Classifications

• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
  • C07C35/48—Halogenated derivatives
  • C07C35/52—Alcohols with a condensed ring system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C43/00—Ethers; Compounds having groups, groups or groups
  • C07C43/02—Ethers
  • C07C43/18—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring
  • C07C43/192—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring containing halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
  • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
  • C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
  • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
• • 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
  • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
  • C07F7/1804—Compounds having Si-O-C linkages

Definitions

• the present invention relates to substituted tetrahydro-naphthalenes and analogous compounds, processes for their preparation and their use in
• Publication US-5 169 857-A2 discloses 7- (polysubstituted pyridyl) -6-heptenoate 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 present invention relates to substituted tetrahydro-naphthalenes and analogous compounds of the general formula (I),
• A stands for cycloalkyl with 3 to 8 carbon atoms, or stands for aryl with 6 to 10 carbon atoms, or for a 5- to 7-membered, saturated, partially unsaturated or unsaturated, optionally benzo-fused heterocycle with up to 4 heteroatoms from the series S, N and / or O is, where aryl and the heterocyclic ring systems listed above, where appropriate, up to 5 times the same or different by cyano, halogen,
• R and R are identical or different and are hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
• R 5 , R 6 and R 9 independently of one another are cycloalkyl having 3 to 6 carbon atoms, or jAryl having 6 to 10 carbon atoms or a 5- to 7-membered, optionally benzocondensed, saturated or unsaturated, mono-, bi- or tricyclic heterocycle with up to 4
• Heteroatoms from the series S, N and / or O mean, the 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, hydroxy, cyano, Carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio,
• O are substituted, and / or by a group of the formula -OR 10 , -SR 11 , -SO 2 R 12 or
• R 10 , R u and R 12 independently of one another are aryl having 6 to 10 carbon atoms, which in turn is substituted up to twice in the same or different way by phenyl, halogen or by straight-chain or branched alkyl having up to 6 carbon atoms,
• R and R are identical or different and have the meaning of R 3 and R given above,
• R 5 and / or R 6 is a radical of the formula
• R 7 represents hydrogen, halogen or methyl
• R is hydrogen, halogen, azido, trifluoromethyl, hydroxyl, 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 1 is hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 6 carbon atoms,
• L is a straight-chain or branched alkylene or alkenylene chain each having up to 8 carbon atoms, which is 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
• T or X represents a bond
• V represents an oxygen or sulfur atom or an -NR group
• R 1 ? Represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or phenyl
• E represents cycloalkyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or hydroxy, or represents phenyl which is optionally substituted by halogen or trifluoromethyl is substituted,
• R 1 and R 2 together form a straight-chain or branched alkylene chain with up to 7 carbon atoms, which is represented by a carbonyl group and / or by a radical of the formula
• a and b are the same or different and represent a number 1, 2 or 3,
• R 19 is hydrogen, cycloalkyl having 3 to 7 carbon atoms, straight-chain or branched silylalkyl having up to 8 carbon atoms or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by hydroxyl, straight-chain or branched alkoxy having up to 6 carbon atoms or by phenyl which in turn is halogen, nitro, trifluoromethyl,
• alkyl is optionally substituted by a group of the formula -OR 22 , wo ⁇ n
• R denotes straight-chain or branched acyl with up to 4 carbon atoms or benzyl
• R 19 denotes straight-chain or branched acyl having up to 20 carbon atoms or benzoyl, which is optionally substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain or branched fluoroacyl having up to 8 carbon atoms and 9 fluorine atoms,
• R 20 and R 21 are the same or different, are hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,
• R 20 and R together form a 3 to 6-membered carbocycle
• alkylene chain formed by R 1 and R 2 optionally up to 6-fold identical or different by trifluoromethyl, hydroxy, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or
• Cycloalkyloxy each having 3 to 7 carbon atoms, substituted by straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio each having up to 6 carbon atoms or by straight-chain or branched alkyl having up to 6 carbon atoms, which in turn is up to 2 times the same or different by hydroxyl, Benzyloxy, trifluoromethyl, benzoyl, straight-chain or branched alkoxy, oxyacyl or carboxyl with each up to 4 carbon atoms and / or phenyl, which in turn can be substituted by halogen, trifluoromethyl or trifluoromethoxy,
• R 1 and R 2 also geminal, optionally up to 5 times the same or different by phenyl, benzoyl,
• Thiophenyl or sulfonylbenzyl which in turn are optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro,
• c represents a number 1, 2, 3 or 4,
• d represents a number 0 or 1
• R 23 and R 24 are identical or different and denote hydrogen, cycloalkyl having 3 to 6 carbon atoms, straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or phenyl, which may be up to 2 times identical or different by halogen,
• W represents either an oxygen or a sulfur atom
• e represents a number 1, 2, 3, 4, 5, 6 or 7,
• f represents a number 1 or 2
• R 25 , R, R, R, R, R and R are identical or different and are hydrogen, trifluoromethyl, phenyl, halogen or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
• R and R or R and R each together form a straight-chain or branched alkyl chain with up to 6 carbon atoms
• R and R or R "* and R each together represent a radical of the formula W CH- form
• g represents a number 1, 2, 3, 4, 5, 6 or 7,
• R and R together form a 3- to 7-membered heterocycle which contains an oxygen or sulfur atom or a group of the formula SO, SO 2 or -NR 34 ,
• R 34 denotes hydrogen, phenyl, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms,
• the compounds 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. Particularly preferred are, for example, 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. For example, sodium, potassium, magnesium or calcium salts and ammonium salts derived from ammonia or organic are particularly preferred
• 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.
• 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, which comprises up to 4 heteroatoms from the series S, N and / or O can contain. Examples include: indolyl,
• A stands for cyclopentyl or for cyclohexyl, or for naphthyl, phenyl, pyridyl, thienyl, imidazolyl, pyrryl or morpholine, which may optionally be 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 each having up to 6 carbon atoms,
• R 5 , R 6 and R 9 independently of one another are cyclopropyl, cyclopentyl or cyclohexyl, or
• R 10 , R 1 1 and R 2 are the same or different and are 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 4 carbon atoms, or
• R 5 and / or R is a radical of the formula
• R represents hydrogen, fluorine, chlorine or bromine
• R is hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxy
• R 1 and R 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,
• L is a straight-chain or branched alkylene or alkenylene chain each having up to 6 carbon atoms, which are optionally substituted up to 2 times by hydroxy,
• T and X are the same or different and represent a straight-chain or branched alkylene chain with up to 6 carbon atoms
• T or X represents a bond
• V for an oxygen or sulfur atom or for a group of
• R 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 represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cyclopropyl, butyl, hexyl, pentyl, heptyl or by hydroxy or is phenyl which is optionally substituted by fluorine, chlorine or trifluoromethyl, R 2 together form a straight-chain or branched alkylene chain with up to 6 carbon atoms, which is represented by a carboxyl group and / or by a radical of the formula
• b represents a number 1, 2 or 3
• R is hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, straight-chain or branched silylalkyl having up to 7 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl, straight-chain or branched alkoxy having up to 4 carbon atoms or by phenyl, which in turn can be substituted by fluorine, chlorine, bromine, nitro, trifluoromethyl, trifluoromethoxy or phenyl substituted by phenyl or tetrazole,
• alkyl is optionally substituted by a group of the formula -OR,
• R denotes straight-chain or branched acyl with up to 3 carbon atoms or benzyl
• R 19 denotes straight-chain or branched acyl having up to 18 carbon atoms or benzoyl, which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain or branched fluoroacyl having up to 6 carbon atoms,
• R 20 and R 21 are the same or different, are hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms,
• R 1 and R 2 optionally up to 5 times the same or different, optionally also geminal, by trifluoromethyl, hydroxy, carboxyl, azido, fluorine, chlorine, bromine, nitro, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, by straight-chain or branched alkoxycarbonyl,
• Alkoxy or alkylthio each with up to about 5 carbon atoms or straight-chain or branched alkyl with up to 5 carbon atoms, which in turn is up to 2 times the same or different by hydroxyl, benzyloxy, benzoyl, straight-chain or branched alkoxy or oxyacyl, each with up to 3 carbon atoms, trifluoromethyl and / or phenyl, which in turn can be substituted by fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy,
• R 1 and R 2 also geminal, optionally up to 4 times the same or different by phenyl, benzoyl,
• Thiophenyl or sulfonylbenzyl which in turn is optionally substituted are substituted by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or nitro,
• c represents a number 1, 2, 3 or 4,
• d represents a number 0 or 1
• R 23 and R 4 are the same or different and are hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, straight-chain or branched
• alkyl with up to 5 carbon atoms benzyl or phenyl, which is optionally substituted by fluorine, chlorine, bromine, phenyl or trifluoromethyl,
• W represents either an oxygen or a sulfur atom
• Y and Y 1 together form a 2- to 5-membered straight-chain or branched alkyl chain
• e represents a number 1, 2, 3, 4, 5 or 6,
• R 25 , R 26 , R 27 and R 28 are identical or different and denote hydrogen, trifluoromethyl, phenyl, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,
• R and R or R and R each together form a straight-chain or branched alkyl chain with up to 5 carbon atoms or
• R and R or R and R each together represent a radical of the formula
• g represents a number 1, 2, 3, 4, 5 or 6,
• A represents phenyl, pyridyl or thienyl, which are optionally substituted up to 2 times, identically or differently, by fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,
• R 6 and R 9 independently of one another are cyclopropyl, cyclopentyl or cyclohexyl, or phenyl, naphthyl, pyridyl, tetrazolyl, pyrimidyl, pyrazinyl, phenoxathiin-2-yl, indolyl, imidazolyl, pyrrolidinyl, morpholinyl, benzothiazolyl, benzoxazolyl, furyl , Quinolyl or Purin-8-yl, the cycles, optionally up to 3 times, in the case of nitrogen-containing rings also via the N function, identically or differently, by fluorine, chlorine, trifluoromethyl, hydroxy, cyano, carboxyl, tri fluoromethoxy, straight-chain or branched alkyl, alkylthio,
• R 10 , R n and R are the same or different and are 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 7 represents hydrogen or fluorine
• R 8 denotes hydrogen, fluorine, chlorine, 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 1 and R are the same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
• R is hydrogen or straight-chain or branched alkyl, alkoxy or acyl each having up to 4 carbon atoms.
• L represents a straight-chain or branched alkylene or alkenylene chain each having up to 5 carbon atoms, which is 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 represents an oxygen or sulfur atom or a group of the formula -NR 18 ,
• R denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms
• Phenyl which is optionally substituted by fluorine or trifluoromethyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxy, R 1 and R 2 together form a straight-chain or branched alkylene chain with up to 5 carbon atoms, which is represented by a carbonyl group and / or a radical of the formula
• R 19 is hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, straight-chain or branched silylalkyl having up to 6 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl, straight-chain or branched alkoxy having up to 3 carbon atoms or by phenyl which in turn is caused by fluorine, chlorine, bromine,
• Nitro, trifluoromethyl, trifluoromethoxy or phenyl substituted by phenyl or tetrazole may be substituted
• alkyl is optionally substituted by a group of the formula -OR
• R 22 denotes straight-chain or branched acyl with up to 3 carbon atoms or benzyl
• R 19 denotes straight-chain or branched acyl having up to 15 carbon atoms or benzoyl, which may be replaced by fluorine, chlorine, bromine,
• Trifluoromethyl, nitro or trifluoromethoxy is substituted, or straight-chain or branched fluoroacyl with up to 4 carbon atoms,
• R 1 and R 2 optionally up to 4 times the same or different, optionally also geminal, by fluorine,
• Carbon atoms is substituted, which in turn is up to 2 times the same or different substituted by hydroxyl, benzyloxy, trifluoromethyl, benzoyl, methoxy, oxyacetyl and / or phenyl, which in turn can be substituted by fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy,
• R 1 and R 2 also geminal, optionally up to 4 times the same or different, is substituted by phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turn are optionally substituted by fluorine, trifluoromethyl, trifluoromethoxy or nitro ,
• a number means 0 or 1
• R 23 and R 24 are the same or different and are hydrogen, cyclopropyl, cyclopentyl, benzyl, straight-chain or branched alkyl with up to 4 carbon atoms or phenyl, which is optionally substituted by fluorine, chlorine or bromine,
• W represents either an oxygen or a sulfur atom
• e represents a number 1, 2, 3, 4 or 5
• R, R, R and R are identical or different and are hydrogen, trifluoromethyl, phenyl, fluorine, chlorine, bromine or straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
• g represents a number 1, 2, 3, 4, 5, 6 or 7,
• A represents phenyl which is optionally substituted by fluorine, in particular 4-fluorophenyl,
• R 6 denotes phenyl or trifluoromethyl-substituted phenyl, with trifluoromethyl-substituted phenyl being preferred, R 7 represents hydrogen,
• R represents hydrogen, fluorine, methoxy or hydroxy, with fluorine being preferred
• cyclopropyl represents cyclopropyl, cyclopentyl or cyclohexyl, or represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxy,
• R, 19 means hydrogen
• the compounds of general formula (I) can be prepared by:
• R 35 and R 6 are identical or different and represent straight-chain or branched alkyl having up to 4 carbon atoms
• R 1 'and R 2 * together represent the straight-chain or branched alkylene chain with up to 7 carbon atoms specified under R 1 and R 2 above, which is substituted by tert-butyl-dimethyl-silanyloxy (OTBS),
• R, 37 represents mesyl, tosyl or sulfonyl
• Halogen is chlorine, bromine or iodine, preferably chlorine,
• the formyl group is converted into the radical D and the TBS group is split off by customary methods,
• R includes the above-mentioned meanings of R and R, in inert solvents and under a protective gas atmosphere into the compounds of the general formula (VIII)
• R and R together represent the carbonyl group
• x represents a number 1, 2 or 3,
• R 39 and R 40 are identical or different and stand for hydrogen or stand for straight-chain or branched alkyl with up to 6 carbon atoms,
• R 39 and R 40 can also be positioned geminal
• R 39 and R 40 together form a spiro-linked carbocycle with 3 to 7 carbon atoms
• R 41 , R 42 and R 43 are the same or different and stand for straight-chain or branched alkyl having up to 10 carbon atoms,
• R, 4 represents metal or semimetal derivatives, preferably that of titanium
• halogenation halogen compounds e.g. the compounds of the general formula (XVII) and / or (XVIIa)
• R 6 , R 39 , R 40 , x, A and E have the meanings given above,
• silylation for example by reaction with chlorinated or trifluoromethanesulfonyl-substituted silyl compounds (-SiR 41 R 42 R 43 )
• Structures of general formulas (XV), (XVI), (XVII), (XVIIa) and (XVIII) can occur in isomeric forms (i.e. enantiomers, diastereomers, regioisomers).
• 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, acetonitrile, acetonitrile, acetonitrile, acetonitrile, acetonitrile. It is also possible to use mixtures of the solvents mentioned. Toluene and dichloromethane are preferred.
• the bases which are customary for the individual steps 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, DBU or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides such as sodium hydride or potassium hydride.
• organolithium compounds such as, for example, n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium
• amides such as, for example, lithium diisopropylamide, sodium amide, DBU or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides such as sodium hydride or potassium hydride.
• the usual inorganic bases are also suitable for the processes. These preferably include 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 hydride or potassium hydroxide is particularly preferably used.
• the reductions are generally carried out using reducing agents, preferably those which are suitable for the reduction of ketones to hydroxy compounds.
• Reduction with complex metal hydrides is preferred such as for example lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoboranate, diisobutylaluminium hydride or
• Lithium aluminum hydride performed.
• 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 DIBAH, 0 ° C to room temperature in the case of NaBH 4 , particularly preferably at -78 ° C, depending on the choice of reducing agent and solvent.
• the reduction generally proceeds at normal pressure, but it is also possible to work at elevated or reduced pressure.
• the bases which are generally suitable for this purpose are the customary strongly basic compounds. These preferably include di- and trialkylamines such as triethylamine or organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or ide such as lithium diisopropylamide, sodium amide or potassium amide, or
• the usual inorganic bases are also suitable as bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide,
• the bases are generally used in an amount of 1 mol to 4 mol, preferably 1 mol to 2 mol, based on 1 mol of the compounds of the general
• 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 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, tetrachloromethane, or dichlorethylene, trichloro-chloro-chloro Ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dichloromethane is preferred.
• the bases which are customary for the individual steps are the customary strongly basic compounds. These preferably include pyridine or organolithium compounds such as, for example, n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or A ide such as, for example, lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides such as sodium hydride or potassium hydride. Pyridine is particularly preferably used.
• the usual inorganic bases are also suitable for processes [B] and [C].
• 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 hydride or potassium hydroxide is particularly preferably used.
• the base is used in an amount of 0.1 mol to 5 mol, preferably 0.5 mol to 2 mol, in each case based on 1 mol of the starting compound.
• the reaction with Grignard reagents is generally carried out in a temperature range from 0 ° C. to 150 ° C., preferably at 25 ° C. to 40 ° C.
• the Grignard reactions are generally carried out at normal pressure. However, it is also possible to carry out the process under negative pressure or under positive pressure (e.g. in a range from 0.5 to 5 bar).
• halogenations are generally carried out in one of the chlorinated hydrocarbons and hydrocarbons listed above, methylene chloride and toluene being preferred.
• Suitable halogenating agents are diethylamino sulfur trifluoride (DAST), molino sulfur trifluoride or SOCk
• 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 halogenation generally takes place at normal pressure, but it is also possible to work at elevated or reduced 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.
• the deprotection with tetrabutylammonium fluoride (TBAF) in THF at room temperature is preferred.
• the compounds of the general formula (VI) are reacted with the compounds of the general formula (VII) 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 -25 ° C.
• 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.
• organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium
• amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide
• 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. These preferably include 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. It may be necessary to carry out a few reaction steps under a protective gas atmosphere.
• the reduction of the carbonyl group in the compounds of the general formula (IX) is generally carried out under the reduction conditions given above, preferably with sodium bis (2-methoxyethoxy) dihydroaluminate in toluene, in a temperature range from -20 ° C. to 140 ° C. , preferably from 0 ° C to 110 ° C and normal pressure.
• Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetrahydrofirirane, 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. Dichloromethane 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 hexamethylsilyl amide, or alkali hydrides such as sodium hydride or potassium hydride.
• 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 formulas (X), (XI) and (XIII) can be converted into compounds of the formula (XV) without isolation of the intermediates (XII) and (XTV).
• Suitable reaction temperatures are between room temperature and -20 ° C.
• Titanium reagents for example mixtures of titanium tetrachloride and titanium tetra-iso-propoxide, in particular in a molar ratio of 3: 1, are preferably used as metal or semimetal reagents.
• the customary inert solvents, in particular dichloromethane, are suitable as solvents.
• Elimination to the compounds of the formula (XVI) generally leads to a mixture of the various possible double bond isomers.
• the elimination is carried out under customary conditions, preferably with thionyl chloride in pyridine at temperatures in the range from -25 to + 25 ° C., preferably from -10 to + 10 ° C.
• halogenation to give compounds of the formula (XVII) leads, starting from the mixture of double bond isomers obtained in the previous step, to a mixture of isomers in relation to the position of the halogen substituents and the double or single bond.
• Conventional reagents for halogenation preferably for allylic halogenation, and optionally a radical initiator are used.
• a radical initiator e.g. N-chlorosuccinimide, bromine
• the customary inert solvents, in particular dichloromethane, are suitable as solvents.
• the subsequent elimination and oxidation to the aromatic can be carried out without isolation of the intermediates in one of the ethers listed above, preferably dioxane, at temperatures from 0 ° C. to 150 ° C., preferably room temperature to 120 ° C.
• mild oxidizing agents such as elemental sulfur or preferably chalcones may be used.
• the terminal phenyl radicals can each have one or more substituents selected from the group halogen, trifluoromethyl, straight-chain or branched alkyl with up to
• the carbon 4-CF 3 -C 6 H 4 -CO-CH CH-C 6 H 4 -4-F is preferably used.
• Amino alcohol such as l-aminoindan-2-ol in anhydrous ethers, especially THF, under protective gas at temperatures from -70 ° C to 50 ° C.
• the resulting hydroxyl group is protected by a trialkylsilyl group, for example the tert-butyldimethylsilyl group.
• the introduction takes place via the usual active silyl derivatives, for example the chlorides or the trifluoromethanesulfonates (triflates) in the presence of sterically hindered bases such as e.g. Lutidine at temperatures from -20 ° C to 0 ° C in inert solvents such as toluene under a protective gas atmosphere.
• the second keto function can be reduced by conventional methods, for example using lithium aluminum hydride in ethers, in particular in THF, at temperatures from 0 ° C. to 50 ° C. If desired, the desired diastereomer can be isolated from the resulting diastereomer mixture, for example by chromatography.
• R and R stand for a straight-chain or branched alkylene chain with up to 7 carbon atoms
• R 45 and R 46 are identical or different and represent straight-chain or branched alkyl having up to 4 carbon atoms
• R and R have the meaning of R and R given above, the alkylene chain being substituted by a carbonyl group
• Substitutene A is generally introduced in two steps, initially reacting with Tf 2 O in pyridine. In a further step, the reaction takes place with the compounds of the general formula (XXVTII)
• Suitable solvents for all processes are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene,
• Suitable palladium compounds in the context of the present invention are generally PdCl 2 ((C 6 H 5 ) 3 ) 2 , palladium-bis-dibenzylidene acetone (Pd (dba) 2 ), [l, l'-bis (diphenylphosphino) ferrocene] -Palladium (II) chloride (Pd (dppf) Cl 2 ) or Pd (P (C 6 H 5 ) 3 ) 4 .
• Pd (P (C 6 H 5 ) 3 ) 4 is preferred.
• the reaction is generally carried out in a temperature range from room temperature to + 150 ° C, preferably from + 40 ° C to + 110 ° C.
• the reaction is generally carried out at normal pressure. However, it is also possible to carry out the process under negative pressure or under positive pressure (e.g. in a range from 0.5 to 5 bar).
• the compounds of the general formula (XIV) are generally reduced in one of the solvents listed above, preferably using DIBAH.
• the reductions are generally carried out using reducing agents, preferably those which are suitable for the reduction of ketones to hydroxy compounds.
• the reduction with complex metal hydrides such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoboranate, diisobutylaluminium hydride or is preferred
• 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 DIBAH, 0 ° C to room temperature in the case of NaBH 4 , particularly preferably at -78 ° C, depending on the choice of reducing agent and solvent.
• the reduction generally proceeds at normal pressure, but it is also possible to work at elevated or reduced pressure.
• the TBS group is then introduced in one of the solvents listed above, preferably with toluene, in a temperature range from -30 ° C. to room temperature, preferably from -20 ° C. to 0 ° C. and normal pressure.
• the alkylation with alkyl halides is generally carried out in inert solvents in
• 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 diisopropylamide alkali alcoholates such as sodium methoxide, sodium ethanolate, potassium methoxide, potassium ethanolate or potassium tert-butoxide, 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 + 80 ° C., preferably from -70 ° C. to 0 ° C.
• the alkylation is generally carried out at normal pressure. However, it is also possible to carry out the process under reduced pressure or excess pressure (e.g. in a range from 0.5 to 5 bar).
• the compounds of the general formulas (III), (XXV), (XXVI), (XXVII), (XXVIII) and (XXX) are known per se or can be prepared by customary methods.
• the compounds of the general formula (XXIX) are new and can be prepared as described above.
• Oxidizing agent in the presence of a base preferably reacted with the SO 3 -pyridine complex.
• Suitable solvents for the individual steps are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, diisopropyl ether or hydrocarbons such as
• 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 (Va).
• the usual basic compounds can be used as bases for the individual steps.
• bases preferably include pyridine or 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.
• Pyridine is particularly preferably used.
• the base 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 (Va).
• the oxidation generally takes place at a temperature of from -50 ° C. to + 100 ° C., preferably from 0 ° C. to room temperature.
• R '"', R 2 and R 47 have the meaning given above,
• E IV represents cycloalkenyl having 3 to 8 carbon atoms, or represents straight-chain or branched alkenyl having up to 8 carbon atoms, or represents a radical of the formula -R -Sn (RRR),
• R> 48 denotes straight-chain or branched alkenyl having up to 8 carbon atoms
• R 49 , R and R are identical or different and denote straight-chain or branched alkyl having up to 8 carbon atoms,
• R, ' iv and R, 21V have the abovementioned meaning of R and RV, the alkylene chain being substituted by hydroxy
• the compounds of the general formula (XVI) are reacted with aqueous solutions of common acids at a temperature of 0 ° C. to 150 ° C., preferably with carboxylic acids such as citric acid and oxalic acid at 60 ° C. and normal pressure.
• 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, carbon tetrachloride, or dichlorethylene, dichlorethylene, trichloromethene, trichloromethene, trichloromethene, trichloromethene, trichloromethane, dichloroethylene, trichloromethene, trichloromethane, dichloroethene, trichloromethene, trichloromethane, dichloroethene, trichloromethene, trichloromethane, dichloroethene,
• Suitable oxidizing agents are, for example, cerium (W) ammonium nitrate, 2,3-dichloro-
• 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 (XXXIII).
• 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.
• the hydroxyl protecting group trifluoromethanesulfonyl is introduced into the compounds of the general formula (XXXIII) in general in pyridine with trifluoromethanesulfonic anhydride in a temperature range from -30 ° C. to + 40 ° C., preferably at -20 ° C. to 0 ° C. and normal pressure.
• dialkylamines listed above preferably ethyldiisopropylamine, are suitable as bases.
• the base is generally used in an amount of 0.5 mol to 5 mol, preferably 1 mol to 3 mol, based on 1 mol of the compounds of the general formula (XXXV).
• Suitable palladium compounds in the context of the present invention are in general PdCl 2 ((C 6 H 5 ) 3 ) 2 , palladium-bis-dibenzylidene acetone (Pd (dba) 2 ), [1,1'-bis (diphenylphos ⁇ hino) ferrocene] -Palladium (II) chloride (Pd (dppf) Cl 2 ), Pd (P (C 6 H 5 ) 3 ) 4 , Pd (PPl-3) 3, Pd (Oac) 2, optionally with the addition of phosphine ligands (e.g. dppe, diphos, dba, chiraphor, etc.)
• phosphine ligands e.g. dppe, diphos, dba, chiraphor, etc.
• the hydrogenation is carried out using conventional methods with hydrogen in the presence of
• Noble catalyst 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 from -20 ° C to + 100 ° C, preferably from 0 ° C to + 50 ° C, at normal pressure or overpressure.
• the reduction to the compounds of the general formula (XXXVIII) is generally carried out in one of the ethers listed above, preferably tetrahydrofuran in a temperature range from 0 ° C. to + 40 ° C., preferably 0 ° C. to room temperature and normal pressure.
• Suitable reducing agents are generally aluminum hydrides such as LiAlH 4 , DIBAH, Red-Al; Borohydrides such as NaBH 4 , NaCNBH 3 , LiBH 4 ; Borane complexes like BH 3 x THF, BH 3 x DMS, BH 3 x (Et 2 ) NC 6 H 5 or borane-dimethyl sulfide solution in tetrahydrofuran. Borane dimethyl sulfide solution in tetrahydrofuran is preferred.
• the borane complexes can be combined with chiral auxiliaries such as chiral amino alcohols; chiral aminoindanol, for example 1R, 2S aminoindanol, is preferred here.
• the TBS group for blocking the hydroxy function is generally introduced in toluene with tert-butyldimethylsilyl triflate and a base, preferably 2,6-lutidine, in a temperature range from -30 ° C. to + 10 ° C., preferably -20 ° C to 0 ° C and normal pressure.
• the reduction of the compounds of the general formula (XXXLX) is generally carried out in ether, THF or in one of the cyclic hydrocarbons listed above, preferably toluene in a temperature range from -78 ° C to - 20 ° C, preferably from -78 ° C to - 40 ° C and normal pressure.
• the reductions are generally carried out using reducing agents, preferably those which are suitable for the reduction of ketones to hydroxy compounds.
• the reduction with complex metal hydrides such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoboranate, diisobutylaluminium hydride or is preferred
• Lithium aluminum hydride performed.
• 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 NaBH 4 , particularly preferably at -78 ° C, depending on the choice of reducing agent and solvent.
• the reduction generally takes place at normal pressure, but it is also possible to work at elevated or reduced pressure.
• the compounds of the general formula (X) can be prepared analogously to the processes described below by way of example for the compound spiro [2,5] non-7-en-3-one.
• the compound spiro [2,5] non-7-en-3-one of the formula (XLIII) is obtained by reaction with p-toluenesulfonic acid (p-TSS) in toluene and isobutanol and subsequent reduction with Red-Al in toluene
• p-TSS p-toluenesulfonic acid
• the reaction takes place in a temperature range from 0 ° C to 60 ° C, preferably from 20 ° C to 50 ° C. Both reaction steps are carried out at normal pressure.
• the reaction can go through the following intermediate stages:
• the compound of the formula (XLII) is prepared by first reacting the compound cyclobutylidene-2-propanone of the formula (XLVI) by reacting cyclobutanone with triphenylphosphoranylidene-2-propanone and benzoic acid
• the compound of the formula (XLVI) is prepared in a temperature range from 80 ° C. to 120 ° C. and normal pressure.
• the compounds of the general formula (XIII) are prepared by reacting the compounds of the formula (LII)
• R 6 has the meaning given above
• 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 to the prior art, in particular they are highly effective inhibitors of cholesterol-ester transfer.
• CETP Proteins (CETP) and stimulate reverse cholesterol transport.
• 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 hypoalphalipoproteinemia, dyslipidemia, hypertriglyceridaemia, hyperlipidaemia or arteriosclerosis.
• CETP is obtained from human plasma by differential centrifuge 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-active fractions are pooled, dialyzed against 50 mM Na acetate pH 4.5 and applied to a CM-Sepharose® (from Pharmacia) column. Elution is then carried out using a linear gradient (0-1 M NaCl).
• the pooled CETP Fractions are dialyzed against 10 mM TrisHCl pH 7.4 and then further purified by chromatography on a Mono Q® column (from Pharmacia).
• the mixture is then adjusted to a density of 1.21 with NaBr and centrifuged in the 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.
• 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.
• Intermediate layer containing HDL is dialyzed against 3 * 100 volumes of PDB buffer at 4 ° C.
• the retentate contains radioactively labeled cmp per ml set is used for the test.
• the activity transferred in the control batches with CETP at 37 ° C. is rated as 100% transfer.
• test substances can also p.o. are done by dissolving the substances in DMSO and suspending 0.5% tylose orally using a pharyngeal tube.
• the control animals receive identical volumes of solvent without test substance.
• Blood is extracted from animals by puncturing the retro-orbital venous plexus (approx. 250 ⁇ l). The coagulation is terminated by incubation at 4 ° C. overnight, followed by centrifugation at 6000 ⁇ g for 10 minutes. In the serum obtained in this way, the CETP activity is determined by the modified CETP test. The transfer of H-cholesterol ester from HD lipoproteins to biotinylated LD lipoproteins is measured as described for the CETP test above.
• the reaction is ended by adding streptavidin-SPA beads (from Amersham) and the radioactivity transferred is determined directly in the liquid scintlation counter.
• CETP test Only 10 ⁇ l CETP are replaced by 10 ⁇ l of the corresponding serum samples for testing the sera. 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.
• 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 treated with physiological conditions
• 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 the substances to be tested in
• the change in the measured parameters is expressed as a percentage change compared to the initial value.
• the invention also relates to the combination of substituted tetrahydronaphthalenes of the general formula (I) with a glucosidase and / or amylase inhibitor for the treatment of familial hyperlipidemia, obesity (obesity) and diabetes mellitus.
• Glucosidase and / or amylase inhibitors in the context of
• Examples include acarbose, adiposins, Voglibose, Miglitol, Emiglitate, MDL-25637, Camiglibose (MDL-73945), Tendamistate, AI-3688, Trestatin, Pradimicin-Q and Salbostatin.
• the compounds according to the invention can be combined with cholesterol-lowering vastatins or ApoB-lowering principles in order 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 carriers or solvents.
• the therapeutically active compound should in each case be present 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.
• reaction solution was worked up. in a mixture of 350 ml of 10% sodium chloride solution. and 175 ml of toluene were stirred in, slowly dropwise added about 14 ml of 1 M hydrochloric acid to pH 5 and the phases were separated. The aqueous phase was extracted again with 90 ml of toluene, and the combined org. Phases with 90 ml 5% sodium bicarbonate solution. and washed twice with water until neutral, dried over sodium sulfate and concentrated. The crude product was dissolved in a little toluene and placed on a short layer of silica gel (60 g) and eluted with toluene. The main fraction was concentrated and crystallized by inoculating with product from a little toluene and dried under vacuum to constant weight. Yield: 2.61 g (78% of theory)
• Washed methylcyclohexane Washed methylcyclohexane.
• Example 8 and Example 9 [IS, 7 (IS)] - 6-cyclopentyl-8- (4-fluorophenyl) -7- [fluoro- (4-trifluoromethylphenyl) methyl] -3,3-dimethyl-1,2 , 3,4-tetrahydro-naphthalene-l-ol
• the reaction is carried out under an argon protective gas atmosphere.
• 0.5 g (0.801 mmol) of the compound from Example XXIV are placed in 13 ml of dioxane, 0.5 g (3.283 mmol) of l, 5-diazabicyclo- [5.4.0] -undec-7-ene (DBU) and 0 , 29 g (0.985 mmol) of l- (4-trifluoromethylphenyl) -3- (4-fluorophene) -propen-3-one are added and the mixture is stirred at 96 ° C. for 20 hours.
• DBU 5-diazabicyclo- [5.4.0] -undec-7-ene
• the mixture was extracted with 10 ml of 1N hydrochloric acid, the aqueous phase was extracted three times with ethyl acetate, the combined organic phases were extracted with saturated aqueous sodium bicarbonate solution and the aqueous phase was extracted twice with

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• 1998
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