Pharmaceutical dry powder inhalation formulations

Abstract

The present invention relates to (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 in the form of one of its salts or solvates or hydrates, 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) of formula (IMI) or (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2- The present invention relates to a pharmaceutical dry powder formulation comprising {[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate (II) in combination with a lactose carrier comprising lactose monohydrate as a mixture of coarse and fine lactose, a process for producing such a pharmaceutical dry powder formulation, and its application for use in the treatment 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 associated with idiopathic interstitial pneumonia (PH-IIP).

Description

Summary of the Invention

[0001] The present invention relates to (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 in the form of one of its salts or solvates or hydrates, 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 of formula (IMI) or (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 of formula (IM-II) The present invention relates to a pharmaceutical dry powder formulation comprising [3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate II in combination with a lactose carrier comprising lactose monohydrate as a mixture of coarse and fine lactose, a process for producing such a pharmaceutical dry powder formulation, and its application for use in the treatment 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 associated with idiopathic interstitial pneumonia (PH-IIP).

[0002] The present invention relates to (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 monohydrate I of formula (IMI) or ...-II) The present invention further relates to a specific manufacturing process for making a pharmaceutical dry powder 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 monohydrate II in a chemically stable form, i.e., a form that is resistant to moisture, and during inhalation, a high fraction of active ingredient inhaled particles are released from the formulation relative to the nominal drug content per unit dose, and the active ingredient exhibits a stable and adequate distribution in the lactose carrier matrix.

[0003] The present invention further relates to the use of pharmaceutical dry powder formulations comprising the compounds of formula (I), (IMI) and (IM-II) in combination with a lactose carrier for use in the treatment of 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 associated with idiopathic interstitial pneumonia (PH-IIP). More particularly, the present invention relates to methods of treating cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), and pulmonary hypertension (PH) associated with chronic lung disease (group 3 PH), such as PH-COPD and PH-IIP.

[0004] (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 corresponds to formula (I). TIFF2025501302000001.tif78165 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 called (IMI) and the monohydrate II of crystalline modification II being called (IM-II). Without further distinction, the compound of formula (I) exists in one or more modifications or as a solvate, in particular a hydrate.

[0005] The novel crystalline 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 is, in particular, the pseudopolymorphic form monohydrate I (IMI) or pseudopolymorphic form monohydrate II (IM-II) corresponding to the formula (IMI), (IM-II), TIFF2025501302000002.tif78165

[0006] The compounds of formula (I), (IMI) and (IM-II) function as activators of soluble guanylate cyclase and can be used as medicaments for the prevention and / or treatment of pulmonary, cardiopulmonary and cardiovascular diseases, such as pulmonary arterial hypertension (PAH), 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 associated with idiopathic interstitial pneumonia (PH-IIP), more particularly it relates to a method of treating cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), and pulmonary hypertension (PH) associated with chronic lung disease (group 3 PH), such as PH-COPD and PH-IIP. [Background technology]

[0007] Pulmonary hypertension (PH) is a progressive lung disorder that, if untreated, leads to death within several years of diagnosis. Pulmonary hypertension is defined by elevated mean pulmonary artery pressure (mPAP) (normal value of <20 mmHg at rest). The pathophysiology of pulmonary hypertension is characterized by vasoconstriction and remodeling of pulmonary vessels. In chronic PH, there is primarily neomuscularization of non-muscularized pulmonary vessels, with an increase in vascular muscle mass around previously muscularized vessels. This increasing obstruction of pulmonary circulation leads to 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, while secondary pulmonary hypertension (non-PAH PH) is very common and 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. Montani and G. Simonneau, in: A. J. Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3rd edition, Hodder Arnold Publ., 2011, pp. 197-206 (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: Hemodynamic definitions and updated clinical classification of pulmonary hypertension]. hypertension, in: European Respiratory Journal, 2018; DOI: 10.1183 / 13993003.01913-2018 (Non-patent Document 4)].

[0008] Despite all the advances in the treatment of PH, there is still no cure in sight for this serious disorder. Available standard therapies (e.g., prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase inhibitors) can improve patients' quality of life, exercise tolerance, and prognosis. These are primarily administered systemically (in addition to inhaled treprostinil and inhaled iloprost or NO) and primarily act hemodynamically by regulating vascular tone. The applicability of these medications is limited due to side effects, some of which are severe, and / or complex administration forms. The period during which a patient's clinical condition can be improved or stabilized by a specific monotherapy is limited (e.g., due to the development of tolerance). Finally, therapy escalates, and therefore, combination therapy is applied, in which multiple medications are given simultaneously. Currently, these standard therapies are approved only for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). In the case of secondary forms of PH associated with lung disease (group 3 PH), such as PH-COPD or PH-IIP, these therapeutic principles (e.g., sildenafil, bosentan) have failed in clinical studies because they result in a reduction in arterial oxygen content (desaturation) in patients as a result of non-selective vasodilation. This is probably due to the adverse effect of systemic administration of non-selective vasodilators on ventilation-perfusion adaptation in the lungs in heterogeneous lung injury [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)].

[0009] New combination therapy is one of the most promising future therapeutic options for the treatment of pulmonary hypertension. In this regard, the discovery of new pharmacological mechanisms for the treatment of PH is particularly interesting (Ghofrani et al., Herz 2005, 30, 296-302 (Non-Patent Document 7); E. B. Rosenzweig, 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 the concepts of already available therapies can form the basis for more efficient treatment 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 of using it for PAH, but also as a first therapeutic option for patients suffering from secondary forms of PH (group 3 PH), since non-selective systemic vasodilation is avoided by targeted application to the ventilated areas of the lung via inhalation application.

[0010] Oxidative stress, associated with many cardiopulmonary diseases, leads to dysfunction in the nitric oxide / soluble guanylate cyclase signaling pathway, which shifts native soluble guanylate cyclase to a heme-free apo-soluble guanylate cyclase. Specifically targeting this NO-insensitive form of sGC offers the potential to unlock unprecedented therapeutic opportunities for treating various cardiopulmonary diseases. sGC activators, through their unique mode of action by restoring critical cGMP signaling under conditions of oxidative stress, combined with novel topical and lung-selective application, could represent a powerful new therapeutic option for patients with pulmonary hypertension, with both enhanced efficacy and fewer adverse effects.

[0011] In an animal model of pulmonary hypertension, inhaled administration of the sGC activator BAY 58-2667 (cinacigato) in microparticle form has been demonstrated to result in a dose-dependent, selective reduction in pulmonary arterial 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 inhaled administration of sGC activators may represent a novel, effective treatment for patients with pulmonary hypertension, particularly when their response to iNO and / or PDE5 inhibitors is reduced as a result of a lack of NO or 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 a sufficient duration of action, and in addition, higher dosages resulted in undesirable systemic side effects.

[0012] Merck Sharp Dohme is developing an inhaled sGC stimulator (MK5475; NCT04609943) as a dry powder for PAH. However, in PH and other lung diseases, responsiveness to inhaled nitric oxide (iNO) and sGC stimulators can be impaired by oxidation of sGC. Inhaled sGC activators targeted to the lungs could overcome this limitation.

[0013] In the field 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 associated with idiopathic interstitial pneumonia (PH-IIP), patients with PH due to underlying lung disease (group 3 PH) are primarily treated with drugs developed for the associated lung disease (e.g., COPD). Certain PH drugs (e.g., IP agonists, PDE5 inhibitors, endothelin antagonists, and sGC stimulators) are approved only for PAH and CTEPH and have only been used experimentally in the treatment of group 3 PH due to the observed desaturating effects of these systemically applied vasodilators.

[0014] 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 local drug concentration and avoid systemic side effects of the drug caused by systemic availability. Generally, less frequent dosing regimens are desirable, for example, to improve patient adherence to therapy (patient compliance), but 24-hour coverage must be ensured for sustained availability of hemodynamically active drugs during the dosing interval. Many lung-targeted inhaled drugs (e.g., iloprost / ventavis) require frequent application schemes due to, for example, their short half-life and / or lung residence time, which necessitates multiple daily applications for 24-hour coverage. In particular, once-daily application is preferred due to the convenience of patients and compliance. However, this goal is often difficult to achieve, depending on the specific behavior and properties of the drug substance, particularly its lung selectivity and lung residence time.

[0015] An additional mode of systemic administration, injection, is still associated with numerous drawbacks (e.g., the inconvenience of requiring a clinical visit, discomfort, patient aversion to needle-based delivery methods, and drug reactions at the site of administration), all of which further call for alternative routes of administration.

[0016] Pulmonary delivery by inhalation is one such alternative route of administration that may offer several advantages over oral and injection administration, including, inter alia, 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.

[0017] For pharmaceutical preparations for inhalation that do not require adjuvants, especially solid preparations for suspension inhalation, the preparation may consist of the active ingredient alone. However, for practical reasons, for example, to facilitate the drug delivery of very low doses of the active ingredient, the preparation often 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 inhalation drug delivery techniques can be found, for example, in the book "Inhalation Drug Delivery - Techniques and Products" by Paolo Colombo, Daniela Traini, and Francesca Buttini (published by Wiley-Blackwell 2013) and the literature described therein. In 2019, Moon et al. published an updated review of delivery techniques for oral inhalation products (Moon et al., AAPS PharmSciTech (2019) 20:117 pp 1-17).

[0018] prior art Various 5-amino-5,6,7,8-tetrahydroquinoline-2-carboxylic acids and their pharmaceutical use in cardiovascular and cardiopulmonary diseases, such as PAH, are disclosed in patent application WO 14 / 012934-A1 (Patent Document 1).

[0019] In-house 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 also disclosed in WO2014 / 012934. Thus, (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 suitable for use in the treatment of cardiopulmonary diseases.

[0020] There has been no disclosure of a specific carrier-based inhaled medicament for use in the treatment of cardiopulmonary diseases, 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 associated with idiopathic interstitial pneumonia (PH-IIP), comprising a dry powder formulation 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 and a lactose carrier.

[0021] To provide a novel, suitable inhalation dosage form for use in the treatment of cardiopulmonary diseases, an inhalation dosage form containing (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 the active ingredient is needed. As a preferred formulation option, dry powder inhalation dosage forms have been selected due to their compatibility, convenience, and patient compliance and adherence. Dry powder inhalation dosage forms require that 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, be provided in a single, defined crystalline form.

[0022] However, as disclosed in Example 23 of WO 14 / 012934-A1 (Patent Document 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 of formula (I) can only be obtained in amorphous form, which is not suitable for use in inhalation dosage forms applied by means of a dry powder inhaler.

[0023] There was therefore a need to provide novel, suitable, dry powder-based inhalation dosage forms for use in the treatment of cardiopulmonary diseases, in particular for use in the treatment of 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 associated with idiopathic interstitial pneumonia (PH-IIP).

[0024] Formulations for pulmonary delivery For inhalation therapy, three drug product formulation options are generally available and can be selected based on the required dose, patient population and related characteristics, and active ingredient stability. If the solubility and stability of the active ingredient allow, one form of formulation is a nebulized solution. Disadvantages of nebulized drugs are often poor delivery efficiency (production of a low fraction of inhaled droplets less than 5 μm), extended application time per treatment, and lack of portable device options for on-demand therapy (and the need for a power source).

[0025] A second option is the pressurized metered dose inhaler (pMDI), which offers enhanced portability, does not require a power source, and offers the opportunity to deliver low doses (higher doses are often not feasible). Disadvantages include the use of organic solvents (propellants), the requirement for special manufacturing techniques, and, very importantly, the need to coordinate breathing technique with device actuation. This often results in inadequate drug delivery (and therapy) and low patient compliance.

[0026] Dry powder inhalers (DPIs) have important advantages, such as a compact, portable design, the ability to deliver drugs over a wide range of doses, independence from drug solubility, and the absence of coordination between breathing and device actuation (passive devices). Thus, for many applications and therapeutic options, DPIs constitute the preferred technology of choice.

[0027] Dry powder inhalers (DPIs) are commonly used to treat pulmonary diseases, such as asthma and pulmonary infections, and consist of a powder formulation in a device that can be inhaled into the lower respiratory tract. Key features that make inhalation an attractive drug delivery mode are optimized drug delivery through direct targeting of the drug to the site of action, reduced systemic side effects, rapid onset of action, and improved patient tolerance, adherence, and compliance due to the non-invasive nature of this drug administration route. The delivery efficiency of dry powder products for inhalation depends on the drug formulation, the inhalation device, and the inhalation technique.

[0028] The general goal when using pharmaceutical formulations for pulmonary delivery is to deliver the highest possible amount of drug relative to the nominal content of the dosage unit.In contrast, the deposition of inactive ingredients in the lungs should be minimized to the lowest possible amount that is justified.There are different general formulation strategies for inhalable formulations, and all of them follow the strategy of optimizing and increasing the active ingredient fine particle deposition of drug particles less than 5 μm, while minimizing exposure to inactive ingredients.

[0029] For DPI, the simplest way to achieve this goal is to deliver the active ingredient in micronized form alone without any carrier, but this strategy is limited due to the nature of drug, more importantly, the target human dose is typically very low.However, for DPI formulation, this approach is of low practical importance.

[0030] Another strategy is to formulate micronized drug particles or dissolved drug into engineered particles, where the drug is formulated with inactive ingredients to yield shaped particles, which can be coated drug microparticles or porous particles or matrix particles with a fairly uniform or narrow particle size distribution of 5 μm or less to increase the amount of drug delivered to the deep lung and airways. One disadvantage of these formulations is that the carrier and drug are bound together and delivered to the site of action together. A comprehensive overview of non-carrier-based dry powder inhalation formulations (engineered particles) has been published by Healy et al. (Advanced Drug Delivery reviews 75 (2014) pp 32-52).

[0031] Although there are several published studies investigating the effects of variables in adhesive drug carrier mixtures, a fundamental understanding remains limited. Overall, it remains difficult to predict aerosol performance for a given mixture, as there are many potential effects that may occur simultaneously and have the potential to be competitive, synergistic, or antagonistic, particularly due to the specific surface and physical properties of the active ingredient compound particles themselves.

[0032] Many years of research and development have been conducted to investigate the mechanisms involved in the formulation and dispersion of carrier-based mixtures for inhalation [de Boer et al. in: A critical view on lactose-based drug formulation and device studies for dry powder inhalation: Which are relevant and what interactions to expect? Advanced Drug Delivery Reviews 64 (2012) 257-274 (Non-Patent Document 14), Grasmejier et al: Recent Advances in the Fundamental Understanding of Adhesive Mixtures for Inhalation; Current Pharmaceutical Design 21 (2015), 5900-5914 (Non-Patent Document 15)].

[0033] However, because different factors and components influence each other and, additionally, are highly dependent on the drug substance properties, there is currently no derivable, clear guidance and guidelines on how to design new carrier-based mixtures for inhalation for new drug substances. As a result, those skilled in the art of drug product development, when faced with the task of developing new carrier-based mixtures for inhalation, need to follow a new design and development approach for each new active ingredient.

[0034] The most common overall strategy is to formulate the active ingredient with an inert carrier compound into a dry powder blend, in which micronized drug particles adhere to an inert carrier, which is most often lactose or other sugar-related compounds, such as sugar alcohols, e.g., mannitol. Here, the basic mechanism of drug delivery is the temporary adhesion of micronized drug particles to larger inert carrier material particles, and the subsequent deagglomeration or release of the micronized active drug particles from the carrier, which is affected by the airflow energy generated in the dry powder inhaler used for applying the formulation. Most of the carrier material is not intended to be inhaled, and due to its size, it settles in the upper respiratory tract, mainly in the mouth and throat. During inhalation, adhesive forces must be overcome to release the drug particles from the carrier, and therefore it is extremely important to control the adhesive forces of the drug on the carrier to enable optimal release of a high portion of the dose available for drug delivery into the deep lung.

[0035] The majority of DPI products are carrier-based formulations consisting of finely ground drug particles mixed with coarse carrier particles, usually lactose monohydrate. However, lactose has several disadvantages when used as an excipient for DPIs, so alternative carriers, such as glucose, trehalose, sorbitol, and (lyophilized) mannitol, are also used. For example, lactose is incompatible with drugs that have primary amine groups and is therefore less suitable for next-generation inhalable products containing sensitive drugs.

[0036] Lactose can be obtained in either of two basic isomeric forms, i.e., α- and β-lactose, or in an amorphous form. α-lactose exists in both monohydrate and anhydrous forms, with the monohydrate form being the most thermodynamically stable. α-lactose monohydrate is prepared by crystallization from a supersaturated solution below 93.5°C. The crystalline shape can be prismatic, pyramidal, or hatchet-shaped, depending on the precipitation and crystallization method. Anhydrous lactose (typically containing 70-80% anhydrous β-lactose and 20-30% anhydrous α-lactose) is most often produced by roller drying a lactose solution above 93.5°C. Both resulting products are then milled to reduce particle size and sieved to select the appropriate particle size distribution. Spray-dried lactose is obtained by spray-drying a suspension of α-lactose monohydrate crystals in water in a lactose solution. At temperatures above 93.5°C, anhydrous β-lactose is formed, below this temperature α-lactose monohydrate is obtained [G. Pilcer, N. Wauthoz, K. Amighi, Lactose characteristics and the generation of the aerosol, Adv Drug Del Reviews 64 (2012) 233-256 (Non-Patent Document 16)].

[0037] There are many different types of lactose with different physicochemical properties that can be used in DPI formulations. Lactose can be processed by either milling, sieving, spray drying, or granulation to produce different properties. Thus, lactose excipients are commercially available in various grades, which have different physicochemical properties, particularly related to coarseness, shape, particle size, particle size distribution, water content, compressibility, or surface area. The aerosol performance of powders is highly dependent on lactose characteristics, such as particle size distribution and shape and surface properties. [G. Pilcer, N. Wauthoz, K. Amighi, Lactose characteristics and the generation of the aerosol, Adv Drug Del Reviews 64 (2012) 233-256 (Non-Patent Document 16)]

[0038] Additional processes for lactose particle manipulation, such as seeding, crystallization, coating, molding, condensation, and precipitation, have been reported and result in materials with different physicochemical properties, such as particle size, size distribution, fines content, shape, surface roughness, flow properties, electrostatic charge, and properties related to solid-state changes [X. Kou, L. Wah Chan, H. Steckel, P.W.S. Sheng, Physico-chemical aspects of lactose for inhalation, Adv. Drug Del. Reviews 64 (2012) 220-232 (Non-Patent Document 17)].

[0039] In carrier-based mixtures for inhalation, a proper balance needs to be established between blend stability during storage and handling and dispersibility during inhalation. It has been shown that variables related to these processes can affect each other in different ways, and that by changing one variable, the effect of several other variables can be reversed. This may explain why opposite conclusions have been drawn in the literature regarding the effect of single variables. [De Boer, 2012]

[0040] There is agreement that a series of subsequent processes, including the selection or preparation of starting materials, the mixing process, dispersion and deagglomeration in an inhalation device, and finally, aerosol characterization, are necessary to identify suitable formulations that yield beneficial in vitro deposition results.

[0041] The carrier properties required depend on the type of drug being processed, the drug concentration (% w / w) in the mixture, the determined drug dose and amount of powder to be metered by (or into) the dosing system, and the type of mixing process intended to be used [De Boer, 2012].

[0042] The interfacial forces between the drug and carrier are considered along with particle preparation techniques, such as milling, condensation, spray drying, precipitation, and crystallization, which result in different particle surface properties that can directly affect the drug-carrier interaction. [De Boer, 2012]

[0043] The main challenge is to find the optimal balance between the three types of forces that determine particle deposition from dry powder inhaler (DPI) systems: interparticle forces in the mixture, dispersion forces generated by the inhalation device during inhalation, and deposition forces for aerosol particles in the respiratory airways [De Boer, 2012].

[0044] The design of the DPI controls powder deagglomeration in the device. All commercially available passive DPIs have three common design features: a mouthpiece, an air inlet, and a powder storage / dispensing system. Other features, such as a grid and a rotating capsule, may also be present to facilitate powder deagglomeration. [De Boer, 2012]

[0045] Additional factors may be the role of the rotating capsule and the influence of airflow rate in the device. De Boer et al. have shown that additional variables that interact with each other have an effect on the preparation and dispersion process of carrier-based formulations for inhalation, including drug properties, carrier surface properties, carrier bulk properties, carrier surface payload, mixing process, mixture properties, inhalation process, storage, and adjustment, to name a few. [de Boer et al. in: Dry powder inhalation: past, present, and future. Expert opinion on drug delivery, 2017 Vol. 14, No. 4, 499-512 (Non-Patent Document 18)]

[0046] Thus, in practice, (a) pharmaceutical formulation of a mixture for inhalation, and (b) selection of a suitable carrier, and (c) selection or design of an inhalation device remain empirical processes that require the development, adaptation, and manipulation of certain parameters to obtain a customized formulation for each drug substance with sufficient stability and good aerosol performance characteristics.

[0047] These constitute important properties that are not predictable from the prior art references.

[0048] There was therefore a need to provide novel, suitable, dry powder-based inhalation dosage forms for use in the treatment of cardiopulmonary diseases, in particular for use in the treatment of 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 associated with idiopathic interstitial pneumonia (PH-IIP).

[0049] The production of DPI carrier-based powders generally involves various steps, such as producing drug and carrier particles in a suitable size range (by sieving, milling, spray drying, etc.), mixing the various components under appropriate blending conditions with optimized parameters, and, if necessary, modifying the surface properties of the particles to enhance aerosol performance.

[0050] Especially for low-drug-dose formulations containing micronized drug particles, optimal mixing is required to achieve drug uniformity. In the case of cohesive powders, such as those encountered in dry powder formulations for inhalation, the presence of small drug particles in combination with coarse lactose particles promotes the formation of a stable, orderly mixture in which the drug particles adhere to larger particles that act as carriers. However, in the case of ternary mixtures to which a certain proportion of fine excipients is added, some mixing problems are encountered, such as agglomeration (the formation of fine and / or drug clusters due to the cohesive properties of these small particles) and segregation (or demixing, which is characterized by differences in particle size, shape, and density, or the separation of coarse particles from fine particles induced by particle aggregation). In fact, fine excipients improve aerosol performance by promoting the adhesion of drug particles to sites with lower energy than the active sites of the carrier. This reduces active ingredient adhesion, thus affecting drug uniformity and redispersion. An optimal dry powder formulation requires a balance between adhesive strength sufficient to ensure drug uniformity and a blend that is stable during handling but weak enough to rapidly release drug particles from the carrier during inhalation. As a result, segregation during mixing can be an additional obstacle in the development of dry powder formulations for inhalation.

[0051] Optimal mixing depends on sufficient expansion of the powder bed, mixer and powder characteristics, and optimization of container filling to ensure mixing conditions. Mixers are based on one or more of the following mechanisms: (1) convection, which is the movement of groups of adjacent particles from one location to another in a blend; (2) shear, which is a change in the configuration of components through the formation of sliding surfaces or shear strain within the powder bed; and (3) diffusion, which is the redistribution of individual particles due to their random movement relative to one another. Mixers can be classified as segregating and non-segregating mixers. The choice of mixer depends on the tendency of the powder blend to segregate and form agglomerates. For mixtures containing powder blends that promote particle segregation, non-segregating mixers must be used; for mixtures that do not suffer from demixing, either type of mixer can be used. In the case of aggregation due to the cohesive nature of smaller components, additional stress (shear) is required to break down the agglomerates during mixing. Therefore, high-shear mixers are frequently used to prepare premixes of cohesive drug substances. Optimal mixing times are required to obtain a homogeneous blend. Increasing the mixing time can improve the homogeneity of non-segregated mixtures, but not necessarily that of segregated mixtures. The use of a pre-blending step, i.e., a step in which the drug is blended with a small amount of excipients, can reduce the total mixing time. In contrast, achieving a multi-component mixture can increase the mixing time to reach homogeneity. [G. Pilcer, N. Wauthoz, K. Amighi, Lactose characteristics and the generation of the aerosol, Adv Drug Del Reviews 64 (2012) 233-256 (Non-Patent Document 16)]. [Prior art documents] [Patent documents]

[0052] [Patent Document 1] WO2014 / 012934 [Non-patent literature]

[0053] [Non-licensed document 1] M.Humbert et al.,J.Am.Coll.Cardiol.2004,43,13S-24S [Non-licensed document 2] M.Humbert and VVMcLaughlin,J.Am.Coll.Cardiol.2009,54(1),S1-S2 [Non-licensed 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

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

[0054] Detailed Description of the Invention Solid forms of the acids of formula (I) The preparation of compounds of formula (I) is disclosed in WO2014 / 012934 (see Example 23) and is 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). Scheme 1: Synthesis 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 disclosed in WO2014 / 012934 TIFF2025501302000003.tif62165

[0055] However, this process provides the compound of formula I only in amorphous form (see Comparative Example 11).

[0056] Another precursor of the compound of formula (I), namely, ethyl-5-([2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]{2-[4-(methoxycarbonyl)phenyl]ethyl}amino)-5,6,7,8-tetrahydroquinolinecarboxylate (compound XII). An improved synthesis of TIFF2025501302000004.tif73165 is disclosed in WO2021 / 233783. However, the synthetic approach to the compound of formula (I) itself is not disclosed in this reference.

[0057] The novel, unpublished process shown in Scheme 2 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 process according to the present invention offers 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 can be prepared by starting from a solid NSA salt of formula (XII-NSA) (process steps [D], [A] and [B] = Route 3). Scheme 2: Novel, undisclosed process for making compounds of formula (I), including process routes 1, 2 and 3 TIFF2025501302000005.tif209165

[0058] The core process (Route 1), including steps [A] and [B], is used in all three alternative routes. This process according to the present invention has several advantages over the prior art process disclosed in WO 2014 / 012934. Some by-products inevitably included in the product of Formula I when prepared according to the prior art procedures can be avoided or at least more easily separated. The inventors 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 perform this step in a reverse manner to control the pH of the reaction mixture (carefully monitored to remain within a pH range of 3.8 to 4.2). Therefore, process Step [B] requires the reverse addition of the disodium salt intermediate of Formula (I-DiNa) to an equimolar amount of the 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, small amounts of the primarily formed monosodium salt and other sparingly soluble impurities can be separated by clarifying filtration of the disodium salt solution. Additionally, further by-products, such as hydrochloride salt, are avoided by reverse addition.

[0059] 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 shown in process steps [C], [A] and [B]).

[0060] In alternative route (3), the compound of formula (I) can be prepared via its NSA salt, characterized in that in the 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 inverse addition to an acid to liberate the free acid of formula (I) (step [B]).

[0061] For the development of pharmaceutical forms, in particular dry powder inhalation forms, 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) in solid form, there is a high demand for the reproducible preparation and isolation of the compound of formula (I) in one defined crystalline form.

[0062] Many attempts were required to finally crystallize the compound of formula I into a defined solid form.

[0063] Surprisingly, the compound of formula I was obtained in several pseudopolymorphic forms, and no anhydrous crystalline form was found.

[0064] However, among several identified pseudopolymorphic forms, the most suitable stable form had to be identified during several steps.

[0065] The dihydrate was found to amorphize during the drying process (see Figure 10a). The crystal lattice of the hemihydrate exhibits disorder (see Figure 5), which can support phase transition and / or amorphization during mechanical processing, e.g., formulation processes. Crystallization of the sesquihydrate was not feasible for scale-up due to the lengthy stirring procedure.

[0066] Both monohydrates were found to overcome these undesirable properties of the different pseudopolymorphic forms.

[0067] Certain studies have 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 of formula (I) exists in certain polymorphic forms, in particular monohydrate form I (IMI) and monohydrate form II (IM-II). TIFF2025501302000006.tif73165

[0068] However, it was finally 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 preparation of inhaled medicaments, particularly dry powder-based inhaled medicaments. Surprisingly, it was found that during micronization, monohydrate II either partially amorphized (see Example 8b, Figure 42) or additionally converted to monohydrate I (see Example 8a, Figure 43), depending on the micronization conditions. Furthermore, it was observed that monohydrate II also converted to monohydrate I during storage (see Example 7b, Figures 40 and 41). Therefore, the pseudopolymorphic 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, particularly dry powder inhaled dosage forms.

[0069] 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). Scheme 3: Selective crystallization of the acid of formula (I) to obtain the monohydrate form TIFF2025501302000007.tif133165

[0070] Depending on the solvent used, either the monohydrate (IMI) or the monohydrate (IM-II) is formed. Surprisingly, crystallization from a mixture of methanol, acetone and water, or methanol and water, selectively yields compound (IMI), while crystallization from acetone water selectively yields the monohydrate in Form II (IM-II).

[0071] Furthermore, it has surprisingly been found that the monohydrate (IMI) ensures that the undesired conversion of the compound of formula (I) into other forms and the associated changes in the properties mentioned above are prevented. Therefore, the monohydrate form I is the most preferred crystalline 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).

[0072] 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 its diffractogram, which is recorded at 25°C and with Cu-K alpha 1 radiation (1.5406 Å). The monohydrate I according to the invention exhibits 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 given as values ​​below.

[0073] 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) that shows at least the following reflections, expressed as 2θ values ​​of ±0.2°, respectively: 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 or at least the following reflectances: 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.

[0074] 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 a 2θ value of ±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 and 25.8, 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.

[0075] 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-Kalpha1 as the radiation source) showing at least the following reflections, each expressed as a 2θ value of ±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.

[0076] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate I of formula (IMI), exhibits an X-ray powder diffractogram (at 25°C and using Cu-K alpha 1 as the radiation source) that shows the following reflections, each expressed as a 2θ value 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, 15.6, 16.0, 16.9, 17.2, 17.5, 17.7, 18.0, 18.4, 18.8, 19.2, 19.9, 20.2, 20.5, 20.7, 21.3, 21.9, 22.2, 22.5, 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.

[0077] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate I of formula (IMI), 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: 3.1 and 9.3, each expressed as a 2θ value of ±0.2°.

[0078] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate I of formula (IMI), 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: 6.1 and 8.5, each expressed as a 2θ value of ±0.2°.

[0079] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate I of formula (IMI), 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: 8.5 and / or 30, each expressed as a 2θ value ±0.2°.

[0080] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate I of formula (IMI), 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: 7.9 and / or 31.6, each expressed as a 2θ value ±0.2°.

[0081] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate I of formula (IMI), 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 of ±0.2°: 7.6.

[0082] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate I of formula (IMI), 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 of ±0.2°: 14.8.

[0083] 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) that shows, expressed as 2θ values ​​of ±0.2°, at least the following reflections: 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. 25.1, 17.7, and 23.7, or at least the following reflections: 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 reflections: 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 reflections: 6.1 and 8.5.

[0084] 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, expressed as 2θ values ​​±0.2°, respectively: 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, 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.

[0085] 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, expressed as 2θ values ​​±0.2°, respectively: 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, while not exhibiting at least the following reflections: 6.1 and 8.5.

[0086] 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 Figure 6.

[0087] The pseudopolymorphic form of the compound of formula (I), monohydrate I of formula (IMI), exhibits Raman spectroscopy with at least the following band maxima: 3073, 2950, ​​2937, 1685, 1616, 1527, 1293, 1278, 1259 cm −1 .

[0088] The pseudopolymorphic form monohydrate I of compound of formula (I) has been shown by IR spectroscopy to have at least the following band maxima: 2933, 1595, 1375, 1327, 1272, 1242, 1167, 1110 cm −1 .

[0089] Embodiment 7 (Monohydrate I of formula (IMI)) The present invention relates to a compound of formula (I) in crystalline form monohydrate I of formula (IMI), TIFF2025501302000008.tif78165 Provided is a compound 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.

[0090] The present invention 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°: 6.9, 7.2 and 7.3.

[0091] 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°: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0 and 15.2.

[0092] The present invention relates to 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, Further provided is a compound 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°: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7 and 23.7.

[0093] The present invention relates to 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, Further provided is a compound 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°: 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.

[0094] Alternatively, the present invention provides a compound of formula (I) in crystalline form monohydrate I of formula (IMI), TIFF2025501302000009.tif78165 Provided is a compound 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.

[0095] 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.

[0096] 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°: 6.9, 7.2 and 7.3, 12.8, 29.2, 23.0 and 15.2.

[0097] The present invention relates to 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, Further provided is a compound 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°: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8 and 25.1.

[0098] The present invention relates to 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, Further provided is a compound 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°: 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.

[0099] The present invention relates to a compound of formula (I) in crystalline form monohydrate I of formula (IMI), Further provided is a compound characterized in that the IR spectrum of the TIFF2025501302000010.tif78165 compound exhibits band maxima at 2933, 1595, 1375, 1327, 1272, 1242, 1167, 1110 cm-1cm-1.

[0100] The present invention relates to a compound of formula (I) in crystalline form monohydrate I of formula (IMI), TIFF2025501302000011.tif78165 Further provided is a compound characterized in that the Raman spectrum of the compound exhibits band maxima at 3073, 2950, ​​2937, 1685, 1616, 1527, 1293, 1278, 1259 cm-1.

[0101] 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.

[0102] In addition to monohydrate I, additional 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.

[0103] 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 diffractograms, which are recorded at 25°C and with Cu-K alpha 1 radiation (1.5406 Å). The pseudopolymorphic forms monohydrate II, hemihydrate, 1,25-hydrate, sesquihydrate and dihydrate exhibit at least 3, often at least 5, particularly at least 7, more particularly at least 10, and in particular all of the reflections indicated as values ​​below.

[0104] 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 shows, expressed as 2θ values ​​of ±0.2°, at least the following reflections: 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. and most preferably 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; also most preferably 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.

[0105] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), 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 a 2θ value 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, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 20.0, 20.1, 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1, 21.2, 21.3, 21.4, 21.5, 21.6, 21.8, 22.0, 22.2 .7, 16.4, 17.3, 17.7, 17.9, 18.3, 18.5, 18.8, 19.2, 19.8, 20.2, 20.8, 21.1, 21.7, 22.0, 22.4, 22.8, 23.1, 23.4, 23.9, 24.2, 24.4, 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.

[0106] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), 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: 3.1 and 9.3, each expressed as a 2θ value of ±0.2°.

[0107] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), 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: 6.9, 7.2, and 7.3, each expressed as a 2θ value of ±0.2°.

[0108] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), 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 of ±0.2°: 29.2.

[0109] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), 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: 7.9 and / or 31.6, each expressed as a 2θ value ±0.2°.

[0110] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), 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: 7.6, each expressed as a 2θ value ±0.2°.

[0111] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), 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 of ±0.2°: 14.8.

[0112] Additionally, the pseudopolymorphic form of the 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, expressed as 2θ values ​​of ±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 reflections: 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 reflections: 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 reflections: 6.9, 7.2 and 7.3.

[0113] The compound of formula (I) in 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 Figure 7.

[0114] The pseudopolymorphic form monohydrate II of compound of formula (IM-II) exhibits Raman spectroscopy with at least the following band maxima: 3073, 2950, ​​2936, 1685, 1615, 1526, 1294, 1279, 1259 cm −1 .

[0115] The pseudopolymorphic form monohydrate I of compound of formula (I) exhibits IR spectroscopy with at least the following band maxima: 2934, 1595, 1375, 1327, 1272, 1242, 1167, 1110 cm −1 .

[0116] Embodiment 8 (Monohydrate II of Formula (IM-II)) The present invention relates to a compound of formula (I) in crystalline form monohydrate II of formula (IM-II), TIFF2025501302000012.tif78165 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 ​​of ±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, 12.7, 23.9, 1 3.9, 23.1 and 12.2, more preferably at least the following reflections: 6.1, 8.1, 12.7, 23.9, 13.9, 23.1, 12.2, 10.8 and 15.3, most preferably at least the following reflections: 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.

[0117] The compound of formula (I) in 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 Figure 7.

[0118] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), 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: 3.1 and 9.3, each expressed as a 2θ value of ±0.2°.

[0119] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), 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: 6.9, 7.2, and 7.3, each expressed as a 2θ value of ±0.2°.

[0120] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), 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 of ±0.2°: 29.2.

[0121] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), 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: 7.9 and / or 31.6, each expressed as a 2θ value ±0.2°.

[0122] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), 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: 7.6, each expressed as a 2θ value ±0.2°.

[0123] Additionally, the pseudopolymorphic form of the compound of formula (I), monohydrate II of formula (IM-II), 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 of ±0.2°: 14.8.

[0124] Embodiment 9 (hemihydrate of the compound of formula (I)) The pseudopolymorphic form of the compound of formula (I), hemihydrate, can be unambiguously characterized by an X-ray powder diffractogram (at 25°C and using Cu-K alpha 1 as the radiation source) showing the following reflections, each expressed as a 2θ value of ±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.

[0125] The pseudopolymorphic form of the compound of formula (I), hemihydrate, can 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: 3.1, 5.3, 6.7, 7.1, 9.3 and 31.1, each expressed as a 2θ value of ±0.2°.

[0126] 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 Figure 5.

[0127] 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) that does not exhibit at least the following reflections: 6.9, 7.2, and 7.3, each expressed as a 2θ value of ±0.2°.

[0128] 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.

[0129] 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: 8.5 and / or 30.0, each expressed as a 2θ value ±0.2°.

[0130] 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: 7.9 and / or 31.6, each expressed as a 2θ value ±0.2°.

[0131] 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) that does not exhibit at least the following reflections, each expressed as a 2θ value of ±0.2°: 7.6.

[0132] 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 of ±0.2°: 14.8.

[0133] Embodiment 10 (a 1.25 hydrate of the compound of formula (I)) The pseudopolymorphic form of the compound of formula (I), the 1.25 hydrate, 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 a 2θ value 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, 18.6, 19.8, 20.4, 21.6, 22.8, 23.2, 24.6, 25.8, 26.6, 27.2, 28.6, 29.2, 30.2, 31.2, 32.2, 33.2, 34.2, 35.2, 36.2, 37.2, 38.2, 39.2, 40.2, 41.2, 42.2, 43.2, 44.2, 45.2, 46.2, 47.2, 48.2, 49.2, 50.2, 51.2, 52.2, 53.2, 54.2, 55.2, 56.2, 57.2, 58.2, 59.2, 60.2, 61.2, 62.2, 63.2, 64.2, 65.2, 66.2, 67.2, 68.2, 69.2, 70.2, 71.2, 7.4, 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.

[0134] The pseudopolymorphic form of the compound of formula (I), the 1.25 hydrate, can 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 a 2θ value of ±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.

[0135] The compound of formula (I) in 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 Figure 8.

[0136] Additionally, the pseudopolymorphic form of the compound of formula (I), the 1.25 hydrate, 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: 3.1 and 9.3, each expressed as a 2θ value of ±0.2°.

[0137] Additionally, the pseudopolymorphic form of the compound of formula (I), the 1.25 hydrate, 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: 6.9, 7.2, and 7.3, each expressed as a 2θ value of ±0.2°.

[0138] 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.

[0139] Additionally, the pseudopolymorphic form of the compound of formula (I), the 1.25 hydrate, 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: 8.5 and / or 30.0, each expressed as a 2θ value ±0.2°.

[0140] 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: 7.9 and / or 31.6, each expressed as a 2θ value ±0.2°.

[0141] 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) that does not exhibit at least the following reflections: 7.6, each expressed as a 2θ value ±0.2°.

[0142] 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 of ±0.2°: 14.8.

[0143] Embodiment 11 (Sesquihydrate of the compound of formula (I)) The pseudopolymorphic form sesquihydrate of 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 a 2θ value of ±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.

[0144] The pseudopolymorphic form of the compound of formula (I), the sesquihydrate, 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 a 2θ value of ±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.

[0145] The pseudopolymorphic form of the compound of formula (I), the sesquihydrate, 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 a 2θ value 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, 26.1, 26.4, 27.0, 27.4, 28.5, 32.2, 36.5.

[0146] 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 Figure 9.

[0147] 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: 3.1 and 9.3, each expressed as a 2θ value of ±0.2°.

[0148] 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) that does not exhibit at least the following reflections: 6.9, 7.2, and 7.3, each expressed as a 2θ value of ±0.2°.

[0149] 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°: 29.2.

[0150] 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: 8.5 and / or 30.0, each expressed as a 2θ value ±0.2°.

[0151] 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: 7.9 and / or 31.6, each expressed as a 2θ value ±0.2°.

[0152] 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°: 14.8.

[0153] Embodiment 12 (Dihydrate of the compound of formula (I)) The pseudopolymorphic form of the compound of formula (I), dihydrate, can 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 a 2θ value of ±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.

[0154] The pseudopolymorphic form of the dihydrate 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) showing the following reflections, each expressed as a 2θ value 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, 15.5, 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.

[0155] 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 the radiation source) shown in Figure 10.

[0156] 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) that does not exhibit at least the following reflections: 3.1 and 9.3, each expressed as a 2θ value of ±0.2°.

[0157] Additionally, the pseudopolymorphic form of the compound of formula (I), dihydrate, may be characterized by an X-ray powder diffractogram (at 25°C and using Cu-K alpha 1 as the radiation source) that does not exhibit at least the following reflections: 6.9, 7.2, and 7.3, each expressed as a 2θ value of ±0.2°.

[0158] Additionally, the pseudopolymorphic form of the compound of formula (I), 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.

[0159] 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: 8.5 and / or 30.0, each expressed as a 2θ value ±0.2°.

[0160] 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: 7.9 and / or 31.6, each expressed as a 2θ value ±0.2°.

[0161] Additionally, the pseudopolymorphic form of the compound of formula (I), dihydrate, may be characterized by an X-ray powder diffractogram (at 25°C and using Cu-K alpha 1 as the radiation source) that does not exhibit at least the following reflections, each expressed as a 2θ value ±0.2°: 7.6.

[0162] Treatment method The crystalline forms of the compound of formula (I) according to the present 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 present invention can open up further therapeutic alternatives and thus enrich pharmaceutical science.

[0163] In the context of the present invention, the term "treatment" or "treating" includes inhibiting, slowing, arresting, ameliorating, attenuating, limiting, reducing, suppressing, reversing or curing a disease, condition, disorder, injury or health impairment, of the onset, course or progression of such condition, and / or the symptoms of such condition, wherein the term "therapy" is understood to be synonymous with the term "treatment."

[0164] 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.

[0165] Treatment or prevention of a disease, condition, disorder, injury or health impairment may be partial or complete.

[0166] The term "therapeutic efficacy" within the context of the present invention is defined as the reduction of 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.

[0167] 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 blood pressure in the pulmonary arteries, and (2) a parameter for assessing the effectiveness of new drugs by substantially reducing this parameter, which is directly related to blood pressure in the pulmonary arteries (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).

[0168] Improved 6-minute walk test results within the context of the present invention are 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 severe disease under treatment.

[0169] 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.

[0170] The physiological function of the lungs is assessed 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 used therapeutically by different drugs to improve lung function in lung diseases with bronchoconstriction, e.g., COPD or asthma.

[0171] The term "improved hemodynamic effect" within the context of the present invention is defined as the vasodilatory effect of a drug to reduce pulmonary arterial 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 the individual patient.

[0172] The term "pulmonary selectivity" in the context of the present invention means that an inhaled active ingredient exerts its pharmacodynamic properties of vasodilatation only in ventilated areas of the lung, and not in non-ventilated areas. This is to prevent a worsening of the mismatch between ventilation and perfusion (due to increased perfusion in non-ventilated areas) that could occur if the active ingredient also reached non-ventilated areas. Intrapulmonary selectivity is ensured in particular by the inhalation administration route, which is achieved by the patient's active inhalation.

[0173] The term "bronchodilator effect" within the context of the present invention is defined as an improvement in a parameter, such as, for example, relaxation of carbachol-preconstricted 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.

[0174] The term "chronic treatment / use" within the context of the present invention is defined as once or twice daily inhaled 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 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).

[0175] The term "once-daily" is well known by 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 simultaneous or sequential administration of two or more dosage forms within a short period of time.

[0176] The term "once or twice daily" is well known by those skilled in the art and refers to the administration of a drug once or twice daily, where administration of a drug at each corresponding time point in the day includes administration of one dosage form, and administration of two or more dosage forms simultaneously or sequentially within a short period of time.

[0177] 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.

[0178] 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 pharmaceutically suitable carrier for inhalation. The combination of the drug substance and the pharmaceutically suitable carrier for inhalation is in the form of a dry powder. Preferably, the dry powder is filled into a cavity, more preferably into a capsule. Preferably, the pharmaceutically suitable carrier is lactose for inhalation.

[0179] 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.

[0180] 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 a functional organ system.

[0181] In the context of cardiopulmonary disorders, "local administration" or "locally controlled" for the purposes of the present invention means administration by inhalation of the active ingredient in an inhalable dosage form primarily to cover the lungs as the target organ, requiring a lower dose and resulting in lower systemic drug exposure, as opposed to oral administration and intravenous administration of dosage forms intended for absorption via the gastrointestinal tract, which results in systemic drug distribution via the bloodstream. Preparations in powder form or in powder-containing suspensions used according to the present invention are inhaled preparations.

[0182] 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 respiratory tract, preferably introduction into and / or via the nasal cavity or oral cavity, in particular introduction via the oral cavity, in order to achieve deposition of the active ingredient in the bronchi and lungs as the site of action.

[0183] The term "endotracheal" or "endotracheal 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, e.g., rats or piglets and dogs (e.g., intratracheal application via a PennCentury device applicable to dry powders, as well as drug solutions and suspensions).

[0184] The compounds according to the present 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, and its pseudopolymorphic forms, such as (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. Furthermore, they have bronchodilatory effects. These activities are mediated through direct heme-independent activation of soluble guanylate cyclase and an increase in intracellular cGMP levels.

[0185] 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 pulmonary administration (E-1).

[0186] In addition, the compounds according to the present 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), can be clinically demonstrated to have good therapeutic efficacy and target engagement. After inhalation administration, 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 engagement) (E-2.1, E-2.2), and a selective decrease in pulmonary arterial pressure and pulmonary vascular resistance (E-2.4) can be clinically demonstrated.

[0187] Furthermore, favorable pharmacokinetic properties of the drug substance for inhalation application can be demonstrated: analysis of plasma concentrations after oral, intravenous and inhalation administration of the drug substance showed the longest half-life of the active ingredient after inhalation application (E-2.3).

[0188] Finally, 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 confirm that the half-life is appropriate for inhaled dry powder administration, allowing for once-daily treatment (as shown for Example 4) for sufficient 24-hour drug coverage of the drug substance in the lungs.

[0189] In conclusion, all 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), 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 associated with idiopathic interstitial pneumonia (PH-IIP), and are suitable for inhaled 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.

[0190] 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.

[0191] 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, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), can 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), 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 associated with idiopathic interstitial pneumonia (PH-IIP), and lung disorders, such as asthma, chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis.

[0192] In the context of the present invention, the term "sGC modulator" encompasses two different classes of compounds capable of modulating 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 modulators. sGC stimulators have a dual mode of action, directly stimulating native sGC independently of NO and sensitizing sGC to low levels of NO by stabilizing the NO-sGC bond. 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 cardiovascular problems in heart failure? Hypertension 2007;49:974-976), providing a rationale for the use of sGC activators in various cardiovascular pathophysiological conditions, such as 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)。.

[0193] In the context of the present invention, the term "pulmonary hypertension" encompasses both its primary and secondary subforms, which are defined below according to their respective etiologies according to the Dana Point / Nizza classification [D. Montani and G. Simonneau, in: A.J. Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3rd edition, Hodder Arnold Publ., 2011, pp. 197-206; M.M. 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: Hemodynamic 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 encompasses, inter alia, idiopathic and familial forms (IPAH and FPAH, respectively). Furthermore, PAH also includes persistent pulmonary hypertension of the newborn, as well as pulmonary arterial hypertension (APAH) associated with connective tissue disease, congenital arteriopulmonary anastomotic 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 telangiectasia, hemoglobinopathies, myeloproliferative disorders, and splenectomy.Group 2 includes PH patients with underlying left heart disorders, such as ventricular, atrial, or valvular disorders. Group 3 includes forms of pulmonary hypertension associated with lung disorders, such as 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, such as thromboembolic obstruction of the proximal and / or distal pulmonary arteries (CTEPH) or non-thrombotic embolism (e.g., as a result of tumor disorders, parasites, or foreign bodies). Less common forms of pulmonary hypertension, such as those in patients with sarcoidosis, histiocytosis X, or lymphangiomatosis, are summarized in Group 5.

[0194] 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.

[0195] In the context of this invention, the term "asthma" encompasses heterogeneous chronic inflammatory diseases of the lung's airways. 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 individuals, 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 symptom patterns, response to therapy over time, and spirometry lung function testing. Asthma is classified according to symptom frequency, forced expiratory volume in 1 second (FEV1), and peak expiratory flow rate. Asthma can also be classified as atopic or nonatopic, with atopic referring to a predisposition to developing type 1 hypersensitivity reactions. There is no known cure for asthma, and asthma can be systematically treated. Symptoms can be prevented by avoiding triggers, such as allergens and respiratory irritants, and suppressed with the use of inhaled corticosteroids. If asthma symptoms remain uncontrolled, long-acting beta-agonists (LABAs) and other substances, such as anti-leukotrienes, can be used in addition to inhaled corticosteroids. Treatment of acute exacerbations 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 etiology of which involves airway inflammation with intrinsic drivers still unclear. To address this, we studied human airway smooth muscle cells (HASMCs), whose relaxation drives airway bronchodilation 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 the oxidoreductases that support sGC function.The majority of HASMCs (12 / 17) and lung samples from severe asthma donors primarily 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. This suggests that severe asthma patients may be 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 optimizing 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 asthma 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 2021). 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).

[0196] 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.

[0197] 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 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 associated with idiopathic interstitial pneumonia (PH-IIP).

[0198] 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 associated with idiopathic interstitial pneumonia (PH-IIP).

[0199] 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 associated with idiopathic interstitial pneumonia (PH-IIP).

[0200] 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 associated with idiopathic interstitial pneumonia (PH-IIP).

[0201] The present invention relates to a method for the treatment and / or prevention of disorders, particularly 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 associated 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, and its pseudopolymorphic forms, for example, (IMI) and (IM-II), in an inhalable dosage form in the form of a dry powder formulation, for example, a dry powder inhaler, for two or more days, preferably for a period of at least 2 to 7 consecutive days, preferably for 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.

[0202] The present invention relates to an sGC activator of formula I, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}} sGC activator of formula I, which is Comparative Example 11, for the manufacture of a medicament for the treatment 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 associated with idiopathic interstitial pneumonia (PH-IIP).

[0023] The present invention further relates to the use of an inhalable dosage form of {{phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid and its pseudopolymorphic forms, such as (IMI) and (IM-II), wherein the inhalable dosage form is administered over a period of two or more days, preferably at least 2 to 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, and wherein the sGC activator has sustained efficacy over a 24-hour period when administered by inhalation to a patient in need thereof.

[0203] 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, e.g., (IMI) and (IM-II), wherein the container contains instructions for use of the dry powder, e.g., instructions for a subject to inhale for about 2 seconds after a single deep inhalation. The present invention further relates to a packaged pharmaceutical composition, further containing instructions for requiring standing and 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 (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP).

[0204] 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 comprises (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). The present invention further relates to a packaged pharmaceutical composition comprising a container containing a dry powder comprising {(4- ...

[0205] 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, pharmaceutically suitable excipients, and to their use for the above-mentioned purposes.

[0206] 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 and its pseudopolymorphic forms, such as (IMI) and (IM-II), together with 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), for example inhibitors of phosphodiesterases (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 W2014 / 068099, prostacyclin analogues and IP receptor agonists, such as, preferably, iloprost, beraprost, treprostinil, epoprostenol or NS-304, endothelin receptor antagonists, such as, 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 highly selective ligand traps for multiple proteins in the TGF-beta superfamily, including activins and GDFs, and others that may have the ability to block TGF-beta superfamily signaling pathways and thereby promote rebalancing of bone morphogenetic protein receptor type II (BMPR-II) signaling, potentially restoring 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, for example, 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, 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, for example BAY1211163), for obstructive sleep apnea (VI-0521, TASK channel blockers and ADRA2C antagonists), for bronchiectasis (mannitol, ciprofloxacin), for bronchiolitis obliterans (cyclosporine, aztreonam), Antithrombotic agents, such as those preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances, may be mentioned.

[0207] Antithrombotic agents are preferably understood as compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.

[0208] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor such as, by way of example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as, by way of example and preferably, coumarin.

[0214] 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.

[0215] 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.

[0216] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin receptor antagonist such as, by way of example and preferably, bosentan, darusentan, asentan or sitaxsentan.

[0217] technical purpose In view of the background and the state of the art, the technical object of the present invention is to provide a compound 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 ... was to provide a suitable carrier-based dry powder 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 monohydrate I of formula (IMI) or (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 of formula (IM-II) in combination with a lactose carrier.

[0218] In order to develop suitable inhaled medications for use in the treatment of cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), 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 associated with idiopathic interstitial pneumonia (PH-IIP), certain technical and medical needs and requirements for drug substances and drug products need to be met.

[0219] First, the active ingredient (drug substance) must have suitable physicochemical, pharmacokinetic, and pharmacodynamic properties. For example, the drug substance must be suitable for inhalation therapy and have sufficient efficacy to treat cardiopulmonary disorders. Furthermore, the active ingredient must also have clear efficacy in the intended PH form in addition to standard therapies (SoCs, e.g., endothelin antagonists, e.g., bosentan, PDE5 inhibitors, e.g., sildenafil, IP agonists, e.g., Ilomedin, calcium channel blockers, and sGC stimulators, e.g., riociguat). Additionally, the active ingredient must have further advantageous properties, particularly regarding its lung-selective action (as opposed to systemic action), e.g., high lung selectivity, low to no VQ mismatch, its lung residence time, and / or its duration of action after pulmonary administration. The drug substance must be suitable for chronic treatment regimens / use. Furthermore, the drug substance should show improved ventilation, e.g., a bronchodilatory effect, and / or an inhibitory effect on airway hyperresponsiveness and inflammation, and should therefore be suitable, in particular, for the treatment of 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 associated with idiopathic interstitial pneumonia (PH-IIP).

[0220] The drug substance 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, and its pseudopolymorphic forms of formulae (IMI) and (IM-II), when administered by inhalation, should have sustained vasodilatory and bronchodilatory efficacy for a period of more than 12 hours up to 24 hours, where sustained vasodilatory and bronchodilatory efficacy is characterized, for example, by improved pulmonary hemodynamics, which can be characterized, for example, by lower pulmonary vascular resistance (PVR), improved walking distance in the 6-minute walk test, and improved pulmonary hemodynamics as measured by the New York Health Association (NYHA). The study results in a shift in FEV1 (Fever Association) patient classification or improved lung function, such as higher FEV1 (the forced expiratory volume a person can exhale in the first second of a forced breath) and lower specific airway resistance (sRaw), a parameter that indicates bronchodilator activity in healthy lungs.

[0221] Furthermore, the active ingredient (drug substance) needs to be provided in a defined, stable, crystalline form so that it is suitable for dry powder pharmaceutical formulation and so that it can be administered in a specific, optimized inhalation dosing regimen for the treatment of cardiopulmonary disorders.

[0222] Additionally, the final drug product (formulation) must possess suitable properties, such as sufficient chemical stability and aerosol performance, to deliver the drug substance in sufficient quantities to the target organ, e.g., the lungs, with minimal to no adverse effects on the patient. Adequate physicochemical stability is necessary to preserve the active ingredient's chemical structure and avoid unacceptable degradation or stereochemical transformation. More importantly, the physical and geometrical form must be maintained so as not to alter the active ingredient's biopharmaceutical properties, which affect its pharmacokinetic behavior. Stable and adequate aerosol performance refers to reproducible drug delivery in terms of average delivered dose and uniformity of delivered dose, as well as reproducible drug delivery of a desirable high fraction of the nominal drug dose available in the final dosage form to the site of action. In practical terms, the majority of micronized active ingredient particles should be recovered as the fine particle dose (alternatively, the mass of fine particles) and the fine particle fraction (%) relative to the delivered dose and / or nominal dose, as tested by an appropriate analytical method, such as aerodynamic particle size distribution by cascade impaction.

[0223] The present inventors have surprisingly discovered 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 can be produced in larger quantities and more reliably through improved chemical processes.

[0224] Additionally, the present inventors have 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 of formula I exists in a stable crystalline form, for example, as monohydrate I of formula (IMI) or monohydrate II of formula (IM-II) 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, preferably as monohydrate I of formula (IMI).

[0225] Furthermore, the inventors have surprisingly found that crystalline 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 of formula I can be made available by a novel selective crystallization process, preferably the monohydrate form I (IMI) can be selectively obtained by crystallization from methanol and water, or methanol, acetone and water.

[0226] Thus, the drug substance 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 made available for the first time in a form suitable for inhalation dosage forms, medicaments, and inhalation dosage forms, preferably DPIs.

[0227] Surprisingly, preclinical experiments have revealed improved pulmonary selectivity and extended duration of action (prolonged selective pulmonary artery pressure (PAP) reduction without systemic blood pressure (BP) reduction after inhalation application) for 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 of formula I, 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 human dose prediction have been investigated. Considering 100 μg / kg as the effective dose in a minipig model, a lung-deposited dose of 300 to 1370 μg is estimated as the effective dose, depending on the consideration of different interspecies protein binding.

[0228] Finally, the pharmacological effects of different pseudopolymorphic forms of the active ingredient have been investigated. All dry powder formulations, including the crystalline form of Comparative Example 11, e.g., Example 6e, which is a sesquihydrate, selectively and dose-dependently reduced PAP after inhalation administration in this model of acute PAH, with a long duration of action of at least 4 hours. A clear dose-response curve was observed with increasing applied doses (see E-1).

[0229] These findings support the use of 240 to 4000 μg, preferably 480 to 2000 μg, of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl]phenyl]propanol, 2-(4-hydroxybenzoates, 2-[ ... This paper 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 of formula I, and its pseudopolymorphic forms monohydrate I (Example 4) or monohydrate II (Example 2), for once or twice daily inhalation treatment regimens containing (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.

[0230] (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 according to the present invention (Comparative Example 11), as well as Comparative Examples 3, 4, and 5, were tested to evaluate their lung selectivity and duration of action in a minipig model (E-1). All three compounds exhibit favorable lung selectivity, but only Comparative Example 11 and Comparative Example 4 exhibit sufficient duration of action. Comparative Example 11 exhibits a selective PAP effect with a maximum effect over the entire observation interval of 240 minutes, while Comparative Example 3 exhibits its maximum effect on PAP 30 minutes after inhalation application, which is completely resolved again after 120 minutes. Comparative Example 11 and Comparative Example 4 were evaluated for duration of action in a conscious hypoxic dog model. In this model, Comparative Example 11 showed a consistent and long duration of effect (PAP reduction) of up to 17 hours, in contrast to Comparative Example 4. Therefore, Comparative Example 11, which corresponds to the present invention, is most suitable for a once-to-twice-daily treatment regimen, in contrast to Comparative Examples 3, 4, and 5 (disclosed as Examples 2, 37, and 39 in WO14 / 012934-A1).

[0231] Furthermore, the inventors have demonstrated in a first clinical study (see Experimental Section E-2.1) 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 I (Example 4), increased cGMP levels (indicating target engagement) as a second messenger molecule for sGC activation as a surrogate for drug concentration in the lungs and a maximum of more than 12 hours after dry powder application. Beneficial bronchodilator properties were found in healthy volunteers over a 24-hour period, including a decrease in total specific airway resistance (sRaw), a parameter indicative of bronchodilator activity in the lungs, 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, particularly in the form of its monohydrate I (Example 4), for successful use in the treatment of cardiopulmonary disease. No clinically significant effects on systemic blood pressure were observed in healthy volunteers at doses up to 4000 μg.

[0232] 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 a clinically relevant effect on systemic blood pressure. This effect persisted without a diminished response until the end of the 3-hour measurement period (measurement periods longer than 3 hours were technically unfeasible). A pulmonary residence time exceeding 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).

[0233] Additionally, analysis of plasma concentrations after oral, intravenous, and inhalation administration of the 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 the pulmonary dose and half-life are appropriate for inhaled dry powder administration, allowing for once-daily treatment for sufficient 24-hour drug coverage of Example 4 in the lungs.

[0234] In conclusion, all 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), 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 associated 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 according to Example 4.

[0235] These findings also support the use of 240 to 4000 μg, preferably 480 to 2000 μg, of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5-hydroxybenzoates for use in the treatment of cardiopulmonary diseases, 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 associated with idiopathic interstitial pneumonia (PH-IIP). This 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, particularly in the form of its monohydrate I (Example 4), for a once or twice daily inhalation treatment regimen 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, particularly in the form of its monohydrate I (Example 4), for a period of two or more days, preferably at least 2 to 7 consecutive days, preferably at least 14 consecutive days, particularly over the entire course of the disease from the start of treatment.

[0236] 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), has beneficial physicochemical properties, such as protein binding and CaCO flux (Experimental Sections E-3.1 (CaCO permeability) and E-3. 2 (protein binding)), which makes (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), a suitable compound for the topical 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 effective reduction of PAP via selective vasodilation in the lung, but also longer-lasting bronchodilator properties compared to cinaciguat, which may be beneficial in once- or twice-daily inhalation treatment of patients with PH (Class 3 PH) who have chronic lung disease, or may even have potential in the treatment of patients with limited lung function, such as asthma patients.

[0237] 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 and selective sGC activator that 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-related 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 (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 negative effects on oxygenation, in contrast to systemically applied vasodilators. In addition to standard of care (SoC) treatments for PAH (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]). Regarding 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, and inhalation), revealing the longest elimination half-life after inhalation application. The emitted (pulmonary) dose has been determined to be 720 μg after inhalation of 1000 μg in humans. The first studies 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 and 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).

[0238] Thus, 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) and its pseudopolymorphic forms (IMI) and (IM-II), have excellent key pharmacological and pharmacodynamic properties in patients, including reduction of 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., blood pressure or heart rate), and low to no increase in VQ mismatch to avoid associated desaturations, as well as sufficient lung residence time and / or sufficient duration of action following pulmonary administration.

[0239] Surprisingly, it has been found that local administration, especially inhalation 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, in particular monohydrate I, has the potential to successfully control cardiopulmonary disorders, 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 associated with idiopathic interstitial pneumonia (PH-IIP). The active ingredient concentration in the lungs can be maintained for a long period of time at a level that is medically desirable for optimal treatment. In addition to higher, longer-lasting active ingredient levels at the site of the disease, it is possible to simultaneously achieve a relatively low systemic concentration of the active ingredient, which can avoid side effects of drug therapy, such as the absence of clinically relevant systemic blood pressure reduction.

[0240] Surprisingly, the drug substance can be provided in a single, crystalline, chemically stable form, monohydrate I of formula (IMI), which is also stable under micronization conditions.

[0241] Surprisingly, the pharmaceutical dry powder formulations according to the present invention are characterized by excellent aerosol performance (e.g., high fine particle dose, high fine particle fraction, and high delivered dose relative to the nominal dose) and sufficient chemical stability. Furthermore, the pharmaceutical dry powder formulations according to the present invention can be produced in a technically reliable manner by novel processes (e.g., blend uniformity).

[0242] 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 in the form of a salt or a solvate or a hydrate, 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 of formula (IMI) Pharmaceutical dry powder formulations comprising {amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate I in combination with a lactose carrier comprising lactose monohydrate as a mixture of coarse and fine lactose are suitable for the inhalation treatment 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 associated with idiopathic interstitial pneumonia (PH-IIP).

[0243] In view of the prior art, these findings were not foreseeable as the superior primary pharmacological and pharmacodynamic properties 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, in particular its longer duration of action compared to similar 5,6,7,8-tetrahydroquinoline-2-carboxylic acids, such as Comparative Examples 3, 4 and 5, were not known or foreseeable.

[0244] Furthermore, these findings were not predictable as pseudopolymorphic forms, in particular stable crystalline hydrates, were not known.

[0245] Surprisingly, monohydrate form I (IMI) (Example 4) was identified as a stable pseudopolymorphic 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 after micronization and stability studies.

[0246] Furthermore, it was surprising that modified I (IMI) was available by selective crystallization from methanol, acetone, and water.

[0247] Furthermore, inhalable solid carrier formulations comprising the acid of formula (I), and neither of its crystalline forms, such as monohydrate form I (IMI) or monohydrate form II (IM-II), were known.

[0248]

[0010] Therefore, the technical object of the present invention is a novel suitable pharmaceutical dry powder formulation for the treatment of cardiopulmonary disorders, 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 in the form of one of its salts or solvates or hydrates, 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 of formula (IMI), and having excellent aerosol performance (e.g. fine particle dose, fine particle fraction and nominal dose delivered). The objective of the present invention was to provide a pharmaceutical dry powder formulation having a high yield (high yield result) and sufficient chemical stability, wherein these attributes are achieved by blending micronized (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 monohydrate I of formula (IMI), in the form of one of its salts or solvates or hydrates, with a particulate lactose carrier consisting of a coarse particle fraction and a fine particle fraction.

[0249] Surprisingly, the inventors have found that novel suitable pharmaceutical dry powder formulations 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 in the form of one of its salts or solvates or hydrates, 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 of formula (IMI), can be prepared by combining the active ingredient with a carrier, wherein the carrier is a lactose carrier and the lactose carrier comprises lactose monohydrate as a mixture of coarse lactose and fine lactose.

[0250] To obtain the pharmaceutical dry powder formulations according to the present invention, it is important to (a) adjust a specific ratio between the drug substance and the lactose carrier, and (b) use an engineered and customized lactose carrier comprising lactose monohydrate as a mixture of coarse and fine lactose, and (c) use drug substance and coarse and fine lactose with specific particle sizes, in particular the following specifications: (A) (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, which is the active ingredient of formula (IMI), having a particle size of X90 of 6 μm or less and / or X50 of 1.0 to 3.0 μm; (B) coarse lactose having a particle size that is at least 115 μm or at least 120 μm or at least 200 μm X 90, and / or coarse lactose having a particle size that is at least 50 μm or at least 75 μm or at least 125 μm X 50, (C) fine lactose having a particle size of less than 30 μm or less than 10 μm X90, and / or fine lactose having a particle size of less than 5 μm or less than 10 μm X50, and the crude lactose content of the formulation / dry powder blend is 94.25% to 75% and 98.25% to 75%.

[0251] The specific combination of drug substance with lactose carrier components, i.e., coarse and fine lactose, in specific ratios, all components having specific particle sizes, and furthermore the defined coarse lactose content of the formulation / dry powder blend, gives rise to the technical effect that the underlying pharmaceutical dry powder formulation exhibits excellent aerosol performance (e.g., resulting in a high fine particle dose, a high fine particle fraction and a high delivered dose relative to the nominal dose) and is sufficiently chemically stable over a certain period of time.

[0252] The excellent aerosol performance results from the effect that drug particles temporarily bind to carrier particles but then need to be released from them in the inhaled aerosol stream during inhalation, thereby reaching the deep lung region. Strong binding of micronized drug particles to lactose carrier particles can occur particularly with compounds such as IMI, which have been observed to have strong adhesive properties to many types of surfaces (e.g., surfaces of analytical glassware and pharmaceutical manufacturing equipment, hard capsules, and surfaces of dry powder inhalation devices). Lactose fine particles can occupy active sites on lactose carrier particles, thereby reducing the ratio of strongly bound drug particles in the adhesive mixture and increasing the fraction released under inhalation conditions (fine particle dose / fine particle fraction). The excellent aerosol performance of the carrier-based dry powder formulation according to the present invention results from the optimal temporary binding of micronized active ingredient particles designed for deep lung delivery; this temporary binding can be overcome by the energy of the airflow in the dry powder inhalation device, allowing the drug particles to separate and deagglomerate from the carrier.

[0253] As a result, the optimum temporary binding of micronized active ingredient particles depends on the following technical parameters: lactose carrier components, i.e., specific ratios of coarse and fine lactose; Selection of specific particle sizes for all components; This is achieved by optimizing and customizing the formulation / dry powder blend and the defined crude lactose content.

[0254] These parameters are important for obtaining a carrier-based dry powder formulation according to the present invention with good aerosol performance.

[0255] In order to provide an improved inhalation dosing regimen for the treatment of cardiopulmonary disorders according to the present invention, it is important to provide a particular drug substance in a defined inhalable form at a specific dosage, the nominal dosage being sufficient to treat the intended cardiopulmonary disease.

[0256] To determine an adequate human dose, it was necessary to select the most predictive animal model for PAH, determine the minimum effective dose, and define the dosing range (minimum effective dose, effective dose, and maximum tolerated dose) to be evaluated in the first clinical studies.

[0257] Thus, the active ingredient should be administered to a patient in need thereof in an inhalable dosage form containing 240 to 4000 μg, preferably 480 to 2000 μg, once or twice daily for a period of at least two days or more, preferably for at least 5 to 7 consecutive days.

[0258] The pharmaceutical dry powder formulation according to the present invention is therefore a suitable medicament for use in the treatment of cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), 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 associated with idiopathic interstitial pneumonia (PH-IIP).

[0259] Human dose estimation Formulations according to the invention can be characterized in terms of the delivered dose (DD) determined by the filter collection tube method and the fine particle dose (FPD) determined by cascade impaction. Analytical methods for determining the delivered dose and the fine particle dose are generally harmonised for inhalable dosage forms, e.g., dry powder inhalation formulations, and are described in the Pharmacopoeia as constituting regulations for the quality control of the release of, e.g., DPI products for clinical use.

[0260] 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, and the fine particle dose characterizes the effective dose as being delivered to the site of action in the deep lung.Theoretically, the delivered dose and the fine particle dose and fraction have a linear relationship with the loaded powder dose, but due to some interaction factors, this is not reliably predictable and may vary in practice, and requires relevant research.It is desirable that the delivered dose is as close as possible to the nominal dose.In practice, because some residue always remains on the surface of the inhalation capsule and on the aerosol path of the dry powder inhaler used, the delivered dose is not 100% consistent with the nominal dose.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 that the fine particle dose and fine particle fraction 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 the 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.

[0261] Due to the nature of inhalable formulations, not all of the nominal content is delivered into the lungs, for example, in contrast to 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 μm size cutoff depends on the definition of FPD) (fine particle dose). For an overview, see Table 1 below.

[0262] [Table 1]

[0263] 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 predicting 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 to the end of the tube to determine the deposited lung dose. Nebulization of Comparative Example 11 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 was considered to be 0.15 μg / kg (see Figure 1).

[0264] The nominal doses of 3, 10, 30, and 100 μg / kg in the minipig model were multiplied by a 5% filter deposition coefficient 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. Therefore, the FPDs reflecting PAP reduction for a 60 kg human are calculated to be 9, 30, 90, and 300 μg.

[0265] Therefore, through direct scale-up from minipigs, the predicted MED (5% PAP reduction) for humans based on a 60 kg body weight is calculated to be an LDD of 9 μg, without considering protein binding in the airways. As a surrogate for the unbound concentration, which is the likely active concentration in the lung, we considered the respective differences in the unbound fraction in plasma between minipigs and humans. This consideration results in a minimum effective lung dose (LD) for a 60 kg participant of 41 μg LDD for a predicted 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 60 kg body weight (see Figure 2).

[0266] [Table 2]

[0267] This conversion was also performed for effective doses (effective PAP reduction of greater than 5 up to 35 percent over longer periods up to the full observation period of 4 hours) based on the relative lung-deposited doses in minipigs listed in Table 2.

[0268] 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.

[0269] Considering 100 μg / kg as the highest effective dose in a minipig model without systemic side effects (BP reduction), with a corresponding maximum effective human LDD of 1370 μg, a lung-deposited dose of 9 to 1370 μg is inferred as the effective dose, depending on different interspecies protein binding (see Table 2). For DPI products, the fine particle dose (FPD) is basically assumed to be equivalent to the human lung-deposited dose.

[0270] 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 manufactured dry powder inhalation capsules, several calculations and approximations were performed. Generally, inhalable products based on powder blend carrier formulations are considered to have excellent performance if a fine particle fraction of more than 20% of the nominal dose is achieved. Furthermore, a higher FPF (%) relative 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 3 and 4.

[0271] [Table 3]

[0272] There are no general (e.g., official) requirements for the relationship between delivered and nominal dose, as this is not definable due to the vastly different properties of different active ingredients and their manufactured pharmaceutical formulations. Rather, the uniformity of delivered dose is defined by Pharmacopoeia 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 inhaler 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 85% limit of the average delivered dose range. The target delivered dose percentage (≥50% to ≥65% of nominal) is defined for all nominal doses; this is not linear and must take into account, for example, the adhesion of relatively higher active ingredient contents to capsule and device surfaces, especially at lower nominal fill doses.

[0273] [Table 4]

[0274] Therefore, the pharmaceutical dry powder formulation according to the present invention is a suitable medicament for the treatment 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 associated with idiopathic interstitial pneumonia (PH-IIP).

[0275] Detailed Description of the Invention Formulations for inhalation 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 monohydrate I of formula (IMI) or of formula (IM-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) 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 within a suitable inhalation-grade carrier matrix for the active compound. The amount of active ingredient is usually 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. Powder blends with an active ingredient content of 3%, 10% or 20% are highly preferred.

[0276] 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 (IM- (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 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 specific particle size suitable for inhalation applications.

[0277] 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 II 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 of monohydrate I of formula (IMI), 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 defined in the table below.

[0278] [Table 5]

[0279] For inhaled drug products, it is important to ensure 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).

[0280] The appropriate specifications for particle size distribution of the active ingredient to achieve this requirement were established as specified in Table 5.

[0281] Therefore, to ensure suitable delivery of the activity at the target sites, in particular in the deep airways and alveoli, the inventors have prepared 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 (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 I, preferably in the form of the monohydrate I of formula (IMI), in a particle size which is at most 6 μm X90 and / or 1-3 μm X50 and / or at most 1 μm X10.

[0282] Lactose Carrier The solid formulations according to the present invention for dry powder inhalation generally contain a suitable carrier in an amount of about 99.25% or less for the active compound. Typically, the amount of inhalation-grade carrier is 99.25% to 80%, preferably 99.25% to 90%. The amount of carrier in the solid formulation 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.

[0283] Different materials of inhalation grade carriers are mainly available.

[0284] The inventors have found that the excellent aerosol performance of formulations for inhalation according to the present invention is achieved by selecting lactose as the carrier material.

[0285] Lactose for inhalation is available in different particle size ranges and with different characteristics.

[0286] It is expected that a coarse lactose carrier alone, which has a particle size distribution centered around 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, and an increased delivered dose relative 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 subsequent separation is often also described as powder or drug dispersion. It can also be expected that aerosol performance behavior will improve with the addition of fine carrier particles or by the use of lactose materials containing an inherent fine lactose fraction, although the degree is not predictable (de Boer et al. 2012, Grasmejier et al. 2015). As a sign 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., the European Pharmacopoeia (Pharm Eur.) or the United States Pharmacopoeia (USP)).

[0287] However, the potential effect and magnitude of the addition of fine lactose is not predictable, as 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 specific drug molecules, making predictions even more difficult.

[0288] The inventors have found that the excellent aerosol performance of formulations for inhalation according to the invention is achieved by selecting fine lactose and coarse lactose as carrier materials with particular particle sizes.

[0289] The coarse lactose material according to the present invention is sieved or milled crystalline lactose monohydrate having a low fines content (e.g., commercially available as Lactohale® 100 or Lactohale® 206).

[0290] Coarse lactose according to the invention with a similar particle size distribution may also be selected from other brands, for example Meggle Inhalac® 120 or DFE Respitose® SV010.

[0291] To select the primary coarse carrier, a lactose quality with a particle size that is at least 10 times larger X90 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 carrier.

[0292] Fine lactose was selected to improve aerosol performance. The inventors assumed that a particle size similar to that of the active ingredient would be suitable for controlling the temporary binding of active ingredient particles to the coarse carrier particles, but other fine lactose particle size specifications were also potentially suitable. Therefore, the selection of fine lactose products with particle sizes of less than 10 μm (X90), or less than 30 μm (X90), or less than 5 μm or 1.0-3.0 μm (X50) was considered appropriate for constructing the lactose carrier.

[0293] The fine lactose material according to the invention is milled or micronized crystalline lactose monohydrate ("fine lactose") having a low particle size of X90 of 10 μm or less (e.g., commercially available as Lactohale® 300), or X90 of less than 30 μm, or X50 of 5 μm or less or 1.0-3.0 μm (e.g., commercially available as Lactohale® 230). Milled or micronized fine lactose with similar properties 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).

[0294] Particle size distributions for commercially available lactose (e.g., Lactohale® 100, Lactohale® 300) for inhalation quality according to the present invention are summarized in Table 6 below.

[0295] [Table 6]

[0296] Solid preparations according to the invention for dry powder inhalation contain a mixture of coarse lactose (eg Lactohale® 100) and fine lactose (eg Lactohale® 300).

[0297] 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 carrier-based formulations according to the present invention.

[0298] According to the present invention, the coarse lactose has a particle size that is 200-250 μm, or 120-160 μm, or 115-170 μm, or 115-250 μm × 90. Furthermore, according to the present invention, the coarse lactose has a particle size that is 250 μm or less, or 170 μm or less, or 160 μm or less × 90. Furthermore, according to the present invention, the coarse lactose has a particle size that is at least 115 μm or at least 120 μm or at least 200 μm × 90.

[0299] According to the present invention, the coarse lactose has a particle size that is 125-145 μm, or 50-100 μm, or 75-95 μm, or 50-145 μm × 50. Furthermore, according to the present invention, the coarse lactose has a particle size that is 145 μm or less, or 100 μm or less, or 95 μm or less × 50. Furthermore, according to the present invention, the coarse lactose has a particle size that is at least 50 μm or at least 75 μm or at least 125 μm × 50, and / or 45-65 μm, or 5-15 μm, or 20-50 μm × 10.

[0300] According to the present invention, the fine lactose has a particle size of 10 μm or less or less than 30 μm x 90, and 5 μm or less or 1.0-3.0 μm x 50. By using Lactohale 200®, which has an intrinsic content of fine particles, it is not necessary to add any additional fine lactose particles to the lactose carrier. Therefore, the carrier-based formulation can be formulated with Lactohale 200® or similar lactose products, which have an intrinsic content of fine lactose.

[0301] According to the invention, Lactohale 100® and Lactohale 300® are preferred.

[0302] Furthermore, the inventors have found that the excellent aerosol performance of the formulation for inhalation according to the present invention is achieved by adjusting the specific content of fine lactose and the specific content of coarse lactose in the dry powder blend.

[0303] The inventors have identified the fine lactose content of the lactose carrier as an important critical parameter. To obtain a formulation for inhalation according to the present invention characterized by excellent 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 blends and formulations according to the present invention can have various contents of fine lactose within the range of 1% to 10%, also 5% to 10%, and that the fine lactose content can also be the intrinsic portion of lactose for inhalation, i.e., the portion calculated as 5 to 15 μm x 10 in the case of Lactohale 2000®, without impairing aerosol performance (see Example 34).

[0304] According to the present invention, the content of fine lactose in the powder blend is 1% to 10%, preferably 5% to 10%, preferably 2.5% to 7.5%, preferably 5% to 7.5%, more preferably 5%.

[0305] However, the inventors have found that the fine particle content can be adjusted up to 15% without compromising aerosol performance, and therefore this range is also intended to be encompassed by the present invention.

[0306] 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.

[0307] 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%, and particularly preferably 90% to 85%.

[0308] The dry powder blend according to the present invention is a ternary mixture, and therefore all three components must be provided in a form with a defined maximum particle size and in a certain ratio.

[0309] The inventors have found that the excellent aerosol performance of formulations for inhalation according to the present invention is achieved by selecting particular ratios of fine and coarse lactose and active ingredient.

[0310] 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.

[0311] 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.

[0312] According to the present 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.

[0313] Further excipients The preparations according to the invention can generally contain further pharmacologically acceptable excipients, including, 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, trisodium citrate), colorants (e.g., inorganic pigments, e.g., iron or titanium oxide).

[0314] cavity According to the present invention, a 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 in which each dose is loaded into the device before use, a multiple-unit-dose inhaler in which several single doses are individually sealed (pre-metered) and discharged into the dosing chamber before each actuation, or a reservoir multiple-unit-dose inhaler in which 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, e.g., a capsule or blister, containing the dry powder blend. Preferably, the cavity is an individual capsule, preferably a hard capsule of gelatin or hydroxypropylmethylcellulose, most preferably a hydroxypropylmethylcellulose capsule.

[0315] Dry powder blends containing the active ingredient, for example, micronized monohydrate I of formula (IMI) or monohydrate II of formula (IM-II) according to Examples 2 or 4, are filled into hard capsules (hydroxypropylmethylcellulose = hypromellose = HPMC, e.g., size 3) or alternative capsules made of hard gelatin or other suitable materials. The size of pharmaceutical hard capsules is standardized and characterized by defined scales, for example, size 3 capsules have a length of 157 mm and a diameter of 57 mm, size 2 capsules have a length of 176 mm and a diameter of 62 mm, and size 1 capsules have a length of 194 mm and a diameter of 68 mm.

[0316] 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 7 below.

[0317] [Table 7]

[0318] 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.

[0319] 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.

[0320] According to the present invention, the following compositions are most preferred:

[0321] [Table 8]

[0322] 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 can 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 can then be administered via a "single unit dose" inhaler, for example, preferably a Plastiape (Berry) RS01 low resistance device.

[0323] According to the present invention, a powder blend having a 10% content 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 hard capsules, preferably size 3 HMPC capsules, which can then be administered via a "single unit dose" inhaler, for example, preferably a Plastiape (Berry) RS01 low resistance device.

[0324] According to the present invention, powder blends having a 20% content 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 hard capsules, preferably size 3 HMPC capsules, which can then be administered via a "single unit dose" inhaler, for example, preferably a Plastiape (Berry) RS01 low resistance device.

[0325] [Table 9]

[0326] According to the present invention, a powder blend having a content of 30 mg / g of active ingredient of formula (I) or (IMI) in the powder blend contains 480 μg of active ingredient of formula (I) or (IMI), 14.72 mg of coarse lactose, and 0.8 mg of fine lactose, and can be filled into hard capsules, preferably size 3 HMPC capsules, as a powder blend with a mass of 16 mg, which can then be administered via a "single unit dose" inhaler, for example, preferably a Plastiape (Berry) RS01 low resistance device.

[0327] According to the present 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 hard capsules, preferably size 3 HMPC capsules, which can then be administered via a "single unit dose" inhaler, for example, preferably a Plastiape (Berry) RS01 low resistance device.

[0328] 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 hard capsules, preferably size 3 HMPC capsules, which can then be administered via a "single unit dose" inhaler, for example, preferably a Plastiape (Berry) RS01 low resistance device.

[0329] Manufacturing Process 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 production of inhalable free-flowing medicaments in powder form.

[0330] The compounds according to the invention can be converted into the administration forms described, which can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients.

[0331] The dry powder formulation and final product (dry powder blend filled hard capsules) are manufactured according to the following flow chart and instructions.

[0332] [Table 10]

[0333] Step 1: Before the start of mixing, a portion of the fine lactose is weighed and layered between the two layers of coarse lactose.

[0334] Step 2: Mixing of the lactose preblend is carried out in a tumble mixer for 20 minutes, 2 times (2 cycles) at 72 rpm, 67 rpm, 34 rpm, 32 rpm, or 30 rpm, preferably 32 rpm, and the lactose preblend is sieved through a 500 μg sieve between cycles.

[0335] Step 3: The active ingredient, micronized monohydrate I or II, Example 2 or 4, is 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 are layered alternately, with six layers of lactose pre-blend and five layers of active ingredient (monohydrate I or II, Example 2 or 4) between them.

[0336] Step 4: The components are mixed in cycles, e.g., 3 to 5 cycles, preferably 3 cycles, in a tumble mixer, e.g., a glass or stainless steel tumble mixer, preferably a stainless steel tumble mixer. Each cycle is carried out at 72 rpm, 67 rpm, 34 rpm, or 32 rpm, preferably 32 rpm, for 20 to 30 minutes, preferably 30 minutes (total mixing time of 90 minutes), preferably 30 minutes at 32 rpm, with a 10-minute rest period between mixing cycles. If necessary (e.g., visual agglomerates), the blend can be sieved between each blending cycle.

[0337] Step 5: The blend is allowed to stand in a stainless steel container at room temperature (15-25°C) and a relative humidity of 35-65% for a specified period of time, preferably 24-72 hours, more preferably 48 hours.

[0338] Step 6: Using a capsule filler (eg, MG2 Flexalab), the blend is filled into capsules at the desired fill weight.

[0339] 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 dry powder formulation by means of a dry powder inhalation device.

[0340] A preferred dry powder inhalation device within the context of the present invention is defined as a capsule-based single-unit dose inhaler, which is a pre-metered inhalation device (see Figures 3a and 3b). In the context of the present invention, the dose was administered using the Plastiape (Berry) RS01 low-resistance device. This device (with a higher resistance type) has been disclosed and described in publications on the treatment of other patient populations, such as 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).

[0341] 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, with the active ingredient particles liberated from the lactose carrier particles and carried into the respiratory tract. The used capsule is removed and discarded. The device may be reused depending on the patient's therapy requirements and the corresponding labeling on the clinical device. The number of capsules administered determines the dose of medication.

[0342] 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).

[0343] Also disclosed in the context of the present invention are devices suitable for administering preparations by inhalation in solid form, i.e. aerosolizers, which can have a receptacle for accommodating preparations containing Example 4 or for incorporating these preparations in capsules or blisters, and which can administer preparations containing the active ingredient, for example Example 2 or 4, as monohydrate I or II, by inhalation in solid form (powder inhaler).

[0344] In pulmonary administration, the active compound (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 administered once or twice a day, preferably twice a day, and particularly preferably once a day.

[0345] However, in appropriate cases, it may be necessary to deviate from the stated amount, especially depending on body weight, administration route, individual response to active compound, type of preparation, and the time or interval at which administration is carried out.Therefore, in some cases, it may be sufficient to use less than the above-mentioned minimum amount, and in other cases, it must exceed the stated upper limit.When relatively large amounts are administered, it may be advisable to distribute them over a day in several single doses.

[0346] Specific Embodiments of the Invention (Formulations) 1. A formulation for inhalation, said formulation comprising: (a) (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 a salt or a solvate or a hydrate, (b) lactose carrier at a concentration by weight of 99.25% (w / w) to 80% (w / w); containing a dry powder blend consisting of a combination of It is characterized by (c) 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 in the form of one of the salts or solvates or hydrates has a particle size of 6 μm or more X90 and / or 1 to 3 μm X50; (d) the lactose carrier is lactose monohydrate for inhalation Further characterized by: (e) the lactose has a particle size of 120 μm or more X90 and / or 50 μm or more X50 and / or 5 to 15 μm X10 The formulation for inhalation further characterized by:

[0347] 2. The formulation contains (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 one of the crystalline modifications, wherein the crystalline modifications are selected from the list consisting of monohydrate I of formula (IMI) or monohydrate II or sesquihydrate of formula (IM-II), and the X-ray powder diffractogram of the compound of formula (IMI), measured at 25°C and using Cu-K alpha 1 as radiation source, is at least 12.8 and 29.2, preferably 2θ values ​​± 0.2°. or the X-ray powder diffractogram of the compound of formula (IM-II), measured at 25°C using Cu-Kalpha1 as the radiation source, comprises peaks at 6.9, 7.2, 7.3, 12.8 and 29.2; or the X-ray powder diffractogram of the compound of formula (IM-II), measured at 25°C using Cu-Kalpha1 as the radiation source, comprises peaks at least at 12.7, 5.7, 6.1 and 7.1, or at 12.7, 5.7 and 8.5; or the X-ray powder diffractogram of the compound in the form of sesquihydrate, measured at 25°C using Cu-Kalpha1 as the radiation source, comprises peaks at at least 12.2 and 7.6, alternatively at 12.2, 8.6 and 14.5, expressed as 2θ values ​​±0.2°.

[0348] 3. The formulation comprises: (a) monohydrate I of formula (IMI) or monohydrate II of formula (IM-II) as the active ingredient, 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 concentration by weight of 0.75% (w / w) to 20% (w / w); 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, the x-ray diffractogram of which (at 25°C and using Cu-K alpha 1 as the radiation source) shows at least the following reflections, expressed in 2θ values ​​of ±0.2°: 12.8 and 29.2, preferably 6.9, 7.2, 7.3, 12.8 and 29.2; (b) lactose carrier at a concentration by weight of 99.25% (w / w) to 80% (w / w); containing a dry powder blend consisting of a combination of It is characterized by (c) 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 in the form of monohydrate I of formula (IMI) or monohydrate II of formula (IM-II) has a particle size of X90 of 6 μm or more and / or X50 of 1 to 3 μm; (d) The lactose carrier is lactose monohydrate for inhalation, which is composed of coarse lactose and fine lactose. Further characterized by: (e) the coarse lactose has a particle size that is X50 of 50 μm or more, or 75 μm or more, or 125 μm or more (f) the fine lactose has a particle size of less than 10 μm or 5 μm or less X50 (g) the crude lactose content of the dry powder blend is 98.25% to 75%, preferably 94.25% to 75%. 3. A formulation for inhalation according to claim 1, further characterized by:

[0349] 4. (e) the coarse lactose has a particle size that is X50 equal to or less than 145 μm, or equal to or less than 100 μm, or equal to or less than 95 μm; (f) A formulation for inhalation according to any one of claims 1 to 3, characterized in that the finely divided lactose has a particle size of less than 10 µm or 5 µm or less X50.

[0350] 5. (e) the coarse lactose has a particle size that is X90 of 115 μm or more, or at least 120 μm or more, or at least 200 μm or more; (f) A formulation for inhalation according to any one of claims 1 to 4, characterized in that the finely divided lactose has a particle size of less than 30 µm or 10 µm or less X90.

[0351] 6. (e) the coarse lactose has a particle size of 250 μm or less, or 170 μm or less, or 160 μm or less; (f) A formulation for inhalation according to any one of claims 1 to 5, characterized in that the finely divided lactose has a particle size of less than 30 µm or 10 µm or less X90.

[0352] 7. The process for producing the formulation comprises: (j) Formulation for inhalation according to any one of claims 1 to 6, characterized in that it includes or does not include sieving between mixing cycles, preferably does not include sieving and includes a rest time of at least 10 minutes between mixing cycles.

[0353] 8. During the process for producing the formulation, (k) A formulation for inhalation according to any one of claims 1 to 6, characterized in that a glass container is not used, but a stainless steel container is used.

[0354] 9. A formulation for inhalation according to any one of claims 1 to 8, characterized in that the content of finely divided lactose in the dry powder blend is 1% to a maximum of 15%, 1% to 10% or 5% to 10%.

[0355] 10. A formulation for inhalation according to any one of claims 1 to 9, characterized in that the ratio of active ingredient to crude lactose is between 1:126 and 1:3.8.

[0356] 11. A formulation for inhalation according to any one of claims 1 to 10, characterized in that the ratio of active ingredient to crude lactose is between 1:31 and 1:3.8.

[0357] 12. A formulation for inhalation according to any one of claims 1 to 11, characterized in that the ratio of active ingredient to crude lactose is 1:31.

[0358] 13. A formulation for inhalation according to any one of claims 1 to 12, characterized in that the ratio of active ingredient to crude lactose is 1:8.5.

[0359] 14. A formulation for inhalation according to any one of claims 1 to 13, characterized in that the ratio of the active ingredient to the crude lactose is 1:3.8.

[0360] 15. A preparation for inhalation according to any one of claims 1 to 14, characterized in that the ratio of the active ingredient to the finely divided lactose is between 1:13 and 1:0.1.

[0361] 16. A preparation for inhalation according to any one of claims 1 to 15, characterized in that the ratio of the active ingredient to the finely divided lactose is between 1:1.67 and 1:0.25.

[0362] 17. A formulation for inhalation according to any one of claims 1 to 16, characterized in that the ratio of the active ingredient to the finely divided lactose is 1:1.67.

[0363] 18. A formulation for inhalation according to any one of claims 1 to 17, characterized in that the ratio of the active ingredient to the finely divided lactose is 1:0.5.

[0364] 19. A formulation for inhalation according to any one of claims 1 to 18, characterized in that the ratio of the active ingredient to the finely divided lactose is 1:0.25 or 1:0.1.

[0365] 20. A preparation for inhalation according to any one of claims 1 to 19, characterized in that the ratio of the coarse lactose to the fine lactose is between 445:5 and 65:5 or between 94.25:5 and 65:5.

[0366] 21. A preparation for inhalation according to any one of claims 1 to 20, characterized in that the ratio of the coarse lactose to the fine lactose is 92:5.

[0367] 22. A formulation for inhalation according to any one of claims 1 to 21, characterized in that the ratio of the coarse lactose to the fine lactose is 85:5.

[0368] 23. A formulation for inhalation according to any one of claims 1 to 22, characterized in that the ratio of the coarse lactose to the fine lactose is 75:5.

[0369] 24. A formulation for inhalation according to any one of claims 1 to 23, characterized in that the active ingredient 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 form of monohydrate I of formula (IMI).

[0370] 25. A formulation for inhalation according to any one of claims 1 to 24, characterized in that the active ingredient 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 monohydrate I, has a particle size of 1 to 3 μm X50.

[0371] 26. A preparation for inhalation according to any one of claims 1 to 25, characterized in that the active ingredient 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 form of monohydrate II of formula (IM-II).

[0372] 27. A preparation for inhalation according to any one of claims 1 to 26, characterized in that 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 in the form of monohydrate II of formula (IM-II), has a particle size of 1 to 3 μm X50.

[0373] 28. A preparation for inhalation according to any one of claims 1 to 27, characterized in that the active ingredient 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 monohydrate I, has a particle size of up to 1 μm x 10.

[0374] 29. A formulation for inhalation according to any one of claims 1 to 28, characterized in that the finely divided lactose has a particle size of less than or equal to 10 μm X50 or less than or equal to 5 μm X50.

[0375] 30. A preparation for inhalation according to any one of claims 1 to 29, characterized in that the finely divided lactose is Lactohale® 300 or Lactohale® 230.

[0376] 31. A formulation for inhalation according to any one of claims 1 to 30, characterized in that the crude lactose is in the form of sieved or milled crystalline lactose.

[0377] 32. A formulation for inhalation according to any one of claims 1 to 31, characterized in that the coarse lactose has a particle size that is X90 of 200 to 250 μm or 120 to 160 μm or 115 to 170 μm.

[0378] 33. A formulation for inhalation according to any one of claims 1 to 32, characterized in that the coarse lactose has a particle size that is X50 of 125 to 145 μm or 50 to 100 μm or 75 to 95 μm.

[0379] 34. A formulation for inhalation according to any one of claims 1 to 33, characterized in that the coarse lactose has a particle size of 45 to 65 μm or 5 to 15 μm or 20 to 50 μm X10.

[0380] 35. A formulation for inhalation according to any one of claims 1 to 34, characterized in that the finely divided lactose has a particle size that is X90 equal to or less than 10 μm or less than 30 μm.

[0381] 36. A formulation for inhalation according to any one of claims 1 to 35, characterized in that the finely divided lactose has a particle size of X50 equal to or less than 5 μm or less than 10 μm.

[0382] 37. A formulation for inhalation according to any one of claims 1 to 36, characterized in that the coarse lactose has a particle size of 1 to 3 μm X10.

[0383] 38. A preparation for inhalation according to any one of claims 1 to 37, characterized in that the crude lactose is Lactohale® 100, Lactohale® 200 or Lactohale® 206.

[0384] 39. A formulation for inhalation according to any one of claims 1 to 38, characterized in that the formulation for inhalation contains a nominal dose of 60 μg to 6000 μg 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 in the form of monohydrate I of formula (IMI).

[0385] 40. A formulation for inhalation according to any one of claims 1 to 39, characterized in that the formulation for inhalation contains a nominal dose of 240 to 4000 μg 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 in the form of monohydrate I of formula (IMI).

[0386] 41. A formulation for inhalation according to any one of claims 1 to 40, characterized in that the formulation for inhalation contains a nominal dose of 480 to 4000 μg 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 in the form of monohydrate I of formula (IMI).

[0387] 42. A formulation for inhalation according to any one of claims 1 to 41, characterized in that the formulation for inhalation contains a nominal dose of 480 to 2000 μg 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 in the form of monohydrate I of formula (IMI).

[0388] 43. A formulation for inhalation according to any one of claims 1 to 42, characterized in that the formulation for inhalation contains a nominal dose of 480 to 1000 μg 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 in the form of monohydrate I of formula (IMI).

[0389] 44. A formulation for inhalation according to any one of claims 1 to 43, characterized in that the formulation for inhalation contains a nominal dose of 240 μg, 480 μg, 1000 μg, 2000 μg or 4000 μg 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 in the form of monohydrate I of formula (IMI).

[0390] 45. A formulation for inhalation according to any one of claims 1 to 44, characterized in that the content of coarse lactose in the dry powder blend is 98.25% to 75%, or preferably 94.25% to 75%, or more preferably 90.00% to 75%, or more preferably 90% to 85%, and the content of fine lactose in the dry powder blend is 1.0% to a maximum of 15%, or preferably 1% to a maximum of 10%, preferably 5% to 10%, or more preferably 2.5% to 7.5%, preferably 5% to 7.5%, or more preferably 3-7%, or more preferably 4% to 6%.

[0391] 46. ​​A formulation for inhalation according to any one of claims 1 to 45, characterized in that the formulation for inhalation has a blend assay of 90 to 110%, preferably 95 to 105% (m / m) and a blend uniformity of RSD (= relative standard deviation) (n=10) of 10%, preferably 7.5%, more preferably 5% NMT (= less).

[0392] 47. A formulation for inhalation according to any one of claims 1 to 46, characterized in that the formulation for inhalation has an FPF (% of the nominal dose of the active, less than 4.5 μm) of 20% or more and an FPF (% of the DD of the active, less than 4.5 μm) of the active ingredient, as measured by a cascade impaction and dose unit sampling apparatus (DUSA), of 30% or more.

[0393] 48. A preparation for inhalation according to any one of claims 1 to 47, characterized in that the preparation for inhalation filled into a hard capsule has a minimum fine particle dose of 8 to 780 μg, depending on the concentration of the active ingredient and the capsule filling mass.

[0394] 49. A preparation for inhalation according to any one of claims 1 to 48, characterized in that the preparation for inhalation filled into the hard capsule has a minimum delivered dose of 26 to 3315 μg, depending on the concentration of the active ingredient and the capsule filling mass.

[0395] 50. A cavity containing a formulation for inhalation according to any one of claims 1 to 49, which can be administered to a patient in need thereof via a dry powder inhaler.

[0396] 51. The cavity of claim 50, which is a capsule or a blister strip.

[0397] 52. The cavity of claim 50, which is a capsule.

[0398] 53. A cavity according to any one of claims 50 to 52, characterized in that the cavity contains a dry powder blend with a fill mass of 8 to 40 mg.

[0399] 54. Cavity according to any one of claims 50 to 52, characterized in that the cavity contains a filling mass of the preparation for inhalation of 10 to 30 mg.

[0400] 55. Cavity according to any one of claims 50 to 52, characterized in that the cavity contains a filling mass of 10 to 20 mg of the preparation for inhalation.

[0401] 56. Cavity according to any one of claims 50 to 52, characterized in that the cavity contains a filling mass of 16 to 20 mg of the preparation for inhalation.

[0402] 57. A manufacturing process for producing a formulation for inhalation according to any one of claims 1 to 49, comprising: a. In the first step (1), prior to the start of mixing of both lactose components, fine lactose is weighed and layered between the two layers of coarse lactose; b. In the second step (2), blending the two components is carried out in a tumble mixer for two cycles at 72 rpm, 67 rpm or 34 rpm or 32 rpm or 30 rpm for 20 minutes, the preblend being sieved through a 500 μm sieve between said cycles; c. In the third step (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 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 monohydrate of formula (IMI) I is pre-sieved through a 500 μm sieve and added to the lactose preblend produced in steps A and B, and before the start of mixing, the layers are alternately layered in 10 layers of the lactose preblend and 9 layers of the active ingredient, 6 layers of the lactose preblend and 5 layers of the active ingredient therebetween (Example 4), or 4 layers of the lactose preblend and 3 layers of the active ingredient therebetween (Example 4), or 2 layers of the lactose preblend and 1 layer of the active ingredient therebetween (Example 4), preferably 6 / 5 layers, d. In the fourth step (4), the pre-layered blend obtained in step (3) is mixed in a vessel (glass or stainless steel) for 3 to 5 cycles, preferably 3 cycles, at 72 rpm, 67 rpm, 34 rpm or 32 rpm, preferably 32 rpm, for 20 to 30 minutes, preferably 30 minutes (total mixing time of 90 minutes), with a rest time of 10 minutes between said mixing cycles, The product obtained in step (4) is mixed in a stainless steel container; said mixing being characterized in that said blend is sieved between each mixing cycle, or preferably said blend is not sieved between mixing cycles; e. In the fifth step E, the product obtained in step 4) is allowed to stand in a stainless steel container at room temperature (15-25°C) and a relative humidity of 35-65% for a certain period of time, preferably 24-72 hours, more preferably 48 hours, after which blend uniformity sampling and final capsule filling are carried out; f. In a sixth step (6), the dry powder blend obtained in step E is finally filled into a capsule.

[0403] 58. Use of a formulation for inhalation according to any one or more of claims 1 to 49 for the manufacture of a medicament for use in the treatment of cardiopulmonary disorders, wherein the medicament comprises an inhalable dosage form containing 240 to 4000 μg 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 in the form of monohydrate I of formula (IMI), wherein the x-ray diffractogram (at 25°C and using Cu-K alpha 1 as radiation source) of monohydrate Form I of formula (IMI) shows at least the following reflections, expressed as 2θ values ​​±0.2°: 6.9, 7.2, 7.3, 12.8 and 29.2, and wherein the medicament is administered once or twice daily to a patient in need thereof for a period of at least 2 consecutive days.

[0404] 59. Use of a preparation for inhalation according to any one or more of claims 1 to 49 in the treatment of cardiopulmonary disorders, characterized in that an inhalable dosage form containing 240 to 4000 μg 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 in the form of the crystalline modification monohydrate I of formula (IMI), in which the X-ray powder diffractogram of said compound (measured at 25°C and using Cu-K alpha 1 as the radiation source) contains peaks at least at 12.8 and 29.2, preferably at 6.9, 7.2, 7.3, 12.8 and 29.2, expressed as a 2θ value ±0.2°, is administered to a patient in need thereof once or twice daily for a period of at least two consecutive days.

[0405] 60. Use of a preparation for inhalation according to any one or more of claims 1 to 49 in a method for treating cardiopulmonary disorders, characterized in that an inhalable dosage form containing 240 to 4000 μg 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 in the form of the crystalline modification monohydrate I of formula (IMI), wherein the X-ray powder diffractogram of said compound (measured at 25°C and using Cu-K alpha 1 as the radiation source) contains peaks at least at 12.8 and 29.2, preferably at 6.9, 7.2, 7.3, 12.8 and 29.2, expressed as a 2θ value ±0.2°, is administered to a patient in need thereof once or twice daily for a period of at least two consecutive days.

[0406] 61. A medicament for use in the inhalation treatment of cardiopulmonary disorders, the medicament comprising an inhalation dosage form containing 240 to 4000 μg 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 in the form of one of its crystalline modifications, wherein the crystalline modifications are selected from the list consisting of monohydrate I of formula (IMI) or monohydrate II or sesquihydrate of formula (IM-II), and the X-ray powder diffractogram of the compound of formula (IMI) (measured at 25°C and using Cu-K alpha 1 as a radiation source) shows at least a 2θ value of ±0.2°. or the X-ray powder diffractogram of the compound of formula (IM-II), measured at 25°C using Cu-Kalpha1 as a radiation source, comprises peaks at least at 12.7, 5.7, 6.1 and 7.1, or 12.7, 5.7 and 8.5; or the X-ray powder diffractogram of the compound in the form of the sesquihydrate, measured at 25°C using Cu-Kalpha1 as a radiation source, comprises peaks at least at 12.2 and 7.6, alternatively 12.2, 8.6 and 14.5, expressed as 2θ values ​​±0.2°; and the inhalation dosage form comprises the active ingredient in the form of a dry powder.

[0407] 62. A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders, the packaged pharmaceutical composition containing a dry powder inhaler and a dry powder formulation, the dry powder formulation comprising 240 to 4000 μg 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 in the form of one of its crystalline modifications, the crystalline modifications being selected from the list consisting of monohydrate I of formula (IMI) or monohydrate II or sesquihydrate of formula (IM-II), and the X-ray powder diffractogram of the compound of formula (IMI) (measured at 25°C using Cu-K alpha 1 as a radiation source) shows at least 12 2θ values ​​± 0.2°. or the X-ray powder diffractogram of the compound of formula (IM-II) (measured at 25°C using Cu-Kalpha1 as the radiation source) comprises peaks at least at 12.7, 5.7, 6.1 and 7.1, or 12.7, 5.7 and 8.5, or the X-ray powder diffractogram of the compound in the form of the sesquihydrate (measured at 25°C using Cu-Kalpha1 as the radiation source) comprises peaks at least at 12.2 and 7.6, alternatively 12.2, 8.6 and 14.5, expressed as 2θ values ​​±0.2°; and the package contains instructions for administering the dry powder formulation once or twice daily for a period of at least two consecutive days.

[0408] Further Specific Embodiments of the Invention (Dosing Regimen) 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 of formula I in the form of one of its salts or solvates or hydrates for use in the inhalation treatment of cardiopulmonary disorders, comprising 240 to 4000 μg 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 an inhalation dosage form 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, wherein the inhalation dosage form is administered once or twice daily for a period of at least two consecutive days to a patient in need thereof.

[0409] 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 of formula I in the form of one of its crystalline modifications, in an amount of 240 to 4000 μg, for use in the inhalation treatment of cardiopulmonary disorders. 2. The method of claim 1, wherein an inhalation dosage form comprising: {phenyl-4-yl]methoxy}-phenyl)-ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid is administered to a patient in need thereof once or twice daily for a period of at least two consecutive days, said crystalline modification being selected from the list consisting of monohydrate I of formula (IMI) or monohydrate II or sesquihydrate of formula (IM-II), and wherein an X-ray powder diffractogram (measured at 25°C and using Cu-K alpha 1 as a radiation source) of said compound of formula (IMI) is or the X-ray powder diffractogram of the compound of formula (IM-II) (measured at 25°C using Cu-K alpha 1 as a radiation source) contains peaks at least at 12.8 and 29.2, preferably at 6.9, 7.2, 7.3, 12.8 and 29.2, expressed as 2θ values ​​±0.2°; or the X-ray powder diffractogram of the compound of formula (IM-II) (measured at 25°C using Cu-K alpha 1 as a radiation source) contains peaks at least at 12.7, 5.7, 6.1 and 7.1, or at 12.7, 5.7 and 8.5; or the X-ray powder diffractogram of the compound in the form of the sesquihydrate contains peaks at least at 12.8 and 29.2, preferably at 6.9, 7.2, 7.3, 12.8 and 29.2, expressed as 2θ values ​​±0.2°; or the X-ray powder diffractogram of the compound of formula (IM-II) (measured at 25°C using Cu-K alpha 1 as a radiation source) contains peaks at least at 12.7, 5.7, 6.1 and 7.1, or at 12.7, 5.7 and 8.5; 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, characterized in that the spectrogram (measured at 25°C and using Cu-K alpha 1 as the radiation source) contains peaks at at least 12.2 and 7.6, alternatively 12.2, 8.6 and 14.5, expressed as 2θ values ​​±0.2°.

[0410] 3.240 to 4000 μg 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 in the form of the monohydrate I crystalline modification of formula (IMI), wherein the X-ray powder diffractogram of said compound (measured at 25°C using Cu-K alpha 1 as the radiation source) shows 2θ values ​​of at least 12.8 and 29 ± 0.2°. 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 for use in inhalation treatment of cardiopulmonary disorders according to claim 1 or 2, characterized in that an inhaled dosage form comprising peaks at 2, preferably 6.9, 7.2, 7.3, 12.8 and 29.2 is administered to a patient in need thereof once or twice daily for a period of at least two consecutive days.

[0411] 4.240 to 4000 μg 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 in the form of the crystalline modification monohydrate I of formula (IMI), wherein the X-ray powder diffractogram of said compound (measured at 25°C and using Cu-K alpha 1 as radiation source) is at least 12.8, 16.0 and 25.8, expressed as 2θ values ​​±0.2°, (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 3, characterized in that an inhalation dosage form preferably comprising peaks at 6.9, 7.2, 7.3, 12.8, 16.0 and 25.8 is administered to a patient in need thereof once or twice daily for a period of at least two consecutive days.

[0412] 5. An inhalation dosage form containing 240 to 4000 μg 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 in the form of the crystalline modification monohydrate I of formula (IMI) is administered once or twice daily for a period of at least two consecutive days to a patient in need thereof, 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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 4, 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 exhibits at least the following reflections in an x-ray diffractogram (at 25°C using Cu-K alpha 1 as the radiation source) expressed as 2θ values ​​of ±0.2°: 12.8, 20.5 and 25.8, preferably 6.9, 7.2, 7.3, 12.8, 20.5 and 25.8.

[0413] 6. An inhalation dosage form containing 240 to 4000 μg 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 in the form of the crystalline modification monohydrate I of formula (IMI) is administered once or twice daily to a patient in need thereof for a period of at least two consecutive days, 6. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 5, 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 exhibits at least the following reflections in an x-ray diffractogram (at 25°C using Cu-K alpha 1 as the radiation source), expressed as 2θ values ​​of ±0.2°: 12.8, 5.7, 6.9, 7.2, 7.3 and 9.9.

[0414] 7. An inhalation dosage form containing 240 to 4000 μg 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 in the form of the crystalline modification monohydrate I of formula (IMI) is administered once or twice daily to a patient in need thereof for a period of at least two consecutive days, to administer to said patient an inhalation dosage form containing 240 to 4000 μg 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 in the form of the crystalline modification monohydrate I of formula (IMI), 7. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 6, 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 exhibits at least the following reflections in an X-ray diffractogram (at 25°C using Cu-K alpha 1 as the radiation source) expressed as 2θ values ​​of ±0.2°: 12.8, 5.7, and 16.0, preferably 12.8, 5.7, 6.9, 7.2, 7.3, and 16.0.

[0415] 8. An inhalation dosage form containing 240 to 4000 μg 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 in the form of the crystalline modification monohydrate I of said formula (IMI) is administered once or twice daily to a patient in need thereof for a period of at least two consecutive days, to administer to said patient an inhalation dosage form containing 240 to 4000 μg 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 in the form of the crystalline modification monohydrate I of said formula (IMI), 8. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 7, 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 exhibits at least the following reflections in an X-ray diffractogram (at 25°C using Cu-K alpha 1 as the radiation source) expressed as 2θ values ​​of ±0.2°: 12.8, 5.7, and 20.5, preferably 12.8, 5.7, 6.9, 7.2, 7.3, and 20.5.

[0416] 9. An inhalation dosage form containing 240 to 4000 μg 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 in the form of the crystalline modification monohydrate I of formula (IMI) is administered to a patient in need thereof once or twice daily for a period of at least two consecutive days, to administer to said patient an inhalation dosage form containing 240 to 4000 μg 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 in the form of the crystalline modification monohydrate I of formula (IMI), 9. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 8, 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 exhibits at least the following reflections in an X-ray diffractogram (at 25°C using Cu-K alpha 1 as the radiation source) expressed as 2θ values ​​of ±0.2°: 12.8, 5.7, and 29.2, preferably 12.8, 5.7, 6.9, 7.2, 7.3, and 29.2.

[0417] 10. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 9, characterized in that the X-ray powder diffractogram further comprises peaks at 23.0, 15.2, 25.8 and 25.1.

[0418] 11. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 10, characterized in that the compound in the form of monohydrate I has the X-ray powder diffraction pattern (measured at 25°C and using Cu-K alpha 1 as the radiation source) shown in Figure 6.

[0419] 12. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 11, characterized in that the compound in the form of monohydrate II has the X-ray powder diffraction pattern (measured at 25°C and using Cu-K alpha 1 as the radiation source) shown in Figure 7.

[0420] 13. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 12, characterized in that the compound in the form of a sesquihydrate has the X-ray powder diffraction pattern (measured at 25°C and using Cu-K alpha 1 as the radiation source) shown in Figure 9.

[0421] 14. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 13, characterized in that the compound in crystalline modification monohydrate I of formula (IMI) is stable during micronization.

[0422] 15. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 14, characterized in that the X-ray powder diffractogram of the compound (measured at 25°C and using Cu-K alpha 1 as the radiation source) contains a peak at at least 12.8 and lacks peaks at 27.2 and 27.5 at diffraction angles 2θ values ​​of ±0.2°.

[0423] 16. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 15, characterized in that the X-ray powder diffractogram of the compound (measured at 25°C and using Cu-K alpha 1 as the radiation source) contains peaks at at least 12.8 and 5.7 at diffraction angles 2θ values ​​of ±0.2° and lacks peaks at 8.5 and 6.1.

[0424] 17. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 16, characterized in that the active ingredient is administered over a period of at least 2 to 7 consecutive days.

[0425] 18. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 17, characterized in that the active ingredient is administered over a period of at least 14 consecutive days, in particular from the start of the treatment throughout the entire course of the disease.

[0426] 19. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 18, characterized in that the inhalation dosage form contains the active ingredient in the form of a dry powder.

[0427] 20. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 19, characterized in that the inhalation dosage form contains the active ingredient in the form of a dry powder in a capsule.

[0428] 21. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 20, characterized in that the inhalation dosage form is administered via a dry powder inhaler.

[0429] 22. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 21, characterized in that the inhalation dosage form comprises the active ingredient in combination with a pharmaceutically suitable carrier.

[0430] 23. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 22, characterized in that the inhalation dosage form comprises lactose monohydrate as a carrier, preferably the carrier comprises a mixture of coarse and fine lactose.

[0431] 24. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 23, characterized in that the coarse lactose has a particle size that is an X50 of 50 μm or more, or 75 μm or more, or 125 μm or more, and the fine lactose has a particle size that is an X50 of less than 10 μm or 5 μm or less.

[0432] 25. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 24, characterized in that the coarse lactose has a particle size that is 145 μm or less, or 100 μm or less, or 95 μm or less, X50, and the fine lactose has a particle size that is less than 10 μm or 5 μm or less, X50.

[0433] 26. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 25, characterized in that the coarse lactose has a particle size that is an X90 of at least 115 μm, or at least 120 μm, or at least 200 μm, and the fine lactose has a particle size that is an X90 of less than 30 μm or 10 μm or less.

[0434] 27. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 26, characterized in that the coarse lactose has a particle size that is an X90 of 250 μm or less, or 170 μm or less, or 160 μm or less, and the fine lactose has a particle size that is an X90 of less than 30 μm or 10 μm or less.

[0435] 28. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 27, characterized in that the monohydrate I of formula (IMI) has a particle size X90 of 6 μm or less.

[0436] 29. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 28, characterized in that the monohydrate I of formula (IMI) has a particle size X50 of 1 to 3 μm.

[0437] 30. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 29, characterized in that the inhalation dosage form contains 480 to 4000 μg 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 in the form of crystalline form monohydrate I.

[0438] 31. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 30, characterized in that the inhalation dosage form contains 480 to 2000 μg 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 in the form of crystalline form monohydrate I.

[0439] 32. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 31, characterized in that the inhalation dosage form contains 480 to 1000 μg 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 in the form of crystalline form monohydrate I.

[0440] 33. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 32, characterized in that the inhalation dosage form contains 240 μg, 480 μg, 1000 μg, 2000 μg or 4000 μg 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 in the form of crystalline form monohydrate I.

[0441] 34. (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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 33, characterized in that 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), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP).

[0442] 35. A method for treating cardiopulmonary disorders, comprising administering once or twice daily for at least two consecutive days an inhalation formulation containing 240 to 4000 μg 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 in the form of one of its crystalline modifications, wherein the crystalline modifications are selected from the list consisting of monohydrate I of formula (IMI) or monohydrate II or sesquihydrate of formula (IM-II), and wherein the X-ray powder diffractogram of the compound of formula (IMI) (measured at 25°C and using Cu-K alpha 1 as a radiation source) is or an X-ray powder diffractogram of the compound of formula (IM-II), measured at 25°C using Cu-K alpha 1 as a radiation source, comprises peaks at least at 12.7, 5.7, 6.1 and 7.1, or 12.7, 5.7 and 8.5; or an X-ray powder diffractogram of the compound in the form of the sesquihydrate, measured at 25°C using Cu-K alpha 1 as a radiation source, comprises peaks at least at 12.2 and 7.6, alternatively 12.2, 8.6 and 14.5, expressed as 2θ values ​​±0.2°.

[0443] 36. The method for treating cardiopulmonary disorders according to claim 35, characterized in that the compound in the form of monohydrate I has the X-ray powder diffraction pattern (measured at 25°C and using Cu-K alpha 1 as the radiation source) shown in Figure 6.

[0444] 37. A method for treating a cardiopulmonary disorder according to claim 35 or 36, characterized in that the X-ray powder diffractogram of the compound (measured at 25°C and using Cu-K alpha 1 as the radiation source) contains a peak at at least 12.8 at a diffraction angle 2θ value of ±0.2° and lacks peaks at 27.2 and 27.5.

[0445] 38. A method for treating cardiopulmonary disorders according to any one of claims 35 to 37, characterized in that the X-ray powder diffractogram of the compound (measured at 25°C and using Cu-K alpha 1 as the radiation source) contains peaks at at least 12.8 and 5.7 at diffraction angles of 2θ values ​​±0.2°, and lacks peaks at 8.5 and 6.1.

[0446] 39. A method for treating cardiopulmonary disorders according to any one of claims 35 to 38, characterized in that the compound in the form of monohydrate II has the X-ray powder diffraction pattern shown in Figure 7 (measured at 25°C using Cu-Kalpha1 as the radiation source).

[0447] 40. A method for treating cardiopulmonary disorders according to any one of claims 35 to 39, characterized in that the compound in the form of a sesquihydrate has the X-ray powder diffraction pattern shown in Figure 9 (measured at 25°C using Cu-Kalpha1 as the radiation source).

[0448] 41. A method for treating cardiopulmonary disorders according to any one of claims 35 to 40, characterized in that the active ingredient is administered over a period of at least 2 to 7 consecutive days.

[0449] 42. A method for treating cardiopulmonary disorders according to any one of claims 35 to 41, characterized in that the active ingredient is administered over a period of at least 14 consecutive days, in particular from the start of the treatment throughout the entire course of the disease.

[0450] 43. A method for treating cardiopulmonary disorders according to any one of claims 35 to 42, characterized in that the inhalation dosage form contains the active ingredient in the form of a dry powder.

[0451] 44. A method for treating cardiopulmonary disorders according to any one of claims 35 to 43, characterized in that the inhalation dosage form contains the active ingredient in the form of a dry powder in a capsule.

[0452] 45. A method for treating cardiopulmonary disorders according to any one of claims 35 to 44, characterized in that the inhalation dosage form comprises the active ingredient in combination with a pharmaceutically suitable carrier.

[0453] 46. ​​A method for treating cardiopulmonary disorders according to any one of claims 35 to 45, characterized in that the inhalation dosage form comprises lactose monohydrate as a carrier, preferably the carrier comprises a mixture of coarse and fine lactose.

[0454] 47. A method for treating cardiopulmonary disorders according to claim 46, characterized in that the coarse lactose has a particle size that is X50 of 50 μm or more, or 75 μm or more, or 125 μm or more, and the fine lactose has a particle size that is X50 of less than 10 μm or 5 μm or less.

[0455] 48. A method for treating cardiopulmonary disorders according to claim 46 or 47, characterized in that the coarse lactose has a particle size that is less than 145 μm or less than 100 μm or less than 95 μm X50, and the fine lactose has a particle size that is less than 10 μm or less than 5 μm X50.

[0456] 49. A method for treating cardiopulmonary disorders according to any one of claims 46 to 48, characterized in that the coarse lactose has a particle size that is X90 of 115 μm or more, or at least 120 μm or at least 200 μm or more, and the fine lactose has a particle size that is X90 of less than 30 μm or 10 μm or less.

[0457] 50. A method for treating cardiopulmonary disorders according to any one of claims 46 to 49, characterized in that the coarse lactose has a particle size that is X90 of 250 μm or less, or 170 μm or less, or 160 μm or less, and the fine lactose has a particle size that is X90 of less than 30 μm or 10 μm or less.

[0458] 51. A method for treating cardiopulmonary disorders according to any one of claims 35 to 50, characterized in that the monohydrate I of formula (IMI) has a particle size X90 of 6 μm or less.

[0459] 52. A method for treating cardiopulmonary disorders according to any one of claims 35 to 51, characterized in that the monohydrate I of formula (IMI) has a particle size X50 of 1 to 3 μm.

[0460] 53. A method for treating cardiopulmonary disorders according to any one of claims 35 to 52, characterized in that the inhalation dosage form contains 480 to 4000 μg 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 in the form of crystalline form monohydrate I.

[0461] 54. A method for treating cardiopulmonary disorders according to any one of claims 35 to 53, characterized in that the inhalation dosage form contains 480 to 2000 μg 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 in the form of crystalline form monohydrate I.

[0462] 55. A method for treating cardiopulmonary disorders according to any one of claims 35 to 54, characterized in that the inhalation dosage form contains 480 to 1000 μg 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 in the form of crystalline form monohydrate I.

[0463] 56. A method for treating cardiopulmonary disorders according to any one of claims 35 to 55, characterized in that the inhalation dosage form contains 240 μg, 480 μg, 1000 μg, 2000 μg or 4000 μg 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 in the form of crystalline form monohydrate I.

[0464] 57. A method for treating cardiopulmonary disorders according to any one of claims 35 to 56, characterized in that 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), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP).

[0465] 58. A medicament for use in the inhalation treatment of cardiopulmonary disorders, the medicament comprising an inhalation dosage form containing 240 to 4000 μg 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 in the form of one of its crystalline modifications, the crystalline modifications being selected from the list consisting of monohydrate I of formula (IMI) or monohydrate II or sesquihydrate of formula (IM-II), wherein the X-ray powder diffractogram of the compound of formula (IMI), measured at 25°C and using Cu-K alpha 1 as a radiation source, is at least 12.8 and 29.2, shown as 2θ values ​​± 0.2°, Preferably, the compound of formula (IM-II) has peaks at 6.9, 7.2, 7.3, 12.8 and 29.2, or the X-ray powder diffractogram of the compound of formula (IM-II), measured at 25°C using Cu-Kalpha1 as a radiation source, has peaks at least 12.7, 5.7, 6.1 and 7.1, or 12.7, 5.7 and 8.5, or the X-ray powder diffractogram of the compound in the form of sesquihydrate, measured at 25°C using Cu-Kalpha1 as a radiation source, has peaks at at least 12.2 and 7.6, alternatively 12.2, 8.6 and 14.5, expressed as 2θ values ​​±0.2°, and wherein the medicament is administered to a patient in need thereof once or twice daily for at least two consecutive days.

[0466] 59. A medicament for use in inhalation treatment of cardiopulmonary disorders according to claim 58, characterized in that the compound in the form of monohydrate I has the X-ray powder diffraction pattern (measured at 25°C and using Cu-K alpha 1 as the radiation source) shown in Figure 6.

[0467] 60. A medicament for use in inhalation treatment of cardiopulmonary disorders according to claim 58 or 59, characterized in that the X-ray powder diffractogram of the compound (measured at 25°C and using Cu-K alpha 1 as the radiation source) contains a peak at at least 12.8 at a diffraction angle 2θ value of ±0.2° and lacks peaks at 27.2 and 27.5.

[0468] 61. A pharmaceutical for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 60, characterized in that the X-ray powder diffractogram of the compound (measured at 25°C and using Cu-K alpha 1 as the radiation source) contains peaks at at least 12.8 and 5.7 at a diffraction angle of 2θ values ​​±0.2°, and lacks peaks at 8.5 and 6.1.

[0469] 62. A pharmaceutical for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 61, characterized in that the compound in the form of monohydrate II has the X-ray powder diffraction pattern shown in Figure 7 (measured at 25°C using Cu-K alpha 1 as the radiation source).

[0470] 63. A pharmaceutical for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 62, characterized in that the compound in the form of a sesquihydrate has the X-ray powder diffraction pattern shown in Figure 9 (measured at 25°C using Cu-K alpha 1 as the radiation source).

[0471] 64. A medicament for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 63, characterized in that the active ingredient is administered over a period of at least 2 to 7 consecutive days.

[0472] 65. A medicine for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 64, characterized in that the active ingredient is administered over a period of at least 14 consecutive days, in particular from the start of the treatment throughout the entire course of the disease.

[0473] 66. A medicament for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 65, characterized in that the inhalation dosage form contains the active ingredient in the form of a dry powder.

[0474] 67. A medicament for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 66, characterized in that the inhalation dosage form contains the active ingredient in the form of a dry powder in a capsule.

[0475] 68. A medicament for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 67, characterized in that the inhalation dosage form comprises the active ingredient in combination with a pharmaceutically suitable carrier.

[0476] 69. A medicament for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 68, characterized in that the inhalation dosage form comprises lactose monohydrate as a carrier, preferably the carrier comprises a mixture of coarse and fine lactose.

[0477] 70. A pharmaceutical for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 69, characterized in that the coarse lactose has a particle size that is X50 of 50 μm or more, or 75 μm or more, or 125 μm or more, and the fine lactose has a particle size that is X50 of less than 10 μm or 5 μm or less.

[0478] 71. A pharmaceutical for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 70, characterized in that the coarse lactose has a particle size that is X50 of not more than 145 μm or not more than 100 μm or not more than 95 μm, and the fine lactose has a particle size that is X50 of less than 10 μm or not more than 5 μm.

[0479] 72. A pharmaceutical for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 71, characterized in that the coarse lactose has a particle size that is X90 of 115 μm or more, or at least 120 μm or at least 200 μm, and the fine lactose has a particle size that is X90 of less than 30 μm or 10 μm or less.

[0480] 73. A pharmaceutical for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 72, characterized in that the coarse lactose has a particle size that is X90 of less than 250 μm or less than 170 μm or less than 160 μm, and the fine lactose has a particle size that is X90 of less than 30 μm or less than 10 μm.

[0481] 74. A medicament for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 73, characterized in that the monohydrate I of formula (IMI) has a particle size X90 of 6 μm or less.

[0482] 75. A medicament for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 74, characterized in that the monohydrate I of formula (IMI) has a particle size X50 of 1 to 3 μm.

[0483] 76. A medicament for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 75, characterized in that the inhalation dosage form contains 480 to 4000 μg 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 in the form of crystalline form monohydrate I.

[0484] 77. A medicament for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 76, characterized in that the inhalation dosage form contains 480 to 2000 μg 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 in the form of crystalline form monohydrate I.

[0485] 78. A medicine for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 77, characterized in that the inhalation dosage form contains 480 to 1000 μg 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 in the form of crystalline form monohydrate I.

[0486] 79. A medicament for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 78, characterized in that the inhalation dosage form contains 240 μg, 480 μg, 1000 μg, 2000 μg or 4000 μg 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 in the form of crystalline form monohydrate I.

[0487] 80. A pharmaceutical for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 79, characterized in that 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), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP).

[0488] 81. A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders, the packaged pharmaceutical composition containing a dry powder inhaler and a dry powder formulation, the dry powder formulation comprising 240 to 4000 μg 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 in the form of one of its crystalline modifications, the crystalline modifications being selected from the list consisting of monohydrate I of formula (IMI) or monohydrate II or sesquihydrate of formula (IM-II), and the X-ray powder diffractogram of the compound of formula (IMI) (measured at 25°C using Cu-K alpha 1 as a radiation source) shows a 2θ value of ±0.2° for at least 12 or the X-ray powder diffractogram of the compound of formula (IM-II) (measured at 25°C using Cu-Kalpha1 as the radiation source) comprises peaks at least at 12.7, 5.7, 6.1 and 7.1, or 12.7, 5.7 and 8.5, or the X-ray powder diffractogram of the compound in the form of the sesquihydrate (measured at 25°C using Cu-Kalpha1 as the radiation source) comprises peaks at least at 12.2 and 7.6, alternatively 12.2, 8.6 and 14.5, expressed as 2θ values ​​±0.2°; and the package contains instructions for administering the dry powder formulation once or twice daily for a period of at least two consecutive days.

[0489] 82. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to claim 81, characterized in that the cardiopulmonary disorder is selected from the list consisting of pulmonary arterial hypertension (PAH) 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 associated with idiopathic interstitial pneumonia (PH-IIP).

[0490] 83. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to claim 81 or 82, characterized in that the package further contains instructions for use of the dry powder formulation for treating cardiopulmonary disorders by inhalation, describing the inhalation procedure as follows: a capsule is placed into the dry powder inhaler, and then after one deep inhalation, the patient should hold their breath for approximately 2 seconds, which will cause the dry powder drug to condense from the airstream onto the surface of the deeper lung regions and deposit near its intended site of pharmacological action.

[0491] 84. A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 83, characterized in that the dry powder inhaler is a capsule-based single unit dose inhaler (see Figure 3a).

[0492] 85. The packaged pharmaceutical composition contains a dry powder formulation, the dry powder formulation comprising 240 to 4000 μg 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 in the form of one of its crystalline modifications, wherein the crystalline modifications are selected from the list consisting of monohydrate I of formula (IMI) or monohydrate II or sesquihydrate of formula (IM-II), and the X-ray powder diffractogram of the compound of formula (IMI), measured at 25°C using Cu-K alpha 1 as a radiation source, is at least 12.8 and 29.2, preferably 6.9, 7.2, 7.3, 1, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 ... 85. The packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 84, wherein the compound of formula (IM-II) in an X-ray powder diffractogram (measured at 25°C using Cu-Kalpha1 as the radiation source) comprises peaks at least 12.7, 5.7, 6.1 and 7.1, or 12.7, 5.7 and 8.5, or the compound in an X-ray powder diffractogram (measured at 25°C using Cu-Kalpha1 as the radiation source) in a sesquihydrate form comprises peaks at least 12.2 and 7.6, alternatively 12.2, 8.6 and 14.5, expressed as 2θ values ​​±0.2°; and wherein the packaged pharmaceutical composition does not contain the dry powder inhaler.

[0493] 86. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 85, characterized in that the dry powder formulation comprises 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, preferably in the form of monohydrate Form I of Formula (IMI) or monohydrate Form II of Formula (IM-II), in combination with lactose monohydrate as a carrier, wherein the carrier comprises a mixture of coarse and fine lactose.

[0494] 87. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 86, characterized in that the compound in the form of monohydrate I has the X-ray powder diffraction pattern (measured at 25°C and using Cu-K alpha 1 as the radiation source) shown in Figure 6.

[0495] 88. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 87, characterized in that the X-ray powder diffractogram of the compound (measured at 25°C and using Cu-K alpha 1 as the radiation source) contains a peak at at least 12.8 at a diffraction angle 2θ value of ±0.2° and lacks peaks at 27.2 and 27.5.

[0496] 89. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 88, characterized in that the X-ray powder diffractogram of the compound (measured at 25°C and using Cu-K alpha 1 as the radiation source) contains peaks at at least 12.8 and 5.7 at a diffraction angle 2θ value of ±0.2°, and lacks peaks at 8.5 and 6.1.

[0497] 90. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 89, characterized in that the compound in the form of monohydrate II has the X-ray powder diffraction pattern (measured at 25°C and using Cu-K alpha 1 as the radiation source) shown in Figure 7.

[0498] 91. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 90, characterized in that the compound in the form of a sesquihydrate has the X-ray powder diffraction pattern (measured at 25°C and using Cu-K alpha 1 as the radiation source) shown in Figure 9.

[0499] 92. A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 91, characterized in that the active ingredient is administered over a period of at least 2 to 7 consecutive days.

[0500] 93. A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 92, characterized in that the active ingredient is administered over a period of at least 14 consecutive days, in particular from the start of the treatment throughout the entire course of the disease.

[0501] 94. A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 93, characterized in that the inhalation dosage form comprises the active ingredient in the form of a dry powder.

[0502] 95. A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 94, characterized in that the inhalation dosage form comprises the active ingredient in the form of a dry powder in a capsule.

[0503] 96. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 95, characterized in that the coarse lactose has a particle size that is X50 of 50 μm or more, or 75 μm or more, or 125 μm or more, and the fine lactose has a particle size that is X50 of less than 10 μm or 5 μm or less.

[0504] 97. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 96, characterized in that the coarse lactose has a particle size that is less than 145 μm or less than 100 μm or less than 95 μm X50, and the fine lactose has a particle size that is less than 10 μm or less than 5 μm X50.

[0505] 98. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 97, characterized in that the coarse lactose has a particle size that is X90 of at least 115 μm or at least 120 μm or at least 200 μm, and the fine lactose has a particle size that is X90 of less than 30 μm or 10 μm or less.

[0506] 99. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 98, characterized in that the coarse lactose has a particle size that is X90 of not more than 250 μm or not more than 170 μm or not more than 160 μm, and the fine lactose has a particle size that is X90 of less than 30 μm or not more than 10 μm.

[0507] 100. A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 99, characterized in that the monohydrate I of formula (IMI) has a particle size X90 of 6 μm or less.

[0508] 101. A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 100, characterized in that the monohydrate I of formula (IMI) has a particle size X50 of 1 to 3 μm.

[0509] 102. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 101, characterized in that the inhalation dosage form contains 480 to 4000 μg 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 in the form of crystalline form monohydrate I.

[0510] 103. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 102, characterized in that the inhalation dosage form contains 480 to 2000 μg 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 in the form of crystalline form monohydrate I.

[0511] 104. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 103, characterized in that the inhalation dosage form contains 480 to 1000 μg 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 in the form of crystalline form monohydrate I.

[0512] 105. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 103, characterized in that the inhalation dosage form contains 240 μg, 480 μg, 1000 μg, 2000 μg or 4000 μg 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 in the form of crystalline form monohydrate I.

[0513] The following exemplary embodiments illustrate the present invention. The present invention is not limited to the examples.

[0514] The percentage data in the following tests and examples are percentages by weight and parts are parts by weight unless otherwise indicated. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are in each case based on volume.

[0515] Experimental Department Abbreviations and acronyms: TIFF2025501302000023.tif243165TIFF2025501302000024.tif214165

[0516] Analysis method DSC / TG DSC thermograms were recorded using a differential scanning calorimeter from Perkin-Elmer (model 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.

[0517] TGA thermograms were recorded using a thermobalance from Perkin-Elmer (model 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.

[0518] XRPD X-ray diffraction patterns were recorded at room temperature using an XRD diffractometer X'Pert PRO (PANalytical) and a STOE STADI-P (Cu K alpha 1 radiation, wavelength 1.5406 Å). No sample preparation was performed. All X-ray reflections are reported as °2θ (theta) values ​​(maximum peak) with a resolution of ±0.2°.

[0519] Raman Raman spectra were recorded at room temperature using an FT-Raman spectrophotometer from Bruker (models RFS 100 and MultiRam). The resolution was 2 cm. Measurements were performed in glass vials or aluminum discs. No sample preparation was performed.

[0520] 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. No sample preparation was performed.

[0521] LC-MS method Method A Equipment: 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.

[0522] HPLC method Method B High-performance liquid chromatograph with thermostatic column oven, UV detector and data evaluation system, measurement wavelength: 206 nm, bandwidth: 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 the sample solvent, injection volume: 5 μl, RT: enantiomer 1: 5.8 min (RRT 1.00), enantiomer 2: 7.2 min RRT 1.25

[0523] Method C High-performance liquid chromatograph with thermostatic column oven, UV detector and data evaluation system, measurement wavelength: 204 nm, bandwidth: 6 nm, oven temperature: 45°C, column: chiralpak AD-H, length: 250 mm, internal diameter: 4.6 mm, particle size: 5 μm, mobile phase: A: n-heptane, B: ethanol + 0.2% 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 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

[0524] 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

[0525] Method M High-performance liquid chromatograph equipped with a thermostatic column oven, a UV detector, and a data evaluation system, measuring wavelength: 226 nm, bandwidth: 40 nm. Column: Zorbax Bonus-RP, length: 150 mm, internal 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 was 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.

[0526] New Method High-performance liquid chromatograph equipped with a thermostatic column oven, a UV detector, and a data evaluation system, measuring wavelength: 226 nm, bandwidth: 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: 1.2 mL / min; UV lamp: 210 nm

[0527] Method N A high-performance liquid chromatograph equipped with a thermostatic column oven, a UV detector, and a data evaluation system was used. The measurement wavelength was 210 nm. The column was an XBridge BEH Phenyl column, 50 mm long, 4.6 mm internal diameter, and 2.5 μm particle size. The mobile phase consisted of A: 0.66 g (NH4)2HPO4 and 0.58 g (NH4)H2PO4 in 1 L of Millipore water; B: ACN. The gradient program was: 0.00 min 95% B → 8.3 min 80% B → 11.0 min 80% B; flow rate: 1.2 ml / min; sample solvent: ACN + water; injection volume: 3 μL.

[0528] 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 TIFF2025501302000025.tif83165 compound was synthesized according to the procedure disclosed in Example 92A of WO2014 / 012934.

[0529] Example 2A Butyl-(5S)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-hydroxyphenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate The TIFF2025501302000026.tif53165 compound was synthesized according to the procedure disclosed in Example 10 of WO2021 / 233783.

[0530] 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 TIFF2025501302000027.tif78165 was synthesized according to the procedure disclosed in Example 11 of WO2021 / 233783.

[0531] A further starting material, 4-(bromomethyl)-3-chloro-4'-(trifluoromethyl)[biphenyl] (compound of formula XI), is commercially available.

[0532] 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 In 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 a weight of 1126.3 g. Yield (crude): 1126.3 g; 94.4% of theoretical yield Enantiomeric purity (HPLC Method B): 95.3% ee Purity (area): 81.8% (Method N), Rt (BP-diester) of 16.11

[0533] 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

[0534] 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.

[0535] To smaller portions of the reaction mixture, different solvents were added to initiate crystallization. The following solvents were tried without any effect: MTBE, MIBK, methylene chloride, toluene. After the addition of a mixture of cyclohexane, n-hexane, and methylcyclohexane, two layers formed.

[0536] 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.

[0537] The solid was separated with methylcyclohexane and HPLC analysis of the solid revealed it to be tartaric acid.

[0538] Water was added to another portion of the reaction mixture before the solid separated. The solid was difficult to separate.

[0539] The solvent was removed from the reaction mixture to give 3.1 g of yellow foam crystals.

[0540] 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.

[0541] No defined salts were detectable.

[0542] 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 vacuo to give an orange oil.

[0543] No salt formation was observable.

[0544] 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 hour, no crystallization occurred.

[0545] The solvent was evaporated in vacuo at 40° C. to give yellow foamy crystals.

[0546] Several solvents were screened to initiate either crystallization or purification.

[0547] Dichloromethane, MIBK, MTBE, ethyl acetate, acetone, acetonitrile, dioxane, n-butanol, methanol, ethanol, tetrahydrofuran, and toluene yielded solutions at room temperature.

[0548] Diisopropyl ether, water, diethyl ether, cyclohexane resulted in sticky agglomerates.

[0549] Further stirring in n-hexane at room temperature again gave a sticky mass.

[0550] No isolable salts.

[0551] 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.

[0552] The solvent was evaporated in vacuo at 40° C. to give yellow foamy crystals.

[0553] Several solvents were screened to initiate either crystallization or purification.

[0554] Dichloromethane, MIBK, ethyl acetate, acetone, acetonitrile, dioxane, n-butanol, methanol, ethanol, tetrahydrofuran, and toluene yielded solutions at room temperature.

[0555] MTBE was added and oil droplets formed.

[0556] Water, diisopropyl ether, diethyl ether, cyclohexane and n-heptane all resulted in only sticky agglomerates.

[0557] No isolable salts.

[0558] 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) TIFF2025501302000029.tif7816515 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 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].

[0559] 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: 70:30 (v / v) carbon dioxide / isopropanol; flow rate: 3 ml / min; UV detection: 210 nm].

[0560] 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: 70:30 (v / v) carbon dioxide / isopropanol; flow rate: 3 ml / min; UV detection: 210 nm].

[0561] 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) TIFF2025501302000030.tif78165 3208 ml of a 4N solution of hydrogen chloride 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 overnight at room temperature. The reaction solution was then concentrated to dryness, and the residue was dried overnight under high vacuum. This gave 448.7 g (641.59 mmol, approximately 100% of theory) of the target product. LC-MS (Method A): Rt=1.06 min; m / z=609 / 611(M+H)+.

[0562] 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) TIFF2025501302000031.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) was taken up in 6869 ml of THF, 268 ml of triethylamine was 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(b r.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).

[0563] Example 9A Ethyl 5-([2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]{2-[4-(methoxy-carbonyl)phenyl]ethyl}amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 1) TIFF2025501302000032.tif83165819A 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, another 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 another 72 hours. After the reaction mixture was cooled, the inorganic salts were filtered off, and the filtrate was evaporated to dryness. The residue was taken up in ethyl acetate, washed twice with 10% strength aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and then evaporated to dryness once more. The residue 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),1.8 5-1.96(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).

[0564] Comparative Example Comparative Example 1 (Cinaciguat) 4-[((4-carboxybutyl)-{2-[(4-phenethylbenzyl)oxy]phenethyl}amino)methyl]benzoic acid The compound TIFF2025501302000033.tif63165 was synthesized analogously to Example 8A of WO01 / 019780-A1.

[0565] Comparative Example 2 Riociguat Methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate The compound TIFF2025501302000034.tif68165 was synthesized analogously to Example 8 of WO03 / 095451-A1.

[0566] Comparative Example 3 (5)-{(4-carboxybutyl)[2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]oxy}-5-fluorophenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (enantiomer 2) The compound TIFF2025501302000035.tif78165 was synthesized in analogy to Example 37 of WO2014 / 012934-A1. LC-MS (Method A):R t =1.10 min; m / z=672 / 674(M+H) + .

[0567] Comparative Example 4 5-{[2-(4-carboxyphenyl)ethyl][2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]oxy}-5-fluorophenyl)-ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (enantiomer 2) The compound TIFF2025501302000036.tif83165 was synthesized in analogy to Example 39 of WO2014 / 012934-A1. LC-MS (Method A):R t=1.28 min; m / z=720 / 722(M+H) + . 1 H-NMR(400 MHz,DMSO-d6):δ[ppm]=1.40-1.72(m,2H),1.88-2.11(m,2H),2.59-2.84(m,10H),4.02-4.13(m,1H),5.00-5.14(m,2H),6.96(d, 1H),7.02(d,2H),7.13(d,2H),7.41-7.57(m,5H),7.75(d,2H),7.83(d,1H),7.93(d,1H),8.11(d,2H),12.05-13.41(br.s,about 2H). [α] D 20 =+58.77°,c=0.405,DMSO.

[0568] Comparative Example 5 (+)-5-{(4-carboxybutyl)[2-(2-{[4-(5-methyl-1,3-benzoxazol-2-yl)benzyl]oxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (enantiomer 2) The compound TIFF2025501302000037.tif83165 was synthesized in analogy to Example 2 of WO2014 / 012934-A1. LC-MS (Method A):R t =1.03min;m / z=634(M+H) + . 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.32-1.70 (m, 7H), 1.89-2.03 (m, 2H), 2.07-2.16 (m, 2H), 2.39-2.64 (m, 3H, partially obscured by signals), 2.46 (s, 3H), 2.65-2.87 (m, 4H), 3.95-4.03 (m, 1H), 5.08(q,2H),6.87(t,1H),6.99(d,1H),7.13(d,1H),7.18(t,1H),7.25(d,1H),7.52( d,2H),7.61(s,1H),7.67(d,2H),7.85(d,1H),8.16(d,2H),11.30-12.97(br.s,2H). [α] D 20 =+62.89°, c=0.380, methanol.

[0569] Comparative Example 6 5-([2-(4-Carboxyphenyl)ethyl]{2-[2-({4-[5-(trifluoromethyl)-1,3-benzoxazol-2-yl]benzyl}oxy)phenyl]-ethyl}amino)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (enantiomer 2) The compound TIFF2025501302000038.tif83165 was synthesized in analogy to Example 24 of WO2014 / 012934-A1. LC-MS (Method A):R t =1.32min;m / z=736(M+H) + . 1 H-NMR (400 MHz,DMSO-d6):δ[ppm]=1.41-1.55(m,1H),1.55-1.71(m,1H),1.88-2.10(m,2H ),2.58-2.89(m,10H),4.01-4.14(m,1H),5.03-5.16(m,2H),6.86(t,1H),6.99 -7.10(m,2H),7.14(d,2H),7.21(t,1H),7.46(d,1H),7.49-7.60(m,3H),7.72- 7.86(m,3H),8.03(d,1H),8.14(d,2H),8.24(s,1H),12.01-13.42(br.s,about 2H).

[0570] Comparative Example 7 5-[(4-Carboxybutyl){2-[2-({4-[5-(trifluoromethyl)-1,3-benzoxazol-2-yl]benzyl}oxy)phenyl]ethyl}amino]-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (Enantiomer 2) The compound TIFF2025501302000039.tif83165 was synthesized in analogy to Example 25 of WO2014 / 012934-A1. LC-MS (Method A):R t=1.07min;m / z=688(M+H) + . 1 H-NMR(400 MHz,DMSO-d6):δ[ppm]=1.30-1.71(m,6H),1.90-2.04(m,2H),2.07-2.18(m,2H ),2.39-2.65(m,4H,partially obscured by DMSO signal),2.65-2.91(m,4H),3.87-4.07(m,1H ),5.10(q,2H),6.87(t,1H),7.00(d,1H),7.10-7.23(m,2H),7.56(d,2H),7.66 (d,1H),7.85(d,2H),8.04(d,1H),8.16-8.30(m,3H),11.10-13.31(br.s,about 2H).

[0571] Comparative Example 8 5-[(4-Carboxybutyl){2-[2-({4-[5-(trifluoromethoxy)-1,3-benzoxazol-2-yl]benzyl}oxy)phenyl]ethyl}-amino]-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (Enantiomer 2) The compound TIFF2025501302000040.tif83165 was synthesized in analogy to Example 28 of WO2014 / 012934-A1. LC-MS (Method A):R t =1.09min;m / z=704(M+H) + . 1 H-NMR (400 MHz,DMSO-d6):δ[ppm]=1.32-1.71(m,6H),1.88-2.05(m,2H),2.07-2.17(m,2H),2 .39-2.64(m,4H,partially obscured by DMSO signal),2.64-2.88(m,4H),3.93-4.05(m,1H),5.10 (q,2H),6.87(t,1H),6.99(d,1H),7.09-7.23(m,2H),7.46(dd,1H),7.54(d,2H),7 .66(d,1H),7.85(d,1H),7.89-7.98(m,2H),8.18(d,2H),11.10-13.04(br.s,about 2H).

[0572] Comparative Example 9 5-([2-(4-Carboxyphenyl)ethyl]{2-[2-({4-[5-(trifluoromethoxy)-1,3-benzoxazol-2-yl]benzyl}oxy)-phenyl]ethyl}amino)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (enantiomer 2) The compound TIFF2025501302000041.tif89165 was synthesized in analogy to Example 29 of WO2014 / 012934-A1. LC-MS (Method A):R t =1.34 min; m / z=752(M+H) + . 1 H-NMR(400 MHz,DMSO-d6):δ[ppm]=1.42-1.55(m,1H),1.55-1.71(m,1H),1.88-2.11(m,2H),2.59-2.87(m,10H),3.99-4.13(m,1H),5.09(q,2H),6.88(t ,1H),6.98-7.09(m,2H),7.15(d,2H),7.20(t,1H),7.41-7.58(m,5H), 7.77(d,2H),7.87-7.96(m,2H),8.12(d,2H),11.89-13.63(br.s,about 2H).

[0573] Comparative Example 10 5-{(4-carboxybutyl)[2-(2-{[4-(5-cyano-1,3-benzoxazol-2-yl)benzyl]oxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (enantiomer 2) The compound TIFF2025501302000042.tif78165 was synthesized in analogy to Example 31 of WO2014 / 012934-A1. LC-MS (Method A):R t =0.93min;m / z=645(M+H) + . 1H-NMR (400 MHz, DMSO-d): δ [ppm] = 1.31-1.77 (m, 6H), 1.90-2.05 (m, 2H), 2.05-2.18 (m, 2H), 2.39-2.64 (m, 4H, partially obscured by DMSO signals), 2.65-2.88 (m, 4H), 3.92-4.05 (m, 1H), 5.10 (q ,2H),6.87(t,1H),6.99(d,1H),7.10-7.22(m,2H),7.55(d,2H),7.67(d,1H),7.85(d ,1H),7.93(d,1H),8.04(d,1H),8.19(d,2H),8.44(s,1H),11.38-12.79(br.s,about 2H).

[0574] 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 TIFF2025501302000043.tif8916524 50 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 1 N aqueous sodium hydroxide solution was added, and the mixture was 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 (a total of about 50 ml of water). The solid was then taken up in 50 ml of water and stirred overnight at room temperature. After another filtration with suction, the solid was washed again with water and then dried overnight under high vacuum at 40° C. 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),7.0 5 (br. d, 2 H), 7.12 (br. d, 2 H), 7.23 (br.

[0575] XRPD: amorphous phase, see Figure 33. Determination of the absolute configuration of Comparative Example 11 via VCD spectroscopy: Vibrational circular dichroism (VCD) is an 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).

[0576] The steps involved in the decision are: 1. Experimental VCD spectra were measured using DMSO. Sample Example 1 was measured at a concentration of 5.5 mg / 0.15 ml.

[0577] 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 signs of all bands or by calculating the VCD of the mirror image structure.

[0578] 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 these two spectra can be calculated using CompareVOA™ software. VCD spectrometer: ChirallR-2X w / DualPEM Concentration: 5.5 mg / 0.15 ml of Example 1 in DMSO Resolution: 4cm-1 PEM setting: 1400cm-1 Number of scans / measurement time: 20 hours Sample cell: BaF2 Path length: 100μm 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 VCD spectral match with a 94% confidence level for the assignment.

[0579] Determination of thermal stability of Comparative Example 11: 0.3 mg of Comparative Example 11 was dissolved in 0.1 ml of dimethyl sulfoxide and 0.4 ml of acetonitrile. Then, 1.0 ml 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). 0.3 mg of the test compound was weighed into another HPLC vial. The vial was capped and stored in a heating block at 90°C for 7 days.

[0580] After this time, the vial was uncapped and 0.1 ml of dimethyl sulfoxide and 0.4 ml of acetonitrile were added to the stress compound. 1.0 ml of water was then added. The HPLC vial was shaken and sonicated to ensure complete dissolution. The sample was analyzed by HPLC (1-week sample). The peak area in percentage was used for quantification.

[0581] [Table 11]

[0582] Comparative Example 11 was found to be stable over the test period.

[0583] 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 ...

Claims

1. 1. A formulation for inhalation comprising a dry powder blend, The dry powder blend (a) a crystalline form of the monohydrate 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; and lactose carrier, A formulation for inhalation comprising:

2. 2. The formulation of claim 1, wherein the monohydrate crystalline form has 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 formulation of claim 2, wherein the monohydrate crystalline form has 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 a radiation source when measured at 25°C.

4. 3. The formulation of claim 2, wherein the monohydrate crystalline form has 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 using Cu—Kalpha1 as a radiation source when measured at 25°C.

5. 2. The formulation of claim 1, wherein the monohydrate crystalline form has 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 formulation of claim 5, wherein the monohydrate crystalline form has 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 a radiation source when measured at 25°C.

7. 6. The formulation of claim 5, wherein the monohydrate crystalline form has an additional reflection 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—K alpha 1 as a radiation source when measured at 25° C.

8. 2. The formulation of claim 1, wherein the monohydrate crystalline form has 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 formulation of claim 8, wherein the monohydrate crystalline form has 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 a radiation source when measured at 25° C.

10. 9. The formulation of claim 8, wherein the monohydrate crystalline form has 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—K alpha 1 as a radiation source when measured at 25° C.

11. The monohydrate crystalline form exhibits X-ray powder diffraction reflections of 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, 11.6±0.2, 11.7±0.2, 11.8±0.2, 11.9±0.2, 12.0±0.2, 12.1±0.2, 12.2±0.2, 12.3±0.2, 12.4±0.2, 13.0±0.2, 13.1±0.2, 13.2±0.2, 13.3±0.2, 13.4±0.2, 13.5±0.2, 13.6±0.2, 13.7±0.2, 13.8±0.2, 13.9±0.2, 14.0±0.2, 14.1±0.2, 14.2±0.2, 14.3±0.2, 14.4±0.2, 14.5±0.2, 14.6±0.2, 14.7±0.2, 14.8±0.2, 14.9 ... 2.0±0.2, 12.3±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, 18.8±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°2θ.

12. 12. The formulation of any one of claims 1 to 11, wherein the monohydrate crystals are at a concentration by weight of about 0.75% (w / w) to about 20% (w / w).

13. 12. The formulation of any one of claims 1 to 11, wherein the lactose carrier is at a concentration by weight of about 80% to about 99.25%.

14. 12. The formulation of any one of claims 1 to 11, wherein the monohydrate crystals have a particle size that is X50 of about 1 to about 3 μm.

15. A formulation according to any one of claims 1 to 11, wherein the lactose carrier is lactose monohydrate for inhalation.

16. 16. The formulation of claim 15, wherein the lactose monohydrate has a particle size that is 50 μm or greater X50.

17. 17. The formulation of claim 16, wherein the lactose monohydrate consists of coarse and fine lactose.

18. (i) the coarse lactose has a particle size that is 50 μm or greater X50; and (ii) the fine lactose has a particle size of 10 μm or less x50; 18. The formulation of claim 17.

19. 19. The formulation of claim 18, wherein the crude lactose content of the dry powder blend is from about 70% to about 98.25%.

20. (i) the monohydrate crystals are at a concentration by weight of about 0.75% (w / w) to about 20% (w / w); (ii) the lactose carrier is at a concentration by weight of about 80% to about 99.25%; (iii) the monohydrate crystals have a particle size of about 1 to about 3 μm X50; and (iv) the lactose carrier is lactose monohydrate for inhalation; The formulation according to any one of claims 1 to 11.

21. (v) the lactose monohydrate has a particle size that is 50 μm or greater X50; and (vi) the lactose monohydrate consists of coarse lactose and fine lactose; 21. The formulation of claim 20.

22. (vii) the coarse lactose has a particle size that is 50 μm or greater X50; (viii) the fine lactose has a particle size of 10 μm or less x50; and (ix) the crude lactose content of the dry powder blend is from about 70% to about 98.25%.

22. The formulation of claim 21.

23. 12. The formulation of any one of claims 1 to 11, wherein the monohydrate crystals are at a concentration by weight of about 5% (w / w), about 10% (w / w), or about 20% (w / w).

24. 24. The formulation of claim 23, wherein the lactose is at a concentration by weight of about 95% (w / w), about 90% (w / w), or about 80% (w / w).

25. 18. The formulation of claim 17, wherein the finely divided lactose is present in a total lactose concentration by weight of about 5% (w / w).

26. 18. The formulation of claim 17, wherein the crude lactose is present in a total lactose concentration by weight of about 90% (w / w), about 85% (w / w), or about 75% (w / w).

27. 18. The formulation of claim 17, wherein the finely divided lactose is present at about 1% to about 10%.

28. 18. The formulation of claim 17, wherein the ratio of monohydrate crystals to crude lactose is from about 1:126 to about 1:3.

8.

29. 18. The formulation of claim 17, wherein the ratio of monohydrate crystals to fine lactose is from about 1:13 to about 1:0.

1.

30. 18. The formulation of claim 17, wherein the ratio of coarse lactose to fine lactose is from about 445:5 to about 75:

5.

31. 18. The formulation of claim 17, wherein the fine lactose is Lactohale® 300 or Lactohale® 230.

32. 12. The formulation of any one of claims 1 to 11, wherein the monohydrate crystal is at a nominal dose of about 480 to about 4000 μg.

33. A capsule comprising the formulation of any one of claims 1 to 11, 16 to 19, 21 to 22 and 24 to 31, which is administered via a dry powder inhaler.

34. A process for producing a formulation according to any one of claims 1 to 11, 16 to 19, 21 to 22 and 24 to 31, comprising: a. In the first step (1), before the start of mixing of both lactose components, fine lactose is weighed and layered between the two layers of coarse lactose; b. In the second step (2), blending the two components is carried out in a tumble mixer for two cycles at 72 rpm, 67 rpm, or 34 rpm, or 32 rpm, or 30 rpm for 20 minutes, the pre-blend being sieved through a 500 μm sieve between said cycles; c. In the third step (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 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 monohydrate I of formula (I-M-I) , pre-sieved through a 500 μm sieve and added to the lactose preblend produced in steps (1) and (2) and layered alternately before the start of mixing in the form of 10 layers of lactose preblend and 9 layers of active ingredient, 6 layers of lactose preblend and 5 layers of active ingredient therebetween (Example 4), or 4 layers of lactose preblend and 3 layers of active ingredient therebetween (Example 4), or 2 layers of lactose preblend and 1 layer of active ingredient therebetween (Example 4), preferably 6 / 5 layers, d. In the fourth step (4), The pre-layered blend obtained in step (3) is mixed in a vessel (glass or stainless steel) for 3 to 5 cycles, preferably 3 cycles, at 72 rpm, 67 rpm, 34 rpm or 32 rpm, preferably 32 rpm for 20 to 30 minutes, preferably 30 minutes (90 minute total mixing time), with a 10 minute rest period between mixing cycles; The product obtained in step (4) is mixed in a stainless steel container; The blend is sieved between each mixing cycle, or preferably, the blend is not sieved between mixing cycles. The mixing is characterized by: e. In the fifth step (5), allowing the product obtained in step (4) to stand in a stainless steel container at room temperature (15-25°C) and 35-65% relative humidity for a certain period of time, preferably 24-72 hours, more preferably 48 hours, after which blend uniformity sampling and final capsule filling are carried out; f. In the sixth step (6), The dry powder blend obtained in step E is finally filled into capsules. The process, characterized by:

35. 32. Use of a formulation according to any one of claims 1 to 11, 16 to 19, 21 to 22 and 24 to 31 for the manufacture of a medicament for use in the treatment of cardiopulmonary disorders.

36. 36. The use according to claim 35, wherein the cardiopulmonary disorder is 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 associated with idiopathic interstitial pneumonia (PH-IIP).

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