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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• Tetrahydroquinolines with pharmacological activity are known from EP-A-818 448, WO 99/15504 and WO 99/1421.
• Substituted tetrahydronaphthalenes with pharmacological activity are known from WO 99/14174.
• the present invention relates to novel tetrahydroquinolines of the general formula (I)
• Nerrisonen of formula (I), in which B is isopropyl are also preferred.
• 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.
• Physiologically acceptable salts of the compounds according to the invention may be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are e.g. Salts with hydrochloric acid,
• Hydrobromic acid sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, ⁇ aphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
• Physiologically acceptable salts may also be metal or ammonium salts of the compounds of the invention which have a free carboxyl group. Particularly preferred are e.g. Sodium, potassium, magnesium or calcium salts, and ammonium salts derived from ammonia, or organic amines such as ethylamine, di- or. Triethylamine, di- or
• R! for a hydroxy protecting group preferably a radical of the formula -S I R2R3R4 sten t 5
• R 2 R 3 and R 1 are identical or different and denote C 1 -C 4 -alkyl
• the reductions are generally carried out with reducing agents, preferably those suitable for the reduction of ketones to hydroxy compounds. Particularly suitable here is the reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane.
• the reduction is preferably carried out with complex metal hydrides such as, for example, lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkylhydridoboranate, diisobutylaluminum hydride or lithium aluminum hydride. Most preferably, the reduction is carried out with diisobutylaluminum hydride and sodium borohydride.
• the reduction generally proceeds 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 atmospheric pressure or overpressure.
• 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 atmospheric pressure or overpressure.
• 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, carbon tetrachloride, dichloroethylene, trichlorethylene or chlorobenzene. It is also possible mixtures of the above
• the oxidation takes place in one of the abovementioned chlorinated hydrocarbons and water.
• Preferred are dichloromethane and water.
• the oxidation generally proceeds at atmospheric pressure. However, it is also possible to carry out the oxidation at elevated or reduced pressure.
• the reducing agent is generally used in an amount of from 1 mol to 6 mol, preferably from 1 mol to 4 mol, based on 1 mol of the compounds to be reduced.
• Hydrocarbons 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 atmospheric pressure.
• Reagents for introducing the silyl protective group are generally tert-butyldimethylsilyl chloride or tert-butyldimethylsilyl trifluoromethanesulfonate. Preference is given to tert-butyldimethylsilyltrifluoromethanesulfonate.
• the reduction for the preparation of the compounds of the general formula (VI) is generally carried out using customary reducing agents, preferably those suitable for the reduction of ketones to hydroxy compounds. Particularly suitable here is the reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkyl borane.
• the reduction is preferably carried out with complex metal hydrides such as, for example, lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trialkyl hydridoboranate, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) dihy- droaluminat or Lithiumalumimumhydrid performed. Most preferably, the reduction is carried out with sodium bis (2-methoxyethoxy) dihydroaluminate.
• the reducing agent is generally used in an amount of from 1 mol to 6 mol, preferably from 1 mol to 3 mol, based on 1 mol of the compounds to be reduced.
• Suitable solvents for the preparation of Neritatien the general formula (II) are the above listed ethers or alcohols. Preference is given to diisopropyl ether.
• Suitable acids for the preparation of Neritatien the general formula (II) are generally suitable organic carboxylic acids and inorganic acids, such as oxalic acid, maleic acid, phosphoric acid, fumaric acid and trifluoroacetic acid. Preference is given to trifluoroacetic acid.
• the reaction is generally carried out at atmospheric pressure. But it is also possible to carry out the reaction at elevated or reduced pressure.
• the reaction generally occurs at the reflux temperature of the particular solvent.
• the Neralten the general formulas (N ⁇ ), (NITI) and (IX) are known or can be prepared by conventional methods.
• the compounds of the general formula (I) according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases.
• the compounds according to the invention are highly effective inhibitors of cholesterol ester transfer protein (CETP) and stimulate reverse cholesterol transport.
• CETP cholesterol ester transfer protein
• the erfmdungswen active ingredients reduce LDL (low density lipoprotein) in the blood while increasing HDL cholesterol (high density lipoprotein). They can therefore be used for the treatment and prevention of hypolipoproteinemia, dyslipidaemias, hypertriglyceridemias, hyperlipidemias or arteriosclerosis.
• the active compounds according to the invention can also be used for
• the active compounds according to the invention are furthermore suitable for the treatment and prevention of strokes (Stroke) and Alzheimer's disease.
• the active compounds according to the invention open up a further treatment alternative and represent an enrichment of pharmacy.
• the compounds according to the invention show an improved range of activity. They are preferably characterized by high specificity, good tolerability and lower side effects, especially in the cardiovascular area.
• An advantage of the compounds according to the invention, in addition to their high activity, is in particular a reduced deposit behavior in adipose tissue.
• the pharmacological effect can be determined by means of known CETP inhibition tests.
• the new active compounds may be used alone and, if required, also in combination with other active substances preferably from the group CETP inhibitors, antidiabetics, antioxidants, cytostatics, calcium antagonists, antihypertensive agents, thyromimetics, inhibitors of HMG-CoA reductase, inhibitors of HMG-CoA
• Reductase gene expression squalene synthesis inhibitors, ACAT inhibitors, bleed-promoting agents, platelet aggregation inhibitors, anticoagulants, atgiotensin II receptor antagonists, cholesterol absorption inhibitors, MTP inhibitors, aldose reductase inhibitors, fibrates, niacin, anorectics, lipase Inhibitors and PPAR agonists.
• Glucosidase and / or amylase inhibitors in the context of the invention are, for example, acarbose, adiposine, voglibose, miglitol, emiglitate,
• compositions of the invention with cholesterol lowering statins, HDL enhancing principles, bile acid absorption blockers, cholesterol absorption blockers, vasoactive principles or ApoB lowering principles to treat dyslipidemias, combined hyperlipidemias, hypercholesterolemias or hypertriglyceridemias.
• the said combinations are also useful for the primary or secondary prevention of coronary heart disease (e.g., myocardial infarction).
• coronary heart disease e.g., myocardial infarction
• Statins in the context of the invention are, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and cerivastatin.
• ApoB lowering agents are, for example, MTP inhibitors
• vascular principles may include, but are not limited to, adhesion inhibitors, chemokine receptor
• Tablets non-coated and coated tablets, for example enteric-coated tablets or film-coated tablets
• capsules dragees, granules, pellets, powders, emulsions, suspensions and solutions.
• the new active ingredients are used in the manufacture of medicines, in particular for the manufacture of medicaments for the prevention and treatment of the abovementioned diseases.
• Medicaments are prepared in a known manner by converting the compounds according to the invention into the customary formulations, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions. This is done using inert nontoxic, pharmaceutically acceptable
• the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of using water as a diluent, organic solvents may optionally be used as auxiliary solvents.
• solutions of the active ingredient may be added
• Example 4 678 mg (5.46 mmol) reacted 4-fluorobenzaldehyde and 834 mg (5.46 mmol) spiro [3.5] nonane-6,8-dione.
• Example 13 500 mg (0.98 mmol) from Example 13 are reacted analogously to the instructions of the compound from Example 21.
• Example 16 295 mg (0.63 mmol) from Example 16 are reacted analogously to the instructions of the compound from Example 21.
• Example 18 1.1 g (2.27 mmol) from Example 18 are reacted analogously to the instructions of the compound from Example 21.
• Example 20 187 mg (0.40 mmol) from Example 20 are reacted analogously to the instructions of the compound from Example 21.
• Example 25 550 mg (1.14 mmol) from Example 25 are prepared analogously to the instructions of the Bond implemented from Example 36.
• Example 41 180 mg (0.35 mmol) from Example 41 are reacted analogously to the instructions of the compound from Example 51/52.
• Example 43 80 mg (0.16 mmol) from Example 43 are reacted analogously to the instructions of the compound from Example 51/52.
• Example 45 774 mg (0.51 mmol) from Example 45 are reacted analogously to the instructions of the compound from Example 51/52.
• Example 47 154 mg (0.31 mmol) from Example 47 are reacted analogously to the instructions of the compound from Example 51/52.
• Example 48 346 mg (0.72 mmol) from Example 48 are reacted analogously to the instructions of the compound from Example 51/52.
• Example 49 83 mg (0.18 mmol) from Example 49 are reacted analogously to the instructions of the compound from Example 51/52.
• Example 50 109 mg (0.23 mmol) from Example 50 are reacted analogously to the instructions of the compound from Example 51/52.
• keto-alcohol from Example 37 735 mg (1.40 mmol) of keto-alcohol from Example 37 are initially charged under argon in toluene (5 ml, pa, dried over molecular sieve), 600 mg (5.60 mmol) of 2,6-lutidine are added at RT and the mixture is chromatographed. 16 ° C. 740 mg (2.81 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate in
• Toluene (1.5 ml) was added dropwise and rinsed twice with 0.25 ml of toluene. After 15 min, the mixture is warmed to 0 ° C. and the reaction mixture is stirred at this temperature for 80 min.
• 0.1N hydrochloric acid (20 ml) is added and, after warming to RT, shaken out with ethyl acetate. The aqueous phase is extracted three more times with ethyl acetate, the combined organic phases washed with a 1: 1 mixture of sodium bicarbonate solution and saturated brine and this aq. Phase extracted again with ethyl acetate.
• Reaction mixture is stirred for 1.5 h with ice cooling, 45 min with slow heating to 13 ° C and 50 min without cooling.
• To stop the reaction is cooled again to 0 ° C and methanol (1 ml) was added.
• methanol (1 ml) was added.
• the aq. Phase is extracted three more times with ethyl acetate, the combined org. Phases dried over sodium sulfate, filtered and concentrated in vacuo.
• the residue (878 mg) is purified by chromatography on silica gel with ethyl acetate / petroleum ether 1:20.
• Example 79 30 mg (0.05 mmol) from Example 79 are initially charged under argon and added to the TBAF
• CETP is recovered from human plasma by differential centrifugation and column chromatography in partially purified form and used for testing.
• human plasma is adjusted with NaBr to a density of 1.21 g per ml and centrifuged for 18 h at 50,000 rpm at 4 ° C.
• the bottom fraction (d> l, 21 g / ml) is applied to a Sephadex ® Phenyl-Sepharose 4B (Fa. Pharmacia) column, washed with 0.15 m NaCl 0.001 M TrisHCl pH 7.4 and then washed with distilled water. Water elutes.
• the CETP-active fractions are pooled, dialyzed against 50 mM Na acetate pH 4.5 and applied to a CM-Sepharose ® (Fa. Pharmacia) column. With a linear gradient (0-1 M NaCl) is then eluted.
• the pooled CETP fractions are dialysed against 10 mM Tris-HCl pH 7.4, then further purified by chromatography on a Mono Q ® column (Fa. Pharmacia).
• the suspension is then sonicated under N 2 - atmosphere for 30 minutes in Braukson ultrasonic bath at about 50 watts, the temperature was maintained at about 20 ° C.
• the acceptor liposomes are obtained analogously from 86 mg cholesteryl oleate, 20 mg triolein and 100 mg phosphatidylcholine dissolved in 1.2 ml dioxane and 114 ml of the above buffer by sonicating for 30 minutes at 50 watts (20 ° C.).
• test mix consisting of 1 part of the above buffer, 1 part of donor liposomes and 2 parts of acceptor liposomes are used.
• test mixture 80 ⁇ l of test mixture are obtained with 1 - 3 ⁇ g of enriched CETP fraction, obtained by hydrophobic chromatography from human plasma, and 2 ⁇ l of the examined
• the change in fluorescence at 485/535 nm is a measure of the CE transfer, the inhibition of the transfer compared to the control batch without substance is determined.
• the following table gives the results for the examples:
• 50 ml fresh human EDTA plasma is adjusted to a density of 1.12 with NaBr and centrifuged at 4 ° C in the Ty 65 rotor for 18 h at 50,000 rpm.
• the upper phase is used to recover cold LDL.
• the lower phase is dialyzed against 3 * 41 PDB buffer (10 mM Tris HCl pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN3).
• 20 ml of 3H-cholesterol are then added per 10 ml of retentate volume (Dupont NET-725, 1 ⁇ C / ⁇ l dissolved in ethanol!) was added and incubated at 37 ° C under N 2 for 72 h.
• the batch is then adjusted to density 1.21 with NaBr and centrifuged in the Ty 65 rotor at 50,000 rpm for 18 h at 20 ° C.
• the upper phase is recovered 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 covered in centrifuge tubes (SW 40 rotor) with 4 ml of a solution of density 1.21 and 4.5 ml of a solution of 1.063 (density solutions of PDB buffer and NaBr) and then 24 h at 38,000 rpm and 20 ° C in the SW
• the intermediate layer containing the labeled HDL between density 1.063 and 1.21 is dialysed against 3 * 100 volume of PDB buffer at 4 ° C.
• the retentate contains radioactively labeled H-CE-HDL, which is used for testing at approximately 5x10 cmp per ml.
• the reaction is stopped by addition of streptavidin-SPA®beads (Amersham) and the radioactivity transferred determined directly in the liquid scintillation counter.
• SPA-streptavidin bead solution (TRKQ 7005) are added, 1 h while shaking further incubated and then measured in scintillation counter.
• the controls are incubations with 10 ⁇ l buffer, 10 ⁇ l CETP at 4 ° C and 10 ⁇ l CETP at 37 ° C.
• the activity transferred in the control mixtures with CETP at 37 ° C is rated as 100% transmission.
• the substance concentration at which this transfer is reduced by half is given as the IC 50 value.
• T2 second time
• an appropriate control group is used for each time point, ie 1, 3 or 6 h, whose animals only receive the formulating agent without substance.
• the two blood withdrawals per animal are the same as for the substance-treated animals in order to determine the change in CETP activity without inhibitor over the corresponding experimental period (1, 3 or 6 h).
• the blood samples are centrifuged at the end of the coagulation and the serum is pipetted off.
• CETP fluoride test To determine the CETP activity, the cholesteryl ester transport over 4 h is determined. For this purpose, 2 ⁇ l of serum are generally used in the test batch, and the test is carried out as described under "CETP fluoride test".
• cholesteryl ester transport (pM CE * / h (T2) - pM CE * / h (Tl)) are calculated for each animal and averaged in the groups. A substance that reduces> 30% cholesteryl ester transport at any one time is considered to be effective.
• DMSO dissolved and 0.5% Tylose suspended orally administered by gavage are administered perorally by means of a gavage.
• the control animals receive identical volumes of solvent without test substance. Subsequently, the animals are deprived of food and taken at different times - up to 24 hours after substance application - by puncture of the retroorbital venous plexus blood.
• the determination of the content of HDL cholesterol is carried out after precipitation of the ApoB-containing lipoproteins by means of a reagent mixture (Sigma 352-4 HDL cholesterol reagent) according to the manufacturer.
• transgenic mice In experiments to determine the oral effect on lipoproteins and triglycerides, transgenic mice (Dinchuck, Hart, Gonzalez, Karmann, Schmidt, Wirak; BBA (1995), 1295, 301) test substance are administered by gavage. Before the start of the experiment, the mice are bled retro-orbitally to determine serum cholesterol and triglycerides. The serum is recovered as described above for hamsters by incubation at 4 ° C overnight and subsequent centrifugation at 6000 x g. After one week, the mice are bled again to determine lipoproteins and triglycerides. The changes in the measured parameters are expressed as a percentage change from baseline.
• PE / EE petroleum ether / ethyl acetate
• the measured LC-MS values were determined by the following methods:

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