WO1999015487A1 - Benzylbiphenyles et composes analogues et leur utilisation pour le traitement de l'arteriosclerose et des dyslipidemies - Google Patents

Benzylbiphenyles et composes analogues et leur utilisation pour le traitement de l'arteriosclerose et des dyslipidemies Download PDF

Info

Publication number
WO1999015487A1
WO1999015487A1 PCT/EP1998/005731 EP9805731W WO9915487A1 WO 1999015487 A1 WO1999015487 A1 WO 1999015487A1 EP 9805731 W EP9805731 W EP 9805731W WO 9915487 A1 WO9915487 A1 WO 9915487A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbon atoms
chain
straight
phenyl
formula
Prior art date
Application number
PCT/EP1998/005731
Other languages
German (de)
English (en)
Inventor
Michael Lögers
Arndt Brandes
Gunter Schmidt
Jürgen Stoltefuss
Klaus-Dieter Bremm
Hilmar Bischoff
Delf Schmidt
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to CA002304274A priority Critical patent/CA2304274A1/fr
Priority to EP98954266A priority patent/EP1017658A1/fr
Priority to JP2000512799A priority patent/JP2001517646A/ja
Priority to AU11458/99A priority patent/AU1145899A/en
Publication of WO1999015487A1 publication Critical patent/WO1999015487A1/fr

Links

Classifications

    • 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
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • 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
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40—Halogenated unsaturated alcohols
    • C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40—Halogenated unsaturated alcohols
    • C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
    • C07C33/48—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts with unsaturation outside the aromatic rings
    • C07C33/486—Polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40—Halogenated unsaturated alcohols
    • C07C33/50—Halogenated unsaturated alcohols containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C07C43/1786—Unsaturated ethers containing hydroxy or O-metal groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to benzyl biphenyls and analogous compounds, processes for their preparation and their use in medicaments.
  • the present invention relates to benzyl biphenyls and analogous compounds of the general formula (I),
  • A represents cycloalkyl having 3 to 8 carbon atoms
  • aryl and the heterocyclic ring systems listed above if appropriate, up to 5 times the same or different by cyano, halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each having up to 7 carbon atoms, or are substituted by a group of the formula -NR 3 R 4 ,
  • R 3 and R 4 are identical or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
  • cycles optionally, in the case of the nitrogen-containing rings also via the N function, up to 5 times the same or different by halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoro- methoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, aryl substituted by aryl or trifluoromethyl each having 6 to 10 carbon atoms or by an optionally benzo-condensed aromatic 5- to 7- structure
  • Heterocycle with up to 3 heteroatoms from the series S, N and / or O are substituted
  • R 10 , R "and R 12 independently of one another are aryl having 6 to 10 carbon atoms, which in turn is substituted up to 2 times in the same or different manner by phenyl, halogen or by straight-chain or branched alkyl having up to 6 carbon atoms,
  • R 13 and R 14 are the same or different and are those given above
  • R 5 and / or R 6 is a radical of the formula
  • R 7 represents hydrogen, halogen or methyl
  • R 8 is hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkyl each having up to 6 carbon atoms or a radical of the formula -NR 15 R 16 ,
  • R 15 and R ! 6 are the same or different and have the meaning of R 3 and R 4 given above,
  • R 17 is hydrogen or straight-chain or branched alkyl
  • L is a straight-chain or branched alkylene or alkenylene chain each having up to 8 carbon atoms, which are optionally substituted up to 2 times by hydroxy,
  • T and X are identical or different and represent a straight-chain or branched alkylene chain with up to 8 carbon atoms
  • V represents an oxygen or sulfur atom or an -NR 18 group
  • R 18 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl
  • R 1 represents straight-chain or branched alkyl having up to 6 carbon atoms, which is by hydroxy or by a group of the formula
  • R 2 represents hydrogen or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which may optionally be hydroxyl, halogen, phenyl, cycloalkyl having 3 to 6 carbon atoms or a group of the formula
  • R 19 represents a radical of the formula -Si (CH 3 ) 2 C (CH 3 ) 3 , or
  • the compounds according to the invention can also be in the form of their salts.
  • salts with organic or inorganic bases or acids may be mentioned here.
  • Physiologically acceptable salts are preferred in the context of the present invention.
  • Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids.
  • Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids.
  • particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
  • Sodium, potassium, magnesium or calcium salts as well as ammonium salts, which are derived from ammonia, or organic amines, such as ethylamine, di- or.
  • ammonium salts which are derived from ammonia, or organic amines, such as ethylamine, di- or.
  • the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates both to the enantiomers or diastereomers and to their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.
  • Heterocycle, optionally benzocondensed, in the context of the invention generally represents a saturated, partially unsaturated or unsaturated 5- to 7-membered, preferably 5- to 6-membered, heterocycle of up to 4 heteroatoms from the series S, N and / or O can contain.
  • Examples include: indolyl, isoquinolyl, quinolyl, benzo [b] thiophene, benzo [b] furanyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, mopholinyl or piperidyl. Quinolyl, furyl, pyridyl and thienyl are preferred.
  • A stands for naphthyl, phenyl, pyridyl, thienyl, imidazolyl, pyrryl or Mo ⁇ holin, which are optionally up to 2 times the same or different by fluorine, chlorine, bromine, amino, hydroxy, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl, or alkoxy are each substituted with up to 6 carbon atoms,
  • D represents phenyl, which may be replaced by nitro, fluorine, chlorine, bromine, phenyl,
  • Trifluormethyl or Trifluormethoxy is substituted, or
  • R, R and R independently of one another Phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, pyrrolidinyl, indolyl, mopholinyl, imidazolyl, benzothiazolyl, phenoxathi-2-yl, benzoxazolyl, furyl, quinolyl or purin-8-yl,
  • the cycles optionally up to 3 times in the case of the nitrogen-containing rings also via the N function, the same or different by fluorine, chlorine, bromine, trifluoromethyl, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio , Alkylalkoxy, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, triazolyl, tetrazolyl, benzoxathiazolyl, or trifluoromethyl-substituted phenyl or phenyl are substituted,
  • R 10 , R 11 and R 12 are identical or different and are phenyl, which in turn is up to 2 times identical or different due to phenyl,
  • Fluorine chlorine or substituted by straight-chain or branched alkyl having up to 4 carbon atoms,
  • R 5 and / or R 6 is a radical of the formula
  • R 7 denotes hydrogen, fluorine, chlorine or bromine
  • R 8 is hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkyl each having up to 5 carbon atoms or a radical of the formula -NR 15 R 16 ,
  • R 15 and R 16 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,
  • R 17 denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms,
  • T and X are the same or different and are straight or branched
  • T or X represents a bond
  • V for an oxygen or sulfur atom or for a group of
  • R 18 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or phenyl
  • E represents cyclopropyl, butyl, pentyl, hexyl or heptyl, or
  • R 1 for a group of the formula -CH 2 OH or
  • R 2 represents hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, which is optionally by hydroxy, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or by a group of the formula
  • R is a radical of the formula -Si (CH 3 ) 2 C (CH 3 ) 3 , or
  • Tetrahydropyranyl, pyridyl, phenyl or benzyl means, optionally up to 2 times the same or different
  • A represents phenyl or pyridyl, which are optionally substituted up to twice in the same or different manner by fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,
  • D represents phenyl which may be replaced by nitro, trifluoromethyl, phenyl,
  • the cycles optionally up to 3 times, in the case of the nitrogen-containing rings also via the N function, identically or differently by fluorine, chlorine, trifluoromethyl, hydroxyl, cyano, carboxyl, trifluoromethoxy, straight-chain or branched alkyl, alkylthio, alkylalkoxy, Alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, triazolyl, tetrazolyl, benzothiazolyl, trifluoromethyl-substituted phenyl or phenyl are substituted and / or are substituted by a group of the formula -OR 10 , -SR 11 or -SO 2 R 12 ,
  • R 10 , R 11 and R 12 are the same or different and represent phenyl, which in turn is substituted up to 2 times the same or different by phenyl, fluorine, chlorine or by straight-chain or branched alkyl having up to 3 carbon atoms,
  • R 5 and / or R is a radical of the formula
  • R 7 represents hydrogen or fluorine
  • R 8 is hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy, trifluoromethoxy, or straight-chain or branched alkoxy or alkyl each having up to 4 carbon atoms or a radical of the formula -NR 15 R 16 ,
  • R 15 and R 16 are identical or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms
  • R 17 denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms,
  • L is a straight-chain or branched alkylene or alkenylene chain each having up to 5 carbon atoms, which are optionally substituted up to 2 times by hydroxy,
  • T and X are identical or different and represent a straight-chain or branched alkylene chain with up to 3 carbon atoms
  • T or X represents a bond
  • V for an oxygen or sulfur atom or for a group of
  • wo ⁇ n R 18 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms
  • R 1 for a group of the formula -CH 2 OH or
  • R 2 stands for hydrogen or for straight-chain or branched alkyl or alkenyl each having up to 5 carbon atoms, which is optionally by
  • R denotes straight-chain or branched alkyl having up to 4 carbon atoms, or
  • R 7 represents hydrogen or fluorine
  • R 8 is hydrogen, fluorine, chlorine, bromine or alkyl, each with up to 4 carbon atoms
  • R 17 denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms,
  • L is a straight-chain or branched alkylene or alkenylene chain each having up to 5 carbon atoms, which are optionally substituted up to 2 times by hydroxy,
  • T and X are identical or different and represent a straight-chain or branched alkylene chain with up to 3 carbon atoms
  • V represents an oxygen or sulfur atom or a group of the formula -NR 18 ,
  • R 18 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms
  • E represents cyclopropyl, cyclopentyl or cyclohexyl or phenyl, which is optionally substituted by fluorine or trifluoromethyl, or
  • R 1 for a group of the formula -CH 2 OH or
  • R 2 represents hydrogen or straight-chain or branched alkyl or alkenyl each having up to 5 carbon atoms, which may optionally be hydroxyl, phenyl, fluorine, chlorine, bromine, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or a group of the formula
  • R 19 denotes straight-chain or branched alkyl having up to 4 carbon atoms, or
  • R 20 , R 20 and R 20 are identical or different and represent straight-chain or branched alkyl having up to 4 carbon atoms
  • R 21 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxy, phenyl, straight-chain or branched alkoxy having up to 6 carbon atoms, amino, alkyl- or dialkylamines having up to 4 carbon atoms in the alkyl part,
  • R includes the scope of R and R given above,
  • R 22 either represents hydrogen or the radical -CO, R 20 , or
  • A, D and E have the meaning given above, depending on the abovementioned meaning of R 2 in the system P (C 6 H 5 ) 3 / diethylazodicarboxylic acid ethyl ester and the corresponding alcohols or amines defined under R 19 ,
  • Suitable solvents for the reaction step (II) - (III) are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether. It is also possible to use mixtures of the solvents mentioned. Diethyl ether is preferred.
  • connections in question preferably include organolithium compounds such as N-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride.
  • organolithium compounds such as N-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride.
  • N-Butyllithium is particularly preferred.
  • the base is generally used in an amount of 1 mol to 2 mol, preferably 1.05 mol to 1.2 mol, based on 1 mol of the compounds of the general formula (II).
  • the reaction generally takes place at a temperature from -30 ° C to room temperature, preferably from -20 ° C to 0 ° C.
  • the reaction generally takes place at normal pressure, but it is also possible to work at elevated or reduced pressure.
  • Suitable solvents for the preparation of the compounds of the general formula (V) according to the invention are hydrocarbons such as benzene, toluene, xylene, chlorobenzene, ethylbenzoate, decalin, benzonitrile, hexane, cyclohexane or petroleum fractions. It is also possible to use mixtures of the solvents mentioned. Xylene is preferred.
  • the reaction can also be carried out without a solvent, or alkyne can be used as the solvent.
  • the reaction generally takes place at a temperature of from -30 ° C. to +250, preferably from 80 ° C. to 180 ° C.
  • the reaction generally takes place at normal pressure, but it is also possible to work at elevated or reduced pressure.
  • the reaction generally takes place without a catalyst, but it is also possible to use Lewis acids as catalysts.
  • Lewis acids include: BF 3 , BF 3 x OEt 2 , A1C1 3 TiCl 4 , A1 (CH 3 ) 3 , A1 (C 2 H 5 ) 3 , (C 2 H 5 ) 2 A1C1, MgCl 2 , ZnCl 2 and BC1 3rd
  • Suitable solvents for the oxidation are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, chlorobloromethylene , Ethyl acetate, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Toluene is preferred.
  • Suitable oxidizing agents are, for example, potassium permanganate, bromine, cerium (IV) ammonium nitrate, 2,3-dichloro-5,6-dicyano-benzoquinone, pyridinium chlorochromate (PCC), pyridinium chlorochromate on basic aluminum oxide, osmium tetroxide, sodium acetate / iodine and manganese dioxide. 2,3-Dichloro-5,6-di-cyanobenzoquinone is preferred.
  • the oxidizing agent is used in an amount of 1 mol to 10 mol, preferably from
  • the oxidation generally takes place in a temperature range from 0 ° C. to + 100 ° C., preferably from room temperature to 80 ° C.
  • the oxidation generally takes place at normal pressure. However, it is also possible to carry out the oxidation at elevated or reduced pressure.
  • hydrocarbons listed above are suitable as solvents for the reduction, with toluene being preferred.
  • the reduction of the compounds of the general formula (VI) is generally carried out using reducing agents, preferably those which are suitable for the reduction of alkoxycarbonyl to hydroxy compounds.
  • the reduction is preferably carried out with complex metal hydrides such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoboranate, diisobutylaluminium hydride or lithium aluminum hydride.
  • the reduction is very particularly preferably carried out using diisobutylaluminum hydride.
  • the reducing agent is generally used in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, based on 1 mol of the compounds to be reduced.
  • the reduction generally takes place in a temperature range from -78 ° C. to + 50 ° C., preferably from -78 ° C. to 0 ° C., particularly preferably at -78 ° C., in each case depending on the choice of the reducing agent and solvent.
  • the reduction generally proceeds at normal pressure, but it is also possible to work at elevated or reduced pressure.
  • Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene,
  • Xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichlorethylene, trichlorethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric acid triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Toluene and dichloromethane are preferred.
  • the protecting group is generally split off in one of the alcohols and THF listed above, preferably methanol / THF in the presence of hydrochloric acid in a temperature range from 0 ° C. to 50 ° C., preferably at room temperature, and normal pressure.
  • the deprotection with tetrabutylammonium fluoride (TBAF) in THF at room temperature is preferred.
  • the compounds of the general formula (VI) are reacted in one of the ethers listed above, preferably in tetrahydrofuran under a protective gas atmosphere in a temperature range from -78 ° C. to -10 ° C., preferably at
  • the usual strongly basic connections can be used as bases for the individual steps.
  • bases preferably include organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride.
  • N-Butyllithium, sodium hydride or lithium diisopropylamide is particularly preferably used.
  • the usual inorganic bases are also suitable as bases.
  • alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate.
  • Sodium hydroxide or potassium hydroxide is particularly preferably used.
  • I also use alcohols such as methanol, ethanol, propanol, butanol or tert-butanol as solvents for the individual reaction steps. Tert is preferred. Butanol.
  • the alkylation with alkyl halides is generally carried out in inert solvents in the presence of a base.
  • Suitable solvents are, depending on the nature of the alkylating agent, all inert organic solvents. These preferably include ethers such as diethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene or xylene, or
  • the usual basic compounds are suitable as bases for the alkylation. These preferably include alkali hydrides such as sodium hydride, alkali amides such as
  • Sodium amide or lithium diisopropyl amide alkali alcoholates such as sodium methanolate, sodium ethanolate, potassium methoxide, potassium ethanolate or potassium ter.butylate, or organic amines such as trialkylamines, e.g. Triethylamine, or organolithium compounds such as butyllithium or phenyllithium. Lithium diisopropylamide is preferred.
  • the alkylation generally takes place in a temperature range from -70 ° C. to + 110 ° C., preferably from 20 ° C. to 80 ° C.
  • the alkylation is generally carried out at normal pressure. However, it is also possible to carry out the process under reduced pressure or elevated pressure (for example in a range from 0.5 to 5 bar).
  • the compounds of the general formula (II) are partly new and can be prepared, for example, by
  • the compounds of the general formula (XI) are reacted in ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether. Preferred in tetrahydrofuran.
  • the bases which are customary for the individual steps are the customary strongly basic compounds.
  • These preferably include organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropylamide, sodium amide or Potassium amide, or lithium hexamethylsilyl amide, or alkali hydrides such as sodium hydride or potassium hydride.
  • organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium
  • amides such as lithium diisopropylamide, sodium amide or Potassium amide, or lithium hexamethylsilyl amide
  • alkali hydrides such as sodium hydride or potassium hydride.
  • N-Butyllithium, sodium hydride or lithium diisopropylamide is particularly preferably used.
  • the base is used in an amount of 0.1 mol to 10 mol, preferably from 1 mol to
  • the reaction is generally carried out in a temperature range from -10 ° C to + 10 ° C, preferably from 5 ° C to 10 ° C and normal pressure.
  • Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene,
  • Xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichlorethylene or chlorobenzene, or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethyl or acetonitrile triamonitrilethane. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran is preferred.
  • the bases which are customary for the individual steps are the customary strongly basic compounds. These preferably include organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali hydrides such as sodium hydride or potassium hydride. N-Butyllithium, sodium hydride or lithium diisopropylamide is particularly preferably used.
  • the base is used in an amount of 0.1 mol to 10 mol, preferably 1 mol to 5 mol, in each case based on 1 mol of the starting compound.
  • the reaction is generally carried out in a temperature range from -10 ° C to + 10 ° C, preferably from 5 ° C to 10 ° C and normal pressure.
  • the compounds of the general formula (XI) are known per se or can be prepared by customary methods.
  • the compounds of the general formula (IX) are known per se or can be prepared by customary methods.
  • the compounds of the general formula (IV) are known per se or can be prepared by customary methods.
  • the compounds of general formula (I) according to the invention have an unforeseeable spectrum of pharmacological activity.
  • the compounds of the general formula (I) according to the invention have valuable pharmacological properties which are superior in comparison with the prior art, in particular they are highly effective inhibitors of cholesterol ester transfer protein (CETP) and stimulate the reverse cholesterol transport.
  • CETP cholesterol ester transfer protein
  • the active substances according to the invention bring about a reduction in the LDL cholesterol level in the blood with a simultaneous increase in the HDL cholesterol level. They can therefore be used to treat and prevent hypolipoproteinemia, dyslipidaemia, hypertriglyceridaemia, hyperlipidaemia or arteriosclerosis.
  • CETP is obtained from human plasma by differential centrifugation and column chromatography in a partially purified form and used for the test.
  • human plasma is adjusted to a density of 1.21 g per ml with NaBr and centrifuged at 50,000 rpm at 4 ° C. for 18 h.
  • the bottom fraction (d> 1.21 g / ml) is applied to a Sephadex®Phenyl-Sepharose 4B (Pharmacia) column, washed with 0.15 m NaCl / 0.001 m TrisHCl pH 7.4 and then with dist. Water eluted.
  • the CETP -type active fractions are pooled, dialyzed against 50 mM Na acetate pH 4.5 and applied to a CM-Sepharose ® (Fa. Pharmacia) column. With a linear
  • the mixture is then adjusted to a density of 1.21 with NaBr and centrifuged in a Ty 65 rotor for 18 h at 50,000 rpm at 20 ° C.
  • the upper phase is obtained and the lipoprotein fractions are purified by gradient centrifugation.
  • the isolated, labeled lipoprotein fraction is adjusted to a density of 1.26 with NaBr.
  • the retentate contains radioactively labeled 3 H-CE-HDL, which is set to approx. 5x10 6 cmp per ml and used for the test.
  • the activity transferred in the control batches with CETP at 37 ° C. is rated as 100%) transfer.
  • the substance concentration at which this transfer is reduced to half is given as the IC 50 value.
  • test substances can also p.o. are carried out by dissolving the substances in DMSO and suspending 0.5% tylose by oral gavage.
  • the control animals receive identical ones
  • the CETP activity is determined by the modified CETP test. As described for the CETP test above, the transfer of 3 H-cholesterol esters from HD lipoproteins to biotinylated LD lipoproteins is measured.
  • the reaction is terminated by adding streptavidin-SPA R beads (from Amersham) and the radioactivity transferred is determined directly in the liquid scintlation counter.
  • the test batch is carried out as described under "CETP test”. Only 10 ⁇ l CETP are replaced by 10 ⁇ l of the corresponding serum samples for testing the serum. Appropriate incubations with sera from untreated animals serve as controls.
  • the activity transferred in the control batches with control sera is rated as 100%) transfer.
  • the substance concentration at which this transfer is reduced to half is given as the ED 50 value.
  • Puncture of the retroorbital venous plexus is taken from blood.
  • the coagulation is terminated by incubation at 4 ° C. overnight, followed by centrifugation at 6000 ⁇ g for 10 minutes.
  • the content of cholesterol and triglycerides in the serum obtained in this way is determined using modified commercially available enzyme tests (cholesterol enzymatically 14366 Merck, triglycerides 14364 Merck). Serum is appropriately diluted with physiological saline.
  • 100 ⁇ l of serum dilution are mixed with 100 ⁇ l of test substance in 96-well plates and incubated for 10 minutes at room temperature. Then will determined the optical density at a wavelength of 492 nm with an automatic plate reader. The triglyceride or cholesterol concentration contained in the samples is determined using a standard curve measured in parallel.
  • the HDL cholesterol content is determined after precipitation of the ApoB-containing lipoproteins using a reagent mixture (Sigma 352-4 HDL cholesterol reagent) according to the manufacturer's instructions.
  • mice from our own breeding were administered the substances to be tested in the feed.
  • blood was taken from the mice retroorbitally in order to determine cholesterol and triglycerides in the serum.
  • the serum was obtained as described above for hamsters by incubation at 4 ° C. overnight and subsequent centrifugation at 6000 ⁇ g.
  • blood was again drawn from the mice to determine lipoproteins and triglycerides. The change in the measured parameters is shown as a percentage change compared to the
  • the invention also relates to the combination of benzyl biphenyls of the general formula (I) with a glucosidase and / or amylase inhibitor for the treatment of familial hyperlipidemia, obesity and obesity
  • Glucosidase and / or amylase inhibitors in the context of the invention are, for example, acarbose, adiposins, Voglibose, Miglitol, Emiglitate, MDL-25637, Camiglibose (MDL-73945), Tendamistate, AI-3688, Trestatin, Pradimicin-Q and Salbostatin.
  • acarbose, miglitol, emiglitate or Voglibose with one of the above-mentioned compounds of the general formulas (I) according to the invention is preferred.
  • Cholesterol-lowering Vastatinen or ApoB-lowering principles can be combined to treat dyslipidemics, combined hyperlipidemics, hypercholesterolemics or hypertriglyceridemics.
  • the combinations mentioned can also be used for primary or secondary prevention of coronary heart diseases (e.g. myocardial infarction).
  • coronary heart diseases e.g. myocardial infarction
  • Vastatins in the context of the invention are, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.
  • ApoB-lowering agents are, for example, MTP inhibitors.
  • cerivastatin or ApoB inhibitors with one of the above-mentioned compounds of the general formulas (I) and (Ia) is preferred.
  • the new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should be in a concentration of about 0.5 to
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, for example in the case of use of water as a diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application takes place in the usual way intravenously, orally, parenterally or perlingually, in particular orally.
  • solutions of the active ingredient can be used using suitable liquid carrier materials.
  • the dosage is about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyrane Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)

Abstract

L'invention concerne des benzylbiphényles et des composés analogues, produit selon un procédé consistant tout d'abord à faire réagir des cétones α et β insaturées pour former des diènes conjugués, substitués de façon correspondante, puis à cycliser ces derniers avec des dérivés d'acétylène, à oxyder les cyclohexanediènes ainsi obtenus pour former des composés aromatiques, et le cas échéant à les faire varier dans les substituants présents, selon des méthodes usuelles. Les composés de l'invention s'utilisent comme principes actifs dans des médicaments, notamment dans des médicaments servant à traiter l'artériosclérose et les dyslipidémies.
PCT/EP1998/005731 1997-09-19 1998-09-09 Benzylbiphenyles et composes analogues et leur utilisation pour le traitement de l'arteriosclerose et des dyslipidemies WO1999015487A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002304274A CA2304274A1 (fr) 1997-09-19 1998-09-09 Benzylbiphenyles et composes analogues et leur utilisation pour le traitement de l'arteriosclerose et des dyslipidemies
EP98954266A EP1017658A1 (fr) 1997-09-19 1998-09-09 Benzylbiphenyles et composes analogues et leur utilisation pour le traitement de l'arteriosclerose et des dyslipidemies
JP2000512799A JP2001517646A (ja) 1997-09-19 1998-09-09 ベンジルビフェニルおよび類似化合物、ならびに動脈硬化症および異脂肪血症を治療するためのそれらの適用
AU11458/99A AU1145899A (en) 1997-09-19 1998-09-09 Benzyl-biphenyls and analogous compounds and the application thereof in order totreat arteriosclerosis and dyslipidaemia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19741400.1 1997-09-19
DE19741400A DE19741400A1 (de) 1997-09-19 1997-09-19 Benzyl-biphenyle

Publications (1)

Publication Number Publication Date
WO1999015487A1 true WO1999015487A1 (fr) 1999-04-01

Family

ID=7842955

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/005731 WO1999015487A1 (fr) 1997-09-19 1998-09-09 Benzylbiphenyles et composes analogues et leur utilisation pour le traitement de l'arteriosclerose et des dyslipidemies

Country Status (6)

Country Link
EP (1) EP1017658A1 (fr)
JP (1) JP2001517646A (fr)
AU (1) AU1145899A (fr)
CA (1) CA2304274A1 (fr)
DE (1) DE19741400A1 (fr)
WO (1) WO1999015487A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002060378A2 (fr) * 2000-12-21 2002-08-08 Nitromed, Inc. Composes aryle substitues en tant que nouveaux inhibiteurs selectifs de la cyclo-oxygenase-2, compositions et methodes d'utilisation
WO2006014413A1 (fr) * 2004-07-02 2006-02-09 Merck & Co., Inc. Inhibiteurs de la cetp
US9023393B2 (en) 2003-08-04 2015-05-05 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
US9486410B2 (en) 2002-02-01 2016-11-08 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
WO2022075645A1 (fr) * 2020-10-08 2022-04-14 재단법인 대구경북첨단의료산업진흥재단 Dérivé d'aminoalcool utilisé en tant qu'inhibiteur de pcsk9, et composition pharmaceutique pour la prévention ou le traitement de l'hypercholestérémie le contenant

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100759635B1 (ko) 2001-06-22 2007-09-17 화이자 프로덕츠 인코포레이티드 비정질 약물의 흡착체의 약학 조성물
PT1404300E (pt) 2001-06-22 2009-11-09 Bend Res Inc Composições farmacêuticas de dispersões de fármacos e polímeros neutros
CL2004001884A1 (es) 2003-08-04 2005-06-03 Pfizer Prod Inc Procedimiento de secado por pulverizacion para la formacion de dispersiones solidas amorfas de un farmaco y polimeros.
EP2548894A1 (fr) 2005-02-03 2013-01-23 Bend Research, Inc. Compositions pharmaceutiques à éfficacité améliorée
WO2006098394A1 (fr) * 2005-03-14 2006-09-21 Japan Tobacco Inc. Méthode pour inhiber l’absorption de lipides et l’inhibiteur de l'absorption de lipides
US8865707B2 (en) * 2005-12-30 2014-10-21 Merck Sharp & Dohme Corp. Cholesteryl ester transfer protein inhibitors
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
AU2017294231B2 (en) 2016-07-05 2021-09-09 Guangzhou Maxinovel Pharmaceuticals Co., Ltd Aromatic acetylene or aromatic ethylene compound, intermediate, preparation method, pharmaceutical composition and use thereof
EP3733659B1 (fr) 2017-12-29 2023-12-20 Guangzhou Maxinovel Pharmaceuticals Co., Ltd. Dérivé de vinyle aromatique ou d'éthyle aromatique, procédé de préparation associé, intermédiaire, composition pharmaceutique et application

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0388732A2 (fr) * 1989-03-22 1990-09-26 Bayer Ag Phényles pentasubstitués
US5169857A (en) * 1988-01-20 1992-12-08 Bayer Aktiengesellschaft 7-(polysubstituted pyridyl)-hept-6-endates useful for treating hyperproteinaemia, lipoproteinaemia or arteriosclerosis
WO1998034895A1 (fr) * 1997-02-05 1998-08-13 Bayer Aktiengesellschaft Phenyles substitues par 5-hydroxy-alkyle et leur utilisation dans des medicaments pour traiter l'arteriosclerose et l'hyperlipoproteinemie

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5169857A (en) * 1988-01-20 1992-12-08 Bayer Aktiengesellschaft 7-(polysubstituted pyridyl)-hept-6-endates useful for treating hyperproteinaemia, lipoproteinaemia or arteriosclerosis
EP0388732A2 (fr) * 1989-03-22 1990-09-26 Bayer Ag Phényles pentasubstitués
WO1998034895A1 (fr) * 1997-02-05 1998-08-13 Bayer Aktiengesellschaft Phenyles substitues par 5-hydroxy-alkyle et leur utilisation dans des medicaments pour traiter l'arteriosclerose et l'hyperlipoproteinemie

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002060378A2 (fr) * 2000-12-21 2002-08-08 Nitromed, Inc. Composes aryle substitues en tant que nouveaux inhibiteurs selectifs de la cyclo-oxygenase-2, compositions et methodes d'utilisation
WO2002060378A3 (fr) * 2000-12-21 2003-12-31 Nitromed Inc Composes aryle substitues en tant que nouveaux inhibiteurs selectifs de la cyclo-oxygenase-2, compositions et methodes d'utilisation
US6825185B2 (en) 2000-12-21 2004-11-30 Nitromed, Inc. Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
US10357455B2 (en) 2002-02-01 2019-07-23 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
US9486410B2 (en) 2002-02-01 2016-11-08 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
USRE47033E1 (en) 2003-08-04 2018-09-11 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
US9023393B2 (en) 2003-08-04 2015-05-05 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
JP4491062B1 (ja) * 2004-07-02 2010-06-30 メルク・シャープ・エンド・ドーム・コーポレイション Ｃｅｔｐ阻害薬
US7652049B2 (en) 2004-07-02 2010-01-26 Merck & Co., Inc. CETP inhibitors
JP2010150269A (ja) * 2004-07-02 2010-07-08 Merck Sharp & Dohme Corp Ｃｅｔｐ阻害薬
EP2415759A1 (fr) * 2004-07-02 2012-02-08 Merck Sharp & Dohme Corporation Inhibiteurs CETP
KR101204336B1 (ko) 2004-07-02 2012-11-27 머크 샤프 앤드 돔 코포레이션 Ｃｅｔｐ 억제제
US8735435B2 (en) 2004-07-02 2014-05-27 Merck Sharp & Dohme Corp. CETP inhibitors
AU2005270058B2 (en) * 2004-07-02 2009-04-23 Merck Sharp & Dohme Corp. CETP inhibitors
EA011130B1 (ru) * 2004-07-02 2008-12-30 Мерк Энд Ко., Инк. Ингибиторы сетр
NO339808B1 (no) * 2004-07-02 2017-02-06 Merck Sharp & Dohme Forbindelse eller et farmasøytisk akseptabelt salt derav som er CETP-inhibitorer, farmasøytisk preparat derav, og anvendelse derav for fremstilling av et medikament for behandling av ateriosklerose.
WO2006014357A1 (fr) * 2004-07-02 2006-02-09 Merck & Co., Inc. Inhibiteurs de la cetp
WO2006014413A1 (fr) * 2004-07-02 2006-02-09 Merck & Co., Inc. Inhibiteurs de la cetp
WO2022075645A1 (fr) * 2020-10-08 2022-04-14 재단법인 대구경북첨단의료산업진흥재단 Dérivé d'aminoalcool utilisé en tant qu'inhibiteur de pcsk9, et composition pharmaceutique pour la prévention ou le traitement de l'hypercholestérémie le contenant

Also Published As

Publication number Publication date
AU1145899A (en) 1999-04-12
JP2001517646A (ja) 2001-10-09
CA2304274A1 (fr) 1999-04-01
DE19741400A1 (de) 1999-03-25
EP1017658A1 (fr) 2000-07-12

Similar Documents

Publication Publication Date Title
EP0818448B1 (fr) Cycloalkano-pyridines comme inhibiteurs de CETP
EP1017692B1 (fr) 4-heteroaryle-tetrahydroquinoleines et leur utilisation comme inhibiteurs de la proteine de transfert cholesterine-ester
EP0796846B1 (fr) Pyridines substituées en position 2 par un reste aryle
EP1017659B1 (fr) Tetrahydronaphtalines substituees et composes analogues
WO1998039299A1 (fr) Quinolines a substitution oxy en position 5 et leur utilisation comme inhibiteurs de la proteine de transfert d'ester de cholesterol
DE19741399A1 (de) Tetrahydrochinoline
EP0825185A1 (fr) Pyridine condensée à dérivés bicycliques
EP0818197A1 (fr) Pyridines condensés hétérocycliques comme inhibiteurs de CETP
WO1999015487A1 (fr) Benzylbiphenyles et composes analogues et leur utilisation pour le traitement de l'arteriosclerose et des dyslipidemies
US6207671B1 (en) Cycloalkano-pyridines
EP0603649A1 (fr) 4-Phenylpyridones et 4-phenyl-2-alkoxypyridines substituées comme inhibiteurs de réductase de HMG-CoA
WO1998034895A1 (fr) Phenyles substitues par 5-hydroxy-alkyle et leur utilisation dans des medicaments pour traiter l'arteriosclerose et l'hyperlipoproteinemie
WO2003028727A9 (fr) Derives de 3-`hydroxy-(-4-trifluoromethylphenyl)-methyl-7-spirocyclobutyl-5,6,7,8- tetrahydroquinolin-5-ol et leur utilisation en tant qu'inhibiteurs de la proteine de transfert du cholesterol esterifie (cetp)
EP0973744A1 (fr) Pyridines substituees par 2-amino s'utilisant pour traiter l'arteriosclerose et l'hyperlipoproteinemie
DE19832159A1 (de) Substituierte Tetrahydro-naphthaline
DE19627419A1 (de) Cycloalkano-pyridine
EP0388732B1 (fr) Phényles pentasubstitués
DD298919A5 (de) Imino-substituierte pyridine
EP0490219A1 (fr) Dibenz-oxo-thiocinones, -12-oxydes et -12,12-dioxydes substituées, procédé pour leur préparation et leur utilisation dans des médicaments
DE4321421A1 (de) Substituierte 4-Phenyl-pyridone und 4-Phenyl-2-alkoxypyridine
DE3841991A1 (de) Substituierte 2-pyridone und pyrid-2-thione, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1998954266

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2304274

Country of ref document: CA

Kind code of ref document: A

Ref document number: 2304274

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2000/002771

Country of ref document: MX

Ref document number: 09509061

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: KR

WWP Wipo information: published in national office

Ref document number: 1998954266

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWW Wipo information: withdrawn in national office

Ref document number: 1998954266

Country of ref document: EP