DE102004061002A1 - New (5'S)-2',4'-dicyclopentyl -3'-9(S)-fluoro(4-(trifluoromethyl) phenyl)methyl)-5',8' -dihydro-6'H-spiro(cyclopropane-1,7'-quinoline)-5'-ol is a cholesterol ester transfer protein inhibitor useful for treating e.g. coronary heart diseases - Google Patents

Abstract

(5'S)-2',4'-Dicyclopentyl-3'-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-quinoline]-5'-ol (I) and its salts, solvates and solvates of the salts are new. (5'S)-2',4'-Dicyclopentyl-3'-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-quinoline]-5'-ol of formula (I) and its salts, solvates and solvates of the salts are new. Independent claims are also included for: (a) the preparation of (I); and (b) a medicament comprising (I) in combination with an inert, non-toxic, pharmaceutically acceptable additives. [Image] ACTIVITY : Cardiant; Vasotropic; Antilipemic; Antiarteriosclerotic; Anorectic; Cerebroprotective; Neuroprotective; Nootropic. MECHANISM OF ACTION : Cholesterol ester transfer protein (CETP) inhibitor. The ability of (I) to inhibit cholesterol ester transfer protein was tested using CETP-fluorescence test in human plasma. The results showed that the median inhibitory concentration of (I) was 80 nM.

Description

Dry Connection and its use

The present application relates to a novel tetrahydroquinoline derivative, a process for its preparation, its use alone or in combinations for the treatment and / or prevention of diseases and its use for the manufacture of medicaments, in particular as an inhibitor of cholesterol ester transfer protein (CETP) Treatment and / or prevention cardiovascular Diseases, in particular hypolipoproteinemias, dyslipidaemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias and Arteriosclerosis.

By Atherosclerosis-related coronary heart disease are among the Major causes of death in modern society. In a variety Studies have shown that low plasma levels of HDL cholesterol is an important risk factor for the development of atherosclerosis [Barter and Rye, Atherosclerosis 121, 1-12 (1996)]. HDL (high density lipoprotein) in addition to LDL (low density lipoprotein) and VLDL (very low density lipoprotein) a class of lipoproteins whose main function is the transport of lipids, such as Example cholesterol, cholesterol esters, triglycerides, fatty acids or phospholipids, is in the blood. High LDL cholesterol levels (> 160 mg / dl) and low HDL cholesterol levels (<40 mg / dl) essential for the development of arteriosclerosis in [ATP III Guidelines, Report of the NCEP Expert Panel]. In addition to coronary heart disease are also peripheral vascular as well as stroke due to unfavorable HDL / LDL ratios promoted in their creation. New methods to increase Consequently, HDL cholesterol in the plasma is a therapeutic agent meaningful enrichment in the prevention and treatment of arteriosclerosis and associated diseases.

Cholesterinester transfer protein (CETP) mediates the exchange of cholesterol esters and triglycerides between the various lipoproteins in the blood [Tall, J. Lipid Res. 34, 1255-74 (1993)]. Of particular importance is the Transfer of cholesterol esters from the HDL to the LDL resulting in a Lowering HDL cholesterol plasma levels leads. The inhibition of CETP should therefore be an increase the plasma level of HDL cholesterol and a lowering in plasma levels of LDL cholesterol and thus to a therapeutically useful Influencing the Lipid Profile in the Plasma [McCarthy, Medicinal Res. Rev. 13, 139-59 (1993); Sitori, Pharmac. Ther. 67, 443-47 (1995); Swenson, J. Biol. Chem. 264, 14318 (1989)].

Tetrahydroquinolines with pharmacological activity are from EP-A-818 448, WO 99/14215, WO 99/15504 and WO 03/028727 known. Substituted tetrahydronaphthalenes with pharmacological Activity from WO 99/14174 known.

task The present invention is the provision of new substances for fighting of diseases, in particular of cardiovascular diseases, which is an improved have therapeutic profile.

sowie ihre Salze, Solvate und Solvate der Salze.The present invention relates to the compound having the systematic name (5'S) -2 ', 4'-dicyclopentyl-3' - {(S) -fluoro [4- (trifluoromethyl) phenyl] methyl} -5 ', 8'-dihydro 6'-H-spiro [cyclopropane-1,7'-quinoline] -5'-ol and Structural Formula (I)

and their salts, solvates and solvates of the salts.

The inventive compound can also be used in other stereoisomeric forms (enantiomers, diastereomers) available. The present invention includes all enantiomers, Diastereomers and their respective mixtures. From such mixtures enantiomers and / or diastereomers can be the stereoisomer isolate uniform components in a known manner. Prefers is the S configuration shown in formula (I) at C-5 'and at C-3'a.

When Salts are physiologically acceptable in the context of the present invention Salts of the compound of the invention prefers. Also included are salts that are suitable for pharmaceutical applications themselves are not suitable, but for example for insulation or cleaning the compound of the invention can be used.

physiological Safe salts of the compound of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic, Sulfuric acid, Phosphoric acid, methane, ethanesulfonic, toluene sulfonic acid, benzenesulfonic, naphthalenedisulfonic, Acetic acid, trifluoroacetic, propionic acid, Lactic acid, Tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and Benzoic acid.

physiological acceptable salts of the compound of the invention also include Salts more usual Bases, such as by way of example and preferably alkali metal salts (e.g. Sodium and potassium salts), alkaline earth salts (e.g., calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atoms, such as by way of example and preferably ethylamine, Diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, Diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, Dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

When Solvates are in the context of the invention, such forms of the compound of the invention designated, which in solid or liquid state by coordination with solvent molecules a complex form. Hydrates are a special form of solvates in which the coordination with water takes place. As solvates are in the frame Hydrate is preferred in the present invention.

It also includes the present invention also prodrugs of the compound of the invention. The term "prodrugs" includes compounds, which may themselves be biologically active or inactive, however only during their residence time in the body to the compound of the invention be implemented (for example, metabolically or hydrolytically).

(C ₁ -C ₄ ) Alkyl in the context of the invention is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

zunächst durch eine asymmetrische Reduktion in die Verbindung der Formel (III)

überführt, diese dann entweder

• [A] durch Einführung einer Hydroxy-Schutzgruppe zu einer Verbindung der Formel (IV)
  
  in welcher PG für eine Hydroxy-Schutzgruppe, vorzugsweise für einen Rest der Formel -SiR¹R²R³ steht, worin R¹, R² und R³ gleich oder verschieden sind und (C₁-C₄)-Alkyl bedeuten, umsetzt und anschließend über eine diastereoselektive Reduktion in eine Verbindung der Formel (V)
  
  in welcher PG die oben angegebene Bedeutung hat, überführt oder in umgekehrter Abfolge der Reaktionssequenz
• [B] zunächst diastereoselektiv zu der Verbindung der Formel (VI)
  
  reduziert und diese dann durch regioselektive Einführung der Hydroxy-Schutzgruppe PG in eine Verbindung der Formel (V) überführt, anschließend die Verbindung der Formel (V) mit Hilfe eines Fluorierungsmittels zu einer Verbindung der Formel (VII)
  
  in welcher PG die oben angegebene Bedeutung hat, umsetzt und dann die Hydroxy-Schutzgruppe PG nach üblichen Methoden unter Erhalt der Verbindung der Formel (I) wieder abspaltet und die Verbindung der Formel (I) gegebenenfalls mit den entsprechenden (i) Lösungsmitteln und/oder (ii) Basen oder Säuren zu ihren Solvaten, Salzen und/oder Solvaten der Salze umsetzt.

The invention further provides a process for the preparation of the compound of the formula (I) according to the invention, which comprises reacting the compound of the formula (II)

first by an asymmetric reduction in the compound of formula (III)

then transferred them either

• [A] by introducing a hydroxy-protecting group into a compound of the formula (IV)
  
  in which PG is a hydroxy-protecting group, preferably a radical of the formula -SiR ¹ R ² R ³ , wherein R ¹ , R ² and R ^{3 are} identical or different and are (C ₁ -C ₄ ) -alkyl and then via a diastereoselective reduction in a compound of formula (V)
  
  in which PG has the meaning given above, transferred or in reverse order of the reaction sequence
• [B] initially diastereoselective to the compound of formula (VI)
  
  and this then by regioselective introduction of the hydroxy-protecting group PG in a verbin compound of formula (V), then the compound of formula (V) with the aid of a fluorinating agent to give a compound of formula (VII)
  
  in which PG has the meaning given above, and then the hydroxy-protecting group PG by customary methods to give the compound of formula (I) again cleaved and the compound of formula (I) optionally with the appropriate (i) solvents and / or (ii) reacting bases or acids to their solvates, salts and / or solvates of the salts.

miteinander in einer 3-Komponenten-Reaktion in Gegenwart einer Protonen- oder Lewis-Säure zu der Verbindung der Formel (XI)

umsetzt und diese dann zu der Verbindung der Formel (II) oxidiert.The compound of the formula (II) can be prepared by reacting the compounds of the formulas (VIII), (IX) and (X)

together in a 3-component reaction in the presence of a protonic or Lewis acid to the compound of formula (XI)

and then oxidized to the compound of formula (II).

The Compounds of the formulas (VIII) and (X) are commercially available, known in the literature or can be found in Analogy to known literature methods are produced (see. WO 99/14215 and WO 03/028727).

The Compound of formula (IX) may be obtained by acid catalyzed Wittig reaction of a cyclopropanone acetal with 1- (triphenylphosphoranylidene) acetone to 1-cyclopropylideneacetone and subsequent reaction with a malonic see Scheme 1, see WO 03/028727 and I. Kortmann, Westermann, Synthesis 1995, 931-933).

Suitable inert solvents for the individual process steps are, for example, ethers, such as diethyls ether, diisopropyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichlorethylene or chlorobenzene. It is also possible to use mixtures of the solvents mentioned.

The Reductions in process steps (II) → (III), (IV) → (V) and (III) → (VI) are generally using reducing agents that are responsible for the reduction of ketones to hydroxy compounds are carried out. For this belong in particular complex aluminum or borohydrides such as Lithium, sodium, potassium, zinc borohydride, lithium aluminum hydride, Diisobutylaluminum hydride (DIBAH), sodium bis (2-methoxyethoxy) -aluminum dihydride, Lithium trialkylborohydrides or lithium trialkoxyaluminum hydrides, or borane complexes such as borane-tetrahydrofuran, borane-dimethylsulfide or borane-N, N-diethylaniline complex.

The asymmetric reduction in process step (II) → (III) takes place in the presence of catalytic amounts (0.01 to 0.3 molar equivalents) of enantiomerically pure (1R, 2S) -1-aminoindan-2-ol as a chiral inductor. When Reducing agent is preferably borane-N, N-diethylaniline complex used. The reaction is generally carried out in one of the ethers listed above or in toluene, preferably in tetrahydrofuran, in a temperature range from -80 ° C to + 50 ° C, preferred from 0 ° C up to + 30 ° C, carried out.

at the reductions (N) → (V) and (III) → (VI) Diisobutylaluminum hydride (DIBAH) is preferred as the reducing agent used. The reactions are generally in one of the above listed Ether or in toluene, preferably in tetrahydrofuran or toluene, in a temperature range from -80 ° C to + 50 ° C, preferably from -60 ° C to + 30 ° C, performed.

When Hydroxy-protecting group in the process steps (III) → (N) or (VI) → (V) is a silyl group such as trimethylsilyl, triethylsilyl, Triisopropylsilyl or tert-butyl-dimethylsilyl, preferred. Especially preferred is tert-butyldimethylsilyl. The introduction of the silyl group takes place generally in one of the abovementioned hydrocarbons, halogenated hydrocarbons, Ether or in dimethylformamide as solvent in the presence of a Base such as triethylamine, N, N-diisopropylethylamine, Pyridine, 2,6-lutidine or 4-N, N-dimethylaminopyridine (DMAP).

in the Process step (III) → (N) tert-Butyldimethylsilyltrifluormethansulfonat is preferred as Silylation reagent used in combination with 2,6-lutidine as the base. The reaction is preferably in dichloromethane or toluene in a Temperature range from -40 ° C to + 40 ° C, preferably from -20 ° C to + 30 ° C, performed.

in the Process step (VI) → (V) tert-butyldimethylsilyl chloride is preferred as the silylating reagent used in combination with triethylamine and DMAP as bases. The Reaction is preferred in dimethylformamide in a temperature range from 0 ° C up to + 100 ° C, preferably from + 20 ° C up to + 80 ° C, carried out.

The Fluorination in process step (VI) → (VII) is generally in one of the hydrocarbons listed above or halogenated hydrocarbons or in acetonitrile, preferably in toluene or dichloromethane, with diethylaminosulfur trifluoride (DAST) or Morpholinoschwefeltrifluorid performed as a fluorinating reagent. The Reaction is generally carried out in a temperature range from -80 ° C to + 40 ° C, preferably from -60 ° C to + 20 ° C.

The Cleavage of a silyl protecting group in process step (VII) → (I) generally with the help of acids, such as hydrochloric acid or trifluoroacetic acid, or with the help of fluorides, such as hydrogen fluoride or tetrabutylammonium fluoride (TBAF). As an inert solvent are the ones listed above Ethers, alcohols such as methanol or ethanol, or mixtures of the above solvent suitable. Preference is given to a cleavage with TBAF in tetrahydrofuran as a solvent. The reaction is generally carried out in a temperature range from -20 ° C to + 60 ° C, preferably from 0 ° C up to + 30 ° C.

The Condensation reaction (VIII) + (IX) + (X) → (XI) is generally in one of the above Ethers, in alcohols such as methanol, ethanol, n-propanol or isopropanol, in acetonitrile or in mixtures of said solvents. Prefers Diisopropyl ether is used.

Suitable proton acids for this process step are generally organic acids, such as, for example, acetic acid, trifluoroacetic acid, oxa acid or para-toluenesulfonic acid, or inorganic acids, such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid. Also suitable are Le Wis acids such as aluminum chloride or zinc chloride. Preference is given to trifluoroacetic acid.

The Reaction generally takes place in a temperature range from 0 ° C to + 120 ° C, preferably from + 20 ° C up to + 80 ° C.

The Oxidation (dehydrogenation) in process step (XI) → (II) generally in one of the halogenated hydrocarbons listed above or optionally in alcohols such as methanol or ethanol, in acetonitrile or carried out in water. Suitable oxidizing agents are, for example, nitric acid, cerium (N) ammonium nitrate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), pyridinium chlorochromate (PCC), osmium tetroxide, manganese dioxide or catalytic dehydrogenation by means of platinum dioxide or palladium on activated carbon. Is preferred oxidation with DDQ in dichloromethane as solvent. The oxidation is generally carried out in a temperature range from -50 ° C to + 100 ° C, preferably from 0 ° C to + 40 ° C.

The individual process steps can at normal, elevated or at a reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.

The Preparation of the compound of the invention can be illustrated by the following synthesis schemes:

Scheme 1

[Abbreviations: tBu = tert-butyl; DAST = dimethylaminosulfur trifluoride; DDQ = 2,3-dichloro-5,6-dicyano ano-l, 4-benzoquinone; DIBAH = diisobutylaluminum hydride; Et = ethyl; Me = methyl; Ph = phenyl; p-TsOH = para-toluenesulfonic acid; TBAF = tetrabutylammonium fluoride; TBDMSOTf = tert-butyldimethylsilyl trifluoromethanesulfonate; TFA = trifluoroacetic acid].

The inventive compound shows an unpredictable, valuable pharmacological activity spectrum. It is therefore suitable for use as a drug for Treatment and / or prophylaxis of diseases in humans and Animals.

The inventive compound open another treatment alternative and provides an asset Pharmacy. Compared to the known and previously used preparations shows the compound of the invention an improved spectrum of action.

she is preferably characterized by high specificity, good compatibility and lower side effects as well as lower toxicity in particular in the cardiovascular area and in the liver area.

One Advantage of the compound of the invention is their high activity in human plasma. Another advantage of the compound of the invention is a reduced interaction potential with metabolizing Enzymes, in particular with the cytochrome P450 enzymes and in particular Dimensions with the cytochrome P450 3A4 enzyme. The compound of the invention also shows a reduced deposition behavior in adipose tissue.

The inventive compound of the formula (I) has valuable pharmacological properties and can be used for the prevention and treatment of diseases. In particular, the compound of the invention is a highly effective Inhibitor of cholesterol ester transfer protein (CETP) and stimulates the reverse Cholesterol transport. It causes an increase in the HDL cholesterol level in blood. The compound of the invention is especially for treatment and for primary or secondary prevention coronary heart disease, e.g. of myocardial infarction, can be used. The compound of the invention can also be used for treatment and prevention used by arteriosclerosis, restenosis, strokes and Alzheimer's disease become. About that In addition, the compound of the invention also for treatment and prevention of hypolipoproteinemias, dyslipidemias, hypertriglyceridemia, hyperlipidemia, hypercholesterolaemia, Obesity (obesity), obesity, pancreatitis, Insulin-dependent and non-insulin-dependent Diabetes, diabetic sequelae, such as retinopathy, nephropathy and neuropathy, of combined hyperlipidemias and the metabolic syndrome.

The pharmacological activity of the compound of the invention can by means of the following CETP inhibition tests are determined.

Another The present invention is the use of the compound of the invention for treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another The present invention is the use of the compound of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another The subject of the present invention is a method of treatment and / or prevention of diseases, in particular the aforementioned diseases; using an effective amount of the compound of the invention.

• • Antidiabetika,
• • antithrombotisch wirkende Substanzen,
• • blutdrucksenkende Substanzen,
• • den Fettstoffwechsel verändernde Substanzen,
• • antientzündlich wirkende Substanzen,
• • den arteriosklerotischen Plaque stabilisierende Substanzen.

Another object of the present invention are pharmaceutical compositions containing the compound of the invention and one or more other active ingredients for the treatment and / or prevention of diseases. As suitable combination active ingredients may be mentioned by way of example and preferably:

• • antidiabetics,
• Antithrombotic substances,
• Hypotensive substances,
• • fat metabolism-altering substances,
• Anti-inflammatory substances,
• • the arteriosclerotic plaque stabilizing substances.

• • Antidiabetika, die in der Roten Liste 2002/II, Kapitel 12 genannt sind,
• • antithrombotisch wirkenden Mitteln, beispielhaft und vorzugsweise aus der Gruppe der Thrombozytenaggregationshemmer oder der Antikoagulantien,
• • den Blutdruck senkenden Wirkstoffen, beispielhaft und vorzugsweise aus der Gruppe der Calcium-Antagonisten, Angiotensin AII-Antagonisten, ACE-Hemmer, beta-Blocker, Phospho diesterase-Inhibitoren, Stimulatoren der löslichen Guanylatcyclase, cGMP-Enhancer sowie der Diuretika, und/oder
• • den Fettstoffwechsel verändernden Wirkstoffen, beispielhaft und vorzugsweise aus der Gruppe der Thyroidrezeptor-Agonisten, der Cholesterinsynthese-Inhibitoren wie HMG-CoA-Reduktase-Inhibitoren, Squalensynthase-Inhibitoren, Squalenepoxidase-Inhibitoren oder Oxidosqualencyclase-Inhibitoren, der ACAT-Inhibitoren, MTP-Inhibitoren, PPAR-Agonisten, Fibrate, Lipase-Inhibitoren, Cholesterinabsorptionshemmer, Gallensäure-Reabsorptionshemmer, polymeren Gallensäureadsorber und der Lipoprotein(a)-Antagonisten

kombiniert werden.The compound of the formula (I) according to the invention may preferably be reacted with one or more

• • antidiabetics mentioned in the Red List 2002 / II, Chapter 12,
• Antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors or anticoagulants,
• Hypertensive agents, for example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, beta-blockers, phosphodiesterase inhibitors, stimulators of soluble guanylate cyclase, cGMP enhancers and diuretics, and / or
• The fat metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors, squalene synthase inhibitors, squalene epoxidase inhibitors or oxidosqualene cyclase inhibitors, the ACAT inhibitors, MTP inhibitors , PPAR agonists, fibrates, lipase inhibitors, cholesterol absorption inhibitors, bile acid reabsorption inhibitors, polymeric bile acid adsorbers and the lipoprotein (a) antagonists

be combined.

Under Antidiabetics are exemplary and preferably insulin and insulin derivatives as well as orally effective hypoglycemic Understood agents.

insulin and insulin derivatives include both insulins animal, human or biotechnological origin as well as mixtures thereof.

The orally effective hypoglycemic Active ingredients include by way of example and preferably sulphonylureas, Biguadine, meglitinide derivatives, oxadiazolidinones, thiazolidinediones, Glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, Insulin sensitizers, inhibitors of liver enzymes involved in stimulation involved in gluconeogenesis and / or glycogenolysis, modulators glucose uptake as well as potassium channel opener, e.g. those, which are disclosed in WO 97/26265 and WO 99/03861.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination administered with insulin.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a sulphonylurea such as by way of example and preferably tolbutamide, Glibenclamide, glimepiride, glipizide or gliclazide.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a biguanide, such as by way of example and preferably metformin, administered.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a meglitinide derivative, as exemplified and preferably Repaglinide or nateglinide.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a PPARgamma agonist, for example, from the class of Thiazolidinediones, as exemplified and preferably pioglitazone or rosiglitazone.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a mixed PPARalpha / gamma agonist as exemplary and preferably GI-262570 (Farglitazar), GW 2331, GW 409544, AVE 8042, AVE 8134, AVE 0847, MK-0767 (KRP-297) or AZ-242.

Under antithrombotic agents are preferably compounds from the group of platelet aggregation inhibitors, as exemplified and preferably aspirin, clopidogrel, ticlopidine or dipyridamole, or anticoagulants.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a thrombin inhibitor, as exemplified and preferably Ximelagatran, melagatran, bivalirudin or Clexane.

In a preferred embodiment of the invention, the compound of formula (I) is administered in combination with a GPIIb / IIIa antagonist, such as by way of example and preferably tirofiban or abciximab enough.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a factor Xa inhibitor, as exemplified and preferably DX 9065a, DPC 906, JTV 803 or BAY 59-7939.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with heparin or a low molecular weight (LMW) heparin derivative administered.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a vitamin K antagonist, as exemplified and preferably Coumarin, administered.

Under Antihypertensive agents are exemplified and preferably Compounds from the group of calcium antagonists, as exemplified and preferably the compounds nifedipine, amlodipine, nitrendipine, Nisoldipine, verapamil or diltiazem, the angiotensin AII antagonist, ACE inhibitors, beta-blockers and diuretics understood.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination administered with an antagonist of alpha 1 receptors.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with reserpine, minoxidil, diazoxide, dihydralazine, hydralazine as well Nitrous oxide releasing substances, such as by way of example and preferably Glycerin nitrate or nitroprusside sodium.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with an angiotensin AII antagonist, as exemplified and preferably Losartan, valsartan, candesartan, telmisartan, embusartan, irbesartan, Olmesartan, tasosartan or saprisartan.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with an ACE inhibitor, such as by way of example and preferably enalapril, Captopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandolapril.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a beta-blocker, such as by way of example and preferably propranolol or atenolol.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a diuretic, such as by way of example and preferably furosemide, administered.

Under changing the fat metabolism Means are exemplified and preferably compounds of the Group of Thyroid Receptor Agonists, Cholesterol Synthesis Inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR agonists, fibrates, Cholesterol absorption inhibitors, bile acid reabsorption inhibitors, lipase inhibitors, polymeric bile acid adsorber as well as the lipoprotein (a) antagonists Understood.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a thyroid receptor agonist, as exemplified and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a squalene synthesis inhibitor, as exemplified and preferably BMS-188494 or TAK 475, administered.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, Eflucimibe or CS-505.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a cholesterol absorption inhibitor, as exemplified and preferably Ezetimibe, Tiqueside or Pamaqueside administered.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a bile acid reabsorption inhibitor, as exemplified and preferably, Barixibat, AZD 7508, SC 435, SC 635, 5-8921, 264W94 or HM 1453.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with an MTP inhibitor, such as by way of example and preferably implitapide, BMS-201038 or R-103757, administered.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a PPARalpha agonist, e.g. the fibrate fenofibrate, Clofibrate, bezafibrate, ciprofibrate or gemfibrozil or as an example and preferably GW 9578, GW 7647, LY-518674 or NS-220.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a PPARdelta agonist, as exemplified and preferably GW 501516 administered.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a mixed PPARalpha / gamma agonist as exemplary and preferably GI-262570 (Farglitazar), GW 2331, GW 409544, AVE 8042, AVE 8134, AVE 0847, MK-0767 (KRP-297) or AZ-242.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a mixed PPARalpha / gamma / delta agonist as exemplified and preferably MCC-555.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a lipase inhibitor from the group of endothelial lipase inhibitors, pancreatic lipase inhibitors, gastric lipase inhibitors, the hormone-sensitive lipase inhibitors or the hepatic lipase inhibitors administered.

at a particularly preferred embodiment The invention relates to the compound of the formula (I) in combination with an inhibitor of pancreatic lipase, preferably from the class of lipstins such as orlistat, for example.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a polymeric bile acid adsorber, as exemplified and preferably cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a lipoprotein (a) antagonist, as exemplified and preferably Gemcabene calcium (CI-1027) or nicotinic acid administered.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with an antagonist of the niacin receptor, as exemplified and preferably Niaspan, Acipimox or Niceritrol.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with an antioxidant, such as by way of example and preferably probucol, AGI 1067 or Bo 653 administered.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with an LDL receptor inducer such as Lifibrol.

at a preferred embodiment The invention relates to the compound of the formula (I) in combination with a HMG-CoA reductase inhibitor from the class of statins, as exemplary and preferably lovastatin, simvastatin, pravastatin, Fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.

Another object of the present invention are combinations of the compound of formula (I) with substances that cause a reduction in HMG-CoA reductase gene expression. Such substances may be, for example, inhibitors of HMG-CoA reductase transcription or HMG-CoA reductase translation. Inhibition of HMG-CoA reductase gene expression can be achieved, for example, by inhibition S1P (site-1) protease or by lowering SREBP (sterol receptor binding protein) levels.

One Another object of the present invention are combinations the compound of formula (I) with substances which are anti-inflammatory and / or act to stabilize the arteriosclerotic plaque. such Substances can For example, drugs from the class of NSAIDs, the PAF-AH antagonists or the chemokine receptor antagonists, such as, for example, IL-8 receptor antagonists or MCP-1 antagonists.

The active compound combinations according to the invention possess valuable pharmacological properties and can be used for Prevention and treatment of diseases can be used.

The active compound combinations according to the invention are especially for treatment and for primary or secondary prevention coronary heart disease, e.g. of myocardial infarction, can be used. You can also for treatment and prevention used by arteriosclerosis, restenosis, strokes and Alzheimer's disease become. About that can out the said drug combinations also for the treatment and prevention of hypolipoproteinemias, dyslipidemias, hypertriglyceridemia, hyperlipidemia, hypercholesterolaemia, Obesity (obesity), obesity, pancreatitis, Insulin-dependent and non-insulin-dependent Diabetes, diabetic sequelae, such as retinopathy, nephropathy and neuropathy, of combined hyperlipidemias and the metabolic syndrome. Also suitable the active compound combinations according to the invention for the treatment of hypertension, heart failure, angina pectoris, ischaemia as well as of inflammatory Diseases.

Another The present invention relates to medicaments containing the Compound of the invention, usually together with one or more inert, non-toxic, pharmaceutical contain suitable excipients, as well as their use to the previously mentioned purposes.

The inventive compound can be systemic and / or local. For this purpose, she can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For this Application routes, the compound of the invention in suitable Administration forms are administered.

For the oral Applicable to the state of the art working, the compound of the invention rapidly and / or modified donating application forms that the inventive compound in crystalline and / or amorphised and / or dissolved form included, e.g. Tablets (non-coated or coated Tablets, for example, with enteric or delayed dissolving or insoluble coatings that control the release of the compound of the invention), in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, Capsules (for example hard or soft gelatine capsules), dragees, Granules, pellets, powders, emulsions, suspensions, aerosols or Solutions.

The Parenteral administration can bypass a resorption step happen (e.g., intravenously, intraarterial, intracardiac, intraspinal or intralumbar) or involving absorption (e.g., 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 or sterile powders.

For the others Application routes are suitable, e.g. Inhalation medicines (i.a. Powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous Suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic Systems (e.g., plasters), milk, pastes, foams, powdered powders, implants or stents.

Prefers are the oral or parenteral administration, especially oral Application.

The compound of the invention can be converted into the mentioned application forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. Such adjuvants include, but are not limited to, excipients (e.g., microcrystalline Cellu bulk, lactose, mannitol), solvents (eg liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecylsulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (eg antioxidants such as ascorbic acid) , Dyes (eg inorganic pigments such as iron oxides) and flavor and / or odoriferous.

in the In general, it has proven to be beneficial in parenteral Application amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight to achieve effective results. For oral administration is the dosage about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.

Nevertheless it may be necessary, if necessary, of the quantities mentioned to deviate, depending on of body weight, Route of administration, individual behavior towards the active substance, type of Preparation and time or interval to which the application he follows. So it can in some cases be sufficient, with less than the aforementioned minimum quantity to get along while in other cases exceeded the mentioned upper limit must become. In case of application of larger quantities it may be recommended be to distribute these in several single doses throughout the day.

The following embodiments explain The invention. The invention is not limited to the examples.

The Percentages in the following tests and examples are provided not stated otherwise, weight percentages; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions each on the volume.

A. Examples

Abbreviations and acronyms:

• CE

  Cholesterinester

  CETP

  Cholesterinester transfer protein

  DAST

  Dimethylaminosulphur

  DCI

  direct chemical Ionization (in MS)

  DDQ

  2,3-dichloro-5,6-dicyano-l, 4-benzoquinone

  de

  diastereomeric

  DMF

  N, N-dimethylformamide

  DMSO

  dimethyl sulfoxide

  d. Th.

  the theory (at yield)

  EDTA

  Ethylenediamine-N, N ', N'-tetraacetic acid

  ee

  enantiomeric excess

  eq.

  Equivalent (s)

  IT I

  Electrospray ionization (in MS)

  H

  Hour (s)

  HDL

  High density lipoprotein

  HPLC

  High pressure, high performance liquid chromatography

  LC / MS

  Liquid chromatography-coupled mass spectroscopy

  LDL

  Low density lipoprotein

  min

  Minute (s)

  MS

  mass spectroscopy

  MTBE

  Methyl tert-butyl ether

  NMR

  Nuclear Magnetic Resonance Spectroscopy

  R _t

  Retention time (at HPLC)

  SPA

  Scintillation Proximity assay

  TBAF

  tetrabutylammonium

  TBDMSOTf

  tert-butyldimethylsilyl trifluoromethanesulfonate

  TFA

  trifluoroacetic

  THF

  tetrahydrofuran

Starting compounds and Intermediate:

Example 1A

1-Cyclopropylidenaceton

274 g (1.57 mol) of [(1-ethoxycyclopropyl) oxy] (trimethyl) silane, 650 g (2.04 mol) of 1- (triphenylphosphoranylidene) acetone and 29.9 g (157 mmol) of para-toluenesulfonic acid monohydrate are dissolved in 1.58 liters of 1,2 -Dichlorobenzene and stirred at 100 ° C for 2.5 hours. Upon heating, the 1- (triphenylphosphoranylidene) acetone goes into solution. The mixture is then cooled to room temperature and the crude product is chromatographed on silica gel (eluent: first petroleum ether, then dichloromethane). The product fractions are concentrated and dried briefly in a high vacuum.
Yield: 78.5 g (46% of theory)
¹ H-NMR (400 MHz, CDCl _3): δ = 6.42 (t, 1H), 2.31 (s, 3H), 1:53 to 1:46 (m, 2H), 1:36 to 1:29 (m, 2H)
MS (DCI, NH _3): m / z = 114 [M + NH _4] ^+.

Example 2A

Spiro [2.5] octane-5,7-dione

37.09 g (687 mmol) of sodium methylate are introduced into 388 ml of methanol and heated to reflux with stirring. 96.2 g (728 mmol) of dimethyl malonate are added, the mixture is stirred at reflux for a further 10 minutes and then cooled to room temperature. Subsequently, 66 g (687 mmol) of 1-cyclopropylideneacetone from Example 1A are added dropwise at room temperature and the mixture is then stirred at reflux for 4 h. After removal of the heating bath, a solution of 84.75 g (1.51 mol) of potassium hydroxide in 264 ml of water is added dropwise rapidly and stirring continued for 1 h at reflux. Then a pH of 1-2 is set with half-concentrated hydrochloric acid (foaming) and stirring is continued for 15 minutes. The methanol is removed at a bath temperature of 55 ° C on a rotary evaporator until a pressure of 60 mbar is reached. The contents of the flask are extracted twice with ethyl acetate, the organic phases are combined, dried and concentrated in vacuo. The resulting oil is dissolved in concentrated dichloromethane and chromatographed on silica gel (eluent: dichloromethane / methanol 95: 5). The product fractions are concentrated and the remaining oil is then stirred in diethyl ether. The resulting solid is filtered off with suction and dried under high vacuum at room temperature. Yield: 37.2 g (39% of theory)
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 3.49 (s, 2H), 2.47 (s, 4H), 0.58 (s, 4H)
MS (DCI, NH _3): m / z = 156 [M + NH _4] ^+.

Example 3A

2 ', 4'-di-cyclopentyl-3' - [4- (trifluoromethyl) benzoyl] -4 ', 8'-dihydro-1'H-spiro [cyclopropane-1,7'-quinoline] -5'(6'H ) -one

9.0 g (31.77 mmol) of 3-amino-3-cyclopentyl-1- (4-trifluoromethylphenyl) propenone (according to WO 03/028727, Example 4) are initially charged in 350 ml of diisopropyl ether and with 4.08 ml (52.95 mmol) of trifluoroacetic acid and 3.66 g (26.47 mmol) of spiro [2.5] octane-5,7-dione (Example 2A). After stirring at room temperature for 10 min, 5.20 g (52.95 mmol) of cyclopentanecarbaldehyde are added and the mixture is subsequently 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: 1.9 g (15% of theory)
¹ H-NMR (400 MHz, CDCl _3): δ = 7.81 (d, 2H), 7.67 (d, 2H), 5.91 (s, 1H), 3.88 (d, 1H), 3:52 (quin, 1H), 2.88 (d, 1H), 2.70 (d, 1H), 2.26-2.14 (m, 1H), 1.94 (dd, 2H), 1.80-1.24 (m, 14H), 1.16-0.88 (m, 2H), 0.62-0.40 (m, 4H)
MS (ESIpos): m / z = 484 [M + H] ⁺ .

Example 4A

2 ', 4'-di-cyclopentyl-3' - [4- (trifluoromethyl) benzoyl] -6'H-spiro [cyclopropane-1,7'-quinoline] -5 '(8' H) -one

4.80 g (9.93 mmol) of the compound from Example 3A are dissolved in 150 ml of dichloromethane and 2.48 g (10.92 mmol) of 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone (DDQ) for 1 h at room temperature touched. The mixture is concentrated on a rotary evaporator and the residue is purified by chromatography (silica gel, mobile phase: cyclohexane / ethyl acetate 20: 1 → 10: 1).
Yield: 2.7 g (56% of theory)
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 7.98 (d, 2H), 7.76 (d, 2H), 3.18-2.97 (m, 3H), 2.72-2.55 (m, 3H), 1.98-1.64 ( m, 10H), 1.60-1.36 (m, 6H), 0.64-0.49 (m, 4H)
MS (DCI): m / z = 482 [M + H] ⁺ .

Example 5A

[(5'S) -2 ', 4'-di-cyclopentyl-5'-hydroxy-5', 8'-dihydro-6'H-spiro [cyclopropane-1,7'-quinoline] -3'-yl] [4- (trifluoromethyl) phenyl] methanone

130 mg (0.84 mmol) (IR, 2S) -1-aminoindan-2-ol are initially charged in 100 ml of THF and at room temperature with 3.66 g (22.43 mmol) of borane-N, N-diethylaniline complex added. After completion of gas evolution is cooled to 0 ° C, and 2.70 g (5.61 mmol) of the compound from Example 4A, dissolved in 150 ml of THF are added. You leave stirring over several Hours to come to room temperature. After the implementation is the reaction mixture with methanol, concentrated and the residue taken up in ethyl acetate. It is twice each with 1 N hydrochloric acid, saturated Sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is over Dried sodium sulfate, filtered and concentrated. The crude product will over column Purified (silica gel, eluent: first cyclohexane, then cyclohexane / ethyl acetate 20: 1).

Yield: 2.8 g (chemical purity: about 83%, enantiomeric excess: 91% ee).

Subsequent chromatographic separation of enantiomers on chiral phase [column: Chiralpak AD, 500 mm × 40 mm; Eluent: isopropanol / isohexane 2.5: 97.5; Flow: 50 ml / min; Temperature: 24 ° C; Detection: 254 nm] yields, starting from 2.65 g of the product obtained above, 2.4 g of the enantiomerically pure title compound:
R _t = 6.78 min [Chiralpak AD, 250 mm × 4.6 mm; Eluent: isopropanol / isohexane 2.5: 97.5; Flow: 1.0 ml / min; Detection: 254 nm]
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.00-7.89 (m, 2H), 7.72 (d, 2H), 5.68-5.59 (m, 1H), 3.36-3.14 (m, 2H), 2.65- 2.50 (m, 2H), 2.34 (d, 1H), 2.20-2.04 (m, 2H), 1.94-1.30 (m, 16H), 0.83-0.73 (m, 1H), 0.72-0.59 (m, 1H) , 0.53-0.41 (m, 2H)
MS (DCI): m / z = 484 [M + H] ⁺ .

Example 6A

((5'S) -5 '- {[tert-butyl (dimethyl) silyl] oxy} -2', 4'-di-cyclopentyl-5 ', 8'-dihydro-6'H-spiro [cyclopropane-1,7' -quinoline] -3'-yl) [4- (trifluoromethyl) phenyl] methanone

Under argon, 2.25 g (4.65 mmol) of the compound from Example 5A and 1.99 g (18.61 mmol) of 2,6-dimethylpyridine are dissolved in 20 ml of absolute toluene and cooled to -20 ° C. At this temperature, a solution of 2.46 g (9.31 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate in 5 ml of absolute toluene added dropwise, then stirred for 15 min at -20 ° C, then warmed to 0 ° C and stirred for 1 h at this temperature. The mixture is mixed with 75 ml of 0.1 N hydrochloric acid and extracted several times with ethyl acetate. The combined organic phases are washed once with a 1: 1 mixture of saturated sodium bicarbonate solution and saturated sodium chloride solution and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel (eluent: first cyclohexane, then cyclohexane / ethyl acetate 15: 1).
Yield: 2.18 g (78% of theory)
¹ H-NMR (300 MHz, CDCl _3): δ = 8.00-7.87 (m, 2H), 7.71 (d, 2H), 5:28 to 5:18 (m, 1 H), 3:38 to 3:11 (m, 1H), 2.96 (d, 1H), 2.80 (d, 1H), 2.65-2.43 (m, 1H), 2.08-1.23 (m, 18H), 0.87 (s, 9H), 0.76-0.58 (m, 2H), 0.46-0.38 (m, 1H), 0.37-0.25 (m, 1H), 0.18 (s, 3H), 0.10 (s, 3H).
MS (ESIpos): m / z = 598 [M + H] ⁺ .

Example 7A

(S) - ((5 'S) -5' - {[tert-butyl (dimethyl) silyl] oxy} -2 ', 4'-di-cyclopentyl-5', 8'-dihydro-6'H-spiro [cyclopropane- 1,7'-quinoline] -3'-yl) [4- (trifluoromethyl) phenyl] methanol

Under Argon 2.10 g (3.51 mmol) of the compound from Example 6A in Submitted to 35 ml of absolute toluene and cooled to -50 ° C. At this temperature Add 17.56 ml (17.56 mmol) of a 1M solution of diisobutylaluminum hydride slowly added dropwise in toluene. It is stirred for 10 min at -50 ° C and then warmed to room temperature within 1 h. The approach is under ice cooling with 20% potassium sodium tartrate solution and mixed several times extracted with ethyl acetate. The combined organic phases become with saturated Sodium chloride solution washed over sodium sulfate dried, filtered and concentrated. There are 2.4 g as a crude product receive.

Subsequent chromatographic Diastereomer separation on chiral phase [column: Chiralpak AD, 500 mm × 40 mm, 20 μm; eluent: Isopropanol / isohexane 2.5: 97.5; Flow: 50 ml / min; Temperature: 24 ° C; detection: 254 nm] gives 1.2 g (56% of theory) of the diastereomerically pure title compound (anti-isomer) and 0.9 g (42% of theory) of the diastereomeric syn isomer.

anti diastereomer:

R _t = 5.25 min [column: Chiralpak AD, 250 mm × 4.6 mm; Eluent: isopropanol / isohexane 2.5: 97.5; Flow: 1.5 ml / min; Detection: 250 nm]
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.58 (d, 2H), 7.41 (d, 2H), 6.23 (br.s, 1H), 5.20 (t, 1H), 3.68-3.55 (m, 1H), 3.08-2.70 (m, 3H), 2.29-2.18 (m, 1H), 2.12-1.94 (m, 2H), 1.90-1.22 (m, 15H), 0.89 (s, 9H), 0.76-0.68 ( m, 1H), 0.62-0.55 (m, 1H), 0.43-0.36 (m, 1H), 0.33-0.25 (m, 1H), 0.13 (s, 3H), 0.11 (s, 3H)
MS (ESIpos): m / z = 600 [M + H] ⁺ .

syn diastereomer:

R _t = 4.36 min [column: Chiralpak AD, 250 mm × 4.6 mm; Eluent: isopropanol / isohexane 2.5: 97.5; Flow: 1.5 ml / min; Detection: 250 nm]
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.56 (d, 2H), 7.34 (d, 2H), 6.23 (br, s, 1H), 5.20 (t, 1H), 3.68-3.55 (m, 1H), 3.13-2.60 (m, 3H), 2.29-2.11 (m, 2H), 2.10-1.98 (m, 1H), 1.90-1.22 (m, 15H), 0.89 (s, 9H), 0.76-0.68 ( m, 1H), 0.62-0.55 (m, 1H), 0.43-0.36 (m, 1H), 0.33-0.25 (m, 1H), 0.13 (s, 3H), 0.11 (s, 3H)
MS (ESIpos): m / z = 600 [M + H] ⁺ .

Example 8A

(5 'S) -5' - {[tert-butyl (dimethyl) silyl] oxy} -2 ', 4'-di-cyclopentyl-3' - {(S) -fluoro [4- (trifluoromethyl) phenyl] methyl} - 5 ', 8'-dihydro-6'H-spiro [cyclopropane-1,7'-quinoline]

Under argon, 500 mg (0.83 mmol) of the compound from Example 7A are dissolved in 10 ml of toluene and cooled to -20 ° C. At this temperature, 0.18 ml (1.38 mmol) of diethylaminosulphur trifluoride are added dropwise. After removing the cooling, stirring is continued for 2 h. The mixture is mixed with water and extracted several times with dichloromethane. The combined organic phases are washed once with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is dried under high vacuum and reacted without further purification. Yield: 485 mg (96% of theory)
¹ H-NMR (400 MHz, CDCl _3): δ = 7.61 (d, 2H), 7:38 (d, 2H), 6.91 (d, 1H), 5.21 (t, 1H), 3.66-3.55 (m, 1H) , 2.97-2.80 (m, 3H), 2.16-2.00 (m, 2H), 1.98-1.60 (m, 12H), 1.50-1.22 (m, 3H), 1.20-1.05 (m, 1H), 0.90 (s , 9H), 0.78-0.70 (m, 1H), 0.63-0.57 (m, 1H), 0.44-0.37 (m, 1H), 0.35-0.28 (m, 1H), 0.13 (s, 1H) , 0.11 (s, 3H)
MS (ESIpos): m / z = 602 [M + H] ⁺ .

Ausführunqgsbeispiele:

example 1

(5'S) -2 ', 4'-di-cyclopentyl-3' - {(S) -fluoro [4- (trifluoromethyl) phenyl] methyl} -5 ', 8'-dihydro-6'H-spiro [cyclopropane-1 , 7'-quinoline] -5'-ol

Under Argon is 475 mg (0.79 mmol) of the compound from Example 8A in 1 ml of THF dissolved, with 3.95 ml (3.95 mmol) of a 1 M TBAF solution in THF and 2 h stirred at room temperature. The mixture is mixed with 50 ml of 0.2 N hydrochloric acid and repeatedly with Extracted ethyl acetate. The combined organic phases become twice with saturated Sodium chloride solution washed over Dried sodium sulfate, filtered and concentrated. The residue will over Silica gel purified by chromatography (eluent: first cyclohexane, then cyclohexane / ethyl acetate 10: 1).

Yield: 293 mg (76% of theory), with a diastereomeric excess of 90%.

The further separation of diastereomer still present in the product by chromatography on a chiral phase [column: KBD 5945, 400 mm × 30 mm, based on the chiral selector poly (N-methacryloyl-L-leucine-tert-butylamide; eluent: MTBE / Isohexane 20:80, flow: 50 ml / min, temperature: 24 ° C, detection: 254 nm] gives 251 mg of the diastereomerically pure title compound:
R _t = 4.67 min [column: KBD 5945, 250 × 4.6 mm; Eluent: MTBE / isohexane 3: 7; Flow: 1.0 ml / min; Detection: 280 nm]
¹ H-NMR (400 MHz, CDCl ₃ ): δ = 7.62 (d, 2H), 7.36 (d, 2H), 6.97 (d, 1H), 5.12 (br.s, 1H), 3.84 (quin, 1H) , 3.24 (dd, 1H), 2.98-2.86 (m, 1H), 2.48 (d, 1H), 2.36 (d, 1H), 2.22-1.52 (m, 14H), 1.49-1.20 (m, 3H), 1.06 -0.90 (m, 1H), 0.80-0.72 (m, 1H), 0.67-0.58 (m, 1H), 0.51-0.40 (m, 2H)
MS (ESIpos): m / z = 488 [M + H] ⁺ .

B. Evaluation of pharmacological effectiveness

BI. CETP Inhibition Testing

B I.1. 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 and 4 ° C. The bottom fraction (d> 1.21 g / ml) is applied to a Sephadex ^® phenyl-Sepharose 4B column (Fa. Pharmacia) eluted with 0.15M NaCl / 0.001 M trisHCl pH 7.4 and then washed with distilled water. The CETP-active fractions are pooled, dialyzed against 50 mM sodium acetate pH 4.5 and applied to a CM-Sepharose ^® column (Pharmacia.) Using a linear gradient (0-1 M NaCl) is then eluted. The pooled CETP fractions are dialysed against 10 mM Tris-HCl pH 7.4 and then further purified by chromatography on a Mono Q ^® column (Fa. Pharmacia).

B-I.2. CETP Fluorescence 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-dimethyl-4-bora-3a, 4a-diaza-s-indacene-3-dodecanoate (cholesteryl BODIPY ^® FL C _12, Fa. Molecular Probes ) with 5.35 mg of triolein and 6.67 mg of phosphatidylcholine in an ultrasonic bath with gentle heating in 600 .mu.l of dioxane and this solution was added very slowly under ultrasonication to 63 ml of 50 mM TrisHCl / 150 mM NaCl / 2 mM EDTA buffer pH 7.3 at room temperature. The suspension is then sonicated under N ₂ atmosphere for 30 min in Branson ultrasonic bath at about 50 watts, the temperature is maintained at about 20 ° C.

The Acceptor liposomes are analogous to 86 mg cholesteryl oleate, 20 mg Triolein and 100 mg phosphatidylcholine, in 1.2 ml dioxane and 114 ml of the above buffer dissolved, in 30 minutes Ultrasound at 50 watts (20 ° C) won.

B-I.2.1. CETP Fluorescence Test with enriched CETP

to Testing is a test mix consisting of 1 part of the above buffer, 1 Part donor liposomes and 2 parts acceptor liposomes used.

50 μl test mix are mixed with 48 μl Enriched CETP fraction (1-3 μg), obtained via hydrophobic chromatography from human plasma, as well as 2 μl a solution the substance to be examined in DMSO and incubated for 4 h at 37 ° C.

The change fluorescence at 485/535 nm is a measure of CE transfer; the inhibition of transfer compared to the control batch without substance determined.

B-I.2.2. CETP Fluorescence Test with human plasma

42 μl (86% v / v) Human plasma (Sigma P9523) is supplemented with 6 μl (12% v / v) donor liposomes as well 1 μl (2% v / v) of a solution the substance to be examined in DMSO and incubated for 24 h at 37 ° C.

The change the fluorescence at 510/520 nm (gap width 2.5 nm) is a measure of the CE transfer; the inhibition of transfer compared to the control batch without substance determined.

B-I.2.3. Ex vivo CETP fluorescence assay

80 μl test mix be with 10 μl Buffer and 2 μl Serum and 4 h at 37 ° C incubated.

The change fluorescence at 485/535 nm is a measure of CE transfer; the inhibition of transfer compared to the control batch without substance determined.

B I.3. Extraction of radioactive marked HDL

50 ml fresh human EDTA plasma is adjusted with NaBr to a density of 1.12 and centrifuged at 4 ° C in 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 × 4 liters of PDB buffer (10 mM TrisHCl pH 7.4, 0.15 mM NaCl, 1 mM EDTA, 0.02% NaN ₃ ). 20 μl of ³ H-cholesterol (Dupont NET-725, 1 μC / μl dissolved in ethanol) are then added per 10 ml of retentate volume and incubated at 37 ° C. under N _{2 for} 72 h.

Of the Approach is then adjusted to density 1.21 with NaBr and Ty 65 rotor centrifuge for 18 hours at 50,000 rpm and 20 ° C. You win the upper phase and purifies the lipoprotein fractions by gradient centrifugation. For this purpose, the isolated, labeled lipoprotein fraction with NaBr set to a density of 1.26. 4 ml each of this solution in centrifuge tubes (SW 40 rotor) with 4 ml of a solution density 1.21 and 4.5 ml of a solution of density 1.063 (Density solutions from PDB buffer and NaBr) and then at 38,000 rpm for 24 h and 20 ° C in SW 40 rotor centrifuge. The density between 1,063 and 1.21 lying, the labeled HDL containing intermediate layer is against 3 × 100 Volume PDB buffer at 4 ° C dialyzed.

The retentate contains radioactively labeled ³ H-CE-HDL, which is used at approximately 5 x 10 6 cmp per ml for testing.

B-I.4. CETP SPA test

To test CETP activity, the transfer of ³ H-cholesterol ester from human HD lipoproteins to biotinylated LD lipoproteins is measured. The reaction is terminated by addition of streptavidin-SPA ^® -Beads (Messrs. Amersham) and the transferred radioactivity is determined directly in a liquid scintillation counter.

In the test batch, 10 .mu.l HDL ³ H-cholesterol ester (ca. 50,000 cpm) with 10 .mu.l of biotin-LDL (Fa. Amersham) in 50 mM Hepes / 0.15M NaCl / 0.1% bovine serum albumin (BSA) /0.05% _NaN3 pH 7.4 with 10 .mu.l of CETP (1 mg / ml) and 3 .mu.l of a solution of the substance to be tested in 10% DMSO / 1% BSA for 18 h at 37 ° C incubated. Subsequently, 200 μl of the SPA-streptavidin bead solution (TRKQ 7005) are added, incubated further for 1 h with shaking and then measured in a 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 called the IC ₅₀ value specified.

B-II.1. Measurement of ex vivo activity on transgenic hCETP mice

to exam on CETP inhibitory activity the substances are transgenic hCETP mice from our own breeding [Dinchuk et al., BBA, 1295-1301 (1995)] were administered orally by gavage. These are male Animals one day before the start of the trial randomized groups with the same Animal number, usually n = 4, assigned. Before the substance application Each mouse is used to determine its basal CETP activity in serum Blood taken by puncture of the retroorbital venous plexus (time T1). Subsequently the test substance is administered to the animals by gavage. At certain times after application of the test substance, the Animals were bled a second time (time T2), usually 16 or 24 h after substance administration; possibly but this can also be done at a different time.

Around the inhibitory activity to be able to evaluate a substance, is for each time, ie 16 or 24 hours, a corresponding control group whose animals use only the formulation agent without substance receive. For the control animals, the two blood samples are taken per animal as in the substance-treated animals to change the CETP activity without inhibitor over determine the corresponding trial period (16 or 24 h) can.

The Blood samples are centrifuged after completion of coagulation and the serum is pipetted off. To determine the CETP activity of the Cholesteryl ester transport over 4 h determined. For this purpose, usually 2 ul serum are used in the test batch; the test becomes as under B-I.2.3. described carried out.

The Differences in cholesteryl ester transport [pM CE / h (T2) - pM CE / h (T1)] are used for each animal is calculated and averaged in the groups. A substance which at one time lowers the cholesteryl ester transport by> 20% considered effective.

B-II.2. Measurement of in vivo activity on Syrian golden hamsters

to Determination of oral effects of CETP inhibitors on serum lipoproteins and triglycerides become 150-200 g of Syrian golden Syrian hamsters from own breed (strain BAY: DSN) used. The animals are pro Cage too Grouped six and two weeks for food and water ad libitum acclimatized.

immediate before the start of the trial and after completion of the substance application blood is taken by retroorbital puncture of the venous plexus, resulting in incubation at room temperature for 30 min and centrifugation for 20 min is obtained at 30,000 g of serum. The substances are dissolved in 20% Solutol / 80% Water dissolved and perorally administered by gavage. The control animals receive identical volumes of solvent without test substance.

The determination of triglycerides, total cholesterol, HDL cholesterol and LDL cholesterol is carried out with the aid of the COBAS INTEGRA 400 plus analyzer (Roche Diagnostics) according to the manufacturer's instructions. From the measured values, the percentage caused by substance treatment is determined for each parameter ale change for each animal is calculated and expressed as mean with standard deviation per group (n = 6 or n = 12). If the effects of the substance are significant compared to the solvent-treated group, the p-value determined by t-test is added (* p ≥ 0.05; ** p ≥ 0.01; *** p ≥ 0.005).

B-II.3. Measurement of in vivo activity on transgenic hCETP mice

to Determination of oral effects on lipoproteins and triglycerides becomes transgenic mice [Dinchuk et al., BBA, 1295-1301 (1995)] test substance by gavage administered. Before the start of the experiment, the mice are bled retro-orbitally, to determine serum cholesterol and triglycerides. The serum will, as above for Hamster by incubation at 4 ° C overnight and subsequent centrifugation won at 6,000 g. After three days, the mice are bled again, to redetermine lipoproteins and triglycerides. The changes the measured parameters are called percentage change across from expressed in baseline.

C. Embodiments for pharmaceutical compositions

The inventive compound can do the following be converted into pharmaceutical preparations:

Tablet:

Composition:

100 mg of the compound of the invention, 50 mg lactose (monohydrate), 50 mg corn starch (native), 10 mg polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The Mixture of compound according to the invention, Lactose and starch is with a 5% solution (m / m) of the PVP in water granulated. The granules will dry after drying mixed with the magnesium stearate for 5 minutes. This mixture will with a usual Pressed tablet press (format of the tablet see above). When Guideline for the compression is used a pressing force of 15 kN.

Orally administrable suspension:

Composition:

1000 of the compound of the invention, 1000 mg of ethanol mg (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water.

one Single dose of 100 mg of the compound of the invention correspond 10 ml oral suspension.

production:

The Rhodigel is suspended in ethanol, the compound of the invention is added to the suspension. While stirring the addition of the water takes place. Until the completion of the swelling of the Rhodigels is stirred for about 6 h.

Orally administrable solution:

Composition:

500 mg of the compound of the invention, 2.5 g polysorbate and 97 g polyethylene glycol 400. A single dose of 100 mg of the compound of the invention correspond to 20 g of oral solution.

production:

The inventive compound is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring process will be up to the full resolution the compound of the invention continued.

iv solution:

The inventive compound becomes in a concentration below the saturation solubility in a physiological acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%) solved. The solution is sterile filtered and placed in sterile and pyrogen-free injection containers bottled.

Claims (11)

Compound of the formula (I)

and their salts, solvates and solvates of the salts. A compound of the formula (I) as defined in claim 1, for treatment and / or prevention of diseases. Use of the compound of formula (I), as in Claim 1, for the manufacture of a medicament for primary and / or secondary prevention of coronary heart disease. Use of the compound of formula (I), as in Claim 1 for the preparation of a medicament for treatment and / or prevention of hypolipoproteinemias, dyslipidemias, Hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, arteriosclerosis, Restenosis, obesity (obesity), obesity, diabetes, Stroke and Alzheimer's Illness. Medicaments containing the compound of the formula (I) as defined in claim 1, in combination with an inert, non-toxic, pharmaceutically acceptable excipient. Medicaments containing the compound of the formula (I) as defined in claim 1, in combination with one or more several other active ingredients selected from the group consisting from antidiabetics, platelet aggregation inhibitors, anticoagulants, Calcium antagonists, angiotensin AII antagonists, ACE inhibitors, beta-blockers, phosphodiesterase inhibitors, stimulators of soluble Guanylate cyclase, cGMP enhancer, Diuretics, thyroid receptor agonists, HMG-CoA reductase inhibitors, Squalene synthase inhibitors, squalene epoxidase inhibitors, oxidosqualene cyclase inhibitors, EIGHT inhibitors, MTP inhibitors, PPAR agonists, fibrates, lipase inhibitors, cholesterol absorption inhibitors, Bile acid reabsorption, polymeric bile acid adsorber and lipoprotein (a) antagonists. Medicament according to claim 5 or 6 to the primary and / or secondary prevention of coronary heart disease. Medicament according to claim 5 or 6 for the treatment and / or prevention of hypolipoproteinemias, dyslipidemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, arteriosclerosis, Restenosis, obesity (obesity), obesity, diabetes, Stroke and Alzheimer's Illness. Method for primary and / or secondary prevention of coronary heart disease in humans and animals by administration an effective amount of the compound of formula (I) as in claim 1 defined, or a medicament, as in any one of claims 5 to 8 defined. Method of treatment and / or prevention of hypolipoproteinemias, dyslipidemias, hypertriglyceridemia, hyperlipidemia, Hypereholesterolämien, Arteriosclerosis, restenosis, obesity (obesity), obesity (Obesity), diabetes, stroke and Alzheimer's disease in Humans and animals by administering an effective amount of A compound of the formula (I) as defined in claim 1 or one Medicament as defined in any one of claims 5 to 8. Process for the preparation of the compound of the formula (I) as defined in claim 1, characterized in that the compound of the formula (II)

first by an asymmetric reduction in the compound of formula (III)

then converting these either [A] by introducing a hydroxy-protecting group to a compound of formula (IV)

in which PG is a hydroxy-protecting group, preferably a radical of the formula -SiR ¹ R ² R ³ , in which R ¹ , R ² and R ^{3 are} identical or different and denote (C ₁ -C ₄ ) -alkyl, followed by a diastereoselective reduction in a compound of formula (V)

in which PG has the abovementioned meaning, or [B] first diastereoselectively converted to the compound of the formula (VI)

then converted by regioselective introduction of the hydroxy-protecting group PG into a compound of the formula (V), then the compound of the formula (V) with the aid of a fluorinating agent to give a compound of the formula (VII)

in which PG has the meaning given above, and then the hydroxy-protecting group PG by customary methods to give the compound of formula (I) again cleaved and the compound of formula (I) optionally with the appropriate (i) solvents and / or (ii) reacting bases or acids to their solvates, salts and / or solvates of the salts.