EP1434581A1

EP1434581A1 - 3- hydroxy-(-4-trifluoromethylphenyl)-methyl-7-spirocyclobutyl-5,6,7,8-tetrahydroquinolin-5-ol derivatives and the use of the same as cholesterol ester transfer protein (cetp) inhibitors

Info

Publication number: EP1434581A1
Application number: EP02772317A
Authority: EP
Inventors: Heike Gielen; Siegfried Goldmann; Jörg Keldenich; Holger Paulsen; Carsten Schmeck; Stephan Siegel; Hilmar Bischoff; Martin Raabe; Delf Schmidt; Christiane Faeste
Original assignee: Bayer Healthcare AG
Current assignee: Bayer Pharma AG
Priority date: 2001-10-01
Filing date: 2002-09-18
Publication date: 2004-07-07
Also published as: DE10148436A1; DOP2002000457A; UY27458A1; CA2462030A1; GT200200195A; WO2003028727A9; US20050043341A1; WO2003028727A1; AR036583A1; JP2005508341A; PE20030604A1; HN2002000278A

Abstract

The invention relates to substituted tetrahydroquinoline derivatives of formula (I), wherein A represents a radical (a), (b), (c), (d), (e), (f), (g), (h) or -(CH2)2CH3 and B represents a radical (f) or (h), and to the salts of the same. The invention also relates to a method for producing said substances and to the use thereof in pharmaceuticals.

Description

- HYDROXY- (4-TRIFLUOROMETHYLPHENYL) -METHYL 1 -7-SPIROCYCLOBUTYL- 5, 6, 7, 8-TETRAHYDR0CHIN0LIN-5-0L DERIVATIVES AND THEIR USE AS CHOLESTEROL ESTER TRANSFER PROTEIN (CETP) INHIBITORS

The present invention relates to substituted tetrab.hydroquinolines, methods for their preparation and their use in medicaments.

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)

in which

A for a rest

- (CH ₂ ) 2CH ₃ stands and

B for a rest or stands.

Preference is given to compounds of the formula (I) in which A is para-fluorophenyl.

Also preferred are Nerbindungen of formula (I), in which B is isopropyl.

The tetrahydroquinolines according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.

In the context of the present invention, 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, Νaphthalenedisulfonic 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

Triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.

The compounds according to the invention can be prepared in stereoisomeric forms which are either like image and mirror image (enantiomers) or which are not like image and Mirror image (diastereomers) behavior, exist. The invention relates to both the enantiomers or diastereomers and their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated in a known manner in the stereoisomerically uniform components.

Preference is given to the compounds in which the hydroxy group form the anti-isomer (Ib).

The compounds of the general formula (I) according to the invention are obtained by reacting compounds of the general formula (II)

in which

A and B have the meanings given above,

first to the compounds of general formula (III)

in which

A and B have the meanings given above,

oxidized these in a next step by an asymmetric reduction to the compounds of general formula (IV)

in which

A and B have the meanings given above,

implements,

this then

[A] by introducing a hydroxy-protecting group into the compounds of general formula (V)

in which

R! for a hydroxy protecting group, preferably a radical of the formula -S _I R2R3R4 _sten t ₅

wherein R 2, R 3 and R 1 are identical or different and denote C 1 -C 4 -alkyl,

convicted

from this in a subsequent step by diastereoselective reduction, the compounds of general formula (VI)

in which

R, A and B have the meanings given above,

manufactures

and then splits off the hydroxy protecting group by conventional methods,

or

[B] the compounds of formula (IV) directly reduced. [A]

[B]

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, dichloroethylene, trichlorethylene or chlorobenzene , or ethyl acetate, or triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of said solvents. Preference is given to dichloromethane.

Suitable bases for the individual steps are the usual strongly basic compounds. These preferably include organolithium compounds such as, for example, n-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium, or amides such as lithium diisopropylamide, sodium amide or potassium amide, or lithium hexamethylsilylamide, or alkali metal hydrides such as sodium hydride or potassium hydride. Particular preference is given to n-butyllithium, sodium hydride or

Lithium diisopropylamide used.

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 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. The reduction generally proceeds 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 NaBFL, more preferably at -78 ° C, in each case depending on the choice of the reducing agent and solvents.

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.

The deprotection is generally carried out in one of the abovementioned alcohols and THF, preferably methanol / THF in the presence of hydrochloric acid in a temperature range from 0 ° C to 50 ° C, preferably at room temperature, and atmospheric pressure. In special cases, the deprotection with tetrabutylammonium fluoride (TBAF) in THF is preferred.

Hydroxy protecting group within the scope of the definition given above generally represents a protecting group from the series: trimethylsilyl, triisopropylsilyl, tert-butyl-dimethylsilyl, benzyl, benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl, tert-butyloxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4 Methoxybenzyloxycarbonyl, tetrahydropyranyl, formyl, acetyl, trichloroacetyl, 2,2,2-trichloroethoxycarbonyl, methoxyethoxymethyl, [2- (trimethylsilyl) ethoxy] methyl, benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl , 4-chlorobenzoyl or 4-methoxybenzoyl. Preference is given to tetrahydropyranyl, tert-butyldimethylsilyl and triisopropylsilyl. Particularly preferred is tert-butyldimethylsilyl. 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

To use solvents.

Suitable oxidizing agents for the preparation of the compounds of the general formula (III) are, for example, nitric acid, cerium (W) -ammonium nitrate, 2,3-dichloro-5,6-dicyano-benzoquinone, pyridinium chlorochromate (PCC), pyridinium chlorochromate on basic aluminum oxide, osmium tetroxide and manganese dioxide. Preference is given to manganese dioxide and nitric acid.

The oxidation takes place in one of the abovementioned chlorinated hydrocarbons and water. Preferred are dichloromethane and water.

The oxidizing agent is used in an amount of from 1 mol to 10 mol, preferably from 2 mol to 5 mol, based on 1 mol of the compounds of the general formula (II).

The oxidation generally proceeds at a temperature of -50 ° C to + 100 ° C, preferably from 0 ° C to room temperature.

The oxidation generally proceeds at atmospheric 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 (TV) is generally carried out in one of the abovementioned ethers or toluene, preferably tetrahydrofuran and toluene. The reduction is generally carried out with enantiomerically pure lR, 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 Preferably, the system is borandiethylaniline / IR, 2S-aminoindanol.

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.

The reduction generally proceeds at a temperature of from -78 ° C to + 50 ° C, preferably from 0 ° C to 30 ° C.

The reduction generally proceeds at atmospheric pressure, but it is also possible to work at elevated or reduced pressure.

The introduction of the hydroxy-protecting group takes place in one of the abovementioned

Hydrocarbons, 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 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.

The reduction generally proceeds at a temperature of -20 ° C to + 110 ° C, preferably from 0 ° C to room temperature.

In the reduction to the compounds of general formula (VI) remain in the mother liquor small residues of the wrong diastereomer. These radicals can be removed with common oxidizing agents, e.g. Pyridiniumchlorochromat (PCC) or activated manganese dioxide, in particular with activated manganese dioxide to be protected (V) reoxidized and thus the synthesis cycle without yield loss are supplied.

The compounds of the general formula (II) can be prepared by

Compounds of the general formulas (XVa), (XViü) and (XIX)

in which

A and B have the meaning given above,

reacted with an acid.

Suitable solvents for the preparation of Nerbindungen the general formula (II) are the above listed ethers or alcohols. Preference is given to diisopropyl ether.

Suitable acids for the preparation of Nerbindungen 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 acid is generally preferred in an amount of 0.1 mol to 5 mol

1 mol, based on 1 mol of Nerbindungen the general formula (IX) used.

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 Nerbindungen the general formulas (Nπ), (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. In particular, the compounds according to the invention are highly effective inhibitors of cholesterol ester transfer protein (CETP) and stimulate reverse cholesterol transport. The erfmdungsgemäßen 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

Treatment and prevention of obesity and obesity. 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. Compared to the known and hitherto used preparations, 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. Preference is given to the combination of the compounds of the general formula (I) according to the invention with a glucosidase and / or amylase inhibitor for the treatment of familial hyperlipidaemias, obesity (obesity) and diabetes mellitus. Glucosidase and / or amylase inhibitors in the context of the invention are, for example, acarbose, adiposine, voglibose, miglitol, emiglitate,

MDL-25637, camiglibose (MDL-73945), tendamistate, AI-3688, trestatin, pradimicin-Q and salbostatin.

Preference is also given to the combination of acarbose, miglitol, emiglitate or voglibose with one of the abovementioned compounds of the general formula (I) according to the invention.

Further preferred are combination of the compounds 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).

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

Antagonists, cell proliferation inhibitors or dilated active substances.

The combination of statins or ApoB inhibitors with one of the abovementioned compounds of the general formula (I) according to the invention is preferred. The active substances can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, transdermally, co-adjunctively, otically or as an implant.

For these administration routes, the active ingredient can be administered in suitable administration forms.

For oral administration are known, the drug rapidly and / or modified donating application forms, such. Tablets (non-coated and coated tablets, for example enteric-coated tablets or film-coated tablets), capsules, dragees, granules, pellets, powders, emulsions, suspensions and solutions.

Parenteral administration can be carried out bypassing a resorption step (intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or using absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.

For the other routes of administration are suitable, for example Inhalant medicines (including powder inhalers, nebulizers), nasal drops / solutions, sprays; lingual, sublingual or buccal tablets or capsules to be applied, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, milk, pastes, powdered powders or implants.

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

Excipients. These include u.a. Carriers (eg microcrystalline cellulose), solvents (eg liquid polyethylene glycols), emulsifiers (eg sodium dodecyl sulfate), dispersants (eg polyvinylpyrrolidone), synthetic and natural biopolymers (eg albumin), stabilizers (eg antioxidants like ascorbic acid), dyes (eg inorganic pigments As iron oxides) or taste and / or odoriferous. Here, the therapeutically active compound should be present in each case in a concentration of about 0.5 to 90 wt .-% of the total mixture, ie in amounts sufficient to achieve the stated dosage margin.

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.

Intravenous, parenteral, perlingual and in particular oral administration are preferred.

In the case of parenteral administration, solutions of the active ingredient may be added

Use of suitable liquid carrier materials can be used.

In general, it has proved to be advantageous for intravenous administration

Quantities of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight to give effective results, and in the case of oral administration cation, the dosage is about 0.01 to 100 mg / kg, preferably 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.

Nevertheless, it may be necessary to deviate from the quantities mentioned, depending on the body weight or the type of

Application route, the individual behavior towards the drug, the nature of its formulation and the time or interval at which the administration takes place. Thus, in some cases it may be sufficient to make do with more than the minimum amount mentioned above, while in other cases the above upper limit must be exceeded. In case of application larger

Quantities may be recommended to distribute them in several single doses throughout the day.

The following examples serve to illustrate the invention. The invention is not limited thereby to the examples.

Examples

1. 1-Isopropyl-3- (4-trifluoromethylphenyl) -propane-1,3-dione

627.6 g (5.59 mol, l, 7Eq.) Of potassium tert-butoxide are placed in 3 1 of THF and

13.9 g (0.05 mol, 0.016 eq.) Of 18-crown-6-ether added. Then, at RT, a solution of 619 g (3.29 mol, equiv.) Of trifluoromethylacetophenone in 1.5 l of THF and a solution of 672 g (6.58 mol, 2 eq.) Of methyl isobutyrate in 1.5 l of THF simultaneously from 2 dropping funnels added dropwise within 15 min. The mixture is then stirred under reflux for 4 hours. After cooling, at 0 ° C 4 1 10%

Hydrochloric acid is added dropwise, the organic phase is separated and the aqueous phase extracted with 2 1 ethyl acetate. The organic phase is washed with four times with 2 1 NaCl solution, dried over sodium sulfate, concentrated and the residue distilled.

Yield: 618 g (69.8%)

1 H NMR (CDCl ₃ , 300 MHz) δ = 1.2 (d, 6H), 2.6 (s, 1H), 6.2 (s, 1H), 7.7 (m, 2H),

8.0 (m, 2H), 16.1 (s, 1H) ppm.

2. 3-amino-3-isopropyl-1- (4-trifluoromethyl-phenyl) -propenone

617 g (2.39 mol, equiv.) Of the compound from Example 1 and 305.7 g (3.97 mol, 1.66 eq.) Of ammonium acetate are dissolved in ethanol and stirred under reflux for 4 hours. The solution is then concentrated, washed with saturated sodium bicarbonate. washed carbonate solution, dried over sodium sulfate and concentrated. The product is crystallized from cyclohexane.

Yield: 502 g (80.3%) 1 H-NMR (CDCl ₃ , 300 MHz) δ = 1.2 (d, 3H), 2.5 (sept, IH), 5.4 (br.s, IH) , 5.7 (s,

IH), 7.7 (m, 2H), 8.0 (m, 2H), 10.5 (br.s, IH) ppm.

3. 1 -cyclopentyl-3- (4-trifluoromethylphenyl) -propane-1,3-dione

226.8 g (2.02 mol) of potassium tert-butylate, 5.05 g (0.019 mol) of 18-crown-6-ether, 225 g

(1.20 mol) trifluoromethylacetophenone and 305.7 g (2.39 mol) of cyclopentylcarboxylic acid methyl ester are reacted analogously to the procedure of Example 1.

Yield: 256 g (75.3%) 1 H NMR (CDCl ₃ , 200 MHz) δ = 1.5-2.0 (complete Ber, 8H), 2.9 (m, IH), 6.2 ( s, IH),

7.7 (m, 2H), 8.0 8m, 2H), 16.1 (s, 1H) ppm.

4. 3-Amino-3-cyclopentyl-1- (4-trifluoromethyl-phenyl) -propenone

1622.6 g (5.7 mol) of the compound from Example 3 and 730 g (9.48 mmol)

Ammonium acetate are reacted analogously to the procedure of Example 2.

Yield: 1028 g (63%)

1 H-NMR (CDCl ₃ , 200 MHz) δ = 1.7 (m, 6H), 2.1 (m, 2H), 2.7 (m, IH), 5.4 (br.s, IH), 5.8 (s, IH), 7.7 (m, 2H), 8.0 (m, 2H), 10.5 (br.s, IH) ppm.

5. cyclobutyl-dimedone (spiro [3,5] nonane-6,8-dione)

500 ml of 30% NaOMe in methanol are initially charged and diluted with 640 ml of methanol. At about 60 ° C for this purpose 359 g of dimethyl malonate are added and heated for 10 min at reflux. Subsequently, 300 g of cyclobutylidene-2-propanone are added and heated under reflux for 4 hours. For saponification, 336 g of KOH dissolved in 1600 ml of water are added and heated under reflux for 1 hour. The mixture is then acidified with 20% hydrochloric acid and stirred at pH 3 to 5 until the end of the CO ₂ evolution. After distillation of the methanol is stirred cold to room temperature and the precipitated solid is isolated and washed neutral and dried at 55 ° C in a vacuum.

Yield: 412 g, corresponding to 99.4% of theory. Th. (NMR, DMSO, 1.7-1.95 ppm m (6H);

2.4 ppm s (4H), 5.2 ppm s (IH); 11.1 ppm br.s (-OH).

6. 2-Isopropyl-4- (4-fluorophenyl) -7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinolin-5-one

507 mg (1.97 mmol, 1.2 eq.) Of the compound from Example 2 are initially charged in 20 ml of diisopropyl ether and 0.253 ml (3.29 mmol, 2 eq.) Of trifluoroacetic acid and 250 mg (1.64 mmol, 1 eq) of spiro [3.5] nonane-6,8-dione was added. After stirring at room temperature for 10 min, 0.264 ml (2.46 mmol, 1.5 eq) of 4-fluorobenzaldehyde is added and the mixture is refluxed for 18 h. After cooling, the mixture is stirred for 15 min in an ice bath, the precipitate obtained is filtered off with suction and washed with cold diisopropyl ether.

Yield: 640 mg (78.3%)

1H-NMR (CDC1 ₃ , 200 MHz) δ = 1.1 (t, 3H), 1.2 (t, 3H), 1.7 (m, 2H), 1.9 (m, 4H), 2, 4 (d, IH), 2.7 (d, IH), 2.6 (s, 2H), 3.1 (sept, IH), 4.9 (s, IH), 5.8 (s, IH ), 6.8 (m, 2H), 7.0 (m, 2H), 7.6 (m, 4H) ppm.

7. 2-Cyclopentyl-4- (4-fluorophenyl) -7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinolin-5-one

Analogously to the procedure of Example 6, 1.03 g (3.64 mmol) of the compound from

Example 4, 678 mg (5.46 mmol) reacted 4-fluorobenzaldehyde and 834 mg (5.46 mmol) spiro [3.5] nonane-6,8-dione.

Yield: 1.41 g (68%)

1 H NMR (CDCl ₃ , 300 MHz) δ = 1.38 - 2.03 (m, 14 H); 2.43 (d, IH); 2.56 (d, IH); 2.59 (m, 2H); 3.06 (m, IH); 4.96 (s, IH); 5.75 (s, IH); 6.77-6.86 (m, 2H); 6.97 to 7.05

(m, 2H); 7.59-7.69 (m, 4H) ppm.

2-iso-propyl-4-phenyl-7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinoline-5-one

Analogously to the procedure of Example 6, 507 mg (1.97 mmol) of the compound from Example 2, 0.25 ml (2.46 mmol) of benzaldehyde and 250 mg (1.64 mmol, 1 eq.) Spiro [3.5] nonane -6,8-dione implemented.

Yield: 272 mg (34.6%)

LC / MS (B) rt 4.82 min, MS (ES ⁺ ): 480 [M + H]

9. 2-cyclopentyl-4-phenyl-7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinolin-5-one

Analogously to the procedure of Example 6, 558 mg (1.97 mmol) of the compound from Example 4, 0.25 ml (2.46 mmol) of benzaldehyde and 250 mg (1.64 mmol, 1 eq) of spiro [3.5] nonane -6,8-dione implemented.

Crude yield: 193 mg (23%)

LC / MS (A) rt 3.5 min, MS (ESI): 506 [M + Η]

10. 2-Isopropyl-4- (2-thienyl) -7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinolin-5-one

Analogously to the procedure of Example 6, 507 mg (1.97 mmol) of the compound from Example 2, 0.23 ml (2.46 mmol) of 2-thiophenecarbaldehyde and 250 mg (1.64 mmol, 1 eq.) Of spiro [3.5 ] nonane-6,8-dione.

Crude yield: 450 mg (56.4%)

11. 2-Cyclopentyl-4- (3-thienyl) -7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinolin-5-one

Analogously to the procedure of Example 6, 558 mg (1.97 mmol) of the compound from Example 4, 0.22 ml (2.46 mmol) of 3-thiophenecarbaldehyde and 250 mg (1.64 mmol,

1 eq.) Spiro [3.5] nonane-6,8-dione.

Crude yield: 261 mg (31%)

LC / MS (A) rt 3.5 min, MS (ESI): 512 [M + Η]

12. 2-Isopropyl-4- (3-thienyl) -7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinolin-5-one

Analogously to the procedure of Example 6, 568 mg (2.21 mmol) of the compound from Example 2, 0.24 ml (2.76 mmol) of 3-thiophenecarbaldehyde and 280 mg (1.84 mmol, 1 eq.) Of sρiro [3.5 ] nonane-6,8-dione.

Yield: 599 mg (67%)

1H-NMR (CDC1 ₃ , 200 MHz) δ = 1.1 (t, 3H), 1.2 (t, 3H), 1.7 (m, IH), 1.8 (m, 2H), 1, 9 (m, 3H), 2.5 (d, IH), 2.7 (d, IH), 2.6 (s, 2H), 3.2 (sept, IH), 5.1 (s, IH ), 5.9 (s, IH), 6.8 (m, 2H), 7.1 (m, IH), 7.7 (m, 4H) ppm.

13. 2-Cyclopentyl-4- (2-thienyl) -7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinolin-5-one

Analogously to the procedure of Example 6, 558 mg (1.97 mmol) of the compound from Example 4, 276 mg (2.46 mmol) of 2-thiophenecarbaldehyde and 250 mg (1.64 mmol, 1 eq.) Spiro [3.5] nonane -6,8-dione implemented.

Crude yield: 500 mg (60%)

14. 2-Isopropyl-4-cyclohexyl-7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -

4,6,7,8-tetrahydro-lH-quinoline-5-one

Analogously to the procedure of Example 6, 1.038 g (4.04 mmol) of the compound from Example 2, 0.611 ml (5.05 mmol) of cyclohexanecarbaldehyde and 571 mg (3.36 mmol, 1 eq.) Of spiro [3.5] nonane-6 , 8-dion implemented.

Yield: 726 mg (44.4%)

1H-NMR (CDC1 ₃ , 200 MHz) δ = 0.9 (m, 6H), 1.1 (d, 3H), 1.3 (d, 3H), 1.5 (m, 4H), 2, 0 (m, 7H9, 2.5 (d, IH), 2.6 (s, 2H), 2.7 (d, IH), 3.5 (sept, IH), 3.7 (d, IH) , 5.9 (s, IH), 7.7 (m, 2H), 7.8 (m, 2H) ppm.

15. 2-Cyclopentyl-4-cyclohexyl-7-spirocyclobutyl-3 - (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinolin-5-one

Analogously to the procedure of Example 6, 893 mg (3.15 mmol) of the compound from Example 4, 0.48 ml (3.94 mmol) of cyclohexanecarbaldehyde and 398 mg (2.62 mmol, 1 eq) of spiro [3.5] nonane -6,8-dione implemented.

Yield: 350 mg (26%)

1 H-NMR (CDCl ₃ , 200 MΗz) δ = 1.0 (m, 6Η), 1.3 (m, 1H), 1.6 (m, 6H), 1.7 (m, 6H), 1, 9 (m, 6H), 2.2 (m, IH), 2.4 (d, IH), 2.6 (s, 2H), 2.7 (d, IH), 3.7 (d, IH ), 5.9 (s, IH), 7.6 (m, 2H), 7.8 (m, 2H) ppm. 16. 2-Isopropyl-4-cyclo-pentyl-7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinolin-5-one

Analogously to the procedure of Example 6, 1.014 g (3.94 mmol) of the compound from Example 2, 0.689 ml (6.57 mmol) of cyclopentanecarbaldehyde and 499 mg (3.28 mmol, 1 eq.) Of spiro [3.5] nonane-6 , 8-dion implemented.

Yield: 299 mg (19%) 1 H-NMR (CDCl ₃ , 200 MΗz) δ = 0.9 (m, 2Η), 1.1 (t, 3H), 1.3 (t, 3H), 1.3 -1.6 (m,

6H), 2.0 (m, 6H), 2.4 (d, IH), 2.6 (s, 2H), 2.7 (d, IH), 3.5 (sept, IH), 3, 8 (d, IH), 7.6 (m, 2H), 7.8 (m, 2H) ppm.

17. 2,4-Dicyclopentyl-7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinolin-5-one

Analogously to the procedure of Example 6, 1.116 g (3.94 mmol) of the compound from Example 4, 0.689 ml (6.57 mmol) of cyclopentanecarbaldehyde and 499 mg (3.28 mmol, 1 eq.) Of spiro [3.5] nonane-6 , 8-dion implemented.

Crude yield: 300 mg (18.3%) 18. 2-Cyclopentyl-4-cyclobutyl-7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinolin-5-one

Analogously to the procedure of Example 6, 1.116 g (3.94 mmol) of the compound from Example 4, 0.591 ml (6.57 mmol) of cyclobutanecarbaldehyde and 499 mg (3.28 mmol, 1 eq.) Of spiro [3.5] nonane-6 , 8-dion implemented.

Crude yield: 1,11 g (70%)

LC / MS (A) rt 3.6 min, MS (ESI): 484 [M + Η]

19. 2-Cyclopentyl-4-isopropyl-7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinolin-5-one

Analogously to the procedure of Example 6, 1.116 g (3.94 mmol) of the compound from Example 4, 2.369 g (32.85 mmol, 10 equivalents) of 2-methyl-propionaldehyde and 499 mg (3.28 mmol, 1 eq.) Of spiro [ 3.5] nonane-6,8-dione.

Yield: 202.5 mg (13.1%)

LC / MS (A) rt 3.69 min, MS (ESI): 472 [M + Η] 20. 2-Cyclopentyl-4- (1-propyl) -7-sρirocyclobutyl-3- (4-trifluoromethylbenzoyl) -4,6,7,8-tetrahydro-1H-quinolin-5-one

1,116 g (3.94 mmol) of the compound from Example 4, 2.96 ml (32.85 mmol, 10 eq.) Butanal and 499 mg (3.28 mmol, 1 eq.) Are spiro analogously to the procedure of Example 6 [3.5] nonane-6,8-dione.

Yield: 192 mg (12.4%)

LC / MS (A) rt 3.71 min, MS (ESI): 472 [M + Η]

21. 2-Isopropyl-4- (4-fluorophenyl) -7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinolin-5-one

635 mg (1.28 mmol, 1 equiv.) Of the compound from Example 6 are dissolved in 20 ml of dichloromethane and treated with 318.7 mg (1.40 mmol, 1.1 eq.) Of 2,3-dichloro-5,6- dicyano-l, 4-benzoquinone (DDQ) for 1 h at room temperature. The mixture is concentrated on a rotary evaporator and the product is isolated by chromatography (silica gel, elution with cyclohexane / ethyl acetate 20: 1-10: 1).

Yield: 573mg (90.6%) 1 H-NMR (CDCl ₃ , 200 MHz) δ = 1.2 (tr, 6H), 2.0 (m, 6H), 2.7 (s, 2H), 2.8 (sept, IH), 3, 4 (s, 2H), 6.5-7.0 (br, m, 4H), 7.6 (m, 4H) ppm.

22. 2-Cyclopentyl-4- (4-fluorophenyl) -7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinolin-5-one

To a solution of 1.375 g (2.43 mmol) of the compound from Example 7 in dichloromethane (30 ml) at room temperature, 10 g (104 mmol) of manganese dioxide (Merck No. 805958 - active, precipitated, about 90%). After stirring for 1 h at room temperature, it is filtered through kieselguhr and a layer of sea sand and washed thoroughly with dichloromethane. The filtrate is concentrated in vacuo and the residue taken up with a mixture of EE / PE 1: 7 with the addition of dichloromethane and purified by flash chromatography with EE / PE 1: 7 on silica gel. After removal of the solvents, a yellowish white, crystalline solid is isolated.

Yield: 1.05 g (83%) MS (ESI): 522 (M + Η)

1Η NMR (CDCl ₃ , 400 MΗz) δ = 1.5-2.1 (m, 14 Η); 2.72 (s, 2Η); 2.85 (m, IH); 3.37 (s, 2H); 6.55-7.13 (br, m, 4H); 7.55-7.62 (m, 4H) ppm.

23. 2-Isopropyl-4-phenyl-7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinolin-5-one

272 mg (0.57 mmol) from Example 8 are reacted analogously to the instructions of the compound from Example 21.

Yield: 262 mg (96.8%)

1 H NMR (CDCl ₃ , 200 MHz) δ = 1.2 (tr, 6H), 2.0 (m, 6H), 2.7 (s, 2H), 2.8 (sec, IH), 3 , 4 (s, 2H), 6.8-7.2 (br, m, 4H), 7.6 (m, 4H) ppm.

24. 2-Cyclopentyl-4-phenyl-7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinolin-5-one

190 mg (0.38 mmol) from Example 9 are reacted analogously to the instructions of the compound from Example 21.

Yield: 20 mg (10.6%)

1 H NMR (CDCl ₃ , 200 MΗz) δ = 1.8-2.1 (m, 12Η), 2.7 (s, 2H), 2.9 (m, IH), 3.4 (s, 2H ), 6.7-7.1 (br, m, 4H), 7.6 (m, 4H) ppm.

25. 2-Isopropyl-4- (3-thienyl) -7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinolin-5-one

596 mg (1.23 mmol) from Example 12 are reacted analogously to the instructions of the compound from Example 21.

Yield: 553 mg (93.2%)

1 H NMR (CDCl ₃ , 200 MHz) δ = 1.2 (m, 6H), 2.0 (m, 6H), 2.7 (s, 2H), 2.8 (sec, IH), 3 , 4 (s, 2H), 6.6 (m, IH), 6.8 (m, IH), 7.0 (m, IH), 7.6 (m, 4H) ppm.

26. 2-Cyclopentyl-4- (3-thienyl) -7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinolin-5-one

220 mg (0.43 mmol) from Example 11 are reacted analogously to the instructions of the compound from Example 21.

Yield: 180 mg (82, 1%)

1 H NMR (CDCl 3, 200 Mz) δ = 1.8-2.1 (br, m, 12Η), 2.7 (s, 2H), 2.9 (m, IH), 3.3 (s, 2H), 6.6 (m, IH), 6.8 (m, IH), 7.0 (m, IH), 7.6 (m, 4H) ppm.

27. 2-Isopropyl-4- (2-thienyl) -7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinolin-5-one

450 mg (0.93 mmol) from Example 10 are reacted analogously to the instructions of the compound from Example 21.

Yield: 400 mg (89.3%)

1 H NMR (CDCl ₃ , 300 MHz) δ = 1.2 (m, 6H), 2.0 (m, 6H), 2.7 (s, 2H), 2.8 (sec, IH),

3.4 (s, 2H), 6.6 (m, IH), 6.7 (m, IH), 7.1 (m, IH), 7.6 (m, 2H), 7.7 (m , 2H) ppm.

28. 2-Cyclopentyl-4- (2-thienyl) -7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinolin-5-one

500 mg (0.98 mmol) from Example 13 are reacted analogously to the instructions of the compound from Example 21.

Yield 100 mg (20, 1%)

1 H-NMR (CDCl ₃ , 200 MΗz) δ = 1.9-2.1 (m, 12Η), 2.8 (s, 2H), 2.9 (m, 1H), 3.4 (s, 2H ), 6.6 (m, IH), 6.7 (m, IH), 7.1 (m, IH), 7.6 (m, 2H), 7.7 (m, 2H) ppm.

29. 2-Isopropyl-4-cyclohexyl-7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinolin-5-one

417 mg (0.86 mmol) from Example 14 are reacted analogously to the instructions of the compound from Example 21.

Yield: 399 mg (96%)

1 H NMR (CDCl ₃ , 300 MHz) δ = 1.0 (t, 3H), 1.1 (t, 3H), 1.4 (m, IH), 1.5-1.7 (m, 8H ), 1.8 (m, IH), 2.0 (m, 6H), 2.6 (sept, IH), 2.8 (s, 2H), 3.2 (m, IH), 3.3 (s, 2H), 7.7 (m, 2H), 8.0 (m, 2H) ppm.

30. 2-Cyclopentyl-4-cyclohexyl-7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -

7,8-dihydro-6H-quinolin-5-one

320 mg (0.63 mmol) from Example 15 are reacted analogously to the instructions of the compound from Example 21.

Yield: 300 mg (94%)

1 H-NMR (CDCl 3, 200 MΗz) δ = 1.1 (m, 2Η), 1.4-1.6 (m, 10H), 1.8 (m, 6H), 2.0 (m,

6H), 2.6 (m, IH), 2.8 (s, 2H), 3.2 (m, IH), 3.3 (s, 2H), 7.7 (m, 2H), 8, 0 (m, 2H) ppm.

31. 2-Isopropyl-4-cyclopentyl-7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinoline-5-one

295 mg (0.63 mmol) from Example 16 are reacted analogously to the instructions of the compound from Example 21.

Yield: 290 mg (98.6%)

1H NMR (CDC1 ₃ , 300 MHz) δ = 1.1 (t, 3H), 1.2 (t, 3H), 1.4 (m, 3H), 1.7 (m, IH), 1, 8-2.1 (m, 10H), 2.6 (sept, IH), 2.8 (s, 2H), 3.0 (m, IH), 3.3 (s, 2H), 7.7 (m, 2H), 7.9 (m, 2H) ppm.

32. 2,4-Dicyclopentyl-7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinolin-5-one

300 mg (0.60 mmol) from Example 17 are reacted analogously to the instructions of the compound from Example 21.

Yield: 200 mg (97.2%)

LC / MS (A) rt 5.27 min, MS (ESI): 496 [M + Η]

33. 2-Cyclopentyl-4-cyclobutyl-7-sorbicocyclobutyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinolin-5-one

1.1 g (2.27 mmol) from Example 18 are reacted analogously to the instructions of the compound from Example 21.

Yield: 379 mg (35.6%)

1 H NMR (CDCl ₃ , 200 MHz) δ = 1.5 (m, 4H), 1.7-2.0 (m, 15H), 2.2 (m, IH), 2.8 (m, 3H ), 3.2 (s, 2H), 4.0 (pent, IH), 7.7 (m, 2H), 7.9 (m, 2H) ppm.

34. 2-Cyclopentyl-4-isopropyl-7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -7,8-dihydro-6H-quinoline-5-one

198 mg (0.42 mmol) from Example 19 are reacted analogously to the instructions of the compound from Example 21.

Yield: 132 mg (66.9%)

1 H NMR (CDCl 3, 300 MHz) δ = 1.1 (t, 3H), 1.2 (t, 3H), 1.5 (m, 2H), 1.8 (m, 4H), 2.0 (m, 8H), 2.6 (m, IH), 2.8 (s, 2H), 3.2 (s, 2H), 3.4 (m, IH), 7.7 (m, 2H) , 7.9 (m, 2H) ppm.

35. 2-Cyclopentyl-4- (1-propyl) -7-spirocyclobutyl-3- (4-trifluoromethylbenzoyl) -

7,8-dihydro-6H-quinolin-5-one

187 mg (0.40 mmol) from Example 20 are reacted analogously to the instructions of the compound from Example 21.

Yield: 121 mg (65%)

1 H NMR (CDCl ₃ , 300 MHz) δ = 0.8 (t, 3H), 1.3-1.6 (m, 4H), 1.8-2.1 (m, 12H), 2.3

(m, IH), 2.7 (m, IH), 2.8 (s, 2H), 3.2 (m, IH), 3.3 (s, 2H), 7.7 (m, 2H) , 7.9 (m, 2H) ppm.

36. [(5S) -2-Isopropyl-4- (4-fluorophenyl) -5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-3-yl] (4-trifluoromethyl-phenyl) -methanone

25.5 mg (0.17 mmol, 0.15 eq.) Of (1R, 2S) -l-aminoindan-2-ol are initially charged in 10 ml of THF and treated at room temperature with 743.5 mg (4.56 mmol, 4 eq .) Borane-N, N-dimethylaniline complex. After completion of gas evolution is cooled to 0 ° C and 564.8 mg (1.14 mmol, 1 eq.) From Example 21, dissolved in 50 ml of tetrahydrofuran are added. It is allowed to come to room temperature over several hours. After the reaction, the reaction mixture is mixed with 1 ml of methanol, concentrated and the product was isolated by chromatography (silica gel, mobile phase cyclohexane / ethyl acetate mixtures). Yield: quantitative

1 H NMR (CDCl ₃ , 300 MHz) δ = 1.2 (t, 6H), 2.0 (m, 6H), 2.1 (m, IH), 2.3 (m, IH), 2, 8 (sept, IH), 3.0 (d, IH), 3.4 (d, IH), 4.8 (br.s, IH), 6.8 (m, 2H), 7.1 (m , 2H), 7.6 (m, 2H), 7.7 (m, 2H) ppm.

37. [(5S) -2-Cyclopentyl-4- (4-fluorophenyl) -5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydro-clolinolin-3-yl] - (4-trifluoromethyl-phenyl) -methanone

830 mg (1.59 mmol) from Example 22 are prepared analogously to the procedure of

Implementation of Example 36 implemented.

Yield: 783 mg (94%)

1 H-NMR (CDCl ₃ , 400 MHz) δ = 1.33-1.45 (br.s, IH); 1.46-1.6 (m, 2H); 1.7-2.15 (m, 13H); 2.20-2.30 (m, IH); 2.82 (m, IH); 2.97 (d, IH); 3.41 (d, IH); 4.75 (br s, IH); 6.75-7.20 (br, m, 4H); 7.55-7.62 (m, 2H); 7.62-7.70 (m, 2H) ppm.

38. [(5S) -2-Isopropyl-4-phenyl-5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydroquinolin-3-yl] - (4-trifluoromethylphenyl) -methanone

254 mg (0.53 mmol) from Example 23 are reacted analogously to the instructions of the compound from Example 36.

Yield: quantitative

1H NMR (CDC1 ₃ , 300 MHz) δ = 1.2 (t, 6H), 2.0 (m, 6H), 2.1 (m, IH), 2.2 (m, IH), 2, 8 (sept, IH), 3.0 (d, IH), 3.4 (d, IH), 4.9 (br.s., IH), 7.1 (m, 4H), 7.6 ( m, 2H), 7.7 (m, 2H) ppm.

39. [(5S) -2-Cyclopentyl-4-phenyl-5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydroquinolin-3-yl] - (4-trifluoromethyl-phenyl) -methanone

66 mg (0.13 mmol) from Example 24 are reacted analogously to the instructions of the compound from Example 36.

Yield: 62 mg (93.6%)

LC / MS (A) rt 3.68 min, MS (ESI): 506 [M + H]

40. [(5S) -2-Isopropyl-4- (3-thienyl) -5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydroquinolin-3-yl] - (4-trifluoromethylphenyl) - methanone

550 mg (1.14 mmol) from Example 25 are prepared analogously to the instructions of the Bond implemented from Example 36.

Yield: quantitative

1H-NMR (CDC1 ₃ , 300 MHz) δ = 1.2 (m, 6H), 2.0 (m, 6H), 2.1 (m, IH), 2.2 (m, IH), 2, 8 (sept, IH), 3.0 (d, IH), 3.4 (d, IH), 4.9 (br.s, IH), 6.8 (m, IH), 7.1 (m , IH), 7.2 (m, IH), 7.6 (m, 2H), 7.7 (m, 2H) ppm.

41. [(5S) -2-Cyclopentyl-4- (3-thienyl) -5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-3-yl] (4-trifluoromethylphenyl) - methanone

230 mg (0.45 mmol) from Example 26 are reacted analogously to the instructions of the compound from Example 36.

Yield: 200 mg (86.6%)

1 H NMR (CDCl ₃ , 300 MHz) δ = 1.8-2.0 (m, 14H), 2.1 (m, IH), 2.2 (m, IH), 2.9 (m, IH ), 3.0 (d, IH), 3.4 (d, 1H9, 4.9 (br.s, IH), 6.8 (m, IH), 7.0 (m, IH), 7, 1 (m, IH), 7.6 (m, 2H), 7.7 (m, 2H) ppm.

42. [(5S) -2-Isopropyl-4- (2-thienyl) -5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydroquinolin-3-yl] - (4-trifluoromethylphenyl) - methanone

400 mg (0.83 mmol) from Example 27 are reacted analogously to the instructions of the compound from Example 36.

Yield: quantitative

1 H NMR (CDCl ₃ , 300 MHz) δ = 1.2 (m, 6H), 1.7 (br.s, IH), 2.0 (m, 6H), 2.1 (m, IH), 2.2 (m, IH), 2.8 (sec, IH), 3.0 (d, IH), 3.4 (d, IH), 5.0 (br.s, IH), 6.9 (m, 2H), 7.2 (m, IH), 7.6 (m, 2H), 7.7 (m, 2H) ppm.

43. [(5S) -2-Cyclopentyl-4- (2-thienyl) -5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydroquinolin-3-yl] (4-trifluoromethylphenyl) - methanone

100 mg (0.20 mmol) from Example 28 are reacted analogously to the instructions of the compound from Example 36.

Yield: 87 mg (87%)

1 H NMR (CDCl 3, 300 MHz) δ = 1.8-2.0 (m, 14H), 2.1 8m, IH), 2.3 (m, IH), 2.8 (m, IH), 3.0 (d, IH), 3.4 (d, IH), 5.0 (br.s, IH), 6.8 (m, 2H), 7.2 (m, IH), 7.6 (m, 2H), 7.7 (m, 2H) ppm.

44. [(5S) -2-Isopropyl-4-cyclohexyl-5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydroquinolin-3-yl] - (4-trifluoromethyl-phenyl) -methanone

590 mg (1.22 mmol) from Example 29 are reacted analogously to the instructions of the compound from Example 36.

Yield: 526 mg (88.8%)

^! H-NMR (CDC1 _3, 200 MHz) δ = 1.1 (m, 8H), 1.4 (m, IH), 1.5-1.7 (m, 6H), 1.9 (m, 6H ), 2.2 (m, 3H), 2.5 (m, IH), 2.9 (d, IH), 3.2 (br.m, IH), 3.4 (d / d, IH) , 5.2 (br.s, IH), 7.7 (m, 2H), 7.9 (br.s, 2H) ppm.

45. [(5S) -2-Cyclopentyl-4-cyclohexyl-5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydroquinolin-3-yl] - (4-trifluoromethyl-phenyl) -methanone

300 mg (0.59 mmol) from Example 30 are reacted analogously to the instructions of the compound from Example 36.

Yield 280 mg (93%)

₁ H-NMR (DMSO-d ₆ , 200 MHz) δ = 1.0-2.0 (complete, 25H), 2.1 (m, IH), 2.3 (m,

IH), 2.8 (d / d, IH), 3.2 (d, IH), 5.0 (m, IH), 7.9 (br.m, 4H) ppm.

46. [(5S) -2-Isopropyl-4-cyclopentyl-5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydroquinolin-3-yl] (4-trifluoromethylphenyl) -methanone

285 mg (0.61 mmol) from Example 31 are reacted analogously to the instructions of the compound from Example 36.

Yield: 263 mg (92%)

1H-NMR (CDC1 ₃ , 300 MHz) δ = 1.2 (m, 6H), 1.5 (m, 4H), 1.7 (m, 2H), 2.0 (m, 6H), 2, 1 (m, IH), 2, 3 (m, 2H), 2.5 (sept, IH), 2.9 (d, IH), 3.3 (m, IH), 3.5 (d / d , IH), 5.1 (m, IH), 7.7 (m, 2H), 7.9 (m, 2H) ppm.

47. [(5S) -2,4-Dicyclopentyl-5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydro-quinolin-3-yl] - (4-trifluoromethyl-phenyl) -methanone

200 mg (0.4 mmol) from Example 32 are reacted analogously to the instructions of the compound from Example 36.

Yield: 175 mg (87.2%)

1 H NMR (CDCl ₃ , 200 MHz) δ = 1.4-2.1 (complete, 22H), 2.3 (m, 2H), 2.6 (m,

IH), 2.9 (d, IH), 3.3 (m, IH), 3.4 (m, IH), 5.1 (m, IH), 7.7 (m, 2H), 7, 9 (m, 2H) ppm. 48. [(5S) -2-cyclopentyl-4-cyclobutyl-5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-3-yl] (4-trifluoromethylphenyl) -methanone

372 mg (0.77 mmol) from Example 33 are reacted analogously to the instructions of the compound from Example 36.

Yield: quantitative

1H-NMR (CDC1 ₃ , 200 MHz) δ = 1.4 (m, 4H), 1.8 (m, 6H), 2.0 (m, 8H), 2.2 (m, 3H), 2, 2 (m, IH), 2.4 (m, IH), 2.7 (m, IH), 2.9 (d / d, IH), 3.2 (d, IH), 5.1 (i.e. / tr, IH), 7.7 (m, 2H), 8.0 (m, 2H) ppm.

49. [(5S) -2-cyclopentyl-4-isopropyl-5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydroquinolin-3-yl] - (4-trifluoromethylphenyl) -methanone

127 g (0.27 mmol) from Example 34 are reacted analogously to the instructions of the compound from Example 36.

Yield: 90 mg (70.7%)

1H-NMR (CDC1 ₃ , 200 MHz) δ = 1.0 (t, 3H), 1.2 (t, 3H), 1.4 (t, 3H), 1.4 (t, 3H), 1, 5 (m, 2H), 1.8 8m, 6H), 2.0 (m, 6H), 2.3 (m, 2H), 2.6 (m, IH), 2, 9 (d, IH) , 3.4 (d / d, IH), 3.4 (m, IH), 5.1 (m, IH), 7.7 (m, 2H), 8.0 (br.s, 2H) ppm , 50. [(5S) -2-cyclopentyl-4- (1-pyropropyl) -5-hydroxy-7-spirocyclobutyl-5,6,7,8-tetrahydroquinolin-3-yl] (4-trifluoromethylphenyl) - methanone

116 mg (0.25 mmol) from Example 35 are reacted analogously to the instructions of the compound from Example 36.

Yield: quantitative

1H-NMR (CDC1 ₃ , 200 MHz) δ = 0.9 (t, 3H), 1.4 (m, 7H), 1.9 (m, 11H), 2.3 (m, IH), 2, 6 (m, IH), 2.9 (d, IH), 3.4 (d / d, IH), 5.0 (m, IH), 7.7 (m, 2H), 7.9 (m , 2H) ppm.

51. (5S) -2-Isopropyl-4- (4-fluorophenyl) -3 - [(S) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline 5-ol (anti-isomer)

52. (5S) -2-Isopropyl-4- (4-fluorophenyl) -3 - [(R) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline 5-ol (syn isomer)

571 mg (1.15 mmol, 1 eq.) From Example 36 are initially charged in 50 ml of THF at 0 ° C., followed by 1.26 ml (1.26 mmol, 1.1 eq.) Of a one molar solution of Lithium aluminum hydride in THF and the solution is stirred for one hour at 0 ° C and for 18 hours overnight. Then 1 ml of methanol is added, the solution is concentrated by evaporation and chromatographed (silica gel, mobile phase cyclohexane / ethyl acetate mixtures).

Yield: 225mg (39%) anti-isomer 294mg (51%) syn isomer anti-isomer: 1 H NMR (CDCl ₃ , 300 MHz) δ = 0.8 (d, 3H), 1.2 (d, 3H ), 1.4 (d, IH), 2.0 (m, 6H), 2.1 (m, IH), 2.2 (d, IH), 2.3 (m, IH), 2.9 (d, IH), 3.0 (sept., IH), 3.4 (d, IH), 4.6

(t / d, IH), 5.7 (d, IH), 7.1 (m, 3H), 7.3 (m, 3H), 7.5 (m, 2H) ppm. syn isomer:

1 H NMR (CDCl ₃ , 300 MHz) δ = 0.7 (d, 3H), 1.2 (d, 3H), 1.3 (d, IH), 1.9 (m, 6H), 2, 1 (m, IH), 2.2 (d, IH), 2.3 (m, IH), 2.9 (d, IH), 3.0 (sept., IH), 3.4 (d, IH), 4.6 (t / d, IH), 5.7 (d, IH), 7.1 (m, 3H), 7.3 (m, 3H), 7.5 (m, 2H) ppm ,

53. (5S) -2-Isopropyl-4-phenyl-3 - [(S) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-5-ol (anti-isomer)

54. (5S) -2-Isopropyl-4-phenyl-3 - [(R) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -

7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-5-ol (syn isomer)

233 mg (0.49 mmol) from Example 38 are reacted analogously to the instructions of the compound from Example 51/52.

Yield: 61 mg (26%) of anti-isomer 127 mg (54%)) syn-isomer anti-isomer:

1H-NMR (CDC1 ₃ , 300 MHz) δ = 0.8 (d, 3H), 1.2 (d, 3H), 1.5 (d, IH), 2.0 (m, 6H), 2, 1 (m, IH), 2.2 (d, IH), 2.2 (m, IH), 2.9 (d, IH), 3.0 (sept., IH), 3.4 (d, IH), 4.7 (t / d, IH), 5.7 (d, IH), 7.1 (m, IH), 7.3 (m, 6H), 7.5 (m, 2H) ppm , syn isomer:

1H-NMR (CDC1 ₃ , 300 MHz) δ = 0.7 (d, 3H), 1.2 (d, 3H), 1.4 (d, IH), 2.0 (m, 6H), 2, 1 (m, IH), 2.2 (d, IH), 2.2 (m, IH), 2.9 (d, IH), 3.0 (sept., IH), 3.4 (d / d, IH), 4.7 (t / d, IH), 5.7 (d, IH), 7.2 (m, IH), 7.3 (m, 3H), 7.4 (m, 3H ), 7.5 (m, 2H) ppm.

55. (5S) -2-Cyclopentyl-4-phenyl-3 - [(S) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-5-ol ( anti-isomer)

56. (5S) -2-Cyclopentyl-4-phenyl-3 - [(R) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-5-ol ( syn-isomer)

58 mg (0.11 mmol) from Example 39 are reacted analogously to the instructions of the compound from Example 51/52.

Yield: 20 mg (33.5%) of anti-isomer

33 mg (56.7%) syn-isomer anti-isomer:

1 H NMR (CDCl ₃ , 300 MHz) δ = 1.0 (m, IH), 1.3 (m, 2H), 1.5 (d, IH), 1.7 (m, 2H),

1.8 (m, IH), 1.9 (m, 7H), 2.0 (m, IH), 2.1 (d, IH), 2.2 (m, IH), 2.9 (i.e. , IH), 3.1 (m, IH), 3.3 (d, IH), 4.7 (t / d, IH), 5.7 (d, IH), 7.1 (m, IH) , 7.3 (m, 6H), 7.5 (m, 2H) ppm. syn isomer:

1 H NMR (CDCl ₃ , 300 MHz) δ = 0.9 (m, IH), 1.3 (m, 2H), 1.4 (d, IH), 1.6 (m, 2H), 1, 7 (m, IH), 1.9 (m, 7H), 2.0 (m, IH), 2.2 (d, IH), 2.2 (m, IH), 2.9 (d, IH ), 3.2 (m, IH), 3.3 (d, IH), 4.7 (t / d, IH), 5.7 (d, IH), 7.2 (m, IH), 7 , 3 (m, 3H), 7.4 (m, 3H), 7.5 (m, 2H) ppm.

57. (5S) -2-Isopropyl-4- (3-thienyl) -3 - [(S) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline 5-ol (anti-isomer)

58. (5S) -2-isopropyl-4- (3-thienyl) -3 - [(R) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline 5-ol (syn isomer)

546 mg (1.12 mmol) from Example 40 are reacted analogously to the instructions of the compound from Example 51/52.

Yield: 186 mg (33.9%) of anti-isomer (2 rotamers) 309 mg (56.3%) of syn isomer (2 rotamers) anti-isomer

1 H NMR (CDCl ₃ , 200 MHz) δ = 0.7 (d, 3H), 0.8 (d, 3H), 1.2 (d, 3H), 1.2 (d, 3H), 1, 7 (d, IH), 2.0 (m, 6H), 2.1 (m, IH), 2.2 (m, IH), 2.9 (d, IH rotamer 1), 2.9 (i.e. , IH

Rotamer 2), 3.0 (sept, IH rotamer 1), 3.1 (d, IH rotamer 2), 3.3 (d, IH rotamer 1),

3.4 (d, IH rotamer 2), 4.7 (t / d, IH rotamer 1), 4.8 (t / d, IH rotamer 2), 5.7 (d, IH

Rotamer 1), 5.8 (d, IH rotamer 2), 6.8 (m, IH, rotamer 1), 7.1 (m, IH), 7.3 (m, 3H, m, IH rotamer 2) , 7.5 (m, 2H) ppm. syn isomer:

1 H NMR (CDCl ₃ , 200 MHz) δ = 0.7 (d, 3H), 0.7 (d, 3H), 1.2 (d, 3H), 1.2 (d, 3H), 1, 4 (d, IH), 1.6 (d, IH), 2.0 (m, 6H), 2.1 (m, IH), 2.2 (m, IH), 2.9 (d, IH rotamer 1), 2.9 (d, IH rotamer 2), 3, 1 (sept, IH rotamer 1), 3.1 (d, IH rotamer 2), 3.3 (d, IH rotamer 1), 3.4 (d, IH rotamer 2), 4.6 (t / d, IH rotamer 1), 4.7 (t / d, IH rotamer 2), 5.8 (d, IH rotamer 1), 5.8 (d , IH rotamer 2), 6.8 (m, IH, Rotamer 1), 7.0 (m, IH rotamer 1), 7.0 (m, IH rotamer 2), 7.1 (m, IH rotamer 1) , 7.2 (m, 2H, m, IH rotamer 2), 7.4 (m, IH), 7.5 (m, 2H) ppm.

59. (5S) -2-Cyclopentyl-4- (3-thienyl) -3 - [(S) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline 5-ol (anti-isomer)

60. (5S) -2-Cyclopentyl-4- (3-thienyl) -3 - [(R) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline 5-ol (syn isomer)

180 mg (0.35 mmol) from Example 41 are reacted analogously to the instructions of the compound from Example 51/52.

Yield: 47 mg (26.0%) anti-isomer (2 rotamers) 120 mg (66.4%) syn isomer (2 rotamers) anti-isomer Η-NMR (CDC1 _3, 300 MHz) δ = 0.9 (m, IH), 1.3 (m, 2H), 1.5 (d, IH), 1.7 (d, IH),

1.7 (m, 3H), 1.8 (m, 2H), 1.9 (m, 6H), 2.1 (m, IH), 2.2 (m, IH), 3.3 (i.e. , IH rotamer 1), 2.9 (d, IH, rotamer 2), 3.1 (m, IH), 3.3 (d, IH rotamer 1), 3.3 (d, IH rotamer 2), 4 , 6 (t / d, IH rotamer 1), 4.8 (t / d, IH rotamer 2), 5.8 (d, IH rotamer 1), 5.9 (d, IH rotamer 2), 6.8 (m, IH rotamer 1), 7.0 (m, IH rotamer 2), 7, 1 (m, IH rotamer 1), 7.3 (m, 3H), 7.4 (m, IH rotamer 2), 7.5 (m, 2H) ppm. syn isomer: 1 H NMR (CDCl ₃ , 300 MHz) δ = 1.0 (m, IH), 1.3 (m, 2H), 1.4 (d, IH), 1.6 (d, IH), 1, 6 (m, 3H), 1.9 (m, 8H), 2.1 (m, IH), 2.2 (m, IH), 2.9 (d, IH rotamer 1), 2.9 (i.e. , IH, rotamer 2), 3.2 (m, IH), 3.3 (d, IH rotamer 1), 3.3 (d, IH rotamer 2), 4.6 (t / d, IH rotamer 1) , 4.7 (t / d, IH rotamer 2), 5.8 (d, IH rotamer 1), 5.8 (d, IH rotamer 2), 6.9 (m, IH rotamer 1), 7.0 (m, IH rotamer 2), 7, 1 (m, IH rotamer 1), 7.2 (m, IH rotamer 2), 7.3 (m, 2H), 7.4 (m, IH), 7, 5 (m, 2H) ppm.

61. (5S) -2-Iso-propyl-4- (2-thienyl) -3 - [(S) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline 5-ol (anti-isomer)

62. (5S) -2-Isopropyl-4- (2-thienyl) -3 - [(R) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline 5-ol (syn isomer)

380 mg (0.78 mmol) from Example 42 are reacted analogously to the instructions of the compound from Example 51/52.

Yield: 80 mg (21.0%) anti-isomer 250 mg (65.5%) syn isomer anti-isomer: 1 H NMR (CDCl ₃ , 300 MHz) δ = 0.7 (d, 3H), 1 , 2 (d, 3H), 2.0 (m, 6H), 2.2 (m, 2H),

2.9 (d, IH), 3.1 (m, IH), 3.4 (d, IH), 4.9 (br.s, IH), 5.8 (brs, IH), 7 , 1 (m, 2H), 7,4

(m, 3H), 7.6 (m, 2H) ppm. syn isomer:

1 H-NMR (CDCl ₃ , 300 MHz) δ = 0.7 (d, 3H), 1.2 (d, 3H), 2.0 (m, 6H), 2.3 (m, 2H), 2, 9 (d, IH), 3.1 (sept, IH), 3.4 (d, IH), 4.8 (br.s, IH), 5.8 (d, IH), 7.1 (m , 2H), 7,3

(m, 2H), 7.4 (m, IH), 7.6 (m, 2H) ppm. 63. (5S) -2-Cyclopentyl-4- (2-thienyl) -3 - [(S) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline 5-ol (anti-isomer)

64. (5S) -2-Cyclopentyl-4- (2-thienyl) -3 - [(R) -hydroxy- (4-trifluoromethylphenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline 5-ol

80 mg (0.16 mmol) from Example 43 are reacted analogously to the instructions of the compound from Example 51/52.

Yield: 21 mg (26%) anti-isomer 48 mg (59%) syn-isomer anti-isomer:

LC / MS (A) rt 2.72 min, MS (ESI): 514 [M + H] syn isomer:

LC / MS (A) rt 2.82 min, MS (ESI): 514 [M + H]

65. (5S) -2-Isopropyl-4-cyclohexyl-3 - [(S) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydro-quinolin-5-ol ( anti-isomer)

66. (5S) -2-Isopropyl-4-cyclohexyl-3 - [(R) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydro-quinolin-5-ol ( syn-isomer)

345 mg (0.71 mmol) from Example 44 are reacted analogously to the instructions of the compound from Example 51/52.

Yield: 94 mg (27%) of anti-isomer 204 mg (59%) of syn-isomer anti-isomer:

1 H-NMR (CDCl ₃ , 300 MHz) δ = 0.6 (d, 3H), 1.1 (d, 3H), 1.4 (m, 3H); 1.5 (d, IH), 1.9 (m, 13H), 2.2 (m, 3H), 2.8 (d, IH), 2.9 (sept, IH), 3.3 (i.e. , IH), 3.5 (br.m, IH), 5.1 (t / d, IH), 6.6 (br.s, IH), 7.4 (m, 2H), 7.6 ( m, 2H) ppm. syn isomer:

1 H NMR (CDCl ₃ , 300 MHz) δ = 0.6 (d, 3H), 1.1 (d, 3H), 1.2 (m, 2H); 1.5 (m, 2H), 1.9 (m, 13H), 2.2 (m, 3H), 2.8 (d, IH), 2.9 (sept, IH), 3.3 (i.e. , IH), 3.5 (br.m, IH), 5.1 (t / d, IH), 6.7 (br.s, IH), 7.4 (m, 2H), 7.6 ( m, 2H) ppm.

67. (5S) -2-Cyclopentyl-4-cyclohexyl-3 - [(S) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-5-ol ( anti-isomer)

68. (5S) -2-Cyclopentyl-4-cyclohexyl-3 - [(R) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-5-ol ( syn-isomer)

774 mg (0.51 mmol) from Example 45 are reacted analogously to the instructions of the compound from Example 51/52.

Yield: 72 mg (27.6%) of anti-isomer 180 mg (69.0%) of syn-isomer anti-isomer:

1H NMR (CDC1 ₃ , 200 MHz) δ = 0.7 (m, IH), 1.2 (m, 5H), 1.5 (d, IH), 1.9 (m, 18H), 2, 2 (m, 3H), 2.8 (d, IH), 3.0 (m, IH), 3.3 (d, IH), 3.5 (m, IH), 5.1 (m, IH ), 6.7 (br.d, IH), 7.4 (m, 2H), 7.6 (m, 2H) ppm. syn isomer:

1 H-NMR (CDCl ₃ , 300 MHz) δ = 0.6 (m, IH), 1.2 (m, 5H), 1.4 (d, IH), 1.7-2.1 (compl ., 18H), 2.2 (m, 3H), 2.8 (d, IH), 3.0 (m, IH), 3.3 (d / d, IH), 3.5 (m, IH ), 5.1 (m, IH), 6.7 (br.d, IH), 7.4 (m, 2H), 7.6 (m, 2H) ppm.

69. (5S) -2-Isopropyl-4-cyclopentyl-3 - [(S) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-5-ol ( anti-isomer)

70. (5S) -2-Isopropyl-4-cyclopentyl-3 - [(R) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-5-ol ( syn-isomer)

237 mg (0.50 mmol) from Example 46 are reacted analogously to the instructions of the compound from Example 51/52.

Yield: 116 mg (49.0%) anti-isomer 102 mg (42.7%) syn-isomer anti-isomer: 1 H NMR (CDCl ₃ , 200 MHz) δ = 0.7 (d, 3H), 1.1 (d, 3H), 1.5 (d, IH), 1.7 (m, 3H), 1, 9 (m, 10H), 2.1 (m, 2H), 2.2 (d, IH), 2.3 (m, IH), 2.9 (d, IH), 2.9 (sept, IH ), 3.3 (d / d, IH), 3.8 (m, IH), 5.1 (t / d, IH), 6.2 (d, IH), 7.4 (m, 2H) , 7.6 (m, 2H) ppm. syn isomer: 1 H NMR (CDCl ₃ , 300 MHz) δ = 0.7 (d, 3H), 1.1 (d, 3H), 1.5 (d, IH), 1.7 (m, 3H )

1.9 (m, 10H), 2.1 (m, IH), 2.2 (m, 3H), 2.8 (d, IH), 2.9 (m, IH), 3.3 (i.e. / d, IH), 3.8 (m, IH), 5.1 (t / d, IH), 6.2 (d, IH), 7.4 (m, 2H), 7.6 (m, 2H) ppm.

71. (5S) -2,4-Dicyclopentyl-3 - [(S) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-5-ol (anti-) Isomer)

72. (5S) -2,4-dicyclopentyl-3 - [(R) -hydroxy- (4-trifluoromethylphenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-5-ol (syn- Isomer)

154 mg (0.31 mmol) from Example 47 are reacted analogously to the instructions of the compound from Example 51/52.

Yield: 65 mg (41.8%) anti-isomer 46 mg (29.6%) syn-isomer anti-isomer:

1 H NMR (CDCl ₃ , 300 MHz) δ = 0.9 (m, IH), 1.3 (m, 2H), 1.5 (d, IH), 1.7 (m, 9H), 1, 9 (m, 9H), 2.1 (m, 2H), 2.2 (d, IH), 2.3 (m, IH), 2.8 (d, IH), 3.0 (m, IH ), 3.3 (d / d, IH), 3.8 (m, IH), 5.1 (t / d, IH), 6.2 (d, IH), 7.4 (m, 2H) , 7.6 (m, 2H) ppm. syn isomer: 1 H NMR (CDCl ₃ , 300 MHz) δ = 0.9 (m, IH), 1.3 (m, 2H), 1.5 (d, IH), 1.7-2.0

(complete Ber, 18H) 2.1 (m, 2H), 2.3 (m, 4H), 2.8 (d, IH), 3.0 (m, IH), 3.3 (d / d , IH), 3.8 (m, IH), 5.1 (t / d, IH), 6.2 (d, IH), 7.4 (m, 2H), 7.6 (m, 2H) ppm.

73. (5S) -2-Cyclopentyl-4-cyclobutyl-3 - [(S) -hydroxy- (4-trifluoromethylphenyl) methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-5-ol ( anti-isomer)

74. (5S) -2-Cyclopentyl-4-cyclobutyl-3 - [(R) -hydroxy- (4-trifluoromethylphenyl) methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinolm-5-ol ( syn-isomer)

346 mg (0.72 mmol) from Example 48 are reacted analogously to the instructions of the compound from Example 51/52.

Yield: 166 mg (47.9%) anti-isomer 57 mg (16.5%) syn isomer anti-isomer: 1 H NMR (CDCl ₃ , 200 MHz) δ = 0.7 (m, IH), 1 , 2 (m, 2H), 1.5 (d, IH), 1.7 8m, 2H),

1-7-2.1 (complete, 14H), 2.3 (d, IH), 2.5 (m, 3H), 2.9 (d, IH), 3.1 (m, IH ), 3,1 (d,

IH), 4.3 (m, IH), 5.2 (t / d, IH), 6.6 (d, IH), 7.3 8m, 2H), 7.5 (m, 2H) ppm. syn isomer:

LC / MS (A) rt 2.32 min, MS (ESI): 486 [M + H]

75. (5S) -2-Cyclopentyl-4-isopropyl-3 - [(S) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-5-ol ( anti-isomer)

76. (5S) -2-Cyclopentyl-4-isopropyl-3 - [(R) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline-5-ol ( syn-isomer)

83 mg (0.18 mmol) from Example 49 are reacted analogously to the instructions of the compound from Example 51/52.

Yield: 26 mg (30.7%) of anti-isomer 16 mg (18.8%) of syn isomer anti-isomer:

LC / MS (A) rt 2.17 min, MS (ESI): 474 [M + H] syn isomer: LC / MS (A) rt 2.24 min, MS (ESI): 474 [M + H]

77. (5S) -2-Cyclopentyl-4- (1-propyl) -3 - [(S) -hydroxy- (4-trifluoromethylphenyl) methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline 5-ol (anti-isomer)

109 mg (0.23 mmol) from Example 50 are reacted analogously to the instructions of the compound from Example 51/52.

Yield: 56 mg (51.4%) of anti-isomer

1H-NMR (CDC1 ₃ , 200 MHz) δ = 1.0 (m, 4H), 1.2 (m, 4H), 1.5 (m, 4H), 1.9 (m, 10H), 2, 2 (m, 3H), 2.8 (d, IH), 3.1 (m, IH), 3.4 (m, IH), 5.1 (t / d, IH), 6.3 (i.e. , IH), 7.4 (m, 2H), 7.6 (m, 2H) ppm. 78. [(5S) -5-tert-butyldimethylsilanyloxy-2-isopropyl-4- (4-fluorophenyl) -7-spirocyclobutyl-5,6,7,8-tetrahydroquinolin-3-yl] - (4-trifluoromethylphenyl) - methanone

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. For work-up, 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. The combined organic phases are dried over sodium sulfate, filtered and concentrated by evaporation in a vacuum. concentrated. The residue is dissolved in ethyl acetate / petroleum ether and a little dichloromethane and purified by chromatography on silica gel with ethyl acetate / petroleum ether 1:20. 889 mg (99% of theory) of a colorless rigid foam are obtained.

Rf (EE / PE 1: 9) = 0.56 MS (FAB): 638 (M + H)

1H-NMR (300 MHz, CDC13) δ [ppm]: -0.65 (br.s, 3H), -0.07 (s, 3H), 0.71 (s, 9H), 1.41-2.11 (m, 14H), 2.17 ( dd, IH, Jl = 14.1 Hz, J2 = 3.2 Hz), 2.20-2.31 (m, IH), 2.82 (br, m, IH), 3.04 (d, IH, J = 16.4 Hz), 3.45 (d, IH , J = 16.4 Hz), 4.96 (br s, IH), 6.60-

7.20 (br, m, 4H), 7.55 (br, m, 4H).

79. [(5S) -5-tert-butyldimethylsilanyloxy-2-isopropyl-3 [(S) -hydroxy- (4-trifluoromethylphenyl) -methyl] -4- (4-fluorophenyl) -7-spirocyclobutyl-5,6 , 7,8-tetrahydroquinoline

828 mg (1.30 mmol) of silyloxy ketone from Example 78 are initially introduced under argon in toluene (5 ml, pa, dried over molecular sieve) while cooling in an ice bath, and 1.50 g (5.19 mmol) of RedAl are added dropwise. Solution 70% in toluene. The

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. After completion of the gas evolution is treated with ethyl acetate and a mixture of aq. Sodium bicarbonate solution and sat. Saline shaken out. 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. This gives 173 mg (21% of theory) of the epimeric alcohol (syn configuration) as rigid foam and after renewed chromatography 607 mg (73%). i.e., the desired alcohol as a crystalline solid. * Sodium bis (2-methoxyethoxy) aluminum dihydride

anti-isomer: Rf (EE / PE 1: 9) = 0.22

MS (ESI pos): 640 (M + H)

1H-NMR (300 MHz, CDC13) δ [ppm]: -0.53 (s, 3H), -0.05 (s, 3H), 0.77 (s, 9H), 1.09-2.28 (m, 17H), 2.97 (d, IH, J = 16.2 Hz), 3.09 (quint, IH), 3.39 (d, IH, J = 16.2 Hz), 4.77 (t, IH), 5.67 (br d, IH), 6.88-7.08 (m, 3H ), 7.09-7.19 (m, IH), 7.29 (d, 2H), 7.53 (d, 2H).

syn isomer:

Rf (EE / PE 1: 9) = 0.31

MS (ESI pos): 640 (M + H).

80. (5S) -2-cyclopentyl-4- (4-fluorophenyl) -3 - [(S) -hydroxy- (4-trifluoromethyl-phenyl) -methyl] -7-spirocyclobutyl-5,6,7,8-tetrahydroquinoline 5-ol

30 mg (0.05 mmol) from Example 79 are initially charged under argon and added to the TBAF

Solution in THF (0.5 ml). The reaction mixture is stirred overnight at RT. After addition of sat. Sodium bicarbonate solution is extracted three times with EA, the combined org. Dried phases over sodium sulfate and the solvent removed in vacuo. The residue (51 mg) is flash chromatographically Silica gel with EE / CH 1: 4 cleaned. A colorless rigid foam is isolated (23 mg, 94% of theory).

Rf (EE / CH 1: 4) = 0.26

MS (ESI): 526 (M + H)

1 H NMR (300 MHz, CDCl ₃ ) δ = 1.0-2.3 (m, 17 H); 2.14 (m, IH); 2.88 (d, IH); 3.13

(m, IH); 3.35 (d, IH); 4.60 (m, IH); 5.74 (d, IH); 6.97-7.11 (m, 3H); 7.20-7.35 (m, 3H); 7.48-7.56 (m, 2H) ppm.

A. CETP inhibition testing

AI. Extraction of CETP

CETP is recovered from human plasma by differential centrifugation and column chromatography in partially purified form and used for testing. For this purpose, 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).

A2. CETP Fluorine Test

Measurement of the CETP-catalyzed transfer of a fluorescent cholesterol ester between liposomes - modified according to the instructions of Bisgaier et al., J. Lipid Res. 34, 1625 (1993). To prepare the donor liposomes, 1 mg of cholesteryl 4,4-difluoro-5,7-dime- thyl-4-bora-3a, 4a-diaza-s-indacenes-3-dodecanoate (cholesteryl BODIPY ^® FL C _12, Fa. Molecular Probes) with 5.35 mg of triolein and 6.67 mg of phosphatidylcholine in an ultrasound bath with gentle warming in 600 .mu.l of dioxane and this solution is added very slowly under ultrasonication to 63 ml of 50 mM Tris / HCl, 150 mM NaCl,

2 mM EDTA buffer pH 7.3 at RT.

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.).

For testing, a test mix consisting of 1 part of the above buffer, 1 part of donor liposomes and 2 parts of acceptor liposomes are used.

80 μl of test mixture are obtained with 1 - 3 μg of enriched CETP fraction, obtained by hydrophobic chromatography from human plasma, and 2 μl of the examined

Substance in DMSO and incubated for 4 hours at 37 ° C.

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:

A3. Recovery of radioactively labeled HDL

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 μC / μl 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. For this purpose, 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

40 rotor centrifuged. 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.

A4. CETP SPA test

To test for CETP activity, the transfer of ³ H-cholesterol esters of human HD lipoproteins to biotinylated LD lipoproteins is measured.

The reaction is stopped by addition of streptavidin-SPA®beads (Amersham) and the radioactivity transferred determined directly in the liquid scintillation counter.

In the test batch, 10 .mu.l HDL ³ H-cholesterol ester (~ 50,000 cpm) with 10 ul biotin-LDL (Fa. Amersham) in 50 mM Hepes / 0.15 m NaCl / 0.1% bovine serum albumin / 0.05% NaN ₃ pH 7.4 with 10 .mu.l of CETP (1 mg / ml) and 3 .mu.l solution of the substance to be tested (dissolved in 10% DMSO / 1% BSA), incubated for 18 h at 37.degree. Subsequently, 200 μl of the 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 μl buffer, 10 μl CETP at 4 ° C and 10 μl 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.

The following table gives the results for the examples:

Bl. Measurement of ex vivo activity on transgenic hCETP mice

To test for CETP-inhibitory activity, the substances of our own breed transgenic hCETP mice (Dinchuk et al., BBA (1995) 1295-301) are administered orally with the

Gavage administered. To this end, male animals are randomly assigned to groups with the same number of animals, usually n = 3, one day before the start of the experiment. Before the administration of the substance, each mouse is used for the determination of its basal CETP activity in the blood serum by puncture of the retroorbital venous plexus taken (Tl). The animals are then given the test substance by gavage. At certain times after application of the test substance, the animals are bled a second time (T2), usually 1, 3 and 6 hours later Substance application, but if necessary, this can also be done at a different time.

In order to be able to evaluate the inhibitory activity of a substance, 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. In the control animals, 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.

To determine the CETP activity, the cholesteryl ester transport over 4 h is determined. For this purpose, 2 μl of serum are generally used in the test batch, and the test is carried out as described under "CETP fluoride test".

The differences in 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.

B2. Measurement of in vivo efficacy on Syrian golden hamsters

In experiments to determine the oral effect on lipoproteins and triglycerides, Syrian golden hamsters are grown on a factory scale

DMSO dissolved and 0.5% Tylose suspended orally administered by gavage. To determine the CETP activity, blood is withdrawn before the start of the experiment by retro-orbital puncture (about 250 μl). Subsequently, the test substances 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.

By incubation of 4 ° C overnight, the coagulation is completed, then centrifuged for 10 minutes at 6000 x g. In the serum thus obtained, the content of cholesterol and triglycerides is determined by means of modified commercially available enzymatic tests (Ecolin 25 cholesterol 1.14830.0001 Merck Diagnostica, Ecoline 25 triglycerides 1.14856.0001 Merck Diagnostica). Serum is diluted appropriately with saline.

10 μl of serum dilution are mixed with 200 μl of Ecoline 25 reagent in 96-well plates and incubated for 10 minutes at room temperature. Subsequently, the optical density at a wavelength of 490 nm is determined with an automatic disk reader. The triglyceride or cholesterol concentration contained in the samples is determined by means of a parallel measured standard curve.

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.

B3. Measurement of in vivo efficacy on transgenic hCETP 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.

Used abbreviations:

Cy cyclohexane EE ethyl acetate PE petroleum ether THF = tetrahydrofuran

DAST = dimethylaminosulfur trifluoride

PTS = para-toluenesulfonic acid

PDC = pyridinium dichromate

PE / EE = petroleum ether / ethyl acetate

Toi = toluene

The measured LC-MS values were determined by the following methods:

LC-MS Method A LC Parameter Solution A Acetonitrile Solution B 0.3g 30% HC1 1 water Column temperature 50 ° C; Column symmetry C18 2.1 x 150 mm

Gradient: Time [min]% A% B Flow [ml / min] 0 10 90 0.9

3 90 10 1.2

6 90 10 1.2

LC-MS Method B LC-Parameter Solution A acetonitrile 0.1% formic acid solution. B water / 0.1% formic acid column temperature 40 ° C; Column symmetry C18 2.1 x 50 mm

Gradient: Time [min]% A% B Flow [ml / min] 0 10 90 0.5

4 90 10 0.5

6 90 10 0.5

6.1 10 90 1.0

Claims

claims

1. Compounds of the formula (I)

in which

A for a rest

- (CH ₂ ) 2CH ₃ stands and

B for a rest

or stands. and their salts.

2. Compounds according to claim 1, in which A is para-fluorophenyl.

3. Compounds according to claim 1 or 2, in which B is isopropyl.

4. Compounds according to claim 1 to 3 in the anti-isomeric form.

5. Compounds of formula (I) as defined in claims 1 to 4, for the prevention and treatment of diseases.

6. A pharmaceutical composition containing a compound as defined in claims 1 to 4 and inert, non-toxic, pharmaceutically suitable excipients, solvents and / or adjuvants.

7. Use of compounds of the formula (I) or medicaments as defined in claims 1 to 6, for the prevention and treatment of diseases.

8. Use of compounds of formula (I) as defined in claims 1 to 5, for the preparation of medicaments.

9. Use of compounds of the formula (I) or medicaments as defined in claims 1 to 6, for the inhibition of the cholesterol ester transfer protein (CETP) and for the stimulation of reverse cholesterol transport.

10. Use of compounds of the formula (I) or medicaments as in the

Claims 1 to 6 defined for lowering the LDL-cholesterol level in the blood while increasing the HDL-cholesterol level.

11. Use according to claims 7 and 8 for the treatment and prevention of hypolipoproteinemia, dyslipidaemias, hypertriglyceridemias, hyperlipidemias, arteriosclerosis, obesity, strokes and Alzheimer's disease.

12. A method for the prevention and treatment of diseases, characterized in that compounds of the formula (I) or pharmaceuticals, such as in claims 1 to 6, administered and allowed to act on animals.

13. A process for the preparation of compounds of the formula (I) as defined in claim 1, which comprises reacting compounds of the general formula (II)

in which

A and B have the meanings given in claim 1,

first to the compounds of general formula (III)

in which

A and B have the meanings given in claim 1,

oxidized

these in a next step by an asymmetric reduction to the compounds of general formula (IV) in which

A and B have the meanings given in claim 1,

implements,

this then

in which

R is a hydroxy-protecting group, preferably a radical of the formula -SiR ² R ³ R ⁴ ,

wherein

R ² , R ³ and R ^{4 are the} same or different and are Cχ-C4-alkyl,

convicted from this in a subsequent step by diastereoselective reduction, the compounds of general formula (VI)

in which

R, A and B have the meanings given in claim 1,

manufactures

and then splits off the hydroxy protecting group by conventional methods,

or

[B] the compounds of formula (IV) directly reduced.