206, 238, 258
• reaction solution is mixed with 8.50 mg (0.048 mmol) of l, 3,5-triazine-2,4,6-trithiol. It is adjusted to pH 4-5 with 5 N trifluoroacetic acid in water and then the solvent is removed in vacuo. The residue is purified by RP-HPLC (Rroma-Sil 50 ⁇ 20 mm, eluent A: water with 0.3% trifluoroacetic acid, eluent B:
• reaction solution is mixed with 30 ml of water and extracted three times with 20 ml of ethyl acetate.
• the combined organic phases are dried with sodium sulfate and freed from the solvent in vacuo. This gives 1.5 g of crude product, which is purified by flash chromatography (silica gel 70-230 mesh, eluent: cyclohexane / ethyl acetate 5: 1). This gives 1.26 g (69% of theory) of
• UV [nm] 204, 246, 280
• a mixture of 45 ml of toluene / acetonitrile (49: 1) is purged with argon for 5 minutes and then admixed with 3.00 g (13.4 mmol) of 4-bromophenylhydrazine. 3.71 ml (48.1 mmol) trifluoroacetic acid are then added slowly, care being taken that the temperature does not exceed 35 ° C. The temperature is then kept at 35 ° C. and a solution of 1.05 g (14.6 mmol) of isobutyraldehyde in 4 ml of toluene / acetonitrile (49: 1) is added dropwise slowly over 2 h.
• the mixture is stirred for 4 h at 35 ° C and 2 h at room temperature.
• the mixture is then cooled to -10 ° C, treated with 4.0 ml of methanol and added within 30 min 819 mg (21.7 mmol) of solid sodium borohydride in portions. The temperature must not exceed -2 ° C.
• the mixture is stirred at 0 ° C for 1 h.
• 150 ml of a 6 wt .-% solution of ammonia in water the phases are separated and the organic phase is mixed with 1.5 ml of acetomtrile and methanol.
• the organic phase is washed with 150 ml of a 15% solution of sodium chloride in water and dried over sodium sulfate. It is filtered through 100 g of silica gel and washed twice with 200 ml of diethyl ether. The organic filtrate is concentrated in vacuo and chromatographed over 100 g of silica gel.
• PAR-delta Peroxisome proliferator-activated receptor delta
• PPAR ⁇ receptor is fused to the DNA binding domain of the yeast transcription factor GAL4.
• the resulting GAL4-PPAR ⁇ chimera is co-transfected into CHO cells with a reporter construct and stably expressed.
• 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 containing five copies of the GAL4 binding site upstream of a thymidine kinase promoter, expresses the firefly luciferase (Photinus pyralis) upon activation and binding of GAL4-PPAR ⁇ .
• CHO (Chinese hamster ovary) cells are grown in CHO-A-SFM medium (GTBCO) supple with 2.5% fetal calf serum and 1% penicillin / streptomycin (GTBCO) at cell density of 2 x 10 3 cells per well seeded in a 384 well plate (Greiner). After culturing for 48 h at 37 ° C, the cells are stimulated. For this purpose, the substances to be tested are taken up in the above-mentioned medium and added to the cells. After a stimulation time of 24
• luciferase activity is measured with the help of a video camera.
• the measured relative light units result in a sigmoidal stimulation curve as a function of the substance concentration.
• the EC 50 values are calculated using the computer program GraphPad PRISM (version 3.02).
• Embodiments 1-96 show ECso values in a range of 1 to 200 nM in this test.
• the substances to be tested for their HDL-C increasing activity in vivo are orally administered to male transgenic hApoAl 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 the ratio 1 + 1 + 8 or in a solution of Solutol HS 15 + saline
• each mouse is sampled for the determination of ApoAl, serum cholesterol, HDL-C and serum triglycerides (TG) by puncture of the retroorbital venous plexus (initial value).
• the animals are given the test substance for the first time with a gavage.
• blood is again drawn from each animal to determine the same parameters by puncture of the retroorbital venous plexus.
• the blood samples are centrifuged and, after recovery of the serum, cholesterol and TG are determined photometrically with an EPOS Analyzer 5060 (Eppendorf device construction, Netheler & Hinz GmbH, Hamburg). The determination is carried out using commercial enzyme assays (Boehringer
• the non-HDL-C fraction is precipitated with 20% PEG 8000 in 0.2 M glycine buffer pH 10. From the supernatant, the cholesterol in a 96-well plate with commercially available reagent (Ecoline 25, Merck, Darmstadt) determined by UV photometry (BIO-TEK Instruments, USA).
• the human mouse ApoAl is determined by 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 by UV photometry (BIO-TEK Instruments, USA) with
• Peroxidase-linked anti-mouse IgG antibody KPL, USA
• peroxidase substrate KPL, USA
• the effect of the test substances on the HDL-C concentration is determined by subtraction of the measured value of the 1st blood sample (pre-value) from the measured value of the 2.
• Substances which increase the HDL-C of the treated animals statistically significantly (p ⁇ 0.05) by at least 15% compared to those of the control group are considered to be pharmacologically active.
• mice with a resistance to msulin and elevated blood glucose levels are used.
• C57B1 / 6J Lep ⁇ ob> mice are treated according to the same protocol as the transgenic ApoAl mice.
• the serum lipids are determined as described above.
• serum glucose is used as a parameter in these animals intended for blood glucose.
• the serum glucose is determined enzymatically on an EPOS Analyzer 5060 (see above) with commercial enzyme assays (Boehringer Mannheim).
• a blood glucose-lowering effect of the test substances is determined by subtracting the measured value of the first blood sample of an animal (pre-value) from the measured value of the second blood sample of the same animal (after treatment). The differences of all serum glucose values of a group are averaged and compared with the mean of the differences of the control group.
• Substances which lower the serum glucose concentration of the treated animals statistically significantly (p ⁇ 0.05) by at least 10% compared with the control group are considered to be pharmacologically active.

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