EP1999123A1 - Derive de chromanol substitue et son utilisation - Google Patents

Derive de chromanol substitue et son utilisation

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Publication number
EP1999123A1
EP1999123A1 EP07711808A EP07711808A EP1999123A1 EP 1999123 A1 EP1999123 A1 EP 1999123A1 EP 07711808 A EP07711808 A EP 07711808A EP 07711808 A EP07711808 A EP 07711808A EP 1999123 A1 EP1999123 A1 EP 1999123A1
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EP
European Patent Office
Prior art keywords
formula
compound
mmol
phenyl
ethyl acetate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07711808A
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German (de)
English (en)
Inventor
Carsten Schmeck
Hilmar Bischoff
Volkhart Li
Klemens Lustig
Michael Thutewohl
Alexandros Vakalopoulos
Olaf Weber
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Sunshine Lake Pharma Co Ltd
Original Assignee
Bayer Healthcare AG
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Publication date
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1999123A1 publication Critical patent/EP1999123A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/96—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings spiro-condensed with carbocyclic rings or ring systems

Definitions

  • the present application relates to substituted chromanol derivatives, processes for their preparation, their use alone or in combinations for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or Prevention of cardiovascular diseases.
  • HDL high-density lipoprotein
  • LDL low-density lipoprotein
  • VLDL very low-density lipoprotein
  • High LDL cholesterol levels (> 160 mg / dl) and low HDL cholesterol levels ( ⁇ 40 mg / dl) contribute significantly to the development of arteriosclerosis [ATP HI Guidelines, Report of the NCEP Expert Panel].
  • peripheral vascular disease and stroke are also promoted by unfavorable HDL / LDL ratios.
  • New methods for increasing HDL cholesterol in the plasma therefore represent a therapeutically useful enrichment in the prevention and treatment of arteriosclerosis and the associated diseases.
  • CETP Cholesterol ester transfer protein
  • the present invention relates to compounds of the general formula (I)
  • R 6 represents a substituent chosen from the series halogen, cyano, (C r C6) alkyl and (C r C6) alkoxy, wherein alkyl and alkoxy in turn can be substituted up to five times by fluorine,
  • D is (C 3 -C 6) -AlkVl, (C 4 -C 8 ) -cycloalkyl, (C 4 -C 8 ) -cycloalkenyl, (C 6 -C 10 ) -aryl, 5- or 6-membered heteroaryl, tetrahydrofuranyl or tetrahydropyranyl, wherein
  • Aryl and heteroaryl in turn with halogen, cyano, (C r C 6 ) alkyl, (C r C 6 ) alkoxy, trifluoromethyl or trifluoromethoxy
  • Cycloalkyl and cycloalkenyl in turn may be substituted by fluorine or (C 1 -Ce) -AlkVl,
  • R 1 is hydrogen, fluorine, hydroxyl, methoxy, mercapto or methyl
  • R 2 is hydrogen
  • R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group
  • R 3 is (C 1 -C 6 ) alkyl or (C 3 -C 7 ) cycloalkyl
  • R 4 and R 5 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 spiro-linked 3- to 5-membered cycloalkyl ring,
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the present invention includes therefore the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • the present invention encompasses all tautomeric forms.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid acetic acid, trifluoroacetic acid, propionic acid
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, trisethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salt
  • solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically). Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
  • Alkyl radical having 1 to 4 carbon atoms is preferred.
  • Alkyl radical having 1 to 4 carbon atoms is preferred.
  • (C 1 -Cs) -alkoxy and (C 1 -Ca) -alkoxy are a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert. Butoxy, n-pentoxy and n-hexoxy.
  • (C 1 -C 4 -cycloalkyl) C 1 -C 4 -cycloalkyl and (C 1 -C 4 -cycloalkyl represent a monocyclic, saturated cycloalkyl group having 4 to 8, 3 to 7 or 3 to 6 carbon atoms
  • (C4-CR) -cycloalkenyl in the context of the invention is a monocyclic cycloalkyl group having 4 to 8 carbon atoms and one double bond.
  • Preferred is a cycloalkenyl radical having 5 or 6 carbon atoms. Examples which may be mentioned are cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • (Cfi-C j n) -aryl is in the context of the invention an aromatic carbocycle having 6 or 10 ring carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • 5- or 6-membered heteroaryl is in the context of the invention for an aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing one or two ring heteroatoms from the series N, O and / or S and a Ring carbon atom or optionally a ring nitrogen atom is linked.
  • aromatic heterocycle heterocycle
  • pyrrolyl thienyl
  • pyrazolyl imidazolyl
  • thiazolyl oxazolyl
  • isoxazolyl isoxazolyl
  • isothiazolyl pyridyl, pyrimidinyl, pyridazinyl and Pyrazinyl.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine and fluorine.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
  • A is a group of the formula
  • R 6 is a substituent selected from the group fluorine, chlorine, cyano, (Ci-C 4 ) -
  • Alkyl and (C r C 4 ) alkoxy wherein alkyl and alkoxy in turn may be substituted up to five times with fluorine,
  • n is the number 0, 1, 2 or 3
  • D is phenyl, thienyl, furyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl, wherein
  • Phenyl, thienyl and furyl in turn with fluorine, chlorine, cyano, (Ci-C 4 ) alkyl, (C 1 -C 4 ) - alkoxy, trifluoromethyl or trifluoromethoxy - T - and
  • Cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl may in turn be substituted by fluorine or (C 1 -C 4 ) -alkyl,
  • R 1 is hydrogen, fluorine, hydroxy or methyl
  • R 2 is hydrogen
  • R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group
  • R 3 is (C 3 -C 6 ) alkyl or (C 3 -C 6 ) cycloalkyl
  • R 4 and R 5 independently of one another represent hydrogen or methyl or together with the carbon atom to which they are attached form a spiro-linked 3- to 5-membered cycloalkyl ring,
  • A is a group of the formula
  • R 6 is trifluoromethyl, trifluoromethoxy or tert-butyl
  • D is phenyl, 4-fluorophenyl, cyclopentyl, cyclohexyl, cyclopent-1-en-1-yl or cyclohex-1-en-1-yl
  • R 1 is hydrogen, fluorine or hydroxy
  • R 2 is hydrogen
  • R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group
  • R 3 is isopropyl or cyclopentyl
  • R 4 and R 5 are methyl or together with the carbon atom to which they are attached form a spiro-linked cyclopropyl or cyclobutyl ring,
  • Another object of the invention is a process for the preparation of the inventive compounds of formula (I), characterized in that either
  • R 7 is hydrogen, methyl or a conventional hydroxy protecting group such as AHyI, benzyl, tetrahydropyranyl or trialkylsilyl,
  • Q is Li, -MgBr, -ZnBr or -B (OH) 2 ,
  • X represents a leaving group such as, for example, chlorine, bromine, iodine, tosylate, mesylate or triflate,
  • R 8 is hydrogen or (C r C 4) -alkyl or together are a -C (CH 3) 2 -C (CH 3) 2 bridge form two radicals,
  • the chromanol hydroxy group may be temporarily protected by a conventional hydroxy-protecting group in these transformations, if necessary or convenient.
  • a trialkylsilyl group is used for this purpose; particularly preferred is tert-butyldimethylsilyl.
  • the introduction and removal of such protecting groups is carried out by known methods [see, e.g. T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].
  • tert-butyldimethylsilyl group preference is given to using tert-butyldimethylsilyl chloride or tert-butyldimethylsilyl trifluoromethanesulfonate in conjunction with triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-lutidine or 4-N, N-dimethylaminopyridine as base ,
  • the Cleavage of the tert.-butyldimethylsilyl group is preferably carried out with the aid of tetra-n-butylammonium fluoride (TBAP).
  • TBAP tetra-n-butylammonium fluoride
  • Suitable reducing agents for the reduction of ketones to secondary alcohols are, for example, complex aluminum or boron hydrides such as lithium, sodium, potassium, zinc borohydride, lithium aluminum hydride, diisobutylaluminum hydride (DIBAL-H), sodium bis (2-methoxyethoxy ) aluminum dihydride, Lithiumtrialkylborhydride or Lithiumtrialkoxyaluminium- hydride, or borane complexes such as borane-tetrahydrofuran, borane-dimethyl sulfide or borane-NN-diethylaniline complex.
  • complex aluminum or boron hydrides such as lithium, sodium, potassium, zinc borohydride, lithium aluminum hydride, diisobutylaluminum hydride (DIBAL-H), sodium bis (2-methoxyethoxy ) aluminum dihydride, Lithiumtrialkylborhydride or Lithiumtrialkoxyaluminium- hydr
  • Inert solvents for process steps (U) + (Iu) ⁇ (TV) and (X) + (UT) ⁇ (XI) are, for example, ethers, such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or hydrocarbons such as benzene, xylene, toluene, pentane, hexane, cyclohexane or petroleum fractions. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to tetrahydrofuran.
  • the reactions (U) + (UT) ⁇ (IV) and (X) + (UI) ⁇ (XI) may optionally be advantageously carried out with the addition of dialkylzinc compounds or palladium or rhodium-phosphine complexes as catalysts [cf. e.g. M. Ueda and ⁇ . Miyaura, J. Org. Chem. 65, 4450-4452 (2000) and literature cited therein].
  • the reactions are generally carried out in a temperature range of -80 0 C to +50 0 C, preferably at -80 0 C to 0 0 C.
  • Suitable oxidizing agents in process step (IV) -> (V) are manganese (IV) oxide, pyridinium chlorochromate (PCC), N-methylmorpholine N-oxide, 2,2,6,6-tetramethylpiperidin-1-yloxy Radical (TEMPO) or Dess-Martin periodinane (1,1-dihydro-1,1,2-triacetoxy-1,2-benziodoxol-3 (1H) -On).
  • Manganese (IV) oxide or Dess-Martin periodinan are preferably used.
  • a trifiato group (trifluoromethylsulfonate) is preferably used.
  • the phenol derivative (Va) or (Ha) in an inert solvent such as dichloromethane or dimethylformamide with trifluoromethanesulfonic anhydride or preferably reacted with N, N-bis (trifluoromethanesulphonyl) aniline in the presence of a base such as potassium carbonate, pyridine, 2,6-lutidine, 4-N, N-dimethylaminopyridine (DMAP), triethylamine or N, N-diisopropylethylamine.
  • a base such as potassium carbonate, pyridine, 2,6-lutidine, 4-N, N-dimethylaminopyridine (DMAP), triethylamine or N, N-diisopropylethylamine.
  • Inert solvents for process steps (VI) + (VII) ⁇ (VTfl) and (DC) + (VU) ⁇ (X) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol , Ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene Glykoldimethylether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, N, N-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ MP), pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Dioxane is preferred.
  • Suitable bases for the process steps (VI) + (VII) ⁇ (Vffl) and (DC) + (VIT) ⁇ (X) are customary inorganic bases. These include in particular alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal bicarbonates such as sodium or potassium bicarbonate, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal hydrogen phosphates such as disodium or dipotassium hydrogen phosphate, or Alkaline phosphates such as trisodium or tripotassium phosphate. Preferably, tripotassium phosphate is used.
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide
  • alkali metal bicarbonates such as sodium or potassium bicarbonate
  • alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate
  • alkali metal hydrogen phosphates such as disodium or
  • the reactions (VI) + (VTT) ⁇ (VTTT) and (DC) + (VIT) ⁇ (X) are generally in a temperature range of +20 0 C to +150 0 C, preferably at +60 0 C to + 120 0 C performed.
  • the reaction is generally carried out in toluene or in an ether such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, preferably in tetrahydrofuran, in a temperature range of -80 0 C to +50 0 C, preferably from 0 0 C to +30 0 C, performed.
  • an ether such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, preferably in tetrahydrofuran, in a temperature range of -80 0 C to +50 0 C, preferably from 0 0 C to +30 0 C, performed.
  • the fluorination in process step (XT) -> (XTT) and analogous reactions is generally carried out in a hydrocarbon such as benzene, toluene, xylene, pentane, hexane or cyclohexane, or in a halohydrocarbon such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-di - Chloroethane, trichlorethylene or chlorobenzene carried out as a solvent. Preference is given to toluene or dichloromethane.
  • the fluorination reagent is preferably diethylaminosulfur trifluoride (DAST) or Morpholinoschwefeltrifluorid used.
  • the reaction is generally carried out in a temperature range of -80 0 C to +40 0 C, preferably at -60 0 C to +20 0 C.
  • the compounds of the formula (Ha) can be prepared by reacting a compound of the formula (XIII)
  • X 1 represents a leaving group such as mesylate, tosylate or in particular triflate
  • a triflate group (trifluoromethylsulfonate) is preferably used.
  • the phenol derivative (XHI) in an inert solvent such as dichloromethane or dimethylformamide with trifluoromethanesulfonic anhydride or preferably with NN-bis (trifluoromethanesulfonyl) aniline in the presence of a base such as potassium carbonate , Pyridine, 2,6-lutidine, 4-N, N-dimethylaminopyridine (DMAP), triethylamine or N, N-diisopropylethylamine.
  • a base such as potassium carbonate , Pyridine, 2,6-lutidine, 4-N, N-dimethylaminopyridine (DMAP), triethylamine or N, N-diisopropylethylamine.
  • Inert solvents for process step (XIV) + (XVa) or (XVb) ⁇ (XVI) are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, Toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using dimethylformamide.
  • DMPU N, N'-dimethylpropyleneurea
  • NMP N-methylpyrrolidone
  • Suitable catalysts for process step (XIV) + (XVa) or (XVb) ⁇ (XVI) ["Negishi-Kumada coupling”] are bis (diphenylphosphino) ferrocene-palladium (II) chloride or palladium (II). acetate in conjunction with triphenylphosphine, with addition of co-catalysts such as copper (I) iodide or lithium chloride, suitable [see. e.g. A. Weichert et al., Synlett, Al.> (1996) and references cited therein].
  • the reaction is generally carried out in a temperature range from -20 0 C to +120 0 C, preferably at 0 0 C to +60 0 C.
  • the Lewis acid suitable is, for example, titanium (IV) chloride, titanium (IV) isopropylate, Zmn (II) chloride or magnesium chloride.
  • titanium (IV) chloride is used.
  • boron trifluoride is particularly suitable as the Lewis acid.
  • agents such as methanesulfonic acid or phosphorus pentoxide can be used.
  • the reaction can be carried out in a hydrocarbon such as benzene, toluene, xylene, hexane or cyclohexane, or in a halohydrocarbon such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichlorethylene or chlorobenzene solvent or else without solvent.
  • R 5A is hydrogen or (C 1 -C 4 ) -alkyl
  • R 5A has the abovementioned meaning
  • X 2 represents a leaving group such as tosylate, mesylate or in particular triflate
  • the leaving group X 2 is preferably a triflate group (trifluoromethylsulfonate).
  • a triflate group trifluoromethylsulfonate
  • the phenol derivative (XX) in an inert solvent such as dichloromethane or dimethylformamide with trifluoromethanesulfonic anhydride or preferably with NN-bis (trifluoromethanesulfbnyl) aniline in the presence of a base such as potassium carbonate, Pyridine, 2,6-lutidine, 4-N, N-dimethylaminopyridine (DMAP), triethylamine or N, N-diisopropylethylamine.
  • a base such as potassium carbonate, Pyridine, 2,6-lutidine, 4-N, N-dimethylaminopyridine (DMAP), triethylamine or N, N-diisopropylethylamine.
  • Inert solvents for process step (XXI) -> (XXII) are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane,
  • Cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ MP) or acetonitrile.
  • Examples of catalysts for process step (XXI) ⁇ (XXS) ["Heck-coupling”] are palladium ( ⁇ ) -acetate or palladium ( ⁇ ) -trifluoroacetate, in combination with triphenyl- or tritolyl- phosphine, or bis (dibenzylideneacetone) palladium (0).
  • the reaction is carried out with the addition of a base such as potassium carbonate or NN-diisopropylethylamine.
  • the reaction is generally carried out in a temperature range from + 2O 0 C to +120 0 C, preferably at + 40 0 C to + 100 0 C.
  • LiAlH 4 , THF, RT; d): (1 ⁇ , 25) -aminoindanol, borane-N, N-diethylaniline complex, THF, RT (when R 6 CF 3 )].
  • the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
  • the compounds according to the invention open up a further treatment alternative and represent an enrichment of the pharmaceutical industry.
  • the compounds according to the invention show an improved spectrum of activity. They are characterized by high specificity and good compatibility.
  • An advantage of the compounds according to the invention is in particular their high activity in human plasma. At the same time they have as a further advantage a reduced deposition behavior in adipose tissue.
  • the compounds of the invention are potent inhibitors of cholesterol ester transfer protein (CETP) and stimulate reverse cholesterol transport. They cause an increase in HDL cholesterol levels in the blood.
  • CETP cholesterol ester transfer protein
  • the compounds according to the invention can be used in particular for the treatment and primary or secondary prevention of coronary heart diseases, for example of myocardial infarction, angina pectoris, cardiac insufficiency, myocardial insufficiency, pulmonary hypertension and ischemia-related damage to the heart (acute coronary syndrome).
  • coronary heart diseases for example of myocardial infarction, angina pectoris, cardiac insufficiency, myocardial insufficiency, pulmonary hypertension and ischemia-related damage to the heart (acute coronary syndrome).
  • the compounds according to the invention can be used for the treatment and prevention of arteriosclerosis, peripheral vascular diseases, restenosis, strokes and Alzheimer's disease.
  • the compounds according to the invention can also be used for the treatment and prevention of hypolipoproteinemias, dyslipidemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, obesity, obesity, pancreatitis, insulin-dependent and non-insulin-dependent diabetes, diabetic late effects such as Retinopathy, nephropathy and neuropathy, combined hyperlipidaemias and the metabolic syndrome.
  • the pharmacological activity of the compounds according to the invention can be determined by means of the CETP inhibition tests listed below.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the compounds of the invention may be used alone or as needed in combination with other agents.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, for the treatment and / or prevention of the aforementioned Erkran- kung.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • the compounds of the invention may preferably be with one or more
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors or anticoagulants,
  • Hypertensive agents for example and preferably from the group of calcium antagonists, angiotensin AH antagonists, ACE inhibitors, renin inhibitors, beta-receptor blockers, alpha-receptor blockers, phosphodiesterase inhibitors, stimulators of the soluble guanylate cyclase, cGMP level enhancers, adenosine receptor agonists, aldosterone antagonists, mineralocorticoid receptor antagonists, endothelin antagonists, ECE inhibitors, vasopeptidase inhibitors and diuretics, and / or
  • the fat metabolism-altering agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors, squalene synthase inhibitors, squalene epoxidase inhibitors or oxydosqualene cyclase inhibitors, the ACAT inhibitors, MTP Inhibitors, PPAR agonists, fibrates, lipase inhibitors, cholesterol absorption inhibitors, bile acid reabsorption inhibitors, polymeric bile acid adsorbers, lipoprotein (a) antagonists, RXR modulators, FXR modulators, LXR modulators, ATP citrate lyase inhibitors , Cannabinoid receptor 1 antagonists, leptin receptor agonists, bombesin receptor agonists, histamine receptor agonists, and antioxidants / radical scavengers
  • cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors,
  • 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-I agonists, DPPIV inhibitors, ghrelin receptor antagonists , CCK1 receptor agonists, leptin receptor agonists, insulin sensitizers, hepatic enzyme inhibitors involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake and potassium channel openers, such as those described in WO 97/26265 and WO 99/03861.
  • the compounds according to the invention are administered in combination with insulin.
  • the compounds according to the invention are administered in combination with a sulphonylurea, such as, by way of example and by way of preference, tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.
  • a sulphonylurea such as, by way of example and by way of preference, tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.
  • the compounds according to the invention are administered in combination with a biguanide, such as by way of example and preferably metformin.
  • the compounds according to the invention are administered in combination with a meglitinide derivative, such as by way of example and preferably repagolinide or nateglinide.
  • a meglitinide derivative such as by way of example and preferably repagolinide or nateglinide.
  • the compounds according to the invention are administered in combination with a PPARgamma agonist, for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • a PPARgamma agonist for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • the compounds according to the invention are used in combination with a mixed PPARalpha / gamma agonist such as, for example and preferably, GI-262570 (Farglitazar), GW 2331, GW 409544, AVE 8042, AVE 8134, AVE 0847, MK-0767 (KRP-297) or AZ-242.
  • a mixed PPARalpha / gamma agonist such as, for example and preferably, GI-262570 (Farglitazar), GW 2331, GW 409544, AVE 8042, AVE 8134, AVE 0847, MK-0767 (KRP-297) or AZ-242.
  • the compounds according to the invention are administered in combination with a glucosidase-inhibitor, such as, by way of example and by way of preference, acarbene, adiposin, voglibose or miglitol.
  • a glucosidase-inhibitor such as, by way of example and by way of preference, acarbene, adiposin, voglibose or miglitol.
  • the compounds according to the invention are administered in combination with a DPPIV inhibitor, such as, for example and preferably, vildaglipitin or sitaglipitin.
  • a DPPIV inhibitor such as, for example and preferably, vildaglipitin or sitaglipitin.
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole, or anticoagulants.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as by way of example and preferably ximelagatran, melagatran, dabigatran, tanogitran, bivalirudin or clexane.
  • a thrombin inhibitor such as by way of example and preferably ximelagatran, melagatran, dabigatran, tanogitran, bivalirudin or clexane.
  • the compounds according to the invention are administered in combination with a GPUb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • the compounds according to the invention are administered in combination with a factor Xa inhibitor, such as, by way of example and by way of preference, apixaban, razaxaban, otamixaban or rivaroxaban.
  • a factor Xa inhibitor such as, by way of example and by way of preference, apixaban, razaxaban, otamixaban or rivaroxaban.
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • antihypertensive agents are, by way of example and by way of example, compounds from the group of calcium antagonists, such as, for example, the compounds nifedipine, amlodipine, nitrendipine, nisoldipine, verapamil or diltiazem, the angiotensin Aü antagonists, ACE inhibitors, renin inhibitors, Beta-blockers, alpha-blockers and diuretics understood.
  • compounds from the group of calcium antagonists such as, for example, the compounds nifedipine, amlodipine, nitrendipine, nisoldipine, verapamil or diltiazem, the angiotensin Aü antagonists, ACE inhibitors, renin inhibitors, Beta-blockers, alpha-blockers and diuretics understood.
  • the compounds according to the invention are administered in combination with reserpine, minoxidil, diazoxide, dihydralazine, hydralazine or nitric oxide-releasing substances, such as, by way of example and by way of preference, glycerol nitrate or nitroprusside sodium.
  • the compounds according to the invention are administered in combination with an angiotensin Aü antagonist, such as by way of example and preferably losartan, valsartan, candesartan, telmisartan, embusartan, irbesartan, olmesartan, tasosartan or saprisartan.
  • an ACE inhibitor such as by way of example and preferably enalapril, captopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandolapril.
  • the compounds according to the invention are administered in combination " with a renin inhibitor, such as by way of example and preferably aliskiren.
  • the compounds according to the invention are administered in combination with a beta-blocker, such as, by way of example and by way of preference, propranolol or atenolol.
  • a beta-blocker such as, by way of example and by way of preference, propranolol or atenolol.
  • the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably furosemide.
  • lipid metabolizing agents are exemplified and preferably compounds from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR agonists, fibrates, Cholesterol absorption inhibitors, bile acid reabsorption inhibitors, lipase inhibitors, polymeric bile acid adsorber, lipoprotein antagonists and the cannabinoid receptor 1 antagonists understood.
  • cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR agonists PPAR agonists
  • fibrates Cholesterol absorption inhibitors
  • bile acid reabsorption inhibitors bile acid reabsorption inhibitors
  • the compounds according to the invention 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'-triiodothyronm (T3), CGS 23425 or axitirome (CGS 26214) ,
  • a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronm (T3), CGS 23425 or axitirome (CGS 26214) ,
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK 475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK 475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, eflucimibe or CS-505.
  • an ACAT inhibitor such as by way of example and preferably avasimibe, eflucimibe or CS-505.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a bile acid reabsorption inhibitor, such as by way of example and by way of preference barixibat, AZD 7508, SC 435, SC 635, S-8921, 264W94 or HM 1453.
  • the compounds according to the invention are administered in combination with an MTP inhibitor, such as by way of example and preferably implitapide, BMS-201038 or R-103757.
  • an MTP inhibitor such as by way of example and preferably implitapide, BMS-201038 or R-103757.
  • the compounds of the invention are administered in combination with a PPARalpha agonist, e.g. the fibrates fenofibrate, clofibrate, bezafibrate, ciprofibrate or gemfibrozil, or as exemplified and preferably GW 9578, GW 7647, LY-518674 or NS-220.
  • a PPARalpha agonist e.g. the fibrates fenofibrate, clofibrate, bezafibrate, ciprofibrate or gemfibrozil, or as exemplified and preferably GW 9578, GW 7647, LY-518674 or NS-220.
  • the compounds according to the invention are administered in combination with a PPARdelta agonist, such as by way of example and preferably GW 501516.
  • the compounds according to the invention are administered in combination with a mixed PPARalpha / gamma agonist such as, for example and preferably, GI-262570 (Farglitazar), GW 2331, GW 409544, AVE 8042, AVE 8134, AVE 0847, MK No. 0767 (KRP-297) or AZ-242.
  • a mixed PPARalpha / gamma agonist such as, for example and preferably, GI-262570 (Farglitazar), GW 2331, GW 409544, AVE 8042, AVE 8134, AVE 0847, MK No. 0767 (KRP-297) or AZ-242.
  • the compounds of the invention are administered in combination with a mixed PPARalpha / gamma / delta agonist, as exemplified and preferably MCC-555.
  • the compounds according to the invention are used in combination with a lipase inhibitor from the group of endothelial lipase inhibitors, pancreatic lipase inhibitors, gastric lipase inhibitors, hormone-sensitive lipase inhibitors or hepatic lipase inhibitors. Administered inhibitors.
  • the compounds according to the invention are administered in combination with an inhibitor of pancreatic lipase, preferably from the class of lipstins such as, for example, orlistat.
  • the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • the compounds according to the invention are administered in combination with a cannabinoid receptor 1 antagonist, such as by way of example and preferably rimonabant.
  • a cannabinoid receptor 1 antagonist such as by way of example and preferably rimonabant.
  • the compounds according to the invention are administered in combination with an antagonist of the niacin receptor, such as by way of example and preferably Niaspan, Acipimox or Niceritrol.
  • the compounds according to the invention are administered in combination with an antioxidant, such as, by way of example and by way of preference, probucol, AGI 1067 or Bo 653.
  • an antioxidant such as, by way of example and by way of preference, probucol, AGI 1067 or Bo 653.
  • the compounds according to the invention are administered in combination with an LDL receptor inducer, such as, for example, Lifibrol.
  • an LDL receptor inducer such as, for example, Lifibrol.
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
  • statins such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
  • Another object of the present invention are combinations of the compounds of the invention with substances that cause a reduction in HMG-CoA reductase gene expression.
  • substances may, for example, be inhibitors of HMG-CoA reductase transcription or of HMG-CoA reductase translation.
  • Inhibition of HMG-CoA reductase gene expression can be caused, for example, by inhibition of the SlP (site I) protease or by lowering the SREBP (sterol receptor binding protein) levels.
  • Another object of the present invention are combinations of the compounds of the invention with substances which have anti-inflammatory and / or the atherosclerotic plaque stabilizing effect.
  • substances may be, for example, agents from the class of NSAIDs, the Lp-PLA 2 antagonists or the chemokine receptor antagonists, such as IL-8 receptor antagonists or MCP-1 antagonists by way of example.
  • the compounds according to the invention are administered in combination with an Lp-PLA 2 antagonist, such as by way of example and preferably darapladib or goxalapladib.
  • the active compound combinations according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases.
  • the active compound combinations according to the invention are in particular for the treatment and for the primary or secondary prevention of coronary heart diseases, e.g. Myocardial infarction, angina pectoris, heart failure, myocardial insufficiency, pulmonary hypertension and ischemia-related damage to the heart (acute coronary syndrome) can be used. They can also be used to treat and prevent atherosclerosis, peripheral vascular disease, restenosis, strokes and Alzheimer's disease.
  • coronary heart diseases e.g. Myocardial infarction, angina pectoris, heart failure, myocardial insufficiency, pulmonary hypertension and ischemia-related damage to the heart (acute coronary syndrome) can be used. They can also be used to treat and prevent atherosclerosis, peripheral vascular disease, restenosis, strokes and Alzheimer's disease.
  • the active substance combinations mentioned can also be used for the treatment and prevention of hypolipoproteinemias, dyslipidaemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, obesity (adipositas), obesity, pancreatitis, insulin-dependent and non-insulin-dependent diabetes, diabetic late effects, such as retinopathy, nephropathy and neuropathy, combined hyperlipidaemias and the metabolic syndrome.
  • the active compound combinations according to the invention are suitable for the treatment of hypertension as well as of inflammatory diseases.
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved
  • Contain mold such as tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings controlling the release of the compound of the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (eg hard or soft gelatin capsules), dragees, granules, pellets, powders , Emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg plasters)
  • milk pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecy
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • UV ultraviolet spectrometry v / v volume to volume ratio (of a solution) w / v weight to volume ratio (of a solution)
  • Device Type Abimed Gilson 305; Column: YMC GEL ODS-AQS-5/15 ⁇ m, 250 mm x 30 mm; Mobile phase: gradient acetonitrile / water 50:50 ⁇ 80:20 (15 min) ⁇ 95: 5 (27 min); Flow: 40 ml / min; UV detection: 210 nm.
  • Method 4 (analytical HPLC, chiral): Device type: HP 1100; Column: Chiralpak IA, 250 mm x 4.6 mm; Mobile phase: isopropanol / isohexane 3:97; Flow: 1.5 ml / min; Temperature: 24 ° C; UV detection: 254 nm.
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; Flow: 0.0 min 1 ml / min ⁇ 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Method 8 (LC / MS): Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - »2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; Flow: 0.0 min 1 ml / min ⁇ 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 208-400 nm.
  • Device type MS Micromass ZQ
  • Device type HPLC HP 1100 Series
  • UV DAD Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm
  • Eluent A 1 liter of water + 0.5 ml of 50% ant acid
  • eluent B 1 liter acetonitrile + 0.5 ml 50% formic acid
  • Flow 0.0 min 1 ml / min ⁇ 2.5 min / 3.0 min / 4.5 min 2 ml / min
  • Oven 50 ° C .
  • UV detection 210 nm.
  • Method 10 Instrument: Micromass GCT, GC 6890; Column: Restek RTX-35MS, 30 m ⁇ 250 ⁇ m ⁇ 0.25 ⁇ m; constant flow with helium: 0.88 ml / min; Oven: 60 ° C; Inlet: 25O 0 C; Gradient: 60 0 C (0.30 keep min), 50 ° C min ⁇ 120 0 C, 16 ° C min ⁇ 250 0 C, 30 ° C (1.7 min hold) / / / min ⁇ 300 0C.
  • Example 4A and Example 5A are Example 4A and Example 5A.
  • Example 7A 100 mg (0.22 mmol) of 7-cyclopentyl-6- ⁇ hydroxy [4- (trifluoromethyl) phenyl] methyl ⁇ -5-methoxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 7A) are dissolved in 5 ml of dichloromethane, mixed with 194 mg (2.23 mmol) of manganese (IV) oxide and the mixture is stirred overnight at room temperature. It is filtered through a silica gel layer, washed well with ethyl acetate and the filtrate is concentrated to dryness.
  • Example 14A [(45) -4 - ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ -7-cyclopentyl-5- (4-fluorophenyl) -2,2-dimethyl-3,4-dihydro-2H chromen-6-yl] [4- (trifluoromethyl) phenyl] methanol
  • the crude product obtained is purified by preparative thick-layer chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 5: 1). There are obtained 47 mg (46% of theory) of the title compound, which is used without further characterization in the next stage.
  • Example 15A tert. Butyl [((4S) -7-cyclopentyl-5- (4-fluoro-phenyl) -6-fluoro [4- (trifluoromethyl) -phenyl] -methyl ⁇ -2,2-dimethyl-3,4-dihydro-2H-chroma -4-yl) oxy] dimethylsilane
  • Example 21 A rac-5- (4-fluorophenyl) -6- ⁇ hydroxy [4- (trifluoromethyl) phenyl] methyl ⁇ -7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromene-4- on
  • Example 22A rac-5- (4-Fluoro-phenyl) -6- ⁇ fluoro [4- (trifluoromethyl) -phenyl] -methyl ⁇ -7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one
  • the filtrate is concentrated and the residue is purified by column chromatography on silica gel (mobile phase: gradient cyclohexane ⁇ cyclohexane / ethyl acetate 20: 1 ⁇ 10: 1).
  • the resulting product is combined with the crystals.
  • the compound is in the form of two atropisomers (1: 1).
  • Example 38A rac-5-cyclopent-1-yl-6- ⁇ - hydroxy [4- (trifluoromethyl) phenyl] methyl ⁇ -7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one
  • the resulting product is treated with 230 ml (2.99 mol) of trifluoroacetic acid, heated to 75 ° C and stirred for 8 hours. It is then cooled, mixed with water and extracted several times with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified on silica gel (eluent: dichloromethane / methanol 100: 1 -> 100: 3). The product fractions are combined and concentrated. The resulting residue is treated with dichloromethane, stirred briefly and the precipitate is filtered off with suction and dried under high vacuum. This gives 2.25 g (5% of theory) of the target compound. The mother liquor is then purified again over a silica gel column (eluent: dichloromethane / methanol 100: 1). In this way, a further 3.41 g (7% of theory) of the title compound are obtained.
  • the mixture After stirring for a total of 5 hours, the mixture is mixed with ammonium chloride solution. It is diluted with water and ethyl acetate, the organic phase separated and the aqueous phase extracted twice more with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is applied to silica gel and purified over a silica gel column (mobile phase: cyclohexane / ethyl acetate 30: 1). There are obtained 28 g (80% of theory) of the title compound.
  • Example 44A The title compound is prepared analogously to Example 44A from 5.5 g of the compound from Example 43 A. 5.4 g (60% of theory) of the target product are obtained.
  • Example 45A The title compound is prepared analogously to Example 46A from 5.4 g of 5-hydroxy-4-oxo-S ⁇ -dihydrospirofchromen ⁇ l-cyclopropan ⁇ -yl-irifluormethansulfonat (Example 45A). There are obtained 5.4 g (89% of theory) of the target product with a purity of about 87%.
  • the main impurity is the propropylene isomer:
  • the main impurity is the propropylene isomer:
  • aqueous phase is extracted three times with ethyl acetate and the combined organic phases are washed twice with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated.
  • the residue is applied to silica gel and purified over a silica gel column (mobile phase: cyclohexane / ethyl acetate 50: 1 ⁇ 20: 1). 1.42 g (42% of theory) of the title compound are obtained.
  • a mixed fraction is purified again over silica gel as described above. In this way, a further 1.94 g (39% of theory) of the target compound having a purity of 65% are obtained.
  • the main impurity is the propropylene isomer:
  • the residue is taken up in 10 ml of ethanol, treated again with the same amount of rhodium on activated charcoal and hydrogenated for a further 18 hours under a hydrogen pressure of 60 bar at room temperature.
  • the suspension is again filtered through kieselguhr, washed with ethyl acetate and the filtrate is concentrated under reduced pressure.
  • the crude product is purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 15: 1).
  • Example 5 and Example 6 (4S) -5- (4-Fluoro-phenyl) -6 - ⁇ (6) -hydroxy [4- (trifluoromethyl) -phenyl] -methyl ⁇ -7-isopropyl-2,2-dimethylchroman-4- ol (Example 5)
  • Example 7 and Example 8 (4S) -5- (4-Fluoro-phenyl) -6 - ⁇ (S) -fluoro [4- (trifluoromethyl) -phenyl] -methyl ⁇ -7-isopropyl-2,2-dimethylchroman-4 ol ⁇ Example 7)
  • the enantiomer of the target product is [(4i) -5- (4-fluorophenyl) -4-hydroxy-7-isopropyl-2,2-dimethyl-3,4-dihydro-2H-chromene -6-yl] [4- (trifluoromethoxy) phenyl] methanone, obtained:

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Abstract

La présente invention concerne un dérivé de chromanol substitué, son procédé de fabrication, son utilisation seul ou en combinaison pour le traitement et/ou la prévention de maladies, ainsi que son utilisation pour la fabrication de médicaments pour le traitement et/ou la prévention de maladies, notamment pour le traitement et/ou la prévention de maladies cardiovasculaires.
EP07711808A 2006-03-18 2007-03-07 Derive de chromanol substitue et son utilisation Withdrawn EP1999123A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006012548A DE102006012548A1 (de) 2006-03-18 2006-03-18 Substituierte Chromanol-Derivate und ihre Verwendung
PCT/EP2007/001930 WO2007107243A1 (fr) 2006-03-18 2007-03-07 Derive de chromanol substitue et son utilisation

Publications (1)

Publication Number Publication Date
EP1999123A1 true EP1999123A1 (fr) 2008-12-10

Family

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Family Applications (1)

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EP07711808A Withdrawn EP1999123A1 (fr) 2006-03-18 2007-03-07 Derive de chromanol substitue et son utilisation

Country Status (20)

Country Link
US (1) US8227511B2 (fr)
EP (1) EP1999123A1 (fr)
JP (1) JP5285594B2 (fr)
KR (1) KR101440633B1 (fr)
CN (1) CN101443321B (fr)
AR (1) AR059831A1 (fr)
AU (1) AU2007229092A1 (fr)
BR (1) BRPI0708851A2 (fr)
CA (1) CA2645884A1 (fr)
CR (1) CR10305A (fr)
DE (1) DE102006012548A1 (fr)
DO (1) DOP2007000043A (fr)
EC (1) ECSP088745A (fr)
MX (1) MX2008011893A (fr)
PE (1) PE20080005A1 (fr)
RU (1) RU2459817C2 (fr)
TW (1) TW200812998A (fr)
UY (1) UY30215A1 (fr)
WO (1) WO2007107243A1 (fr)
ZA (1) ZA200807809B (fr)

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EP2025674A1 (fr) 2007-08-15 2009-02-18 sanofi-aventis Tetrahydronaphthaline substituée, son procédé de fabrication et son utilisation en tant que médicament
EA201000675A1 (ru) * 2007-12-18 2011-06-30 Гленмарк Фармасьютикалс, С.А. Производные хромана как модуляторы trpv3
WO2011072064A1 (fr) 2009-12-08 2011-06-16 Array Biopharma Inc. Spiro[chromane-4,4'-imidazol]ones en tant qu'inhibiteurs de bêta-sécrétase
EP2582709B1 (fr) 2010-06-18 2018-01-24 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
EP2683704B1 (fr) 2011-03-08 2014-12-17 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
EP2766349B1 (fr) 2011-03-08 2016-06-01 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
US9938228B2 (en) * 2014-09-09 2018-04-10 Boehringer Ingelheim International Gmbh Process for the preparation of spiro[2.5]octane-5,7-dione and spiro[3.5]nonane-6,8-dione
CN105501108B (zh) 2014-10-08 2020-07-07 福特全球技术公司 具有点亮的车轮总成的车辆照明系统
CN105546443B (zh) 2014-10-27 2019-10-18 福特全球技术公司 具有照明的排气装置的车辆照明系统
CN112326830A (zh) * 2020-11-03 2021-02-05 湖南迪诺制药股份有限公司 一种阿托伐他汀钙异构体的检测方法
BR112023020381A2 (pt) 2021-05-12 2023-11-21 Boehringer Ingelheim Int Derivados de piridina com substituintes cíclicos ligados por c como inibidores de cgas

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AR059831A1 (es) 2008-04-30
JP2009530322A (ja) 2009-08-27
KR101440633B1 (ko) 2014-09-22
RU2459817C2 (ru) 2012-08-27
PE20080005A1 (es) 2008-03-14
KR20090004997A (ko) 2009-01-12
TW200812998A (en) 2008-03-16
CA2645884A1 (fr) 2007-09-27
JP5285594B2 (ja) 2013-09-11
MX2008011893A (es) 2008-09-30
UY30215A1 (es) 2007-10-31
ECSP088745A (es) 2008-10-31
RU2008141240A (ru) 2010-04-27
HK1132731A1 (en) 2010-03-05
BRPI0708851A2 (pt) 2011-06-14
CN101443321A (zh) 2009-05-27
ZA200807809B (en) 2009-11-25
CR10305A (es) 2009-02-19
US8227511B2 (en) 2012-07-24
DOP2007000043A (es) 2007-09-30
AU2007229092A1 (en) 2007-09-27
US20090306197A1 (en) 2009-12-10
DE102006012548A1 (de) 2007-09-20
CN101443321B (zh) 2012-09-26
WO2007107243A1 (fr) 2007-09-27

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