EP1017677A1 - 4-phenyltetrahydroquinolines utilisees comme inhibiteur de la proteine de transfert de l'ester de cholesterol - Google Patents

4-phenyltetrahydroquinolines utilisees comme inhibiteur de la proteine de transfert de l'ester de cholesterol

Info

Publication number
EP1017677A1
EP1017677A1 EP98948921A EP98948921A EP1017677A1 EP 1017677 A1 EP1017677 A1 EP 1017677A1 EP 98948921 A EP98948921 A EP 98948921A EP 98948921 A EP98948921 A EP 98948921A EP 1017677 A1 EP1017677 A1 EP 1017677A1
Authority
EP
European Patent Office
Prior art keywords
compounds
general formula
given above
meaning given
different
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Withdrawn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
EP98948921A
Other languages
German (de)
English (en)
Inventor
Gunter Schmidt
Jürgen Stoltefuss
Michael Lögers
Arndt Brandes
Carsten Schmeck
Klaus-Dieter Bremm
Hilmar Bischoff
Delf Schmidt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Bayer AG
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 AG filed Critical Bayer AG
Publication of EP1017677A1 publication Critical patent/EP1017677A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to tetrahydroquinolines, processes for their preparation and their use in medicaments.
  • Publication US-5 169 857-A2 discloses 7- (polysubstituted pyridyl) -6-heptenoates for the treatment of arteriosclerosis, lipoprotein anemia and hyperprotein anemia.
  • 7- (4-aryl-3-pyridyl) -3,5-dihydroxy-6-heptenoate is described in the publication EP-325 130-A2.
  • the compound 5 (6H) - quinolones, 3-benzyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl, from the publication Khim. Heterotics Soedin. (1967), (6), 1118-1120.
  • the present invention relates to tetrahydroquinolines of the general formula (I),
  • A represents phenyl, which may be identical or different up to 2 times through halogen, trifluoromethyl or straight-chain or branched alkyl or
  • Alkoxy is each substituted with up to 3 carbon atoms
  • R means hydrogen
  • R represents halogen or hydroxy
  • R 5 and R 6 are hydrogen
  • R 7 and R 8 are the same or different and are phenyl, naphthyl,
  • Benzothiazolyl, quinolyl, pyrimidyl or pyridyl which may be up to 4 times the same or different
  • R 9 and R 10 are the same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
  • E represents cycloalkyl having 3 to 6 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms,
  • R 1 represents hydroxy
  • R represents hydrogen or methyl
  • R 3 and R 4 are identical or different and represent straight-chain or branched alkyl having up to 3 carbon atoms
  • R 3 and R 4 together form a spiro-linked alkyl chain with 2 to 4 carbon atoms
  • tetrahydroquinolines according to the invention can also be present 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.
  • Ammonium salts derived from ammonia, or organic amines such as for example ethylamine, di- or. Triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
  • 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.
  • A represents phenyl, which is optionally substituted up to twice in the same or different way by fluorine, chlorine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy,
  • R 5 means hydrogen
  • R is fluorine or hydroxy
  • R and R are hydrogen
  • R 7 and R 8 are the same or different and are phenyl, naphthyl, benzothiazolyl, quinolyl, pyrimidyl or pyridyl, which are optionally up to 3 times the same or different by fluorine, chlorine, bromine, trifluoromethyl, nitro, cyano, trifluoro- methoxy, amino or dimethylamino are substituted,
  • E represents cyclopropyl, cyclobutyl, cyclopentyl or straight-chain or branched alkyl having up to 6 carbon atoms,
  • R 1 represents hydroxy
  • R 2 represents hydrogen or methyl
  • R and R are the same or different and represent methyl
  • R and R 4 together form a spiro-linked cyclopropyl, cyclobutyl or cyclopentyl ring,
  • A represents phenyl, which is optionally substituted up to 2 times by the same or different fluorine, chlorine, trifluoromethyl, methyl, methoxy or ethoxy.
  • R means hydrogen
  • R 6 represents fluorine or hydroxy
  • R 5 and R 6 are hydrogen
  • R 7 and R 8 are the same or different and are phenyl, naphthyl, benzothiazolyl, quinolyl, pyrimidyl or pyridyl, which optionally up to 3 times the same or different are substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro, cyano, trifluoromethoxy, amino or dimethylamino,
  • E represents cyclopropyl or cyclopentyl, or represents straight-chain or branched alkyl having up to 3 carbon atoms,
  • R 1 represents hydroxy
  • R 2 represents hydrogen or methyl
  • R 3 and R 4 are the same or different and represent methyl
  • R 3 and R 4 together form a spiro-linked cyclopropyl, cyclobutyl or cyclopentyl ring,
  • organometallic reagents in the sense of a Grignard, Wittig or organolithium reaction to synthesize the substituent D in inert solvents,
  • D represents the radical of the formula R 8 -CH 2 -O-CH 2 , in which R 8 has the meaning given above,
  • Z represents halogen, preferably chlorine or bromine
  • R 1 ' represents straight-chain alkyl having up to 4 carbon atoms
  • R 8 has the meaning given above
  • R for a hydroxy protecting group, preferably for a radical of the formula
  • R, R and R are identical or different and are C C alkyl
  • R, R, R, R, A and E have the meaning given above, manufactures,
  • R> 3 R, R, R, 12, A and E have the meaning given above,
  • 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 effects, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene, dichloroethylene
  • organolithium compounds such as, for example, N-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides, such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilyl amide, or alkali metal hydrides such as sodium hydride or potassium hydroxide or lithiumdusopropylamide used
  • the customary inorganic bases are also suitable for processes [B] and [C]. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate. Particular preference is given to using sodium hydroxide or potassium hydroxide
  • Suitable organometallic reagents are, for example, systems such as the corresponding Wittig reagents, for example Mg / bromobenzene fluoride, and the corresponding organic lithium compounds, for example p-tnfluoromethylphenylhthium
  • the reductions are generally carried out with reducing agents, preferably with those which are suitable for the reduction of ketones to hydroxy compounds.
  • reducing agents preferably with those which are suitable for the reduction of ketones to hydroxy compounds.
  • Reduction with complex metal hydrides such as, for example, lithium boronate, sodium ⁇ umboranate, kahumboranate, zinc boranate, lithium t ⁇ alkylhyd ⁇ do- boranate, diisobutylaluminium hydride or lithium aluminum hydride.
  • the reduction is very particularly preferably carried out using diisobutylaluminum hydride and sodium borohydride.
  • 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. in the case of the DIBAH, 0 ° C. to room temperature in the case of the NaBFLj, particularly preferably at -78 ° C, depending on the choice of
  • the reduction generally takes place at normal pressure, but it is also possible to work at elevated or reduced pressure.
  • the hydrogenation is carried out by conventional methods with hydrogen in the presence of noble metal catalysts, such as Pd / C, Pt / C or Raney nickel in one of the solvents listed above, preferably in alcohols such as methanol, ethanol or propanol, in a temperature range of -20 ° C to + 100 ° C, preferably from 0 ° C to + 50 ° C, at normal pressure or gauge pressure.
  • noble metal catalysts such as Pd / C, Pt / C or Raney nickel in one of the solvents listed above, preferably in alcohols such as methanol, ethanol or propanol, in a temperature range of -20 ° C to + 100 ° C, preferably from 0 ° C to + 50 ° C, at normal pressure or gauge pressure.
  • 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. In special cases, the removal of the protective group with tetrabutylammonium fluoride (TBAF) in THF is preferred.
  • THF tetrabutylammonium fluoride
  • Hydroxy protective group in the context of the definition given above generally represents a protective group from the series: trimethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, benzyl, benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl, tert. Butyloxycarbonyl,
  • Suitable solvents for the individual steps are ethers such as diethyl ether, dioxane,
  • Tetrahydrofuran glycol dimethyl ether, diisopropyl ether or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichlorethylene, trichlorethylene or chlorobenzene. It is also possible to use mixtures of the solvents mentioned.
  • Suitable oxidizing agents for the preparation of the compounds of the general formula (IX) are nitric acid, cerium (IV) ammonium nitrate, 2,3-dichloro-5,6-dicyanobenzoquinone, pyridinium chlorochromate (PCC), pyridinium chlorochromate on basic aluminum oxide, osmium tetroxide and Manganese dioxide. Manganese dioxide and nitric acid are preferred.
  • the oxidation takes place in one of the chlorinated hydrocarbons and water listed above. Dichloromethane and water are preferred.
  • the oxidizing agent is used in an amount of 1 mol to 10 mol, preferably 2 mol to 5 mol, based on 1 mol of the compounds of the general formula (Vm).
  • the oxidation generally takes place at a temperature of from -50 ° C. to + 100 ° C., preferably from 0 ° C. to room temperature.
  • the oxidation generally takes place at normal pressure. However, it is also possible to carry out the oxidation at elevated or reduced pressure.
  • the asymmetric reduction to the compounds of the general formula (X) is generally carried out in one of the ethers or toluene listed above, preferably tetrahydrofuran and toluene.
  • the reduction is generally carried out using enantiomerically pure IR, 2S-aminoindanol and borane complexes such as BH 3 x THF, BH 3 x DMS and BH 3 x (C 2 H 5 ) 2 NC 6 H 5 .
  • the system is preferably borane diethylaniline / IR, 2S-aminoindanol.
  • 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 at a temperature of -78 ° C to + 50 ° C, preferably from 0 ° C to 30 ° C.
  • the reduction generally proceeds at normal pressure, but it is also possible to work at elevated or reduced pressure.
  • the hydroxyl protective group is introduced in one of the hydrocarbons listed above, dimethylformamide or THF, preferably in toluene in the presence of lutidine in a temperature range from -20 ° C to + 50 ° C, preferably from -5 ° C to room temperature and normal pressure.
  • Reagents for introducing the silyl protective group are generally tert-butyldimethylsilyl chloride or tert-butyldimethylsilyltrifluoromethanesulfonate.
  • Tert-butyldimethylsilyl trifluoromethanesulfonate is preferred.
  • the reduction for the preparation of the compounds of the general formula (XII) is generally carried out using customary reducing agents, preferably those which are suitable for the reduction of ketones to hydroxy compounds.
  • Reduction with complex metal hydrides such as lithium boranate is preferred, Sodium borate, potassium borate, zinc borate, lithium trialkylhydridoborate, diisobutylaluminium hydride, sodium bis (2-methoxyethoxy) dihydroaluminate or lithium aluminum hydride.
  • the reduction is very particularly preferably carried out with sodium bis (2-methoxyethoxy) dihydroaluminate.
  • the reducing agent is generally used in an amount of 1 mol to 6 mol, preferably 1 mol to 3 mol, based on 1 mol of the compounds to be reduced.
  • the reduction generally takes place at a temperature of from -20 ° C. to + 110 ° C., preferably from 0 ° C. to room temperature.
  • the reduction generally takes place at normal pressure, but it is also possible to work at elevated or reduced pressure.
  • the fluorine substituent is generally introduced in one of the hydrocarbons or methylene chloride listed above, preferably in toluene and under a protective gas atmosphere.
  • SF derivatives generally include diethylaminosulfur trifluoride (DAST) or
  • the reaction generally takes place at a temperature of -78 ° C. to 100 ° C., preferably in the case of diethylaminosulfur trifluoride at -78 ° C. to RT and in the case of
  • the protective 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. In special cases, the protective group is split off preferred with Tetrabutylammomumfluo ⁇ d (TBAF) in THF at room temperature
  • Suitable bases for the individual sections are the customary strongly basic compounds. These preferably include organolithium compounds such as, for example, n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides, such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydroxides like Nat ⁇ umhyd ⁇ d or Kakumhyd ⁇ d
  • N-Butylhthium, Nat ⁇ umhyd ⁇ d or Lithiumdusopropylamid is particularly preferably used
  • Suitable bases are also the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as, for example, sodium hydroxide,
  • Potassium hydroxide or potassium hydroxide or alkali carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate. Particular preference is given to using sodium hydroxide or potassium hydroxide
  • Alcohols such as methanol, ethanol, propanol, butanol or tert-butanol are also suitable as solvents for the individual reaction mixtures.
  • Tert-butanol is preferred
  • halogenations are generally carried out in one of the chlorinated hydrocarbons listed above, methylene chloride being preferred.
  • Suitable halogenating agents are diethylamino sulfur trifluoride (DAST), morpholino sulfur trifluoride or SOCl 2 .
  • the halogenation generally takes place in a temperature range from -78 ° C. to + 50 ° C., preferably from -78 ° C. to 0 ° C., in each case depending on the choice of the halogenating agent and solvent.
  • the halogenation generally takes place at normal pressure, but it is also possible to work at elevated or reduced pressure.
  • R 17 and R 18 including a carbonyl group, comprise the scope of R 1 and R 2 given above,
  • the alkoxycarbonyl group (R 16 ) is converted into an aldehyde group by a reduction-oxidation sequence.
  • 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, dichlorethylene or trichlorethylene
  • Suitable oxidizing agents are cerium (IV) ammonium nitrate, 2,3-dichloro-5,6-dicyano-benzoquinone, pyridinium chlorochromate (PCC), pyridinium chlorochromate on basic aluminum oxide, osmium tetroxide and manganese dioxide. Sulfur trioxide-pyridine complex in DMSO / methylene chloride and pyridinium chlorochromate on basic aluminum oxide are preferred.
  • the oxidizing agent is used in an amount of 1 mol to 10 mol, preferably 2 mol to 5 mol, based on 1 mol of the compounds of the general formula (XVII).
  • the oxidation generally takes place in a temperature range from -50 ° C. to + 100 ° C., preferably from 0 ° C. to room temperature.
  • the oxidation generally takes place at normal pressure. However, it is also possible to carry out the oxidation at elevated or reduced pressure.
  • the compounds of the general formulas (IV), (V), (VII), (XIV), (XV) and (XVI) are known per se or can be prepared by customary methods. Some of the compounds of the general formulas (VI) and (XV) are known or new and can then be prepared as described above.
  • Suitable solvents for the preparation of the compounds of the general formula (VIII) are the ethers or alcohols listed above. Dusopropyl ether is preferred.
  • Suitable acids for the preparation of the compounds of the general formula (VIII) are generally organic carboxylic acids and inorganic acids, such as, for example, oxalic acid, maleic acid, phosphoric acid, fumaric acid and trifluoroacetic acid. Trifluoroacetic acid and oxalic acid are preferred
  • the acid is generally used in an amount of 0.1 mol to 5 mol, preferably 1 mol, based on 1 mol of the compounds of the general formula (XTX)
  • the reaction is generally carried out at normal pressure. However, it is also possible to carry out the reaction at elevated or reduced pressure.
  • the reaction generally takes place at the reflux temperature of the particular solvent
  • the compounds of the general formula (XVIII) are new and can be prepared by first reacting the compounds of the general formula (XX)
  • R 19 represents Ci-CrAlkyl
  • R 7 has the meaning given above
  • Suitable solvents for the first step of the process are the ethers and hydrocarbons listed above, tetrahydrofuran being preferred.
  • Suitable solvents for the reaction with the compounds of the general formula (XXII) are alcohols, such as, for example, methanol, ethanol, propanol or isopropanol.
  • Ethanol is preferred.
  • the compounds of general formulas (I) and (Ia) according to the invention have an unforeseeable spectrum of pharmacological activity.
  • the compounds of the general formulas (I) and (Ia) according to the invention have valuable pharmacological properties which are superior compared to the prior art, in particular they are highly effective inhibitors of cholesterol ester transfer protein (CETP) and stimulate 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. You can therefore go to
  • hypolipoproteinemia Treatment and prevention of hypolipoproteinemia, dyslipidaemia, hypertriglyceridaemia, hyperlipidaemia or arteriosclerosis can be used.
  • CETP is obtained from human plasma by differential centrifugation and
  • 50 ml of fresh human EDTA plasma is adjusted to a density of 1.12 with NaBr and centrifuged at 4 ° C. in a Ty 65 rotor for 18 h at 50,000 rpm.
  • the upper phase is used to obtain cold LDL.
  • the lower phase is against 3 * 4 1 PDB buffer (10 mM Tris HCl pH 7.4, 0, 15 mM NaCl, 1 mM EDTA,
  • the mixture is then adjusted to the density 1.21 with NaBr and in the Ty 65
  • Centrifuge rotor at 50,000 rpm at 20 ° C for 18 h.
  • 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.
  • 4 ml of this solution are overlaid in centrifuge tubes (SW 40 rotor) with 4 ml of a solution with a density of 1.21 and 4.5 ml with a solution of 1.063 (sealing solutions made of PDB buffer and NaBr) and then 24 hours at 38,000 rpm and 20 ° C centrifuged in the SW 40 rotor.
  • the retentate contains radioactively labeled 3 H-CE-HDL, which is set to approx. 5x10 6 cmp per ml and used for the test.
  • Sy ⁇ sche golden hamsters from in-house breeding are anesthetized after a 24-hour fast (0.8 mg / kg atropine, 0.8 mg kg Ketavet® sc, 30 'later 50 mg / kg Nembutal ip).
  • the vjugularis is then freely prepacked and cannulated.
  • the test substance is taken dissolved in a suitable solvent (generally Adalat placebo solution 60 g glycerol, 100 ml H 2 O, ad 1000 ml PEG-400) and administered to the animals via a PE catheter inserted into the Vjugula ⁇ s
  • Control animals receive the same volume of solvent without test substance.
  • the vein is then tied off and the wound is closed.
  • the test substances can also be administered po by dissolving the substances in DMSO and suspending 0.5% tylose by gavage.
  • the control animals receive identical volumes
  • the CETP activity is determined by the modified CETP test. As described for the CETP test above, the transfer of H-cholesterol esters of HD lipoproteins measured for biotinylated LD-lipoproteins. The reaction is ended by adding streptavidin-SPA R beads (from Amersham) and the radioactivity transferred is determined directly in the liquid scintlation counter
  • test batch is carried out as described under "CETP test". Only 10 ml of CETP are replaced by 10 ml of the corresponding serum samples for testing the serum. Corresponding incubations also 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
  • 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.
  • Triglyceride or cholesterol concentration 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.
  • the invention also relates to the combination of tetrahydroquinolines of the general formula (I) with a glucosidase and / or amylase inhibitor
  • Glucosidase and / or amylase inhibitors in the context of the invention are, for example, acarbose, adiposine, voghbose, Mightol, Emightate, MDL-25637, Camig bose (MDL-73945), tendamistate, AI-3688, Trestatin, Pradimicin-Q and Salbostatin
  • the compounds according to the invention can be combined in combination with cholesterol-lowering vastatins or ApoB-lowering principles in order to treat dyslipidemics, combined hyperl pidemics, hypercholesterolemics or hypertglycemia
  • 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
  • Vastatme in the context of the invention are, for example, Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin and Ce ⁇ vastatin ApoB-lowering agents are, for example, MTP inhibitors
  • cenvastatin or ApoB inhibitors with one of the above-mentioned compounds of the general formula (I) according to the invention is preferred.
  • the new active compounds can be converted into the customary formulations in a known manner, such as tablets, coated tablets, pills, granules, aerosols, syrups, Emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents.
  • the therapeutically active compound should be present in each case in a concentration of about 0.5 to 90% by weight of the total mixture, ie in amounts which are sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the 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.
  • PE / EE petroleum ether / ethyl acetate
  • the reaction solution is concentrated in 600 ml.
  • the two diastereomers (Dia A and Dia B) are separated by chromatography on 1 kg of silica gel - conditioned with cyclohexane by eluting the crude product in 60 ml of cyclohexane / THF (9: 1). After concentration of the fractions, the 2 pairs of diastereomers are obtained: Yields: Dia A: 18.5 g (78.2% of theory)
  • Example VIII Analogously to Example VIII, 6.3 g (10 mmol) of the compound Dia B from Example VI in 200 g of dichloromethane p a are reacted with 2.0 ml (15 mmol, 1.5 eq) of DAST at -78 ° C.
  • reaction was quenched after about 20 hours with 2.4 ml of 1,2-ethanediol.
  • the tetrahydrofuran was distilled off, the resulting oil was taken up in ethyl acetate and the organic phase, after washing with 2N hydrochloric acid and saturated sodium bicarbonate solution, was dried and concentrated.
  • the residue was recrystallized hot from cyclohexane. A total of 1.4 g of colorless crystals with a melting point of 166-168 ° C. resulted.
  • the reaction is quenched with 10% aqueous ammonium chloride solution, the organic phase is washed with 0.1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution and dried. After the solvent has been distilled off in vacuo, the residue is purified on a column. 620 mg of colorless crystals with a melting point of 128 ° C.-129 ° C. are obtained.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (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)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

Selon l'invention, des tétrahydroquinolines peuvent être produites selon un procédé consistant à condenser des aldéhydes de tétrahydroquinoline substitués de façon correspondante, avec des substances appropriées, puis à faire varier les substituants présents, selon des méthodes usuelles. Ces tétrahydroquinolines s'utilisent comme principes actifs dans des médicaments, notamment dans des médicaments servant à traiter l'artériosclérose et les dyslipidémies.
EP98948921A 1997-09-19 1998-09-07 4-phenyltetrahydroquinolines utilisees comme inhibiteur de la proteine de transfert de l'ester de cholesterol Withdrawn EP1017677A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19741399 1997-09-19
DE19741399A DE19741399A1 (de) 1997-09-19 1997-09-19 Tetrahydrochinoline
PCT/EP1998/005658 WO1999015504A1 (fr) 1997-09-19 1998-09-07 4-phenyltetrahydroquinolines utilisees comme inhibiteur de la proteine de transfert de l'ester de cholesterol

Publications (1)

Publication Number Publication Date
EP1017677A1 true EP1017677A1 (fr) 2000-07-12

Family

ID=7842954

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98948921A Withdrawn EP1017677A1 (fr) 1997-09-19 1998-09-07 4-phenyltetrahydroquinolines utilisees comme inhibiteur de la proteine de transfert de l'ester de cholesterol

Country Status (6)

Country Link
US (4) US6291477B1 (fr)
EP (1) EP1017677A1 (fr)
JP (1) JP2001517655A (fr)
AU (1) AU9537098A (fr)
DE (1) DE19741399A1 (fr)
WO (1) WO1999015504A1 (fr)

Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19741399A1 (de) * 1997-09-19 1999-03-25 Bayer Ag Tetrahydrochinoline
JPH11185506A (ja) * 1997-12-24 1999-07-09 Koito Mfg Co Ltd 車輌用前照灯
DE69935992T4 (de) * 1998-09-25 2008-05-29 Monsanto Co., Chicago Polycyclische aryl und heteroaryl substituierte tertiäre heteroalkylamine, für die hemmung der aktivität des cholesteryl-ester-transfer-proteins
US7115279B2 (en) * 2000-08-03 2006-10-03 Curatolo William J Pharmaceutical compositions of cholesteryl ester transfer protein inhibitors
OA12619A (en) * 2001-06-21 2006-06-12 Pfizer Prod Inc Self-emulsifying formulations of cholesteryl estertransfer protein inhibitors.
ES2333645T3 (es) 2001-06-22 2010-02-25 Bend Research, Inc. Composiciones farmaceuticas de dispersiones de medicamentos y polimeros neutros.
OA12625A (en) 2001-06-22 2006-06-12 Pfizer Prod Inc Pharmaceutical compositions of adsorbates of amorphous drug.
DE10148436A1 (de) * 2001-10-01 2003-04-17 Bayer Ag Tetrahydrochinoline
US7202247B2 (en) 2001-12-19 2007-04-10 Atherogenics, Inc. 1,3-bis-(substituted-phenyl)-2-propyn-1-ones and their use to treat disorders
MXPA04005864A (es) 2001-12-19 2004-10-29 Atherogenics Inc Derivados de charcona y su uso para tratar enfermedades.
AR038375A1 (es) 2002-02-01 2005-01-12 Pfizer Prod Inc Composiciones farmaceuticas de inhibidores de la proteina de transferencia de esteres de colesterilo
EP1469832B2 (fr) 2002-02-01 2016-10-26 Bend Research, Inc. Compositions pharmaceutiques de dispersions amorphes de medicaments et materiaux formant des microphases lipophiles
ES2310676T3 (es) 2002-12-20 2009-01-16 Pfizer Products Inc. Formas de dosificacion que comprenden un inhibidor de cetp y un inhibidor de hmg-coa reductasa.
CA2532931A1 (fr) * 2003-08-04 2005-02-10 Pfizer Products Inc. Compositions pharmaceutiques a base d'adsorbats de medicaments amorphes et de produits aptes a former des microphases lipophiles
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.
EP1670446A2 (fr) * 2003-09-26 2006-06-21 Japan Tobacco Inc. Procede pour inhiber la production de lipoproteines restantes
WO2006065842A2 (fr) * 2004-12-13 2006-06-22 Synta Pharmaceuticals Corp. 5,6,7,8-tetrahydroquinoleines et composes associes et leurs utilisations
BRPI0519602A2 (pt) * 2004-12-18 2009-02-25 Bayer Healthcare Ag derivados de tetrahidroquinolina substituÍdos com 4-cicloalquila e seu uso como medicamento
BRPI0519566A2 (pt) * 2004-12-18 2009-01-27 Bayer Healthcare Ag derivados de (5s)-3-[(s)-fléor(4-trifluormetilfenil)metil]-5,6,7,8-tet raidroquinolin-5-ol e seu uso como inibidores de cetp
WO2006082518A1 (fr) 2005-02-03 2006-08-10 Pfizer Products Inc. Compositions pharmaceutiques a efficacite amelioree
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
US7737155B2 (en) 2005-05-17 2010-06-15 Schering Corporation Nitrogen-containing heterocyclic compounds and methods of use thereof
DE102006012548A1 (de) 2006-03-18 2007-09-20 Bayer Healthcare Ag Substituierte Chromanol-Derivate und ihre Verwendung
US20110243940A1 (en) 2008-12-16 2011-10-06 Schering Corporation Bicyclic pyranone derivatives and methods of use thereof
US20110245209A1 (en) 2008-12-16 2011-10-06 Schering Corporation Pyridopyrimidine derivatives and methods of use thereof
WO2012005343A1 (fr) 2010-07-09 2012-01-12 第一三共株式会社 Composé de pyridine substitué
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
ES2599757T3 (es) * 2012-01-06 2017-02-03 Daiichi Sankyo Company, Limited Sales de aducto de ácido de un compuesto de piridina sustituido como inhibidores de la proteína de transferencia de ésteres de colesterilo (PTEC)
US9126906B2 (en) * 2012-02-21 2015-09-08 Celgene Corporation Asymmetric synthetic processes for the preparation of aminosulfone compounds
MX2015001099A (es) * 2012-08-24 2015-04-08 Hoffmann La Roche Nuevos derivados biciclicos de piridina.
DE102013223272A1 (de) * 2013-11-14 2015-05-21 Bombardier Transportation Gmbh Verfahren zur Herstellung eines rohrförmigen Ausstattungselements für ein Schienenfahrzeug

Family Cites Families (9)

* 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
US5506219A (en) 1988-08-29 1996-04-09 E. R. Squibb & Sons, Inc. Pyridine anchors for HMG-CoA reductase inhibitors
ZA911046B (en) * 1990-02-26 1992-10-28 Squibb & Sons Inc Quinoline and pyridine anchors for hmg-coa reductase inhibitors
HRP970330B1 (en) * 1996-07-08 2004-06-30 Bayer Ag Cycloalkano pyridines
DE19707199A1 (de) 1997-02-24 1998-08-27 Bayer Ag Neues Verfahren zur Herstellung von Cycloalkanopyridinen
US6207671B1 (en) * 1996-07-08 2001-03-27 Bayer Aktiengesellschaft Cycloalkano-pyridines
DE19627419A1 (de) 1996-07-08 1998-01-15 Bayer Ag Cycloalkano-pyridine
DE19709125A1 (de) * 1997-03-06 1998-09-10 Bayer Ag Substituierte Chinoline
DE19741399A1 (de) * 1997-09-19 1999-03-25 Bayer Ag Tetrahydrochinoline

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9915504A1 *

Also Published As

Publication number Publication date
US6562976B2 (en) 2003-05-13
US6291477B1 (en) 2001-09-18
US20020165252A1 (en) 2002-11-07
US20030232990A1 (en) 2003-12-18
AU9537098A (en) 1999-04-12
DE19741399A1 (de) 1999-03-25
JP2001517655A (ja) 2001-10-09
WO1999015504A1 (fr) 1999-04-01
US20020042515A1 (en) 2002-04-11
US6897317B2 (en) 2005-05-24

Similar Documents

Publication Publication Date Title
EP0818448B1 (fr) Cycloalkano-pyridines comme inhibiteurs de CETP
EP1017677A1 (fr) 4-phenyltetrahydroquinolines utilisees comme inhibiteur de la proteine de transfert de l'ester de cholesterol
EP1017692B1 (fr) 4-heteroaryle-tetrahydroquinoleines et leur utilisation comme inhibiteurs de la proteine de transfert cholesterine-ester
EP0818197B1 (fr) Pyridines condensés hétérocycliques comme inhibiteurs de CETP
EP0796846B1 (fr) Pyridines substituées en position 2 par un reste aryle
WO1998039299A1 (fr) Quinolines a substitution oxy en position 5 et leur utilisation comme inhibiteurs de la proteine de transfert d'ester de cholesterol
EP0825185A1 (fr) Pyridine condensée à dérivés bicycliques
EP1017659B1 (fr) Tetrahydronaphtalines substituees et composes analogues
WO2006072362A1 (fr) Derives de (5s)-3-[(s)-fluor(4-trifluoromethylphenyl)methyl]-5,6,7,8-tetrahydroquinolein-5-ol, et leur utilisation en tant qu'inhibiteurs de la proteine de transfert des esters de cholesterol (cetp)
EP1828137B1 (fr) Dérivés de tétrahydrochinoline substituée par 4-cycloalkyle et leur utilisation comme médicaments
EP0968162A1 (fr) Phenyles substitues par 5-hydroxy-alkyle et leur utilisation dans des medicaments pour traiter l'arteriosclerose et l'hyperlipoproteinemie
EP1017658A1 (fr) Benzylbiphenyles et composes analogues et leur utilisation pour le traitement de l'arteriosclerose et des dyslipidemies
WO2003028727A1 (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)
WO1998034920A1 (fr) Pyridines substituees par 2-amino s'utilisant pour traiter l'arteriosclerose et l'hyperlipoproteinemie
DE19627419A1 (de) Cycloalkano-pyridine
DE19832159A1 (de) Substituierte Tetrahydro-naphthaline
DE102004060997A1 (de) Chemische Verbindung und ihre Verwendung
DE102004061001A1 (de) Chemische Verbindung und ihre Verwendung
DE102004061003A1 (de) Chemische Verbindung und ihre Verwendung
DE102004061002A1 (de) Chemische Verbindung und ihre Verwendung
DE4039860A1 (de) Substituierte dibenz-oxa-thiocinone verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln
DE102004060998A1 (de) Chemische Verbindung und ihre Verwendung
DE102004061000A1 (de) Chemische Verbindung und ihre Verwendung
DE102004060999A1 (de) Chemische Verbindung und ihre Verwendung

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20000419

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER HEALTHCARE AG

17Q First examination report despatched

Effective date: 20070910

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER SCHERING PHARMA AG

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20100108