Process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid and its crystalline forms for use as a pharma-ceutically active compound

Abstract

The present invention relates to a new and improved process for the preparation of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I) and to a new crystalline form thereof, namely the pseudopolymorphic form monohydrate I (IMI) or said pseudopolymorphic form monohydrate II (IM-II), further the present invention relates to a new selective crystallization process for the preparation of the pseudopolymorphic form monohydrate I (IMI) or the pseudopolymorphic form monohydrate II (IM-II), preferably the monohydrate I of formula (IMI), as well as to pharmaceutical compositions comprising the monohydrate I of formula (IMI) and to their use for the treatment and / or prevention of diseases, in particular the treatment and / or prevention of pulmonary and cardiopulmonary and cardiovascular diseases. TIFF2025502842000182.tif50128

Description

Summary of the Invention

[0001] The present invention relates to a compound represented by formula (I) A novel and improved process for the preparation of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of TIFF2025502842000002.tif83165 and its novel crystalline forms, i.e., pseudopolymorphic forms monohydrate I (IMI) or monohydrate II (IM-II) TIFF2025502842000003.tif78165 and its novel crystalline form.

[0002] Furthermore, the present invention relates to a novel selective crystallization process for preparing the pseudopolymorphic form monohydrate I (IMI) or the pseudopolymorphic form monohydrate II (IM-II), preferably the monohydrate I of formula (IMI), as well as to pharmaceutical compositions comprising the monohydrate I of formula (IMI) or the pseudopolymorphic form monohydrate II (IM-II), preferably the monohydrate I of formula (IMI), and to their use for the treatment and / or prevention of diseases, in particular pulmonary, cardiopulmonary and cardiovascular diseases, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0003] In the context of the present invention, (IA) refers to the compound of formula (I) in amorphous form, the monohydrate I of crystalline modification I being designated (IMI) and the monohydrate II of crystalline modification II being designated (IM-II). Without further distinction, the compound of formula (I) exists in one or more modifications or as a solvate, in particular as a hydrate.

[0004] Unpublished pharmacological studies have surprisingly revealed that Example 23 of WO2014 / 012934, i.e. (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I), has improved pharmacological properties, e.g. a longer duration of action, compared to the similar 5,6,7,8-tetrahydroquinoline-2-carboxylic acid disclosed in WO2014 / 012934. The acid of formula I is therefore suitable for use in the treatment of cardiopulmonary diseases and for use in the manufacture of inhaled medicaments for these diseases.

[0005] As the preferred pharmaceutical form, dry powder inhalation formulations were selected due to their suitability in target pulmonary diseases, convenience, and patient compliance and adherence.

[0006] However, as disclosed in Example 23 of WO14 / 012934-A1, (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I) can only be obtained in amorphous form (see Comparative Example 11), which is not suitable for use in inhalation dosage forms administered by dry powder inhalers.

[0007] For the development of pharmaceutical formulations comprising the (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I) in solid form, in particular in the form of a dry powder inhalation form, there is a high demand for the reproducible preparation and isolation of the compound of formula (I) in one defined crystalline form.

[0008] Many attempts were required to finally crystallize the compound of formula I into a defined solid form.

[0009] Typically, (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I has a tendency to solidify in the amorphous state. To overcome this property, salt selection screens were performed in an attempt to find new crystalline materials with beneficial properties. All attempts resulted in amorphous or highly disordered materials and no salt formation was observed.

[0010] As an example, the resulting residue XRPD pattern of an experiment with L-arginine is presented (see FIG. 4).

[0011] Surprisingly, the compound of formula I is obtained in several pseudopolymorphic forms and no anhydrous crystalline form has been found.

[0012] The following crystalline forms of the compound of formula (I) have been identified as pseudopolymorphic forms monohydrate I and II ((IMI) and (IM-II)), hemihydrate, sesquihydrate, dihydrate, and 1,25-hydrate (see Example 6, Figures 5-32). In this context, modification, polymorphic form, and polymorph have the same meaning. In addition, there is an amorphous form. All of the pseudopolymorphic forms and amorphous forms together are different solid forms of the compound of formula (I).

[0013] Compound stability and homogeneity are important requirements for pharmaceuticals and are prerequisites for approval by health authorities, which increase the safety and quality of preparations and formulations containing the compound of formula (I) and therefore reduce the risk to patients.

[0014] However, among several identified pseudopolymorphic forms, the most suitable stable form had to be identified during several stages.

[0015] The dihydrate was found to amorphize during the drying process (see FIG. 10a). The crystal lattice of the hemihydrate exhibits disorder (see FIG. 5), which may support phase transition and / or amorphization during mechanical processing, e.g., formulation processes. The crystallization of the sesquihydrate was not feasible for scale-up due to the very long stirring procedure.

[0016] It was found that both monohydrates overcome these undesirable properties of the different pseudopolymorphic forms. However, in the end, it was found that only one of these monohydrate forms is stable during micronization and is therefore the most suitable form for use, for example, in the manufacture of inhaled medicaments, in particular dry powder-based inhaled medicaments. Surprisingly, it was found that during micronization, monohydrate II either showed partial amorphization (see Example 8b, Figure 42) or additionally converted to monohydrate I (see Example 8a, Figure 43), depending on the micronization conditions. Moreover, it was observed that monohydrate II also showed conversion to monohydrate I during storage (see Example 7b, Figures 40 and 41). Thus, the pseudopolymorphic form monohydrate I is suitable for use in the pharmaceutical field and is preferred over other solid forms of the compound of formula I, in particular for pharmaceutical compositions, in particular for dry powder inhalation dosage forms.

[0017] In particular, the monohydrate I form of the compound of formula (I) ensures that undesired conversion of the compound of formula (I) into other forms and the associated changes in the properties mentioned above are prevented.

[0018] The compounds of formulae (I), (IMI) and (IM-II) act as activators of soluble guanylate cyclase and can be used as drugs for the prevention and / or treatment of pulmonary, cardiopulmonary and cardiovascular diseases, such as pulmonary arterial hypertension (PAH), as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP), more particularly it relates to a method for treating cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as PH-COPD and PH-IIP. [Background technology]

[0019] 2. Background of the Invention Pulmonary hypertension (PH) is a progressive lung disorder that, if untreated, leads to death within a few years after diagnosis. Pulmonary hypertension is defined by an elevation in mean pulmonary artery pressure (mPAP) (normal value of less than 20 mmHg at rest). The pathophysiology of pulmonary hypertension is characterized by pulmonary vascular vasoconstriction and remodeling. In chronic PH, there is primarily neomuscularization of nonmuscularized pulmonary vessels, with an increase in vascular muscle in the surroundings of already muscularized vessels. This increasing obstruction of the pulmonary circulation leads to a progressive stress on the right heart, which results in reduced output from the right heart and ultimately right heart failure [M. Humbert et al., J. Am. Coll. Cardiol. 2004, 43, 13S-24S (Non-Patent Document 1)]. Idiopathic (primary) pulmonary arterial hypertension (IPAH) is a very rare disorder, whereas secondary pulmonary hypertension (non-PAH PH) is very common, and secondary pulmonary hypertension is currently considered to be the third most common group of cardiovascular disorders after coronary heart disease and systemic hypertension.Since 2008, pulmonary hypertension has been classified into various subgroups according to their etiology according to the Dana Point classification [M. Humbert and VV McLaughlin, J. Am. Coll. Cardiol. 2009, 54(1), S1-S2 (Non-Patent Document 2); 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 (Non-Patent Document 3); updated Nizza classification Gerald Simonneau, David Montani, David S. Celermajer, Christopher P. Denton, Michael A. Gatzoulis, Michael Krowka, Paul G. Williams, Rogerio Souza: Haemodynamic definitions and updated clinical classification of pulmonary hypertension, in: European Respiratory Journal, 2018; DOI: 10.1183 / 13993003.01913-2018 (Non-patent Document 4)].

[0020] Despite all the progress in the therapy of PH, there is still no cure in sight for this serious disorder. The standard therapies available on the market (e.g. prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase inhibitors) can improve the quality of life, exercise tolerance and prognosis of patients. These are mainly systemically administered (in addition to inhaled treprostinil, and inhaled Iloprost or NO) and are therapeutic principles that act mainly hemodynamically by regulating vascular tone. The applicability of these medicines is limited due to side effects, some of which are severe, and / or complex administration forms. The time period during which the clinical situation of the patient can be improved or stabilized by a particular monotherapy is limited (e.g. due to the development of tolerance). Finally, the therapy is escalated and therefore combination therapy must be applied, in which several medicines are given simultaneously. Currently, these standard therapies are only approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). In the case of secondary forms of PH (group 3 PH) associated with lung disease, such as PH-COPD or PH-IIP, these therapeutic principles (e.g. sildenafil, bosentan) have failed in clinical studies, because they lead to a reduction in arterial oxygen content (de-saturation) in patients as a result of non-selective vasodilatation.The reason for this is probably the adverse effect on ventilation-perfusion adaptation in the lungs in heterogeneous lung disorders, which is caused by the systemic administration of non-selective vasodilators [I.Blanco et al., Am.J.Respir.Crit.Care Med.2010,181,270-278 (Non-Patent Document 5); D.Stolz et al., Eur.Respir.J.2008,32,619-628 (Non-Patent Document 6)].

[0021] New combination therapy is one of the most promising future therapeutic options for the treatment of pulmonary hypertension. In this context, the discovery of new pharmacological mechanisms for the treatment of PH is of particular interest [Ghofrani et al., Herz 2005,30,296-302 (Non-Patent Document 7); EBRosenzweig, Expert Opin.Emerging Drugs 2006,11,609-619 (Non-Patent Document 8); T.Ito et al., Curr.Med.Chem.2007,14,719-733 (Non-Patent Document 9)]. In particular, new therapeutic approaches that can be combined with concepts of already commercially available therapies can form the basis of more efficient treatments and therefore be of great benefit to patients. In addition, the selective pulmonary applicability of such a novel principle of action may not only provide the option to use it for PAH, but also as a first therapeutic option for patients suffering from secondary forms of PH (group 3 PH), especially since non-selective systemic vasodilation is avoided by targeted application to the ventilated areas of the lung via inhalation application.

[0022] In an animal model of pulmonary hypertension, it was demonstrated that inhalation administration of the sGC activator BAY 58-2667 (cinacigaut) in the form of microparticles results in a dose-dependent selective reduction in pulmonary artery pressure. In this model, intravenous administration of 1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which oxidizes the heme prosthetic group of sGC, reduced the vasodilatory effect of inhaled NO (iNO), which was increased by BAY 58-2267. These results led to the hypothesis that inhalation administration of sGC activators may represent a new and effective method of treatment for patients suffering from pulmonary hypertension, especially when the response of these patients to iNO and / or PDE5 inhibitors is reduced as a result of the lack of NO or the oxidation of sGC [OVEvgenov et al., Am.J.Respir.Crit.Care Med.2007,176,1138-1145 (Non-Patent Document 10)]. However, in this model, cinaciguat by itself did not have sufficient duration of action, and in addition, higher dosages resulted in undesirable systemic side effects.

[0023] Merck Sharp Dohme is developing an inhaled sGC stimulator application as a dry powder for PAH (MK5475; NCT04609943). However, in PH and other lung diseases, responsiveness to inhaled nitric oxide (iNO) and sGC stimulators can be compromised by oxidation of sGC. Inhaled sGC activators targeted to the lungs could overcome this limitation.

[0024] For this purpose, it should be possible to combine (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid with the approved and established standard therapies for pulmonary hypertension and also with the basic therapies for chronic lung diseases in the secondary PH form, e.g. COPD and IIP.

[0025] Oral application is often the preferred administration route for active drugs. For cardiopulmonary indications, local application of drugs to the target organ, the lung, is preferred to improve efficacy by increasing the local drug concentration and to avoid systemic side effects of the drug caused by systemic availability. Generally, less frequent dose regimens are desirable, for example, to improve patient adherence to therapy (patient compliance), but 24-hour coverage needs to be confirmed for sustained availability of the hemodynamically active drug during the dosing interval. Many lung-targeted inhaled drugs (e.g., Iloprost / Ventavis), for example, require frequent application schemes due to their short half-life and / or lung residence time, which requires multiple daily applications for 24-hour coverage. In particular, once-daily application is preferred due to convenience for patients and compliance. However, this goal is often difficult to achieve depending on the specific behavior and properties of the drug substance, in particular its lung selectivity and lung residence time.

[0026] An additional mode of systemic administration, injection, is still associated with a number of drawbacks (e.g., the inconvenience of a required clinical visit, discomfort, patient aversion to needle-based delivery methods, drug reactions at the site of administration), all of which further require alternative routes of administration.

[0027] Pulmonary delivery by inhalation is one such alternative route of administration that can offer several advantages over oral and injection administration, including, among others, the potential for greater efficacy and reduced systemic drug side effects due to increased local concentrations, as well as the convenience of patient self-administration, ease of delivery by inhalation, and elimination of needles.

[0028] For pharmaceutical preparations for inhalation that do not require adjuvants, especially in the case of solid preparations for suspension inhalation, the preparation may consist of the active ingredient alone. However, for practical reasons, for example to facilitate drug delivery of very low doses of the active ingredient, the preparation is often a pharmaceutical that contains one or more pharmacologically inert physiologically acceptable excipients or carriers in addition to the active ingredient. A review of various suitable preparations and corresponding administration aids can be found, for example, in R. Stangl, “An Overview of Innovative Inhalation Devices”, European Pharmaceutical Review, pages 50-55, (2002) (Non-Patent Document 11) and the literature described therein. In 2019, Moon et al. published an updated review of delivery technologies for oral inhalation products (Moon et al., AAPS PharmSciTech 20, 2019 117 pp 1-17 (Non-Patent Document 12)).

[0029] prior art The compound of formula (I) in amorphous form (see Comparative Example 11) and its preparation process are described in patent application WO2014 / 012934 (see Example 23) and are outlined in Scheme 1 below, starting from the precursor ethyl-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 (Example 92A in WO2014 / 012934).

[0030] Scheme 1: Preparation of compounds of formula (I) according to WO2014 / 012934 TIFF2025502842000004.tif65165

[0031] The compound of formula (I) (mosliciguat) was obtained as an amorphous solid by concentration of chromatographic fractions. No defined process for final crystallization to prepare the polymorph has been described so far.

[0032] A further disadvantage of this manufacturing method is that it results in increased formation of monosodium salt, which is of low solubility (see, for example, Comparative Example 12). It is not possible to convert this monosodium salt to free acid by adding additional acid. This results in a large amount of unused monosodium salt, which is not acceptable for the quality requirements of the drug substance and needs to be filtered out, thus reducing the yield of the compound of formula I.

[0033] Furthermore, in the process disclosed in WO2014 / 012934, dioxane is used as a solvent, which does not comply with the ICH guidelines, in contrast to the present process, in which dioxane is replaced by THF.

[0034] Another precursor of the compound of formula (I), namely, butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (compound XII). An improved synthesis of TIFF2025502842000005.tif78165 is disclosed in WO2021 / 233783 (Patent Document 2). However, the synthetic method of the compound of formula (I) itself is not disclosed in this reference.

[0035] There was therefore a need for an improved synthesis, viable on a large industrial scale, which reproducibly provides the compound of formula (I), in particular the crystalline monohydrate I (IMI) and / or II (IM-II), preferably the monohydrate I of formula (IMI), in high overall yield, at low production costs and with high purity meeting all regulatory requirements. [Prior art documents] [Patent documents]

[0036] [Patent Document 1] WO2014 / 012934 [Patent Document 2] WO2021 / 233783 [Non-patent literature]

[0037] [Non-Patent Document 1] M. Humbert et al., J. Am. Coll. Cardiol. 2004, 43, 13S-24S [Non-Patent Document 2] M. Humbert and VVMcLaughlin, J. Am. Coll. Cardiol. 2009, 54(1), S1-S2 [Non-Patent Document 3] D.Montana and G.Simonneau, in: AJPeacock et al. (Eds.), Pulmonary Circulation.Diseases and their treatment, 3rd edition, Hodder Arnold Publ., 2011, pp.197-206

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

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Non-licensed Document 8

Non-licensed literature 9

Non-licensed literature 10

[0038] Detailed Description of the Invention method As shown in Scheme 2, the method according to the present invention is characterized in that the purification step of the intermediate is carried out via salt formation / extraction / clarification filtration, thereby avoiding a chromatographic purification step. Additionally, the method according to the present invention provides high flexibility, since the target compound of formula (I) can be obtained via the following three routes: A) Route 1 starts from an ester of formula (XII) (process steps [A] and [B] = Route 1), B) Route 2 starts from the intermediate of formula (X) of the telescoping process (WO2021 / 233783) (process steps [C], [A] and [B] = Route 2), C) Route 3 starts from a solid NSA salt of formula (XII-NSA) (Process steps [D], [A] and [B] = Route 3) This is because it can be produced by

[0039] TIFF2025502842000006.tif222165

[0040] The core process (pathway 1), including steps [A] and [B], is used in all three alternative routes. This process according to the invention has several advantages over the prior art process disclosed in WO2014 / 012934. Some by-products inevitably included in the product of formula I when made according to the prior art procedure can be avoided or at least easier to separate. The inventors have identified the formation of the target acid of formula (I) from the disodium salt of formula (I-diNa) in step [B] as the main problem. It is important to carry out this step in a reverse manner to control the pH of the reaction mixture. Thus, process step [B] requires the reverse addition of the disodium salt intermediate of formula (I-DiNa) to an equimolar amount of acid equivalent. This reverse addition significantly reduces the formation of the poorly soluble monosodium salt of the compound of formula (I) compared to the prior art process (see Comparative Example 11). However, the small amount of the monosodium salt and other poorly soluble impurities mainly formed can be separated by clarification filtration of the disodium salt solution. Additionally, further by-products, such as hydrochloride salts, are avoided by reverse addition.

[0041] Alternatively, compounds of formula (I) can be prepared starting from compounds (X) and (XI) by coupling without isolating intermediates, followed by cleavage of the diester and liberating the acid (see, for example, Scheme 2 (Route 2) as depicted in process steps [C], [A] and [B]).

[0042] In alternative route 3), the compound of formula (I) can be prepared via its NSA salt, characterized in that in a first step [D], the dibutyl ester needs to be liberated from the NSA salt of formula (XII-NSA), which is then further converted to the free acid via two steps: basic saponification of the dibutyl ester (step [A]) followed by back addition to an acid to liberate the free acid of formula (I) (step [B]).

[0043] Thus, the process according to the invention provides (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I) in increased yield and high purity in contrast to the process disclosed in WO2014 / 012934.

[0044] To provide the desired crystalline form monohydrate I of formula (IMI) in high purity, a selective crystallization method was required.

[0045] As illustrated in scheme 3, the selective crystallization process according to the invention is characterized in that the (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I) is obtained in pure crystalline form, in particular in the form of the monohydrate modification I (IMI) or the monohydrate modification II (IM-II), preferably in the form of the monohydrate modification I (IMI).

[0046] TIFF2025502842000007.tif139165

[0047] Depending on the solvent used, either the monohydrate (IMI) or the monohydrate (IM-II) is formed. Surprisingly, crystallization from a mixture of acetone, methanol and water, or methanol and water (process [E]) selectively leads to the monohydrate I compound of formula (IMI), and crystallization from a mixture of acetone and water (process [F]) selectively leads to the monohydrate II compound of formula (IM-II).

[0048] The described manufacturing process (see Scheme 2), including all three process routes 1, 2 and 3 according to the present invention, can be advantageously combined with the described crystallization process (see Scheme 3) to obtain a crystalline form of the acid of formula (I), preferably the monohydrate I of formula (IMI), selectively and in high yield and purity, by using crystallization from a mixture of methanol and water (process [E]).

[0049] Thereby, the process according to the invention is suitable for reproducibly preparing the acid of formula (I), in particular in the form of the monohydrate modification I (IMI) or the monohydrate modification II (IM-II), preferably in the form of the monohydrate modification I (IMI), in high yield and purity in an industrial-scale synthesis.

[0050] The following Schemes 4, 5 and 6 exemplarily show processes (Route 1), (Route 2) and (Route 3) according to the invention.

[0051] TIFF2025502842000008.tif151165

[0052] The process comprises the following steps: base cleavage of a diester of compound of formula (XII) (step [A]), e.g. a dibutyl ester of formula (XII), and subsequent acid liberation of the final acid of formula (I) in process step [B] of scheme 4). The process is characterized in that a disodium salt (I-DiNa) is added in small portions to a solution of a mineral acid in a suitable solvent, e.g. THF, and the end point pH of the solution is carefully monitored to remain within a pH value window of 3.8-4.2.

[0053] Process Step [A] To prepare the target acid of formula (I) from the diester (XII), the diester (XII) is first cleaved.

[0054] Compounds of formula (XII) are available, for example, via the coupling reaction of their precursor (X) with 4-(bromomethyl)-3-chloro-4'-(trifluoromethyl)[biphenyl] (XI) in an inert polar solvent (as disclosed in Example 11 of WO2021 / 233783).

[0055] For the ester cleavage (XII)→(I-DiNa) (step [A]), the compound of formula (XII) is dissolved in THF or dioxane, preferably THF, and a suitable base, such as sodium hydroxide, potassium hydroxide or lithium hydroxide solution, preferably sodium hydroxide solution, particularly preferably 4% sodium hydroxide solution (1N), is added in excess, preferably in a 4-fold molar excess, and stirred at a temperature between 20° C. and 70° C., preferably 60° C., until complete conversion of the compound of formula (I) to the disodium, dilithium or dipotassium salt. To purify the reaction mixture, a suitable ester, preferably ethyl acetate and optionally deionized water, as solvent, is added, preferably at a temperature between 10° C. and 40° C., preferably 23° C., and the aqueous phase containing the dialkali metal salt (I-DiM), such as (I-DiNa), (I-DiK) or (I-DiLi), preferably (I-DiNa), is separated. Extraction is preferably carried out again with a suitable ester, preferably ethyl acetate. The residual ester solvent in the aqueous phase is distilled off under reduced pressure at a temperature below 40° C., preferably 36° C. Optionally, the reaction mixture can be filtered and the filtration residue is discarded. The filtrate is used in the next step.

[0056] Process Step [B] The liberation of the dicarboxylic acid of formula (I) from the dialkali metal salt (I-DiM), e.g. (I-DiNa), (I-DiK) or (I-DiLi), preferably the disodium salt of the compound of formula (I) (I-DiNa), is surprisingly not quantitatively achievable by adding a mineral acid to a solution of the disodium salt of the compound of formula (I). This leads to incomplete conversion and the formation of a significant amount of the monosodium salt of the compound of formula (I), which precipitates and is not convertible to the compound of formula (I) even by further addition of mineral acid.

[0057] Surprisingly, it has been found that the preparation of the compound of formula (I) is possible by adding a solution of the disodium salt (I-DiNa) of the compound of formula (I) to a defined amount of acid until a narrowly defined pH value is adjusted. In the manner described below (the "reverse process"), the reaction (I-DiNa) → (I) is possible with a high degree of efficiency.

[0058] A mixture of THF and a mineral acid, preferably hydrochloric acid, is suggested.

[0059] It is important to adjust the acid to equimolar amounts, since reaction with excess hydrochloric acid leads to the formation of undesired hydrochloride salts of the compound of formula (I), while a lack of hydrochloric acid leads to residual amounts of sodium salts. As a result, the compound of formula I contains two basic carboxylic acid functions, and therefore needs to be reacted with two equivalents of acid, for example, preferably two equivalents of hydrochloric acid. According to the process of the present invention, the main precursor dibutyl ester of formula (XII) can be presented in several forms: a) in a defined content (for example, by liberation from NSA salt) or b) as an intermediate solution obtained from the telescoping process. Thus, optionally, a small amount of the disodium salt solution can be triturated with a defined amount of acid solution, preferably hydrochloric acid, in order to determine the content of the disodium salt solution and to calculate the corresponding required amount of acid.

[0060] The consumption of disodium salt solution is then set in relation to the amount of hydrochloric acid presented and the amount of hydrochloric acid for the conversion of further portions is calculated correspondingly.

[0061] The pH of the initially charged HCl / THF mixture is less than 3.8. The solution of the compound of formula (I-DiNa) obtained in step [A] is added to this mixture in several portions, and the end point of the pH of the solution is carefully monitored so that it remains within the pH value window of 3.8-4.2. The organic phase of the reaction mixture is then separated off.

[0062] The separation is preferably carried out after addition of sodium chloride and THF to the reaction mixture and subsequent stirring.

[0063] For the isolation / purification and / or crystallization of the target compound of formula (I), the organic phase is concentrated. The concentration of the organic phase is preferably carried out at reduced atmospheric pressure, very preferably at 200 mbar, and at a temperature preferably between 20 and 50° C., very preferably at 40° C.

[0064] Optionally, the target compound of formula I can be isolated as a solid, for example by drying at elevated temperature, for example at 60° C., in a stream of nitrogen under vacuum at reduced atmospheric pressure, very preferably at 200 mbar.

[0065] The present invention also provides a combination of the partial reactions introduced above for preparing the compound of formula (I) in crystalline modification I, monohydrate I of formula (IMI) or modification II, monohydrate II of formula (IM-II), preferably monohydrate I of formula (IMI).

[0066] Instead of the dibutyl ester derivatives, in the above "reverse" process, other ester derivatives can also be used as starting materials in the alkaline hydrolysis step with sodium hydroxide solution.

[0067] Compared with the prior art process (WO2014 / 012934, Example 23), the new process has the advantage that the formation of poorly soluble monosodium salt is reduced (see, for example, Comparative Example 12).This monosodium salt cannot be converted to free acid by adding additional acid, so this results in a large amount of unused monosodium salt that needs to be filtered out, thus reducing the yield of the compound of formula I.This surprising result is obtained by reversely adding disodium salt solution to 2 equivalents of mineral acid.

[0068] Moreover, the compound of formula I is obtained in high purity.Therefore, in contrast to the prior art (WO2014 / 012934), complex chromatography can be omitted.Additionally, in this process, residual sodium salt can be separated by filtration before crystallization.

[0069] Furthermore, in the process disclosed in WO2014 / 012934, dioxane is used as a solvent, which does not comply with the ICH guidelines, in contrast to the present process, in which dioxane is replaced by THF.

[0070] Surprisingly, the (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I is obtained in defined crystalline forms a) monohydrate I of formula (IMI), b) monohydrate II of formula (IM-II), depending on the choice of solvent. By contrast, by prior art syntheses, the compound of formula I can only be obtained in amorphous form.

[0071] Surprisingly, (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I is obtained in one defined crystalline form as monohydrate I of formula (IMI) when crystallized from solvent mixtures comprising methanol, acetone and water, or methanol and water.

[0072] Surprisingly, (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I is obtained in one defined crystalline form as monohydrate II of formula (IM-II) when crystallized from a solvent mixture comprising acetone and water.

[0073] It has been found that the (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid obtained by the above crystallization process selectively crystallizes in the form of monohydrate I of formula (IMI) in high yield and purity.

[0074] (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid is not formed in amorphous form, but in the crystalline form of monohydrate I of formula (IMI), and is formed in high overall yield, for example 71% of theory, including the steps of saponification, disodium salt formation and further conversion to the free acid of formula I, and the final purification and crystallization, especially on a large scale. Starting from the biarylbenzyl bromide of formula XI, an overall yield of 67% of theory was achieved. Furthermore, the compound is obtained in high purity, for example the sodium salt can be separated by filtration before crystallization, and the hydrochloride and further impurities are separated off by the crystallization process according to the invention.

[0075] Thus, in contrast to the prior art (WO2014 / 012934), complex chromatography can be omitted and the target compound acid of formula I is finally obtained in high purity and yield, for example in the form of crystalline monohydrate I of formula (IMI).

[0076] Embodiment 1 (Route 1) The present invention relates to a process for preparing a compound of formula (I), comprising the steps of: In the first step [A], a compound of formula (XII-1) solubilized in a suitable solvent is TIFF2025502842000009.tif67128, where R3 and R4 are independently C1-C4-alkyl, is reacted with a base selected from sodium hydroxide, lithium hydroxide, or potassium hydroxide solution to form a dialkali metal salt (I-DiM). TIFF2025502842000010.tif78165, where M is Na, Li or K, which, after extractive purification but without further isolation, is reacted in a second step [B] by adding the reaction solution in portions to a mixture of mineral acids in a suitable solvent until a pH value of 3.8 to 4.2 is reached, where the pH value of the initially charged mineral acid mixture has a value below 3.8 and contains up to 2 equivalents of acid with respect to the disodium salt, and finally to a compound of formula (I) The present invention provides a method for producing a compound of formula (TIFF2025502842000011.tif69128).

[0077] The present invention relates to a process for preparing a compound of formula (I), comprising the steps of: In the first step [A], a compound of formula (XII-1) according to embodiment 1 is solubilized in a suitable solvent. The compound of formula TIFF2025502842000012.tif72128, where R3 and R4 are independently C1-C4-alkyl, is reacted with sodium hydroxide solution to give the disodium salt (I-DiNa). TIFF2025502842000013.tif83165, which, after extractive purification but without further isolation, is reacted in a second step [B] by adding the reaction solution in portions to a mixture of mineral acids in a suitable solvent until a pH value of 3.8 to 4.2 is reached, where the pH value of the initially charged mineral acid mixture has a value below 3.8 and contains up to 2 equivalents of acid with respect to the disodium salt, and finally to a compound of formula (I) The present invention further provides a method for producing a compound of formula (I) having a structure of formula (I) of the formula (I).

[0078] The present invention relates to a process for preparing a compound of formula (I) as defined above according to embodiment 1 and one or more further embodiments as defined above, wherein sodium hydroxide solution is used as the base in step [A] to obtain a disodium salt The method is further characterized in that TIFF2025502842000015.tif78165 is obtained as an intermediate.

[0079] The present invention further provides a method for preparing a compound of formula (I) according to embodiment 1 and one or more further embodiments as described above, wherein in formula (XII-1), residues R3 and R4 are identical, and it is particularly preferred when R3=R4=butyl.

[0080] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 1 and one or more further embodiments as defined above, wherein the solvent in the first step [A] is tetrahydrofuran or dioxane, preferably tetrahydrofuran.

[0081] Another object of the present invention is a process for preparing a compound of formula (I) as defined above according to embodiment 1 and one or more further embodiments as defined above, wherein in the first step [A], a sodium or potassium hydroxide solution is used, preferably an excess of 4% sodium hydroxide solution (1N), preferably 4 equivalents, based on the compound of formula (XII-1).

[0082] The present invention further provides a process for preparing a compound of formula (I) according to embodiment 1 and one or more further embodiments above, wherein the first step [A] is carried out at a temperature between 40°C and 70°C, preferably 60°C.

[0083] The present invention also provides a process for preparing a compound of formula (I) as defined above according to embodiment 1 and one or more further embodiments as defined above, wherein the disodium salt solution is purified by extraction with an organic solvent, preferably ethyl acetate.

[0084] The present invention further provides a process for preparing a compound of formula (I) according to embodiment 1 and one or more further embodiments as above, wherein the mineral acid in the second step [B] is hydrochloric acid.

[0085] The present invention also provides a process for preparing a compound of formula (I) as defined above according to embodiment 1 and one or more further embodiments as defined above, wherein in the second step [B], an organic product layer is separated after addition of sodium chloride to the mixture.

[0086] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 1 and one or more further embodiments as defined above, characterized in that the concentration of the organic product layer is carried out at reduced atmospheric pressure, preferably at 200 mbar, preferably at a temperature of 20-50°C, very preferably at 40°C.

[0087] The present invention further provides a process for preparing the compound of formula (I) as defined above according to embodiment 1 and one or more further embodiments as defined above, characterized in that the compound of formula (I) is isolated as a solid, alternatively the organic product layer is concentrated in the residual volume.

[0088] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 1 and one or more further embodiments as defined above, wherein the target compound of formula I may be isolated as a solid, for example by drying at elevated temperature, for example at 60° C., in a nitrogen stream under vacuum, at reduced atmospheric pressure, very preferably at 200 mbar.

[0089] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 1 and one or more further embodiments as defined above, characterized in that the compound of formula (I) is isolated as a solid.

[0090] The present invention relates to a process for preparing a compound of formula (I) as defined above according to embodiment 1 and one or more further embodiments as defined above, characterized in that the compound of formula (I) is isolated either as a solid by filtration or as a concentrated residue volume, The organic product layer is separated from the mixture; The organic product layer is concentrated and solids are separated. The solids are separated by filtration, The separated solid is dried, Alternatively, the organic product layer is concentrated into the residue volume. The present invention further provides a method comprising the steps of:

[0091] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 1 and one or more further embodiments as defined above, characterized in that the organic solvent is separated after addition of brine.

[0092] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 1 and one or more further embodiments as defined above, characterized in that the concentration of the organic solvent is carried out at reduced atmospheric pressure, preferably at 200 mbar, preferably at a temperature of 20-50°C, very preferably at 40°C.

[0093] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 1 and one or more further embodiments as defined above, characterized in that the solid is separated by filtration.

[0094] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 1 and one or more further embodiments as defined above, characterized in that the solid is subjected to drying at a temperature between 40° C. and 50° C. and at a reduced atmospheric pressure between 40 mbar and 30 mbar.

[0095] Alternatively, compounds of formula (I) can be prepared starting from compounds (X) and (XI) by coupling without isolating intermediates, followed by cleavage of the diester and liberating the acid (as shown, for example, in Route 2 (see Scheme 5) which includes process steps [C], [A] and [B]).

[0096] TIFF2025502842000016.tif151165

[0097] In the following, an alternative process according to the invention for preparing compound (I) is described in detail.

[0098] Process Step [C] Alternatively, the compound of formula (I) can be prepared from the compound of formula (X) without isolating the intermediate (telescopic process). For this purpose, a coupling reaction is carried out (step [C]) analogous to process step 11 in scheme 2, as disclosed in WO2021 / 233783.

[0099] The compound of formula (X) is available, for example, via an acid esterification reaction of its precursor in n-butanol as a solvent (disclosed in WO2021 / 233783, Example 10).

[0100] To obtain the compound according to formula (XII), butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate of formula (X) is solubilized in an inert polar solvent, such as ether, acetone or acetonitrile, preferably acetonitrile, at a temperature between 10° C. and 40° C., preferably at 25° C. Preferably, the reaction mixture is distilled at reduced pressure, preferably between 80 mbar and 120 mbar, very preferably at 120 mbar, at a temperature between 40° C. and 60° C., and more acetonitrile is added. This procedure can be repeated.

[0101] 4-(bromomethyl)-3-chloro-4'-(trifluoromethyl)[biphenyl] of formula (XI) is preferably added in an amount of 1 to 2 equivalents relative to compound (X), very preferably 1.2 equivalents. To the solution, a base is added, the base being selected from the group consisting of an alkali carbonate, such as sodium, potassium or cesium carbonate, or an alkali hydroxide, such as sodium or potassium hydroxide, or a tetraalkylammonium carbonate, preferably cesium carbonate. The base is added in a molar excess, preferably in an amount of 2 to 4 equivalents relative to compound (X), very preferably 2 equivalents. The reaction mixture is stirred until completion of the reaction to obtain compound (XII). Preferably, a further amount of base, preferably cesium carbonate, can be added to the reaction mixture under continuous stirring. The resulting suspension is filtered. Before discarding the filter residue (cake), it is preferably washed with acetonitrile. The liquid reaction mixture may be further reacted in a further reaction step, such as reaction step [A], without isolating the compound of formula (XII).

[0102] Alternatively, the compound of formula (XII) can be isolated as an oil, which can then be reacted in further reaction steps, such as reaction step [A]. For isolation of the oil, the mixture is preferably concentrated to an oil, after washing with acetonitrile, at a temperature of 15° C. to 60° C., preferably 30° C. to 50° C., particularly preferably at 40° C. The concentration is preferably carried out at reduced atmospheric pressure.

[0103] The liquid reaction solution is used as an oil in the next step without isolating the compound of formula (XII) by first changing the solvent by distillation to THF or dioxane, preferably THF is used.

[0104] The ester cleavage step [A] is then carried out analogously to process step [A] above, and the liberation step [B] of the dicarboxylic acid of formula (I) from the disodium salt of formula (I-DiNa) is carried out analogously to process step [B] above.

[0105] Embodiment 2 (Route 2) The present invention relates to a process for preparing a compound of formula (I), comprising the steps of: In the first step [C], a compound represented by the formula (X-1) TIFF2025502842000017.tif45128, where R3 and R4 are independently C1-C4-alkyl, in the presence of a base selected from the group consisting of an alkali carbonate, an alkali hydroxide, or a tetraalkylammonium carbonate, to form a compound of formula (XI): TIFF2025502842000018.tif55128 to form a compound of formula (XII-1) TIFF2025502842000019.tif83165, wherein R3 and R4 are independently C1-C4-alkyl. The compound of formula (XII-1) solubilized in a suitable solvent is reacted, without purification, with a base selected from sodium hydroxide, lithium hydroxide or potassium hydroxide solution in a second step [A] to obtain a dialkali metal salt (I-DiM). TIFF2025502842000020.tif83165 (wherein M is Na, Li or K), which, after extractive purification but without further isolation, is reacted in a second step [B] by adding the reaction solution in portions to a mixture of mineral acids in a suitable solvent until a pH value of 3.8 to 4.2 is reached, where the pH value of the initially charged mineral acid mixture has a value below 3.8 and contains up to 2 equivalents of acid with respect to the disodium salt, and finally to a compound of formula (I) The method is further characterized by providing a compound of formula TIFF2025502842000021.tif73128.

[0106] The present invention relates to a method for preparing a compound of formula (I) according to embodiment 2, comprising the steps of: TIFF2025502842000022.tif45128, where R3 and R4 are independently C1-C4-alkyl, in the presence of a base selected from the group consisting of an alkali carbonate, an alkali hydroxide, or a tetraalkylammonium carbonate, to form a compound of formula (XI): TIFF2025502842000023.tif52128 to form a compound of formula (XII-1) TIFF2025502842000024.tif83165, wherein R3 and R4 are independently C1-C4-alkyl. The compound of formula (XII-1) solubilized in a suitable solvent is reacted, without purification, with a sodium hydroxide solution in a second step [A] to obtain a disodium salt (I-DiNa). TIFF2025502842000025.tif89165, which, after extractive purification but without further isolation, is reacted in a second step [B] by adding the reaction solution in portions to a mixture of mineral acids in a suitable solvent until a pH value of 3.8 to 4.2 is reached, where the pH value of the initially charged mineral acid mixture has a value below 3.8 and contains up to 2 equivalents of acid with respect to the disodium salt, and finally to a compound of formula (I) The present invention further provides a method, further characterized by providing a compound of formula TIFF2025502842000026.tif79128.

[0107] The present invention further provides a method for preparing a compound of formula (I) according to embodiment 2 and one or more further embodiments as described above, wherein in formula (XII-1), residues R3 and R4 are identical, and it is particularly preferred when R3=R4=butyl.

[0108] Another object of the invention is a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, characterized in that in the first step [C] a suitable solvent is used selected from the group consisting of ether, acetone or acetonitrile, preferably acetonitrile.

[0109] Another object of the invention is a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, characterized in that in the first step [C] a suitable base is used selected from the group consisting of alkali carbonates, for example sodium carbonate, potassium carbonate or caesium carbonate, preferably caesium carbonate.

[0110] Another object of the invention is a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, characterized in that in the first step [C], the base is an alkali hydroxide selected from the group consisting of sodium hydroxide or potassium hydroxide.

[0111] Another object of the invention is a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, characterized in that in the first step [C] a tetraalkylammonium carbonate is used as base.

[0112] Another object of the invention is a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, characterized in that in the first step [C], a base selected from the group consisting of alkali carbonates, alkali hydroxides or tetraalkylammonium carbonates is used in molar excess, preferably in an amount between 2 and 4 equivalents with respect to the compound of formula (X), particularly preferably in an amount of 2 equivalents with respect to compound (X).

[0113] Another object of the present invention is a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, characterized in that in the first step [C], a compound of formula (XI) is preferably used in a molar ratio of 1:1 to 2:1 with respect to the compound of formula (X), particularly preferably in a molar ratio of 1.2:1 with respect to the compound of formula (X).

[0114] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, wherein in the second step [A], the solvent is tetrahydrofuran or dioxane, preferably tetrahydrofuran.

[0115] Another object of the present invention is a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, wherein in the second step [A], a sodium or potassium hydroxide solution is used, preferably an excess of 4% sodium hydroxide solution (1N), preferably 4 equivalents, based on the compound of formula (XII-1).

[0116] The present invention further provides a process for preparing a compound of formula (I) according to embodiment 2 and one or more further embodiments above, wherein in the second step [A], the step is carried out at a temperature between 40°C and 70°C, preferably 60°C.

[0117] The present invention also provides a process for preparing a compound of formula (I) above according to embodiment 2 and one or more further embodiments above, wherein the disodium salt solution is purified by extraction with an organic solvent, preferably ethyl acetate.

[0118] The present invention further provides a process for preparing a compound of formula (I) according to embodiment 2 and one or more further embodiments above, wherein in the third step [B], the mineral acid is hydrochloric acid.

[0119] The present invention also provides a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, wherein in the third step [B], an organic product layer is separated after addition of sodium chloride to the mixture.

[0120] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, wherein the target compound of formula I may be isolated as a solid, for example by drying at elevated temperature, for example at 60° C., in a nitrogen stream under vacuum, at reduced atmospheric pressure, very preferably at 200 mbar.

[0121] The present invention further provides a process for preparing the compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, characterized in that the compound of formula (I) is isolated as a solid, alternatively the organic product layer is concentrated in the residual volume.

[0122] The present invention also relates to a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, characterized in that the compound of formula (I) is isolated either as a solid by filtration or as a concentrated residue volume, The organic product layer is separated from the mixture; The organic product layer is concentrated and solids are separated. The solids are separated by filtration, The separated solid is dried, Alternatively, the organic product layer is concentrated into the residue volume. The present invention further provides a method comprising the steps of:

[0123] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, characterized in that the organic solvent is separated after addition of brine.

[0124] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, characterized in that the concentration of the organic solvent is carried out at reduced atmospheric pressure, preferably at 200 mbar, preferably at a temperature of 20-50°C, very preferably at 40°C.

[0125] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, characterized in that the solid is separated by filtration.

[0126] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 2 and one or more further embodiments as defined above, characterized in that the solid is subjected to drying at a temperature between 40° C. and 50° C. and at a reduced atmospheric pressure between 40 mbar and 30 mbar.

[0127] Another alternative process route for preparing target compounds of formula (I) via an NSA salt of formula (XII-NSA) is outlined in Scheme 6.

[0128] TIFF2025502842000027.tif94165

[0129] This process is characterized in that the solid NSA salt of formula (XII-NSA) (available via reaction step [G], see Scheme 7) is converted to the free acid via three steps: first: base liberation of the dibutyl ester of formula (XII) (step [D]), second: base cleavage of the dibutyl ester (step [A]) and then reverse addition of the disodium salt of formula (I-DiNa) to the acid (step [B]).

[0130] Process Step [D] To obtain the compound of formula (I) starting from the compound of formula (XII-NSA), in a first step the compound of formula (XII) is liberated from the salt [step D]. Thus, the compound of formula (XII-NSA) is treated with a suitable ether, preferably THF, and stirred with water and aqueous ammonia at a temperature between 10° C. and 25° C., whereby finally a pH value of 7.8 to 8.2 is reached. Phase separation is achieved by the addition of an organic solvent not miscible with water, for example, preferably diisopropyl ether.

[0131] Surprisingly, phase separation was only possible when aqueous ammonia was used as the base. Other bases, such as potassium carbonate, potassium hydroxide or sodium hydroxide, failed due to the formation of an extensive duff layer.

[0132] The aqueous phase is discarded. The organic phase is preferably washed with a mixture of water and aqueous ammonia (pH value of 7.8-8.2) and dried over sodium sulfate, and then concentrated to an evaporation residue. The evaporation residue obtained is reacted in the next step. The concentration is carried out at a temperature of up to 40° C. and at reduced atmospheric pressure.

[0133] Surprisingly, the process via NSA salt formation and release has the advantage that oily dibutyl ester can be converted into a solid, which makes the overall processability even more convenient. Surprisingly, the inventors have found that only NSA forms a stable solid, despite other common acids such as toluenesulfonic acid, hydrochloric acid.

[0134] Process Step [A] For the ester cleavage (XII)→(I-DiNa) (reaction step [A]), the diester of formula (XII) obtained in step [D] is dissolved in THF or dioxane, preferably THF, and a suitable base, such as sodium hydroxide, potassium hydroxide or lithium hydroxide solution, is added, preferably sodium hydroxide solution, particularly preferably 4% by weight sodium hydroxide solution, in excess, preferably 4 equivalents, at a temperature between 40° C. and 70° C., preferably 60° C. The reaction mixture is stirred until complete conversion of the compound of formula (I) to the disodium, dilithium or dipotassium salt.

[0135] For the reactions described, it is also possible to use, instead of a compound of formula (XII), a compound of formula (XII-1) A diester of TIFF2025502842000028.tif68128 may be used, where R1 and R2 are independently C1-C4-alkyl.

[0136] To purify the reaction mixture, a suitable ester as solvent, preferably ethyl acetate and optionally deionized water, is added, preferably at a temperature between 10° C. and 40° C., preferably at 23° C., and the aqueous phase containing the dialkali metal salt (I-DiM), for example (I-DiNa), (I-DiK) or (I-DiLi), preferably (I-DiNa), is separated. Preferably, the extraction with the same ester is repeated. Residual ester solvent in the aqueous phase is distilled off under reduced pressure at a temperature of up to 40° C., preferably at 36° C. Optionally, the reaction mixture can be filtered and the filtration residue is discarded. The reaction mixture is used in the next reaction step (process step [B]).

[0137] Process Step [B] The liberation of the dicarboxylic acid of formula (I) from the dialkali metal salt (I-DiM), e.g. (I-DiNa), (I-DiK) or (I-DiLi), preferably the disodium salt of the compound of formula (I) (I-DiNa), is surprisingly not quantitatively achievable by adding a mineral acid to a solution of the disodium salt of the compound of formula (I). This leads to incomplete conversion and the formation of a significant amount of the monosodium salt of the compound of formula (I), which precipitates and is not convertible to the compound of formula (I) even by further addition of mineral acid.

[0138] Surprisingly, it has been found that the preparation of compounds of formula (I) is possible by adding a solution of the disodium salt (I-DiNa) of the compound of formula (I) to an excess of acid until a narrowly defined pH value is adjusted. In the manner described below (the "reverse process"), the reaction (I-DiNa) → (I) is possible with a high degree of efficiency.

[0139] A mixture of THF and a mineral acid, preferably hydrochloric acid, is suggested.

[0140] It is important to adjust the acid to equimolar amounts, because reaction with excess hydrochloric acid leads to the formation of undesired hydrochloride salts of the compound of formula (I), and lack of hydrochloric acid leads to residual amounts of sodium salts.As a result, the compound of formula I contains two basic carboxylic acid functional groups, so it needs to react with two equivalents of acid, for example, preferably two equivalents of hydrochloric acid.Therefore, optionally, a small amount of the disodium salt solution can be triturated with a defined amount of acid solution, preferably hydrochloric acid, to determine the content of the disodium salt solution and calculate the corresponding required amount of acid.

[0141] The consumption of disodium salt solution is then set in relation to the amount of hydrochloric acid presented and the amount of hydrochloric acid for the conversion of further portions is calculated correspondingly.

[0142] The pH of the initially charged hydrochloric acid / THF mixture is less than 3.8. The solution of the compound of formula (I-DiNa) obtained in step [A] is added to this mixture in portions until a pH of 3.8-4.2 is reached. The organic phase of the reaction mixture is then separated off.

[0143] The separation is preferably carried out after addition of sodium chloride and THF to the reaction mixture and subsequent stirring.

[0144] For the isolation / purification and / or crystallization of the target compound of formula (I), the organic phase is concentrated. The concentration of the organic phase is preferably carried out at reduced atmospheric pressure, very preferably at 200 mbar, and at a temperature preferably between 20 and 50° C., very preferably at 40° C.

[0145] Optionally, the target compound of formula I can be isolated as a solid, for example by drying at elevated temperature, for example at 60° C., in a stream of nitrogen under vacuum at reduced atmospheric pressure, very preferably at 200 mbar.

[0146] Embodiment 3 (NSA Salts) The NSA salt of formula (XII-NSA) is novel.

[0147] A further embodiment of the present invention is a compound of the formula The synthesis of the NSA salt of formula (XII-NSA) is outlined in Scheme 7 below.

[0148] TIFF2025502842000030.tif73165

[0149] Process Step [G] To obtain the compound according to formula (XII-NSA) in reaction step [G] (Scheme 7), the compound of formula (XII) is solubilized in THF at a temperature between 15° C. and 40° C., preferably at 25° C., and naphthalene-1,5-disulfonic acid is added and stirred until the reaction is complete. The reaction mixture is concentrated at a temperature between 15° C. and 60° C., preferably between 30° C. and 50° C., very preferably at 40° C., and finally the residue is subjected to drying at the same temperature until a constant weight is reached. The drying process is preferably carried out under an inert gas, preferably under nitrogen and / or under reduced atmospheric pressure.

[0150] Embodiment 4 (Route 3) The present invention relates to a process for preparing a compound of formula (I), comprising the steps of: In the first step [D], a compound represented by the formula (XII-NSA-1) TIFF2025502842000031.tif83165, where R1 and R2 are independently C1-C4-alkyl, is treated with a suitable ether and stirred with water and aqueous ammonia at a temperature of 10°C to 25°C, whereby a pH value of 7.8-8.2 is finally reached, after which the reaction mixture is treated with an organic solvent not miscible with water, the phases are separated, and finally the organic phase is concentrated; in a second step [A], the NSA salt of formula (XII-1) solubilized in a suitable solvent is obtained. TIFF2025502842000032.tif73128, where R1 and R2 are independently C1-C4-alkyl, is reacted with a base selected from sodium hydroxide, lithium hydroxide, or potassium hydroxide solution to form a dialkali metal salt (I-DiM). TIFF2025502842000033.tif83165 (wherein M is Na, Li or K), which, after extractive purification but without further isolation, is reacted in a third step [B] by adding the reaction solution in portions to a mixture of mineral acids in a suitable solvent until a pH value of 3.8 to 4.2 is reached, where the pH value of the initially charged mineral acid mixture has a value below 3.8 and contains up to 2 equivalents of acid with respect to the disodium salt, and finally to a compound of formula (I) The method is further characterized by providing a compound of formula TIFF2025502842000034.tif71128.

[0151] The present invention relates to a process for preparing a compound of formula (I) according to embodiment 4, comprising: In the first step [D], a compound represented by the formula (XII-NSA-1) TIFF2025502842000035.tif78165, where R1 and R2 are independently C1-C4-alkyl, is treated with a suitable ether and stirred with water and aqueous ammonia at a temperature of 10°C to 25°C, whereby a pH value of 7.8-8.2 is finally reached, after which the reaction mixture is treated with an organic solvent not miscible with water, the phases are separated, and finally the organic phase is concentrated; in a second step [A], NSA salt of formula (XII-1) solubilized in a suitable solvent is obtained. The compound of formula TIFF2025502842000036.tif73128, where R1 and R2 are independently C1-C4-alkyl, is reacted with sodium hydroxide solution to give the disodium salt (I-DiNa). TIFF2025502842000037.tif83165, which, after extractive purification but without further isolation, is reacted in a third step [B] by adding the reaction solution in portions to a mixture of mineral acids in a suitable solvent until a pH value of 3.8 to 4.2 is reached, where the pH value of the initially charged mineral acid mixture has a value below 3.8 and contains up to 2 equivalents of acid with respect to the disodium salt, and finally to a compound of formula (I) The present invention further provides a method, further characterized by providing a compound of formula TIFF2025502842000038.tif70128.

[0152] The present invention further provides a method for preparing a compound of formula (I) according to embodiment 4 and one or more further embodiments as described above, wherein in formula (XII-1), residues R3 and R4 are identical, and it is particularly preferred when R3=R4=butyl.

[0153] The present invention further provides a process for preparing a compound of formula (I) according to embodiment 4 and one or more further embodiments above, wherein in the first step [D], the ether is tetrahydrofuran.

[0154] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 4 and one or more further embodiments as defined above, wherein in the first step [D], the added solvent is diisopropyl ether.

[0155] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 4 and one or more further embodiments as defined above, wherein in a first step [D], after phase separation, the aqueous phase is discarded and the organic phase is washed with aqueous ammonia (pH value of 7.8-8.2), preferably a mixture of water and aqueous ammonia, and concentrated to a solid after drying over sodium sulfate.

[0156] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 4 and one or more further embodiments as defined above, wherein in the second step [A], the solvent is tetrahydrofuran or dioxane, preferably tetrahydrofuran.

[0157] Another object of the present invention is a process for preparing a compound of formula (I) as defined above according to embodiment 4 and one or more further embodiments as defined above, wherein in the second step [A], a sodium or potassium hydroxide solution is used, preferably an excess of 4% sodium hydroxide solution (1N), preferably 4 equivalents, based on the compound of formula (XII-1).

[0158] The present invention further provides a process for preparing a compound of formula (I) according to embodiment 4 and one or more further embodiments above, wherein in the second step [A], the step is carried out at a temperature between 40°C and 70°C, preferably 60°C.

[0159] The present invention also provides a process for preparing a compound of formula (I) as defined above according to embodiment 4 and one or more further embodiments as defined above, wherein the disodium salt solution is purified by extraction with an organic solvent, preferably ethyl acetate.

[0160] The present invention further provides a process for preparing a compound of formula (I) according to embodiment 4 and one or more further embodiments above, wherein in the third step [B], the mineral acid is hydrochloric acid.

[0161] The present invention also provides a process for preparing a compound of formula (I) as defined above according to embodiment 4 and one or more further embodiments as defined above, wherein in the third step [B], an organic product layer is separated after addition of sodium chloride to the mixture.

[0162] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 4 and one or more further embodiments as defined above, characterized in that the concentration of the organic product layer is carried out at reduced atmospheric pressure, preferably at 200 mbar, preferably at a temperature of 20-50°C, very preferably at 40°C.

[0163] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 4 and one or more further embodiments as defined above, characterized in that the compound of formula (I) is isolated as a solid, alternatively the organic product layer is concentrated in the residual volume.

[0164] The present invention also relates to a process for preparing a compound of formula (I) as defined above according to embodiment 4 and one or more further embodiments as defined above, characterized in that the compound of formula (I) is isolated either as a solid by filtration or as a concentrated residue volume, The organic product layer is separated from the mixture; The organic product layer is concentrated and solids are separated. The solids are separated by filtration, The separated solid is dried, Alternatively, the organic product layer is concentrated into the residue volume. The present invention further provides a method comprising the steps of:

[0165] The present invention further provides a process for preparing a compound of formula (I) as defined above according to embodiment 4 and one or more further embodiments as defined above, characterized in that the solid is subjected to drying in a nitrogen stream at a temperature of up to 60° C. and at reduced atmospheric pressure, for example at a reduced atmospheric pressure of 40 mbar to 30 mbar.

[0166] The present invention also provides a combination of the partial reactions introduced above for preparing the compound of formula (I) in crystalline modification I, monohydrate I of formula (IMI) or modification II, monohydrate II of formula (IM-II), preferably monohydrate I of formula (IMI).

[0167] As an example, the compound of formula (I) which can be obtained via one of the above process routes 1, 2 or 3 (see Scheme 2) Further purification of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of TIFF2025502842000039.tif89165 is described to finally obtain monohydrate I of formula (IMI).

[0168] Depending on the scale and process route, it may be preferable to purify the compound of formula I before the final crystallization. Thus, the crystallization may include process steps [H] and [E] in combination. It is also possible to simply crystallize the compound of formula (I) according to step [E]. This is illustrated exemplarily.

[0169] Process Step [H]: Purification of target compound I (1. Crystallization): The crude organic phase containing the free acid of formula I, for example, obtained via one of the above process routes 1, 2 or 3 (see scheme 2), was concentrated in vacuum and dissolved in tetrahydrofuran, preferably in 0.8-1.1 g amounts relative to the evaporation residue of tetrahydrofuran, and then a 2.2:1 mixture of methanol and water, preferably a mixture of 2.2:1 methanol and water in about 5 g amounts relative to the butyl ester, was added dropwise, preferably at 20° C., with stirring. Seed crystals of (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4′-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate I were added, which was stirred for a period of time, preferably 12 hours. The solid was separated and washed with a 1:1 mixture of methanol and water. The solid was then subjected to drying in vacuum at 20°C.

[0170] Drying is preferably carried out at temperatures between 40° C. and 50° C. and at 40 mbar to 30 mbar.

[0171] Process Step [E]: Crystallization / formation of monohydrate form I (IMI): Methanol, acetone, water crystallization The compound of formula I obtained via one of the above process routes 1, 2 or 3, for example route 3 (either in solid form, in the form of evaporation residue or even as a concentrate in THF) is heated to high temperature, preferably to 50°C, and cooled to 20°C with a 1:1 mixture of acetone and methanol, preferably 4-8 times the amount of each solvent with respect to the amount of solid compound of formula I, preferably about 4 times the amount. The resulting solution is filtered, for example through a Seitz filter plate, heated to 50°C, and finally water, preferably 1.8 times the amount of water with respect to the amount of solid compound of formula I, is added dropwise over a period of time, preferably 30 minutes. As a result, the compound is finally stirred in a 2.2:2.2:1 mixture of acetone, methanol and water, the amount of g of solvent with respect to g of solid acid of formula (I) being about 10:1. The solution is seeded with a small amount of seed crystals of the monohydrate I of formula (IMI), depending on the scale in small quantities up to a few grams, the solution is stirred for 30 minutes, cooled to 20° C. within at least 30 minutes, and the solid is filtered off with suction. The wet product is preferably stirred with water, preferably with 10 times the amount of water relative to the amount of the solid compound of formula I, for a period of time, preferably 12 hours. Finally, the solid is filtered off with suction and washed twice with water, preferably with 2 times the amount of water relative to the amount of the solid compound of formula I. The wet product is subjected to drying to constant weight under vacuum in a nitrogen stream at 20° C. to obtain the compound of formula I in the crystalline modification I, the monohydrate I of formula (IMI).

[0172] Alternatively, the crude organic phase containing the free acid of formula I, for example, obtained via one of the above process routes 1, 2 or 3 (see scheme 2), for example route 2, was concentrated in vacuum and dissolved in tetrahydrofuran, preferably in an amount of 0.8 to 1.1 times the g amount relative to the evaporation residue of tetrahydrofuran, and then a 2.3:1 mixture of methanol and water, preferably a mixture of 2.3:1 methanol water in an amount of about 7 times relative to the butyl ester, was added, preferably with stirring at 20°C. Seed crystals of (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate I were added. Then, another approximately 17.3 times the amount of a 2.3:1 methanol water mixture was weighed in. As a result, the compound was finally stirred in a 2.3:1 methanol water mixture with 24.3 times the amount (g) of the solid compound, which was stirred for a period of time, preferably overnight. The solid was separated and washed with a 1:1 mixture of methanol and water. The solid was then subjected to drying in vacuum, preferably at 40-50° C. and 40-30 mbar.

[0173] Alternatively, the solid compound of formula I is dissolved in a 4:1 mixture of methanol and water, the solvent to solid ratio is 4 times the amount (g) of methanol, which correlates with the amount (g) of the compound of formula (I), and about 1 time the amount (g) of water, which correlates with the amount (g) of the compound of formula (I). Then, a 4:1 mixture of acetone and water is added, the solvent to solid ratio is as follows: 4 times the amount of acetone and about 1 time the amount of water is added. As a result, the compound is finally stirred in a 4:4:2 mixture of acetone, methanol and water, the amount (g) of solvent relative to the amount (g) of solid acid of formula (I) is about 10:1. It is stirred overnight. The solid is filtered off with suction, washed with 1 time the amount of acetone / water (8:2) mixture, and dried overnight with nitrogen air in vacuum at 60°C.

[0174] Embodiment 5 (Crystallization method [E] for monohydrate I) The present invention relates to a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IMI), comprising the steps of: Formula (I) The compound of formula (IMI) is crystallized from a mixture of polar solvents, the polar solvent being selected from the list consisting of methanol, acetone, and water, and a mixture of at least methanol and water is required at a temperature between 20° C. and 100° C. The method is characterized in that the compound of TIFF2025502842000041.tif78165 is isolated, optionally after cooling.

[0175] The present invention also relates to a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IMI) according to embodiment 5 above, comprising For example, a process is provided, characterized in that a crude organic phase containing the free acid of formula I, for example obtained via one of the above process routes 1, 2 or 3 (see scheme 2), is concentrated in vacuum and dissolved in tetrahydrofuran, preferably in 0.8-1.1 g amount relative to the evaporation residue of tetrahydrofuran, and then a 2.2:1 mixture of methanol and water, preferably a mixture of 2.2:1 methanol water in about 5 times the amount relative to the butyl ester, is added dropwise, preferably at 20° C. with stirring.

[0176] The present invention also provides a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IMI) according to embodiment 5 and one or more further embodiments described above, characterized in that the compound of formula (I) is stirred in a 2.2:1 or 2.3:1 mixture of methanol and water at a temperature of about 20°C to about 50°C.

[0177] The present invention also provides a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IMI) according to embodiment 5 and one or more further embodiments described above, characterized in that the compound of formula (I) is stirred in a 2.2:1 or 2.3:1 mixture of methanol and water at a temperature of about 20°C to about 50°C, the amount of the mixture of methanol and water being about 5 to 24, preferably about 10 times the amount (g) of the solid compound of formula I.

[0178] The present invention also provides a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IMI) according to embodiment 5 and one or more further embodiments described above, characterized in that the compound of formula (I) is first dissolved in a 1:1 mixture of methanol and acetone at a temperature of about 50°C, cooled to room temperature and filtered for clarification of the solution.

[0179] The present invention also provides a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IMI) according to embodiment 5 and one or more further embodiments described above, characterized in that the acid of formula I is first dissolved in a 1:1 mixture of acetone and methanol, each solvent being provided in a 4-8 fold amount (g) relative to the amount (g) of the solid compound of formula I.

[0180] The present invention also provides a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IMI) according to embodiment 5 and one or more further embodiments described above, characterized in that the acid of formula I is first dissolved in a 1:1 mixture of methanol and acetone, preferably in a 4-fold amount (g) of each solvent relative to the amount (g) of the solid compound of formula I (8-fold amount for a 1:1 mixture), at a temperature of 50°C, cooled to room temperature, preferably to 20°C, the solution clarified by filtration, heated to 50°C and water is added dropwise over a period of time.

[0181] The present invention also provides a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IMI) according to embodiment 5 and one or more further embodiments described above, characterized in that water is added dropwise over a period of 30 minutes.

[0182] The present invention also provides a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IMI) according to embodiment 5 and one or more further embodiments described above, characterized in that water is added dropwise in a 1.8-fold amount (g) relative to the amount (g) of the solid compound of formula I over a period of 30 minutes.

[0183] The present invention also provides a process for the preparation of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IMI) according to embodiment 5 and one or more further embodiments described above, characterized in that after the addition of water, preferably 1.8 times the amount (g) of seed crystals of the compound of formula (IMI) relative to the amount (g) of the solid compound of formula I are added to the stirred mixture.

[0184] The present invention also provides a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IMI) according to embodiment 5 and one or more further embodiments described above, characterized in that after the addition of water, preferably 1.8 times the amount (g) of seed crystals of the compound of formula (IMI) relative to the amount (g) of the solid compound of formula I are added to the stirred mixture, stirring is continued for a period of time, preferably 30 minutes, the mixture is cooled to 20°C and finally the solid is filtered off.

[0185] The present invention also provides a process for the preparation of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline modification monohydrate I (IMI) according to embodiment 5 and one or more further embodiments described above, characterized in that after the addition of water, seed crystals of the compound of formula (IMI) are seeded, preferably in an amount (g) of 1.8 times relative to the amount (g) of the solid compound of formula I, stirring is continued for a period of time, preferably 30 minutes, filtration is performed and the wet product is stirred with water, preferably in an amount of 10 times relative to the amount of the solid compound of formula I, for a period of time, preferably 12 hours.

[0186] The present invention also provides a process for the preparation of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IMI) according to embodiment 5 and one or more further embodiments described above, characterized in that at the end, the solid is filtered off with suction and washed twice with water, preferably with a double amount of water with respect to the amount of the solid compound of formula I.

[0187] The present invention also provides a process for the preparation of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IMI) according to embodiment 5 and one or more further embodiments described above, characterized in that after filtration of the solid, the wet product is subjected to drying to constant weight under vacuum, for example at 40 to 30 mbar, in a nitrogen stream at 20°C.

[0188] The present invention also provides a process for the preparation of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IMI) according to embodiment 5 and one or more further embodiments described above, characterized in that after filtration of the solid, the wet product is subjected to drying to constant weight at elevated temperature, for example 40°C to 50°C, under vacuum, for example under a vacuum of 40 to 30 mbar.

[0189] As an example, the compound of formula (I) which can be obtained via one of the above process routes 1, 2 or 3 (see Scheme 2) Further purification of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of TIFF2025502842000042.tif89165 is described to finally obtain monohydrate II of formula (IM-II).

[0190] This will be explained exemplarily.

[0191] Process Step [F] Crystallization / formation of monohydrate form II (IM-II): Acetone-water crystallization (see Scheme 3 above) The compound of formula I obtained via one of the above process routes 1, 2 or 3, for example route 3 (either in solid form, in the form of evaporation residue or even as concentrate in THF) is heated to high temperature, preferably to 50°C, together with a mixture of acetone and water, the ratio of acetone to water varying from 7.8:1, 9:1 to 22.2:1, characterized in that the total amount of solvent with respect to the solid compound of formula I is about 2 to 3 times the amount (g). The resulting solution is cooled to 20°C, filtered, for example through a Seitz filter plate, and heated to 50°C. It was cooled to 45° C. and seeded with (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4′-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the form of monohydrate II, which was cooled to 20° C., stirred and heated to 40° C. for a period of time, preferably about 3 hours (crystallizations 1 and 2 heated to 50° C.). The suspension was stirred, cooled to 20° C., stirred and the solid was filtered off with suction. The wet product was dried to constant weight under vacuum in a nitrogen stream at 25° C. to obtain the compound of formula I in monohydrate II of formula (IM-II) in crystalline modification II.

[0192] Alternatively, the solid compound of formula I is dissolved in an 8:1 mixture of acetone and water, the ratio of solvent to solid is 8 times the amount (g) of acetone, which correlates with the amount (g) of the compound of formula (I), and about 1 time the amount (g) of water, which correlates with the amount (g) of the compound of formula (I). As a result, the compound is finally stirred in an 8:1 mixture of acetone and water, the amount (g) of solvent relative to the amount (g) of solid acid of formula (I) is about 9:1. It is stirred overnight. The solid is filtered off with suction, washed with 1 time the amount of acetone / water (8:2) mixture, and dried overnight with nitrogen air in vacuum at 60°C.

[0193] Embodiment 6 (Crystallization method [F] for monohydrate II) The present invention relates to a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate II (IM-II), comprising the steps of: Formula (I) The compound of formula (IM-II) is crystallized from a mixture of acetone and water at a temperature of 20° C. to 100° C. The method is characterized in that the compound of TIFF2025502842000044.tif71128 is isolated, optionally after cooling.

[0194] The present invention also provides a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in crystalline modification monohydrate II (IM-II) according to embodiment 6, characterized in that the compound of formula (I) is stirred in a mixture of acetone and water at a temperature of 50°C, the ratio of acetone to water being from 23:1 to 4:1, preferably from 23:1 to 7:1.

[0195] The present invention also provides a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate II (IM-II) according to embodiment 6 and one or more further embodiments described above, characterized in that the acid of formula I is stirred in a mixture of acetone and water, the ratio of acetone to water being from 23:1 to 7:1, and further characterized in that acetone is provided in an amount (g) of 4 to 8 times with respect to the amount (g) of the solid compound of formula I and water is provided in an amount (g) of 0.2 to 0.8 times with respect to the amount (g) of the solid compound of formula I.

[0196] The present invention also provides a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate II (IM-II) according to embodiment 6 and one or more further embodiments described above, characterized in that the acid of formula I is stirred in a mixture of acetone and water, the ratio of acetone to water being 23:1 to 7:1, further characterized in that acetone is provided in an amount (g) of 4 to 8 times with respect to the amount (g) of the solid compound of formula I, water is provided in an amount (g) of 0.2 to 0.8 times with respect to the amount (g) of the solid compound of formula I, the mixture is heated to 50°C and filtered for clarification of the solution.

[0197] The present invention also provides a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate II (IM-II) according to embodiment 6 and one or more further embodiments described above, characterized in that the acid of formula I is stirred in a mixture of acetone and water, the ratio of acetone to water being 23:1 to 7:1, further characterized in that acetone is provided in an amount (g) of 4 to 8 times with respect to the amount (g) of the solid compound of formula I, water is provided in an amount (g) of 0.2 to 0.8 times with respect to the amount (g) of the solid compound of formula I, the mixture is heated to 50°C and filtered for clarification of the solution, then at a temperature of 45 to 50°C, seed crystals of the compound of formula (IM-II) are added to the stirred mixture.

[0198] The present invention also relates to a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in crystalline modification monohydrate II (IM-II) according to embodiment 6 and one or more further embodiments described above, comprising stirring the acid of formula I in a mixture of acetone and water, the ratio of acetone to water being between 23:1 and 7:1, wherein acetone is provided in an amount (g) of 4-8 times with respect to the amount (g) of the solid compound of formula I, water is provided in an amount (g) of 0.2-0.8 times with respect to the amount (g) of the solid compound of formula I, the mixture is heated to 50°C and filtered for clarification of the solution, then at a temperature of 45-50°C, seed crystals of the compound of formula (IM-II) are added to the stirred mixture, stirring is continued for a period of time, preferably 30 minutes, the mixture is cooled to 20°C, and finally the solid is filtered off.

[0199] The present invention also provides a process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (IM-II) according to embodiment 6 and one or more further embodiments described above, characterized in that after filtration of the solid, the wet product is subjected to drying to constant weight under vacuum, for example at 40 to 30 mbar, in a nitrogen stream at 25°C.

[0200] (pseudo)polymorphic form WO2014 / 012934 discloses only (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I) as an amorphous solid. The corresponding X-ray diffractogram of the compound of formula (I) prepared according to the synthesis described in Example 23 of WO2014 / 012934 is shown in Figure 33 (see Comparative Example 11), which is not suitable for use in an inhalation dosage form administered by a dry powder inhaler.

[0201] For the development of pharmaceutical formulations comprising the (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I) in solid form, in particular in the form of a dry powder inhalation form, there is a high demand for the reproducible preparation and isolation of the compound of formula (I) in one defined crystalline form.

[0202] Many attempts were required to finally crystallize the compound of formula I into a defined solid form.

[0203] Initial attempts to convert (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid into a crystalline form were unsuccessful and yielded only an undesirable amorphous form exhibiting uncontrolled phase changes.

[0204] To overcome this property, salt selection screens were performed in an attempt to find new crystalline materials with beneficial properties, however, all attempts resulted in amorphous or highly disordered materials and no salt formation was observed (see Figure 4: Salt screening experiment with L-arginine).

[0205] Surprisingly, the compound of formula I is obtained in several pseudopolymorphic forms and no anhydrous crystalline form has been found.

[0206] The following crystalline forms of the compound of formula (I) have been identified as pseudopolymorphic forms monohydrate I and II ((IMI) and (IM-II)), hemihydrate, sesquihydrate, dihydrate, and 1,25-hydrate (see Example 6 and Figures 5-32). In this context, modification, polymorphic form, and polymorphism have the same meaning. In addition, there is an amorphous form. All pseudopolymorphic forms and amorphous forms together are different solid forms of the compound of formula (I).

[0207] Compound stability and homogeneity are important requirements for pharmaceuticals and are prerequisites for approval by health authorities, which increase the safety and quality of preparations and formulations containing the compound of formula (I) and therefore reduce the risk to patients.

[0208] However, among several identified pseudopolymorphic forms, the most suitable stable form had to be identified during several stages.

[0209] The dihydrate was found to amorphize during the drying process (see FIG. 10a). The crystal lattice of the hemihydrate exhibits disorder (see FIG. 5), which may support phase transition and / or amorphization during mechanical processing, e.g., formulation processes. The crystallization of the sesquihydrate was not feasible for scale-up due to the very long stirring procedure.

[0210] It was found that both monohydrates overcome these undesirable properties of the different pseudopolymorphic forms. However, in the end, it was found that only one of these monohydrate forms is stable during micronization and is therefore the most suitable form for use, for example, in the manufacture of inhaled medicaments, in particular dry powder-based inhaled medicaments. Surprisingly, it was found that during micronization, monohydrate II either showed partial amorphization (see Example 8b, Figure 42) or additionally converted to monohydrate I (see Example 8a, Figure 43), depending on the micronization conditions. Moreover, it was observed that monohydrate II also showed conversion to monohydrate I during storage (see Example 7b, Figures 40 and 41). Thus, the pseudopolymorphic form monohydrate I is suitable for use in the pharmaceutical field and is preferred over other solid forms of the compound of formula I, in particular for pharmaceutical compositions, in particular for dry powder inhalation dosage forms.

[0211] In particular, the monohydrate I form of the compound of formula (I) ensures that undesired conversion of the compound of formula (I) into other forms and the associated changes in the properties mentioned above are prevented.

[0212] It is therefore an object of the present invention to provide a pseudopolymorph having excellent application properties, such as mechanical stability during the micronization process and storage stability with respect to solid state transformation.

[0213] Surprisingly, it has now been found that the monohydrate I obtained by applying specific crystallization conditions has such excellent properties.In particular, the monohydrate I shows improved properties, such as mechanical stability in the micronization process, enhanced storage stability and better processability, when compared with the amorphous forms known from the prior art or all other pseudopolymorphic forms described herein.In particular, the monohydrate I shows increased stability, thereby ensuring that the undesired conversion of the compound of formula (I) to another pseudopolymorphic form and the associated changes in the above-mentioned properties are prevented.The increase in stability enhances the safety and quality of the formulations containing the compound of formula (I).

[0214] Therefore, the pseudopolymorphic form monohydrate I (IMI) of the compound of formula I is the most preferred form of the compound of formula I for industrial applications.

[0215] Using the process according to the invention (see Schemes 2 and 3 above), it was possible to selectively isolate the compound of formula (I) in the crystalline form of monohydrate I of formula (IMI) in high yield and purity.

[0216] Pseudopolymorphic forms, in particular hydrates, preferably monohydrates in forms I and II, can be prepared by crystallization of the acid of formula (I) (see Scheme 3).

[0217] Depending on the solvent used, either the monohydrate (IMI) or the monohydrate (IM-II) is formed. Crystallization from a mixture of methanol and water or a mixture of acetone, methanol and water selectively gives (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I in the form of monohydrate I of formula (IMI), and crystallization from a mixture of acetone and water selectively gives the monohydrate (IM-II) in form II.

[0218] The monohydrate I of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid can be characterized by X-ray powder diffractometry on the basis of the respective diffractograms, which are recorded at 25°C and with Cu-K alpha 1 radiation (1.5406 Å). The monohydrate I according to the invention exhibits at least 2, often at least 3, often at least 5, in particular at least 7, more in particular at least 10, in particular all of the reflections given as values ​​below.

[0219] The monohydrate I of formula (IMI), which is a pseudopolymorphic form of the compound of formula (I), has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of at least the following reflections, each expressed as 2θ values ​​of ±0.2°: 12.8 and 29.2, or at least 6.9, 7.2 and 7.3, or at least 6.9, 7.2, 7.3, 12.8 and 29.2, or at least 6.9, 7.2, 7.3, 12.8, 29.2, 23.0 and 15.2, or at least 25.1, 17.7, and 23.7, or at least the following reflectances: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7, and 23.7, or at least the following reflectances: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7, and 23.7, or at least the following reflectances: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7, 23.7, 9.9, 5.7, and 11.5.

[0220] In another embodiment, the pseudopolymorphic form of compound of formula (I), monohydrate I of formula (IMI), has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of at least the following reflections, each expressed as 2θ values ​​±0.2°: 12.8, 16.0 and 25.8, or at least 6.9, 7.2 and 7.3, or at least 6.9, 7.2, 7.3, 12.8, 16.0 and 2 5.8, or at least 6.9, 7.2, 7.3, 12.8, 16.0, 25.8, 15.2 and 25.1, or at least 6.9, 7.2, 7.3, 12.8, 16.0, 25.8, 15.2, 25.1 and 23.7, or at least 6.9, 7.2, 7.3, 12.8, 16.0, 25.8, 15.2, 25.1, 23.7, 9.9, 5.7 and 11.5.

[0221] In another embodiment, the pseudopolymorphic form of compound of formula (I), monohydrate I of formula (IMI), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) showing at least the following reflections, each expressed as 2θ values ​​±0.2°: 12.8, 20.5 and 25.8, or at least 6.9, 7.2 and 7.3, or at least 6.9, 7.2, 7.3, 12.8, 20.5, 25.8, 15.2 and 25.1, or at least 6.9, 7.2, 7.3, 12.8, 20.5, 25.8, 15.2, 25.1 and 23.7, or at least 6.9, 7.2, 7.3, 12.8, 20.5, 25.8, 15.2, 25.1, 23.7, 9.9, 5.7 and 11.5.

[0222] Additionally, the monohydrate I of formula (IMI), which is a pseudopolymorphic form of the compound of formula (I), has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of the following reflections, each expressed as 2θ values ​​of ±0.2°: 5.7, 6.9, 7.2, 7.3, 9.9, 10.4, 10.6, 11.1, 11.5, 12.0, 12.3, 12.4, 12.8, 13.7, 14.1, 14.3, 15.2, 23.0, 23.4, 23.7, 24.1, 25.1, 25.8, 26.0, 26.4, 28.9, 29.2, 29.4, 30.6, 31.1, 32.2, 35.3.

[0223] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate I of formula (IMI), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections: 3.1 and 9.3, each expressed as a 2θ value ±0.2°.

[0224] Additionally, monohydrate I of formula (IMI), which is a pseudopolymorphic form of the compound of formula (I), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections: 6.1 and 8.5, each expressed as a 2θ value ±0.2°.

[0225] Additionally, monohydrate I of formula (IMI), which is a pseudopolymorphic form of compound of formula (I), may be characterized in that its X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) does not exhibit at least the following reflections, each expressed as a 2θ value ±0.2°: 8.5 and / or 30.

[0226] Additionally, monohydrate I of formula (IMI), which is a pseudopolymorphic form of the compound of formula (I), may be characterized in that its X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) does not exhibit at least the following reflections, each expressed as a 2θ value ±0.2°: 7.9 and / or 31.6.

[0227] Additionally, monohydrate I of formula (IMI), which is a pseudopolymorphic form of the compound of formula (I), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 7.6.

[0228] Additionally, monohydrate I of formula (IMI), which is a pseudopolymorphic form of the compound of formula (I), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 14.8.

[0229] Additionally, the pseudopolymorphic form of compound of formula (I), monohydrate I of formula (IMI), has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of at least the following reflections, each expressed as 2θ values ​​±0.2°: 12.8 and 29.2, or at least 6.9, 7.2 and 7.3, or at least 6.9, 7.2, 7.3, 12.8 and 29.2, or at least 6.9, 7.2, 7.3, 12.8, 29.2, 23.0 and 15.2, or at least the following reflections: 6.9 , 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8 and 25.1, or at least the following reflectances: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7 and 23.7, or at least the following reflectances: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7, 23.7, 9.9, 5.7 and 11.5, while not exhibiting at least the following reflectances: 6.1 and 8.5.

[0230] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate I of formula (IMI), has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of at least the following reflections, each expressed as 2θ values ​​±0.2°: 12.8, 16.0 and 25.8, or at least 6.9, 7.2 and 7.3, or at least 6.9, 7.2, 7.3, 12.8, 16.0 and 25.8, or at least 6.9, 7.2, 7.3, .2, 7.3, 12.8, 16.0, 25.8, 15.2 and 25.1, or at least 6.9, 7.2, 7.3, 12.8, 16.0, 25.8, 15.2, 25.1 and 23.7, or at least 6.9, 7.2, 7.3, 12.8, 16.0, 25.8, 15.2, 25.1, 23.7, 9.9, 5.7 and 11.5, while not exhibiting at least the following reflections: 6.1 and 8.5.

[0231] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate I of formula (IMI), has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of at least the following reflections, each expressed as 2θ values ​​±0.2°: 12.8, 20.5, and 25.8, or at least 6.9, 7.2, and 7.3, or at least 6.9, 7.2, 7.3, 12.8, 20.5, 2 5.8, 15.2 and 25.1, or at least 6.9, 7.2, 7.3, 12.8, 20.5, 25.8, 15.2, 25.1 and 23.7, or at least 6.9, 7.2, 7.3, 12.8, 20.5, 25.8, 15.2, 25.1, 23.7, 9.9, 5.7 and 11.5, while not exhibiting at least the following reflections: 6.1 and 8.5.

[0232] The compound of formula (I) in its polymorphic form, monohydrate I, can also be clearly characterized by the X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) shown in FIG.

[0233] The pseudopolymorphic form of the compound of formula (I), monohydrate I of formula (IMI), may be characterized by Raman spectroscopy exhibiting at least the following band maxima: 3073, 2950, ​​2937, 1685, 1616, 1527, 1293, 1278, 1259 cm −1 .

[0234] The pseudopolymorphic form monohydrate I of compound of formula (I) may be characterized by IR spectroscopy exhibiting at least the following band maxima: 2933, 1595, 1375, 1327, 1272, 1242, 1167, 1110 cm −1 .

[0235] Embodiment 7 (Monohydrate I of formula (IMI)) The present invention relates to a compound of formula (IMI) Provided is a compound of formula (I) in crystalline form monohydrate I of TIFF2025502842000045.tif69128, characterized in that the x-ray diffractogram of the compound (at 25° C. and using Cu-K alpha 1 as the radiation source) shows at least the following reflections, expressed as 2θ values ​​±0.2°: 12.8 and 29.2.

[0236] The present invention further provides a compound of formula (I) in the crystalline form of monohydrate I of formula (IMI) according to embodiment 7, characterized in that the x-ray diffractogram (at 25° C. and using Cu-K alpha 1 as radiation source) of the compound exhibits at least the following reflections, expressed as 2θ values ​​±0.2°: 6.9, 7.2 and 7.3.

[0237] The present invention further provides a compound of formula (I) in the crystalline form of monohydrate I of formula (IMI) according to embodiment 7, characterized in that the x-ray diffractogram (at 25° C. and using Cu—K alpha 1 as radiation source) of the compound exhibits at least the following reflections, expressed as 2θ values ​​±0.2°: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0 and 15.2.

[0238] The invention further provides a compound of formula (I) in the crystalline form of monohydrate I of formula (IMI) according to embodiment 7 and one or more further embodiments as described above, characterized in that the x-ray diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound shows at least the following reflections, expressed as 2θ values ​​±0.2°: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7 and 23.7.

[0239] The present invention further provides a compound of formula (I) in crystalline form monohydrate I of formula (IMI) according to embodiment 7 and one or more further embodiments as described above, characterized in that the x-ray diffractogram (at 25° C. and using Cu—K alpha 1 as radiation source) of the compound shows at least the following reflections, expressed as 2θ values ​​±0.2°: 6.9, 7.2 and 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7, 23.7, 9.9, 5.7 and 11.5.

[0240] Alternatively, the present invention relates to a compound of formula (IMI) Provided is a compound of formula (I) in crystalline form monohydrate I of TIFF2025502842000046.tif69128, characterized in that the x-ray diffractogram of the compound (at 25° C. and using Cu-K alpha 1 as the radiation source) shows at least the following reflections, expressed as 2θ values ​​±0.2°: 12.8, 16.0 and 25.8.

[0241] The present invention further provides a compound of formula (I) in the crystalline form of monohydrate I of formula (IMI) according to embodiment 7, characterized in that the x-ray diffractogram of the compound (at 25° C. and using Cu-K alpha 1 as radiation source) shows at least the following reflections, expressed as 2θ values ​​±0.2°: 12.8, 16.0, 25.8, 6.9, 7.2 and 7.3.

[0242] The present invention further provides a compound of formula (I) in the crystalline form of monohydrate I of formula (IMI) according to embodiment 7, characterized in that the x-ray diffractogram (at 25° C. and using Cu—K alpha 1 as radiation source) of the compound shows at least the following reflections, expressed as 2θ values ​​±0.2°: 6.9, 7.2 and 7.3, 12.8, 29.2, 23.0 and 15.2.

[0243] The invention further provides a compound of formula (I) in the crystalline form of monohydrate I of formula (IMI) according to embodiment 7 and one or more further embodiments as described above, characterized in that the x-ray diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound shows at least the following reflections, expressed as 2θ values ​​±0.2°: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8 and 25.1.

[0244] The present invention further provides a compound of formula (I) in crystalline form monohydrate I of formula (IMI) according to embodiment 7 and one or more further embodiments as described above, characterized in that the x-ray diffractogram (at 25° C. and using Cu—K alpha 1 as radiation source) of the compound shows at least the following reflections, expressed as 2θ values ​​±0.2°: 6.9, 7.2 and 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7, 23.7, 9.9, 5.7 and 11.5.

[0245] The present invention relates to a compound of formula (IMI) There is further provided a compound of formula (I) in the crystalline form of monohydrate I of TIFF2025502842000047.tif67128, characterized in that the IR spectrum of the compound exhibits band maxima at 2933, 1595, 1375, 1327, 1272, 1242, 1167, 1110 cm-1cm-1.

[0246] The present invention relates to a compound of formula (IMI) There is further provided a compound of formula (I) in the crystalline form of monohydrate I of TIFF2025502842000048.tif68128, characterized in that the Raman spectrum of the compound exhibits band maxima at 3073, 2950, ​​2937, 1685, 1616, 1527, 1293, 1278, 1259 cm-1.

[0247] Other different forms of the compound of formula (I) may be distinguished by X-ray powder diffraction, differential scanning calorimetry (DSC), IR and Raman spectroscopy.

[0248] In addition to monohydrate I, further pseudopolymorphic forms have been identified: monohydrate II, hemihydrate, 1,25-hydrate, sesquihydrate and dihydrate (see Example 6, Figures 2-29), which are further characterized below.

[0249] The pseudopolymorphic forms of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, monohydrate II, hemihydrate, 1,25-hydrate, sesquihydrate and dihydrate, can be characterized by X-ray powder diffraction based on their respective diffractograms, which are recorded at 25°C and with Cu-K alpha 1 radiation (1.5406 Å). The pseudopolymorphic forms of monohydrate II, hemihydrate, 1,25-hydrate, sesquihydrate and dihydrate exhibit at least 3, often at least 5, in particular at least 7, more in particular at least 10, and in particular all of the reflections shown below as values.

[0250] The pseudopolymorphic form monohydrate II of compound of formula (I) has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) which has at least the following reflections, expressed as 2θ values ​​of ±0.2°, respectively: 6.1 and 8.5, also at least 6.1, 8.5, 12.7, 23.9 and 13.9, preferably at least the following reflections: 6.1, 8.5, 12.7, 23.9, 13.9, 23.0 and 12.2, more preferably at least the following reflections: 6.1, 8.5 , 12.7, 23.9, 13.9, 23.0, 12.2, 10.8 and 15.3, and most preferably by exhibiting at least the following reflections: 6.1, 8.5, 12.7, 23.9, 13.9, 23.0, 12.2, 10.8, 15.3, 17.3, 21.7 and 22, and also most preferably by exhibiting at least the following reflections: 6.1, 8.5, 12.7, 23.9, 13.9, 23.0, 12.2, 10.8, 15.3, 17.3, 21.7 and 22.

[0251] Additionally, monohydrate II of formula (IM-II), which is a pseudopolymorphic form of compound of formula (I), has an X-ray powder diffractogram (at 25° C. and using Cu-K alpha 1 as the radiation source) of the following reflections, each expressed as 2θ values ​​of ±0.2°: 5.7, 6.1, 7.1, 8.5, 9.9, 10.2, 10.8, 11.4, 11.6, 11.8, 12.0, 12.2, 12.7, 13.0, 13.9, 14.2, 15.2, 15.3, 15.4, 15.6, 15.8, 16.0, 16.2, 16.4, 16.6, 16.8, 17.0, 17.2, 17.6, 17.8, 17.8, 17.9, 18.0, 18.2, 18.6, 18.8, 18.9, 19.0, 20.0, 20.2, 20.4, 20.6, 20.8 ... 25.1, 25.5, 25.7, 26.2, 26.4, 26.8, 27.2, 27.5, 28.9, 30.0, 30.1, 30.6, 32.2, 32.4.

[0252] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections: 3.1 and 9.3, each expressed as a 2θ value ±0.2°.

[0253] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections: 6.9, 7.2, and 7.3, each expressed as a 2θ value of ±0.2°.

[0254] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 29.2.

[0255] Additionally, the pseudopolymorphic form of compound of formula (I), monohydrate II of formula (IM-II), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 7.9 and / or 31.6.

[0256] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 7.6.

[0257] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 14.8.

[0258] Additionally, the pseudopolymorphic form of compound of formula (I), monohydrate II of formula (IM-II), has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of at least the following reflections, each expressed as 2θ values ​​±0.2°: 6.1 and 8.5, also at least 6.1, 8.5, 12.8, 23.0 and 15.2, preferably at least the following reflections: 6.1, 8.5, 12.8, 23.0, 15.2, 25.8 and 25.1, more preferably at least the following reflections: 6.1, 8.5, 12.8, 23.0, 15.2, 25.8, 25.1, 17.7 and 23.7, and most preferably at least the following reflectances: 6.1, 8.5, 12.8, 23.0, 15.2, 25.8, 25.1, 17.7, 23.7, 9.9, 5.7 and 11.5, and also most preferably at least the following reflectances: 12.8, 23.0, 15.2, 25.8, 25.1, 17.7, 23.7, 9.9, 5.7, 6.1, 8.5 and 11.5, while not exhibiting at least the following reflectances: 6.9, 7.2 and 7.3.

[0259] The compound of formula (I) in the pseudopolymorphic form monohydrate II can also be clearly characterized by the X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as radiation source) shown in FIG.

[0260] The pseudopolymorphic form monohydrate II of compound of formula (IM-II) may be characterized by Raman spectroscopy exhibiting at least the following band maxima: 3073, 2950, ​​2936, 1685, 1615, 1526, 1294, 1279, 1259 cm −1 .

[0261] The pseudopolymorphic form monohydrate I of compound of formula (I) may be characterized by IR spectroscopy exhibiting at least the following band maxima: 2934, 1595, 1375, 1327, 1272, 1242, 1167, 1110 cm −1 .

[0262] Embodiment 8 (Monohydrate II of Formula (IM-II)) The present invention relates to a compound represented by formula (IM-II) 2. The compound of formula (I) in the crystalline form of monohydrate II of TIFF2025502842000049.tif66128, wherein the x-ray diffractogram of the compound (at 25° C. and using Cu—K alpha 1 as radiation source) shows at least the following reflections, expressed as 2θ values ​​±0.2°: 6.1 and 8.1, preferably 6.1, 8.1, 12.7, 23.9 and 13.9, preferably at least the following reflections: 6.1, 8.1, More preferably, said compounds exhibit at least the following reflexes: 6.1, 8.1, 12.7, 23.9, 13.9, 23.1, 12.2, 10.8 and 15.3, and most preferably, said compounds exhibit at least the following reflexes: 6.1, 8.1, 12.7, 23.9, 13.9, 23.1, 12.2, 10.8, 15.3, 17.3, 21.7 and 22.0.

[0263] The compound of formula (I) in the pseudopolymorphic form monohydrate II can also be clearly characterized by the X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as radiation source) shown in FIG.

[0264] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections: 3.1 and 9.3, each expressed as a 2θ value ±0.2°.

[0265] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections: 6.9, 7.2, and 7.3, each expressed as a 2θ value of ±0.2°.

[0266] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 29.2.

[0267] Additionally, the pseudopolymorphic form of compound of formula (I), monohydrate II of formula (IM-II), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 7.9 and / or 31.6.

[0268] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 7.6.

[0269] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 14.8.

[0270] Embodiment 9 (hemihydrate of compound of formula (I)) The pseudopolymorphic form of the compound of formula (I), hemihydrate, may be unambiguously characterized by its X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) showing the following reflections, each expressed as 2θ values ​​±0.2°: 3.1, 5.3, 6.7, 7.1, 9.3, 10.6, 12.4, 14.3, 16.1, 19.7, 20.8, 24.0, 31.1.

[0271] The pseudopolymorphic form of the compound of formula (I), hemihydrate, may be unambiguously characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) showing at least the following reflections, each expressed as 2θ values ​​±0.2°: 3.1, 5.3, 6.7, 7.1, 9.3 and 31.1.

[0272] The compound of formula (I) in the pseudopolymorphic form hemihydrate can also be clearly characterized by the X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) shown in FIG.

[0273] Additionally, the pseudopolymorphic form of the compound of formula (I), hemihydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections: 6.9, 7.2, and 7.3, each expressed as a 2θ value ±0.2°.

[0274] Additionally, the pseudopolymorphic form of the compound of formula (I), hemihydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 29.2.

[0275] Additionally, the pseudopolymorphic form of the compound of formula (I), hemihydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 8.5 and / or 30.0.

[0276] Additionally, the pseudopolymorphic form of the compound of formula (I), hemihydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 7.9 and / or 31.6.

[0277] Additionally, the pseudopolymorphic form of the compound of formula (I), hemihydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 7.6.

[0278] Additionally, the pseudopolymorphic form of the compound of formula (I), hemihydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 14.8.

[0279] Embodiment 10 (1,25-hydrate of the compound of formula (I)) The pseudopolymorphic form of the compound of formula (I), the 1,25-hydrate, has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of the following reflections, each expressed as 2θ values ​​of ±0.2°: 5.9, 6.1, 7.9, 10.5, 11.9, 12.2, 12.5, 13.2, 13.6, 13.7, 14.4, 15.2, 15.3, 15.4, 15.7, 15.9, 16.5, 16.9, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9 ... .4, 17.6, 17.8, 18.3, 18.6, 18.7, 19.0, 19.5, 19.6, 19.8, 20.5, 20.7, 21.0, 21.4, 22.0, 23.2, 23.8, 24.0, 24.4, 24.6, 25.0, 25.2, 25.6, 26.1, 26.8, 27.4, 27.6, 28.4, 28.8, 30.2, 30.7, 31.1, 31.6, 32.3.

[0280] The pseudopolymorphic form of the compound of formula (I), the 1,25-hydrate, may be unambiguously characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) showing at least the following reflections, each expressed as 2θ values ​​±0.2°: 7.9, 10.5, 12.2, 12.5, 13.6, 15.2, 16.9, 19.0, 24.0, 24.4, 24.6, 31.6.

[0281] The compound of formula (I) in the pseudopolymorphic form 1,25-hydrate can also be clearly characterized by the X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as radiation source) shown in FIG.

[0282] Additionally, the pseudopolymorphic form of the compound of formula (I), the 1,25-hydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections: 3.1 and 9.3, each expressed as a 2θ value ±0.2°.

[0283] Additionally, the pseudopolymorphic form of the compound of formula (I), the 1,25-hydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections: 6.9, 7.2, and 7.3, each expressed as a 2θ value ±0.2°.

[0284] Additionally, the pseudopolymorphic form of the compound of formula (I), the 1,25-hydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 29.2.

[0285] Additionally, the pseudopolymorphic form of the compound of formula (I), the 1,25-hydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 8.5 and / or 30.0.

[0286] Additionally, the pseudopolymorphic form of the compound of formula (I), the 1,25-hydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 7.9 and / or 31.6.

[0287] Additionally, the pseudopolymorphic form of the compound of formula (I), the 1,25-hydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 7.6.

[0288] Additionally, the pseudopolymorphic form of the compound of formula (I), the 1,25-hydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 14.8.

[0289] Embodiment 11 (Sesquihydrate of compound of formula (I)) The pseudopolymorphic form sesquihydrate of the compound of formula (I) can be clearly characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) showing at least the following reflections, each expressed as 2θ values ​​±0.2°: 12.2, 25.1 and 14.5, preferably at least 12.2, 25.1, 14.5, 18.7 and 26.4, preferably at least the following reflections: 12.2, 25.1, 14.5, 18.7, 26.4, 18.3 and 23.4, more preferably at least the following reflections: most preferably at least the following reflections: 12.2, 25.1, 14.5, 18.7, 26.4, 18.3, 23.4, 21.5, 8.6 and 5.1 and 7.6.

[0290] The sesquihydrate, which is a pseudopolymorphic form of the compound of formula (I), may also be unambiguously characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) showing at least the following reflections, each expressed as 2θ values ​​±0.2°: 5.1, 7.6, 8.6, 12.2, 14.5, 18.3, 18.7, 21.5, 23.4, 24.7, 25.1, 26.4.

[0291] The pseudopolymorphic form of the compound of formula (I), the sesquihydrate, has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of the following reflections, each expressed as 2θ values ​​of ±0.2°: 5.1, 6.3, 7.6, 8.6, 11.4, 12.2, 12.5, 12.9, 13.3, 14.3, 14.5, 15.2, 15.5, 15.8, 1 27.0, 27.4, 28.5, 32.2, 36.5.

[0292] The compound of formula (I) in the pseudopolymorphic form sesquihydrate can also be clearly characterized by the X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) shown in FIG.

[0293] Additionally, the sesquihydrate, which is a pseudopolymorphic form of the compound of formula (I), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections: 3.1 and 9.3, each expressed as a 2θ value ±0.2°.

[0294] Additionally, the pseudopolymorphic form of the compound of formula (I), the sesquihydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 6.9, 7.2, and 7.3.

[0295] Additionally, the sesquihydrate, which is a pseudopolymorphic form of the compound of formula (I), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 29.2.

[0296] Additionally, the sesquihydrate, which is a pseudopolymorphic form of the compound of formula (I), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 8.5 and / or 30.0.

[0297] Additionally, the sesquihydrate, which is a pseudopolymorphic form of the compound of formula (I), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 7.9 and / or 31.6.

[0298] Additionally, the sesquihydrate, which is a pseudopolymorphic form of the compound of formula (I), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 14.8.

[0299] Embodiment 12. Dihydrate of the compound of formula (I) The pseudopolymorphic form of the compound of formula (I), the dihydrate, may be unambiguously characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) showing at least the following reflections, each expressed as 2θ values ​​±0.2°: 10.1, 10.5, 11.2, 12.5, 13.6, 14.8, 15.5, 20.2, 20.5, 21.1, 22.2, 23.2, 25.1, 29.6.

[0300] The dihydrate, which is a pseudopolymorphic form of the compound of formula (I), exhibits an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of the following reflections, each expressed as 2θ values ​​of ±0.2°: 6.1, 6.8, 10.1, 10.5, 11.2, 11.3, 12.3, 12.5, 13.1, 13.6, 14.6, 14.8, 15.0, 16.0, 17.0, 18.0, 19.0, 20.0, 21.0, 22.0, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0, 51.0, 52.0, 53.0, 54.0, 55.0, 56.0, 57.0, 58.0, 59.0, 60.0, 61.0, 62.0, 63.0, 64.0, 65.0, 66.0, 67.0, 68.0, 69.0, 70.0, 71.0, 72.0, 73.0, 74.0, 75.0, 7 5.5, 16.2, 16.4, 16.8, 17.1, 17.3, 17.9, 18.5, 18.8, 19.5, 20.2, 20.5, 21.1, 21.4, 22.2, 23.2, 24.3, 25.1, 25.4, 25.6, 26.3, 26.9, 27.4, 28.5, 28.7, 29.6.

[0301] The compound of formula (I) in the pseudopolymorphic form dihydrate can also be clearly characterized by the X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as radiation source) shown in FIG.

[0302] Additionally, the pseudopolymorphic form of the compound of formula (I), the dihydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections: 3.1 and 9.3, each expressed as a 2θ value ±0.2°.

[0303] Additionally, the pseudopolymorphic form of the compound of formula (I), the dihydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections: 6.9, 7.2, and 7.3, each expressed as a 2θ value ±0.2°.

[0304] Additionally, the pseudopolymorphic form of the compound of formula (I), the dihydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 29.2.

[0305] Additionally, the pseudopolymorphic form of the compound of formula (I), the dihydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 8.5 and / or 30.0.

[0306] Additionally, the pseudopolymorphic form of the compound of formula (I), the dihydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 7.9 and / or 31.6.

[0307] Additionally, the pseudopolymorphic form of the compound of formula (I), the dihydrate, may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) not exhibiting at least the following reflections, each expressed as a 2θ value ±0.2°: 7.6.

[0308] Methods for Treatment The crystalline forms of the compound of formula (I) according to the invention, preferably monohydrate I (IMI) or monohydrate II (IM-II), more preferably monohydrate I (IMI), have useful pharmacological properties and can be used for the prevention and treatment of disorders in humans and animals. The forms of the compound of formula (I) according to the invention can open up further alternative treatments and thus enrich pharmacy.

[0309] In the context of the present invention, the term "treatment" or "treating" includes inhibiting, slowing, halting, ameliorating, attenuating, limiting, reducing, suppressing, reversing or curing a disease, condition, disorder, injury or health impairment, of the onset, course or progression of such a condition, and / or of the symptoms of such a condition, where the term "therapy" is understood to be synonymous with the term "treatment".

[0310] In the context of the present invention, the terms "prevention", "prophylaxis" or "precaution" are used synonymously and refer to the avoidance or reduction of the risk of becoming, suffering from, or having a disease, condition, disorder, injury or health impairment, the onset or progression of such a condition, and / or the symptoms of such a condition.

[0311] The treatment or prevention of a disease, condition, disorder, injury or health impairment may be effected partially or completely.

[0312] The term "therapeutic efficacy" within the context of the present invention is defined as reducing the mean pulmonary artery pressure in a patient by administering a therapeutically effective amount of a pharmaceutical dry powder formulation comprising a compound of formula (I), in particular that of Comparative Example 11, or a salt, solvate or polymorphic form or crystalline modification of a solvate or salt of the compound of formula (I), or a metabolite of the compound of formula (I), in particular its pseudopolymorphic forms, e.g., (IMI) and (IM-II), without a concomitant clinically relevant change in systemic blood pressure.

[0313] The term "pulmonary vascular resistance (PVR)" within the context of the present invention is defined as 1) a parameter for characterizing the severity of pulmonary hypertension as wall tension in the main pulmonary vessels analyzed by invasive methods measuring the blood pressure in the pulmonary artery and 2) a parameter for evaluating the effect of new drugs by substantially reducing this parameter, which is directly related to the blood pressure in the pulmonary artery (see D. Singh, R. Tal-Singer, I. Faiferman, S. Lasenby, A. Henderson, D. Wessels, A. Goosen, N. Dallow, R. Vessey & M. Goldman, Plethysmography and impulse oscillometry assessment of tiotropium and ipratropium bromide; a randomized, double-blind, placebo-controlled, cross-over study. in healthy subjects, Br. Journal Clin Pharmacol, 2006, 61, 398-404).

[0314] Improved 6-minute walk test result within the context of the present invention is defined as an improvement in the distance a patient can walk within a 6 minute time frame, which corresponds to increased physical performance in patients with critical illness under treatment.

[0315] A transition in "NYHA class" within the context of the present invention is defined as an improvement from a higher class to a lower class number of the NYHA classification, corresponding to improved cardiac function with better cardiac performance.

[0316] The physiological function of the lungs is evaluated under standardized conditions in pulmonary function tests, e.g. spirometry or body plethysmography, to obtain standardized and validated measurements of parameters, e.g. forced expiratory volume in 1 second (FEV1), which allow the direct assessment of drug effects, e.g. bronchodilation, an effect that is therapeutically used by different drugs to improve lung function in lung diseases with bronchoconstriction, e.g. COPD or asthma.

[0317] The term "improved hemodynamic effect" within the context of the present invention is defined as the vasodilatory effect of a drug to reduce pulmonary artery pressure, improve blood circulation in the ventilated areas of the lungs, improve pulmonary function without systemic side effects, thereby causing a clinically relevant improvement in physical performance and general condition for an individual patient.

[0318] The term "intrapulmonary selectivity" within the context of the present invention means the property of an inhaled active ingredient to develop its pharmacodynamic properties of vasodilatation only in the ventilated areas of the lungs and not in the non-ventilated areas. This is to prevent an exacerbation of the mismatch between ventilation and perfusion (due to increased perfusion in the non-ventilated areas) that could occur if the active ingredient also reached the non-ventilated areas. Intrapulmonary selectivity is ensured in particular by the inhalation application route, which is implemented by active inhalation of the patient.

[0319] The term "bronchodilatory effect" within the context of the present invention is defined as an improvement in a parameter, such as, for example, relaxation of carbachol precontracted guinea pig trachea, pulmonary resistance (RL) and dynamic compliance (Cdyn), specific airway resistance (E-2.1) in humans, FEV1 in humans, or other parameter indicative of an improvement in ventilation.

[0320] The term "chronic treatment / use" within the context of the present invention is defined as once or twice daily inhalation treatment of a patient for at least 2 consecutive days, preferably over a period of at least 2-7 consecutive days, preferably over a period of at least 14 consecutive days, in particular from the start of treatment and throughout the entire course of the disease, and optionally in combination with standard of care (SoC, e.g. endothelin antagonists, e.g. bosentan, PDE5 inhibitors, e.g. sildenafil, IP agonists, e.g. Ilomedin or treprostinil, calcium channel blockers, sotatercept, and sGC stimulators, e.g. riociguat).

[0321] The term "once daily" is well known to those skilled in the art and refers to the administration of a drug once a day, and includes the administration of one dosage form, as well as the administration of two or more dosage forms simultaneously or sequentially within a short period of time.

[0322] The term "once or twice daily" is well known to those skilled in the art and refers to administration of a drug once or twice daily, where administration of a drug at each corresponding time point throughout the day includes administration of one dosage form, as well as administration of two or more dosage forms simultaneously or sequentially within a short period of time.

[0323] The term "consecutive days" means a period of days occurring one after the other with no intervening days, and does not mean sequential or cyclic days.

[0324] The term "inhalation dosage form" refers to a combination of a drug substance, i.e. an active ingredient, preferably in one crystalline form, for example in the form of monohydrate I or monohydrate II or sesquihydrate, preferably in the form of monohydrate I or monohydrate II, more preferably in the form of monohydrate I of formula (IMI), and a pharma- ceutically suitable carrier for inhalation. The combination of the drug substance and the pharma-ceutically suitable carrier for inhalation is in the form of a dry powder. Preferably, the dry powder is filled in a cavity, more preferably in a capsule. Preferably, the pharma-ceutically suitable carrier is lactose for inhalation.

[0325] The terms "reflection(s)" or "peak(s)" are synonymous and have the same meaning in relation to X-ray values ​​and diffractograms. Crystalline forms are most commonly characterized by X-ray powder diffraction (XRPD). The XRPD pattern of reflections (typically peaks expressed in °2 theta) is generally considered a fingerprint of a particular crystalline form.

[0326] The term "respiratory system" (or respiratory system) for the purposes of the present invention refers to the airways, including the nose, oral cavity and pharynx, larynx, trachea, bronchi, and lungs, as functional organ systems.

[0327] In the context of cardiopulmonary disorders, the term "local administration" or "local control" refers for the purposes of the present invention to administration by inhalation of active ingredients in inhalable dosage forms primarily to cover the lungs as a target organ, requiring lower doses and resulting in lower systemic drug exposure, as opposed to oral and intravenous administration of dosage forms intended for absorption via the gastrointestinal tract, which results in systemic drug distribution via the bloodstream. The preparations in powder form or in powder-containing suspensions used according to the present invention are inhaled preparations.

[0328] The term "inhalation" or "administration by inhalation" in this context refers to introduction into the respiratory tract, in particular introduction into and / or via the airways, preferably introduction into and / or via the nasal passages or oral cavity, particularly preferably introduction via the oral cavity, to achieve deposition of the active ingredient in the bronchi and lungs as sites of action.

[0329] The term "intracereal" or "intracereal administration" for purposes of this invention refers to the non-inhalational introduction of a compound into the trachea, particularly its introduction for the control of pulmonary disease in experimental animals as models of administration, such as rats or piglets and dogs (e.g., intratracheal application via a PennCentury device, which is applicable to dry powders, as well as drug solutions and suspensions).

[0330] The compounds according to the invention, for example (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, for example (IMI) and (IM-II), are potent activators of soluble guanylate cyclase. They result in vasorelaxation, inhibition of platelet aggregation and a reduction in blood pressure, as well as increased coronary blood flow and microcirculation. In addition, they have a bronchodilatory effect. Their activity is mediated via a direct heme-independent activation of soluble guanylate cyclase and an increase in intracellular cGMP levels.

[0331] In addition, the compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), have further advantageous pharmacological properties, in particular with regard to their lung-selective (as opposed to systemic) action, their pulmonary residence time and / or their duration of action after intrapulmonary administration (E-1).

[0332] Also, the good therapeutic efficacy and target association of the compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), can be clinically demonstrated. After inhalation application, reduced total specific airway resistance (E-2.1), an increase in plasma cGMP concentration as a surrogate for drug concentration in the lung (indicating target association) (E-2.1, E-2.2), and a selective decrease in pulmonary artery pressure and pulmonary vascular resistance (E-2.4) were observed.

[0333] Furthermore, suitable pharmacokinetic properties of the drug substance for inhalation application can be shown. Analysis of the plasma concentration after oral, intravenous and inhalation administration of the drug substance showed the longest half-life after inhalation application (E-2.3). The emitted dose has been determined to be 720 μg after inhalation of 1000 μg in humans. The results from this study confirm the deposited lung dose and that the half-life is suitable for inhalation dry powder administration, allowing once-daily treatment (as shown for Example 4) for sufficient 24-hour drug coverage of the drug substance in the lungs.

[0334] In conclusion, all the results show that (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms such as (IMI) and (IM-II), in particular the monohydrate I of formula (IMI), are particularly suitable for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP), and are suitable for inhaled dry powder administration allowing once-daily treatment for sufficient 24-hour drug coverage in the lungs of Example 4.

[0335] The compound according to the invention, (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), are particularly suitable for the treatment and / or prevention of cardiovascular, cardiopulmonary and pulmonary disorders, preferably cardiopulmonary disorders.

[0336] Thus, the compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), may be used in medicine for the treatment and / or prevention of cardiovascular and cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), as well as pulmonary hypertension (PH) associated with chronic lung disease (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP), and also pulmonary disorders, such as asthma, chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis.

[0337] In the context of the present invention, the term "sGC regulator" encompasses two different classes of compounds capable of regulating sGC: sGC stimulators and sGC activators (Sandner P, Becker-Pelster EM, Stasch JP. Discovery and development of sGC stimulators for the treatment of pulmonary hypertension and rare diseases. Nitric Oxide 2018; 77: 88-95. Hoenicka M, Becker EM, Apeler H, Sirichoke T, Schroder H, Gerzer R, Stasch JP. Purified soluble guanylyl cyclase expressed in a baculovirus / Sf9 system: stimulation by YC-1, nitric oxide, and carbon monoxide. J Mol Med (Berl) 1999; 77: 14-23, Evgenov OV, Kohane DS, Bloch KD, Stasch JP, Volpato GP, Bellas E, Evgenov NV, Buys ES, Gnoth MJ, Graveline AR, Liu R, Hess DR, Langer R, Zapol WM. Inhaled agonists of soluble guanylate cyclase induce selective pulmonary vasodilation.Am J Respir Crit Care Med 2007;176:1138-1145). Both classes of compounds bind directly to sGC as allosteric regulators. sGC stimulators have a dual mode of action, directly stimulating native sGC independent of NO and also sensitizing sGC to low levels of NO by stabilizing NO-sGC binding. In contrast, sGC activators bind to the unoccupied heme-binding domain, thereby mimicking NO-bound heme and activating pathologically altered NO-unresponsive apo-sGC. Recent evidence indicates that oxidative stress, associated with many cardiopulmonary diseases, shifts intracellular levels of native sGC to the apo-sGC form (Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 2006;5:755-768; Munzel T, Genth-Zotz S, Hink U. Targeting heme-oxidized soluble guanylate cyclase: solution for all cardiorenal problems in heart failure? Hypertension 2007;49:974-976), providing a rationale for sGC activators in various cardiovascular pathophysiological conditions, e.g., PH (Wood KC, Durgin BG, Schmidt HM, Hahn SA, Baust JJ, Bachman T,Vitturi DA,Ghosh S,Ofori-Acquah SF,Mora AL,Gladwin MT,Straub AC.Smooth muscle cytochrome b5 reductase 3 deficiency accelerates pulmonary hypertension development in sickle cell mice.Blood Adv 2019;3:4104-4116.、Rahaman MM,Nguyen AT,Miller MP,Hahn SA,Sparacino-Watkins C,Jobbagy S,Carew NT,Cantu-Medellin N,Wood KC,Baty CJ,Schopfer FJ,Kelley EE,Gladwin MT,Martin E,Straub AC.Cytochrome b5 Reductase 3 Modulates Soluble Guanylate Cyclase Redox State and cGMP Signaling.Circ Res 2017;121:137-148.、Durgin BG,Hahn SA,Schmidt HM,Miller MP,Hafeez N,Mathar I,Freitag D,Sandner P,Straub AC.Loss of smooth muscle CYB5R3 amplifies angiotensin II-induced hypertension by increasing sGC heme oxidation.JCI Insight 2019;4:e129183.、Sandner P,Zimmer DP,Milne GT,Follmann M,Hobbs A,Stasch JP.Soluble guanylate cyclase stimulators and activators.Handb Exp Pharmacol 2019;doi:10.1007 / 164_2018_197)。.

[0338] In the context of the present invention, the term "pulmonary hypertension" encompasses both its primary and secondary sub-forms, which are defined below according to their respective etiology by the Dana Point / Nizza classification [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; MM Hoeper et al., J. Am. Coll. Cardiol. 2009, 54(1), S85-S96] updated Nizza classification Gerald Simonneau, David Montani, David S. Celermajer, Christopher P. Denton, Michael A. Gatzoulis, Michael Krowka, Paul G. Williams, Rogerio Souza: Haemodynamic definitions and updated clinical classification of pulmonary hypertension, in:European Respiratory Journal,2018;DOI:10.1183 / 13993003.01913-2018]. These include, in particular, group 1 pulmonary arterial hypertension (PAH), which includes, inter alia, idiopathic and familial forms (IPAH and FPAH, respectively). In addition, PAH also includes persistent pulmonary hypertension of the newborn, as well as pulmonary arterial hypertension (APAH) associated with collagen disease, congenital systemic arteriopulmonary anastomosis lesions, portal hypertension, HIV infection, pulmonary arterial hypertension associated with the ingestion of certain drugs and medications (e.g., appetite suppressant ingestion), pulmonary arterial hypertension associated with disorders with a significant venous / capillary component, such as pulmonary veno-occlusive disorder and pulmonary capillary hemangiomatosis, or pulmonary arterial hypertension associated with other disorders, such as thyroid disorders, glycogen storage disease, Gaucher disease, hereditary telangiectasias, hemoglobinopathies, myeloproliferative disorders, and splenectomy.Group 2 includes PH patients with underlying left heart disorders, e.g. ventricular, atrial or valvular disorders. Group 3 includes forms of pulmonary hypertension associated with pulmonary disorders, e.g. chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary fibrosis (IPF) and / or hypoxemia (e.g. sleep apnea syndrome, alveolar hypoventilation, chronic altitude sickness, genetic malformations). Group 4 includes PH patients with chronic thrombotic and / or embolic disorders, e.g. thromboembolic obstruction of the proximal and / or distal pulmonary arteries (CTEPH) or non-thrombotic embolism (e.g. as a result of tumor disorders, parasites, foreign bodies). Less common forms of pulmonary hypertension, e.g. in patients with sarcoidosis, histiocytosis X or lymphangiomatosis, are summarized in group 5.

[0339] The compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), are also suitable for the treatment and / or prevention of lung disorders, such as asthma, chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis.

[0340] In the context of the present invention, the term "asthma" encompasses heterogeneous chronic inflammatory diseases of the airways of the lungs. Asthma is characterized by variable and recurrent symptoms ranging from reversible airflow obstruction to bronchospasm, often caused by bronchial hyperresponsiveness. Symptoms include episodes of wheezing, coughing, chest tightness and shortness of breath. These may occur several times a day or several times a week. In some people, asthma symptoms may worsen at night or with exercise. Asthma is thought to be caused by a combination of genetic and environmental factors. Environmental factors include exposure to air pollution and allergens. Other potential triggers include medications, such as aspirin and beta-blockers. Diagnosis is usually based on the pattern of symptoms, response to therapy over time, and spirometry lung function tests. Asthma is classified according to the frequency of symptoms, forced expiratory volume in 1 second (FEV1) and peak expiratory flow rate. Asthma may also be classified as atopic or non-atopic, with atopic referring to a predisposition to developing type 1 hypersensitivity reactions. There is no known cure for asthma, and asthma is treatable systematically. Symptoms may be prevented by avoiding triggers, such as allergens and respiratory irritants, and may be suppressed with the use of inhaled corticosteroids. If asthma symptoms remain uncontrolled, long-acting beta agonists (LABAs) and other substances, such as anti-leukotrienes, may be used in addition to inhaled corticosteroids. Treatment of acute exacerbation symptoms is usually performed with inhaled short-acting beta 2 agonists, such as salbutamol, and corticosteroids. In severe cases, systemic corticosteroids, magnesium sulfate, and hospitalization may be required. A subset of asthma patients develop severe forms of the disease, the pathogenesis of which involves airway inflammation with intrinsic drivers that remain undetermined. To address this, we studied human airway smooth muscle cells (HASMCs), whose relaxation drives airway bronchiectasis and whose dysfunction contributes to airway obstruction and hyperresponsiveness in severe asthma. Because HASMC relaxation can be driven by the NO-soluble guanylyl cyclase (sGC)-cGMP signaling pathway, HASMCs from severe asthma donors may have inherent defects in sGC or in oxidoreductases that support sGC function in severe asthma donors.The majority of severe asthma donor HASMCs (12 / 17) and lung samples predominantly expressed dysfunctional sGC, which was NO-unresponsive, had low heterodimer content, and high Hsp90 association. This sGC phenotype correlated with lower expression levels of the supporting oxidoreductases cytochrome b5 reductase, catalase, and thioredoxin 1, and higher expression of heme oxygenases 1 and 2, suggesting the hypothesis that severe asthma patients are predisposed to defective NO-sGC-cGMP signaling in their airway smooth muscle due to intrinsic sGC dysfunction, which in turn is associated with intrinsic changes in cellular oxidoreductases that affect sGC maturation and function.Therefore, sGC activators may be a new target option for these patients with regard to optimized bronchodilation under these pathophysiological conditions (see, for example, the following references: Arnab Ghosh, Cynthia J. Koziol-White, William F. Jester Jr., Serpil C. Erzurum, Kewal Asosingh, Reynold A. Panettieri Jr., Dennis J. Stuehr: An inherent dysfunction in soluble guanylyl cyclase is present in the airway of severe asthmatics and is associated with aberrant redox enzyme expression and compromised NO-cGMP signaling in Redox Biology 39(2021)101832, Maggie Lam, Jane E. Bourke, Ph.D., A New Pathway to Airway Relaxation: Targeting the “Other” Cyclase in Asthma American Journal of Respiratory Cell and Molecular Biology Volume 62 Number 1|January 2020, Cynthia J. Koziol-White, Arnab Ghosh, Peter Sandner, Serpil E. Erzurum, Dennis J. Stuehr, and Reynold A. Panettieri, Jr.: Soluble Guanylate Cyclase Agonists Induce Bronchodilation in Human Small Airways, Am J Respir Cell Mol Biol Vol 62, Iss 1, pp 43-48, Jan 2020.).

[0341] Due to the activity profile of the compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), are particularly suitable for the treatment and / or prevention of vascular and cardiopulmonary disorders, such as primary and secondary forms of pulmonary hypertension.

[0342] The present invention further provides the use of the compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), for the treatment and / or prevention of disorders, in particular cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0343] The present invention further provides the use of the compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, and its pseudopolymorphic forms, such as (IMI) and (IM-II), for the preparation of a medicament for the treatment and / or prevention of disorders, in particular cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0344] The present invention further provides a medicament comprising at least one of the compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, and its pseudopolymorphic forms, such as (IMI) and (IM-II), for use in the treatment and / or prevention of disorders, in particular cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0345] The present invention further provides the use of the compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, and its pseudopolymorphic forms, such as (IMI) and (IM-II), in a method for the treatment and / or prevention of disorders, in particular cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0346] The present invention relates to a method for the treatment and / or prevention of disorders, in particular cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung disease (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP), comprising administering to a patient in need thereof a compound of formula I (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}- Further provided is a method comprising administering 5,6,7,8-tetrahydroquinoline-2-carboxylic acid, in particular Comparative Example 11, as well as its pseudopolymorphic forms, e.g., (IMI) and (IM-II), in an inhalable dosage form in the form of a dry powder formulation, e.g., a dry powder inhaler, for 2 or more consecutive days, preferably over a period of at least 2-7 consecutive days, preferably over a period of at least 14 consecutive days, in particular once or twice daily from the start of treatment throughout the entire course of the disease, wherein the sGC activator has sustained efficacy over a 24 hour period when administered by inhalation to a patient in need thereof.

[0347] The present invention relates to a sGC activator of formula I, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}}

[0023] It further relates to the use of an inhaled dosage form of sGC activator, such as sGC activator 1,2,3,4,5-trimethylphenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, as well as pseudopolymorphic forms thereof, such as (IMI) and (IM-II), wherein the inhaled dosage form is administered for a period of 2 or more days, preferably at least 2-7 consecutive days, preferably at least 14 consecutive days, in particular once or twice daily from the start of treatment throughout the entire course of the disease, wherein the sGC activator has a sustained efficacy over a 24 hour period when administered by inhalation to a patient in need thereof.

[0348] The present invention relates to a packaged pharmaceutical composition comprising a dry powder inhaler (=DPI) and a container housing a pharmaceutical formulation comprising (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, and pseudopolymorphic forms thereof, such as (IMI) and (IM-II), wherein the container contains instructions for use of the dry powder, such as instructions for inhaling the dry powder for about 2 seconds after a single deep inhalation. The present invention further relates to a packaged pharmaceutical composition, further comprising instructions for administering the dry powder drug to a patient in need of breath-holding, whereby the dry powder drug condenses from the airstream onto the surface of the deeper lung regions and deposits near its intended site of pharmacological action to treat cardiopulmonary disorders, preferably pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung disease (Class 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0349] In a preferred embodiment, the present invention provides a packaged pharmaceutical composition comprising a dry powder inhaler (=DPI) and a container housing a pharmaceutical formulation comprising (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, and pseudopolymorphic forms thereof, such as (IMI) and (IM-II), wherein the packaged pharmaceutical composition is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, The present invention further relates to a packaged pharmaceutical composition comprising a container housing a dry powder comprising {biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, the container further housing instructions for administering the dry powder once or twice daily to treat a cardiopulmonary disorder, preferably pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung disease (Class 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP), as well as a pulmonary disorder.

[0350] The present invention further relates to medicaments containing at least one compound according to the invention, usually together with one or more inert, non-toxic, pharma- ceutically suitable excipients, and to their use for the abovementioned purposes.

[0351] The compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), may be used alone or, if necessary, in combination with other active compounds. The present invention further relates to medicaments containing at least one of the compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), and one or more further active compounds, in particular for the treatment and / or prevention of the above-mentioned diseases. As suitable combined active compounds, the inventors consider, for example, preferably organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO; Ca channel blockers, used in PAH patients with preserved vascular responsiveness, compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterase (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 3 inhibitors, such as ensifentrine, PDE 4 inhibitors, such as roflumilast, tanimilast or levamilast, and PDE 5 inhibitors, such as sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, mirodenafil or lodenafil, NO-independent heme-dependent stimulators of guanylate cyclase, in particular riociguat and the compounds described in WO00 / 06568, WO00 / 06569, WO02 / 42301, WO03 / 095451, WO2011 / 147809, WO2012 / 004258, WO2012 / 028647, WO2012 / 059549 and WO2014 / 068099, - prostacyclin analogues and IP receptor agonists, such as, preferably, iloprost, beraprost, treprostinil, epoprostenol or NS-304; - endothelin receptor antagonists, for example, preferably bosentan, darusentan, ambrisentan or sitaxsentan, human neutrophil elastase (HNE) inhibitors, such as, preferably, sivelestat or DX-890 (Reltran); compounds that inhibit signal transduction cascades, in particular from the group of tyrosine kinase inhibitors, such as, preferably, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib, masitinib or tanzutinib, - Compounds that act as ligand traps with high selectivity for multiple proteins in the TGF-beta superfamily, including activins, GDFs, and others that are believed to have the ability to block TGF-beta superfamily signaling pathways and thereby promote rebalancing of bone morphogenetic protein receptor type II (BMPR-II) signaling and potentially restore vascular homeostasis, such as sotatercept, Rho kinase inhibitors, for example and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049, anti-obstructive agents, such as those used for the therapy of chronic obstructive pulmonary disease (COPD) or bronchial asthma, for example, preferably inhaled or systemically administered beta-receptor mimetics (e.g. salbutamol, salmeterol) or inhaled antimuscarinic agents (e.g. ipratropium, tiotropium); anti-inflammatory and / or immunosuppressive agents, such as those used for the therapy of chronic obstructive pulmonary disease (COPD), bronchial asthma or pulmonary fibrosis, such as, preferably, systemic or inhaled corticosteroids, flutiform, pirfenidone, acetylcysteine, azathioprine or BIBF-1120, nintedanib, or treprostinil; active compounds used for the systemic and / or inhaled treatment of lung disorders, such as, for example, for cystic fibrosis (alpha 1 antitrypsin, aztreonam, ivacaftor, lumacaftor, ataluren, amikacin, levofloxacin), for chronic obstructive pulmonary disease (COPD) (tiotropium, LABA / LAMA, LAS40464, PT003, SUN-101), for acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) (interferon beta-1a, traumakin, PEG-adrenomedullin, inhaled sGC modulators, e.g. BAY1211163), for obstructive sleep apnea (VI-0521, TASK channel blockers and ADRA2C antagonists), for bronchiectasis (mannitol, ciprofloxacin), for bronchiolitis obliterans (cyclosporine, aztreonam); Antithrombotic agents, for example preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances Examples include:

[0352] Antithrombotic agents are preferably understood as compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.

[0353] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.

[0354] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, for example and preferably, ximelagatran, melagatran, dabigatran, bivalirudin or Clexane.

[0355] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, for example and preferably, tirofiban or abciximab.

[0356] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a factor Xa inhibitor, such as, for example and preferably, rivaroxaban, apixaban, fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

[0357] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

[0358] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as, for example and preferably, coumarin.

[0359] Agents for lowering pulmonary blood pressure are preferably understood as compounds from the group of calcium antagonists, PDE5 inhibitors, sGC stimulators and activators, prostacyclin analogues and IP receptor agonists, and endothelin receptor antagonists.

[0360] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and preferably, nifedipine, amlodipine, verapamil or diltiazem.

[0361] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin receptor antagonist, such as, for example and preferably, bosentan, darusentan, asentan or sitaxsentan.

[0362] Detailed Description of the Invention Formulations for inhalation The present invention further relates to medicaments containing at least one crystalline form of the compound of formula (I) according to the invention, preferably the monohydrate I of formula (IMI) or the monohydrate II of formula (IM-II), particularly preferably the monohydrate I of formula (IMI), usually together with one or more inert, non-toxic, pharma- ceutically suitable excipients, and their use for the abovementioned purposes.

[0363] A preferred embodiment of the present invention is a pharmaceutical composition comprising mainly the monohydrate I of the compound of formula (I), without a significant fraction of other forms of the compound of formula (I), and optionally further pharma- ceutically acceptable excipients. More preferably, the pharmaceutical composition contains more than 85% by weight, more preferably more than 90% by weight, and most preferably more than 95% by weight of the monohydrate I of the compound of formula (I) relative to the total amount of all forms of the compound of formula (I) present in the composition.

[0364] active ingredient The solid preparations according to the invention for dry powder inhalation contain an amount of about 20% or less of the active ingredient (i.e. (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, preferably (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the form of the monohydrate I of formula (IMI) or the monohydrate I of formula (IMI) (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the form of monohydrate II of formula I), particularly preferably (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid) in the form of monohydrate I of formula (IMI), is contained in a matrix of a suitable inhalation grade carrier for the active compound. Usually, the amount of active ingredient is 0.5% to 20%, preferably 0.75% to 10%. The amount of active ingredient in the matrix is ​​usually at least 0.75% by weight, or at least 3% by weight, or at least 5% by weight, or at least 10% by weight, based on the ready-to-use preparation. Amounts of active ingredient of 3%, 10% or 20% are highly preferred.

[0365] The solid preparation according to the invention for dry powder inhalation comprises the active ingredient (i.e. (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, preferably (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the form of the monohydrate I of formula (IMI) or the compound of formula (I M-II) in the form of monohydrate II, particularly preferably (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid), in the form of monohydrate I of formula (IMI), in a certain particle size suitable for inhalation application.

[0366] The active ingredient according to the invention is ((5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, preferably (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the form of monohydrate I of formula (IMI) or monohydrate I of formula (IM-II). The particle size distribution for (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the form I, particularly preferably (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid) in the form of the monohydrate I of formula (IMI) is defined in the following table.

[0367] Table 1. Particle size distribution of active ingredients, e.g., compounds of formula (IMI) or (IM-II) TIFF2025502842000050.tif21157

[0368] For inhaled drug products, it is important to guarantee a homogeneous drug substance with a defined particle size of less than 5 μm to ensure delivery to the deep lung compartment. This technical requirement can be achieved by micronization of the drug substance particles (see Experimental Section B, Example 8).

[0369] The appropriate specifications for particle size distribution of the active ingredient to achieve this requirement have been established as specified in Table 1.

[0370] Therefore, in order to ensure suitable delivery of the active substance at the target sites, in particular in the deep airways and alveoli, the inventors have developed a method for the preparation of the active ingredient of formula I, (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, preferably in the form of monohydrate I of formula (IMI) or monohydrate I of formula (IM-II). It has been found that it is important to provide the (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the form of hydrate II, preferably in the form of monohydrate I of formula (IMI), in a particle size of X90 of 6 μm and / or X50 of 1-3 μm and / or X10 of maximum 1 μm.

[0371] Lactose Carrier The solid preparation according to the invention for dry powder inhalation generally contains a suitable carrier in an amount of about 99.25% or less for the active compound. Usually, the amount of inhalation grade carrier is 99.25%-80%, preferably 99.25%-90%. The amount of carrier in the solid preparation is usually at least 99.25% by weight or at least 97% by weight or at least 95% by weight or at least 90% by weight, based on the dry powder blend.

[0372] A variety of inhalation grade carrier materials are available.

[0373] The inventors have found that superior aerosol performance of formulations for inhalation according to the invention is achieved by selecting lactose as the carrier material.

[0374] Lactose for inhalation is available in different particle size ranges and with different characteristics.

[0375] It is expected that coarse lactose carrier alone, with a particle size distribution centered on a higher particle size compared to the active ingredient, may result in poor aerosol performance due to the relatively strong binding of fine drug particles to the active sites of the coarse carrier particles (Paolo Colombo, Daniela Traini and Francesca Buttini “Inhalation Drug Delivery-Techniques and Products” (published by Wiley-Blackwell 2013). Advanced aerosol performance is characterized by an increased fine particle dose and fraction, as well as an increased delivered dose with respect to the nominal dose. This is expected by the equilibrium between the adhesion of the drug to the carrier and the subsequent separation of the drug from the carrier when the powder is aerosolized, which is often also described as powder or drug dispersion. It can also be expected that the aerosol performance behavior will improve with the addition of fine carrier particles or by the use of lactose materials that contain an inherent fine lactose fraction, although the degree is not predictable (de Boer et al 2012, Grasmejier et al 2013). 2015). As an indication of improved drug dispersion and release from the carrier, cascade impactor measurements are the established method of choice for fine particle dose (alternatively, fine particle mass) and fine particle fraction (the percentage fraction of drug mass with a defined particle size limit, e.g., 5 μm or 4.5 μm, relative to the delivered or nominal dose of a single dosage unit). These methods are also established as mandatory quality control methods for inhaled products in current pharmacopoeias (e.g., Pharm Eur. or USP).

[0376] However, the potential effect and its extent of the addition of fine lactose is not predictable since there may be other major effects within the dry powder adhesive mixture that overlap with the fine lactose effect. Very importantly, the properties of the micronized drug itself may have an effect on the adhesive and cohesive properties (e.g., cohesive:adhesive balance (CAB) or surface energy) of binary or ternary mixtures of particles of a particular drug molecule, making predictions even more difficult.

[0377] The inventors have found that the excellent aerosol performance of the formulation for inhalation according to the invention is achieved by selecting fine lactose and coarse lactose as carrier materials having specific particle sizes.

[0378] A coarse lactose material according to the present invention is sieved or milled crystalline alpha-lactose monohydrate having a low fines content (e.g. commercially available as Lactohale® 100 or Lactohale® 206).

[0379] Coarse lactose according to the invention with a similar particle size distribution may also be selected from other brands, such as Meggle Inhalac® 120 or DFE Respitose® SV010.

[0380] To select the main coarse carrier, a lactose quality with a particle size at least 10 times larger than the X90 of the active ingredient and a low inherent fines content was selected to allow for consistent quality of the majority of the carriers.

[0381] Fine lactose was selected to improve aerosol performance. We assumed that a particle size similar to that of the active ingredient may be suitable to control the temporary binding of the active ingredient particles to the coarse carrier particles, but also other fine lactose particle size specifications were potentially suitable. Therefore, the selection of fine lactose products with particle sizes of X90 less than 10 μm, or X90 less than 30 μm, or X50 less than 5 μm or 1.0-3.0 μm, was considered appropriate to constitute the lactose carrier.

[0382] The fine lactose material according to the invention is milled or micronized crystalline a-lactose monohydrate ("fine lactose") having a low particle size of X90 below 10 μm (e.g. commercially available as Lactohale® 300), or X90 below 30 μm, or X50 below 5 μm or between 1.0 and 3.0 μm (e.g. commercially available as Lactohale® 230). Milled or micronized fine lactose with similar characteristics and particle size may also be selected from, for example, Meggle Inhalac® 500. The particle size distribution of materials and powder mixtures is usually measured by laser diffraction spectroscopy, microscopic techniques, or traditional sieve analysis and classification [BY Shekunov, P. Chattopadhyay, HHY Tong and AHL Chow, Particle size analysis in pharmaceutics, Pharm. Res. 2007, 24(2), S203-S227] (see also D.4).

[0383] The particle size distribution for commercially available lactose for inhalation quality according to the invention (eg, Lactohale® 100, Lactohale® 300) is summarized in Table 2 below.

[0384] Table 2: Particle size distribution (specifications) for lactose for inhalation according to the invention TIFF2025502842000051.tif85140

[0385] The solid preparation according to the invention for dry powder inhalation contains a mixture of crude lactose.

[0386] The inventors have found that the coarse lactose particle size can be varied over a certain range without compromising the aerosol performance or blend uniformity of the carrier-based formulation according to the invention.

[0387] According to the invention, the crude lactose has an X90 particle size of 200-250 μm or 120-160 μm or 115-170 μm or 115-250 μm. Furthermore, according to the invention, the crude lactose has an X90 particle size of 250 μm or less or 170 μm or less or 160 μm or less. Furthermore, according to the invention, the crude lactose has an X90 particle size of at least 115 μm or at least 120 μm or at least 200 μm.

[0388] According to the invention, the crude lactose has a particle size X50 of 125-145 μm or 50-100 μm or 75-95 μm or 50-145 μm. Furthermore, according to the invention, the crude lactose has a particle size X50 of 145 μm or less or 100 μm or less or 95 μm or less. Furthermore, according to the invention, the crude lactose has a particle size X50 of at least 50 μm or at least 75 μm or at least 125 μm and / or a particle size X10 of 45-65 μm or 5-15 μm or 20-50 μm.

[0389] According to the present invention, the fine lactose has a particle size of X90 less than 10 μm or less than 30 μm, and X50 less than 5 μm or 1.0-3.0 μm. By using Lactohale 200® with its inherent fine particle content, it is not necessary to add any additional fine lactose particles to the lactose carrier. Thus, the carrier-based formulation can be formulated with Lactohale 200® or similar lactose products with inherent fine lactose content.

[0390] According to the invention, Lactohale 100® and Lactohale 300® are preferred.

[0391] Furthermore, the inventors have found that excellent aerosol performance of the formulation for inhalation according to the invention is achieved by adjusting the specific content of fine lactose and the specific content of coarse lactose in the dry powder blend.

[0392] The inventors have identified the fine lactose content of the lactose carrier as an important parameter. In order to obtain a formulation for inhalation according to the invention characterized by good aerosol performance, the content of fine lactose should be selected within a certain range. For example, it has been found that a higher content of fine lactose in the powder blend / lactose carrier, for example a content of 20% or more, has a negative impact on blend uniformity (see, for example, Comparative Example 20). It has been shown that the powder blend and formulation according to the invention can have various contents of fine lactose in the range of 1% to 10%, also 5% to 10%, and the fine lactose content can also be the intrinsic part of lactose for inhalation, i.e., the part calculated as X10 of 5 to 15 μm in the case of Lactohale 2000® (see embodiment 34), without impairing the aerosol performance.

[0393] According to the present invention, the content of fine lactose in the powder blend is 1%-10%, preferably 5%-10%, preferably 2.5%-7.5%, preferably 5%-7.5%, more preferably 5%.

[0394] The inventors have also identified the crude lactose content of the powder blend as an important parameter: in order to obtain a formulation for inhalation according to the invention characterized by good aerosol performance, the crude lactose content should be selected within a certain range.

[0395] According to the present invention, the content of crude lactose in the powder blend is 98.25% to 75%, preferably 94.25% to 75%, preferably 92.00% to 75%, more preferably 90.00% to 75%, particularly preferably 90% to 85%.

[0396] The dry powder blend according to the present invention is a ternary mixture, therefore all three components must be provided in a defined maximum particle size form and in a certain ratio.

[0397] The inventors have found that superior aerosol performance of formulations for inhalation according to the invention is achieved by selecting particular ratios of fine and coarse lactose and active ingredient.

[0398] According to the invention the ratio of coarse to fine lactose in the powder blend is between 445:5 and 65:5, preferably between 94.25:5 and 65:5, preferably between 94.25:5 and 75:5, 91.75:7.5 and 89.25:10, preferably between 92:5 and 75:5, with ratios of 92:5, 85:5 and 75:5 being particularly preferred.

[0399] According to the invention, the ratio of active ingredient of formula (I) or (IMI) to crude lactose in the powder blend is from 1:126 to 1:3.8, preferably from 1:31 to 1:3.8.

[0400] According to the invention, the ratio of active ingredient of formula (I) or (IMI) to finely divided lactose in the powder blend is from 1:13 to 1:0.1, preferably from 1:13 to 1:0.25, preferably from 1:1.67 to 1:0.25.

[0401] Further excipients The preparations according to the invention can generally contain further pharmacologically acceptable excipients, which include, inter alia, carriers (e.g., inhalation grade lactose, lactose monohydrate, mannitol), dispersants, wetting agents, lubricants (e.g., magnesium stearate), surface active compounds (e.g., sodium lauryl sulfate, distearoylphosphatidylcholine), ionic compounds (e.g., calcium chloride, sodium chloride, potassium chloride), synthetic and natural polymers (e.g., carrageenan, hydroxypropylmethylcellulose, gelatin) or pH adjusters (e.g., sodium hydroxide, sodium chloride, citrate salts, trisodium citrate), colorants (e.g., inorganic pigments, e.g., iron or titanium oxide).

[0402] cavity According to the present invention, the dry powder blend comprising the active ingredient in the form of monohydrate form IMI or IM-II and lactose can be administered via a dry powder inhaler, such as a single unit dose inhaler, where each dose is loaded into the device before use, a multiple unit dose inhaler, where several single doses are individually sealed (pre-metered) and can be discharged into the dosing chamber before each actuation, or a reservoir multiple unit dose inhaler, where a bulk supply of drug is pre-loaded into the device and discharged (metered by the device) into the dosing chamber before each actuation. Preferably, the dry powder blend according to the present invention is administered via a single unit dose inhaler equipped / loaded with a cavity, such as a capsule or blister, that contains the dry powder blend. Preferably, the cavity is an individual capsule, preferably a hard capsule of gelatin or hydroxypropylmethylcellulose, most preferably a hydroxypropylmethylcellulose capsule.

[0403] The dry powder blends containing the active ingredient, for example the micronized monohydrate I of formula (IMI) or monohydrate II of formula (IM-II) according to example 2 or 4, are filled into hard capsules (hydroxypropylmethylcellulose = hypromellose = HPMC, for example size 3) or alternative capsules made of hard gelatin or other suitable materials. The sizes of pharmaceutical hard capsules are standardized and characterized by defined measures, for example a size 3 capsule has a length of 157 mm and a diameter of 57 mm, a size 2 capsule has a length of 176 mm and a diameter of 62 mm, and a size 1 capsule has a length of 194 mm and a diameter of 68 mm.

[0404] Depending on the fill weight and active ingredient concentration, different nominal doses can be achieved. Exemplary compositions for capsules having different nominal doses of active ingredient, for example, monohydrate I of formula (IMI) or monohydrate II of formula (IM-II) according to Examples 2 or 4, are described in exemplary embodiments 1-3 and shown in Table 3 below.

[0405] Table 3: Examples of formulations according to the invention with defined nominal doses (powder filled in hard capsules) TIFF2025502842000052.tif39156

[0406] In pulmonary administration, the amount (nominal dose) of the active ingredient (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, preferably (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate I (see Example 4) is about 10 μg to 50,000 μg per inhalation, preferably about 100 μg to 10,000 μg per inhalation, more preferably about 100 to 600 μg per inhalation. 0 μg, more preferably about 120 to 4000 μg per inhalation, even more preferably about 200 to 4000 μg per inhalation, very particularly preferably about 240 μg to 4000 μg, very particularly preferably about 240 μg to 2000 μg, very particularly preferably about 240 μg to 1000 μg, very particularly preferably about 240 μg to 480 μg, very particularly preferably about 480 μg to 4000 μg, very particularly preferably about 480 μg to 2000 μg, very particularly preferably about 480 μg to 1000 μg, very particularly preferably about 1000 μg to 4000 μg, very particularly preferably about 1000 μg to 2000 μg, very particularly preferably about 1000 μg, very particularly preferably about 2000 μg, very particularly preferably about 4000 μg.

[0407] The hollow, preferably hard capsule, very preferably size 3 HMPC-based hard capsule according to the invention contains a formulation for inhalation with a fill mass of 8 to 40 mg, preferably a formulation for inhalation with a fill mass of 10 to 30 mg, more preferably a formulation for inhalation with a fill mass of 10 to 20 mg, more preferably a formulation for inhalation with a fill mass of 16 to 20 mg.

[0408] According to the present invention, the following compositions are most preferred:

[0409] Table 4: Final capsule formulation according to the present invention containing dry powder blends, percentage basis TIFF2025502842000053.tif90162

[0410] According to the present invention, a powder blend having a content of 3% of the active ingredient of formula (I) or (IMI) in the powder blend may be filled into a hard capsule, preferably a size 3 HMPC capsule, as a powder blend with a mass of 16 mg, containing 480 μg of the active ingredient of formula (I) or (IMI), 92% coarse lactose and 5% fine lactose, which may then be administered via a "single unit dose" inhaler, for example, preferably a Plastiape (Berry) RS01 low resistance device.

[0411] According to the present invention, a powder blend having a content of 10% of the active ingredient of formula (I) or (IMI) in the powder blend, containing 1000 μg, 2000 μg, 3000 μg or 4000 μg of the active ingredient of formula (I) or (IMI), 85% coarse lactose and 5% fine lactose, can be filled (as a corresponding mass of powder blend of 10 mg, 20 mg, 30 mg or 40 mg) into a hard capsule, preferably a size 3 HMPC capsule, which can then be administered via a "single unit dose" inhaler, for example, preferably a Plastiape (Berry) RS01 low resistance device.

[0412] According to the present invention, a powder blend having a content of 20% of the active ingredient of formula (I) or (IMI) in the powder blend, containing 2000 μg, 3000 μg or 4000 μg of the active ingredient of formula (I) or (IMI), 75% coarse lactose and 5% fine lactose, can be filled (as a corresponding mass of powder blend of 10 mg, 15 mg or 20 mg) into a hard capsule, preferably a size 3 HMPC capsule, which can then be administered via a "single unit dose" inhaler, for example, preferably a Plastiape (Berry) RS01 low resistance device.

[0413] Table 5. Final capsule formulations according to the invention containing dry powder blends, percentage-based characterization TIFF2025502842000054.tif96160

[0414] According to the present invention, a powder blend having an active ingredient of formula (I) or (IMI) content of 30 mg / g in the powder blend, containing 480 μg of active ingredient of formula (I) or (IMI), 14.72 mg of coarse lactose, and 0.8 mg of fine lactose, can be filled into a hard capsule, preferably a size 3 HMPC capsule, as a powder blend with a corresponding mass of 16 mg, which can then be administered via a "single unit dose" inhaler, such as, preferably, a Plastiape (Berry) RS01 low resistance device.

[0415] According to the invention, a powder blend having a content of 100 mg / g of active ingredient of formula (I) or (IMI) in the powder blend, containing 1000 μg, 2000 μg, 3000 μg or 4000 μg of active ingredient of formula (I) or (IMI), 8.9 mg, 8.75 mg, 8.5 mg, 17.0 mg, 25.5 mg or 34.0 mg of coarse lactose and 0.1 mg, 0.25 mg, 0.5 mg, 1.0 mg, 1.5 mg or 2.0 mg of fine lactose, can be filled (for a corresponding mass of powder blend of 10 mg, 20 mg, 30 mg or 40 mg) into a hard capsule, preferably a size 3 HMPC capsule, which can then be administered via a "single unit dose" inhaler, such as, preferably, a Plastiape (Berry) RS01 low resistance device.

[0416] According to the present invention, a powder blend having a content of 200 mg / g of active ingredient of formula (I) or (IMI) in the powder blend, containing 2000 μg, 3000 μg or 4000 μg of active ingredient of formula (I) or (IMI), 7.5 mg, 11.25 mg or 15.0 mg of coarse lactose and 0.5 mg, 0.75 mg or 1.0 mg of fine lactose, can be filled (for a corresponding mass of powder blend of 10 mg, 15 mg or 20 mg) into a hard capsule, preferably a size 3 HMPC capsule, which can then be administered via a "single unit dose" inhaler, such as, preferably, a Plastiape (Berry) RS01 low resistance device.

[0417] Manufacturing Process The preparations according to the invention may generally be produced by micronising the active ingredient and, optionally, blending the micronised active ingredient with an inert carrier compound, as is customary in the manufacture of inhalable free-flowing medicaments in powder form.

[0418] The compounds according to the present invention can be converted into the dosage forms described. This can be done by mixing with inert non-toxic pharma- ceutically suitable excipients in a manner known per se. The dry powder formulation and the final product (dry powder blend filled hard capsule) are produced according to the following flow chart and description.

[0419] (Table 6) TIFF2025502842000055.tif197150

[0420] Step 1: The fine lactose portion was weighed and layered between the two layers of coarse lactose before mixing began.

[0421] Step 2: Mixing of the lactose preblend was carried out in a tumble mixer for 20 minutes at 72 rpm, 67 rpm or 34 rpm or 32 rpm or 30 rpm, preferably 32 rpm, for two cycles. The lactose preblend was sieved through a 500 μg sieve between cycles.

[0422] Step 3: The active ingredient, micronized monohydrate I or II, Example 2 or 4, was sieved through a 500 μm sieve and added to the pre-blended lactose. Prior to the start of the mixing cycle, the lactose pre-blend and active ingredient were layered alternately with six layers of lactose pre-blend and five layers of active ingredient (monohydrate I or II, Example 2 or 4) in between.

[0423] Step 4: The components were mixed in cycles, for example 3-5 cycles, preferably 3 cycles, in a tumble mixer, for example a glass or stainless steel tumble mixer, preferably a stainless steel tumble mixer. Each cycle was carried out at 72 rpm, 67 rpm, 34 rpm or 32 rpm, preferably 32 rpm for 20-30 minutes, preferably 30 minutes (total mixing time of 90 minutes), preferably 30 minutes at 32 rpm, with a rest time of 10 minutes between mixing cycles. If necessary (e.g. visual agglomerates), the blend can be sieved between each blending cycle.

[0424] Step 5: The blend was allowed to stand in a stainless steel container at room temperature (15-25° C.) and 35-65% relative humidity for a specified period of time, preferably 24-72 hours, more preferably 48 hours.

[0425] Step 6: Using a capsule filler (eg, MG2 Flexalab), the blend was filled into capsules at the desired fill weight.

[0426] Inhalation Devices In the context of the present invention, the sGC activator, for example Example 2 or 4, is applied as a dry powder or a dry powder formulation by means of a dry powder inhalation device.

[0427] A preferred dry powder inhalation device within the context of the present invention is defined as a capsule-based single unit dose inhaler that is a pre-metered inhalation device (see Figs. 1a and 1b). In the context of the present invention, the dose is applied using the Plastiape (Berry) RS01 low resistance device. This device (in higher resistance type) has been disclosed and described in publications on the treatment of other patient populations, for example cystic fibrosis (CF) or non-CF bronchiectasis (ELKINS et al. Inspiratory Flows and Volumes in Subjects with Cystic Fibrosis Using a New Dry Powder Inhaler Device, The Open Respiratory Medicine Journal, 2014, 8, 1-7 and ELKINS et al. Inspiratory Flows and Volumes in Subjects with Non-CF Bronchiectasis Using a New Dry Powder Inhaler Device, The Open Respiratory Medicine Journal, 2014, 8, 8-13).

[0428] The inhaler operates by inserting a single capsule filled with the dry powder formulation into the device. Two buttons are pressed to puncture the capsule and the user places their mouth around the mouthpiece and inhales deeply and forcefully. The energy from the inhalation draws the drug formulation from the capsule and disperses the powder as an aerosol, and the active ingredient particles are liberated from the lactose carrier particles and carried into the airways. The used capsule is removed and discarded. The device may be reused depending on the patient's therapy requirements and the corresponding markings on the clinical device. The number of capsules administered determines the dose of drug therapy.

[0429] Other pre-metered dry powder inhalation devices, such as blister strip-based multiple unit dose devices, may also be used for the preferred application method and may provide equivalent results if the aerosol pathway has a similar design or characteristics (e.g., device resistance and pressure drop at a defined flow rate).

[0430] Also disclosed in the context of the present invention are devices that can have a receptacle for accommodating the preparations containing Example 1 or for incorporating these preparations in capsules or blisters and that are suitable for administering the preparations by inhalation in solid form, i.e. aerosolizers, with which the preparations containing the active ingredients, for example the monohydrates I or II, Examples 2 or 4, can be administered by inhalation in solid form (powder inhaler).

[0431] Human Dose Estimation The formulations according to the invention can be characterized in terms of delivered dose (DD) determined by the filter collection tube method and fine particle dose (FPD) determined by cascade impaction. Analytical methods for determining delivered dose and fine particle dose are generally described in the Pharmacopoeia as they are harmonised for inhalable dosage forms, e.g., dry powder inhalation formulations, and constitute regulations for the quality control of the release of DPI products for clinical use, e.g.

[0432] It has been found that different formulations with different nominal doses result in different delivered doses, and more importantly, result in a certain fine particle dose, which characterizes the effective dose as being delivered to the site of action in the deep lung.Theoretically, the delivered dose, as well as the fine particle dose and fraction, have a linear relationship in correlation with the loaded powder dose, but due to some interaction factors, this is not reliably predictable and may differ in practice, requiring related research.It is desirable that the delivered dose is as close as possible to the nominal dose.In practice, the delivered dose is not 100% consistent with the nominal dose, since residues always remain to some extent on the surface of the inhalation capsule and on the aerosol path of the dry powder inhaler used.Of course, this characteristic is highly dependent on the physicochemical properties of the active ingredient and its release behavior from the powder blend. Similarly, it is desirable for the fine particle dose and fine particle fraction to be as high as possible relative to the nominal active ingredient content packed in order to make the best possible use of the available drug amount and to reduce losses of active ingredient (e.g., by swallowing via oral impaction of larger drug particles) or to reduce the portion delivered to compartments other than the deep lung.

[0433] Due to the nature of inhalable formulations, not all of the nominal content is delivered into the lungs, in contrast to, for example, oral solid formulations.Several fractions can be defined and characterized by specific in vitro analytical methods to support the estimation of the dose fraction delivered to the patient during inhalation (delivered dose or emitted dose), as well as the fraction of fine particles expected to reach the deep airways and alveoli, for example, the fraction of fine particles less than 5 μm or 4.5 μm (the size cutoff in μm depends on the definition of FPD) (fine particle dose).For an overview, see the table below.

[0434] Table 7. Definitions of Dosage Terms for Inhaled Drug Products TIFF2025502842000056.tif173162

[0435] Assessment of pharmacokinetic / pharmacodynamic (PK / PD) relationships The anesthetized thromboxane A2-exposed PAH minipig model (see Experimental Section E-1) is considered to be the most relevant sensitivity model for prediction of human minimum effective and effective doses (MED, ED). To determine the effective LD, the experiment was repeated with the difference that an absorption filter was attached at the end of the tube to determine the deposited lung dose. The nebulization of Example 1 resulted in an average nebulization efficiency of 5% of the nominal applied dose, which resulted in LD of approximately 0.15 μg / kg (ND of 3 μg / kg), 0.5 μg / kg (ND of 10 μg / kg), 1.5 μg / kg (ND of 30 μg / kg) and 5 μg / kg (ND of 100 μg / kg). Assuming a minimum effective ND of 3 μg / kg (5% reduction in PAP), the minimum effective deposited LD is considered as 0.15 μg / kg.

[0436] The nominal doses of 3, 10, 30 and 100 μg / kg in the minipig model were multiplied by a filter deposition coefficient of 5% to yield lung deposited doses of 0.15, 0.5, 1.5 and 5 μg / kg in the minipig. These values ​​were multiplied by 60 kg to arrive at the lung dose in humans. The FPD reflecting PAP reduction for a 60 kg human is therefore calculated to be 9, 30, 90 and 300 μg.

[0437] Thus, via direct scale-up from minipigs, the predicted MED for humans (5% PAP reduction) based on a body weight of 60 kg is calculated to be an LDD of 9 μg, without considering protein binding in the airways. As an alternative to the unbound concentration, which is the likely active concentration in the lung, we considered the respective differences in the unbound fraction in plasma of minipigs and humans. This consideration results in a minimum effective lung dose (LD) for a 60 kg participant of an LDD of 41 μg for a 5% reduction in PAP. As a result, the predicted minimum human effective dose ranges from an LDD of 9 μg to an LDD of 41 μg, based on a body weight of 60 kg (see FIG. 3).

[0438] Table 8. Effective lung doses with and without consideration of species differences in protein binding TIFF2025502842000057.tif120156

[0439] This conversion was also made for the effective doses (effective PAP reduction of greater than 5 up to 35 percent over longer periods up to the full observation period of up to 4 hours) based on the relative lung-deposited doses in minipigs listed in Table 8.

[0440] Therefore, the effective lung-deposited dose in humans based on the minipig data was predicted to be in the range of 9 μg to 1370 μg.

[0441] Considering 100 μg / kg as the highest effective dose in the minipig model without systemic side effects (BP reduction), with the corresponding maximum effective human LDD of 1370 μg, a lung-deposited dose of 9 to 1370 μg is deduced as the effective dose, depending on different interspecies protein binding (see Table 7). For DPI products, the fine particle dose (FPD) is basically assumed to be equivalent to the human lung-deposited dose.

[0442] In order to address the need for a wide range of lung deposition doses and convert them into technical specifications for the fine particle dose (FPD target) of the dry powder inhalation capsules to be manufactured, several calculations and approximations were made. In general, inhalable products based on powder blend carrier formulations are considered to have excellent performance when a fine particle fraction of more than 20% of the nominal dose is achieved. Furthermore, a higher FPF(%) related to the delivered dose is desired for high-performance inhalation products. The FPF(%) was targeted to be 30% or higher. Taking into account technical and practical considerations (active concentration in the powder blend and capsule fill mass of the blend), the FPD target was then used to establish a defined nominal dose for the final dry powder inhalation capsule. The FPD and DD targets, as well as the corresponding nominal doses, are outlined in the following two tables 9 and 10.

[0443] Table 9. Nominal dose targets and targets for fine particle dose and % fraction (ds) TIFF2025502842000058.tif112159

[0444] There is no general binding (e.g., prescriptive) requirement for the relationship between delivered and nominal dose, since this is not definable due to the very different nature of different active ingredients with different properties and their manufactured pharmaceutical formulations. Rather, the uniformity of the delivered dose is defined by the Pharmacopoeia Act to ensure dose-to-dose consistency. The target delivered dose is an empirical parameter resulting from multiple determinations of a defined dosage form in a defined dry powder inhalation device under standardized conditions. The expected average delivered dose should be within 85-115% of the target DD. The minimum delivered dose requirement occupies the lower limit of 85% of the average delivered dose range. The target delivered dose percentage (50% or more to 65% or more of nominal) is defined for all nominal doses, which is not linear and must take into account, in particular, the relatively higher content of active ingredient adhesion on the capsule and device surfaces at lower nominal filled doses.

[0445] Table 10. Nominal doses, DD targets and associated minimum delivered doses TIFF2025502842000059.tif95163

[0446] Surprisingly, preclinical experiments revealed improved pulmonary selectivity and extended duration of action (prolonged selective pulmonary artery pressure (=PAP) reduction without systemic blood pressure (=BP) reducing effect after inhalation application) for the sGC activator of formula I, (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, as well as its pseudopolymorphic forms, e.g., (IMI) and (IM-II) (see E-1) in PAH animal models (see Experimental Section E-1). Furthermore, prediction of duration of action and prediction of human dose have been investigated. Considering 100 μg / kg as effective dose in minipig model, lung deposited doses of 300-1370 μg are deduced as effective doses depending on different interspecies protein binding considerations.

[0447] Finally, the pharmacological effects of different pseudopolymorphic forms of active ingredient have been investigated.All dry powder formulations, including the crystal form of Comparative Example 11, e.g., Example 6e, which is sesquihydrate, selectively and dose-dependently reduce PAP after inhalation application in this model of acute PAH, and have a long duration of action of at least 4 hours.A clear dose-response curve was observed for increasing applied doses (see E-1).

[0448] Furthermore, the inventors have demonstrated that the sGC activator (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, particularly in the form of its monohydrate II (Example 2), exhibits increased cGMP levels (indicating target association) as a second messenger molecule for sGC activation instead of drug concentration in the lungs and increased cGMP levels (indicating target association) for more than 12 hours up to 2 hours after dry powder application. We found beneficial bronchodilator properties in healthy volunteers over a 4-hour period, such as a decrease in total specific airway resistance (sRaw), a parameter indicating bronchodilator activity in the lung, which clinically supports the long lung residence time and supports the suitability of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, especially in its monohydrate II form (Example 2), for successful use in the treatment of cardiopulmonary disease. Up to a dose of 4000 μg, no clinically significant effect on systemic blood pressure was observed in healthy volunteers.

[0449] We also found a selective reduction in pulmonary artery pressure and pulmonary vascular resistance in patients with pulmonary hypertension at doses up to and including 4000 μg, without any clinically relevant effect on systemic blood pressure. This effect continued without a decrease in response until the end of the 3-hour measurement period (measurement periods longer than 3 hours were technically not feasible). A pulmonary residence time beyond the 3-hour measurement (presumably over a period of more than 12 hours and up to 24 hours after dry powder application) can be concluded from the long plasma half-life of Example 4 measured in this study (see Experimental Section E-2.4).

[0450] Additionally, analysis of plasma concentrations after oral, intravenous and inhalation administration of drug substance (Example 4) showed the longest half-life of the active ingredient after inhalation administration (E-2.3). The emitted (pulmonary) dose was determined to be 720 μg after inhalation of 1000 μg in humans. The results from this study confirm that the pulmonary dose and half-life are appropriate for inhalation dry powder administration, allowing once-daily treatment for sufficient 24-hour drug coverage of Example 4 in the lungs.

[0451] In conclusion, all the results show that (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms such as (IMI) and (IM-II), in particular the monohydrate I of formula (IMI), are particularly suitable for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP), and are suitable for inhaled dry powder administration allowing once-daily treatment for sufficient 24-hour drug coverage in the lungs of Example 4.

[0452] Additionally, the inventors have demonstrated that (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, particularly in the form of its monohydrate I (Example 4), exhibits beneficial physicochemical properties, such as protein binding and CACO flux (Experimental Parts E-3.1 (Caco Permeability) and E-3. It has been found that (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, particularly in the form of its monohydrate I (Example 4), is a suitable compound for the local treatment of cardiopulmonary diseases by dry powder inhalation into the lungs. Our data also show that (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, particularly in the form of its monohydrate I (Example 4) (IMI), not only exhibits an effective reduction in PAP via selective vasodilation in the lungs, but also longer-lasting bronchodilator properties compared to cinaciguat, which may be beneficial in once or twice daily inhalation treatment of PH patients with chronic lung disease (Class 3 PH) or may even have potential in the treatment of patients with limited lung function, e.g., asthma patients.

[0453] Thus, the drug substance according to the present invention, for example (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I) as well as its pseudopolymorphic forms (IMI) and (IM-II) have the following excellent main pharmacological properties: • (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid is a potent selective sGC activator and offers a new approach in the treatment of PH after inhalation. ●(5S)-{[2-(4-Carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid selectively reduced elevated PAP after inhalation application in different disease-relevant animal models (thromboxane- and hypoxia-exposed rats, pigs and dogs) and had a long duration of action, suggesting twice-daily application. In a unilaterally ventilated minipig model as a surrogate for VQ mismatch, inhaled application of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid reduced PAP without having a negative effect on oxygenation, in contrast to systemically applied vasodilators. In addition to PAH standard of care (SoC) (e.g., bosentan, sildenafil, ilomedin, and riociguat), (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid selectively reduced elevated PAP after inhalation application in a PAH minipig model. ●The efficacy of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid was enhanced under experimental conditions of oxidative stress (treatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one [ODQ], a highly selective irreversible heme site inhibitor of soluble guanylyl cyclase, and L-Nω-nitroarginine methyl ester [L-NAME]). With regard to ventilation, (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid showed bronchodilatory effects (acetylcholine [ACh] rat model) and inhibitory effects on airway hyperresponsiveness and inflammation (chronic ovalbumin asthma mouse model). The plasma concentrations of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, particularly in the form of its monohydrate I (Example 4), were measured after three types of administration (oral, intravenous, inhalation), revealing the longest elimination half-life after inhalation application. The emitted (pulmonary) dose has been determined to be 720 μg following inhalation of 1000 μg in humans. The first study in humans with the sGC activator (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the form of the crystalline modification monohydrate I of formula (IMI) (Example 4) showed activation of sGC and a long pulmonary residence time in combination with bronchodilator properties, as well as a selective reduction in pulmonary arterial pressure and pulmonary vascular resistance with good local and systemic tolerance up to the highest tested dose of 4000 μg (including 4000 μg).

[0454] Thus, the drug substances according to the invention, such as (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I), as well as its pseudopolymorphic forms (IMI) and (IM-II), have excellent key pharmacological and pharmacodynamic properties in patients, including reduction in pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR), bronchodilation, e.g. as measured by FEV1, pulmonary selectivity with low to no systemic adverse effects (in particular clinically relevant changes in systemic hemodynamic effects, e.g. clinically relevant changes in blood pressure or heart rate) and low to no increase in VQ mismatch to avoid associated desaturations, furthermore sufficient lung residence time and / or sufficient duration of action following intrapulmonary administration.

[0455] The pharmaceutical dry powder formulation according to the invention is therefore a suitable medicament for the treatment of cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0456] The weight data in the following tests and examples are percentages by weight and the parts are parts by weight, unless stated otherwise. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are in each case based on volume.

[0457] Specific embodiments of the present invention (pseudopolymorphic forms) Monohydrate I 1.Formula (IMI) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate modification I of TIFF2025502842000060.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound comprises peaks at diffraction angles of at least 12.8 and 29.2, or at least 6.9, 7.2, 7.3, 12.8 and 29.2, 2θ values ​​of ±0.2°.

[0458] 2.Formula (IMI) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate I of TIFF2025502842000061.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound comprises peaks at diffraction angles of at least 12.8, 16.0 and 25.8, or at least 6.9, 7.2, 7.3, 12.8, 16.0 and 25.8 at 2θ values ​​of ±0.2°.

[0459] 3.Formula (IMI) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate modification I of TIFF2025502842000062.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound comprises peaks at diffraction angles of at least 12.8, 20.5 and 25.8, or at least 6.9, 7.2, 7.3, 12.8, 20.5 and 25.8 at 2θ values ​​of ±0.2°.

[0460] 4.Formula (IMI) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate modification I of TIFF2025502842000063.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound contains at least peaks at diffraction angles 2θ values ​​of 12.8, 5.7, 6.9, 7.2, 7.3, and 9.9 of 12.8, 5.7, 6.9, 7.2, 7.3, and 9.9 of 0.2°.

[0461] 5.Formula (IMI) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate modification I of TIFF2025502842000064.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound comprises peaks at least 12.8, 5.7 and 16.0, or at least 6.9, 7.2, 7.3, 12.8, 5.7 and 16.0 at diffraction angles of 2θ values ​​±0.2°.

[0462] 6.Formula (IMI) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate modification I of TIFF2025502842000065.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound comprises at least peaks at diffraction angles of 12.8, 5.7 and 20.5, or at least 6.9, 7.2, 7.3, 12.8, 5.7 and 20.5 at 2θ values ​​of ±0.2°.

[0463] 7.Formula (IMI) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate modification I of TIFF2025502842000066.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound comprises at least peaks at 12.8, 5.7 and 29.2, or at least 6.9, 7.2, 7.3, 12.8, 5.7 and 29.2 at diffraction angles of 2θ values ​​of ±0.2°.

[0464] 8. The compound according to any one of claims 8 to 14, wherein the x-ray powder diffractogram further comprises peaks at 23.0, 15.2, 25.8 and 25.1.

[0465] 9.Formula (IMI) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate modification I of TIFF2025502842000067.tif83165, The compound has an X-ray powder diffraction pattern (measured at 25° C. and using Cu—K alpha 1 as the radiation source) as shown in FIG.

[0466] 10. The compound according to any one of claims 8 to 16, wherein the crystalline form is stable during micronization.

[0467] 11.Formula (IMI) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate modification I of TIFF2025502842000068.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound comprises a peak at at least 12.8 at diffraction angles 2θ values ​​of ±0.2°, and the compound has the DSC thermogram shown in FIG.

[0468] 12.Formula (IMI) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate modification I of TIFF2025502842000069.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound contains a peak at at least 12.8 at diffraction angles 2θ values ​​of ±0.2° and lacks peaks at 27.2 and 27.5.

[0469] 13.Formula (IMI) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate modification I of TIFF2025502842000070.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound contains peaks at least 12.8 and 5.7 at diffraction angles 2θ values ​​of ±0.2°, and lacks peaks at 8.5 and 6.1.

[0470] 14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a pharma- ceutically acceptable excipient.

[0471] 15. A compound according to any one of claims 1 to 13 for use in the treatment and / or prevention of cardiopulmonary diseases.

[0472] 16. The pharmaceutical composition according to claim 15 for use in the treatment and / or prevention of cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary hypertension (PH) associated with chronic lung disease (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0473] 17. Use of a compound according to any one of claims 1 to 13 for the preparation of a pharmaceutical composition for the treatment or prevention of cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung disease (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0474] 18. Use of a compound according to any one of claims 1 to 13 for the manufacture of a stable inhalation dosage form for use in a dry powder inhaler.

[0475] 19. A method for treating or preventing a cardiopulmonary disorder, wherein the cardiopulmonary disorder is selected from the group consisting of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung disease (group 3 PH), including pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP), the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 13.

[0476] 20. The method of claim 19, wherein the cardiopulmonary disorder is pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) or pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0477] Monohydrate II 1. Formula (IM-II) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate II modification of TIFF2025502842000071.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound contains peaks at at least 12.7, 13.9, 21.7, and 16.4 diffraction angles 2θ values ​​of ±0.2°.

[0478] 2. Formula (IM-II) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate II modification of TIFF2025502842000072.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound comprises peaks at at least 12.7, 13.9, 21.7 and 24.4 at diffraction angles 2θ values ​​of ±0.2°.

[0479] 3. Formula (IM-II) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate II modification of TIFF2025502842000073.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound comprises peaks at at least 12.7, 21.7, and 25.5 at diffraction angles 2θ values ​​of ±0.2°.

[0480] 4. Formula (IM-II) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate II modification of TIFF2025502842000074.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound comprises peaks at diffraction angles of at least 12.7, 5.7, 6.1, and 7.1 2θ values ​​of ±0.2°.

[0481] 5. Formula (IM-II) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate II modification of TIFF2025502842000075.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound contains peaks at diffraction angles of at least 12.7, 5.7, and 8.5 2θ values ​​of ±0.2°.

[0482] 6. Formula (IM-II) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate II modification of TIFF2025502842000076.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound contains peaks at at least 12.7, 6.1, and 9.9 diffraction angles 2θ values ​​of ±0.2°.

[0483] 7. Formula (IM-II) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate II modification of TIFF2025502842000077.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound contains peaks at at least 12.7, 7.1, and 8.5 diffraction angles 2θ values ​​of ±0.2°.

[0484] 8. Formula (IM-II) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate II modification of TIFF2025502842000078.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound contains peaks at at least 12.7, 7.1, and 6.1 diffraction angles 2θ values ​​of ±0.2°.

[0485] 9. Formula (IM-II) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate II modification of TIFF2025502842000079.tif83165, The compound has an X-ray powder diffraction pattern (measured at 25° C. and using Cu—K alpha 1 as the radiation source) as shown in FIG.

[0486] 10. Formula (IM-II) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate II modification of TIFF2025502842000080.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound comprises a peak at at least 12.7 with a diffraction angle 2θ value of ±0.2°, and the compound has the DSC thermogram shown in FIG.

[0487] 11. Formula (IM-II) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the crystalline monohydrate II modification of TIFF2025502842000081.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound contains a peak at at least 12.7 at diffraction angles 2θ values ​​of ±0.2° and lacks peaks at: (1) 11.1 and 20.5; (2) 11.1 and 29.2; (3) 20.5 and 29.2; (4) 11.1 and 16.0; (5) 11.1 and 16.9; and / or (6) 16.0 and 16.9.

[0488] 12. The compound of claim 11, lacking peaks at 11.1 and 29.2 at diffraction angles of 2θ values ​​±0.2°.

[0489] 13. The compound of claim 11, lacking peaks at 11.1 and 20.5 at diffraction angles of 2θ values ​​±0.2°.

[0490] 14. The compound according to any one of claims 1 to 13, wherein the x-ray powder diffractogram comprises peaks at least 12.7, 23.9, 13.9, 23.0 and 12.2 at diffraction angles of 2θ values ​​±0.2°.

[0491] 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a pharma- ceutically acceptable excipient.

[0492] 16. A compound according to any one of claims 1 to 14 for use in the treatment and / or prevention of cardiopulmonary diseases.

[0493] 17. The pharmaceutical composition according to claim 15 for use in the treatment and / or prevention of cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary hypertension (PH) associated with chronic lung disease (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0494] 18. Use of a compound according to claims 1 to 14 for the preparation of a pharmaceutical composition for the treatment or prevention of cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung disease (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0495] 19. Use of a compound according to any one of claims 1 to 14 for the manufacture of a stable inhalation dosage form for use in a dry powder inhaler.

[0496] 20. A method for treating or preventing a cardiopulmonary disorder, wherein the cardiopulmonary disorder is selected from the group consisting of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung disease (Group 3 PH), including pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP), the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 14.

[0497] 21. The method of claim 20, wherein the cardiopulmonary disorder is pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) or pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0498] Sesquihydrate 1. Crystalline modification sesquihydrate of formula (I) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of TIFF2025502842000082.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound contains peaks at at least 12.2 and 7.6 at diffraction angles 2θ values ​​of ±0.2°.

[0499] 2. Crystalline modification sesquihydrate of formula (I) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of TIFF2025502842000083.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound comprises peaks at at least 12.2, 5.1, and 26.4 at diffraction angles 2θ values ​​of ±0.2°.

[0500] 3. Crystalline modification of sesquihydrate of formula (I) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of TIFF2025502842000084.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound contains peaks at at least 12.2, 8.6, and 14.5 at diffraction angles 2θ values ​​of ±0.2°.

[0501] 4. Crystalline modification of sesquihydrate of formula (I) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of TIFF2025502842000085.tif83165, The compound has an X-ray powder diffraction pattern (measured at 25° C. and using Cu—K alpha 1 as the radiation source) as shown in FIG.

[0502] 5. Crystalline modification of sesquihydrate of formula (I) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of TIFF2025502842000086.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) of the compound comprises a peak at at least 12.2 diffraction angle 2θ values ​​of ±0.2°, and the compound has the DSC thermogram shown in FIG.

[0503] 6. Crystalline modification sesquihydrate of formula (I) A compound which is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of TIFF2025502842000087.tif83165, The compound, wherein the X-ray powder diffractogram (measured at 25° C. and using Cu—K alpha 1 as the radiation source) contains a peak at at least 12.2 at diffraction angles 2θ values ​​of ±0.2° and lacks peaks at: (1) 10.6; (2) 25.8 and 6.7; (3) 25.8 and 7.1; (4) 25.8 and 10.6; (5) 10.4; (6) 5.7 and 6.7; and / or (6) 25.5, 5.7 and 6.7.

[0504] 7. The compound of claim 6, lacking a peak at 10.6 at diffraction angles of 2θ values ​​±0.2°.

[0505] 7. The compound of claim 6, lacking peaks at 5.7 and 6.7 at diffraction angles of 8.2θ values ​​±0.2°.

[0506] 9. The compound according to any one of claims 1 to 8, wherein the x-ray powder diffractogram comprises peaks at least 12.2, 14.5, 18.7, 25.1 and 27.0 at diffraction angles of 2θ values ​​±0.2°.

[0507] 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharma- ceutically acceptable excipient.

[0508] 11. A compound according to any one of claims 1 to 9 for use in the treatment and / or prevention of cardiopulmonary diseases.

[0509] 12. The pharmaceutical composition according to claim 10 for use in the treatment and / or prevention of cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary hypertension (PH) associated with chronic lung disease (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0510] 13. Use of a compound according to any one of claims 1 to 9 for the preparation of a pharmaceutical composition for the treatment or prevention of cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung disease (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0511] 14. Use of a compound according to any one of claims 1 to 9 for the manufacture of a stable inhalation dosage form for use in a dry powder inhaler.

[0512] 15. A method for treating or preventing a cardiopulmonary disorder, wherein the cardiopulmonary disorder is selected from the group consisting of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung disease (group 3 PH), including pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP), the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 9.

[0513] 16. The method of claim 15, wherein the cardiopulmonary disorder is pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) or pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

[0514] Experimental Department Abbreviations and acronyms: TIFF2025502842000088.tif223126TIFF2025502842000089.tif57128

[0515] Analysis method DSC / TG DSC thermograms were recorded using a differential scanning calorimeter from Perkin-Elmer (models DSC7, Pyris-1 or Diamond). Measurements were carried out at a heating rate of 20 K min-1 using non-hermetic aluminum pans. The flow gas was nitrogen. No sample preparation was performed.

[0516] TGA thermograms were recorded using a thermobalance from Perkin-Elmer (models TGA7 and Pyris 1). Measurements were performed using an open platinum pan at a heating rate of 10 K min-1. The flow gas was nitrogen. No sample preparation was performed.

[0517] XRPD X-ray diffraction patterns were recorded at room temperature using an XRD diffractometer X'Pert PRO (PANalytical) and a STOE STADI-P (radiation Cu K alpha 1, wavelength 1.5406 Å). No sample preparation was performed. All X-ray reflections are given as °2θ (theta) values ​​(maximum peak) with a resolution of ±0.2°.

[0518] Raman Raman spectra were recorded at room temperature using an FT-Raman spectrometer from Bruker (models RFS 100 and MultiRam). The resolution was 2 cm-1. Measurements were performed in glass vials or aluminum disks. No sample preparation was performed.

[0519] IR IR-ATR spectra were recorded at room temperature using a FT-IR spectrophotometer Tensor 37 with a Universal Diamond ATR device from Bruker. The resolution was 4 cm-1. No sample preparation was performed.

[0520] LC-MS method Method A Instrument: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8 μm 50 × 1 mm; Eluent A: 1 l Wasser + 0.25 ml 99% formic acid, Eluent B: 1 l acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; Oven: 50 °C; Flow rate: 0.40 ml / min; UV detection: 210 nm.

[0521] HPLC method Method B High performance liquid chromatograph with thermostatic column oven, UV detector and data evaluation system, measurement wavelength: 206 nm, band width: 6 nm, oven temperature: 30° C., column: chiralpak AD-H, length: 250 mm, internal diameter: 4.6 mm, particle size: 5 μm, mobile phase: A: n-heptane, B: ethanol + 0.1% diethylamine, gradient program: start 1 ml / min 70% eluent a, 30% eluent B; 12 min 1 ml / min 40% eluent A, 60% eluent B. Sample solvent: ethanol + 0.1% diethylamine, test solution: approximately 1.0 mg / ml of substance dissolved in sample solvent, injection volume: 5 μl, RT: enantiomer 1: 5.8 min (RRT 1.00), enantiomer 2: 7.2 min RRT 1.25

[0522] Method C High performance liquid chromatograph with thermostatic column oven, UV detector and data evaluation system, measurement wavelength: 204 nm, band width: 6 nm, oven temperature: 45° C., column: chiralpak AD-H, length: 250 mm, inner diameter: 4.6 mm, particle size: 5 μm, mobile phase: A: n-heptane, B: ethanol + 0.2% trifluoroacetic acid + 0.1% diethylamine, gradient program: 1.5 ml / min 60% eluent a, 40% eluent b; sample solvent: ethanol, test solution: approximately 1.0 mg / ml of substance dissolved in sample solvent, injection volume: 10 μl, RT: enantiomer 1: 2.9 min RRT 1.00, enantiomer 2: 3.7 min RRT 1.28

[0523] Method L Device type MS: Waters Synapt G2S; Device type UPLC: Waters Acquity I-CLASS; Column: Waters, HSST3, 2.1×50 mm, C18 1.8 μm; Eluent A: 1 l water + 0.01% formic acid; Eluent B: 1 l acetonitrile + 0.01% formic acid; Gradient: 0.0 min 2% B → 2.0 min 2% B → 13.0 min 90% B → 15.0 min 90% B; Oven: 50° C.; Flow rate: 1.20 ml / min; UV detection: 210 nm.

[0524] Method M High performance liquid chromatograph with thermostatic column oven, UV detector and data evaluation system, measuring wavelength: 226 nm, band width: 40 nm. Column: Zorbax Bonus-RP, length: 150 mm, inner diameter: 3.0 mm, particle size: 3.5 μm, mobile phase: A: water + 0.1% TFA, B: ACN + 0.1% TFA / methanol = 2 + 1, gradient program: 0.0 min 50% B → 12.0 min 70% B → 17.0 min 90% B → 25.0 min 90% B; flow rate: 0.60 ml / min; sample solvent: isopropanol + 0.1% diethylamine, test solution: approximately 35 mg of substance is dissolved in 25 ml of ACN and filled up to 50 ml with water + 0.1% TFA. (0.7 mg / mL); injection volume: 3 μL.

[0525] New Method M High performance liquid chromatograph with thermostatic column oven, UV detector and data evaluation system, measurement wavelength: 226 nm, band width: 40 nm; Column: XBridge Phenyl, length: 50 mm, inner diameter: 4.6 mm, particle size: 2.5 μm; column oven temperature: 22 °C Mobile phase: A: pH 7 buffer (0.66 g / L (NH4)2HPO4 and 0.58 g / L NH4H2PO4); B: ACN Gradient program: 0.00 min = 95% A, 5% B; time 8.3~11 = 20% A, 80% B Flow rate: 1.2mL / min; UV lamp: 210nm

[0526] Method N High performance liquid chromatograph with thermostatic column oven, UV detector and data evaluation system, measuring wavelength: 210 nm. Column: XBridge BEH Phenyl, length: 50 mm, inner diameter: 4.6 mm, particle size: 2.5 μm, mobile phase: A: 0.66 g (NH4)2HPO4 and 0.58 g (NH4)H2PO4 in 1 L millipore water; B: ACN, gradient program: 0.00 min 95% B → 8.3 min 80% B → 11.0 min 80%; flow rate: 1.2 ml / min; sample solvent: ACN + water, injection volume: 3 μL.

[0527] A-Chemical Examples Starting Materials and Intermediates Example 1A (5S)-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) The compound TIFF2025502842000090.tif83165 was synthesized according to the procedure disclosed in Example 92A of WO2014 / 012934.

[0528] Example 2A Butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate The compound TIFF2025502842000091.tif53165 was synthesized according to the procedure disclosed in Example 10 of WO2021 / 233783.

[0529] Example 3A Butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate The compound TIFF2025502842000092.tif78165 was synthesized according to the procedure disclosed in Example 11 of WO2021 / 233783.

[0530] The further starting material, 4-(bromomethyl)-3-chloro-4'-(trifluoromethyl)[biphenyl] (compound of formula XI), is commercially available.

[0531] Example 4A Naphthalene-1,5-disulfonic acid-butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (1:1) adduct TIFF2025502842000093.tif78165In a 3 L flask, 889.1 g (1.06 mol) of butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (oil) was dissolved in 1850 ml of tetrahydrofuran. 304.6 g (1.06 mol) of naphthalene-1,5-disulfonic acid was added at room temperature and the mixture was stirred until completely dissolved. The solution was then concentrated in a rotary evaporator at 40° C. The residue (solid) was dried in a vacuum drying cabinet at 40° C. in a nitrogen stream to 1126.3 g. Yield (crude product): 1126.3 g; 94.4% of theoretical yield Enantiomeric purity (HPLC Method B): 95.3% ee Purity (area): 81.8% (Method N), Rt of 16.11 (BP-diester)

[0532] Examples 4B to 4E Attempts to form stable salts of butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate with different acids

[0533] 4B: Addition of (+)-di-p-toluoyl-D-tartaric acid 4 g (0.005 mol) of butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (oil) was slowly dissolved in a total amount of 75 ml of methanol at a temperature of 50°C. A warm solution of 1.8 g (0.005 mol) of (+)-di-p-toluoyl-D-tartaric acid in 2.5 ml of methanol was added. Finally, the mixture was stirred over the weekend.

[0534] Different solvents were added to smaller portions of the reaction mixture to initiate crystallization. The following solvents were tried without any effect: MTBE, MIBK, methylene chloride, toluene. Two layers formed after the addition of a mixture of cyclohexane, n-hexane and methylcyclohexane.

[0535] Several drops of the reaction mixture were dried on a watch glass, the resulting dry mass was scraped off and finally stirred in a mixture of cyclohexane, n-hexane and methylcyclohexane. The resulting solid melted.

[0536] The solid was separated with methylcyclohexane and HPLC analysis of the solid revealed it to be tartaric acid.

[0537] Water was added to another portion of the reaction mixture and the solids were then separated. The solids were difficult to separate.

[0538] The solvent was removed from the reaction mixture to give 3.1 g of yellow foam crystals.

[0539] To the foam crystals, 31 ml of methylcyclohexane was added and stirred for 4 hours to obtain 2.8 g of a pale yellow solid.

[0540] No defined salts were detectable.

[0541] 4C: Addition of trifluoroacetic acid (=TFA) 0.21 g (0.2 mmol) of butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (oil) was dissolved in 2 ml of acetonitrile. 0.1 ml of TFA was added. An orange solution was formed. The solvent was evaporated in vacuum to give an orange oil.

[0542] No salt formation was observable.

[0543] 4D: Addition of methanesulfonic acid 0.26 g (0.3 mmol) of butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (oil) was dissolved in 1.5 ml of dichloromethane. 20.1 μl of methanesulfonic acid was added. An orange solution was formed. After stirring at room temperature for 1 h, no crystallization occurred.

[0544] The solvent was evaporated in vacuum at 40° C. to give yellow foamy crystals.

[0545] Several solvents were screened to initiate either crystallization or purification.

[0546] Dichloromethane, MIBK, MTBE, ethyl acetate, acetone, acetonitrile, dioxane, n-butanol, methanol, ethanol, tetrahydrofuran, toluene gave solutions at room temperature.

[0547] Diisopropyl ether, water, diethyl ether, cyclohexane resulted in sticky masses.

[0548] Further stirring in n-hexane at room temperature gave again a sticky mass.

[0549] No isolable salts.

[0550] 4E: Addition of camphorsulfonic acid 0.29 g (0.34 mmol) of butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (oil) was dissolved in 1.5 ml of dichloromethane. 80.05 μg of camphorsulfonic acid was added. An orange solution was formed.

[0551] The solvent was evaporated in vacuum at 40° C. to give yellow foamy crystals.

[0552] Several solvents were screened to initiate either crystallization or purification.

[0553] Dichloromethane, MIBK, ethyl acetate, acetone, acetonitrile, dioxane, n-butanol, methanol, ethanol, tetrahydrofuran, toluene gave solutions at room temperature.

[0554] MTBE was added and oil droplets formed.

[0555] Water, diisopropyl ether, diethyl ether, cyclohexane and n-heptane all yielded only sticky agglomerates.

[0556] No isolable salts.

[0557] Example 5A and Example 6A Ethyl 5-{(tert-butoxycarbonyl)[2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomers 1 and 2) TIFF2025502842000094.tif7316515 g (21.42 mmol) of racemic ethyl 5-{(tert-butoxycarbonyl)[2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 22A) was separated into its enantiomers by supercritical fluid chromatography (SFC) on a chiral phase [column: Chiralpak OD-H, 20 μm, 400 mm×50 mm; mobile phase: 70:30 (v / v) carbon dioxide / isopropanol; flow rate: 400 ml / min; pressure: 80 bar; UV detection: 220 nm; temperature: 37° C.].

[0558] Example 5A (Enantiomer 1): Yield: 5830mg Rt=2.83 min; >99.9% chemical purity; >99% ee [Column: Chiralpak OD-H, 5 μm, 250 mm × 4.6 mm; mobile phase: carbon dioxide / isopropanol 70:30 (v / v); flow rate: 3 ml / min; UV detection: 210 nm].

[0559] Example 6A (Enantiomer 2): Yield: 6330mg Rt=5.30 min; >99% chemical purity; >98% ee [Column: Chiralpak OD-H, 5 μm, 250 mm × 4.6 mm; mobile phase: carbon dioxide / isopropanol 70:30 (v / v); flow rate: 3 ml / min; UV detection: 210 nm].

[0560] Example 7A Ethyl 5-{[2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate dihydrochloride (enantiomer 1) TIFF2025502842000095.tif78165 3208 ml of 4N hydrogen chloride solution in dioxane was diluted with an additional 2240 ml of dioxane and added to 455 g (641.56 mmol) of ethyl 5-{(tert-butoxycarbonyl)[2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (enantiomer 1, Example 1A) and the mixture was stirred at room temperature overnight. The reaction solution was then concentrated to dryness and the residue was dried under high vacuum overnight. This gave 448.7 g (641.59 mmol, about 100% of theory) of the target product. LC-MS (Method A): Rt=1.06 min; m / z=609 / 611(M+H)+.

[0561] Example 8A Ethyl 5-{[2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 1) TIFF2025502842000096.tif78165448.7 g (641.59 mmol) of ethyl 5-{[2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate dihydrochloride (enantiomer 1, example 3A) were taken up in 6869 ml of THF, 268 ml of triethylamine were added and the mixture was stirred at room temperature for 1 hour. The precipitated triethylammonium chloride crystals were then filtered off and washed with THF. The filtrate obtained was evaporated to dryness. The residue was dissolved in ethyl acetate, washed twice with 10% strength aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated once more to dryness. This gave 391 g (620.59 mmol, 97% of theory) of the target compound. LC-MS (Method A): Rt=1.08 min; m / z=609 / 611(M+H)+. 1H-NMR (400 MHz, DMSO-d6, δ / ppm): 1.27 (t, 3H), 1.57-1.72 (m, 2H), 1.76-1.87 (m, 1H), 1.87-1.95 (m, 1H), 1.95-2.07 (m, 1H), 2.65-2.88 (m, 6H), 3.75 (br. s, 1H), 4.28 (q, 2H), 5.19 (s, 2H), 6.92 (t, 1H), 7.08 (d, 1H), 7.16-7.26 (m, 2H), 7.65-7.77 (m, 3H), 7.84 (d, 3H), 7.89 (s, 1H), 7.95 (d, 2H).

[0562] Example 9A Ethyl 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 1) A suspension of 378 g (620.59 mmol) of ethyl 5-{[2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 1, Example 4A), 360 g (1241.19 mmol) of methyl 4-(2-iodoethyl)benzoate, and 98.66 g (930.89 mmol) of anhydrous sodium carbonate in 1 ml of dry acetonitrile was stirred overnight at a bath temperature of 110°C. Then, a further 360 g (1241.19 mmol) of methyl 4-(2-iodoethyl)benzoate and 128.65 g (930.89 mmol) of powdered potassium carbonate were added and the mixture was heated under reflux for a further 72 h. After cooling the reaction mixture, the inorganic salts were filtered off and the filtrate obtained was evaporated to dryness. The residue obtained was taken up in ethyl acetate, washed twice with 10% strength aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then evaporated once more to dryness. The residue obtained was purified by chromatography in two portions on silica gel (9 kg) (mobile phase: petroleum ether / ethyl acetate 8:2→7:3). This gave 397 g (551.32 mmol, 89% of theory) of the target compound. LC-MS (Method A): Rt=1.67 min; m / z=771 / 773(M+H)+. 1H-NMR (400 MHz, DMSO-d6, δ / ppm): 1.27 (t, 3H), 1.37-1.52 (m, 1H), 1.52-1.67 (m, 1H), 1.85-1.96 (m, 1H), 1.96-2.05 (m, 1H), 2.56-2.80 (m, 10H), 3.81 (s, 3H), 3.97-4.09 (m, 1H), 4.26 (q, 2H), 5.07 (m, 2H), 6.87 (t, 1H), 7.01-7.16 (m, 4H), 7.23 (t, 1H), 7.35-7.48 (m, 2H), 7.53 (d, 1H), 7.61 (d, 1H), 7.74 (d, 2H), 7.77-7.89 (m, 5H).

[0563] Comparative Example Comparative Example 11 (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid TIFF2025502842000098.tif891652450 mg (3.18 mmol) of ethyl (5S)-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 (Example 1A, enantiomer 2) was dissolved in 25 ml of dioxane, 9.5 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was then stirred at room temperature overnight. After the reaction was complete, the dioxane was removed on a rotary evaporator and the remaining mixture was diluted with about 50 ml of water. The mixture was then acidified to pH 4-5 using acetic acid. The precipitated solid was filtered off with suction and washed repeatedly with water (total of about 50 ml of water). The solid was then taken up in 50 ml of water and stirred at room temperature overnight. After another filtration with suction, the solid was washed again with water and then dried overnight at 40° C. under high vacuum. In this way, 2300 mg (2.9 mmol, 93% purity, containing an unknown amount of monosodium salt, with the same retention time) of the title compound was obtained. LC-MS (Method A): Rt=1.37 min; m / z=729 / 731(M+H)+. 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.38-1.71 (m, 2H), 1.84-2.08 (m, 2H), 2.59-2.84 (m, 10H), 3.97-4.11 (m, 1H), 4.99-5.16 (m, 2H), 6.87 (t, 1H), 7.05 (br. d, 2H), 7.12 (br. d, 2H), 7.23 (br. t, 1H), 7.38-7.48 (m, 2H), 7.54 (d, 1H), 7.62 (d, 1H), 7.71-7.91 (m, 7H), 11.90-13.60 (br. s, about 2H). XRPD: amorphous phase, see Figure 33

[0564] Determination of the absolute configuration of Comparative Example 11 via VCD spectroscopy: Vibrational circular dichroism (VCD) is a well-established method for determining the absolute configuration of chiral molecules (see United States Pharmacopeial Convention (USP) and The National Formulary (USP-NF), second suppl. USP-NF 34, chapters 782 and 1782, June 1, 2016 and Abs. config. by VCD, white paper BioTools, 2017).

[0565] The steps involved in the decision are:

[0566] 1. Experimental VCD spectra were measured using DMSO. Sample Example 1 was measured at a concentration of 5.5mg / 0.15ml.

[0567] 2. The VCD of one of the enantiomers was calculated using first-principles calculations. Calculations are performed using Gaussian09™ (a commercially available software package). The VCD spectrum of the other enantiomer is then obtained by inverting the sign of all bands or by calculating the VCD of the mirror image structure.

[0568] 3. The final step is to compare the experimental spectrum with the two calculated spectra to determine the enantiomer that gives the best correlation between sign and signal intensity. The confidence level of the overlap between two such spectra can be calculated using the CompareVOA™ software. VCD spectrometer: ChirallR-2X w / DualPEM Concentration: 5.5mg / 0.15ml of Example 1 in DMSO Resolution: 4cm-1 PEM setting: 1400cm-1 Number of scans / measurement time: 20 hours Sample cell: BaF2 Path length: 100□m Calculation details: Gaussian version:Gaussian 09 Total low energy conformers used for Boltzmann summation: 92 Methods and basis sets for DFT calculations: B3LYP / 6-31G(d) Calculated absolute configuration: S The absolute configuration of Comparative Example 11 was assigned as the (S)-enantiomer based on the VCD spectral match with a confidence level of 94%.

[0569] Determination of thermal stability of Comparative Example 11: 0.3mg of Comparative Example 11 was dissolved in 0.1ml of dimethylsulfoxide and 0.4ml of acetonitrile. Then, 1.0ml of water was added. The HPLC vial was shaken and sonicated to ensure complete dissolution. This solution was immediately analyzed by HPLC (reference at t0). 0.3mg of test compound was weighed into another HPLC vial. The vial was capped and stored at 90°C in a heating block for 7 days.

[0570] After this time, the vials were uncapped and 0.1 ml of dimethylsulfoxide and 0.4 ml of acetonitrile were added to the stress compound. Then, 1.0 ml of water was added. The HPLC vials were shaken and sonicated to ensure complete dissolution. Samples were analyzed by HPLC (1 week sample). Peak areas in percentages were used for quantification.

[0571] (Table 11) TIFF2025502842000099.tif59162

[0572] Comparative Example 11 was found to be stable over the test period.

[0573] In addition, some examples disclosed in WO14 / 012934-A1, such as Example 2 (Comparative Example 5, experimental part), 24 (Comparative Example 6, experimental part), 25 (Comparative Example 7, experimental part), 28 (Comparative Example 8, experimental part), 29 (Comparative Example 9, experimental part) and Example 31 (Comparative Example 10, experimental part), show only limited thermal stability (90° C., 7 days).

[0574] Comparative Example 12 (5R)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (enantiomer 1) TIFF2025502842000100.tif83165291 g (377.29 mmol) of ethyl 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 1, example 5A) was dissolved in 3000 ml of dioxane, 1132 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was then stirred at room temperature overnight. After the reaction was complete, the dioxane was removed on a rotary evaporator and the remaining mixture was diluted with about 6000 ml of water. The mixture was then acidified to pH 4-5 using acetic acid. The precipitated solid was filtered off with suction and washed repeatedly with water (total of about 3000 ml of water). The solid was then dried under high vacuum at room temperature using the desiccant phosphorus pentoxide for 3 days. The desiccant was then removed and the solid was dried for a further 48 hours at 40° C. In this way, 249 g (342.15 mmol, 91% of theory) of the title compound was obtained. LC-MS (Method A): Rt=1.33 min; m / z=729 / 731(M+H)+. 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.37-1.66 (m, 2H), 1.84-2.05 (m, 2H), 2.56-2.81 (m, 10H), 3.98-4.08 (m, 1H), 5.01-5.14 (m, 2H), 6.87 (t, 1H), 7.05 (d, 2H), 7.12 (d, 2H), 7.23 (t, 1H), 7.39-7.47 (m, 2H), 7.54 (d, 1H), 7.62 (d, 1H), 7.71-7.90 (m, 7H), 11.60-13.85 (br. s, about 2H).

[0575] For Comparative Example 11, the absolute configuration was determined to be (5S). The corresponding absolute configuration for Comparative Example 12 should be the opposite, i.e., (5R).

[0576] Comparative Example 13 Monosodium (5R)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (enantiomer 1) A vessel was charged with 60 g of amorphous (5R)-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 (Comparative Example 12) and 800 g of acetone. The vessel was heated to reflux temperature. The solid formed under reflux temperature was filtered after cooling to room temperature. Yield: 8 g of dry product, 13% of theory Enantiomeric purity (HPLC Method C): 100% ee (ICP): Sodium Content: 3.1% sodium

[0577] Comparative Example 14 (5R)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate II (enantiomer 1) TIFF2025502842000101.tif83165174.2 g of Comparative Example 12 was stirred with 2003.3 g of acetone under reflux. The mixture was cooled to 20° C. and the insoluble solid (19.5 g after drying) was filtered off. 273 g of acetone was added to the filtrate, which was heated to 57° C. and 1101.4 g of water and 0.4 g of seed crystals of monohydrate II, R enantiomer (prepared similarly to this procedure from a small-scale preliminary experiment) were added. An additional 1101.4 g of water was added and it was stirred at room temperature overnight. The product was filtered off and dried to 143.8 g in vacuum (30 mbar) at 55° C.

[0578] An additional 20.3 g was obtained from 21.0 g of Comparative Example 12, prepared following the same procedure.

[0579] The solids were combined to 164.1 g, and 161.0 g of these solids were stirred with 1993.0 g of acetone under reflux. At this temperature, 930.0 g of water and 0.8 g of seed crystals of monohydrate II, R enantiomer (prepared similarly to this procedure from a small-scale preliminary experiment) were added, and it was cooled to 50° C. An additional 200.0 g of water and 400.0 g of acetone were added to improve the stirrability. It was stirred at 50° C. for 1 hour, 1263.0 g of water was added, it was stirred for 30 minutes, cooled to 20° C. within 2 hours, and stirred at room temperature overnight. The product was filtered off and dried at 55° C. in vacuum (30 mbar) to 154.4 g.

[0580] A portion of the solid (95.0 g) was dissolved in 916.7 g of acetone at 40° C., cooled to room temperature, and the solution was filtered for clarification. 170.1 g of water was added, and after 30 minutes, the seed crystals of the R enantiomer of monohydrate II (prepared similarly to this procedure from a small-scale preliminary experiment) were added, and it was stirred overnight. The thin suspension was heated to 50° C., and the resulting solution was cooled to room temperature, seeded with the seed crystals of the R enantiomer of monohydrate II (prepared similarly to this procedure from a small-scale preliminary experiment), and stirred overnight. The solid was filtered off, washed with a mixture of 76.0 g of acetone and 19.0 g of water (8:2), sucked, and dried to 68.4 g.

[0581] The filtrate was concentrated at 40°C / 250-15 mbar and the precipitated solid was filtered off. 28.2 g of the solid was dissolved in 157.2 g of acetone water mixture (9:1 w / w) at 55°C and cooled to 15°C. After adding 10 g of water, it was seeded with seed crystals of monohydrate II R enantiomer (prepared similarly to this procedure from a small scale preliminary experiment) and stirred at 15°C overnight. The suspension was heated to 50°C, stirred for 30 min and cooled to 20°C within 4 h. It was heated again to 50°C within 1 h, cooled to 15°C within 4.5 h and stirred at 15°C overnight. The solid was filtered off, washed with 28 g of acetone water (8:2 w / w) mixture, sucked and dried to 20.6 g.

[0582] The solids were combined to give 87.0 g of the target compound. Enantiomeric purity (HPLC Method C): 99.8% ee Purity (Method M, Area): 99.7%, Rf 9.33 min XRPD: Monohydrate II EXAMPLES

[0583] Example 1 (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate II (seed crystals) TIFF2025502842000102.tif781652.0 g of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I) (prepared similarly to Comparative Example 11) was dissolved in 16.2 g of acetone and 1.8 g of water (8:1 mixture) and an additional 1.8 g of water was added. The clear solution was stirred overnight and crystallization started after 1.5 hours. The solid was filtered off with suction, washed with 2 g of acetone / water (8:2) and dried overnight with nitrogen air in vacuum at 60°C. Yield: 1.5 g of white solid, 75% of theory XRPD: Monohydrate II, X-ray powder diffractogram is shown in FIG. TIFF2025502842000103.tif69128TIFF2025502842000104.tif23433TIFF2025502842000105.tif19333

[0584] Example 2 (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid as monohydrate II (Route 3, crystallization from acetone, methanol and water) TIFF2025502842000106.tif781651067 g of tetrahydrofuran was placed in a 6 L glass stirring apparatus and 333 g (0.396 mol) of naphthalene-1,5-disulfonic acid-butyl(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (1:1) adduct (Example 4A) was added in portions with stirring. 1335 ml of water, then aqueous ammonia (27%) was added at 20°C-25°C until a pH of 7.8-8.2 was reached (approximately 46 g). 1440 g of diisopropyl ether were added, the aqueous phase was separated off, the organic phase was washed again with 1335 ml of water / 1 ml of 27% aqueous ammonia, then with 1335 ml of water, the organic phase was filtered through a Seitz filter plate covered with 200 g of sodium sulfate (anhydrous), which was rinsed with 200 g of diisopropyl ether, and the filtrate was concentrated in vacuum at 40° C. to obtain an evaporation residue of 267 g.

[0585] The residue after evaporation was dissolved in 848 g of dioxane, 1583 g of 1N sodium hydroxide solution was added and the mixture was stirred for 5.5 hours at 60° C. Then 1480 g of ethyl acetate was added at 20° C., the aqueous product phase (disodium salt solution) was separated off and washed with 1480 g of ethyl acetate and the residual ethyl acetate was distilled off in a vacuum at a maximum of 40° C. The residue was diluted with 2500 g of water and a portion of the disodium salt solution (1178 g) was added dropwise to a mixture of 1095 g of tetrahydrofuran and 137 g of 10% hydrochloric acid until a pH of 4.0 was reached.

[0586] The consumption of disodium salt solution is set in relation to the amount of hydrochloric acid submitted and the amount of hydrochloric acid for converting further portions is calculated. A second aliquot of disodium salt solution (1789 g) is added dropwise to the calculated amounts of tetrahydrofuran (1789 g) and 10% strength hydrochloric acid (208 g) until a pH of 4.0 is reached.

[0587] A third aliquot of the disodium salt solution (1510 g) was added dropwise to calculated amounts of tetrahydrofuran (1505 g) and 10% strength hydrochloric acid (175 g) until a pH of 4.0 was reached.

[0588] The combined organic phases were concentrated in vacuum at a maximum of 40° C. until the solvent-free water was condensed in the reflux condenser. The precipitated solid was filtered off with suction and washed with 750 g of water.

[0589] Using the same procedure, the second and third portions of 333 g each of naphthalene-1,5-disulfonate butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (1:1) adduct (Example 4A) were converted according to the procedure described above.

[0590] The combined wet products were dried under vacuum in a nitrogen stream at 60° C. to give 587 g (about 91% o.th.) of the target compound of formula I.

[0591] Crystallization: The solid (587 g) was heated to 50° C. with a mixture of 3674 g acetone and 470 g water. The resulting solution was filtered through a Seitz filter plate and heated to 40° C. The filtrate was mixed with 1.5 g of (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4′-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate II (Example 1) seed crystals, cooled to 20° C. within 2 hours, stirred for 0.5 hours, and heated again to 50° C. within 2 hours. The mixture was stirred for 0.5 hours, cooled to 20° C. within 3 hours, stirred for 0.5 hours, and heated again to 50° C. over the course of 2 hours. It was cooled to 20° C. within 3 hours, stirred for 0.5 hours, and the solid was filtered off with suction. The wet product was washed with a mixture of 800 g acetone and 90 g water and dried under vacuum in a nitrogen stream at 25° C. to a constant weight of 361 g.

[0592] The quality of the obtained product and the in-process control of transformation did not meet the requirements, therefore it was recrystallized again.

[0593] The solid (361 g) was heated to 50° C. with a mixture of 1949 g acetone and 217 g water. The resulting solution was filtered through a Seitz filter plate and heated to 50° C. It was mixed with 1.5 g of (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4′-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate II (Example 1) seed crystals, cooled to 20° C. within 3 hours, stirred for 0.5 hours, and heated again to 50° C. within 3 hours. The mixture was stirred for 0.5 hours, cooled to 20° C. within 3 hours, stirred for 0.5 hours, heated again to 50° C. for 3 hours, and stirred for 0.5 hours. It was cooled to 20° C. within 3 hours, stirred for 0.5 hours and the solids were filtered off with suction. The wet product was dried under vacuum in a nitrogen stream at 25° C. to a constant weight of 271 g.

[0594] In-process controls confirmed sufficient quality but not the desired modification of the product obtained, which was therefore recrystallized again.

[0595] The solid (271 g) was heated to 50° C. with a mixture of 1668 g acetone and 75 g water. The resulting solution was filtered through a Seitz filter plate and heated to 50° C. It was cooled to 45° C. and seeded with 1.5 g of (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4′-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate II (Example 1), cooled to 20° C. within 3 hours, stirred for 0.5 hours, and heated to 40° C. within 1 hour. The suspension was stirred for 0.5 hours, cooled to 20° C. within 3 hours, stirred, and the solid was filtered off with suction. The wet product was dried to constant weight under vacuum in a nitrogen stream at 25° C.

[0596] In-process controls confirmed product quality and transformation according to requirements. Yield: 117 g of monohydrate II; 18% of theoretical yield. Enantiomeric purity (HPLC Method C): 99.6% ee Purity (area): 99.8% (Method M, Rt 9.33 min) XRPD: Monohydrate II, X-ray powder diffractogram is shown in Figure 35 After micronization: Enantiomeric purity (HPLC Method C): 100.0% ee Purity (area): 99.7% (Method M, Rt 9.35 min) XRPD: Monohydrate II with partial amorphization, X-ray powder diffractogram is shown in FIG. Monohydrate II before micronization: see Figure 35 TIFF2025502842000107.tif49128TIFF2025502842000108.tif23431TIFF2025502842000109.tif23431TIFF2025502842000110.tif21128Monohydrate II after microparticulation (partially amorphized), Fig. 36 TIFF2025502842000111.tif19331TIFF2025502842000112.tif173128

[0597] Example 3 (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate I (seed crystals) 2.0 g of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I) (prepared similarly to Comparative Example 11) was dissolved in 8.1 g of methanol and 1.8 g of water, and 8.1 g of acetone and a further 1.8 g of water were added. It was stirred overnight. The solid was filtered off with suction, washed with 2 g of acetone / water (8:2) and dried overnight with nitrogen air in vacuum at 60°C. Yield: 1.8 g of a white solid, 90% of theory. Enantiomeric purity (HPLC Method C): 92.0% ee Purity (area): 97.3% (Method M, Rt 8.94 min) XRPD: Monohydrate I, see Figure 37 TIFF2025502842000113.tif124128TIFF2025502842000114.tif142128

[0598] Example 4 (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid as monohydrate I Release of the dibutyl ester from the NSA salt: 800 g of tetrahydrofuran was placed in a 6 L glass stirring apparatus and 250 g (0.30 mol) of naphthalene-1,5-disulfonic acid-butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4'-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (1:1) (Example 4A) was added in portions with stirring. 1 L of water, then 27% aqueous ammonia was added at 20°C-25°C until a pH of 7.8-8.2 was reached (approximately 27 g). 1080 g of diisopropyl ether was added, the aqueous phase was separated off and the organic phase was extracted again with 1 L of water / 0.8 ml of 27% aqueous ammonia, then washed with 1 L of water. The organic phase was filtered through a Seitz filter plate covered with 150 g of sodium sulfate (anhydrous), which was rinsed with 150 g of diisopropyl ether, and the filtrate was concentrated in vacuum at 40° C. to give 192 g of evaporation residue.

[0599] Saponification of dibutyl ester: The evaporation residue was dissolved in 610 g of tetrahydrofuran, 1139 g of 1N sodium hydroxide solution were added and the mixture was stirred for 24 hours at 60° C. Then 875 g of ethyl acetate were added at 20° C., the aqueous product phase (disodium salt solution) was separated off and the residual ethyl acetate was distilled off in vacuum at a maximum of 40° C.

[0600] Formation of the free acid of formula I: The residue was diluted with 1875 g of water, filtered through a Seitz filter plate and a portion of the disodium salt solution (835 g) was added dropwise to a mixture of 821 g of tetrahydrofuran and 103 g of 10% hydrochloric acid until a pH value of 4.0 was reached. 174 g of sodium chloride and 420 g of tetrahydrofuran were added and the organic product phase was separated off.

[0601] The consumption of disodium salt solution is set in relation to the amount of hydrochloric acid submitted and the amount of hydrochloric acid for converting further portions is calculated. A second aliquot (2000 g) of disodium salt solution is added dropwise to the calculated amount of tetrahydrofuran (2116 g) and 10% strength hydrochloric acid (246 g) until a pH of 4.0 is reached. 174 g of sodium chloride and 420 g of tetrahydrofuran are added and the organic product phase is separated off. 261 g of sodium chloride and 1043 g of tetrahydrofuran are added to the combined aqueous phase and the organic product phase is separated off. The combined organic phase is concentrated in vacuum at a maximum of 40° C. to a residue volume of 800 ml.

[0602] Crystallization: 184 g of tetrahydrofuran was added, and a mixture of 646 g of methanol and 291 g of water was added dropwise with stirring at 20° C. It was mixed with 0.8 g of (5S)-5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4′-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate I (Example 3) and stirred for 12 hours. The solid was separated and washed with a mixture of 112 g of methanol and 112 g of water. The solid was then dried in vacuum at 20° C. to 127 g. A second portion of 128 g was prepared using the same procedure.

[0603] The combined solids were heated to 50° C. with a mixture of 1020 g acetone and 1020 g methanol and cooled to 20° C. The resulting solution was filtered through a Seitz filter plate, heated to 50° C., and 460 g water was added dropwise over a period of 30 minutes. It was seeded with 1.5 g seed crystals of monohydrate I (Example 3), stirred for 30 minutes, cooled to 20° C. within at least 30 minutes, and the solids were filtered off with suction. The wet product was stirred with 2550 g water for 12 hours, then filtered off with suction and washed twice with 510 g water. The wet product was dried to constant weight under vacuum in a nitrogen stream at 20° C. Yield: 230 g of monohydrate I (IMI); 71% of theory Purity (area): 96.0% (Method M, Rt 8.94 min) Enantiomeric purity (HPLC Method C): 99.3% ee XRPD: Monohydrate Form I; see Figure 38 TIFF2025502842000115.tif159128TIFF2025502842000116.tif22833

[0604] Example 5 (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid as monohydrate I In a deactivated 2L reactor, butyl (5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 2A, WO2021 / 233783) was dissolved in acetonitrile (380 mL) at a temperature of 22° C. (50.8 g, 1.0 eq.). The solution was distilled at a temperature of 50° C. and 120 mbar. Then acetonitrile (380 ml) was added again and the mixture was distilled again under the same conditions. Acetonitrile (660 mL) was added to the solution and stirred for 5 minutes. 4-(Bromomethyl)-3-chloro-4'-(trifluoromethyl)[biphenyl](biarylbenzyl bromide) (53.5 g, 1.2 eq.) was then added and the mixture was stirred again for 5 min until it was dissolved. Cesium carbonate (83.1 g, 2.0 eq.) was then added and the mixture was stirred for 4 h. Cesium carbonate (20.8 g, 0.5 eq.) was again added to the suspension and the mixture was stirred for 1 h. The product suspension was clarified by filtration and the filter cake was washed once with acetonitrile (110 mL) in the kettle. The filter cake was discarded.

[0605] The organic reaction solution was concentrated in an inerted 2 L reactor at 90 mbar and 45° C. Tsheath until the distillate was dry. At a Tsheath of 23° C., THF (425 mL) was added. The solution was concentrated at a Tsheath of 150 mbar and 45° C. until the distillate was dry. THF (425 mL) and 4% NaOH (680 mL) were added to the solution. The emulsion was heated to a Tinternal of 60° C. and stirred for an additional 20 h.

[0606] The solution was cooled to 23°C Tinternal, deionized water (800ml) and ethyl acetate (435ml) were added and the mixture was stirred for 15 minutes. The phases were separated. The organic phase was discarded and the aqueous phase was extracted with ethyl acetate (435mL). The organic phase was discarded and the aqueous phase was distilled at 140-160mbar and 45-40°C Tsheath-36°C Tinternal. The product solution was clarified by filtration and the filter cake was washed once with deionized water (80mL). The residue was discarded.

[0607] The product solution was titrated. For this purpose, 25% HCl, deionized water and THF were placed in an inerted 4 liter reactor. The organic product solution was added at 20°C ± 5°C Tinternal up to a pH of 3.8-4.2. Then THF (360 mL) and sodium chloride (471 g) were added and the mixture was stirred for 30 minutes. The phases were separated and the aqueous phase was extracted with THF (450 mL). The aqueous phase was discarded and the organic phase was crystallized. For this purpose, it was concentrated to a sump mass at 200 mbar and a ΔT of 30°C. Then THF was added and the mixture was distilled again under the same conditions to 4 times the theoretical yield. At 22°C Tinternal, a mixture of deionized water (49 mL, 49 g) and methanol (144 ml, 114 g) was weighed, seeded and stirred for 15 minutes. A mixture of deionized water (113 ml, 113 g) and methanol (335 mL, 265 g) was further metered in and the mixture was stirred overnight. The suspension was filtered and the product was washed once in a kettle with a mixture of deionized water and methanol (1:1). It was then dried at 40-50° C. and 40-30 mbar. Yield: 23.4 g, 67% of theory Purity (area): 99.3% (new method M, Rt of 6.28) XRPD: Monohydrate I, see Figure 39

[0608] Example 6 Study to investigate the crystal / polymorphic form of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I

[0609] Example 6a (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid hemihydrate 2.9 g of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate I (material prepared similarly to Example 3 / 4) was suspended in 20 ml of acetone. The suspension was stirred at ambient conditions for 3 days. The residue was filtered and the resulting solid was dried at ambient conditions. Water Content: 1.5% water Raman: see Table 13, see Figure 12 IR: See Table 14, see Figure 19 XRPD: see Table 12; see Figure 5

[0610] Example 6b (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahyd...

Claims

1. The monohydrate crystalline form of Compound 1: 。

2. 2. The monohydrate crystalline form of claim 1, having X-ray powder diffraction reflections at 12.8±0.2 and 29.2±0.2 degrees 2θ using Cu—K alpha 1 as the radiation source when measured at 25° C.

3. 3. The monohydrate crystalline form of claim 2, having an additional reflection at at least one of 6.9±0.2, 7.2±0.2 or 7.3±0.2 degrees 2θ using Cu—K alpha 1 as the radiation source when measured at 25° C.

4. 3. The monohydrate crystalline form of claim 2, having additional reflections at at least one of 6.9±0.2, 7.2±0.2, 7.3±0.2, 15.2±0.2 or 23.0±0.2 degrees 2θ when measured at 25°C using Cu—Kalpha1 as a radiation source.

5. 2. The monohydrate crystalline form of claim 1 having X-ray powder diffraction reflections at 12.8±0.2, 16.0±0.2, and 25.8±0.2 degrees 2θ using Cu—K alpha 1 as the radiation source when measured at 25° C.

6. 6. The monohydrate crystalline form of claim 5, having an additional reflection at at least one of 6.9±0.2, 7.2±0.2 or 7.3±0.2 degrees 2θ using Cu—K alpha 1 as the radiation source when measured at 25° C.

7. 6. The monohydrate crystalline form of claim 5, having additional reflections at at least one of 6.9±0.2, 7.2±0.2, 7.3±0.2 or 15.2±0.2 degrees 2θ using Cu—Kalpha1 as the radiation source when measured at 25° C.

8. 2. The monohydrate crystalline form of claim 1 having X-ray powder diffraction reflections at 12.8±0.2, 20.5±0.2, and 25.8±0.2 degrees 2θ using Cu—K alpha 1 as the radiation source when measured at 25°C.

9. 9. The monohydrate crystalline form of claim 8, having an additional reflection at at least one of 6.9±0.2, 7.2±0.2 or 7.3±0.2 degrees 2θ using Cu—K alpha 1 as the radiation source when measured at 25° C.

10. 9. The monohydrate crystalline form of claim 8, having additional reflections at at least one of 6.9±0.2, 7.2±0.2, 7.3±0.2, 15.2±0.2 or 25.1±0.2 degrees 2θ using Cu—Kalpha1 as the radiation source when measured at 25° C.

11. The X-ray powder diffraction reflections measured at 25°C using Cu-K alpha 1 as the radiation source were 5.7±0.2, 6.9±0.2, 7.2±0.2, 7.3±0.2, 9.9±0.2, 10.4±0.2, 10.6±0.2, 11.1±0.2, 11.5±0.2, 12.0±0.2, 12.3±0.

2. ±0.2, 12.4±0.2, 12.8±0.2, 13.7±0.2, 14.1±0.2, 14.3±0.2, 15.2±0.2, 15.6±0.2, 16.0±0.2, 16.9±0.2, 17.2±0.2, 17.5±0.2, 17.7±0.2, 18.0±0.2, 18.4±0.2, 1 8.8±0.2, 19.2±0.2, 19.9±0.2, 20.2±0.2, 20.5±0.2, 20.7±0.2, 21.3±0.2, 21.9±0.2, 22.2±0.2, 22.5±0.2, 23.0±0.2, 23.4±0.2, 23.7±0.2, 24.1±0.2, 25.1±0. 2, 25.8±0.2, 26.0±0.2, 26.4±0.2, 28.9±0.2, 29.2±0.2, 29.4±0.2, 30.6±0.2, 31.1±0.2, 32.2±0.2 and 35.3±0.2 degrees 2θ.

12. 3. The monohydrate crystalline form of claim 2, having no X-ray powder diffraction reflections at 3.1±0.2 or 9.3±0.2 degrees 2θ using Cu—K alpha 1 as the radiation source when measured at 25°C.

13. 6. The monohydrate crystalline form of claim 5, having no X-ray powder diffraction reflections at 3.1±0.2 or 9.3±0.2 degrees 2θ using Cu—K alpha 1 as the radiation source when measured at 25°C.

14. 9. The monohydrate crystalline form of claim 8, having no X-ray powder diffraction reflections at 3.1±0.2 or 9.3±0.2 degrees 2θ using Cu—K alpha 1 as the radiation source when measured at 25°C.

15. 12. The monohydrate crystalline form of claim 11, having no X-ray powder diffraction reflections at 3.1±0.2 or 9.3±0.2 degrees 2θ using Cu—Kalpha1 as the radiation source when measured at 25°C.

16. 3. The monohydrate crystalline form of claim 2, having no X-ray powder diffraction reflections at 6.1±0.2 or 8.5±0.2 degrees 2θ using Cu—K alpha 1 as the radiation source when measured at 25°C.

17. 6. The monohydrate crystalline form of claim 5, having no X-ray powder diffraction reflections at 6.1±0.2 or 8.5±0.2 degrees 2θ using Cu—K alpha 1 as the radiation source when measured at 25°C.

18. 9. The monohydrate crystalline form of claim 8, having no X-ray powder diffraction reflections at 6.1±0.2 or 8.5±0.2 degrees 2θ using Cu—K alpha 1 as the radiation source when measured at 25°C.

19. 12. The monohydrate crystalline form of claim 11, having no X-ray powder diffraction reflections at 6.1±0.2 or 8.5±0.2 degrees 2θ using Cu—Kalpha1 as the radiation source when measured at 25°C.

20. 3. The monohydrate crystalline form of claim 2, having no reflections at any one of 3.1±0.2, 6.1±0.2, 7.6±0.2, 7.9±0.2, 8.5±0.2, 9.3±0.2, 14.8±0.2, 30.0±0.2, or 31.6±0.2 degrees 2θ in X-ray powder diffraction using Cu—Kalpha1 as the radiation source when measured at 25° C.

21. 6. The monohydrate crystalline form of claim 5, having no reflections at any one of 3.1±0.2, 6.1±0.2, 7.6±0.2, 7.9±0.2, 8.5±0.2, 9.3±0.2, 14.8±0.2, 30.0±0.2, or 31.6±0.2 degrees 2θ in X-ray powder diffraction using Cu—Kalpha1 as the radiation source when measured at 25° C.

22. 9. The monohydrate crystalline form of claim 8, having no reflections at any one of 3.1±0.2, 6.1±0.2, 7.6±0.2, 7.9±0.2, 8.5±0.2, 9.3±0.2, 14.8±0.2, 30.0±0.2, or 31.6±0.2 degrees 2θ in X-ray powder diffraction using Cu—Kalpha1 as the radiation source when measured at 25° C.

23. 12. The monohydrate crystalline form of claim 11, having no reflections at any one of 3.1±0.2, 6.1±0.2, 7.6±0.2, 7.9±0.2, 8.5±0.2, 9.3±0.2, 14.8±0.2, 30.0±0.2, or 31.6±0.2 degrees 2θ in X-ray powder diffraction using Cu—Kalpha1 as the radiation source when measured at 25°C.

24. 10. The monohydrate crystalline form of claim 1 having the X-ray powder diffractogram shown in Figure 6.

25. At least the following maximum bands: 3073, 2950, ​​2937, 1685, 1616, 1527, 1293, 1278, 1259 cm-1 2. The monohydrate crystalline form of claim 1, having a Raman spectrum having

26. A process for preparing a compound of formula (I), comprising: In the first step [A], a compound of formula (XII-1) solubilized in a suitable solvent is (In the formula, R ３ and R ４ became independent and became C １ ~C ４ -alkyl) is reacted with sodium hydroxide solution to give the disodium salt (I-DiNa) which, after extractive purification but without further isolation, is reacted in a second step [B] by adding the reaction solution in portions to a mixture of mineral acids in a suitable solvent until a pH value of 3.8 to 4.2 is reached, wherein the initially charged mineral acid mixture has a pH value of less than 3.8 and contains a maximum of 2 equivalents of acid relative to the disodium salt, and finally to a compound of formula (I) which results in a compound of formula The method.

27. In the first step [C], a compound represented by the formula (X-1) (In the formula, R ３ and R ４ became independent and became C １ ~C ４ -alkyl) in the presence of a base selected from the group consisting of alkali carbonates, alkali hydroxides, or tetraalkylammonium carbonates, to form a compound of formula (XI) to react with a compound of formula (XII-1) (In the formula, R ３ and R ４ became independent and became C １ ~C ４ -alkyl), The compound of formula (XII-1) is further characterized in that it reacts without further purification in the sequential steps [A] and [B] according to claim 26.

27. A process for preparing a compound of formula I according to claim 26.

28. In the first step [D], a compound of formula (XII-NSA-1) (In the formula, R ３ and R ４ became independent and became C １ ~C ４ 27. A process for preparing a compound of formula I according to claim 26, characterized in that an NSA salt of (XII-1), (XII-1 is -alkyl), is treated with a suitable ether and stirred with water and aqueous ammonia at a temperature of 10°C to 25°C, whereby a pH value of 7.8 to 8.2 is finally reached, after which the reaction mixture is treated with a water-immiscible organic solvent, the phases are separated, and finally the organic phase is concentrated to give a butyl ester of formula (XII-1), which is reacted without further purification in the sequential steps [A] and [B] according to claim 26.

29. 1. A process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in crystalline form, comprising: Formula (I) is crystallized from a mixture of polar solvents, the polar solvents being selected from the list consisting of methanol, acetone, and water, and a mixture of at least methanol and water is required at a temperature between 20°C and 100°C, and compound (IM-I) is isolated, optionally after cooling, the X-ray diffractogram (at 25° C. and using Cu—K alpha 1 as radiation source) of said compound of formula (IMI) is characterized in that it shows at least the following reflections, expressed as 2θ values ​​±0.2°: 12.8 and 29.2; The method.

30. 30. A process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in crystalline form according to claim 29, comprising:

1. A process for the preparation of a solid compound of formula I, comprising the steps of: first dissolving the acid of formula I in a 1:1 mixture of methanol and acetone, preferably in an amount (g) of each solvent that is 4 times the amount (g) of the solid compound of formula I (8 times the amount (g) of said 1:1 mixture), at a temperature of 50° C.; cooling to room temperature, preferably 20° C.; the solution is clarified by filtration; heating again to 50° C.; and adding dropwise over a period of time water in an amount (g) of 1.8 times the amount (g) of the solid compound of formula I. The method.

31. 31. Process for preparing (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (I) in the crystalline monohydrate I (I-M-I) according to claim 29 or 30, characterized in that the acid of formula I is prepared by one of the processes according to any one of claims 26 to 28.

32. Formula (XIII): Compound.

33. A pharmaceutical composition comprising crystalline form monohydrate I of formula (IMI) of the compound of formula (I) according to any one of claims 1 to 25, and optionally further pharmaceutically acceptable excipients.

34. Crystalline form monohydrate I of formula (IMI) of the compound of formula (I) according to any one of claims 1 to 25 for use in the treatment and / or prevention of cardiopulmonary diseases.

35. 34. The pharmaceutical composition of claim 33 for use in the treatment and / or prevention of cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

36. Use of a compound according to any one of claims 1 to 25 for the preparation of a pharmaceutical composition for the treatment or prevention of cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

37. Use of a compound of formula (IMI) according to any one of claims 1 to 25 for the manufacture of a stable inhalation dosage form for use in a dry powder inhaler.

38. Use of a compound of formula (IMI) according to any one of claims 1 to 25 in the manufacture of a medicament for the treatment or prevention of cardiopulmonary disorders.

39. 39. The use of claim 38, wherein the cardiopulmonary disorder is selected from the group consisting of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH) in mammals, and pulmonary hypertension (PH) associated with chronic lung disease (Group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

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