5-AMINOTETRA-HYDROQUINOLINE-2-CARBOXYLIC ACIDS, PROCESSES FOR ITS PREPARATION, ITS USES IN THE TREAT

专利摘要:
new 5-aminotetrahydroquinoline-2-carboxylic acids and their use. The present application relates to new 5-amino-5,6,7,8-tetrahydroquinoline-2-carboxylic acids, processes for their preparation, their use in the treatment and / or prevention of diseases, and the its use in the production of medicines for the treatment and / or prevention of diseases, especially for the treatment and / or prevention of cardiovascular and cardiopulmonary diseases.
公开号:BR112015001211B1
申请号:R112015001211-6
申请日:2013-07-16
公开日:2020-12-15
发明作者:Michael Hahn；Markus Follmann；Walter Hübsch；Eva-Maria BECKER-PELSTER；Johannespeter Stasch；Joerg Keldenich；Martina Delbeck；Hanna Tinel；Frank Wunder；Joachim Mittendorf；Ildiko Terebesi；Dieter Lang；René Martin
申请人:Bayer Pharma Aktiengesellschaft；
IPC主号:

专利说明:

[001] The present application concerns new 5-amino-5,6,7,8-tetrahydroquinoline-2-carboxylic acids, processes for their preparation, their use in the treatment and / or prevention of diseases , and its use in the production of medicines for the treatment and / or prevention of diseases, especially for the treatment and / or prevention of cardiovascular and cardiopulmonary diseases.
[002] One of the most important cellular transmission systems in mammalian cells is cyclic guanosine monophosphate (cGMP). Together with nitric oxide (NO), which is released by the endothelium and transmits hormonal and mechanical signals, it forms the NO / cGMP system. Guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP). The representatives of this family revealed to date can be divided according to structural characteristics and according to the type of ligands, into two groups: particulate guanylate cyclases, which can be stimulated by natriuretic peptides, and soluble guanylate cyclases that can be stimulated by NO. Soluble guanylate cyclases consist of two subunits and contain one heme per heterodimer, which is part of the regulation site. The latter is of central importance in the activation mechanism. NO binds to the iron atom in heme and thus dramatically increases the activity of the enzyme. On the contrary, preparations without heme cannot be stimulated by NO. Carbon monoxide (CO) can also bind to the central iron atom in heme, but CO stimulation is distinctly less than that achieved by NO.
[003] Through the production of cGMP and the resulting regulation of phosphodiesterases, ion channels and protein kinases, guanylate cyclase plays a crucial part in several physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, in aggregation and platelet adhesion and transmission of neuronal signals, and in disorders caused by a weakening of the aforementioned processes. Under pathophysiological conditions, the NO / cGMP system can be suppressed and this can lead, for example, to pulmonary hypertension, high blood pressure, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, thrombosis , stroke and myocardial infarction.
[004] A way of treating these disorders that does not depend on NO and aims to influence the cGMP signaling pathway in organisms is a promising approach considering the high efficiency and the few expected side effects.
[005] Compounds such as organic nitrates, the effect of which is based on NO, have so far been used exclusively for the therapeutic stimulation of soluble guanylate cyclase. NO is produced by bioconversion and activates soluble guanylate cyclase by binding to the central iron atom of heme. In addition to the side effects, the development of tolerance is one of the crucial disadvantages of this treatment method [O.V. Evgenov et al., Nature Rev. Drug Disc. 5 (2006), 755],
[006] In recent years, substances that directly stimulate, that is, without prior release of NO, soluble guanylate cyclase have been identified. The indazole derivative YC-1 was the first NO-independent but heme-dependent sGC stimulator, described [Evgenov et al., Ibid.]. Based on YC-1, other substances have been discovered that are more potent than YC-1 and do not have a relevant inhibition of phosphodiesterases (PDE). This led to the identification of the pyrazolopyridine derivatives BAY 41-2272, BAY 41-8543 and BAY 63-2521 (Riociguat). Together with the structurally different substances recently published CMF-1571 and A-350619, these compounds form a new class of sGC stimulators [Evgenov et al., Ibid.]. A common feature of this class of substances is a selective and NO-independent activation of heme-containing sGC. In addition, sGC stimulators in combination with NO have a synergistic effect on sGC activation due to the stabilization of the nitrosyl-heme complex. If the heme group is removed from the soluble guanylate cyclase, the enzyme still has a detectable base catalytic activity, that is, cGMP is still formed. The remaining base catalytic activity of the enzyme without heme cannot be stimulated by any of the aforementioned stimulators [Evgenov et al., Ibid.].
[007] Additionally, activators of NO and heme-independent sGC were identified, with BAY 58-2667 (Cinaciguat) being the prototype of this class. The common characteristics of these substances are that, in combination with NO, they have only an additive effect on the activation of the enzyme, and the activation of the oxidized enzyme or without heme is significantly superior to that of the enzyme containing heme [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]. Spectroscopic studies demonstrate that BAY 58-2667 replaces the oxidized heme group, which, as a result of weakened ferrohistidine binding, binds only weakly to sGC. It has also been shown that the characteristic Tyr-x-Ser-x-Arg binding motif to the heme group of sGC is absolutely essential both for the interaction of negatively charged propionic acids in the heme group and for the action of BAY 58-2667. In this context, it is assumed that the BAY 58-2667 binding site in sGC is identical to the heme group binding site [J.P. Stasch et al., J. Clin. Invest. 116 (2006), 2552], Recently, crystallization studies with the Nostoc H-NOX domain of a prokaryotic heme binding domain with high sequence homology to sGC, demonstrated that BAY 58-2667 binds at the binding site heme [F. van den Akker et al., J. Biol. Chem. 285 (2010), 22651],
[008] Pulmonary hypertension (PH) is a progressive pulmonary disorder that, without treatment, leads to death within a few years after diagnosis. By definition, the mean pulmonary arterial pressure (PAPm) in the case of chronic pulmonary hypertension is> 25 mmHg at rest, or> 30 mmHg during physical exercise (normal value <20 mmHg). The pathophysiology of pulmonary hypertension is characterized by vasoconstriction and remodeling of the pulmonary vessels. In chronic PH, neomuscularization occurs, mainly of the non-muscularized pulmonary vessels, and the vascular muscles of the muscularized vessels increase in circumference. This increase in pulmonary circulation obliteration results in progressive stress on the right side of the heart, which leads to reduced performance on the right side of the heart and eventually ends in heart failure on the right side [M. Humbert et al., J. Am. Coll. Cardiol. 2004, 43, 13S-24S]. Idiopathic (or primary) pulmonary arterial hyperpressure (PAH) is a very rare disorder, in which secondary pulmonary hypertension (non-PAH) is very common, and the latter is currently thought to be the third most common group of disorders cardiovascular diseases after coronary disease and systemic hypertension. Since 2008, pulmonary hypertension has been classified according to the Dana Point classification into several subgroups according to their etiology [M. Humbert and V.V. McLaughlin, J. Am. Coll. Cardiol. 2009, 54 (1), S1-S2; D. Montana and G. Simonneau, in: A.J.Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3rd edition, Hodder Arnold Publ., 2011, pp. 197-206].
[009] Despite all the advances in PH therapy, there are still no expectations of a cure for this serious disorder. Conventional therapies available on the market (eg, prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase inhibitors) are able to improve quality of life, exercise tolerance and patient prognosis. These therapeutic principles are administered systemically and act essentially at the hemodynamic level, through the modulation of vascular tone. The applicability of these drugs is limited due to their side effects, some of which are serious, and / or their complicated administration methods. The period during which the clinical situation of patients can be improved or stabilized by specific monotherapy is limited (for example, due to the development of tolerance). Eventually, therapy becomes complicated and combination therapy is applied, through which a plurality of drugs are administered in parallel. At present, these conventional therapies are approved only for the treatment of pulmonary arterial hyperpressure (PAH). In the case of secondary forms of PH, such as HP-COPD, these therapeutic principles (eg, sildenafil, bosentan) fail in clinical trials since, as a result of non-selective vasodilation, they lead to a reduction (desaturation) of the arterial oxygen in patients. The probable reason for this is an unfavorable effect on the adaptation of lung-perfusion ventilations to heterogeneous pulmonary disorders due to the systemic administration of non-selective vasodilators [I. Blanco et al., Am. J. Respir. Crit. Care Med. 2010, 181, 270-278; D. Stolz et al., Eur. Respir. J. 2008, 32, 619-628].
[010] New combination therapies are one of the most promising future therapeutic options for the treatment of pulmonary hypertension. In this regard, the discovery of new pharmacological mechanisms for the treatment of PH is of particular interest [Ghofrani et al., Herz 2005, 30, 296-302; E.B. Rosenzweig, Expert Opin. Emerging Drugs 2006, 11, 609-619; T. Ito et al., Curr. Med. Chem. 2007, 14, 719-733], In particular, new therapeutic approaches that can be combined with the concepts of therapy already available on the market can form the basis of a more efficient treatment, thus presenting a great advantage for patients. In addition, the selective pulmonary applicability of this new principle of action could offer the alternative of use not only for PAH, but especially as a first therapeutic option for patients suffering from secondary forms of PH.
[011] In an animal model of pulmonary hypertension, inhaled administration of sGC activator BAY 58-2667 (Cinaciguat) in the form of microparticles has been shown to lead to a selective and dose-dependent reduction in pulmonary arterial pressure. In this model, intravenous administration of 1 / - / - 1,2,4-oxadiazolo [4,3-a] quinoxalin-1-one (ODQ), which oxidizes the prosthetic heme group of sGC, reduced the vasodilator effect of Inhaled NO (NOi), while increased by BAY 58-2267. These results led to the hypothesis that inhaled administration of a sGC activator may represent a new method of effective treatment for patients suffering from pulmonary hypertension, particularly if their response to NOi and / or PDE5 inhibitors is reduced by consequence of lack of NO or oxidation of sGC [OV Evgenov et al., Am. J. Respir. Crit. Care Med. 2007, 176, 1138-1145]. However, in this model, Cinaciguat did not, on the other hand, have a sufficient duration of action, and additionally higher doses led to unwanted systemic side effects.
[012] Consequently, it was an objective of the present invention to provide new compounds that act in the manner described above as activators of soluble guanylate cyclase and, as such, could be used in particular in the treatment and prevention of cardiovascular disorders. In addition, these new compounds should have an improved selectivity of pulmonary action and therefore be especially suitable for the treatment of pulmonary hypertension and its secondary forms. To that end, it should be possible to combine the new compounds not only with conventional PAH therapy, but also with the basic therapy used in secondary forms of PH.
[013] Various aminodicarboxylic acid derivatives for the treatment of cardiovascular disorders are disclosed in patent applications WO 01/19780-A2, WO 02/070459-A1, WO 02/070460-A1, WO 02/070461-A1, WO 02 / 070462-A1 and WO 02/070510-A2. WO 2009/023669-A1 describes 5,6,7,8-substituted tetrahydroquinolines as modulators of the C5a receptor for the treatment of inflammatory and immune disorders. WO 95/18617-A1 and WO 00/35882-A1 describe 1-amino-1,2,3,4-tetrahydronaphthalene derivatives for the treatment of neurological disorders. WO 2006/104826-A2 discloses 5-amino-5,6,7,8-tetrahydronaphthalene-2-carboxamides acylated as glucagon receptor antagonists for the treatment of diabetes.
[014] The present invention provides compounds of the general formula (I)
where R1 represents hydrogen or fluorine, L1 represents ethane-1,2-diyl or 1,4-phenylene, and A represents a group of the formula
in which a. designates the respective point of attachment to the rest of the molecule, L2 represents straight chain alkanediyl- (C1-C6) L3 represents a bond, -O-, -CH2-, -CH2-CH2- or -CH = CH-, R2 represents alkyl - (C1-C4) which can be substituted up to six times with fluorine, or represents cycloalkyl- (C3-C6) which can be mono- or disubstituted with identical or different radicals selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl and alkyl- (Ci-C4), or represents a 4- to 6-membered heterocycle containing one or two identical ring members or different heteroatoms selected from the group consisting of N (R4), O, S and S (O) a in which R4 represents alkyl- (C 1 -C 4) or alkylcarbonyl- (C 1 -C 4) or, in the case where N (R 4) represents a ring nitrogen atom through which said heterocycle bonds to the adjacent phenyl group, is not present, or represents a 5-membered heteroaryl that contains one, two or three identical or different ring heteroatoms, selected from the group co N, O and S, and may optionally be fused to a phenyl ring, wherein the heteroaryl ring and the optionally fused phenyl ring can each be mono- or disubstituted with identical or different radicals selected from the group consisting of fluorine , chloro, cyano, difluoromethyl, trifluoromethyl, (C1-C4) alkyl, difluoromethoxy, trifluoromethoxy and (C1-C4) alkoxy, or represents chlorine, and R3A, R3B, R3C and R3D independently of each other represent hydrogen or a substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, alkyl- (C1 -C4), difluoromethyl, trifluoromethyl, alkoxy- (C1-C4), difluoromethoxy and trifluoromethoxy, and their salts, solvates and solvates of the salts.
[015] The compounds according to the invention are the compounds of formula (I) and their salts, solvates and solvates of the salts, the compounds of the formulas mentioned below and covered by formula (I) and their salts, solvates and solvates of the salts, and the compounds which are hereinafter referred to as exemplary embodiments and encompassed by formula (I) and their salts, solvates and solvates of the salts, provided that the compounds encompassed by formula (I) and hereinafter are no longer salts , solvates and solvates of the salts.
[016] The salts referred to for the purposes of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are in themselves unsuitable for pharmaceutical uses, but which can be used, for example, to isolate, purify or store the compounds according to the invention.
[017] The physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid , benzenesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, benzoic acid and embonic.
[018] The physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, such as, by way of example and preferably, alkali metal salts (for example, sodium and potassium salts), salts of alkaline earth metals (eg calcium and magnesium salts), zinc salts and ammonium salts derived from ammonia or organic amines with 1 to 16 C atoms, such as, by way of example and preferably, ethylamine, diethylamine , triethylamine, A /, A / -diisopropylethylamine, monoethanolamine, diethanolamine, triethanolamine, tromethamine, dimethylaminoethanol, diethylaminoethanol, choline, procaine, dicyclohexylamine, / d-benzylamine, / V-methylmorpholine, W-methylpiperidine, 1,2-arginine, lysine and 1,2-arginine.
[019] Solvates in the context of the invention are designated as those forms of the compounds according to the invention that form a complex in the solid or liquid state upon coordination with solvent molecules. Hydrates are a specific form of solvates, in which coordination occurs with water. Hydrates are preferred solvates in the context of the present invention.
[020] Depending on their structure, the compounds according to the invention can exist in different stereoisomeric forms, that is, in the form of configuration isomers or, if applicable, also as conformational isomers (enantiocrine and / or diastereomers, including those in the case of atropisomers). Accordingly, the present invention encompasses enantiomers and diastereomers and their respective mixtures. Stereoisomerically uniform constituents can be isolated from such mixtures of enantiomers and / or diastereomers in a known manner; for this purpose, chromatographic processes, in particular HPLC chromatography, are preferably used in an achiral or chiral phase.
[021] When the compounds according to the invention occur in tautomeric forms, the present invention encompasses all tautomeric forms.
[022] The present invention also encompasses all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is understood here as a compound in which at least one atom in the compound according to the invention has been exchanged for another atom of the same atomic number, but with an atomic mass different from the atomic mass that occurs normally or predominantly in nature. Examples of the isotopes that can be incorporated into a compound according to the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C , HQ 15N 170 180 32p 33p 33s 34s 35S 36S 18F 36CI 82Br 123l 124l 129l and 131l Specific isotopic variants of a compound according to the invention, especially those in which one or more radioactive isotopes have been incorporated, can be advantageous, for example, to examine the mechanism of action or the distribution of the active compound in the body; due to the relative ease of preparation and detection, compounds specially labeled with the 3H or 14C isotopes are suitable for this purpose. Additionally, the incorporation of isotopes, for example, deuterium, can lead to certain therapeutic benefits as a result of the greater metabolic stability of the compound, such as, for example, an extension of the half-life in the body or a reduction of the necessary active dose; such modifications of the compounds according to the invention may therefore, in some cases, also constitute a preferred embodiment of the present invention. The isotopic variants of the compounds according to the invention can be prepared by standard procedures known to those skilled in the art, for example by the methods described below and by the methods described in the working examples, using the corresponding isotopic modifications of the respective reagents and / or materials of departure referred to here.
[023] In addition, the present invention also includes prodrugs of the compounds according to the invention. The term "prodrugs" here refers to compounds which themselves may be biologically active or inactive, but which are converted (for example, metabolically or hydrolytically) into compounds according to the invention during their time in the body.
[024] As prodrugs, the present invention comprises in particular hydrolyzable ester derivatives of the carboxylic acids of formula (I) according to the invention. These are to be understood as esters that can be hydrolyzed to free carboxylic acids, such as compounds that are mainly biologically active in physiological medium, under the conditions of the biological tests described below, and in particular in vivo, by enzymatic or chemical routes. (C1 -C4) alkyl esters, in which the alkyl group may be straight or branched, are preferred as such esters. Special preference is given to methyl, ethyl or fer-butyl esters.
[025] In the context of the present invention, substituents have the following meaning, unless otherwise specified:
[026] Alkyl- (C1-4) in the context of the invention represents a monovalent straight or branched chain alkyl radical with 1 to 4 carbon atoms. They may be mentioned by way of example and preferably: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
[027] Alcanodiyl-fCi-Cβ) and alkanediyl- (C3-C5) in the context of the invention represents a straight chain alkyl radical, α, <o-divalent having 1 to 6 or 3 to 5 carbon atoms. They may be mentioned by way of example and preferably: methylene, ethane-1,2-diyl (1,2-ethylene), propane-1,3-diyl (1,3-propylene), butane-1,4-diyl (1,4-butylene), pentane-1,5-diyl (1,5-pentylene) and hexane-1,6-diyl (1,6-hexylene).
[028] Alkylcarbonyl- (C1 -C4) in the context of the invention represents a straight or branched chain alkyl radical with 1 to 4 carbon atoms that is linked by a carbonyl group [-C (= O) -] to the rest of the molecule . They can be mentioned by way of example and preferably: acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl and pivaloyl.
[029] Alkoxy- (C1-4) in the context of the invention represents a straight or branched chain alkoxy radical with 1 to 4 carbon atoms. They may be mentioned by way of example and preferably: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tera-butoxy.
[030] Cycloalkyl- (C3-C6) in the context of the invention represents a saturated monocyclic carbocycle with 3 to 6 ring carbon atoms. They may be mentioned by way of example and preferably: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[031] 4 to 6 membered heterocycle in the context of the invention represents a saturated monocyclic heterocycle with a total of 4 to 6 ring atoms containing one or two identical or different ring hetero atoms from the group consisting of N, O, S and S (O) ae is linked by a carbon atom or optionally by a nitrogen ring atom. Preference is given to a 5- or 6-membered heterocycle containing a nitrogen ring atom and may additionally contain another ring hetero atom of the group consisting of N and O. Examples that can be cited are: azetidinyl, oxetanyl, tietanyl, pyrrolidinyl , pyrazolidinyl, tetrahydrofuranyl, thiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-oxazinanyl , morpholinyl and thiomorpholinyl. Preference is given to pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
[032] 5-membered heteroaryl in the context of the invention represents an aromatic heterocycle (heteroaromatic ring) which has a total of 5 ring atoms, contains up to three identical or different ring heteroatoms from the group consisting of N, O and S and is bonded through a carbon ring atom or optionally through a nitrogen ring atom. Preference is given to a 5-membered heteroaryl that contains a nitrogen ring atom and in addition to one or two other ring heteroatoms of the group consisting of N, O and S. Examples that can be cited are: furyl, pyrrolyl, thienyl, pyrazolyl , imidazolyl, 1,2-oxazolyl (isoxazolyl), 1,3-oxazolyl, 1,2-thiazolyl (isothiazolyl), 1,3-thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1 , 2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl. Preference is given to 1,2-oxazolyl (isoxazolyl), 1,3-oxazolyl, 1,2-thiazolyl (isothiazolyl), 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl.
[033] In the context of the present invention, all radicals that occur more than once are defined independently of each other. If the radicals in the compounds according to the invention are substituted, they can be mono- or polysubstituted, unless otherwise specified. Substitution with one, two or three identical or different substituents is preferred. Particular preference is given to substitution with one or two identical or different substituents.
[034] A particular embodiment of the present invention comprises compounds of formula (I) wherein R1 represents hydrogen, and its salts, solvates and solvates of the salts.
[035] Another particular embodiment of the present invention comprises compounds of the formula (I) in which R1 represents fluorine located in the para position with respect to the ACH2O group, and its salts, solvates and solvates of the salts.
[036] Another particular embodiment of the present invention comprises compounds of the formula (I) in which L1 represents ethane-1,2-diyl, and their salts, solvates and solvates of the salts.
[037] Another particular embodiment of the present invention comprises compounds of the formula (I) in which L1 represents 1,4-phenylene, and their salts, solvates and solvates of the salts.
[038] Preference is given, in the context of the present invention, to compounds of formula (I) in which R1 represents hydrogen or fluorine, L1 represents ethane-1,2-diyl or 1,4-phenylene, A represents a group of the formula
where it indicates the respective point of attachment to the rest of the molecule, L2 represents straight chain alkanediyl- (C3-C5), L3 represents a bond, -CH2-CH2- or -CH = CH-, R2 represents alkyl- (C1-C4 ) which can be substituted up to three times with fluorine, or represents cyclopentyl or cyclohexyl which can be mono- or disubstituted with identical or different radicals selected from the group consisting of fluorine, methyl and trifluoromethyl, or represents a 5- or 6-membered heterocycle of the formula
where ** designates the respective point of attachment to the adjacent phenyl group and R4 represents methyl, acetyl or propionyl, or represents 5-membered heteroaryl selected from the group consisting of 1,2-oxazolyl, 1,3-oxazolyl, 1,2- thiazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl, wherein the heteroaryl groups mentioned may each be one, substituted with methyl or trifluoromethyl and where 1,2-oxazolyl, 1,3-oxazolyl, 1,2-thiazolyl and 1,3-thiazolyl can be fused with a phenyl ring which, in turn, can be replaced with fluorine, chlorine, cyano, methyl, trifluoromethyl or trifluoromethoxy, R3A represents hydrogen, fluorine, chlorine, methyl or trifluoromethyl, R3B represents hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy, R3C represents hydrogen, trifluoromethyl, and R3D represents hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy, and their salts ions, solvates and solvates of the salts.
[039] In the context of the present invention, special preference is given to the compounds of formula (I) in which R1 represents hydrogen or fluorine, L1 represents ethane-1,2-diyl or 1,4-phenylene, and A represents a group of formula
where it designates the respective point of attachment to the rest of the molecule, L2 represents straight chain alkanediyl- (C3-C5), L3 represents a bond, -CH2-CH2- or -CH = CH-, R2 represents alkyl- (Ci- C4) which can be replaced up to three times with fluorine, or represents cyclopentyl or cyclohexyl which can be mono- or disubstituted with identical or different radicals selected from the group consisting of fluorine, methyl and trifluoromethyl, or
represents a 6-membered heterocycle of formula H where ** designates the point of attachment to the adjacent phenyl group and R4 represents methyl, acetyl or propionyl, or represents 1,3-benzoxazol-2-yl, 1,2-benzoxazol-3 -yl or 1,3-benzothiazol-2-yl which may be substituted with a radical selected from the group consisting of fluorine, chlorine, cyano, methyl, trifluoromethyl and trifluoromethoxy, R3A represents hydrogen, fluorine, chlorine, methyl or trifluoromethyl, R3B represents hydrogen, fluorine, chlorine, methyl, trifluoromethyl or trifluoromethoxy, R3C represents hydrogen, fluorine, chlorine, methyl or trifluoromethyl, and R3D represents hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl or trifluoromethoxy, and their salts, and their salts and their salts .
[040] Very special preference is given, in the context of the present invention, to the compounds of formula (I) in which R1 represents hydrogen or fluorine, L1 represents ethane-1,2-diyl or 1,4-phenylene, and A represents a formula group
where it designates the respective point of attachment to the rest of the molecule, L3 represents a bond or -CH2-CH2-, R2 represents tert-butyl, cyclohexyl, 4- (trifluoromethyl) cyclohexyl or 1,3-benzoxazol-2-yl which may be substituted with chlorine, cyano, methyl or trifluoromethyl, R3C represents hydrogen or chlorine, and R3D represents hydrogen, fluorine or trifluoromethyl, and their salts, solvates and solvates of the salts.
[041] Definitions of radicals specifically indicated in the respective preferred combinations or combinations of radicals are replaced, as desired, regardless of the specific combinations of radicals indicated, by definitions of radicals from other combinations. Combinations of two or more of the above ranges are particularly preferred.
[042] In addition, the invention provides a process for preparing the compounds of formula (I) according to the invention, characterized by [A] a compound of formula (II)
where R1 and L1 have the meanings given above and T1 and T2 are identical or different and represent alkyl- (C1-C4), it is reacted in the presence of a base with a compound of the formula (H1)
where A has the meanings given above and X1 represents an leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, or [B] a compound of the formula (IV)
wherein R1 and A have the meanings given above and T2 represents (C1 -C4) alkyl, to be reacted in the presence of a base with a compound of the formula (V)
where L1 has the meanings given above, T1 represents (C1 -C4) alkyl, and X2 represents a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, and the respective compound of the formula (VI) resulting
where R1, A, L1, T1 and T2 have the meanings given above,
[043] is then converted by hydrolysis of the ester groups -C (O) OT1 and -C (O) OT2 to the corresponding dicarboxylic acid of formula (I), and the compounds of formula (I) obtained in this way are optionally separated into their enantiomers and / or diastereomers and / or optionally converted, with the appropriate (i) solvents and / or (ii) bases or acids, in their solvates, salts and / or solvates of the salts.
[044] Inert solvents suitable for process steps (II) + (III) -> (VI) and (IV) + (V) -> (VI) are, for example, ethers such as diethyl ether, diisopropyl ether, ether methyl tert-butyl, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis- (2-methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane or mineral oil fractions , or dipolar aprotic solvents such as acetone, methyl ethyl ketone, acetonitrile, / V, A / -dimethylformamide (DMF), / /, / / - dimethylacetamide (DMA), dimethylsulfoxide (DMSO), / V, / V'-dimethylpropylenourea (DMPU) or A / -methylpyrrolidinone (NMP). It is also possible to use mixtures of these solvents. Preference is given to the use of acetonitrile or dimethylformamide.
[045] Suitable bases for process steps (II) + (III) -> (VI) and (IV) + (V) (VI) are in particular alkali metal carbonates, such as sodium carbonate, potassium carbonate or cesium carbonate, alkali metal alkoxides, such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium tert-butoxide or potassium tert-butoxide, alkali metal hydrides such as sodium hydride or hydride potassium, amides, such as sodium amide, lithium bis (trimethylsilyl), potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organometallic compounds such as n-butyl lithium or lithyl phenyl. The base used is preferably sodium carbonate, potassium carbonate or cesium carbonate. In certain cases the addition of an alkylation catalyst such as, for example, lithium bromide, sodium iodide or potassium iodide, tetra-n-butyl ammonium bromide or benzyltriethylammonium chloride can be advantageous.
[046] The reactions (II) + (III) -> (VI) and (IV) + (V) -> (VI) are generally carried out in a temperature range of 0 ° C to + 150 ° C, preferably + 50 ° Ca + 100 ° C.
[047] The hydrolysis of the ester groups -C (O) OT1 and -C (O) OT2 in the process step (VI) -> (I) is carried out by usual methods in the treatment of esters, in inert solvents with acids or bases , in which in the last variant the salts initially formed are converted by treatment with acid to the free carboxylic acids. In the case of tert-butyl esters, the cleavage of the ester is preferably carried out by means of acids.
[048] If the groups T1 and T2 are different, the hydrolysis can optionally be carried out simultaneously, in a single step process (one-pot reaction) or in two separate reaction steps.
[049] The inert solvents suitable for these reactions are water or the organic solvents commonly used in cleavage of esters. They preferably include alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or other solvents such as dichloromethane, acetone , methyl ethyl ketone, A /, A / -dimethylformamide or dimethylsulfoxide. It is also possible to use mixtures of these solvents. In the case of a basic ester hydrolysis, preference is given to the use of mixtures of water with dioxane, tetrahydrofuran, methanol, ethanol, dimethylformamide and / or dimethylsulfoxide. In the case of reaction with trifluoroacetic acid, preference is given to the use of dichloromethane, and in the case of reaction with hydrogen chloride, preference is given to the use of tetrahydrofuran, diethyl ether, dioxane or water.
[050] Suitable bases are common 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 carbonates or alkaline earth metal carbonates, such as such as sodium carbonate, potassium carbonate or calcium carbonate. Preference is given to lithium hydroxide, sodium hydroxide or potassium hydroxide.
[051] Acids suitable for cleavage of esters are, in general, sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, or mixtures thereof, if appropriate with the addition of water. Preference is given to hydrogen chloride or trifluoroacetic acid in the case of tert-butyl esters, and to hydrochloric acid in the case of methyl esters.
[052] Cleavage of esters is generally carried out in a temperature range of -20 ° C to + 120 ° C, preferably from 0 ° C to + 80 ° C.
[053] The process steps described above can be performed at normal, elevated or reduced pressure (for example, in the range of 0.5 to 5 bar); ■ in general, all reactions are carried out at atmospheric pressure.
[054] In turn, the compounds of formula (II) can be prepared by converting 5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile (VII)
by reductive amination with a 2- (2-methoxyphenyl) ethylamine of the formula
in which R1 has the meanings given above, in a secondary amine of the formula (IX)
in which R1 has the meanings given above, followed by alkylation in the presence of a base with a compound of the formula (V)
where L1, T1 and X2 have the meanings given above to produce a tertiary amine of the formula (X)
in which L1, R1 and T1 have the meanings given above, then removing the methylphenolic ether group by treatment with boron tribromide or hydrogen bromide and finally converting the resulting formula (XI) compound
wherein L1, R1 and T1 have the meanings given above by acid-catalyzed solvolysis of the nitrile group with an alcohol of the formula (XII)
wherein T2 has the meaning given above in the dicarboxylic ester of formula (II).
[055] The reaction (VII) + (VIII) (IX) is carried out in a common solvent in reductive aminations and inert under the reaction conditions, in the presence of an acid and / or a dehydrating agent as a catalyst, if appropriate. These solvents include, for example, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, N, / V-dimethylformamide, and alcohols such as methanol, ethanol, n-propanol or isopropanol; it is also possible to use mixtures of these solvents. Preference is given to the use of toluene, methanol and / or ethanol. Suitable catalysts are usual organic acids, such as acetic acid or p-toluenesulfonic acid.
[056] Reducing agents especially suitable for these amination reactions are boroidides such as, for example, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride or tetra-butylammonium borohydride; Preference is given to the use of sodium borohydride.
[057] The reaction (VII) + (VIII) -> (IX) is preferably carried out in a two-step process, initially in a temperature range of + 50 ° C to + 120 ° C (for the condensation of the imine) and then from 0 ° C to + 30 ° C (for the reduction of borohydride).
[058] Regarding the solvent, base and temperature, the alkylation process in process step (IX) + (V) -> (X) is carried out under reaction conditions analogous to those described above for reaction (IV) + (V) -> (VI).
[059] The cleavage of the methylphenolic ether group in the process step (X) -> (XI) is carried out by usual methods, by treatment with boron tribromide in dichloromethane between -20 ° C and + 10 ° C, or by heating with a solution of hydrogen bromide in glacial acetic acid or water between + 100 ° C and + 130 ° C. If, in these reaction conditions, the ester group -C (O) OT1 and / or the nitrile group are totally or partially hydrolyzed at the same time, the dicarboxylic acid of the formula (XIII)
wherein L1 and R1 have the meanings given above, formed in this way can be re-esterified in the dicarboxylic ester of formula (II), for example by subsequent treatment with methanol or ethanol in the presence of hydrogen chloride or thionyl chloride | T1 = T2 = methyl or ethyl in (II)].
[060] The compounds of the formula (IV) can be prepared by initially converting the compound of the formula (IX) described above
where R1 has the meanings given above, with the aid of aqueous hydrobromic acid, in the hydroxycarboxylic acid of the formula (XIV)
where R1 has the meanings given above, followed by esterification under acid catalysis with an alcohol of the formula
where T2 has the meaning given above, to produce a compound of the formula (XV)
where R1 and T2 have the meanings given above, then converting the amine compound (XV) into a protected derivative of formula (XVI)
wherein R1 and T2 have the meanings given above and PG represents a suitable temporary protecting group for the amino group, such as, for example, tert-butoxycarbonyl, followed by alkylation in the presence of a base with a compound of the formula (III)
where A and X1 have the meanings given above, to produce a compound of the formula (XVII)
where A, PG, R1 and T2 have the meanings given above, and finally removing the temporary protection group PG again.
[061] The transformation (IX) -> (XIV) -> (XV) is carried out in a manner similar to that described above for the reaction sequence (X) -> (XI) [or (XIII)] (II).
[062] The PG protecting groups suitable for compound (XVI) are the usual protecting groups of the amino group, in particular the non-benzyl carbamate type, such as, for example, allyloxycarbonyl (Alloc), tert-butoxycarbonyl (Boc) or 9-fluorenylmethoxycarbonyl (Fmoc). Here, the protection group PG is chosen so that the conditions for its removal in the process step (XVII) -> (IV) are compatible with the respective T2 ester radical used. The introduction and removal of the protecting group are carried out by common methods [see, for example, T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999]. Preference is given to the use of the tert-butoxycarbonyl group (Boc).
[063] Regarding the solvent, base and temperature, alkylation in the process step (XVI) + (III) -> (XVII) is carried out under reaction conditions analogous to those described above for reaction (II) + (III ) -> (VI).
[064] The compound of the formula (VII)
presented above is new in itself and can be prepared by palladium-catalyzed halogen / cyanide exchange, starting with the chlorine compound (XVIII)

[065] which is known in the literature (see Reaction Scheme 1 below). The reaction is preferably carried out using zinc cyanide, with the aid of tetrakis (triphenylphosphine) palladium as a catalyst, in a dipolar aprotic solvent such as A /, A / -dimethylformamide or A /, / V-dimethylacetamide, in a temperature range of + 80 ° C to +150 ° C.
[066] The reactions described above can be carried out at normal, elevated or reduced pressure (for example, in the range of 0.5 to 5 bar); in general, all reactions are carried out at atmospheric pressure.
[067] The separation of the compounds according to the invention in the corresponding enantiomers and / or diastereomers can even be carried out, if convenient, in the phase of the compounds (II), (IV), (VI), (IX), (X ), (XI), (XIII), (XIV), (XV), (XVI) or (XVII), which are then subjected to the reaction in separate form according to the process sequences described above. The separation of stereoisomers can be carried out by usual methods known to the person skilled in the art. In the context of the present invention, preference is given to the use of chromatographic processes with aquiral or chiral separation phases; in the case of carboxylic acids as intermediates or final products, it may also be possible, alternatively, to achieve a separation via the diastereomeric salts using chiral bases.
[068] The compounds of formulas (III), (V), (VIII), (XII) and (XVIII) can be obtained commercially or are described in the literature, or can be prepared in an obvious way for an expert person in the specialty, in a similar way to the methods published in the literature. Numerous detailed processes and literature references for preparing starting materials can also be found in the Experimental Part of the section on preparing starting materials and intermediates.
[069] The preparation of the compounds according to the invention can be illustrated in an exemplary way by the following reaction schemes: Scheme 1

[070] [see also SJ Stachel et al., Bioorg. Med. Chem. Lett. 22, 240-244 (2012); M. Vanejevs et al., J. Med. Chem. 51 (3), 634-647 (2008); GR Pettit et al., J. Org. Chem. 33 (3), 1089-1092 (1968)]. Layout 2
Layout 3
[X1 = Cl or Br; X2 = Cl or I].
[071] The compounds according to the invention have useful pharmacological properties and can be used for the prevention and treatment of disorders in humans and animals.
[072] In the context of the present invention, the term "treatment" or "treating" includes inhibiting, delaying, stopping, ameliorating, mitigating, limiting, reducing, suppressing, reversing or curing a disease, condition, disorder, injury or weakening health, development, course or progression of these states and / or the symptoms of those states. Here, the term "therapy" is understood as a synonym for the term "treatment".
[073] In the context of the present invention, the terms "prevention", "prophylaxis" or "precaution" are used interchangeably and refer to the prevention or reduction of the risk of acquiring, contracting, suffering from or having a disease, condition, disorder, injury or weakened health, development or progression of these states and / or symptoms of those states.
[074] Treatment or prevention of a disease, condition, disorder, injury or impaired health can occur partially or completely.
[075] The compounds according to the invention are potent activators of soluble guanylate cyclase. They lead to vasorelaxation, inhibition of platelet aggregation and a drop in blood pressure, as well as an increase in coronary blood flow and microcirculation. These activities are mediated by direct heme-independent activation of soluble guanylate cyclase and by an increase in intracellular cGMP levels.
[076] In addition, the compounds according to the invention have other advantageous properties, in particular with regard to their selective action on the lungs (in contrast to the systemic action), their retention time in the lung and / or the its duration of action after intrapulmonary administration.
[077] The compounds according to the invention are particularly suitable for the treatment and / or prevention of cardiovascular, cardiopulmonary, thromboembolic, fibrotic and pulmonary disorders.
[078] Consequently, the compounds according to the invention can be used in medicines for the treatment and / or prevention of cardiovascular and cardiopulmonary disorders such as, for example, high blood pressure (hypertension), heart failure, coronary heart disease, angina stable and unstable chest, pulmonary arterial hyperpressure (PAH) and secondary forms of pulmonary hypertension (PH), renal hypertension, peripheral and cardiac vessel disorders, arrhythmias, atrial and ventricular arrhythmias and impaired conduction such as, for example, atrioventricular blocks of grade l-lll, supraventricular tachyarrhythmia, atrial fibrillation, atrial palpitation, ventricular fibrillation, ventricular palpitation, ventricular tachyarrhythmia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sinus node syndrome, syncope, atrioventricular nodal reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary artery disease (ACS), autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies), boxer's cardiomyopathy, aneurysms, shock such as cardiogenic shock, septic shock and anaphylactic shock, and for the treatment and / or prevention of thromboembolic disorders and ischemias such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, pre-eclampsia, inflammatory cardiovascular disorders, spasms of coronary arteries and peripheral arteries, formation of edema such as pulmonary edema , cerebral edema, renal edema or edema induced by heart failure, weakened peripheral perfusion, reperfusion injury, arterial and venous thrombosis, microalbuminuria, heart failure, endothelial dysfunction, micro- and macrovascular injury (vasculitis), and also to prevent restenosis, for example, after thrombolytic therapies, percutaneous transluminal angioplasties (A PT), percutaneous transluminal coronary angioplasty (ACTP), heart transplant and bypass operations.
[079] In the context of the present invention, the term "pulmonary hypertension" encompasses its two subforms, primary and secondary, as defined below by the Dana Point classification according to their etiology [see D. Montana and G. Simonneau, in : AJ Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3rd edition, Hodder Arnold PubL, 2011, pp. 197-206; M.M. Hoeper et al., J. Am. Coll. Cardiol. 2009, 54 (1), S85-S96]. These include, in particular, Group 1 pulmonary arterial hyperpressure (PAH), which, among others, includes the idiopathic and familial forms (PAH and PAH, respectively). In addition, PAH also encompasses persistent pulmonary hypertension in newborns and associated pulmonary arterial hyperpressure (PAH) with collagenosis, lesions of congenital systemic-pulmonary shunts, portal hypertension, HIV infections, ingestion of certain drugs and medications ( for example, appetite suppressants), with disorders having an important venous / capillary component, such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, or associated with other disorders such as thyroid disorders, glycogen storage disorders, Gaucher disease, hereditary teleangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy. Group 2 of the Dana Point classification comprises PH patients with a damaging disorder on the left side of the heart, such as ventricular, atrial or valvular disorders. Group 3 comprises forms of pulmonary hypertension associated with a lung disorder, for example, chronic obstructive lung disease (COPD), interstitial lung disease (DPI), idiopathic pulmonary fibrosis (IPF), and / or hypoxemia (for example, sleep apnea, alveolar hypoventilation, chronic high altitude sickness, hereditary deformities). Group 4 includes PH patients with thrombotic and / or chronic embolic disorders, for example in the case of thromboembolic obstruction of proximal and distal pulmonary arteries, or non-thrombotic embolisms (for example, as a result of tumor disorders, parasites, foreign bodies) . Less common forms of pulmonary hypertension, such as in patients suffering from sarcoidosis, histiocytosis X or lymphanangiomatosis, are summarized in Group 5.
[080] In the context of the present invention, the term "heart failure" includes both acute and chronic forms of heart failure, as well as more specific or related types of disease, such as decompensated acute heart failure, right heart failure, 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 valve stenosis, mitral valve insufficiency, stenosis aortic valve failure, aortic valve failure, tricuspid valve stenosis, tricuspid valve failure, pulmonary valve stenosis, pulmonary valve failure, combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, myocarditis viral, heart failure d iabetic, alcoholic cardiomyopathy, cardiac storage disorders, and also diastolic heart failure and systolic heart failure.
[081] Additionally, the compounds according to the invention can be used for the treatment and / or prevention of arteriosclerosis, disturbed lipid metabolism, hypolipoproteinemias, dyslipidemias, hypertriglyceridemias, hyperlipidemias, combined hyperlipidemias, hypercholesterolemias, abetantopoproteinemia, sytosterolemia, sytosterolemia, sytosterolemia, sytosterolemia , adiposity, obesity, and also metabolic syndrome.
[082] In addition, the compounds according to the invention can be used for treatment and / or prevention of primary and secondary Raynaud's phenomenon, microcirculation disorders, lameness, tinnitus, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, ulcers diabetic extremities, gangrene, CREST syndrome, erythematosis, onychomycosis and rheumatic disorders.
[083] The compounds according to the invention can also be used to prevent ischemia and / or reperfusion injury in organs or tissues and also as additives for solutions for the perfusion and preservation of organs, parts of organs, tissues or parts of tissue of human or animal origin, particularly in surgical interventions or in the field of transplant medicine.
[084] Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of kidney disorders, especially kidney failure and kidney failure. In the context of the present invention, the terms kidney failure and kidney failure include both their acute and chronic manifestations, as well as underlying or related kidney diseases, such as renal hypoperfusion, intradialitic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis , tubulointerstitial diseases, nephropathic diseases like primary and congenital kidney disease, nephritis, immune kidney diseases like kidney graft rejection and immune complex kidney diseases, toxic substance-induced nephropathy, contrast agent-induced nephropathy, diabetic and non-nephropathy diabetic, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which can be diagnostically characterized, for example, by abnormally reduced creatinine and / or water excretion, abnormally increased blood concentrations of urea, nitrogen, potassium and / or creatinine , altered activity of en Renal enzymes such as, for example, altered glutamyl synthase, osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, lesions in the glomeruli and arterioles, tubular dilation, hyperphosphatemia and / or need for dialysis. The present invention also includes the use of the compounds according to the invention for treatment and / or prophylaxis of sequelae of renal failure, for example hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disturbances (for example hyperkalaemia, hyponatremia) and disturbances in bone and carbohydrate metabolism.
[085] Additionally, the compounds according to the invention are suitable for treating and / or preventing urological disorders, for example benign prostatic syndrome, benign prostatic hyperplasia (BPH), benign enlargement of the prostate, urinary obstruction, urinary tract syndrome inferior (STUI), neurogenic overactive bladder (BHN), incontinence, for example mixed urinary incontinence (IUM), urgency (UI), exertion (SUI), or overflow, pelvic pain, and also erectile dysfunction and female sexual dysfunction .
[086] The compounds according to the invention are also suitable for the treatment and / or prevention of asthmatic disorders, chronic obstructive pulmonary disease (COPD), acute respiratory failure syndrome (ARI) and acute lung injury (ALI), deficiency of alpha-1 -antitrypsin, pulmonary fibrosis, pulmonary emphysema (eg cigarette smoke-induced pulmonary emphysema) and cystic fibrosis (CF).
[087] The compounds described in the present invention are also active compounds for controlling disorders of the central nervous system characterized by disorders of the NO / cGMP system. These compounds are especially suitable for improving perception, concentration, learning or memory after cognitive difficulties such as those that occur especially in association with situations / diseases / syndromes, such as mild cognitive difficulties, age-related learning and memory difficulties, memory loss associated with age, vascular dementia, craniocerebral trauma, thrombosis, dementia after strokes (post-stroke dementia), post-traumatic craniocerebral trauma, general concentration difficulties, concentration difficulties in children with learning and memory problems, Alzheimer's disease , Lewy body dementia, dementia with frontal lobe degeneration including Pick's syndrome, Parkinson's disease, progressive nuclear paralysis, dementia with cortical-basal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, demyelination, multiple sclerosis, degeneration thalamic, Creutzfeld-Jacob dementia, dementia of HIV, schizophrenia with dementia or Korsakoff's psychosis. These compounds are also suitable for the treatment and / or prevention of disorders of the central nervous system, such as anxiety, tension and depression states, CNS-related sexual disorders and sleep disturbance, and for the control of pathological disorders of alcohol consumption. food, stimulants and addictive substances.
[088] In addition, the compounds according to the invention are also suitable for regulating cerebral blood flow and are thus effective agents for controlling migraines. They are also suitable for prophylaxis and control of sequelae of cerebral infarction (Apoplexia cerebri), such as stroke, cerebral ischemia and craniocerebral trauma. The compounds according to the invention can likewise be used to control pain states.
[089] Furthermore, the compounds according to the invention have anti-inflammatory action and can therefore be used as anti-inflammatory drugs for the treatment and / or prevention of septicemia (SIRS), multiple organ failure (FMO, SDMO), inflammatory kidney disorders, chronic inflammation of the intestine (Dll, Crohn's disease, ulcerative colitis), pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin disorders and inflammatory eye disorders.
[090] In addition, the compounds according to the invention are suitable for the treatment and / or prevention of fibrotic disorders of Organs internal organs, for example the lung, heart, kidneys, bone marrow and especially the liver and also of dermatological fibrosis and fibrotic eye disorders. In the context of the present invention, the term "fibrotic disorders" includes especially disorders such as liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, fibrotic injury resulting from diabetes, myelofibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring, nevi, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue disorders (eg, sarcoidosis). The compounds according to the invention can likewise be used to promote deferred healing, to control post-operative healing, for example, resulting from operations on glaucoma, and cosmetically, for aged and keratinized skin.
[091] Due to their activity profile, the compounds according to the invention are particularly suitable for the treatment and / or prevention of cardiovascular and cardiopulmonary disorders, such as the primary and secondary forms of pulmonary hypertension, heart failure, angina of chest and hypertension, and also for the treatment and / or prevention of thromboembolic disorders, ischemia, vascular disorders, impaired microcirculation, renal failure, fibrotic disorders and arteriosclerosis.
[092] The present invention further provides the use of the compounds according to the invention for the treatment and / or prevention of disorders, in particular of the disorders mentioned above.
[093] The present invention further provides the use of the compounds according to the invention in the preparation of a medicament for the treatment and / or prevention of disorders, in particular of the disorders mentioned above.
[094] The present invention further provides a medicament comprising at least one of the compounds according to the invention for the treatment and / or prevention of disorders, in particular of the disorders mentioned above.
[095] The present invention further provides the use of the compounds according to the invention in a method for the treatment and / or prevention of disorders, in particular of the disorders mentioned above.
[096] The present invention further provides a method for the treatment and / or prevention of disorders, in particular of the disorders mentioned above, using an effective amount of at least one of the compounds according to the invention.
[097] The compounds according to the invention can be used alone or in combination with other active compounds, if necessary. The present invention also relates to medicaments that contain at least one of the compounds according to the invention and one or more of other active compounds, intended in particular for the treatment and / or prophylaxis of the diseases mentioned above. As an appropriate combination of active compounds, mention may be made, by way of example and preferably:
[098] organic nitrates and NO donors, for example sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhalable NO;
[099] compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), for example phosphodiesterase inhibitors (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 4 inhibitors, such as roflumilast or revamilast, and PDE 5 inhibitors, such as sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, mirodenafil or iodenafil;
[100] NO-independent but heme-dependent guanylate cyclase stimulators, in particular riociguat and the compounds described in WO 00/06568, WO 00/06569, WO 02/42301, WO 03/095451, WO 2011/147809, WO 2012/004258, WO 2012/028647 and WO 2012/059549;
[101] prostacyclin analogues and IP receptor agonists, by way of example and preferably, iloprost, beraprost, treprostinil, epoprostenol or NS-304;
[102] endothelin receptor antagonists, by way of example and preferably, bosentan, darusentan, ambrisentan or sitaxsentan;
[103] human neutrophil elastase (HNE) inhibitors, by way of example and preferably, sivelestat or DX-890 (Reltran);
[104] compounds that inhibit the signal transduction cascade, in particular the tyrosine kinase inhibitor group, by way of example and preferably, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib, masitinib or tandutinib;
[105] Rho-kinase inhibitors, by way of example and preferably, fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049;
[106] antiobstructive agents as used, for example, in the therapy of chronic obstructive pulmonary disease (COPD) or bronchial asthma, by way of example and preferably, mimetics of beta receptors (eg, bedoradrine) administered inhaled or systemically or substances antimuscarinergics administered inhalably;
[107] anti-inflammatory and / or immunosuppressive agents as used, for example, in the therapy of chronic obstructive pulmonary disease (COPD), bronchial asthma or pulmonary fibrosis, by way of example and preferably, corticosteroids administered systemically or inhaled, flutiform, pirfenidone, acetylcysteine, azathioprine or BIBF-1120;
[108] chemotherapy used, for example, in the therapy of neoplasms of the lung or other organs;
[109] active compounds used for the systemic and / or inhalation treatment of lung disorders, for example, cystic fibrosis (alpha-1-antitrypsin, aztreonam, ivacaftor, lumacaftor, ataluren, amikacin, levofloxacin), chronic obstructive pulmonary diseases (COPD) (LAS40464, PT003, SUN-101), acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) (interferon-beta-1a, traumaquines), obstructive sleep apnea (VI-0521), bronchiectasis (mannitol, ciprofloxacin ), Bronchiolitis obliterans (cyclosporine, aztreonam) and septicemia (pagibaximab, Voluven, ART-123);
[110] active compounds used in the treatment of muscular dystrophy, for example idebenone;
[111] antithrombotic agents, by way of example and preferably, from the group of inhibitors of platelet aggregation, anticoagulants or profibrinolytic substances;
[112] active compounds to lower blood pressure, by way of example and preferably, from the group of calcium antagonists, angiotensin All antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha blockers, beta blockers, antagonists mineralocorticoid receptor and diuretics; and / or
[113] active compounds that alter the fat metabolism, by way of example and preferably, of the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as, by way of example and preferably, HMG-CoA inhibitors -reductase or squalene synthesis, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR alpha agonists, PPAR gamma and / or PPAR delta, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile salt adsorbents, inhibitors the resorption of bile acids and lipoprotein (a) antagonists.
[114] Antithrombotic agents are preferably to be understood as compounds in the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
[115] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, by way of example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.
[116] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, by way of example and preferably, ximelagatran, melagatran, dabigatran, bivalirudin or Clexane.
[117] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / llla antagonist, by way of example and preferably, tirofiban or abciximab.
[118] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a factor Xa inhibitor, by way of 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.
[119] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight heparin derivative (LMWH).
[120] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, by way of example and preferably coumarin.
[121] Blood pressure lowering agents are preferably to be understood as compounds in the group of calcium antagonists, angiotensin All antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha blockers, beta blockers, receptor antagonists mineralocorticoid and diuretics.
[122] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, by way of example and preferably, nifedipine, amlodipine, verapamil or diltiazem.
[123] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1 receptor blocker, by way of example and preferably, prazosin.
[124] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a beta blocker, by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol , metipranolol, nadolol, mepindolol, carazolol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
[125] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin All antagonist, by way of example and preferably, losartan, candesartan, valsartan, telmisartan or embursatane.
[126] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor, by way of example and preferably, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
[127] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist, by way of example and preferably, bosentan, darusentane, ambrisentan or sitaxsentan.
[128] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a renin inhibitor, by way of example and preferably, aliskiren, SPP-600 or SPP-800.
[129] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, by way of example and preferably, spironolactone or eplerenone.
[130] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic, by way of example and preferably, furosemide, bumetanide, Torsemide, bendroflumethiazide, chlortiazide, hydrochlorothiazide, hydroflumethiazide, methylclothiazide, polythiazide, trichlormetiazide, chlortalidone, indapamide, metolazone, quinetazone, acetazolamide, dichlorphenamide, metazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
[131] Agents that alter fat metabolism are preferably to be understood as compounds in the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis , ACAT inhibitors, MTP inhibitors, PPAR alpha agonists, PPAR gamma and / or PPAR delta, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein antagonists ( The).
[132] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, by way of example and preferably, torcetrapib, (CP-5294/4), JJT-705 or vaccine against CETP (Avant).
[133] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thyroid receptor agonist, by way of example and preferably, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitome (CGS 26214).
[134] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a statin class HMG-CoA reductase inhibitor, by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
[135] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an inhibitor of squalene synthesis, by way of example and preferably, BMS-188494 or TAK-475.
[136] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, by way of example and preferably, avasimib, melinamide, pactimib, eflucimib or SMP-797.
[137] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor, by way of example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
[138] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR gamma agonist, by way of example and preferably, pioglitazone or rosiglitazone.
[139] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR delta agonist, by way of example and preferably, GW 501516 or BAY 68-5042.
[140] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, by way of example and preferably, ezetimibe, tiqueside or pamaqueside.
[141] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, by way of example and preferably, orlistat.
[142] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent, by way of example and preferably, cholestyramine, cholestipol, colesolvam, CholestaGel or colestimide.
[143] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a bile acid reabsorption inhibitor, by way of example and preferably ASBT inhibitors (= IBAT), for example, AZD -7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.
[144] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipoprotein antagonist (a), by way of example and preferably, calcium gemcabene (CI-1027) or nicotinic acid .
[145] The present invention also relates to medicaments that contain at least one compound according to the invention, usually in conjunction with one or more pharmaceutically suitable, inert, non-toxic excipients, and their use for the purposes mentioned above.
[146] The compounds according to the invention can have a systemic and / or local action. For this purpose, they can be applied in an appropriate manner, for example, by oral, parenteral, intrapulmonary, nasal, sublingual, lingual, mouthpiece, rectal, dermal, transdermal, conjunctival, or optic administration, or as an implant or stent.
[147] For these application routes, the compounds according to the invention can be administered in suitable pharmaceutical forms.
[148] For oral administration, dosage forms which work according to the prior art, for rapid and / or modified release of the compounds according to the invention, which contain the compounds according to the invention in crystalline form and / are suitable or amortized and / or dissolved, for example, tablets (uncoated or coated tablets, for example with enteric coatings or delayed dissolving coatings or insoluble coatings, which control the release of the compound according to the invention), tablets or films / wafers which disintegrate rapidly in the oral cavity, films / lyophilisates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
[149] Parenteral administration may occur in the absence of an absorption step (for example, intravenously, intraarterial, intracardiac, intraspinal or intralumbar) or with inclusion of absorption (eg, intramuscular, subcutaneous, intracutaneous , percutaneous, or intraperitoneal). Suitable forms of administration for parenteral administration are, among others, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilized or sterile powders.
[150] For other routes of administration, for example, pharmaceutical forms for inhalation (including powder inhalers, nebulizers, aerosols), nasal drops, solutions, sprays, tablets for lingual administration, sublingual or mouthpiece administration, films / wafers or capsules, suppositories, auricular and ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, stirring mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powders for sprinkling, implants or stents.
[151] Oral, intrapulmonary (inhalable) and intravenous routes of administration are preferred.
[152] The compounds according to the invention can be converted into the indicated forms of administration. This can occur in a manner known per se, by mixing with non-toxic pharmaceutically suitable excipients. These excipients include, but are not limited to, vehicles (eg microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycols), emulsifiers and dispersants or humectants (eg sodium dodecyl sulphate, polyoxysorbitan oleate), binders (for example, polyvinylpyrrolidone), synthetic and natural polymers (for example, albumin), stabilizers (for example, antioxidants such as, for example, ascorbic acid), dyes (for example, inorganic pigments such as iron oxides) and flavor correction agents and / or odors.
[153] In parenteral administration, it has generally been proven to be advantageous to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, to achieve effective results. For oral administration, doses vary between about 0.01 and 100 mg / kg, preferably between about 0.01 and 20 mg / kg, and most particularly preferably between about 0.1 and 10 mg / kg of body weight. In intrapulmonary administration, the amount is generally about 0.1 to 50 mg per inhalation.
[154] However, it may be necessary, where appropriate, to deviate from the indicated amounts, in particular depending on body weight, route of administration, individual response to the active compound, the type of preparation and the time or interval at which administration occurs . Thus, in some cases, an amount less than the minimum quantity mentioned above may be sufficient, while in other cases the upper limit mentioned must be exceeded. When large quantities are administered, it may be advisable to distribute them in several single doses throughout the day.
[155] The following exemplary embodiments illustrate the invention. The invention is not restricted by the examples.
[156] The percentage data in the tests and examples that follow are, unless otherwise stated, percentages by weight; the parts are parts by weight. The solvent ratios, dilution ratios and concentration values of liquid / liquid solutions are based, in each case, on volume. Examples
[157] Abbreviations and acronyms: abs. absolute Ac acetyl aq. aqueous, aqueous solution Boc tert-bttoxycarbonyl Ex example Bu butyl and cat. catalytic Cl Chemical ionization (in MS) d day (s) TLC thin layer chromatography DCI direct chemical ionization (in MS) of diastereomeric excess DMA N, / V-dimethylacetamide DMF N, / V-dimethylformamide DMSO dimethylsulfoxide and enantiomeric excess El ionization by electronic impact (in MS) then enantiomerically pure, eq. ESI equivalent (s) electrospray ionization (in MS) Et Ethyl GC sat. gas chromatography. Saturated hour (s). HPLC high performance liquid chromatography, high pressure iPr isopropyl cone. concentrated LC-MS Mass spectroscopy coupled to liquid chromatography Me methyl min minute (s) MS mass spectroscopy NMR nuclear magnetic resonance spectroscopy P for Ph phenyl Pr racemic rac propyl, R racemate retention index (in TLC) RP reverse phase ( in HPLC) RT room temperature tR retention time (in HPLC or GC) tBu ferc-butyl TFA trifluoroacetic acid THF tetrahydrofuran Ts toluenesulfonyl (tosyl) UV ultraviolet spectroscopy v / v volume ratio (of a solution) GC-MS and LC-MS methods:
[158] Method 1 (LC-MS):
[159] Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 μ, 50 mm x 1 mm; mobile phase A: 1 L of water + 0.25 ml of 99% formic acid, mobile phase B: 1 L of acetonitrile + 0.25 ml of 99% formic acid; gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; flow rate: 0.40 ml / min; greenhouse: 50 ° C; UV detection: 210-400 nm.
[160] Method 2 (LC-MS):
[161] Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9 μ, 50 mm x 1 mm; mobile phase A: 1 L of water + 0.5 ml of 50% formic acid, mobile phase B: 1 L of acetonitrile + 0.5 ml of 50% formic acid; gradient: 0.0 min 97% A -> 0.5 min 97% A 3.2 min 5% A -> 4.0 min 5% A; flow rate: 0.3 ml / min; greenhouse: 50 ° C; UV detection: 210 nm.
[162] Method 3 (LC-MS):
[163] Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 μ, 50 mm x 1 mm; mobile phase A: 1 L of water + 0.25 ml of 99% formic acid, mobile phase B: 1 L of acetonitrile + 0.25 ml of 99% formic acid; gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; flow rate: 0.40 ml / min; greenhouse: 50 ° C; UV detection: 208-400 nm.
[164] Method 4 (LC-MS):
[165] Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 μ, 30 mm x 2 mm; mobile phase A: 1 L of water + 0.25 ml of 99% formic acid, mobile phase B: 1 L of acetonitrile + 0.25 ml of 99% formic acid; gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; flow rate: 0.60 ml / min; greenhouse: 50 ° C; UV detection: 208-400 nm.
[166] Method 5 (GC-MS):
[167] Instrument: Thermo DFS, Trace GC Ultra; column: Restek RTX-35, 15 m x 200 μm x 0.33 μm; constant helium flow: 1.20 mL / min; oven: 60 ° C; inlet: 220 ° C; gradient: 60 ° C, 30 ° C / min 300 ° C (maintained for 3.33 min).
[168] Method 6 (LC-MS):
[169] Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 μ, 50 mm x 1 mm; mobile phase A: 1 L of water + 0.25 ml of 99% formic acid, mobile phase B: 1 L of acetonitrile + 0.25 ml of 99% formic acid; gradient: 0.0 min 95% A 6.0 min 5% A -> 7.5 min to 5% A; flow rate: 0.35 ml / min; greenhouse: 50 ° C; UV detection: 210-400 nm. Starting and intermediate materials: Example 1A
[170] 3-Aminocycloex-2-en-1-one

[171] A solution of 250 g (2.2 mol) of cyclohexane-1,3-dione and 180.45 g (2.3 mol) of ammonium acetate in 1.3 liters of toluene was heated under reflux for 2 hours using a reflux condenser water separator. The reaction mixture was then concentrated to dryness. The residue was taken up in 1.3 liters of ethyl acetate and 100 ml of methanol and heated to 110 ° C. The solution was filtered while hot and slowly cooled to room temperature. The solution was kept overnight at about 4 ° C in the refrigerator. The resulting crystalline precipitate was removed by filtration and dried under reduced pressure. This yielded 66.59 g (0.60 mol) as a first batch of the desired product. Under reduced pressure, the recovered filtrate was concentrated to a volume of about 800 ml, seeded with a small crystalline product and then stored at about 4 ° C for 12 days. The resulting crystalline precipitate was removed by filtration and dried under reduced pressure. This yielded an additional 13.28 g (0.12 mol) of the desired product. Under reduced pressure, the recovered filtrate was concentrated to dryness. The residue was dissolved in 100 ml of a mixture of ethyl acetate and methanol (10: 1), applied to silica gel and chromatographically purified on silica gel (mobile phase: ethyl acetate / methanol 10: 1). This yielded an additional 113.79 g (1.02 mol) of the desired product as a yellow solid. In this way, a total of 193.66 g (1.74 mol, 78% of theory) of the desired product was obtained.
[172] 1H-NMR (400 MHz, DMSO-cfe, δ / ppm): 1.71-1.84 (m, 2H), 2.01 (t, 2H), 2.25 (t, 2H), 4.91 (s, 1H), 6.39-6.99 (br. S, 2H). Example 2A
[173] 7,8-Dihydroquinoline-2,5 (1 / - /, 6H) -dione

[174] With stirring, 113.79 g (1.02 mol) of 3-aminocyclohex-2-en-1-one and 114.37 ml (1.19 mol) of methyl propionate were heated at 105 ° C , for 1 hour. The dark homogeneous solution formed was then slowly heated to 170 ° C. After 20 min (temperature: 135 ° C), a viscous material was formed and a marked evolution of gas was observed. After another 15 min (temperature: 160 ° C), the reaction material became even more viscous, while the gas evolution persisted. After a total of 42 min, a temperature of 170 ° C was reached. After an additional 13 min at this temperature, the reaction material was cooled to room temperature. 200 ml of dichloromethane was added, the mixture was briefly heated and placed in an ultrasonic bath, and the crystalline residue formed was removed by filtration. This procedure was repeated once more with an additional 200 ml of dichloromethane. The crystalline residues obtained in this way were combined, taken in 1.6 liters of methanol and heated with stirring until the solid had completely dissolved. This solution was then slowly cooled to room temperature and kept in a refrigerator at about 4 ° C for 2 days. The crystalline precipitate was removed by filtration and dried under reduced pressure. This yielded 47.65 g (0.29 mol, 29% of theory) of the desired product.
[175] 1H-NMR (400 MHz, DMSO-cfe, δ / ppm): 1.90-2.07 (m, 2H), 2.42 (t, 2H), 2.78 (t, 2H), 6.23 (d, 1H), 7.76 (d, 1H), 12.06 (br. S, 1H). Example 3A
[176] 2-Chloro-7,8-dihydroquinolin-5 (6H) -one

[177] Under nitrogen, 21.02 g (0.13 mol) of 7,8-dihydroquinoline-2.5 (1 H, 6H) -dione was suspended in 100 ml of acetonitrile (anhydrous, <30 ppm of H2O), and 135.28 ml (density of 1.46 g / ml, 1.29 mol) of phosphorus oxychloride was added. The yellowish suspension was heated to 75 ° C and stirred at this temperature for 1.25 hours. The clear yellow solution was then cooled to room temperature and 150 ml of toluene was added. The solution was concentrated on a rotary evaporator to about 100 ml, and an additional 150 ml of toluene was added. The solution was concentrated to dryness on a rotary evaporator. 300 ml of ethyl acetate was added to the obtained orange oil. Subsequently, the solution was carefully (gas evolution) added to 500 ml of saturated aqueous sodium bicarbonate solution and stirred for 15 min. The phases were separated and the aqueous phase was extracted with 200 ml of ethyl acetate. The combined organic phases were washed twice with 250 ml of water and once with 100 ml of saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated to dryness under reduced pressure. This yielded 22.58 g (0.12 mmol, 96% of theory) of the desired compound as a slightly yellowish solid.
[178] 1H-NMR (400 MHz, DMSO-dβ, δ / ppm): 2.06-2.17 (m, 2H), 2.61-2.70 (m, 2H), 3.05 (t , 2H), 7.51 (d, 1H), 8.18 (d, 1H). Example 4A
[179] 5-Oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile

[180] Under nitrogen, 42.25 g (0.23 mol) of 2-chloro-7,8-dihydroquinolin-5 (6H) -one, 54.64 g (0.47 mol) of zinc cyanide and 13.44 g (0.01 mol) of tetrakis (triphenylphosphine) palladium in 200 ml of anhydrous A /, A / -dimethylacetamide (water content <0.01%, previously degassed with nitrogen), heated at 100 ° C and stirred at this temperature for 2 hours. After the conversion was complete (monitored by TLC, mobile phase petroleum ether / ethyl acetate 2: 1), the reaction mixture (gray suspension) was cooled to room temperature and filtered through Celite, and the filter cake was washed with 500 mL of ethyl acetate. 200 ml of saturated aqueous sodium chloride solution was then added to the resulting organic solution. A white precipitate formed, which was removed by filtration and discarded. The organic phase was separated, washed three times with, in each case, 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. The residue obtained was applied to 20 g of silica gel and purified by silica gel column chromatography (80 g cartridge; flow rate: 60 mL / min; mobile phase: petroleum ether / ethyl acetate 95: 5 - - > 60:40 for 40 min, then isocratic petroleum ether / ethyl acetate 60:40 for 30 min). This yielded 26.35 g (0.15 mmol, 66% of theory) of the desired compound.
[181] MS (El): m / z = 172 (M) +.
[182] 'H-NMR (400 MHz, CDCb, δ / ppm): 2.19-2.30 (m, 2H), 2.70-2.79 (m, 2H), 3.20 (t, 2H), 7.67 (d, 1H), 8.39 (d, 1H). Example 5A
[183] rac-5 - {[2- (2-Methoxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carbonitrile

[184] 41.10 g (0.24 mol) of 5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile was dissolved in 500 ml of toluene and 35.51 ml ( 0.25 mol) of 2- (2-methoxyphenyl) ethylamine and 4.54 g (0.024 mol) of monohydrated p-toluenesulfonic acid. The reaction solution was stirred at reflux for 5 hours (using a water separator). Subsequently, the solution was evaporated to dryness and the residue was taken up in 500 ml of ethanol (anhydrous) and, with stirring, cooled to 0 ° C. Gradually (careful: the reaction mixture forms foam), 18.06 g (0.48 mol) of sodium borohydride was added to the reaction solution, and the mixture was stirred overnight. Subsequently, the reaction mixture was concentrated on a rotary evaporator to about 100 ml, and 300 ml of water and 300 ml of ethyl acetate were added. The phases were separated and the aqueous phase was extracted twice with, in each case, 150 ml of ethyl acetate. The combined organic phases were washed twice with, in each case, 250 ml of saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated to a volume of about 150 ml on a rotary evaporator. The solution thus obtained was applied to 50 g of silica gel and purified by silica gel column chromatography (80 g cartridge; flow rate: 75 ml / min; mobile phase: petroleum ether / ethyl acetate 85:15 -> 50:50 for 45 min). This yielded 39.03 g (0.10 mol, 80% content, 43% of theory) of the desired compound.
[185] 1H-NMR (400 MHz, CDCI3, δ / ppm): 1.68-1.88 (m, 2H), 1.98-2.10 (m, 2H), 2.76-3.02 (m, 6H), 3.80 (s, 3H), 3.81-3.91 (m, 1H), 6.81-6.93 (m, 2H), 7.15 (dd, 1H), 7.24 (tt, 1H), 7.43 (d, 1H), 7.82 (d, 1H). Example 6A
[186] rac-5 - ethyl {(2-Cyano-5,6,7,8-tetrahydroquinolin-5-yl) [2- (2-methoxyphenyl) ethyl] amino} -pentanoate

[187] 17.07 mL (0.11 mol) of ethyl 5-bromopentanoate, 8.43 g (0.05 mol) of potassium iodide and 22.61 g (0.21 mol) of carbonate were added sodium hydroxide to a solution of 31.22 g (0.10 mol) of 5 - {[2- (2-methoxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carbonitrile in 300 ml of dry acetonitrile, and the mixture was heated to reflux for 4 days. The reaction mixture was then concentrated to a volume of about 50 ml on a rotary evaporator. The obtained solution was taken in 250 ml of ethyl acetate and 400 ml of saturated aqueous sodium chloride solution and the organic phase was then removed. The aqueous phase was extracted twice with, in each case, 150 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness. The obtained residue was applied to 25 g of silica gel and purified by silica gel column chromatography (80 g cartridge; flow rate: 60 mL / min; mobile phase: petroleum ether / ethyl acetate 95: 5 - » 80:20 for 30 min). This yielded 28.89 g (0.05 mol, 80% content, 52% of theory) of the desired compound as an orange oil.
[188] 1H-NMR (400 MHz, DMSO-d6, δ / ppm): 1.11-1.19 (m, 1H), 1.16 (t, 3H), 1.33-1.60 (m , 5H), 1.61 - 1.79 (m, 1H), 1.93-2.09 (m, 3H), 2.23 (t, 2H), 2.39-2.55 (m, 1H , partially obscured by the DMSO signal), 2.56-2.75 (m, 2H), 2.772.88 (m, 2H), 3.64 (s, 3H), 3.96-4.09 (m, 4H), 6.84 (t, 1H), 6.88 (d, 1H), 7.07 (d, 1H), 7.17 (t, 1H), 7.65 (d, 1H), 7, 84 (d, 1H). Example 7A
[189] rac-5 - ethyl {(5-Ethoxy-5-oxopentyl) [2- (2-hydroxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate

[190] Under nitrogen, 23.23 g (0.05 mol) of 5 - {(2-cyano-5,6,7,8-tetrahydroquinolin-5-yl) [2- (2- methoxyphenyl) ethyl] amino} ethyl pentanoate in 175 ml hydrobromic acid (48% in water). The syrup-like solution was heated to 120 ° C and stirred at this temperature for 5 hours. The clear yellow reaction solution was then cooled to room temperature and concentrated to dryness. Subsequently, 350 ml of anhydrous ethanol and 25 ml of a solution of 4N hydrogen chloride in dioxane were added to the obtained residue, and the mixture was stirred at 65 ° C overnight. The reaction mixture was then concentrated on a rotary evaporator to about 50 ml, 550 ml of saturated aqueous sodium bicarbonate solution was carefully added and the mixture was extracted three times with, in each case, 150 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness. The obtained residue (brown oil) was dissolved in 100 ml of ethyl acetate, 65 g of silica gel was added and the mixture was again concentrated to dryness. The residue was then purified by silica gel column chromatography (58 x 8 cm metal column, 1600 ml silica gel; mobile phase: ethyl acetate / petroleum ether 1: 5, after about 3 liters 1: 4 , after about 3.5 liters 1: 3). This yielded 9.43 g (0.02 mol, 38% of theory) of the desired compound as a colorless oil.
[191] MS (El): m / z = 468 (M) +.
[192] 1H-NMR (400 MHz, DMSO-dβ, δ / ppm): 1.12-1.19 (m, 1H), 1.15 (t, 3H), 1.31 (t, 3H), 1.35-1.61 (m, 5H), 1.61-1.79 (m, 1H), 1.93-2.09 (m, 3H), 2.22 (t, 2H), 2, 40-2.62 (m, 2H, partially obscured by the DMSO signal), 2.62-2.78 (m, 1H), 2.78-2.88 (m, 2H), 3.97-4, 09 (m, 4H), 4.32 (q, 2H), 6.62-6.75 (m, 2H), 6.927.02 (m, 2H), 7.71 (d, 1H), 7.92 (d, 1H), 9.14 (s, 1H). Example 8A
[193] rac-5 - {[2- (2-Hydroxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylic acid

[194] 14.6 g (47.5 mmol) of 5 - {[2- (2-methoxyphenyl) ethyl] amino} - 5,6,7,8-tetrahydroquinoline-2-carbonitrile in 100 were taken mL of hydrobromic acid (48% in water) and stirred at boiling point for 5 hours. The reaction solution was then cooled to room temperature, diluted with water and adjusted to pH 6 with saturated sodium bicarbonate solution. The crystals formed were removed by suction filtration, washed with water and air dried. This yielded 14.6 g (46.76 mmol, 98% of theory) of the desired compound. LC-MS (Method 2): t R = 1.08 min; m / z = 313 (M + H) +. Example 9A
[195] ethyl rac-5 - {[2- (2-Hydroxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate

[196] 645 ml of anhydrous ethanol and 52 ml of a solution of 4N hydrogen chloride in dioxane were added to 25.8 g (82.59 mmol) of 5 - {[2- (2-hydroxyphenyl) ethyl] acid] amino} -5,6,7,8-tetrahydroquinoin-2-carboxylic, and the mixture was stirred under reflux overnight. The reaction solution was then cooled to room temperature and, first, ethyl acetate and then, slowly, saturated aqueous sodium bicarbonate solution was added. Subsequently, the organic phase was separated, dried over sodium sulfate, filtered and concentrated to dryness. This yielded 23.9 g (70.21 mmol, 85% of theory) of the desired compound.
[197] LC-MS (Method 4): t R = 0.57 min; m / z = 341 (M + H) +.
[198] 1H-NMR (400 MHz, CDCh, δ / ppm): 1.42 (t, 3H), 1.85-2.02 (m, 4H), 2.77-2.86 (m, 2H ), 2.86-3.05 (m, 2H), 3.06-3.23 (m, 2H), 3.92-4.00 (m, 1H), 4.46 (q, 2H), 6.77 (t, 1H), 6.91 (d, 1H), 7.00 (d, 1H), 7.14 (t, 1H), 7.89 (d, 1H), 7.96 (d , 1H). Example 10A
[199] rac-5 - ethyl {(tert-bButoxycarbonyl) [2- (2-hydroxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate

[200] 23.85 g (70.06 mmol) of ethyl 5 - {[2- (2-hydroxyphenyl) ethyl] - 5,6,7,8-tetrahydroquinoline-2-carboxylate was dissolved in 530 ml of dichloromethane and, with stirring, cooled to 0 ° C. A solution of 16.06 g (73.56 mmol) of di-tert-butyl dicarbonate in 30 ml of dichloromethane was then slowly added dropwise, and the reaction mixture was stirred at room temperature overnight. The reaction solution was then concentrated to dryness and the residue was triturated with ethanol. After filtration, the filter cake was washed several times with ethanol and air dried. This yielded 27.2 g (61.74 mmol, 88% of theory) of the desired compound.
[201] LC-MS (Method 4): tR = 1.19 min; m / z = 441 (M + H) +.
[202] 1H-NMR (400 MHz, CDCl3, S / ppm): 1.01-1.24 (m, 4H), 1.24-1.37 (m, 3H), 1.39-1.58 (m, 5H), 1.65-1.90 (m, 1H), 1.90-2.12 (m, 3H), 2.64-3.00 (m, 5H), 3.14-3 .55 (m, 1H, partially obscured by the H2O signal), 4.32 (q, 2H), 4.63-4.85 (m, 0.5H), 5.08-5.30 (m, 0 , 5H), 6.59-6.83 (m, 2H), 6.91-7.14 (m, 2H), 7.40-7.64 (m, 1H), 7.79-7.87 (m, 1H), 9.31 (s, 1H). Example 11A
[203] 4- (Chloromethyl) -A / - (2-hydroxy-5-methylphenyl) benzamide

[204] Under stirring, 37.52 g (446.6 mmol) of sodium bicarbonate were added to 50 g (406 mmol) of 2-amino-4-methylphenol in 250 ml of 2-methoxyethanol. 84.4 g (446.6 mmol) of 4-chloromethylbenzoyl chloride dissolved in 250 ml of 2-methoxyethanol was added dropwise over 15 min. During this time, an increase in the reaction temperature from room temperature to 40 ° C was observed. After 4 hours of stirring, 1 liter of water and 10 ml of concentrated hydrochloric acid were added to the reaction mixture. The crystals formed were removed by filtration and dried under reduced pressure. This yielded 116 g of the desired compound, which was subjected to further reactions without further purification.
[205] LC-MS (Method 3): tR = 1.10 min; m / z = 276 (M + H) +. Example 12A
[206] 2- [4- (Chloromethyl) phenyl] -5-methyl-1,3-benzoxazole

[207] With stirring, 5 g (26.3 mmol) of p-toluenesulfonic acid monohydrate were added to 116 g (about 406 mmol) of 4- (chloromethyl) - A / - (2-hydroxy-5 -methylphenyl) benzamide in 700 mL of 1,2-dichlorobenzene. The reaction solution was then heated to 175 ° C (oil bath temperature) and stirred at this temperature in a water separator for 3 hours. The reaction solution was then cooled to room temperature, 200 ml of hexane was added and the mixture was stirred for about 1 hour. The precipitated solid was removed by filtration, washed with hexane and air dried. This yielded 56 g (217.29 mmol, 53% of theory) of the desired compound.
[208] LC-MS (Method 3): tR = 1.29 min; m / z = 258 (M + H) +.
[209] 1H-NMR (400 MHz, CDCh, δ / ppm): 2.45 (s, 3H), 4.88 (s, 2H), 7.26 (dd, 1H), 7.61 (S, 1H), 7.67 (dd, 3H), 8.20 (d, 2H). Example 13A
[210] 1 - {4- [4- (Chloromethyl) phenyl] pi perid in-1 -il} propan-1 –one

[211] 5 g (23 mmol) of 1- (4-phenylpiperidin-1-yl) propan-1-one, 4.84 g (161 mmol) of paraformaldehyde and 4.7 g (34.5 mmol) of chloride of zinc were initially added to 200 ml of dichloromethane. Under vigorous stirring, hydrogen chloride gas was bubbled through the reaction mixture for 30 min. At the end of the gas introduction, the reaction mixture was stirred at room temperature overnight. Water was then added to the reaction solution, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness on a rotary evaporator. The obtained residue was purified by preparative HPLC. During concentration, some of the product hydrolyzed to the 4- (hydroxymethyl) analog compound. The product mixture obtained (3.68 g) was then taken under stirring in 100 ml of THF, and 500 mg of zinc chloride and then 2 ml of thionyl chloride were added. This mixture was stirred at room temperature for 1 hour. After adding water and ethyl acetate to the reaction solution, the organic phase was separated, dried over sodium sulfate, filtered and concentrated to dryness. This yielded 3.4 g (12.79 mmol, 56% of theory) of the desired compound.
[212] LC-MS (Method 2): tR - 2.18 min; m / z = 266 (M + H) +.
[213] 1H-NMR (400 MHz, DMSO-d6, δ / ppm): 1.00 (t, 3H), 1.36-1.61 (m, 2H), 1.69-1.84 (m , 2H), 2.35 (q, 2H), 2.52-2.63 (m, 1H, partially obscured by the DMSO signal), 2.70-2.82 (m, 1H), 3.02- 3.14 (m, 1H), 3.91-3.99 (m, 1H), 4.504.60 (m, 1 H), 4.73 (s, 2H), 7.25 (d, 2H), 7.36 (d, 2H). Example 14A
[214] 1- (Bromomethyl) -4- [trans-4- (trifluoromethyl) cyclohexyl] benzene

[215] Under argon, 2 g (7.74 mmol) of {4- [frans-4- (trifluoromethyl) cyclohexyl] phenyl} methanol [for preparation, see patent application WO 2009/032249-A1 , Example 8 / Steps CE] in 40 ml of THF, and 2.437 g (9.29 mmol) of triphenylphosphine and 3.081 g (9.29 mmol) of carbon tetrabromide were added successively. The reaction mixture was stirred at room temperature overnight. Subsequently, water was added first and then ethyl acetate. The organic phase was separated and dried over magnesium sulfate, filtered and concentrated to dryness. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1). This yielded 2.07 g (6.44 mmol, 83% of theory) of the desired compound.
[216] GC-MS (Method 5): tR = 6.14 min; m / z = 422 (M + H) +.
[217] 1H-NMR (400 MHz, CDCh, δ / ppm): 1.32-1.59 (m, 4H), 1.68-1.78 (m, 1H), 1.81-1.91 (m, 2H), 1.91-2.01 (m, 2H), 2.27-2.42 (m, 1H), 4.68 (s, 2H), 7.22 (d, 2H), 7.37 (d, 2H). Example 15A
[218] rac-5 - {(5-Ethoxy-5-oxopentyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8 -tetrahydroquinoline-2-carboxylate

[219] Under argon, 500 mg (1.07 mmol) of 5 - {(5-ethoxy-5-oxopentyl) [2- (2-hydroxyphenyl) ethyl] amino} -5,6,7,8 ethyl-tetrahydroquinoline-2-carboxylate, 246 mg (1.07 mmol) of 1- (chloromethyl) -4- (2-phenylethyl) benzene and 295 mg (2.13 mmol) of potassium carbonate in 5 ml of DMF at 80 ° C and stirred at this temperature for 6 hours. After cooling, water and ethyl acetate were added to the reaction mixture and the phases were separated. The organic phase was washed twice with water and once with saturated sodium chloride solution, and concentrated to dryness. 760 mg (1.01 mmol, 88% content, 94% of theory) of the desired compound were obtained.
[220] LC-MS (Method 1): tR = 1.37 min; m / z = 663 (M + H) +.
[221] Similar to Example 15A, the following compounds were prepared from the starting materials indicated in each case:


Example 18A
[222] rac-5 - {(fer-Butoxycarbonyl) [2- (2 - {[4- (5-methyl-1,3-benzoxazol-2-yl) benzi!] Oxy} phenyl) ethyl] amino} - Ethyl 5,6,7,8-tetrahydroquinoline-2-carboxylate

[223] 5 g (11.35 mmol) of 5 - {(ferc-butoxycarbonyl) [2- (2-hydroxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate ethyl, 3.51 g (13.62 mmol) of 2- [4- (chloromethyl) phenyl] -5-methyl-1,3-benzoxazole and 3.92 g (28.37 mmol) of potassium carbonate in 50 ml of acetonitrile at 110 ° C and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed several times with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 4: 1 -> 2: 1). 6.59 g (9.96 mmol, 87% of theory) of the desired compound were obtained.
[224] LC-MS (Method 3): t R = 1.62 min; m / z = 662 (M + H) +.
[225] 1H-NMR (400 MHz, CDCI3, δ / ppm): 1.01-1.21 (m, 4H), 1.22-1.35 (m, 3H), 1.37-1.59 (m, 5.5H), 1.60-1.74 (m, 0.5H), 1.74-1.97 (m, 3H), 2.46 (s, 3H), 2.57-2 .79 (m, 2H), 2.79-3.04 (m, 3H), 3.16-3.30 (m, 0.5H), 3.40-3.54 (m, 0.5H) , 4.27 (q, 2H), 4.44-4.64 (m, 0.5H), 5.03-5.28 (m, 2.5H), 6.83-6.95 (m, 1H), 6,977.04 (m, 0.5H), 7.04-7.14 (m, 1H), 7.14-7.29 (m, 3H), 7.40-7.49 (m, 0.5H), 7,497.72 (m, 4H), 7.82 (d, 1H), 8.06 (d, 1H), 8.14 (d, 1H).
[226] Similar to Example 18A, the following compounds were prepared from the starting materials indicated in each case:


Example 22A
[227] rac-5 - {(tert-Butoxycarbonyl) [2- (2 - {[3-chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} -5.6, Ethyl 7,8-tetrahydroquinoline-2-carboxylate

[228] 250 mg (0.57 mmol) of rac-5 - {(ferc-butoxycarbonyl) [2- (2-hydroxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2- ethyl carboxylate (Example 10A), 277 mg (0.68 mmol) of 4- (bromomethyl) -3-chloro-4 '- (trifluoromethyl) biphenyl and 118 mg (0.85 mmol) of potassium carbonate in 10 ml acetonitrile at 110 ° C and stirred at this temperature for 4 h. After cooling, the reaction mixture was filtered, the filter cake was washed several times with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 10: 1 -> 4: 1). The product thus obtained was purified again by preparative HPLC (mobile phase: methanol / water 9: 1). 182 mg (0.26 mmol, 45% of theory) of the desired compound were obtained.
[229] LC-MS (Method 3): tR = 1.70 min; m / z = 709/711 (M + H) +.
[230] Also analogous to Example 18A, the following compounds were prepared from the starting materials indicated in each case:

Example 25A and Example 26A
[231] 5 - {(tert-Butoxycarbonyl) [2- (2 - {[4- (5-methyl-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyljarnino} -õ, 6.7 , 8-ethyl tetrahydroquinoline-2-carboxylate (Enantiomers 1 and 2)

[232] 6.59 g (9.96 mmol) of 5 - {(tert-butoxycarbonyl) [2- (2 - {[4- (5-methyl-1,3-benzoxazol-2-yl) were separated) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-racemic ethyl carboxylate (Example 18A) in its enantiomers by supercritical fluid chromatography (SFC) in a chiral phase [column: Daicel Chiracel OD-H, 5 μm, 250 mm x 20 mm; mobile phase: 75:25 carbon dioxide / ethanol (v / v); flow rate: 125 ml / min; pressure: 150 bar; UV detection: 210 nm; temperature: 38 ° C]: Example 25A (Enantiomer 1):
[233] (+) - 5 - {(fer-Butoxycarbonyl) [2- (2 - {[4- (5-methyl-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate
[234] Yield: 2864 mg
[235] IR = 2.92 min; chemical purity> 99%; > 99.9% enantiomeric excess [column: Chiralpak OD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: 75:25 carbon dioxide / ethanol (v / v); flow rate: 4 ml / min; temperature: 34.3 ° C; UV detection: 210 nm].
[236] [OC] D20 = + 6.345 °, c = 0.415, methanol.
[237] LC-MS (Method 3): IR = 1.62 min; m / z = 662 (M + H) +.
[238] 1H-NMR (400 MHz, CDCI3, δ / ppm): 1.01-1.21 (m, 4H), 1.22-1.35 (m, 3H), 1.37-1.59 (m, 5.5H), 1.60-1.74 (m, 0.5H), 1.74-1.97 (m, 3H), 2.46 (s, 3H), 2.57-2 .79 (m, 2H), 2.79-3.04 (m, 3H), 3.16-3.30 (m, 0.5H), 3.40-3.54 (m, 0.5H) , 4.27 (q, 2H), 4.44-4.64 (m, 0.5H), 5.03-5.28 (m, 2.5H), 6.83-6.95 (m, 1H), 6,977.04 (m, 0.5H), 7.04-7.14 (m, 1H), 7.14-7.29 (m, 3H), 7.40-7.49 (m, 0.5H), 7,497.72 (m, 4H), 7.82 (d, 1H), 8.06 (d, 1H), 8.14 (d, 1H). Example 26A (Enantiomer 2):
[239] (-) - 5 - {(tert-Butoxycarbonyl) [2- (2 - {[4- (5-methyl-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate
[240] Yield: 2359 mg
[241] t R = 4.52 min; chemical purity> 99%; > 99.9% enantiomeric excess [column: Chiralpak OD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: 75:25 carbon dioxide / ethanol (v / v); flow rate: 4 ml / min; temperature: 34.3 ° C; UV detection: 210 nm],
[242] [a] D20 = -6.082 °, c = 0.589, methanol.
[243] LC-MS (Method 3): IR = 1.62 min; m / z = 662 (M + H) +.
[244] 1H-NMR (400 MHz, CDCl3, δ / ppm): 0.98-1.20 (m, 4H), 1.21-1.33 (m, 3H), 1.37-1.59 (m, 5.5H), 1.60-1.74 (m, 0.5H), 1.74-1.98 (m, 3H), 2.46 (s, 3H), 2.58-2 , 79 (m, 2H), 2.79-3.03 (m, 3H), 3.17-3.30 (m, 0.5H), 3.40-3.54 (m, 0.5H) , 4.27 (q, 2H), 4.44-4.64 (m, 0.5H), 5.02-5.27 (m, 2.5H), 6.83-6.96 (m, 1H), 6,967.04 (m, 0.5H), 7.04-7.13 (m, 1H), 7.14-7.30 (m, 3H), 7.40-7.49 (m, 0.5H), 7,497.72 (m, 4H), 7.82 (d, 1H), 8.06 (d, 1H), 8.14 (d, 1H). Example 27A
[245] 5 - {[2- (2 - {[4- (5-methyl-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7 dihydrochloride, Ethyl 8-tetrahydroquinoline-2-carboxylate (Enantiomer 1)

[246] 5 ml of a solution of 4 N hydrogen chloride in dioxane to 581 mg (0.88 mmol) of (+) - 5 - {(tert-butoxycarbonyl) [2- (2 - {[4 - Ethyl (5-methyl-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 25A) and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated to dryness and the residue was dried under high vacuum overnight. 564 mg (0.88 mmol, 100% of theory) of the desired product was obtained as a beige solid.
[247] LC-MS (Method 3): IR = 0.96 min; m / z = 562 (M + H) +.
[248] 1H-NMR (400 MHz, DMSO-dβ, δ / ppm): 1.28 (t, 3H), 1.76-1.89 (m, 1H), 1.97-2.10 (m , 2H), 2.10-2.19 (m, 1H), 2.80-2.92 (m, 1H), 2.92-3.03 (m, 1H), 3.05-3.14 (m, 2H), 3.14-3.72 (m, 2H), 3.54-3.61 (m, 1H), 3.57 (s, 3H), 4.29 (q, 2H), 4.62-4.71 (m, 1H), 5.26 (s, 2H), 6.96 (t, 1H), 7.12 (d, 1H), 7.22-7.32 (m, 3H), 7.62 (s, 1H), 7.65 (m, 3H), 7.84 (d, 1H), 8.20 (d, 3H), 9.29-9.46 (br. S , 2H). Example 28A
[249] 5 - {[2- (2 - {[4- (5 methyl-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8 dihydrochloride ethyl-tetrahydroquinoline-2-carboxylate (Enantiomer 2)

[250] 6.1 ml of a 4 N solution of hydrogen chloride in dioxane at 620 mg (0.94 mmol) of (-) - 5 - {(tert-butoxycarbonyl) [2- (2- { [4- (5-methyl-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 26A), and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated to dryness and the residue was dried under high vacuum overnight. 604 mg (about 0.95 mmol, about 100% of theory) of the desired product was obtained as a beige solid.
[251] LC-MS (Method 3): t R = 1.05 min; m / z = 562 (M + H) +.
[252] Similar to Examples 27A and 28A, the following compounds were prepared:




Example 35A
[253] (-) - 5 - {(5-Ethoxy-5-oxopentyl) [2- (2 - {[4- (5-methyl-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 1)

[254] 0.27 ml (1.70 mmol) of ethyl 5-bromopentanoate, 14 mg (0.09 mmol) of potassium iodide and 372 mg (2.57 mmol) of anhydrous sodium carbonate were added to a solution of 543 mg (0.86 mmol) of 5 - {[2- (2- {[4- (5-methyl-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] dihydrochloride] amino} -5,6,7,8-ethyl tetrahydroquinoline-2-carboxylate (Enantiomer 1, Example 27A) in 10 ml of dry acetonitrile and the mixture was heated under reflux overnight. An additional 0.2 ml of ethyl 5-bromopentanoate was then added and the mixture was stirred under reflux for 8 hours. An additional 0.2 ml of ethyl 5-bromopentanoate and about 14 mg of potassium iodide were added, and the mixture was again heated under reflux overnight. After adding an additional 0.2 ml of ethyl 5-bromopentanoate, the mixture was stirred under reflux for another 8 hours. Finally, about 14 mg more potassium iodide was added and the mixture was heated under reflux overnight. The reaction mixture was then filtered, the filter cake was washed with acetonitrile and the filtrate was concentrated to dryness. The residue obtained was purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 3: 1). 396 mg (0.57 mmol, 67% of theory) of the title compound was obtained as a colorless oil.
[255] LC-MS (Method 3): tn = 1.36 min; m / z = 690 (M + H) +.
[256] 1H-NMR (400 MHz, DMSO-de, δ / ppm): 1.10 (t, 3H), 1.26 (t, 3H), 1.30 1.70 (m, 7H), 1 , 89-2.04 (m, 2H), 2.09-2.20 (m, 2H), 2.35-2.64 (m, 3H, partially obscured by the DMSO signal), 2.45 (s , 3H), 2.65-2.86 (m, 4H), 3.92-4.02 (m, 3H), 4.26 (q, 2H), 5.04-5.15 (m, 2H ), 6.87 (t, 1H), 6.99 (d, 1H), 7.097.21 (m, 2H), 7.25 (d, 1H), 7.52 (d, 2H), 7.61 (s, 1H), 7.63-7.68 (m, 2H), 7.87 (d, 1H), 8.15 (d, 2H).
[257] [ot] D20 = -52.70 °, c = 0.420, methanol. Example 36A
[258] (+) - 5 - {(5-Ethoxy-5-oxopentyl) [2- (2 - {[4- (5-methyl-1,3-benzoxazol-2- i!) Benzyl] oxy} phenyl ) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 2)

[259] 0.28 ml (1.78 mmol) of ethyl 5-bromopentanoate, 15 mg (0.09 mmol) of potassium iodide and 283 mg (2.67 mmol) of anhydrous sodium carbonate were added to a solution of 564 mg (0.89 mmol) of 5 - {[2- (2- {[4- (5-methyl-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] dihydrochloride] amino} -5,6,7,8-tetrahydroquinoline-2-carboxy ethyl acetate (Enantiomer 2, Example 28A) in 10 ml of dry acetonitrile and the mixture was heated under reflux overnight. An additional 0.2 ml of ethyl 5-bromopentanoate was added and the mixture was stirred under reflux for another 8 hours. An additional 0.2 ml of ethyl 5-bromopentanoate and about 14 mg of potassium iodide were added and the mixture was again heated under reflux overnight. After adding an additional 0.2 ml of ethyl 5-bromopentanoate, the mixture was stirred under reflux for another 8 hours. Finally, about 14 mg more potassium iodide was added and the mixture was heated under reflux overnight. The reaction mixture was filtered, the filter cake was washed with acetonitrile and the filtrate was concentrated to dryness. The residue obtained was purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 3: 1). 320 mg (0.46 mmol, 52% of theory) of the title compound were obtained as a colorless oil.
[260] LC-MS (Method 3): tn = 1.37 min; m / z = 690 (M + H) +.
[261] 1H-NMR (400 MHz, DMSO-d6, δ / ppm): 1.10 (t, 3H), 1.26 (t, 3H), 1.301.70 (m, 7H), 1.89- 2.04 (m, 2H), 2.10-2.19 (m, 2H), 2.38-2.64 (m, 3H, partially obscured by the DMSO signal), 2.45 (s, 3H) , 2.65-2.87 (m, 4H), 3.91 -4.03 (m, 3H), 4.26 (q, 2H), 5.04-5.15 (m, 2H), 6 , 87 (t, 1H), 6.99 (d, 1H), 7.097.21 (m, 2H), 7.25 (d, 1H), 7.52 (d, 2H), 7.61 (s, 1H), 7.66 (dd, 2H), 7.87 (d, 1H), 8.15 (d, 2H).
[262] [CI] D20 = + 54.95 °, c = 0.330, methanol.
[263] Similar to Examples 35A and 36A, the following compounds were prepared:




Example 43A
[264] rac-5 - [(2- {2 - [(4-tert-Butylbenzyl) oxy] phenyl} ethyl} {2- [4- (methoxycarbonyl) - phenyl] ethyl} amino] -5,6,7 , 8-tetrahydroquinorma-2-carboxylate

[265] 129 mg (0.65 mmol) of methyl 4- (2-chloroethyl) benzoate and 91 mg (0.86 mmol) of anhydrous sodium carbonate were added to a 210 mg (0.43 mmol) solution ) ethyl 5 - [(2- {2 - [(4-tert-butylbenzyl) oxy] phenyl} ethyl) amino] - 5,6,7,8-tetrahydroquinoline-2 carboxylate dihydrochloride in 4 ml of dry acetonitrile , and the mixture was initially heated under reflux for 4 hours. An additional 0.1 ml of methyl 4- (2-chloroethyl) benzoate was added and the mixture was stirred under reflux for 4 hours. An additional 0.1 ml of methyl 4- (2-chloroethyl) benzoate was added and the mixture was heated under reflux overnight. Subsequently, an additional 0.1 ml of methyl 4- (2-chloroethyl) benzoate and 100 mg of anhydrous sodium carbonate were added and the mixture was stirred under reflux for another 5 hours. Finally, an additional 0.1 ml of methyl 4- (2-chloroethyl) benzoate and 0.2 ml of methyl 4- (2-iodoethyl) benzoate were added and the reaction mixture was stirred under reflux for 2 days. The reaction mixture was concentrated to dryness. The obtained residue was purified by preparative HPLC. 38 mg (0.06 mmol, 92% content, 14% of theory) of the title compound were obtained as a colorless oil.
[266] LC-MS (Method 4): IR = 1.66 min; m / z = 649 (M + H) +. Example 44A and Example 45A
[267] 5 - [(2- {2 - [(4-fer-Butylbenzyl) oxy] phenyl} ethyl) (5-ethoxy-5-oxopentyl) amino] - 5,6,7,8-tetrahydroquinoline-2- ethyl carboxylate (Enantiomers 1 and 2)

[268] 765 mg (1.24 mmol) of 5 - [(2- {2 - [(4-tert-butylbenzyl) oxy] phenyl} ethyl) (5-ethoxy-5-oxopentyl) amino] - Racemic 5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 38A) in the respective enantiomers by preparative HPLC in a chiral phase [column: chiral silica gel phase based on the poly (/ V-methacryloyl- L-phenylalanine-D-neomentylamide) on spherical silica gel SH, 10 μm, 250 mm x 20 mm; mobile phase: ethyl acetate / isohexane 20:80 (v / v); flow rate: 20 ml / min; UV detection: 270 nm; temperature: 25 ° C]: Example 44A (Enantiomer 1):
[269] Yield: 318 mg
[270] t R = 2.84 min; chemical purity> 98%; > 99.9% enantiomeric excess [column: chiral phase of silica gel based on the poly (/ V-methacryloyl-L-phenylalanine-D-neomentylamide) selector on SH spherical silica gel, 5 μm, 250 mm x 4 mm; mobile phase: ethyl acetate / isohexane20: 80 (v / v); flow rate: 1.5 ml / min; UV detection: 260 nm; temperature: 25 ° C]. Example 45A (Enantiomer 2):
[271] Yield: 316 mg
[272] tR = 3.50 min; chemical purity> 98%; > 99% enantiomeric excess [column: chiral phase of silica gel based on the poly (A / -methacryloyl-i-phenylalanine-D-neomentylamide) selector on SH spherical silica gel, 5 μm, 250 mm x 4 mm ; mobile phase: ethyl acetate / isohexane 20:80 (v / v); flow rate: 1.5 ml / min; UV detection: 260 nm; temperature: 25 ° C]. Example 46A and Example 47A
[273] 5 - {[2- (2 - {[3-Chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] (5-ethoxy-5-oxopentyl) amino} -5, Ethyl 6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomers 1 and 2)

[274] 69 mg (0.09 mmol) of 5 - {[2- (2 - {[3-chloro-4'- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] (5 -ethoxy-5-oxopentyl) amino} -5,6,7,8- racemic ethyl tetrahydroquinoline-2-carboxylate (Example 40A) in the respective enantiomers by preparative HPLC in a chiral phase [column: Daicel Chiralcel OZ-H, 5 μm , 250 mm x 20 mm; mobile phase: 50:50 ethanol / isohexane + 0.2% diethylamine (v / v); flow rate: 15 ml / min; UV detection: 220 nm; temperature: 40 ° C]: Example 46A (Enantiomer 1):
[275] Yield: 28 mg
[276] IR = 4.34 min; chemical purity> 99%; > 99% enantiomeric excess [column: Daicel Chiralcel OZ-H, 5 μm, 250 mm x 4.6 mm; mobile phase: 50:50 ethanol / isohexane + 0.2% diethylamine (v / v); flow rate: 1 ml / min; UV detection: 220 nm; temperature: 40 ° C].
[277] LC-MS (Method 3): IR = 1.51 min; m / z = 737 (M + H) +.
[278] [a] D20 = + 61.09o, c = 0.275, methanol. Example 47A (Enantiomer 2):
[279] Yield: 29 mg
[280] IR = 5.14 min; chemical purity> 99%; > 99% enantiomeric excess [column: Daicel Chiralcel OZ-H, 5 μm, 250 mm x 4.6 mm; mobile phase: 50:50 ethanol / isohexane + 0.2% diethylamine (v / v); flow rate: 1 ml / min; UV detection: 220 nm; temperature: 40 ° C].
[281] LC-MS (Method 3): IR = 1.50 min; m / z = 737 (M + H) +.
[282] [OC] D20 = -81.21 °, c = 0.330, methanol. Example 48A and Example 49A
[283] 5 - [(5-Ethoxy-5-oxopentyl) (2- {2 - [(5-phenylpentyl) oxy] pheni!} Ethyl) amino] - 5,6,7,8-tetrahydroquinoline-2-carboxylate ethyl (Enantiomers 1 and 2)

[284] 67 mg (0.11 mmol) of 5 - [(5-ethoxy-5-oxopentyl) (2- {2 - [(5-phenylpentyl) oxy] phenyl} ethyl) amino] -5, Racemic ethyl 6,7,8-tetrahydroquinoline-2-carboxylate (Example 41 A) in the respective enantiomers by preparative HPLC in a chiral phase [column: Daicel Chiralcel OZ-H, 5 μm, 250 mm x 20 mm; mobile phase: ethanol / isohexane 15:85 (v / v); flow rate: 15 ml / min; UV detection: 220 nm; temperature: 40 ° C]: Example 48A (Enantiomer 1):
[285] Yield: 14 mg
[286] tn = 5.84 min; chemical purity> 99%; > 99% enantiomeric excess [column: Daicel Chiralcel OZ-H, 5 μm, 250 mm x 4.6 mm; mobile phase: ethanol / isohexane 15:85 + 0.2% diethylamine (v / v); flow rate: 1 ml / min; UV detection: 220 nm; temperature: 40 ° C].
[287] LC-MS (Method 3): IR = 1.38 min; m / z = 615 (M + H) +. Example 49A (Enantiomer 2):
[288] Yield: 10 mg
[289] tR = 7.30 min; chemical purity> 99%; > 99% enantiomeric excess [column: Daicel Chiralcel OZ-H, 5 μm, 250 mm x 4.6 mm; mobile phase: ethanol / isohexane 15:85 + 0.2% diethylamine (v / v); flow rate: 1 ml / min; UV detection: 220 nm; temperature: 40 ° C].
[290] LC-MS (Method 3): tn = 1.39 min; m / z = 615 (M + H) +. Example 50A and Example 51A
[291] 5 - {(5-Ethoxy-5-oxopentyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} - 5,6,7,8-tetrahydroquinoline Ethyl -2-carboxylate (Enantiomers 1 and 2)

[292] 760 mg (1.15 mmol) of 5 - {(5-ethoxy-5-oxopentyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] was separated] amino} -5,6,7,8-tetrahydroquinoline-2-racemic ethyl carboxylate (Example 15A) in the respective enantiomers by preparative HPLC in a chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 20 mm; mobile phase: isopropanol (+ 0.2% diethylamine) / 50:50 isohexane (v / v); flow rate: 20 ml / min; UV detection: 210 nm; temperature: 20 ° C]: Example 50A (Enantiomer 1):
[293] Yield: 261 mg
[294] IR = 8.78 min; chemical purity> 98%; > 99% enantiomeric excess [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: isopropanol / isohexane 15:85 (v / v); flow rate: 1 ml / min; UV detection: 230 nm; temperature: 20 ° C].
[295] LC-MS (Method 4): tn = 1.40 min; m / z = 663 (M + H) +. Example 51A (Enantiomer 2);
[296] Yield: 276 mg
[297] tR = 9.89 min; chemical purity> 86%; > 98.5% enantiomeric excess [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: isopropanol / isohexane 15:85 (v / v); flow rate: 1 ml / min; UV detection: 230 nm; temperature: 20 ° C].
[298] LC-MS (Method 4): IR = 1.40 min; m / z = 663 (M + H) +. Example 52A and Example 53A
[299] 5 - [(5-Ethoxy-5-oxopentyl) {2- [2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy) phenyl] - ethyl} amino] -5.6 , Ethyl 7,8-tetrahydroquinoline-2-carboxylate (Enantiomers 1 and 2)

[300] 603 mg (0.89 mmol) of 5 - [(5-ethoxy-5-oxopentyl) {2- [2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy were separated ) phenyl] ethyl} amino] -5,6,7,8-tetrahydroquinoline-2-racemic ethyl carboxylate (Example 16A) in the respective enantiomers by preparative HPLC in a chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 20 mm; mobile phase: isopropanol / isohexane 10:90 (v / v); flow rate: 20 ml / min; UV detection: 230 nm; temperature: 25 ° C]: Example 52A (Enantiomer 1);
[301] Yield: 70 mg
[302] IR = 10.83 min; chemical purity> 97.5%; > 99% enantiomeric excess [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: isopropanol (+ 0.2% diethylamine) / isohexane 10:90 (v / v); flow rate: 1 ml / min; UV detection: 230 nm; temperature: 40 ° C]
[303] LC-MS (Method 4): t R = 1.40 min; m / z = 681 (M + H) +.
[304] Example 53A (Enantiomer 2):
[305] Yield: 72 mg
[306] t R = 12.69 min; chemical purity> 93.5%; > 98% enantiomeric excess [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: isopropanol (+ 0.2% diethylamine) / isohexane 10:90 (v / v); flow rate: 1 ml / min; UV detection: 230 nm; temperature: 40 ° C].
[307] LC-MS (Method 4): tR = 1.40 min; m / z = 681 (M + H) +. Example 54A and Example 55A
[308] 5 - {(5-Ethoxy-5-oxopentyl) [2- (2 - {[4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} - phenyl) ethyl] amino} -5,6,7 , 8-ethyl tetrahydroquinoline-2-carboxylate (Enantiomers 1 and 2)

[309] 642 mg (0.91 mmol) of 5 - {(5-ethoxy-5-oxopentyl) [2- (2 - {[4'- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) was separated ) ethyl] amino} -5,6! 7) racemic ethyl 8-tetrahydroquinoline-2-carboxylate (Example 17A) in the respective enantiomers by preparative HPLC in a chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 20 mm; mobile phase: isopropanol / isohexane 20:80 (v / v); flow rate: 15 ml / min; UV detection: 220 nm; temperature: 40 ° C]: Example 54A (Enantiomer 1):
[310] Yield: 161 mg
[311] tn = 5.50 min; chemical purity> 99%; > 99% enantiomeric excess [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: isopropanol (+ 0.2% diethylamine) / isohexane 20:80 (v / v); flow rate: 1 ml / min; UV detection: 220 nm; temperature: 40 ° C].
[312] LC-MS (Method 4): IR = 1.44 min; m / z = 703 (M + H) +. Example 55A (Enantiomer 2):
[313] Yield: 168 mg
[314] t R = 7.01 min; chemical purity> 97.5%; > 99% enantiomeric excess [column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: isopropanol (+ 0.2% diethylamine) / isohexane 20:80 (v / v); flow rate: 1 ml / min; UV detection: 220 nm; temperature: 40 ° C].
[315] LC-MS (Method 4): IR - 1.44 min; m / z = 703 (M + H) +.
[316] Similar to Example 11 A, the following compound was prepared from the indicated starting materials:

[317] In an analogous way to Example 12A, the following compound was prepared from the indicated starting materials:

[318] Similar to Example 18A, the following compound was prepared from the indicated starting materials:

Example 59A and Example 60A
[319] 5 - {(tert-Butoxycarbonyl) [2- (2 - {[4- (5-chloro-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} -5.6 , Ethyl 7,8-tetrahydroquinoline-2-carboxylate (Enantiomers 1 and 2)

[320] 494 mg (0.72 mmol) of 5 - {(tert-butoxycarbonyl) [2- (2 - {[4- (5-chloro-1,3-benzoxazol-2-yl) benzyl] was separated] oxy} phenyl) ethyl] amino} -5,6,7,8-racemic ethyl tetrahydroquinoline-2-carboxylate (Example 58A) in the respective enantiomers by supercritical fluid chromatography (SFC) in a chiral phase [column: Daicel Chiracel OD- H, 5 μm, 250 mm x 20 mm; mobile phase: carbon dioxide / ethanol 70:30 (v / v); flow rate: 100 ml / min; pressure: 100 bar; UV detection: 210 nm; temperature: 40 ° C]: Example 59A (Enantiomer 1):
[321] Yield: 247 mg
[322] tn = 4.47 min; chemical purity> 99.9%; > 99% enantiomeric excess [column: Chiralpak OD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: carbon dioxide / ethanol 70:30 (v / v); flow rate: 3 ml / min; UV detection: 210 nm].
[323] LC-MS (Method 3): t R = 1.62 min; m / z = 682/684 (M + H) +. Example 60A (Enantiomer 2):
[324] Yield: 213 mg
[325] t R = 9.22 min; chemical purity> 99%; > 99% enantiomeric excess [column: Chiralpak OD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: carbon dioxide / ethanol 70:30 (v / v); flow rate: 3 ml / min; UV detection: 210 nm],
[326] LC-MS (Method 3): t R = 1.62 min; m / z = 682/684 (M + H) +. Example 61A
[327] 5 - {[2- (2 - {[4- (5-Chloro-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} - [1], 7,8- ethyl tetrahydroquinoline-2-carboxylate (Enantiomer 1)

[328] 10 ml of a solution of 4N hydrogen chloride in dioxane to 247 mg (0.36 mmol) of 5 - {(tert-butoxycarbonyl) [2- (2 - {[4- (5-chlorine) -1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 1, Example 59A), and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated to dryness and the residue was dried under high vacuum overnight. 210 mg of the title compound were obtained as the hydrochloride as a solid. This solid was mixed with 5 ml of THF, 0.13 ml of triethylamine was added and the mixture was stirred at room temperature for one hour. To the mixture, water and ethyl acetate were added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. 149 mg (0.26 mmol, 72% of theory) of the desired compound were obtained.
[329] LC-MS (Method 3): t R = 1.06 min; m / z = 582/584 (M + H) +.
[330] 1H-NMR (400 MHz, DMSO-d6, δ / ppm): 1.27 (t, 3H), 1.63-1.77 (m, 2H), 1.81-2.02 (m , 2H), 2.71-2.91 (m, 6H), 3.44-3.54 (m, 0.5H), 3.64-3.74 (m, 0.5H), 3.75 -3.84 (br. S, 1H), 4.27 (q, 2H), 5.23 (s, 2H), 6.90 (t, 1H), 7.05 (d, 1H), 7, 14-7.24 (m, 2H), 7.49 (dd, 1H), 7.67 (d, 2H), 7.74 (d, 1H), 7.82-7.90 (m, 2H) , 7.95 (d, 1H), 8.20 (d, 2H).
[331] In an analogous way to Example 61 A, the following compound was prepared:

Example 63 IA
[332] 5 - ([2- (2 - {[4- (5-chloro-1,3-Benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] {2- [4- (methoxycarbonyl) phenyl] ethyl} amino) -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 1)

[333] 112 mg (0.39 mmol) of methyl 4- (2-iodoethyl) benzoate and 41 mg (0.39 mmol) of anhydrous sodium carbonate were added to a solution of 149 mg (0.26 mmol) ) of 5 - {[2- (2 - {[4- (5-chloro-1,3-benzoxazol-2-yl) benzyl] oxy} - phenyl) ethyl] amino} -5,6,7,8- ethyl tetrahydroquinoline-2-carboxylate (Enantiomer 1, Example 61 A) in 10 ml of dry acetoylitrile, and the mixture was heated under reflux overnight. Another 112 mg of methyl 4- (2-iodoethyl) benzoate was added and the mixture was again heated under reflux overnight. The reaction mixture was then evaporated to dryness, the residue was mixed with water and ethyl acetate and the phases were separated. The organic phase was evaporated to dryness and the residue obtained was purified by preparative HPLC. 72 mg (0.10 mmol, 38% of theory) of the title compound were obtained.
[334] LC-MS (Method 3): tR = 1.60 min; m / z = 744/746 (M + H) +.
[335] In an analogous way to Example 63A, the following compound was prepared
Example 65A
[336] 5 - {[2- (2 - {[4- (5-Methyl-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} - 5,6,7,8- ethyl tetrahydroquinoline-2-carboxylate (Enantiomer 1)

[337] 3.8 g (5.99 mmol) of 5 - {[2- (2 - {[4- (5-methyl-1,3-benzoxazol-2-yl) benzyl] oxy dihydrochloride was dissolved } phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 1, Example 27A) in 50 ml of THF, 2.5 ml of triethylamine was added and the mixture was stirred at room temperature for 1 h. Water and ethyl acetate were added to the mixture and the phases were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. 2.48 g (4.42 mmol, 74% of theory) of the desired compound were obtained.
[338] LC-MS (Method 3): IR = 1.06 min; m / z = 562 (M + H) +.
[339] 1H-NMR (400 MHz, DMSO-d6, δ / ppm): 1.27 (t, 3H), 1.59-1.79 (m, 2H), 1.99 (s, 3H), 2.01-2.16 (m, 1H), 2.69-2.92 (m, 6H), 3.42-3.55 (m, 1H), 3.64-3.87 (m, 1H ), 3.98-4.07 (m, 1H), 4.28 (q, 2H), 5.22 (s, 2H), 6.84-6.95 (m, 1H), 7.007.09 ( m, 1H), 7.20 (s, 3H), 7.58-7.70 (m, 4H), 7.71-7.79 (m, 1H), 7.83-7.94 (m, 1H), 8.18 (d, 2H).
[340] In an analogous way to Example 65A, the following compound was prepared:

[341] In an analogous way to Example 63A, the following compounds were prepared:


Example 69A
[342] 5 - {(tert-Butoxycarbonyl) [2- (2-hid roxifenil) ethyl] amino} -5,6,7,8-ethyl tetrahydroquinoline-2-carboxylate (Enantiomer 2)

[343] 10 g (15.11 mmol) of (-) - 5 - {(ferc-butoxycarbonyl) [2- (2 - {[4- (5-methyl-1,3-benzoxazol-2- il) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 26A) in 500 ml of ethanol and 9.53 g (151 , 10 mmol) of ammonium formate and 161 mg (1.51 mmol) of 10% palladium on activated carbon. The reaction mixture was heated to 80 ° C and stirred at this temperature overnight. The mixture was then cooled to room temperature, an additional 100 mg of the palladium catalyst was added and the mixture was stirred at 80 ° C for another 6 h. The reaction mixture was then again cooled to room temperature and filtered, and the filtrate was evaporated to dryness. The obtained residue was purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 20: 1 2: 1). 6.55 g (14.87 mmol, 98% of theory) of the title compound were obtained.
[344] LC-MS (Method 3): tR = 1.17 min; m / z = 441 (M + H) +.
[345] An alternative way of preparing Example 69A is shown in the description of Example 147A (q.v.).
[346] In an analogous way to Example 11A, the following compounds were prepared from the indicated starting materials:


[347] In an analogous way to Example 12A, the following compounds were prepared from the indicated starting materials:
Example 74A
[348] 5 - {(tert-Butoxycarbonyl) [2- (2 - {[3-chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} -5,6,7, Ethyl 8-tetrahydroquinoline-2-carboxylate (Enantiomer 2)

[349] A suspension of 51.21 g (116.24 mmol) of 5 - {(tert-butoxycarbonyl) [2- (2-hydroxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2- ethyl carboxylate (Enantiomer 2, Example 69A), 44.70 g (127.86 mmol) of 4- (bromomethyl) -3-chloro-4 '- (trifluoromethyl) biphenyl and 40.16 g (290.60 mmol) of potassium carbonate in 1420 ml of acetonitrile was heated to 110 ° C and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed several times with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified by chromatography on silica gel (2.5 kg) (mobile phase: petroleum ether / ethyl acetate 4: 1). 79 g (111.39 mmol, 96% of theory) of the desired compound were obtained.
[350] LC-MS (Method 3): IR = 1.69 min; m / z = 709 (M + H) +.
[351] 1H-NMR (400 MHz, DMSO-cfe, δ / ppm): 1.05-1.20 (m, 4H), 1.21-1.34 (m, 4H), 1.45 (S , 6H), 1.56-1.74 (m, 2H), 1.75-1.93 (m, 2H), 2.76-2.99 (m, 3H), 4.30 (q, 2H ), 5.00-5.24 (m, 3H), 6.86-6.99 (m, 1H), 7.03-7.16 (m, 1.5H), 7.17-7.29 (m, 1.5H), 7.38-7.45 (m, 0.5H), 7.50-7.56 (m, 0.5H), 7.58-7.68 (m, 1H) , 7.69-7.78 (m, 1.5H), 7.79-7.93 (m, 5H), 8.01-8.12 (m, 1.5H).
[352] An alternative way of preparing Example 74A is shown in the description of Example 148A (q.v.).
[353] Similar to Example 74A described above, the following compounds were prepared from the starting materials indicated in each case:




Example 80A
[354] 5 - {[2- (2 - {[3-chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline dihydrochloride Ethyl -2-carboxylate (Enantiomer 2)

[355] 557 ml of a solution of 4N hydrogen chloride in dioxane was added, diluted with an additional 389 ml of dioxane, added to 79 g (111.39 mmol) of 5 - {(tert-butoxycarbonyl) [2- (2 - {[3-chloro-4 '- (trifluoromethyl) biphenyl-4-yl] - methoxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate ( Enantiomer 2, Example 74A), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated to dryness and the residue was dried under high vacuum overnight. 78 g (111.39 mmol, about 100% of theory) of the desired product were obtained.
[356] LC-MS (Method 3): t R = 1.07 min; m / z = 609/611 (M + H) +.
[357] In an analogous way to Example 80A, the following compounds were prepared:




Example 86A
[358] 5 - {[2- (2 - {[3-Chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} - 5,6,7,8-tetrahydroquinoline-2 -ethyl carboxylate (Enantiomer 2)

[359] 78 g (111.39 mmol) of 5 - {[2- (2 - {[3-chloro-4'- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] dihydrochloride] amino} -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 2, Example 80A) in 1200 ml of THE, 47 ml of triethylamine was added and the mixture was stirred at room temperature for 1 h. The precipitated triethylammonium chloride crystals were filtered and washed with THE. The filtrate obtained was evaporated to dryness. The residue was dissolved in ethyl acetate, washed twice with 10% aqueous sodium chloride solution, dried over magnesium sulfate, filtered and again evaporated to dryness. 69 g (111.24 mmol, 99.9% of theory) of the desired compound were obtained.
[360] LC-MS (Method 3): IR = 1.07 min; m / z = 609/611 (M + H) +.
[361] 1H-NMR (400 MHz, DMSO-d6, δ / ppm): 1.27 (t, 3H), 1.59-1.71 (m, 2H), 1.76-1.87 (m , 1H), 1.87-1.95 (m, 1H), 1.96-2.06 (m, 1H), 2.66-2.89 (m, 6H), 3.75 (br. S , 1H), 4.27 (q, 2H), 5.19 (s, 2H), 6.91 (t, 1H), 7.07 (d, 1H), 7.16 - 7.27 (m, 2H), 7.65-7.77 (m, 3H), 7.83 (d, 3H), 7.88 (s, 1H), 7.94 (d, 2H).
[362] In an analogous way to Example 86A, the following compounds were prepared:




Example 92A
[363] 5 - ([2- (2 - {[3-Chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] {2- [4- (methoxycarbonyl) phenyl] ethyl} amino ) -5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2)

[364] A 69 g (111.24 mmol) suspension of 5 - {[2- (2 - {[3-chloro-4'- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate ethyl (Enantiomer 2, Example 86A), 129 g (444.98 mmol) of methyl 4- (2-iodoethyl) benzoate and 17.68 g (166 , 87 mmol) of anhydrous sodium carbonate in 1500 ml of dry acetonitrile was stirred at a bath temperature of 110 ° C overnight. A further 65.54 g of methyl 4- (2-iodoethyl) benzoate and 23.06 g (166.87 mmol) of powdered potassium carbonate were added and the mixture was heated under reflux for another 48 h. After cooling the reaction mixture, the inorganic salts were filtered and the filtrate obtained was evaporated to dryness. The resulting residue was mixed with ethyl acetate, washed twice with 10% aqueous sodium chloride solution, dried over magnesium sulfate, filtered and again evaporated to dryness. The residue obtained was purified by chromatography on silica gel (3 kg) (mobile phase: petroleum ether / ethyl acetate 8: 2 -> 7: 3). 42 g (54.45 mmol, 49% of theory) of the desired compound were obtained.
[365] LC-MS (Method 3): tR = 1.69 min; m / z = 771/773 (M + H) +.
[366] 1H-NMR (400 MHz, DMSO-d6, δ / ppm): 1.27 (t, 3H), 1.37-1.52 (m, 1H), 1.52-1.67 (m , 1H), 1.85-1.95 (m, 1H), 1.96-2.05 (m, 1H), 2.56-2.79 (m, 10H), 3.80 (S, 3H ), 3.97-4.09 (m, 1H), 4.26 (q, 2H), 5.07 (m, 2H), 6.88 (t, 1H), 7.01-7.16 ( m, 4H), 7.24 (t, 1H), 7.36-7.48 (m, 2H), 7.53 (d, 1H), 7.61 (d, 1H), 7.74 (d , 2H), 7.77- 7.88 (m, 5H).
[367] In an analogous way to Example 92A, the following compounds were prepared:






[368] Similar to Examples 35A and 36A, the following compounds were prepared:




Example 103A
[369] rac-5 - {[2- (5-Fluoro-2-methoxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carbonitrile

[370] 21.98 g (127.66 tetrahydroquinoline-2-carbonitrile, 21.6 g (127.66 mmol) of 2- (5-fluoro-2-methoxyphenyl) ethanamine) were dissolved [CAS Reg.-No. 1000533-03-8] and 3.64 g (19.15 mmol) of p-toluenesulfonic acid monohydrate in 511 ml of toluene, and the solution was stirred under reflux overnight using a water separator. of toluene and, after cooling, it was replaced with new toluene.The reaction solution was evaporated to dryness and the resulting residue was mixed with 511 ml of anhydrous ethanol and 511 ml of anhydrous THF. With stirring and at a temperature of 15 ° at 20 ° C, 9.66 g (255.32 mmol) of sodium borohydride were added to the solution, a little at a time (caution: reaction mixture foamed). The reaction solution was then stirred at the same temperature during 10% aqueous sodium chloride solution was added carefully and the reaction mixture was extracted twice with ethyl acetate The combined organic phases were dried over sodium sulfate sodium, filtered and concentrated to dryness. The residue thus obtained was purified by silica gel column chromatography (mobile phase: cyclohexane / ethyl acetate 2: 1). 19.5 g (59.93 mmol, 46% of theory) of the desired compound were obtained.
[371] LC-MS (Method 2): t R = 1.55 min; m / z = 326 (M + H) +.
[372] 1H-NMR (400 MHz, DMSO-dβ, δ / ppm): 1.63-1.81 (m, 2H), 1.84-2.04 (m, 2H), 2.12 (br . s, 1H), 2.63-2.93 (m, 6H), 3.74 (s, 3H), 3.80 (br. s, 1H), 6.87 - 7.08 (m, 3H), 7.78 (d, 1H), 7.94 (d, 1H). Example 104A
[373] rac-Acid 5 - {[2- (5-fluoro-2-hydroxyphenyl) ethyl] amino} -5,6,7,8-

[374] 72.8 g (223.73 mmol) of rac-5 - {[2- (5-fluoro-2-methoxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2 were mixed -carbonitrile with 360 ml hydrobromic acid (48% in water), was initially stirred at boiling point for 12 h, then cooled to room temperature and left to stand at this temperature overnight. The reaction solution was then diluted with 400 ml of water and adjusted to pH 6 with saturated sodium bicarbonate solution. The crystals formed were suction filtered, washed with water and dried under reduced pressure, at 50 ° C. 59 g (178.59 mmol, 80% of theory) of the desired compound were obtained.
[375] LC-MS (Method 2): tp = 1.30 min; m / z = 331 (M + H) +. Example 105A
[376] ethyl rac-5 - {[2- (5-Fluoro-2-hydroxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate

[377] 40 ml of anhydrous ethanol and 4 ml of a solution of 4N hydrogen chloride in dioxane were added to 1.93 g (5.84 mmol) of rac-acid 5 - {[2- (5-fluoro- 2-hydroxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylic acid, and the mixture was stirred under reflux overnight. The reaction solution was then cooled to room temperature and then ethyl acetate was added first and then slowly saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated to dryness. 1.67 g (4.66 mmol, 80% of theory) of the desired compound was obtained.
[378] LC-MS (Method 3): tR = 0.60 min; m / z = 359 (M + H) +.
[379] 1H-NMR (400 MHz, DMSO-cfe, δ / ppm): 1.32 (t, 3H), 1.69-1.82 (m, 2H), 1.93 (m, 1H), 1.94-2.08 (m, 1H), 2.64-2.77 (m, 4H), 2.79-2.91 (m, 2H), 3.81 - 3.90 (m, 1H ), 4.33 (q, 2H), 6.68-6.75 (m, 1H), 6.77-6.85 (m, 1H), 6.87-6.94 (m, 1H), 7.83 (d, 1H), 7.91 (d, 1H), 10.56-10.73 (m, 1H). Example 106A
[380] rac-5 - ethyl {(tert-Butoxycarbonyl) [2- (5-fluoro-2-hydroxyphenyl) ethyl] amino} - 5,6,7) 8-tetrahydroquinoline-2-carboxyate

[381] 3.73 g (10.41 mmol) of rac-5 - {[2- (5-fluoro-2-hydroxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2 was dissolved ethyl carboxylate in 30 ml of dichloromethane and, with stirring, cooled to 0 ° C. A solution of 2.95 g (13.53 mmol) of di-tert-butyl dicarbonate in 10 ml of dichloromethane was then added slowly dropwise and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated to dryness and the residue was treated with diethyl ether. After filtration, the filter cake was washed several times with diethyl ether and then dried in air. 4.17 g (9.09 mmol, 87% of theory) of the desired compound were obtained.
[382] LC-MS (Method 3): tR = 1.18 min; m / z = 459 (M + H) +.
[383] 1H-NMR (400 MHz, CDCh, δ / ppm): 1.12 (br. S, 4H), 1.31 (t, 3H), 1.47 (s, 5H), 1.67- 1.90 (m, 1H), 1.91-2.11 (m, 3H), 2.63-2.98 (m, 5H), 3.20-3.55 (m, 1H, partially obscured by H2O signal), 4.32 (q, 2H), 4.64-4.87 (m, 0.5H), 5.08-5.27 (m, 0.5H), 6.65-7.00 (m, 3H), 7.43-7.63 (m, 1H), 7.83 (d, 1H), 9.37 (s, 1H). Example 107A
[384] rac-5 - {(tert-Butoxycarbonyl) [2- (2 - {[4- (5-chloro-1,3-benzoxazol-2-yl) benzyl] oxy} -5-fluorophenyl) ethyl] amino } -5,6,7,8-tetrahydroquinoline-2-carboxylate

[385] 4.17 g (9.09 mmol) of rac-5 - {(tert-butoxycarbonyl) [2- (5-fluoro-2-hydroxyphenyl) ethyl] amino} -5,6,7 was heated, Ethyl 8-tetrahydroquinoline-2-carboxylate, 3.04 g (10.91 mmol) of 5-chloro-2- [4- (chloromethyl) phenyl] -1,3-benzoxazole and 3.14 g (22.74 mmol) of potassium carbonate at 110 ° C in 120 ml of acetonitrile and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed several times with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 10: 1 -> 4: 1). 5.43 g (7.75 mmol, 85% of theory) of the desired compound were obtained.
[386] LC-MS (Method 3): IR = 1.60 min; m / z - 700/702 (M + H) +. Example 108A and Example 109A
[387] 5 - {(tert-Butoxycarbonyl) [2- (2 - {[4- (5-chloro-1,3-benzoxazol-2-yl) benzyl] oxy} -5-fluorophenyl) ethyl] amino} - Ethyl 5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomers 1 and 2)

[388] 2.5 g (3.57 mmol) of 5 - {(tert-butoxycarbonyl) [2- (2 - {[4- (5-chloro-1,3-benzoxazol-2-yl) were separated benzyl] oxy} -5-fluorophenyl) ethyl] amino} -5,6,7,8- racemic ethyl tetrahydroquinoline-2-carboxylate (Example 107A) in the respective enantiomers by supercritical fluid chromatography (SFC) in a chiral phase [column : Daicel Chiracel OD-H, 5 μm, 250 mm x 20 mm; mobile phase: 75:25 carbon dioxide / ethanol (v / v); flow rate: 100 ml / min; pressure: 80 bar; UV detection: 220 nm; temperature: 40 ° C]: Example 108A (Enantiomer 1):
[389] Yield: 1020 mg
[390] IR = 3.477 min; chemical purity> 99.9%; > 99% enantiomeric excess [column: Chiralpak OD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: carbon dioxide / ethanol 70:30 (v / v); flow rate: 3 ml / min; UV detection: 210 nm],
[391] LC-MS (Method 3): tR = 1.60 min; m / z = 700/702 (M + H) +. Example 109A (Enantiomer 2):
[392] Yield: 1040 mg
[393] IR = 4.97 min; chemical purity> 99%; > 95% enantiomeric excess [column: Chiralpak OD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: carbon dioxide / ethanol 70:30 (v / v); flow rate: 3 ml / min; UV detection: 210 nm],
[394] LC-MS (Method 3): t R = 1.60 min; m / z = 700/702 (M + H) +.
[395] 1H-NMR (400 MHz, DMSO-cfe, δ / ppm): 1.09 (br. S, 4H), 1.27 (m, 3H), 1.43 (S, 5H), 1, 50-1.62 (m, 0.5H), 1.63-1.75 (m, 0.5H), 1.76-1.97 (m, 3H), 2.59-2.80 (m , 2H), 2.81-3.04 (m, 3H), 3.20-3.40 (m, 0.5H, partially obscured by the H2O signal), 3.42-3.57 (m, 0, 5H), 4.27 (q, 2H), 4.39-4.60 (m, 0.5H), 5.00- 5.11 (m, 0.5H), 5.11-5.26 ( m, 2H), 6.90-6.98 (m, 0.5H), 6.99-7.17 (m, 2.5H), 7.44 (d, 0.5H), 7.51 ( d, 1.5H), 7.59 (d, 1H), 7.69 (d, 1H), 7.76-7.89 (m, 2H), 7.93 (d, 1H), 8.06 (d, 1H), 8.16 (d, 1H).
[396] Analogously to Example 107A, the following compound was prepared:

Example 111A and Example 112A
[397] 5 - {(ferc-Butoxycarbonyl) [2- (2 - {[3-chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} -5-fluorophenyl) ethyl] amino} -5.6 , Ethyl 7,8-tetrahydroquinoline-2-carboxylate (Enantiomers 1 and 2)

[398] 2.59 g (3.56 mmol) of 5 - {(tert-butoxycarbonyl) [2- (2 - {[3-chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy) was separated } -5-fluorophenyl) ethyl] amino} -5,6,7,8- racemic ethyl tetrahydroquinoline-2-carboxylate (Example 110A) in the respective enantiomers by supercritical fluid chromatography (SFC) in a chiral phase [column: Daicel Chiracel OD, 20 μm, 250 mm x 30 mm; mobile phase: 80:20 carbon dioxide / ethanol (v / v); flow rate: 175 ml / min; pressure: 135 bar; UV detection: 210 nm; temperature: 40 ° C]: Example 111A (Enantiomer 1):
[399] Yield: 1130 mg
[400] t R = 2.24 min; chemical purity> 85%; > 99% enantiomeric excess [column: Chiralpak OD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: carbon dioxide / ethanol 70:30 (v / v); flow rate: 3 ml / min; UV detection: 210 nm].
[401] LC-MS (Method 3): IR = 1.65 min; m / z = 727/729 (M + H) +. Example 112A (Enantiomium 2):
[402] Yield: 1170 mg
[403] t R = 3.33 min; chemical purity> 99%; > 90% enantiomeric excess [column: Chiralpak OD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: carbon dioxide / ethanol 70:30 (v / v); flow rate: 3 ml / min; UV detection: 210 nm].
[404] LC-MS (Method 3): tn = 1.65 min; m / z = 727/729 (M + H) +. Example 113A
[405] 5 - {[2- {2 - {[4- (5-chloro-1,3-benzoxazol-2-yl) benzyl] oxy} -5-fluorophenyl) ethyl dihydrochloride]
[406] amino} -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 2)

[407] 11 ml of a solution of 425 hydrogen chloride in dioxane at 1025 mg (1.46 mmol) of 5 - {(tert-butoxycarbonyl) [2- (2 - {[4- (5-chlorine) -1,3-benzoxazol-2-yl) benzyl] oxy} -õ-fluorophenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 2, Example 109A), and The mixture was stirred at room temperature for 2 h. The precipitated solid was filtered, washed several times with diethyl ether and dried under high vacuum at 40 ° C overnight. 980 mg (1.46 mmol, about 99% of theory) of the desired product were obtained.
[408] LC-MS (Method 3): tn = 1.01 min; m / z = 600/602 (M + H) +.
[409] In an analogous way to Example 113A, the following compounds were prepared:


Example 117A
[410] 5 - {[2- (2 - {[4- (5-Chloro-1,3-benzoxazol-2-yl) benzyl] oxy} -5-fluorophenyl) ethyl] amino} -5,6,7 Ethyl 8-tetrahydroquinoline-2-carboxylate

[411] 980 mg (1.46 mmol) of 5 - {[2- (2 - {[3-chloro-4'- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] dihydrochloride] amino} -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 2, Example 113A) in 20 ml of THF, 0.81 ml of triethylamine was added and the mixture was stirred at room temperature for 1 H. Ethyl acetate and water were added to the reaction solution, the phases were separated and the organic phase was extracted once more with ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. 760 mg (1.27 mmol, 87% of theory) of the desired compound was obtained.
[412] LC-MS (Method 3): IR = 1.03 min; m / z = 600/602 (M + H) +.
[413] 1H-NMR (400 MHz, DMSO-de, δ / ppm): 1.28 (t, 3H), 1.62-1.78 (m, 2H), 1.80-2.01 (m , 2H), 2.03-2.17 (m, 1H), 2.70-2.92 (m, 6H), 3.65-3.89 (m, 1H), 4.28 (q, 2H ), 5.21 (s, 2H), 6.94-7.15 (m, 3H), 7.48 (dd, 1H), 7.66 (d, 2H), 7.71-7.79 ( m, 1H), 7.85 (d, 2H), 7.94 (d, 1H), 8.19 (d, 2H).
[414] In an analogous way to Example 117A, the following compound was prepared:


[415] Similar to Examples 35A and 36A, the following compounds were prepared:


Example 121A
[416] 5 - ([2- (2 - {[4- (5-Chloro-1,3-benzoxazol-2-yl) benzyl] oxy} -5-fluorophenyl) ethyl] {2- [4- (methoxycarbonyl ) phenyl] ethyl} amino) -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 2)

[417] A 375 mg (0.63 mmol) suspension of 5 - {[2- (2 - {[4- (5-chloro-1,3-benzoxazol-2-yl) benzyl] oxy} -5- fluorophenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 2, Example 117A), 272 mg (0.94 mmol) of methyl 4- (2-iodoethyl) benzoate and 99 mg (0.94 mmol) of anhydrous sodium carbonate in 10 ml of dry acetonitrile was stirred overnight at a bath temperature of 110 ° C. Another 272 mg of methyl 4- (2-iodoethyl) benzoate and 99 mg of sodium carbonate were added and the mixture was again heated under reflux overnight. A further 272 mg of methyl 4- (2-iodoethyl) benzoate and 99 mg of sodium carbonate were added and the mixture was heated under reflux again overnight. After cooling the reaction mixture, ethyl acetate and water were added, the organic phase was separated and the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and evaporated to dryness. The residue obtained was purified by chromatography on silica gel (mobile phase: petroleum ether / ethyl acetate 4: 1 -> 2: 1). 324 mg (0.42 mmol, 68% of theory) of the desired compound was obtained.
[418] LC-MS (Method 3): t R = 1.63 min; m / z = 762/764 (M + H) +.
[419] 1H-NMR (400 MHz, DMSO-dβ, δ / ppm): 1.26 (t, 3H), 1.41-1.55 (m, 1H), 1.55-1.69 (m , 1H), 1.89-2.08 (m, 2H), 2.57-2.83 (m, 10H), 3.76 (s, 3H), 4.02-4.12 (m, 1H ), 4.26 (q, 2H), 5.02-5.12 (m, 2H), 6.95 (d, 1H), 7.03 (d, 2H), 7.11 (d, 2H) , 7.41 (d, 1H), 7.45-7.56 (m, 4H), 7.72 (d, 2H), 7.82 (d, 1H), 7.92 (d, 1H), 8.09 (d, 2H).
[420] Similar to Example 121 A, the following compound was prepared:
Example 123A
[421] 5 - ([2- (2 - {[3-Chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} -5-fluorophenyl) ethyl] {2- [4- (methoxycarbonyl) phenyl] ethyl} amino) -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 2)

[422] 685 mg (2.36 mmol) of methyl 4- (2-iodoethyl) benzoate and 188 mg (1.77 mmol) of anhydrous sodium carbonate were added to a solution of 740 mg (1.18 mmol) ) dihydrochloride 5 - {[2- (2 - {[3-chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} - 5-fluorophenyl) ethyl] amino} -5,6,7,8- ethyl tetrahydroquinoline-2-carboxylate, (Enantiomer 2, Example 116A) in 20 ml of dry acetonitrile, and the mixture was heated under reflux overnight. An additional 342 mg of methyl 4- (2-iodoethyl) benzoate was added and the mixture was stirred under reflux overnight. This procedure was repeated two more times in the following days. An additional 342 mg of methyl 4- (2-iodoethyl) benzoate and 188 mg of anhydrous sodium carbonate were then added and the mixture was stirred again under reflux overnight. An additional 342 mg of methyl 4- (2-iodoethyl) benzoate was added to the reaction solution, the mixture was heated under reflux overnight and then cooled to room temperature. The reaction mixture was filtered, the filter cake was washed with acetonitrile and the filtrate was concentrated to dryness. The residue was taken up in ethyl acetate, and water was added again. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to dryness. The residue obtained was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 10: 1 -> 4: 1). 588 mg (0.40 mmol, 63% of theory) of the title compound were obtained.
[423] LC-MS (Method 3): t R = 1.68 min; m / z = 789/791 (M + H) +.
[424] 1H-NMR (400 MHz, DMSO-d6, δ / ppm): 1.27 (t, 3H), 1.38-1.51 (m, 1H), 1.51 -1.68 (m , 1H), 1.87-2.05 (m, 2H), 2.57-2.80 (m, 10H), 3.81 (s, 3H), 4.00-4.08 (m, 1H ), 4.26 (q, 2H), 5.00-5.10 (m, 2H), 6.92-6.98 (m, 1H), 7.01-7.15 (m, 4H), 7.35-7.42 (m, 2H), 7.53 (d, 1H), 7.61 (d, 1H), 7.74 (d, 2H), 7.77-7.88 (m, 5H).
[425] In an analogous way to Example 123A, the following compound was prepared:

Example 125Á
[426] 4 - [(EZ7) -2- (4-Fluorophenyl) vinyl] methyl benzoate

[427] 79.75 g (176.70 mmol) of (4-fluorobenzyl) (triphenyl) phosphonium bromide and 29.59 g (180.24 mmol) of methyl 4-formylbenzoate were dissolved in 250 ml of methanol , the solution was cooled to 0 ° C and 10.98 g (203.21 mmol) of sodium methoxide was added a little at a time. The reaction mixture was then slowly warmed up to room temperature and stirred at this temperature overnight. The reaction solution was again cooled to 0 ° C, an additional 4.77 g (88.35 mmol) of sodium methoxide was added to the portions and, after heating to room temperature, the mixture was again stirred for at night. The precipitated solid was filtered, washed with methanol and dried in a drying oven at 40 ° C and under reduced pressure overnight. 21.08 g (82.25 mmol, 46.5% of theory) of the desired compound were obtained. The filtrate was evaporated to dryness and the residue obtained was purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1). An additional 23.75 g (92.67 mmol, 52% of theory) of the title compound was obtained.
[428] LC-MS (Method 2): IR = 2.80 min; m / z = 257 (M + H) + (fraction 1); IR - 2.82 min; m / z = 257 (M + H) + (fraction 2). Example 126A
[429] methyl 4- [2- (4-fluorophenyl) ethyl] benzoate

[430] 2 g of 10% palladium on carbon was added to 44 g (171.70 mmol) of methyl 4 - [(E / Z) -2- (4-fluorophenyl) vinyl] benzoate in 500 ml of THF and the mixture was stirred at room temperature, overnight, under a hydrogen atmosphere and at standard pressure. An additional 1 g of 10% palladium on charcoal was added and the mixture was again stirred at room temperature overnight under a hydrogen atmosphere at standard pressure. The reaction mixture was then filtered and the resulting filtrate was concentrated to dryness. 35 g (135.5 mmol, 79% of theory) of the title compound were obtained.
[431] LC-MS (Method 2): IR = 2.76 min; m / z = 259 (M + H) +. Example 127A
[432] {4- [2- (4-Fluorophenyl) ethyl] phenyl} methanol

[433] Under reflux, 45 ml of a solution of 3.5 M lithium aluminum hydride in toluene was slowly added to a solution of 35.4 g (136.98 mmol) of 4- [2- (4- fluorophenyl) ethyl] methyl benzoate in 500 ml of dry THF. At the end of the addition, the reaction mixture was stirred at reflux for one hour. The reaction mixture was then cooled to 0 ° C and then, slowly and carefully, 500 ml of ice cold 1M hydrochloric acid was added. 750 ml of ethyl acetate was added, the aqueous phase was removed and the organic phase was washed successively, in each case, once with 1M hydrochloric acid and saturated sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered and concentrated to dryness. 31.5 g (136.7 mmol, 99.9% of theory) of the title compound were obtained.
[434] LC-MS (Method 3): t R = 1.05 min; m / z = 213 (M + H-H2O) +.
[435] 1H-NMR (400 MHz, DMSO-d6, δ / ppm): 2.84 (s, 4H), 4.44 (d, 2H), 5.09 (t, 1H), 7.08 ( t, 2H), 7.13-7.27 (m, 6H). Example 128A
[436] 1 - (Chloromethyl) -4- [2- (4-fluorophenyl) ethyl] benzene

[437] At 0 ° C, 14.96 ml of thionyl chloride in 100 ml of dichloromethane was slowly added dropwise to a solution of 31.5 g (136.7 mmol) of {4- [2- ( 4-fluorophenyl) ethyl] phenyl} methanol in 400 ml of dichloromethane. At the end of the addition, the reaction mixture was warmed to room temperature and stirred for another 2 hours at this temperature. The reaction mixture was again cooled to 0 ° C and, slowly and carefully, 200 ml of saturated aqueous sodium bicarbonate solution was added under vigorous stirring. Then, small portions of solid sodium bicarbonate were added to the solution until the pH was adjusted to 6. The phases were separated and the organic phase was dried over magnesium sulfate, filtered and concentrated to dryness. 28.5 g (114.5 mmol, 84% of theory) of the title compound were obtained.
[438] 1H-NMR (400 MHz, DMSO-c / e, δ / ppm): 2.86 (s, 4H), 4.72 (s, 2H), 7.08 (t, 2H), 7, 19-7.28 (m, 4H), 7.33 (d, 2H). Example 129A
[439] rac-5 - [(tert-Butoxycarbonyl) {2- [2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} - oxy) phenyl] ethyl} amino] -5,6,7 Ethyl 8-tetrahydroquinoline-2-carboxylate

[440] 5.60 g (12.71 mmol) of rac-5 - {(tert-butoxycarbonyl) [2- (2-hydroxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline- Ethyl 2-carboxylate, 3.79 g (15.25 mmol) of 1- (chloromethyl) -4- [2- (4-fluorophenyl) ethyl] benzene and 2.64 g (19.07 mmol) of carbonate potassium in 200 ml of acetonitrile up to 110 ° C and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed several times with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 10: 1 -> 4: 1). 6.8 g (10.42 mmol, 82% of theory) of the desired compound were obtained.
[441] LC-MS (Method 3): t R = 1.62 min; m / z = 653 (M + H) +. Example 130A and Example 131A
[442] 5 - [(ferc-Butoxycarbonyl) {2- [2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy) phenyl] - ethyl} amino] -5,6,7,8 ethyl-tetrahydroquinoline-2-carboxylate (Enantiomers 1 and 2)

[443] 6.8 g (10.42 mmol) of 5 - [(ferc-butoxycarbonyl) {2- [2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy) were separated ] ethyl} amino] racemic ethyl -5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 129A) in the respective enantiomers by supercritical fluid chromatography (SFC) in a chiral phase [column: Chiracel OD-H, 20 μm , 250 mm x 30 mm; mobile phase: carbon dioxide / ethanol 83:17 (v / v); flow rate: 185 ml / min; pressure: 135 bar; UV detection: 210 nm; temperature: 38 ° C]: Example 130A (Enantiomer 1):
[444] Yield: 3240 mg
[445] tR = 2.83 min; chemical purity> 99.9%; > 99% enantiomeric excess [column: Chiralpak OD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: carbon dioxide / ethanol 70:30 (v / v); flow rate: 3 ml / min; UV detection: 210 nm].
[446] LC-MS (Method 3): IR = 1.57 min; m / z = 653 (M + H) +. Example 131A (Enantiomer 2):
[447] Yield: 3180 mg
[448] tR = 4.12 min; chemical purity> 99%; > 99% enantiomeric excess [column: Chiralpak OD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: carbon dioxide / ethanol 70:30 (v / v); flow rate: 3 ml / min; UV detection: 210 nm].
[449] LC-MS (Method 3): t R = 1.57 min; m / z = 653 (M + H) +. Example 132A
[450] 5 - ({2- [2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy) phenyl] ethyl} amino) -5,6,7,8-tetrahydroquinoline-2 dihydrochloride -ethyl carboxylate (Enantiomer 2)

[451] 12 ml of a solution of 4N hydrogen chloride in dioxane to 3180 mg (4.87 mmol) of 5 - [(tert-butoxycarbonyl) {2- [2 - ({4- [2- ( 4-fluorophenyl) ethyl] benzyl} oxy) phenyl] ethyl} amino] -5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 131 A), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness. 3290 mg of the desired product were obtained, which was further reacted without further characterization.
[452] In an analogous way to Example 132A, the following compound was prepared:
Example 134A
[453] 5 - ({2- [2 - ({4- [2- (4-Fluorophenyl) ethyl] benzyl} oxy) phenyl] ethyl} amino) -5,6,7,8-tetrahydroquinoline-2-carboxylate ethyl (Enantiomer 2)

[454] 3290 mg (5.58 mmol) of 5 - ({2- [2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy) phenyl] ethyl} amino dihydrochloride was taken) -5,6,7,8-tetrahydroquinoline-2-carboxylate ethyl (Enantiomer 2, Example 132A) in 50 ml THE, 3.11 ml triethylamine was added and the mixture was stirred at room temperature for one hour. Ethyl acetate and water were added to the reaction solution, the phases were separated and the aqueous phase was extracted once more with ethyl acetate. The combined organic phases were washed again with water, dried over magnesium sulfate, filtered and evaporated to dryness. 2150 mg (3.89 mmol, 70% of theory) of the desired compound were obtained.
[455] LC-MS (Method 3): IR = 1.06 min; m / z = 553 (M + H) +.
[456] 1H-NMR (400 MHz, DMSO-dβ, δ / ppm): 1.30 (t, 3H), 1.60-1.74 (m, 2H), 1.78-1.89 (m , 1H), 1.89-2.06 (m, 2H), 2.65-2.92 (m, 10H), 3.76 (br. S, 1H), 4.31 (q, 2H), 5.04 (s, 2H), 6.86 (t, 1H), 6.99-7.11 (m, 3H), 7.13-7.27 (m, 6H), 7.31 (d, 2H), 7.76 (d, 1H), 7.85 (d, 1H).
[457] In an analogous way to Example 134A, the following compound was prepared:

Example 136A
[458] 5 - ({2- [2 - ({4- [2- (4-Fluorophenyl) ethyl] benzyl} oxy) phenyl] ethylH2- [4- (methoxycarbonyl) phenyl] ethyl} amino) -5.6 , Ethyl 7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2)

[459] 3118 mg (10.75 mmol) of methyl 4- (2-iodoethyl) benzoate and 570 mg (5.37 mmol) of anhydrous sodium carbonate were added to a solution of 1980 mg (3.58 mmol ) of 5 - ({2- [2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy) - phenyl] ethyl} amino) -5,6,7,8-tetrahydroquinoline-2-carboxylate of ethyl (Enantiomer 2, Example 134A) in 30 ml of dry acetonitrile, and the mixture was heated to reflux overnight. An additional 379 mg of methyl 4- (2-iodoethyl) benzoate was added and the mixture was again stirred under reflux overnight. Then, an additional 379 mg of methyl 4- (2-iodoethyl) benzoate was added. The mixture was then stirred another three days under reflux and, finally, it was cooled to room temperature. The reaction mixture was filtered, the filter cake was washed with acetonitrile and the filtrate was concentrated to dryness. The residue obtained was purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1 -> 4: 1 - + 2: 1). 715 mg (2.40 mmol, 97% content, 67% of theory) of the title compound were obtained.
[460] LC-MS (Method 3): to = 1.57 min; m / z = 715 (M + H) +.
[461] [CX] D20 = + 60.75 °, c = 0.40, methanol.
[462] In an analogous way to Example 136A, the following compound was prepared:
Example 138A
[463] rac-5 - [(tert-Butoxycarbonyl) {2- [5-fluoro-2 - ({4- [2- (4-fluorophenyl) ethyl] - benzyl} oxy) phenyl] ethyl} amino] -5 , 6,7,8-tetrahydroquinorm-2-carboxylate

[464] 10 g (21.81 mmol) of rac-5 - {(ferc-butoxycarbonyl) [2- (5-fluoro-2-hydroxyphenyl) ethyl] amino} -5,6,7,8- ethyl tetrahydroquinoline-2-carboxylate (Example 106A), 5.98 g (23.99 mmol) of 1- (chloromethyl) -4- [2- (4-fluorophenyl) ethyl] benzene and 4.52 g (32, 71 mmol) of potassium carbonate in 240 ml of acetonitrile up to 110 ° C and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed several times with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 10: 1 -> 4: 1). 14.11 g (21.03 mmol, 96% of theory) of the desired compound were obtained.
[465] LC-MS (Method 3): t R = 1.57 min; m / z = 671 (M + H) +. Example 139A and Example 140A
[466] 5 - [(tert-Butoxycarbonyl) {2- [5-fluoro-2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} - oxy) phenyl] ethyl} amino] -5.6 , Ethyl 7,8-tetrahydroquinoline-2-carboxylate (Enantiomers 1 and 2)

[467] 14.11 g (21.03 mmol) of 5 - [(ferc-butoxycarbonyl) {2- [5-fluoro-2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl were separated) } racemic ethyl oxy) phenyl] ethyl} amino] -5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 138A) in the respective enantiomers by supercritical fluid chromatography (SFC) in a chiral phase [column: Daicel Chiralpak AZ -H, 5 μm, 250 mm x 50 mm; mobile phase: carbon dioxide / ethanol 70:30 (v / v); flow rate: 200 ml / min; pressure: 80 bar; UV detection: 220 nm; temperature: 15 ° C]: Example 139A (Enantiomer 1):
[468] Yield: 5690 mg
[469] tR = 3.98 min; chemical purity> 99.9%; > 99% enantiomeric excess [column: Daicel Chiralpak AZ-H, 5 μm, 250 mm x 4.6 mm; mobile phase: carbon dioxide / ethanol 70:30 (v / v); flow rate: 3 ml / min; UV detection: 220 nm],
[470] LC-MS (Method 3): t R = 1.61 min; m / z = 671 (M + H) +. Example 140A (Enantiomium 2):
[471] Yield: 6080 mg
[472] t R = 6.41 min; chemical purity> 99%; > 99% enantiomeric excess [column: Daicel Chiralpak AZ H, 5 μm, 250 mm x 4.6 mm; mobile phase: carbon dioxide / ethanol 70:30 (v / v); flow rate: 3 ml / min; UV detection: 220 nm],
[473] LC-MS (Method 3): IR = 1.61 min; m / z = 671 (M + H) +. Example 141A
[474] 5 - ({2- [5-fluoro-2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy) phenyl] ethyl} amino) -5,6,7,8 dihydrochloride ethyl-tetrahydroquinoline-2-carboxylate (Enantiomer 2)

[475] 23 ml of a solution of 4N hydrogen chloride in dioxane to 6080 mg (9.06 mmol) of 5 - [(tert-butoxycarbonyl) {2- [5-fluoro-2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy) phenyl] ethyl} amino] -5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 140A), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness. 6240 mg of the desired product was obtained, which was further reacted without further characterization.
[476] In an analogous way to Example 141 A, the following compound was prepared:
Example 143A
[477] 5 - ({2- [5-Fuoro-2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy) phenyl] ethyl} amino) - 5,6,7,8-tetrahydroquinoline Ethyl -2-carboxylate (Enantiomer 2)

[478] 6240 mg (10.28 mmol) of 5 - ({2- [5-fluoro-2- ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy) phenyl] dihydrochloride was taken] ethyl} amino) -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 2, Example 141 A) in 103 ml of THF, 5.7 ml of triethylamine was added and the mixture was stirred at temperature for an hour. Ethyl acetate and water were added to the reaction solution, the phases were separated and the aqueous phase was extracted once more with ethyl acetate. The organic phases were washed again with water, dried over magnesium sulfate, filtered and finally evaporated to dryness. 3600 mg (6.31 mmol, 61% of theory) of the desired compound were obtained, which was further reacted without further characterization.
[479] In an analogous way to Example 143A, the following compound was prepared:

Example 145A
[480] 5 - ({2- [5-Fluoro-2 - ({4- [2- (4-fluorophenyl) ethyl] benzi)} oxy) phenyl] ethyl} {2- [4- (methoxycarbonyl) phenyl] ethyl} amino) -5,6,7,8 ethyl tetrahydroquinoline-2-carboxylate (Enantiomer 2)

[481] 305 mg (1.05 mmol) of methyl 4- (2-iodoethyl) benzoate and 56 mg (0.53 mmol) of anhydrous sodium carbonate were added to a 200 mg (0.35 mmol) solution ) of 5 - ({2- [5-fluoro-2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} - oxy) phenyl] ethyl} amino) -5,6,7,8-tetrahydroquinoline Ethyl -2-carboxylate (Enantiomer 2, Example 143A) in 3 ml of dry acetonitrile, and the mixture was stirred in a microwave (Biotage Initiator) at 140 ° C for 4 hours. The reaction solution was cooled and purified directly by preparative HPLC (mobile phase: acetonitrile / water 9: 1). 75 mg (0.10 mmol, 29% of theory) of the title compound were obtained.
[482] LC-MS (Method 3): t R = 1.58 min; m / z = 733 (M + H) +.
[483] 1H-NMR (400 MHz, DMSO-de, δ / ppm): 1.29 (t, 3H), 1.40-1.53 (m, 1H), 483.53- 67 (m, 1H), 1.87-2.06 (m, 2H), 2.56-2.86 (m, 14H), 3.83 (S, 3H), 4.00-4.09 (m, 1H), 4, 29 (q, 2H), 4.82-4.94 (rn, 2H), 6.91 (d, 1H), 6.96-7.02 (m, 2H), 7.037.26 (m, 10H) , 7.34-7.44 (m. 2H), 7.80 (d, 2H).
[484] In an analogous way to Example 145A, the following compound was prepared:
Example 147A and Example 69A
[485] 5 - {(tert-Butoxycarbonyl) [2- (2-hydroxyphenyl) ethyl] amino} -5,6,7,8-ethyl tetrahydroquinoline-2-carboxylate (Enantiomers 1 and 2)

[486] 25 g (56.74 mmol) of 5 - {(tert-butoxycarbonyl) [2- (2-hydroxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate was separated racemic ethyl (Example 10A) in the respective enantiomers by supercritical fluid chromatography (SFC) in a chiral phase [column: Daicel Chiralpak AZ-H, 5 μm, 250 mm x 50 mm; mobile phase: carbon dioxide / isopropanol 85:15 (v / v); flow rate: 400 ml / min; pressure: 80 bar; UV detection: 220 nm; temperature: 37 ° C]: Example 147A (Enantiomer 7):
[487] Yield: 11.3 g
[488] tR = 5.98 min; chemical purity> 99.9%; > 99% enantiomeric excess [column: Daicel Chiralpak OZ-H, 5 μm, 250 mm x 4.6 mm; mobile phase: isohexane / ethanol 80:20 (v / v); flow rate: 1 ml / min; UV detection: 220 nm]. Example 69A (Enantiomer 2):
[489] Yield: 11.9 g
[490] IR = 4.36 min; chemical purity> 99%; > 92% enantiomeric excess [column: Daicel Chiralpak OZ-H, 5 μm, 250 mm x 4.6 mm; mobile phase: isohexane / ethanol 80:20 (v / v); flow rate: 1 ml / min; UV detection: 220 nm]. Example 148A and Example 74A
[491] 5 - {(tert-Butoxycarbonyl) [2- (2 - {[3-chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} -5,6,7, Ethyl 8-tetrahydroquinoline-2-carboxylate (Enantiomers 1 and 2)

[492] 15 g (21.42 mmol) of 5 - {(ferc-butoxycarbonyl) [2- (2 - {[3-chloro-4l- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) were separated ethyl] amino} -5,6,7,8- racemic ethyl tetrahydroquinoline-2-carboxylate (Example 22A) in the respective enantiomers by supercritical fluid chromatography (SFC) in a chiral phase [column: Chiralpak OD-H, 20 μm, 400 mm x 50 mm; mobile phase: carbon dioxide / isopropanol 70:30 (v / v); flow rate: 400 ml / min; pressure: 80 bar; UV detection: 220 nm; temperature: 37 ° C]: Example 148A (Enantiomer 7):
[493] Yield: 5830 mg
[494] t R = 2.83 min; chemical purity> 99.9%; > 99% enantiomeric excess [column: Chiralpak OD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: carbon dioxide / isopropanol 70:30 (v / v); flow rate: 3 ml / min; UV detection: 210 nm]. Example 74A (Enantiomer 2):
[495] Yield: 6330 mg
[496] t R = 5.30 min; chemical purity> 99%; > 98% enantiomeric excess [column: Chiralpak OD-H, 5 μm, 250 mm x 4.6 mm; mobile phase: carbon dioxide / isopropanol 70:30 (v / v); flow rate: 3 ml / min; UV detection: 210 nm]. Example 149A
[497] 4 - {(E / Z) -2- [4- (Trifluoromethyl) phenyl] vinyl} methyl benzoate

[498] 59.13 g (94.36 mmol) of [4- (trifluoromethyl) benzyl] (triphenyl) phosphonium bromide and 15.80 g (96.24 mmol) of methyl 4-formylbenzoate were dissolved in 160 ml of methanol, the mixture was cooled to 0 ° C and 5.86 g (108.51 mmol) of sodium methoxide was added a little at a time. The reaction mixture was then slowly warmed up to room temperature and stirred at this temperature overnight. The reaction solution was again cooled to 0 ° C, an additional 2.55 g (47.18 mmol) of sodium methoxide was added to the portions and, after heating to room temperature, the mixture was again stirred for at night. The reaction mixture was concentrated to dryness and the residue was chromatographed on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1). 12.39 g (40.45 mmol, 43% of theory) of the title compound were obtained.
[499] LC-MS (Method 2): IR = 2.87 min; m / z = 307 (M + H) +. Example 150A
[500] 4- {2- [4- {Trifluoromethyl) phenyl] ethyl} methyl benzoation

[501] 427 mg of 10% palladium on carbon was added to 12.3 g (40.16 mmol) of 4 - {(E / Z) -2- [4- (trifluoromethyl) phenyl] vinyl} benzoate methyl in 150 ml of THF and 150 ml of ethanol, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere at standard pressure. The reaction mixture was filtered and the resulting filtrate was concentrated to dryness. 11.52 g (37.37 mmol, 93% of the theoretical value) of the title compound were obtained.
[502] LC-MS (Method 2): t R = 2.86 min; m / z = 309 (M + H) +.
[503] 1H-NMR (400 MHz, DMSO-d6, δ / ppm): 2.93-3.05 (m, 4H), 3.83 (s, 3H), 7.38 (d, 2H), 7.45 (d, 2H), 7.63 (d, 2H), 7.87 (d, 2H). Example 151A
[504] (4- {2- [4- (Trifluoromethyl) phenyl] ethyl} phenyl) methanol

[505] At room temperature and under argon, 12.3 ml of a 1M solution of lithium aluminum hydride in THF was slowly added dropwise to a solution of 11.5 g (37.30 mmol) of 4 - Methyl {2- [4- (trifluoromethyl) phenyl] ethyl} benzoate in 150 ml of dry THF. At the end of the addition, the reaction mixture was stirred at room temperature for another hour. The reaction mixture was then cooled to 0 ° C and, slowly and carefully, 150 ml of ice cold 1M hydrochloric acid was added. About 250 ml of ethyl acetate was added, the aqueous phase was separated and the organic phase was washed successively, in each case, once with 1M hydrochloric acid and with saturated sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered and concentrated to dryness. 9.69 g (34.57 mmol, 93% of theory) of the title compound were obtained.
[506] LC-MS (Method 2): t R = 2.55 min; m / z = 263 (M + H-H2O) +.
[507] 1H-NMR (400 MHz, DMSO-cfe, δ / ppm): 2.85-2.93 (m, 2H), 2.93-3.02 (m, 2H), 4.45 (d , 2H), 5.09 (t, 1H) 7.19 (q, 4H), 7.45 (d, 2H), 7.62 (d, 2H). Example 152A
[508] 1- (Chloromethyl) -4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzene

[509] At 0 ° C, 3.78 ml of thionyl chloride in 30 ml of dichloromethane was slowly added dropwise to a solution of 9.69 g (34.57 mmol) of (4- {2 - [4- (trifluoromethyl) phenyl] ethyl} phenyl) methanol in 100 ml of dichloromethane. At the end of the addition, the reaction mixture was warmed to room temperature and stirred for two hours at this temperature. The reaction mixture was again cooled to 0 ° C and, slowly and carefully, 100 ml of saturated aqueous sodium bicarbonate solution was added under vigorous stirring until a pH of 6 was reached. The phases were separated and the organic phase was dried over magnesium sulfate, filtered and concentrated to dryness. 8.64 g (28.92 mmol, 84% of theory) of the title compound were obtained.
[510] GC-MS (Method 5): tR - 5.96 min; m / z = 298/300 (M + H) +. Example 153A
[511] 5 - [(tert-Butoxycarbonyl) (2- {2 - [(4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzyl) oxy] phenyl} ethyl) amino] -5,6,7 , 8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 2)

[512] 1 g (2.27 mmol) of 5 - {(tert-butoxycarbonyl) [2- (2-hydroxyphenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate ethyl (Enantiomer 2, Example 69A), 746 mg (2.50 mmol) of 1- (chloromethyl) -4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzene and 784 mg (5.68 mmol) of potassium carbonate in 25 ml of acetonitrile up to 110 ° C and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed several times with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 20: 1 -> 10: 1). 1110 mg (1.48 mmol, 65% of theory) of the desired compound was obtained.
[513] LC-MS (Method 3): tn = 1.66 min; m / z = 703 (M + H) +.
[514] Example 154A
[515] 5 - [(2- {2 - [(4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzyl) oxy] phenyl} ethyl) amino] -5,6,7,8- dihydrochloride ethyl tetrahydroquinoline-2-carboxylate (Enantiomer 2)

[516] 12 ml of a 1100 mg (1.57 mmol) solution of 4N hydrogen chloride in dioxane of 5 - [(tert-butoxycarbonyl) (2- {2 - [(4- {2- [ Ethyl 4- (trifluoromethyl) phenyl] ethyl} benzyl) oxy] phenyl} ethyl) amino] -5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 153A), and the mixture was stirred at temperature room for 2 h. The reaction mixture was concentrated to dryness. 1045 mg of the desired product were obtained, which was further reacted without further characterization. Example 155A
[517] 5 - [(2- {2 - [(4- {2- [4- (Trifluoromethyl) phenyl] ethyl} benzyl) oxy] phenyl} ethyl) amino] - 5,6,7,8-tetrahydroquinoline- Ethyl 2-carboxylate (Enantiomer 2)

[518] 1045 mg (1.55 mmol) of 5 - [(2- {2 - [(4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzyl) oxy] phenyl} ethyl dihydrochloride was taken ) amino] -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 2, Example 154A) in 15 ml of THF, 0.65 ml of triethylamine was added and the mixture was stirred at room temperature for one hour. To the reaction solution, ethyl acetate and water were added, the phases were separated and the aqueous phase was extracted once more with ethyl acetate. The combined organic phases were again washed with water, dried over magnesium sulfate, filtered and concentrated to dryness. 800 mg (1.33 mmol, 86% of theory) of the desired compound was obtained.
[519] LC-MS (Method 3): t R = 1.03 min; m / z = 603 (M + H) +. Example 156A
[520] 5 - [{2- [4- (Methoxycarbonyl) phenyl] ethyl} (2- {2 - [(4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzyl) oxy] phenyl} ethyl) amino] -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 2)

[521] 300 mg (1.04 mmol) of methyl 4- (2-iodoethyl) benzoate and 55 mg (0.52 mmol) of anhydrous sodium carbonate were added to a solution of 208 mg (0.35 mmol) ) of 5 - [(2- {2 - [(4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzyl) - oxy] phenyl} ethyl) amino] -5,6,7,8-tetrahydroquinoline- Ethyl 2-carboxylate (Enantiomer 2, Example 155A) in 3 ml of dry acetonitrile and the mixture was stirred in a microwave (Biotage Initiator) at 140 ° C for 4 h. The reaction solution was then cooled and purified directly by preparative HPLC (mobile phase: acetonitrile / water 9: 1). 102 mg (0.13 mmol, 39% of theory) of the title compound were obtained.
[522] LC-MS (Method 3): IR = 1.64 min; m / z = 765 (M + H) +. Example 157 A
[523] rac-5 - [(tert-Butoxycarbonyl) (2- {5-fluoro-2 - [(4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzyl) oxy] phenyl} ethyl) amino] -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate

[524] 2 g (4.36 mmol) of rac-5 - {(tert-butoxycarbonyl) [2- (5-fluoro-2-hydroxyphenyl) ethyl] amino} -5,6,7,8- ethyl tetrahydroquinoline-2-carboxylate (Example 106A), 1433 mg (4.80 mmol) of 1- (chloromethyl) -4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzene and 1507 mg (10.90 mmol) of potassium carbonate in 50 ml of acetonitrile to 110 ° C and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed several times with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 20: 1 -> 10: 1). 2490 mg (3.29 mmol, 95% of theory) of the desired compound was obtained.
[525] LC-MS (Method 3): IR = 1.60 min; m / z = 721 (M + H) +. Example 158A
[526] 5 - [(2- {5-fluoro-2 - [(4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzyl) oxy] phenyl} ethyl) amino] -5 rac-dihydrochloride, Ethyl 6,7,8-tetrahydroquinoline-2-carboxylate

[527] 5.2 ml of a solution of 4N hydrogen chloride in dioxane to 500 mg (0.69 mmol) of rac-5 - [(tert-butoxycarbonyl) (2 ~ (5-fluoro-2- [(4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzyl) oxy] phenyl} ethyl) amino] -5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 15A), and The mixture was stirred at room temperature for 2 h The reaction mixture was concentrated to dryness 479 mg of the desired product was obtained, which was further reacted without further characterization. Example 159A
[528] rac-5 - [(2- {5-Fiuoro-2 - [(4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzyl) oxy] - phenyl} ethyl) amino] -5.6 , 7,8-tetrahydroquinoline-2-carboxylate

[529] 479 mg (0.64 mmol) rac-5 - [(2- {5-fluoro-2 - [(4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzyl] dihydrochloride was taken ) oxy] phenyl} ethyl) amino] -5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 158A) in 4.7 ml of THF, 0.27 ml of triethylamine was added again and the mixture was stirred at room temperature for one hour. Ethyl acetate and water were added to the reaction solution, the phases were separated and the aqueous phase was extracted once more with ethyl acetate. The combined organic phases were washed again with water, dried over magnesium sulfate, filtered and concentrated to dryness. 383 mg (0.62 mmol, 96% of theory) of the desired compound was obtained.
[530] LC-MS (Method 3): t R = 1.04 min; m / z = 621 (M + H) +. Example 160A
[531] rac-5 - [(2- {5-Fluoro-2 - [(4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzyl) oxy] phenyl} ethyl) {2- [4- ( methoxycarbonyl) phenyl] ethyl} amino] - 5,6,7,8-tetrahydroquinoline-2-carboxylate

[532] 533 mg (1.84 mmol) of methyl 4- (2-iodoethyl) benzoate and 97 mg (0.92 mmol) of anhydrous sodium carbonate were added to a solution of 380 mg (0.61 mmol) ) of rac-5 - [(2- {5-fluoro-2 - [(4- {2- [4- (trifluoromethyl) phenyl] ethyl} - benzyl) oxy] phenyl} ethyl) amino] -5.6, 7,8-tetrahydroquinoline-2-carboxylate (Example 159A) in 5 ml of dry acetonitrile and the mixture was stirred in a microwave (Biotage Initiator) at 140 ° C for 4 h. The reaction solution was then cooled and purified directly by preparative HPLC (mobile phase: acetonitrile / water 9: 1). 178 mg (0.23 mmol, 37% of theory) of the title compound were obtained.
[533] LC-MS (Method 3): t R = 1.62 min; m / z = 783 (M + H) +. Examples of work: Example 1
[534] (-) - 5 - {(4-Carboxybutyl) [2- (2 - {[4- (5-methyl-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino acid } -5,6,7,8-tetrahydroquinoline-2-carboxylic (Enantiomer 1)

[535] 752 mg (1.09 mmol) of (-) - 5 - {(5-ethoxy-5-oxopentyl) [2- (2 - {[4- (5-methyl-1,3- benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 1, Example 35A) in 9 ml of THF and 4, 6 ml of water and 137 mg (3.27 mmol) of lithium hydroxide monohydrate. The reaction mixture was stirred at 60 ° C overnight. At the end of the reaction, the THF was removed on a rotary evaporator and the remaining mixture was diluted with water. The mixture was acidified with acetic acid at pH 4-5 and extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. 590 mg (0.93 mmol, 86% of theory) of the title compound was obtained as a yellowish foam.
[536] LC-MS (Method 3): te = 1.03 min; m / z = 634 (M + H) +.
[537] 1H-NMR (400 MHz, DMSO-de): δ [pm] = 1.10-1.71 (m, 7H), 1.89-2.04 (m, 2H), 2.05- 2.17 (m, 2H), 2.35-2.64 (m, 3H, partially obscured by DMSO Sinai), 2.45 (s, 3H), 2.65-2.88 (m, 4H) , 3.94-4.05 (m, 1H), 5.08 (q, 2H), 6.87 (t, 1H), 6.99 (d, 1H), 7.13 (d, 1H), 7.18 (t, 1H), 7.25 (d, 1H), 7.52 (d, 2H), 7.61 (S, 1H), 7.68 (d, 2H), 7.85 (d , 1H), 8.16 (d, 2H), 11.31-12.96 (br. S, 2H).
[538] [α] D20 = -61.61 °, c = 0.455, methanol. Example 2
[539] (+) - 5 - {(4-Carboxybutyl) [2- (2 - {[4- (5-methyl-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylic (Enantiomer 2)

[540] 735 mg (1.07 mmol) of (+) - 5 - {(5-ethoxy-5-oxopentyl) [2- (2 - {[4- (5-methyl-1,3- benzoxazol-2-yl) benzyl:] oxy} phenyl) ethyl] amino} -5,6,7,8-. if tetraid roquinoline-2-ethyl carboxylate (Enantiomer 2, Example 36A) in 9 ml of THF and 4.5 ml of water, and 134 mg (3.20 mmol) of lithium hydroxide monohydrate was added. The reaction mixture was stirred at 60 ° C overnight. At the end of the reaction, THF was removed on a rotary evaporator and the remaining mixture was diluted with water. The mixture was acidified with acetic acid to pH 4-5 and extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. 617 mg (0.97 mmol, 91% of theory) of the title compound was obtained as a yellowish foam.
[541] LC-MS (Method 3): t R = 1.03 min; m / z = 634 (M + H) +.
[542] 1H-NMR (400 MHz, DMSO-d6): δ [pm] = 1.32-1.70 (m, 7H), 1.89-2.03 (m, 2H), 2.07- 2.16 (m, 2H), 2.39-2.64 (m, 3H, partially obscured by the DMSO signal), 2.46 (s, 3H), 2.65-2.87 (m, 4H) , 3.95-4.03 (m, 1H), 5.08 (q, 2H), 6.87 (t, 1H), 6.99 (d, 1H), 7.13 (d, 1H), 7.18 (t, 1H), 7.25 (d, 1H), 7.52 (d, 2H), 7.61 (s, 1H), 7.67 (d, 2H), 7.85 (d , 1H), 8.16 (d, 2H), 11.30-12.97 (br. S, 2H).
[543] [a] D20 = + 62.89 °, c = 0.380, methanol.
[544] In an analogous way to Examples 1 and 2, the following compounds were prepared:







Example 12
[545] rac-Acid 5 - {(2- {2 - [(4-tert-butylbenzyl) oxy] phenyl} ethyl) [2- (4-carboxyphenyl) ethyl] amino} -5,6,7,8- tetrahydroquinoline-2-carboxylic

[546] 35 mg butylbenzyl) oxy] phenyl} ethyl) {2- [4- (methoxycarbonyl) phenyl] ethyl} amino] -5,6,7,8-ethyl tetrahydroquinoline-2-carboxylate (Example 43A ) in 1 ml of THF and 1 ml of water, and 7 mg (0.16 mmol) of lithium hydroxide monohydrate was added. The reaction mixture was stirred at 50 ° C overnight. At the end of the reaction, the THF was removed on a rotary evaporator and the remaining mixture was diluted with water. The mixture was then acidified with 1M hydrochloric acid and extracted several times with a 1: 1 mixture of ethyl acetate and dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. 29 mg (0.04 mmol, 91% content, 81% of theory) of the titanium compound were obtained as a yellowish solid.
[547] LC-MS (Method 4): t R = 1.29 min; m / z = 607 (M + H) +.
[548] 1H-NMR (400 MHz, DMSO-c / 6): δ [pm] = 0.77-0.90 (m, 0.5H), 1.12-1.31 (m, 10H), 1.42-1.87 (m, 2H), 1.88-2.14 (m, 2H), 2.22-2.34 (m, 0.5H), 2.41 3.07 (m , 7H, partially obscured by the DMSO signal), 3.98-4.11 (m, 0.5H), 4.84-5.13 (m, 2H), 5.13-5.26 (m, 0 , 5H), 6.79-6.89 (m, 0.5H), 6.95-7.52 (m, 11H), 7.55-7.62 (m, 0.5H), 7.74 -7.88 (m, 2H), 7.90-8.00 (m, 1H), 8.54-8.68 (m, 0.5H), 10.39-10.58 (m, 0, 5H), 11.69-14.09 (br. S, about 1H). Example 13
[549] 5 - {(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2- carboxylic (Enantiomer 1)

[550] 259 mg (0.39 mmol) of 5 - {(5-ethoxy-5-oxopentyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] were taken] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylate ethyl (Enantiomer 1, Example 50A) in 4 ml of dioxane, 2 ml of a solution of 2M potassium hydroxide in water was added and the mixture was stirred at room temperature overnight. At the end of the reaction, the reaction mixture was slightly acidified with 0.75 ml of acetic acid and 1N hydrochloric acid and concentrated to dryness. The obtained residue was purified by preparative HPLC. 183 mg (0.30 mmol, 77% of theory) of the title compound were obtained.
[551] LC-MS (Method 4): IR = 1.02 min; m / z = 607 (M + H) +.
[552] 1H-NMR (400 MHz, DMSO-c / 6): δ [pm] = 1.30-1.68 (m, 6H), 1.89-2.04 (m, 2H), 2, 08-2.18 (m, 2H), 2.39-2.47 (m, 2H), 2.47-2.58 (m, 1H, obscured by the DMSO signal), 2.58-2.84 (m, 5H), 2.86 (S, 4H), 3.92-4.01 (m, 1H), 4.82- 4.97 (m, 2H), 6.84 (t, 1H), 6.97 (d, 1H), 7.10 (d, 1H), 7.13-7.21 (m, 6H), 7.21-7.30 (m, 4H), 7.66 (d, 1H), 7.83 (d, 1H), 11.20-13.00 (br. S, about 2H).
[553] Similar to Example 13, the following compounds were prepared:




Example 19
[554] 5 - {[2- (4-carboxyphenyl) ethyl] [2- (2 - {[4- (5-chloro-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylic (Enantiomer 1)

[555] 68 mg (0.09 mmol) of 5 - ([2- (2 - {[4- (5-chloro-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl were taken ] Ethyl {2- [4- (methoxycarbonyl) phenyl] ethyl} amino) -5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 1, Example 63A) in 4 ml of THF and 2 ml of water, and 12 mg (0.27 mmol) of lithium hydroxide monohydrate was added. The reaction mixture was stirred at 60 ° C overnight. At the end of the reaction, the THF was removed on a rotary evaporator and the remaining mixture was diluted with water. The mixture was acidified to pH 4-5 with acetic acid and extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. 33 mg (0.04 mmol, 48% of theory) of the title compound were obtained.
[556] LC-MS (Method 3): t R = 1.26 min; m / z = 702/704 (M + H) +.
[557] 1H-NMR (400 MHz, DMSO-de): δ [pm] = 1.41-1.55 (m, 1 H), 1.55-1.70 (m, 1H), 1.89 -2.08 (m, 2H), 2.59-2.87 (m, 10H), 4.01-4.14 (m, 1H), 5.01-5.15 (m, 2H), 6 , 86 (t, 1H), 7.01 (d, 1H), 7.06 (d, 1H), 7.14 (d, 2H), 7.20 (t, 1H), 7.42-7, 57 (m, 5H), 7.76 (d, 2H), 7.83 (d, 1H), 7.93 (d, 1H), 8.11 (d, 2H), 12.03-13.45 (br. s, about 2H). Example 20
[558] 5 - {[2- (4-carboxyphenyl) ethyl] [2- (2 - {[4- (5-chloro-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylic

[559] 45 mg (0.06 mmol) of 5 - ([2- (2 - {[4- (5-chloro-1,3-benzoxazol-2-yl) benzyl] oxy} phenyl) ethyl ] {2- [4- (methoxycarbonyl) phenyl] ethyl} amino) -5,6,7,8-ethyl tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 64A) in 4 ml of THF and 2 ml of water, and 8 mg (0.18 mmol) of lithium hydroxide monohydrate was added. The reaction mixture was stirred at 60 ° C overnight. At the end of the reaction, the THF was removed on a rotary evaporator and the remaining mixture was diluted with water. The mixture was then acidified to pH 4-5 with acetic acid and extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. 13 mg (0.02 mmol, 32% of theory) of the title compound were obtained.
[560] LC-MS (Method 3): t R = 1.26 min; m / z = 702/704 (M + H) +.
[561] 1H-NMR (400 MHz, DMSO-d6): δ [pm] = 1.40-1.55 (m, 1H), 1.55-1.70 (m, 1H), 1.88- 2.08 (m, 2H), 2.58-2.87 (m, 10H), 4.02-4.13 (m, 1H), 5.01-5.15 (m, 2H), 6, 86 (t, 1H), 7.02 (d, 1H), 7.06 (d, 1H), 7.14 (d, 2H), 7.20 (t, 1H), 7.42-7.57 (m, 5H), 7.76 (d, 2H), 7.84 (d, 1H), 7.93 (d, 1H), 8.11 (d, 2H), 11.69-13.84 (br. s, about 2H).
[562] In an analogous way to Example 20, the following compounds were prepared:

Example 23
[563] 5 - {[2- (4-carboxyphenyl) ethyl] [2- (2 - {[3-chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino acid - 5,6,7,8-tetrahydroquinoline-2-carboxylic (Enantiomer

[564] 49 g (54.46 mmol) of 5 - ([2- (2 - {[3-chloro-4'- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] {2 - Ethyl [4- (methoxycarbonyl) phenyl] ethyl} - 5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 92A) in 429 ml of dioxane, 163 ml of a solution was added aqueous 1N sodium hydroxide and the mixture was stirred at room temperature overnight. At the end of the reaction, dioxane was removed on a rotary evaporator and the remaining mixture was diluted with about 750 ml of water. The mixture was acidified to pH 4-5 with acetic acid. The precipitated solid was filtered off with suction and washed several times with water (about 250 ml of water in total). The solid was taken up in 750 ml of water and stirred at room temperature overnight. After another suction filtration, the solid was again washed with water and dried under high vacuum overnight using the drying agent phosphorus pentoxide. The drying agent was then removed and the solid was dried at 40 ° C for an additional 24 h. In this way, 35 g (48 mmol, 88% of theory) of the title compound were obtained.
[565] LC-MS (Method 3): tR = 1.39 min; m / z = 729/731 (M + H) +.
[566] 1H-NMR (400 MHz, DMSO-d6): δ [pm] = 1.37-1.68 (m, 2H), 1.85-2.06 (m, 2H), 2.59- 2.83 (m, 10H), 3.98-4.10 (m, 1H), 4.99-5.15 (m, 2H), 6.87 (t, 1H), 7.05 (d, 2H), 7.12 (d, 2H), 7.23 (t, 1H), 7.38-7.48 (m, 2H), 7.54 (d, 1 H), 7.62 (d, 1H), 7.71-7.91 (m, 7H), 11.60-13.85 (br. S, about 2H).
[567] [α] D20 = + 61.75 °, c = 0.420, methanol.
[568] In an analogous way to Example 20 and Example 23, the following compounds were prepared:













Example 38
[569] 5 - {[2- (4-carboxyphenyl) ethyl] [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} -5,6,7,8 -tetrahydroquinoline-2-carboxylic (Enantiomer 2)

[570] 3.64 g (5.22 mmol) of 5 - ({2- [4- (methoxycarbonyl) phenyl] ethyl] [2- (2 - {[4- (2-phenylethyl) benzyl] was taken) oxy} phenyl) ethyl] amino) -5,6,7,8-tetrahydroquinoline-2-ethyl carboxylate (Enantiomer 2, Example 97A) in 40 ml of dioxane and 20 ml of water, 658 mg (15, 67 mmol) of lithium hydroxide monohydrate and the mixture was stirred at room temperature overnight. At the end of the reaction, dioxane was removed on a rotary evaporator and the remaining mixture was diluted with water. The mixture was then acidified to pH 4-5 with acetic acid. The precipitated solid was filtered off with suction and washed several times with water. The solid was then taken up in water and stirred at room temperature. After another suction filtration, the solid was again washed with water and dried under high vacuum, at 40 ° C, overnight. 3.24 g (4.95 mmol, 95% of theory) of the title compound were obtained.
[571] LC-MS (Method 3): IR = 1.27 min; m / z = 655 (M + H) +.
[572] 1H-NMR (400 MHz, DMSO-dg): δ [pm] = 1.38-1.53 (m, 1H), 1.54-1.68 (m, 1H), 1.89- 2.08 (m, 2H), 2.57-2.87 (m, 14H), 4.01-4.10 (m, 1H), 4.90 (q, 2H), 6.83 (t, 1H), 6.93-7.06 (m, 2H), 7.09-7.30 (m, 12H), 7.39-7.50 (m, 2H), 7.80 (d, 2H) , 12.03-13.45 (br. S, about 2H).
[573] [CX] D20 = + 64.36 °, c = 0.380, methanol. Example 39
[574] 5 - {[2- (4-carboxyphenyl) ethyl] [2- (2 - {[4- (5-chloro-1,3-benzoxazol-2-yl) benzyl] oxy} -5-fluorophenyl ) ethyl] amino} -5,6,7,8-tetrahydroquinoline-2-carboxylic (Enantiomer 2)

[575] 5.4 g (7.08 mmol) of 5 - ([2- (2 - {[4- (5-chloro-1,3-benzoxazol-2-yl) benzyl] oxy} - were dissolved 5-fluorophenyl) ethyl] {2- [4- (methoxycarbonyl) phenyl] ethyl} amino) -5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 121 A) in 50 ml of dioxane , 21 ml of 1N aqueous sodium hydroxide solution was added and the mixture was stirred at room temperature overnight. At the end of the reaction, dioxane was removed on a rotary evaporator and the remaining mixture was diluted with water. The mixture was then acidified to pH 4-5 with acetic acid. The precipitated solid was filtered off with suction, washed several times with water and air dried overnight. 4.8 g (6.66 mmol, 94% of theory) of the title compound were obtained.
[576] LC-MS (Method 3): t R = 1.28 min; m / z = 720/722 (M + H) +.
[577] 1H-NMR (400 MHz, DMSO-cfe): δ [pm] = 1.40-1.72 (m, 2H), 1.88-2.11 (m, 2H), 2.59- 2.84 (m, 10H), 4.02-4.13 (m, 1H), 5.00-5.14 (m, 2H), 6.96 (d, 1H), 7.02 (d, 2H), 7.13 (d, 2H), 7.41-7.57 (m, 5H), 7.75 (d, 2H), 7.83 (d, 1H), 7.93 (d, 1H ), 8.11 (d, 2H), 12.05-13.41 (br. S, about 2H).
[578] [a] D20 = + 58.77 °, c = 0.405, DMSO. Example 40
[579] 5 - ([2- (4-carboxyphenyl) ethyl] {2- [2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy) phenyl] ethyl} amino acid -5, 6,7,8-tetrahydroquinoline-2-carboxylic (Enantiomer 2)

[580] 1.76 g (2.46 mmol) of 5 - ({2- [2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy) phenyl] ethylX2- [4 - ethyl (methoxycarbonyl) phenyl] ethyl} amino) -5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 136A) in 50 ml of dioxane, 7.4 ml of an aqueous solution was added of 1N sodium hydroxide and the mixture was stirred at room temperature overnight. An additional 0.2 ml of 1 M aqueous sodium hydroxide solution was added and the mixture was stirred at room temperature for two hours. At the end of the reaction, dioxane was removed on a rotary evaporator and the remaining mixture was diluted with water. The mixture was then acidified to pH 4-5 with acetic acid. The precipitated solid was filtered under suction, washed several times with water and dried in a drying oven under reduced pressure, at 40 ° C, for three days. 673 mg (2.31 mmol, 94% of theory) of the title compound was obtained.
[581] LC-MS (Method 3): t R = 1.33 min; m / z = 673 (M + H) +.
[582] 1H-NMR (400 MHz, DMSO-d6): δ [pm] = 1.39-1.53 (m, 1 H), 1.54-1.70 (m, 1H), 1.87 -2.07 (m, 2H), 2.57-2.89 (m, 14H), 3.98-4.11 (m, 1H), 4.90 (q, 2H), 6.84 (t , 1H), 6.96-7.28 (m, 13H), 7.38-7.50 (m, 2H), 7.79 (d, 2H), 11.79-13.60 (br. S , about 2H).
[583] [OC] D20 = + 85.73 °, C = 0.285, DMSO.
[584] Similar to Example 40, the following compounds were prepared:

Example 43
[585] 5 - ([2- (4-carboxyphenyl) ethyl] {2- [5-fluoro-2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy) phenyl] ethyl} amino acid ) -5,6,7,8-tetrahydroquinoline-2-carboxylic (Enanti6mer 2)

[586] 75 mg (0.10 mmol) of 5 - ({2- [5-fluoro-2 - ({4- [2- (4-fluorophenyl) ethyl] benzyl} oxy) phenyl] ethylH2- [4- (methoxycarbonyl) phenyl] ethyl} amino) -5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 145A) in 2 ml of dioxane, 0.3 ml of an 1N aqueous sodium hydroxide solution and the mixture was stirred at room temperature overnight. At the end of the reaction, dioxane was removed on a rotary evaporator and the remaining mixture was diluted with water. The mixture was then acidified to pH 4-5 with acetic acid. The precipitated solid was filtered under suction, washed several times with water and dried in a drying oven, under reduced pressure, at 40 ° C, for three days. 58 mg (0.08 mmol, 78% of theory) of the title compound were obtained.
[587] LC-MS (Method 3): to = 1.29 min; m / z = 691 (M + H) +.
[588] 1H-NMR (400 MHz, DMSO-cfe): δ [pm] = 1.41 -1.53 (m, 1H), 1.54-1.69 (m, 1H), 1.88- 2.07 (m, 2H), 2.58-2.88 (m, 14H), 3.99-4.10 (m, 1H), 4.88 (q, 2H), 6.92 (d, 1H), 6.99 (d, 2H), 7.03-7.27 (m, 10H), 7.41 (s, 2H), 7.79 (d, 2H), 12.25-13.34 (br. s, about 2H).
[589] [a] D20 = +77.21 °, c = 0.335, DMSO. Example 44
[590] 5 - {[2- (4-carboxyphenyl) ethyl] (2- {2 - [(4- {2- [4- (trifluoromethyl) phenyl] -ethyl} benzyl) oxy] phenyl} ethyl) amino acid } -5,6,7,8-tetrahydroquinoline-2-carboxylic (Enantiomer 2)

[591] 98 mg (0.13 mmol) of 5 - [{2- [4- (methoxycarbonyl) phenyl] ethyl} (2- {2 - [(4- {2- [4- (trifluoromethyl)) was dissolved - phenyl] ethyl} benzyl) oxy] phenyl} ethyl) amino] -5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 156A) in 2.5 ml of dioxane, 0 , 4 ml of 1N aqueous sodium hydroxide solution and the mixture was stirred at room temperature overnight. At the end of the reaction, dioxane was removed on a rotary evaporator and the remaining mixture was diluted with water. The mixture was acidified to pH 4-5 with acetic acid. The precipitated solid was filtered under suction, washed several times with water and dried in a drying oven, under reduced pressure, at 40 ° C, for three days. 71 mg (73% of theory) of the title compound were obtained.
[592] LC-MS (Method 3): ta = 1.33 min; m / z = 723 (M + H) +.
[593] 1H-NMR (400 MHz, DMSO-d6): δ [pm] = 1.40-1.43 (m, 1H), 1.54-1.69 (m, 1H), 1.88- 2.09 (m, 2H), 2.57-2.99 (m, 14H), 3.97-4.11 (m, 1H), 4.90 (q, 2H), 6.83 (t, 1H), 7.00 (dd, 2H), 7.09-7.27 (m, 7H), 7.37-7.52 (m, 4H), 7.61 (d, 2H), 7.80 (d, 2H), 11.77-13.56 (br. s, about 2H). Example 45
[594] rac-Acid 5 - {[2- (4-carboxyphenyl) ethyl] (2- {5-fluoro-2 - [(4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzyl) oxy] phenyl} ethyl) amino} -5,6,7,8-tetrahydroquinoline-2-carboxylic

[595] 173 mg (0.22 mmol) of rac-5 - [(2- {5-fluoro-2 - [(4- {2- [4- (trifluoromethyl) phenyl] ethyl} benzyl) oxy were dissolved ] phenyl} ethyl) {2- [4- (methoxycarbonyl) phenyl] ethyl} amino] - 5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 160A) in 4 ml of dioxane, 0 , 7 ml of 1N aqueous sodium hydroxide solution and the mixture was stirred at room temperature overnight. At the end of the reaction, dioxane was removed on a rotary evaporator and the remaining mixture was diluted with water. The mixture was acidified to pH 4-5 with acetic acid. The precipitated solid was filtered under suction, washed several times with water and dried in a drying oven, under reduced pressure, at 40 ° C, for three days. 134 mg (75% of theory) of the title compound were obtained.
[596] LC-MS (Method 3): tn = 1.34 min; m / z = 741 (M + H) +.
[597] 1H-NMR (400 MHz, DMSO-d6): δ [pm] = 1.37-1.70 (m, 2H), 1.85-2.09 (m, 2H), 2.57- 2.98 (m, 14H), 3.96-4.15 (m, 1H), 4.80-4.99 (m, 2H), 6.85-7.05 (m, 3H), 7, 16 (br. S, 6H), 7.42 (br. S, 4H), 7.61 (d, 2H), 7.79 (d, 2H). B. Assessment of pharmacological activity
[598] The pharmacological effect of the compounds according to the invention is evidenced by the following tests: B-1. In vitro stimulation of recombinant soluble guanylate cyclase (GCs)
[599] Investigations on the in vitro stimulation of recombinant soluble guanylate cyclase (GCs) by the compounds according to the invention, with and without sodium nitroprusside and with and without the heme-dependent GC inhibitor 1H- 1,2,4 -oxadiazolo [4,3a] quinoxalin-1-one (ODQ), were carried out by the method described in detail in the following reference: M. Hoenicka, EM Becker, H. Apeler, T. Sirichoke, H. Schroeder, R. Gerzer and J.-P. Stasch, "Purified soluble guanylyl cyclase expressed in a baculovirus / Sf9 system: Stimulation by YC-1, nitric oxide, and carbon oxide", J. Mole. Med. 77 (1999), 14-23. Heme-free guanylate cyclase was obtained by adding Tween 20 to the sample buffer (0.5% as final concentration).
[600] The activation of GCs by a test substance is expressed as the number of times x of stimulation in relation to the base activity. The results of Example 2 are shown in Table 1A, those of Example 23 in Table 1B and those of Example 39 in Table 1C. Table 1A: In vitro stimulation (number of times x) of recombinant soluble guanylate cyclase ^ by Example 2
Table 1B: In vitro stimulation (number of times x) of recombinant soluble guanylate cyclase (GCs) by Example 23
Table 1C: In vitro stimulation (number of times x) of soluble guanylate cyclase
[DEA / NO = 2- (A /, A / -diethylamino) diazenolate-2-oxide; ODQ = 1H-1,2,4-oxadiazole- [4,3a] quinoxalin-1-one].
[601] As can be seen in Tables 1A, 1B and 1C, stimulation of both the heme-containing enzyme and the enzyme without heme was achieved. In addition, the combination of Example 2, Example 23 or Example 39 and 2- (N, N-diethylamino) diazenolate-2-oxide (DEA / NO), a NO donor, does not have a synergistic effect, that is, the The effect of DEA / NO is not enhanced as would be expected from an activator of GCs that acts by a heme-dependent mechanism. Furthermore, the activating effect of GCs according to the invention is not blocked by 1H-1,2,4-oxadiazole [4,3a] quinoxalin-1-one (ODQ), which is a heme-dependent inhibitor of guanylate cyclase soluble, and is even increased. The results of Tables 1 A, 1B and 1C thus confirm the mechanism of action of the compounds according to the invention as activators of soluble guanylate cyclase. B - 2. Action on a recombinant guanylate cyclase reporter cell line
[602] The cellular action of the compounds according to the invention was determined on a recombinant guanylate cyclase reporter cell line as described in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).
[603] The representative results obtained for the compounds according to the invention are shown in Table 2: Table 2: Activation activity of GCs in CHO reporter cells in vitro

(CME = minimum effective concentration) B-3. Vasorelaxant effect in vitro
[604] Rabbits are anesthetized and sacrificed by intravenous injection of sodium thiopental (about 50 mg / kg) and bled. The saphenous artery is removed and divided into 3 mm wide rings. The rings are mounted separately, in each case on a pair of triangular hooks opened at one end and made of a special wire (Remanium®) 0.3 mm thick. Each ring is placed under initial tension in a 5 ml organ bath, with Krebs-Henseleit solution, at 37 ° C, carbonated with carbogen and with the following composition: 119 mM NaCI; 4.8 mM KCI; 1 mM CaCl2 x 2 H2O; 1.4 mM MgSO4 x 7 H2O; 1.2 mM KH2PO4; 25 mM NaHCOa; 10 mM glucose; bovine serum albumin 0.001%. The contraction force is detected with Statham UC2 cells, amplified and digitized via A / D converters (DAS-1802 HC, Keithley Instruments, Munich) and recorded in parallel on a graphic recorder. Contractions are induced by adding phenylephrine.
[605] After several (usually 4) control cycles, the test substance is added with a dose increase in each subsequent test and the level of contraction achieved under the effect of the test substance is compared with the level of contraction achieved in previous test. The concentration required to reduce the contraction achieved in the previous control by 50% is calculated from this (Ciso). The volume normally applied is 5 μl. The proportion of DMSO in the bath solution corresponds to 0.1%.
[606] The representative results obtained for the compounds according to the invention are shown in Table 3: Table 3: Vasorelaxant effect in vitro
B-4. Bronchodilator effect in vitro and in vivo B-4.1 Bronchial relaxation in vitro
[607] Bronchial rings (2-3 segments) are removed from the rat, mouse or guinea pig and individually mounted on a pair of triangular hooks made of a special 0.3 mm diameter metallic wire (Remanium®), opened at one end. With pre-tension applied, each ring is introduced into a 5 ml organ bath containing carbonated carbonated buffer solution, at a temperature of 37 ° C (Krebs-Henseleit solution for example). Bronchial rings are pre-contracted with methacholine (1 μM) to examine bronchial relaxation by adding increasing concentrations (10 9 to 10'6 M) of the respective test substance. The results are evaluated as a percentage of relaxation with reference to pre-constriction by methacholine. B-4.2 Animal testing to assess the effect on bronchoconstriction in the asthma model
[608] Prior to the challenge test, all animals (rats, mice) are treated intragastrically by an esophageal tube, or by inhalation. Here, the animals in the treatment groups receive the test substance, the control animals receive a vehicle solution accordingly. After the waiting period, the animals are anesthetized and intubated. Once the esophageal catheter is placed and the steady state of breathing is reached, lung function is measured initially, before provocation. The parameters measured are, among others, pulmonary resistance (PR) and dynamic compliance (Cdin) and also tidal volume (CV) and respiratory rate (f). Data storage and statistical evaluation are performed with calculation programs developed specifically for pulmonary function tests (Notocord HEM).
[609] This is followed by a specific inhalation exposure of the test animals to a methacholine (MC) aerosol (asthmatic bronchoconstriction model not specifically induced). The recording of lung function parameters continues for 3 minutes after exposure. The concentration and dose of MC in the inhaled air are controlled and monitored by a system developed to control the dose by feedback (by measuring the aerosol concentration and volume per minute). The test is stopped when the desired dose is reached. The inhibitory effect of the test substances is determined by the increase in resistance compared to the simulated positive control. Study on the allergic asthma model:
[610] All animals, except the negative control group, are systemically sensitized with the allergen ovalbumin and adjuvant (alum). The negative control group receives saline (NaCl). Then, all groups are challenged with ovalbumin. The study employs 6 treatment groups - 2 test substances, each for 3 dose groups. In addition, there is a reference group treated with dexamethasone via intraperitoneal injection, a simulated treated group and a provoked negative control group, and a simulated treated group and a positive control group challenged with ovalbumin. The sensitization, treatment and provocation protocol is as follows: on days 0.14 and 21 all animals are sensitized with ovalbumin and adjuvant via intraperitoneal injection, while the negative control is treated with NaCI. On days 28 and 29, the animals are provoked by the intratracheal administration of an ovalbumin solution. The test substances are administered intragastrically or inhalably 1 h before each intratracheal challenge with allergen. 18 h and 1 h before each intratracheal challenge with allergen, a reference group is treated via intraperitoneal injection with dexamethasone. The positive and negative control groups are treated accordingly with the vehicle. Airway hyper-reactivity and inflammatory response:
[611] Animals are initially assessed for airway hyperreactivity to nonspecific stimuli. For this purpose, a hyperreactivity test in the form of a gradually increasing inhaled methacholine challenge is performed approximately 24 h after the challenge with ovalbumin.
[612] Animals are anesthetized and intubated via the orotracheal route and, before challenge, lung function is measured by body plethysmography (including parameters such as tidal volume, respiratory rate, dynamic compliance and lung resistance). At the end of the measurements, the dose-activity curve is plotted for each animal and the hyper-reactivity of the positive control is assessed in relation to the negative control or its inhibition in the treatment groups.
[613] The animals are then sacrificed without pain, blood samples are taken and the lungs are subjected to bronchoalveolar lavage (BAL). The washing liquid is used to determine the total number of cells and for a differential leukocyte count, including the number of eosinophils in the BAL fluid. The remaining fluid from the BAL is initially frozen. This allows other parameters (for example, cytokines) to be determined at a later stage, if necessary. The lung tissue is stored for an optional histopathological examination. B-5. Isolated perfused heart according to Lanqendorff
[614] Male Wistar rats (strain HsdCpb: WU) with a body weight of 200-250 g are anesthetized with Narcoren® (100 mg / kg). The chest is opened and the heart is exposed, excised and connected to a Langendorff device, placing a cannula in the aorta. The heart is perfused retrograde at 9 ml / min, at constant flow, with a Krebs-Henseleit buffer solution (aerated with 95% O2 and 5% CO2, pH 7.4, 35 ° C; composition in mmol / l : NaC1118; KCI3; NaHCOa 22; KH2PO4 1.2; MgSCU 1.2; CaCI 1.8; Glucose 10; Sodium pyruvate 2). To measure the contractility of the heart, a balloon, made of a thin plastic film, connected to a PE tube and filled with water, is introduced into the left ventricle through an opening in the left atrium of the heart. The balloon is connected to a pressure transducer. The final diastolic pressure is adjusted to 5-10 mmHg by the volume of the balloon. The perfusion pressure is detected with the help of a second pressure transducer. The data is sent via a bridge amplifier to a computer and recorded.
[615] After an equilibrium period of 40 min, the test substance is added to a final concentration of 10'7 mol / l of the infusion solution over 20 min, leading to a reduction in the perfusion pressure, which it is a symptom of coronary dilation. The hearts are then perfused without the test substance for an additional 120 min (elimination phase). To determine the reversibility of the reduction in the perfusion pressure (elimination score), the perfusion pressure value after 60 min of the elimination phase is based on the maximum reduction in the perfusion pressure by the test substance and expressed as a percentage. The elimination score obtained in this way is taken as a measure for the residence time of the substance at the site of action. B-6. Hemodynamics in anesthetized piglet
[616] Ellegaard Gottingen Minipigs® (Ellegaard, Denmark) healthy piglets of both sexes and weighing 2-6 kg are used. The animals are sedated by intramuscular administration of 25 mg / kg of ketamine and 10 mg / kg of azaperone. Anesthesia is initiated by intravenous administration of about 2 mg / kg ketamine and 0.3 mg / kg midazolam. Anesthesia is maintained by intravenous administration of about 7.5-30 mg / kg / h of ketamine and about 1-4 mg / kg / h of midazolam (infusion rate: 1-4 ml / kg / h) and about 150 μg / kg / h of pancuronium bromide (for example Pancuronium-Actavis). After intubation, the animals are connected to a ventilator at a constant respiratory volume (10-12 ml / kg, 35 breaths / min; AVEA®, Viasys Healthcare, USA, or Engstrom Carestation, GE Healthcare, Freiburg, Germany) in order to reach a CO2 concentration at the end of expiration of about 5%. Ventilation is carried out with ambient air enriched with about 40% oxygen (normoxia). For the measurement of hemodynamic parameters, such as pulmonary arterial pressure (PAP), blood pressure (BP) and heart rate (HR), catheters are inserted into the carotid artery to measure blood pressure and a Swan-Ganz® catheter it is introduced in the direction of flow, through the jugular vein, into the pulmonary artery. Hemodynamic signals are recorded and evaluated by means of pressure transducers (Combitransducer, B. Braun, Melsungen, Germany) / amplifiers and Ponemah® data acquisition software.
[617] After instrument placement in animals, continuous perfusion of a thromboxane A2 analogue is initiated to increase pulmonary arterial pressure. About 0.3-0.75 μg / kg / min of 9,11-didesoxy-9α, 11a- epoxyethaneprostaglandin F2a (U-44069; Sigma, cat. No. D0400, or Cayman Chemical Company, cat No. 16440), dissolved in saline, in order to increase the mean pulmonary arterial pressure to values above 25 mmHg. After 30 minutes after the start of the infusion, a threshold is reached and the test is started.
[618] Test substances are administered by intravenous infusion or by inhalation. In order to prepare the solution for inhalation, the following procedure is adopted: in the case of an animal weighing 4 kg, to prepare the stock solution (300 μg / kg), weigh 1.2 mg of the compound in test and dissolve in a total volume of 3 ml (1% DMSO, 99% 0.2% citric acid solution, and 1N aqueous sodium hydroxide solution to adjust the pH to 8). The solution is then diluted to the usage concentration with 0.2% citric acid, the pH having been previously adjusted to 8 with an aqueous sodium hydroxide solution. In each test, 3 ml of the test compound solution is nebulized per 4 kg animal in the inhalation section of the respiratory circuit using the Aeroneb® Pro nebulization system. The average nebulization time is about 7 min from the beginning nebulization. B-7. Inhalational administration of GC activators in animal models of Pulmonary Arterial Hyperpressure
[619] The tests are performed with anesthetized Gottingen minipigs, anesthetized and conscious rats, and dogs with telemetry instruments. Acute pulmonary hypertension is induced, for example, by perfusion of a thromboxane A2 analogue, by treatment of acute hypoxia or by treatment of hypoxia over several weeks, and / or by the administration of monocrotaline. The test substances are nebulized using the Nebutec®or Aeroneb® Pro nebulization system, using powder applicators and / or a solution for experimental intratracheal administration (Liquid MicroSprayer®, Dry Powder Insufflator ™, MicroSprayer®, Penn-Century Inc ., Wyndmoor, PA, USA) or after nebulization of solids inserted in the ventilation inspiration section. The substances are used as solids or solutions depending on the molecular structure. Hemodynamic signals are recorded and evaluated using pressure transducers / amplifiers (Combitransducer B. Braun, Melsungen, Germany or CardioMEMS Inc., Atlanta, GA, USA) and with Ponemah® or CardioMems® data acquisition software. After long tests (for example, monocrotaline in rats), it is also possible to carry out a histological evaluation. B-8. Radiotelemetric measurement of blood pressure and heart rate in conscious rats
[620] A commercially available telemetry system from Data Sciences International DSI, USA, is employed to perform measurements on conscious mice as described below. The system consists of 3 main components: (1) implantable transmitters (Physiotel® telemetry transmitter), (2) receivers (Physiotel® receiver) connected via a multiplexer (DSI Data Exchange Matrix) to (3) a data acquisition computer . The telemetry system allows to continuously record blood pressure, heart rate and body movements of conscious animals in their usual habitat.
[621] Investigations are performed on adult female Wistar rats weighing> 200 g. After implantation of the transmitter, the test animals are housed separately in type 3 Makrolon cages. They have free access to normal food and water. The day / night cycle is changed by lighting the experimental laboratory at 6:00 am and 7:00 pm. Implementation of the transmitter:
[622] The telemetry transmitters (TA11 PA-C40, DSI) employed are surgically implanted under aseptic conditions in the experimental animals, at least 14 days before the first experimental use. In this way, animals with implanted instruments can be used repeatedly after the wound has healed and the implant has consolidated.
[623] For implantation, fasting animals are anesthetized with pentobarbital (Nembutal®, Sanofi, 50 mg / kg by intraperitoneal injection) and are scraped and disinfected over a large area of their abdomen. After the abdominal cavity has been opened along the linea alba, the liquid-filled measuring catheter of the system is inserted into the descending aorta, in the cranial direction and behind the bifurcation, and is fixed with tissue glue (VetBonD ™, 3M) . The transmitter's body is fixed intraperitoneally to the abdominal wall muscle and the wound is closed with layers. An antibiotic (10% Oxytetracyclin®, 60 mg / kg by subcutaneous injection, 0.06 ml / 100 g body weight, Beta-Pharma GmbH, Germany) and an analgesic (Rimadyl®, 4 mg / kg by subcutaneous injection, Pfizer, Germany) are administered postoperatively for prophylaxis of infection. Substances and solutions:
[624] Unless otherwise specified, the test substances are administered in each case orally, by gavage, to a group of animals (n = 6). The test substances are dissolved in suitable solvent mixtures, or suspended in 0.5% Tylose, appropriately for an administration volume of 5 ml / kg of body weight. A group of solvent treated animals is used as a control. Experimental procedure
[625] The telemetric measurement unit is configured for 24 animals. Each test is registered under a test number.
[626] Each of the mice with implanted instruments is assigned an individual receiving antenna (1010 Receiver, DSI). The implanted transmitters can be activated externally using a built-in magnetic switch and, in preparation for the test, are switched to transmission. The emitted signals can be detected online by a data acquisition system (Dataquest ™ A.R.T. for Windows, DSI) and processed appropriately. The data are stored in each case in a file created for this purpose with the test number.
[627] In the normal procedure, the following parameters are measured for periods of 10 seconds in each case: (1) systolic blood pressure (SBP), (2) diastolic blood pressure (DBP), (3) average blood pressure ( MAP), (4) heart rate (HR) and (5) activity (TA).
[628] The acquisition of measured values is repeated, under computer control, at 5 minute intervals. The original data obtained as absolute values are corrected in the diagram for the barometric pressure measured at the time (Ambient Pressure Reference Monitor, APR-1) and stored as individual data. Further technical details are given in the manufacturer's documentation (DSI).
[629] Unless otherwise specified, test substances are administered at 9.00 am on the test day. After administration, the parameters described above are measured over 24 hours. Evaluation:
[630] At the end of the test, the individual data acquired is sorted by the Dataquest ™ A.R.T. 4.1 Analysis. The idle time is assumed to be the period of 2 hours before the substance is administered, so that the selected data includes the period from 7.00 on the test day until 9.00 on the following day.
[631] The data is smoothed over a pre-established period, by averaging (average of 15 minutes), and transferred as a text file to a storage medium. The measured values pre-ordered and compressed in this way are transferred to Excel models and tabulated. The data recorded on each test day are stored in a separate file, labeled with the test number. The test protocols and results are stored in files in numerical order. Literature:
[632] K. Witte, K. Hu, J. Swiatek, C. Müssig, G. Ertl and B. Lemmer, Experimental heart failure ir rats: effects on cardiovascular circadian rhythms and on myocardial β-adrenergic signaling, Cardiovasc. Res. 47 (2), 350-358 (2000) B-9. Testing for the desaturation potential of substances (ventilation / perfusion incompatibility)
[633] Healthy Ellegaard Gottingen Minipigs® piglets (Ellegaard, Denmark) of both sexes, weighing 4-5 kg, are used. The animals are sedated by the intramuscular administration of about 25 mg / kg of ketamine and 10 mg / kg of azaperone. Anesthesia is initiated by intravenous administration of about 2 mg / kg ketamine and about 0.3 mg / kg midazolam. Anesthesia is maintained by intravenous administration of about 7.5-30 mg / kg / h of ketamine, about 1 -4 mg / kg / h of midazolam (infusion rate: 1 - 4 ml / kg / h) and about 150 μg / kg / h of pancuronium bromide (for example Pancuronium-Actavis). After intubation, the animals are connected to a ventilator at a constant respiratory volume (50-60 ml, 35 breaths / min; AVEA®, Viasys Healthcare, USA, or Engstrom Carestation, GE Healthcare, Freiburg, Germany) in order to achieve a CO2 concentration at the end of expiration of about 5%. Ventilation is carried out with ambient air enriched with about 40% oxygen (normoxia) and is adjusted in such a way that a positive end-expiratory pressure in a 5 cm water column is achieved. For the measurement of hemodynamic parameters, such as pulmonary arterial pressure (PAP), blood pressure (BP) and heart rate (HR), the catheters are inserted into the carotid artery to measure blood pressure, and a Swan-Ganz catheter ® is introduced in the direction of flow through the jugular vein in the pulmonary artery. Hemodynamic signals are recorded and evaluated using pressure transducers (Combitransducer, B. Braun, Melsungen, Germany / amplifiers and Ponemah® data acquisition software. A 4 French oximetry catheter (Edwards Lifesciences, Irvine, CA, USA) is placed in the left femoral artery and connected to a Vigilance monitor (Edwards Lifesciences, Irvine, CA, USA) to measure arterial oxygen saturation (SaO2).
[634] All hemodynamic parameters are measured continuously; for the evaluation, averages are determined at stable intervals of at least 1 min (in the case of extreme values, for example, a maximum increase in PAP) and / or 3 min (baseline conditions). Blood gases (Stat Profile pHOx plus L; Nova Biomedical, Waltham, MA, USA) are measured 3 min after the start of each unilateral bronchial obstruction cycle. Univentilation of the right lung is performed by advancing the tracheal tube in the right main bronchus and disconnecting the left side of the lung from ventilation by inflating a balloon. The placement of the tube is confirmed by auscultation. Each animal is subjected to several 10-minute univentilation cycles, interrupted in each case by 30 min of biventilation. The first cycles are used as control cycles to ensure reproducibility of the cycles. Subsequently, the effect of the solvent (vehicle) and the test substance dissolved in it is measured after intravenous and / or inhalation administration for the following main parameters: blood pressure (BP), pulmonary pressure (PAP) and arterial oxygen saturation (SaCh) . This animal model is used to identify substances that cause a relatively large reduction in PAP, or an increase in PAP induced by hypoxia (the desired effect) without increasing oxygen desaturation by dilating the pulmonary arteries in regions without lung ventilation ( unwanted effect). Literature:
[635] E.M. Becker et al., "V7Q mismatch" bei sekundàrer pulmonaler Hypertonie - Riociguat im Vergleich, Pneumologie 65 (Suppl. 2), S122-S123 (2011). C. Exemplary embodiments of pharmaceutical compositions
[636] The compounds according to the invention can be converted into pharmaceutical preparations in the following ways: Pills: Composition:
[637] 100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
[638] 212 mg tablet weight, 8 mm diameter, 12 mm radius of curvature. Production:
[639] The mixture of compound according to the invention, lactose and starch is granulated with a 5% (w / w) solution of PVP in water. The granules are dried and then mixed with the magnesium stearate for 5 minutes. This mixture is compacted in a conventional tablet press (see above for the shape of the tablet). A compression force of 15 kN is suggested. Suspension that can be administered orally: Composition:
[640] 1000 mg of the compound according to the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.
[641] 10 ml of oral suspension corresponds to a single dose of 100 mg of the compound according to the invention. Production:
[642] Rhodigel is suspended in ethanol and the compound according to the invention is added to the suspension. Water is added under agitation. The mixture is stirred for about 6 h until Rhodigel is fully expanded. Solution that can be administered orally: Composition:
[643] 500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution correspond to a single dose of 100 mg of the compound according to the invention. Production:
[644] The compound according to the invention is suspended in a mixture of polyethylene glycol and polysorbate under stirring. Stirring is continued until the compound according to the invention is completely dissolved. Intravenous solution:
[645] The compound according to the invention is dissolved at a concentration below saturation solubility in a physiologically tolerated solvent (for example, isotonic saline, 5% glucose solution and / or 30% PEG 400 solution). The solution is sterilized by filtration and used to fill sterile and pyrogen-free injection vials.

权利要求:
Claims (12)
[0001]
1. Compound of formula (I)
[0002]
2. A compound of formula (I) according to claim 1, characterized in that R1 represents hydrogen or fluorine, L1 represents ethane-1,2-diyl or 1,4-phenylene, and A represents a group of the formula
[0003]
3. A compound of formula (I) according to claim 1 or 2, characterized in that R1 represents hydrogen or fluorine, L1 represents ethane-1,2-diyl or 1,4-phenylene, and A represents a group of the formula
[0004]
Compound of formula (I) according to any one of claims 1 to 3, characterized in that R1 represents hydrogen or fluorine, L1 represents ethane-1,2-diyl or 1,4-phenylene, and A represents a group of formula
[0005]
5. Compound characterized by being 5 - {[2- (4-carboxyphenyl) ethyl] [2- (2 - {[3-chloro-4 '- (trifluormethyl) biphenyl-4-yl] methoxy} -phenyl) - ethyl] amino} -5,6,7,8-tetrahydrochinoline-2-carboxylic of the formula below
[0006]
6. Compound characterized by being 5 - {(4-carboxybutyl) [2- (2 - {[3-chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) -ethyl] - amino} -5,6,7,8- tetrahydrochinoline-2-carboxylic formula below
[0007]
Process for the preparation of a compound of formula (I), as defined in any one of claims 1 to 6, characterized in that [A] a compound of formula (II)
[0008]
8. Use of the compound, as defined in any one of claims 1 to 6, characterized in that it is in the preparation of a medicament for the treatment and / or prevention of diseases selected from the group consisting of cardiovascular, cardiopulmonary, thromboembolic, fibrotic and pulmonary diseases.
[0009]
Use of the compound, as defined in any one of claims 1 to 6, characterized in that it is in the preparation of a medicament for the treatment and / or prevention of primary and secondary forms of pulmonary hypertension, heart failure, angina pectoris, hypertension, thromboembolic disorders, ischemia, vascular disorders, impaired microcirculation, renal failure, fibrotic disorders and arteriosclerosis.
[0010]
Medicament characterized in that it comprises a compound, as defined in any one of claims 1 to 6, in combination with one or more non-toxic inert pharmaceutically suitable auxiliary substances.
[0011]
Medicament characterized by comprising a compound, as defined in any one of claims 1 to 6, in combination with one or more other active compounds selected from the group consisting of organic nitrates, NO donors, PDE 5 inhibitors, prostacyclin analogs , IP receptor agonists, endothelin receptor antagonists, guanylate cyclase stimulators, tyrosine kinase inhibitors, antiobstructive agents, anti-inflammatory and / or immunosuppressive agents, antithrombotic agents, blood pressure lowering agents and agents that alter blood pressure fat metabolism.
[0012]
Medicament according to claim 10 or 11, characterized in that it is for the treatment and / or prevention of primary and secondary forms of pulmonary hypertension, heart failure, angina pectoris, hypertension, thromboembolic disorders, ischemia, vascular disorders, microcirculation impaired, renal failure, fibrotic disorders and arteriosclerosis.

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

SE8004002L|1980-05-29|1981-11-30|Arvidsson Folke Lars Erik|THERAPEUTICALLY APPLICABLE TETRALIN DERIVATIVES|

---

IL65501A|1981-05-08|1986-04-29|Astra Laekemedel Ab|1-alkyl-2-aminotetralin derivatives,process for their preparation and pharmaceutical compositions containing them|

---

DE3718317A1|1986-12-10|1988-06-16|Bayer Ag|SUBSTITUTED BASIC 2-AMINOTETRALINE|

---

DE3719924A1|1986-12-22|1988-06-30|Bayer Ag|8-SUBSTITUTED 2-AMINOTETRALINE|

---

DE69032725T2|1989-05-31|1999-04-08|Upjohn Co|CNS-active 8-heterocyclyl-2-aminotetralin derivatives|

---

FR2659853A1|1990-03-22|1991-09-27|Midy Spa|Use of 2-aminotetralin derivatives for the preparation of medicaments intended for combating disorders of intestinal motor function|

---

EP0738149B1|1994-01-10|2006-11-29|Teva Pharmaceutical Industries, Ltd.|1-aminoindan derivatives and compositions thereof|

---

ES2212570T3|1998-06-01|2004-07-16|Ortho-Mcneil Pharmaceutical, Inc.|TETRAHYDRONAFTALENO COMPOUND AND ITS USE FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES.|

---

DE19834047A1|1998-07-29|2000-02-03|Bayer Ag|Substituted pyrazole derivatives|

---

DE19834044A1|1998-07-29|2000-02-03|Bayer Ag|New substituted pyrazole derivatives|

---

GB9827467D0|1998-12-15|1999-02-10|Zeneca Ltd|Chemical compounds|

---

DE19943635A1|1999-09-13|2001-03-15|Bayer Ag|Novel aminodicarboxylic acid derivatives with pharmaceutical properties|

---

AR031176A1|2000-11-22|2003-09-10|Bayer Ag|NEW DERIVATIVES OF PIRAZOLPIRIDINA SUBSTITUTED WITH PIRIDINE|

---

DE10109858A1|2001-03-01|2002-09-05|Bayer Ag|Novel halogen-substituted aminodicarboxylic acid derivatives|

---

DE10109859A1|2001-03-01|2002-09-05|Bayer Ag|Novel aminodicarboxylic acid derivatives|

---

DE10109861A1|2001-03-01|2002-09-05|Bayer Ag|Novel side chain halogenated aminodicarboxylic acid derivatives|

---

DE10110750A1|2001-03-07|2002-09-12|Bayer Ag|Novel aminodicarboxylic acid derivatives with pharmaceutical properties|

---

DE10110749A1|2001-03-07|2002-09-12|Bayer Ag|Substituted aminodicarboxylic acid derivatives|

---

DE10220570A1|2002-05-08|2003-11-20|Bayer Ag|Carbamate-substituted pyrazolopyridines|

---

US20050032873A1|2003-07-30|2005-02-10|Wyeth|3-Amino chroman and 2-amino tetralin derivatives|

---

GB0318094D0|2003-08-01|2003-09-03|Pfizer Ltd|Novel combination|

---

CN101146763A|2005-03-30|2008-03-19|默克公司|Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use|

---

DE102005047946A1|2005-10-06|2007-05-03|Bayer Healthcare Ag|Use of soluble guanylate cyclase activators for the treatment of acute and chronic lung diseases|

---

DE102005050377A1|2005-10-21|2007-04-26|Bayer Healthcare Ag|Heterocyclic compounds and their use|

---

DE102006031175A1|2006-07-06|2008-01-10|Bayer Healthcare Ag|Aqueous drug formulation of 4 - [ - oxy] -phenethyl) amino) methyl] benzoic acid|

---

US20090048295A1|2007-08-13|2009-02-19|Joseph Kent Barbay|Substituted 5,6,7,8-tetrahydroquinoline derivatives, compositions, and methods of use thereof|

---

MX2010002608A|2007-09-06|2010-06-01|Merck Sharp & Dohme|Soluble guanylate cyclase activators.|

---

EP2331498B1|2008-08-19|2016-11-09|Janssen Pharmaceutica NV|Cold menthol receptor antagonists|

---

DE102010020553A1|2010-05-14|2011-11-17|Bayer Schering Pharma Aktiengesellschaft|Substituted 8-alkoxy-2-aminotetralin derivatives and their use|

---

DE102010021637A1|2010-05-26|2011-12-01|Bayer Schering Pharma Aktiengesellschaft|Substituted 5-fluoro-1H-pyrazolopyridines and their use|

---

CA2803688A1|2010-06-25|2011-12-29|Bayer Intellectual Property Gmbh|Use of stimulators and activators of soluble guanylate cyclase for treating sickle-cell anemia and conserving blood substitutes|

---

MX2013000198A|2010-07-09|2013-01-28|Bayer Ip Gmbh|Ring-fused pyrimidines and triazines and use thereof for the treatment and/or prophylaxis of cardiovascular diseases.|

---

DE102010040233A1|2010-09-03|2012-03-08|Bayer Schering Pharma Aktiengesellschaft|Bicyclic aza heterocycles and their use|

---

DE102010043379A1|2010-11-04|2012-05-10|Bayer Schering Pharma Aktiengesellschaft|Substituted 6-fluoro-1H-pyrazolo [4,3-b] pyridines and their use|

---

EP2683710B1|2011-03-10|2017-07-19|Boehringer Ingelheim International GmbH|Soluble guanylate cyclase activators|

---

CN104245663B|2012-04-16|2016-10-26|东亚荣养株式会社|bicyclic compound|

---

CN104703964B|2012-07-20|2017-04-12|拜耳制药股份公司|Substituted aminoindane- and aminotetralincarboxylic acids and use thereof|

---

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---

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---

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---

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---

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---

FR3000065A1|2012-12-21|2014-06-27|Univ Lille Ii Droit & Sante|BICYCLIC COMPOUNDS HAVING ACTIVITY POTENTIATING THE ACTIVITY OF AN ACTIVE ANTIBIOTIC AGAINST MYCOBACTERIA-PHARMACEUTICAL COMPOSITION AND PRODUCT COMPRISING SUCH COMPOUNDS|

---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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---

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law|

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2018-03-06| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2018-03-13| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2018-03-20| B06I| Technical and formal requirements: publication cancelled|Free format text: ANULADA A PUBLICACAO CODIGO 6.6.1 NA RPI NO 2462 DE 13/03/2018 POR TER SIDO INDEVIDA. |

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2019-04-16| B07E| Notice of approval relating to section 229 industrial property law|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-08-13| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|

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2020-03-10| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application according art. 36 industrial patent law|

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2020-09-01| B09A| Decision: intention to grant|

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2020-12-15| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 16/07/2013, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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EP12177284|2012-07-20|

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EP12177284.2|2012-07-20|

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EP13167967.2|2013-05-16|

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EP13167967|2013-05-16|

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PCT/EP2013/065017|WO2014012934A1|2012-07-20|2013-07-16|Novel 5-aminotetrahydroquinoline-2-carboxylic acids and use thereof|

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