US20110130445A1 - Substituted 3-phenylpropionic acids and the use thereof - Google Patents

Substituted 3-phenylpropionic acids and the use thereof Download PDF

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Publication number
US20110130445A1
US20110130445A1 US12/914,101 US91410110A US2011130445A1 US 20110130445 A1 US20110130445 A1 US 20110130445A1 US 91410110 A US91410110 A US 91410110A US 2011130445 A1 US2011130445 A1 US 2011130445A1
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Prior art keywords
amino
methyl
trifluoro
mmol
chlorophenyl
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US12/914,101
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Inventor
Thomas Lampe
Michael Hahn
Johannes-Peter Stasch
Karl-Heinz Schlemmer
Frank Wunder
Sherif El Sheikh
Volkhart Min-Jian Li
Eva-Maria Becker
Friederike Stoll
Andreas Knorr
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Bayer Intellectual Property GmbH
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Bayer Schering Pharma AG
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Publication of US20110130445A1 publication Critical patent/US20110130445A1/en
Assigned to BAYER SCHERING PHARMA AKTIENGESELLSCHAFT reassignment BAYER SCHERING PHARMA AKTIENGESELLSCHAFT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SCHLEMMER, KARL-HEINZ, DR., HAHN, MICHAEL, DR., BECKER, EVA-MARIA, DR., LI, VOLKHART MIN-JIAN, DR., EL SHEIKH, SHERIF, DR., LAMPE, THOMAS, DR., STOLL, FRIEDERIKE, DR., WUNDER, FRANK, DR., KNORR, ANDREAS, DR., STASCH, JOHANNES-PETER, DR.
Assigned to BAYER INTELLECTUAL PROPERTY GMBH reassignment BAYER INTELLECTUAL PROPERTY GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BAYER PHARMA AKTIENGESELLSCHAFT
Priority to US14/045,630 priority Critical patent/US9018414B2/en
Abandoned legal-status Critical Current

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Definitions

  • the present application relates to novel 3-phenylpropionic acid derivatives, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular disorders.
  • cyclic guanosine monophosphate cGMP
  • NO nitric oxide
  • GTP guanosine triphosphate
  • the soluble guanylate cyclases consist of two subunits and very probably contain one haem per heterodimer, which is part of the regulatory site. The latter is of central importance for the mechanism of activation. NO is able to bind to the iron atom of haem and thus markedly increase the activity of the enzyme. Haem-free preparations cannot, by contrast, be stimulated by NO. Carbon monoxide (CO) is also able to attach to the central iron atom of haem, but the stimulation by CO is distinctly less than that by NO.
  • CO Carbon monoxide
  • guanylate cyclase plays a crucial part in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, in platelet aggregation and adhesion and in neuronal signal transmission, and in disorders caused by an impairment of the aforementioned processes.
  • the NO/cGMP system may be suppressed, which may lead for example to high blood pressure, platelet activation, increased cellular proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, thromboses, stroke and myocardial infarction.
  • NO- and haem-independent sGC activators with BAY 58-2667 as prototype of this class, have been identified. Common characteristics of these substances are that in combination with NO they only have an additive effect on enzyme activation, and that the activation of the oxidized or haem-free enzyme is markedly higher than that of the haem-containing enzyme [Evgenov et al., ibid.; J. P. Stasch et al., Br. J. Pharmacol. 136 (2002), 773; J. P. Stasch et al., J. Clin. Invest. 116 (2006), 2552].
  • the compounds described in the present invention are now likewise capable of activating the haem-free form of soluble guanylate cyclase. This is also confirmed by the fact that these novel activators firstly have no synergistic action with NO at the haem-containing enzyme and that secondly their action cannot be blocked by the haem-dependent inhibitor of soluble guanylate cyclase, 1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), but is even potentiated by this inhibitor [cf. O. V. Evgenov et al., Nature Rev. Drug Disc. 5 (2006), 755; J. P. Stasch et al., J. Clin. Invest. 116 (2006), 2552].
  • WO 00/64888-A1 EP 1 216 980-A1, EP 1 375 472-A1, EP 1 452 521-A1, US 2005/0187266-A1 and US 2005/0234066-A1 describe various arylalkanecarboxylic acid derivatives as PPAR agonists for the treatment of diabetes, dyslipidemia, arteriosclerosis, obesity and other disorders.
  • EP 1 312 601-A1 and EP 1 431 267-A1 disclose substituted arylalkanecarboxylic acids as PGE 2 receptor antagonists for the treatment of, for example, pain, urological disorders, Alzheimer's disease and cancer.
  • arylalkanecarboxylic acids are claimed in WO 2005/086661-A2 as GPR40 modulators for the treatment of diabetes and dyslipidemias, and WO 2004/099170-A2, WO 2006/050097-A1 and WO 2006/055625-A2 describe phenyl-substituted carboxylic acids as PTP-1B inhibitors for the treatment of diabetes, cancer and neurodegenerative disorders.
  • individual phenylacetamido-substituted phenylalkanecarboxylic acids which, in the form of non-covalent mixtures, improve the provision of active peptide compounds within the body are known from WO 96/12473-A1 and WO 96/30036-A1.
  • oxoheterocyclically substituted carboxylic acid derivatives which act as activators of soluble guanylate cyclase have been disclosed in WO 2009/127338-A1.
  • the present invention provides compounds of the general formula (I)
  • R 7 represents hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl, ethyl, methoxy or trifluoromethoxy,
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts; the compounds, encompassed by formula (I), of the formulae specified below and their salts, solvates and solvates of the salts; and the compounds, encompassed by formula (I), specified below as examples and their salts, solvates and solvates of the salts, where the compounds, encompassed by formula (I), specified below are not already salts, solvates and solvates of the salts.
  • the compounds according to the invention can exist in various stereoisomeric forms, i.e. in the form of configurational isomers or, if appropriate, also as conformational isomers (enantiomers and/or diastereomers, including those in the case of atrop isomers), depending on their structure.
  • the present invention therefore includes the enantiomers and diastereomers and their particular mixtures.
  • the stereoisomerically uniform constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner; chromatographical processes are preferably used for this, in particular HPLC chromatography on an achiral or chiral phase.
  • the present invention includes all the tautomeric forms.
  • Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds according to the invention are also included.
  • Physiologically acceptable salts of the compounds according to the invention also include in particular the salts of conventional bases, such as, by way of example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g.
  • ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropyl-amine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, N-methylpiperidine, arginine, lysine and ethylenediamine.
  • Solvates in the context of the invention are designated as those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present invention.
  • the present invention moreover also includes prodrugs of the compounds according to the invention.
  • prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their dwell time in the body.
  • the present invention comprises in particular hydrolyzable ester derivatives of the carboxylic acids of the formula (I) according to the invention.
  • esters which can be hydrolyzed to the free carboxylic acids, as the compounds that are mainly active biologically, in physiological media, under the conditions of the biological tests described later and in particular in vivo by enzymatic or chemical routes.
  • (C 1 -C 4 )-alkyl esters in which the alkyl group can be straight-chain or branched, are preferred as such esters. Particular preference is given to methyl, ethyl or tert-butyl esters.
  • (C 1 -C 4 )-Alkyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. There may be mentioned by way of example and preferably: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.
  • (C 2 -C 4 )-Alkenyl and (C 2 -C 3 )-Alkenyl in the context of the invention represent a straight-chain or branched alkenyl radical having a double bond and 2 to 4 or, respectively, 2 or 3 carbon atoms. Preference is given to a straight-chain or branched alkenyl radical having 2 or 3 carbon atoms.
  • radicals in the compounds according to the invention are substituted, the radicals can be mono- or polysubstituted, unless specified otherwise. Substitution by one or by two or by three individual or different substituents is preferred. Substitution by one or by two identical or different substituents is particularly preferred.
  • the present invention embraces compounds of the formula (I) in which
  • R 1B and R 2B have the meanings mentioned above, or
  • a further preferred embodiment of the present invention embraces compounds of the formula (I) in which
  • a further particularly preferred embodiment of the present invention embraces compounds of the formula (I) in which
  • a particular embodiment of the present invention embraces compounds of the formula (I) in which
  • a further particular embodiment of the present invention embraces compounds of the formula (I) in which
  • a further particular embodiment of the present invention embraces compounds of the formula (I) in which
  • a further particular embodiment of the present invention embraces compounds of the formula (I) in which
  • a further particular embodiment of the present invention embraces compounds of the formula (I) in which
  • a further particular embodiment of the present invention embraces compounds of the formula (I) in which
  • a further particular embodiment of the present invention embraces compounds of the formula (I) in which
  • a further particular embodiment of the present invention embraces compounds of the formula (I-A)
  • radicals indicated specifically in the respective combinations or preferred combinations of radicals are replaced as desired irrespective of the particular combinations indicated for the radicals also by definitions of radicals of other combinations.
  • Another embodiment of the present invention encompases combinations of two or more of the abovementioned preferred definitions of substituents.
  • the invention furthermore provides a process for preparing the compounds of the formula (I) according to the invention, characterized in that a carboxylic acid of the formula (H)
  • R 5A , R 5B , R 6 and R 7 have the meanings given above are coupled in an inert solvent with the aid of a condensing agent or via the intermediate of the corresponding carbonyl chloride in the presence of a base with an amine of the formula (III)
  • R 1A , R 1B , R 2A , R 2B , R 3 and R 4 have the meanings given above and T 1 represents (C 1 -C 4 )-alkyl or benzyl, to give a carboxamide of the formula (IV)
  • ester radical T 1 is then removed by basic or acidic solvolysis or, if T 1 represents benzyl, also by hydrogenolysis, giving the carboxylic acid of the formula (I), and the compounds of the formula (I) are optionally separated by methods known to the person skilled in the art into their enantiomers and/or diastereomers, and/or optionally reacted with the appropriate (i) solvents and/or (ii) bases to give the solvates, salts and/or solvates of the salts thereof.
  • Inert solvents for the process step (II)+(III) ⁇ (IV) [amide coupling] are, for example, ethers such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, acetonitrile, ethyl acetate, pyridine, dimethyl sulphoxide (DMSO), N,N-dimethylformamide (DMF), N,N′-dimethylpropyleneurea (
  • Suitable condensing agents for this coupling reaction are, for example, carbodiimides such as N,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N,N′-carbonyldiimidazole (CDI), 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or isobutyl chloroformate, 1-chloro-2-methyl-1-dimethyl
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate
  • reaction (II)+(III) ⁇ (IV) is generally carried out in a temperature range of from 0° C. to +60° C., preferably at from +10° C. to +40° C.
  • the coupling with the amine component (III) is carried out in the presence of a customary organic auxiliary base such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine, pyridine, 4-N,N-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo-[4.3.0]non-5-ene (DBN).
  • a customary organic auxiliary base such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine, pyridine, 4-N,N-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo-[4.3.0]non-5-ene (DBN).
  • DBU 1,8
  • the reaction of the amine (III) with the carbonyl chloride is generally carried out in a temperature range of from ⁇ 20° C. to +60° C., preferably in the range from ⁇ 10° C. to +30° C.
  • the carbonyl chlorides may be prepared in a customary manner by treating the carboxylic acid (II) with thionyl chloride or oxalyl chloride.
  • the removal of the ester group T 1 in process step (IV) ⁇ (I) may be carried out by customary methods by treating the ester in inert solvents with acids or bases, where in the latter variant the salt initially formed is converted by treatment with acid into the free carboxylic acid.
  • the ester cleavage is preferably carried out using acids.
  • Benzyl esters are preferably cleaved by hydrogenolysis (hydrogenation) in the presence of a suitable catalyst, such as, for example, palladium on activated carbon.
  • Suitable inert solvents for these reactions are water or the organic solvents customary for ester cleavage. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane, dimethylformamide or dimethyl sulphoxide. It is also possible to use mixtures of the solvents mentioned.
  • Suitable bases are the customary inorganic bases. These include in particular alkali metal or alkaline earth metal hydroxides such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate or calcium carbonate. Preference is given to lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • Suitable acids for the ester cleavage are, in general, sulphuric acid, hydrogen chloride/hydrochloric acid, hydrogen bromide/hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulphonic acid, methanesulphonic acid or trifluoromethanesulphonic acid or mixtures thereof, if appropriate with addition of water.
  • the ester cleavage is generally carried out in a temperature range of from ⁇ 20° C. to +100° C., preferably at from 0° C. to +60° C.
  • the intermediates of the formula (H) can be prepared, for example, by initially deprotonating a carboxylic ester of the formula (V)
  • R 5A and R 5B have the meanings given above and T 2 represents (C 1 -C 4 )-alkyl or benzyl, in an inert solvent with the aid of a base, then arylating it in the presence of a suitable palladium catalyst with a phenyl bromide of the formula (VI)
  • R 5A , R 5B , R 6 , R 7 and T 2 have the meanings given above, and subsequently removing the ester radical T 2 by basic or acidic solvolysis or, in the case that T 2 represents benzyl, also by hydrogenolysis, giving the carboxylic acid (II).
  • the arylation reaction in process step (V)+(VI) ⁇ (VII) is preferably carried out in toluene or toluene/tetrahydrofuran mixtures in a temperature range of from +20° C. to +100° C.
  • the base used for deprotonating the ester (V) is preferably lithium bis(trimethylsilyl)amide.
  • Suitable palladium catalysts are, for example, palladium(II) acetate or tris(dibenzylideneacetone)di-palladium, in each case in combination with an electron-rich, sterically demanding phosphine ligand such as 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl or 2-di-tert-butylphosphino-2′-(N,N-dimethylamino)biphenyl [cf., for example, W. A. Moradi, S. L. Buchwald, J. Am. Chem. Soc. 123, 7996-8002 (2001)].
  • phosphine ligand such as 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl or 2-di-tert-butylphosphino-2′-(N,N-dimethylamino)
  • the removal of the ester group T 2 in process setp (VII) ⁇ (II) may be carried out in a manner analogous to that described above for the ester radical T 1 .
  • R 6 and R 7 have the meanings given above, can also be prepared by initially converting a phenylacetic ester of the formula (VIII)
  • Suitable for deprotonating the phosphonic ester (X) in the olefination reaction (X)+(XI) ⁇ (XII) are in particular non-nucleophilic strong bases such as, for example, sodium hydride or potassium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(tri-methylsilyl)amide or lithium diisopropylamide; preference is given to using sodium hydride.
  • the hydrogenation in the process step (XII) ⁇ (III-A) or (XIX) ⁇ (III-C) is generally carried out under a stationary hydrogen atmosphere at atmospheric pressure.
  • the catalyst used is preferably palladium on activated carbon (as support).
  • a preferred palladium catalyst for the reaction (XVII)+(XVIII) ⁇ (XIX) [Heck reaction] is palladium(II) acetate in combination with a phosphine ligand such as, for example, triphenyl- or tri-2-tolylphosphine [for the reaction (XIII)+(XIV) ⁇ (XVI), cf., for example, N. Miyaura et al., Organometallics 16, 4229 (1997) and also T. Hayashi, Synlett , Special Issue 2001, 879-887; for the reaction (XIII)+(XV) ⁇ (XVI), cf., for example, P. Knochel et al., Tetrahedron 56, 2727-2731 (2000), Angew. Chem. 120, 6907-6911 (2008)].
  • a phosphine ligand such as, for example, triphenyl- or tri-2-tolylphosphine
  • non-nucleophilic strong bases such as, for example, sodium hydride or potassium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide; here, preference is given to using lithium diisopropylamide.
  • process steps described above can be carried out at atmospheric pressure, at elevated pressure or at reduced pressure (for example in the range of from 0.5 to 5 bar); in general, they are in each case carried out at atmospheric pressure.
  • Separation of the compounds according to the invention into the corresponding enantiomers and/or diastereomers can take place where appropriate, depending on expediency, even at the stage of the compounds (II), (III), (IV), (VII), (XVI), (XXII) or (XXIII), which are then reacted further in separated form in accordance with the above-described process sequences.
  • Such a separation of the stereoisomers can be carried out by conventional methods known to the person skilled in the art. Preference is given to using chromatographic methods on achiral or chiral separation phases; in the case of carboxylic acids as intermediates or end products, separation may alternatively also be via diastereomeric salts.
  • the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of disorders in humans and animals.
  • the compounds according to the invention are potent activators of soluble guanylate cyclase. They lead to vasorelaxation, inhibition of platelet aggregation and lowering of blood pressure and increase of coronary blood flow. These effects are mediated by direct haem-independent activation of soluble guanylate cyclase and an increase of intracellular cGMP.
  • the compounds according to the invention have good pharmacokinetic properties, in particular with respect to their bioavailability and their half-life in the body.
  • the compounds according to the invention can therefore be employed in medicaments for the treatment and/or prevention of cardiovascular disorders such as, for example, of high blood pressure (hypertension) and heart failure, stable and unstable angina pectoris, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), renal hypertension, peripheral and cardiac vascular disorders, and also of arrhythmias, for the treatment of thromboembolic disorders and ischemias such as myocardial infarction, stroke, transitory and ischemic attacks and also disturbances of peripheral blood flow, prevention of restenoses as after thrombolysis therapies, percutaneous transluminal angioplasties (PTAs), percutaneous transluminal coronary angioplasties (PTCAs) and bypass, for the treatment of arteriosclerosis, for promoting wound healing and for the treatment of osteoporosis, glaucoma and gastroparesis.
  • cardiovascular disorders such as, for example, of high blood pressure (hypertension) and heart failure, stable and unstable angina pectoris, pulmonary arterial
  • heart failure includes both acute and chronic manifestations of heart failure, as well as more specific or related types of disease, such as acute decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary valve insufficiency, combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, and also diastolic and systolic heart failure.
  • myocardial inflammation myocarditis
  • the compounds according to the invention can additionally be used for the treatment and/or prevention of primary and secondary Raynaud's phenomenon, of microcirculation impairments, claudication, tinnitus, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers on the extremities, Crest syndrome, erythematosis, onchomycosis and rheumatic disorders.
  • the compounds according to the invention can be used for preventing ischemia- and/or reperfusion-related damage to organs or tissues and also as additives for perfusion and preservation solutions of organs, organ parts, tissues or tissue parts of human or animal origin, in particular for surgical interventions or in the field of transplantation medicine.
  • kidney diseases in particular of renal insufficiency and kidney failure.
  • renal insufficiency and kidney failure comprise both acute and chronic manifestations thereof, as well as underlying or related kidney diseases such as renal hyperfusion, intradialytic hypertension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic diseases such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as kidney graft rejection and immunocomplex-induced kidney diseases, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome,
  • the present invention also comprises the use of the compounds according to the invention for the treatment and/or prevention of sequelae of renal insufficiency, for example hypertension, pulmonary oedema, heart failure, uremia, anaemia, electrolyte disturbances (for example hypercalemia, hyponatremia) and disturbances in bone and carbohydrate mechanism.
  • sequelae of renal insufficiency for example hypertension, pulmonary oedema, heart failure, uremia, anaemia, electrolyte disturbances (for example hypercalemia, hyponatremia) and disturbances in bone and carbohydrate mechanism.
  • the compounds according to the invention are suitable for the treatment and/or prevention of disorders of the urogenital system such as, for example, hyperactive bladder, disturbance of micturition, lower urinary tract syndrome (LUTS), incontinence, benign prostate hyperplasia (BPH), erectile dysfunction and female sexual dysfunction.
  • disorders of the urogenital system such as, for example, hyperactive bladder, disturbance of micturition, lower urinary tract syndrome (LUTS), incontinence, benign prostate hyperplasia (BPH), erectile dysfunction and female sexual dysfunction.
  • the compounds according to the invention can furthermore be used for the treatment of asthmatic disorders, chronic obstructive pulmonary disorders (COPD) and respiratory distress syndromes.
  • COPD chronic obstructive pulmonary disorders
  • the compounds described in the present invention also represent active compounds for controlling central nervous system diseases characterized by disturbances of the NO/cGMP system. They are suitable in particular for improving perception, concentration, learning or memory after cognitive impairments like those occurring in particular in association with situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory loss, vascular dementia, craniocerebral trauma, stroke, dementia occurring after strokes (post-stroke dementia), post-traumatic craniocerebral trauma, general concentration impairments, concentration impairments in children with learning and memory problems, Alzheimer's disease, Lewy body dementia, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis. They are also suitable for the
  • the compounds according to the invention are furthermore also suitable for controlling cerebral blood flow and thus represent effective agents for controlling migraine. They are also suitable for the prophylaxis and control of the sequelae of cerebral infarctions (Apoplexia cerebri) such as stroke, cerebral ischemias and craniocerebral trauma.
  • the compounds according to the invention can likewise be employed for controlling states of pain.
  • the compounds according to the invention have antiinflammatory action and can therefore be used as antiinflammatory agents for the treatment and/or prevention of sepsis, multiple organ failure, inflammatory disorders of the kidney, chronic intestinal inflammations such as Colitis ulcerosa and Crohn's disease, pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin diseases and inflammatory eye diseases.
  • the compounds according to the invention are particularly suitable for the treatment and/or prevention of cardiovascular disorders such as heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, disturbances of microcirculation, thromboembolic disorders and arteriosclerosis.
  • cardiovascular disorders such as heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, disturbances of microcirculation, thromboembolic disorders and arteriosclerosis.
  • the present invention further relates to the use of the compounds according to the invention for the treatment and/or prevention of disorders, especially of the aforementioned disorders.
  • the present invention further relates to the use of the compounds according to the invention for producing a medicament for the treatment and/or prevention of disorders, especially of the aforementioned disorders.
  • the present invention further relates to the use of the compounds according to the invention in a method for the treatment and/or prevention of disorders, especially of the aforementioned disorders.
  • the present invention further relates to a method for the treatment and/or prevention of disorders, especially of the aforementioned disorders, by using an effective amount of at least one of the compounds according to the invention.
  • the compounds according to the invention can be employed alone or, if required, in combination with other active compounds.
  • the present invention further relates to medicaments comprising at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and/or prevention of the aforementioned disorders.
  • suitable combination active compounds which may be preferably mentioned are:
  • Agents having antithrombotic activity preferably mean compounds from the group of platelet aggregation inhibitors, of anticoagulants or of profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor such as, for example and preferably, aspirin, clopidogrel, ticlopidin or dipyridamole.
  • a platelet aggregation inhibitor such as, for example and preferably, aspirin, clopidogrel, ticlopidin or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor such as, for example and preferably, ximelagatran, melagatran, bivalirudin or clexane.
  • a thrombin inhibitor such as, for example and preferably, ximelagatran, melagatran, bivalirudin or clexane.
  • the compounds according to the invention are administered in combination with a GPIIb/IIIa antagonist such as, for example and preferably, tirofiban or abciximab.
  • the compounds according to the invention are administered in combination with a factor Xa inhibitor such as, for example and preferably, rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as, for example and preferably, rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • the compounds according to the invention are administered in combination with heparin or with a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist such as, for example and preferably, coumarin.
  • the compounds according to the invention are administered in combination with a calcium antagonist such as, for example and preferably, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, for example and preferably, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an alpha-1-receptor blocker such as, for example and preferably, prazosin.
  • the compounds according to the invention are administered in combination with a beta-receptor blocker such as, for example and preferably, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
  • a beta-receptor blocker such as, for example and preferably, propranolol, atenolol, timolol,
  • the compounds according to the invention are administered in combination with an angiotensin AII antagonist such as, for example and preferably, losartan, candesartan, valsartan, telmisartan or embursatan.
  • angiotensin AII antagonist such as, for example and preferably, losartan, candesartan, valsartan, telmisartan or embursatan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor such as, for example and preferably, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as, for example and preferably, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist such as, for example and preferably, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, for example and preferably, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds according to the invention are administered in combination with a renin inhibitor such as, for example and preferably, aliskiren, SPP-600 or SPP-800.
  • a renin inhibitor such as, for example and preferably, aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist such as, for example and preferably, spironolactone or eplerenone.
  • a mineralocorticoid receptor antagonist such as, for example and preferably, spironolactone or eplerenone.
  • Agents which modify lipid metabolism preferably mean compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, of ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and of lipoprotein (a) antagonists.
  • cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR-alpha PPAR-gamma and/or PPAR-delta agonists
  • cholesterol absorption inhibitors polymeric bile acid a
  • the compounds according to the invention are administered in combination with a CETP inhibitor such as, for example and preferably, torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • a CETP inhibitor such as, for example and preferably, torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).
  • the compounds according to the invention are administered in combination with a thyroid receptor agonist such as, for example and preferably, D-thyroxine, 3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist such as, for example and preferably, D-thyroxine, 3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor such as, for example and preferably, BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as, for example and preferably, BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or ITT-130.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or ITT-130.
  • the compounds according to the invention are administered in combination with a PPAR-gamma agonist such as, for example and preferably, pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist such as, for example and preferably, pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR-delta agonist such as, for example and preferably, GW 501516 or BAY 68-5042.
  • a PPAR-delta agonist such as, for example and preferably, GW 501516 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor such as, for example and preferably, orlistat.
  • the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent such as, for example and preferably, cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.
  • a polymeric bile acid adsorbent such as, for example and preferably, cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.
  • the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist such as, for example and preferably, gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, for example and preferably, gemcabene calcium (CI-1027) or nicotinic acid.
  • the present invention further relates to medicaments which comprise at least one compound according to the invention, normally together with one or more inert, non-toxic, pharmaceutically suitable excipients, and to the use thereof for the aforementioned purposes.
  • the compounds according to the invention can act systemically and/or locally.
  • they can be administered in a suitable way such as, for example, by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic routes or as implant or stent.
  • the compounds according to the invention can be administered in administration forms suitable for these administration routes.
  • Suitable for oral administration are administration forms which function according to the prior art and deliver the compounds according to the invention rapidly and/or in modified fashion, and which contain the compounds according to the invention in crystalline and/or amorphized and/or dissolved form, such as, for example, tablets (uncoated or coated tablets, for example having enteric coatings or coatings which are insoluble or dissolve with a delay and control the release of the compound according to the invention), tablets which disintegrate rapidly in the mouth, or films/wafers, films/lyophilisates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets, for example having enteric coatings or coatings which are insoluble or dissolve with a delay and control the release of the compound according to the invention
  • tablets which disintegrate rapidly in the mouth or films/wafers, films/lyophilisates
  • capsules for example hard or soft gelatin capsules
  • Parenteral administration can take place with avoidance of an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with inclusion of an absorption (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • Administration forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Suitable for the other administration routes are, for example, pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops, solutions or sprays; tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, preparations for the ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, dusting powders, implants or stents.
  • pharmaceutical forms for inhalation inter alia powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • tablets for lingual, sublingual or buccal administration films/wafers or capsules, suppositories, preparations for the ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems
  • the compounds according to the invention can be converted into the stated administration forms. This can take place in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants such as, for example, ascorbic acid), colorants (e.g. inorganic pigments such as, for example, iron oxides) and masking flavours and/or odours.
  • carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents e.g. liquid polyethylene glycols
  • Instrument Micromass GCT, GC 6890; Column: Restek RTX-35, 15 m ⁇ 200 ⁇ m ⁇ 0.33 ⁇ m; constant helium flow: 0.88 ml/min; Oven: 70° C.; inlet: 250° C.; gradient: 70° C., 30° C./min ⁇ 310° C. (maintain for 3 min)
  • MS instrument type Micromass ZQ
  • HPLC instrument type HP 1100 Series
  • UV DAD Column: Phenomenex Gemini 3 ⁇ 30 mm ⁇ 3.00 mm
  • mobile phase A 1 l of water+0.5 ml of 50% strength formic acid
  • mobile phase B 1 l of acetonitrile+0.5 ml of 50% strength formic acid
  • flow rate 0.0 min 1 ml/min ⁇ 2.5 min/3.0 min/4.5 min 2 ml/min
  • UV detection 210 nm.
  • MS instrument type Micromass ZQ
  • HPLC instrument type Waters Alliance 2795
  • mobile phase A 1 l of water+0.5 ml of 50% strength formic acid
  • mobile phase B 1 l of acetonitrile+0.5 ml of 50% strength formic acid
  • flow rate 2 ml/min
  • UV detection 210 nm.
  • Instrument Micromass Quattro Premier with Waters HPLC Acquity; Column: Thermo Hypersil GOLD 1.9 ⁇ 50 mm ⁇ 1 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A ⁇ 0.1 min 90% A ⁇ 1.5 min 10% A ⁇ 2.2 min 10% A; flow rate: 0.33 ml/min; oven:50° C.; UV detection: 210 nm.
  • MS instrument type Waters Micromass Quattro Micro
  • HPLC instrument type Agilent 1100 Serie
  • mobile phase A 1 l of water+0.5 ml of 50% strength formic acid
  • mobile phase B 1 l of acetonitrile+0.5 ml of 50% strength formic acid
  • oven 50° C.
  • flow rate 2 ml/min
  • UV detection 210 nm.
  • MS instrument type Waters ZQ; HPLC instrument type: Agilent 1100 Series; UV DAD; Column: Thermo Hypersil GOLD 3 ⁇ 20 mm ⁇ 4 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 100% A ⁇ 3.0 min 10% A ⁇ 4.0 min 10% A ⁇ 4.1 min 100% A (Flow rate 2.5 ml/min); oven: 55° C.; flow rate: 2 ml/min; UV detection: 210 nm.
  • Instrument Micromass GCT, GC 6890; Column: Restek RTX-35, 15 m ⁇ 200 ⁇ m ⁇ 0.33 ⁇ m; constant helium flow: 0.88 ml/min; oven: 70° C.; inlet: 250° C.; gradient: 70° C., 30° C./min ⁇ 310° C. (maintain for 12 min)
  • Instrument Micromass Quattro Premier with Waters HPLC Acquity; Column: Thermo Hypersil GOLD 1.9 ⁇ 50 mm ⁇ 1 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A ⁇ 0.3 min 90% A ⁇ 3.0 min 10% A ⁇ 4.8 min 10% A; flow rate: 0.33 ml/min; oven: 50° C.; UV detection: 210 nm.
  • Instrument Thermo DFS, Trace GC Ultra; Column: Restek RTX-35, 15 m ⁇ 200 ⁇ m ⁇ 0.33 ⁇ m; constant helium flow: 1.20 ml/min; Oven: 60° C.; Inlet: 220° C.; Gradient: 60° C., 30° C./min ⁇ 300° C. (maintain for 3.33 min).
  • Solution A obtained above was cooled to ⁇ 40° C.
  • Solution B was then slowly added dropwise.
  • the combined solutions were slowly warmed to ⁇ 20° C. and stirred at this temperature for 1 h.
  • 50 ml of an ice-cold semi-saturated ammonium chloride solution were then added to the reaction mixture.
  • the phases were separated, the aqueous phase was then extracted three more times with ethyl acetate and the combined organic phases were dried over magnesium sulphate and concentrated to dryness.
  • the crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 2.1 g (5.2 mmol, 39% of theory) of the title compound.
  • racematee obtained above was separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 ⁇ m, 250 mm ⁇ 20 mm; injection volume: 0.15 ml; temperature: 30° C.; mobile phase: 90% isohexane/10% ethanol; flow rate: 15 ml/min; detection: 220 nm]. 7.25 g of racematee gave 3.43 g of enantiomer 1 (Example 22A) and 3.35 g of enantiomer 2 (Example 23A):
  • racematee obtained above was separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 ⁇ m, 250 mm ⁇ 20 mm; injection volume: 0.15 ml; temperature: 35° C.; mobile phase: 50% isohexane/50% isopropanol; flow rate: 15 ml/min; detection: 220 nm]. 10.3 g of racematee gave 4.0 g of enantiomer 1 (Example 26A) and 3.7 g of enantiomer 2 (Example 27A):
  • racematee obtained above was separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 ⁇ m, 250 mm ⁇ 20 mm; injection volume: 0.43 ml; temperature: 30° C.; mobile phase: ethanol; flow rate: 15 ml/min; detection: 220 nm].
  • 3.22 g of racematee gave 1.22 g of enantiomer 1 (Example 30A) and 1.27 g of enantiomer 2 (Example 31A):
  • racematee obtained above was separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 ⁇ m, 250 mm ⁇ 20 mm; injection volume: 0.15 ml; temperature: 30° C.; mobile phase: 90% isohexane/10% ethanol; flow rate: 15 ml/min; detection: 220 nm].
  • 5.0 g of racematee gave 2.1 g of enantiomer 1 (Example 34A) and 1.8 g of enantiomer 2 (Example 35A):
  • racematee obtained above was separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 ⁇ m, 250 mm ⁇ 20 mm; injection volume: 0.15 ml; temperature: 35° C.; mobile phase: 65% isohexane/35% ethanol; flow rate: 15 ml/min; detection: 220 nm].
  • 6.0 g of racematee gave 2.44 g of enantiomer 1 (Example 38A) and 1.92 g of enantiomer 2 (Example 39A):
  • Example 45A and Example 46A are Example 45A and Example 46A.
  • reaction solution was then cooled to ⁇ 78° C., and 7.2 ml (86.1 mmol) of 2-cyclopentene-1-one, dissolved in 60 ml of THF, were added slowly. After the addition had ended, the solution was stirred at this temperature for 1 h. After TLC check (mobile phase cyclohexane/ethyl acetate 9:1), saturated ammonium chloride solution was added and the mixture was taken up in ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate. After filtration, the solvent was removed under reduced pressure.
  • Diastereomer ratio about 10:1.
  • Diastereomer ratio about 9:1.
  • HATU 1.0 to 2.0 eq.
  • a solution of the 4,4,4-trifluoro-3-methyl-2-phenylbutanoic acid derivative in question (about 0.8 to 1.5 eq., 0.15 to 1.5 mol/l) and an aniline (about 0.8 to 1.5 eq., 0.15 to 1.5 mol/l) in a mixture of DMF and pyridine (mixing ratio about 3:1 to 1.5:1).
  • pyridine it is also possible to use N,N-diisopropylethylamine (2.0 to 5.0 eq.).
  • the resulting mixture is stirred at a temperature of from RT to 60° C. for 4 h to 48 h.
  • the crude product can be purified, after removal of the solvent under reduced pressure, by preparative RP-HPLC (mobile phase: acetonitrile/water gradient) or alternatively, after aqueous work-up of the reaction mixture, by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate or dichloromethane/methanol mixtures).
  • the mixture was diluted with ethyl acetate, and the solution was washed successively with 1 N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution.
  • the organic phase was dried over magnesium sulphate and concentrated under reduced pressure.
  • the residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave 998 mg (98.4% of theory) of the target compound.
  • racemate obtained above was separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 ⁇ m, 250 mm ⁇ 20 mm; flow rate: 20 ml/min; detection: 220 nm; injection volume: 0.28 ml; temperature: 22° C.; mobile phase: 93% isohexane/7% isopropanol].
  • 962 mg of racemate gave 434 mg of enantiomer 1 (Example 137A) and 325 mg of enantiomer 2 (Example 138A):
  • reaction mixture was then stirred at 110° C. for 2.0 h. After cooling, saturated aqueous ammonium chloride solution and ethyl acetate were added and the reaction mixture was filtered off with suction through kieselguhr. After phase separation, the organic phase was washed with sat ammonium chloride solution and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 80:1). This gave 4.44 g of the title compound in still slightly contaminated form (about 83% of theory).
  • racemate obtained above was separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 ⁇ m, 250 mm ⁇ 20 mm; flow rate: 20 ml/min; detection: 220 nm; injection volume: 0.30 ml; temperature: 35° C.; mobile phase: 70% isohexane/30% ethanol]. 924 mg of racemate gave 405 mg of enantiomer 1 (Example 146A) and 403 mg of enantiomer 2 (Example 147A):
  • racemate obtained above was separated into the enantiomers by preparative HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 ⁇ m, 250 mm ⁇ 20 mm; flow rate: 15 ml/min; detection: 220 nm; injection volume: 0.20 ml; temperature: 35° C.; mobile phase: 70% isohexane/30% isopropanol]. 4.49 g of racemate gave 2.02 g of enantiomer 1 (Example 152A) and 2.04 g of enantiomer 2 (Example 153A):

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